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Claims for Patent: 4,415,558

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Claims for Patent: 4,415,558

Title: CRF And analogs
Abstract:CRF (Corticotropin Releasing Factor) has the formula: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-L eu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu- Leu-Asp-Ile-Ala-NH.sub.2. Analogs have been synthesized that are at least as potent as CRF, and CRF or these analogs or pharmaceutically acceptable salts thereof, dispersed in a pharmaceutically acceptable liquid or solid carrier, can be administered to mammals to achieve a substantial elevation of ACTH, .beta.-endorphin, .beta.-lipotropin and corticosterone levels and/or a lowering of blood pressure over an extended period of time. In the analogs, one or more of the first three N-terminal residues may be deleted or may be substituted by a peptide up to 10 amino acids long and/or by an acylating agent containing up to 7 carbon atoms. Ala in the 41-position may also be substituted or deleted so long as the remaining C-terminus is amidated. Several other substitutions may also be made throughout the chain.
Inventor(s): Vale, Jr.; Wylie W. (La Jolla, CA), Spiess; Joachim (Encinatas, CA), Rivier; Catherine L. (La Jolla, CA), Rivier; Jean E. F. (La Jolla, CA)
Assignee: The Salk Institute for Biological Studies (San Diego, CA)
Application Number:06/378,999
Patent Claims: 1. A pharmaceutical composition for lowering the blood pressure of a mammal and/or for elevating the secretion of ACTH and corticosteroids comprising CRF or analogs of CRF or the nontoxic addition salts thereof having the formula:

Z-R.sub.1 -Pro-Pro-Ile-Ser-R.sub.8 -Asp-Leu-R.sub.11 -R.sub.12 -R.sub.13 -Leu-Leu-Arg-R.sub.17 -R.sub.18 -R.sub.19 -Glu-R.sub.21 -R.sub.22 -Lys-R.sub.24 -R.sub.25 -R.sub.26 -R.sub.27 -R.sub.28 -Gln-Gln-Ala-R.sub.32 -R.sub.33 -Asn-Arg-R.sub.36 -Leu-Leu-Asp-R.sub.40 -R.sub.41 -NH.sub.2

wherein Z is an acyl group having 7 or less carbon atoms or hydrogen; R.sub.1 is Ser-Gln-Glu or pGlu-Gly or Gln-Glu or Glu or D-Ser-Gln-Glu or D-pGlu-Gly or desR.sub.1 ; R.sub.8, R.sub.12, R.sub.19, R.sub.24 and R.sub.40 are selected from the group consisting of Leu, Ile, Ala, Gly, Val, Nle, Phe and Gln; R.sub.11 is Thr or Ser; R.sub.13 is His, Tyr or Glu; R.sub.17 is Glu or Lys; R.sub.18 is Val or Met; R.sub.21 is Met, Met(O), Ile, Ala, Leu, Gly, Nle, Val, Phe or Gln; R.sub.22 is Thr or Glu; R.sub.25 is Asp or Glu; R.sub.26 is Gln or Lys; R.sub.27 is Leu, Ile, Ala, Gly, Val, Nle, Phe, Asp, Asn, Gln or Glu; R.sub.28 is Ala or Lys; R.sub.32 is His, Tyr or Ala; R.sub.33 is Ser, Asn, Thr or Ala; R.sub.36 is Lys or Leu; R.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Gln or des R.sub.41, provided however that when R.sub.13 is His, then R.sub.17 is Glu, R.sub.18 is Val, R.sub.22 is Thr, R.sub.26 is Gln, R.sub.28 is Ala, and R.sub.36 is Lys; and provided that when R.sub.13 is Glu, R.sub.17 is Lys, R.sub.18 is Met, R.sub.22 is Glu, R.sub.26 is Lys, R.sub.28 is Lys, R.sub.32 is Ala and R.sub.36 is Leu, then either R.sub.1 is not pGlu-Gly or R.sub.8 is not Ile or R.sub.11 is Thr or R.sub.12 is not Leu or R.sub.19 is not Ile or R.sub.21 is not Ile or R.sub.24 is not Gln or R.sub.27 is not Glu or R.sub.33 is not Asn or R.sub.40 is not Thr or R.sub.41 is not Ile, and a pharmaceutically acceptable liquid or solid carrier therefor.

