Annual reports in medicinal chemistry. / Volume 9 PDF
Preview Annual reports in medicinal chemistry. / Volume 9
ii CONTRIBUTORS . . . . . . . . . . . . . . . . . Adelstein. G W 67 Herzig. D J 85 . . . . . . . . . . . . . . . . . . . Amer. M S 203 Hodson. A 151 . . . . . . . . . . . . . . . . . Archer. R A 253 Holland. G F 172 . . . . . . . . . . . . . . . . . . Bindra. J S 214 Jerina. D M 290 . . . . . . . . . . . . . . . . . . Bloch. A 139 Johnson. A G 244 Campbell. W . C . . . . . . . 115 Katzenellenbogen. J . A . . . 222 . . . . . . . . . . . . . . . . . . Carlson. R G 270 Kenyon. G L 260 . . . . . . . . . . . . . . . . . . . Chang. A Y 182 Leitner. F 95 Chignell. C . F . . . . . . . 280 MacNintch. J . .E. . . . . . 75 . . . . . . . . . . . . . . . . Claridge. C A 95 McKinney. G R 203 Daly. J . W . . . . . . . . . 290 Metcalf. R . L . . . . . . . 300 . . . . . . . . . . . . . . . . . . . Dean. R R 67 Mrozik. H 115 . . . . . . . . . . . . . . . . DuCharme. D W 50 Mueller. R A 162 . . . . . . . . . . . . . . . Eargle. D H., Jr 260 Partyka. R A 27 . . . . . . . . . . . . . . . . Flanders. L E 162 Pereira. J N 172 Fleming. J . S . . . . . . . . 75 Rando. R . R . . . . . . . . 234 . . . . . . . . . . . . . . . . Francis. J E 57 Rosenthale. M E 193 . . . . . . . . . . . . . . . . Fullerton. D S 260 Schwartz. A R 128 . . . . . . . . . . . . . . . . . . . Giles. R E 85 Shadomy. S 107 . . . . . . . . . . . . . . . . Gordon. M 38 Tomeszewski. J E 290 . . . . . . . . . . . . . . . . . . Gylys. J A 27 Vernier. V G 19 Harbert. C . A . . . . . . . . 1 Welch. W . M . . . . . . . . 1 . . . . . . . . . . . . . . . Hardy. R A., Jr 11 Wheelock. E F 151 ANNUAL REPORTS IN MEDICINAL CHEMISTRY Volume 9 Sponsored by the Division of Medicinal Chemistry of the American Chemical Society Editor-in- Chief: RICHARD V. HEINZELMAN THE UPJOHN COMPANY KALAMAZOO, MICHIGAN SECTION EDITORS MAXWELL GORDON FRANK CLARKE GEORGE WARREN WALTER MORELAND WILLIAM WECHTER ROBERT WILEY @ ACADEMIC PRESS New York and London 1974 A Subsidiary of Harcourt Brace Jovanovich, Publishers ACADEMIC PRESS RAPID MANUSCRIPT REPRODUCTION COPYRIGHT 0 1974, BY ACADEMIPCR ESS, INC. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER. ACADEMIC PRESS, INC. 111 Fifth Avenue, New York. New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London NWl LIBRARYO F CONGRESCSA TALOCGA RDN UMBER6:6 - 26843 PRINTED IN THE UNITED STATES OF AMERICA xi PREFACE Our editorial policy continues to be to report annually on the more active fields of interest to medicinal chemists and to cover less reg- ularly new or maturing biomedical topics or fields which have passed their prime. Less than half of this year's topics appeared also in last year's Annual Reports. It may be well to remind the reader that it is not our intent to provide comprehensive literature coverage for the expert in the field; plenty of other publications already serve this purpose. Our aim is to re- port significant highlights to enable the worker in a related field to rec- ognize developments or concepts which may broaden his approach to his own area or even cause him to delve into a new one. Just as the increasing availability of massive computer-generated bibliographies on a particular topic poses a growing problem for a researcher who wishes to read selec- tively in a new field, so this same capability makes it more difficult for our chapter authors to be selective in what they choose to discuss. In fact this problem constitutes the editor's most arduous task; the ten-page chapter limit is designed both to achieve desired selectivity of subject matter and to keep the volume within a reasonable price range in this era of soaring costs. For the first time section editors have been given the opportunity to include one-page editorial overviews of their sections; among the objec- tives of these overviews are to highlight major new developments, emphasize common features in drug actions or disease etiologies or just to permit speculation as a stimulus for new ideas. While