Claims
- 1. A peptide of formula A
- X--B--Asp--Z A
- wherein B is an .alpha.-hydrophobic amino acid residue whose side chain has a length of about 2 to about 5 methylene groups;
- X is a group amide-linked to the nitrogen atom of B, said group having a ring structure bonded to the carbonyl carbon of said amide-linkage by a spacer having a length of zero to about two methylene groups, said ring structure being a 5-, 6-, fused 6,6- or fused 6,5-membered ring which, optionally, contains one or more nitrogen, sulfur and oxygen atoms, the length of X, including said spacer and carbonyl carbon, being about that of 3-quinolinecarbonyl or smaller, unless: (I) said ring structure of X is substituted with a C.sub.1 -C.sub.2 alkyl or hydroxyl group, (ii) the .alpha.-amino group of the X amino acid residue is acylated with a C.sub.1 -C.sub.6 acyl group or (iii) X together with the nitrogen atom of said Leu forms a phthalimido, a 1,2,3,4-tetrahydroquinazoline-2,4-dione-3-yl or 5-phenylhydantoin-3-yl group; and
- Z is p1 Xaa--NCy.sup.1 where Xaa is Val, Ile, Leu or an amino acid residue having a side chain that contains one or two fused aromatic rings and NCy.sup.1 is a cyclic ring-containing group having a ring nitrogen atom that forms an amide bond with the .alpha.-carboxyl group of Xaa, and whose cyclic ring contains 5- or 6-atoms including said ring nitrogen atom, wherein the cyclic ring of NCy.sup.1 is optionally substituted with one or two substituent groups selected from the group consisting of carboxyl, C.sub.1 -C.sub.4 alkylenecarboxyl, carboxamide, C.sub.1 -C.sub.4 alkylenecarboxamide, hydroxyl, hydroxymethyl, (CH.sub.2 CH.sub.2 O).sub.n H, where n is 1, 2 or 3, and C.sub.1 -C.sub.4 alkyl.
- 2. The peptide according to claim 1, wherein B is selected from the group consisting of leucine, cyclohexylalanine, norleucine, methionine, homoserine, threonine, phenylalanine, valine, norvaline and isoleucine.
- 3. The peptide according to claim 2, wherein the ring structure of said X group contains an aromatic ring.
- 4. The peptide according to claim 1, wherein Xaa is an amino acid residue having a side chain that contains one or two fused aromatic rings.
- 5. The peptide according to claim 4, wherein the cyclic ring of NCy.sup.1 is substituted with one or two substituent groups selected from the group consisting of carboxyl, C.sub.1 -C.sub.4 alkylenecarboxyl, carboxamide, C.sub.1 -C.sub.4 alkylenecarboxamide, hydroxyl, hydroxymethyl, (CH.sub.2 CH.sub.2 O).sub.n H, where n is 1, 2 or 3, and C.sub.1 -C.sub.4 alkyl.
- 6. The peptide of claim 1, wherein B is leucine.
- 7. The peptide according to claim 6, wherein the ring structure of said X group contains an aromatic ring.
- 8. The peptide according to claim 7, wherein said aromatic ring is substituted with a C.sub.1 -C.sub.2 alkyl or hydroxyl group.
- 9. The peptide according to claim 7, wherein Z is Xaa--NCy.sup.1.
- 10. The peptide according to claim 9, wherein Xaa is an amino acid residue having a side chain that contains one or two fused aromatic rings.
- 11. The peptide according to claim 10, wherein said amino acid residue is tryptophyl.
- 12. The peptide according to claim 7, wherein Z is Xaa--NCy.sup.1, and Xaa is an amino acid residue whose side chain has one or two fused aromatic rings.
- 13. The peptide according to claim 12, wherein the cyclic ring of NCy.sup.1 is substituted with one or two substituent groups selected from the group consisting of carboxyl, C.sub.1 -C.sub.4 alkylenecarboxyl, carboxamide, C.sub.1 -C.sub.4 alkylenecarboxamide, hydroxyl, hydroxymethyl, (CH.sub.2 CH.sub.2 O).sub.n H, where n is 1, 2 or 3, and C.sub.1 -C.sub.4 alkyl.
- 14. The peptide according to claim 6, wherein X is an amino acid residue having a cyclic ring side chain.
- 15. The peptide according to claim 14, wherein the nitrogen atom of the .alpha.-amino group of the X amino acid residue is acylated with a C.sub.1 -C.sub.6 acyl group.
- 16. The peptide of claim 6, wherein
- X is phenylacetyl;
- Z is Xaa--NCy.sup.1 ;
- Xaa is phenylalanine; and
- NCy.sup.1 is NCy.sup.3 that is selected from the group consisting of morpholinamido, thiomorpholinamido, 4-(thiadioxo)piperidinamide, D-2-(carboxamide)-pyrrolidinamido, piperidinamido, 4-substituted piperidinamido whose substituent is selected from the group consisting of hydroxy, carbamyl and carboxyl, piperazinamido and 4-substituted piperazinamido whose substituent is selected from the group consisting of carboxymethyl, carboxamidomethyl, (5-hydroxyethylen-oxyethylene) and p-toluenesulfonamido and pyrrolidinamido groups.