2. A method for lowering the blood pressure of a mammal, which method comprises administering to said mammal an effective amount of a material selected from the class consisting of CRF, analogs of CRF, and the nontoxic addition salts thereof, having the formula:

Z-R.sub.1 -Pro-Pro-Ile-Ser-R.sub.8 -Asp-Leu-R.sub.11 -R.sub.12 -R.sub.13 -Leu-Leu-Arg-R.sub.17 -R.sub.18 -R.sub.19 -Glu-R.sub.21 -R.sub.22 -Lys-R.sub.24 -R.sub.25 -R.sub.26 -R.sub.27 -R.sub.28 -Gln-Gln-Ala-R.sub.32 -R.sub.33 -Asn-Arg-R.sub.36 -Leu-Leu-Asp-R.sub.40 -R.sub.41 -NH.sub.2

wherein Z is an acyl group having 7 or less carbon atoms or hydrogen; R.sub.1 is Ser-Gln-Glu or pGlu-Gly or Gln-Glu or Glu or D-Ser-Gln-Glu or D-pGlu-Gly or desR.sub.1 ; R.sub.8, R.sub.12, R.sub.19, R.sub.24 and R.sub.40 are selected from the group consisting of Leu, Ile, Ala, Gly, Val, Nle, Phe and Gln; R.sub.11 is Thr or Ser; R.sub.13 is His, Tyr or Glu; R.sub.17 is Glu or Lys; R.sub.18 is Val or Met; R.sub.21 is Met, Met(O), Ile, Ala, Leu, Gly, Nle, Val, Phe or Gln; R.sub.22 is Thr or Glu; R.sub.25 is Asp or Glu; R.sub.26 is Gln or Lys; R.sub.27 is Leu, Ile, Ala, Gly, Val, Nle, Phe, Asp, Asn, Gln or Glu; R.sub.28 is Ala or Lys; R.sub.32 is His, Tyr or Ala; R.sub.33 is Ser, Asn, Thr, or Ala; R.sub.36 is Lys or Leu; R.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Gln or des R.sub.41, provided however that when R.sub.13 is His, then R.sub.17 is Glu, R.sub.18 is Val, R.sub.22 is Thr, R.sub.26 is Gln, R.sub.28 is Ala, and R.sub.36 is Lys; and provided that when R.sub.13 is Glu, R.sub.17 is Lys, R.sub.18 is Met, R.sub.22 is Glu, R.sub.26 is Lys, R.sub.28 is Lys, R.sub.32 is Ala and R.sub.36 is Leu, then either R.sub.1 is not pGlu-Gly or R.sub.8 is not Ile or R.sub.11 is Thr or R.sub.12 is not Leu or R.sub.19 is not Ile or R.sub.21 is not Ile or R.sub.24 is not Gln or R.sub.27 is not Glu or R.sub.33 is not Asn or R.sub.40 is not Thr or R.sub.41 is not Ile.

3. A method in accordance with claim 2 wherein said administering is carried out either orally, intravenously, subcutaneously, intranasally, intracerebrospinally or intramuscularly.

4. Z-R.sub.1 -Pro-Pro-Ile-Ser-R.sub.8 -Asp-Leu-R.sub.11 -R.sub.12 -R.sub.13 -Leu-Leu-Arg-R.sub.17 -R.sub.18 -R.sub.19 -Glu-R.sub.21 -R.sub.22 -Lys-R.sub.24 -R.sub.25 -R.sub.26 -R.sub.27 -R.sub.28 -Gln-Gln-Ala-R.sub.32 -R.sub.33 -Asn-Arg-R.sub.36 -Leu-Leu-Asp-R.sub.40 -R.sub.41 -NH.sub.2 wherein Z is an acyl group having 7 or less carbon atoms or hydrogen; R.sub.1 is Ser-Gln-Glu or pGlu-GLy or Gln-Glu or GLu or D-Ser-Gln-Glu or D-pGlu-Gly or desR.sub.1 ; R.sub.8, R.sub.12, R.sub.19, R.sub.24 and R.sub.40 are selected from the group consisting of Leu, Ile, Ala, Gly, Val, Nle, Phe and Gln; R.sub.11 is Thr or Ser; R.sub.13 is His, Tyr or Glu; R.sub.17 is Glu or Lys; R.sub.18 is Val or Met; R.sub.21 is Met, Met(O), Ile, Ala, Leu, Gly, Nle, Val, Phe or Gln; R.sub.22 is Thr or Glu; R.sub.25 is Asp or Glu; R.sub.26 is Gln or Lys; R.sub.27 is Leu, Ile, Ala, Gly, Val, Nle, Phe, Asp, Asn, Gln or Glu; R.sub.28 is Ala or Lys; R.sub.32 is His, Tyr or Ala; R.sub.33 is Ser, Asn, Thr or Ala; R.sub.36 is Lys or Leu; R.sub.41 is Ala, Ile, Gly, Val, Leu, Nle, Phe, Gln or des R.sub.41, provided however that when R.sub.13 is His, then R.sub.17 is Glu, R.sub.18 is Val, R.sub.22 is Thr, R.sub.26 is Gln, R.sub.28 is Ala, and R.sub.36 is Lys; and provided that when R.sub.13 is Glu, R.sub.17 is Lys, R.sub.18 is Met, R.sub.22 is Glu, R.sub.26 is Lys, R.sub.28 is Lys, R.sub.32 is Ala and R.sub.36 is Leu, then either R.sub.1 is not pGlu-Gly or R.sub.8 is not Ile or R.sub.11 is Thr or R.sub.12 is not Leu or R.sub.19 is not Ile or R.sub.21 is not Ile or R.sub.24 is not Gln or R.sub.27 is not Glu or R.sub.33 is not Asn or R.sub.40 is not Thr or R.sub.41 is not Ile; or a nontoxic addition salt thereof.

