Renin inhibitors

• US 5,284,849 A
• Filed: 08/14/1992
• Issued: 02/08/1994
• Est. Priority Date: 05/11/1990
• Status: Expired due to Fees

• Current Assignee: Abbott Laboratories
• Original Assignee: Abbott Laboratories
• Inventors: Rosenberg, Saul H., Denissen, Jon F.
• Primary Examiner(s): TSANG, CECILIA J
• Application Number:
  US07/928,190
• Time in Patent Office: 543 Days
• Field of Search: 514/252, 514/218, 544/369, 544/370, 544/371, 540/575
• US Class Current: 514/254.02
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 295/26 Sulfur atoms
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic

Abstract

A renin inhibiting compound of the formula: ##STR1## wherein R₁ is 4-piperazinyl, 1-methyl-4-piperazinyl, 1-methyl-1-oxo-4-piperazinyl, 2-oxo-4-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl or 1-methyl-4-homopiperazinyl;

R₂ is benzyl, 2-phenylethyl, 1-naphthylmethyl or 2-naphthylmethyl;

R₃ is 4-thiazolyl, 2-amino-4-thiazolyl, 2-thiazolyl, 5-thiazolyl, 1-pyrazolyl, 3-pyrazolyl, 1-imidazolyl, n-propyl, isopropyl, CH₃ S--, or CH₃ SCH₂ --;

R₄ is isobutyl or cyclopropyl;

R₅ is hydrogen or loweralkyl; and

X is CH₂ or NH; or a pharmaceutically acceptable salt, ester or prodrug thereof; with the proviso that when X is NH and R₃ is 2-amino-4-thiazolyl, then R₄ is cyclopropyl.

Claims

1. A compound of the formula:

##STR9## wherein R₁ is 4-piperazinyl, 1-methyl-4-piperazinyl, 1-methyl-1-oxo-4-piperazinyl, 2-oxo-4piperazinyl or 1-methyl-4-homopiperazinyl;

R₂ is benzyl, 2-phenylethyl, 1-naphthylmethyl or 2-naphthylmethyl;

R₃ is 4-thiazolyl, 2-amino-4-thiazolyl, 2-thiazolyl, 5-thiazolyl, 1-pyrazolyl, 3-pyrazolyl or 1-imidazolyl;

R₄ is isobutyl or cyclopropyl;

R₅ is hydrogen or loweralkyl; and

X is CH₂ ;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

2. The compound of claim 1 wherein R₂ is benzyl and R₃ is 4-thiazolyl, 2-amino-4-thiazolyl, 2-thiazolyl or 5-thiazolyl.

8. A method for inhibiting renin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

9. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.

10. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need a therapeutically effective amount of a compound or claim 1.

11. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 in combination with another cardiovascular agent.

12. A pharmaceutical composition for treating hypertension or congestive heart failure comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1 in combination with another cardiovascular agent.

3. A compound of the formula:

##STR10## wherein R₁ is 4-piperazinyl, 1-methyl-4-piperazinyl, 1-methyl-1-oxo-4-piperazinyl, 2-oxo-4-piperazinyl or 1-methyl-4-homopiperazinyl;

R₂ is benzyl, 2-phenylethyl, 1-naphthylmethyl or 2-naphthylmethyl;

R₃ is 4-thiazolyl or 2-amino-4-thiazolyl;

R₄ is isobutyl or cyclopropyl; and

R₅ is hydrogen or loweralkyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

4. The compound of claim 3 wherein R₁ is 1-methyl-4-piperazinyl, R₂ is benzyl and R₃ is 4-thiazolyl or 2-amino-4-thiazolyl.

16. A method for inhibiting renin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 3.

17. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 3.

18. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need a therapeutically effective amount of a compound of claim 3.

19. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 3 in combination with another cardiovascular agent.

20. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 3 in combination with another cardiovascular agent.

5. (2S)-2-Benzyl-3-(1-methyl-piperazin-4-ylsulfonyl)propionyl-(L)-(4-Thiazolyl)Ala Amide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6methylheptane;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

13. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 5.

14. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need a therapeutically effective amount of a compound of claim 5.

21. A method for inhibiting renin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 5.

22. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 5 in combination with another cardiovascular agent.

23. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 5 in combination with another cardiovascular agent.

6. (2S)-2-Benzyl-3-(1-methyl-piperazin-4-ylsulfonyl)propionyl-(L)-(4-Thiazolyl)Ala Amide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane hydrochloride.

24. A method for inhibiting renin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 6.

25. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 6.

26. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need a therapeutically effective amount of a compound of claim 6.

27. A method for treating hypertension or congestive heart failure comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 6 in combination with another cardiovascular agent.

28. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 6 in combination with another cardiovascular agent.

7. A compound selected from the group consisting of:

2S)-2-Benzyl-3-(1-methylpiperazin-4-ylsulfonyl)propionyl-(L)-(2-aminothiazol-4-yl)Ala Amide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;

(2S)-2-Benzyl-3-(1-methylpiperazin-4-ylsulfonyl)propionyl-(L)-(4-Thiazolyl)Ala Amide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-4-(cyclopropyl)butane; and

(2S)-2-Benzyl-3-(1-methylpiperazin-4-ylsulfonyl)propionyl-(L)-(2-aminothiazol-4-yl)Ala Amide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-4-(cyclopropyl)butane;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

15. (2S)-2-Benzyl-3-(1-methyl-piperazin-4-ylsulfonyl)propionyl-(L)-4-Thiazolyl)Ala Amide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane methanesulfonate.