- 17. The peptide of claim 6, wherein X has the formula
- Ar--Y--C(O)--
- wherein Ar is pyrazolyl, phenyl, dihydroxyphenyl, pyridyl, or 3-quinolinyl; and Y is a spacer that is absent, --CH.sub.2 --, --CH(NH)--, --O-- or --NH--;
- or Ar--Y--C(O)-- together with the nitrogen atom of said Leu forms a phthalimido, a 1,2,3,4-tetrahydroquinazoline-2,4-dione-3-yl or 5-phenylhydantoin-3-yl group;
- and Z is Xaa--NCy.sup.1 and
- Xaa is an aromatic amino acid residue; and
- NCy.sup.1 is an amine-containing 5- or 6-membered cyclic ring group whose depicted nitrogen atom is within the ring and forms an amide bond with .alpha.-carboxyl of Xaa.
- 18. The peptide according to claim 17, wherein Y is absent.
- 19. The peptide according to claim 17, wherein Xaa is selected from the group consisting of phenylalanyl, tryptophyl and tyrosyl.
- 20. The peptide according to claim 17, wherein Ar--Y--C(O)-- is a substituent selected from the group consisting of benzoyl, phenylacetyl, 3-pyridinecarbonyl, 4-pyridinecarbonyl, 3-pyridineacetyl, phenoxycarbonyl, anilinocarbonyl, pyrazolecarbonyl, and 3,4-dihydroxybenzoyl groups.
- 21. The peptide according to claim 17, wherein NCy.sup.1 is selected from the group consisting of morpholinamido, thiomorpholinamido, 4-(thiadioxo)piperidinamide, piperidamido, 4-substituted piperidinamido whose substituent is selected from the group consisting of hydroxy, carbamyl and carboxyl, L-2-(carboxamide)pyrrolidinamido, D-2-(carboxamide)pyrrolidinamido, pyrrolidinamido, 3,4-dihydroxy-pyrrolidinamido, 2-(hydroxymethyl)pyrrolidinamido, piperazinamido and 4-substituted piperazinamido whose substituent is selected from the group consisting of carboxymethyl, carboxamidomethyl, (5-hydroxyethylenoxy-ethylene) and p-toluenesulfonamido groups.
- 22. The peptide according to claim 21, wherein Ar--Y--C(O)-- together with the nitrogen atom of said Leu forms a phthalimido group.
- 23. The pharmaceutical composition comprising the peptide of claim 3 and a pharmaceutically acceptable carrier.
- 24. A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier.
- 25. The pharmaceutical composition comprising the peptide of claim 16 and a pharmaceutically acceptable carrier.
- 26. A pharmaceutical composition comprising the peptide of claim 6 and a pharmaceutically acceptable carrier.
- 27. The pharmaceutical composition comprising the peptide of claim 12 and a pharmaceutically acceptable carrier.
- 28. The pharmaceutical composition comprising the peptide of claim 17 and a pharmaceutically acceptable carrier.
- 29. A method of treating inflammation comprising administering to a mammal having said inflammation an effective amount of the pharmaceutical composition of claim 24.
- 30. A method of treating inflammation comprising administering to a mammal having said inflammation an effective amount of the pharmaceutical composition of claim 26.
- 31. The method according to claim 29 or 30, wherein said inflammation is due to asthma.
- 32. The method according to claim 31, wherein said inflammation is a skin inflammation.
- 33. The method according to claim 29 or 31, wherein said inflammation is due to rheumatoid arthritis or osteoarthritis.
- 34. The method according to claim 29 or 31, wherein said inflammation is due to allograft rejection.
- 35. The method according to claim 29 or 31, wherein said administration is parenteral.
- 36. The method according to claim 29 or 31, wherein said administration is by inhalation.
CROSS-REFERENCE TO RELATED APPLICATION
This is a continuation of application Ser. No. 08/349,024, filed Dec. 2, 1994, now abandoned, which is a continuation-in-part of application Ser. No. 08/164,101, filed Dec. 6, 1993, now abandoned whose disclosures are incorporated by reference.
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Esser and Roos, "N-Terminal Cyclization of Peptides with N, N.sup.1 -Carbonyldiimidazole or N, N.sup.1 -Thiocarbonyldiimidazole," Angew. Chem. Int. Ed. Engl. 17:467-468 (1978). |
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Continuations (1)
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Number |
Date |
Country |
Parent |
349024 |
Dec 1994 |
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Continuation in Parts (1)
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Number |
Date |
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164101 |
Dec 1993 |
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