Volume
The Organic Chemistry
of Drug Synthesis
Daniel Lednicer

THE ORGANIC CHEMISTRY OF
DRUG SYNTHESIS


Volume 5




THE ORGANIC
CHEMISTRY OF DRUG
SYNTHESIS
Volume 5
DANIEL LEDNICER
National Cancer Institute
Bethesda, Maryland

A Wiley-Interscience Publication
JOHN WILEY & SONS, INC.
New York / Chichester / Brisbane / Toronto / Singapore

This text is printed on acid-free paper.
Copyright @ 1995 by John Wiley & Sons. Inc.
All rights reserved. Published simultaneously in Canada.
Reproduction or translation of any part of this work beyond
that pennitted by Section 107 or 108 of the 1976 United
States Copyright Act without the pennission of the copyright
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infonnation should be addressed to the Pennissions Department.
John Wiley & Sons. Inc.. 605 Third Avenue. New York, NY
10158-00 12.
Library of Congress CaJaloging in Publication Data:
Lednicer, Daniel, 1929-
The organic chemistry of drug synthesis.
.. A Wiley-Interscience publication."
Includes bibliographical references and Index.
I. Chemistry, Phannaceutical. 2. Drugs. 3. Chemistry.
Organic-Synthesis.
I. Title. [DNLM 1. Chemistry, Organic.
2. Chemistry, Phannaceutical. 3. Drugs-Chemical
synthesis. QV 744 L4730 1977]
RS403.L38 615' .19
ISBN 0-471-58959-4(v. 5)
76-28387
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1

To Beryle-my wife, friend, and companion

The quotation below appeared as the frontpiece in Volume 1 of this series.
It is still an apt description of drug discovery close to two decades later.
The three princes of Se ren dip , Balakrama, Vijayo and Rajasigha, as
they traveled. .. "... were always making discoveries by accident and
sagacity, of things they were not in quest of ,'*
*Horace Walpole, in a letter of January 28, 1754, as quoted in The
Three Princes of Serendip, by E. J. Hodges, Athaneum, New York,
1964.

CONTENTS
PREFACE xi
1 ACYCLIC AND ALICYCLIC COMPOUNDS 1
1 . Acyclic Compounds / 1
2. Alicyclic Compounds / 5
References / 13
2 MONOCYCLIC AROMA TIC COMPOUNDS 14
1 . Pheny lethanolamines / 14
2. Phenoxypropanolamines / 16
3. Benzoic Acid Derivatives / 19
4. Sulfonamides and Sulfonylanilides / 22
5. Arylalkylamines / 25
6. Miscellaneous Monocyclic Aromatic Compounds / 28
References / 33
3 POLYCYCLIC AROMA TIC AND HYDROAROMA TIC
COMPOUNDS 35
References / 47
4 STEROIDS 48
References / 62
vii

viii CONTENTS
5 FIVE-MEMBERED HETEROCYCLES
64
1. Compounds with One Heteroatom / 64
2. Compounds with Two Heteroatoms / 68
3. Compounds with Three Heteroatoms / 75
References / 78
6. SIX-MEMBERED HETEROCYCLES
80
1 . Compounds with One Ring Heteroatom / 80
2. Compounds with Two Ring Heteroatoms / 90
3. Rings Containing Three Heteroatoms / 100
References / 102
7 FIVE-MEMBERED BENZOHETEROCYCLES
105
1 . Benzene Rings Fused to Rings Containing Two
Heteroatoms / 115
References / 118
8 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES 120
1. Six-Membered Benzoheterocycles Containing One Ring
Heteroatom / 120
2. Six-Membered Benzoheterocycles Containing Two
Heteroatoms / 130
3. Benzene Fused to Seven-Membered Ring Heterocycles /
135
References / 139
9 BICYCLIC FUSED HETEROCYCLES
141
1. Five-Membered Heterocycles Fused to Pyridines / 141
2. Five-Membered Heterocycles Fused to Pyrimidines / 144
3. Thienothiopyrans / 147
4. Pyridopyridines / 149
5. Miscellaneous Bicyclic Fused Heterocycles / 152
References / 154
1 0 BETA LACT AMS
155
References / 162

CONTENTS ix
11 MISCELLANEOUS FUSED HETEROCYCLES 163
1 . Linear Tricyclic Compounds / 163
2. Angular Tricyclic Compounds / 170
3. Four or More Fused Heterocyclic Rings / 177
References / 181
Cross Index of Drugs 183
Cumulative Index, Volumes 1-5 191
Subject Index 213

PREFACE
This volume, like its predecessors, is based on the premise that the opera-
tional manipulations involved in preparing new therapeutic agents consist of
synthetic organic chemistry. Once a target compound has been designed
using the tools of medicinal chemistry, it is up to the practitioner to actually
synthesize the compound so that it may be evaluated for biological activity.
Broad areas of organic chemistry are used to prepare the highly diverse
group of chemical structures utilized as therapeutic agents. The emphasis of
this series continues to be the exposition of that chemistry as this is probably
of interest to chemists outside the confines of medicinal chemistry. Since all
target compounds included in this volume have shown biological activity,
that infonnation is included as well. An attempt has been made to place
actual or potential utility of the agents in context by providing thumbnail
sketches of the relevant therapeutic areas. Readers are referred to some of
the more specialized medicinal chemistry or phannacology texts for more
detailed descriptions of those subjects.
The criterion for inclusion of a specific compound in the book is its
appearance in the annual compilation of United States Adopted Names
(USAN) published by the United States Phannacopeia in "USAN and the
USP Dictionary of Adopted Names." The existence of such a designation,
known commonly as a generic name and shown in boldface type in the
book, is an indication that the sponsoring laboratory considers the compound
to show sufficiently promising activity to merit evaluation in the clinic. The
current volume includes compounds from approximately 1988, where Vol-
xi

xii PREFACE
ume 4 left off, to those that appear in USAN 1993. Readers familiar with
the previous volumes will note the smaller number of compounds discussed
in this book; whereas over 300 agents each with USAN were included in
Volumes 3 and 4, approximately 250 appear in this volume. It would be
interesting, but beyond the scope of this book, to speculate whether this
represents a drop in the rate of discovery of new therapeutic agents or the
adoption of stricter criteria for declaring compounds candidates for clinical
trial. The changing nature of medicinal chemistry, as reflected by this series,
has been noted in the earlier books. The most profound change indicated by
Volume 5 is in the field of antibiotics: a mere nine compounds comprise the
section on 13-lactams (Chapter 10), while that on quinolone antibiotics in
Chapter 8 has grown to over a dozen compounds. A sizeable number of
new therapeutic targets such as lypoxygenase inhibitors, leukotriene antag-
onists, and renin inhibitors make their debut in this volume. It is too early
to assess their significance since none have yet been approved for clinical
practice.
The large number of entries whose synthesis appears only in the patent
literature, most often in European Patent Applications, precluded consulting
original sources; the syntheses for those agents were of necessity recon-
structed from condensations in Chemical Abstracts. The reader should bear
in mind too that the syntheses presented here, more often than not, represent
those aimed at efficiently preparing analogue series. The actual route for
preparing a commercialized drug may in fact be quite different.
Finally, I will take this opportunity to acknowledge the help provided by
my colleague, Dr. Ravi Vanna. Ravi offered cogent comments and sugges-
tions on the manuscript and provided invaluable help in insuring that the
numbers in the flow diagrams match those in the text. Any remaining errors
of course remain my sole responsibility.
DANIEL LEDNICER
Rockville, Maryland
September 1994

THE ORGANIC CHEMISTRY OF
DRUG SYNTHESIS
Volume 5

CHAPTER 1
ACYCLIC AND ALICYCLIC
COMPOUNDS
1. ACYCLIC COMPOUNDS
It is generally recognized that the action of a majority of biologically active
compounds, and especially drugs, is due to their interaction with receptors
or enzymes. The recognition sites on those substrates are composed of de-
fined, intricate arrays of atoms that are part of biopolymers. The complexity
of the receptor site is thus often mirrored by an equal level of complexity
in the molecules with which it interacts. Consequently, it is not surprising
to find few drugs based on alicyclic skeletons. Those that fall into this
category often owe their activity to physiochemical properties rather than to
interaction with a receptor, as for example, in the case of amifostine.
Ionizing radiation remains one of the more effective first line therapeutic
methods for treatment of cancers. It is however often accompanied by a
large number of unwanted effects due to the inability to limit cell damage
to the cancerous tissue. Considerable work has consequently been devoted
to developing compounds that limit radiation damage to healthy cells. Many
of these compounds resulted from the finding that mercaptans tend to have
anti radiation activity, possibly because of their ability to remove radiation-
generated free radicals. The phosphorothioate amifostine, 4, may be viewed
as a highly modified mercaptan derivative. Preparation of the compound
starts in straightfolWard fashion by alkylation of 1,3-diaminopropane (1)
with 2-chloroethanol; reaction of the product, 2, with hydrogen bromide
gives the corresponding bromo derivative 3; the presence of excess hydrogen
1

2 ACYCLIC AND ALICYCLIC COMPOUNDS
bromide may prevent self-alkylation of the product by protonating the amino
groups. Nucleophilic displacement of bromine by sulfur in sodium thio-
phosphonate leads, after acidification, to amifostine, 4. 1
H2NNH2

H2NNR
H
2, R=OH
3, R...Br
1
o
H2NNSP(OH)2
H
4
Calcium channel-blocking agents have found increasing use over the past
decade as antianginal and antihypertensive drugs. Most compounds in this
class typically consist of heterocycles such as dihydropyridines or benzo-
thiazepines. An acyclic bisphosphonate also reportedly exhibits this activity.
Alkylation of the anion from diethyl malonate with bromoethylphenol 5
(itself the product of phenoxide and dibromoethane) leads to malonate 6.
Reduction of the ester with LAH followed by acylation of the thus produced
diol (7) with p-toluenesulfonyl chloride gives the bistosylate 8. Displacement
of the tosylates by means of sodium dibutyl phosphonate (9) gives the cal-
cium channel-blocking agent belfosdil, 10. 2
 1>- °v Br
:>
(\ I>- OC02Et
C0 2 El
5
6
9
1
C}-- 0VYOR
OR
(\ 1>- 0VY(OBU)2
P(OBu)2
I
o
o
I
NaP(OBu)2
.-
7, R-H
1 0
8, R- p-02SCeH.CH3

1. ACYCLIC COMPOUNDS 3
The most important mechanism for regulating blood pressure involves
constriction or dilation of blood vessels on the arterial side. This vascular
musculature is in turn under the control of both the involuntary nelVous
system, via its neurotransmitter catecholamines, and the set of peptide hor-
mones that comprise the renin-angiotensin system. The very potent vaso-
constrictor angiotensin II is this system's ultimate effector. The cascade that
leads to production of this octapeptide starts with the cleavage of the peptide
angiotensinogen to the decapeptide angiotensin I, which is catalyzed by the
enzyme renin. Removal of a dipeptide fragment from that intennediate,
catalyzed by angiotensin converting enzyme (ACE), gives the physiologi-
cally active angiotensin II. IntelVention with the cascade at a number of
links seemed like an attractive approach for developing agents that reverse
vasoconstriction and consequently lower elevated blood pressure. The clin-
ical efficacy of ACE inhibitors such as captopril and enalapril indicated
the viability of this approach. Inhibition of the first step in the cascade, by
blocking the action of renin, seemed to some to offer the possibility of
developing more specific agents.
The renin inhibitors described below are all designed as mimics of the
peptide bond cleavage involved in the synthesis of angiotensin I from an-
giotensinogen I. Though not immediately apparent from the structures, the
compounds include a minimal number of peptides or peptide surrogates for
recognition by renin. A crucial element in each compound is a moiety closely
related to statine (14). This dipetide-like fragment of the fennentation prod-
uct, pepstatin, closely resembles the hydrated amide transition state for
peptide cleavage and inhibits peptidases at the transition point when part of
a larger molecule that is recognized by one of those enzymes. The synthesis
of statine 3 illustrates the general approach to these necessary moieties. Thus
reduction of leucine as its tert-butylcarbonyl (BOC) derivative I I with diiso-
butylaluminum hydride at low temperature leads to the corresponding al-
dehyde 12. Condensation of 12 with the lithium salt of ethyl acetate gives
the protected statine derivative 13.
:> :>
BOCNH BOCNH R 1 NH co R 2
2
OH
1 1 1 2 R 1 =BOC, R 2 =Et
13,
14, R 1 =R 2 =H
BOC=(CH 3 )3C0 2

4 ACYCLIC AND ALICYCLIC COMPOUNDS
Preparation of the renin inhibitor terlakiren starts by removal of the BOC
protecting group from statine analogue 15 in which the isopropyl group of
statine has been replaced by cyclohexyl. Condensation of the amino group
under standard peptide synthesis conditions with the S-methyl ether of BOC-
cysteine gives the intermediate 17. This is again deprotected (18) and the
product is condensed with the N' -morpholylurea derivative of phenylalanine.
There is thus obtained the renin inhibitor terlakiren (19).4
OiP,
:>
o
RNH
. N
- H
'SWe
OiP,
-
OH
OH
15; R-BOC
1 6; R = H
/
17; R=BOC
1 8: R - H
o
O
H 0
N
_ N
-= H
'SMe
OiP,
OH
1 9
A somewhat lengthier series of amino acid condensations leads to the
renin inhibitor ditekiren. 5 In this case, the transition state mimic moiety is
not located at the terminal position and is more complex than statine. A key
reaction in the sequence involves condensation of the aminomethylpyridyl-
amide derivative 20 of isoleucine with the statine surrogate 21. The remain-
ing amino acids are then coupled with the product to give ditekiren (22). 5
Enalkiren (23) represents a renin inhibitor whose structure is yet a further
departure from the polypetide motif in that the terminal portion of the mol-
ecule, which presumably functions like statine, is an aliphatic group rather
than a carboxylic acid derivative. 6
The virus that causes AIDS, HIV, depends on a series of peptidases coded
by its own genome for final assembly of new viral particles. The very
extensive work on renin inhibitors provided a vital clue to the design of
protease inhibitors which acted on the viral enzyme and consequently showed

2. ALICYCLIC COMPOUNDS 5
o
BOCHN lJ
_ N /"
 H I
I 
BOCNH
OR
o
y
2 1
20
QyM
N
Me
o
H 0
N
_ N
- H
"I
I
22
NH 2
-MN
H
OCH 3
o
NH
H _ N
.
OH
YNH
N -=:/
23
in vitro antiviral activity. Several of these compounds are currently headed
for clinical trials as AIDS antiviral agents.
2. ALICYCLIC COMPOUNDS
The early phannacological studies on the prostaglandins were based in part
on the speculation that these agents might be a new class of endocrine
honnones. As more compounds in this class were isolated and their activities
elucidated, it was recognized that many had profoundly injurious effects at
the cellular level, particularly on the circulatory system. It was recognized

6 ACYCLIC AND ALICYCLIC COMPOUNDS
as well that they were all products of the arachidonic acid cascade, origi-
nating from that compound by a complex biogenic pathway. Thromboxane
A 2 (24), one of the earliest intennediates on the pathway catalyzed by the
enzyme cyclooxygenase, is a potent vasoconstrictor and platelet aggregating
agent. The highly substituted cyclopentane vapiprost (25), which shares
many structural features of prostaglandins, interestingly acts as a blocker of
thromboxane A 2 at its receptor site.
.",'"
CO H
2
-
OH
24
CH 2 Q.
\\   C02H
HO 0
25
Synthesis of vapiprost begins with resolution of the bicyclic adduct from
ketene and cyclopentadiene. Addition to the double bond of the elements of
hypobromous acid (bromodimethyl hydantoin in acetic acid) gives the bromo
acetate 27. This undergoes a skeletal rearrangement when treated with pi-
peridine, whose net effect is migration of the methylene bond on the cyclo-
butanone to fonnally replace bromine. The acetate is then removed (28) and
the free hydroxyl group alkylated by means of p-phenylbenzyl bromide to
give intennediate 29. Following along the lines of prostaglandin syntheses,
the ketone is then oxidized to a lactone by Baeyer- Villiger reaction to yield
30. Reduction by means of diisobutylaluminum hydride (diBALH) yields
hydroxyaldehyde 31, which is then homologated by reaction with methoxy-
methylenephosphorane to give 32. The remaining four-carbon fragment is
added by a second Wittig reaction, this time with the ylide from
4-triphenylphosphonium butyrate; reaction conditions are carefully con-
trolled to insure fonnation of the cis olefin instead of the trans isomer
nonnally favored in ylide condensations. Note that the hydroxyl group on

2. ALICYCLIC COMPOUNDS 7
the six-membered ring is in the wrong configuration in the first condensation
intennediate. This is inverted by Swern oxidation followed by reduction
with diBALH under carefully controlled conditions. The presence of the
large biphenylmethyl grouping may help control the stereochemistry of this
last step, and vapiprost 25 7 is thus finally obtained.
o
)(
"'A
\d
:)
o
)(
......... 0 .
).
Br OAe
:)
OR
26
27
28 t R-H
29, R-CeH6CeH.-
RO
(x"CH-O
 o
HO
<
10
OR
31, R-CeHsCeH.-
30, R-CeHsCeH.-
!
R CH-O
-: ,,
9: 0
HO
:)
RO _
 ,\,,-C02H
9: 0
HO
32, R-CeH6CeH,-
33 R-C8HsC8H-
An alternate pathway from arachidonic acid, catalyzed by lipoxygenase,
leads to a series of open-chain products known collectively as leukotrienes.
These compounds are intimately involved in such allergic manifestations as
bronchoconstriction. A significant effort has been devoted to developing

8 ACYCLIC AND ALICYCLIC COMPOUNDS
leukotriene antagonists and lipoxygenase inhibitors. The synthesis of one of
the latter, docebenone (42), begins with the reaction of 2,3,5-trimethyl
hydroquinone (34) with dihydrofuran to fonn the furyl ether 35. Treatment
of that compound with a Lewis acid leads to migration of the tetrahydrofuryl
group to the ortho position (36) in a reaction reminiscent of the Fries rear-
rangement. Following protection of the phenol groups as their methyl ethers
(37), the benzylic ether bond is cleaved reductively by palladium-catalyzed
hydrogenation (38); the tenninal hydroxyl group is then converted to the
iodide (39). Alkylation of the Grignard reagent from diacetylene, 40, gives
the long-chain alcohol 41 after hydrolysis of the tetrahydropyranyl protecting
group. Treatment of that intennediate with a cerium + IV salt simultaneously
cleaves the methyl ethers and oxidizes the ring to the quinone to fonn
docebenone (42). 8
OH OH OR
* ----+ * :. :.
R
08 °u CBs
S8; R-OH
S9; R-[
34 35 38; R-H
S7; R-CH s
 CBaOTHP
40
°
CHaO H

°
OCH s
CHaO B
41
42
Compounds related to retinoic acid (43) have been investigated in some
detail for their putative anticarcinogenic and keratolytic activity. The anti-
keratinizing activity, which may be of use in treating acne, is retained when
the tenninal unsaturated acid moiety is replaced by a benzoic acid. Reaction
of a-bromobenzyl benzoate 44 with triethyl phosphite leads to fonnation of
phosphonate 45 by a classical Arbuzov reaction. Condensation of the ylide
from that phosphonate with aldehyde 47, itself available by Wittig homo-
logation of the naturally occurring terpene {J-ionone 46, gives the olefin 48.
In this case the usual tendency of y lide reactions to fonn trans olefins is
allowed to prevail. Saponification of that product affords pelretin (49). 9

2. ALICYCLIC COMPOUNDS 9
OCC02H
,Cr C0 2 Et
"
/.
BrH 2 C
,Cr eo z ! t
,
:. 0 I
II /.
(EtO)2 PH 2 C
oco
48 l
OCCH.O
43
4.
45
47
OCC02R
48; R-Et
49; R-H
Extensive effort has been expended in the search for drugs to treat severe
pain. Drugs related to morphine, the so-called opioids, are still the sole class
effective for this indication. The shortcomings of the opioids, the most prom-
inent of which is their propensity for causing addiction, have spurred con-
tinued research. There is some evidence that compounds which bind to
subsets of opioid receptors, the kappa receptors, may have reduced addic-
tion liability. One of these compounds, spiradoline (63), departs markedly
from the connectivity at one time through necessary for opioid analgesic
activity. The preparation starts with addition of the lithium reagent from
l-ethoxyethyl-2-bromoethane to the monoacetal of 1,4-cyclohexanedione
(50). Removal of the protective group leads to diol 52. Exposure of that
product to acid under aprotic conditions probably results first in loss of the
tertiary hydroxyl to fonn a carbocation; the observed spiro-fused tetrahy-
drofuran product 53 results from attack of the hydroxyl on that cation. The
acetal is then removed by hydrolysis and the resulting ketone (54) is reduced
to the corresponding alcohol 55. Dehydration, followed by epoxidation of
the olefin (56), gives the oxirane 57, which is of unspecified stereochemistry.
Ring opening of the oxirane with N-methyl-N-benzylamine affords a mixture
of the two possible isomeric aminoalcohols 58 and 59. The amino and
hydroxyl group should be trans to each other in each isomer as a conse-
quence of diaxial opening of the epoxide. The mixture is then treated in

10 ACYCLIC AND ALICYCLIC COMPOUNDS
turn with tosyl chloride and piperidine. This sequence again produces a
mixture of isomers, 61, and the compound in which piperidine and benzyl-
amine are interchanged. The stereochemistry of the amines indicates that
the sequence does not represent a simple displacement of the tosylate from
58 since that would lead to inversion and fonnation of the cis diamine. It is
probable that both tosylates undergo internal displacement to an intennediate
such as the aziridinium salt 60; ring opening by piperidine would then give
the observed products. Debenzylation of the desired isomer 61 by means of
reduction over palladium followed by acylation of the secondary amine (62)
with 3,4-dichloroacetic acid gives spiradoline (63). 10
o=O<J
> H0-J-\/J
ROO
51: R- EtCHCB R
52; R-a
>
CO:J
50
53
R I
cxJ-RZ c
c)CJZ
<
j
OC>=R
5B:R 1 .OH:R Z .NYeCH Z Ph
59:R I -NYeCH z Ph:R z -OH
56: Z-Bond
54: R-O
55: R-B,OB
57; z-O
+
60jZ-N YeCHzPh
1
oo  ,R
 N
'CH
 3
o
:.
oo  °YCHz -V- C 1
'- N 
. 'c H 3 C 1
O
61: R-CBzPh
62: R-H
63
The clinical utility of estrogen antagonists such as the nonsteroid tamox-
iCen in the treatment of breast cancer has led to a search for the corresponding
androgen antagonists which might be useful for treating prostatic cancer.
The only antiandrogen with established clinical utility, finasteride (see

2. ALICYCLIC COMPOUNDS 11
Chapter 5), is in fact a highly modified steroid. The nonsteroidal compound
cioteronel has demonstrated both anti androgen and antineoplastic activity
in vitro. 11 Coupling of the Grignard reagent from 5-methoxy-I-chlorohep-
tane (64) with chlorocyclopent-2-ene gives the alkylated product by dis-
placement of the reactive allylic halogen. Addition of dichloroketene, ob-
tained from 2,2-dichloroacetyl chloride, to the double bond leads to the
bicyclic product 67; the stereochemistry is inferred from the method of
synthesis. Reaction of the cyclobutanone carbonyl group with diazomethane
leads to addition and then ring enlargement in a classical Demjanow rear-
rangement to give 68. Reductive dechlorination by means of zinc in acetic
acid affords cioteronel (69). 12
OC1 +
OCH S
Cl

65
64
66
!
o
C 1 Jd.'"
C 1 >(' .
II(
67
88
!
69
The serendipitous discovery of the antitumor compound cisplatin, 70,
led to the synthesis of a host of analogues; several have shown sufficient
activity to be used in clinical trials. The tetravalent platinum compound
ormaplatin, 72, can be prepared by direct reaction of cis-l ,2-diaminocy-
clohexane (DACH) with hexachloroplatinate under strongly 'oxidizing con-
ditions. 13 Replacing racemic DACH with the resolved (R, R) isomer leads
to the corresponding chiral drug dexormaplatin. 14

12 ACYCLIC AND ALICYCLIC COMPOUNDS
C 1 -" /NH 2
pt+ 2
_/ "
Cl NH 2
a NH2
NH 2
:>
C 1
a \\NH 2 I C 1
. ,,/
P t
/ 1 "
NH 2 C 1
C 1
70
7 1
72
The very narrow therapeutic index of most cancer chemotherapy agents
means that it is imperative to tightly control blood levels-there will be little
effect if these are too low and too much toxicity if they are too high. The
majority of these drugs are thus administered parenterally to avoid the highly
variable blood levels that result from oral administration. Solubility of drugs
in aqueous media is consequently an important consideration. Zeniplatin
was designed to deliver a platinum drug in soluble fonn.
HO X R
HO R
:>
HO X NH2 CI-
pt+ 2
HO NH 'CI-
73; R=Br
74; R-N
3
75; R=NH
2
76
H02C
H02C
77
HO X NH2 ;02C >o
pt+ 2
/ "
HO NH 2 -0 C
2
78
Displacement of bromine by azide in the diol 73 leads to bisazide 74 in
straightforward fashion. The azide groups are then reduced to yield the
diamine moiety 75; reaction of that with tertachloroplatinate affords the
platinum complex 76. The anionic part of the molecule is prepared by cy-
cloalkylation of diethyl malonate with 1,3-dibromoethane to a cyclobutane
derivative, which gives the diacid 77 on saponification. Reaction of 77 as
its silver salt with dihalide 76 leads to displacement of the chlorine ions by
carboxylate anions and fonnation of zeniplatin (78).15

REFERENCES 13
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Chan, S. Smith, R. W. Thies, and L. J. Schift, J. Med. Chern., 27, 1516
( 1984 ) .
10. L. J. Kaplan, US Patent 4,483,130 (1984); Chern. Abstr., 101,54912 (1984).
11. L. C. Ford, W. S. Kasha, N. H. C. Chang, and R. L. Delange, Chernotherapy,
31,362 (1985).
12. W. S. Kasha and C. S. Bumison, US Patent 4,689,345 (1987); Chem. Abstr.,
111,38925 (1989).
13. W. K. Anderson, D. A. Quagliato, R. D. Haugwitz, V. L. Narayanan, and
M. K. Wolpert-Filipes, Cancer Treatment Rep., 70, 997 (1986).
14. R. J. H. Clark, V. B. Croud, and A. R. Khokar, Inorg. Chern., 26, 3284
( 1987).
15. P. Bitha, S. G. Carrajal, R. V. Citarella, R. G. Child, E. F. D. Santos, T. S.
Dunne, F. E. Durr, J. J. Hlavka, S. A. Lang, H. J. Lindsay, G. O. Morton,
J. P. Thomas, R. E. Wallace, Y. I. Lin, R. C. Haltiwanger and C. G. Pierpont,
J. Med. Chem., 32, 2015 (1989).

CHAPTER 2
MONOCYCLIC AROMATIC
COMPOUNDS
The ready availability of a host of variously substituted derivatives of ben-
zene have made this one of the most thoroughly investigated nuclei as the
basis of biologically active compounds. This fact has been put to good
advantage in preparing modified agonists or antagonists of endogenous com-
pounds which are themselves based on simple benzene derivatives such as
the {J-agonists and antagonists. In addition, the benzene ring constitutes a
flat, electron-rich moiety with bonds that project at set, defined angles. This
provides a suitable base for positioning portions of phannacophores at de-
fined spatial positions, and led to the discovery of drugs based on benzene
rings some of which bear little relation to endogenous compounds.
1. PHENYLETHANOLAMINES
The catecholamines norepinephrine (1) and epinephrine (2) are the main
neurotransmitters of the sympathetic nervous system. These endogenous
compounds are of particular importance in the regulation of involuntary
musculature, particularly that of the cardiovascular and bronchial systems.
Norepinephrine itself is generally considered to act on a-sympathetic recep-
tors while epinephrine acts mostly on l3-sympathetic receptors; highly de-
tailed pharamacology has revealed that the latter is further subdivided into
at least two other branches. Stimulation of {31-sympathetic receptors, which
14

1. PHENYLETHANOLAMINES 15
are found mostly in the cardiovascular system, results in an increase in heart
rate and force of contraction which can lead to a rise in blood pressure.
Action on the 132-receptors, which predominate in lung tissue, leads to di-
lation of the bronchioles.
One of the sequelae of heart disease is the loss of force of contraction of
heart muscle to the point where it may be insufficient to support the circu-
latory system. The l3-sympathetic agonists have been used to treat this dis-
ease because of their cardiostimulant action. Some effort has been devoted
to synthesizing analogues of epinephrine since the endogenous compound is
too poorly biovailable and unstable to be used per see Synthesis of the N-
substituted epinephrine derivative arbutamine, 5, starts with reductive al-
kylation of 2 with aldehyde 3 to give intennediate 4. Removal of the benzyl
protecting group by hydrogenolysis leads to arbutamine (5).1
HO
NHR 1
OR 2
+
HO
1 I R 1 - H
2. R 1 -CH s
2
3. R -CH 2 C e Hf)
/
HO
H
N
OR 2
HO
(. I R 2 -CH 2 C e Hf)
5. R 2 - H
Beta-sympathetic agonists have been one of the mainstays for the relief
of asthmatic attacks since the advent of isoproterenol (1, R I = i Pr). Ex-
tensive research in the area revealed that activity was retained even when
significant changes were made in the catechol function. Interposition of a
methylene group between the benzene ring and the meta phenolic group led
to the compound albuterol (6), which shows some selectivity for the 132-
receptors which predominate in the lung; this selectivity led to a better-
tolerated drug. Preparation of a significantly more lipophilic analogue begins
with alkylation of 2-phenylethanol with 1,6-dibromohexane to give the

16 MONOCYCLIC AROMATIC COMPOUNDS
HO
MBR
Br(CB2)eO
+
HO
8, R-IPr
8
7, R-H
/
HO
H
N(CH2)e O
HO
9
monohalide 8. Alkylation of the primary amine 7 2 corresponding to albu-
terol with that side chain leads to the l3-agonist salmeterol (9). 3
It is interesting that l3-sympathetic agonist activity seems to be retained
when the phenolic hydroxyl is replaced by a weakly basic aniline group.
Though only a single enantiomer is responsible for the activity of most
l3-agonists, and for that matter most antagonists, the majority of these com-
pounds are sold as their racemates. Recent developments in methods for
enantioselective synthesis have placed increasing importance on the prepa-
ration of drugs as single enantiomers. The synthesis of picumetrol represents
an interesting exercise in enantioselective synthesis based on transfer of
chirality. Alkylation of the bromoalkyl derivative 10, prepared in a manner
analogous to the benzene analogue 8, with the reduction product of L-phen-
ylglycine (S-phenylglycinol, 11), gives the chiral derivative 12. Alkylation
with highly substituted bromoacetophenone 13 leads to the aminoketone 14.
Reduction of the carbonyl group by means of sodium borohydride occurs in
highly stereoselective fashion with transfer of chirality from the phenylgly-
cinol moiety to the newly fonned hydroxyl group. The chiral transfer group,
which has also served as a protecting group to avoid overalkyation, is then
removed by hydrogenolysis over palladium on carbon. There is thus obtained
picumetrol (15). 4
2. PHENOXYPROPANOLAMINES
As noted in the earlier volumes, it was found empirically that insertion of
an oxymethylene function in phenylethanolamines yielded compounds that
acted as {3-adrenergic antagonists, as long as the benzene ring did not include

2. PHENOXYPROPANOLAMINES 17
Gt--
I /'
N O(CH 2 )e Br
OH
'" X 
o OB
> NO(CH2)eN
H
1 0
1 1
1 2
B::2
C 1
13
c
o
O (CB!) eN.L.OB
C 1
Gt--
I /' H
H O(CH 2 )e N
HB 2
15
14
C 1
OH
HH 2
C 1
a phenolic group at the para position. These agents, as predicted by theory,
exhibited antiarrhythmic activity in man. Data from the clinic revealed that
they also fortuitously acted as antihypertensive agents. Their therapeutic
utility is by now well established, as evidenced by the commercial avail-
ability of a host of drugs. Efforts to locate compounds with somewhat dif-
ferent biological profiles continue in the hope of finding a special niche in
the market. The structures of the great majority of these compounds include
the phenoxypropanolamine function.
The preparation of a typical compound in this class starts by selective
saponification of the less-hindered phenol of the hydroquinone diacetate 16
to give the monoacetate 17. Alkylation of the phenol group with epichlo-
rohydrin proceeds to the glycidic ether 18. The product may result in
straightforward fashion by simple SN2 displacement of chlorine; alterna-
tively, the phenoxide may first attack the oxirane ring to lead to a choro-
alkoxide, as an intennediate; internal displacement of halogen would then
afford 18. Reaction of the oxirane with isopropylamine proceeds via attack
at the less-hindered position to give the {J-blocker metipronalol (19). 5 In
much the same vein, application of the standard scheme to the phenol 20
gives the {J-blocker propafenone (21). 6 Preparation of the starting material
for 21 is not described; one can, however, imagine several schemes, such

18 MONOCYCLIC AROMATIC COMPOUNDS
HsC CBS
OAC V OR
BSC
)I
HsC CBs
OAC V\
8 S C
o ----+
/ \
HaC CBs
OAC V OKHiPr
HsC OR
18. R-OAe
17. R-H
18
18

OH
OKHiPr
OH
o
20
2 1
as reaction of salicylaldehyde with a phenethy I Grignard reagent followed
by oxidation.
The finding that l3-blockers can lower intraocular pressure have led to the
use of this class of agents for the treatment of glaucoma. It is desirable that
the effects of such topically applied drugs be limited to the eye to avoid any
cardiovascular effects. Beta blockers designed for intravenous use in treating
cardiovascular infarcts present an analogous situation; in that case it is very
important that circulating drug levels be reduced on demand to avoid ex...
cessive cardiac depression. The development of the tJ-blocker esmolol, 7
which contains a carefully designed metabollic weak link, provided a com-
pound whose levels can be finely tuned. The metabolite is an inactive car-
boxylic acid. The ophthalmic drug adaprolol (27) differs from esmolol in
that the simple methyl ester of the latter is replaced by the more lipophilic
and presumably more slowly hydrolyzed 2-adamantylethoxy group; how-
ever, both compounds give the same inactive acid metabolite. Successive
reaction of 4-hydroxyphenylacetic acid (22) with ethanol and dihydropyran
leads to the corresponding tetrahydropyrany I (THP) ethyl ester 23. The acid
24, obtained on saponification, is converted to the desired ester by reaction
with 2-( l-adamantyl)ethanol; removal of the THP group in mild acid gives
phenol 26. Successive reaction with epichlorohydrin and isopropylamine
affords adaprolol 27. 8 An alternative strategy for avoiding the cardiovas-
cular effects of classical /3-blockers consists of modifying the structure to
make the agent selective for the eye. The oxime alprenoxime (29) which
corresponds to the well-known {3-blocker alprenolol (28) is described as an

3. BENZOIC ACID DERIVATIVES 19
OR t OR 1 ONHiPr
y OH
:. I; :. I;
/co R 2
2 CO 2 CO 2
22, R 1 .R 2 .H 25, R-THP 27
23, R 1 .THP, R 2 -Et 28, R-H
24, R 1 =THP, R 2 =H
OH
 NHiPr
I'
,/ 
NOH
 NHiPr
I'
,/ 
28
29
agent which has potent occular hypotensive action and weak systemic
l3-blocking and cardiovascular action. 9
3. BENZOIC ACID DERIVATIVES
The majority of recent cholesterol-lowering agents are relatively complex
compounds related structurally to the natural product mevalonate inhibitor
lovastatin (see Chapter 3). It is thus of interest that a seemingly simple
derivative of 2-phenylbenzoic acid has been described as a hypolipidemic
compound. The synthesis of this agent, xenalipin, starts by protection of
2-bromobenzaldehyde (30) as its dimetyl acetal (31). This compound is then
treated with magnesium to fonn Grignard reagent 32. The second half of
the molecule starts from iodo compound 33; this is converted to the palla-
dium derivative 34 by means oftetra(triphenylphosphonium)palladium. Con-
densation of the two organometallics fonns the biphenyl bond. Hydrolysis
of the thus obtained intennediate acetal yields aldehyde 35; oxidation by
means of pennanganate affords xenalipin (36).10
Amides of hindered anilines such as lidocaine (37) have a venerable
history as local anesthetics. A number of structurally related compounds has
been prepared more recently as antiarrhythmic agents. It is interesting that
a seemingly minor change leads to a compound described as an anticonvul-
sant agent. Acylation of p-nitrobenzoyl chloride (38) with 2,6-dimethyl-

20 MONOCYCLIC AROMATIC COMPOUNDS
(, /(- 8r
CB-O
__ (, /(- 1
CB(OIl')a
31, X-Sr
32. 1-IiISr
30
((C.HI)aP)ad V Cra +-- ' v cra
34
33
Q-V- cr s
CO.B
o H {j 3 C
II -
CN'CH2C \ /
H 3 C
37
Q-V- cr s
CB-O
+---
38
35
H 3 C
02N V COC 1  R2N -V- ld -{)
H 3 C
38
39 I R=O
40, R=H
aniline yields the hindered benzamide 39. Reduction of the nitro group to a
primary amine under any of several conditions gives ameltolide (40).11
Cholecystokinin is one of a series of oligopeptide honnones that occurs
in both the intestinal tract and the central nervous system. In the fonner,
the compound causes contraction of the gall bladder and mediates the satiety;
its role in the CNS is still under active investigation. A relatively simple
benzamide aspartate interestingly exhibits potent CCK antagonist activity.
Acylation of free aspartic acid (42) with the substituted benzoyl chloride 41
gives the benzamide 43. Heating the dicarboxylic acid with acetic anhydride
leads to fonnation of the cyclic anhydride 44. Reaction of that intennediate
with di-n-amylamine proceeds nonselectively at both carboxyl groups of the
anhydride to give a mixture of acids. The isomer fonned by attack at the
carboxyl adjacent to the amide is then isolated from the mixture by selective
extraction made possible because the carboxyl group from alternate ring
opening is hydrogen bonded to the adjacent amide, whereas that in the
desired product is free. Lorglumide is thus obtained (45).12
Though the benzamide metoclopramide (46) was originally developed
as an antipsychotic drug, its main usage is stimulating gastric motility and,
more importantly, effectively countering the nausea caused by cancer chemo-
therapy. These activities, originally attributed to the dopamine antagonist
action of the compound, are now attributed to its antagonist action at 5-HT
(5-hydroxytryptamine, serotonin) receptors. The preparation of an antiemetic

3. BENZOIC ACID DERIVATIVES 21
C10 H2NC2H C 1
I + :>
Cl ./": COel e0 2 H e 1
4 1 42
e 1
H
Nl: 2 H
e0 2 H
43
1
H °
N U
"
°
44
C 1
e 1
C 1
H 1°1 <:
NyC(nC5Hll)2
e02H
45
analogue of that drug starts with metoclopramide (46, R = CH 3 ) itself.
Thus reaction with the sodium salt of ethyl sulfide in DMF leads to the free
phenol 46 (R = H). Alkylation of that intennediate with 3-chloro-propan-
2-one affords batanopride (47).13 A similar sequence starting from the an-
tiemetic zacopride (48) would lead to pancopride (50). (The method de-
scribed in the patent literature involves acylation of the free acid correspond-
ing to 50 with 2-aminoquinuclidine. 14 )
H H
o NN(Et)2 NN(Et)2
OR 00:(
:>
C 1 C 1
NH 2 NH 2
46, R=H 47
:-0 :-0
OR 0 1
:>
C 1 C 1
NH 2 NH 2
48, R-CH 50
- 3
49, R=H

22 MONOCYCLIC AROMATIC COMPOUNDS
The protein elastin is essential for maintaining flexibility in those tissues
whose function requires elasticity. The enzyme elastase, elaborated by neu-
trophils, is a protease which fonns part of the tissue repair mechanism; it
has particular affinity for elastin. Excessive elastase or elastase activity leads
to destruction of elastin and consequent loss of flexibility in many tissues.
The best-known clinical example of this is emphysema, which results from
loss of pulmonary elastase. A carboxylic acid derivative, which shares the
bipolar nature of some detergents, interestingly acts as an elastin inhibitor.
Acylation of the acid chloride from acid 51 with 1, I-dimethylethanolamine
leads to amide 52. Dehydration of the amide by means of thionyl chloride
gives the oxazoline 53, the newly fonned heterocycle serving as an a non-
electrophilic acid-protecting group. The bromine in this group is then ex-
changed for lithium by treatment with butyllithium. Reaction with n-hep-
tadecanal then leads to the alcohol 54. Acid hydrolysis of this last product
leads to removal of the protecting group and fonnation of lodelaben (55). 15
Br V C02H
C 1
> Br : -f- oH
Cl H
> Br -o- X
C 1
5 1
52
53
1
CH 3 (CH 2 ) 16 r-O-
\ / C0 2 H
HO
C 1
<:
CH 3 (CH 2 )16
HO
C 1
55
54
4. SULFONAMIDES AND SULFONYLANILIDES
Two rather closely related compounds, sulotraban and daltroban, show
activity as thromboxane A2 receptor antagonists and consequently have po-
tential therapeutic activity in treating thromboxane-mediated inflammatory
processes. Alkylation of the phenolic group in 56 with ethyl bromoacetate
gives the aryloxyacetic ester 57; treatment with strong acid gives the cor-
responding free amino acid 58. Reaction of 58 with benzenesulfonyl chloride
gives sulotraban (59).16 The analogue daltroban (61) is obtained on treat-
ment of amino acid 60 with p-chlorobenzenesulfonyl chloride. 16

4. SULFONAMIDES AND SULFONYLANILIDES 23
AcHN 
OH
RHNLJ="\ <\>- S02NH 
) O,---,C02R' -----. O,---,C02R'
56
57, R = Ac; R' = Et
58. R = R' = H
59
H2N  C02H

> CI -V- S02NH C 02H

60
61
Early work on the adrenergic phenylethanolamines revealed that activity
was retained even when one of the phenolic groups from norepinephrine
was deleted. The resulting compound, octopamine (63), still shows consid-
erable cardiovascular activity. The design of the analogue sotalol (62) prob-
ably relied on the fact that the proton on a sulfonyl anilide shows a pK Q not
too far removed from that on phenolic hydroxyl. This replacement in fact
led to one of the very first -blockers; this compound was so far ahead of
its time that the clinical utility of this class of compounds was barely ap-
prehended. In the event, clinical trials on sotalol revealed that the compound
showed valuable antiarrhythmic activity. More recent extensive investigation
of l3-blockers for this indication suggested that the activity of sotalol was
not typical of its class; the sulfonamide moiety seems to contribute to its
antiarrhythmic activity beyond acting as a simple surrogate phenolic group.
A group of more recent antiarrhythmic agents, which do not act by direct
effects on the adrenergic system, in fact incorporate this moiety.
 NHiPr
CH 3 S0 2 NH \ /
OH
 NH2
HO \ /
OH
6 2
6 3
The first of these agents to be considered, ibutilide (67), retains the
benzylic hydroxyl group of sotalol; the side chain connecting the amine has
however been extended by two methylene groups. The tertiary amine in this
compound is quite inconsistent with adrenergic activity. The starting material
for this compound, 65, is obtained by acylation of methanesulfonalide proper
(64) with succinic anhydride. Condensation of the acid with ethylheptyl-
amine under any of several conditions affords the corresponding amide 66.

