Somatostatin antagonists

• US 9,133,262 B2
• Filed: 04/13/2009
• Issued: 09/15/2015
• Est. Priority Date: 12/04/1996
• Status: Expired due to Fees

• Current Assignee: Ipsen Pharma Sas (Ipsen Sa)
• Original Assignee: Administrators Of The Tulane Educational Fund (ADMINISTRATORS|DAVID H. COY), Ipsen Pharma Sas (Ipsen Sa)
• Inventors: Coy, David H., Morgan, Barry, Murphy, William
• Primary Examiner(s): AUDET, MAURY A
• Application Number:
  US12/422,625
• Publication Number:
  US 20090253638A1
• Time in Patent Office: 2,346 Days
• Field of Search: None
• US Class Current: 1/1
• 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:

2. The compound of claim 1 having the formula:

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-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)-β

-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-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;

(H)(CH₃CO)-β

-Nal-D-Cys-Pal-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-DCys-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-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-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-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-Pal-D-Trp-Lys-Abu-Cys-β

-Nal-NH₂;

H₂-Phe-D-Cys-Pal-D-Trp-Lys-Abu-Cys-β

-Nal-NH₂;

H₂-Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-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-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-Npa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Tyr-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-p-CN-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-CN-Phe-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;

or

H₂-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Cha-Cys-p-Cl-Phe-NH₂;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein:

A¹ is p-X-Phe, where X is halo;

A⁶ is Thr or Val;

A⁸ is β

-Nal;

R₁ is H;

R₂ is H; and

R₃ is NH₂.

6. The compound of claim 5, wherein:

A¹ is p-Cl-Phe.

7. The compound of claim 6, wherein said compound is:

H₂-p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β

-Nal-NH₂.

3. A compound of the formula:

4. A compound of claim 3, of the formula:

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-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-

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-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-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(H)(CH₃CO)-β

-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)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-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

(H)(CH₃CO)-β

-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)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-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

(H)(CH₃CO)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)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-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

(H)(CH₃CO)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

or

(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide;

or a pharmaceutically acceptable salt thereof.