IP Library › Granted Patent US 8,377,865
Granted Patent B2
US 8,377,865 · App. 12/157,224 · Granted Feb 19, 2013

Growth hormone releasing peptides

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Quick Facts
Patent No.
US 8,377,865
App. No.
12/157,224
Granted
Feb 19, 2013
Kind
B2
Abstract

Disclosed are peptide and peptidomimetic compounds generally according to formula (I), and pharmaceutically acceptable salts thereof, that are useful as GHRP analogs: 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 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, (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 ; and pharmaceutical compositions and methods of use thereof.

Claims (222)

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 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 or D-Trp;

A 4 is 2Fua, Orn, 2 Pal, 3 Pal, 4 Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, or Thr(Bzl);

A 5 is Apc or Lys;

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 Lys, then:

A 2 is D-Bip, D-Bpa, D-Dip or D-Bal; or

A 3 is D-Bal; or

A 4 is 2Thi, 3Thi, Taz, 2Fua, 2 Pal, 3 Pal, 4 Pal, Orn, Thr(Bzl), or Pff; and

a compound of formula (I) is not H-Inp-D-Bal-D-Trp-Phe-Apc-NH 2 .

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

H-Inp-D-1Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-4 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH 2 ;

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

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

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2 ;

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

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

H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-Pff-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-Phe-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-Taz-Lys-NH 2 ;

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

H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH 2 ;

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

H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH 2 ;

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

H-Inp-D-1Nal-D-Trp-Pff-Lys-NH 2 ;

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

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

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

H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH 2 ;

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

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

H-Inp-D-Bal-D-Bal-2Fua-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-3Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-Pff-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-Phe-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-Taz-Lys-NH 2 ;

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

H-Inp-D-Bal-D-Trp-2Fua-Lys-NH 2 ;

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

H-Inp-D-Bal-D-Trp-3Thi-Lys-NH 2 ;

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

H-Inp-D-Bal-D-Trp-Pff-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-2Fua-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-2Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-3Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-Pff-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-Taz-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-2Fua-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-3Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-Pff-Lys-NH 2 ; or

H-Inp-D-Bip-D-Trp-Taz-Lys-NH 2 ;

or a pharmaceutically acceptable salt thereof.

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

H-Inp-D-1Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-4 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH 2 ;

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

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

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2 ;

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

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

H-Inp-D-2Nal-D-Trp-3Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-3Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-2Fua-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Pff-Lys-NH 2 ;

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

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

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

H-Inp-D-Bal-D-Bal-Phe-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-3Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-Taz-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-2Fua-Lys-NH 2 ;

H-Inp-D-Bal-D-Bal-Pff-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-3Thi-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-2Fua-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-Pff-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-Phe-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-2Thi-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-3Thi-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-Taz-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-2Fua-Lys-NH 2 ;

H-Inp-D-1Nal-D-Bal-Pff-Lys-NH 2 ;

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

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

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

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

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

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

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

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

H-Inp-D-Bip-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-3Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-2Fua-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-Pff-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-2Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-3Thi-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-Taz-Lys-NH 2 ;

H-Inp-D-Bip-D-Bal-2Fua-Lys-NH 2 ; or

H-Inp-D-Bip-D-Bal-Pff-Lys-NH 2 ;

or a pharmaceutically acceptable salt thereof.

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

H-Inp-D-1Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-4 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2 ;

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

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH 2 ;

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

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

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

or a pharmaceutically acceptable salt thereof.

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

H-Inp-D-1Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-4 Pal-Lys-NH 2 ;

H-Inp-D-Bip-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Thr(Bzl)-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH 2 ;

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

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

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2 ;

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

H-Inp-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-Inp-D-1Nal-D-Trp-3 Pal-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH 2 ;

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

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

H-Inp-D-1Nal-D-Trp-Taz-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2 ;

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

H-Inp-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-Inp-D-2Nal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-2Thi-Lys-NH 2 ;

H-Inp-D-Bal-D-Trp-Phe-Lys-NH 2 ;

H-Inp-D-1Nal-D-Trp-2Thi-Lys-NH 2 ;

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

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2 ;

or a pharmaceutically acceptable salt thereof.

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

H-Inp-D-2Nal-D-Trp-2Thi-Lys-NH 2 ;

or a pharmaceutically acceptable salt thereof.

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

H-Inp-D-Bal-D-Trp-Taz-Lys-NH 2 ;

or a pharmaceutically acceptable salt thereof.

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

H-Inp-D-2Nal-D-Trp-Orn-Lys-NH 2 ;

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH 2 ;

H-Inp-D-Dip-D-Trp-Phe-Lys-NH 2 ; or

H-Inp-D-Bpa-D-Trp-Phe-Lys-NH 2 ;

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 10 , wherein said compound is according to the formula:

H-Inp-D-2Nal-D-Trp-Pff-Lys-NH 2 ; or

H-Inp-D-Dip-D-Trp-Phe-Lys-NH 2 ;

or a pharmaceutically acceptable salt thereof.

12. A compound according to the formula:

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

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

or a pharmaceutically acceptable salt thereof.

Assignments (6)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 8, 2018
From: DONG, ZHENG XIN
To: BIOMEASURE, INCORPORATED
Reel/Frame 044556/0126 →
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR NAME PREVIOUSLY RECORDED ON REEL 296336 FRAME 0777. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Jan 5, 2016
From: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
To: IPSEN PHARMA S.A.S.
Reel/Frame 037430/0194 →
CORRECTIVE ASSIGNMENT TO CORRECT THE ADDRESS PREVIOUSLY RECORDED ON REEL 023034 FRAME 0251. ASSIGNOR(S) HEREBY CONFIRMS THE ADDRESS SHOULD BE 65 QUAI GEORGES GORSE, 92100 BOULOGNE-BILLANCOURT, FRANCE. Recorded Jan 16, 2013
From: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATION SCIENTIFIQUES (S.C.R.A.S.)
To: IPSEN PHARMA S.A.S.
Reel/Frame 029636/0777 →
CHANGE OF NAME Recorded Jul 31, 2009
From: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATION SCIENTIFIQUES (S.C.R.A.S.)
To: IPSEN PHARMA S.A.S.
Reel/Frame 023034/0251 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 18, 2008
From: BIOMEASURE, INCORPORATED
To: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.
Reel/Frame 021402/0410 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 15, 2008
From: DONG, ZHENG XIN
To: BIOMEASURE, INCORPORATED
Reel/Frame 021399/0643 →