only one section editor chose to accept the invitation this year, it is hoped that more will do so in future volumes. As always, your constructive suggestions for improvement or for new topics are earnestly solicited. Kalamazoo, Michigan June, 1974 - Section I CNS Agents Editor: Maxwell Gordon Bristol Laboratories, Syracuse, New York Chapter 1. Antipsychotic and Antianxiety Agents Charles A. Harbert and Willard M. Welch Pfizer Inc., Groton, Conn. 06340 - Introduction Although several promising agents have progressed to ad- vanced clinical stages, no fundamentally new antipsychotic or antianxiety agents were introduced in the U.S. in 1973. Clozapine has emerged as the focus of clinical and theoretical interest in the antipsychotic area based on its extremely low incidence of extrapyramidal side reactions. This discovery has given new impetus to research directed toward an un- derstanding of the biochemical and neurophysiological correlates of anti- psychotic action and extrapyramidal manifestations. Act2vity in the antianxiety area again largely focused on agents structurally and mechan- istically related to the benzodiazepines. Extensive treatises have covered the chemistry, biochemistry, pharmacology and clinical utility of the benzodiazepinesl and the neuroleptics. 2 - - Antipsychotic Agents Tricyclics Structure-activity relationships (SAR) of the tricyclic psychotherapeutics3 and clinical experience with the long-acting neuroleptics495 have been reviewed. Emphasis continued to shift from structures with 6,6,6 ring systems to the 6,7,6-tricyclics. Among the latter, clozapine (A) has attracted the most interest. A recent review6 highlights the unique profile of this agent and the author points out some troublesome side effects (hypotension, tachycardia) that may limit its clinical use. Regardless, the emergence of clozapine has re- emphasized the feasibility of disassociating antipsychotic activity from the cataleptic properties that have been classically regarded as a pre- requisite for clinical therapeutic activity. 7 a ) X m H ; Z I C H b ) X r C l ; Z n C H c ) X = H ; Z = N d) X I C1 ; Z = N e) X = OEt; Z = CH f) X I OCH3;Z = CH _. 6 4 H Continuing SAR studies in the dibenzo[b,f]thiepin and related 6,7,6 systems have shown that substitution by chlorine in the 9-position of perathiepin (&) results in diminished activity .8 All eight possible aryl-monochloro isomers of perathiepin have now been synthesized, and of - -2 Sect. I CNS Agents Gordon, Ed. these only the 8-C1 isomer (octoclothepin, &) is more potent than the parent compound. Octoclothepin enantiomers and the racemate were found to differ little from each other in CNS depressant effects or in toxicity.' The 4-aza analogs & and 2d showed markedly reduced depres- sant and cataleptic activity compared with 3 and 2, respectively.lO,ll Among several 8-alkoxy analogs prepared, only the 8-Et0 isomer (&) exhibited activity (1OX chlorpromazine [CPZ] in the rotating rod test) equivalent to the known 8-Me0 derivative (2f, octometothepin) .I2 Oxi- dation of the S atom and/or 4'-N atom in a number of dibenzo[b,f]thie- 1. pins related to resulted in a uniform loss of CNS depressant activity.13 (3) EX 11-582A possesses potent activity in the fighting mouse (ED50 0.9 mg/kg) and antiamphetamine toxicity (ED50 0.28 mg/kg) tests.14 Like cloz- apqine, this compound was yinactive against apomor phine-induced emesis. a;Q - L c1 CaF)3 R CH,; Z I S c1 CHCHzCHzN(CH3 )2 NI N (CH, ) 2 = R b) R I C H 2 9 ; Z S -3 -4 -5 A recent paper of theoretical interest reported potent neuroleptic activity for a number of piperidylidene thioxanthenes (4,Z=S) and related (4, 4a 4b structures Z=O or NCH3); for example, and were respectively 7 and 18X CPZ in the rat ptosis test.15 Significantly, many of these compounds were more potent than their corresponding tricyclic congeners with non- k rigid si(dze) c,h ains. Since cannot assume the solid state configuration of CPZ the authors questioned earlier speculations that the active