24 MONOCYCLIC AROMATIC COMPOUNDS
o
CH3S02HN -{ /) + CO _CH3S02HN  C02H
\\
o
64
65
1
G-{J H ",CH2CH3
C H 3S 0 2 HN \ / N, If:
( CH 2)6 CH 3
-Q-{J- 0' / C H 2 CH 3
C H 3S02 HN \ / N CH CH
' ( 2)6 3
67
66
Treatment of this keto amide with LAH at aoc leads to reduction of the
amide carbonyl to a methylene group and the ketone to the benzylic alcohol.
There is thus obtained ibutilide (67). 16
The next two compounds demonstrate that a considerable degree of free-
dom apparently exists as to the identity of the atoms fonning the four-
membered chain separating the phenyl group and the amine. Thus acylation
of the methyl ester of p-aminobenzoic acid (68) with methanesulfonyl chlo-
ride gives the derivative 69. Heating that compound neat with N, N-dieth-
ylethylenediamine affords the antiarrhythmic agent sematilide (70).17 Sul-
fones or sulfoxides, which are to some extent isosteric with carbonyl groups,
are occasionally biosisosteric as well. Such proves to be the case in this
series of antiarrhythmic compounds. Reaction of methanesulfonalide with
chlorosulfonic acid affords sulfonyl chloride 71. Condensation of that re-
active intennediate with N, N' -diisisopropyl-ethylenediamine gives risotilide
(72). 18
1  2
R HNC02R
 o H2CHs
> CH s S0 2 HN \ / ;-N,
N CH 2 CH s
H
68. R 1 =R 2 =H
69. R 1 -CH s S0 2 . R 2 -Et
70
CH3S02HN  S02CI
 ,CH(CH 3 )2
:> CH3S02HNS\\
I
CH(CH s )2
7 1
72

5. ARYLALKYLAMINES 25
5. ARYLALKYLAMINES
The tricyclic antidepressant drugs, which have now been available for close
to 40 years, are undoubtedly quite effective. But the serious effect these
drugs have on cardiac function in many patients has led to the development
of a series of drugs that differs markedly in structure and side effects from
the tricyclics. One of the best known is fluoxetine (76), which has gained
notoriety in the press under its trade name, Prozac@. The N-demethyl deriv-
ative, which corresponds to one of its metabolites, has antidepressant activity
in its own right. Nucleophilic aromatic substitution of fluorine in p-tri-
fluomethylfluorbenzene with the alkoxide from hydroxyphthalimide, 73, af-
fords the corresponding aromatic ether 74. The phtalimide group is then
removed by treatment of the intennediate with hydrazine. The primary amine
seproxetine (75)20 is thus obtained.
o 1:5\ /)
o
o 1:5\ /)
o
:)I V o
I'
FsC /.
OH
74-
/
73
NHR
V o
I'
'sC /.
75. R-H
76 I R-CH s
Synthesis of a distantly related compound, sibutramine (80), starts by
internal bis-alkylation of the anion from p-chlorophenylacetonitrile with 1,4-
dibromopropane to give the cyclobutane 77. Reaction of the nitrile group
with the Grignard reagent from 2-methyl-l-bromopropane gives the imine
78 as the first isolable intennediate. The most direct route to the final product
consists of carefully isolating the hydrolytically labile imine and reducing it

26 MONOCYCLIC AROMATIC COMPOUNDS
with LAH to afford the primary amine 79. Bis N-methylation of the amine
by means of fonnaldehyde and fonnic acid (Clark-Eshweiler reaction) leads
to the antidepressant sibutramine (80).21 It is of interest that the relation of
the aromatic ring and the amino group in this compound and that which
follows is the same as in amphetamine, which also has some mood-ele-
vating activity.
C 1
C 1
C 1
)0
)0
77
78
79, R-H
80, R-CH s
In a somewhat similar vein, the anion from p-methoxyphenylacetonitrile
is condensed with cyclohexanone to afford the tertiary carbinol 82. The
nitrile group in that intennediate is then reduced with hydrogen over rhodium
on alumina to give the primary amine 83. Dimethylation under Clark-Esh-
weiler conditions leads to the antidepressant venlafaxine (84).22
CH 3 0 Q
"
/: CN
CH 3 0
CH 3 0
CN
:>
OH
NR 2
:>
8 1
82
83,
84,
R=H
R-CH
- 3
The first of the antiulcer histamine H2 antagonists, cimetidine, retained
many structural elements of the histamine molecule, whose action it antag-
onized. Subsequent compounds demonstrated that many of these moieties,
such as the imidazole ring and histamine-like side chain, could be dispensed
with. A relatively simple phenolic ether histamine H2 antagonist, roxatidine
(89), represents one of the furthest departures from the prototype. Reductive
alkylation of m-hydroxybenzaldehyde (85) with piperidine affords the cor-
responding piperidylmethyl derivative 86. Alkylation of the phenoxide from
that intennediate with l-(N-phthalimido )-3-bromopropane leads to the phtal-
imide 87; the free primary amine 88 is obtained when 87 is treated with
hydrazine. Acylation of the amine with glycolic acid followed by acylation

5. ARYLALKYLAMINES 27
o
0" cZ0 0B
H
o
 CNH2COH
88
o 0
 CNH2CO(CH2)a N
87 0
85
C 0 0 0
NH2CO (CH 2 ) a:'CCH 2 0'c'CH a ..
8S
1
o
CNH2CO(CH2)aNH2
88
of the tenninal hydroxyl with acetic anhydride gives roxatidine (89).23 It
has been suggested that the tenninal array of carbonyl groups mimics the
thiourea surrogates present at the tenninus in most compounds of this class.
Dopamine, 90, is one of the more important brain neurotransmitters. The
action of this compound is limited by its ready reuptake and metabolic
inactivation, and it was thought that locating transient higher concentrations
would make it possible to correlate brain function with neurotransmitter
levels. This theoretical possibility was converted to practicality by the avail-
ability of the positron-emitting fluorine isotope 18p and the development of
positron emission tomography (PET) together with the observation that
2-fluorodopamine showed virtually the same activity as the parent com-
pound. The extremely short half-life of this isotope, 110 minutes, makes it
ideal for clinical studies because of the self-limiting exposure to radiation.
This very short half-life puts a premium on superfast and efficient preparative
chemistry. While dopamine itself does not cross the blood brain barrier, its
metabolic precursor, DOPA (91, dihdroxyphenylalanine), is readily taken
into the CNS by an energy-dependent transport system; the same, it has
been established, is true for the 2-fluoro derivative. Fluorodopa 18F (95) is
thus the agent actually used for PET scans. The synthesis of the compound
starts in a cyclotron, with the bombardment of a mixture of about 0.5 % cold
fluorine and neon to generate 18p. This gas is then passed through a mixture
of sodium acetate in acetic acid, thus producing acetyl fluoride. In a con-
vergent synthesis, DOPA (91) is converted in several steps to the triply
protected derivative 92. Treatment of that compound with mercuric trifluo-
roacetate yields the isolable organomercury derivative 93. When freshly
generated CH 3 C0 18 p is passed through a solution of 93, the mercury is
replaced by fluorine to give 94. Exposure of the compound to hydriodic acid
serves to remove all three protecting groups to give fluorodopa 18F (95).24,25
The scale of the work can be judged from the fact that the product is purified

28 MONOCYCLIC AROMATIC COMPOUNDS
HO  R
I ; NH 2
HO
CH30  C02Et
:. I NHCOCr 9
CH 0 /'
3
CHSO  C02It
:. I MBCOCY S
CHSO /. HgCOCf s
90, R-B
91, R-C0 2 H
92
93
1
HO  C02H
I NH 2
/'
HO 18,

CH S 0 JG() C0 2 Et
I /' NHCOCr S
CHSO 18y
95
94
by reverse phase HPLC; its time frame is such that synthesis and purification
must be completed within one hour.
6. MISCELLANEOUS MONOCYCLIC AROMATIC COMPOUNDS
The first branch of the arachidonic cascade to be recognized led to the
prostaglandins and thromboxanes; the involvement of those products in tis-
sue injury has already been noted. A more recently recognized pathway
leads to a set of closely related acyclic compounds known as the leuko-
trienes. These arachidonic acid derivatives, typified by leukotriene E4 (96),
are probably the direct causes of many allergic symptoms and the broncho-
constriction of asthma. While antiallergy compounds owe their actions to
effects on leukotriene levels, antagonism of those agents at the cellular level
could offer better efficacy.
OH
C >--- -
_____ (CH 2 )4 CH 3 s
H 2 N C0 2 H
C0 2 H
96
The leukotriene antagonist sulukast (109) incorporates many of the fea-
tures of the endogenous agonists; it should be noted that replacement of the
tenninal carboxyl group by a tetrazole, a moiety with roughly the same pK a ,

6. MISCELLANEOUS MONOCYCLIC AROMATIC COMPOUNDS 29
is characteristic of this class of compounds. The quite complex synthesis
starts with the bromination of m-toluonitrile (97) to the a-halo derivative
98; this is then oxidized to benzaldehyde 99. Perkin reaction of the aldehyde
with malonic acid leads to condensation followed by decarboxylation to give
the cinnamic acid 100. The acid chloride, obtained by means of oxalyl
chloride, is then treated with sodium borohydride to selectively reduce the
carbonyl group in the presence of the nitrile to afford the cinnamyl alcohol
101.
o = HCCN
. v
y
HOCN
 l
XH 2 C  CN

97, X = H
98, X = Br
99
100, Y = 0
101, Y = H 2
HO
N
N - ,\ N
I /
N
R .
I N
N - "N
HON
V R
104, R = CPH 3
1
102, R = H
103, R = CPh3
N
N - "N
I /
N
R
o
o = HC 
 "
N
N - " N
I /
N
R
105, R = CPH 3
106, R = CPH 3
1
OH
_N
N \'N
I /
N
R
.
nCgH 1 9 /
N
N -,' N
I ,
N
R
nC 9 H 1 9   =.
S I
C C02R
107, R = CPH 3
108, R = CPh3 R = Et
109, R = R = H

30 MONOCYCLIC AROMATIC COMPOUNDS
The nitrile group is converted to the tetrazole (102) with sodium azide in
the presence of mineral acid; the acidic proton on the heterocycle is then
converted to an ester-like function (103) by alkylation with trityl chloride.
Sharpless oxidation of the olefin then stereospecifically introduces chirality;
thus treatment of allylic alcohol 103 with butyl hydroperoxide in the presence
of Ti(OiPr)4 and diisopropyl-L-tartrate gives epoxide 104 as a single enan-
tiomer. Swem oxidation of the alcohol (oxalyl chloride, DMSO) converts
this compound to aldehyde 105. Condensation of that compound with the
phosphorane, (C6Hs)3P=CHCH=O, gives the bishomollogated derivative
106; the fonnation of the trans olefin follows from the nonnal course of
ylide condensations. The remaining carbon atoms are then added by reaction
of the aldehyde group with the ylide from triphenyl-n-decyl bromide; this
reaction is carried out under" salt free" conditions so as to obtain the newly
fonned olefin as its cis isomer (107). Reaction of this last product with ethyl
3-mercaptopropionate gives the epoxide ring-opening product 108. The syn-
thesis of sulukast (109) is completed by removal of the trityl protecting
group with an acid resin and saponification of the ester. 26
A somewhat simpler compound, which shares only the fatty side chain
and tetrazole ring of sulukast, retains activity as a leukotriene receptor
antagonist. The synthesis of the compound starts by acylation of catechol
to the acetophenone 111; alkylation by means of allyl bromide takes place
at the hydroxyl para to the acyl group, the reactivity of the other phenol
being reduced by chelation, Claisen rearrangement interestingly proceeds to
give the more highly hindered product 112. This is then reduced catalytically
to 113. 27 Alkylation of this intennediate with 1,4-dibromobutane again pro-
ceeds at the nonchelated phenol para to the acyl group (114). The remaining
halide is then displaced by cyanide to lead to nitrile 115. That functionality
is converted to a tetrazole ring by treatment with sodium azide in the pres-
ence of acid to afford tomelukast (116).28
Nonsteroidal antiinflammatory agents (NSAIDS) owe their activity to in-
hibition of the cyclooxygenase enzymes, which convert arachidonic acid
into prostaglandins and thromboxanes. The SAR of this enonnous series of
compounds leaves little doubt that a carboxylic acid group is essential for
this interaction. This functional group in fact occurs in the great majority of
NSAIDS. The few exceptions to this rule include moieties that are capable
of in vivo metabolic conversion to carboxylic acids. Though the tenninal
ethynyl group of the NSAID tebufelone (118) would seem a prime candidate
for such a transfonnation, one of the main metabolites of this drug in fact
consists of the compound hydroxylated at one of the tert-butyl methyl groups.
Tebufelone (118) is obtained by Friedel-Crafts acylation of 2,6-di-tert-butyl
phenol with 5-hexynoyl chloride. 29
A compound related to the naturally occurring guaiaretic acids has been

6. MISCELLANEOUS MONOCYCLIC AROMATIC COMPOUNDS 31
o
i  OR
HO
>
>
O
Br
110, R=H
111, R=CH 2 CH=CH 2
X
112 , R- CH-CH 2
113 , R= CH 2 CH S
114
j
O <
/IH
N, N
N
o
CN
11 6
11 5
HO
:>
HO
117
1 1 8
described as a lipoxygenase inhibitor which inhibits tumors and has anti-
psoriatic activity. Alkylation of the bromination product, 120, from 3,4-
dimethoxypropiophenone (119) with the carbanion from the same ketone,
yields the symmetric product 121 as a single isomer. The stereochemical
outcome of this reaction is probably guided by the fact that the product
results from the sterically favored transition state; the alternate intennediates
that would lead to the isomeric product involve a greater number of non-
bonding interactions. Hydride reduction of the diketone leads to the ste-
reochemically undefined diol 122. Catalytic reduction over palladium serves
to remove the benzylic hydroxyl groups (123). That product is then de-
methylated with hydrogen bromide to afford masoprocol (124).30
Malignancies in organs that are honnonally supported, such as breast and
prostate cancer, should in theory be arrested by blocking stimulation by the
specific honnone. This theory has been borne out by the finding that estro-

32 MONOCVCLlC AROMATIC COMPOUNDS
o
OCH S
CHSO ;)0 CHsO
OCH s OCB S
1 1 9 . R-H 121
120 . R-Br
\
OR OCH S
OR OCH S
<
RO CHSO
OR OCH S
1 23 . R-OCH S 122
124. R-H
.
OR
o
 ;
I'
/.
o

OC H 2 Ph
125
126
127, R = CH2Ph
128, R = H
Me2 N L 0
1
c
HO
+-
131, X = CI
132, X = H
130
129

REFERENCES 33
gen-receptor positive breast cancer can be treated with estrogen-receptor
antagonists. The nonsteroidal antagonist tamoxifen (132) has consequently
gained wide acceptance as an adjuvant for treating breast cancer. Synthesis
of an analogue of that drug starts with the alkylation of desoxybenzoin (125)
with the benzyl ether of 2-bromoethanol to afford the product 126. Addition
of the Grignard reagent from the tetrahydropyranyl ether (THP) of p-bro-
mophenol gives the benzhydryl alcohol 127. The benzyl blocking group on
the primary alcohol on the side chain is then removed by hydrogenation
over palladium catalyst. Treatment of the product, 128, with strong acid
leads initially to fonnation of the carbocation at the benzhydryl center by
loss of the hydroxyl group; addition of the free primary side chain alcohol
leads to fonnation of the tertrahydrofuran ring; concomitant loss of the acid
labile tetrahydropyranyl group give the observed phenol 129. The free phenol
function is then alkylated with 2-chloroethyldimethylamine to give the basic
ether 130. Treatment of that product with hydrogen chloride leads to the
ring-opened olefin in which oxygen has been replaced by chlorine. There is
thus obtained the estrogen receptor antagonist, toremifine (131).31
REFERENCES
1. R. R. Tuttle and C. E. Browne, Eur. Pat. Appl. EP 329464 (1989); Chern.
Abstr., 114,602 (1991).
2. D. Lednice,r and L. A. Mitscher, Organic Chernistry of Drug Synthesis, vol.
2, Wiley, New York, 1980, p. 43.
3. I. F. Skidmore, L. H. C. Lunts, H. Finch, and A. Naylor, Ger. Offen. 3414752
(1984); Chern Abstr., 102,95383 (1986).
4. B. D. Judkins, B. Evans, and J. D. Meadows, Eur. Pat. Appl. EP 460924
(1991); Chern. Abstr., 116,128677 (1992).
5. L. Blaha, J. Weichet, J. Horodva, and V. Trcka, Czech. Patent 128471 (1968);
Chern. Abstr., 71,3129 (1969).
6. R. Sachse, Ger. Offen. 200143 (1971); Chern. Abstr., 75, 151538 (1971).
7. D. Lednicer and L. A. Mitscher, Organic Chernistry of Drug Synthesis, vol.
4, Wiley, New York, 1980, p. 47.
8. N. Bodor, A. A. EI-Khousi, M. Kano, and M. M. Khalifa, J. Med. Chern.,
31, 1651 (1988).
9. N. Bodor and A. A. EI-Khousi, S. T. P. Pharma. Sci. 2,61 (1992).
10. J. F. Eaddy, U.S. Patent 4578522 (1986); Chern. Abstr., 105,6311 (1986).
11. C. R. Clark, R. T. Sansom, C. M. Lin, and G. Norris, J. Med. Chern., 28,
1259 (1985).
12. F. Makovec, C. Rolando, M. Bani, and L. Revel, Eur. J. Med. Chern., 21, 9
( 1986).

34 MONOCYCLIC AROMATIC COMPOUNDS
13. I. Monkovic, Drugs Future, 14,41 (1989).
14. R. Aguire Alpunte, J. Boix Iglesias, and A. Vega Noverola, Spanish Patent
2019042 (1991); Chern. Abstr., 116,6421 (1992).
15. R. A. Mueller and R. A. Partis, U.S. Patent 4469885 (1984); Chern. Abstr.,
101,210751 (1984).
16. D. E. Mais, F. Mohamadi, G. P. Dube, W. L. Kutz, K. A. Brune, B. G.
Utterback, M. M. Spees, and J. A. Jakubowski, Eur. J. Med. Chern., 26, 821
( 1 991 ) .
17. J. B. Hester, J. K. Gibson, M. G. Cimini, D. E. Emmert, P. K. Locker, S.
C. Perricone, L. L. Skaletzky, J. K. Sykes, and B. E. West, J. Med. Chern.,
34, 308 (1991).
18. W. C. Lumma, R. A. Wohl, D. D. Davey, T. M. Argentieri, R. J. DeVita,
R. P. Gomez, V. K. Jain, A. J. Marisca, T. K. Morgan, H. J. Reiser, M. E.
Sullivan, J. Wiggins and S. S. Wong, J. Med. Chern., 30, 755 (1987).
19. G. C. Buzby and T. J. Colatsky, U.S. Patent 4721809 (1988); Chern. Abstr.,
110,212382 (1989).
20. R. W. Fuller, D. W. Robertson, and D. T. Wong, Eur. Pat. A ppl., 369685
( 1990); Chern. Abstr., 113, 190895 (1990).
21. W. R. Beckett and P. J. Harris, Drugs Future, 13, 736 (1988).
22. J. P. Yardley, G. E. M. Husbands, G. Stack, J. Butch, J. Bickler, J. A. Moyer,
G. A. Muth, T. Andree, H. Fletcher, M. N. G. James, and A. R. Sielecki, J.
Med. Chern., 33, 2899 (1990).
23. N. Yamakoshi, N. Kurata, N. Koizumi, M. Yarutan, H. Sakuma, and K.
Konishi, U.S. Patent, 4293557 (1981); Drugs Future, 10, 995 (1985).
24. A. Luxen and J. R., Bario, Tetrahedron Lett., 29, 1501 (1988).
25. M. Namavari, A. Bishop, N. Satyamurthy, G. Bida, and J. R. Bario, Appl.
Radiat. Isot., 43, 986 (1992).
26. S. R. Baker, J. R. Boot, R. Lucas, and G. Wishart, Drugs Fdture, 16, 432
( 1 991 ) .
27. W. Baker and O. M. Lothian, J. Chern. Soc., 628 (1935).
28. W. S. Marshall, T. Goodson, G. J. Cullinan, D. Swanson-Bean, K. D. Haisch,
L. E. Rinkema, and J. H. Fleisch, J. Med. Chern., 30, 628 (1987).
29. J. A. Miller and R. S. Matthews, J. Org. Chern., 57, 2514 (1992).
30. C. W. Perry, M. V. Kalnins, and K. H. Deitcher, J. Org. Chern., 37 (1972).
31. R. J. Toivola, A. J. Karjlaainen, K. O. A. Kurkelka, M. J. Sodervall, L. V.
M. Kangas, L. G. Blanco, and H. K. Sundquist, Eur. Pat. Appl. 95875 (1983);
Chern. Abstr., 102, 166452 (1985).

CHAPTER 3
POLYCYCLIC AROMATIC AND
HYDROAROMATIC COMPOUNDS
At least two of the reasons for the use of benzene rings as centers for the
construction of biologically active compounds extend to polycyclic com-
pounds. Polycyclic arrays afford rigid nuclei which allow the positioning of
putative phannacophores over an even larger span than do simple benzene
rings; these rings further provide centers of higher electron density than
single benzene rings. Few if any endogenous mammalian compounds in-
corporate such ring systems. This is in distinct contrast to secondary metab-
olites from plants and microorganisms, where polycyclic aromatics are quite
common.
The sulfonylurea functionality has a venerable association with oral an-
tidiabetic agents, the great majority of which incorporate this group or an
isostere thereof. A sulfonyl urea, which is virtually devoid of effects on
sugar metabolism, interestingly exhibits antitumor activity in a number of
experimental animal cancer models. Chlorosulfonation of indan (1) leads to
the corresponding arylsulfonyl chloride 2. Reaction of that intennediate with
ammonia gives the sulfonamide 3. Condensation of the sulfonamide with
p-chlorobenzeneisocyanate leads to addition of the amide to the reactive
isocyanate N=C bond and fonnation of a sulfonylurea; sulofenur (4)1 is
thus obtained.
Structural requirements in the nontricyclic antidepressants would seem to
be quite liberal. The benzylic tertiary amine 13, dapoxetine, which owes
its activity to inhibition of serotonin reuptake, bears only a passing resem-
blance to the more classical drug ftuoxetine (Chapter 2). One of the enan-
35

36 POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS
ccY R
D CI
O 2 0 I
ccr S..w.. /"
""" .......N/.......N
I/" H H
:>
1 , R=H
2, R=S02 C1
3 , R=S02 NH 2
4
tiomers is responsible for the activity of the compound, as is true of many
biologically active compounds. The synthesis of that enantiomer starts with
the reduction of the t-butyloxycarbonyl (t-BOC) derivative of R phenylgly-
cine (5) to the corresponding alcohol 6. This intennediate is then homolo-
gated using one of the standard schemes. Thus the alcohol is first converted
to the methanesulfonate (7) and the newly fonned leaving group i}displaced
by cyanide to give the nitrile 8. This is then saponified to the aCId (9); the
homologated alcohol 10 is obtained by reduction of the carboxyl group by
means of a hydride reagent. Reaction of the alkoxide from 10 with
I-fluoronaphthalene leads to fonnation of the I-naphthyl ether 11 by nu-
cleophilic aromatic replacement of fluorine. The t-BOC protecting group is
then removed by treatment with strong anhydrous acid to afford the primary
amine 12. Dimethylation of this last intennediate with fonnaldehyde and
fonnic acid (Clark-Eschweiler reaction) gives dapoxetine (13). 2
o
COzH
NHBOC
 0
OR
NHBOC
o
R
NHBOC
5
8, R-H
7, R-SOzYe
8, R-CN
BOC-tBuOCO
9, R-COzH
o
o .
N(CHs>z
-8 \
"
I - c
o \/
NHR
\
o
OH
NHBOC
1 :3
11. R-BOC
12. R-H
10
A series of polyenes related to Vitamin A have an important role in
epithelial cell proliferation and differentiation. The all-trans retinoic acid
tretinoin (14) is indicated for treating severe acne and is in addition currently

POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS 37
C02H
1 4
being investigated in the clinic as an agent that may cause cancer cells to
redifferentiate. This drug has also achieved some fame under the trade name
Retin-A as a compound that will rejuvenate skin.
A series of tetramethyl tetralins seem to exhibit activity similar to that of
the monocyclic prototype. Including elements of the extended conjugated
side chain of 14 in aromatic rings would seem to offer increased stability
over that of the polyene. Acylation of the tetralin 15 with acetic anhydride
or acetyl chloride leads to the acyl derivative 16. The carbonyl group is then
reduced to an alcohol (17) and that group is converted to a bromide (18).
Displacement of halogen with triphenylphosphine leads to the phosphonium
salt 19. This compound is then converted to its y lide with strong base.
Condensation of the phosphorane with p-ethylsulfonyl-benzaldehyde affords
etarotene (20);3 sumarotene (21) is obtained by condensation with p-methyl-
sulfonylbenzaldehyde. It is worth noting that olefinic linkage can be replaced
by nitrogen. The p-sulfonyl-hydrazone of the key acetyl compound, Iinar-
otene (22) shows the same activity as its congeners.
=-
=-
1 5
1 6
17, R=OH
18. R-Br
+
19, R-PPh s
/
H
 ....N ,o
N "
'/
S02 CH S
22
20. Rz:CH s
2 1, R - H

38 POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS
Inclusion of a hydroxyl group in the alicyclic ring leads to a somewhat
more hydrophobic compound which retains the same activity. The Wittig
condensation sequence needs to be reversed in this case since the ring hy-
droxyl would interfere with the original approach. Thus condensation of M'te
phosphorane from phosphonate 24 with the acetyl tetralin 23 leads to the
olefin 25; all these reactions lead to transoid olefins since they involve
stabilized intennediates. Reduction of the ester in 25 with LAH gives do-
retinel (26). 4
HO
O C0 2 Et
 I ,/
(EtO)2 PH 2 C
+
23

24
HO
j} CH 2 0H
"
,/ HO
4:
0COzEt

26
25
The naphthalene adapalene (34), described as an antiacne agent, seems
to bear little structural relation to the retinoids or the tetramethyltetralins
derived therefrom. However, this compound features the highly lipophilic
center at one end of the molecule, in this case an adamantyl moiety, also
found in the retinoids. The acidic group in this case is separated from that
lipophilic center by the highly conjugated phenylnaphthalene group; this
could be envisaged as a surrogate for the trans polyene of the retinoids. It
is well known that phenoxide anions often display reactions typical of enolate
anions. Thus alkylation of the phenoxide from m-bromophenol with
I-bromoadamantane leads to a mixture of the 2- and 4-adamantyl-
bromophenols (29, 28). 5 The latter, once separated, is methylated to anisole
30. The key reaction in the sequence involves nickel-catalyzed coupling of
a bromonaphthalene with an aryl Grignard reagent. Condensation of bro-
monaphthalene 31 with the Grignard reagent from 30 and magnesium in the
presence of the complex from nickel chloride and the bisphosphine 32 leads

POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS 39
A)Br
> +
OH Br
27
28
29 I R=H
30, R=CH 3
3 1
I
Br

C0 2 R
CeHs
I
HsC s , P,
P C e H 5
I
H 5 C e
C0 2 R
32
33, R=Et
3 4, R = H
to the phenyl naphthalene 33. Saponification of the ester gives adapalene
(34). 6
The classical antipsychotic agents, typified by the phenothiazines, largely
acted as dopamine antagonists. A more recent compound, alentomol (52),
which bears only the most distant structural relation to those agents, also
acts as a dopamine antagonist antipsychotic. The seemingly simple structure
of this agent includes a dihydroperylene nucleus, that is difficult to reach
and requires a somewhat involved synthetic scheme. The preparation starts
with the bromination of the 2,5-dihydroxybenzaldehyde 36 to give bromo-
phenol 37; the hydroxyl group is then converted to its p-toluenesulfonate
(Ts). In a convergent scheme, furfuraldehyde is converted to 39 by base-
catalyzed condensation with nitromethane; catalytic reduction leads to 40.
Reaction of the latter with benzaldehyde (38) in the presence of piperidine
gives the addition product 41, piperidine having apparently displaced the
initially fonned hydroxyl. Treatment of 41 with acid leads to fonnation of
the conjugated nitroolefin 42. Hydrogenation of that intennediate reduces
the double bond to give 43; reducing the nitro group gives primary amine
44. The ordinarily sensitive amine function needs to be protectd from some
of the strenuous conditions involved in subsequent steps; conversion of the
amine to a pyrrole (45) by means of hexane-2,5-dione greatly reduces its

40 POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS
basicity and sensitivity. The key reaction to building the perylene nucleus
involves an intramolecular Diels- Alder condensation using a benzyne as
dienophile and furan as the diene. Thus reaction of 45 with the strong base
phenyllithium results in fonnal ortho elimination of the elements of tolu-
enesulfonyl bromide and fonnation of the hypothetical benzyne 46.
CH = 0 CH = 0
O OH O OTS
I ---+ I
CH30 /' X CH30 /' Br
36, X = H
37, X = Br
38
CH30
C H 3 0
41
42
NO;- N02
39 40
j
.
..
NR2 I\:
o
OTs
CH30
C H 3 0
CH3 0
46
45
43, R = 0
44, R = H
The product of the internal electrocyclization reaction is the fused 1 ,4
oxide 47. The isolated double bond is then reduced and the ensuing product,
48, treated with the strong Lewis acid BF3 with net loss of oxygen and
aromatization of the newly fonned ring (49). Treatment of that compound
with hydroxylamine leads to an interesting exchange reaction involving the
pyrrole ring and involving the presumable fonnation of the bisoxime of
hexane-2,S-dione and concomitant restoration of the primary amine (50).
Dialkyation of the primary amine by means of n-propyl chloride (51) fol-
lowed by O-demethylation affords alentomol (52). 7
An enonnous amount of effort has been invested in modifying the mor-
phine molecule to produce an agent with the pain-killing efficacy of the
parent but devoid of its adverse side effects, the most notable of which is
the addiction liability associated with the majority of opioids related to mor-
phine. It was discovered that introduction of a hydroxyl group on the bridge-
head position, as in oxymorphone, greatly increased potency. The starting

POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS 41

N

N

N
;)
;)
CHsO
CHsO
CHsO
.7
48
49
1
N
c
RO
CHSO
51. R-CH S
52. R-H
50
material for 14 hydroxylated compounds is obtained by peroxide oxidation
of the natural product thebaine 53. These can be envisaged, at least fonnally,
as products of 1,4 addition to the conjugated diene in 53.
H3
N
o
Oxymorphone
A related 1 ,4 addition reaction on thebaine leads to an analgesic that
contains basic nitrogen at the bridgehead position. Thus reaction of 53 with
tetranitromethane in methanol leads to the product of fonnal addition of
methyl nitrate across the double bond. The stereochemistry of the product,
54, as in the case of peroxidation, represents addition to the less-hindered
face of thebaine. 8 The newly introduced nitro group is then reduced to the
primary amine 55. That function is then acylated with pentanoic acid and

42 POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS
H3
N
H3
N
:>
53
5 4. R = 0
5 5. R = H
!
<
H3
N
NH
58
56 I R=O
57. R=H 2
the resulting amide, 56, is reduced with LAH to give the secondary amine
57. Treatment of this product with boron trifluoride at once demethylates
the aromatic methyl ether and hydrolyzes the dimethyl acetal function. The
analgesic pentamorphone (58)9 is thus obtained.
The clinical antileukemic agent mitoxantrone (59) was developed in the
course of structure activity studies on a compound lacking the two ring
hydroxyls. That compound was in fact a ball point ink dye submitted for
testing in the National Cancer Institute antitumor screen. The clinical effi-
cacy of 59 together with a suggestive structural relationship to the anthra-
cyclines (see below) spurred additional studies on antitumor anthraquinones.
H
HNNOH
HNNOH
H
59

POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS 43
Two closely related anthraquinone derivatives in which one of the car-
bonyl groups has been incorporated in a fused pyrrazole ring have shown
considerable antitumor activity in animal models. The preparation of the first
is made relatively straightforward by the symmetry of the starting material
(60). The scheme begins with conversion of the phenolic hydroxyls in 60
to their benzyl ethers (61). Reaction of that compound with a controlled
amount of the substituted hydrazine 62 leads to fonnation of the pyrrazole
ring; this can be rationalized to involve fonnation of a hydrazone and sub-
sequent displacement of halogen by the remaining basic hydrazine nitrogen.
Displacement of the remaining chlorine with 1,3-propylenediamine gives
64. The benzyl ethers are then removed by hydrogenation over palladium
catalyst to afford piroxantrone (65).10.11
o C 1
RO
B
N - N  N-......../'o H
B
+ B NNNOB
2 H
)I
RD 0 C 1
60. R-H
8 1 I R-CH 2 C e H(i
RO 0 Cl
62
63, R-CB 2 C e H s
/
RO
H
N - N  H -......../' 0 H
RO 0 HNNH2
84, R-CH 2 C e H 15
85, R-B
The synthesis of losoxantrone, 70 (fonnerly biantrazole), is complicated
by the regioisomers made possible by the unsymmetrical nature of starting
anthraquinone 66. The 2,4,6-trimethylbenzyl protecting group, used for this
synthesis, adds to the solubility of the anthraquinones in nonpolar solvents
and may decrease the reactivity of the adjacent carbonyl due to steric bulk.
In the event, reaction of 67 with hydrazine 62 gives the anthrapyrrazole 68
as a 4: 1 mixture with its regi0isomer. The compound is converted to its
N-t- BOC derivative to facilitate separation of the regioisomeric products.
Treatment of the purified isomer with hydrogen chloride simultaneously

44 POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS
o
C 1
H
N-NNOH

o
C 1
RO
o
C 1
88. R-H
87. R-CHaC.BaKeS
88. R-CHaC.BaK8s
89. R-H
H
H-NNOH
HNNOH
H
70
removes the (-BOC and 2,4,6-trimethylbenzyl protecting groups to afford
69. Displacement of the remaining chlorine with N-(2-hydroxyethyl)-
ethylenediamine gives losoxantrone, 70. 10 . 11
Polynuclear aromatic hydrocarbons are some of the earliest human car-
cinogens to be identified. The identification of dimethylbenzathracene as the
causative agent of scrotal cancer among chimney sweeps ranks among the
triumphs of epidemiology. It is thus of interest that a closely related com-
pound has shown antitumor activity in animal models. Fonnylation of chrys-
ene 71 with dichloromethyl methyl ether catalyzed by stannic chloride yields
aldehyde 72. Reductive alkylation of that compound with 1,2-bishydroxy-
metylethylamine affords crisnatol (73).12
:>
OH
-fCH3
OH
R
71, R=H
72, R=CH=O
73

POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS 45
The discovery that the antitumor activity of two structurally closely re-
lated Streptomyces metabolites in lower species carried over to humans ush-
ered in a new area of cancer chemotherapy. These compounds, daunorubi-
cin (74) and doxorubcin (75), called anthracyclines, have found numerous
applications in the treatment of malignancies. This is particularly true for
the latter under its more familiar name adriamycin. The design of total
syntheses for these compounds was particularly difficult because no good
method could be devised for controlling the relative regiochemistry of the
sole methoxyl group at the 4-position in ring D and the hydroxyacetone
substituent at 9 in ring A. A totally synthetic compound intended to over-
come that difficulty by omitting the 4-methoxyl not only retained good an-
titumor activity but, unlike the prototypes, fortuitously, displayed oral ac-
ti vity .
R
CHSO OCH s =
o
HaCM
OH NH 2
7 4, R = H
75, R=OH
A number of different methods have been used for the preparation of the
key bicyclic intennediate 77. The most direct involves addition of
I-methoxyvinyl lithium to the tetralone 75. Hydrolysis of the enol ether in
product 76 leads to the required hydroxyacetone side chain for future position
9. 13 Lack of an ionizable center precludes resolution of 77 by the usual
method involving salt fonnation with an optically active acid. Instead, the
carbonyl function is reacted with S-a-benzylamine to fonn the imine 78.
The two diastereomers of this product can fortuitously be separated by direct
crystallization. Hydrolysis of the separated imines affords the pure enatio-
mers of 77.
Acylation of the R isomer of 77 with the acid chloride from the monoester
of phthalic acid leads to the benzoy lated product. The ester group is then
saponified and the resulting keto acid cyclized under somewhat more stren-
uous conditions to give intennediate 79, which has all four rings in place
and lack only functionality at position 9. Introduction of that group has
proven to be one of the more difficult steps in the synthesis. (It might be

OCH 3
"1/ 
OH
> >
OCH s OCH s OCH 3
76 77
75 
A
N CeH5
I
46 POLYCYCLIC AROMATIC AND HYDROAROMATIC COMPOUNDS
OCH S
78
added that a large number of claimed partial syntheses of anthracylines stop
at 9 deoxy derivatives such as 79.) The side chain carbonyl group is then
converted to its ethylene acetal 80. Free-radical bromination (bromine,
AN) proceeds at the benzylic 9 position to give the stereochemically
undefined bromide 81. This is then carefully hydrolyzed to the 9-a alcohol;
the acetal is lost during this sequence to give 82. This aglycone, as well as
its counterparts in the 4-methoxy series, is quite devoid of biological activity.
OYe 0
»
OWe
R
79 80, R-B
8 1 I R-Br
I
0 0
Olde 0
»
OYe
77
c
OYe
o

HO NHR
83, R-COCf s
84. R-H
OYe
OH
82

REFERENCES 47
Addition of the very necessary amino sugar is accomplished by condensation
of alcohol 82 with the bromo derivative obtained from N-trifluoracetyl-
daunosamine. Saponification using mild base serves to remove the
N-trifluoroacetyl group and idarubicin (84) 14,15 is thus obtained.
REFERENCES
1. J. J. Howbert, C. S. Grossman, T. A. Crowell, B. J. Rieder, K. E. Kramer,
E. V. Tao, J. Aikins, G. P. Poore, S. M. Rinzel, G. B. Grindey, W. N. Shaw
and G. C. Todd, J. Med. Chern., 33, 2393 (1990).
2. W. J. Wheeler and D. D. O'Bannon, J. Labelled Cornpd. Radiopharm., 31,
305 (1992).
3. M. Klaus, W. Bollag, P. Huber, and W. Kueng, Eur. J. Med. Chern., 18, 425
(1983).
4. F. F. Frickel, H. H. Wuest, and A. Nuerrenbach, Gennan Offen., 3434942
(1986); Chern. Abstr., 108, 150070 (1988).
5. Soon, Ng, Aust. J. Chern., 26, 2303 (1973).
6. B. Schroot, J. Eustache, and J. M. Bernardon, Eur. Pat. Appl., 86-400785;
Chern. Abstr., 106, 84197 (1987).
7. W. H. Darlington and J. Szmuszkovicz, Tetrahedron Left., 29, 1883 (1988).
8. R. M. Allen, G. W. Kirby, and D. J. McDougal, J. Chern. Soc. Perkin Trans.
I, 1143 (1981).
9. R. J. Kobylecki, I. G. Guest, J. W. Lewis, and G. W. Kirby, Gennan Offen.,
2812581 (1978); Chern. Abstr., 90, 39100 (1979); Anon., Drugs Future, 15,
352 (1990).
10. H. D. H. Showalter, J. L. Johnson, J. M. Hoftiezer, W. R. Turner, L. M.
Werbel, W. R. Leopold, J. L. Shillis, R. C. Jackson, and E. E. Elslager, J.
Med. Chern., 30, 121 (1987).
11. V. G. Beylin, N. L. Colbry, O. P. Goel, J. E. Haky, D. R. Johnson, J. L.
Johnson, G. D. Kanter, R. L. Leeds, B. Leja, E. P. Lewis, C. D. Rithner, H.
D. H. Showalter, A. O. Serces, W. P. Turner, and S. E. Uhlendorf, J. Het-
erocycl. Chern., 26, 85 (1989).
12. K. W. Bair, U. S. Patent 4719046 (1988); Chern. Abstr., 111,96882 (1989).
13. J. R. Wiseman, N. I. French, R. K. Hallmark, and K. G. Chiong, Tetrahedron
Left., 40, 3765 (1978).
14. F. Arcamone, L. Bernardi, B. Patelli, P. Giardino, A. Di Marco, A. M. Cas-
azza, C. Soranzo, and G. Pratesi, Experientia, 34, 1255 (1978).
15. F. Arcamone, Doxorubicin, Anticancer Antibiotics, Academic Press, New York,
1981, p. 48.

CHAPTER 4
STEROIDS
Medicinal chemistry SAR probes perfonned during the last half century have
finnly established that the four-ring steroid ring system is a virtual require-
ment for compounds that exhibit androgenic, progestational, corticoid, and
Vitamin D type activity. Estrogens and their antagonists fonn a notable
exception to this rule; the varied number of structures which exhibit at least
some degree of estrogenic activity reflect the low discriminatory power of
the estrogen receptor.
Antagonists to endogenous androgens such as testosterone (1), have been
sought for some time because of their potential utility in treating conditions
exacerbated by excessive stimulation of androgen receptors. These range
from the relatively mild, such as acne and benign prostatic hypertrophy, to
life-threatening prostatic cancer.
4
1
Modification of ring A of testosterone seems to have been a profitable
approach to developing compounds that show antiandrogenic activity. Com-
48

STEROIDS 49
plete omission of the ring as in incoterone (10), leads to an antiacne agent.
The profound departure in structure from natural steroids means that total
synthesis is more expeditious than modification of the steroid nucleus. The
synthesis starts by construction of the CD portion of the molecule by one
of the classical approaches. Thus Robinson annulation of cyclopentanedione
3 with the methylvinyl ketone analogue 2 leads to the hydrindanone 4; the
ketone at the future 17 position is then reduced to an alcohol; steroid ste-
reochemistry prevails so that this affords a 17 -{3 hydroxy group. Saponifi-
cation of the ester gives acid S. Catalytic hydrogenation of 5 leads to re-
duction of the double bond in the enone; addition from the less-hindered
side away from the angular methyl group establishes the all important trans
CD ring fusion. It should be noted that the thennodynamically favored fusion
for hydrindanes is in fact cis. Treatment of the resulting keto acid 6 with
acetic anhydride leads to the cyclic enol ether 7. 1 Condensation of that
intennediate with propylmagnesium bromide proceeds to the hypothetical
diketone 8 by addition to the lactone carbonyl group. Reaction of the crude
product from this Grignard reaction with base leads to annulation of the
diketone to fonn ring B and afford 9; the 17 acetate group is lost in the
course of that reaction. Treatment of 9 with acetic anhydride then leads to
the antiandrogen inocoterone (10). 2
OH
) )j
+ :)
0'" °
Ue0 2 C R 2 0 C
2
2 3 4, R1-0, R 2 -Ke
5, 1 R 2 -H
R -8,08,
OH

°
H0 2 C
6
1
OAe
OR
08
c
c
9, R-H
10, R-OAc
8
7
Replacement of ring A by a piperidone and addition of a hindered amide
at the 17 position also leads to an antiandrogenic compound, in this case,
finasteride, 17, which has been approved in the United States for treatment
of benign prostatic hypertrophy. The starting material, 11, for the published

50 STEROIDS
synthesis can be prepared by oxidation of the 17 -acetyl side chain of pro-
gesterone. Oxidative cleavage of the 3-4 double bond by sodium periodate
and potassium pennanganate leads to the ring-opened keto acid 12. Reduc-
tive amination of that compound with ammonia recloses ring A as a piper-
idone (13). 3 Any amide fonned at the 17 position of the acid is presumably
hydrolyzed on workup. Treatment of 13 with trimethylsilyl chloride under
the usual conditions converts the acid to the silyl ester and the lactam to the
corresponding silyl iminoether (14). Reaction of that intennediate with a
classical steroid dehydrogenating agent, 2, 3-dichloro- 5, 6-dicyanoquinone
(DDQ), introduces a double bond at the 1 position in ring A. Removal of
the protecting groups by acid affords intennediate 15. Special conditions
must be used to convert the acid at 17 to an amide, possibly because of its
hindered nature as well as possible competing reactions of the unsaturated
lactam. Thus treatment of that acid with carbonyldiimidazole gives the ac-
ti vated fonn of the acid. Reaction of this imidazo amide with the salt from
tert-butylamine and ethylmagnesium bromide leads to fonnation of the amide
finasteride 17. 4
--+
C02H
C0 2 H
.
C0 2 H
o
o
11
12
13
COR
1
C02SiMe3
.
C0 2 H
c
o
Me3SiO
r=\
16, R = NvN
17, R = NHCMe3
15
14
Endogenous estrogens, all of which possess an aromatic ring A, are de-
rived from molecules closely related to testosterone. A key reaction in the
biosynthesis of these molecules involves removal of the angular methyl
group; an early step in the sequence involves oxidation of that group to an
aldehyde. Inhibition of the enzyme involved in this sequence, aromatase,
should reduce levels of endogenous estrogens. This should in theory provide
an alternate treatment for estrogen-stimulated breast cancer. The aromatase

STEROIDS 51
inhibitor plomestane, 24, is designed to provide a reactive group at the
position attacked by the enzyme; interaction with the active site should fonn
a covalent bond and inactivate the enzyme irreversibly. The 19-nor steroid
starting material, 18, for this agent can be prepared from estradiol in a short
sequence whose key step involved Birch reduction of the A ring. This in-
tennediate is then converted to its bis acetal 19 by reaction with ethylene
glycol. Reaction with N-bromosuccinimide in aqueous DMF in effect adds
HOBr to the double bond. The stereochemical outcome follows from for-
mation of the initial bromonium ion on the less-hindered (3 face of the
molecule. Treatment with base leads to fonnation of the a-epoxide by in-
ternal displacement of bromide. Condensation of the epoxide in the presence
of cuprous chloride with the lithium reagent from the silyl derivative of
propyne gives the silylpropyne 22. The acetal groups on the resulting 10-(3
propargyl derivative 22 are then removed by exchange with acetone in the
presence of acid. The resulting (3-ketol dehydrates in the presence of base;
the silyl protecting group is lost in the same reaction to afford plomestane
(24) . 5
.
O/j
o
o
18
19
20
1
.
.
O
o
R
24
22, R = OCH2CH20
23, R = 0
21
The majority of oral contraceptive drugs include as the progestational
component a 19-nor steroid that carries an acetylenic carbinol at the 17
position. It has in fact been speculated that at least a portion of this com-
ponent may be metabolized to the very potent 17-ethynyl aromatic A-ring
estrogens. Compounds devoid of oxygen at the 3 position interestingly retain

52 STEROIDS
--+
--+
o
o
o
o
25
26
27
!
+--

31
!
29, R = 0
30, R = CH2
28
--+
32
33
34
progestational activity. The 3-desoxy-I9-nor steroid desogestrel, 34, pro-
vides the progestin in several oral contraceptives.
The synthesis starts with the free radical induced functionalization of the
otherwise inert methyl group at the 13 position. Thus reaction of the II-{3
alcohol 25 with lead tetraacetate and iodine in the presence of AIBN leads
to oxidation of the 18 methyl, a reaction probably initiated by an II-oxy
free radical. The oxidation product then cyclizes to 26. Condensation of that
lactone with methyl Grignard reagent leads to the I3-acetyl derivative 27;
reduction of the carbonyl by Wolf-Kishner reaction gives the 18 homologue
28 of the starting material. The hydroxyl at 11 is then oxidized to the
corresponding ketone (29) and the product is reacted with methylene tri-
phenylphosphorane to give the II-methylene intennediate 30. Acid-cata-
lyzed interchange with acetone removes the ethylene ketal groups at 3 and
17; the 5,6 double bond shifts into conjugation in the process (31). For-
mation of a cyclic acetal with ethylene dithiol proceeds preferentially at the
3 position (32); the nonnally lower reactivity of the 17 ketone is emphasized
by the additional steric hindrance due to the added methylene group at carbon

STEROIDS 53
18. Reaction of this ketone with lithium acetylide proceeds with the expected
steric outcome to give the 17-a ethynyl derivative 33. Reductive cleavage
of the thioacetal by means of sodium in liquid ammonia leads to the
3-desoxy derivative; there is thus obtained the orally active progestin de-
sogestrel (34). 6
As noted in Chapter 1, the estrogen antagonists (e. g., the nonsteroidal
agent tamoxifen), have provided a noncytotoxic alternative for treatment of
breast cancer; the recently approved androgen antagonist finasteride, dis-
cussed above, is under intense investigation as an agent for treatment of
prostatic cancer. Compounds that acted as antagonists at progestin and cor-
ticoid receptors were the last to be discovered. It is of interest that most
agents of this class show antagonist activity at both of these receptors. The
prototype antiprogestin mifepristone is currently the center of much emo-
tional debate under the more familiar sobriquet RU-486.
The synthesis of that agent starts with the diene 35, which constitutes an
intennediate for total synthesis of 19-nor steroids. 7 Oxidation of that com-
pound with a reagent prepared from trifluoroacetic anhydride:hydrogen per-
oxide proceeds selectively at the tetrasubstituted 5, 10 double bond to afford
exclusively the a-epoxide 36. The key reaction, which provides entry to the
progestin/corticoid antagonists, may be viewed as a vinylogue of nonnal
epoxide opening. Thus condensation of 36 with the Grignard reagent from
4-bromo-N,N-dimethylaniline results in addition of the reagent at the 11-{3
position; this results in rearrangement of the olefin to 9, 10 and opening of
the epoxide. The stereochemistry of the product, 37, is consistent with trans
opening of the oxirane, albeit at a remove of two carbon atoms. Mild hy-
drolysis removes the silyl cyanohydrin protecting group at the 17 position.
Reaction of the resulting ketone (38) with propargyl lithium leads to 39.
Hydrolysis of that product under more strenuous conditions results first in
removal of the acetal at 3; the resulting {3-hydroxyketone then dehydrates to
afford the 4,1 O(9)-dieneone 40. 8 This product, mifepristone, is an orally
active progestin antagonist, which has only minor activity at corticoid re-
ceptors. The compound is an effective, orally active abortifacient in humans;
its antiprogestational activity deprives the early conceptus of its necessary
honnonal support and leads to tennination of pregnancy.
An unusual degree of configurational freedom seems to be consistent with
antiprogestational activity in this series. The progestin receptor antagonist
onapristone, 47, displays a configuration inverted with respect to the natural
series and the prototype, 40, at both the CD ring junction and at carbon 17.
It should, however, be noted that a good three-point overlay can be obtained
with models of the two molecules involving the carbonyl group at position
3, the basic anilino nitrogen, and the hydroxyl group at position 17.
Epoxidation of the total synthesis intennediate 41, analogous to that used

54 STEROIDS
CN CN CN
.,\\ OSi Me3 .,\\ OSi Me 3 .,\\ OSiMe3
. o
OH
35 36 37
1
Me2N OH CH3 Me2 N
.,\
. .....-.-
0
40 39 38
above, with a strong oxidant affords the 9,10-a oxirane 42. The 4-N,N-
dimethylaniline moiety is added to the steroid by conjugate addition, exactly
as described above, to give 43; oxidation of the alcohol at 17 leads to the
corresponding 17-keto compound 44. Photolysis of this compound results
in net inversion of the angular methyl group at carbon 13 to afford 45. This
reaction can be rationalized by assuming initial scission of the 13-14 ring
fusion; reclosure of the hypothetical intennediate to a thennodynamically
favored cis hydrindane would lead to the observed product. Condensation
of that compound with the Grignard reagent from the tetrahydropyranyl ether
(THP) of 3-bromopropanol gives the carbinol 46. The predominant isomer
from that reaction, in distinct contrast to the course of addition to nonnal
Me2 N

41 42
Me2N !
Me2 N
OH OTHP
.
- -
OH OH
47 46 45

STEROIDS 55
steroidal 17-ketones, results from attack of the reagent at the {3 face of the
molecule. The steric course of this reaction reflects the now sterically more
accessible nature of the (3 face. Hydrolysis of this last compound results in
overall loss of the acetal and the THP groups as well as dehydration of the
hydroxy I at position 5. Onapristone, 47, 9 is thus obtained.
High levels of serum cholesterol have by now been finnly associated with
increased risk of cardiovascular disease. Attempts to lower cholesterol levels
are complicated by the fact that a significant fraction of those levels come
from endogenous synthesis of this very necessary steroid starting material.
The recently developed drugs, such as lovastatin, interfere with cholesterol
biosynthesis at a very early stage; the close derivative of cholesterol itself,
colestolone, probably acts at a very late stage as a false substrate or end-
product feedback inhibitor. One of the more direct syntheses for the com-
pound starts by bromination of cholesterol benzoate (48) to give a mixture
of 7 -bromides (49). Dehydrobromination of this intennediate leads to the
5,7 endocyclic diene 50. The double bonds then migrate in the presence of
hydrogen chloride. The extended 9( 10), 14 diene 51 is obtained in quite
modest yield; the driving force for the transfonnation may be the fonnation
of an all trans conjugated system. Oxidation by means of chromium trioxide
proceeds on the extremities of the diene to give the 9-a-hydroxy-15-ketone
52. The allylic hydroxyl at position 9 is then removed reductively with zinc
in acetic acid (53). Saponification of the benzoate at 3 affords colestolone
(54).10

48, R-H
50
49. R-Br
1
c:
RiO
52, R I -C e H 6 CO. R 2 -OH
53, Rl.C e H 5 CO ' R 2 _H
54. Rl_R2_H
5 1

56 STEROIDS
The first several volumes of this series chronicled the immense effort that
went into research on corticosteroids, which was aimed at finding agents
that retained the profound antiinflammatory activity of the series without the
attendant honnonal effects. The realization that this was an unattainable goal
has relegated the research to development of analogues that exert strictly
local action and are inactivated as they enter the circulation. In the course
of such work it has been noted that elements of the dihydroxyacetone side
chain at the 17 position, once considered the landmark of the series, can be
replace by mere bulk. The key reaction sequence to one of these agents
starts with copper salt catalyzed conjugate addition of methyl magnesium
bromide to pregnenolone acetate 55. The intennediate enolate, 56, is then
treated in situ with methyl iodide. Both the conjugate addition and alkylation
steps involve the approach of reagents from the less-hindered side to afford
the 16/3, 17/3-dimethyl derivative 57. II
)I
o
)I
AcO
AcO
AcO
55
56
57
The II-acetoxy intennediate required for the synthesis (58) can be ob-
tained in principle from a similar sequence on an II-oxygenated intennediate
or by introduction of that group by fennentation of a suitable derivative of
57. Enolization of the acetyl group in 58, with lithium diisopropylamide
followed by treatment with methyl iodide, gives the homologated derivative
59. Hydrolytic removal of the acetal at the 3-position proceeds with con-
comitant loss of the II-acetyl group (60); this is reacetylated to 61. Treat-
ment of this compound with the potent dehydrogenative agent 2,3-dichloro-
5,6-dicyanoquinone (DDQ) introduces double bonds at the 1 and 4 positions
(62). Saponification of the acyl group at the II position affords the antiin-
flammatory steroid rimexolone (63). 12
Antiinflammatory activity is retained when the carbonyl group at the 20
position is present as a carboxylate group; the side chain can thus consist
of esters. These are presumably readily cleaved by esterases when they reach
the circulation and are thus inactivated. Preparation of the topical ophthalmic
agent loteprednol, 68, starts with prednisolone (64). Oxidation with sodium
periodate cleaves the tenninal hydroxyketone function to give hydroxy acid
65. Reaction of this product with propionyl chloride leads to the mixed
17 -ester anhydride 66, which is readily hydrolyzed to the free acid 67. The

STEROIDS 57
MeO
MeO
:>
58
59
<:
j
. I III
62, R-OAc
63, R=H
60, R=H
61, R...OAc
key reagent in this reaction, chloromethyl chlorosulfonyl chloride
(CICH 2 0S0 2 CI), can readily be prepared from chlorobromomethane and
chlorosulfonic acid. Esterification of acid 67 with that reagent under phase
transfer conditions leads to loteprednol (68).14
Addition of halogen, and particularly fluorine, at positions 9 and 6 in
corticosteroids is known to markedly increase antiinflammatory potency;
combining this substitution with replacement of the 21-hydroxyl by chlorine
leads to a compound that is extremely effective for treating topical inflam-
mations. The preparation of this agent, halobetasol (78), involves some
classical transfonnation used in steroid chemistry. Treatment of beclometh-
asone (69), itself the product of a lengthy sequence, with ethyl orthofonnate
leads to cyclic orthofonnate 69 by exchange of ethoxy groups with the
steroid hydroxyls. The double bond at 1,2 is then reduced by hydroge-
nation in the presence of Wilkinson's catalyst (70). Fonnation of the anion
from the sole remaining free hydroxyl, that at 11{3, results in internal dis-
placement of chlorine to fonn the {3 epoxide 71; this oxirane in effect

58 STEROIDS
:.
CO R t
a
IIIOR 2
o
o
o
8'
85. RI_R2_8
ee, R1_R2-COC2BS
87. R1_B. R2-COC 1 B&
!
O-CH 2 C 1
o
88
consists of a protected latent fonn of the fluorohydrin present in the final
product. Exposure of the orthoacetate to mild acid leads to preferential cleav-
age of the ring at the 21 position, presumably owing to the sterically more
open approach to that oxygen and the higher Lewis basicity of the primary
acetal oxygen; the net effect, after loss of ethanol, is fonnation of 17-
propionate (72). The hydroxyl at 21 is then converted to its mesylate (73),
and that is displaced by chlorine using lithium chloride to give the 21-chloro
derivative 74. Introduction of fluorine at the 6 position involves activation
of that position by fonnation of the enol ether 75, extending the conjugation
to 6. Reaction of that intennediate with fluorine perchlorate (FCI0 3 ) may
be rationalized as a 1,6 addition reaction with concomitant hydrolysis of the
enol ether. There is thus obtained the 6a-fluoro derivative 76. The 9,10
oxirane is then opened by treatment with the hydrogen fluoride:urea complex
to give the 11 {3-hydroxy-9a-fluoro derivative 77. Restoration of the unsat-
uration at 1,2 by treatment with DDQ completes the synthesis of halobetasol
78. 15

o
.
o
69
70
o
C2 H 5 0
+---

-
F
76
75
STEROIDS 59
.
o
71
1
72, R = OH
73, R = OMs
75, R = CI
.
0 0 -
 -
F F
77 78
Structurally modified derivatives of Vitamin D have therapeutic value in
the treatment of diseases related to faults in calcium transport. Addition of
hydroxyl groups to the side chain is a particularly fruitful approach to in-
creasing potency. The starting material for the synthesis, 79, can in principle
be obtained from pregnenolone by extension of the side chain using an
appropriate reaction at the 21-carbony I group and introducing of the 5, 7
diene by a sequence such as that used to prepare 50 (TMBDS = tert-
butyldimethylsilyl). Condensation of the aldehyde with isopropenylmagne-
sium bromide affords carbinol 80. The tenninal olefin in then oxidized to
give epoxide 81. Reduction of this function with lithium aluminum hydride
leads to the diol 82; the sily I protecting group is removed by treatment with
fluoride ion (83). Photolysis of that intennediate leads to the electrocyclic
ring-opening reaction characteristic of steroidal 5,7-dienes. The initial prod-
uct in the reaction typically consists of the 5(lO),6,9-triene (steroid num-
bering); this rearranges to the observed triene on thennal isomerization and
secalciferol, 84 16 is thus obtained.

