Somatostatin Antagonists
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Abstract
The invention features somatostatin antagonists having a D-amino acid at the second residue.
20 Citations
32 Claims
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1-2. -2. (canceled)
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3. A compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein A1 is an L-aromatic amino acid; A3 is an aromatic amino acid; A6 is Thr, Thr(Bzl), Gly, Ser, an Eaa, or an aliphatic amino acid; A8 is a D- or L-isomer selected from the group consisting of Thr, Ser, an aromatic amino acid, and an aliphatic amino acid; each of R1 and R2 is, independently, H or substituted or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, E1SO2 or E1CO (where E1 is aryl, aryl lower alkyl, heterocycle or heterocycle lower alkyl), wherein said substituent is halo, lower alkyl, hydroxy, halo lower alkyl, or hydroxy lower alkyl; R3 is OH, NH2, C1-12 alkoxy or NH—
Y—
CH2-Z, wherein Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2, or R3, together with the carbonyl group of A8 attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl; anda disulfide bond links the sidechains of A2 and A7; provided that if A1 is p-NO2-Phe, A3 is Phe or Tyr, and A6 is Thr or Val, then A8 is β
-Nal.- View Dependent Claims (4, 5, 6, 7)
H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2 (V);(H)-(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)-(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)-(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)-(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-ONal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2; H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2; (H)(CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH2; H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;
(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;H(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2;H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β
-Nal-NH2;H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2; (H)(CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2; H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2; (H)(CH3CO)-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH2; H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;H2-Phe-D-Cys-Pal-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2;H2-Phe-D-Pen-Tyr-D-Trp-Lys-Val-Pen-β
-Nal-NH2;
orH2,-Phe-D-Pen-Pal-D-Trp-Lys-Thr-Pen-Thr-NH2; H2-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH2; H2—
F5-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-F5-Phe-NH2;H2-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-m-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-m-F-Phe-NH2; H2-o-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-o-F-Phe-NH2; H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-F-Phe-NH2; H2—
F5-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-F5-Phe-NH2;H2—
F5-Phe-D-Cys-2-Pal-D-Trp-Lys-Val-Cys-F5-Phe-NH2;H2-β
-Nal-D-Cys-His-D-Trp-Lys-Val-Cys-D-Dip-NH2;H2-Dip-D-Cys-His-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-Dip-D-Cys-His-D-Trp-Lys-Val-Cys-Dip-NH2; H2-β
-Nal-D-Cys-His-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-Trp-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-β
-Nal-NH2;H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-p-F-Phe-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β
-Nal-NH2;H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Nle-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Ile-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Gly-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Ala-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Leu-Cys-β
-Nal-NH2;H2-Bip-D-Cys-Tyr-D-Trp-Lys-Ile-Cys-Bip-NH2; H2-p-F-Phe-D-Cys-His-D-Trp Lys-Val-Cys-p-F-Phe-NH2; H2-Npa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Tyr-NH2; H2-m-F-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-m-F-Phe-NH2; H2-o-F-Phe-D-Cys-His-D-Trp-Lys-Val-Cys-o-F-Phe-NH2; H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH2;H2-Cpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Cpa-NH2; H2-Igl-D-Cys-Pal-D-Trp-Lys-Val-Cys-Igl-NH2; H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-Dip-NH2;H2-β
-Nal-D-Cys-3-I-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-p-CN-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-CN-Phe-NH2; H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-D-Dip-NH2;H2-β
-Nal-D-Cys-Bta-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-p-F-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β
-Nal-NH2;H2-Bpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Bpa-NH2; H2-Iph-D-Cys-Pal-D-Trp-Lys-Val-Cys-Iph-NH2; H2-Trp-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β
-Nal-NH2;H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β
-Nal-NH2;H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-p-Cl-Phe-NH2; H2-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Cha-Cys-p-Cl-Phe-NH2; H2-p-Cl-Phe-D-Cys-Tr(I)-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2; H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-p-Cl-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Tle-Cys-β
-Nal-NH2;H2-p-F-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-p-F-Phe-D-Cys-Tyr(I)-D-Trp-Lys-Tle-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;H2-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β
-Nal-NH2;H2-p-NO2-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-Nal-NH2; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Tyr-NH2; H2-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β
-Nal-NH2;H2-β
-Nal-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-β
-Nal-NH2;
or(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr(Bzl)-D-Trp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2;
or a pharmaceutically acceptable salt thereof.
