Synthesis and antihypertensive properties of some N-(guanidinoalkyl

Synthesis and antihypertensive properties of some N-(guanidinoalkyl)pyrrolidines. David Miller, Brian P. Curwain, Charles S. Fake, John L. Gordon, Min...
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Journal of Medicinal Chemistry, 1971, Vol. 14, No. 8 737

N-(GVANIDINOALKYL)PYRROLIDINES arom), 4.70, (s, 2 H, OH), 6.80 (9, J = 7 cps, 1 H, benzylic), 7.8-9.5 [broad envelope, 26 H, (C6HIlCH2)21* Further chayscterieation and yield data for the catechols are presented in Table 11.

Acknowledgment.-We are pleased to acknowledge the able technical ass&ance of Mr. Stephen G. Columbia College, 1967.

Synthesis and Antihypertensive Properties of Some

N-( Guanidinoalky1)pyrrolidines BRIANP. CURWAIN, CHARLES S. FAKE, JOHN L. GORDON, MILLER,*ROBERT H. POYSER, AND ERICA . WATTS MINOOD. MEHTA,DAVID Beecham Research Ldoratories, Brockham Park, Betchworth, Surrey, England Received October IS, 1970 The synthesis of 21 N-(guanidinoalky1)pyrrolidines is described. Some of these, 7a,7b,10,11,12,12a,12b,13, and 21, exhibited an antihypertensive activity similar to that of guanethidine when tested in renal hypertensive rats. Structure-activity relationships are discussed.

Since the discovery of the antihypertensive action of guanethidine,’ many related compounds have been synthesized and several have been found to be active antihypertensives2 which, like guanethidine, mediate their effect via adrenergic neurone blockade. This paper describes the preparation and pharmacological properties of a series of N-(guanidinoalky1)pyrrolidines.3 Details and antihypertensive activities of these compounds are shown in Table I. Chemistry.-The majority of the compounds listed in Table I were prepared by treating the appropriate N-(aminoalky1)pyrrolidine with S-methylpseudothiouronium sulfate in aq EtOH and then neutralizing with 5 N HzS04 (method A). Compounds 16-18 were prepared as described in the Experimental Section. The N-(aminoalky1)pyrrolidine precursors to 1-4, 7a, 8, 9, 12-14, and 16-20, were synthesized as outlined in Schemes I and 11. The first step of these syntheses SCHEME I OH R

Rl-C

I -CHCl I I C=C%

NHdCHdzNH,

involved the formation of pyrroles from acetylenic carbinols in a manner suggested by the work of Perveev and ~ t h e r s . ~ J The precursor to 5 was obtained by catalytic hydrogenation of 1- (2-aminoet hyl)-3-phenylpyrrole. When the pyrrole ring carried substituents on 2 or more C atoms, the catalytic hydrogenation step of ( 1 ) R. A. Maxwell, A. J. Plummer, F . Schneider, H. Povalski, and A. I . Daniel, J . Pharmacal. E x p . Ther., 128, 22 (1960). (2) R . P . Mull and R . A. Maxwell, “Antihypertensive Agents,” E. Schlittler. Ed., Academic Press, New York, N.Y.,1967, p 115. (3) Many of these eompds are described by D. Miller and C. S. Fake in British Patent 1,185,080 (1970) and other patents. (4) F . Y a . Perveev and E. M . Kuznetsova, Z h . Obsheh. Khim., 28, 2360 (1958); Chem. Abslr., 68, 3190 (1959). (5) E.R . Catlin, Ph.D. Thesis, Oxford, England (1964).