60 STEROIDS
TMBDSO
TMBDSO
-
TMBDSO
CH = 0
79
80
81
1
RO
84
82, R = TMBDS
83, R = H
The presence of a hydroxyl group at the I position, which also occurs in
an endogenous metabolite of Vitamin D, also enhances activity. The syn-
thesis in this case starts with an advanced intennediate which already con-
tains the I-hydroxyl. 17 Construction of the side chain begins with conden-
sation of the ylide from phosphonium salt 85 with pivalaldehyde to give the
unsaturated olefin 86. The carbonyl group is then reduced and the resulting
allylic alcohol epoxidized under Sharpless conditions [tert-BuOOH,
Ti(i-OPr)4] in the presence of (-) diisopropyl tartrate. The rate of reaction
of the undesired allylic alcohol is sufficiently accelerated to pennit isolation
of the S alcohol 87; this is then protected as the tert-butyldimethylsilyl ether.
Ozonization of that intennediate gives the chiral side-chain synthon 88.
The aldehyde group in intennediate 80 is then activated to function as a
nucleophile by conversion to its bis-methylselenyl acetal, 90. Reaction with
buty llithium leads to fonnation of an anion by a lithio-demethy lselenation
sequence. Condensation with aldehyde, 88, leads to the product 91. The
free hydroxyl in 91 is converted to a mesylate and the crude product is
treated with triethylamine. This leads to elimination of the elements of meth-
ylselenous acid and fonnation of the olefin (92). Removal of the TMBDS
protecting group then affords calcipotriene, 93,18 an agent which has shown
antipsoriatic activity.
At least some of the tissue damage that accompanies traumatic shock has
been attributed to the generation of oxygen free radicals, which results in
lipid peroxidation; considerable evidence points to the toxic nature of these
peroxidation products. A steroid that incorporates both a highly nitrogenated
heterocyclic system and a corticosteroid precursor has shown activity in a
number of animal models of traumatic shock. The initial steps in the prep-

STEROIDS 61
CH = 0
SeMe
SeMe
.
.
89
90
91
1
85
86, R = 0
87, R = ,8-
OH
88

o
Ph3P+ -
 \<>TMBDS
. V--O=HC V
92, R = TMBDS
93, R = H
aration of this compound involve classical heterocyclic transfonnations. Thus
displacement of chlorine in trichloropyrimidine 94 by means of pyrrolidine
leads to incorporation of two of the five-membered ring bases. Reaction with
piperazine under somewhat more forcing conditions leads to the trisubsti-
tuted intennediate 96. The steroidal starting material consists of the classical
corticoid intennediate 97. 19 Reaction with bromine leads to fonnation of the
21-bromomethyl derivative 98. Reaction of this intennediate with piperazine
(96) leads to displacement of bromine and fonnation of tirilazad (99).20
C 1 0 0
N -=\ N -=\ 1\ N -=\
ClN > ClN :. HN'--INN
C 1 tJ tJ
94 95 96

62 STEROIDS
:>
o
1\ N =<
N "----IN N
o
R
o
97, R-H
98 J R=Br
99
REFERENCES
1. G. Nominee, G. Amiardo, and V. Torelli, Bull. Soc. Chirn. Fr., 3664 (1968).
2. H. Morales-Alanis, M. J. Brienne, J. Jacques, M. M. Bouton, L. Nedelec, V.
Torelli, and V. Tournemine, J. Med. Chern., 28, 1796 (1985).
3. G. H. Rasmusson, G. F. Reynolds, N. G. Steinberg, E. Walton, G. F. Patel,
T. Liang, M. Cacieri, A. H. Cheung, J. R. Brooks, and C. Bennan, J. Med.
Chern., 29, 2298 (1986).
4. A. Bhattacharya, L. M. De Michele, U. H. Dolling, A. W. Douglas, and E.
J. Grabowski, J. Arn. Chern. Soc., 110, 3318 (1988).
5. P. J. Bednarski, and S. D. Nelson, J. Med. Chern., 32, 203 (1989).
6. A. J. van den Broek, C. Van Bokhoven, P. M. J. Hobbelen, and J. Leemhuis,
Reel. Trav. Chirn. Pays-Bas, 94, 35 (1975).
7. L. Velluz, G. Nominee, T. Bucourt, andJ. Mahieu, Cornpt. Rend., 257, 569
( 1963) .
8. G. Teutsch, R. Deraedt, and D. Philbert, in Chronicles of Drug Discovery,
Vol. 3, D. Lednicer, Ed., ACS Books, Washington, DC, 1993, p. 1.
9. G. Neef, S. Beier, W. Elger, D. Henderson, and R. Wiechert, Steroids, 44,
349 (1984).
10. T. Bakas, J. Horvath, and I. Vincze, Chern. Phys. Lipids, 63,23 (1992).
II. J. Cairns, C. L. Hewett, R. T. Logan, G. McGarry, D. F. M. Stevenson, and
G. F. Woods, J. Chern. Soc. Perkin 1, 1558 (1976).
12. J. Cairns, R. T. Logan, G. McGarry, G. Roy, R. G. Stevenson, and G. F.
Woods, J. Chern. Soc. Perkin 1,2306 (1981).
13. E. Binderup and E. T. Hansen, Synth. Cornrnun., 14,857 (1984).
14. P. Druzgala, G. Hochhaus, and N. Bodor, J. Steroid Biochern. Mol. Bioi., 38,
149 (1 991 ) .

REFERENCES 63
15. J. Kavolda, J. Grob, K. Jakel, R. Maier, P. Moser, H. Fuhrer, E. G. Weirich,
and S. J. Yawalkar, Chimia, 46, 338 (1992).
16. S. Nakagawa, Y. Ando, S. Sakane, M. Shiono, Japanese Pat. Appl., 04273894;
Chern. Abstr., 118, 213356 (1993).
17. For closely related compounds see D. Lednicer and L. A. Mitscher, Organic
Chemistry of Drug Synthesis, Vol. 3, Wiley, New York, 1984, p. 103.
18. M. Calverly, Synlett., 157 (1990).
19. For closely related compounds see D. Lednicer and L. A. Mitscher, Organic
Chemistry of Drug Synthesis, Vol. 1, Wiley, New York, 1977, p. 188.
20. J. E. Jacobson, J. M. McCall, D. E. Ayer, F. J. VanDoomik, J. R. Palmer,
K. L. Belonga, M. J. Braughler, E. D. Hall, D. J. Houser, M. A. Krook and
T. A. Runge, J. Med. Chern., 33, 1145 (1990).

CHAPTER 5
FIVE-MEMBERED HETEROCYCLES
Heterocylic rings, like their carbocyclic counterparts, play many different
roles in biologically active compounds. In some cases these ring systems
act as simple aromatic rings, supplying a flat electron-rich moiety. Some-
times, as in the case of the pyrrolidine ring of the ACE inhibitors, the ring
fonns part of the recognition pattern for the enzyme the drug is to inhibit.
Basic heterocycles not infrequently simply provide basic nitrogen in a cyclic
milieu.
1. COMPOUNDS WITH ONE HETEROATOM
By far the majority of nonsteroidal antiinflammatory agents (NSAIDs) in-
clude a strongly acidic center. This typically consists of a frankly acidic
group such as the carboxylic acids in aspirin or ibuprofen; the strongly
acidic proton in the enol fonn of piroxicam fulfills the same role. The
-diketone nitrile function in prinomide (4), provides the acidic proton for
that NSAID. The synthesis of this compound begins with the methylation
of pyrrolidine carboxylic acid 1 with base and methyl iodide. Condensation
with the anion from acetonitrile affords the -cyano derivative 3. Reaction
of that intennediate with phenyl isocyanate in the presence of triethylamine
leads to addition of the methyne anion to the isocyanate carbonyl carbon.
Thus prinomide (4), I is obtained.
64

1. COMPOUNDS WITH ONE HETEROATOM 65
f0-
N C0 2 R
I
CH 3

:> I..:..CN
CH 3
>
 N 
'N ' 0
I 0 ° I
CH 3 /
1, R-H
3
4
2, R=CH 3
The cyclized amino acid, pyroglutamic acid, fonns the nucleus for an
antihyperlipidemic agent. Thus condensation of the pyroglutamic 5, bearing
a carbobenzyloxy (CBZ) protecting group on nitrogen with 3-cis-5,5-tri-
methylcyclohexanol in the presence of DCC, gives the corresponding ester
(6). The protecting group is then removed by hydrogenation over palladium
on carbon to yield crilavastine (7). 2
0-:.:-Gc0 2 H
N
I
CBZ
0-:':-/\ 0
:> N/1-r
, 0
R
5
6, R=CBZ
7, R=H
Though phosphorus is a rather common constituent of enzymes and other
biological messenger compounds, this element is present in surprisingly few
therapeutic agents. A pair of angiotensin converting enzyme (ACE) inhibitor
antihypertensive compounds do incorporate phosphorus. Many of the clas-
sical ACE inhibitors contain proline as a central element; this is then coupled
to a center that complexes with the putative zinc pocket in ACE. This
consists of a thiol in the case of captopril. The phosphorus containing
functional groups in ceronopril and fosinopril presumably interact with that
same site.
Condensation of the benzyl ester 9 of proline with chiral, protected, amino
acid 8 leads to amide 10. Preparation of the phosphorus-containing moiety
involves free radical addition of phosphite from sodium phosphite, to the
tenninal olefin in 11 catalyzed by AIBN to afford the phosphinous acid
derivative 12. The DCC mediated esterification of the hydroxyl group in 10
in the presence of 4-dimethylaminopyridine (DMAP) gives the ester 13. The
phosphorus-hydrogen bond in phosphinous ester 13 is then oxidized;3 re-
moval of the CBZ and benzyl groups by catalytic hydrogenation affords the
ACE inhibitor ceronapril (14).4

66 FIVE-MEMBERED HETEROCYCLES
CBZNH(CH 2 ),
HOC02H +
HN
C0 2 CH 2 Ph
CBZNH(CH 2 ),
> HON
C0 2 CH 2 Ph
8
9
1 0
(\ / (CH2)2CH-CH2
o
> (\ }- ( C H 2 ) .-' 0 H
H
1 1
1 2
H 2 N(CH 2 ),
(, />- (CH2).-'-ON c
OH CO H
2
CBZNH(CH 2 ),
(, />- (CH2).-'-ON
H
C0 2 CH 2 Ph
14
1 3
Alkylation of phosphinic acid 12 with benzyl bromoacetate in the pres-
ence of excess base interestingly occurs on phosphorus, the more nucleo-
philic center, to afford the P-alkylation product 15. Reaction of the alkoxide
from that intennediate with chloroester 16 leads to alkylation on oxygen and
fonnation of the ether 17. This product is then converted to the free acid
(18) by removal of the benzyl group by hydrogenolysis and that resolved by
classical diastereomeric salt fonnation. Condensation of this chiral acid with
the proline derivative 19 leads to fonnation of the amide fosinopril (20). 5
The five-membered, nitrogen-containing ring in tropine 21 may be used
to classify this compound as a pyrrolidine. Its function in the following two
compounds in all probability consists of simply providing a basic side chain.
Acylation of the alkoxide from tropine with 3,5-dichlorobenzoyl chloride
affords the antiemetic serotonin inhibitor bemsetron (22), 6 a compound dis-
tantly related to the metoclopramide antiemetics (Chapter 2).
Acylation of tropine with the half ester-half acid chloride from phenyl-
malonic acid yields the intennediate 23. Alkylation with methyl iodide gives
the quaternary ammonium anticholinergic compound tematropium 24. 7 The
presence of the positively charged center presumably assures that it will not
show CNS activity since this should not cross the blood-brain barrier.

1. COMPOUNDS WITH ONE HETEROATOM 67
C 1
 HsC-N Vl 0
OCl
o
22
HSC I
\ +
HsC-X Vl
o
o
(, It- (CHz) 4'_CHzC OzCBzPh +
08
( CH s)zCHCO z C z HI5
I
C I
15
16
o
° Q
 II/CO H
(CHa),-CHICO 2
o
I
( CB S)ZCBCO Z C Z HI5
20
HS C- N\J::::\
l) 1H
2 1
1
HsC-X Vl
o
C0 2 C 2 H 5
:.
23
o
(, II- (CHZ) 4'_CHZC OZR
o
I
(CHS)2CHC02CZ8S
17. R-C8 2 Ph
18. R-8
/0
HQ
C 0 2 8
1 9
C0 2 C 2 H 5
24
The antiinflammatory activity of the 3,5-di-tert-butyl-4-hydroxyphenyl-
alkyne tebufelone (Chapter 2, 118) can be rationalized by assuming in vivo
oxidation of the tenninal acetylene to the carboxylic acid present in the
majority of NSAIDs. No such simple explanation can be invoked for the
activity of prifelone (26), which shares only the highly hindered phenol

68 FIVE-MEMBERED HETEROCYCLES
(CH 3 )3 C
HO  COC I
(CH 3 )3 C
(CH 3 )3 C
:>
HO
(CH 3 )3 C
2 5
26
with the alkyne. The compound is prepared in a single step by Friedel-Crafts
acylation of thiophene by substituted benzoyl chloride 25. 8
2. COMPOUNDS WITH TWO HETEROA TOMS
Yet another NSAID, this one bearing the traditional carboxylic acid, is built
around an oxazole nucleus. Reaction of ethyl 2-chloroacetoacetate with
p-chlorobenzoic acid in the presence of sodium carbonate leads to fonnation
of the acetoacetate ester 27. Treatment of that intennediate with fonnamide
in the presence of acid gives the oxazole 28. The reaction can be rationalized
by assuming addition-elimination of ammonia or its equivalent to the enol
fonn of the -keto ester; the resulting amine could then cyclize by fonning
an imine with the benzoyl carbonyl group. The ester in the product is then
reduced to the carbinol (29) by means of lithium aluminum hydride; the
resulting hydroxyl is replaced by chlorine with thionyl chloride (30). Dis-
placement of chlorine with the alkoxide from 2,2-dimethylglycolic acid gives
the ether 31. The ester group in this product is saponified to afford the
NSAID romazerit (32).9
The compound azumolene, which contains two five membered hetero-
cycles, each of which has two heteroatoms, has been described as a muscle
relaxant. The sequence for preparing this agent starts with fonnation of the
imine 34 from the N-amino imidazolinedione 33 and glyoxylic acid. Con-
densation of the tenninal carboxy I group with 2' -amino-p-chloroacetophe-
none affords the amide 35. Reaction of that compound with phosphorus
oxychloride results in internal dehydration of the 1 ,4-dicarbony I array and
fonnation of an oxazole ring. Azumole (36)10 is thus obtained.
Arachidonic acid, as noted earlier, leads to agents that promote inflam-
mation by two diverse pathways: the cyclooxygenase pathway leads to
thromboxanes and prostaglandins and the lipoxygenase pathway produces
leukotrienes. A relatively simple heterocyclic compound, tepoxalin (40), is
a potent inhibitor of both pathways. The starting acid 37 is obtained by
acylation of the anion from 4-chloroacetophenone with succinic anhydride. 11
Treatment with acetic anhydride leads to fonnation of the reactive enol

2. COMPOUNDS WITH TWO HETEROATOMS 69
 o
Cl A_
o COaCaH,
· CI : J[
O a
27
28. R-COICIH a
29, a-CH 2 0H
so, R-CHICl
1
Cl : y 0 co R
O X 2
3 1, R - C H R
32. R-H
lactone 38. Reaction of that compound with N-methylhydroxylamine gives
a mixture of the desired N-acylated product 39 and its O-acylated isomer;
reaction of the latter with excess N-methylhydroxylamine leads its conver-
sion to 39. Condensation of this intennediate with 4-methoxyphenylhydra-
zine proceeds to the pyrazine tepoxalin (40), with high regioselectivity. 12
o
//
1\
RN-N NH
)(
o
:)
/0
 o n
C 1 \ / /  N-N NH
N )(
H 0
33. R-H 2
35
34.
R- H0 2 CCH-
/0
 rl
C 1 \ / \ r N-N NH
)(
N 0
36

70 FIVE-MEMBERED HETEROCYCLES
0
C0 2 H ifP
:- '/
C 1 C 1
37 38
CH3  j
N-NH
,\ CONOH CONOH
I c: I
CH 3 CH S
C 1 C 1
40 39
Many antiarrhythmic agents consist of amides from aromatic acids and
alkyl diamines. Activity is retained when the aromatic acid is replaced by a
diphenylpyrazine. The key intennediate heterocyclic compound 43 can in
principle be obtained by condensation of fonnylated desoxybenzoin 42 with
ethyl N-aminoglycinate (42 can be prepared by reaction of desoxybenzoin
41 with ethyl fonnate in the presence of alkoxide). Heating 43 with l-amino-
3-N,N-diethylaminopropane results in the interchange of ethoxide in ester
43 with the primary amine and fonnation of an amide. There is thus obtained
ipazilide (44).13
:.
N
,
N
l.COalt
)I
N
,
N H
NNEla
o
R
o
41. R-H
42. R-CH-O
43
44
Imidazolines bearing a substituted amino group at the 2 position are well-
known a-adrenergic agonists. The centrally acting compound clonidine has
a long history of use as an antihypertensive agent; its more recent congener

2. COMPOUNDS WITH TWO HETEROATOMS 71
apraclonidine (73), has been found useful in treating the increased intra-
ocular pressure associated with glaucoma. It is thus noteworthy that a set of
structurally different imidazoles, closely related to each other, also exhibit
a-agonist activity.
Reaction of the Grignard reagent from 2,3-dimethylbromobenzene with
imidazole aldehyde 45 gives the carbinol 47. Removal of the benzylic hy-
droxyl by hydrogenolysis over palladium on carbon affords the a-agonist
detomidine (48).14.15 Reaction of the same Grignard reagent with imidazole
ester 46 stops at addition of 1 equivalent of the organometallic and fonnation
of the ketone 49. This is then treated with methyl magnesium bromide to
give the tertiary alcohol 50. The sequence is completed by dehydration of
the alcohol (50) and reduction of the resulting olefin. There is thus obtained
the a-agonist medetomidine (52).16.17 Resolution of this compound reveals
that the activity resides in the d isomer dexmedetomidine.
°
 CH s
'- R CH s
HN :. 
\:::-- N
45, R-H 49, R-O
5 1
46, R-OKe 50, R-CHs,OH
1
1
R
CH s CH s
47, R-OH
52
48, R-H
The indanylimidazole atipamezole (58), which includes structural ele-
ments similar to the foregoing compounds, also shows similar activity, with
some selectivity for a2 receptors. The preparation of this agent begins with
the alkylation of a,a' -dibromoxylene 53 with the anion from ketone 54.
The methyl group on the ketone is then brominated (56); reaction of this
intennediate with fonnamide leads to conversion of the bromoketone to an
imidazole (57). Catalytic reduction of the vinyl group leads to atipamezole
(58). 18.19

72 FIVE-MEMBERED HETEROCYCLES
Sr
+ <=
 0'
:>
R
Sr
53 54
55, R=H
56, R=Br
1
<:
NH
N
NH
N
58
57
An impressive amount of work in many laboratories has been devoted to
the conazole class of anti fungal agents. Perusal of the various structures that
have shown activity can easily leave the impression that activity requires
only the presence in the molecule of an imidazole ring and one or more 2,4-
dichlorobenzene rings (see, however, fluconazole, 89, below). An oxime
O-ether serves as the link in the antifungal agent oxiconazole (61). Reaction
of the imidazophenone 59, obtainable in principle from the chloroketone
and imidazole, with hydroxylamine gives the corresponding oxime 60. Al-
kylation on oxygen with 2,4-dichlorobenzyl chloride affords oxiconazole
(61).20
C 1
C 1
:>
C 1
G G
N N
59, R= 0 6 1
60, R= =NOH

2. COMPOUNDS WITH TWO HETEROATOMS 73
A number of antiprotozoal 4-nitroimidazoles such as misonidazole sen-
sitize anoxic solid tumors to radiation. It has recently been detennined that
2-nitroimidazoles show this same activity. Alkylation of 2-nitroimidazole,
62, with ethyl bromoacetate affords the ester 63. Heating that compound
with ethanolamine leads to the amide radiosensitizing agent etanidazole
64. 21
r=\
NyNH
N0 2
r=\ C0 2 Et
> NyN-./
N0 2
:>
°
r::=\ "
I - \ ----./'"  ° H
N" N N
Y H
N0 2
62
63
64
As noted previously, treatment of hypertension with ACE inhibitors de-
pends on diminishing the levels of the vasoconstricting peptide, angiotensin
II. Research on analogues of that peptide produced a number of congeners
which acted as angiotensin receptor antagonists. Poor oral absorption and
relatively quick metabolic inactivation precluded use of these as drugs. The
recent discovery of relatively simple nonpeptide compounds that antagonize
angiotensin II at its receptor site promise drugs that will be more specific
and will presumably show even fewer unwanted effects. The preparation of
one of these starts with the alkylation of the highly substituted imidazole 65
with bromomethylbiphenyl derivative 66 to give the N-alkylated imidazole
67. Treatment of that compound with the elements of hydrazoic acid (sodium
azide in acid) converts the nitrile group to a tetrazole, and losartan (68)22
is thus obtained.
HOCH 2 C 1
'r=<
NyNH
n-C.Hg
+
BrCH z -(, /) ,/)
CM
HOCHZ 'r=< C I 
. NyN-CHz U 
n-C.Hg CM
65
88
87
/
HOCH 2 C 1
'r=<
N y M-CH2
n-C.H,
88

74 FIVE-MEMBERED HETEROCYCLES
The increase in intraocular pressure caused by glaucoma often responds
to antihypertensive agents. Routine use of these drugs is circumscribed by
their effect on the systemic circulation; research has consequently been aimed
at developing locally acting drugs whose absorption will be limited by their
polarity. The primary amino group is the para position of the locally acting
a-blocker apraclonidine (73), for example, makes this compound consid-
erably more polar than the prototype clonidine, which bears hydrogen at
that position. Reaction of nitroaniline 69 with ethyl fonnate leads to the
corresponding fonnamide 70; this is converted to the bischloroimino deriv-
ative 71 by treatment with a mixture of sulfuryl chloride and thionyl chloride.
Displacement of halogen with 1,2-ethylenediamine leads to fonnation of the
imidazoline ring (72). Reaction of this intennediate with iron and hydro-
chloric acid selectively reduces the nitro group to an amine. There is thus
obtained apraclonidine (73).23
C 1 C 1 C 1 H
02 N -Q- NHR -Q- CI R 2 N -Q- N =<: J
)I 02N \-/ H==( )I
C 1
C 1 C 1 C 1 H
89, R-H 7 1 72, R-O
70, R-CH-O 73, R-H
The majority of oral hypoglycemic agents contain a sulfonylurea group.
Some of the newer high-potency compounds also incorporate an extended
side-chain tenninating in aromatic rings. The sulfonylurea function in the
hypoglycemic agent pioglitazone (78) is replaced by a hydantoin ring; the
drug does however contain the extended chain. Nucleophilic aromatic dis-
placement of fluorine from 4-flurobenzonitrile with the alkoxide from 74
leads to the aromatic ether 75. The nitrile is converted to an aldehyde (76)
by reduction with Raney nickel in fonnic acid. Condensation of the carbonyl
group with hydantoin, 79, gives intennediate 77. The double bond is finally
reduced to afford pioglitazone (78).24
  1GJ CN
I" ----+ I" 1/
N OH N 0
74
75
o
NH
so
79
o
 NH
I M s +-
N 0 0
78
 ACH = 0
. I" 
N 0
76
I
o
 NH
M' M s
N 0 0
77

3. COMPOUNDS WITH THREE HETEROATOMS 75
Five-membered compounds whose complement of heterocyclic atoms
consists of only two sulfur atoms are quite rare among drugs. One agent in
this class, matotilate (85), is described as a drug for treatment of liver
disease. The synthesis begins with the seemingly simple base-catalyzed con-
densation of diisopropyl malonate with carbon disulfide. The initial product
probably results from addition of the malonate anion to carbon disulfide to
afford an anion such as 80. Loss of a second malonate proton would lead
to dianion 81. The first reaction intennediate, which is not isolated, likely
consists of the dianion 82 which carries both charges on sulfur, this being
a weaker base than its predecessor. Treatment of the intennediate with methyl
sulfate affords the bis methylsulfide 83. Treatment of this compound with
1,1-2-trichloroethane leads to the heterocycle 84. The reaction in this case
probably involves successive alkylations on sulfur to fonn the sulfonium
salts; these eliminate methyl chloride under vigorous reaction conditions to
give neutral sulfides. Elimination of hydrogen chloride from 83 completes
the synthesis of matotilate (85).25
I -s C0 2 iPr -s C0 2 iPr -s C0 2 iPr I
H s H- -- F<
:- --
S C0 2 iPr S C0 2 iPr S C0 2 iPr
80 8 1 82
CH 3 S C0 2 iPr
) <
CH 3 S C0 2 iPr
 ClS>C02iPr
S C0 2 iPr
> [S>C02iPr
S C0 2 iPr
83
84
85
3. COMPOUNDS WITH THREE HETEROATOMS
The considerable degree of freedom that exists as to structural requirements
for activity in the conazole series has been noted above. Thus fluorine re-
places chlorine and 1,2,4 triazole replaces imidazole in the antifungal agent
fluconazole (89), which has proven of particular value in treating some
AIDS-related opportunistic fungal infections. The starting material, 86, for
the sequence is obtained by Friedel-Crafts acylation of 1,3-difluorobenzene
with chloroacetyl chloride. Displacement of the active chlorine by 1,2,4-
triazole affords triazolophenone 87. The carbonyl function is then condensed
with the sulfur ylide resulting from treatment of trimethylsulfonium iodide

76 FIVE-MEMBERED HETEROCYCLES
with strong base. The reaction starts by addition of an anionic methylene
group to the ketone; the newly formed alkoxide group then displaces the
methyl sulfide from the adjacent positively charged sulfonium center. The
net result is addition of a carbon and formation of the oxirane 88. Ring
opening of the epoxide with 1,2 ,4-triazole takes place predominantly at the
more open primary center to afford the symmetrical alcohol and fluconazole
(89)26 is thus obtained.
C 1 N_N N_N
F F l:'> F l:'>
N N
:> :>
F F F
86 87 88
/
OH
N-N N_N
(;:::JF l:'>
N N
F
89
The development of the histamine H 2 antagonists depended in large part
on a systematic investigation of the SAR of the endogenous agonist for that
receptor, histamine. The first antiulcer H 2 antihistamine to be commercial-
ized, cimetidine, in fact shared the imidazole ring with the agonist. Further
structural investigations in this series led to antiulcer agents in which the
imidazole was replaced by other five- and sometimes six-membered het-
erocycles. One of the most widely used antiulcer compounds in this class,
ranitidine, contains a furan ring as the central element. The triazole ring,
which is isosteric with an imidazole, can also serve as the core of histamine
H 2 antagonists. Acylation of the amine on 90 with acetylglycolyl chloride
gives the corresponding amide 91. Reaction of that intermediate with the
hydrazone from N-methylhydrazine and benzaldehyde results in net displace-
ment of one of the methylthioether groups, probably by an addition-elimi-

3. COMPOUNDS WITH THREE HETEROATOMS 77
nation sequence. The driving force for the reaction is the loss of methyl
mercaptan. The second methylthioether group is then displaced by reaction
with the primary amino group in 93 to give the acylguanidine 94. Acid
hydrolysis of this intennediate leads to cleavage of the hydrazone; the newly
liberated amino group then reacts with the adjacent amide carbonyl to fonn
a triazole ring (95). The acyl protecting group is then removed by saponi-
fication with weak base to give the antiulcer compound, lavoltidine (96).27
CHSS)fSCH S
NR
:>
CH 3
I
CHsS)fNN-CHPh
N10
OAe
0»
N '/
o..(CH 2 )sNH 2
90, R-H
91, R-COCH 2 0Ae
92
93
\
0»
N I / CH
O-(CH 2 )sN liN 'N s
N\
OR
<
O 0 CH
No- (CH 2 ) sNII)NcHPh
N 1 0
OAe
95, R-Ae
96, R-H
94
An analogous sequence is used to construct the compound in which a
sulfone replaces the hydroxyl group. The starting material 97 is obtained by
acylation of 90 with methylthioacetyl chloride. This is then reacted with the
hydrazone from N-methylhydrazine and benzaldehyde to give the guanidine
98. Cyclization as described above leads to the triazole 99. Oxidation of the
sulfide to a sulfone completes the synthesis of the H 2 antagonist sufotidine
(100).28.29
CBss 9CH
11 3
HR

CH 3
I
cBsSIlNN - CHPh
H 0
1 scH
s
Sl8
)i
O
N I / CH s
O' (CH 2 ) sN"N'N
N
R
99, R:o:SCH 3
100, R-S0 2 CH s
90 I R:o:H
97 I R-COCH 2 SCH s

78 FIVE-MEMBERED HETEROCYCLES
Cl
Cl  '0
C 1
;::::-- N
 N, ;::J
:> C1  '0 N
C 1
N
 N, ;::J
> Cl \ I H
C 1
C 1
101
102
103
A relatively simple triazole derivative which contains an unusual enol
chloride function represents a novel anticonvulsant agent which is not related
structurally to other compounds of this class. In the absence of a published
synthesis, it may be speculated that the key intennediate 102 is obtained by
alkylation of 2' -chloro-2,4-dichloroacetophenone (101) with 1,3,4-triazole.
Reaction of the product, 102, with a halogenating agent such as thionyl
chloride would afford loveclazole (103).30
REFERENCES
1. W. G. Walker, U.S. Patent. 4256759 (1981) Chern. Abstr., 95, 7046 (1981).
2. C. Laruelle, M. Lepant, and B. Raynier, Eur. Pat. Appl. 261017 (1988) Chern.
Abstr., 110, 213345 (1989).
3. J. K. Thottathil and M. K. Y. Wong, Tetrahedron Leu.. 27, 5441 (1986).
4. D. S. Karanewsky, M. C. Badia. D. W. Cushman, J. M. DeForrest, T. Dejneka,
M. L. Loots, M. G. Perri, E. W. Petrillo, and J. R. Powell, J. Med. Chern.,
31,204 (1988).
5. E. W. Petrillo, D. S. Karanewsky, J. K. Thottathil, J. E. Heikes. and J. A.
Grosso, Ger. Offen., 3833082, (1989) Chern. Abstr., 111,214701 (1989).
6. J. R. Fozard and M. W. Gittos, Eur. Pat. Appl. 67770 (1982) Chern. Abstr.,
98, 149950 (1983).
7. R. H. HammerandN. S. Bodor, Int. Pat. Appl. 8705603 (1987); Chern. Abstr.,
108, 167767, (1988).
8. G. G. I. Moore, U.S. Patent 4172082 (1979); Chern. Abstr., 92, 76276 (1980).
9. C. R. Self, W. E. Barber, P. J. Machin, J. M. Osbond, C. E. Smithen, B. P.
Tong, J. C. Wickens, D. P. Bloxham, D. Bradshaw, C. H. Cashin, B. B.
Dodge, E. S. Lewis, and D. Westmacott, J. Med. Chern., 34, 772 (1991).
10. R. L. White, F. L. Wessels, T. J. Swan, and K. O. Ellis, J. Med. Chern., 30,
236 (1987).
11. W. V. Murray, M. Wachter, D. Barton, and Y. Forero-Kelly, Synthesis, 18
( 1 991 ) .
12. W. V. Murray, and s. K. Hadden, J. Org. Chern., 57, 6662 (1992).
13. D. M. Bailey, U.S. Patent 4916150 (1990); Chern. Ahstr., 113,59173 (1990).
14. A. J. Katjalaynen and K. o. A. Kurkela, Eur. Pat. Appl. 24829 (1981); Chern.
Abstr., 95, 115545 (1981).

REFERENCES 79
15. Anon., Drugs Future, 10, 17 (1985).
16. A. J. KaIjalaynen, E. K. Pojhala, and K. O. A. Kurkela, Brit. Pat. Appl.
2101114 (1983) Chern. Abstr., 99, 38462 (1983).
17. Anon., Drugs Future, 12, 1021 (1987).
18. A. J. KaIjalaynen, A. L. KaIjalainen. R. E. K. Virtanen, and K. O. A. Kurkela,
Eur. Pat. Appl. 183492 (1986) Chern. Abstr., 105, 115070 (1986).
19. Anon., Drugs Future, 15, 448 (1990).
20. G. Mixich and K. Thiele, U.S. Patent 4550175 Chern. Abstr., 105, 6508
(1986).
21. A. G. Beaman, W. Tautz, and R. Duschinsky, Antirnicrob. Agents Chernother.,
1967, 520 (1968).
22. D. J. Carini, P. C. B. Wong, and J. J. V. Duncia, Eur. Pat. Appl. 324337
(1989) Chern. Abstr., 112, 118817 (1990).
23. B. Ruout, and G. Leclerc, Bull. Chirn. Soc. Fr., 9-10 (Pt.2), 520 (1979).
24. Y. Momose, K. Megurao, H. Ikeda, C. Hatanaka, S. Oi, and T. Sohda, Chern.
Phann. Bull., 39, 1440 (1991).
25. H. Matsui, H. Tanaka, K. Yabutani, and K. Hitoshi, U.S. Patent 4327223
(1982) Chern. Abstr., 97, 72349 (1982).
26. R. K. Richardson, Brit. Pat. Appl. 2099818 (1982); Chern. Abstr., 99, 38467
(1983).
27. J. W. Cliterow, J. Bradshaw, B. J. Price, M. Martin-Schmith, J. W. M. Mack-
inon, D. B. Judd, R. Hayes, and L. Carey, Eur. Pat. Appl., 16565 (1980);
Chern. Abstr., 94, 192345 (1981).
28. J. W. Cliterow, J. Bradshaw, J. W. M. Mackinon; D. B. Judd, D. E. Bays,
R. Hayes, A. Pearce, Fr. Demande 2477150 (1981); Chern. Abstr., 96, 35271
( 1982) .
29. For a review see D. E. Bays and H. Finch, Natural Prod. Rept., 408 (1990).
30. A. Wauquier, J. Fransen, W. Mellis, D. Ashton, J. M. Gillardin, P. J. Lewi,
G. Van Clemen, J. Vaught, and P. A. J. Jansen, Drug Dev. Res., 19, 376
( 1990).

CHAPTER 6
SIX-MEMBERED HETEROCYCLES
1. COMPOUNDS WITH ONE RING HETEROATOM
Thromboxane, one of the products from the arachidonic acid cascade, plays
a central role in various injurious tissue responses including inflammation
and platelet aggregation. Some compounds that inhibit the end effect of this
metabolite, such as vapiprost (25, Chapter 1), act directly at the receptor
level by competing with thromboxane for the binding site. Agents that lower
levels of this arachidonic acid metabolite by inhibiting the enzyme throm-
boxane synthetase are more common. The pyridyl-phenyl ketone derivative
ridogrel, 6, falls into the latter category. Reaction of the Grignard reagent
from m-trifluoromethylbromobenzene with nicotinaldehyde (1) affords the
carbinol 2. This product is then oxidized and the resulting ketone, 3, is
converted to its oxime. Alkylation of the enolate of the oxime with methyl
4-bromobutyrate gives the corresponding O-alkylated product 5. Saponifi-
cation of the ester group gives the corresponding carboxylic acid, ridogrel
( 6). 1
Estrogen-dependent breast cancer, which also involves an endogenous
honnone can in theory be treated by either blocking a receptor or diminishing
production of the honnone. The stimulating effect of the honnone on tumor
growth can be blocked at the receptor level with antagonists such as ta-
moxifen (132, Chapter 2). A considerable amount of research has also been
devoted to diminishing endogenous levels of estrogens by inhibition of one
of the principal enzymes involved in their synthesis, aromatase. It was dis-
80

1. COMPOUNDS WITH ONE RING HETEROATOM 81
:>
CF 3
:>
CF 3
cr CH - O
I'
/'
N
"" ,.0,
N (CH2)3C02R
1
2, R=H,OH
3 , R=O
4 . R..NOH
5. R-CH 3
6, R=H
covered adventitiously some time ago that the sedative-hypnotic glutarimide
glutethimide, 7, had some modest aromatase inhibiting activity. Inclusion
of an amino group led to aminoglutetimide, 8, an agent which has found
some use in the clinic. Aromatase-inhibiting activity is retained when the
basic nitrogen is moved directly into the aromatic ring. Alkylation of the
anion from ethyl homoisonicotinate 9 with ethyl bromide stops at the mono-
alkylated product 10. Michael addition of acrylamide to this intennediate
leads to 11. Reversing the order of the steps leads to far inferior yields.
Base-catalyzed cyclization gives the glutarimide rogletimide (12). 2
CONH 2
::>
::>
9
1 0
1 1
/
R
7, R=H
8, R=NH 2
1 2

82 SIX-MEMBERED HETEROCYCLES
The thiazide diuretics are a well-known and venerable class of drugs. All
these agents possess one or more sulfonamide groups. The classical oral
hypoglycemic agents, which also trace their parentage back to the sulfon-
amide antibacterial agents, were based on the sulfonylurea function. Intro-
duction of the sulfonylurea function into an aminopyridine interestingly leads
to a compound that functions as a diuretic. Sulfonation of 4-hydroxypyridine
with oleum affords the sulfonic acid 13. Reaction of that compound with
phosphorus pentachloride serves to replace the ring hydroxy I by chlorine
and to also convert the acid to the sulfonyl chloride (14). Treatment with
ammonia leads to fonnation of the sulfonamide 15. Condensation of 15 with
isopropyl isocyanate leads to fonnation of the sulfonylurea function in 16.
Nucleophilic aromatic displacement of chloride in the pyridine ring by means
of m-toludine leads to the 4-aminopyridine torsemide, (17). 3
R I
(J S02 R2
I'
"
N
C 1
(J S02NHCONHlpr
I'
"
N
o
NB
& S02NHCONHiPr
I'
"
N
;)I
:.
1S, R 1 .OR. RI.OR
14. R I -R 2 -Cl
16
1 7
I I
15, R -CI. R -NB 2
The majority of dihydropyridine calcium channel-blocking cardiovascular
drugs contain a strongly electron withdrawing group in the aromatic ring,
such as nitro in the case of the prototype of this class, nifedipine. It is thus
of interest that an acrylate seemingly can serve the same function. The
synthesis of the two agents in this subclass starts with the Wittig conden-
sation of phthalaldehyde with one equivalent of the ylide from tert-butyl
2-triphenylphosphonium acetate. This reaction affords the product 18 from
reaction of a single aldehyde group. The heterocyclic ring is then constructed
by the classic Hantsch reaction typical of this series. Condensation of the
remaining aldehyde function with ethyl 3-aminocrotonate, from ethyl ace-
toacetate and ammonia, leads to dihydropyridine 19 in a single step. The
reaction can be rationalized as addition of two successive acetoacetate de-
rivatives to the aldehyde, the first by aldol condensation and the second by
conjugate addition to the resulting aldol dehydration product. Internal ad-
dition-elimination of an amino group forms the ring, and lacidipine, (19)4
is thus obtained. Reaction of this product with pyridinium bromide hydro-

1. COMPOUNDS WITH ONE RING HETEROATOM 83
HaC
19. R-B
20. R-Br

C02tBU
CH-O
H&CZOZC
.
H 3 C
18
H&CZOZC
CH.H(CHa)a
21
bromide results in halogenation of the allylic methyl group and fonnation
of 20. Displacement of that activated bromine with dimethylamine gives the
antihypertensive taludipine, (21). 5
The synthetic opioid fentanyl (desfluoro 25, where propionyl replaces
methoxyactyl) has long been known as an extremely potent central analgetic.
The bulk of research has centered on the search for opioids that would be
devoid of the addiction potential of morphine. The elusive nature of that
goal has served to focus attention back on classical central analgetics; be-
cause of its high potency, fentanyl has often served as the structural model.
Condensation of piperidone 22 with o-fluoroaniline leads to the Schiff base
23, which is then reduced to give intennediate 24. Acylation of the second-
ary amino group with 2-methoxyacety I chloride affords ocfentanil, (25). 6
It has been established by research in both the fentanyl and related series
that potency is further enhanced by the presence of a methyl group at the
ring position next to the anilide nitrogen. The synthesis of a compound
bearing this potentiating group starts with the condensation of piperidone 26
with o-fluoroaniline followed by reduction of the intennediate imine to give
27 as a cis-trans mixture. The cis isomer is then isolated and acylated as
above to afford the amide 29. Catalytic hydrogenolysis using a palladium
catalyst gives the piperidine 30. Extensive prior work on the SAR in the
fentanyl series has demonstrated the marked potentiating effect of an aryl-

84 SIX-MEMBERED HETEROCYCLES
F\/J= 0

>
F\ r N J N F
 
22
23
!
o OCH 3
r
 NJ-N F
  <
 NJ-NH F
 
25
24
ethyl group on the piperidine nitrogen. It is of some interest that a tetrazolone
ring can replace the more traditional benzenoid aromatics. Construction of
that ring starts by reaction of ethyl isocyanate with aluminum azide, from
sodium azide and aluminum chloride, to give an initial hypothetical adduct
such as 32 (depicted only to show connectivity). Cyclization leads to the
tetrazolone 33. The second urea nitrogen is then reacted with base and 1,2-
bromochloroethane to give the key intennediate (34). 7 Alkylation of the
secondary amino group in 30 with 34 affords the central analgetic brifentanil
(31). 8
It has been established previously that analgetic activity is retained when
an additional carbon is present on the ring position bearing anilide nitrogen.
The finding that activity is retained when the aromatic group on the arylethyl
moiety is replaced by an ester offers the possibility of designing short-acting
central analgetics whose blood levels can be closely regulated. Serum es-
terases would be expected to convert the tenninal ester to a polar acid that
will not penetrate the blood-brain barrier, in effect inactivating such a com-
pound. Reaction of the desmethyl analogue of piperidone 26 with hydrogen
cyanide and N-methylaniline leads to the a-aminonitrile 35. Hydrolysis of
the nitrile followed by esterification gives the ester 36; this is then acylated
with propiony I chloride to yield amide 37; debenzy lation by hydrogenation
over palladium affords the secondary amine 38. 9 Michael addition of the
amine to ethyl acrylate affords remifentanil (39). 10
A compound that combines some of the structural elements of central
analgetics with those of {j-blockers shows neither activity; the product is

1. COMPOUNDS WITH ONE RING HETEROATOM 85
C8HeCHZ-NO
----+
CIHeCRz-N8-NH ,
b
__ CIReCHZ-NNH ,
b
26
27
28
I
 o OCHs
'f-/
o N N
HeCz-Hf >=\
N-N 
c
,--( Or----' 0 C H 8
R-NN
d
31
28, R- C.H 6 CB 2
30, R- H
I +)' - I
He C 2 H 0 1f- J. r""
\ - I '"
N-N "
o
A
» B 5 C 2 -N NR
\ - I
N-N
32
33, R-B
34, R- CH 2 CB 2 C 1
,CN
C6H5CH2-N -g
N \ I
H
>
C02C2H5
C6H5CH2-N -g
N \ I
R
35
36, R=H
37, R=COC 2 H 5
!
H 5 C 2 0
ONJC02C2H5
N -<\ /)
<l
o C 2 H 5
<
C02C2H5
HN
N -{ /)
/l
o C 2 H 5
39
38

86 SIX-MEMBERED HETEROCYCLES
instead a quite effective anticonvulsant agent. Condensation of aminopiper-
idine 40 with phenylisothiocyanate leads cleanly to thiourea 41. This is then
treated with bromine in one of the standard schemes for fonning benzothia-
zoles. This can be rationalized by assuming bromination on sulfur as the
first step; cleavage of the sulfur-halogen bond would then afford a sulfur
cation which would cyclize into the aromatic ring by electrophilic attack to
afford 42. Saponification serves to remove the urethane protecting group
(43). The second half of the molecule, epoxide ether 44, is obtained in
straightfolWard manner by alkylation of p-fluorophenol with epichlorohy-
drin. Reaction of epoxide 44 with secondary amine 43 affords the anticon-
vulsant sabeluzole (45). II
B 6 C 2 0 C}- ,CHs
>,-N NB
o
H 6 C 2 0 C}- ,CBs
>t-N N
 0 >,-NB
S b
C}- ,CHs
RN N
 '-
'D
40
41
42. R-C0 2 C 2 H.
43. R-H
/
44
OH
r v oNC}-/H3
'F N
5'0
45
r v °r-\V°
The anilide encainide, 46, has proven to be a clinically useful antiar-
rhythmic agent. Acylation of the encainide intennediate 47 12 with an acti-
vated derivative of 3-methoxy-4-hydroxybenzoic acid affords the closely
related antiarrhythmic agent modecainide (48).
OCHS
OH
--+
OCB a
48
47
48
I
.j

