J. Med. Chem. 1986,29,411-417
411
Angiotensin Converting Enzyme Inhibitors as Antihypertensive Agents: I-[ (2-Mercaptocycloalkyl)carbonyl]-~-prolines Romeo Ciabatti,* Giovanna Padova, Elvio Bellasio, Giorgio Tarzia, Adele Depaoli, Franco Battaglia, Mario Cellentani, Domenico Barone, and Emiliana Baldoli Lepetit Research Center, Gruppo Lepetit S.p.A. via Durando, 38-20158Milano, Italy. Received March 27, 1985 The synthesis of 1-[(2-mercaptocyclopentyl)carbonyl]-~-prolines, 1-[(2-mercaptocyclobuty1)carbonyl] +prolines and related benzoyl derivatives as pure isomers is described. The abilities of all the compounds to inhibit angiotensin converting enzyme (ACE) in vitro and in vivo and to lower the systolic blood pressure in renal hypertensive dogs were determined. Three of them, namely 1-[[2-(benzoylthio)cyclopentyl]carbonyl]-~-proline(10f(R,S)), 1-[(2mercapt~cyclopentyl)carbonyl]- proli line (lOg(R,S)), and 1-[[2-(benzoylthio)cyclobutyl]carbonyl]-~-proline (16f(R,S)), were found to be as potent as captopril in reducing blood pressure. The influence of chirality and ring size on the ACE inhibition is described.
The discovery by Ondetti et al.' of a new class of orally active angiotensin converting enzyme (ACE) inhibitors that act as antihypertensive agents,2 of which captopril was reported to be the most potent compound, has prompted a great deal of work in this new In this paper we report the synthesis and the ACE inhibitory activity of a new class of compounds, 1, related to captopril but with a semirigid structure and hence a restricted number of conformations.
Scheme Ia
20 17.2 b:n m 3
3a. n 2 b,n - 3 9
D
b, n 8 3 : R ' = CH&O 60. n = 2 : R ' = H b,n-3: R'=H captopril
l . n = l . 2 . 3 .R.H.CH3
Chemistry. Compounds 6a and 6b were prepared as
i, CH,COSH; ii, SOCl, ;iii, L-proline/NaOH-H,O; iv, NH,-CH, OH ;V, HCl.
Scheme 11' (1) (a) Ondetti, M. A.; Rubin, B.; Cushman, D. W.; Science 1977, 196, 441. (b) Cushman, D. W.; Cheung, H. S.; Sabo, E. F.; Ondetti, M. A. Biochemistry 1977,16,5484.(c) Cushman, D. W.; Cheung, H. S.; Sabo, E. F.; Ondetti, M. A. Prog. Cardiovasc. Dis. 1978,21, 176. (2) (a) Heel, R. C.; Brogden, R. N.; Speight, T. M.; Avery, G. S. Drugs 1980, 20, 409. (b) Cushman, D. W.; Ondetti, M. A.; Cheung, H. S.; Sabo, E. F.; Antonaccio, H. J.; Rubin, B. In "Enzyme Inhibitors as Drugs"; Sandler, M., Ed.; Macmillan: London, 1980;p 231;(c) Ondetti, M. A.; Cushman, D. W. In "Biochemical Regulation of Blood Pressure"; Soffer, R. L., Ed.; Wiley: New York, 1981;p 165. (d) Cushman, D. W.; Powell, J. R.; De Forrest, J. M.; Petrillo, E. W.; Krapcho, J.; Rubin, B.; Ondetti, M. A. Prog. Pharmacol. 1984,5,5. (3) Sugie, A.; Katsube, J. Chem. Pharm. Bull. 1979,27,1708. (4) Petrillo, E. N., Jr.; Spitzmiller, E. R. Tetrahedron Lett. 1979, 4929. ( 5 ) Patchett, A. A.; Harris, E.; Tristram, E. W.; Wyvratt, M. J.; Wu, M. T.; Tamb, D.; Peterson, E. R.; Ikeler, T. J.; ten Broeke, J.; Payne, L. G.; Ondeyka, D. L.; Thorsett, E. D.; Greenlec, W. J.; Lohr, N. S.; Hoffsommer, R. D.; Joshua, H.; Ruyle, W. V.; Rothroc k, J. W.; Aster, S. D.; Maycock, A. L.; Robinson, F. M.; Hirschmann, R.; Sweet, C. S.; Ulm, E. H.; Gross, D. M.; Vassil, T. C.; Stone, C. A. Nature (London) 1980,288,280. (6) Klutchko, S.;Hoefle, M. L.; Smith, R. D.; Essenburg, A. D.; Parker, R. B.; Nemeth, V. L.; Ryan, M. J.; Dugan, D. H.; Kaplan, R. J. Med. Chem. 1981,24,104. (7) Oya, M.; Baba, T.; Kato, E.; Kawashima, Y.; Watanabe, T. Chem. Pharm. Bull. 1982,30,440. (8) Hassall, C. H.; Krohn, A.; Moody, C. J.; Thomas, W. A. FEES Lett. 1982,147,175. (9) McEvoy, F. J.; Lai, F. M.; Albright, J. D. J. Med. Chem. 1983, 26,381. (10) Kim, D. H.; Guinosso, C. J.; Buzby, G. C., Jr.; Herbst, D. R.; McCaully, R. J.; Wicks, T. C.; Wendt, R. L. J. Med. Chem. 1983,26, 394. (11) Stanton, J. L.;Gruenfeld, N.; Babiarz, J. E.; Ackerman, M. H.; Friedmann, R. C.; Kuan, A. M.; Macchia, W. J.Med. Chem. 1983,26, 1267,1277.