configuration of antipsychotics resembles that of crystalline CPZ. Rather, their findings are consistent with the S-configuration of anti- psychotic drugs frequently depicted by Janssen.7 In a related paper, NMR shift reagents were used to determine the stereochemistry of and trans aminoalkylidene xanthenes and thioxanthenes .I6 As expected, cis neuroleptic activity predominated in the series. An important pharmacokinetic study correlated CPZ plasma levels with therapeutic response and found that plasma levels in the range of 150-300 ng/ml usually corresponded to clinical improvement .I7 Significantly, con- comitant administration of an antiparkinson agent (trihexyphenidyl) tended to lower plasma levels of CPZ, an effect ascribed to reduced gastric mo- tility and decreased absorption of CPZ. - Butyrophenones, Phenylpiperazines, and Related Compounds Bromoperidol (&) is essentially equal to haloperidol in potency and duration of action.18 The trans-4-aryl-4-methoxycyclohexylaminobutyrophenone 6b exceeded haloperidol on several behavioral endpoints and exhibited- &, highly selective (vs. 5-HT) NE uptake blockade.19 Compound the most potent (15X CPZ in conditioned avoidance response [CAR]) in a series of substituted pyrazino[2',1':6,l]pyrido[3,4-b]indoles, was reported to have a prolonged duration of action and few cardiovascular Chap. 1 Antipsychotic and Antianxiety Agents Harbert, Welch 2 effects .20 Centpyraquin (6d, compound 69-183) combined neuroleptic activity (ca. CPZ in CAR) with significant hypotensive effects.21 AHR-2277 (lenperone, 6e) exerted a rapid and favorable effect on psychotic symptomatology, and was claimed to produce a very low incidence of neurological side reactions.22 A double-blind study of AL-1021 (6f) in hospitalized schizophrenics failed to confirm earlier encouraging re- sults obtained in pilot study. 23 Milipertine (&) produced troublesome EPS side effects in schizophrenics at doses well below those required to produce antipsychotic activity.24 Compound j’& was one of a series re- ported to exhibit CNS depressant activity in animals roughly in the CPZ range. 25 Oxazolidinone 7c blocked isolation-induced aggression in mice (ca. 0.5X CPZ);26 a similar level of activity in this test was seen with the related compounds 8a and &.27 -6 H -7 m - R -8 COCH3 7b) X OCH3; Y = H; R = CH2CHOHCH206 I 8b) R (CH,),OCONHCH, Miscellaneous Compounds - A benzodiazep ne, SCH- 2,041 (2, halazepam), showed evidence of efficacy against acute psychotic symptoms in an un- (10) controlled tria1.28 CI-686 was predicted to have major tranquilizer activity of short duration on the basis of quantitative pharmaco-EEG studies.2 9 Butaclamol (-11, AY-23,028) possessed pharmacological actions resembling fluphenazine, with activity residing solely in the (+)-enan- tiomer.30,31 The SAR of several cannabinoids nas been reexamined and -4 Sect. I - CNS Agents Gordon, Ed. found to differ significantly from earlier reports.32 A comparison 12 study in the same paper showed to be 3-15X CPZ in decreasing motor activity and in blocking fighting behavior in mice. OH -9 -10 -11 -12 Antianxiety Agents-Benzodiazepines and Related Compounds - The drug therapy of anxiety33~3 4 and the effect of benzodiazepines in controlling aggressive behavior35 were reviewed. It was argued that conformational similarities between diphenylhydantoin and diazepam36 do not constitute an appropriate basis for comparing their biological activities.37 A ser- ies of benzodiazepines with a,a-dihydroperfluoroalkyl groups at N-1 were found to successfully block metabolism at N-1 as predicted. One of these, nalazepam (Sch 12,041, 2), appeared to be more specific than diazepam in anticonvulsant (pentylenetetrazole, PTZ) and traction endpoints, with lower side effect potential (therapeutic index 4X diazepam). 38 The e) related compound, fletazepam (Sch 15,698, ,39 and ID-540 (13b)hO were claimed to be skeletal muscle relaxants. Clonazepam (Ro 5-4023, 13c) was more active against seizures induced by i.v. lidocaine than e, =her Ro 8-4192 (E)or diazepam.41 Compound from a novel series of 7-azidobenzodiazepines, demonstrated sedative and anticonvulsant properties equivalent to diazepam. 