Claims
- 1. A compound of the formula ##STR428## and pharmaceutically acceptable salts thereof wherein: X is ##STR429## R.sub.9, R'.sub.9, R.sub.10 and R'.sub.10 are independently selected from hydrogen and lower alkyl or R'.sub.9, R.sub.10, R'.sub.10 are hydrogen and R.sub.9 is ##STR430## R.sub.11 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl;
- R.sub.12 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy;
- m is zero, one, two or three;
- p is one, two or three provided that p is more than one only if R.sub.11 or R.sub.12 is hydrogen, methyl, methoxy, chloro, or fluoro;
- R.sub.21 is hydrogen, lower alkyl, cycloalkyl, phenyl or ##STR431## R.sub.22 is hydrogen, lower alkyl, ##STR432## r is an integer from 1 to 4; R.sub.1 is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, ##STR433## wherein q is zero or an integer from 1 to 7; and R.sub.11 and p are as defined above; and
- R.sub.19 and R.sub.20 are independently selected from the group consisting of hydrogen, lower alkyl, halo substituted lower alkyl, ##STR434## wherein m, R.sub.11 and p are as defined above; R.sub.2 is hydrogen, lower alkyl, halo substituted lower alkyl, ##STR435## wherein r is as defined hereinbefore; R.sub.3 and R.sub.6 are independently selected from hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal or ##STR436## wherein R.sub.15 is hydrogen, lower alkyl, cycloalkyl, or phenyl, and R.sub.16 is hydrogen, lower alkyl, lower alkoxy, phenyl, or R.sub.15 and R.sub.16 taken together are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3, --CH.dbd.CH-- or ##STR437##
- 2. A compound of claim 1 wherein:
- R.sub.9, R'.sub.9, R.sub.10 and R'.sub.10 are all hydrogen, or R.sub.9 is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl and R'.sub.9, R.sub.10 and R'.sub.10 are hydrogen;
- m is zero, one or two;
- R.sub.11 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy;
- R.sub.2 is hydrogen, lower alkyl or 1 to 4 carbons, CF.sub.3, or amino substituted lower alkyl of 1 to 4 carbons;
- R.sub.1 is alkyl of 1 to 10 carbons, ##STR438## --(CH.sub.2).sub.q -cycloalkyl wherein cycloalkyl is of 5 or 6 carbons, ##STR439## wherein q is zero or an integer from 1 to 4 and R.sub.11 is as defined above;
- R.sub.19 and R.sub.20 are independently selected from lower alkyl of 1 to 4 carbons or ##STR440## wherein q and R.sub.11 are as defined above; R.sub.3 and R.sub.6 are independently selected from hydrogen, alkali metal salt, lower alkyl of 1 to 4 carbons, or ##STR441## R.sub.15 is hydrogen, methyl or isopropyl; and R.sub.16 is lower alkyl of 1 to 4 carbons or phenyl.
- 3. A compound of claim 2 wherein X is ##STR442## m is zero, one or two; R.sub.11 is hydrogen, methyl, methoxy, methylthio, bromo, fluoro, or hydroxy;
- and R.sub.6 is hydrogen, ##STR443## or an alkali metal salt; R.sub.1 is ##STR444## R.sub.21 is cycloalkyl or H, R.sub.22 is H or benzyl; R.sub.2 is hydrogen or lower alkyl; and R.sub.3 is hydrogen, alkali metal or benzyl.
- 4. A compound of claim 1 wherein
- R.sub.1 is phenylalkyl or ##STR445## wherein R.sub.19 is phenylalkyl and R.sub.20 is phenyl; R.sub.2 is hydrogen, methyl, or --(CH.sub.2).sub.4 --NH.sub.2 ; and
- R.sub.3 is hydrogen, phenylmethyl, ##STR446## or an alkali metal CH(CH.sub.3).sub.2 salt.
- 5. A compound of claim 2 wherein R.sub.1 is alkyl of 1 to 10 carbons.
