Claims for Patent: 4,105,776

Summary for Patent: 4,105,776

Title:	Proline derivatives and related compounds
Abstract:	New proline derivatives and related compounds which have the general formula ##STR1## are useful as angiotensin converting enzyme inhibitors.
Inventor(s):	Ondetti; Miguel Angel (Princeton, NJ), Cushman; David W. (West Windsor, NJ)
Assignee:	E. R. Squibb & Sons, Inc. (Princeton, NJ)
Application Number:	05/751,851
Patent Claims:	1. A compound of the formula ##STR37## wherein R is hydroxy, NH.sub.2 or lower alkoxy; R.sub.1 and R.sub.4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl; R.sub.2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoylaminomethyl, ##STR38## R.sub.6 -S- or R.sub.7 ; R.sub.3 is hydrogen, hydroxy or lower alkyl; R.sub.5 is lower alkyl, phenyl or phenyl-lower alkyl; R.sub.6 is lower alkyl, phenyl, substituted phenyl, wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, hydroxy-lower alkyl or amino(carboxy)lower alkyl; ##STR39## M is 0 or S; m is 2; n and p each is 0, 1 or 2; and basic salts thereof, said lower alkoxy, lower alkyl and lower alkanoyl groups having up to seven carbon atoms. 2. A compound as in claim 1 wherein R is hydroxy or lower alkoxy; R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen, R.sub.5 --CO, R.sub.6 --S--, or R.sub.7 ; R.sub.3 and R.sub.4 each is hydrogen; R.sub.5 is lower alkyl or phenyl; R.sub.6 is lower alkyl; R.sub.7 is ##STR40## wherein R, R.sub.1 and R.sub.4 have the same meaning as above; n is 0, 1 or 2; and p is 0. 3. A compound as in claim 1 wherein R.sub.3 and R.sub.4 each is hydrogen. 4. A compound as in claim 1 wherein R.sub.3 is hydrogen. 5. A compound of the formula ##STR41## wherein R is hydroxy or lower alkoxy; R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen or lower alkanoyl; n is 0, 1 or 2; and physiologically acceptable salts thereof, said lower alkoxy, lower alkyl and lower alkanoyl groups having up to seven carbon atoms. 6. A compound as in claim 5 wherein R is hydroxy. 7. A compound as in claim 5 wherein n is 1. 8. A compound as in claim 5 wherein R.sub.2 is hydrogen or lower alkanoyl. 9. A compound as in claim 5 wherein R.sub.2 is hydrogen. 10. A compound as in claim 5 wherein R.sub.2 is acetyl. 11. A compound as in claim 5 wherein R.sub.1 is hydrogen or lower alkyl. 12. A compound as in claim 5 wherein R.sub.1 is hydrogen or methyl. 13. A compound as in claim 5 wherein R is hydroxy and R.sub.1 is hydrogen or methyl. 14. A compound as in claim 5 wherein R is hydroxy, R.sub.1 is hydrogen or methyl, R.sub.2 is hydrogen or acetyl and n is 0, 1 or 2. 15. A compound as in claim 5 wherein R is hydroxy, R.sub.1 and R.sub.2 each is hydrogen and n is 0. 16. A compound as in claim 5 wherein R is hydroxy, R.sub.1 is hydrogen, R.sub.2 is acetyl and n is 1. 17. A compound as in claim 5 wherein R is hydroxy, R.sub.1 is methyl, R.sub.2 is acetyl and n is 1. 18. A compound as in claim 5 wherein R is hydroxy, R.sub.1 and R.sub.2 each is hydrogen and n is 1. 19. A compound as in claim 5 wherein R is hydroxy, R.sub.1 is methyl, R.sub.2 is hydrogen and n is 1. 20. A compound as in claim 5 wherein R is hydroxy, R.sub.1 is hydrogen, R.sub.2 is benzoyl and n is 1. 21. The L-form of a compound of claim 5. 22. The compound of claim 19 in which the proline is in the L-form. 23. A compound as in claim 1 wherein R is hydroxy, R.sub.1 is hydrogen, R.sub.2 is lower alkylthio and n is 1. 24. A compound as in claim 1 wherein R.sub.2 is ##STR42## each R is hydroxy; each R.sub.1 is hydrogen or lower alkyl; and each n is 0 to 2. 25. A compound as in claim 24 wherein each R is hydroxy; each R.sub.1 is hydrogen and each n is 1. 26. The compound according to claim 1 having the name 1-(3-mercapto-2-D-methylpropanoyl)-L-proline. 27. The compound according to claim 1 having the name 1,1'-[dithiobis(2-D-methyl-3-propanoyl)]-bis-L-proline. 28. The compound of claim 18 in which the proline is in the L-form. 29. The compound of claim 17 in which the proline is in the L-form. 30. A composition for reducing blood pressure comprising about 10 to 500 mg. of a compound of claim 1 and a pharmaceutically acceptable vehicle therefor. 31. A composition for reducing blood pressure comprising about 10 to 500 mg. of a compound of claim 19 and a pharmaceutically acceptable vehicle therefor. 32. A composition for reducing blood pressure comprising about 10 to 500 mg. of a compound of claim 18 and a pharmaceutically acceptable vehicle therefor. 33. A composition for reducing blood pressure comprising about 10 to 500 mg. of the compound of claim 26 and a pharmaceutically acceptable vehicle therefor. 34. A composition for reducing blood pressure comprising about 10 to 500 mg. of the compound of claim 27 and a pharmaceutically acceptable vehicle therefor. 35. A method for reducing blood pressure which comprises administering a composition comprising a compound having the formula in claim 1 or a physiologically acceptable salt thereof and a pharmaceutically acceptable vehicle therefor. 36. A method for reducing blood pressure which comprises administering a composition comprising a compound of claim 19 and a pharmaceutically acceptable vehicle therefor. 37. A method for reducing blood pressure which comprises administering a composition comprising a compound of claim 18 and a pharmaceutically acceptable vehicle therefor. 38. A method for reducing blood pressure which comprises administering a composition comprising the compound of claim 27 and a pharmaceutically acceptable vehicle therefor. 39. A compound of the formula ##STR43## wherein R is hydroxy or lower alkoxy; R.sub.1 and R.sub.4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl; R.sub.2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoylamidomethyl, ##STR44## R.sub.6 -S- or R.sub.7 ; R.sub.3 is hydrogen, hydroxy or lower alkyl; R.sub.5 is lower alkyl, phenyl or phenyl-lower alkyl; R.sub.6 is lower alkyl, phenyl, substituted phenyl, wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, hydroxy-lower alkyl or amino(carboxy)lower alkyl; ##STR45## M is 0 or S; m is 2; n and p each is 0, 1 or 2; and physiologically acceptable salts thereof, said lower alkoxy, lower alkyl and lower alkanoyl groups having up to seven carbon atoms. 40. A compound as in claim 39 wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen, R.sub.5 --CO, R.sub.6 --S--, or R.sub.7 ; R.sub.3 and R.sub.4 each is hydrogen; R.sub.5 is lower alkyl or phenyl; R.sub.6 is lower alkyl; R.sub.7 is ##STR46## wherein R is hydroxy or lower alkoxy; and R.sub.1 and R.sub.4 have the same meaning as above; and n is 0, 1 or 2. 41. A compound as in claim 39 wherein R.sub.3 and R.sub.4 each is hydrogen. 42. A method for reducing blood pressure which comprises administering a composition comprising the compound of claim 26 and a pharmaceutically acceptable vehicle therefor.