Biologically active lysine containing octapeptides

• US 4,725,577 A
• Filed: 03/28/1986
• Issued: 02/16/1988
• Est. Priority Date: 04/25/1985
• Status: Expired due to Term

• Current Assignee: Administrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY)
• Original Assignee: Administrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY)
• Inventors: Cai, Ren Z., Schally, Andrew V.
• Primary Examiner(s): NOT, DEFINED
• Application Number:
  US06/843,539
• Time in Patent Office: 690 Days
• Field of Search: 530/328, 530/327, 530/329, 530/311, 514/11, 514/15
• US Class Current: 424/489
• 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 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides

Abstract

Novel compositions of the formula ##STR1## wherein A represents an L, D or DL amino-acid selected from the group consisting of Ala, Val, Phe, p-Cl-Phe, Trp, Pro, Ser, Thr, Glu, Gly, Beta Ala, Abu, N-Me Ala, 5-F-Trp, 5-Br-Trp, 5-Cl-Trp, their acetylated derivatives or a pharmaceutically acceptable acid addition salt thereof;

B represents an L, D or DL amino acid amide selected from the group consisting of Thr NH₂, Val NH₂, Pro NH₂, HO-Pro NH₂, Ser NH₂, Tyr NH₂, Trp NH₂, 5-F-Trp NH₂, For-Trp NH₂, Ala NH₂, Gly NH₂, Me Ala NH₂ ;

X represents L-Phe or L-Tyr,

Y represents L-Thr or L-Val;

Z is L, D or DL-5-F-Trp, 5-Br-Trp, 5-Cl-Trp, 5-I-Trp or D-Trp; and

C" and C'"'"' represent L or D Cys, Abu, Asp or Lys; and the pharmaceutically acceptable acid addition salts thereof; are useful as agents for inhibiting the release of growth hormone, for the treatment of gastrointestinal disorders and for therapy of certain cancers and the management of diabetes. These biologically active octapeptides all possess a terminal amino acid amide at position 8 and are prepared by solid phase methods.

Claims

1. A compound of the formula ##STR41## wherein A is an L, D or DL amino acid selected from the group consisting of tryptophan (Trp), its acetylated derivatives or a pharmaceutically acceptable acid addition salt thereof;

B is an L, D or DL amino acid selected from the group consisting of threonine amide (Thr NH₂), tyrosine amide (Tyr NH₂) and tryptophan amide (Trp NH₂);

X is L-phenylalanine (L-Phe) or L-tyrosine (L-Tyr);

Y is L-valine (L-Val) or L-threonine (L-Thr)

Z is D-tryptophan (D-Trp); and

C" and C'"'"' are L or D-cysteine (Cys), α

-aminobutyric acid (Abu), aspartic acid (Asp) or lysine (Lys);

provided that where C'"'"' is Cys, C" is also Cys and where C'"'"' or C" are other than Cys, C" is different from C'"'"' and is other than Cys;

the connecting line between C" and C'"'"' signifies a bridge selected from the group consisting of carbon/carbon, carbon/sulfur, sulfur/sulfur and amide bridges; and

the pharmaceutically acceptable acid addition salts thereof.

2. a compound according to claim 1 wherein

C" is Cys;

X is Phe;

Z is D-Trp;

Y is Thr; and

C'"'"' is Cys.

3. A compound according to claim 1 wherein

C" is Cys;

X is Phe;

Z is D-Trp;

Y is Thr;

C'"'"' is Cys; and

A is D-Trp.

4. A compound according to claim 1 wherein

C" is Cys;

X is Tyr;

Z is D-Trp;

Y is Val; and

C'"'"' is Cys.

5. A compound according to claim 1 wherein

C" is Cys;

X is Phe;

Y is Thr; and

C'"'"' is Cys.

6. A compound according to claim 1 wherein

C" is Cys;

X is Tyr;

Y is Val; and

C'"'"' is Cys.

7. A compound according to claim 1 wherein

C" is Lys;

X is Tyr;

Z is D-Trp;

Y is Val; and

C'"'"' is Asp.

8. A compound according to claim 1 which is D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂.

9. A compound according to claim 1 which is:

##STR42##

13. A pharmaceutical composition which comprises an octapeptide of claim 1 its reduced form or a pharmaceutically acceptable acid addition salt thereof in a pharmaceutically acceptable liquid or solid carrier thereof.

14. A pharmaceutical composition of claim 13 which comprises an octapeptide of claim 1, its reduced form or a pharmaceutically acceptable acid addition salt thereof, encapsulated in poly(d,1-lactide-co-glycolide)microcapsules.

15. A method of treating excess release of growth hormone, gastrointestinal disorders, and diabetes in a mammal in need of such therapy which comprises administering to said mammal an effective dose of octapeptide of claim 1, its reduced form, or a pharmaceutically acceptable acid addition salt thereof.

10. An octapeptide (reduced form) of the formula

View Dependent Claims (11)

11. A compound according to claim 10 which is:

space="preserve" listing-type="equation">D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH.sub.2.

12. A compound which is:

space="preserve" listing-type="equation">D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Ser-NH.sub.2.