SCHEME I1 OH R

I I

Rl-C-CHCl

I

NHdCHdnHN, n I2,3,8

&H~C==CH

Schemes I and I1 yielded N-(aminoalky1)pyrrolidines as mixtures of stereoisomers. Usually no attempt was made to separate these isomers. In the case of the precursor to 12, however, the cis and trans isomers of the N-(aminoalky1)pyrrolidine were separated by preparative glpc and converted to the N-(guanidinoalky1)pyrrolidines 12a and 12b, respectively. The configurational assignments were made from the pmr spectra on the basis of the mutual shielding effect of Me groups in close proximity. Compound 12a was also isolated by fractional crystallization of a mixture of the isomeric N-(guanidinoalky1)pyrrolidine sulfate salts. I n the case of 7a, the catalytic hydrogenation step of Scheme I1 gave predominantly the cis isomer of the N-(aminoalkyljpyrrolidine intermediate as shown by glpc. The cis configuration of the Me substituents was confirmed by X-ray crystallographic analysis of the N-brosyl derivative.6 However, synthesis of the N-(aminoalky1)pyrrolidine as outlined in Scheme 111, followed by purification as described in the Experimental Section, gave predominantly the trans isomer. Guanylation of this isomer mixture gave 7b. The precursor to 21 was obtained from a mixture of isomeric branched-chain compounds. The precursor to 15 was obtained by catalytic hydrogenation of 2,4-dimethyl-l-(2-methylaminoethyl)pyrrole which was prepared as described in the Ex-. perimental Section. The N-(2-aminoethyljpyrrolidine intermediates for 6, 10, and 11 were synthesized as outlined in Scheme IV. (6) Professor G . Sim. University of Susaex, Sussex, England, unpublished work.

POYSER, et al.

738 Journal of Medicinal Chemistry, 1971, Vol. 1.6, No. 8 TABLE I N - (GIJANIDINOALKYL)PYRROLIDINES

Antihypertensive act.d (guanethedine = 1.00)

Yield,c Compd R 1 H 2 3 4 5

H H H H

6 7aO 7bA 8 9

H H H H H hle

RI

Rz

hle

H

Ra H

Et n-Pr n-BU Cyolohexyl Ph Me Me

H H H H H H H H H H hle H H H H H H H H H H H H

Et

lert-Bu H 10 M e hle 11 Me Me lZk 12am M e Me 12bn M e M e 13 Me M e 14 H Me Me 15 H 16 H Me 17 H Me hle 18 H Me 19 H Me 20 H 21 H hle

R4

Rs

Re

H

H

H

X (CHz)z

H H H H

H

H H H H

H H H H

(CHdz (CH2)2 (CHz)z (CHZ)~

M p , 'Casb 243.5245.5 259-261 HzS04 H z S 0 1 ~ 0 . 5 H ~ 0 >300 HzSO4 194-197 H ~ S 0 4 ~ 1 . 5 H z O 208-211

H Me Me Me Me Me H H H H Me Et hle Me We Me Me hle Me

H H H H H H H H H H H H Me H H H H

H H H H H H H H H H H

H H H H H H H H H H H

H

H

(CHZ)~ (CH2)z (CH2)z (CHh (CH2)z (CHz)z (CHdz (CH2)z (CHz)z (CHZ)~ (CHZ)~ (CHz)z (CH2)z (CHz)z (CHz)z (CHZ)~ (CHz), (CHZ)~ CHMeCH:!

HzSO1.0.5Hz0 HzSO4.Hz0 HzSOI.H~O His04 HzS04~0.5Hz0 HzSOi His04 HzS04.0.5HzO HzSO4 H2S04.0.5HzO His04 HzSO4 HzS04.1.5Hz0 HC1 HI HzSOi.Hz0 HzS04.0.5HzO HzS01.Hz0 HzSO4.0.5Hz0

H H H

H H

H H NO:! H NHz H CHzCH2 H H H H H H

Salt &SO4

227-237 291-292 292-296 248-250.5 246-249 295-298 291-294 272-274' 292-295 294-295 275-278 272-274 254-258 158q 113-114s 219-221' 292-294

% 68

Formula CsHzoN404S

74 32 73 81 54

50 70 70 70 65 66 86 48

75 72 71 40 46' 67' 88'

u

56 95

308-309

66

Analyses C, H, N, S

SC

PO

0.25

0.41

C, H, S; N e COHZZN~O~S H , N ; SI C I O H Z ~ N ~ O I S . O . ~ HC,Z O C , H , N, S CIIHZ~N~O~S CiaHzsN104S.1.5HzO C , H , N , S

