Melanocortin receptor-specific peptides

Patent metadata

Field	Value
Publication number	US-9040663-B2
Application number	US-201313886864-A
Country	US
Kind code	B2
Filing date	May 3, 2013
Priority date	Jun 8, 2009
Publication date	May 26, 2015
Grant date	May 26, 2015

Abstract

The invention relates to melanocortin receptor-specific cyclic peptides of Formula (I)

or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , x and y are as defined in the specification. These compounds are particularly useful in the treatments of energy homeostasis and metabolism related (e.g. diabetes), food intake related and/or energy balance and body weight related diseases, disorders and/or conditions, including obesity, overweight and diseases, disorders and/or conditions associated with obesity and/or overweight, such as type 2 diabetes and metabolic syndrome.

First claim

The invention claimed is:

1. A cyclic peptide of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —NH—C(═O)— or —C(═O)—NH—;
R 2 is —H or —CH 2 —, wherein if R 2 is —CH 2 —, then R 2 forms with R 3 a pyrrolidine ring, wherein the pyrrolidine ring is optionally substituted with —OH;
R 3 is —(CH 2 ) 2 — if R 2 is —CH 2 —, and otherwise R 3 is selected from the group consisting of: —(CH 2 ) 1-4 NH 2 , CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OH, —CH(OH)CH 3 , —(CH 2 ) 1-2 CONH 2 , —CH 2 (imidazole), —(CH 2 ) 1-2 CO 2 H, —CH 2 OBz, —CH(CH 3 )OBz, —CH 2 Ph(CONH 2 ), —(CH 2 ) 2 NHCOCH 3 , —(CH 2 ) 3 NHC(═NH)NH 2 and —(CH 2 ) 2 SO 2 CH 3 ;
R 4a , R 4b and R 4c are each independently selected from the group consisting of: —H, —Cl, —F, —CN, —OH, —CF 3 , —CH 3 , —OCH 3 , —NO 2 , -Ph and —NH 2 , with the provisos that at least one of R 4a , R 4b and R 4c is not hydrogen and that R 4a , R 4b and R 4c cannot all be —Cl, —CH 3 or —OCH 3
R 5 is —OH or —N(R 6a )(R 6b );
R 6a and R 6b are each H;
x is 1 to 4; and
y is 1 to 4.

2. The cyclic peptide of claim 1 which is of Formula (II):

or a pharmaceutically acceptable salt thereof.

3. The cyclic peptide of claim 1 ,
wherein:
R 1 is —C(═O)—NH—;
x is 2; and
y is 3.

4. The cyclic peptide of claim 1 ,
wherein:
R 1 is —NH—C(═O)—;
x is 3; and
y is 2.

5. The cyclic peptide of claim 1 ,
wherein:
R 2 is H or —CH 2 —, wherein if R 2 is —CH 2 —, then R 2 forms with R 3 a pyrrolidine ring, wherein the pyrrolidine ring is optionally substituted with —OH; and
R 3 is —(CH 2 ) 2 — if R 2 is —CH 2 —, and otherwise R 3 is selected from the group consisting of: —(CH 2 ) 1-4 NH 2 , —CH 3 , —CH 2 OH, —CH(OH)CH 3 , —(CH 2 ) 1-2 CONH 2 , —(CH 2 ) 2 NHCOCH 3 , —(CH 2 ) 3 NHC(═NH)NH 2 and —(CH 2 ) 2 SO 2 CH 3 .

6. The cyclic peptide of claim 1 ,
wherein:
R 2 is H; and
R 3 is selected from the group consisting of:

7. The cyclic peptide of claim 1 , wherein R 2 and R 3 together form an unsubstituted pyrrolidine ring.

8. The cyclic peptide of claim 1 wherein R 4a is in the 4-position and is —C≡N and wherein R 4b and R 4c are each —H.

9. The cyclic peptide of claim 1 , wherein R 4a is in the 4-position and is —F and wherein R 4b and R 4c are each —H.

10. A cyclic peptide selected from the group consisting of:
Ac-Arg-cyclo(Glu-Asn-D-Phe(4-CN)-Arg-Trp-Orn)-NH 2 (SEQ ID NO:48);
Ac-Arg-cyclo(Glu-Gln-D-Phe(4-CN)-Arg-Trp-Orn)-NH 2 (SEQ ID NO:51);
Ac-Arg-cyclo(Glu-Asn-D-Phe(4-F)-Arg-Trp-Orn)-NH 2 (SEQ ID NO:74);
Ac-Arg-cyclo(Glu-Asn-D-Phe(4-CN)-Arg-Trp-Orn)-OH (SEQ ID NO:90);
Ac-Arg-cyclo(Glu-Gln-D-Phe(4-CN)-Arg-Trp-Orn)-OH (SEQ ID NO:91);
Ac-Arg-cyclo(Glu-Gln-D-Phe(4-F)-Arg-Trp-Orn)-NH 2 (SEQ ID NO:97);
Ac-Arg-cyclo(Glu-Pro-D-Phe(4-CN)-Arg-Trp-Orn)-NH 2 (SEQ ID NO:44);
Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-NH 2 (SEQ ID NO:72); and
Ac-Arg-cyclo(Glu-Pro-D-Phe(4-F)-Arg-Trp-Orn)-OH (SEQ ID NO:107);
or a pharmaceutically acceptable salt of any of the foregoing.

11. A pharmaceutical composition comprising a cyclic peptide or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.

Assignees

• Astrazeneca Ab

Inventors

• Dodd John H
• Shi Yi-Qun
• Yang Wei

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title