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Generated: September 21, 2017

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Title: Cyclic peptide somatostatin analogs
Abstract:This invention relates to therapeutic reagents and peptides, including radiotherapeutic reagents and peptides, and radiodiagnostic reagents and peptides. Specifically, the invention relates to cyclic peptide derivatives and analogs of somatostatin, and embodiments of such peptides radiolabeled with a radioisotope, as well as methods for using such peptides for radiodiagnostic and radiotherapeutic purposes.
Inventor(s): Dean; Richard T. (Bedford, NH), McBride; William (Manchester, NH), Lister-James; John (Bedford, NH)
Assignee: Diatech, Inc. (Londonberry, NH)
Filing Date:Jul 29, 1994
Application Number:08/282,980
Claims:1. A composition comprising a somatostatin receptor-binding peptide having a formula:

cyclo(A.sup.4 -B.sup.1 B.sup.2 B.sup.3 B.sup.4 -C.sup.4)

wherein

B.sup.1 is D- or L-Phe or D- or L-Tyr or D- or L-Nal or Ain or a substituted derivative thereof;

B.sup.2 is D- or L-Trp or a substituted derivative thereof;

B.sup.3 is D- or L-Lys or Hly, Achxa, Amf, Aec, Apc, Aes, Aps or a substituted derivative thereof;

B.sup.4 is Thr, Ser, Val, Phe, Ile, Abu, Nle, Leu, Nva or Aib;

C.sup.4 is an .alpha.-amino acid having a sidechain covalently linked to an amino acid, an amino acid amide, a monosaccharide, an oligosaccharide comprising from 2 to about 10 saccharide residues, a polyoxanion, a thiol, an hydroxyl, a sulfonyl, a sulfonamide, a second peptide comprising from 2 to about 10 amino acid residues and having a carboxyl terminal carboxylic acid, or a second peptide comprising from 2 to about 10 amino acid residues and having a carboxyl terminal amide; and

A.sup.4 is a lipophilic D-amino acid or a lipophilic L-(.alpha.-N-alkyl) amino acid or L-proline or a substituted derivative thereof;

wherein the peptide is cyclized through a covalent linkage between an .alpha.-amino terminus of residue A.sup.4 and an .alpha.-carboxyl terminus of residue C.sup.4.

2. The composition of claim 1, wherein the sidechain of residue C.sup.4 is covalently linked through a bivalent linking group selected from the group consisting of:

a sulfur atom, an oxygen atom, an amine or substituted amine, --HNO--, --CR.sub.2 --CR.sub.2 --, --CR.sub.2 --O--, --CR.sub.2 --S--, --CR.sub.2 --C(O)--, --C(O)--CR.sub.2 --, --O--CR.sub.2 --, --S--CR.sub.2 --, --NRC(O)--, --CR.sub.2 --SO--, --SO--CR.sub.2 --, --COO--, --NHSO.sub.2 --, --SO.sub.2 --NH--, --SC(O)--, --C(O)S--, --C.dbd.C--, --CR.dbd.CR--, and --C(O)NR--,

wherein each R is independently H or lower alkyl, and two geminal R groups may be taken together as a lower alkylidene.

3. The composition of claim 2, wherein the sidechain of residue C.sup.4 is covalently linked through a thioether group to an amino acid, or to an amino acid amide, or to a second peptide comprising from 2 to about 10 amino acid residues and having a carboxyl terminal carboxylic acids or to a second peptide comprising from 2 to about 10 amino acid residues and having a carboxyl terminal amide.

4. The composition of claim 1, wherein B.sup.1 is phenylalanine or tyrosine, B.sup.2 is D-tryptophan, B.sup.3 is lysine, and B.sup.4 is threonine or valine.

5. A composition comprising a somatostatin receptor-binding peptide having a formula:

cyclo(A.sup.4 -B.sup.1 B.sup.2 B.sup.3 B.sup.4 -C.sup.4)

wherein

B.sup.1 is D- or L-Phe or D- or L-Tyr or D- or L-Nal or Ain or a substituted derivative thereof;

B.sup.2 is D- or L-Trp or a substituted derivative thereof;

B.sup.3 is D- or L-Lys or Hly, Achxa, Amf, Aec, Apc, Aes, Aps or a substituted derivative thereof;

B.sup.4 is Thr, Ser, Val, Phe, Ile, Abu, Nle, Leu, Nva or Aib;

A.sup.4 is a lipophilic D-amino acid or a lipophilic L-(.alpha.-N-alkyl) amino acid or

L-proline or a substituted derivative thereof;

C.sup.4 is an Lo:-amino acid having a sidechain

where n is an integer from 1-4 and R.sup.1 is H, lower alkyl, substituted alkyl, hydroxyalkyl, or alkoxyalkyl;

wherein the peptide is cyclized through a covalent linkage between an .alpha.-amino terminus of residue A.sup.4 and an .alpha.-carboxyl terminus of residue C.sup.4.

