Claims
- 1. A compound of the formula: ##STR43## wherein: R is hydrogen; loweralkyl; aralkyl; or, aryl;
- R.sup.1 is hydrogen; alkyl of from 1 to 12 carbon atoms which include branched, cyclic and unsaturated alkyl groups; substituted loweralkyl wherein the substituent can be halo, hydroxy, carboxy, carboxamido, loweralkylthio, loweralkoxy, loweralkoxycarbonyl, loweraralkoxycarbonyl, amino, loweralkylamino, lowerdialkylamino, acylamino; substituted loweralkylamino, wherein the substituent can be halo, hydroxy, alkoxy or cyano; arloweralkylamino; cyclic amino; oxo, thio or ureido; aryloxy; arylthio; aralkyloxy; aralkylthio; benzofused cycloalkyl or bicycloalkyl of from 8-12 carbon atoms; aryl or heteroaryl which may be mono-, di- or trisubstituted by loweralkyl, hydroxy, loweralkoxy, halo, amino, acylamino, loweralkylthio or aminoloweralkyl; benzofused cycloalkyl or bicycloalkyl of from 8 to 12 carbon atoms; arloweralkyl; arloweralkenyl; heteroloweralkyl and heteroloweralkenyl in which the aryl or heteroaryl rings may be mono-, di- or tri-substituted by halo, loweralkyl, hydroxy, loweralkoxy, amino, loweralkylamino, diloweralkylamino, aminoloweralkyl, acylamino, carboxy; haloloweralkyl, nitro, cyano or sulfonamido; aralkyl or heteroaralkyl which include branched loweralkyl groups; substituted aralkyl or substituted heteroaralkyl which include branched loweralkyl groups wherein the loweralkyl groups can be substituted by amino, acylamino, or hydroxyl and the aryl and heteroaryl groups can be substituted by halo, dihalo, loweralkyl, hydroxy, loweralkoxy, aryloxy, aroyl, arylthio, amino, aminoloweralkyl, loweralkanoylamino, aroylamino, lowerdialkylamino, loweralkylamino, hydroxy, hydroxyloweralkyl, trihaloloweralkyl, nitro, cyano, or sulfonamido; any of the arloweralkyl or alkenyl and heteroloweralkyl or alkenyl groups described above in which the aryl or heteroaryl ring is partially or completely hydrogenated; substituted loweralkyl having the formula R.sub.A.sup.1 (CH.sub.2).sub.n -Q-(CH.sub.2).sub.m wherein n is 0-2, m is 1-3, R.sub.A.sup.1 is aryl or heteroaryl optionally substituted by amino, lowerdialkylamino, loweralkylamino, hydroxy, hydroxyloweralkyl, aminoloweralkyl, trihaloloweralkyl, cyano, nitro, sulfonamido, aroyl, loweralkyl, halo, dihalo, and loweralkoxy, and Q is O, S, SO, SO.sub.2, N--R.sub.B.sup.1, CONR.sub.C.sup.1, NR.sub.C.sup.1 CO, CH.dbd.CH wherein R.sub.B.sup.1 is hydrogen, loweralkyl, aryl, aralkyl, loweralkanoyl, or aroyl, and R.sub.C.sup.1 is hydrogen, or loweralkyl; in the group: ##STR44## y is 0 to 4; A is
- (a) alkyl, including branched unsaturated and cyclic alkyl of 3 to 8 carbon atoms;
- (b) benzofused cycloalkyl or bicycloalkyl of 8 to 12 carbon atoms;
- (c) aryl or heteroaryl groups which may be mono-, di- or trisubstituted by loweralkyl; loweralkoxy, halo, amino, acylamino, hydroxy, acyl or acyloxy, and corresponding groups in which the aryl or heteroaryl groups are partially or completely hydrogenated;
- (d) loweralkyl including branched and unsaturated groups which may be substituted by aryl or heteroaryl groups and corresponding groups in which the aryl or heteroaryl rings are partially or completely hydrogenated;
- B is hydrogen or loweralkyl; or
- A and B may be joined, together with the carbon atoms to which they are attached to form a ring having the formulae: ##STR45## wherein X and Y taken together are ##STR46## R.sup.5 and R.sup.6 individually are hydrogen; loweralkyl; cycloalkyl; aryl; aralkyl; heteroaryl; loweralkyloxy; loweralkylthio; aryloxy; arylthio; arloweralkyloxy; arloweralkylthio; hydroxy; acyloxy; acylloweralkyl; halo; amino; mono- or disubstituted loweralkylamino; arloweralkylamino; heteroloweralkylamino acylamino in which the acyl group may be loweralkanoyl, aroyl, heteroaroyl or heteroloweralkanoyl; carbamoyl or N-substituted carbamoyloxy; including any of these groups containing an aromatic ring wherein said ring may be mono-, di- or trisubstituted by loweralkyl, loweralkoxy, loweralkylthio, halo, hydroxy, aryl, aryloxy, arylthio or aralkyl; any of the groups recited above containing an aryl or heteroaryl group in which these groups are partially or completely hydrogenated;
- R.sup.7 is hydrogen, loweralkyl, cycloalkyl, aryl, substituted aryl wherein the substituent can be halo, hydroxy, alkoxy, amino or loweralkyl; or
- R.sup.6 and R.sup.7 taken together may be oxo or together with the carbon atoms to which they are attached form a 3 to 6 membered ring which may contain 0, 1 or 2 atoms of N, S or O;
- p and q are independently 0 to 3; ##STR47## wherein R.sup.6 and R.sup.7 are as defined above and r is 0, 1 or 2; ##STR48## wherein: W is absent; --CH.sub.2 --; ##STR49## N; or S; Z is --(CH.sub.2).sub.t, wherein t is 0 to 2, provided that m may not be O when W is absent; --O--; --N--, or --S--.
