Conformationally constrained backbone cyclized somatostatin analogs

1. A backbone cyclized somatostatin analog comprising a peptide sequence of four to twelve amino acids that incorporates at least one building unit, said building unit containing one nitrogen atom of the peptide backbone connected to a bridging group comprising an amide, thioether, thioester, or disulfide, wherein the at least one building unit is connected via the bridging group to form a cyclic structure with a moiety selected from the group consisting of a second building unit, the side chain of an amino acid residue of the sequence or the N-terminal amino acid residue, wherein the sequence includes a non-cyclized chain of 4, 5 or 6 amino acids.

2. The backbone cyclized somatostatin analog of claim 1 having the general formula 7:

wherein

n is 1 to 5;

X designates a terminal carboxy acid, amide or alcohol group;

Q is hydrogen or a mono- or di-saccharide

R 5 is gamma amino butyric acid, diamino butyric acid, Gly, α-Ala, 5-amino pentanoic acid or amino hexanoic acid;

R 6 is (D)- or (L)-Phe or Tyr;

R 7 is (D)- or (L)-Trp, (D)- or (L)-Phe, (D)- or (L)-1Nal, (D)- or (L)-2Nal, or Tyr;

R 8 is (D)- or (L)-Trp;

R 9 is (D)- or (L)-Lys;

R 10 is Thr, Gly, Abu, Ser, Cys, Val, (D)- or (L)-Ala, or (D)- or (L)-Phe;

R 11 is (D)- or (L)-Phe, (D)- or (L)-Ala, Nle, or Cys;

R 12 is Gly, Val, Leu, (D)- or (L)-Phe, 1Nal, or 2Nal; and

Y is amide, thioether, thioester or disulfide.

3. The backbone cyclized somatostatin analog of claim 2 wherein:

Q is hydrogen;

R 5 is GABA;

R 6 is Phe;

R 7 is Trp;

R 8 is (D)-Trp;

R 9 is Lys;

R 10 is Thr;

R 11 is Phe;

R 12 is Gly;

n is 3; and

Y is an amide.

4. The backbone cyclized somatostatin analog of claim 2 wherein:

Q is galactose;

R 5 is Dab;

R 6 is Phe;

R 7 is (L)-Trp;

R 8 is (D)-Trp;

R 9 is Lys;

R 10 is Thr;

R 11 is Phe;

R 12 is Gly;

n is 3; and

Y is an amide.

5. The backbone cyclized somatostatin analog of claim 1 having the general formula 8:

wherein:

m and n are 1 to 5;

X designates a terminal carboxy acid, amide or alcohol group;

R 6 is (D)- or (L)-Phe, or (D)- or (L)-Ala;

R 7 is Tyr, (D)- or (L)-Ala, or (D)- or (L)-Phe;

R 10 is Thr, Val, Ser, or Cys;

R 11 is Val, (D)- or (L)-1Nal, (D)- or (L)-2Nal, or (D) or (L)-Phe;

R 12 is Gly, (D)- or (L)-Ala, or (D) or (L)-Phe; and

Y is amide, thioether, thioester or disulfide.

6. The backbone cyclized somatostatin analog of claim 5 wherein:

R 6 is (D)- or (L)-Phe;

R 7 is Tyr or Phe;

R 10 is Thr, Val or Ser;

R 11 is Val, 1Nal, or 2Nal;

R 12 is Gly; and

Y is amide.

7. The backbone cyclized somatostatin analog of claim 1 having the general formula 9:

wherein:

m and n are 1 to 5;

X designates a terminal carboxy acid, amide or alcohol group;

R 6 is (D)- or (L)-Phe, or (D)- or (L)-Ala;

R 7 is Tyr or (D)- or (L)-Phe;

R 8 is (D)- or (L)-Trp, (D)- or (L)-1Nal, or (D)- or (L)-2Nal;

R 10 is Thr, Val, Ser, or Cys;

R 11 is Gly or (D) or (L)-Phe;

R 12 is Thr, GABA, (D)- or (L)-1Nal, (D)- or (L)-2Nal, or (D) or (L)-Phe; and

Y is amide, thioether, thioester or disulfide.

8. The backbone cyclized somatostatin analog of claim 7 wherein:

R 6 is (D)- or (L)-Phe;

R 7 is Tyr;

R 8 is (D)Trp, (D)1Nal, or (D)2Nal;

R 10 is Val;

R 11 is Gly;

R 12 is Thr, 1Nal, or 2Nal; and

Y is amide.