1. COMPOUNDS WITH ONE RING HETEROATOM 87
A sizeable number of the newer nontricyclic antidepressant compounds
consist of aryl ethers of p-ftuorophenylalkylamines. The structure is exem-
plified by the highly successful drug fluoexetine and its close analogue
seproxetine (76 and 75 respectively in Chapter 2). Antidepressant activity
is retained when the amino group is located in a piperidine fonned by fonnal
cyclization of the alkyl chain. Alkylation of the alkoxide from the fairly
complex piperidine 49, whose preparation is not readily accessible, with
substituted ftuorobenzene 50 affords paroxetine (51).13
F -O---C NH +
F Ct °
I/,>
o
> F -O---C NH
{
0-- 0= 0
1/ >
o

OH
50
49
5 1
A small series of compounds distantly related to open-chain opioids has
afforded a series of clinically useful antiarrhythmic agents. A common met-
abolic mono-N-dealkyaltion reaction of one of these, disobutamide (57, in
which the open-chain nitrogen bears two isopropyl groups), would lead to
a secondary amine. The acetamide of this hypothetical derivative, bidiso-
mide (57), is an antiarrhythmic drug in its own right. Alkylation of the
carbanion from substituted arylacetonitrile 52, itself obtained from alkylation
of 2-chloroacetonitrile, 14 with chloroethylamine 53 affords the diaminoaceto-
nitrile 54. Hydrolysis of the nitrile group with strong acid leads to amide
55. The benzyl protecting group is then removed by hydrogenation over
palladium. Acetylation of the resulting secondary amine 56 affords bidiso-
mide (57). 15
The very high rate of endogenous synthesis of cholesterol, which may be
measured in grams per day, seriously complicates efforts to control hyper-
cholesterolemia by diet alone. One of the more successful drugs for treating
elevated cholesterol levels is the fennentation product lovastatin (58). This
compound and its descendants inhibit cholesterol synthesis at a very early
stage by inhibiting the synthesis of the five carbon starting compound mev-
alonic acid (3,5-dihydroxy-3-methylvaleric acid). Considerable research has
demonstrated that the presence of the lactone is essential for activity, though
there is considerable latitude regarding the nature of the lipophilic moiety.
The synthesis of the hypocholesterolemic agent dalvastatin (65) begins
with the reaction of the cyclohexanone 59 with DMF and phosphorus oxy-
chloride. The resulting Vilsmeyer aldehyde 60 is then reacted with the Grig-

88 SIX-MEMBERED HETEROCYCLES
o y y
N,
+ C 1 N'R R
>
CN 0
52 53, R-CH 2 C 8 H 6
54, R=CH 2 C 8 H 5
/'
y y
NCOCH 3 N,
R
0 I( 0
55, R-C e H 5 CH 2
57
56, R-H
o

HODO
\\\\
5 8
nard reagent from 2-fluoro-3-bromotoluene in the presence of a cuprous salt.
The product 61 can be rationalized by assuming initial conjugate addition
of the transient cuprate to the carbon that bears chlorine. Loss of chloride
ion from the resulting enolate ion affords 61. The aldehyde is then extended
by condensation with the carbanion from the cyclohexylamine Schiff base
of acetaldehyde; treatment of the first-fonned product with silica gel serves
to hydrolyze the imine and to dehydrate the 13-hydroxyl group; the bis-
homologated product 62 is obtained. Treatment of methyl acetoacetate with

1. COMPOUNDS WITH ONE RING HETEROATOM 89
two equivalents of LDA affords the corresponding dianion. Reaction of that
reagent with aldehyde 62 leads to addition of the more nucleophilic tenninal
carbanion to the carbonyl group to afford the aldol product 63, which now
contains all the required carbon atoms for the final product. This last product
is racemate since this reaction introduces a chiral center.
CH=O
C 1 F
:> :-
H 3 C
59 60
6 1
H 3 C
°rC02CH3
jOH

I
F
F
<
H 3 C
63
62
Reduction of the side chain ketone in 63 with sodium borohydride and
triethylborane at -78°C leads to the diol (64) predominantly as a single
diatereoisomer. Saponification of the ester followed by cylization of the
resulting dihydroxy acid by means of ethyl chlorofonnate completes the
synthesis of dalvastatin (65). 16
F
HO r;: CO CH
2 3
..OH

F
HO g O
\,0
,\

:>
H 3 C
H 3 C
64
65

90 SIX-MEMBERED HETEROCYCLES
The majority of anticonvulsant agents used in the treatment of epilepsy
contain an acidic proton located on nitrogen, often in the fonn of imide.
The relatively acidic sulfonamide group in the anticonvulsant drug topira-
mate (68) apparently fulfills the same role. Reaction of the common sugar
fructose (66) with acetone affords the bisacetal 67. 17 The reactivity of the
remaining free hydroxyl group is greatly diminished by steric hindrance.
The group thus needs to be converted to the corresponding alkoxide by
means of sodium hydride for further elaboration. Reaction of that alkoxide
with sulfamoyl chloride (CI0 2 SNH 2 ), leads to topiramate (68)}8
OH
h:n/OH
HO HOo
;)0
h,Ok OH
0'tor
67
:.
o
h,OOS02NH2
0'tor
68
66
2. COMPOUNDS WITH TWO RING HETEROATOMS
The piperazine ring is one of the most common groups found among com-
pounds that have CNS activity. This group, which is included in the next
10 entries, may sometimes be replaced by a simple ethylenediamine moiety.
The fact that a piperazine is often more active than its open chain analogue
suggests that the ring structure leads to better receptor recognition.
o
 N
NJL N /\N-1 
\ \ '-------I N d
o
69
The discovery of the benzodiazepines, close to three decades ago, af-
forded the first series of drugs for the treatment of anxiety. The increasingly
widespread use, and incidental abuse, of those agents led to the search for
non-benzodiazepine anxiolytics. It was discovered adventitiously that the
piperazine derivative buspirone (69), a failed antipsychotic compound,
showed good clinical antianxiety activity. Detailed studies showed that this
compound offered advantages over benzodiazepine, perhaps as a result of a
different mechanism of action; the compounds do not interact with the ben-

2. COMPOUNDS WITH TWO RING HETEROATOMS 91
zodiazepine receptor. The clinical success of buspirone spurred research
aimed at developing related compounds.
Sequential reaction of the disulfide from thiosalicylic acid with thionyl
chloride and chlorine leads to the intennediate dichloride 70. Treatment of
the crude product without prior isolation with aqueous ammonia gives the
benzoisothiazole 71; this is converted to the halide 72 by means of phos-
phorus oxychloride. Reaction with a single equivalent of piperazine affords
the monoalkylated product 73. Alkylation of that product with 1,4-dibro-
mobutane leads to the dialky lation on the free piperazine nitrogen atom with
fonnation of the spirocyclic quaternary salt 74. Condensation of the salt with
imide 75 in the presence of base leads to ring opening of the quaternary
salt. There is thus obtained the anxiolytic agent tiospirone (76).19
o
II
Cl )GJ
1/
C 1 S
R
N trQ l'
\ /
S

HN!\N 1!v N_ S
'---/ ."
 I

70
71, R-OH
72, R-Cl
73
\
cxj:H
o
/0
CX!JL<=x-U 4
o 
Crf:\X 1!v N_ S
'---/ ."
Br-  I
75
76
7.
Anxiolytic activity is interestingly retained when the spirocyclic imide in
buspirone is replaced by a simpler, more readily available, bicyclic imide.
Alkylation of the abundantly available reduction product 77 from the Diels-
Alder adduct of maleimide and cyclopentadiene with propargyl bromide
affords 78. The tenninal acetylenic carbon is sufficiently nucleophilic to
undergo Mannich reaction. Thus condensation of 78 with the piperazine 79
and fonnaldehyde leads to adduct 80. Catalytic hydrogenation of this inter-
mediate leads to tandospirone (81). 20
Activity is retained in the face of even more drastic modification of the
side chain substituent, such as replacement by an aromatic imide-like het-
erocycle, saccharine (82). Alkylation of the anion from that starting material
with 1,4-dibromobutane gives the halide 83. Reaction of that intennediate
with piperazine (79) leads to the antianxiety agent ipsapirone (84).21

92 SIX-MEMBERED HETEROCYCLES
o
NH
o
----+
o
NCH2C == CH
o
1\ N )
HN N-\'-/
'--.J N
77
78

79
1\ N )
N N-\'-/
'--.J N
c
ac  1\ N )
NCH 2 C =: CCH 2 "N N-\' I
\\ '--.J N
o
B 1
80
02
NH
o

02
}Br
o
:.
02
C( s /\ r-'\ N )
I /' 'N-..I "-N N-<, /
\ '--I N
o
82
83
84
Piperazine derivative 85, trazodone, in which one of the piperazine ni-
trogen atoms is attached via a three carbon chain, exhibits antidepressant
activity; this compound was in fact one of the first clinically useful nontri-
cyclic antidepressant drugs. This activity is retained when the molecule is
simplified by replacing the fused aromatic ring with two ethyl groups. The
synthesis of this compound, which illustrates another entry to the piperazine
ring, starts by alkylation of triazole 86 with I-bromo-3-chloropropane. Dis-
placement of the remaining halogen in the product (87) with N,N-dietha-
nolamine affords the diol 88; the two hydroxyl groups are then replaced by
chlorine by reaction with thionyl chloride to give 89. Double alkylation of
the amino group in m-chloroaniline with the dichloride affords the antide-
pressant, etoperidone (90).22
Restoration of the side chain to four atoms by inclusion of ether oxygen
restores anxiolytic activity. Ring opening of glycidic ether 91 (obtained from
I-hydroxy-3,4,5-trimethoxybenzene) with aryl piperazine 92, leads to ami-
noalcohol 93. This compound, enciprazine (93), which bears a passing
resemblance to a t3-blocker, is described as an antianxiety agent. 23
A piperazine ring fOnTIS the central element in a platelet aggregation
inhibitor. Alkylation of piperazine with bromodiphenylmethane affords the
monoalkylated product 94. Alkylation of the remaining secondary amine
with chloromethylimidazole 95 affords Iifarazine 96, in a single step.24

2. COMPOUNDS WITH TWO RING HETEROATOMS 93
H5 C 2 N"R
/N
H5C2 0
---.
R
H C N r H5C2N,  V
5 2-r::: 'N-(C H 2)J-N ----+ r- N N-(CH2)3-N N \ I
H C ....N"r<  H C .,  '---.I
5 2 0 R 5 2 0 CI
86, R = H
87, R = ( CH 2)JCI
88, R = OH
89, R = CI
90
a N r---\ -Q
/' - N-(CH2)jN N \ I
:--... N  '-----'
o CI
85
CH 3 0
CH 9 0 -{}- O'V° + HN=> i /) --
CH 3 0 Cl
CHSO OH
CH90 -{}- ON) --<\ /)
CHsO Cl
9 1
92
93
r\
BI If
'---I
+
 R CBs
Ba C '-I /1I-- j
RCl
B
85
84
. CB a
BaC-V--X 11-- 1 r\
RN If
B '---I
88

94 SIX-MEMBERED HETEROCYCLES
It sometimes happens that reinvestigation of old compounds using modem
phannacological methods rekindles interest in those venerable agents. This
seems to have happened in the case of the piperazine-substituted quinazo-
linone pelanserin, 99, whose antihypertensive and vasodilator action is now
attributed to its serotonin-blocking action. Alkylation of quinazolinone 97
with I-bromo-3-chloropropane under basic conditions proceeds by way of
the ion fonned by removal of the more acidic proton (98). Displacement of
the side-chain chlorine with 4-phenylpiperazine gives pelanserin (99).25
o
NH
N.J.O
H
:.
o
G( Cl
I' N
/ N.J. O
H
97
98
o I\ 
G( NN'---IN
1/ .J.
N 0
H
99
The 2,6-xylilglycinnamide moiety has been incorporated in a great many
antiarrhythmic agents since the discovery of the first compound of this class,
lidocaine. A compound that includes this fragment in addition to a {3-blocker-
like phenoxypropanolamine moiety instead shows antianginal activity. It
should be noted that the propanolamine side-chain nitrogen is tertiary; a
large amount of SAR exists to show that this nitrogen must be secondary
for compounds to act as {3-blockers. The synthesis does however follow the
familiar pattern. Thus reaction of the product 100 from methylcathechol and
epichlorohydrin with piperazine gives the amino alcohol 101. Acylation of
101 with choroacetyl chloride gives chloroamide 102. Displacement of chlo-
rine with 2,6-xylidine leads to ranolazine (103).26
A piperazine ring provides the basic nitrogen atom for an analgesic com-
pound that does not follow the structural pattern for either central or pe-
ripheral analgesics. Reaction of 1,4-pyridazinediol 104 with phosphorus
oxychloride gives dichloride 105. Displacement of chlorine with the piper-
azine 106, which probably proceeds by an addition-elimination sequence,
gives the analgesic lorcinadol (107).27

2. COMPOUNDS WITH TWO RING HETEROATOMS 95
O
.'
V OCH3
OH
ONNH
V LJ
OC H 3
OH
ONr-->N-{
V OCH3 '---/ CI
----.

100
101
102
/
OH
OrN-'t _
V OCH3  
103
N-N /\ N-=N /\
RR + HN'----IN > ClN'----IN
104 I R-OH 0 0
105 I R-Cl 106 107
All anthracycline antibiotic antitumor compounds, such as doxorubicin
(75, Chapter 3), cause cardiac damage that is closely related to the cumu-
lative lifetime dose. The absolute necessity to limit the course of treatment
places real constraints on the use of these compounds in treating tumors.
The imide related to EDT A, razoxane (110), reduces anthracycline-caused
cardiac damage in a number of animal models. The dextrorotary isomer of
the compound bearing a side-chain methyl group shows significantly im-
proved potency. Alkylation of the enantiomerically pure diamine 108 with
chloroacetic acid gives the tetracarboxilic acid 109. Reaction of that inter-
mediate with fonnamide probably involves initial simple amide exchange;
cyclization of the acid-amide leads to the corresponding imide. Dexrazox-
ane (110)28 is thus obtained.
CH
HN j;:- S
2NH
e

H02C CH
\  S
M----\ {COeB
BOeCJ '--I
LCO B
2

o
h Jt
HN N  o
},-I N NB
o y
o
lOB
109
110, a-CH s
111, a-H

96 SIX-MEMBERED HETEROCYCLES
A pyridazine fonns the nucleus of a structurally rather untypical com-
pound active on the central nervous system. Reaction of itaconic anhydride,
112, with benzene in the presence of a Lewis acid gives the product from
acylation by the less hindered carbonyl group, 113. Reaction of that com-
pound with hydrazine leads to pyridazinone, 114, by hydrazide and hydra-
zone fonnation; the unsaturation shifts into the ring during the course of the
reaction. Treatment of that intennediate with phosphorus oxychloride leads
to the chloropyridazine 115. Displacement of halogen by means of 3-(N-
morpholino )propyl-l-amine leads to minaprine (116).29
I; I;
o il a  C 02H  \ =0
0 N-N
H
112 113
11 4
1
1\
N(CH2)3-N 0 <: C 1
H '--J
116
115
Antineoplastic drugs by and large depend on very subtle, poorly under-
stood differences between nonnal and cancerous cells. Most drugs rely on
the fact that the latter tend to divide at a higher rate. Modified nucleotides
that inhibit cell division by partly mimicking their nonnal counterparts have
proven of some value in the treatment of cancer. The antineoplastic com-
pound gemcitabine, 127, closely related to the anticancer agent cytarabine,
differs from it by incorporating the gem diftuoro group on sugar. The syn-
thesis starts with the chiron 117, obtained in a few steps from mannitol.
Condensation of that compound with ethyl bromodifturoacetate in the pres-
ence of zinc (Refonnatskii reaction) affords the alcohol 118 as a mixture of
isomers; the free hydroxyl in then protected as its benzyl ether. Treatment
under acidic conditions serves to remove the acetonide group and to cause
fonnation of the transient hydroxy ester 120. This undergoes internal lac-
tonization to the butyrolactone 121. The isomer corresponding to the natural
sugar is obtained from the mixture by careful separation. The free hydroxyl
is protected as a benzyl ether, (122). Reduction of the lactone carbonyl group

2. COMPOUNDS WITH TWO RING HETEROATOMS 97
by means of lithium aluminum tri-tert-butoxyhydride gives the correspond-
ing lactol 123 as a mixture of anomers. Reaction of this last intennediate
with methanesulfonyl chloride affords reactive mesylate 124.
-J-o
°0CH=0
-J-o F F
:. 0C02Et
OR
HO F F
HO \ 1'" x'
 "C0 2 Et
OBz
:>
117
118. R=H
120
119. R=Bz
l
BZO b
o OS02 CH S
F .:
B z 0 r
BZO b
o OH
F
.&
B Z 0 r
.:
R0 -p
o .........0
.........
F
&
-
B Z 0 F
124
123
121, R-H
122, R=Bz
Bz=C e H 5 CH 2 -
The next step in the sequence consists of coupling the sugar moiety and
the pyrimidine base. Cytosine is first converted to its bis silyl ether 125, a
modification which enhances the electrophilicity of ring nitrogen. Reaction
with the mesylate 124, which may proceed through the carbocation from
loss of methanesulfonate, affords the coupling product 126 as a 1 : 1 mixture
of isomers at the anomeric carbon. Removal of the benzyl groups by means
of ammonia followed by separation gives the antineoplastic agent gemci-
tabine (127).30
N iKe s
uJ + 121
WesSiO N
>
N
uJ,
N 0
B Z 0\1
BzO r F
::.
N
u
N 0
H°ti
HO F F
125
126
127

98 SIX-MEMBERED HETEROCYCLES
When considering antiviral therapy it should be recalled that viruses do
not live independent of living cells. Viruses can be produced or reproduced
only by a living host which has incorporated the viral genome. Virustatic
agents thus need to act selectively on the subtly different populations of
infected cells. Nucleosides have thus far proven the most reliable source of
antiviral agents since enzymes encoded by viruses seem somewhat less dis-
criminating for these compounds than the host enzymes. The modified nu-
cleoside fiacitabine, 131, showed very good initial activity against hepatitis
B virus in early clinical trials. The widely publicized, late blooming, severe
toxicity manifested by this drug during chronic treatment caused it to be
abandoned. The compound is prepared by the standard coupling reaction
between bis-trimethylsiliyl-5-iodocytosine, 129, and the bromosugar 128.
Treatment of the product 130 with ammonia removes both the benzyl ether
and acetate groups to afford fiacitabine (131).31
BZ0 ty  NHSies]
Br N "
OA: + MesSiON/
NI
ONjJ
:. R 1 0
1 2 a
129
130. R 1 ..Bz. R 2 .Ac
131 R l_ R 2_ H
.
Nucleosides that lack ring hydroxyl groups such as zidovudine (AZT)
have proven particularly active against the AIDS virus. Preparation of one
of the more recent agents in this class, zalcitabine, 137 (DOC), starts with
conversion of diol 132 to its methanesulfonate 133. Treatment with sodium
hydroxide leads to backside attack of the ring oxygen enolate on the mesylate
and fonnation of the transient bridged ether 134. A somewhat complex
transfonnation, which probably involves addition of hydroxide to the het-
erocyclic ring, results in rearrangement to the observed product, 135. Treat-
ment of this intennediate with strong base causes eliminative ring opening
of the strained oxetane to give the dihydrofuran 136. Catalytic reduction
affords the anti-HIV agent zalcitabine (137).32

2. COMPOUNDS WITH TWO RING HETEROATOMS 99
N5 NH N5
II
}3
O-:lN I O-:lN I
o N
RO MeS0 3 TI 
:- >
OR
1 3 2 , R=H 134 135
1 3 3 , R=MeOS0 2 /
N5 N5
o//l N I < o-:L N I
Hot) HO 
137 136
The poor discriminating capacity of the viral enzymes is emphasized by
the fact that AIDS antiviral activity is retained when one of the ring carbon
atoms in the sugar moiety is replaced by sulfur. Condensation of the benzoyl
ester, 138, of glycolaldehyde with the acetal, 139, from thioglycoladehyde
probably starts by addition of the thiol to the free carbonyl; exchange of the
newly fonned hydroxyl with one of the methyl acetal groups leads to cy-
clization and fonnation of 140 as a mixture of isomers. Reaction of that
intennediate with silyl ether 125, fonned in situ from cytosine and trimeth-
ylsilyl triflate (Me3SiOS02CF3), leads to the nucleoside-like compound 141
as a 1: 1 mixture of the two anomers. Separation of the isomers, followed
by removal of the benzoate group by means of an ion exchange resin, leads
to lamivudine (142).33
The antimycotic agent amorolfine, 145, is obtained by the straightfor-
ward reductive alkylation of the morpholine 144 with the substituted phe-
nylisobutyraldehyde 143. 34 Details on the preparation of these starting ma-
terials are not readily available.

100 SIX-MEMBERED HETEROCYCLES
C S H S C0 2 CH 2 CH-O + HSCH 2 CH(OCH s )2
CSHSC021/0
> \yOCH s
138 139
140
N
O)J
H0l;
<
/
N
ONJJ
C8H5C02l;
142
14-1
-ffi-< CH S CHs
C 2 H 5 \ /
CH s CH-O

1\
+ HH 0
'-/
>
-fV-( CH S CH s ;-
C 2 H 5 \ / r-\
C Hs N 0
'-/
,


143
144
145
3. RINGS CONTAINING THREE HETEROA TOMS
Preparation of the poultry coccidiostat toltazuril, 148, involves a somewhat
more complex scheme. Reaction of the urea 146 with chlorofonnyl iso-
cyanate (CICON=C=O) proceeds by initial alkylation on the more basic
tenninal nitrogen rather than addition to the carbonyl group. The intenne-
diate, 147, which is probably not isolated, then cyclizes to fonn the tri-
azinedione ring which affords toltazuril (148).35
The activity of modified nucleosides as antineoplastic agents has been
discussed above. Addition of a nitrogen ring to fonn a triazine ring still
allows the compound to be recognized as a nucleoside substrate; this same
modification causes the compound to block nonnal metabolic processes. The
venerable synthesis of this agent illustrates an approach to the synthesis of
nucleosides which relies on construction of the hetero ring in situ. Reaction
of chloro sugar 149 with silver isocyanate leads to the product 150, appar-
ently as the desired single anomer. Condensation with urea-O-methyl ether

3. RINGS CONTAINING THREE HETEROATOMS 101
F s S -V-- 0 V NH
>t-NH
a 'c H3
:.
J=L V a - CN
FsS U- 0 \-/ NH '>=0
>t- N,
a CHs
146
1.7
/
J=L  °y.-NH
FsS -U-0-U-- N FO
>t-l\
o CH 3
148
leads to addition across the imine bond and fonnation of substituted urea
151. Treatment of that intennediate with methyl orthofonnate leads to ad-
dition of the remaining carbon atom and cyclization of triazine 152. Expo-
sure to ammonia replaces the ring O-methyl ether by an amino group, prob-
ably by an addition-elimination sequence; the benzoyl protecting groups
hydrolyze under the reaction conditions. There is thus obtained the antineo-
plastic agent decitabine (153).36
BZO0"vv-
 Cl
OBz
Bz01:J-C.O
OBz
=-
OCH s
H NN
2
HNO
Bz°tJ
=-
OBz
149
150
151
Bz-C e H 6 CO
NH 2
NN

N 0
HO
c:
OB
153
I
OCR s
NN
l!.NO
BzO
OBz
152

102 SIX-MEMBERED HETEROCYCLES
The well established cytotoxic agent cyclophosphamide, 154, is now
known to undergo metabolic activation in the liver to the hydroxylated de-
rivative 156. The carbinolamine in this product then opens to an aldehyde;
this undergoes reverse Michael addition to give acrolein and the active al-
kylating agent, phosphoramide mustard [H 2 NP0 2 N(CH 2 CH 2 CI)2]. Preacti-
vation of cyclophosphamide should provide more generally active drugs by
avoiding the need for liver hydroxylation. Reaction of cyclophosphamide
with ozone in the presence of hydrogen peroxide, leads to hydroperoxide
155, possibly via the ring imine. This product, perfosfamide (152), has
undergone clinical development as a cytotoxic agent. 37
o CI
( 0,  r
P-N
N ' 
H CI
:.-
<= 0, 110 rCI
P-N
N ' 
H 0 0 H CI

o CI
<= 0, 11 r
P-N
N ' 
H 0 H CI
154
155
156
158
I
0- r\ 1I0 NrCI
NH 3 + )-N ' 
_ ---.r S H CI
°3 S
./".... -" S H
HO S' 
3
157
Irritation of the urinary bladder ranks among the many serious side effects
of cyclophosphamide. Some evidence indicates this may be due to the direct
action of metabolically produced acrolein. The soluble thiol Michael nu-
cleophile mesna, 158, which is concentrated in the bladder, has been used
as an acrolein trap for treating that side effect. The cytotoxic agent mafos-
famide, 157, incotporates this moiety directly. Reduction of the hydrope-
roxide group in 155 affords the alcohol 156. Reaction of this carbinolamine
with the cyclohexylamine salt of mesna, 158, leads directly to mafosfamide
(157).38
REFERENCES
1. E. J. Freyne, A. H. M. Rayemaekers, M. G. Venet, V. K. Sipido, and F. De
Clerk, Drugs Future, 15, 463 (1990).

REFERENCES 103
2. A. I. Boss, D. W. Clissold, J. Mann, A. J. Markson, and C. P. Thickitt,
Tetrahedron, 45, 6011 (1989).
3. J. Delarge, Arznei.-Forsch., 38(IA), 144 (1988).
4. C. Semeraro, D. Micheli, D. Pieraccioli, G. Gaviraghi, and D. A. Borthwick,
Ger. Offen. 3529997 (1986); Chern. Abstr., 105, 97322 (1986).
5. C. Semeraro, D. Micheli, D. Pieraccioli, G. Gaviraghi, and D. A. Borthwick,
Ger. Offen. 3628215 (1987); Chern. Abstr., 107,23240 (1987).
6. B. S. Huang, K. H. Deutsche, N. L. Lalinde, R. C. Terrell, and L. V. Kudzma,
Eur. Pat. Appl. 160422 (1985); Chern. Abstr., 104, 186308 (1986).
7. F. Janssens, J. Torremans, and P. A. J. Janssen, J. Med. Chern., 29, 2290
(1986).
8. N. Lalinde, J. Moliterni, D. Wright, H. K. Spencer, M. H. Ossipov, T. C.
Spaulding, and F. G. Rudo, J. Med. Chern., 33, 2876 (1990).
9. D. Lednicer and L. A. Mitscher, Organic Chernistry of Drug Synthesis, Vol.
3 , Wiley, 1984, p. 117.
10. P. L. Feldman, M. K. James, M. C. Brackeen, F. Marcus, J. M. Billota, S.
V. Schuster, A. P. Lahey, M. R. Johnson, and H. J. Leighton, J. Med. Chern.,
34, 2202 (1991).
11. L. Werbrouck, A. A. H. P. Megens, R. A. Stokbroekx, and C. J. E. Nieme-
geers, Drug Dev. Res., 24,41 (1991).
12. D. Lednicer and L. A. Mitscher, Organic Chernistry of Drug Synthesis, Vol.
3, Wiley, 1984, p. 55.
13. Anon., Drugs Future, 11,112 (1986).
14. P. K. Yonan, R. L. Novotney, C. M. Woo, K. A. Prodan, and F. M. Her-
shenson, J. Med. Chern., 23,1102 (1980).
15. B. N. Desai, R. J. Chorvat, and K. J. Rorig, Eur. Pat. Appl. 170901 (1986);
Chern. Abstr., 105,97320 (1986).
16. Anon., Drugs Future, 17,377 (1992).
17. R. F. Brady, Carbohydr. Res., 15, 35 (1970).
18. B. E. Maryanoff, S. O. Nortey, J. F. Gardocki, R. P. Shank, and S. P. Dodg-
son, J. Med. Chern., 30, 880 (1987).
19. J. P. Yevich, J. S. New, D. W. Smith, W. G. Lobeck, J. D. Catt, J. L.
Minelli, M. S. Eison, D. P. Taylor, L. A. Riblet and D. L. Temple, J. Med.
Chern., 29, 359 (1886).
20. K. Ishizumi, A. Kojima, and F. Antoku, Chern. Phann. Bull., 39, 2288 (1991).
21. W. Dompert, T. Glaser, H. Horstmann, T. Schuunnan, P. R. Seidel, and T.
Joerg, Ger. Offen. 3321969 (1984); Chern. Abstr., 102,220896 (1985).
22. Anon., Austrian Pat. 336021 (1977); Chern. Abstr., 87, 85033 (1977).
23. J. Engel, I. Fleischhauer, V. J akov lev, A. Kleeman, B. Kutscher, B. Nickel,
H. Rauer, U. Werner, I. Szeleny, C. E. Johauser and C. R. Schuster, J. Med.
Chern., 33, 2976 (1990).
24. J. C. Pascal, C. H. Lee, B. J. Alps, H. Pinhas, R. L. Whiting, and S. Beranger,
Eur. Pat. Appl. 289277 (1988); Chern. Abstr., 110, 135273 (1989).

104 SIX-MEMBERED HETEROCYCLES
25. H. Shin, U. S. Patent 3274194 (1966); Chern. Abstr., 66,65510 (1966).
26. A. F. Kluge, R. D. Clark, A. M. Strosberg, J. C. Pascal, and R. L. Whiting,
Eur. Pat. Appl., 126449 (1984); Chern. Abstr., 102, 166777 (1985).
27. Anon., Jpn. Kokai 62029575 (1987); Chern. Abstr., 106, 176427 (1987).
28. C. Y. Tu, G. W. Clark, and G. Borsotti, Eur. Pat. Appl. 330381 (1989);
Chern. Abstr., 112, 118848 (1990).
29. T. S. Chou, P. C. Heath, L. E. Patterson, L. M. Poteet, R. E. Lakin, and A.
H. Hunt, Synthesis, 565 (1992).
30. C. G. Wennuth and A. Exinger, Agressologie, 13,285 (1972).
31. K. A. Watanabe, U. Reichman, K. Hirota, C. Lopez, and J. J. Fox, J. Med.
Chern., 22, 21 (1979).
32. J. P. HOlWitz, J. Chua, M. Noel, and J. T. Donatti, J. Org. Chern., 32, 817
( 1967) .
33. R. Storer, I. R. Clemens, B. Lamont, S. A. Noble, C. Williamson, and B.
Belleau, Nucleosides Nucleotides, 12, 225 (1992).
34. A. Pfiffner, Eur. Pat. Appl., 24334 (1981); Chern. Abstr., 95, 80987 (1981).
35. R. Lantzsch, Ger. Offen. 3516631; Chern. Abstr., 106,67365 (1987).
36. J. Piml and F. Sonn, Collect. Czech. Chern. Cornrnun., 29, 2576 (1964).
37. G. Peter and H. J. Hohorst, Cancer Chernother. Pharmacol., 3, 181 (1979).
38. U. Niemeyer, J. Engel, G. Scheffler, K. Molge, D. Sauerbier, and W. Weigert,
Inv. New Drugs, 2, 133 (1984).

CHAPTER 7
FIVE-MEMBERED
BENZOHETEROCYCLES
The apparently broad tolerance for structural modification in the hypocho-
lesterolemic agents related to lovastatin (Chapter 6, 57) was noted above.
Full activity is retained when the tetralin moiety in the prototype is replaced
by a substituted indole. Construction of the heterocyclic moiety for this
agent, fluvastatin (14) starts by alkylation of N-isopropylaniline with 4-
fluorophenacyl chloride to afford the derivative 2. Treatment with a strong
Lewis acid leads to cyclodehydration to indole 3. Reaction of this product
with DMF in the presence of phosphorus oxychloride leads to fonnylation
of the only open position of the indole ring and fonnation of aldehyde 4.
This is then reduced to carbinol 5 by means of sodium borohydride. They
hydroxyl is replaced by chlorine with oxalyl chloride. Reaction of that in-
tennediate with trimethyl phosphite [(MeO)3P] leads initially to a transient
phosphonium salt; the chlorine counterion then attacks one of the methoxyl
groups on carbon to eliminate methyl chloride. The net result of this Arbusov
reaction is fonnation of phosphonate 6.
The side chain in fluvastatin corresponds to the open-chain fonn of the
lactone moiety in lovastatin and the synthetic hypolipidemic compound
dalvastatin (Chapter 6, 64). Construction of the side chain in chiral fonn
requires an extended reaction sequence involving manipulation of protecting
groups. The sequence starts by reduction of the free carboxyl group of the
monomethyl ester 8 of L-malic acid 7. The primary hydroxyl group in the
product, 9, is then converted selectively to the trityl ether by reaction with
triphenylmethyl chloride to give 10. Saponification converts that intenne-
105

106 FIVE-MEMBERED BENZOHETEROCYCLES
F
F
:>
Cl o -
,/
N
)-
:>
F
C I
1
2
3
/
F
F
'"
4, R= CH=O
6
5, R= CH 2 0H
diate to the free acid 11. Reaction of that acid with the magnesium enolate
from monoallyl malonate in the presence of carbonyldiimidazole effects acy-
lation on the malonate methyne group with subsequent monodecarboxylation
of the bis-(3-carboxylate. There is thus obtained the keto ester 12. The sec-
ondary hydroxyl group from malic acid is now protected as the tert-butyl-
dimethylsilyl ether (TBDM) 13. Reduction with sodium borohydride in the
presence of trimethylborane leads selectively to the erythto compound 14;
the newly introduced hydroxyl group is again protected as its tert-butyldi-
methylsilyl ether (15). Treatment of this product with acid selectively cleaves
the trityl ether to afford the alcohol 16, which is taken on to aldehyde 17
by Swem oxidation.
Assembly of the target molecule concludes by condensation of the ylide
from treatment of the phosphonate 6 with base with aldehyde 17. The allyl

FIVE-MEMBERED BENZOHETEROCYCLES 107
CO R 1
HOUh( 2
CO R 2
2
CO R 2
HOlill e 2
OR 1
rlC02A 1 y
HOIIO'n:_
OTr
:.
>
7. Rl_R2_H
9. Rl_H. R 2 -CH 3
10. RI-Tr. R 2 -CH 3
11. R 1 =Tr. R 2 =H
1 2
8. R 1 =CH 3 . R 2 =H
III
TBDKO 
C0 2 Aly
.,\,OTBDK
CH=O
RiO
 C02AlY
,\\,0 TBDK
OR 2
<
0 y COA I Y
,\OR
"
OR 2
1 7
1 4 .
1 2
R -H. R -Tr
1 2 .
1 2
R -H. R -Tr
15. R 1 =TBDM. R 2 =Tr
16. R 1 =TBDM. R 2 =H
13.
1 2
R -TBDM. R -Tr
Tr- (C e H 5 )3 C
Aly- Allyl
TBDK- t-BuSiKe 2
ester protecting group is then removed by treatment with a palladium-tri-
phenylphosphine complex; reaction of the intennediate product with tetra-
butylammonium fluoride selVes to cleave the silyl ethers. Fluvastatin (18)1.2
is thus obtained.
,
TBDKOrC02AIY
'1'\'\ 0 T B MD
CH-O
:.
,
+
6
17
18

108 FIVE-MEMBERED BENZOHETEROCYCLES
An indole, 25, related structurally to the neurotransmitter serotonin 19
exhibits antimigraine activity; it is noteworthy that the pKa of the acidic
proton in the sulfonamide is not too far removed from that of the phenol in
the serotonin. Aniline 20 is converted to the hydrazine 21 by the standard
diazotization-reduction sequence. Condensation with the acetal from 3-cy-
anopropionaldehyde gives the hydrazone 22. Treatment of this last inter-
mediate with acid under classic Fischer indole conditions leads to the product
23. The nitrile is then reduced to the primary amine 24; dimethylation of
the amine by a modem version of the Clark-Eschweiler reaction affords
sumatriptan (25)3.
H0 'Grf NH2
" '\
./ N
H
19
H
CH3S 0 2 N 
NHR
H
C H 3S02 N  , I CN
 ./ N
N'
H
22
20, R = H
21, R = NH2
1
H  NR2
C H 3S 0 2 N I' '\
./ N
H
c
H  CN
C H 3S 0 2 N I' '\
./ N
H
24, R = H
25, R = CH3
23
An indole provides the nucleus for an analgetic said to act through a
nonopioid mechanism. Friedel-Crafts acylation of 2-methylindole (26) with
4-anisoyl chloride affords the ketone 27. This intennediate is then converted
to the nitrogen anion with sodium hydride; treatment with N-(2-chloro-
ethyl)morpholine leads to alkylation on nitrogen. There is thus obtained
pravadoline (28). 4
CB3
Nr-
B

OCH s
OCH s

'\
H
"
H)
Co
26
27
28

FIVE-MEMBERED BENZOHETEROCYCLES 109
The utility of 5-hydroxytryptamine antagonists such as metoclopramide
(Chapter 2, 46) for the treatment of cancer chemotherapy induced emesis
occasioned a large amount of work on the SAR for agents of this class.
Activity is retained when both the ortho methoxyl group and amide linkage
of the prototype are replaced. The first step in the preparation of this agent
is conversion of indole-3-carboxylic acid, 29, to the mixed anhydride 30.
Reaction with the rather complex bridged bicylic amino alcohol 31 gives the
ester dolasetron (32). 5
Gd 0 2 R +
H
H 0 I"
:.
0'1
I,
o
29. R-H
3 1
32
30. R-OCCF s
The importance of the presence of acidic ionizable protons for NSAID
activity was discussed in greater detail in Chapter 2. The first step in the
construction of an NSAID which contains such a group consists of the
conversion of indolone 33 to its carbamate 34. The protons on the methylene
group are sufficiently acidic to afford at least some of the carbanion on
treatment with 4-dimethylaminopyridine (DMAP). Reaction of 34 with the
acid chloride from thiophene-2-carboxylic acid in the presence of DMAP
leads to acylation on the methylene group. The product, shown as its enol
tautomer, is the NSAID tenidap (35). 6
CI lGQ
I" ==0
/' N
H

C 1 'GO==
I" -0
/' N
I
CONH 2
:.
HO
Cl  :s/
N/
I
CONH 2
33
34
35
Cardiac glycosides such as digitoxin were for many years the only drugs
available for stimulating the weakening heart muscle that denotes congestive
heart failure. The advent of the cardiotonic pyridone amrinone, 36, offered
the first of a series of drugs that avoided the very narrow therapeutic ratio
of the cardiac glycosides. Extensive investigation of the SAR in this area

110 FIVE-MEMBERED BENZOHETEROCYCLES
showed that considerable latitude exists in the structure of both heterocyclic
moieties. Exhaustive methylation of indolone 37 with methyl iodide in the
presence of sodium hydride gives the dimethyl derivative 39; the acetyl
protecting group is then removed with aqueous base. Friedel-Crafts acyla-
tion with succinic anhydride and AICI) leads to keto ester 40. Condensation
of this intennediate with hydrazine leads to successive hydrazone and hy-
drazide fonnation, though not necessarily in that order. The pyrazinone
indolidan (41)7 is thus obtained.
H
° XJ N
"
,I
H 2 N 
N
0f\ 0
N/
Ac
:>
36
37
HO
38, R=Ac
39, R=H
1
<
4 1
40
The utility of angiotensin converting enzyme (ACE) inhibitors as anti-
hypertensive agents is by now finnly established. All ACE inhibitors to date
consist of a proline like moiety and a side chain that interacts with the
putative zinc pocket on ACE (e.g., see ceronapril, 14, and fosinopril, 20,
in Chapter 5). The side chain for the analogue in which a perhydroindole
serves as the surrogate proline is constructed by reductive alkylation by
means of sodium cyanoborohydride of S-norvaline with pyruvic acid. Asym-
metric induction by the chiral center in the amino acid leads to stereoselective
fonnation of the chiral product 44.
n-C 3 H 7 CHNH 2
,
C0 2 Et
42
C0 2 H
+ ° <
CH 3
:>
n-C 3 H 7 CHNHCHC0 2 H
, ,
Et0 2 C CH 3
43
44

FIVE-MEMBERED BENZOHETEROCYCLES 111
Hydrogenation of the chiral fonn of ester 45 over palladium on carbon
gives the cis-perhydroindole ester 46; the fonnation of the cis isomer is
favored by both the direction of attack of the catalyst and thennodynamic
preference for cis 5,6-ring fusions. The ester group is then interchanged to
tert-butyl by successive saponification (47) and reaction with isobutylene
(48). Condensation of acid 44 with indoline 48 catalyzed DCC leads to
fonnation of the amide 49. The tert-butyl protecting group is then removed
preferentially to give the ACE inhibitor perindopril (50).8
C02Et _
N
H
H
C02R
N
Ii H

H
C02R
N
- \
H COCHNHCH-ftC 3 H 7
- -
- -
- -
- -
45 46. R-Et
47. R-H
48. R-t-Bu
CH 3 C0 2 E t
49. R...t-Bu
50. R-H
A benzofuran ring provides the nucleus for the NSAID tifurac, 56, which
contains the acidic proton as a traditional carboxylic acid. Acylation of
benzofuran 51 with acetyl chloride gives the methyl ketone 52. Treatment
of that compound with sulfur and morpholine leads to transposition of the
carbonyl group to the end of the chain by the Wilgerodt reaction. The product
from this seemingly simple, but in effect mechanistically complex, reaction
is the arylacetyl morpholide 53. The amide is then hydrolyzed with strong
acid, and the resulting acid is esterified to ethyl ester 54. Acylation of this
compound with 4-thioanisoyl chloride under Friedel-Crafts conditions leads
to the ketone 55; saponification of the ester gives the acid tifurac (56). 9
The SAR of antiemetic compounds related to metoclopramide had es-
tablished the need for a methoxyl group located on the ring carbon adjacent
to the amide group; it was later found that the ortho ether can be present as
part of a fused hydrofuran ring. IO Separate lines of research indicate that
activity is enhanced by including the basic amino group in a bicyclic frame-
work. The antiemetic compound zatosetron, 65, combines both of these
activity-enhancing features. Construction of the bicylic amine begins by
conversion of readily available tropanone 57 to its benzylimine 58. Catalytic
reduction of this compound proceeds by addition of hydrogen from the more
open face to give the a-benzylamine derivative. The benzyl group is lost by
hydrogenolysis during the course of the reaction to give the primary amine
59.
Alkylation of the phenolic group in 60 with methallyl chloride gives the
ether 61. This compound undergoes Claisen rearrangement to the phenol 62

112 FIVE-MEMBERED BENZOHETEROCYCLES
00 :- :>
./' °
5 1 52 53
C0 2 R /
C0 2 C 2 H 5
<
CH 3 S
54
55, R-C 2 H e
56, R-H
/CH3
0/ 
CH3
> C e H 5 CHN7 
CH3
H 2 N
>
57
58
59
on heating. Treatment of this intennediate with fonnic acid brings about
cylization to fonn the dihydrofuran ring (63). The free acid, 64, is obtained
by saponification of the ester. Reaction of the acid chloride from 64 with
amine 59 affords the amide, zatosetron, (65).11
The enzyme 5-lypoxygenase is the factor ultimately responsible for re-
lease of arachidonic acid, source of thromboxanes and leukotrienes, from
fatty stores. It has been established that corticosteroids exert their antiinflam-
matory effect by inhibition of this enzyme. A structurally simple benzothio-
phene N-hydroxyurea, is one of the few nonsteroids reported to have the
same activity. Stepwise acylation of hydroxylamine with phenyl chlorofor-
mate leads to successive fonnation of the O-acylated (66) and O,N-diacy-
lated (67) derivative. Reaction of 67 with 2-hydroxyethyl benzothiophene
68 in the presence of diethyl azodicarboxylate (DEAD) and triphenylphos-
phine results in net displacement of the hydroxyl by hydroxylamine nitrogen

FIVE-MEMBERED BENZOHETEROCYCLES 113
 
Cl
C0 2 CH S
C16
:>
C I
60
6 1
62
NCH3
0, H "V
I
<:
C 1
C 1
65
63, R=CH S
64 I R=H
and fonnation of the dicarbonate 69 in a Mitsonobu reaction. Exposure of
this intennediate to ammonia leads to ammonolysis of the N-carbonate to a
urea and loss of the O-carbonate ester. There is thus obtained the 5-lyp-
oxygenase inhibitor zileutron (70). 12
o
I I
H 2 NOCOC e H 5
o 0
I I I I
> CeHeOCHNOCOCeH5
66
67
:>
o :.
I I
NCOC e H 5
I
o,C,OC e H 5
o
o
I I
NCNH 2
I
OH

sr-'OH
67
68
69
70
Inclusion of the trisubstituted double bond of the estrogen antagonists
such as tamoxifen (132, Chapter 2), in a fused ring leads to compounds
which retain both activity and potency. Dihydronaphthalenes of this general
type, such as trioxifene and nafoxidine, were discussed in previous vol-
umes. Replacement of the dihydronaphthalene ring of trioxifene with the
isosteric benzothiophene, as well as addition of a hydroxyl group in the

114 FIVE-MEMBERED BENZOHETEROCYCLES
fused benzene ring, leads to raloxifene (78). Friedel-Crafts cyclization of
the substituted acetophenone 71, which can be obtained from 4-methoxy-
bromoacetophenone and 3-mercaptoanisole, with PPA, leads to benzothio-
phene 72. Note that the anisoyl ring in 72 has in fact shifted from its position
in the initial cyclization of the product. To avoid later complications resulting
from the methyl protecting groups, these are first removed (73) and replaced
by methanesulfonate (74) groups known to be inert under Friedel-Crafts
conditions. Construction of the side chain begins by alkylation of methyl 4-
hydroxy benzoate with N-(2-chloroethyl)piperidine to ether; the ester is then
saponified to the acid 76. Acylation of 74 with the acid chloride from
76 in the presence of aluminum chloride gives the ketone 77. Exposure to
mild aqueous base then affords raloxifene (78). 13
ycr OCH 3
o 1/
I"' .. I"' \; - OR
C H 3 0 U- S · RO
71
72; R = CH3
73; R = H
74; R = OS02CH3
o

o
I "
--.
o0

C02H
76
>-RO
OR
OH
rQJ
77; R = OS02CH3
78; R = H
C02 CH 3
75
The wide latitude of the SAR of the "conazole" antifungal compounds
has been noted before (e.g., see fluconazole, Chapter 5, 89). The observed
activity of compounds that share only an imidazole ring and halogenated
aryl groups with other compounds in this class is yet another indication of
the looseness of the structural requirements. Alkylation of the starting ma-
terial, the rather complex dihydrothiophene 79, whose preparation is not
readily retrievable, with difluorinated benzyl bromide 80 affords the anti-
fungal agent cisconazole (81).14
r
OH r F O-CH2  ';;
r BrCH2 \ ';;
I' F
+ 
/' S N\\ N\\
N r N
79 80 8 1

1. BENZENE RINGS FUSED TO RINGS CONTAINING TWO HETEROATOMS 115
1. BENZENE RINGS FUSED TO RINGS CONTAINING TWO
HETEROATOMS
The histamine H 2 receptor antagonists, which block the release of stomach
acid stimulated by histamine, represented the first family of specific antiulcer
agents. The more recently developed antiulcer agent omeprazole, 82, di-
minishes gastric acid secretion by a quite different pathway: this compound
inhibits the sodium-potassium pump, which powers acid secretion. The net
effect is similar to that of the older series of compounds.
CH30  N
I J.-so
........: H H 9 C
H
CBs
OCB s
82
Gastric acid secretion inhibiting activity is retained when the substitution
pattern in the pyridine ring on the side chain is changed. Aromatic nitration
of the dimethoxy N-oxide 83 affords the nitrated product 84. The ring is
sufficiently activated by the N-oxide group so that treatment with methoxide
results in replacement of the nitro group by a methoxyl, probably by an
addition-elimination sequence. Treatment of this last intennediate with acetic
anhydride leads first to the fonnation of a transient O-acetate; this undergoes
migration to the adjacent ring methyl group with simultaneous oxidation
(Polonovski reaction). Saponification of the acetate first obtained gives the
hydroxymethyl derivative 86. Reaction with thionyl chloride converts the
hydroxyl to chloro (87). Alkylation of 2-mercaptobenzothiazole with 87
proceeds by attack of the nucleophilic sulfur. Oxidation of the alkylation
product with a controlled amount of m-chloroperbenzoic acid affords the
antiulcer agent pantoprazole (88). 15
The preparation of a closely related compound begins with nitration of
the N-oxide of 2,3-dimethylpyridine (89). In this case the nitro group is
replaced by the anion from trifluoroethanol to give ether 90. This is then
carried through the sequence described above to afford finally the antiulcer
compound lansoprazole (94).16
The benzimidazole ring system provides the nucleus for a compound that
promotes excretion of uric acid, the nucleoside metabolite associated with
gout. Reaction of the ortho diamine function in benzophenone 95 with the
iminoether from acetonitrile, [CH 3 C(OCH 3 ) = NH], leads to fonnation of
the benzimidazole 96 by two successive addition-elimination reactions. The

116 FIVE-MEMBERED BENZOHETEROCYCLES
o
H3 c iJ
CH 3 0

o
H 3 c -Q
CH 0 R
3
:>
)
HO I R
CH 0 OCH 3
3
83 84. Rc: N0 2 86
85. R=OCH 3
/
N,>--S  )1 
N CH 0 OCH 3
H 3
rl
CII R
CH 0 OCH 3
3
87
88
o
H3 c iJ
H 3 C

o
H 3 c -Q
H C R
3
:>
rl)
HO I R
H C OCH 2 CF s
3
89 90, R-N0 2 92
91, R-OCH 2 CF s
/
r01s  )1 
N H C OCH 2 CF 3
H 3
rl =;>
CII R
H C OCH 2 CF s
3
93
94

1. BENZENE RINGS FUSED TO RINGS CONTAINING TWO HETEROATOMS 117
carbonyl group is then reduced to an alcohol (97). Displacement of the
activated hydroxyl on the diphenylmethane carbon with imidazole leads to
fonnation of the uricosuric agent irtemazole (98). 17
[[
a R N
NH2 N N
I  I; ---. ,>"-CH s ---+ ,>"-c Hs
N N
NH 2 H H
95 96 ; R-a 98
97: R-H,OH
The pyridazinone function that fonns the phannacophore in cardiotonic
agents such as idolidan, 41, leads to the same activity when substituted on
a benzimidazole. Acylation of the amino group of 99, which can be obtained
by acylation of 2-nitroaniline with succinic anhydride, with anisoyl chloride
gives the amide 100. Reaction of that intennediate with hydrazine leads to
fonnation of the pyridazinone ring (101). The nitro group is then reduced
to an amine by catalytic hydrogenation to give 102. Treatment with acid
leads to cyclization of the ortho amino amide array to an imidazole. There
is thus obtained the cardiotonic agent pimobendan (103). 18
0 2 /
H2NC02CB3
°2 N
w N  C02CB3
CHaO \ /
o

99
100
I
CHSO 
I' H
./ N
\ -
N
o
c
N
CHaa,o
a
103
101; R-a
102; R-H
Further exploration of the SAR of 5-HT antagonist-based antiemetic com-
pounds showed that the indole ring present in dolasetron, 32, can be re-

118 FIVE-MEMBERED BENZOHETEROCYCLES
placed by an indazole. A [3,3, l]azabicyclononane linked via an amide pro-
vides the requisite rigid bicyclic amine in this case. This last is prepared
by first converting ketone 104 to its oxime, 105. Reduction of this inter-
mediate with a hydride reagent proceeds by attack of the reagent from the
open exo side of the molecule with fonnation of the endo amine 106. 19
Acylation of this amine with indazole 107 as its acid chloride leads to the
corresponding amide. There is thus obtained the antiemetic compound grani-
setron (108).20
R =\ >CH 3 )
> H 2 NI" < >CH 3 )
C0 2 H
cd ' 'N
./" '
N
\
CH 3
104; R=O
106
107
105; R=NOH
II' < >CH 3 )
lOB
REFERENCES
1. K. M. Cheng, G. E. Hardtman, G. T. Lee, J. Linder, S. Wattanasin, and K.
P. Kapa, Eur. Pat. Appl. 244364 (1987); Chern. Abstr., 108, 131038 (1988).
2. J. Prous and J. Castaner, Drugs Future, 16, 804 (1991).
3. A. W. Oxford, Ger. Offen. 3527648 (1986); Chern. Abstr., 105, 78831 (1986).
4. M. R. Bell, U.S. Patent 4973587 (1989); Chern. Abstr., 114,20702 (1991).
5. P. B. Anzeveno, Eur. Pat. Appl. 339669 (1989); Chern. Abstr., 112, 118673
( 1990).
6. R. G. Schulte and F. J. Ehrgott, Eur. Pat. Appl. 421749 (1991); Chern. Abstr.,
115,71392 (1991).
7. D. W. Robertson, J. H. Krushinski, E. E. Beedle, V. Wyss, G. D. Pollock,
H. Wilson, R. F. Kauffman, and J. S. Hayes, J. Med. Chern., 29, 1832 (1986).

