[1,4]benzodiazepines and pyrrolo[1,2,3-ef][1,5 ... - ACS Publications

Sep 1, 1970 - ... Nicola J. Curtin, Suzanne Kyle, Huw D. Thomas, Lan-Zhen Wang, A. Hilary Calvert, Bernard T. Golding, Roger J. Griffin, and David R. ...
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Journal of Medicinal Chemistry, 1970, vel. 13, N o . 6 8 8

BENZODIAZEPINES

Pyrrolo[S,2,1 -j k][1,4]benzodiazepines and Pyrrolo[l,2,3=ej][l,5] benzodiazepines Which Have Central Nervous System Activity ,JACKSOSB. HESTER, JK.,ALLAND. RUDZIK, A 4 S DWILLIAJIYELDKAMP I ? f h i (11

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Kectzvecl January 13, 1970

h series of pyrrolo [3,2,1-jk] [ 1,4]beiizodiazepiiies and pyrrole[ 1,2,3-rf][ l,5]benzodiazepines which is related to the clinically effective benzodiazepine, diazepam, has been prepared. Pharmacological data are presented xhich demonstrate that some of the compounds have CKS activity in mice.

The remarkable clinical success of the 1,4-benzodiazepine antianxiety drugs'-3 (viz. diazepam, 1) prompted our interest in the chemistry of the related pyrrolo [3,2,1-jk][1,4]benzodiazepines (viz. 2) as a possible route to compounds with useful CXS activity.

0 1

0 2

Casual inspection of structure 2 will reveal that it differs from 1 only by the insertion of a CH, between the K - I I e furict,ion and C-9 of the benzodiazepine nucleus to form a ne\\- five-membered ring. At the outset n-e were also intrigued by the possibility of aromatizing the pyroline ring to give a system, formally a 1,7-disubstituted indole, which might have both interesting biological activity and chemical re:IC tivity . For one approach t'o this system, we envisioned a Beckmann-type ring expansion of 1-ketolilodidine (4). The preparation and chemistry of 4 had been studied previously by Astill and Boekelheide4 and by Rapoport and Tretterj who were interested in intermediates suitable for t'he preparation of apo-@-erythroidine. The former investigators4 explored both t'he Beckmann and the Schmidt reactions o n this ketone. They reported t'hat although various attempts to accomplish the Beckmann rearrangement were unsuccessful the reaction of 4 in CHC1, with ?;ax3and H,SO, gave a lo\\- >.ield of a substance which had a composition and physical properties that could accommodate either structure 14 or 12 (Scheme I). Because of our previous experience6 and the absence of experimental detail in the paper cited, we reinvestiaged the Beckmann rearrangement of 4-oxime. I n agreement with the previous reaction of the oxime with either polyphosphoric acid7 or refluxing HC02H8 or reaction of the tosyloxy oxime with neut'ral alumina which had ( 1 ) G. Zbinden and L. 0. Randall, I l d r a ? ~ Pharmacal., . 5 , 213 (1967). (2) L. 11. Sternhacli, I.. 0. Randall, R . nanziger, a n d H. Letlr, in " D r l i p ~ .\ffecting t h e Central Nervous $ysteiri," Yol. I. A . I?irryrr, kki., Marcel I k k k e r , Inc., X e w York (3) S. J. Childress and J f . I . Gluckman, J . P h a r m . Yci., 63, 5 i 7 (1064). (4) B. I). Astill and V. Boekelheide, J . Org. Chem., 23, 316 (1958). ( 5 ) H. Kapoport a n d J. R . Tretter, i b i d . , 23, 248 (1958). ( l i l , I . K . Heslrr, Jr., i!,ield of 15 and 13 n i t h an isomer ratio of 11:l. The low yield of 13 prompted an alternate method for its preparation (Scheme 11). Sitration of 1-acet! 1-3chloroindoline with fuming HN03 in AcOH-Ac20 gave (9) J. C. Craig and -1. R. S a i k . J . d m e r . Chem. S O C . 84, , 3410 (1962). (10) S . J. Doorenbos and R . E. Ha\-ranek. J . Org. Chem., 3 0 , 2474 (1965). (11) Spectral d a t a supporting the ~triietiiremay Ile found a i tile eriil of the Experimental Section. (12) >I, S.S e w m a n and H. L. Gildenhorn, J . A m e r . Chem. S O C . 70, , 3li (1948). (13) P. A . 9. Smith, ibid., 70, 320 (1948). (14) R . liiiisyen, .J. Witte, and I. Egi, C h r m . Ber., 90, 18-14 ( l Y 3 i ) . (15) For an excellent recent dir;aussion of t lie I%rcktnanna n d S r l i t i i i d t rearrangemenis see P. A. Y. Smith in "Molecular Kearranyenieiita." Par1 I , P. de Mayo, Ed., Interscience. Xew Tork, London, 1963, Chapier 8. (16) Preparation of 61 b y direct chlorination of 1-acetylindoline folluwed by acid hydrolysis of t h e amide in an impro\.emtnt over t h e lileratrlrr inethod [ R . I k a n , F;. RoRman, F:. I). Hergmanxl, u t d .\. Gnlun. I h ) . ~ i r l . I . Chem., 2, :37 (1064) 1. This method is similar to that used hy IV, G . Gall. 13. D. Astill. and V. Uoekelheide [ J . O r g , Chem.. 20, 1538 (195511 t o prepare 5-bromoindoline.

