Claims
- 1. A compound of the formula I:
- 2. The compound of claim 1, wherein R1, X1, X2, X3, Z, Q, R5, R6, R7, R8, R9, R10 and Y are as defined in claim 1,
R2 is H or optionally substituted alkyl or an optionally substituted carbocyclic ring, R3 is optionally substituted alkyl or an optionally substituted mono- or polycyclic ring, optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring; or R2 and R3 together form an optionally substituted mono- or polycyclic ring optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring; and pharmaceutically acceptable salts thereof.
- 3. The compounds of claim 1, wherein R2 or R3, or R2 and R3 together, represent an optionally substituted mono- or polycyclic ring.
- 4. The compound of claim 1, wherein R5and R6 are H and Q is O so that the compounds are thyrotropin-releasing hormone (TRH) derivatives having L-asparagine residue (Asn) in the P1′ position.
- 5. The compound of claim 2, comprising L-asparagine (Asn) in the P1′ position of the peptide with the general formula:
- 6. The compound of claim 1, wherein Z is —CH2— and R7 and R8 are H.
- 7. The compound of claim 1, wherein X1, X2 and X3 are —CO—
- 8. The compound of claim 1, wherein R2 or R3, or R2 and R3 together, represent a large hydrophobic group.
- 9. The compound of claim 1, wherein the group —N(R2)Y R3 or the group R3 is at least one optionally substituted amino acid residue.
- 10. The compound of claim 1, wherein R1 is selected from any of the following:
- 11. The compound of claim 10, wherein Q is O.
- 12. The compound of claim 1, wherein R1 is a five-membered pyrrolidinone, thiazolidinone or butyrolactone ring.
- 13. The compound of claim 1, wherein R1 is:
- 14. The compound of claim 1, wherein substituents present which do not interfere substantially with the function of the compounds as inhibitors of activity of
- 15. A compound having the formula:
- 16. A compound having the formula (Glp-L-Asn-L-Pro-L-Tyr-L-TrpAMC):
- 17. A compound having the formula:
- 18. A novel compound selected from the group consisting of Glp-Asn-Pro-isopropylamide, Glp-Asn-Pro-cyclohexamide, Glp-Asn-Pro-piperazide, Glp-Asn-Pro-5-amidoquinoline (or 6-amidoquinoline or 8-amidoquinoline), Glp-Asn-Pro-5-amido-isoquinoline, Glp-Asn-Pro-Anilide, Glp-Asn-Pro-7-amido(trifluoromethyl)coumarin, Glp-Asn-Pro-6-amido-3,4-benzocoumarin, Glp-Asn-Pro-1,2,3,4-tetrahydro-1-naphthylamide, Glp-Asn-Pro-5,6,7,8-tetrahydro-1-naphthylamide, Glp-Asn-Pro-benzylamide, Glp-Asn-Pro-2-thiazolamide, Glp-Asn-Pro- 1-naphthylmethylamide, Glp-Asn-Pro-p-Anisidide, Glp-Asn-Pro-para amidobenzoic acid, Glp-Asn-Pro-m-anisidide, Glp-Asn-Pro-o-anisidide, Glp-Asn-Pro-5-chloro-2-methoxy anilide, Glp-Asn-Pro-3-hydroxy-4-methoxy anilide, Glp-Asn-Pro-2-hydroxy anilide, Glp-Asn-Pro-2-(hydroxymethyl-) anilide, Glp-Asn-Pro-4- trifluoromethyl anilide, Glp-Asn-Pro-Tyr-NH2, Glp-Asn-Pro-Trp-Ser-Tyr-NH2, Glp-Asn-Pro-Trp-Tyr-NH2, Glp-Asn-Pro-Trp-NH2, Glp-Asn-Pro-Tyr-Trp-NH2, Glp-Asn-Pro-Trp-AMC, Glp-Asn-Pro-Tyr-Trp-AMC, Glp-Asn-Pro-Trp-Trp-AMC, Glp-Asn-Pro-Tyr-Trp-Trp-AMC, Glp-Asn-Pro-Phe-TyrAMC, Glp-Asn-Pro-Ala-TrpAMC, Glp-Asn-Pro-Val-Tyr-TrpAMC and pharmaceutically acceptable salts thereof.
- 19. The compound of claim 18, selected from the group consisting of Glp-Asn-Pro-1,2,3,4-tetrahydro-1-naphthylamide, Glp-Asn-Pro-5,6,7,8- tetrahydro-1-naphthylamide, Glp-Asn-Pro-benzylamide, Glp-Asn-Pro-p-anisidide, Glp-Asn-Pro-m-anisidide, Glp-Asn-Pro-o-anisidide, Glp-Asn-Pro-5-chloro-2-methoxy anilide, Glp-Asn-Pro-3-hydroxy-4-methoxy anilide, Glp-Asn-Pro-2-hydroxy anilide, Glp-Asn-Pro-2-(hydroxymethyl-) anilide, and pharmaceutically acceptable salts thereof.
- 20. The compound of claim 1, 18 or 19, or a pharmaceutically acceptable salt of any of the foregoing, for use in a method for treatment of the human or animal body by therapy or a diagnostic method optionally practised on the human or animal body.
- 21. A compound of formula Ia:
- 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, for use in potentiating thyrotropin-releasing hormone.
- 23. A compound having the formula:
- 24. The compound of claim 21, or a pharmaceutically acceptable salt thereof, for use in inhibiting activity of TRH-DE.
- 25. The compound of claim 24, for use in potentiating endogenous thyrotropin-releasing hormone (TRH) and/or in protecting exogenously administered TRH or TRH analogues from degradation by TRH-DE.
- 26. A pharmaceutical composition comprising an effective amount of a compound of claim 21, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
- 27. The pharmaceutical composition according to claim 26, further comprising a TRH or a TRH analogue.
- 28. A compound of claim 21, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for potentiating endogenous thyrotropin-releasing hormone (TRH) and/or in protecting exogenously administered TRH or TRH analogues from degradation by TRH-DE.
- 29. The compound of claim 21, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of brain or spinal injuries, or other central nervous systems disorders, or other TRH dependent disorders in tissues in which TRH-DE is the principal enzyme influencing TRH levels.
- 30. A method of treating brain or spinal injuries, other central nervous systems disorders, or other TRE dependent disorders in tissues in which TRH-DE is the principal enzyme influencing TRH levels, which comprises administering to a patient suffering from such injuries or disorders an amount of a compound of claim 21, or a pharmaceutically acceptable salt thereof, effective to potentiate endogenous TRH and/or protect exogenously administered TRH or TRH analogues from degradation by TRH-DE.
Priority Claims (2)
Number |
Date |
Country |
Kind |
IE000135 |
Feb 2000 |
IE |
|
IE000240 |
Mar 2000 |
IE |
|
Parent Case Info
[0001] The present invention claims priority under 35 U.S.C. §120 from copending PCT Application Ser. No. PCT/IE01/00027, filed Feb. 16, 2001, which designated the United States, the entire content of which is hereby incorporated by reference without disclaimer, and to Irish Applications IE 000135 and IE 000240, filed Feb. 17 and Mar. 20, 2000, respectively, the entire content of which is hereby incorporated by reference without disclaimer.
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
PCT/IE01/00027 |
Feb 2001 |
US |
Child |
10223590 |
Aug 2002 |
US |