REFERENCES 119
8. M. Vincent, G. Remond, B. Portevin, B. Serkiz, and M. Laubie, Tetrahedron
Lett., 23, 1677 (1982).
9. J. P. Dunn, N. A. Ackennan, and A. J. Tomolonis, J. Med. Chern., 29, 2326
(1986).
10. D. LednicerandJ. H. Sun, U.S. Patent 4888353 (1989).
11. D. W. Robertson, W. B. Lacefield, W. Blomquist, W. Pfeifer, R. L. Simon,
and M. L. Cohen, J. Med. Chern., 35, 310 (1992).
12. A. O. Stewart and D. W. Brooks, J. Org. Chern., 57, 5020 (1992).
13. C. D. Jones, M. G. Jevnikar, A. J. Pike, M. K. Peters, L. J. Black, A. R.
Thompson, J. F . Falcone, and J. A. Clemens, J. M ed. Chern., 27, 1057 (1984).
14. D. F. Rane, J. A. Desai, and R. E. Pike, Eur. Pat. Appl. 185381 (1986);
Chern. Abstr., 105, 152918 (1986).
15. B. Kohl, E. Stunn, J. Senn-Bilfinger, A. W. Simon, U. Krueger, H. Schaefer,
G. Rainer, V. Figala, and K. Klemm, J. Med. Chern., 35,1049 (1992).
16. K. Kubo, K. Oda, T. Kaneko, H. Sato, and A. Nohara, Chern. Pharm. Bull.,
38, 2853 (1990).
17. A. H. M. Raeyemaekers, E. J. E. Freyne, and G. C. Sanz, Eur. Pat. Appl.
260744 (1988); Chern. Abstr., 109,73437 (1988).
18. V. Austel, K. Noll, E. Wolfgang, J. Heider, J. Van Meel, W. Diederen, and
W. Haannann, Ger. Offen. 3728244 (1989); Chern. Abstr., 111, 97263 (1989).
19. P. Donatsch, E. Guenter, G. Huegi, B. P. Richardson, and P. Stadler, Ger.
Offen. 3322574 (1983); Chern. Abstr., 100,209629 (1984).
20. J. Bennudez, C. S. Fake, G. F. Joiner, K. A. Joiner, F. D. King, W. D.
Miner, and G. S. Sanger, J. Med. Chern., 33, 1924 (1990).

CHAPTER 8
SIX- AND SEVEN-MEMBERED
BENZOHETEROCYCLES
1. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING ONE
RING HETEROA TOM
As noted earlier, one of the branches of the arachidonic acid cascade leads
to the injurious mediators typified by leukotriene L4 (96, Chapter 2). An-
tagonists such as sulukast (109, Chapter 2) have shown some activity against
leukotriene-mediated effects. The quinoline ring systems serves as the nu-
cleus for two leukotriene antagonists. Each of these agents, it should be
noted, shares the ionizable acidic proton common to this class.
Displacement of chlorine in chloromethyl quinoline 1 by the phenoxide
from 2 affords the corresponding ether 3. Catalytic hydrogenation of that
intennediate then reduces the nitro group to the aniline (4). Acylation of the
amine with triftuoromethylsulfonyl chloride leads to sulfonamide (5). The
highly electron-withdrawing trifturomethyl group significantly increases the
acidity of the amide proton in the product, ritolukast (5).1
Condensation of the anion on the methyl group from quinoline 6 with
m-phthalaldehyde leads to the product from reaction of a single carbonyl
group 7. The synthetic schemes reported for preparation of the pure enan-
tiomers of the final product, 2 as well as the nonstereoselective one described
below, in vol ve fonnation of a thioacetal as the next step. Thus reaction of
7 with N,N-dimethyl 3-mercaptopropionamide in the presence of hexamethyl
disilazane leads to the silylated thioacetal 8. This is then allowed to react
with ethyl 3-mercaptopropionamide in the presence of boron trifluoride. The
120

1. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING ONE RING HETEROATOM 121
NC I
 +
o
HON02
JGl
N 1/
0AO NR 2

>
1
2
3, R-Q
4, R=H
/
JGl
N I /'
0AO NHSOCF 3

5
strong acid presumably leads to elimination of the trimethyl silyloxy group;
the resulting carbocation then reacts with nucleophilic sulfur to fonn 9.
Saponification of the ester completes the synthesis of the leukotriene antag-
onist verlukast (10). 3
o 
CINCH3 CINCH=O CINOSi(CH3}J
 ----+  ----+  SCON (CH 3 )2
6
7
8
/

CINSC02R
 S.............. CON (CH 3)2
9, R = C2HS
10, R = H
The quinoline carboxylic acid derivative brequinar (15) has shown an-
tineoplastic activity in a number of animal models. The mechanism of action
of this agent, which bears little or no structural relation to other antitumor
agents, remains to be defined. The compound is prepared by the one-step
condensation of the biphenyl derivative 12, which may be obtained by acy-
lation of 2-ftuorobiphenyl, with isatin, 11. The transfonnation can be ra-
tionalized by assuming first the condensation of the aliphatic methylene
group next to the carbonyl with the isatin ketone to fonn a transient inter-
mediate such as 13. The isatin amide group can then hydrolyze under the

122 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
protic basic reaction conditions to given an amino carboxylate such as 14.
Intramolecular condensation of the carbonyl with the primary amine then
fonns the quinoline ring. The end product of this one-pot sequence is bre-
quinar (15).4
1 1
1 2
0
F
>
1 3
1
0
F
I(
o
o
F lGr) "
I =0
/ N
H
+
r
15
14
The ubiquity of piperazine rings among compounds that interact with the
CNS and cardiovascular sites, discussed at greater length in Chapter 6,
carries over to the quinolone series. Bisalkylation of the primary amino group
on quinolone 16 with N,N-di-(2-bromoethyl)amine gives the piperazine 17.
Acylation of this compound with 3,4-dimethoxybenzoyl chloride leads to
the corresponding amide. The cardiotonic agent vesnarinone (18)5 is thus
obtained.
()Cr NB I
"
ON/.
----.
rXB
()Cr N-J
"
ON/.
---+
o
rlfOCHI
If-J VOCHI
ON
18
17
18
Modem antibacterial agents owe their selectivity to the fact that these
drugs inhibit enzymes involved in bacterial replication that have no mam-
malian counterparts. The best known case is that of the 13-lactams, which
inhibit enzymes involved in cell wall synthesis. More subtle differences can
also lead to selectivity. If the DNA in the average cell were extended to its

1. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING ONE RING HETEROATOM 123
full length, its span could be measured in inches. The DNA in cells thus
exists in a highly coiled or supercoiled fonn. Those portions of DNA that
must be read for replication need to be straightened out. Unwinding this coil
is somewhat akin to unraveling a tight snarl of monofilament fishing line.
The most efficient way to straighten a portion of the chain involves cutting
snarls, passing the line through, and retying the cuts. The topoisomerase
enzymes temporarily hold the cut ends until the chain is passed through;
other enzymes then repair the cut. Inhibitors of the topoisomerases in effect
replace the enzyme, but then fonn a covalent bond which holds the cut ends
apart. The disrupted DNA chain then becomes nonfunctional. The quinolone
antibiotics typified by the compounds in Table 1 result from several decades
of investigation of the SAR of this heterocyclic nucleus. These compounds
act as inhibitors of DNA gyrase, a special class of topoisomerases whose
unique occurrence in bacteria leads to selective inhibition of prokaryotes.
The 7 -amino substituted quinolone antibiotics listed in Table 1 are ac-
cessible by a common synthetic scheme. The actual routes used for the
individual compounds differ in the halogen atoms on the monocyclic starting
materials; all include fluorine at the 3 position; the halogen substituent at
position 2 and 4 may be either fluorine or chlorine. The first step consists
of construction of the benzoyl acetate ester 21. This is accomplished by the
Claisen-like condensation of benzoic acid 19 with the magnesium salt of
ethyl acetate. 9 An alternative procedure for preparing the intennediate con-
sists of carbethoxylation of acetophenone 20 with methylmagnesium car-
bonate. 10 Condensation of 21 with ethyl orthofonnate in the presence of base
leads to the fonnyl derivative 22. This is then reacted with the appropriate
amine to provide the quinoline nitrogen in the fonn of an enamide (23),
probably by an addition-elimination sequence. Treatment of this intenne-
diate with a strong base, such as sodium hydride, fonns the anion on nitro-
gen. This undergoes an internal aromatic nucleophilic displacement to fonn
the quinolone ring 24. Reaction of this compound with the selected second-
ary amine results in a second aromatic nucleophilic displacement reaction
to afford 25 (Y=NR 2 ); the presence of the para carbonyl group activates
the halogen at 7 to displacement. Saponification of the ester groups lead to
the quinolone antibiotic 26 (Y = NR 2 ).
The order in which the steps are carried out can be changed. Thus aro-
matic nucleophilic displacement on 20 with 2-methylpiperazine affords in-
tennediate 27. The secondary amine group is protected as its tert-butoxy-
carbonyl derivative; carbethoxylation of the acetophenone function leads to
the intennediate 28. This is then taken through the sequence depicted above;
deprotection affords the antibiotic temafloxacin (37). 11
An alternate route to the key enamide consists of direct acylation of an
enamide. For example, reaction of the benzoyl chloride 29 with 30 in the

124 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
0 0
FC02H F C0 2 Me F
I'  
/"
r r F r
X X X
1 9 2 1 20
0 0 0
r C0 2 Me r C0 2 Me r C0 2 Me
+- 
F F NH F
X X I X
R
24 23 22

0
F CO R'
2
Y
X
25, R-Me, Y-NR 2
26, R=H. Y=NR 2
0 0
r r COllie
20  r N · r N
HNy fBOCNy
27 28
FCOCI C02)(e F C0 2 Me
I' + > "
/. C I 'NH
C I C I NH C I
29 L L
30 3 1

1. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING ONE RING HETEROATOM 125
./
TABLE 1
0
F C0 2 H
Y
X
R X Y
# (Ref)
32 (6)
33 (7)
34 (8)
35 (9)
3 6 (1 0 )
37 (11)
3 8 (1 2 )
3 9 (1 3 )
USAN
Lomeflo:xacin
Binaf 1 oxac in
Enroflo:xacin
Danfloxacin
Saraflo:xacin
Temaflo:xacin
Fleroxacin
Cl inaf lox&cin
C 2 H 5
H
r\
N NH
'----\
l()'N
'--/
C 2 H 5
H
<J
r\
N NC 2 H 5
\........J
H
<J
NNC2H5
H
4-FC e H,
r\
N NH
\........J
H
2.4-F 2 C e H 3 H
r\
N NH
'----\
FCH 2 CH 2
F
r\
N NCH s
\........J
<J
N:=l.NH
2
r

126 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
presence of triethylamine leads directly to 31. 8 Cyclization, followed by
displacement of the chlorine at 7 by N-ethylpiperazine and finally saponifi-
cation gives enrofloxacin (34). 8
Addition of a second nitrogen atom on the fused benzene ring depends
on the different reactivities of the fluorine atoms on the 5 and 7 positions.
The starting material, 40, is presumably prepared from pentafluorobenzoic
acid by the standard sequence. Nucleophilic aromatic displacement on this
compound with benzylamine in an aprotic solvent, in this case toluene, leads
to displacement of the fluorine at the 5 position and fonnation of 41. This
is then converted to the primary aniline 42 by removal of the benzyl group
by hydrogenation over palladium on carbon; acetylation gives the amide 43.
A second nucleophilic aromatic displacement reaction, this time using 2,6-
dimethylpiperazine in the polar solvent ethanol, leads to replacement of the
fluorine at the 7 position and fonnation of 44. Saponification using sodium
hydroxide removes the N-acetyl and ester groups, and sparfloxacin (45)14
is thus obtained.
r 0 RBN 0 RBN 0
F C0 2 Et r C0 2 1t r C0 2 R'
 ---+ YN
F r
r F HNy F
40 4 1 , R-PhCH 2
44, R-Ac, R'-It
42, R-B
45, R-R'-H
43, R-Ac
The synthetic route for fonning the quinolone antibiotics is sufficiently
versatile that it can be applied to analogues in which the fused benzene ring
is replaced by pyridine. An analogue that incorporates nitrogen in both fused
rings, tosulfoxacin (47), is prepared from pyridine 46 using the general
route outlined above. 15
o 0
F  II C02Et F )fX) "
I I" I
,/    ,/
Cl N 46 Cl 9 N F
H 2 N Y
F
47

1. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING ONE RING HETEROATOM 127
The very potent, broad spectrum activity of the quinolone antibiotics has
led to an unusually detailed investigation of the SAR in this series, which
has resulted in the synthesis of inumerable analogues. One result of this
investigation is the finding that fusion of an additional ring onto the quin-
alone nucleus is quite compatible with activity. In a sequence used in earlier
routes to these compounds, tetrahydroquinoline 48 is condensed with meth-
oxymethylenemalonate in the presence of polyphosphoric acid. The reaction
can be rationalized as involving replacement of the methoxyl by the tetra-
hydroquinolone nitrogen and Friedel-Crafts acylation of the benzene ring,
though the order of the steps may in fact be reversed. The product tricyclic
ester 49 is then saponified to afford the antibiotic ibafloxacin (50).16
F
Et02CC02Et
"
+ OCH
3
F
C0 2 R
:>
H 3 C
H 3 C
48
49, R=Et
5 0, R = H
The most prominent functionality shared by the quinolone antibiotics is
the presence of the electrophilic Michael acceptor ene-dicarbonyl array. In-
dependent work has shown that this array is not actually involved in the
mode of action of these agents. Support for this conclusion comes from the
observation that replacement of the carboxy lie ester by a sulfoxide function
leads to an antihypertensive agent apparently devoid of antibacterial activity.
Acylation of the aniline function in 51 by means of methyl fonnate leads to
fonnamide 52. Thennolysis of this intennediate in hot ethylene glycol mono-
methyl ether brings about aldol condensation of the fonnamide carbonyl
with the activated side-chain methylene group. There is thus obtained the
antihypertensive agent flosequinan (53). 17
a
o
o
r
saCH 3
r
saCHS
r
saCHS
>
>
5 1
52
53

128 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
Although the majority of antiarrhythmic agents are based on hindered
amides related to the local anesthetics, several agents that depend on ami-
noalkyl ethers of phenols have also shown promising activity. Friedel-Crafts
acylation of 2,6-xylenol with the chromone acid chloride 54 leads to the
ketone 55 which on alkylation with 3-chloro-N,N-di-n-butylamine, affords
bucromanone (56).18
O¥COC 1

II
o
>
CH 3
OH
CH 3
54
55
/
CH 3
O(CH 2 )3 N (nC 4 H g )2
CH 3
56
The large amount of research devoted to the -blockers was chronicled
in the earlier volumes in the series and to lesser extent in Chapter 2 of this
book. It has been established that the ethanolamine function characteristic
of this class can be attached to a benzofuran ring (bufuraloI 19 ). Replacement
of that heterocycle by benzopyran more closely mimics the classical {3-
blocker oxypropanolamine side chain; in this case the molecule is interest-
ingly doubled. Catalytic hydrogenation of chromone 57 reduces both the
double bond and the carbonyl group to afford benzopyran 58. The carboxylic
acid is then reduced with DIBAL to the aldehyde 59. Reaction of this in-
tennediate with the ylide from trimethylsulfonium iodide leads to the oxirane
60. This is then used to alkylate benzylamine to afford the bis-alkylation
product 61, a compound with four chiral centers. Hydrogenation with pal-
ladium on carbon removes the benzyl protecting group to give the -blocker
nebivolol (62).20
A benzopyran provides the nucleus for the leukotriene antagonist ablu-
kast (71). The synthesis of this agent starts with the preparation of chromone
(64) by cyclization of dihydroxyacetophenone (63) with diethyl oxalate.
Exhaustive catalytic hydrogenation leads to the benzopyran 65. Friedel-
Crafts acylation then gives the acetyl derivative 66. The free phenol is

1. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING ONE RING HETEROATOM 129
>'
o
:>
COR
o
C0 2 H
F
F
F
57
58, R=OH
5 9, R = H
60
/
o
OH R
N
OH 0
F F
61, R=PhCH 2
6 2, R = H
alkylated with 5-acetoxy-l-bromopentane to give the phenol ether 67. The
tenninal ester grouping is saponified and the resulting alcohol converted to
a good leaving group by reaction with methanesulfonyl chloride to give 68.
In a convergent scheme the starting acetophenone 63 is converted to the
propyl derivative 69 by the same scheme used to prepare 113 in Chapter 2.
Alkylation of this phenol with mesylate 68 proceeds on the less-hindered,
nonchelated hydroxyl to give 70. Saponification of the ester group in this
last intennediate gives ablukast (71).21
63
o
ro -CO
 1/ 1 --. 1/
HO 0 C02 E t HO 0 C02 Et
64 65
o

HO O,1 C02 Et
66
o

HOOH
W HO 0
I'" 
/ 0 1/
o (C H 2)5 0 C02R ·
70, R = Et
71, R = H
1
o

RO(C H 2)S OO..l C02 Et
69
67, R = Ac
68, R = S02Me

130 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
2. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING TWO
HETEROATOMS
The pyridazinone ring serves as a cardiotonic phannacophore in a large
variety of benzoheterocycles, several of which are discussed in earlier chap-
ters. Attachment of that ring onto a benzopyrimidinone is quite consistent
with activity. Condensation of diamine 72 with carbonyl dimidazole leads
to the bicyclic intennediate 73. This is then acylated in the usual way with
the half-acid chloride, half ester of succinic acid to give keto ester 74.
Reaction with hydrazine fonns the pyridazinone ring. There is thus obtained
prinoxodan (75).22
CH S 0 2 C
NCH 3
NO
H
GC:NHCH 3
NH 2
-----+
cc ' NCH3
/" 
N 0
H
)I
72
73
o
/
74
NCH s
NO
H
75
Leukotriene antagonist activity also seems to be consistent with a variety
of heterocyclic nucleii. The quinazolinone tiacrilast, 79, shares little but an
acidic proton with most agents of this class. Condensation of the ortho
anthranilate 76 with fonnamide leads to fonnation of quinazolinone 77; the
reason for the unusual location of the double bond in the product is not
readily apparent. Alkylation of the anion from the amide nitrogen with methyl
3-chloroacrylate gives the eneamide 78, probably by an addition-elimination
sequence. Saponification of the ester group completes the synthesis of ti-
acrilast (79). 23
CHSS  C02CHS
I'
/.
NH 2
o
CHSS 'C( NH
)I I /. 
N
o
CHSS 'C( NC02R
)I I /. 
N
76
77
78. R=CH s
'79. R-H

2. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING TWO HETEROATOMS 131
A deceptive simple quinazolinone devoid of the ubiquitous pyridazinone
function also shows cardiotonic activity. One synthesis for this compound
starts from the tonnage chemical vanillin 80. The free phenol group is first
protected as its benzenesulfonate 81; nitration gives the expected mixture of
products in which the desired isomer, 82, predominates in a 2 to 1 ratio.
The protecting group is then removed by hydrolysis and the resulting free
phenol alkylated with methyl iodide to give 84. The aldehyde group is then
oxidized to the acid 85. Reaction of the corresponding acid chloride with
diethylmalonate followed by treatment with sodium hydroxide leads to bis
decarboxy lation of the intennediate acylation product to afford the methyl
ketone 86. The nitro group is then reduced (87) and the resulting aniline
converted to the carbamate 88. Reaction of 88 as a melt with ammonium
acetate fonns the quinazolinone ring, and bemarinone (89)24 is thus ob-
tained.
RO RO CH 3 0
CHsO'&CH-O CH30'OCH-O CH 3 0'QC0 2 H
" :. 1/ :. I'
/ /
N0 2 N0 2
80, R=H 82, R=S02 Ph 85
81, R=S02 Ph 83, R-H
84, R-CH 3 1
CH 3 0 CH s
CH30 'CC
' 'N
1/ 
N 0
H
1(
CH 0 CH 3
CH S 0 1G( ' ....0
I 0 +--
/ N)-.J... 0 C H s
H
tc CH30 0
CH 3 0
I ; CH s
NR 2
89
88
86, R-O
87, R=H
Diabetes, particularly if it is uncontrolled, leads to profound changes in
body chemistry. The buildup of excessive levels of the enzyme aldose re-
ductase is one of the more insidious changes which leads to accumulation
of the sugar reduction product sorbitol in the lens of the eye, a condition
that leads to loss of vision. Considerable research has consequently been
devoted to developing inhibitors of aldose reductase. Two compounds based
on the phthalazine nucleus have shown activity against this enzyme. Reac-
tion of phthalic anhydride with the ylid from ethyl triphenylphosphonium

132 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
acetate leads to condensation of the reagent with one of the carbonyl groups
to fonn ester 90. Reaction of that intennediate with hydrazine fonns the key
phthalazine 91. The methyl group in benzothiazole 92 is then brominated
in a convergent scheme to give 93. Alkylation of the amide nitrogen in 91
with 93 affords zolporestat (94).25
erS C02C2H5
I" 0
,/
\
o
:.
....... N
I
NH
o
>--
0: ..... CIIOzCzH5
I I N  CF3
,/ N"--./ ,/
 I
os"
90
9 1
N  CF3
RH 2 C-(; ,/ I
s "
94
92 I R-H
93 I R-Br
Alkylation of the phthalazine 91 with substituted benzyl bromide 95 in-
stead of a benzothiazole gives the aldose reductase inhibitor ponalrestat
(96).26
91 + BrHzC V Br
F

CO Z C Z H5
Br
o
F
95
96
The incorporation of polar substituents into imidazolines to restrict
a-adrenergic antagonists to the periphery was noted earlier in the discussion
of aproclonidine (73, Chapter 5). The quinoxaline serves as the polar func-
tion in the antiglaucoma agent brimodine (99). The bromine substituent at
the a-position may provide the steric hindrance required to hold the imi-
dazoline orthogonal. Reaction of the amino group in 97 with ammonium
isothiocyanate leads to the thiourea 98; condensation with ethylenediamine
then affords brimodine (99).27

2. SIX-MEMBERED BENZOHETEROCYCLES CONTAINING TWO HETEROATOMS 133
Br Br H N 
N0NH2 :0N'1fNH2
I ..... " N: : '[J
./ ./ :. ::.
N
97
98 99
The breadth of the SAR of the cardiotonic activity of pyridazinone car-
diotonic agents is reinforced by the finding that activity is retained when the
ring is attached to a benzomorpholinone ring. Mannich reaction with di-
methylamine and fonnaldehyde on propiophenone 100, which may come
from acylation of benzomorpholinone, affords the dimethyl amino methyl de-
rivative 101. This is converted to the quaternary methiode 102. Reaction of
that intennediate with cyanide may proceed to the nitrile 103 by direct
displacement of trimethylamine. Alternatively, the quaternary salt may first
undergo elimination to the unsaturated ketone; conjugate addition of cyanide
would then afford the same product. Hydrolysis of the nitrile function then
yields the keto acid 104. Ring closure with hydrazine completes the synthesis
of bemoradan (105).28
o
II 0
H31
; N 0
H
(CH 3 )n NCH 2
o
N10
H
:>
100
101. n=2
102. n=3.(+)I-
1
R
:1 0
H
o
N)O
H
<
105
103. R=CN
104. R-C0 2 H

134 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
The majority of the "spirone" anxiolytic agents derived from buspirone
retain the pyrimidopiperazine moiety of the original drug (see tiospirone,
74, et. seq., Chapter 6). Replacing that moiety with an aminomethyl group
but retaining the spiroglutarimide of the parent still maintains anxiolytic
activity. Reaction of catechol with a-chlorocyanoacrylate gives the benzo-
dioxane 106. Catalytic reduction of the double bond (107) followed by
treatment with lithium aluminum hydride leads to the aminomethyl deriva-
tive 108. In a convergent scheme, the spiroglutarimide is then alkylated with
I-bromo-2-chloroethane to give intennediate 110. Use of the latter to al-
kylate amine 108 affords the tranquilizer binospirone (111).29
0 ° Jr CN
I'" I
/.
°
-----+
0 0 r R
°
106
10'7, R-CN
>-
0 0 ) M-F:
I '" H °
/.
o
108, R-CH 2 NH 2
111
H:
/
o
- -F:hv-,
CI 
o
109
11 0
Addition of an oxygen atom to the dimeric J3-blocker nebivolol, 62, by
replacing the benzopyran with a benzodioxane ring, retains the adrenergic
blocking activity of the parent. Alkylation of salicylaldehyde with trans-
1,4-dichloro-2-butene gives the phenol ether 112. Oxidation of this com-
pound with m-chloroperbenzoic acid converts the olefin to an oxirane and
at the same time effects a Baeyer- V illiger reaction on the aldehyde to convert
the group to a phenolic fonnyl ester 114. Saponification with mild base leads
to the corresponding phenoxide. This attacks the reactive oxirane intramo-
lecularly to fonn a benzodioxane ring; the resulting alkoxide then displaces
the chlorine on the adjacent carbon to restore an oxirane function, now
moved over by one bond (115). This oxirane is then converted to the dimeric
ethanolamine bendacalol, 117, in the same manner as its benzopyran ana-
logue. 3o

3. BENZENE FUSED TO SEVEN-MEMBERED RING HETEROCYCLES 135
G( 0C 1
1/
CH=O
----+
o
00Cl
OR
GC:
:.
112
113, R-CHO
114, R-H
115
/
GC::::cD
116, R-CH 2 Ph
117, R-H
3. BENZENE FUSED TO SEVEN-MEMBERED RING
HETEROCYCLES
The prototype for angiotensin-converting enzyme inhibitors, captopril, con-
tains proline as a central structural element. Extensive research in this series
had led to a large number of ACE inhibitors which involve other, apparently
quite different, ring systems. The synthesis of an ACE inhibitor based on a
benzazepinone starts by chlorination of lactam 118 to the dichloro derivative
119. Catalytic reduction removes one of the gem chi oro substituents to give
120; the halogen is then displaced with sodium azide to give intennediate
121. Alkylation of the amide with ethyl bromoacetate in the presence of
base yields the ester 122. Hydrogenation then converts the azide to an amino
group (123); that intennediate is then resolved by classical salt fonnation
and crystallization. Saponification of the S enantiomer, 124, with sodium
hydroxide affords amino acid 125. Reductive alkylation of that intennediate
with keto ester 126 and sodium cyanoborohydride gives the desired product
as a 70: 30 mixture of diastereoisomers; the enantiomeric excess is due to
the proximity of the ring chiral center. Isolation of the predominant isomer
gives benazepril (127).31
An unusual nitrogen-bridged dibenzoheptane acts as an antagonist to the
hallucinogen PCP. However, the anticonvulsant action of the compound is
of more direct therapeutic interest. Reaction of dibenzocycloheptenone 128
with methylmagnesium bromide proceeds to give the methyl carbinol 129.
Condensation of that alcohol with hydroxylamine leads to replacement of

136 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
Rl
w-l'R2
N 0
H
:.
G(}R
N 0
H
:.
G(}R
N 0
(
C0 2 E t
IlB, R1_R2_H
119, R 1 =R 2 =CI
120, R-CI
121, R=N 3
122, R-N s
123, R=NH 2
GO H C0 2 Et
I '" OIIiN-!
/. '",
N°h
(C0 2 H (;)
C0 2 Et
-I
0-_
' 

<
126
GO"'IHH2
N 0
(
C0 2 R
127
124, R-Et
125, R=H
the activated bisbenzylic tertiary alcohol to fonn 130, almost certainly via
the carbocation. Cyclization of that intennediate by unspecified means leads
to an unusual addition of nitrogen to the transannular double bond and
fonnation of the bicyclic nucleus. Catalytic hydrogenation converts the hy-
droxylamine function to a secondary amine, and dizocilpine (132)32 is thus
obtained.
=- :.
0 H 3 C R CH 3
1 2 B 129, R-OH 1 3 1 . R=OH
130, R-NHOH 132, R-H
The benzodiazepines have a venerable history as CNS agents, and more
specifically as anxiolytic drugs. It is interesting that transposing the phenyl
substituent from the position adjacent to the fused benzene ring and changing
the heterocyclic ring to aI, 3-diazepine yields a compound that has antide-
pressant activity. The synthetic sequence starts by protection of the amine
in 133 as its tBOC derivative 134. Reaction of that compound with butyl-
lithium affords the corresponding benzyl anion; this adds to the Schiff base

3. BENZENE FUSED TO SEVEN-MEMBERED RING HETEROCYCLES 137
from benzaldehyde and methylamine to give the phenethylamine 135. The
protecting group is then removed to give diamine 136. Condensation of that
intennediate with ethyl orthoacetate closes the benzodiazepine ring, and
dazepinil (137)33 is thus obtained.
(): NHR
I'
/"
CH 3
::.
::.
N
NCH 3
133. R-H
134. R=COztBu
135. R=COztBu
136. R=H
137
Peptides are very difficult to develop as drugs because they are often
poorly bioavailable and are subject to rapid metabolism. Consequently,
translating into drug therapy the enonnous strides made in recent years in
detennining the structures of biologically active peptides and developing
antagonists for those compounds is a slow process. The parallel detenni-
nation of the detailed three-dimensional structure of peptide receptor sites
has however made it possible to design topological analogues of those pep-
tides that have quite different connectivities. The design of an orally effective
benzodiazepine, which acts as an antagonist to the peptide cholecystokinin
(CCK) at peripheral receptors, is one of the first recorded successes of this
strategy. The synthesis of this agent starts, as do many benzodiazepine
preparations, with the chloroacetamide 138. Finklestein reaction gives the
corresponding iodide 139; treatment with hydroxylamine gives 140. Cycli-
zation of that intennediate leads to the N-oxide 141. The N-oxide function
is then used to oxidize the adjacent methylene group. Thus reaction of 141
with acetic anhydride leads to the acetate 142 by means of the Polonovsky
rearrangement. The acetate is then saponified and the resulting alcohol con-
verted to the chloro derivative 143 by means of thionyl chloride. Displace-
ment with ammonia gives the amine 144. This is then acylated with indole-
2-carboxylic acid to give 145. Methylation of the anion obtained from 145
by treatment with sodium hydride and methyl iodide completes the synthesis
of devazepide (146).34
The synthesis of the chlorinated analogue of the well-tried calcium chan-
nel blocker diltiazem (deschloro 153) involves a stereoselective adaptation
of the route used for the original drug. Thus condensation of the thiophenol
147 with the chiral glycidate 148 affords a mixture of regioisomers. The
desired hydroxy ester 149 is separated from that mixture and reduced cata-
lytically to the amine 150. That product is then cyclized thennally to the

H
NY'R
o
=-
:>
H
N1-R
-N
1 3 8 , R-Cl 141 142, R=OAc
139 , R = I 143. R=Cl
140. R=NHOH 144, R-NH 2
!
CH 3 H
ki--N < Ni--N
- N I I I - N I I I
o N ,/ o N ,/
H H
146
145
+ 0
=-
Cl 'O S
I OH
/'
NR 2 C0 2 CH 3
OCH 3
C1 'C! SH
I'
/.
N0 2
OCH s
" C 0 C H
2 3
147
148
Cl 'O S
I'
/'
N 0
\
N(CH S )2
OCB s
149, R=O
150 t R=H
!
<
CI 'O S
I'
/'
N
H
OCB s
o
151
152, R-H
153 t R-Ac
138

REFERENCES 139
lactam 151. Alkylation of the anion from treatment of the amide with base
with 2-chlorothyldimethylamine gives intennediate 152. Acylation by means
of acetic anhydride affords the calcium channel blocker clentiazem (153).35
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106,196291 (1987).
16. R. M. Stem, Eur. Pat. Appl. 109284 (1984); Chern. Abstr., 101, 110764 (1984).

140 SIX- AND SEVEN-MEMBERED BENZOHETEROCYCLES
17. L. Maclean, D. L. Roberts, K. Barron, K. J. Nichol, and A. E. Harrison, Eur.
Pat. Appl. 317149 (1989); Chern. Abstr., 111, 232593 (1989).
18. C. Nicolas, M. Vemy, J. C. Maurizis, M. Payard, and M. Faurie, J. Labeled
Corn pd. Radiopharm., 23, 837 (1986).
19. D. Lednicer and L. A. Mitscher, Organic Chernistry of Drug Synthesis, vol.
2, Wiley, NY, 1980, p. 110.
20. G. R. VanLommen, M. F. L. De Bruyn, and M. F. J. Schroven, Eur. Pat.
Appl. 145067 (1985); Chern. Abstr., 104, 5773; Drugs Future, 14, 957 (1989).
21. S. P. Manchand, R. A. Micheli, and S. J. Saposnik, Tetrahedron, 48, 9391
( 1992).
22. D. E. Kuhla, H. F. Campbell, W. L. Studt, W. C. Faith, and B. F. Molino,
PCT Int. Appl., 8703201 (1987); Chern. Abstr., 108, 6037 (1988).
23. V. Aguire Onnaza, Spanish Patent 549881 (1986); Chern. Abstr., 107, 236726
(1987).
24. J. B. Press, V. T. Bandurco, E. M. Wong, G. Z. Hajos, R. M. Kanojia, R.
A. Mallory, E. G. Deegan, J. J. McNally, J. R. Roberts, M. L. Coffer, D.
W. Gradan and J. R. Lloyd, J. Heterocycl. Chern., 23,1821 (1986).
25. B. L. Mylari, E. R. Larson, T. A. Beyer, W. J. Zembrowski, C. E. Aldinger,
M. F. Dee, T. W. Siegel, and D. H. Singleton, J. Med. Chern., 34, 108 (1991).
26. D. R. Brittain and R. Wood, Eur. Pat. Appl. 2895 (1979); Chern. Abstr., 92,
76533 (1980).
27. J. T. Pento, Drugs Future, 10, 578 (1985).
28. D. W. Combs and J. P. Demers, PCT Int. Appl. 9211256 (1992); Chern.
Abstr., 118, 38933 (1993).
29. M. Hibert and M. W. Gittos, Eur. Pat. Appl. 170213 (1986); Chern. Abstr.,
105, 24193 (1986).
30. C. F. Huebner and H. W. Gschwend, U.S. Patent 4380653 (1983); Chern.
Abstr., 99,53771 (1983).
31. J. W. H. Watthey, J. L. Stanton, M. Desai, J. E. Babiarz, and B. M. Finn,
J. Med. Chern., 28, 1511 (1985).
32. D. R. Bender, S. Karady, and T. Rothauser, Eur. Pat. Appl. 91071 (1983);
Chern. Abstr., 101, 23329 (1984).
33. G. E. Lee and T. B. K. Lee, Eur. Pat. Appl. 66773 (1982); Chern. Abstr., 98,
197754 (1983).
34. B. E. Evans, K. E. Rittle, R. M. DiPardo, R. M. Freidinger, W. L. Whitter,
G. F. Lundell, D. F. Veber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D.
J. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P. Springer and J.
Hirschfield, J. Med. Chern., 31, 2235 (1988).
35. H. Inoue, M. Konda, T. Hasiyama, H. Otsuka, K. Takahashi, M. Gaino, T.
Date, K. Aoe, M. Takeda, S. Murata, H. Narita and T. Nagao, J. Med. Chern.,
34, 675 (1991).

CHAPTER 9
BICYCLIC FUSED HETEROCYCLES
1. FIVE-MEMBERED HETEROCYCLES FUSED TO PYRIDINES
As noted earlier in this volume, aromatase inhibitors promise to have ap-
plication in the treatment of estrogen-dependent neoplasms by diminishing
the endogenous conversion of androgens to estrogens. The great majority of
those agents consist of modified steroids or derivatives of aminogluteth-
emide. The imidazopyridine fadrazole, 10, represents a marked departure
from those structural types. The synthesis of this agent starts by conversion
of the arylpiperidine 1 to its N-oxide. Treatment with cyanide in dimethyl
sulfate leads to introduction of a cyano group at the 2-position in a reaction
reminiscent of the Polonovsky rearrangement; an intennediate N-O sulfate
may playa role in this reaction. The newly introduced nitrile group is then
reduced to the primary amine (4) and this is acylated to give the fonnamide
5. This intennediate cyclizes to fonn the imidazole 6 on treatment with
POCI 3 . Catalytic hydrogenation of this product leads to apparently selective
reduction of the pyridine ring to afford 7. The ester group in the intennediate
is then saponified (8) and converted to the amide 9 via its acid chloride.
Treatment of the amide with POCl 3 leads to dehydration of the amide to a
nitrile. The aromatase inhibitor fadrazole (10) 1 is thus obtained.
A more highly reduced imidazopyridine which bears some structural re-
semblance to the classical immunoregulatory 6-phenylimidazothiazole lev-
amisole retains the same activity. Treatment of the heterocycle 11 with
butyllithium leads to lithiation on the six-membered ring at the position ex
141

142 BICYCLIC FUSED HETEROCYCLES
:)
CN
:)
::.
MRR
C0 2 Et C0 2 E t C0 2 Et C0 2 Et
1 2 3 .. , R-H
5 , R-CH-O

c:
I(
I(
CN COR C0 2 Et C0 2 Et
1 0 B I R-H 7 S
9. R-NH 2
to the carbon at an acid oxidation stage. Exposure of the anion to diphenyl
disulfide gives the sulfide 12. Oxidation of 12 by means of Chloramine T
in methanol leads to the dimethyl acetal 13, oxamisole.
....C 8 "6
s H 3 C (;3-v
(r-> (, ';; ::. a->-v ::.
1 1 12 13
The amide from the acid of a fully unsaturated analogue of 13 interest-
ingly displays anxiolytic activity. Reaction the acid 14, whose synthesis is
not described, via its acid chloride with disopropylamine gives aldipem
(15). 3
C 1
:>
N
C I N_I
C 1
CON(iPr)2
1 4
1 5

1. FIVE-MEMBERED HETEROCYCLES FUSED TO PYRIDINES 143
The highly substituted nicotinaldehyde vitamin precursor pyridoxal pro-
vides the starting material for an antihypertensive agent. Condensation of
the acetal 16 from pyridoxal and acetone with 4-chlorophenylmagnesium
bromide gives the addition product 17. Reaction of that with strong acid
probably leads initially to the hydrolysis product 18, which is not observed
per see The benzylic hydroxyl group probably eliminates to give the car-
bocation under the strongly acid conditions. Addition of the adjacent primary
hydroxyl group leads to fonnation of the hydrofuran ring, and cicletanine,
(19)4 is thus obtained.
0'><-0 0'><-0 80 HO
HsC{i HsC HsC HsC
I' ----+ ----+ 
N/ C H - 0
16
C 1 C 1 C 1
17 1 B 19
The by-now familiar aryl piperazine group leads to a neuroleptic com-
pound when attached to a triazolopiperidine nucleus. One of the starting
materials for the synthesis of this agent may well be derived initially from
the Michael addition product from o-tolyl piperazine 23 and methyl acrylate.
Hydrazinolysis of the product would give 21. Condensation of that inter-
mediate with the iminoether 20 from piperidone leads directly to the con-
densed heterocyclic system. The reaction may start with the addition-elim-
ination of the tenninal hydrazide nitrogen to the iminoether. Cyclization
of the carbonyl group with the now basic ring nitrogen completes the scheme.
There is thus obtained the antipsychotic compound dapiprazole (24).5
20
B 2 N, H C
NH s
OJ-.CH2CH2H)  '1
2 1
cr;N HsC
\ l\ u M
CB2CH2N'--IN
r'/(0CH S
N +

2.
CHsO
04 +
I\ HS
HN'--IN
22
23

144 BICYCLIC FUSED HETEROCYCLES
The more recent antiallergic antihistamines depart quite markedly from
the ethylamine derivative structures typical for this activity. A detailed pe-
rusal of the imidazopyridine nobevastine, 28, will reveal vestiges of that
grouping in the aminopiperidine side chain. The starting material, 25, is
probably obtained by alkylation of the unsubstituted imidazole with 5-methyl-
2-chloromethyl furan. Reaction of that compound with the protected ami-
nopiperidine 26 results in displacement of the halogen on the imidazole by
the primary amino group to fonn the alkylation product 27. Acid hydrolysis
of the product removes the protecting group to afford noberastine (28). 6
CH3
N N
;>-C I + H2N-CNC02E t
CH3
N N
 ri°'::Y- I>-N -C NR
N H
25 26
27 I R-C0 2 Et
2 8 I R = H
2. FIVE-MEMBERED HETEROCYCLES FUSED TO PYRIMIDINES
The imidazopyrimidine natural product theophylline, 29, has been used as
an antiasthmatic bronchodilator for well over half a century. The undoubted
efficacy of this drug is unfortunately compromised by a very narrow thera-
peutic index and a host of side effects within the effective dosage range.
There has thus been in existence a long-running effort to find congeners that
are better tolerated. Alkylation of theophylline with the acetal 30 from
bromoacetaldehyde affords the bronchodilator doxofylline (31). 7
o
II H
H3 C 'N Jr N
l I /)
o N N
I
CH 3
o
+r<J
Br 0
:>
o
o r-< J
H3 C 'N Jr II N 0
l I /)
all N N
I
CH 3
30
29
3 1
Theophylline also provides the nucleus for a compound described as a
veterinary sedative. The starting material, 32, for this derivative can be
obtained from 29 by alkylation with I-bromo-2-chloroethane. Displacement
of the remaining halogen by the more basic amine on piperidyl indole, 33,
leads to the alkylation product tameridone (34). 8

2. FIVE-MEMBERED HETEROCYCLES FUSED TO PYRIMIDINES 145
:5 0 ,cR2CR2C 1
HsC'N H
 I /) +
o K H
I
CH 3

:5 0 ,cB2CH2N
HSC'N N
 I /)
o N N
I
CH 3
32
33
34
As noted in more detail in Chapter 6, the majority of the modified pyrim-
idine nucleosides developed as drugs show activity as antiviral or antineo-
plastic agents. Much the same holds true for the purine (imidazopyrimidine)
nucleosides. Oxidation of the carbon atom at the 2 position of the fused
pyrimidine ring changes the activity to that of an immunostimulant. Dis-
placement of the halogen atom on 2-bromoguanosine with the anion from
allyl alcohol affords the corresponding ether 36. This intennediate undergoes
Claisen rearrangement on heating to afford the N-allyl compound; bond
reorganization leads to a carbonyl function at the 2 position. There is thus
obtained loxoribine (37). 9
0 o  1 0 ;/
HN:k N HNN,>-o
HN:k N
 I ,>-Br  I )= 0
H 2 N N N H2NN N H 2 N N N
HO :) HO :) HO
HO OH
HO OH
HO OH
35
36
37
Omission of the 3 hydroxyl group from the ribose moiety of nucleosides
often results in compounds that exhibit antiviral activity. The best known
case is of course the pyrimidine nucleoside zidovudive (AZT) in which the
hydroxyl is replaced by an azide group. Complete omission of hydroxyl
groups at 2 and 3 in purine nucleosides has led to a series of antiviral agents,
some of which are effective against HIV. Reaction of inosine 38 with
a-acetoxyisobutyryl bromide leads to a complex series of reactions. The
bromine in this reagent is sufficiently active to displace a ring hydroxyl at
2 or 3; it also serves to protect the primary hydroxyl at 5' as a complex
acetal (R I = Z). There is consequently obtained a mixture of the bromoh-
ydrins 40 and 41; the stereochemistry on the sugar is undefined. Treatment
of the mixture with zinc copper couple leads to elimination of bromohydrin
and fonnation of the olefin 42. Reduction of the double bond (43) followed

146 BICYCLIC FUSED HETEROCYCLES
o
Jr " N
HN, I '>
l:N N
o
H C 'X "
3 Br
+
H 3 C OCOCH 3
o
Jr l' N
HN, I '>
l:N N
>
HO
39
RiO
HO OH
38 40, 123
R =Z,R =Br,R =OH
4 1 , 123
R =Z,R =OH,R =Br
1
0 0
N N
HN, I '> < HN, I '>
0V: H3 l:N N l::: N N
Z = H 3 C - RiO RiO
CH 3
43, R=Z
42
44, R=H
by acid hydrolysis of the acetal group leads to didanosine, 44,10 known
colloquially as 001.
The nucleoside analogue in which the ribose in guanosine is replaced by
a simple CH 2 0CH 2 CH 2 0H group, acyclovir, is a well-established antiviral
agent effective mainly against herpes viruses. Substitution of an additional
hydroxymethyl group on the surrogate sugar leads to a drug effective against
cytomegalovirus; this is particularly significant since this virus leads to loss
of sight in AIDS patients. Construction of the side chain begins with the
reaction of epichlorohydrin, 45, with the anion from benzyl alcohol. This
leads largely to the 1 ,3-bis-benzyloxy derivative 47, possibly via the epoxide
46. Chloromethylation of the free hydroxyl in 47 with fonnaldehyde and
hydrogen chloride gives the reactive intennediate 48. Reaction of 48 with
the tris trimethylsilyl ether 49 of guanine gives the N-alkylated product 50.
Removal of the benzyl groups by reduction with sodium in liquid ammonia
affords the antiviral ganciclovir (51). II

3. THIENOTHIOPYRANS 147
O{CI

O{ __
OCH 2 C e H 5
48
{ OCH 2 C e H 6
HO
OCH 2 C e H 5
{ OCH 2 C e H 5
---+ CICH 2 0
OCH 2 C e H 5
45
47
48
49
°
 If
If I '>
H2NN N
ROoJ
OR
t: + 48 --
KesSiIfH If 
SiKes
50, R-CH 2 C e H 5
51, R-H
3. THIENOTHIOPYRANS
Heterocyclic sulfonamides have a venerable history as diuretics which act
by inhibiting the enzyme carbonic anhydrase. The thiazole derivative ace-
tozolamide ranks among the first clinically useful diuretic agents. The find-
ing that the increased intraocular pressure related to glaucoma can be alle-
viated with carbonic anhydrase inhibitors led to the development of two
closely related thienothiopyran sulfonamides. Lithiation of thiophene leads
to the 2-lithio derivative 53; reaction with sulfur gives the lithio salt 54 of
the corresponding 2-thiol. This is treated without prior isolation with
3-bromopropionic acid to afford the alkylation product 55. Friedel-Crafts
cyclization by means oftrifluoroacetic anhydride gives the ketone 56. Exposure
to sodium periodate oxidizes the thiopyran sulfur to the sulfone. The car-
bonyl group is then reduced with a chiral oxazaborolidine hydride reagent
to give alcohol 58 in chiral fonn. Conversion of the tosylate 59 followed
by treatment with isobutylamine leads to the amine 60 by displacement of
the tosy late. The chirality is retained, although the amine now has the op-
posite configuration from the alcohol. Reaction with fuming sulfuric acid
serves to introduce the sulfonic acid function at the 2 position of the fused
thiophene. That intennediate is converted to the acid chloride with thionyl
chloride. Treatment with ammonia converts this to a sulfonamide and com-
pletes the synthesis of sezolamide, 61. 12
A related scheme is used to prepare the analogue dorzolamide, 68. Al-
kylation of the lithio derivative 54 with chiral 3-toluenesulfonyloxybutyric
acid affords the methylated thiopyran 62. This is cyclized as described above.

