IP Library › Granted Patent US 8,859,729
Granted Patent B2
US 8,859,729 · App. 13/734,314 · Granted Oct 14, 2014

Growth hormone releasing peptides

Inventor: Zheng Xin Dong (Holliston, MA)
Assignee: Ipsen Pharma S.A.S.
C07K7/06C07K7/02A61K38/00C07K5/0205C07K14/60C07K5/1024C07K5/06034C07K5/1016
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Quick Facts
Patent No.
US 8,859,729
App. No.
13/734,314
Granted
Oct 14, 2014
Kind
B2
Abstract

Disclosed are peptide and peptidomimetic compounds generally according to formula (I) that are useful as GHRP analogs: R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2   (I) wherein: A 1 is Aib, Apc or Inp; A 2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A 3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A 4 is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); A 5 is Apc, Dab, Dap, Lys, Orn, or deleted; R 1 is hydrogen, (C1-6)alkyl, (C5-14)aryl, (C1-6)alkyl(C5-14)aryl, (C3-8)cycloakyl, or (C2-10)acyl; and R 2 is OH or NH 2 ; and pharmaceutical compositions and methods of use thereof.

Claims (169)

1. A compound according to formula (I):

R 1 -A 1 -A 2 -A 3 -A 4 -A 5 -R 2   (I)

or a pharmaceutically acceptable salt thereof, wherein:

A 1 is Apc;

A 2 is D-Bal, D-1Nal, or D-2Nal;

A 3 is D-Bal or D-Trp;

A 4 is 2Fua, 2Pal, 3Pal, 4Pal, Pff, Phe, Taz, 2Thi, or 3Thi;

A 5 is Apc or deleted;

R 1 is hydrogen, (C 1-6 )alkyl, (C 5-14 )aryl, (C 1-6 )alkyl(C 5-14 )aryl, (C 3-8 )cycloakyl, or (C 2-10 )acyl; and

R 2 is OH or NH 2 ;

provided that:

when A 5 is deleted, then:

A 4 is 2Fua, Pff, or Taz; or

A 1 is Apc and—

A 2 is D-Bal; or

A 3 is D-Bal; or

A 4 is 2Thi, 3Thi, 2Pal, 3Pal, or 4Pal.

2. A compound according to claim 1 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-NH 2 ;

H-Apc-D-1Nal-D-Trp-Taz-NH 2 ;

H-Apc-D-Bal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Taz-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Pal-NH 2 ;

H-Apc-D-1Nal-D-Trp-3Pal-NH 2 ;

H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-3Thi-NH 2 ;

H-Apc-D-1Nal-D-Trp-4Pal-NH 2 ;

H-Apc-D-1Nal-D-Trp-Pff-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Pal-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-3Pal-NH 2 ;

H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-3Thi-NH 2 ;

H-Apc-D-2Nal-D-Trp-4 Pal-NH 2 ;

H-Apc-D-2Nal-D-Trp-Pff-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-2Fua-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-2Fua-NH 2 ;

H-Apc-D-Bal-D-Bal-2Pal-NH 2 ;

H-Apc-D-Bal-D-Bal-2Thi-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-2Thi-NH 2 ;

H-Apc-D-Bal-D-Bal-3Pal-NH 2 ;

H-Apc-D-Bal-D-Bal-3Thi-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-3Thi-NH 2 ;

H-Apc-D-Bal-D-Bal-4Pal-NH 2 ;

H-Apc-D-Bal-D-Bal-Pff-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-Pff-NH 2 ;

H-Apc-D-Bal-D-Bal-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-Phe-NH 2 ;

H-Apc-D-Bal-D-Bal-Taz-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-Taz-NH 2 ;

H-Apc-D-Bal-D-Trp-2Fua-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-2Fua-NH 2 ;

H-Apc-D-Bal-D-Trp-2Pal-NH 2 ;

H-Apc-D-Bal-D-Trp-3Pal-NH 2 ;

