Biologically active amides

• US 4,254,106 A
• Filed: 09/10/1979
• Issued: 03/03/1981
• Est. Priority Date: 01/26/1976
• Status: Expired due to Term

• Current Assignee: Burroughs Wellcome Co. (GSK plc)
• Original Assignee: Burroughs Wellcome and Co.
• Inventors: Wilkinson, Samuel
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/074,408
• Time in Patent Office: 540 Days
• Field of Search: 260/112.5 R, 424/177
• US Class Current: 514/18.4
• 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: C07K 14/6755 with at least 1 amino acid in D-form
• CPC Class Codes: C07K 14/70 Enkephalins
• CPC Class Codes: C07K 14/702 with at least 1 amino acid in D-form

Abstract

The present invention provides novel peptides of formula (I):

R--(X.sup.1).sub.m --(X.sup.2).sub.n --X.sup.3 --X.sup.4 --X.sup.5

--X⁶ --X⁷ --(X⁸)_p --(X⁹)_q --R¹ (I)

together with their salts, esters, amides, N-alkylamides and N,N-dialkylamides and acid addition salts thereof.

These compounds exhibit morphine agonist activity in both in vitro and in vivo tests and may be used in the treatment of mammals in the fields of both human and veterinary medicine in any condition where an agent with a morphine-like effect is indicated.

Claims

1. A compound of the formula:

space="preserve" listing-type="equation">H.Tyr.Gly.Gly.Phe.X.sup.7.OR

wherein;

X⁷ is selected from the group consisting of Ile, Nle,Pro, Val, Ala, NVa, D-Leu and D-Met;

R is lower alkyl of 1 to 6 carbon atoms;

and the stereochemical configuration of the Tyr and Phe residues may independently be D, L or DL.

2. A compound according to claim 1 or a salt, ester, amide, N-alkylamide or N,N-alkylamide or a pharmaceutically acceptable acid addition salt thereof.

3. A pharmacologically and pharmaceutically acceptable salt or acid addition salt of a compound or derivatives thereof according to claim 1.

4. A compound according to claim 1 wherein X⁷ is D-Leu and R is methyl, or a salt, ester, amide, N-alkylamide or N,N-dialkylamide , thereof, or a pharmaceutically acceptable acid addition salt thereof.

5. A compound according to claim 1 wherein X⁷ is D-Met and R is methyl, or a salt, ester amide, N-alkylamide or N,N-dialkyamide thereof, or a pharmaceutically acceptable acid addition salt thereof.

6. A pharmaceutical formulation for obtaining a morphine-like effect comprising a pharmaceutically acceptable carrier and an effective morphine-like treatment amount of a compound of the formula:

space="preserve" listing-type="equation">H.Tyr.Gly.Gly.Phe.X.sup.7.OR

or a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof, or a pharmacologically and pharmaceutically acceptable acid addition salt thereof, wherein;

X⁷ is selected from the groups consisting of Ile, Nle, Pro, Val, Ala, NVa, D-Leu and D-Met;

R is lower alkyl of 1 to 6 carbon atoms; and

the stereochemical configuration of the Tyr and Phe residues may independently be D, L or DL.

7. The formulation of claim 6 which comprises a pharmacologically and pharmaceutically acceptable ester of said peptide or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

8. The formulation of claim 6 which comprises a pharmacologically and pharmaceutically acceptable amide of said peptide or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

9. The formulation of claim 6 which comprises a pharmacologically and pharmaceutically acceptable N-alkylamide or N,N-diakylamide of said peptide or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

10. The formulation of claim 6, suitable for administration by a route selected from oral, rectal, nasal, buccal, vaginal and parenteral.

11. The formulation of claim 6, suitable for administration by a route selected from oral, rectal, vaginal and parenteral.

12. The formulation of claim 6 which comprises the peptide or derivative thereof, or acid addition salt thereof, in solution in an aqueous medium.

13. The formulation of claim 6 in unit dosage form.

14. The formulation of claim 13 wherein each unit dosage contains the peptide or derivative thereof, or acid addition salt thereof, in an amount in the range 0.125 μ

g. to 2g., calculated with reference to the peptide base.

15. The formulation of claim 6 in the form of a tablet suitable for oral administration.

16. The formulation of claim 6 wherein said compound is:

space="preserve" listing-type="equation">H.Tyr.Gly.Gly.Phe.D-Leu-OMe

or a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof, or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

17. The formulation of claim 6 wherein said compound is:

space="preserve" listing-type="equation">H.Tyr.Gly.Gly.Phe.D-Met.OMe

or a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof, or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

18. A method for the treatment of a mammal for a condition therein an agent with a morphine-like effect is indicated, comprising the administration to the mammal of an effective morphine-like treatment, non-toxic amount of a peptide of the formula:

space="preserve" listing-type="equation">H-Tyr.Gly.Gly.Phe.X.sup.7.OR

or a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof, or a pharmacologically and pharmaceutically acceptable acid addition salt thereof, wherein

X⁷ is selected from the group consisting of Ile, Nle, Pro, Val, Ala, NVa, D-Leu and D-Met;

R is lower alkyl of 1 to 6 carbon atoms;

and the stereochemical configuration of the Tyr and Phe residues may independently be D, L or DL.

19. The method of claim 18 which comprises administration of a pharmacologically and pharmaceutically acceptable ester of said peptide or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

20. The method of claim 18 which comprises administration of a pharmacologically and pharmaceutically acceptable amide of said peptide or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

21. The method of claim 18 which comprises administration of a pharmacologically and pharmaceutically acceptable N-alkylamide or N,N-dialkylamide of said peptide or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

22. The method of claim 18 which comprises administration by a route selected from oral, rectal, nasal, buccal, vaginal and parenteral.

23. The method of claim 18 which comprises administration by a route selected from oral, rectal, vaginal and parenteral.

24. The method of claim 18 for the relief of pain, for the suppression of cough, for the induction of constipation or for the treatment of diarrhea or dysentery.

25. The method of claim 18 wherein the peptide or derivative thereof, or acid addition salt thereof, is administered at a dosage in the range 0.0025 μ

g. to 40 mg per kilogram bodyweight of the mammal, calculated with reference to the peptide base.

26. The method of claim 18 wherein the mammal is man.

27. The method of claim 18 wherein said compound is:

space="preserve" listing-type="equation">H.Tyr.Gly.Gly.Phe.D-Leu.OMe

or a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof, or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.

28. The method of claim 18 wherein said compound is:

space="preserve" listing-type="equation">H.Tyr.Gly.Gly.Phe.D-Met.OMe

or a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof, or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.