Somatostatin antagonists

• US 6,703,481 B1
• Filed: 09/26/2000
• Issued: 03/09/2004
• Est. Priority Date: 12/04/1996
• Status: Expired due to Term

• Current Assignee: Administrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY), Ipsen Pharma Sas (Ipsen Sa)
• Original Assignee: Administrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY), Societe de Conseils de Recherches et d'Applications Scientifiques
• Inventors: Murphy, William, Morgan, Barry, Coy, David H.
• Primary Examiner(s): Jones, Dwayne C.
• Assistant Examiner(s): DELACROIX MUIRHEI, CYBILLE
• Application Number:
  US09/670,249
• Time in Patent Office: 1,260 Days
• Field of Search: 530/311, 530/317, 530/328, 530/329, 514/11, 514/16
• US Class Current: 530/311
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form

Abstract

The invention features somatostatin antagonists having a D-amino acid at the second residue.

Claims

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

A¹ 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 and an aliphatic amino acid;

R₁ is substituted or unsubstituted E₁CO wherein E₁ is aryl, aryl lower alkyl, heterocycle or heterocycle lower alkyl; and

R₃ is OH, NH₂, C_1-12 alkoxy or NH—

Y—

CH₂—

Z, wherein Y is a C_1-12 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;

provided that a disulfide bond links the sidechains of A² and A⁷.

2. A compound of claim 1, wherein R₁ is substituted or unsubstituted E₁CO and E₁ is phenyl, β

-naphthylmethyl, β

-pyridinylmethyl, or 3-indolylmethyl;

A³ is β

-Nal, o-X-Phe wherein X is H, OH, CH₃, halo, OCH₃, NH₂, CN, or NO₂, p-X-Phe wherein X is H, OH, CH₃, halo, OCH₃, NH₂, CN, or NO₂, m-X-Phe wherein X is H, OH, CH₃, halo, OCH₃, NH₂, CN, or NO₂, F₅-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, 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 wherein X is H, OH, CH₃, halo, OCH₃, NH₂, CN, or NO₂, o-X-Phe wherein X is H, OH, CH₃, halo, OCH₃, NH₂, CN, or NO₂, m-X-Phe wherein X is H, OH, CH₃, halo, OCH₃, NH₂, CN, or NO₂, Igl, Tyr(Bzl), or β

-Nal.

3. A compound of claim 2, wherein R₁ is E₁CO and E₁ is 4-hydroxy-phenyl, β

-naphthylmethyl, or phenyl;

A³ is Tyr, Tyr(I), or Pal;

A⁶ is Val, Tle, Nle, Ile, or Leu;

A⁸ is p-F-Phe, β

-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; and

R₃ is NH₂.

4. A compound of claim 3, wherein A³ is Pal.

5. A compound of claim 2, of the formula

(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β -Nal-NH₂;

(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-β

-Nal-NH₂;

(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β

-Nal-NH₂;

(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β

-Nal-NH₂;

(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂;

(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH₂;

(H) (3-phenylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH₂;

(H) (3-phenylpropionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β

-Nal-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β

-Nal-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-β

-Nal-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys-β

-Nal-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β

-Nal-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Thr-Cys Thr-NH₂;

(H) (3-[2-naphthyl]propionyl)-D-Cys-Pal-D-Trp-Lys-Thr-Cys Thr-NH₂;

(H) (3-[p-hydroxyphenyl])-D-Cys-Tyr-D-Trp-Lys-Val-Cys-β

-Nal-NH₂;

(H) (3-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β

-Nal-NH₂;

(H) (3-naphthyl]propionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂;

(H) (3-phenylylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-β

-Nal-NH₂;

or

(H) (3-phenylylpropionyl)-D-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂;

or

a pharmaceutically acceptable salt thereof.