148 BICYCLIC FUSED HETEROCYCLES
10
R S
H0 2 C,
  J0
S S
0
 m
S S
R
58, R--
5 ? , R-0 2

OH
m
S S
°2
52, R-H
53, R-Li
54, R-SLi
55
58
I
HiBu
S02NH2
S S
O 2
NHiBu
V
--00
S S
O 2
c
&
s S
°2
6 1
60
59
The presence of a chiral center near the carbonyl group in 63 leads to the
alcohol 64 with good stereochemical control on reduction with lithium alu-
minum hydride. The ring sulfur is then oxidized to the sulfone as above.
Ritter reaction with acetonitrile leads to replacement of the hydroxyl by the
acetamide group with retention of configuration (66). This observation can
be rationalized by assuming the intervention of a double inversion with
stabilization of charged intennediates by the transannular prochiral sulfone
HO:) J0 ° OH
:> :> j):;>
S S S S
R
62 63 64, R=-
65, R.- 02
1
HCH2CH3 HCOCHs J}03
T S02NH2
S02 NH 2 < <
s s s S
°2 °2
67 66
68

4. PYRIDOPYRIDINES 149
group. The sulfonamide group is then introduced exactly as above. Reduc-
tion of the acetamide group to an ethylamine with lithium aluminum hydride
completes the synthesis of the carbonic anhydrase inhibitor dorzolamide
(68). 13
4. PYRIDOPYRIDINES
A pyridopyridone represents yet another cardiotonic agent that lacks the
ubiquitous pyridazinone pharmacophore. The starting pyridone 70 is pre-
pared by condensation of the enamine 69 obtained from acetylacetone and
ammonia with methyl propiolate. The reaction can be envisaged as conjugate
addition of the enamine to the acetylene followed by cyclization of the ester
group with the amino group. Reaction of the pyridone with a special version
of DMF acetal (Brederick's reagent) adds an extra carbon to the pyridone
methyl group in the aldehyde oxidation state (71). Reaction of this inter-
mediate with ammonium acetate leads to formation of the fused pyridine
ring. There is thus obtained medorinone (72). 14
+
NH 2 0
C0 2 Me
:>
69
70
I
<:
7 1
72
Cyclized analogues of open-chain biologically active compounds often
lead to equally or more active agents because the rigid versions provide a
better fit for the putative receptor. A case in point is the well-known an-
tiarrhythmic agent disopyramide, 73. Hydrogenation of that agent over
platinum catalyst reduces the pyridine ring to a piperidine. Acetylation of

150 BICYCLIC FUSED HETEROCYCLES
the product, 74, gives the acetamide 75. Treatment of that intennediate with
base leads the newly introduced acetyl group to condense with the adjacent
amide nitrogen. There is thus obtained the antiarrhythmic agent actisomide
(76). 15

----+
N(iPr)2
N(iPr)2
N(iPr)2
73
74. R-H
75. R-COCH s
76
The search for mediator release inhibitors as potential antiallergic and
antiasthmatic drugs covered many heterocyclic systems. Reaction of the
2-aminopyridine 77 with ethoxymethylene cyanoacetate gives the product
of addition-elimination, 78. Thennal cyclization leads to fonnation of pyr-
idopiperidone, 79. Treatment with sodium azide converts the nitrile to the
tetrazole characteristic of the potential mediator inhibitor and fonnation of
pemirolast (80). 6
Gr:jCN 0 o HN-\
Q jyCN Yl
1/   " " I 
NH 2 N
CH s CH H CH s CH s
s
77 78 79 80
The same bicyclic ring system provides the nucleus for an antipsychotic
compound. Friedel-Crafts acylation of 1,3-difluorobenzene with the a'cid
chloride from N-acetylpiperidine-4-carboxylic acid affords the ketone 81.
The acetyl group is then removed (82) and the ketone is converted to the
oxime 83. Treatment of that derivative with base leads to displacement of
fluorine by the oxime alkoxide and fonnation of a fused isoxazole ring 84.
Alkylation of this product with chloride 85 affords risoperidone (86).17
In much the same vein, alkylation of fully unsaturated pyridopyrimidine
87 with benzoylpiperidine 88 affords the veterinary muscle relaxant me-
trenperone (89).18 The fused heterocyclic starting material can, at least in
principle, by prepared by a scheme similar to that used to prepare 79, starting
with 2-amino-5-methyl piperidine and ethyl 2-(2-bromoethylacetoacetate),

4. PYRIDOPYRIDINES 151
F NOH F
---+ ----+
F F
81, R-COCH S 83
82, R-H
F
84
84
o
 Q)::N
N-O
I
o
Q)::Cl +
F
85
86
which is available by alkylation of ethyl acetoacetate with bromochloro-
ethane.
o
HscBr
__J1,.u +
N CH s
o
rN
HN V,
o
o rN
H3CN Vr
uJ1,.n
N CH s
----+
87
88
89
The pteridine folate antagonist methotrexate is one of the earliest cancer
chemotherapy agents. The efficacy of the drug combined with its extremely
poor tolerability has led to extensive investigation of the SAR aimed at
developing better drugs. It has been found that antineoplastic activity is
retained in the face of major changes in the structure. The analogue lome-
trexol omits the nitrogen atom in the reduced fused ring as well as that
on the position of the pendant benzene ring para to the carbonyl group. The
fused ring intennediate 91 which replaces the pteridine is prepared by con-
densation of diaminopyrimidone 90 with 2-bromomalonaldehyde. The free
amino group is then protected as its pivaloyl amide (92). Palladium-catalyzed
coupling with the sHyl ether from acetylene affords 93; the silyl group is
then removed with fluoride ion to give 94. In a convergent scheme, diethyl
glutamate is then acylated with 4-iodobenzoyl chloride to afford intennediate
95. A second palladium-catalyzed coupling involving the iodo group in 95
and free acetylene in 94 leads to the compound 96, which now contains the
completed carbon skeleton. Catalytic hydrogenation reduces both the acet-
ylene function and the pyridyl ring in the heterocyclic nucleus to give com-

152 BICYCLIC FUSED HETEROCYCLES
o
HN
H2N).lNH2
o 0
HNBr HN  R
RHNl:::NY-NJ - pVHNl:::NY-NJ

90
91, R=H
93, R-SiKe S
94, R - H
92, R=Pv
Pv- CO C(C HS)S
p
IN102Et
C0 2 Et
+ 94 
o
Ni02Et
CO 2 Et
95
96
/
o
CO R 2
HN-Z 2
CO R 2
2
1 2
97, R -Pv, R -Et
98, R 1 _R 2 _H
pound 97. Saponification removes the ester and amide protecting groups to
afford the antineoplastic agent lometrexol (98). 19
5. MISCELLANEOUS BICYCLIC FUSED HETEROCYCLES
Another pteridine, edatrexate (106), combines the full pteridine nucleus of
methotrexate with a deaza connecting link to the para aminobenzoic acid
moiety. One of the syntheses for this compound starts with the fully fonned
pteridine nucleus 99, which contains a bromomethyl group at the point of
attachment of the side chain. Reaction with triphenylphosphine leads to
phosphonium salt 100. Condensation of the ylide obtained on base treatment
of this with 4-carbethoxypropiophenone affords the olefin 101 as a mixture
of isomers, only one of which is shown below. When this intennediate is
hydrogenated in order to reduce the side-chain olefin, the pyrazine ring takes

5. MISCELLANEOUS BICYCLIC FUSED HETEROCYCLES 153
up hydrogen as well to afford 102. Treatment of that compound with hy-
drogen peroxide restores the ring to its desired oxidation state, 103. The
ester group is then saponified and the resulting acid, 104, condensed with
diethyl glutamate to give 105. Hydrolysis of the ester groups on the glutamyl
moiety than affords the antineoplastic compound edatrexate (106).20
NH2 NH2  C02Et NH2H  C02Et
NJvNCH2R NJvN I /. NN I /.
,l.R  -. ;.R: --+: II
H2N N N H2 N N N H2 N N N
H
102
101
99, R = Br
100, R = P + (C S HS)3
NH2
tR N
N....... ......
...... I .......
H2NN N
o
; C0 2 R
I' N
./ H
C02 R
I
NH2 rc? C0 2 R
Jc N 1./
+--- N....... "
...... I .......
H2N N N
105, R = Et
106, R = H
103, R = Et
104, R = H
Although it is built around a pyridooxazepine nucleus, the antihistamine
rocastine, 111, hews relatively close to the known SAR for such compounds
in that it includes an ethylamine side chain. The key reaction in the synthesis
of this compound involves an unusual rearrangement. Thus treatment of the
sodium salt 107 of the alkylation product from 2-chloronicotinic acid and
3-hydroxy-l-methylpyrrolidine with oxalyl chloride leads directly to the fused
bicyclic compound 110. The first step in this transfonnation no doubt in-
volves fonnation of acid chloride 108 as the first step. This transient inter-
mediate can then undergo internal acylation to fonn the bridged bicyclic
ammonium salt 109; attack by the chloride counterion on the two-membered
bridge will open that ring to give the observed product 110. Displacement
of the tenninal chlorine with dimethylamine leads to the fonnation of ro-
castine (111).21
N 0
Gl:oP
\
CH s

N 0 Q H: O /  N\ R
rI-;Y0 _--  >
, CI
o CH s 0 CH s
107, R=O-Na+
109
liD. R=CI
Ill. R-N(CH 3 )2
lOB. R=CI

154 BICYCLIC FUSED HETEROCYCLES
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9. J. Come, L. Burr, and R. Chen, Tetrahedron Lett., 32,4823 (1991).
10. V. Bhat, E. Stocker, and B. G. Ugarkar, Synth. Cornrnun., 22, 1481 (1992).
11. J. P. H. Verheyden, in Chronicles of Drug Discovery, D. Lednicer, Ed., ACS
Books, Washington, DC, 1993, p. 299.
12. T. K. Jones, J. J. Mohan, L. C. Xavier, T. J. Blacklock, D. J. Mathre, P.
Sohar, E. T. T. Jones, R. A. Reamer, F. E. Roberts, and E. J. J. Grabowski,
J. Org. Chern., 56, 763 (1991).
13. T. J. Blacklock, P. Sohar, J. W. Butcher, T. Lamanec, and E. J. J. Grabowski,
J. Org. Chern., 58, 1672 (1993).
14. B. Singh and G. Y. Lesher, J. Heterocycl. Chern., 27, 2085 (1990).
15. R. J. Chorvat, K. A. Prodan, G. W. Adelstein, R. M. Rydzewski, K. T.
McLaughlin, M. H. Stamm, L. G. Frederick, H. C. Schniep, and J. L. Stick-
ney, J. Med. Chern., 28, 1285 (1985).
16. P. F. Juby, U.S. Patent 4122274 (1978); Chern. Abstr., 90, 103998 (1979).
17. L. E. J. Kennis and J. Vandenberk, Eur. Pat. Appl. 196132 (1986); Chern.
Abstr., 106,67291 (1987).
18. L. E. J. Kennis and J. C. Mertens, Eur. Pat. Appl. 37265 (1981); Chern. Abstr.,
96, 122814 (1982).
19. E. C. Taylor, D. Kuhnt, C. Shih, S. M. Rinzel, G. B. Grindey, J. Barredo,
M. Jannatipour, and R. G. Moran, J. Med. Chern., 35,4450 (1992).
20. J. R. Piper, C. A. Johnson, G. M. Otter, and F. M. Sirotnak, J. Med. Chern.,
35,3002 (1992).
21. A. D. Cale, T. W. Gero, K. R. Walker, Y. S. Lo, W. J. Welstead, L. W.
Jaques, A. F. Johnson, C. A. Leonard, J. C. Nolan, and D. N. Johnson, J.
Med. Chern., 32, 2178 (1989).

CHAPTER 10
BETA LACTAMS
The beta lactam antibiotics could justifiably have been included in the pre-
vious chapter on the basis of their chemical structures. Tradition, as well as
their somewhat distinctive chemistry, has led to their grouping in a separate
section. The outstanding efficacy and good tolerability of antibiotics based
on the beta lactam pharmacophore has led to four decades of intensive
research on this class of compounds. This research, whose successes are
detailed in the earlier volumes of this series, resulted in many drugs which
greatly expanded the antibacterial spectrum over the original antibiotic, pen-
icillin, and which showed activity against microbes that developed resistance
to some of the agents in this class. It is consequently of more than passing
interest that this particular chapter has shrunk to a mere seven entries in this
volume, emphasis during the past few years having apparently shifted to the
synthetic quinolones discussed in Chapter 8.
The discovery of the monobactams demonstrated that an unfused, appro-
priately substituted beta lactam ring could lead to clinically effective anti-
biotics. The synthesis of one of these agents, tigemonam (9), starts by
formation of the amide from chiral hydroxy amino acid 1 with O-benzyl-
hydroxylamine to afford amide 2. Reaction of that compound with carbon
tetrachloride and triphenylphosphine probably leads initially to conversion
of the alcohol to chloride. This cyclizes to the lactam 3 under reaction
conditions. Catalytic hydrogenation then serves to remove the benzyl group.
Treatment of the product, 4, with sulfur trioxide in DMF gives the corre-
sponding sulfuric ester S. Exposure to trifluoro acetic acid (TF A) serves to
155

156 BETA LACTAMS
remove the protecting group on nitrogen to afford amino acid 6. Conden-
sation with the side-chain acid 7 catalyzed by DCC leads to the amide 8.
The protecting group on the ester is removed by means of TF A to afford
tigemonam (9).1
H
BOCN CH s
\-t-CH s
I OH
C0 2 H
=-
H
BOCN CH s
CH3
// NOCH 2 C e H 5
o H
2
H
BOCN CH s
 LtCH s
0 ' , N,
OR
1
3, R-CH 2 C H H 6
4, R=H
H 2 N
} C02H
N......
o
l
C0 2 tBu
!
H N C Hs
2 LtCH 3
0' N... OSO H
s
<
H
BOCN CH s
CHs
,k
o 'oso H
s
6
5
7
y
H 2 M
)-- N 0
/ H
S  N u CHs
, CH s
N
'1 0' , O SOH
COR s
2
B, R=tBu
9, R-H
One of the more common mechanisms by which bacteria resist the action
of this class of antibiotics involves the elaboration of enzymes, the beta
lactamases, which specifically cleave the phannacophore. Several natural
agents, such as clavulanic acid as well as some penicillin sulfones, which
have no antibacterial action in their own right, are useful lactamase inhibi-
tors. The synthesis of the beta lactamase inhibitor tazobactam, 19, starts
with the readily available 6-aminopenicillanic acid 10. Diazotization of this

BETA LACTAMS 157
compound in the presence of bromide ion leads to the bromo derivative 11.
The sulfur is then oxidized to a sulfoxide and the acid protected as a
p-nitrobenzyl ester. Treatment with zinc in acid removes the bromine to give
13. Reaction of that compound with 2-mercaptobenzothiazole leads to
a well-known, albeit complex, penicillin rearrangement-ring opening reac-
tion to give the olefin 14. In the presence of cuprous chloride, the disulfide
bond cleaves heterolytically to give a species that adds stereospecifically to
the double bond; the transient intennediate then picks up chloride from the
medium to give chloride 15. Nucleophilic displacement with sodium azide
then affords 16; the sulfur is then oxidized to the sulfone, 17, by means of
pennanganate. A reaction of the azide with acetylene in a 1,3-dipolar cy-
cloaddition leads to the triazine derivative 18. Mild hydrolysis to remove
the nitrobenzyl ester affords tazobactam (19). 2
ROW)<
C0 2 H
°
· ) c:x
C0 2 PNB
:)0
""R
S
I
s
)J-}l
C0 2 PNB
10, R-NH 2
11, R-Br
PNB-p-nitrobenzyl
12, R-Br
13, R-H
14, R-2-Benzothiazole
1
N-N
 x 2 '" J
/L  'I'
o /  /
C0 2 R

LT X 2 ""/ R
01'  /
C0 2 PNB
+--
,i OC R
° 
C0 2 PNB
18, R-PNB
19, R-H
1 7
15 t R-C]
18, R-N s
Absorption of ionic molecules from the gastrointestinal (GI) tract tends
to be poor, often leading to lack of oral absorption of polar drugs. One of
the classical methods for overcoming this obstacle involves the protection
of ionizable groups with functions that are labile to enzymes found in the
blood stream such as esterases. The penicillin derivative pivampicillin was
one of the first of the so-called prodrugs which relied on a mixed ester of
fonnaldehyde. Preparation of the prodrug side chain for a cephalosporin
begins with the free-radical chlorination of ethyl chlorofonnate by means of
sulfuryl chloride and benzoyl peroxide to give 21. This is converted to ester

158 BETA LACTAMS
22 by means of isopropanol; reaction with sodium iodide replaces chlorine
by iodine to afford the key intennediate 23. Solvolysis of the antibiotic
cefotaxime, 24, in acidic methanol replaces the allylic acetoxy group by a
methyl ether to give 25. Alkylation of the carboxylate salt from 25 with
iodide 23 gives the mixed ester cefpodoxine protexil (26). 3 Removal of the
isopropyl group by serum esterases will leave the highly unstable ester of
acetaldehyde hydrate; this presumably spontaneously decomposes to leave
the biologically active cephalosporin free acid.
C 1 0
o)..lc 1

R 0
o)..locH (CH s ) 2
2 1
22, R-Cl
23, R=I
lz3 N
H 2 N S  'iTl
N OYeo........LNOR
C0 2 H
lzv.. N
23 H 2 N S  
:. II'
N. OM eO"".... N"""" 0 C H s
000
OJ.tOCH (CH S ) 2
24, R=COCH S
25, R-CH s
26
Extension of the side chain on the six-membered ring is consistent with
antibacterial activity. Solvolysis of the diphenylmethyl ester of 7 -aminoce-
phalosporanic acid 27 in the presence of chloride ion gives the product 28
from displacement of the allylic acetate. The free amino group is then acy-
lated with an amino-protected derivative of 4-hydroxyphenylglycine to give
amide 29. Alkylation of that intennediate with triphenyhlphosphine gives
the phosphonium salt 30. The ylide from treatment of that intennediate with
strong base gives olefin 31 as predominantly the cis isomer on condensation
with acetaldehyde. Exposure to TFA removes both protecting groups to
afford cefprozil (32). 4
Nucleophilic displacement of the allylic acetate in BOC-protected ace-
tylcephalosporanic acid (ACA) 33 with cyclopentanopyridine leads to the
quaternary betaine 34. The protecting group is then removed with TF A to
give the primary amine 35. Condensation of that with the thiazoleacetic acid
36 affords the antibiotic cefpirone (37). 5

BETA LACTAMS 159
H2N.
=-
NHBOC
NS
{}-R
C0 2 CHPh 2
R
C0 2 CHPh 2
HO
27, R=OAC
29, R=CI
+ 1-
30, R=P Ph 3 C
28, R=Cl
/
NHR 1
NS
'0 //L" I -""-
o /
CO R 2
2
HO
31, R 1 =BOC I R 2 =CHPh 2
32, R 1 =R 2 =H
BOCHN 4 S
OQOAC
C0 2 H
RHN.;.: S
> OQNI
CO 2 -
33
34, R=BOC
35 J R=H
36
1 36
H 2 N
f=: N 0
SNRr--T'  S I
NOM e /L  /. + N
0/
CO 2 -
H 2 N
f=: N
SC02H
I I
NOMe
37

160 BETA LACTAMS
Further investigation into the structural requirements for the now almost
ubiquitous oxime ether side chain led to a compound in which this substituent
is replaced by an all-carbon chain. Fonnylation of the diphenylmethyl thi-
azoleacetate 38 with ethyl fonnate leads to the hydroxymethyl derivative
39. Condensation of 39 with the phosphorane from benzyl 2-triphenylphos-
phonium acetate leads to the unsaturated ester 40; the double bond shifts
from its original position to the thennodynamically more favored conjugated
position. Exposure of the product to TF A selectively cleaves the diphenyl-
methyl over the benzyl ester to give acid 41. Condensation of the acid with
the free amino group in the desmethyl cephalosporin 42 6 affords the amide
43. The remaining benzyl ester protecting groups are then removed by means
of aluminum chloride to afford ceftibuten (44). 7
HzN
'F N
S  COzCHPhz
>
HzN
'F N
S  C02CHPh2
OH
HZN
'F N
 S02R
COzCHzPh
.0, R-CHPh z
.1, R-H
38
39
!
H2N4[(  S
" N /.
o
COzCHzPh
HzN
')-N 0
I NH
S / '\ /:q)
COzR co R
z
42
.3 t R-CHzPh
4., R-H
Condensation of the desmethyl cephalosporin 42 with a rather complex
thiazoleacetic acid based side chain leads to the potent broad spectrum an-
tibiotic cefetecol (45).
It has been known for some time that penicillins and cephalosporins in
which carbon replaced sulfur in the fused ring often showed enhanced ac-
tivity over the natural product-based analogues. Development of such com-
pounds as therapeutic agents was hindered by the often lengthy and difficult
total syntheses required for their preparation. A number of relatively short
syntheses to such agents have been recently been developed which start from
more readily available fennentation products. The phenoxyacetyl deacetyl-
cephalosporin sulfoxide 46 is accessible in a very few steps from the tonnage

BETA LACTAMS 161
H 2 N
 N 0
S NHII",----(  S
N,O , /.
o
C0 2 H
C 02H
45
fennentation product, penicillin V. 8 Condensation with fonnaldehyde adds
a methlyene group at the highly activated position a to the sulfoxide group
to fonn 47. Conjugate addition of phenyl mercaptan to that intennediate
gives the sulfide 48. Heating that compound with AIBN (a,a' -azobisiso-
butyronitrile) results in free-radical fragmentation of the six-membered ring
followed by loss of sulfur dioxide. The ring then recloses with concomitant
loss of the remaining sulfur function to give the carabacephem 49. 9
H O 2
PhOCH2CON fl S
// N /.
o
C0 2 CH 2 CH=CH 2
H O 2
PhOCH2CON ft S 
> /L  /.
0/
C0 2 CH 2 CH=CH 2
46
47
1
H \
PhOCH 2 CON ¥ <
// N /"
o
C0 2 CH 2 CH=CH 2
H O 2
PhOCH2CON 7 SPh
// N /.
o
C0 2 CH 2 CH=CH 2
49
48
The starting material 51 for a carbacephalosporin could in principle be
derived from an analogous scheme starting with 50, a compound readily
obtainable from an intennediate for cefaclor. 10 Acylation of 51 with phe-

162 BETA LACTAMS
RHNt( fl 2
// N /'
o C 1
C0 2 R
H2N 
// N ./'
o C 1
C0 2 R

O N 
I '0'
/' / N ./'
0/ CI
C0 2 H
50
5 1
52
nylglycine, followed by removal of the protecting groups, affords loracarbef
(52)" 1
REFERENCES
1. C. Yoshida, T. Hori, K. Momonoi, K. Nagumo, J. Nakano, T. Kitani, Y.
Fukuoaka, and I. Saikawa, J. Antibiot., 38, 1536 (1985).
2. R. G. Micetich, S. N. Maita, P. Spevak, T. W. Hall, S. Yamabe, N. Ishida,
M. Tanaka, T. Yamazaki, A. Nakai, and K. Ogawa, J. Med. Chern., 30, 1469
( 1987).
3. K. Fujimoto, S. Ishihara, H. Yanagisawa, I. Hiroaki, J. Ide, E. Nakayama, H.
Nakao, S. Sugawara, and M. Iwata, J. Antibiot., 40, 370 (1987).
4. T. Naito, H. Hoshi, S. Aburaki, Y. Abe, J. Okumura, K. Tomatsu, and H.
Kawagushi, J. Antibiot., 40, 991 (1987).
5. M. Hashimoto, S. Shiozawa, M. Aoki, and T. Watanabe, Jpn. Kokai 02069483
(1990); Chern. Abstr., 113,78017 (1990).
6. T. Takaya, H. Takasugi, K. Tsuji, and T. Chiba, Ger. Offen. 2810922 (1978);
Chern. Abstr., 90, 204116 (1979).
7. Y. Hamashima, T. Kubota, K. Minami, K. Ishikura, T. Konoike, M . Yoshioka,
Y. Mitsuru, T. Toshida, H. Nakashimizu, and K. Motokawa, J. Antibiot., 40,
1468 (1987).
8. See, for example, Organic Chernistry of Drug Synthesis, Vol. 3, D. Lednicer
and L. A. Mitscher, Wiley, New York, (1984), p. 211.
9. L. Chris, Eur. Pat. Appl. 359540 (1990); Chern. Abstr., 113, 131868 (1990).
10. R. R. Chauvette and P. A. Pennington, J. Med. Chern., 18,403 (1975).
11. M. T. Eckrich and R. C. Hoying, Eur. Pat. Appl. 369687 (1990); Chern.
Abstr., 114,88369 (1990).

CHAPTER 11
MISCELLANEOUS FUSED
HETEROCYCLES
1. LINEAR TRICYCLIC COMPOUNDS
The oxypropanolamine phannacophore imparts beta sympathetic antagonist
activity to a plethora of aromatic nuclei. It is thus not entirely surprising
that a carbazole serves as the nucleus for a beta blocker. The key epoxide
1 is obtained by the now familiar alkylation of 5-hydroxycarbazole with
epichlorohydrin. Reaction of this intennediate with amine 2, itself obtained
starting from 2-methylcatechol, affords the oxypropanolamine, carvedilol
(3), I a compound that exhibits antihypertensive activity.
+
H 2 N
 -F\
0t-'l'
CHsO

ONH
08 
° i /)
CHsO
O
o
1
2
3
The nausea produced by administration of cancer chemotherapy agents
such as cisplatin is resistant to most conventional antiemetic agents. The
finding that the drug metoclopramide was partially effective led to intensive
investigation on related agents (see Chapter 2). Detailed phannacological
examination of those compounds revealed that the anti nauseant activity was
163

164 MISCELLANEOUS FUSED HETEROCYCLES
due to their antagonism of 5-hydroxytriptamine (serotonin) receptors rather,
than as had originally been thought, their antidopamine activity. It is inter-
esting that one of the most effective new antiemetics, ondansetron, incor-
porates some of the structural features of serotonin. Mannich reaction of
carbazolone 4, which is based on the Fischer indole synthesis product from
phenylhydrazine and cyclohexane-l,3-dione, affords the dimethylamino-
methyl derivative 5. Reaction of that compound with 2-methylimidazole
leads to replacement of dimethylamine by imidazole. This reaction may
involve either direct displacement or loss of methylamine to form the exo-
methylene derivative followed by conjugate addition of imidazole. There is
thus obtained ondansetron (6). 2
o
CH S
N-1
l::::/N
:.
R
4, R-H
6
5, R-CH 2 N(CH S )2
Inclusion of additional nitrogen on one of the rings of a carbazole leads
to an unusual antipsychotic agent. Acid-catalyzed ring closure of the indole
aminoalcohol 7 leads to the tricyclic derivative 8. Alkylation of this inter-
mediate with 3(3-bromopropyl)pyridine affords gevotroline (9). 3
NH
OH
=-
7
/
B
9
The association of acidic functions with NSAID activity has been a re-
curring topic in this and previous volumes. An acetic acid derivative of a
reasonably complex heterocyclic compound thus shares this activity. Re-

1. LINEAR TRICYCLIC COMPOUNDS 165
ductive ami nation of the indole derivative 10 leads to the corresponding
amino ester 11; this is converted to the corresponding fonnyl derivative 12.
The ester is then reduced to the alcohol to give the amidoalcohol 13. Acid-
catalyzed condensation of that intennediate with the {3-keto ester enol ether
14 leads to fonnation of the fused hydropyran ring. The steps leading to
fonnation of the product, 15, involve exchange of the alkoxide groups on
the enol ether and condensation of the nucleophilic enol with the electrophilic
indole 2-position; the order in which these steps occur is not clear. Hydrol-
ysis of the diastereomeric mixture in the presence of parafonnaldehyde leads
to alcohol 16, again as a mixture of stereoisomers. Reaction of 16 with
benzylmagnesium chloride in the presence of titanium tetrachloride probably
involves initial loss of hydroxyl and fonnation of a trigonal carbocation-like
center at that position. The substituents at the transannualar position cause
the benzyl group to approach from a position trans to the ethyl group; 17
is thus formed as the main stereoisomer. Saponification of the ester group
completes the synthesis of pemedolac (18).4
o
Gof C0 2 CH 9
I/,I
N
H

NHR
 C02CB3
I/,I
N
B
NHCH-O
---+
10
11. R-H
12. R-CH-O
1 3
CHSO COaCH s
(:
R
c
COaCH s
17. R-CH s
18. R-H
15. R-MHCH-O
18, R-OH
The imidazoquinazoline ring system has been associated in the past with
compounds such as anagrelide, which inhibit platelet antiaggregation. It is
of interest that addition of an alky lamido side chain leads to a cardiotonic

166 MISCELLANEOUS FUSED HETEROCYCLES
agent. The preparation of this agent starts with the alkylation of the phenolic
group in 19 with ethyl 4-bromobutyrate to give 20. The ester is then hydro-
lyzed and the resulting acid converted to its acid chloride. Reaction with
N-methylcyclohexylamine gives the amide 21. Reductive alkylation of the
aldehyde group in this last intennediate with ethyl glycinate leads to the
amine 22; diamine 23 is obtained by catalytic hydrogenation of the nitro
group. Reaction of this last product with cyanogen bromide proceeds by
substitution on the more basic nitrogen atom to give the N-cyano derivative
24. Reaction of this key intermediate with ammonia can be visualized as a
series of condensations beginning with the addition of the anilino group to
the cyano function. The imidazoquinazoline lixazinone (25)5 is thus fonned.
ROCB-O
}fO
2
BaC.. I
O }fC(CBI)aOCB-O
JrO
.
BsC, I
O }fC(CB.)I0 -O:: JrCO It
I H ·
/. IR
I


li, i-H
20, i- ItO.C(CB I ).
21
22. R-O
23. R-B
/
Ba C , I
O IC(CBI).O  I 0
I /: .F
I I
B
BaC.. I
O JfC(CBI)'0 -CC .co It
I CIf I
/. IfB
I

26
2'
A deficit in brain acetyl choline levels or poor sensitivity of receptors for
that neurotransmitter has been associated with Alzheimer's disease. Drugs
that increase levels of that compound by inhibiting the enzyme, acetyl cho-
linesterase, responsible for turnover of the compound offer a treatment" for
this devastating disease. The relatively simple aminotetrahydroacridine, tac-
rine (28), has shown some activity against Alzheimer's. One of several
synthesis for this compound starts by sodium amide catalyzed reaction of
isatin 26 with cyclohexanone. The first step probably involves ring opening
of the isatin ring to an amino amide; this is followed by fonnation of an
eneamine from the ketone with the amino group of ring-opened isatin. Con-
densation of the activated {3 position with the isatin ketone serves to close
the quinoline ring and fonn product 27. Reaction of 27 with bromine in the
presence of sodium hydroxide leads to Hofmann degradation of the side
chain to an amine; tacrine (28)6 is thus obtained.

1. LINEAR TRICYCLIC COMPOUNDS 167
o
M o
N/
H
CONH 2

26
27
NH 2
:>
28
The relatively poor bioavailability of the parent compound encouraged
the search for analogues that might show better absorption. The preparation
of a more hydrophilic congener starts by fonnation of enamine 30 from
2-cyanoaniline 29 and 1,3-cyclohexanedione. Reaction of the product with
base and cuprous chloride leads direct! y to the aminoacridine 31. Reduction
of the carbonyl group by means of lithium aluminum hydride gives velna-
crine (32). 7 Alkylation of intennediate 31 with benzyl chloride gives the
corresponding N-benzyl derivative 33. Reduction of the carbonyl group in
this compound affords suronacrine (34). 8
0
Q):CN Ct CN 0)
I' > I" I 
./ /" ./
NH 2 N
H
29
30 3 1
/ 1
<
34
33
OH
32
An aminopyrimidine fused to a hexahydroquinoline provides a compound
that exhibits antihypertensive activity. It should however be noted that the
same activity is displayed by the analogue, quinpirole, in which pyrazole
replaces the aminopyrimidine. Reaction of perhydroquinolone 35 with
tris(dimethylamino)methane affords the aminomethylene derivative 36. Con-

168 MISCELLANEOUS FUSED HETEROCYCLES
o
lNY
I
nPr

cttN{CH S )2 --
I
nPr
NNH2
I 'I
/' N
35
36
37
densation of that intennediate with guanidine leads to fonnation of the py-
rimidine ring. Quinelorane (37)9 is thus obtained.
Dibenzocycloheptanes and -azocines bearing an amino group attached at
the tenninus of a three-carbon chain have a venerable history as antidepres-
sants and muscle relaxants. The latter activity is retained when one of the
aromatic rings is replaced by a pyrrole. The preparation of this agent starts
by ring opening of styrene oxide with 2-carbethoxypyrrole to afford the
intennediate 38. Dehydration leads to the styrene 39; this is cyclized with
a strong acid such as PP A to the tricyclic product 40; reduction of the double
bond leads to 41. Condensation of that compound with the Grignard reagent
from N-(3-bromopropyl)-N,N-dimethylamine gives the tertiary carbinol 42.
This is dehydrated to afford nelezaprine (43).10
HO
c)rjC0 2 Et
O"rj 0 2 Et
>
>
38
39
o
40
!
<
<
o
4 1
43
42
Replacement of the side chain in the dibenzocycloheptanes by a pipera-
zine group has led to a large series of relatively well-tolerated antipsychotic
agents. Activity is also retained in this case when one of the fused benzene
rings is replaced by a heterocyclic moiety. Reaction of 2-nitrophenyl-

1. LINEAR TRICYCLIC COMPOUNDS 169
acetonitrile with methanolic hydrogen chloride affords the iminoether 44.
Condensation of that intennediate with acetylhydrazide leads to fonnation
of a triazole ring. Hydrogenation of that product, 45, leads to reduction of
the nitro group and fonnation of diamine 46. Treatment with carbonyl diim-
idazole leads to reaction of those two groups to fonn imide 47. The carbonyl
function is then converted to imino chloride 48 by means of phosphorus
oxychloride. Displacement of chlorine by means of N-methylpiper-
azine completes the synthesis of batelapine (49). 11
NH
 OCH s
N0 2

Gr:f; N
/ ,/ /yCH s
 HN-N
NR 2

Q::: N
/ ,/ Ij-CH s
 N-N
N
H 0
44
45. R=O
46. R=H
47
/
CJC:; N
/ ,/ Ij-CH s <
 N-N
N -=<
N)
C N
,
CH s
CJC:; N
/ ,/ Ij-CH s
 N-N
N -=(
C 1
48
49
In a similar vein, displacement of the amine in the thiophenobenzodiaze-
pine derivative 50 12 with N-methylpiperazine affords the antipsychotic agent
olanzapine (51).13
 y  S CH
 \ / s
N
NH 2
   S CH
)0  \ / 3
N
N)
C N
\
CH s
50
5 1

170 MISCELLANEOUS FUSED HETEROCYCLES
The good clinical efficacy of the acyclic aryloxyalkylamine amine fluox-
etine (76, Chapter 2) has led to the preparation a number of analogues,
including the closely related seproxtine (75, Chapter 3). A tricyclic pyrrol-
idinobenzodioxan which incorporates some of the structural features of the
open chain compounds also exhibits antidepressant activity. Alkylation of
the catechol 52 with the functionalized derivative 53 of meso butanetetrol
affords the fused dioxan 54. The benzyl protecting groups are then removed
by treatment with aluminum chloride and the resulting diol 56 is converted
to the corresponding bis mesylate 56. Reaction of that intennediate with
benzylamine results in double alkylation on nitrogen and fonnation of the
pyrrolidine ring (57). Hydrogenation over palladium on carbon leads to
removal of the benzyl group and fonnation of the serotonin reuptake inhibitor
fluparoxan (58).14
F OCH 2 Ph F r
et° H OTS &orO R &0
I; + I; ° .",......OR -........:
I NR
:) :. / oJ:
OH OTs
52 OCH 2 Ph
53 54-. R-CH 2 Ph 57, R=CH 2 Ph
55, R-H 58, R-H
56, R-OS0 2 CH s
2. ANGULAR TRICYCLIC COMPOUNDS
Fennentation products have proven an unusually rich source for potential
antineoplastic agents. The pyrroloindole trimer, CC-I065, seemed a partic-
ularly promising candidate because of its high potency in various animal
models as well as its mechanism of action. Detailed biochemical studies
revealed that the compound owed its cytotoxic activity to binding to specific
CC-I065

2. ANGULAR TRICYCLIC COMPOUNDS 171
sequences of bases in the minor groove of DNA. Delayed liver toxicity
precluded clinical development of the compound. Molecular dissection of
CC-I065 by means of synthetic models revealed that the activity was due
mainly to the left-hand cyclopropylquinone, whereas the major contributor
to toxicity was the right-hand moiety.
That observation prompted the preparation of a number of analogues, all
of which have been shown to be cytotoxic by the same mechanism as the
natural product. One of the published synthesis for the key intennediate,
71, starts by conversion of diol 59 to the bis-mesylate 60; catalytic hydro-
genation results in reduction of the nitro group to the corresponding amine;
this product, 61, undergoes spontaneous internal alkylation to afford the
cyclized product 62. The amine is then protected as a mesylate. Nitration
proceeds to give the derivative 64. The nitro group is then reduced (65) and
the O-mesylate is converted to acetate 66 by a saponification-acylation se-
quence. Introduction of the second pyrrole ring involves the Gassman in-
dolone synthesis, an electrocyclic rearrangement based on the Hauser ortho-
substitution rearrangement. The sequence starts by alkylation of the anilino
nitrogen in 66 with the product from methyl 2-thiomethylpropionate and
thionyl chloride to give sulfonium salt 67. The anion on the carbon bearing
the sulfonium salt, from treatment with strong base, adds to the aromatic
ring; electrocyclic bond reorganization leads to a transient intennediate such
as 68. This spontaneously cyclizes to give the observed product, indolone
69. Reduction with borane leads to indole 70 with simultaneous loss of
methyl mercapatan. The remaining protecting groups are then removed and
the product resolved optically by means of its tryptophan derivative pyr-
roloindole 71. 15
Acylation of the free amino group in 71 with carboxylic acid 72 gives
the corresponding amide 74. The hydroxymethyl group on the fused pyrrole
ring is then converted to chloromethyl (76) via its mesylate 75. Reductive
removal of the benzyl protecting group affords the free phenol 77. Treatment
of this intennediate with aqueous triethylamine can be visualized as involv-
ing initially fonnation of the phenoxide, which can the undergo internal
alkylation with the adjacent chloromethyl group at its para position to fonn
a fused cyclopropyl ring. The observed product from that reaction is the
antineoplastic agent adozelesin (78). 16
An analogous sequence starting from the intennediate bearing additional
substitution on the benzofuran ring, 73, would lead to the correspondingly
substituted analogue of 77. Reaction of the free phenol with phenylisocy-
anate gives the corresponding carbamate and the antineoplastic drug car-
zelesin (79). 16
Condensation of both carboxylic acids in indole dimer 80 with intenne-
diate 71 affords the symmetrical derivative 81. This is then converted to the
chloromethyl free phenol in much the same manner as that used to obtain

 OMI
I'
PbCHZO /. N
R
172 MISCELLANEOUS FUSED HETEROCYCLES
 OR:RI
I'
PhCHZO /. NR Z

59, R 1 .H, R2.0
80, R I .Ms, RZ-O
61, R I .Ws, RZ.H
82, R.H
83, R-Ws

R I N JG6 0RZ
Z ,
1/
PbCHzO N
Ws
84, RI.0, RZ.Ws
65 , R 1 .H, R2.Ws
88, RI_H, RZ_!e
1
I(
CH 3
HsC,+co We
 ri5 z OAe
HN
I'
PhCHzO / N
Ws
O!e
CH 3
HsCS COzMe
OAe
HzN
I(
PhCH 2 0
69
!
NH m CH3 OAe
I'
PhCHzO / N
Ws
68
67
@ CH S .... OH
NH :-
I'
PhCHzO /. N
H

70
H
N
71+H02C, OOR
H
-+
72, R = H
73, R = NEt2
m CH3 - CI
HN :
I' H
o /' NN
ONH 6/-'\N OONEt2
 H
V
79
7 1
H N  CH3, R 2
I' H
RIO /' NN
6/ \N O
H
74, R 1 = PhCH2, R 2 = OH
75, R I = PhC H 2, R 2 = Ms
76, R I = PhCH2, R 2 = CI
1 2
77, R = H, R = CI

C H 3
H: D5  
ON oo-Z:?
H
78

2. ANGULAR TRICYCLIC COMPOUNDS 173
B H
H02CNyNC02H
N N
H H
80
CBS
R2
...
H B
NyN
o
81, R 1 .OH. R 2 .Ph
82, R 1 .Cl. R 2 .H
77. There is thus obtained an extraordinarily potent cytotoxic agent which
incorporates two reactive groups bizelesin (82).17
The highly varied biological activities shown by the angularly fused tri-
cyclic compounds emphasize the lack of common phannacophores in this
structural class. The synthesis of an imidazoquinoline, described as an im-
munomodulator, starts by nucleophilic aromatic displacement of halogen
from quinoline 83 by means of isobutylamine to afford 84. Reduction of the
nitro group leads to diamine 85; this is cyclized by means of ethyl ortho-
fonnate to give the imidazole ring in 86. The quinoline nitrogen is then
converted to the N-oxide (87) by means of peracid. Treatment of this last
intennediate with phosphorus oxychloride leads to a well-known Polonov-
sky-like reaction and fonnation of the chloride 88. A second nucleophilic
displacement, this time using aqueous ammonia, affords imiquimod (89).18
An imidazoquinoxaline, which is described as an anxiolytic agent, carries
through the theme of varied activities. Condensation of ester 90 with the
unusual cyclopropyl carboxylic acid derivative 91 leads to fonnation of an
oxadiazle ring in a single step. There is thus obtained panadiplon (92).19
It has been shown that the symptoms of Parkinson's disease can be treated
by increasing levels of the neurotransmitter dopamine. The very short half-
life of that endogenous compound has led to the search for dopaminergic
drugs that are longer lasting and more bioavailable. A tricyclic heterocycle
that incorporates the phenethylamine function of dopamine has shown prom-
ising activity as a dopamine agonist. Condensation of the Grignard reagent

174 MISCELLANEOUS FUSED HETEROCYCLES
N0 2
NR 2
c-
N\\
N
C 1
"CH
:>

83 84, R=O
85, R=H
C-
N\\
N
<:
R
88, R = C 1
89, R=NH
2
86
!
C-
N\\
N
B7
 N 0
N /. /
 ' OEt
N 0
A
+
H N-O
2
H N>r---<J
:>
N N-O
'  N
 J'n
N 0
A
9 1
92
90
from 4-methoxyphenethyl chloride with ethyl oxalate leads to the corre-
sponding a-keto ester 94; this is then saponified to keto acid. Reaction of
the free acid with methyl carbamate affords the eneamine derivative 95.
Hydrogenation of the double bond over the chiral catalyst Chirophos affords
amino acid derivative 96 as a single optical antipode. Friedel-Crafts cycli-
zation of the acid gives the tetralone derivative 97. Reduction of the carbonyl
group with sodium bis(methoxyethoxy)aluminum hydride leads to the cor-
responding aminoalcohol 98, again as a single enantiomer. The carbamate
group is then removed and replaced by a propionamide by sequential hy-
drolysis and acylation; reduction of the amide leads to the N-propyl deriv-

2. ANGULAR TRICYCLIC COMPOUNDS 175
ative 99. Reaction of the aminoalcohol with chloracetyl chloride gives the
motpholinone 100 by sequential acylation on nitrogen followed by fonnation
of an ether. Reduction of the amide using sodium bis(methoxy-
ethoxy)aluminum hydride followed by cleavage of the methyl ether affords
the dopamine agonist naxogilide (102).20
°
 C02It
'/
CHsO
NHCOaWe
COIB
CB o
s
JfHCOaWe
COIB
CH o
s
---+

g.
g5
88
1
1GO.
'/ 
CHsO _ HC B
ijJol 7

CBsONHR
OH
c

CHsOJfBC02We
o

98, R-COzWe
88, a-.-C S B 7
g.,
100

ROIC B
 a 7
101, R-CB s
102, R-H
An unusual pyranoquinoline has been described as an antiasthmatic agent
which inhibits the release of allergic mediators. Condensation of 2,3-di-
methylaniline with diethyl acetylmalonate in one of the classical quinolone
syntheses leads to starting material 103. Base-catalyzed reaction of the methyl
group on the acetyl side chain with diethyl oxalate gives the acylation prod-
uct 104, shown in its enol fonn. Treatment with acid yields the pyranone
ring by fonnation of a cyclic ether, possibly by an addition-elimination
sequence. The product from that reaction, 106, is then converted to the acid
chloride with thionyl chloride. Reaction with 3-methyl-I-butanol affords
repirinast (107).21
The preponderance of products of the arachidonic acid cascade are as-
sociated with deleterious biological effects such as inflammation and platelet
aggregation. An exception to this generalization is the bicyclic enol ether
product prostacyclin (PGI 2 ), which is a vasodilator and also inhibits throm-

176 MISCELLANEOUS FUSED HETEROCYCLES
OH
.::J, CO 2 R
::-
H 3 C H 3 C
CH 3 CH 3
103 104, R=Et
1 0 5 , R=H
J
C0 2 H
<:
CH 3
H 3 C
H 3 C
CH 3
107
106
boxane-induced platelet aggregation. The fact that the half life of this agent
is measured in minutes precludes its use as a drug. Fusion of a benzene ring
to the bicyclic moiety of prostacylin has been among the more successful
strategies used to overcome that instability. Thus reaction of the phosphorane
from phosphite 109 with the aldehyde group in tricyclic intennediate 108
gives the condensation product 110. Reduction of the carbonyl group by
means of sodium borohydride, followed by removal of the acetyl protecting
group, affords beraprost (111).22
° B OICB S
.$:- I"
1'\.,\\ /. +
AcOJ--(
CB.O
° 0
I II
(ltO)2PCB2CCBC = CCH s
I
CBs
109
-+
° B OICHS
I-S.." I :
R I O k
CH3
CH s
108
110, a I .Ac, a 2 .o
,
11 1, R 1 . H, a 2 · H , oS

3. FOUR OR MORE FUSED HETEROCYCLIC RINGS 177
3. FOUR OR MORE FUSED HETEROCYCLIC RINGS
The activity of piperazinodibenzazepines and -diazepines is quite well es-
tablished. Antidepressant activity is not unexpectedly retained when one of
the fused benzene rings is replaced by pyridine. Nucleophilic aromatic dis-
placement of chlorine from 2-chloronicotinonitrile by the secondary nitrogen
in 2-phenyl-4-methylpiperazine leads to the tricyclic intennediate 112. The
nitrile is then hydrolyzed to the corresponding acid 113, which is reduced
with diborane to afford the carbinol 114. Treatment with sulfuric acid closes
the azepine ring to afford mirtazepine (115).23
(t CN
I'
,/
N N
C N
'c Hs

OH
C(R
N N
C N
,
CH s
--+
112
113, R=O
114, R=H2
115
The strategy used to prepare the benzodiazepine anxiolytic agent sera-
zepine, 119 differs somewhat in that the piperazine ring is built in situ. This
scheme starts by acylation of the amino group in 116 with chloroacetyl
chloride to give 117. Reaction of that intennediate with methylamine prob-
ably involves as the first step displacement of the activated chlorine; inter-
change of the adjacent ester with the newly fonned amine leads to pipera-
zinedione 118. Reduction of that compound with diborane affords serazepine
(119).24
Anxiolytic activity presists in a tertracyclic benzodiazepine in which the
traditional pendant benzene ring is replaced by a fused imidazole. Conden-
sation of L-proline with isatoic anhydride derivative 120 leads directly to the
chiral benzodiazepinedione 121. The reaction can be rationalized as stepwise
fonnation of an amide by proline nitrogen with ring opening of the anhy-
dride, loss of carbon dioxide, and fonnation of a second amide bond. This
intennediate is then condensed with tert-butyl 2-isocyanoacetate
[CNCH 2 C0 2 C(CH 3 )3] to give bretazenil (122).25
Though the natural product camptothecin, 136, had shown very prom-
ising antineoplastic activity in an array of animal models, the compound
eventually failed in the clinic. This was attributed to the extremely poor

178 MISCELLANEOUS FUSED HETEROCYCLES
QrN I QrN I
 / -   / -
N C0 2 E t N C0 2 E t
H C0 2 Et ° < C0 2 E t
1 1 6 CH 2 Cl
1 1 7
!
QrN I QrN I
 / - <:  / -
N C0 2 Et N C0 2 Et
C N o C N =0
'c H 'c H
3 3
119 118
 c(p 0
c(N
I' 0 
./ NJ:.. O >
H N 0 N \ C0 2 C(CH S )S
H ........
120 121
122
bioavailability of the parent compound and, it should be added, lack of
activity of the acid from opening of the lactone ring. The availability of
more soluble derivatives has revived interest in this class of compounds.
The natural product is sufficiently difficult to obtain to make total synthesis
an attractive alternative. A recent synthesis, which leads to d,l-camptothecin,
starts by condensation of pyrrole derivative 123 with the chi or ogluta rate
124. The resulting pyridone 125 probably arises by addition to the allene
fonned from 124 under reaction conditions followed by lactam fonnation.
Alkylation with ethyl iodide in the presence of base introduces the required
side-chain substituent to give 126. Reaction with parafonnaldehyde in the
presence of acid leads to addition of a carbinol function on the pyridone
ring; lactone fonnation gives the intennediate 127. The carbonyl group on
the pyrrolidine ring needed for addition of the second half of the compound

3. FOUR OR MORE FUSED HETEROCYCLIC RINGS 179
C0 2 Me
",:,'
cr:
fC02Me
+ Cl
CO 2 Me

CO 2 Me

123
124
o
125
o
126
/
c
o
o
o
o
128
127
is introduced in two steps by oxidation with molecular oxygen in the pres-
ence of triethyl phosphite followed by oxidation to a ketone (128).
Construction of the second half of the molecule starts by addition of
vinylmagnesium bromide to aldehyde 129 to give the corresponding carbinol
130; the alcohol is then oxidized to the ketone 131. Catalytic hydrogenation
of this intennediate results in reduction of both the double bond and the
nitro group to afford aniline 132.
 N02  N02  N02 o::: NH2
I ---+ I -+ I -. I
CH30 /. CH = 0 CH3 0 /.  CH3 0 /.  C H 3 0 /.
OH 0 0
129 130 131 132
The two halves of the molecule incorporate the functionality required for
the classical Friedlander quinoline synthesis. Thus reaction of aniline 132
with pyridone 128 gives the pentacyclic condensation product 133. The now
superfluous carboxyl group on the pyridone is removed by treatment with
hydrogen bromide to afford 134; reaction of 134 with oxygen in the presence
of cupric chloride and base serves to introduce the hydroxyl group on the
tertiary carbon adjacent to the lactone carbonyl (135). Cleavage of the phe-
nolic methyl ether affords racemic lO-hydroxycamptothecin 137. 26 Reaction
of the isomer obtained from the natural product or a chiral version of this
from total synthesis with fonnaldehyde and dimethylamine gives the Man-
nich base 138. There is thus obtained the antineoplastic agent topotecan
(138) .

