IP Library › Granted Patent US 9,133,262
Granted Patent B2
US 9,133,262 · App. 12/422,625 · Granted Sep 15, 2015

Somatostatin antagonists

Inventors: David H. Coy (New Orleans, LA); Barry Morgan (Franklin, MA); William Murphy (Slidell, LA)
Assignees: Ipsen Pharma S.A.S.; The Administrators of the Tulane Educational Fund
C07K14/6555
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Quick Facts
Patent No.
US 9,133,262
App. No.
12/422,625
Granted
Sep 15, 2015
Kind
B2
Abstract

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

Claims (131)

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

A 1 is β-Nal; o-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; p-X-Phe, where X is H, OH CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; m-X-Phe, where X is H, OH CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; F 5 -Phe; Trp; Dip; 2-Pal; Tyr(Bzl); His; Igl; Tyr(I); Bta; Bip; Npa; or Pal;

A 3 is Pal, 2-Pal, or 4-Pal;

A 6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, β-Ala, Gaba, or Val;

A 8 is a D- or L-isomer of Thr; F 5 -Phe; p-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; o-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; m-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; Igl; Tyr(Bzl); or β-Nal;

each of R 1 and R 2 is, independently, H or substituted or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, E 1 SO 2 or E 1 CO, where E 1 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;

R 3 is OH, NH 2 , C 1-12 alkoxy or NH—Y—CH 2 —Z, wherein Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ; or R 3 , together with the carbonyl group of A 8 attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl; and

a disulfide bond links the sidechains of A 2 and A 7 ;

provided that if A 6 is Thr or Val, then A 8 is β-Nal.

2. The compound of claim 1 having the formula:

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

(H)(CH 3 CO)-β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

(H)-(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

(H)-(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

(H)(CH 3 CO)-β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

H 2 -Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

(H)(CH 3 CO)Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

H 2 -Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

(H)(CH 3 CO)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-Thr-NH 2 ;

(H)(CH 3 CO)-β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

(H)(CH 3 CO)-β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-βNal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH 2 ;

(H)(CH 3 CO)-β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH 2 ;

H 2 -Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

(H)(CH 3 CO)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl) Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ;

H 2 -Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH 2 ;

(H)(CH 3 CO)-Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-Thr-NH 2 ;

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

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

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Abu-Cys-β-Nal-NH 2 ;

H 2 -Phe-D-Cys-Pal-D-Trp-Lys-Abu-Cys-β-Nal-NH 2 ;

H 2 -Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH 2 ;

H 2 -Dip-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

H 2 -m-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-m-F-Phe-NH 2 ;

H 2 -o-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-o-F-Phe-NH 2 ;

H 2 -p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-F-Phe-NH 2 ;

H 2 —F 5 -Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-F 5 -Phe-NH 2 ;

H 2 —F 5 -Phe-D-Cys-2-Pal-D-Trp-Lys-Val-Cys-F 5 -Phe-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-p-F-Phe-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β-Nal-NH 2 ;

H 2 -p-F-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Nle-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Ile-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Gly-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Ala-Cys-β-Nal-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Leu-Cys-β-Nal-NH 2 ;

H 2 -Npa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Tyr-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-Dip-NH 2 ;

H 2 -Cpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Cpa-NH 2 ;

H 2 -Igl-D-Cys-Pal-D-Trp-Lys-Val-Cys-Igl-NH 2 ;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-D-Dip-NH 2 ;

H 2 -p-CN-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-p-CN-Phe-NH 2 ;

H 2 -p-F-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β-Nal-NH 2 ;

H 2 -Bpa-D-Cys-Pal-D-Trp-Lys-Val-Cys-Bpa-NH 2 ;

H 2 -Iph-D-Cys-Pal-D-Trp-Lys-Val-Cys-Iph-NH 2 ;

H 2 -Trp-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β-Nal-NH 2 ;

H 2 -p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ;

H 2 -p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-β-Nal-NH 2 ;

H 2 -p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Tle-Cys-p-Cl-Phe-NH 2 ; or

H 2 -p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Cha-Cys-p-Cl-Phe-NH 2 ;

or a pharmaceutically acceptable salt thereof.

3. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

A 1 is a D- or L-isomer of β-Nal; o-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; p-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; m-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ); F 5 -Phe; Trp; Dip; 2-Pal; Tyr(Bzl); His; Igl; Tyr(I); Bta; Bip; Npa; or Pal;

A 3 is Pal, 2-Pal, or 4-Pal;

A 6 is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, β-Ala, Gaba, or Val;

A 8 is a D- or L-isomer of Thr; Dip; F 5 -Phe; p-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; o-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; m-X-Phe, where X is H, OH, CH 3 , halo, OCH 3 , NH 2 , CN, or NO 2 ; Igl; Tyr(Bzl); or β-Nal;

each of R 1 and R 2 is, independently, H or substituted or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, E 1 SO 2 or E 1 CO, where E 1 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;

R 3 , together with the carbonyl group of A 8 attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl; and

a disulfide bond links the sidechains of A 2 and A 7 ;

provided that if A 6 is Thr or Val, then A 8 is β-Nal.

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

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(CH 3 CO)-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;

H 2 -β-Nal-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(CH 3 CO)-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-

H 2 -Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R,3R-(2hydroxymethyl)-3-hydroxy)propylamide;

H(CH 3 CO)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;

H 2 -Phe-D-Cys-Pal-D-Trp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide;

(H)(CH 3 CO)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;

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

(H)(CH 3 CO)-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)-βNal-D-Cys-Pal-D-Trp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide;

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

(H)(CH 3 CO)-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;

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

(H)(CH 3 CO)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;

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

(H)(CH 3 CO)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.

5. The compound of claim 1 , wherein:

A 1 is p-X-Phe, where X is halo;

A 6 is Thr or Val;

A 8 is β-Nal;

R 1 is H;

R 2 is H; and

R 3 is NH 2 .

6. The compound of claim 5 , wherein:

A 1 is p-Cl-Phe.

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

H 2 -p-Cl-Phe-D-Cys-Pal-D-Trp-Lys-Val-Cys-β-Nal-NH 2 .

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2013
From: MORGAN, BARRY A.
To: BIOMEASURE, INCORPORATED
Reel/Frame 031414/0282 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2013
From: COY, DAVID H.; MURPHY, WILLIAM A.
To: THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
Reel/Frame 031414/0357 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2013
From: BIOMEASURE, INCORPORATED
To: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
Reel/Frame 031414/0397 →
CHANGE OF NAME Recorded Oct 16, 2013
From: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
To: IPSEN PHARMA S.A.S.
Reel/Frame 031414/0441 →
Continuity (5)
Continuation 10712081 · Nov 13, 2003
Division 09670249 · Sep 26, 2000
Continuation 08855204 · May 13, 1997
Provisional Application 60032358 · Dec 4, 1996
Related Publication 20090253638A1 · Oct 8, 2009