- 6. A compound of claim 5 wherein X is ##STR447##
- 7. The compound of claim 3 wherein R.sub.1 is phenylbutyl; R.sub.2 is methyl; and R.sub.3 and R.sub.6 are an alkali metal salt.
- 8. The compound of claim 2 wherein R.sub.1 is ##STR448## R.sub.2 is methyl; R.sub.3 is ethyl; and R.sub.6 is an alkali metal salt.
- 9. The compound of claim 2 wherein R.sub.1 is ##STR449## R.sub.2 is methyl; R.sub.3 is ##STR450## and R.sub.6 is an alkali metal salt.
- 10. The compound of claim 6 wherein R.sub.1 is ##STR451## R.sub.2 is methyl; and R.sub.3 and R.sub.6 are an alkali metal salt.
- 11. The compound of claim 6 wherein R.sub.1 is ##STR452## R.sub.2 is hydrogen; and R.sub.3 and R.sub.6 are an alkali metal salt.
- 12. The compound of claim 7 wherein R.sub.1 is ##STR453## R.sub.2 is methyl; and R.sub.3 and R.sub.6 are an alkali metal salt.
- 13. The compound of claim 1 wherein R.sub.1 is ##STR454## and R.sub.19 and R.sub.20 are independently selected from lower alkyl of 1 to 4 carbons or ##STR455## wherein q is zero or an integer from 1 to 4 and R.sub.11 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
- 14. The compound of claim 2 wherein
- R.sub.21 is hydrogen, methyl, phenyl, cyclopentyl or cyclohexyl;
- R.sub.22 is hydrogen, lower alkyl of 1 to 4 carbons, ##STR456## --(CH.sub.2).sub.4 --NH.sub.2, --CH.sub.2 SH, --(CH.sub.2).sub.2 --S--CH.sub.3, ##STR457##
- 15. A compound of claim 14 wherein X is ##STR458## and R.sub.6 is hydrogen, ##STR459## or an alkali metal salt.
- 16. The compound of claim 1 having the name (S)-N-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-N-cyclohexylglycine, or its dilithium salt.
- 17. The compound of claim 1 having the name N-[(S)-6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-phenylalanine or its dilithium salt.
- 18. The compound of claim 1 having the name 3-[(S)-6-amino-2-[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-4-thiazolidine carboxylic acid, or its dilithium salt.
- 19. A composition useful for treating hypertension comprising a pharmaceutically acceptable carrier and an effective amount of a hypotensive agent or pharmaceutically acceptable salt thereof of the formula ##STR460## wherein X, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1.
- 20. The composition of claim 20 also including a diuretic.
- 21. The method of alleviating hypertension in a mammalian specie which comprises administering an effective amount of the composition of claim 20.
REFERENCE TO OTHER APPLICATIONS
This application is a continuation-in-part of application Ser. No. 764,449, filed Aug. 12, 1985, now abandoned, which is a division of U.S. application Ser. No. 608,752, filed May 10, 1984, now abandoned which is a division of U.S. application Ser. No. 391,884, filed June 23, 1984, now U.S. Pat. No. 4,452,790.
US Referenced Citations (21)
Foreign Referenced Citations (5)
Number |
Date |
Country |
868532 |
Oct 1978 |
BEX |
0009183 |
Apr 1980 |
EPX |
2027025 |
Feb 1980 |
GBX |
2028327 |
Mar 1980 |
GBX |
2039478 |
Aug 1980 |
GBX |
Non-Patent Literature Citations (4)
Entry |
Galardy, "Inhibition of Angiotensin . . . " Biochem. Biophs. Res. Comm., 1980, vol. 97, pp. 94-99. |
Mauger, "Analogs and Homologs of Proline . . . ", Chem. Review, vol. 66, pp. 47-86 (1966). |
Thorsett et al., "Phosphorus Containing Inhibitors . . . ", 182 National Meeting, ACS, New York, Aug. 1981, MEDI-7. |
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Divisions (2)
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Number |
Date |
Country |
Parent |
608752 |
May 1984 |
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Parent |
391884 |
Jun 1984 |
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Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
764449 |
Aug 1985 |
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