2 a , n = 2 ;R = H
7
8
9
a i, C,H,COSH, 120 "C.
oily mixtures of the four diastereoisomers from 2a and 2b (Scheme I). The unsuccessful efforts to separate the four isomers of 6a by classical methods suggested to us to do the Michael reaction on 2a with thiobenzoic acid in order to obtain solid intermediates that should be easier to separate than the liquid mixtures 3a,4a. This reaction gave a trans-cis soIid mixture 7a (Scheme 11) from which the two isomers Sa and 9a were separated by crystallization and condensed with L-proline 1,l-dimethylethyl ester12 (procedure A) to give the diastereoisomeric mixtures 10e,lle and 12e,13e (Schemes I11 and IV). These were separated by preparative liquid chromatography and then deprotected fiist with CF3COOHlb(procedure B) and then with NH4OHlb(procedure C) to give l(t13g in good yields. The Michael reaction of 2c with thiobenzoic acid gave only (12) (a) Anderson, G. W.; Callahan, F. M. J.Am. Chem. SOC. 1960, 82, 3359. (b) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978,4475.
0022-2623/86/1829-0411$01.50/00 1986 American Chemical Society
412 Journal of Medicinal Chemistry, 1986, Vol. 29, No. 3
Ciabatti et al.
Table I. Physical Properties of l-[(2-Mercaptocycloalkyl)carbonyl]-~-proline and in Vitro ACE Inhibitory Activity
R%T
R'S
compd"
n
R
R'
R"
re1 config CB-Ca
IC,,*
WM
mp, "C
0
COOR"
recrystn solvent
procedueC
yield,
[aIzoD, deg
%
(c 1, CHC13)
formula
anal.
6a 2 H H H mixture 1.64 glass 75.4 C11H17N03S 95.0 C12HlgN03S C,d H, N, S 6b 3 H H H mixture 11.35 glass 250 73.5 hexanee A 42.1 10e(R,S) 2 H COC6H5 t-C4Hs trans -107.5 CzzHzsN04S C, H, N, S hexane' A 40.5 250 67 lle(S,R) 2 H COCBH5 t-C4Hg trans +4.8 C22HZsN04S C,H, N, S hexanee A 50.1 250 81.5 COC6H5 t-C4Hs cis 12e(S,S) 2 H -153.5 CzzH29NO4S C, H, N, S 68 hexane' A 44.6 124 COC6H, t-C4H9 cis 13e(R,R) 2 H -2.7 CzZH29N04S C, H, N, S 14e(S,S) 2 CH3 COC6H5 t-C4Hg trans 250 170 Et20e A 42.3 -82.5 CZ4H33NO4S C, H, N, S 15e(R,R) 2 CH3 COC6H5 t-C4Hg trans 250 119, 136 Et20' A 43.2 -34.6 C24H33NO4S C,H, N, S 16e(R,S) 1 H COC6H, t-C4Hg trans 250 103 Et20e A 36.4 -138.8 C21HZTNO4S C,H, N, S 17e(S,R) 1 H COC6H5 t-C4Hs trans 250 112 Et20' A 42.5 +12.8 CzlH27NO4S C, H, N, S 10f(R,S) 2 H COC6H5 H trans 0.58 106 EtOAc B 95.0 -119.9 ClBH,1N04S C, H, N, S llf(S,R) 2 H COC&, H trans 144 88 %t,O B 94.0 -81.8 C18H21NOdS C, H, N, S 12f(S,S) 2 H COCsH5 H cis 144 152 EtOAc B 95.1 -183.4 CiBH21N04S C, H, N, S 13f(R,R) 2 H COC& H cis 250 glass B 95.0 -59.7 C18H21NO4S 14f(S,S) 2 CH, COC& H trans 250 187 EtOAc B 85.0 -90.5 C2oH25NO4S C, H, N, S 15f(R,R) 2 CH3 COC6H5 H trans 250 153 EtzO' B 74.3 -141.2 CzoH25N04S C, H, N, S 16f(R,S) 1 H COC6H5 H trans 5.50 107 Et20e B 76.0 -119.6 C17HisNOdS C, H, N, S 17f(S,R) 1 H COC& H trans 250 124 EtzO' B 95.0 -86.3 C17HiSNO4S C,H, N, S 10g(R,S) 2 H H H trans 1.11 118 Et20 C 72.2 -237.4 CilH17N03S C, H, N, S llg(S,R) 2 H H H trans 34.25 102,lld EtzO C 77.8 -61.6 C11H17NO3S C, H, N, S 12g(S,S) 2 H H H cis 19.50 88 Et20 C 77.7 -149.6 