180 MISCELLANEOUS FUSED HETEROCYCLES
128+132  CH 0
s
 CHSO
133 134, R-H
135 , R-OH
!
HO
R
138
136, R-H
137, R-OH
A much less highly functionalized pentacyclic compound whose structure
is somewhat reminiscent of camptothecin also exhibits antineoplastic activ-
ity. Condensation of tetrahydroisoquinoline 139 with naphthoquinone 140
affords the completely assembled ring system 141 in a single step. Hydrol-
ysis of the acetate protecting group leads to the free phenol 141. The re-
mainder of the sequence consists of introduction of the phosphonic acid side
chain intended to improve solubility in aqueous media. Alkylation of the
0
ro COZH C1W
I /' N,c H . 0 + I I/, >
0 OAe
139 140
141 , R-Ac
142, R-H
!

O-P-( OCH 2 Ph) 2
I
o
0- P-O C H 2 Ph
I
O-Na+
144
143

REFERENCES 181
phenol by treatment with chlorodibenzyloxyphosphonate gives the corre-
sponding phosphonate ether 143. Reaction with sodium iodide leads to phos-
phonate 144 by an Arbuzov-like reaction with benzyl iodide presumably
fonned as a byproduct. Fosquidone (145)27 is thus obtained.
Certain seemingly complex structures are sometimes available by quite
simple, straightfolWard processes. This is aptly illustrated by the example
given below, which is admittedly out of place at this point in the chapter.
Reaction of cyanoquinoline 145 with sodium azide and ammonium chloride
affords 146 in a single step. Conversion of a nitrile to a tetrazole is well
precedented; the fonnation of the fused tetrazole ring is more unusual. The
glucamine salt of the product is the antiallergic compound tetrazolast. 28
Ger CN
" "
1/ /'
N C 1
:>
N .........N
---,
NH
........./
N
145
146
REFERENCES
1. F. Wiedeman, W. Kampe, M. Thiel, G. Sponer, E. Roesch, and K. Dietman,
Ger. Offen. 2815926 (1979); Chern. Abstr., 92, 12871 (1980).
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4. A. H. Katz, C. A. Demerson, C. C. Shaw, A. A. Asselin, L. G. Humber, K.
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J. Schmid, U. Sleah, D. Van Eugen, T. T. Chau, and B-M. Weichman, J.
Med. Chern, 31, 1244 (1988).
5. M. C. Venuti, G. H. Jones, R. Alvarez, and J. J. Bruno, J. Med. Chern., 30,
303 (1987).
6. J. Bielavsky, Collect. Czech. Chern. Comrnun., 42, 2802 (1977).
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9. C. L. Nichols and E. C. Kornfeld, U. S. Patent 4501890 (1985);, Chern. Abstr.,
103, 123525 (1985).

182 MISCELLANEOUS FUSED HETEROCYCLES
10. C. S. Rooney, J. Rokach, and J. G. Atkinson, U. S. Patent 4112112 (1978);
Chern. Abstr., 91,91624 (1979).
11. I. Vlattas, Eur. Pat. Appl. 129509 (1984); Chern. Abstr., 102,149293 (1985).
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Organic Chernistry of Drug Synthesis, Vol. 4, Wiley, New York, (1989),
p. 212.
13. J. K. Chakrabarti, T. M. Hotten, and D. E. Tupper, Eur. Pat. Appl. 454436
(1991); Chern. Abstr., 116,83703 (1992).
14. J. Kitchin, P. C. Cherry, A. J. Pipe, A. J. Crame, and A. D. Borthwick, Brit.
UK Pat. Appl. 2157691 (1985); Chern. Abstr., 105, 208896 (1986).
15. M. A. Warpenhoski, Tetrahedron Leu. 27,4103 (1986).
16. R. C. Kelly, I. Gebhard, N. A. Wicnienski, P. A. Aristoff, P. D. Johnson,
and D. G. Martin, J. Arn. Chern. Soc. 109,6837 (1987).
17. M. A. Mitchell, R. C. Kelly, N. A. Wicnienski, N. T. Hatzenbuhler, M. G.
Williams, G. L. Petzold, J. L. Slightom, and D. R. Siemieniak, J. Arn. Chern.
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18. J. F. Gerster, Eur. Pat. Appl. 145340 (1985); Chern. Abstr. 103, 196090 (1985).
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20. D. G. Melillo, R. D. Larsen, D. J. Mathre, W. F. Shukis, A. W. Wood, and
J. R. Colleluori, J. Org. Chern., 52, 5143 (1987).
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28. N. Peet, private communication.

CROSS INDEX OF DRUGS
Cenazepril
Fosinopril
Ace Inhibitors
Ceronapril
Perindopril
Aldose Reductase Inhibitors
Ponalrestat
Alpha Blockers
Apraclonidine Atipamezole
Brimodine Dapiprazole
Analgesic, Unclassified
Detomidine Dexmedetomidine
Medetomidine Lorcinadol
Brifentanil
Ocfentanil
Remi fentanil
Analgesic, Opioid
Mirfentanil
Pentamorphone
Spiradoline
Angiotensin Antagonist
Losartan
183

184 CROSS INDEX OF DRUGS
Sibutramine
Adapalene
Cioteronel
Ranolazine
Actisomide
Bucromanone
Ipazilide
Propafenone
Sematilide
Lodelaben
Binfloxacin
Cefpiromine
Cefprozil
Clinafloxacin
Enrofloxacin
Ibafloxacin
Loracarbef
Sparfloxacin
Tigemonam
Anorexic
Antiacne
Inocoterone
Antiandrogen
Finasteride
Antianginal
Antiarrhythmic
Bidisomide
Ibutilide
Modecainide
Risotilide
Antiarthritic
Antibiotic
Cefetecol
Cefpodoxime
Ceftibuten
Danofloxacin
Fleroxacin
Lomefloxacin
Sarafloxacin
Temafloxacin
Tosufloxacin
Anticholinergic
Tematropium
Ameltolide
Sabeluzole
Dapoxetine
Etoperidone
Anticonvulsant
Loreclezole
Topiramate
Antidepressant
Dazepinil
Fluparoxan

Mirtazapine
Seproxetine
Pioglitazone
Batanopride
Dolasetron
Ondansetron
Zatosetron
Amorolfine
Fluconazole
Alprenoxime
Noberastine
Cicletanine
Pelanserin
CROSS INDEX OF DRUGS 185
Paroxetine
Venlafaxine
Antidiabetic
Antiemetic
Bemesetron
Granisetron
Pancopride
Antifungal
Cisconazole
Oxiconazole
Antiglaucoma
Antihistamine
Rocastine
Antihypertensive
Flosequinan
Quinelorane
Antiinflammatory, Steroid
Halobetasol Loteprednol
Antiinflammatory, Nonsteroid
Pemedolac Pravadoline
Prifelone Romazarit
Rimexolone Tebufelone
Tenidap Tifurac
Antimigraine
Sumatriptan
Adozelesin
Brequinar
Crisnatol
Dexonnaplatin
Fosquidone
Antineoplastic
Bizelesin
Carzelesin
Decitabine
Edatrexate
Gemcitabine

186 CROSS INDEX OF DRUGS
Antineoplastic (Continued)
Idarubicin Lometrexol
Losoxantrone Mafosfamide
Masoprocol Onnaplatin
Perfosfamide Piroxantrone
Topotecan Zeniplatin
Antipsoriatic
Tepoxalin
Calcipotriene
Alentomol
Gevotroline
Olanzapine
Prinomide
Antipsychotic
Batelapine
Minaprine
Risperidone
Antirheumatic
Antiulcer
Lansoprazole Pantoprazole
Antiulcer, H 2 Antihistamine
Lavoltidine Roxatidine
Sufotidine
Didanosine
Ganciclovir
Zalcitabine
Alpidem
Bretazenil
Ipsapirone
Serazepine
Tiospirone
Antiviral
Fiacitabine
Lamivudine
Anxiolytic
Binospirone
Enciprazine
Panadiplon
Tandospirone
Aromatase Inhibitor
Fadrozole Plomestone
Rogletimide
Salmeterol
Beta Agonist

Adaprolol
Carvedilol
Nebivolol
CROSS INDEX OF DRUGS 187
Beta Blocker
Bendacalol
Metipranolol
Picumetrol
Beta Lactamase Inhibitor
Tazobactam
Bronchodilator
Doxofylline
Calcium Channel Blocker
Belfosdil Clentiazem
Lacidipine Taludipine
Calcium Regulator
Calcipotriene Secalciferol
Carbonic Anhydrase Inhibitor
Dorzolamide Sezolamide
Cardioprotectant
Dexrazoxone
Arbutamine
Bemoradan
Lixazinone
Pimobendan
Vesnarinone
Cardiotonic
Bemarinone
Indolidan
Medorinone
Prinoxodan
Cholecystokinin Antagonist
Devazepide Lorglumide
Cholinesterase Inhibitor
Suronacrine Tacrine
Velnacrine
T 01 trazuril
Torsemide
Coccidiostat
Diuretic

188 CROSS INDEX OF DRUGS
Dopaminergic
Naxogilide
Estrogen Antagonist
Raloxifene Toremifene
Glomerulonephritis Treatment
Sulotraban
Colestolone
Dal vastin
Xenalipin
Hypolipidemic
Crilavastine
Fluvastatin
Daltroban
Loxoribine
Immune Modulator
Imiquimod
Oxamisole
Doretinel
Pelretin
Linarotine
Keratolytic
Etarotene
Sumarotene
Leukotriene Antagonist
Ablukast Ritolukast
Sulukast Tiacrilast
Tomelukast Verlukast
Lipid Peroxidation Inhibitor
Tirilazad
Lipoxygenase Inhibitor
Docebenone Zileutron
Liver Disease Treatment
Malotilate
Mediator Release Inhibitor
Pemirolast Repirinast
Tetrazolast Tibenlast
Muscle Relaxant
Metrenperone
Azumolene
Nelezaprine

CROSS INDEX OF DRUGS 189
Neuroprotective
Dizocilpine
PET Imaging Agent
Fluorodopa 18F
Platelet Aggregation Inhibitor
Acadesine Beraprost
Lifarizine
Progestin
Desogestrel
Progestin Antagonist
Mifepristone Onapristone
Radioprotectant
Amifostine
Radiosenstizer
Etanidazole
Di tekiren
Terlakiren
Renin Inhibitor
Enalkiren
Sedative
Tameridone
Thromboxane Antagonist
Vapiprost
Thromboxane Synthetase Inhibitor
Ridogrel
Uricosoric
Irtemazole

CUMULATIVE INDEX, VOLUMES 1-5
Ablukast. 5, 128
Acebutolol, 2, 109
Aceclidine. 2, 295
Acedapsone, 2, 112
Acenocoumarole, 1, 331
Aceperone. 2, 332
Acephylline. 1, 425
Acetaminophen, 1, III
Acetanilide, 1, III
Acetazolamide, 1, 249
Acetohexamide, 1, 138
Acetyl methoxprazine, 1, 131
Acetylmethadol, 1, 81
Aciclovir, 3, 229
Acifran, 4, 78
Acitretin, 4, 35
Acivicin, 4, 85
Aclomethasone, 3, 96
Acodazole, 4, 215
Acrivastine, 4, 105
Acitsomide, 5, 150
Actodigin, 3, 99
Adapalene, 5, 38
Adaprolol, 5, 18
Adinazolam, 2, 353
Adiphenine, 1, 81
Adozelesin, 5, 171
Adrenalone, 2, 38
Alaproclate, 4, 33
Albendazole, 2, 353
Albuterol, 2, 43
Albuterol, 5, 15
Albutoin. 2, 261
Alclofenac, 2, 68
Aldosterone, 1, 206
Alentomol, 5, 39
Aletamine, 2, 48
Alfaprostol, 4, 9
Alfentanyl, 3, 118
Alfuzocin, 4, 149
Algestone acetonide, 2, 171
Alipamide, 2, 94
Allobarbital, 1, 269
Allopurinol, 1, 152
Allyiestrenol, 1, 172
Alonimid, 2, 295
Aloxidone, 1, 232
Alpertine, 2, 342
Alpha eucaine, 1, 8
Alphaprodine, 1, 304
Alpidem, 5, 142
Alprazolam, 3, 197
Alprenolol, 1, 177
Alprenoxime, 5, 18
Alprostadil, 3, 2
Alrestatin, 3, 72
Altanserin, 4, 151
Althiazide, I, 359
191

192 CUMULATIVE INDEX, VOLUMES 1-5
Altrenogest, 4, 66
Alverine, 2, 55
Ambucaine. I, II
Ambucetamide, 1, 94
Ambuside, 2, 116
Amcinafal, 2, 185
Amcinafide. 2, 185
Amdinocillin. 3, 208. 4, 177
Amedalin. 2, 348
Ameltolide. 5, 20
Ametantrone. 3, 75
Amfenac, 3, 38
Amflutizole, 4, 94
Amicibone, 2, II
Amicycline. 2, 228
Amidephrine. 2, 41
Amidoquine, 1, 342
Amifloxacin, 4, 144
Amifostine, 5, I
Amiloride, 1, 278
Aminitrozole, 1, 247
Aminoglutetimide, 1, 257
Aminometetradine, 1, 265
Aminophenazole, 1, 248
Aminophylline, 1, 427
Aminopromazine, 1, 390
Aminopropylon, 1, 234
Aminopyrine, 1, 234
Aminorex, 2, 265
Amiodarone, 4, 127
Amiquinsin, 2, 363
Amisometradine, 1, 266
Amitraz, 4, 36
Amitriptyline, 1, 151
Amlodipine, 4, 108
Amobarbital, 1, 268
Amodiaquine, 4, 140
Amoproxan, 2, 91
Amopyroquine, 1, 342
Amorolfine, 5, 99
Amoxapine, 2, 428
Amoxycillin, 1, 414
Amphecloral, 2, 48
Amphetamine, 1, 37
Amphetaminil, 2, 48
Ampicillin, 1, 413
Amprolium, 1, 264
Ampyzine, 2, 298
Amqinate, 2, 370
Amrinone, 3, 147
Anagesterone acetate, 2, 165
Anagrelide, 3, 244
Androstanolone, 1, 173
Anidoxime, 2, 125
Anileride, 1, 300
Anilopam, 3, 121
Aniracetam, 4, 39
Anirolac, 4, 158
Anisindandione, 1, 147
Anitrazafen, 1, 147
Antazoline, 1, 242
Antipyrine, 1, 234
Apalcillin, 4, 179
Apazone, 2, 475
Apraclonidine, 5, 74
Aprophen, 1, 91
Aptazapine, 4, 215
Ara-A, 4, 122
Arbaprostil, 3, 8
Arbutamine, 5, 15
Arildone, 3, 45
Arprinocid, 4, 165
Astemizole, 3, 177
Atenolol, 2, 109
Atipamezole, 5, 71
Atiprosin, 4, 211
Atropine, 1, 35
A vridine, 4, I
Azabon, 2, 115
Azaclorzine, 3, 241
Azacosterol, 2, 161
Azacyclonol, 1, 47
Azaloxan, 4, 138
Azanator, 2, 457
Azaperone, 2, 300
Azarole, 3, 129
Azastene, 3, 89
Azatadine, 2, 424
Azathioprine, 2, 464
Azelastine, 4, 152
Azepinamide, 1, 137
Azepindole, 3, 242
Azipramine, 3, 246
Azlocillin, 3, 206
Azoconazole, 3, 137
Azolimine, 2, 260
Azomycin, 1, 238
Azosemide, 3, 27
Aztreonam, 4, 193
Azumolene, 5, 68
Bacampicillin, 3, 204
Baclofen, 2, 121

CUMULATIVE INDEX, VOLUMES 1-5 193
Bamethan, 2, 39
Bamiphylline, 1, 426
Bamipine, I, 51
Bamnidazole, 3, 132
Barbital, 1, 267
BAS, 2, 96
Batanopride, 5, 2 I
Batelapine, 5, 169
Becanthone, 2, 413
Belfosdil, 5, 2
Beloxamide, 2, 56
Bemarinone, 5, 131
Bemidone, I, 305
Bemigride. 1, 258
Bemitradine, 4, 168
Bemoradan, 5, 133
Bemsetron, 5, 66
Benactyzine, I, 93
Benapryzine, 2, 74
Benazepril, 5, 135
Bendacalol, 5, 134
Bendazac, 2, 351
Bendroflumethazide, 2, 358
Benfurodil, 2, 355
Benorterone, 2, 156
Benoxaprofen, 2, 356
Benperidol, 2, 290
Bentiromide, 3, 60
Benzbromarone, 2, 354
Benzestrol, 1, 103
Benzetimide, 2, 293
Benzilonium bromide, 2, 72
Benzindopyrine, 2, 343
Benziodarone, 1, 3 13
Benzocaine, 1, 9
Benzoctamine, 2, 220
Benzodepa, 2, 122
Benzphetamine, 1, 70
Benzquinamide, 1, 350
Benztriamide, 2, 290
Benzydamine, 1, 323
Benzylpenicillin, 1, 408
Bepridil, 3, 46
Beraprost, 5, 176
Beta eucaine, 1, 9
Betahistine, 2, 279
Betamethasone, 1, 198
Betaxolol, 4, 26
Bethanidine, 1, 55
Bevantolol, 3, 28
Bezafibrate, 3, 44
Biantrazole, 5, 43
Bicifadine, 3, 120
Biclodil, 4, 38
Bidisomide, 5, 87
Bifonazole, 4, 93
Binafloxacin, 5, 125
Binospirone, 5, 134
Bipenamol, 4, 45
Biperiden, 1, 47
Bisantrene, 4, 62
Bishydroxycoumarin, 1, 331
Bisoprolol, 4, 28
Bitolterol, 3, 22
Bizelesin, 5, 173
Bolandiol diacetate, 2, 143
Bolasterone, 1, 173
Boldenone, 2, 153
Bolmantalate, 2, 143
Boxidine, 2, 99
Brequinar,5, 121
Bretazenil, 5, 177
Bretylium tosylate, 1, 55
Brifentanil, 5, 84
Brimodine, 5, 132
Brocrinat, 4, 130
Brofoxine, 3, 191
Bromadoline, 4, 6
Bromdiphenhydramine, 1, 42
Bromfenac, 4, 46
Bromhexine, 2, 96
Bromindione, 2, 210
Bromisovalum, 1, 22 I
Bromoxanide, 2, 94
Bromperidol, 2, 331
Brompheniramine, 1, 77
Brompirimine, 4, 116
Broperamole, 3, 139
Brotizolam, 4, 219
Bucainide, 2, 125
Bucindolol, 3, 28
Bucromanone, 5, 128
Budesonide, 3, 95
Bufonnin, 1, 221
Bufuralol, 2, 110
Bumetanide, 2, 87
Bunaftine, 2, 211
Bunamidine, 2, 212
Bunitridine, 2, 215
Bunitrolol, 2, 106
Bunolol, 2, 110
Bupicomide, 2, 280
Bupivacaine, 1, 17
Buprenorphine, 2, 321

194 CUMULATIVE INDEX, VOLUMES 1-5
Bupropion, 2, 124
Buquinolate, 1, 346
Burimamide, 2, 251
Buspirone, 2, 300
Butabarbital, 1, 268
Butacaine, 1, 12
Butacetin, 2, 95
Butaclamol, 2, 226
Butalbital, 1, 268
Butamirate, 2, 76
Butamisole, 3, 226
Butaperazine, 1, 381
Butaprost, 4, 13
Butazolamide, 1, 249
Buterizine, 3, 175
Butethal, 1, 268
Butoconazole, 3, 134
Butoprozine, 4, 156
Butorphanol, 2, 325
Butoxamine, 1, 68
Butriptyline, 1, 151
Butropium bromide, 2, 308
Butylallonal, 1, 269
Butylvynal, 1, 269
Caffeine, 1, 111
Calcifediol, 3, 101
Calcipotriene, 5, 60
Calcitriol, 3, 103
Calusterone, 2, 154
Cambendazole, 2, 353
Canrenoate, 2, 174
Canrenone, 2, 174
Capobenic acid, 2, 94
Captodiamine, 1, 44
Captopril, 3, 128
Caracemide, 4, 1
Caramiphen, 1, 90
Carbacephalothin, 2, 390
Carbacycline, 4, 14
Carbadox, 2, 390
Carbamazepine, 1, 403
Carbantel, 3, 57
Carbazeran, 3, 195
Carbencillin, 1, 414
Carbetidine, 1, 90
Carbidopa, 2, 119
Carbimazole, 1, 240
Carbinoxamine, 1, 43
Carbiphene, 2, 78
Carboplatin, 4, 16
Carboprost, 3, 7
Carbutamide, 1, 138
Carbuterol, 2, 41
Carfentanyl, 3, 117
Carisoprododol, 1, 219
Carmantidine, 2, 20
Cannustine, 2, 12
Camidazole, 2, 245
Caroxazone, 3, 191
Carphenazine, 1, 383
Carpipramine, 2, 416
Carprofen, 2, 169
Cartazolate, 2, 469
Carteolol, 3, 183
Carumonam, 4, 193
Carvedilol, 5, 163
Carzelesin, 5, 171
Cefaclor, 3, 209
Cefadroxyl, 2, 440
Cefamandole, 2, 441
Cefaparole, 3, 212
Cefatrizine, 3, 211
Cefazaflur, 3, 213
Cefazolin, 3, 442
Cefbuperazone, 4, 189
Cefetamet, 4, 184
Cefetecol, 5, 160
Cefixime, 4, 184
Cefmenoxime, 4, 187
Cefmetazole, 4, 190
Cefonicid, 3, 213
Cefoperazone, 4, 185
Ceforanide, 3, 214
Cefotaxime, 3, 216
Cefotetan, 4, 191
Cefotiam, 3, 215
Cefoxitin, 2, 435
Cefpimizole, 4, 185
Cefpiramide, 4, 188
Cefpiromine, 5, 158
Cefpodoxime proxetil, 5, 158
Cefprozil, 5, 158
Cefroxadine, 3, 210
Cefsulodin, 3, 214
Ceftazidine, 3, 216
Ceftibuten, 5, 160
Ceftiofur, 4, 187
Ceftizoxime, 3, 218
Ceftriaxone, 4, 190
Cefuroxime, 3, 216

CUMULATIVE INDEX, VOLUMES 1-5 195
Celiprolol, 4, 27
Cephalexin, 1, 417
Cephaloglycin,I,417
Cephaloridine, 1, 417
Cephalothin, 1, 420
Cephapyrin, 2, 441
Cephradine, 2, 440
Ceronapril, 5, 65
Cetaben, 3, 60
Cetamole, 4, 26
Cetiedil, 3, 42
Cetirizine, 4, 118
Cetophenicol, 2, 46
Cetraxate, 4, 6
Chloraminophenamide, 1, 133
Chlorbenzoxamine, 1, 43
Chlorcyclizine, 1, 58
Chlordiazepexoxide, 1, 365
Chlorexolone, 1, 321
Chlorfluperidol, 1, 306
Chlorguanide, 1, 115
Chlorimpiphene, 1, 385
Chlorindandione, I, 147
Chlonnadinone acetate, 1, 181
Chlonnidazole, 1, 324
Chlorophenylalanine, 2, 52
Chloroprocaine, 1, 11
Chloropyramine, 1, 402
Chloroquine, 1, 341
Chlorothen, 1, 54
Chlorothiazide, 1, 321
Chlorotrianisine, 1, 104
Chlorphenamide, 1, 133
Chlorphendianol, 1, 46
Chlorphenesin, I, 118
Chlorpheniramine, 1, 77
Chlorphenoxamine, 1, 44
Chlorphentennine, 1, 73
Chlorproethazine, 1, 379
Chlorproguanil, 1, 115
Chlorpromazine, 1, 319
Chlorpropamide, 1, 137
Chlorprothixene, 1, 399
Chlorpyramine, 1, 51
Chlortetracycline, 1, 212
Chlorthalidone, 1, 322
Chlorzoxazone, 1, 323
Chromoglycate, 1, 313
Chromonar, 1, 331
Cibenzoline, 4, 87
Ciclafrine, 2, 226
Ciclazindol, 4, 217
Cicletanine, 5, 143
Cicloprofen, 2, 217
Cicloprolol, 4, 25
Cicloprox, 2, 282
Ciglitazone, 4, 33
Ciladopa, 4, 22
Cilazapril, 4, 170
Cimaterol, 4, 23
Cimetidine, 2, 253
Cinanserin, 2, 96
Cinepazet, 3, 157
Cinepazide, 2, 30 I
Cinflumide, 4, 35
Cingestol, 2, 145
Cinnameridine, 2, 39
Cinnarizine, 1, 58
Cinoxacin, 2, 388
Cinromide, 3, 44
Cintazone, 2, 388
Cintriamide, 2, 121
Cioteronel, 5, II
Ciprefadol, 3, 119
Ciprocinonide, 3, 94
Ciprofibrate, 3, 44
Ciprofloxacin, 4, 141
Ciprostene, 4, 14
Ciramadol, 3, 122
Cisplatin, 4, 15
Citenamide, 2, 221
Clamoxyquin, 2, 362
Clavulanic acid, 4, 180
Clazolam, 2, 452
Clazolimine, 2, 260
Clebopride, 4, 42
Clemastine, 2, 32
Clemizole, 1, 324
Clentiazem, 5, 139
Clinafloxacin, 5, 125
Clioxanide, 2, 94
Cliprofen, 2, 65
Clobazam, 2, 406
Clobetasol propionate, 4, 72
Clobetasone butyrate, 4, 72
Clobutinol, 2, 121
Clocapramine, 2, 416
Clocental, 1, 38
Clocortolone acetate, 2, 193
Clodanolene, 3, 130
Clodazon, 2, 354
Clofenpyride, 2, 101

196 CUMULATIVE INDEX, VOLUMES 1-5
Clofibrate, 1, 119
Clofilium phosphate, 3, 46
Clogestone, 2, 166
Clomacran, 2, 414
Clomegestone acetate, 2, 170
Clomethrone, 2, 170
Clomifene, 1, 105
Clominorex, 2, 265
Clonidine, 1, 241
Clonitazene, 1, 325
Clonixeril, 2, 281
Clonixin, 2, 281
Clopamide, 1, 135
Clopenthixol, 1, 399
Cloperidone, 2, 387
Cloperone, 3, 150
Clopimozide, 2, 300
Clopipazam, 3, 237
Clopirac, 2, 235
Cloprednol, 2, 182
Cloprenaline, 2, 39
Cloprostenol, 2, 6
Clorsulon, 4, 50
Closantel, 3, 43
Closiramine, 2, 424
Clothiapine, I, 406
Clothixamide, 2, 412
Cloticasone propionate, 4, 75
Cloxacillin, 1, 413
Cloxazepam, 1, 370
Clozapine, 2, 425
Codeine, 1, 287
Codorphone, 3, 112
Codoxime, 2, 318
Colchicine, 1, 152
Colestolone, 5, 55
Colterol, 3, 21
Connethasone acetate, 2, 194
Cortisone, 1, 188
Cortisone acetate, 1, 190
Crilavastine, 5, 65
Crisnatol, 5, 44
Cromitrile, 4, 137
Cromoglycate, 3, 66
Cyclacillin, 2, 439
Cyclandelate, 1, 94
Cyclazocine, 1, 298
Cyclindole, 3, 168
Cyclizine, 1, 58
Cyclobarbital, 1, 269
Cyclobendazole, 2, 353
Cyclobenzaprine, 3, 77
Cycloguanil, 1, 281
Cyclomethycaine, 1, 14
Cyclopal, 1, 269
Cyclopenthiazide, 1, 358
Cyclopentolate, 1, 92
Cyclophosphamide, 3, 161
Cyclopyrazolate, 1, 92
Cycloserine, 3, 14
Cyclothiazide, 1, 358
Cycrimine, 1, 47
Cyheptamide, 2, 222
Cypenamine, 2, 7
Cyprazepam, 2, 402
Cyproheptadine, 1, 151
Cyprolidol, 2, 31
Cyproquinate, 2, 368
Cyproterone acetate, 2, 166
Cyproximide, 2, 293
Dacarbazine, 2, 254
Daledalin, 2, 348
Daltroban, 5, 22
Dalvastatin, 5, 87
Danazol, 2, 157
Danfloxacin, 5, 125
Dantrolene, 2, 242
Dapiprazole, 5, 143
Dapoxetine, 5, 36
Dapsone, 1, 139
Darodipine, 4, 107
Dazadrol, 2, 257
Dazepinil, 5, 137
Dazoxiben, 4, 91
Debrisoquine, 2, 374
Decitabine, 5, 101
Declenperone, 3, 172
Decoquinate, 2, 368
Delapril, 4, 58
Delmadinone acetate, 2, 166
Demoxepam, 2, 401
Deprostil, 2, 3
Desciclovir, 4, 165
Descinolone acetonide, 2, 187
Deserpidine, 1, 320
Desipramine, 1, 402
Desogestrel, 5, 52
Desonide, 2, 179
Desoximetasone, 4, 70
Deterenol, 2, 39
Detomidine, 5, 71

CUMULATIVE INDEX, VOLUMES 1-5 197
Devazepide, 5, 137
Dexamethasone, 1, 199
Dexbrompheniramine, 1, 77
Dexmedetomidine, 5, 71
Dexnorgestrel acetime, 2, 152
Dexonnaplatin, 5, 11
Dexrazoxone, 5, 95
Dextroamphetamine, 1, 70
Dextromoramide, 1, 82
Dextromorphan, 1, 293
Dextrothyroxine, 1, 92
Dezaguanine, 4, 162
Dezocine, 4, 59
Diacetolol, 3, 28
Diamocaine, 2, 336
Dianithazole, 1, 327
Diapamide, 2, 93
Diaveridine, 2, 302
Diazepam, 1, 365
Diaziquone, 4, 51
Dibenamine, 1, 55
Dibenzepin, 1, 405
Dibucaine, 1, 15
Dichlorisone, 1, 203
Dichloroisoproterenol, 1, 65
Dichlorophenamide, 1, 133
Diclofenac, 2, 70
Dicloxacillin, 1, 413
Dicoumarol, 1, 147
Dicyclomine, 1, 36
Didanosine, 5, 146
Dienestrol, 1, 102
Diethyl carbamazine, 1, 278
Diethy lstibestrol, 1, 101
Diethylthiambutene, 1, 106
Difenoximide, 2, 331
Difenoxin, 2, 331
Difloxacin, 4, 143
Diflucortolone, 2, 192
Diflumidone, 2, 98
Diflunisal, 2, 85
Difluprednate, 2, 191
Diftalone, 3, 246
Dihexyverine, 1, 36
Dihydralizine, 1, 353
Dihydrocodeine, 1, 288
Dilevalol, 4, 20
Diltiazem, 3, 198
Dimefadane, 2, 210
Dimefline, 2, 391
Dimetacrine, 1, 397
Dimethisoquine, 1, 18
Dimethisterone, 1, 176
Dimethothiazine, 1, 374
Dimethoxanate, 1, 390
Dimethylpyrindene, 1, 145
Dimethy lthiambutene, 1, 106
Dimetridazole, 1, 240
Dinoprost, 1, 27
Dinoprostone, 1, 30
Dioxadrol, 2, 285
Dioxyline, 1, 349
Di phenhydrami ne, 1, 41
Diphenidol, 1, 45
Diphenoxylate, 1, 302
Diphenylhydantoin, 1, 246
Diphepanol, 1, 46
Dipivefrin, 3, 22
Dipyridamole, 1, 248
Dipyrone, 2, 262
Disobutamide, 3, 41
Disopyramide, 2, 81
Disoxaril, 4, 86
Disulfiram, 1, 223
Ditekiren, 5, 4
Dithiazanine, 1, 327
Dixyrazine, 1, 384
Dizocilpine, 5, 136
Dobutamine, 2, 53
Docebenone, 5, 8
Doconazole, 3, 133
Dolasetron, 5, 109
Domazoline, 2, 256
Domperidone, 3, 174
Donetidine, 4, 114
Dopamantine, 2, 52
Dopexamine, 4, 22
Dorastine, 2, 457
Doretinel, 5, 38
Dorzolamide, 5, 149
Dothiepin, 3, 239
Doxapram, 2, 236
Doxaprost, 2, 3
Doxazocin, 4, 148
Doxepin, 1, 404
Doxofylline, 5, 144
Doxpicomine, 3, 122
Doxylamine, 1, 44
Dribendazole, 4, 132
Drindene, 3, 65
Drobuline, 3, 47
Drocinonide, 2, 186

198 CUMULATIVE INDEX, VOLUMES 1-5
Dromostanolone, 1, 173
Droperidol, 1, 308
Droprenylamine, 3, 47
Droxacin, 3, 185
Duoperone, 4, 199
Dydrogesterone, 1, 185
Ebastine, 4, 48
Eclanamine, 4, 5
Eclazostat, 4, 131
Econazole, 2, 249
Ectylurea, 1, 221
Edatrexate, 5, 152
Edifolone, 4, 69
Edoxudine, 4, 117
Eflomithine, 4, 2
Elantrine, 2, 418
Elfazepam, 3, 195
Elucaine, 2, 44
Emilium tosylate, 3, 47
Enalapril, 4, 81
Enalkiren, 5, 4
Encainide, 3, 56
Enciprazine, 5, 92
Encyprate, 2, 27
Endralazine, 3, 232
Endrysone, 2, 200
Enilconazole, 4, 93
Enisoprost, 4, 11
Enolicam, 4, 148
Enpiroline, 4, 103
Enprofylline, 4, 165
Enprostil, 4, 10
Enrofloxacin, 5, 125
Enviradene, 4, 131
Enviroxime, 3, 177
Ephedrine, 1, 66
Epimestrol, 2, 138
Epinephrine, 1, 95
Epirazole, 3, 152
Epithiazide, 1, 359
Epoprostenol, 3, 10
Epostane, 4, 68
Eprazinone, 1, 64
Eprozinol, 2, 44
Eritadenine, 2, 467
Erytriptamine, 1, 317
Esmolol, 4, 27
Esproquin, 2, 373
Estradiol, 1, 162
Estradiol benzoate, 1, 162
Estradiol cypionate, 1, 162
Estradiol dipropionate, 1, 162
Estradiol hexabenzoate, 1, 162
Estramustine, 3, 83
Estrazinol, 2, 142
Estrofurate, 2, 137
Estrone, 1, 156
Eta fed rine, 2, 39
Etanidazole, 5, 73
Etarotene, 5, 37
Etazolate, 2, 469
Eterobarb, 2, 304
Ethacrynic acid, 1, 120
Ethambutol, 1, 222
Ethamivan, 2, 94
Ethionamide, 1, 255
Ethisterone, 1, 163
Ethithiazide, 1, 358
Ethoheptazine, 1, 303
Ethonam, 2, 249
Ethopropropazine, 1, 373
Ethosuximide, 1, 228
Ethotoin, 1, 245
Ethoxzolmide, 1, 327
Ethy lestrenol, 1, I 70
Ethylmorphine, 1, 287
Ethynerone, 2, 146
Ethynodiol Diacetate, 1, 165
Ethynodrel, 1, 164
Ethynylestradiol, 1, 162
Etibendazole, 4, 132
Etidocaine, 2, 95
Etintidine, 3, 135
Etintidine, 4, 89
Etoclofene, 2, 89
Etofenamate, 4, 42
Etomidate, 3, 135
Etonitazine, 1, 325
Etoperidone, 5, 92
Etoprine, 3, 153
Etorphine, 2, 321
Etoxadrol, 2, 285
Fadrozole, 5, 141
Famotidine, 2, 37
Fanetizole, 4, 95
Fantridone, 2, 421
Fazarabine, 4, 122
Febantel, 4, 35

CUMULATIVE INDEX, VOLUMES 1-5 199
Felbinac, 4, 32
Felodipine, 4, 106
Felsantel, 3, 57
Fenalamide, 2, 81
Fenbendazole, 3, 176
Fenbufen, 2, 126
Fencamfine, 1, 74
Fenclofenac, 3, 37
Fenclorac, 2, 66
Fenclozic acid, 2, 269
Fendosal, 2, 170
Fenestrel, 2, 9
Fenethylline, 1, 425
Fenfluramine, 1, 70
Fengabine, 4, 47
Fenimide, 2, 237
Feniprane, 1, 76
Fenisorex, 2, 391
Fenmetozole, 2, 257
Fenobam, 3, 136
Fenoctimine, 4, 109
Fenoldapam, 4, 147
Fenoprofen, 2, 67
Fenoterol, 2, 38
Fenpipalone, 2, 293
Fenprinast, 4, 213
Fenprostalene, 4, 9
Fenquizone, 3, 192
Fenretidine, 4, 7
Fenspiriden, 2, 291
Fentanyl, 1, 299
Fentiazac, 4, 96
Fenticonazole, 4, 93
Fenyripol, 2, 40
Fetoxylate, 2, 331
Fezolamine, 4, 87
Fiacitabine, 5, 98
Finasteride, 5, 49
Flavodilol, 4, 137
Flavoxate, 2, 392
Flazolone, 2, 337
Flecainide, 3, 59
Fleroxacin, 5, 125
Flestolol, 4, 41
Fletazepam, 2, 403
Floctacillin, 1, 413
Floctafenine, 3, 184
Flordipine, 4, 107
Flosequinan, 5, 127
Fluandrenolide, 2, 180
Fluanisone, 1, 279
Fluazepam, 1, 366
Flubanilate, 2, 98
Flubendazole, 2, 354
Flucindolol, 3, 168
Flucinolone, 3, 94
Flucinolone acetonide, 1, 202
Fludalanine, 3, 14
Fludarabine, 4, 167
Fludorex, 2, 44
Fludrocortisone, 1, 192
Fludroxycortide, 1, 202
Flufenamic acid, 1, 110
Flumazenil, 4, 220
Flumequine, 3, 186
Flumethasone, I, 200
Flumethiazide, 1, 355
Flumetramide, 2, 306
Fluminorex, 2, 265
Flumizole. 2, 254
Flumoxonide, 3, 95
Flunarizine, 2, 31
Flunidazole, 2, 246
Flunisolide, 2, 181
Flunitrazepam, 2, 406
Flunixin, 2, 281
Fluorocortolone, 1, 204
Fluorodopa F18, 5, 27
Fluorogestone acetate, 2, 183
Fluorometholone, 1, 203
Fluoroprednisolone, 1, 292
Fluorouracil, 3, 155
Fluotracen, 3, 73
Fluoxetine, 3, 32
Fluoxymestrone, 1, 175
Fluparoxan, 5, 170
Fluperamide, 2, 334
Fluperolone acetate, 2, 185
Fluphenazine, 1, 383
Flupirtine, 4, 102
Fluproquazone, 3, 193
Fluprostenol, 2, 6
Fluquazone, 3, 193
Fluradoline, 4, 202
Flurbiprofen, 1, 86
Fluretofen, 3, 39
Fluspiperone, 2, 292
Fluspirilene, 2, 292
Flutamide, 3, 57
Flutiazine, 2, 431

200 CUMULATIVE INDEX, VOLUMES 1-5
Fluticasone propionate, 4, 75
Flutroline, 3, 242
Fluvastatin, 5, 105
Fluzinamide, 4, 29
Fonnocortal, 2, 189
Fosarilate, 4, 31
Fosazepam, 3, 195
Fosinopril, 5, 66
Fosquidone, 5, 181
Fostedil, 4, 134
Frentizole, 3, 179
Fumoxicillin, 4, 179
Furaltadone, 1, 229
Furaprofen, 4, 127
Furazolidone, 1, 229
Furegrelate, 4, 125
Furethidine, 1, 301
Furobufen, 2, 416
Furodazole, 4, 215
Gamfexine, 2, 56
Ganciclovir, 5, 146
Gemcadiol, 3, 15
Gemcitabine, 5, 96
Gemeprost, 4, 11
Gemfibrozil, 3, 45
Gepirone, 4, 120
Gestaclone, 2, 169
Gestodene, 3, 85
Gestonorone, 2, 152
Gestrinone, 3, 85
Gevotroline, 5, 164
Glaphenine, 1, 342
Gliamilide, 2, 286
Glibomuride, 2, 117
Glicetanile, 3, 61
Gliflumide, 3, 61
Glipizide, 2, 117
Gloxinonam, 4, 195
Glutethemide, 1, 257
Glyburide, 2, 139
Glybuthiazole, 1, 126
Glycosulfone, 1, 140
Glyhexamide, 1, 138
Glymidine, 1, 125
Glyoctamide, 2, 117
Glyparamide, 2, 117
Glyprothiazole, 1, 125
Granisetron, 5, 118
Griseofulvin, 1, 314
Guaiaphenesin, 1, 118
Guanabenz, 2, 123
Guanacycline, 1, 260
Guanadrel, 1, 400
Guanethidine, 1, 282
Guanfacine, 3, 40
Guanisoquin, 2, 375
Guanoclor, 1, 117
Guanoxabenz, 2, 123
Guanoxan, 1, 352
Guanoxyfen, 2, 101
Halcinonide, 2, 187
Halobetasol, 5, 57
Halofantrine, 3, 76
Halofenate, 2, 80
Halopemide, 3, 174
Haloperidol, 1, 306
Haloprednone, 3, 99
Haloprogesterone, 3, 173
Heptabarbital, 1, 269
Hepzidine, 2, 222
Heroin, 1, 288
Hetacillin, 1, 414
Heteronium bromide, 2, 72
Hexahydroamphetamine, 4, 4
Hexesterol, 1, 102
Hexethal, 1, 268
Hexobarbital, 1, 273
Hexobendine, 2, 92
Hexylcaine, 1, 12
Histapyrrodine, 1, 50
Hoquizil, 2, 381
Hycanthone, 1, 398
Hydracarbazine, 2, 305
Hydrochlorothiazide, 1, 358
Hydrocodone, 1, 288
Hydrocortisone, 1, 190
Hydrocortisone acetate, 1, 190
Hydroflumethiazide, 1, 358
Hydromorphone, 1, 288
Hydroxyamphetamine, 1, 71
Hydroxychloroquine, 1, 342
Hydroxyphenamate, 1, 220
Hydroxyprocaine, 1, 11
Hydroxyprogesterone, 1, 176
Hydroxyzine, 1, 59
Ibafloxacin, 5, 127
Ibu fenac , 1, 86
Ibuprofen, 1, 86
Ibutilide, 5, 23

CUMULATIVE INDEX, VOLUMES 1-5 201
Icotidine, 4, 113
Idarubicin, 5, 47
Ifenprodil, 2, 39
Ifosfamide, 3, 151
Imafen, 3, 226
Imazodan, 4, 90
Imidoline, 2, 259
Imiloxan, 4, 88
Imipenem 4, 181
Imipramine, 1, 401
Imiquimod, 5, 173
Imolamine, 1, 249
Incoterone, 5, 49
Indacrinone, 3, 67
Indapamide, 2, 349
Indecainide, 4, 62
Indeloxazine, 4, 59
Indolapril, 4, 128
Indolidan, 5, 110
Indomethacin, 1, 318
Indoprofen, 3, 171
Indoramine, 2, 344
Indorenate, 3, 167
Indoxole, 2, 254
Inocoterone, 5, 49
Intrazole, 2, 354
Intriptyline, 2, 223
lodothiouracil, 1, 265
Ipazilide, 5, 70
Ipexidine, 3, 157
Ipratropium bromide, 3, 160
Iprindol, 1, 318
Iproniazide, 1, 254
Ipronidazole, 2, 244
Iproplatin, 4, 17
Ipsapirone, 5, 91
Irtemazole, 5, 117
Isamoxole, 3, 138
Isoaminile, 1, 82
Isobucaine, 1, 12
Isobuzole, 2, 272
Isocarboxazide, 1, 233
Isoetharine, 2, 9
Isomazole, 4, 163
Isomethadone, 1, 79
Isomylamine, 2, 11
Isoniazide, 1, 254
Isopentaquine, 1, 346
Isopyrine, 1, 234
Isothiopendyl, 1, 430
Isotiquamide, 4, 139
Isotretinoin, 3, 12
Isoxepac, 3, 328
Isoxicam, 2, 394
Isoxsuprine, 1, 69
Isradipine, 4, 107
ltazigrel, 4, 96
Ketamine, 1, 57
Ketanserin, 3, 193
Ketasone, 1, 237
Ketazocine, 2, 238
Ketazolam, 1, 369
Ketobemidone, 1, 303
Ketoconazole, 3, 132
Ketoprofen, 2, 64
Ketorfanol, 4, 60
Ketorolac, 4, 81
Ketotifen, 3, 239
Khellin, 1, 313
Labetolol, 3, 24
Lacidipine, 5, 82
Lamivudine, 5, 99
Lamotrigine, 4, 120
Lansoprazole, 5, 115
Lavoltidine, 5, 77
Leniquinsin, 2, 363
Lenperone, 2, 286
Lergotrile, 2, 480
Letimide, 2, 393
Levalorphanol, 1, 293
Levamisole, 4, 217
Levarterenol, 1, 63
Levocabastine, 4, 110
Levonantrodol, 3, 188
Levonordefrine, 1, 68
Levophenacylmorphan, 1, 294
Levopropoxyphene, 1, 50
Levothypoxine, 1, 97
Lidamidine, 3, 56
Lidocaine, 1, 16
Lidoflazine, 1, 279
Lifarizine, 5, 92
Lifibrate, 1, 103
Linarotine, 5, 37
Linogrilide, 4, 80
Liothyronine, 1, 97
Lisinopril, 4, 83
Lixazinone, 5, 166
Lobendazole, 2, 353
Lobenzarit, 4, 43