H-Apc-D-Bal-D-Trp-3Thi-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-3Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-4Pal-NH 2 ; or

H-Apc-D-Bal-D-Trp-Pff-Apc-NH 2 ;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-NH 2 ;

H-Apc-D-Bal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Taz-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-3Thi-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-2Fua-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Pff-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-2Thi-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-3Thi-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-Taz-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-2Fua-Apc-NH 2 ;

H-Apc-D-Bal-D-Bal-Pff-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-3Thi-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Fua-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-Pff-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-3Thi-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Fua-Apc-NH 2 ;

H-Apc-D-2Nal-D-Trp-Pff-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-3Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-2Fua-NH 2 ;

H-Apc-D-Bal-D-Trp-Pff-NH 2 ;

H-Apc-D-Bal-D-Trp-4Pal-NH 2 ;

H-Apc-D-Bal-D-Trp-3Pal-NH 2 ;

H-Apc-D-Bal-D-Trp-2Pal-NH 2 ;

H-Apc-D-Bal-D-Bal-Phe-NH 2 ;

H-Apc-D-Bal-D-Bal-2Thi-NH 2 ;

H-Apc-D-Bal-D-Bal-3Thi-NH 2 ;

H-Apc-D-Bal-D-Bal-Taz-NH 2 ;

H-Apc-D-Bal-D-Bal-2Fua-NH 2 ;

H-Apc-D-Bal-D-Bal-Pff-NH 2 ;

H-Apc-D-Bal-D-Bal-4Pal-NH 2 ;

H-Apc-D-Bal-D-Bal-3Pal-NH 2 ;

H-Apc-D-Bal-D-Bal-2Pal-NH 2 ;

H-Apc-D-1Nal-D-Trp-3Thi-NH 2 ;

H-Apc-D-1Nal-D-Trp-4Pal-NH 2 ;

H-Apc-D-1Nal-D-Trp-3Pal-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Pal-NH 2 ;

H-Apc-D-2Nal-D-Trp-3Thi-NH 2 ;

H-Apc-D-2Nal-D-Trp-4Pal-NH 2 ;

H-Apc-D-2Nal-D-Trp-3Pal-NH 2 ; or

H-Apc-D-2Nal-D-Trp-2Pal-NH 2 ;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-NH 2 ;

H-Apc-D-Bal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Taz-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Thi-NH 2 ; or

H-Apc-D-2Nal-D-Trp-2Thi-NH 2 ;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-NH 2 ;

H-Apc-D-Bal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Taz-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH 2 ; or

H-Apc-D-Bal-D-Trp-Taz-Apc-NH 2 ;

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-Bal-D-Trp-Phe-NH 2 ;

H-Apc-D-Bal-D-Trp-2Thi-NH 2 ;

H-Apc-D-2Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-1Nal-D-Trp-Taz-Apc-NH 2 ; or

H-Apc-D-Bal-D-Trp-Taz-Apc-NH 2 ;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ;

H-Apc-D-1Nal-D-Trp-2Thi-NH 2 ;

H-Apc-D-1Nal-D-Trp-Phe-Apc-NH 2 ; or

H-Apc-D-2Nal-D-Trp-2Thi-NH 2 ;

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 7 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ; or

H-Apc-D-1Nal-D-Trp-2Thi-NH 2 ;

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 7 , wherein said compound is according to the formula:

H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH 2 ;

or a pharmaceutically acceptable salt thereof.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2013
From: DONG, ZHENG XIN
To: BIOMEASURE, INCORPORATED
Reel/Frame 029727/0612 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2013
From: BIOMEASURE, INCORPORATED
To: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
Reel/Frame 029727/0681 →
CHANGE OF NAME Recorded Jan 31, 2013
From: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
To: IPSEN PHARMA S.A.S.
Reel/Frame 029727/0744 →
Continuity (4)
Continuation 12157224 · Jun 9, 2008
Continuation 10484473
Provisional Application 60402263 · Aug 9, 2002
Related Publication 20130123170A1 · May 16, 2013