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31

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lt 32. I3 = (W 33, K =(CH,)-S(C?H,) 34. R = (CH-),N(CH,),

I

il 35

Journal of Xedicinal Chemistry, 1970, Vol. 13, S o . 6 829

BESZODIAZEPISES

ii““

H4P)

Ph

0

13

38

/

+

Ph 39

40

I C1

41

42

PClj and PhLiZ3resulted in the 1-chloro derivative 64 of 18. Suclear chlorination by PClj has been observed previously.24 An attempt to apply the former series of reactions to the preparation of 1,2,4,5-tetrahydro-6- phenylpyrrolo [1,2,3- ef] [1,5]bensodiasepine failed due to the unsuccessful reaction of lactam 12 I\ ith triethyloxoniumfluoroborate. Apparently in this case alkylation occurs a t E-3 rather than a t the lactam carbonyl. The 6-phenylpyrrolo [1,2,3-ef] [l,Z]benzodiazepines were prepared (Scheme 11) via the reaction of 37 with ethylben~oylacetate.~~ I n addition to 38 the isomeric compound 40 was also obtained from this reaction. Reduction of 38 with LAH was not successful. The reduction product 39 could, however, be obtained in 72% yield by the reaction of 38 n-ith BH8.26 Acidification of enamine 40 with HC104 gave iminium perchlorate 42 which could then be reduced with NaBH, to 41.27 An alternate method for the preparation of T-phenylpyrrolo [3,2,l-jk][ 1,4]benzodiazepines is shown in Scheme 111. Kitrosation of 5-chloroindoline (61) with KaSOz and HSO, gave 5-chloro-1-nitrosoindoline which was reduced to 1-amino-5-chloroindoline (63) with LAH.2a Condensation of 63 with l-phenyl-2( 2 3 ) E. E. Smissman and J. L. Diebold, J . Org. Chem.. S O , 4002 (1963). (24) W.Autenrieth and P. hlilhlinghaus. Chem. Eer., 99, 40Y8 (1906). ( 2 5 ) W.Ried a n d P. S. Stalllhofen, ibid., 90, 828 (1957). (26) Li. C . I3roxn and P. Heim, J . Amer. Chem. S o c . , 8 6 , 3566 (271 N . .I. Selson. J. E. Ladbury and R. S. P. Hsi. abid., 8 0 , 6633 (1958). (28) D. E. hxnes and H. Z. Kucharska. J . Chem. Soc., 1509 (1962).

(1964).

propanone gave a hydrazone which without isolation was cyclized to indole 44 with H,S04 in EtOHeZ9Oxidation of 44 with NaIOd30in TTarm dioxane-H20 gave a mixture of ketoamide 47 (R‘ = H) and its hydrolysis product 51. A facile conversion of 47 (R’ = H ) into 51 was accomplished with 6 N HC1 in EtOH. Condensation of 51 with bromoacetyl bromide followed by cyclization of the resulting bromoacetyl derivative (47, R’ = Br) with methanolic _UHs31gave 9-chloro-1,Z dihydro-7-phenylpyrrolo [3,2,l-jk][1,4]benzodiazepin-4(5H)-one (2). Applicatiori of this sequence to indoles 4329and 4 P 2 gave the corresponding benzodiazepines 54 and 5633 without difficulty. I n the latter series the reaction of amino ketone 53 with ethyl glycinate. HC1 in refluxing pyridine31 (method E)gave a better yield of 56 than did the bromoacetyl bromide-lle0HSH, (method 31) sequence. Sitration of l-acetyl-7benzoylindoline (46, R’ = H) with fuming HKO8 in AcOH-.4c20 gave an 84.2% yield of the pure 5-nitro derivative (48, R’ = H ) . Conversion of 48 (R’ = H) to 1,2-dihydro-9- nitro-7-phenylpyrrolo [3,2,1- j k ][1,4]benzodiazepin-4 (5H)-one (55) was accomplished via amino ketone 52 by either method 31 or, preferably; method S. Reduction of 54 with LAH gave the hexahydro derivative 58. Dehydrogenation of 58 with a Pd-C cat(29) A. N. Kost, L. G. Yudin, T u . A. Berlin, and A . P. Terent’ev, J . Gen. Chem. U S S R , 29, 3782 (1959). (30) L. J. Dolby and D. L. Booth, J . Amer. Chem. Sac., 88, 1049 (1966). (31) L. H . Sternbach, R . I. Fryer, M. hletlesics. E. Reeder, G. Sach, G . Saucy, and A. Stempel, J . Org. Chem., 27, 3788 (1962). (321 A. N. Kost, L. G. Yudin, and A. N. Terent’ev, J . Gen. Chem.. C S S R , 29, 1820 (1959). (33) A synthesis of tlie 10-cliloro derivative of 66 has been reported [li.P. Harter and S.Lilsberg, Acto Chzm. Scund., 22, 3382 (lY68)l.

