Somatostatin analogs for the treatment of cancer

• US 6,316,414 B1
• Filed: 07/31/2000
• Issued: 11/13/2001
• Est. Priority Date: 07/31/2000
• Status: Expired due to Fees

• Current Assignee: Dabur Pharma Limited (Fresenius SE & Co. KGaA)
• Original Assignee: Dabur Pharma Limited (Fresenius SE & Co. KGaA)
• Inventors: Jaggi, Manu, Mukherjee, Rama, Singh, Anu T., Burman, Anand C., Prasad, Sudhanand, Mathur, Archna
• Primary Examiner(s): Davenport, Avis M.
• Application Number:
  US09/629,371
• Time in Patent Office: 470 Days
• Field of Search: 514/16, 530/300, 530/311, 530/328
• US Class Current: 514/19.3
• 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 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form

Abstract

The present invention encompasses novel peptides that are agonists to somatostatin and the use of the agonists for treatment of cancer. The invention particularly relates to the design and synthesis of novel analogs of somatostatin incorporating α, α-dialkylated amino acids in a site specific manner. The invention encompasses methods for the generation of these peptides, compositions containing the peptides and the pharmacological applications of these peptides especially in the treatment and prevention of cancer.

Claims

1. A peptide of the formula:

2. A peptide according to claim 1, wherein the alkyl portion of the alkanoyl group is from 2 to 12 carbon atoms.

3. The peptide of claim 1, wherein X is deleted and A1 is Orn, A2 is Deg and A3 is Pen;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Orn-Deg-Pen-Thr-NH₂ (SEQ ID NO;

     2).

4. The peptide claim 1, wherein X is deleted and A1 is Orn, A2 is Ac5c and A3 is Pen;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Orn-Ac5c-Pen-Thr-NH₂ (SEQ ID NO;

     3).

5. The peptide of claim 1, wherein X is deleted and A1 is Orn, A2 is Deg and A3 is Cys;

and the said peptide is D-Phe-Cys-Tyr-D-Trp-Orn-Deg-Cys-Thr-NH₂ (SEQ ID NO;

     4).

6. The peptide of claim 1, wherein X is deleted and A1 is Orn, A2 is AcSc and A3 is Cys;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Orn-AcSc-Cys-Thr-NH₂ (SEQ ID NO;

     5).

7. The peptide of claim 1, wherein X is deleted and A1 is Lys, A2 is Ac5c and A3 is Pen;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Lys-Ac5c-Pen-Thr-NH₂ (SEQ ID NO;

     6).

8. The peptide of claim 1, wherein X is deleted and A1 is Lys, A2 is Ac5c and A3 is Cys;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Lys-Ac5c-Cys-Thr-NH₂ (SEQ ID NO;

     7).

9. The peptide of claim 1, wherein X is deleted and A1 is Lys, A2 is Aib and A3 is Pen;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Lys-Aib-Pen-Thr-NH₂ (SEQ ID NO;

     8).

10. The peptide claim 1, wherein X is deleted and A1 is Orn, A2 is Aib and A3 is Pen;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Orn-Aib-Pen-Thr-NH₂ (SEQ ID NO;

     9).

11. The peptide claim 1, wherein X is deleted and A1 is Orn, A2 is Aib and A3 is Cys;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Orn-Aib-Cys-Thr-NH₂ (SEQ ID NO;

     10).

12. The peptide of claim 1, wherein X is deleted and A1 is Lys, A2 is Deg and A3 5 is Cys;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Lys-Deg-Cys-Thr-NH₂ (SEQ ID NO;

     11).

13. The peptide of claim 1, wherein X is deleted and A1 is Lys, A2 is Deg and A3 is Pen;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Lys-Deg-Pen-Thr-NH₂ (SEQ ID NO;

     12).

14. The peptide of claim 1, wherein X is deleted and A1 is Orn, A2 is Dpg and A3 is Pen;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Orn-Dpg-Pen-Thr-NH₂ (SEQ ID NO;

     13).

15. The peptide of claim 1, wherein X is deleted and A1 is Orn, A2 is Dpg and A3 is Cys;

and the peptide is D-Phe-Cys-Tyr-D-Trp-Orn-Dpg-Cys-Thr-NH₂ (SEQ ID NO;

     14).

16. The peptide of claim 1, wherein X is acetyl and A1 is Orn, A2 is Deg and A3 is Pen;

and the peptide is Acetyl-D-Phe-Cys-Tyr-D-Trp-Orn-Deg-Pen-Thr-NH₂ (SEQ ID NO;

     15).

17. The peptide of claim 1, wherein X is butanoyl and A1 is Orn, A2 is Deg and A3 is Pen;

and the peptide is Butanoyl-D-Phe-Cys-Tyr-D-Trp-Orn-Deg-Pen-Thr-NH₂ (SEQ ID NO;

     16).

18. The peptide of claim 1, wherein X is octanoyl and A1 is Orn, A2 is Deg and A3 is Pen;

and the peptide is Octanoyl-D-Phe-Cys-Tyr-D-Trp-Orn-Deg-Pen-Thr-NH₂ (SEQ ID NO;

     17).

24. A composition comprising an effective amount of a polypeptide according to claim 1, and a pharmaceutically acceptable carrier.

25. A method of treatment of cancer in mammals which comprises the administration of an effective amount of polypeptide according to claim 1.

19. A solid phase synthesis process for the preparation of a peptide analog of formula (I):

20. The process as claimed in claim 19, wherein said α

-α

-dialkylated amino acid is protected at its α

-amino groups by a 9-fluorenyl methoxy carbonyl (Fmoc) group.

21. The process as claimed in claim 19, wherein the coupling is carried out in the presence of activated agents selected from the group consisting of DCC, DIPCDI, DIEA, BOP, PyBOP, HBTU, TBTU, and HOBt.

22. The process as claimed in claim 19, wherein the coupling is carried out in the presence of a solvent selected from the group consisting of DMF, DCM, and NMP or a mixture thereof.

23. The process as claimed in claim 19, wherein said peptide is cleaved from said peptide-resin assembly by treatment with trifluoroacetic acid, crystalline phenol, thioanisole, ethanedithiol and water for 1.5 to 5 hours at room temperature.

26. A method according to claim 20 further comprising administering a chemotherapeutic compound.