202 CUMULATIVE INDEX, VOLUMES 1-5
Lodelaben, 5, 22
Lodoxamide, 3, 57
Lofemizole, 4, 90
Lofentanyl, 3, 117
Lofepramine, 4, 201
Lofexidine, 4, 88
Lomefloxacin, 5, 125
Lometraline, 2, 214
Lometrexol, 5, 151
Lomustine, 2, 12
Lonapalene, 4, 57
Loperamide, 2, 334
Lorazepam, 1, 368
Lorbamate, 2, 21
Lorcai nide, 3, 40
Lorcinadol, 5, 94
Lorglumide, 5, 20
Lonnetazepam, 3, 196
Lortalamine, 4, 404
Lorzafone, 4, 48
Losartan, 5, 73
Losoxantrone, 5, 43
Losulazine, 4, 139
Loteprednol, 5, 56
Loveclazole, 5, 78
Loxapine, 2, 427
Loxoribine, 5, 145
Lucanthone, 1, 397
Lupitidine, 4, 115
Lynestrol, 1, 166
Mafenide, 2, 114
Mafosfamide, 5, 102
Maprotiline, 2, 220
Masoprocol, 5, 31
Matotilate, 5, 75
Mazindol, 2, 462
Mebendazole, 2, 353
Mebeverine, 2, 54
Mebhydroline, 1, 319
Mebromphenhydramine, 1, 44
Mebutamate, 1, 218
Meccnu, 2, 12
Mecillinam, 3, 208
Meclastine, 1, 44
Meclizine, 1, 59
Meclofenamic acid, 1, 110
Meclorisone butyrate, 3, 95
Medazepam, 1, 368
Medibazine, 2, 30
Mediquox, 2, 390
Medorinone, 5, 149
Medrogestone, 1, 182
Medroxalol, 3, 25
Medroxyprogesterone, 1, 180
Medrylamine, 1, 41
Medrysone, 2, 200
Mefenamic acid, 1, 110
Mefenidil, 4, 89
Mefenorex, 2, 47
Mefexamide, 2, 103
Mefruside, 1, 134
Megesterol acetate, 1, 180
Melengesterol acetate, 1, 182
Melitracen, 2, 220
Melphalan, 2, 120
Memotine, 2, 378
Menabitan, 4, 210
Menoctone, 2, 217
Meobentine, 3, 45
Meparfynol, 1, 38
Meperidine, 1, 300
Mephenhydramine, 1, 44
Mephenoxalone, 1, 119
Mephensin, 1, 118
Mephensin carbamate, 1, 118
Mephentermine, 1, 72
Mepivacaine, 1, 17
Meprobamate, 1, 218
Mequoqualone, 1, 354
Meralluride, 1, 224
Mercaptomerine, 1, 224
Meseclazone, 1, 254
Mesoridazine, 1, 389
Mesterolone, 1, 174
Mestranol, 1, 162
Mesuprine, 2, 41
Metabutoxycaine, 1, 11
Metalol, 2, 41
Metampicillin, 1, 41
Metaproterenol, 1, 64
Metaxalone, 1, 119
Meteneprost, 3, 9
Methacycline, 2, 227
Methadone, 1, 79
Methallenestril, 1, 187
Methamphetamine, 1, 37
Methandrostenolone, 1, 173
Methantheline bromide, 1, 393
Methaphencycline, 1 53
Methaphenyline, 1, 52
Methaprylon, 1, 259

CUMULATIVE INDEX, VOLUMES 1-5 203
Methapyriline, 1, 54
Methaqualone, 1, 353
Metharbital, 1, 273
Methazolamide, 1, 250
Methdilazine, 1, 387
Methenolone acetate, 1, 175
Methicillin, 1, 412
Methimazole, 1, 240
Methisazone, 2, 350
Methitural, 1, 275
Methixine, 1, 400
Methocarbamol, 1, 118
Methohexital, 1, 269
Methopholine, 1, 349
Methopromazine, 1, 374
Methoxsalen, 1, 333
Methoxypromazine, 1, 387
Methsuximide, 1, 228
Methyclothiazide, 1, 360
Methylchromone, 1, 335
Methyldihydromorphinone, 1, 292
Methyldopa, 1, 95
Methylphenidate, 1, 88
Methylprednisolone, 1, 193
Methylprednisolone, 16-B. 1, 196
Methyltestosterone, 1, 172
Methylthiouracil, 1, 264
Methynodiol diacetate, 2, 149
Methyridine, 1, 256
Methysergide, 2, 477
Metiamide, 2, 252
Metiapine, 2, 429
Metioprim, 3, 155
Metipranolol, 5, 17
Metizoline, 2, 256
Metoclopramide, 5, 20
Metolazone, 2, 384
Metopimazine, 1, 153
Metoprolol, 2, 109
Mexrenoate, 2, 175
Mexrenone, 2, 175
Mezlocillin, 3, 206
Mianserin, 2, 451
Mibolerone, 2, 144
Miconazole, 2, 249
Midaflur, 2, 259
Midazolam, 3, 197
Midodrine, 4, 23
Mifepristone, 5, 53
Milenperone, 3, 172
Milipertine, 2, 341
Mimbane, 2, 347
Minaprine, 4, 120
Minaprine, 5, 96
Minaxolone, 3, 90
Minocycline, 1, 214
Minoxidil, 1, 262
Mioflazine, 4, 119
Mirtazapine, 5, 177
Misonidazole, 3, 132
Mitindomine, 4, 218
Mitoxantrone, 3, 75
Mixidine, 2, 54
Moclobemide, 4, 39
Modaline, 2, 299
Modecainide. 5, 86
Mofebutazone, 1, 234
Molinazone, 2, 395
Molindone, 2, 455
Molsidomine, 3, 140
Mometasone, 4, 73
Moprolol, 2, 109
Morantel, 1, 266
Morazone, 2, 261
Moricizine, 4, 200
Momiflumate, 3, 146
Morphazineamide, 1, 277
Morphedrine, 1, 300
Morphine, 1, 286
Motretinide, 3, 12
Moxalactam, 3, 218
Moxazocine, 3, 114
Moxisylyte, 1, 116
Moxnidazole, 2, 246
Muzolimine, 3, 137
4abazenil, 4, 209
Nabilone, 3, 189
Nabitan, 3, 190
Naboctate, 4, 209
Nadolol, 2, 110
Nafcillin, 1, 412
Nafenopin, 2, 214
Nafimidone, 4, 90
Naflocort, 4, 75
Nafomine, 2, 212
Nafoxidine, 1, 147
Nafronyl, 2, 213
Naftidine, 3, 372
Naftifine, 4, 55
Nalbufine, 2, 319

204 CUMULATIVE INDEX, VOLUMES 1-5
Nalidixic acid, 1, 429
Nalmefene, 4, 62
Naloxone, 1, 289
Naltrexone, 2, 319
Namoxyrate, 1, 86
N androlone, 1, 164
Nandrolone decanoate, 1, 171
Nandrolone phenpropionate. 1, 171
Nantradol, 3, 186
Napactidine, 3, 71
Napamazole, 4, 87
Naphazoline, 1, 241
Naproxen, 1, 86
Naranol, 2, 454
Naxogilide, 5, 175
Nebivolol, 5, 128
Nedocromil, 4, 209
Nefazodone, 4, 98
Neflumozide, 4, 133
Nefopam, 2, 447
Nelezaprine, 5, 168
Negostigmine. 1, 114
Nequinate, 2, 369
Netobimin, 4, 36
Nexeridine, 2, 17
Nialamide, 1, 254
Nicardipine, 3, 150
Nicergoline, 2, 478
N iclosamide, 2, 94
Nicordanil, 3, 148
Nicotinic acid, 1, 253
Nictotinyl alcohol, 1, 253
Nidroxyzone, 1, 228
Nifedipine, 2, 283
Nifenazone, 1, 234
Nifluminic acid, 1, 256
Nifuratrone, 2, 238
Nifurdazil, 2, 239
Nifurimide, 2, 239
Nifuroxime, 2, 238
Nifurpirinol, 2, 240
Nifurprazine, 1, 231
Nifurquinazol, 2, 383
Nifursemizone, 2, 238
Nifurthiazole, 2, 241
Nikethamide, 1, 253
Nilvadipine, 4, 107
Nimazone, 2, 260
Nimodipine, 3, 149
Nimorazole, 2, 244
Niridazole, 2, 269
Nisbuterol, 3, 23
Nisobamate, 2, 22
Nisoxetine, 3, 32
Nistremine acetate 3, 88
Nithiazole, 2, 268
Nitrafudam, 3, 130
Nitrazepam, 1, 366
Nitrimidazine, 1, 240
Nitrofurantel, 1, 229
Nitrofurantoin, 1, 230
Nitrofurazone, 1, 229
Nitrofuroxime, 1, 228
Nitromifene. 3, 51
Nivazol, 2, 159
Nivimedone, 3, 67
Nocodazole, 3, 176
Nomifensine, 4, 146
Noracylmethadol, 2, 58
Norbolethone, 2, 151
Norephedrine, 1, 260
Norethandrolone, 1, 170
Norethindrone, 1, 164
Norethindrone acetate, 1, 165
Norethynodrel, 1, 168
Norfloxacin, 4, 141
Norgestatriene, 1, 168
Norgestatrienone, 1, 186
Norgestrel, 1, 167
Nonneperidine, 1, 300
Nonnethadone, 1, 81
Nonnethandrolone, 1, 170
Norpipanone, 1, 81
Nortriptyline, 1, 151
Nufenoxole, 3, 42
Nylidrin, 1, 69
Ocfentanil, 5, 83
Octazamide, 2, 448
Octopamine, 5, 23
Octriptyline, 2, 223
Ofloxacin, 4, 141
Ofomine, 4, 102
Olanzapine, 5, 169
Olsalazine, 4, 42
Olvanil, 4, 35
Omeprazole, 4, 133
Onapristone, 5, 53
Ondansetron, 5, 164
Orconazole, 3, 133
Onnaplatin, 5, 11
Onnetoprim, 2, 302

CUMULATIVE INDEX, VOLUMES 1-5 205
Palmoxiric acid, 4, 4
Paludrine, 1, 115
Pamaquine, 1, 345
Pamatolol, 3, 28
Panadiplon, 5, 173
Pancopride, 5, 21
Pancuronium chloride, 2, 163
Pantoprazole, 5, 115
Papaverine, 1, 347
Para-aminosalicylic acid, 1, 109
Paraethoxycaine, 1, 10
Paramethadione, 1, 232
Paramethasone, 1, 200
Paranyline, 2, 218
Parapenzolate bromide, 2, 75
Parconazole, 3, 133
Pargyline, 1, 54
Paroxetine, 5, 87
Pazoxide, 2, 395
Pecazine, 1, 387
Pefloxacin, 4, 141
Pelanserin, 5, 94
Pelretin, 5, 8
Pelrinone, 4, 116
Pemedolac, 5, 165
Pemerid, 2, 288
Pemirolast, 5, 150
Penfluridol, 2, 334
Pentamorphone, 5, 42
Pentapiperium, 2, 76
Pentaquine, 1, 346
Pentazocine, 1, 297
Pentethylcyclanone, 1, 38
Pentiapine, 4, 220
Pentizidone, 4, 86
Pentobarbital, 1, 268
Pentomone, 3, 248
Pentopril, 4, 128
Pentoxiphyline, 2, 466
Pentylenetetrazole, 1, 281
Perazine, 1, 381
Perfosfamide, 5, 1
Pergolide, 3, 249
Perindopril, 5, III
Perlapine, 2, 425
Phenacaine, 1, 19
Phenacemide, 1, 95
Phenacetin, 1, III
Phenadoxone, 1, 80
Phenaglycodol, 1, 219
Phenazocine, 1, 298
Phenazopyridine, 1, 255
Phenbencillin, 1, 410
Omidazole, 3, 131
Orpanoxin, 3, 130
Orphenadrine, 1, 42
Oxacephalothin, 1, 420
Oxacillin, 1, 413
Oxagrelate, 4, 151
Oxamisole, 5, 142
Oxamniquine, 2, 372
Oxanamide, 1, 220
Oxandrolone, 1, 174
Oxantel, 2, 303
Oxaprotiline, 4, 63
Oxaprozin, 2, 263
Oxarbazole, 3, 169
Oxatomide, 3, 173
Oxazepam, 1, 366
Oxazolapam, 1, 370
Oxeladine, 1, 90
Oxendolone, 4, 66
Oxethazine, 1, 72
Oxetorene, 3, 247
Oxfendazole, 3, 353
Oxibendazole, 2, 352
Oxiconazole, 5, 72
Oxifungin, 3, 233
Oxilorphan, 2, 325
Oximonam, 4, 195
Oxiperomide, 2, 290
Oxiramide, 2, 290
Oxiramide, 3, 40
Oxolamine, 1, 248
Oxolinic acid, 2, 370
Oxprenolol, 1, 117
Oxybutynin, 1, 93
Oxycodone, 1, 290
Oxyfedrine, 2, 40
Oxymestrone, 1, 173
Oxymetazoline, 1, 242
Oxymetholone, 1, 173
Oxymorphone, 1, 290
Oxypendyl, 1, 430
Oxypertine, 2, 343
Oxyphenbutazone, 1, 236
Oxyphencyclimine, 2, 75
Oxyphenisatin, 2, 350
Oxypurinol, 1, 426
Oxytetracycline, 1, 212
Ozolinone, 3, 140

206 CUMULATIVE INDEX, VOLUMES 1-5
Phenbenzamine, 2, 50
Phenbutalol, 2, 110
Phencarbamide, 2, 97
Phencyclidine, 1, 56
Phendimetrazine, 1, 260
Phenelizine, 1, 74
Pheneridine, 1, 301
Phenethicillin, 1, 410
Phenfonnin, 1, 75
Phenindandone, 1, 147
Pheniprazine, 1, 74
Pheniramine, 1, 77
Phenmetrazine, 1, 260
Phenobarbital, 1, 268
Phenomorphan, 1, 294
Phenoperidine, 1, 302
Phenoxybenzamine, 1, 55
Phenoxymethylpenicillin, 1, 410
Phensuximide, 1, 226
Phentennine, 1, 72
Phentolamine, 1, 242
Phenyl aminosalycilate, 2, 89
Phenylbutazone, 1, 236
Phenylephrine, 1, 63
Phenylglutarimide, 1, 257
Phenyltoloxamine, 1, 115
Phenyramidol, 1, 165
Pholcodeine, 1, 287
Phthaloyl sulfathiazole, 1, 132
Physostigmine, 1, III
Picenadol, 4, 108
Picumetrol, 5, 16
Pimetine, 2, 286
Piminodine, 1, 301
Pimobendan, 5, 117
Pimozide, 2, 290
Pinacidil, 4, 102
Pinadoline, 4, 202
Pindolol, 2, 342
Pinoxepin, 2, 419
Pioglitazone, 5, 74
Pipamazine, 1, 385
Pipamperone, 2, 288
Pipazethate, 1, 390
Pipecurium bromide, 4, 70
Piperacetazine, 1, 386
Piperacillin, 3, 207
Piperidolate, 1, 91
Piperocaine, 1, 13
Piperoxan, 1, 352
Pipobroman, 2, 299
Piposulfan, 2, 299
Pipradol, 1, 47
Piprandamine, 2, 459
Piprozolin, 2, 270
Piquindone, 4, 205
Pirbencillin, 3, 207
Pirbuterol, 2, 280
Pirenperone, 3, 231
Piretanide, 3, 58
Pirexyl, 1, 115
Piridicillin, 1, 260
Piridocaine, 1, 13
Pirindol, 1, 45
Pirintramide, 1, 308
Piriprost, 4, 160
Piritrexim, 4, 169
Pinnagrel, 4, 161
Pinnenol, 3, 48
Piroctone, 3, 149
Pirogliride, 3, 57
Pirolate, 3, 245
Piromidic acid, 2, 470
Piroxantrone, 5, 43
Piroxicam, 2, 394
Piroximone, 4, 94
Pirprofen, 2, 69
Pirqinozol, 3, 243
Pivampicillin, 1, 414
Pivopril, 4, 7
Pizotyline, 2, 420
Plomestone, 5, 51
Poldine mesylate, 2, 74
Poly thiazide , 1, 360
Ponalrestat, 5, 132
Practolol, 2, 106
Pramoxine, 1, 18
Pranolium chloride, 2, 212
Pravadoline, 5, 108
Prazepam, 2, 405
praziquantel, 4, 213
prazocin, 2, 382
Prednicarbate, 4, 71
Prednimustine, 3, 93
Prednisolone, 1, 192
Prednisolone acetate, 1, 192
Prednisone, 1, 192
Prednival, 2, 179
Prednylene, 1, 197
Prenalterol, 3, 30
Prenylamine, 1, 76
Pridefine, 3, 49

CUMULATIVE INDEX, VOLUMES 1-5 207
Prifelone, 5, 67
Prilocaine, 1, 17
Primidone, 1, 276
Primodolol, 3, 29
Prinomide, 5, 64
Prinoxodan, 5, 130
Prizidilol, 3, 151
Probarbital, 1, 268
Probenecide, 1, 135
Probicromil, 4, 207
Probucol, 2, 126
Procainamide, 1, 14
Procaine, 1, 9
Procarbazine, 2, 27
Procaterol, 3, 184
Prochlorperazine, 1, 381
Procinonide, 3, 94
Procyclidine, 1, 47
Progabide, 4, 47
Progesterone, 2, 164
Proglumide, 2, 93
Proguanil, 1, 280
Prolintane, 1, 70
Promazine, 1, 377
Promethazine, 1, 373
Pronethalol, 1, 66
Prontosil, 1, 212
Propafenone, 5, 17
Propanidid, 2, 79
Propantheline bromide, 1, 394
Proparacai ne, 1, 11
Propenzolate, 2, 75
Properidine, 1, 299
Propicillin, 1, 410
Propiomazine, 1, 376
Propionylpromazine, 1, 380
Propizepine, 2, 472
Propoxorphan, 3, 113
Propoxycaine, 1, 10
Propoxyphene, 1, 50
Propranolol, 1, 117
Propylhexedrine, 1, 37
Propylphenazone, 1, 234
Propylthiouracil, 1, 265
Proquazone, 2, 386
Proquinolate, 2, 368
Prorenone, 2, I 75
Prostalene, 2, 5
Prothipendyl, 1, 430
Protriptyline, 1, 152
Proxazole, 2, 271
Proxicromil, 4, 205
Pyrantel, 1, 266
Pyrathiazine, 1, 373
Pyrazineamide, 1, 277
Pyrilamine, 1, 51
Pyrimethamine, 1, 262
Pyrindamine, 1, 145
Pyrinoline, 2, 34
Pyrovalerone, 2, 124
Pyroxamine, 2, 42
Pyrrobutamine, 1, 78
Pyrrocaine, 1, 16
Pyrroliphene, 2, 57
Pyrroxan, 3, 191
Quazepam, 3, 196
Quazinone, 4, 212
Quazodine, 2, 379
Quazolast, 4, 216
Quinacrine, 1, 396
Quinapril, 4, 146
Quinazocin, 2, 382
Quinbolone, 2, 154
Quinelorane, 5, 168
Quinethazone, 1, 354
Quinfamide, 3, 186
Quinine, 1, 337
Quinodinium bromide, 2, 139
Quinpirole, 4, 205
Quinterol, 2, 366
Racemoramide, 1, 82
Racemorphan, 1, 293
Ranitidine, 3, 131
Ranolazine, 5, 94
Recainam, 4, 37
Reclazepam, 4, 153
Remifentanil, 5, 84
Remoxipride, 4, 42
Repirinast, 5, 175
Reproterol, 3, 231
Rescinnamine, 1, 319
Ridogrel, 5, 80
Rimantidine, 2, 19
Rimcazole, 4, 201
Rimexolone, 5, 56
Rimiterol, 2, 278
Riodipine, 4, 107
Rioprostil, 4, 13
Ripazepam, 3, 234

208 CUMULATIVE INDEX, VOLUMES 1-5
Risocaine, 2, 91
Risotilide, 5, 24
Risperidone, 5, 150
Ristianol, 4, 102
Ritodrine, 2, 39
Ritolukast, 5, 120
Rocastine, 5, 153
Rodocaine, 2, 450
Rogletimide, 5, 81
Roletamide, 2, 103
Rolgamidine, 4, 80
Rolicyprine, 2, 50
Rolitetracycline, 1, 216
Rolodine, 2, 468
Romazarit, 5, 68
Ronidazole, 2, 245
Ropitoin, 3, 139
Rosoxacin, 3, 185
Rotoxamine, 2, 32
Roxatidine, 5, 26
Rozaxane, 5, 95
Sabeluzole, 5, 86
Salbutamol, 2, 280
Salicylamide, 1, 109
Salmeterol, 5, 16
Salsalate, 2, 90
Salvarsan, 1, 223
Sarafloxacin, 5, 125
Sarmoxicillin, 3, 205
Sarpicillin, 3, 204
Secalciferol, 5, 59
Secobarbital, 1, 269
Sematilide, 5, 24
Semustine, 2, 12
Seproxetine, 5, 25
Serazepine, 5, 177
Sennetacin, 3, 166
Sertraline, 4, 57
Setoperone, 4, 172
Sezolamide, 5, 147
Sibutramine, 5, 25
Solypertine, 2, 342
Somantidine, 4, 4
Sontoquine, 1, 344
Sotalol, 1, 66
Sotalol, 5, 23
Soterenol, 2, 40
Spirapril, 4, 83
Spirilene, 2, 292
Spiromustine, 4, 5
Spironolactone, 1, 206
Spiropiperone, 1, 306
Spiroplatin, 4, 16
Spirothiobarbital, 1, 276
Stanazole, 1, 174
Stenbolone acetate, 2, 155
Styramate, 1, 219
Succinyl sulfathiazole, 1, 132
Sudoxicam, 2, 394
Sufentanil, 3, 118
Sufotidine, 5, 77
Sulazepam, 2, 403
Sulbactam pivoxil, 4, 180
Sulconazole, 3, 133
Sulfabenzamide. 2, 112
Sulfacarbamide, 1, 123
Sulfacetamide, 1, 123
Sulfachloropyridazine, 1, 124
Sulfacytine, 2, 113
Sulfadiazine, 1, 124
Sulfadimethoxine, 1, 125
Sulfadimidine, 1, 125
Sulfaethidole, 1, 125
Sulfaguanidine, 1, 123
Sulfaisodimidine, 1, 125
Sulfalene, 1, 125
Sulfamerazine, 1, 124
Sulfameter, 1, 125
Sulfamethizole, 1, 125
Sulfamethoxypyridine, 1, 124
Sulfamoxole, 1, 124
Sulfanilamide, 1, 121
Sulfanitran, 2, 115
Sulfaphenazole, 1, 124
Sui faproxy line, 1, 123
Sulfapyridine, 1, 124
Sulfasalaszine, 2, 114
Sulfasomizole, 1, 124
Sulfathiazole, 1, 124
Sulfathiourea, 1, 123
Sulfazamet, 2, 113
Sulfinalol, 3, 25
Sulfinpyrazone, 1, 238
Sulfisoxazole, 1, 124
Sulfonterol, 2, 42
Sulfonnethoxine, 1, 125
Sulfoxone, 1, 140
Sulindac, 2, 210
Sulnidazole, 2, 245

CUMULATIVE INDEX, VOLUMES 1-5 209
Suloctidil, 3, 26
Sulofenur, 5, 35
Sulotraban, 5, 22
Sulpiride, 2, 94
Sulprostene, 3, 9
Sulthiame, 2, 306
Sulukast, 5, 28
Sumarotene, 5, 37
Sumatriptan, 5, 108
Suporofen, 2, 65
Suricainide, 4, 49
Syrosingopine, 1, 319
Testolactone, 1, 160
Testosterone cypionate, 1, 172
Testosterone, decanoate, 1, 172
Testosterone propionate, 1, 172
Tetracaine, 1, 110
Tetracycline, 1, 212
Tetrahydrocannabinol, 1, 394
Tetrahydrozoline, 1, 242
Tetramisole, 1, 431
Tetrantoin, 1, 246
Tetrazolast, 5, 181
Tetroxyprim, 3, 154
Tetrydamine, 2, 352
Thalidomide, 1, 257
Thenium closylate, 2, 99
Theobromine, 1, 423
Theophylline, 1, 423
Thiabarbital, 1, 275
Thiabendazole, 1, 325
Thiabutazide, 1, 358
Thiamphenicol, 2, 45
Thiamprine, 2, 464
Thiamylal, 1, 274
Thiazinum chloride, 3, 240
Thiofuradene, 1, 231
Thioguanine, 2, 464
Thiopental, 1, 274
Thiopropazate, 1, 383
Thioridazine, 1, 389
Thiothixene, 1, 400
Thonzylamine, 1, 52
Thozalinone, 2, 265
Thyromedan, 2, 79
Thyroxine, 1, 95
Tiaconazole, 3, 133
Tiacrilast, 5, 130
Tiacrilast, 4, 150
Tiacrilast, 5, 130
Tiamenidine, 3, 137
Tiapamil, 4, 34
Tiaramide, 4, 134
Tiazofurin, 4, 96
Tibolone, 2, 147
Tibric acid, 2, 87
Ticabesone propionate, 4, 75
Ticarcillin, 2, 437
Ticlopidine, 3, 228
Ticrynafen, 2, 104
Tifurac, 5, III
Tigemonam, 5, 155
Taclamine, 2, 224
Tacrine, 5, 166
Talampicillin, 2, 438
Talniflumate, 3, 146
Talopram, 2, 357
Taludipine, 5, 83
Tameridone, 5, 144
Tametraline, 3, 68
Tamoxifen. 2, 127
Tampramine, 4, 203
Tandamine, 2, 347
Tandospirone, 5, 91
Tazadolene, 4, 6
Tazifylline, 4, 165
Tazobactam, 5, 156
Tazolol 2, 110
Tebufelone, 5, 30
Tebuquine, 4, 28
Teclozan, 2, 28
Tegafur, 3, 155
Temafloxacin, 5, 125
Tematropium, 5, 66
Temazepam, 2, 402
Temlastine, 4, 113
Temocillin, 4, 178
Tenidap, 5, 109
Tenoxicam, 4, 173
Tepoxalin, 5, 69
Terazocin, 3, 194
Terbinafine, 4, 55
Terconazole, 3, 137
Terlakiren, 5, 4
Terolidine, 2, 56
Teroxirone, 4, 122
Tertrabenazine, 1, 350
Tesicam, 2, 379
Tesimide, 2, 296

210 CUMULATIVE INDEX, VOLUMES 1-5
Tigesterol, 2, 145
Tiletamine, 2, 15
Tilomisole, 4, 217
Tilorone, 2, 219
Timefurone, 4, 208
Timobesone propionate, 4, 75
Timolol 2, 272
Tinabinol, 4, 210
Tiodazocin, 3, 194
Tioperidone, 3, 192
Tiopinac, 3, 238
Tiospirone, 5, 91
Tioxidazole, 3, 179
Tipentosin, 4, 129
Tiprednane, 4, 74
Tiprinast, 4, 173
Tipropidil, 3, 28
Tiquinamide, 2, 372
Tirilazad, 5, 61
Tixanox, 3, 236
Tixocortol, 4, 73
Tocainide, 3, 55
Tolamolol, 2, 110
Tolazamide, 1, 241
Tolbutamide, 1, 136
Tolciclate, 3, 69
Tolgabide, 4, 47
Tolimidone, 3, 156
Tolindate, 2, 208
Tolmetin, 2, 234
Tolnaftate, 2, 211
Tolpyrramide, 2, 116
Tolrestat, 4, 56
Toltazuril 5, 100
Tolycaine, 1, 17
Tomelukast, 5, 30
Tomoxetine, 4, 30
Tonazocine, 3, 115
Topterone, 3, 88
Toremifene, 5, 33
Torsemide, 5, 82
Tosifen, 3, 62
Tosufloxacin, 5, 126
Tralonide, 2, 198
Tramadol, 2, 17
Tramazoline, 1, 243
Tranexamic acid, 2, 9
Tranilast, 4, 44
Transcainide, 4, 112
Tranylcypromine, 1, 73
Trazodone, 2, 472
Treloxinate, 2, 432
Trepipam, 4, 146
Triacetamide, 2, 94
Triafungin, 3, 233
Triamcinolone, 1, 201
Triamcinolone acetonide, 1, 201
Triampyzine, 2, 298
Triamterine, 1, 427
Triazolam, 1, 368
Triazuryl, 2, 305
Trichlormethiazide, 1, 359
Triclonide, 2, 198
Trifenagrel, 4, 282
Triflocin, 2, 282
Triflubazam, 2, 406
Triflumidate, 2, 98
Trifluperidol, 1, 306
Triflupromazine, 1, 380
Trihexyphenidyl, 1, 47
Triiodothyronine, 1, 95
Trilostane, 2, 158
Trimazocin, 2, 382
Trimeprazine, 1, 378
Trimethadone, 1, 232
Trimethobenzamide, 1, 110
Trimethoprim, 1, 262
Trimethoquinol, 2, 374
Trimetozine, 2, 94
Trimetrexate, 4, 149
Trioxasalen, 1, 334
Trioxyfene, 3, 70
Tripamide, 4, 51
Tripelennamine, 1, 51
Triprolidine, 1, 78
Trofosfamide, 3, 161
Tropanserin, 4, 39
Tropocaine, 1, 7
Tubulozole, 4, 91
Tybamate, 2, 22
Vapiprost, 5, 5
Velnacrine, 5, 167
Venlafaxine, 5, 26
Verilopam, 3, 121
Verlukast, 5, 121
Verofylline, 2, 230
Vesnarinone, 5, 122
Viloxazine, 2, 306
Vinbarbital, 1, 269
Viprostol, 4, 13
V olazocine, 2, 327

CUMULATIVE INDEX, VOLUMES 1-5 211
Warfarin, 1, 131
Zeniplatin, 5, 12
Zidomethacin, 3, 166
Zileutron, 5, 113
Zimeldine, 3, 49
Zindotrine, 4, 168
Zinoconazole, 4, 92
Zofenopril, 4, 83
Zolamine, 1, 52
Zolazepam, 4, 174
Zolpidem, 4, 162
Zolporestat, 5, 132
Zolterine, 2, 301
Zometapine, 3, 234
Zompirac, 3, 128
Zonisamide, 4, 130
Xenalipin, 5, 19
Xilobam, 3, 56
Xipamide, 2, 93
Xorphanol, 4, 61
Xylamidine, 2, 54
Xylazine, 2, 307
Xylometazoline, 1, 242
Zacopride, 4, 42
Zalcitabine, 5, 98
Zaltidine, 4, 95
Zatosetron, 5, III

SUBJECT INDEX
ACE, 3, 65, 73
receptor antagonist, 73
AIDS, 4, 98
opportunistic infection, 75, 146
AZT, 98, 145
Ablukast, 128
Abortifacient, 53
Acetozolamide, 147
Acetylcholine, 166
Actisomide, 150
Acyclovir, 146
Adapalene, 38
Adaprolol, 18
Adozelesin, 171
Adrenergic antagonists, 16
Adriamycin, 45
Albuterol, 15
Aldose reductase, 131
Alentomol, 39
Allene, 178
Alpha adrenergic agonist, 71
Alpha blocker, 132
Alpidem, 142
Alprenolol, 18
Alprenoxime, 18
Alzheimer's disease, 166
Amifostine, 1
Aminoglutethimide, 81, 141
Amorolfine, 99
Amphetamine, 26
Amrinone, 109
Anagrelide, 165
Analgesic, 108
central, 9
Analgetic, 83
short -acting, 84
Androgen antagonist, 48
Angiotensin, 3
Angiotensin converting enzyme, 3
Anthracyclines, 45
Anthraquinones, 42
Anti-anxiety, 90
Antiallergic, 144, 150
Antiandrogen, 10, 48-49
Antianginal, 2
Antiarrhythmic, 23-24, 70, 86-87
Antiasthmatic, 15
Antibacterial, 122
Antibiotic, 122
quinolone, 123
Anticholinergic, 66
Anticonvulsant, 19, 78, 86, 90, 135
Antidepressant, 25, 87, 92, 136, 168, 170,
177
Antidopamine, 164
Antiemetic, 20, 109, 111, 117, 164
Antifungal, 72, 114
Antihistamine, 144, 153
213

214 SUBJECT INDEX
Antihyperlipidemic, 64
Antihypertensive, 127, 143, 163, 167
Antiinflammatory, 56
Antileukemic, 42
Antimigraine, 108
Antimycotic, 99
Antiprotozoal, 73
Antipsoriatic, 31
Antipsychotic, 150, 164, 168
Antitumor, 35,42,44, 121
Antiulcer, 26, 76, 115
Antiviral, 98, 145
Anxiolytic, 90, 134, 136, 142, 173, 177
Apraclonidine, 71, 74
Arachidonic acid, 5, 7, 28,80,120,175
Arbuzov reaction, 105, 181
Aromatic coupling, 38, 151
Aromatic displacement, 36, 74, 82, 87,
123, 150, 173, 177
Aspirin, 64
Asthma, 28
Atipamezole, 71
Azumolene, 68
Bacteria:
resistant, 156
Batanopride, 21
Batelapine, 169
Bayer- Villiger oxidation, 6, 134
Beclomethasone, 57
Belfosdil, 2
Bemarinone, 131
Bemoradan, 133
Bemsetron, 66
Bendacalol, 134
Benzodiazepines, 90
Benzodioxane, 134
Benzofuran, 128
Benzopyran, 128
Benzyne, 40
Beraprost, 176
Beta agonist, 16
Beta blocker, 15, 17,23, 128, 134
Beta lactamase, 156
Biantrazole, 43
Bidisomide, 87
Binafloxacin, 125
Binospirone, 134
Bioavailability, 167
Bioisostere :
carbon, 160
Bioisosteric, 24
Birch reduction, 51
Bisphosphonate, 2
Bizelesin, 173
Blood-brain barrier, 66, 84
Breast cancer, 33, 50, 80
Brequinar, 121
Bretazenil, 177
Brimodine, 132
Bromonium ion, 51
Bronchodilator, 144
Bufuralol, 128
Buspirone, 90, 134
CC-I065, 170
CCK antagonist, 137
Calcipotriene, 60
Calcium channel blocker, 2, 82, 137
Calcium transport, 59
Camptothecin, 177
Camptothecin, 1 O-hydroxy, 179
Cancer chemotherapy, 12, 20, 45, 80,
95-96, 99, 102, 151, 163, 170, 177-178,
180
Cancer:
breast, 50, 80
prostatic, 48
Captopril, 3, 65
Carbacephem, 161
Carbonic- anhydrase, 147
Carcinogens, 44
Cardiac glycoside, 109
Cardiostimulant, 15
Cardiotonic, 109, 117, 122, 130, 131, 133,
149, 165
Cardiotoxicity, 95
Carvedilol, 163
Carzelesin, 171
Cefaclor, 161
Cefotaxime, 158
Cefpirone, 158
Cefpodoxime protexil, 158
Cefprozil, 158
Ceftecol, 160
Ceftibuten, 160
Cell wall synthesis, 122
Cephalosporanic acid:
7-amino, 158
Ceronapril, 65
Chemistry :
superfast, 27
Chiral transfer, 16
Chirophos, 174

Cholecystokinin, 20, 137
Cholesterol synthesis, 87
Chromone, 128
Cicletanine, 143
Cimetidine, 26, 76
Cioteronel, 11
Cisplatin, 163
Claisen condensation, 123
Claisen rearrangement, 30
Clark-Eschweiler reaction, 26, 36, 108
Clavulanic acid, 156
Clentiazem, 139
Clinafloxacin, 125
Clonidine, 74
Coccidiostat, 99
Colestolone, 55
Conazole, 72, 75, 114
Conjugate addition, 56, 81, 84, 88
Contraceptive, oral, 51
Corticosteroids, 56
Crilavastine, 64
Crisnatol, 44
Cuprate reagent, 88
Cyclooxygenase, 30
Cyclophosphamide, 102
Cyclotron, 27
Cytarabine, 96
Cytomegalovirus, 146
Cytotoxic, 170
DACH, 11
DOC, 98
DDQ, 50, 56, 58
DEAD, 112
DMF acetal, 149
DNA, 123
DNA, minor grove, 171
Daltroban, 22
Dalvastatin, 87, 105
Danfloxacin, 125
Dapiprazole, 143
Dapoxetine, 35
Daunorubicin, 45
Dazepinil, 137
Decitabine, 100
Demjanow rearrangement, 11
Desogestrel, 52
Detomidine, 71
Devazepide, 137
Dexmetomidine, 71
Dexonnaplatin, II
SUBJECT INDEX 215
Dexrazoxane, 95
Diabetes, 13 I
Didanosine, 146
Diels- Alder condensation, 40
Digitoxin, 109
Dihydroperylene, 39
Dihydropyridine, 82
Diketiren, 4
Diltiazem, 137
Disobutamide, 87
Dizocilpine, 136
Docebenone, 8
Dolasetron, 109, 117
Dopamine, 27, 173
Dopamine agonist, 175
Dopamine antagonist, 39
Doretinel, 38
Dorzolamide, 147
Doxofylline, 144
Doxorubicin, 45, 95
Edatrexate, 152
Elastase, 22
Elastin, 22
Emphysema, 22
Enalapril, 3
Enalkiren, 4
Enantiomers, resolution, 45, 66, 71, 135
Enantioselecti ve sy nthesis, 16, 36, 105,
110,137,147,155,174,177
Encainide, 86
Enciprazine, 92
Enrofloxacin, 125
Epinephrine, 14
Esmolol, 18
Esterases, 157
Estrogen antagonist, 10, 33, 113
Etanidazole, 73
Etarotene, 37
Etoperidone, 92
Fadrozole, 141
Fentanyl, 83
Fiacitabine, 98
Finasteride, 10, 49
Finkelstein reaction, 137
Fischer indole synthesis, 108, 164
Fleroxacin, 125
Flosequinan, 127
Fluconazole, 75

216 SUBJECT INDEX
HIV, 4, 145
Halobetasol, 57
Hantsch synthesis, 82
Hauser rearrangement, 1 71
Hepatitis, 98
Herpes virus, 146
Histamine, 26
Histamine H2 antagonist, 26
Histamine antagonist, 76, 115
Hofmann degradation, 166
Homologation, 36
Hypercholesterolemia, 55, 87
Hypocholesterolemic, 19, 87, 105
Hypoglycemic, 74
Hypolipidemic, 19
Indolidan, 110, 117
Inhibitor:
ACE, 3,65. 110. 135
aldose reductase, 13 I
aromatase, 50, 80, 141
beta lactamase, 156
calcium channel, 2
carbonic anhydrase. 147
cholinesterase, 166
cyclooxygenase, 30
elastase, 22
feedback, 55
lipoxygenase, 31. 112
mediator release, 150, I 75. 181
mevalonate, 87. 105
platet aggregation, 92
protease, 4
renin, 3
serotonin, 35, 66, 94. 109. 117, 164
thromboxane, 80
topoisomerase, 123
transition state, 3
Ink:
ball point, 42
Inosine, 145
Ipazilide, 70
I psapi rone, 91
Irtemazole, 117
Isatin, 121, 166
Isoproterenol, 15
Isosteric, 24
Fluorine:
potentiating effect, 57
Fluorodopa, 27
Fluorodopa F18, 27
Fluorodopamine, 27
Fluoxetine, 25, 35, 87
Fluparoxan, 170
Fluvastatin, 105
Folate antagonist, 151
Fosinopril, 65
Fosquidone, 181
Fries rearrangement, 8
Ganciclovir, 146
Gassman indolone synthesis, 171
Gemcitabine, 96
Gevotroline, 164
Glaucoma, 18. 74, 132, 147
Glutethimide, 81
Glycosidation, 45, 97-99
Gout, 115
Granisetron, 118
Guanosine, 146
Gyrase, 123
Kappa receptors, 9
Ibafloxacin, 127
Ibuprofen, 64
Ibutilide, 23
Imidazopyridine, 141
Imidazoquinazoline, 164
Imiquimod, 173
Immunomodulator. 173
Immunoregulatory. 141
Immunostimulant, 145
Incoterone. 49
Lacidipine, 82
Lamivudine, 99
Lansoprazole, 115
Latent functionality, 58
Lavoltidine, 77
Leukotriene antagonist, 28, 120, 128, 130
Leukotrienes, 7, 28
Levamisole, 141
Lidocaine, 19, 94
Lifarazine, 92
Linarotene, 37
Lipid peroxidation, 60
Lipoxygenase, 7
Lixinazone, 166
Locarbef, 162
Lodelaben, 22

Lomefloxacin, 125
Lorcinadol, 94
Lorglumide, 20
Losarten, 73
Losoxantrone. 43
Loteprednol, 56
Lovastatin, 19. 55, 105
Loveclazole. 78
Loxoribine. 145
Mafosfamide, 102
Medorinone. 149
Mesna, 102
Metabolic activation, 102
Metipronalol, 17
Metoclopramide, 20, 66, Ill, 163
Metrenperone, 150
Mevalonic acid, 87
Mifepristone. 53
Minaprine, 96
Mirtazepine, 177
Misonidazole, 73
Mitoxantrone, 42
Mitsonobu reaction, 113
Modecainide, 86
Monobactam, 155
Muscle relaxant, 68. 168
N-Dealkylation, metabolic, 87
NSAID, 64, 67, 68, 109, Ill, 164 (see
Non-steroid antiinflammatory)
Nafoxidine, 113
Nausea, 163
Naxogilide, 175
Nebivolol, 128
N elezaprine, 168
Neuroleptic, 143
Neurotransmitters, 14, 27
Niche:
special, 17
Noberastine, 144
Non-steroid antiinflammatory, 30
Norepinephrine, 14, 23
Ocfentanil. 83
Octopamine, 23
Olanzapine, 169
Onapristone, 53
Ondansetron, 164
SUBJECT INDEX 217
Opioids, 9, 40, 83
Oral absorption, 157
Oral contraceptive, 51
Ormaplatin, 11
Overlay:
three-point, 53
Oxamisole, 142
Oxazole, 68
Oxiconazole, 72
Oxygen free radicals, 60
Oxymorphone, 40
Oxypropanolamine, 163
PCP, 135
PET scan, 27
PGI2. 175
Panadiplon, 173
Pancopride. 21
Paroxetine, 87
Pelanserin, 94
Pelretin, 8
Pemedolac, 165
Pemirolast, 150
Penicillanic acid:
6-amino, 156
Penicillin, 155
Penicillin V, 161
Pentamorphone, 42
Pepstatin, 3
Peptidase, 4
Peptide drugs, 137
Peptide receptors, 137
Perfosfamide, 102
Perhydroindole, 110
Perindopril, III
Phencyclidine (PCP), 135
Phenyethanolamines, 23
Photolysis, 54, 59
Phthalazine, 131
Picumetrol, 16
Pimobendan, 117
Pioglitazone, 74
Piridoxal, 143
Piroxantrone, 43
Piroxicam, 64
Pivampicillin, 157
Plomestane, 50
Polonovsky reaction, 115, 137, 141, 173
Ponalrestat, 132
Positron emission tomography, 27
Pravadoline. 108 .

218 SUBJECT INDEX
Prednisolone, 56
Pregnancy:
tennination, 53
Pregnenolone, 56, 59
Prilefone, 67
Prinodoxan, 130
Prinomide, 64
Prodrug, 157
Progestin. 51
Progestin antagonist, 53
Propafenone, 17
Prostacyclin, 175
Prostaglandin, 28
Prostaglandins, 5. 176
Prostatic hypertrophy, 10, 49
Protease, 4
Prozac, 25
Pteridine, 151
Purine, 145
Pyrazine, 69
Pyrazinone, 110, 117
Pyridazinone, 130, 132
Romazerit, 68
Roxatidine, 26
RU-486, 53
Radiation therapy, 1
Radiosensitizer, 73
Raloxifene, 114
Ranitidine, 76
Ranolazine, 94
Razoxane, 95
Refonnatskii reaction, 96
Remifentanil, 84
Renin, 3
Renin-angotensin system, 3
Repirinast, 175
Resolution, 66, 71, 135
Retin-A, 37
Retinoic acid, 8, 36
Ridogrel, 80
Rigid analogue, 149
Rimexolone, 56
Risotilide, 24
Risperidone, 150
Ritolukast, 120
Robinson annulation, 49
Rocastine, 153
Rogletimide, 81
Sabeluzole, 86
Saccharin, 91
Sameterol, 16
Sarafloxacin, 125
Secalciferol, 59
Sematilide, 24
Seproxetine, 25, 87
Serazepine, 177
Serotonin, 20, 108, 164
Sezolamide, 147
Sharpless oxidation, 60
Sibutramine, 25
Sna rl :
monofilament, 123
Sodium-potassium pump, 115
Sorbitol, 131
Sotalol, 23
Sparfloxacin, 126
Spiradoline, 9
Statine, 3
Steric hindrance, 52
Substrate:
false, 55
Sufotidine, 77
Suicide inhibitor, 51
Sui fonamide, 108, 147
Sulfonylurea, 35, 74, 82
Sulofenur, 35
Sultroban, 22
Sulukast, 28, 120
Suronacrine, 167
Swem oxidation, 30, 106
Sympathetic nervous system, 14
Quinazolinone, 131
Quinerolane, 167
Tacrine, 166
Taludipine, 83
Tameridone, 144
Tamoxifen, 10, 53, 80, 113
Tandispirone, 91
T azobactam, 156
Tebufelone, 30, 67
Temafloxacin, 123
Tematropium, 66
T enidap, 109
Tepoxalin, 68
Terlakiren, 4
Testosterone, 48

SUBJECT INDEX 219
Tetrazolast, 181
Tetrazole, 73, 150, 181
as surrogate acid, 28
Tetrazolone, 84
Thebaine, 41
Theophylline, 144
Thiazide diuretics, 82, 147
Thromboxane, 6, 28, 80
Thromboxane inhibitor, 80
Thromboxane receptor blocker, 22
Tiacrilast, 130
Tifurac, III
Tigemonam, 155
Tiospirone, 91
Tirilazad, 61
Toltazuril, 99
T opi ramate, 90
Topoisomerase, 123
Topological analogues, 137
Topotecan, 179
Toremefine, 33
Tosufloxacin, 126
Traumatic shock, 60
Trazodone, 92
Tretinoin, 36
Triazolopiperidine, 143
Trioxyfene, 113
Tropine, 66
U ricosoric, 11 7
Vapiprost, 6, 80
Vasodilator, 175
Velnacrine, 167
Venflaxine, 26
Verlukast) 121
Vesnarinone, 122
Villsmeyer reaction, 87, 105
Weak link:
metabolic, 18
Wilgerodt reaction, III
Wittig reaction, 6, 8, 30, 37, 38, 52, 60,
82, 106, 131, 152, 158, 160
Wolf-Kischner reduction, 52
Xenalipin, 19
Zacopride, 21
Zalcitabine, 98
Zatosetron, III
Zeniplatin, 12
Zidovudine, 98, 145
Zileutron, 113
Zolporestat, 132

The OrganIc ChemIstry of Drug Synthesis, Volume 5 cov-
ers the literature on the synthesis of medicinal agents from
1988-1993. This well-received series meets the needs of
practitioners in the field who seek a quick overview of the
synthetic routes that have been used to access specific class-
es of therapeutic agents.
While most books on medicinal chemistry are organized
on the basis of therapeutic or biochemical classes, materials
in this series are arranged and discussed in terms of chem-
ical structure. Thus, the preparation and detailed organic
chemistry of the classes are presented in a unified way.
Only drugs which have been granted a u.s. Adopted Name
are included in this series.
Synthetic organic, pharmaceutical, medicinal, and hetero-
cyclic chemists will find this series an invaluable resource for
their research in the synthetic chemistry of drug development.
DANIEL LEDNICER is a chemist with the National Cancer
Institute He received his PhD in organic chemistry from
Ohio State University. He is the author or coauthor of
the previous four volumes in the Wiley series, The OrganIc
Chemistry of Drug Synthesis He is also Series Editor of
Chemistry and Pharmacology of Drugs, published by Wiley.
Cover Design: Watts Design
WI LEY-I NTE RSCI E NCE
John Wiley & Sons, Inc.
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