Selective small molecule peptidomimetic melanocortin ligands

Patent metadata

Field	Value
Publication number	US-11932628-B2
Application number	US-202217567201-A
Country	US
Kind code	B2
Filing date	Jan 3, 2022
Priority date	Jan 4, 2021
Publication date	Mar 19, 2024
Grant date	Mar 19, 2024

Abstract

The invention provides compounds having the general formula I:

and salts thereof, wherein the variables R 1 , R 2 , R 3 and R 4 have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

First claim

What is claimed is:

1. A compound of formula I:

wherein:
R 1 is H, or C 1-30 alkyl; wherein the C 1-30 alkyl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, nitro, cyano, C 1-6 alkoxy, —NR a 2 , —NHC(═NH)NR a 2 , —C(═O)NR a 2 , —COOR a , and —SR a ;
R 2 is H, C 1-8 alkyl or -L 2 -A 2 ; wherein the C 1-8 alkyl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, nitro, cyano, C 1-6 alkoxy, —NR b 2 , —NHC(═NH)NR b 2 , —C(═O)NR b 2 , —COOR b , and —SR b ;
R 3 is H, or C 1-30 alkyl; wherein the C 1-30 alkyl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, nitro, cyano, C 1-6 alkoxy, —NR c 2 , —NHC(═NH)NR c 2 , —C(═O)NR c 2 , —COOR c , and —SR c ;
R 4 is H, C 1-30 alkyl or -L 4 -A 4 ; wherein the C 1-30 alkyl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, nitro, cyano, C 1-6 alkoxy, —NR d 2 , —NHC(═NH)NR d 2 , —C(═O)NR d 2 , —COOR d , and −SR d ;
L 2 is absent or C 1-4 alkylene;
L 4 is absent or C 1-4 alkylene;
A 2 is cycloalkyl, aryl, or heteroaryl; wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and phenyl;
A 4 is cycloalkyl; wherein the cycloalkyl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and phenyl;
each R a is independently H or C 1-6 alkyl;
each R b is independently H or C 1-6 alkyl;
each R c is independently H or C 1-6 alkyl; and
each R d is independently H or C 1-6 alkyl;
or a salt thereof.

2. The compound of claim 1 which is a compound of formula Ia:

or a salt thereof.

3. The compound of claim 1 , wherein R 1 is selected from the group consisting of:
a) a side chain of an amino acid selected from the group consisting of: D-Leu, D-Val, D-Ile, D-Nle, D-Nva, D-Thr, D-Ala, Gly, Ala, D-Ser, Val, Nva, Thr, Leu, Nle, Ile, and Ser; and
b) C 1-30 alkyl, substituted with one or more COOH.

4. The compound of claim 1 , wherein R 2 is a side chain of an amino acid having 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.

5. The compound of claim 4 , wherein the amino acid is selected from the group consisting of: D-Cha, Cha, D-Nle, D-Phe, D-Ser, D-Leu, D-Nva, Ala(2-naphtyl), Ser, Phg, D-Ala(2-naphtyl), Val, Ile, D-Thr, Nle, Tyr, D-Tyr, D-Ile, D-Ala, Ala, D-Val, Phe, Nva, Gly, and Thr.

6. The compound of claim 1 , wherein:
R 2 is -L 2 -A 2 ;
L 2 is C 1-4 alkylene; and
A 2 is cycloalkyl or aryl.

7. The compound of claim 1 , wherein R 2 is:

8. The compound of claim 1 , wherein R 3 is a side chain of an amino acid selected from the group consisting of: D-Thr, D-Nva, D-Val, D-Ile, Gly, D-Ala, D-Leu, D-Nle, D-Ser, Ala, Nle, Thr, Val, Nva, Ile, and Leu.

9. The compound of claim 1 , wherein R 3 is C 1-8 alkyl which is optionally substituted with hydroxy.

10. The compound of claim 1 , wherein:
R 4 is C 1-8 alkyl or -L 4 -A 4 ;
L 4 is absent or C 1-4 alkylene; and
A 4 is cycloalkyl; wherein the cycloalkyl is optionally substituted with one or more groups selected from the group consisting of halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and phenyl.

11. The compound of claim 1 , wherein R 4 is selected from the group consisting of:
—CH 2 CH 2 CH(CH 3 ) 2 ,

12. The compound of claim 1 which is selected from the group consisting of:

or a salt thereof.

13. A pharmaceutical composition comprising a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A dietary supplement comprising a compound of formula I as described in claim 1 , or a salt thereof.

15. A method of treating obesity, anorexia, cachexia, failure to thrive, modulation of food intake and the desire to eat or a disease associated with obesity, anorexia, cachexia, failure to thrive, modulation of food intake and the desire to eat in humans or in an animal in need thereof, comprising administering an effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, to the human or animal.

16. The method of claim 15 , wherein the disease associated with obesity is diabetes, cardiovascular disease or hypertension.

17. A method of modulating the activity of a melanocortin receptor in vitro or in vivo comprising contacting the receptor with an effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof.

18. The method of claim 17 , wherein the melanocortin receptor is melanocortin-3 receptor (MC3R).

19. A method of selectively activating melanocortin-3 receptor (MC3R) over melanocortin-4 receptor (MC4R) in vitro or in vivo comprising contacting the receptors with an effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof.

20. A method of modulating appetite in an animal in need thereof, comprising administering an effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, to the animal.

21. The compound of claim 1 having the structure:

22. The compound of claim 1 having the structure:

Assignees

• Univ Minnesota
• Torrey Pines Inst For Molecular Studies

Inventors

• Haskell-Luevano Carrie
• Doering Skye Ross
• Giulianotti Marcello A
• Pinilla Clemencia
• Santos Radleigh G
• Houghten Richard A

Classifications

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/2027

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61K9/2059

  Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin · CPC title