Journal of M e d i c i n d Chemistry, 1970, Vol. 13, S o . 6

A

I'

A

ESTER. RTDZIK,\KD 5'ELDIh spectrum tn ' e 296, 298 (>I+).

Uv max 234.5 ( e 31,050), 272 ( e 8600), 281 ( e 7800), 333 3900); ir 3300 (NH),1655 cm-l (C=O). 42: Uv max 220 ( e 28,600), 236 ( e 20,850), 262 ( e 20,3\50),272 ( E 27,150), 282 ( e 27,150), 314 ( E MOO), 425 ( e 1050), inflection 324 mp ( e 16j0); ir 1690 (C=O), 1620 cm-I ( C = S ) . 46: Uv max 243 ( E 24,800), 313 mp ( e 23.N); ir 1670 cm-' (C=O). 48:s' Uv max 343 (E 11,300), iiiflectioiis 223 ( E 1x,300), nip ( e 17,930); 54: Uv max 236 ( E 20,9>0), 323 111p ( e 3150j; ir 1670 cm-' (C=Oj. 57: L-v max 25% ( C 16,630): 30s i e 7230), inflection 31% m p (E 6400); ir 1710 cm-' (C=O): iimr (CDC1,) 6 4.6s ( s j 2, H-5); ma.. 5pectrum m c 260 (AI+). O ) , 304 ( e 6030), iiiflec60: Uv max 246 ( e 20,410), 296 ( E t i o i i 2% nip (E 3290); ir 8340 (NH), 90 em-' (C=O); nmr [iCl)a)rSO] 6 3.49 (s, 1, H-7)] 3.83 ( 5 , 2, H--5). 62: 1-v max 244 ( E Ih,930), 437 (E 6250), iriflection 273 nip 41:

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(E

.>TOO). 64:38 Vv niax 22.5 ( e 19,h00), 2>2 (l%,X.iO), 276 (9800), 356 0); ir 1615 cni-' ( C = S ) ; mass spectrum

ill

(J

280, 2h2 (>I-).

Acknowledgment.-The author- are indebted t o Dr. E C. 01so11 and hi- ahzociate- for phyqical arid analytical data and to Mr. J. Robert Greene for laborator) a--istance. fX7) The ninr spectrum [ C C U 3 ) 6 0 ] of 62 had peaks a t 6 8.17 ( d . J = 2 I l a ) and 7 . 9 9 [broad singlet) for H-6 and H-4 which thus estblished t h e location of t h e S O ! . ( 3 8 ) T h e ninr spectrum [ ( C l ) d n S O I of 64 was essentially the same as t h a t of 18 except t h a t in 64 11-1 ( 6 6.89, d. J = 3 Hz) was absent and H-2 v a s represented I)?. a singlet a t 8.01.

4- Substituted Piperidines.

Local Anesthetic 4-Aminoalkoxy -4-arylpiperidines

BERTHERMANS, HCGOYEHHOEVEK, Janssen Pharniaceutica

12.2'.,

AND P A U L

JASSSEX

Research Laborafol ia,8340 Bcerse, Belgium

Keceiced A p r i l

4,197'0

The synthesis of a new series of 4,4-disubstituted piperidines is described. These 4-aminoalkoxy-4-arylpiperidines are obtained by performing successively a Grignard reaction on .l*-carbethoxy-4-piperidone, transformation of the tertiary alcohol in an ether, decarbethoxylation, and finally reaction of the secondary amine with a halide. The compounds are good local conduction anesthetics in laboratory animals.

I n previous publications1 of thiq serie.: the synthesis and pharmacological activity of several 4,4-disubstituted and 4-monosubstituted piperidines were described. One of the most important series was that of the n-ellknon 11 4-aryl-4-hydroxypiperidine compound