5. The compound of claim 4 wherein R.sub.13 is His.

6. The compound of claim 5 wherein R.sub.21 is Met.

7. The compound of claim 4 wherein R.sub.13 is Tyr.

8. The compound of claim 4 wherein R.sub.32 is Tyr.

9. The compound of either claim 7 or 8 wherein R.sub.21 is Nle.

10. The compound of claim 5 wherein R.sub.25 is Glu.

11. The compound of claim 5 wherein R.sub.25 is Asp.

12. The compound of claim 11 wherein R.sub.33 is Ser.

13. The compound of claim 12 wherein R.sub.41 is Ala.

14. The compound of claim 13 wherein R.sub.11 is Thr.

15. The compound of claim 11 wherein R.sub.8 is Leu, R.sub.12 is Phe, R.sub.19 is Leu, R.sub.24 is Ala, R.sub.27 is Leu and R.sub.40 is Ile.

16. The compound of claim 4 wherein R.sub.1 is Ser-Gln-Glu and Z is H.

17. The compound of claim 4 wherein Z is Ac and R.sub.1 is des R.sub.1.

18. The compound of claim 4 wherein R.sub.41 is des R.sub.41.

19. The compound of claim 4 wherein R.sub.41 is Nle.

20. The compound of claim 4 having the formula:

H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-L eu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu- Leu-Asp-Ile-Ala-NH.sub.2

and being at least about 93% pure.

21. The compound of claim 4 having the formula:

H-Pro-Pro-Ile-Ser-Ile-Asp-Leu-Ser-Leu-Glu-Leu-Leu-Arg-Lys-Met-Ile-Glu-Ile-G lu-Lys-Gln-Glu-Lys-Gly-Lys-Gln-Gln-Ala-Ala-Asn-Asn-Arg-Leu-Leu-Leu-Asp-Thr- Ile-NH.sub.2.

22. The compound of claim 4 wherein R.sub.11 is Glu, R.sub.18 is Val, R.sub.22 is Thr, R.sub.25 is Asp, R.sub.26 is Gln, R.sub.28 is Ala and R.sub.36 is Lys.

23. The compound of claim 22 wherein R.sub.8 is Leu, R.sub.11 is Thr, R.sub.12 is Phe, R.sub.19 is Leu, R.sub.24 is Ala, R.sub.27 is Leu, R.sub.33 is Ser and R.sub.40 is Ile.

24. The compound of claim 23 wherein R.sub.32 is Tyr.

25. The compound of claim 24 wherein R.sub.21 is Nle.

26. The compound of claim 24 or 25 wherein R.sub.13 is Tyr.

27. The compound of claim 22 wherein R.sub.13 is Tyr and R.sub.21 is Nle.

28. The compound of either claim 25 or 27 wherein R.sub.1 is Ser-Gln-Glu and R.sub.41 is Ala.

29. The compound of claim 4 wherein R.sub.21 is Met(O).

30. A method of elevating the secretion of ACTH and corticosteroids which comprises administering an effective amount of the compound of claim 4.

31. A method of elevating the secretion of .beta.-END-LI, which comprises administering an effective amount of the compound of claim 4.
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