42 1 ‘ 2 7 5 -13 2 K 3 -N 14a) 2 -NHOCH2CH2= CH2 c1 14b) 2 -NHCONHCOOC2 Hcj 14c) 2-N7-H \’. 0 -14 Chap. 1 Antipsychotic and Antianxiety Agents Harbert, Welch 2 3) Pharmacological studies indicated uldazepam (U-31,920, to be an = effective antianxiety drug with weak sedative and muscle relaxant pro- perties.43 The urea derivative was nearly equivalent to diazepam in several behavioral and convulsant (thiosemicarbazide) end points ,44 where- as the related 2-imidazolidones (&) were less active in the same tests. A number of 1,3-dialkylpyrazolo[4,3-e]diazepinones exhibited potent CNS activity and one of these, pyrazapon (CI-683, 2)s howed anxiolytic activity equivalent to diazepam in man.45 SAR studies showed that hydro- gen is preferred at N-4 and that 1,3-dialkyl substitution is superior to (16). the 2,3-pattern of the isomeric series -15 -16 -18 (17) Several series of triazolobenzodiazepines with CNS depressant activity have been reported. D-40TA (E)t,he most potent of the 3- unsubstituted triazoles, was highly active as a tranquilizer, sedative- animal^.^^-^^ hypnotic and muscle relaxant in Triazolam (U-33,030, =) exhibited hypnotic activity in man at 0.25-2.0 mg. 49 The anticonvulsant and antiaggressive potencies of U-31,957 (G)an d U-35,005 (G) exceeded those of the corresponding diazepam analogs, but they were only weakly active in end points measuring overt depression (traction, EtOH) .50 Alprazolam (U-31,889, 17e)51 demonstrated a marked and rapid anxiolytic effect in man as had been predicted from its EEG profile.52 Chlordiaze- 17f) poxide isosteres in the triazolobenzodiazepine series (e.g. were consistently inactive.46,53 The triazinodione 18 was equal to diazepam on several behavioral end points and was 0.3X diazepam against PTZ convulsions and EtOH narcosis.44 The 1,5-benzodiazepine triflubazepam (ORF-8063, =)p ossessed anti- anxiety properties in man at 40-160 mg/day,54,55 with a profile similar to diazepam.56 Like most lY4-benzodiazepines it was primarily metabol- ized through N-dealkylation, but was otherwise hydroxylated in the N-phenyl ring rather than at C-3.57 Pharmacokinetic studies with - 6 Sect. I CNS Agents Gordon, Ed. - triflubazepam showed clinical improvement to be correlated with blood (w) levels of 0.5 to 1.0 ng/m1.58 Clobazam was claimed to be better tolerated than chlordiazepoxide in pharmacological and toxicological studies. 59 The 1,5-benzodiazepine relatives of chlordiazepoxide, 20a E, and protected mice against convulsions produced by PTZ, strychnine (ST) and tremorine, and were less disruptive than chlordiazepoxide on tests of motor coordination.60 CH3 2 Q;Jo 7 I OZN l o 19a) 7-CF3 20a) 2-M12 -19 C6H5 19b) 7-C1 -20 C6H5 20b) 2-N(CH3 )2 Other Structures with Antianxiety Activity - The oxypertine analogs 21a and 21b induced ataxia, decreased locomotor activity and antagonized- (=. electroshock (ES) and ST co(nvzulsi)ons in mice 0.25 diazepam).61 (G) Indole derivatives U-5092 and U-13,625 protected mice against ES-induced convulsions and produced a CPZ-like tranquilizing effect. 62 (22) In a double-blind study against anxiety, 200 mg opipramol was 23 equivalent to 30 mg chlordiazepoxide .63 The isoquinoline derivative and the benzothiazepine derivative 24 possessed marked CNS activity in mice characterized by general depression and anticonvulsant (ES, PTZ, ST) activity.64,65 The R enantiomers of a series of 1-aminotetralins 25) (e.g. suppressed conditioned emotional response (CER) in rats at 10 mg/kg. Interestingly, the S isomers were devoid of CER activity, but possessed marked anticataleptic (tetr abenazine) activity. 66 Although 26a 26b and resemble known metabolites of 1,4-benzodiazepine tranquilizers, they exhibited only very weak anti-PTZ and ES activity, and showed no taming effect in isolated mice.67 2 la
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