9. The backbone cyclized somatostatin analog of claim 1 having the general formula 13:

wherein m and n are 1 to 5;

X designates a terminal carboxy acid, amide or alcohol group;

R 6 is (D)- or (L)-Phe or Tyr;

R 7 is (D)- or (L)-Trp,(D)- or (L)-Phe, (D)- or (L)-1Nal or (D)- or (L)-2Nal, or Tyr;

R 10 is Thr, Gly, Abu, Ser, Cys, Val, (D)- or (L)-Ala, or (D)- or (L)-Phe;

R 11 is (D)- or (L)-Phe or (D)- or (L)-Ala;

R 12 is Gly, Val, or (D)- or (L)-Phe; and

Y is thioether, thioester or disulfide.

10. The backbone cyclized somatostatin analog of claim 9 wherein:

R 6 is Phe;

R 7 is Trp;

R 10 is Thr;

R 11 is Phe;

R 12 is Gly; and

Y is disulfide.

11. The backbone cyclized somatostatin analog of claim 1 having the general formula 14:

wherein

m and n are 1 to 5;

X designates a terminal carboxy acid, amide or alcohol group;

R 4 is (D)- or (L)-Phe or Tyr;

R 6 is (D)- or (L)-Phe or Tyr;

R 7 is (D)- or (L)-Trp, (D)- or (L)-Phe, (D)- or (L)-1Nal or (D)- or (L)-2Nal, or Tyr;

R 10 is Thr, Gly, Abu, Ser, Cys, Val, (D)- or (L)-Ala, or (D)- or (L)-Phe;

R 11 is (D)- or (L)-Phe or (D)- or (L)-Ala;

R 12 is Gly, Val, or (D)- or (L)-Phe; and

Y is thioether, thioester or disulfide.

12. The backbone cyclized somatostatin analog of claim 11 wherein:

R 4 is (D)Phe;

R 6 is Phe;

R 7 is Trp;

R 10 is Thr;

R 11 is Phe;

R 12 is Gly; and

Y is disulfide.

13. The backbone cyclized somatostatin analog of claim 1 having the general formula 15:

wherein

m and n are 1 to 5;

X designates a terminal carboxy acid, amide or alcohol group;

R 5 is (D)- or (L)-Phe or (D)- or (L)-Ala;

R 7 is (D)- or (L)-Trp, (D)- or (L)-Phe, (D)- or (L)-1Nal or (D)- or (L)-2Nal, or Tyr;

R 10 is Thr, Gly, Abu, Ser, Cys, Val, (D)- or (L)-Ala, or (D)- or (L)-Phe;

R 12 is Gly, Val, or (D)- or (L)-Phe, or is absent;

R 13 is (D)- or (L)-Phe or (D)- or (L)-Ala; and

Y is amide, thioether, thioester or disulfide.

14. The backbone cyclized somatostatin analog of claim 13 wherein:

R 5 is Phe;

R 7 is Phe;

R 10 is Thr;

R 12 is Gly, Val, or (D)- or (L)-Phe, or is absent;

R 13 is Phe; and

Y is amide.

15. The backbone cyclized somatostatin analog of claim 1 having the formula:

Phe(N2)-Tyr-(D)2Nal-Lys-Val-Gly(C2)-Thr-X;

Phe(N2)-Tyr-(D)Trp-Lys-Val-Gly(C2)-2Nal-X;

Phe(N2)-Tyr-(D)Trp-Lys-Val-Val-Gly(C2)-X;

Phe(N2)-Tyr-(D)Trp-Lys-Ser-2Nal-Gly(C2)-X;

Phe(N2)-Phe-(D)Trp-Lys-Thr-2Nal-Gly(C2)-X;

GABA*-Phe-Trp-(D)Trp-Lys-Thr-Phe-Gly(C3)-X;

Cys*-Phe-Trp-(D)Trp-Lys-Thr-Phe-Gly(S2)-X;

Phe(C3)-Cys*-Phe-(D)Trp-Lys-Thr-Cys*-Phe-Phe(N3)-X;

(D)Phe-Cys*-Phe-Trp-(D)Trp-Lys-Thr-Phe-Gly(S2)-X; or

Galactose-Dab*-Phe-Trp-(D)Trp-Lys-Thr-Phe-Gly(C3)-X;

wherein X designates a terminal carboxy acid, amide, or alcohol group; the asterisk denotes that the bridging group is connected between the N α -ω-functionalized derivative of an amino acid and the N-terminus of the peptide or the side chain of the Cys residue.

16. A pharmaceutical composition comprising a backbone cyclized somatostatin analog according to claim 1 and a pharmaceutically acceptable carrier.

17. The composition according to claim 16 wherein the backbone cyclic analog is selective for one somatostatin receptor subtypes.

18. The composition according to claim 16 wherein the backbone cyclic analog is selective for two somatostatin receptor subtypes.