Arg-arg-arg-vasopressin antagonists

• US 4,724,229 A
• Filed: 09/30/1986
• Issued: 02/09/1988
• Est. Priority Date: 09/30/1986
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham Corporation (GSK plc)
• Original Assignee: Smithkline Beecham Corporation (GSK plc)
• Inventors: Ali, Fadia E.
• Primary Examiner(s): NOT, DEFINED
• Application Number:
  US06/913,439
• Time in Patent Office: 497 Days
• Field of Search: 517/11, 517/87, 530/315
• US Class Current: 514/10.9
• 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 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: C07K 7/16 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: Y10S 930/15 Oxytocin or vasopressin; related peptides

Abstract

Vasopressin antagonists which have a tripeptide side chain comprised of three basic amino acids, such as arginine, lysine or ornithine, demonstrate potent V₁ and V₂ -antagonist activity. A species of the invention, which is prepared by conventional peptide sequencing, is [1-(β-mercapto-β,β-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-arginine-8-arginine-9-arginine]-vasopression.

Claims

1. A compound having the formula:

##STR14## in which;

P is a D or L isomer of Arg, Lys, Orn, HArg, MeArg, MeLys or MeHArg;

A is a D or L isomer of Arg, Lys, Orn, HArg, MeArg, MeLys or MeHArg;

E is a D or L isomer of Arg, Lys, Orn, HArg, MeArg, MeLys or MeHArg;

B is OH, NH₂ or NHAlk;

Z is Phe, 4'"'"'-Alk Phe, O-Alk Tyr, Ile or Tyr;

X is a D or L isomer of Phe, 4'"'"'-Alk Phe, Val, Nva, Leu, Ile, Pba, Nle, Cha, Abu, Met, Chg, Tyr or O-Alk Tyr;

Y is Val, Ile, Abu, Ala, Chg, Gln, Lys, Cha, Nle, Thr, Phe, Leu or Gly; and

R₁ and R₂ are, each, hydrogen, methyl, ethyl or, when taken together and with the β

-carbon to which they are attached, a cycloalkylene ring of 4 to 6 members; and

wherein Alk is an alkyl of 1 to 4 carbons;

or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound according to claim 1 in which R₁ and R₂, taken together, form a spiropentamethylene ring.

3. The compound according to claim 1 in which P-A-E-B is Arg-Arg-Arg(NH₂).

4. The compound according to claim 1 in which P-A-E-B is Orn-Orn-Orn(NH₂).

5. The compound according to claim 1 in which P-A-E-B is Lys-Lys-Lys(NH₂).

6. The compound according to claim 1 in which P-A-E-B is Arg-Lys-Orn(NH₂).

7. The compound of claim 1 in which the compound is 1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-arginine-8-arginine-9arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

8. The compound of claim 1 in which the compound is 1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-D-arginine-8-D-arginine-9-D-arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

9. The compound of claim 1 in which the compound is [1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-methyl)-L-tyrosine-4-valine-7-arginine-8-D-arginine-9-D-arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

10. The compound of claim 1 in which the compound is [1-(β

-mercaptopropionic acid)-2-(O-ethyl)-D-tyrosine-3-isoleucine-4-threonine-7-arginine-8-arginine-9-arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

11. The compound of claim 1 in which the compound is 1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-D-arginine-8-arginine-9-arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

12. The compound of claim 1 in which the compound is [1-(β

-mercaptopropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-N-methylarginine-8-arginine-9-arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

13. The compound of claim 1 in which the compound is [1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-N-methyl-arginine-8-D-arginine-9-arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

14. The compound of claim 1 in which the compound is [1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)2-(O-ethyl)-D-tyrosine-4-valine-7-arginine-8-arginine-9-N-methylarginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

15. The compound of claim 1 in which the compound is [1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-arginine-8-lysine-9-arginine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

16. The compound of claim 4 in which the compound is [1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-ornithine-8-ornithine-9-ornithine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

17. The compound of claim 5 in which the compound is [1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-lysine-8-lysine-9-lysine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

18. The compound of claim 6 in which the compound is [1-(β

-mercapto-β

,β

-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-7-arginine-8-lysine-9-ornithine]-vasopressin or a pharmaceutically acceptable, acid addition salt thereof.

19. A pharmaceutical composition having vasopressin antagonist activity comprising a pharmaceutical carrier and, dispersed therein, an effective therefor but nontoxic quantity of the compound of claim 1.

20. A pharmaceutical composition having vasopressin antagonist activity comprising a pharmaceutical carrier and, dispersed therein, an effective therefor but nontoxic quantity of the compound of claim 3.

21. A pharmaceutical composition having vasopressin antagonist activity comprising a pharmaceutical carrier and, dispersed therein, an effective therefor but nontoxic quantity of the compound of claim 7.

22. A method of producing vasopressin antagonist activity in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 1.

23. A method of producing vasopressin antagonist activity in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 3.

24. A method of producing vasopressin antagonist activity in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 7.

25. A method of treating congestive heart failure in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 1.

26. A method of treating congestive heart failure in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 3.

27. A method of treating congestive heart failure in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 7.

28. A method of treating hypertension in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 1.

29. A method of treating hypertension in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 3.

30. A method of treating hypertension in a patient in need thereof which comprises administering parenterally or intranasally to the patient an effective therefor, nontoxic quantity of the compound of claim 7.