0.38 0.21 0.43 0.15

0.35 0.26

CiaHzzN~O~S~0.5HzC 0 , H , N, S CPHZZNIOIS~HZO C . H, N , S C O H Z Z N ~ O & . H ~ O C , H , N ; Si C , H, N . S CIOHZIN~OIS CizHz8N404S.0.5HzO C , H , N , S C, H, N, S CnHzzN104S C , H , N ; Si CioHzrN104S CeHzzN~04S.0.5HzO C , H , N , S CSHZZN~OIS C, H, N, S C, H, N, S CeKzzN401S.0.5HzO C, H, N, s CIOHZINIOIS H , N ; C, So CioHzrNiOiS , NH; ~SP C I O H Z ~ N ~ O ~ S ~C~. H .~ O C , H, N , CI CgHzoClNa02 C . H , Ii,I CsHzzINs C, H , N , S CiiH~N404S.Hz0 C, H , N , S CioHzrXrOiS.0.5HzO C. H . N , S CisHsrN404S.HzO C. H , N , S CioHzrN401S.0.5HzO

., nip 64.3-66O. *ann!. (C14HslBrN,02S) C, 11, X, Br, S. Similarly, the .V-iodosyl deriv 69 was obtained as colorle-h C, TI, S , I, S. prisms, mp 8 2 4 3 " . A n d . JC14HplIN?O?Q) a-Methyllevulinic Acid (70) (See Scheme III).--%-LIethylpent-4-ynoic acid [bp 100-104" (11 mm), n 2 0 ~1.4439; lit.2i ~ wa> prepared by the method of bp 109" (20 mix), n z o 1.44351 The Colonge aiid G e l i i ~ . ~ ~ pentyiioic acid (78.40 g, 0.70 mole) was then hydrated by treatment with a 3?: suln of HgSO, iii 1 0 5 H2S04(700 ml) at 100" for 1 hr. After cooling, the aoln was extd thoroughly with EtyO, the est- were dried (JIgSO,) and evapd mider vacuum, and disrn afforded 70 161.60 g, 6Yc; 1: bp 106-114' (0.7 mm): TZ**II 1,439S ilit.28tip 10;;" ( 1 n i m ) ; n19u 1.43891. 1-( 2-Aminoethyl)-2,4-dimethyl-5-pyrrolidone(71) (See Scheme III).-A suspension of hdamq catalyst (1.0 g ) iii EtOH (100 ml) was hydrogenated to Pt. A sohi of 70 (26.00 g, 0.20 mole) and ethylenediamine (72.00 g, 1.20 moles) in EtOH (200 ml) was then added arid the mist was hydrogeiiated a t atmospheric presbure aiid room temp. After 24 hr the theoretical vol of H2 had been absorbed arid the mixt \+-as filtered through kieselguhr to remove catalyst. EtOII and excess ethylenediamine were removed under vacuum arid the residual oil wa.. dissolved in 3 S HC1. The acidic s o h wa5 washed with CHC13, basified with 40"; S a O H ,soln, arid estd thoroughly Iyith CIICL. ( 2 i ) J. Colonge and R . Gelin, Bull. SOC.Ciiim. F r . , 797 (1954). (28) E. A. Braude and C . .J. Timmons, J . Ciiem. Soc., 3313 (1953).

POYSER, et al. After drying (RIgSO,), the exts were evapd under vacuum and distn gave 71 (24.00 g, 7757): bp 94-98' (0.4 m m ) ; n19% 1.4X61. A n d . (CsH,s?jyO)H, S ; C : calcd, 61.31; found, 61.04. Mainly Trans Isomer of 1-(2-Aminoethyl)-2,4-dimethylpyrrolidine (42) (See Scheme III).--A soln of 71 (7.80 g, 0.05 mole) iri EtpO(60 ml) was added dropwise to a stirred suspension of IAII (3.70 g, 0.1.; mole) iii E t 2 0 (60 ml) iii 0.5 hr. The mixt was refluxed overnight and worked up in the usual way to give a colorless oil (5.59 g), bp 70-71° (11 mm), shown by glpc to be a mixt of 42 isor;, cis and trans isomer:, present in the ratio 51:39, respj and an unidentified product (loci). Fractional distil of this mist through a htainless steel spinning-band column afforded g) coiitg 42 ( 9 1 5 , cis and trans isomers present 69, respj arid the iuiidentified product (9