Nonapeptide and decapeptide analogs of LHRH, useful as LHRH agonist

• US 4,530,920 A
• Filed: 11/07/1983
• Issued: 07/23/1985
• Est. Priority Date: 11/07/1983
• Status: Expired due to Fees

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Nestor, John J., Vickery, Brian H.
• Primary Examiner(s): Phillips, Delbert R.
• Assistant Examiner(s): Moezie, F. T.
• Application Number:
  US06/549,355
• Time in Patent Office: 624 Days
• Field of Search: 260/112.5 R, 260/112.5 LH
• US Class Current: 514/10.2
• 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 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 7/23 Luteinising hormone-releasing hormone [LHRH]; Related peptides
• CPC Class Codes: Y10S 930/13 Luteinizing hormone-releasing hormone; related peptides

Abstract

Synthetic nonapeptide and decapeptide LHRH agonists analogs having a novel gaunadino-substituted, amidine, tertiary or quatrinary aminoacyl residue at position 6 are disclosed herein.

Claims

1. A compound of the formula

View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)

2. The compound of claim 1 wherein

C is an amino acyl residue selected from the group consisting of the radicals represented by the following structrual formulas:

(a) ##STR21## wherein n is 4;

R₁ is --NRR₃ wherein R is hydrogen, R₃ is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl or fluoroalkyl;

R₂ is alkyl of 1 to 12 carbon atoms, cycloalkyl or fluoroalkyl;

or

R₁ and R₂ comprise a ring represented by the following structural formula;

##STR22## wherein n is 1; and

A is hydrogen.

3. The compound of claim 2 wherein C is an amino acyl residue wherein R is hydrogen and R₃ is methyl, ethyl, or hexyl;

R₂ is the same as R₃ or R₁ and R₂ together form the ring of formula IID.

4. The compound of claim 3 which is (pyro)Glu-L-Hi s-L-Trp-L-Ser-L-Tyr-D-Eth-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

5. The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

6. The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Dhh-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

7. The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser -L-Tyr-D-Deh-L-MeLeu-L-Arg-L-Pro-NHET and its pharmaceutically acceptable salts.

8. The compound of claim 3 which is (pyro)Glu-L-His-L-Nal(2) -L-Ser-L-Tyr-D-Deh-L-Leu-L-Arg-L-Pro-NHEt and its pharmaceutically acceptable salts.

9. The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Leu-L-Arg-L-Pro-GlyNH₂ and its pharmaceutically acceptable salts.

10. The compound of claim 3 which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Den-L-MeLeu-L-Arg-L-Pro-GlyNH₂ and its pharmaceutically acceptable salts.

11. The compound of claim 3 which is (pyro)Glu-L-His-L-Nal(2) -L-Ser-L-Tyr-D-Deh-L-MeLeu-L-Arg-L-Pro-GlyNH₂ and its pharmaceutically acceptable salts.

12. The compound of claim 1 wherein A is Trp, B is Tyr, D is Leu and E is Gln.

13. The compound of claim 12 wherein D is D-Deh and F is GlyNH₂ which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Den-L-Leu-L-Gln-L-Pro-GlyNH₂ and its pharmaceutically acceptable salts.

14. The compound of claim 12 wherein D is D-Deh and F is NHEt which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Leu-L-Gln-L-Pro-NHEt and its pharmaceutically acceptable salts.

15. The compound of claim 1 wherein A is Trp, B is Tyr, D is Trp and E is Leu.

16. Tne compound of claim 15 wherein C is Deh and F is GlyNH₂ which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Trp-L-Leu-L-Pro-GlyNH₂ and the pharmaceutically acceptable salts thereof.

17. The compound of claim 15 wherein C is Deh and F is NHEt which is (pyro)Glu-L-His-L-Trp-L-Ser-L-Tyr-D-Deh-L-Trp-L-Leu-L-Pro-NHEt and the pharmaceutically acceptable salts thereof.

18. A method of inhibiting ovulation in a female mammalian subject which method comprises administering to said subject an effective amount of a compound of claim 1.

19. A method of treating benign prostatic hypertrophy in a male mammalian subject which method comprises administering to said subject an effective amount of a compound of the formula of claim 1 either alone or in admixture with a pnarmaceutically acceptable excipient.

20. A metnod of treating fibrocystic breast disease in a mammalian subject wnich method comprises administering to said subject an effective amount of a compound of tne formula of claim 1 or a pharmaceutical composition containing same.

21. A method of lowering, blocking or abolishing gonadal steroid output which method comprises administering to a mammalian subject an effective amount of a compound of the formula of claim 1 or a pharmaceutical composition therof.

22. A pharmaceutical composition for depression of spermatogenesis and circulating and testicular levels of testosterone comprising a compound of tne formula of claim 1 in admixture witn a pharmaceutically acceptable, non-toxic carrier.

23. A slow release pharmaceutical composition comprising a compound of claim 1 in the amount of 1% and a glycolide/lactide polymer in the amount of 99% in the form of microspheres or an implant.