CllH17N03S C, H, N, S 13g(R,R) 2 H H H cis 206 97 Et20 C 76.2 -181.7 C1,H,,NO3S C,H, N, S 14g(S,S) 2 CH3 H H trans 215 139 Et20e C 65.8 -132.8 C13H21NO3S C, H, N, S 15g(R,R) 2 CH3 H H trans 250 147 Et2O' C 80.0 -63.7 C13H21N03S C, H, N, S 16g(R,S) 1 H H H trans 1.26 145 EtzO' C 85.0 -192.3 Cl,H15NO,S C, H, N, S 17g(S,R) 1 H H H trans 12.73 137 Et,O C 86.0 -44.2 C10H15N03S C,H, N, S cautouril 0.59 "Parenthetical R and S designations indicate the absolute stereochemistry. The first letter in the grouping refers to the p carbon configuration and the second letter to the (Y carbon configuration. * Micromolar concentration required for 50% ACE inhibition. e See Experimental Section. d C : calcd, 56.00;found, 56.61. eSolvent used to triturate the solid residue. fTwo crystalline forms.
~
~~
Scheme I V
Scheme I11
n
-
9a
80, n = 2 ; R = H C,n.2;R-CH3 d.n 1 ;R - H
-
13
12
b, R ' . C O C e H s . R " = r - C 4 H e
10.n.2;R.H 14, n - 2 ; R =CH3 16. n - 1 ; R - H
1 1 , n = 2; RmH 15. n * 2 ; R = C H 3 1 7 . n = 1 ; RmH
b, R ' = C O C e H s : R ' ~ t - C 4 H s f , R' 9 COCsHs; R' * H 9 , R' = R" H
the trans isomer 8c. The cis isomer probably was not formed because of the considerable steric interaction that a cis arrangement of the methyl, thiobenzoyl, and carboxylic groups would have. The trans isomer 8c was condensed with L-proline, 1,l-dimethylethyl ester, and the resulting isomers 14e and 15e were separated and deprotected as before to give 14g and 15g (Scheme 111). In a similar way 2d was converted to the trans-cis mixture 7d, the two isomers 8d and 9d were separated by crystallization (Scheme 11),and the trans isomer & was I transformed to 16g and 17g (Scheme 111).
-
t , R ' 9 COCe Hs; R' g, R ' = R' H
9
H
The relative configurations of 8 and 9 were established on the basis of the chemical shifts and coupling constants of the two methine protons from the 1iterat~re.l~The absolute configurations of the a and ,6 cycloalkylic carbon atoms of the four pairs of compounds IOe,lle, 12e,13e, 14e,15e, and 16e,17e (Table I) were assigned tentatively on the basis of their IH NMR spectra, which displayed different populations of trans and cis conformers around the prolyl-amide bond9,l4(Table 111). In fact, the NMR (13) (a) Jackman, L. M.; Sternhell, S. "Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry", 2nd ed.; Pergamon Press: New York, 1978;p 234. (b) Einsley, J. W.; Feeney, J.; Sutcliffe, L. H. "Progress in NMR Spectroscopy"; Pergamon Press: New York, 1969;Vol. 5,p 196. (c) Ibid., p 214.
Angiotensin Converting E n z y m e Inhibitors
Journal of Medicinal Chemistry, 1986, Vol. 29, No. 3 413
Table 11. ACE Inhibitory Activity in Conscious Normotensive Rats and Antihypertensive Activity in Conscious Renal Hypertensive Dogs antihypertensive act. dose, % reduction of ICSO! compd mg/ kg iv Ang I responsec mg/kg PO % SBP decreaseOsd PM -18" 0.58 -80** 30 10f(R,S) 10 -15" 1 -65** 10 -17" 5.5 -60** 30 16f(R,S) 10 -15' 1 -45** 10 -1900 >250 -30* 30 17f(S,R) 10