6. The composition of claim 5, wherein R.sup.1 is --CH.sub.2 COR.sup.2, where R.sup.2 is selected from the group consisting of an amino acids an amino acid amides a second peptide comprising from 2 to about 10 amino acid residues and having a carboxyl terminal carboxylic acids and a second peptide comprising from 2 to about 10 amino acid residues and having a carboxyl terminal amide.

7. The composition of claim 6, wherein B.sup.1 is phenylalanine or tyrosine, B.sup.2 is D-tryptophan, B.sup.3 is lysine and B.sup.4 is threonine or valine.

8. A composition comprising at least two somatostatin receptor-binding peptides having a formula:

(cyclo(A.sup.4 -B.sup.1 B.sup.2 B.sup.3 B.sup.4 -C.sup.4)).sub.m

wherein

B.sup.1 is D- or L-Phe or D- or L-Tyr or D- or L-Nal or Ain or a substituted derivative thereof;

B.sup.2 is D- or L-Trp or a substituted thereof;

B.sup.3 is D- or L-Lys or Hly, Achxa, Amf, Aec, Apc, Aes, Aps or a substituted thereof;

B.sup.4 is Thr, Ser, Val, Phe, Ile, Abu, Nle, Leu, Nva or Aib;

A.sup.4 is a lipophilic .alpha.-amino acid or a lipophilic L-((.alpha.-N-alkyl) amino acid or L-proline or a substituted derivative thereof;

C.sup.4 is an .alpha.-amino acid having a sidechain --(CH.sub.2).sub.n SR.sup.2

where n is an integer from 1-4 and R.sup.2 is selected from the group consisting of a bond covalently linking said peptides and a polyvalent linking moiety covalently linked to said peptides;

m is an integer from 2 to 6;

and wherein each of said peptides is cyclized through a covalent linkage between an .alpha.-amino terminus of residue A.sup.4 and an .alpha.-carboxyl terminus of residue C.sup.4.

9. The composition of claim 8, wherein B.sup.1 is phenylalanine or tyrosine, B.sup.2 is D-tryptophan, B.sup.3 is lysine and B.sup.4 is threonine or valine.

10. The composition of claim 8, wherein the polyvalent linking moiety is selected from the group consisting of bis-succinimidylmethylether, 4-(2,2-dimethylacetyl)benzoic acid, N-(2-(N',N'bis(2-succinimido-ethyl)aminoethyl))-N.sup.6,N.sup.9 -bis(2-methyl-2-mercapto-propyl)-6,9-diazanonanamide, tris(succinimidylethyl)amine, bis-succinimidohexane, 4-(O-CH.sub.2 CO-Gly-Gly-Cys.amide)-2-methylpropiophenone, tris(acetamidoethyl)amine, bis-acetamidomethyl ether, bis-acetamidoethyl ether, .alpha.,.epsilon.-bis-acetyllysine, lysine, 1,8-bis-acetamido-3,6-dioxa-octane, a derivative of bis-succinimidylmethylether, a derivative of 4-(2,2-dimethylacetyl)benzoic acid, a derivative of N-(2-(N',N'bis(2-succinimido-ethyl)aminoethyl))-N.sup.6, N.sup.9 -bis(2-methyl-2-mercapto-propyl)-6,9-diazanonanamide, a derivative of tris(succinimidylethyl)amine, a derivative of bis-succinimidohexane, a derivative of 4-(O--CH.sub.2 CO--Gly-Gly-Cys.amide)-2-methylpropiophenone, a derivative of tris(acetamidoethyl)amine, a derivative of bis-acetamidomethyl ether, a derivative of bis-acetamidoethyl ether, a derivative of .alpha.,.epsilon.-bis-acetyllysine, a derivative of lysine and a derivative of 1,8-bis-acetamido-3,6-dioxa-octane.

11. A composition according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 further comprising a radioisotope of iodine.

12. The composition of claim 11, wherein the radioisotope I-125 or I-131.

13. A pharmaceutical composition comprising the composition of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and a pharmaceutically-acceptable carrier or excipient.

14. A method of performing radioisotope-guided surgery, or a radiodiagnostic or radiotherapeutic procedure using the composition of claim 11.

15. The composition of claims 1, 2, 5 or 8, wherein the somatostatin receptor-binding peptide is chemically synthesized in vitro.

16. The composition of claim 15, wherein the peptide is synthesized by solid phase peptide synthesis.

17. A method for alleviating a somatostatin-related disease in an animal comprising the step of administering a therapeutically effective amount of the composition of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 to the animal.

18. The method of claim 17 wherein the animal is a human.

19. The composition of claim 1, wherein the sidechain of C.sup.4 is covalently linked to an amino acid, an amino acid amide, or a peptide comprised of 2 to 10 amino acids.

20. A pharmaceutical composition comprising the composition of claim 11 and a pharmaceutically-acceptable carrier or excipient.

21. A pharmaceutical composition comprising the composition of claim 12 and a pharmaceutically-acceptable carrier or excipient.

22. A method for alleviating a somatostatin-related disease in an animal comprising the step of administering a therapeutically effective amount of the composition of claim 11 to the animal.

23. A method for alleviating a somatostatin-related disease in an animal comprising the step of administering a therapeutically effective amount of the composition of claim 12 to the animal.
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