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8-17. -17. (canceled)
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18. A compound of the formula:
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or a pharmaceutically acceptable salt thereof, wherein A1 is a D- or L-isomer of an aromatic amino acid, or is deleted; A3 is an aromatic amino acid; A6 is Thr, Thr(Bzl), Gly, Ser, an Eaa, or an aliphatic amino acid; A8 is a D- or L-isomer selected from the group consisting of Thr, Ser, an aromatic amino acid, or an aliphatic amino acid; each of R1 and R2 is, independently, H or substituted or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, E1SO2 or E1CO (where E1 is aryl, aryl lower alkyl, heterocycle, or heterocycle lower alkyl), where said substituent is halo, lower alkyl, hydroxy halo lower alkyl, or hydroxy lower alkyl; R3, together with the carbonyl group of A8 attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl; and a disulfide bond links the sidechains of A2 and A7; provided that if A1 is D-Phe or p-NO2-Phe, A3 is Phe or Tyr, and A6 is Thr or Val, then A8 is β
-Nal.- View Dependent Claims (19, 20, 21, 22)
(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;H2,-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2hydroxymethyl)-3-hydroxy)propylamide;(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2hydroxymethyl)-3-hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3hydroxy)propylamide; H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2hydroxymethyl)-3-hydroxy)propylamide; H(CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2hydroxymethyl)-3-hydroxy)propylamide; (H)(CH3CO) Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(CH3CO)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide; H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;(H)(CH3CO)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;H2-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;(H)(CH3CO)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;H2-Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide; (H)(CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Tyr-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide; H2-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide; (H)(CH3CO)Phe-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide; H2-Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide; (H)(CH3CO)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide; H2-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide; (H)(CH3CO)Phe-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide; (H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide; H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R-(2-naphthyl)ethylamide;H2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R-(2-naphthyl)ethylamide; H2-β
-Nal-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
orH2-Phe-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;
or a pharmaceutically acceptable salt thereof.
-
-
23. A compound of the formula:
-
or a pharmaceutically acceptable salt thereof, wherein A1 is a D- or L-isomer of an aromatic amino acid, or is deleted; A2 is a D-aromatic amino acid or a D-aliphatic amino acid; A3 is an aromatic amino acid; A6 is Thr, Thr(Bzl), Gly, Ser, an Eaa, or an aliphatic amino acid; A7 is an aromatic amino acid or an aliphatic amino acid; A8 is a D- or L-isomer selected from the group consisting of Thr, Ser, an aromatic amino acid, and an aliphatic amino acid; each of R1 and R2 is, independently, H or substituted or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, E1SO2 or E1CO (where E1 is aryl, aryl lower alkyl, heterocycle, or heterocycle lower alkyl), where said substituent is halo, lower alkyl, hydroxy, halo lower alkyl, or hydroxy lower alkyl; and R3 is OH, NH2, C1-12 alkoxy, or NH—
Y—
CH2-Z, wherein Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO, H, or CONH2, or R3, together with the carbonyl group of A8 attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl;provided that if A2 is D-Cys or D-Pen, and A7 is Cys or Pen, then a disulfide bond links the sidechains of A2 and A7; and
if A1 is D-Phe or p-NO2-Phe, A2 is D-Cys, A3 is Phe or Tyr, A6 is Thr or Val, and A7 is Cys, then A8 is β
-Nal.- View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32)
H2-Phe-D-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; (H)(CH3CO)-β
-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-DCpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2;H2-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;(H)(CH3CO)-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Val-Phe-Thr-NH2;H2-β
-Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;(H)(CH3CO)-β
-Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-DCpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;H2-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;(H)(CH3CO)-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
-Nal-D-Cpa-Pal-D-Trp-Lys-Thr-Phe-Thr-NH2;H2-β
-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-β
-Nal-NH2;(H)(CH3CO)-β
-Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-β
-Nal-NH2;
(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β
-Nal-DCpa-Tyr-D-Trp-Lys-Val-Phe-β
-Nal-NH2;
or(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β
Nal-D-Cpa-Tyr-D-Trp-Lys-Val-Phe-β
-Nal-NH2;or a pharmaceutically acceptable salt thereof.
-
-
28. A compound of claim 23, wherein A1 is a D-amino acid and A2 is a D-aromatic amino acid.
-
29. A compound of claim 28, wherein A1 and A2, independently, is D-β
- -Nal, D-o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa, or DPal;
A3 and A7, independently, is β
-Nal, o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), F5-Phe, Trp, Dip, 2-Pal, His, Igl, Tyr(I), Bta, Bip, Npa, Tyr(Bzl), or Pal;
A6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, β
-Ala, Gaba, or Val; and
A8 is the D- or L-isomer of Thr, Dip, F5-Phe, p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), o-X-Phe (where X is H, OH CH3, halo, OCH3, NH2, CN, or NO2), m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), Igl, Tyr(Bzl), or β
-Nal.
- -Nal, D-o-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-p-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-m-X-Phe (where X is H, OH, CH3, halo, OCH3, NH2, CN, or NO2), D-F5-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa, or DPal;
-
30. A compound of claim 29, wherein A1 is D-β
- -Nal or D-Phe;
A2 is D-Cpa or D-Phe;
A3 is Phe or Tyr;
A6 is Thr or Val;
A7 is Phe; and
A8 is Thr;
R1 is H, CH3CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1piperizineethanesulfonyl;
R2 is H; and
R3 is NH2.
- -Nal or D-Phe;
-
31. A compound of claim 29 of the formula:
-
H2-D-β
-Nal-D-Cpa-Phe-D-Trp-Lys-Val-Phe-Thr-NH2;H2-D-β
-Nal-D-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2;
orH2-D-Phe-D-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; a pharmaceutically acceptable salt thereof.
-
-
32. A method of promoting the release of growth hormone in a subject in need thereof, which comprises administering to said subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 23.
Specification