- R.sup.8 is hydrogen; loweralkyl; loweralkoxy; hydroxy; halo; loweralkylthio; amino; acylamino; or cyano;
- s is 1 to 3;
- R.sup.2 is ##STR50## where k is 2 to 5; R.sup.3 is hydrogen; loweralkyl and substituted loweralkyl where the substituents are carboxy, hydroxy, and amino; or aralkyl, substituted aralkyl, heteroaralkyl, and substituted heteroaralkyl where the aryl and heteroaryl substituents are carboxy, hydroxy, and amino; and D is COOR; CONH.sub.2 ; or CH.sub.2 OH; and a pharmaceutically acceptable salt thereof.
- 2. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-L-proline.
- 3. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-L-proline.
- 4. A compound of claim 1 which is: N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-L-proline.
- 5. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 carboxymethyl-L-lysyl]-N-indanylglycine.
- 6. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-N-indanylglycine.
- 7. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-N-indanylglycine.
- 8. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
- 9. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
- 10. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
- 11. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-perhydroindole-2-carboxylic acid.
- 12. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-perhydroindole-2-carboxylic acid.
- 13. A compound of claim 1 which is:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-perhydroindole-2-carboxylic acid.
- 14. A pharmaceutical composition useful in treating hypertension comprising a pharmaceutically acceptable carrier; and, an antihypertensively effective amount of a compound of claim 1.
- 15. A composition of claim 14 wherein said compound is a member selected from the group consisting essentially of:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(2(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylptopyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylptopyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-perhydroindole-2-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl-N.sup.6 -carbamoylmethyl-L-lysyl]-perhydroindole-2-carboxylic acid; and,
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-perhydroindole-2-carboxylic acid.
- 16. A method of treating hypertension comprising administering to a patient in need of such treatment an antihypertensively effective amount of a compound of claim 1.
- 17. The method of claim 16 wherein said compound is a member selected from the group consisting essentially of:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(2(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline -3-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl-N.sup.6 -carbamoylmethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl-N.sup.6 -carbamoylmethyl-L-lysyl]-perhydroindole-2-carboxylic acid; and,
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl-N.sup.6 -hydroxyethyl-L-lysyl]-perhydroindole-2-carboxylic acid;
- 18. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 1; and, an antihypertensive and/or diuretic compound selected from the group consisting of acetazolamide, amiloride, aminophylline, atenolol, benzofluoromethiazide, benzthiazide, bumetanide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, cyclothiazide, deserpidine, diazoxide, diltiazem, (S)-1-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-3-[[4-(2-thienyl)-1H-imidazol-2-yl]phenoxy]-2-propanol, ethacrynic acid, fluoromethiazide, furosemide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazaide, hydrofluoromethiazide, (+)-4-[3-[-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]-benzoic acid, indacrinone and variable ratios of its enantiomers, merethoxylline procaine, methylclothiazide, methyldopa, methyldopate hydrochloride, metolazone, metoprolol tartate, minoxidil, naldolol, nifedipine, pargyline hydrochloride, pindolol, polythiazide, prazosin, propranolol, quinethazone, rauwolfia serpentina, rescinnamine, reserpine, sodium ethacrynate, sodium nitroprusside, spironolactone, ticrynafen, timolol, triamterene, trichlormethiazide, trimethophan camsylate, verapamil.
- 19. The composition of claim 18 wherein said compound of claim 1 is a member selected from the group consisting essentially of:
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-L-proline;
- N-[N.sup.2 -(2(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl] -N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-N-indanylglycine;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carboxymethyl-L-lysyl]-perhydroindole-2-carboxylic acid;
- N-[N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -carbamoylmethyl-L-lysyl]-perhydroindole-2-carboxylic acid; and,
- N-[N.sup. 2 -(1(S)-carboxy-3-phenylpropyl)-N.sup.6 -hydroxyethyl-L-lysyl]-perhydroindole-2-carboxylic acid.
- 20. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 19; and a therapeutically effective amount of hydrochlorothiazide.
- 21. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of claim 19; and a therapeutically effective amount of timolol.
- 22. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an anti-hypertensively effective amount of a compound of claim 19; and a therapeutically effective amount of manipulated indacrinone enantiomer ratio.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This application is a continuation-in-part of application Ser. No. 374,834 filed May 5, 1982, now abandoned.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
4113715 |
Ondetti et al. |
Sep 1978 |
|
4129571 |
Ondetti et al. |
Dec 1978 |
|
4154960 |
Ondetti et al. |
May 1979 |
|
Foreign Referenced Citations (3)
Number |
Date |
Country |
0012401 |
Jun 1980 |
EPX |
0050800 |
May 1983 |
EPX |
2095682 |
Oct 1982 |
GBX |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
374834 |
May 1982 |
|