Compositions and methods for treatment of insulin resistance

Patent metadata

Field	Value
Publication number	US-2020392075-A1
Application number	US-201916977676-A
Country	US
Kind code	A1
Filing date	Mar 7, 2019
Priority date	Mar 7, 2018
Publication date	Dec 17, 2020
Grant date	—

Abstract

Compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is selected from the group consisting of —O—, —S—, —NR 14 —O—, —O—NR 14 —, —NR 14 —NR 15 — and —S—S—; R 1 -R 15 , m, n, o, p, q and r are as defined herein, are provided for treatment for increasing insulin sensitivity, reducing insulin resistance, preventing insulin resistance and treating insulin resistance disorders.

First claim

We claim:

1 . A method for increasing insulin sensitivity, reducing insulin resistance and/or preventing insulin resistance in a subject in need thereof comprising administering to the subject an effective amount of a compound according to Formula I, or pharmaceutically acceptable salt thereof:

wherein:
X is selected from the group consisting of —O—, —S—, —NR 14 —O—, —O—NR 14 —, —NR 14 —NR 15 — and —S—S—;

R 1 is selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, —(C 1 -C 8 )alkenyl, —(C 1 -C 8 )alkynyl, unsubstituted or substituted -ara(C 1 -C 6 )alkyl, unsubstituted or substituted -heteroara(C 1 -C 6 )alkyl, where the substituents on said substituted ara(C 1 -C 6 )alkyl and substituted heteroara(C 1 -C 6 )alkyl are selected from the group consisting of halogen, —CN, —NO 2 , —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl)] 2 , —OH, halo(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —SH, thio(C 1 -C 6 )alkyl, —SONH 2 , —SO 2 NH 2 , —SO—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —NHSO 2 (C 1 -C 6 )alkyl, and —NHSO 2 NH 2 ;
R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 12 , and R 13 are independently selected from the group consisting of hydrogen and —(C 1 -C 6 )alkyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl and —OH, provided that both R 4 and R 5 cannot be —OH;
R 10 and R 11 are independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl and —OH, provided that both R 10 and R 11 cannot be —OH;
R 14 and R 15 are independently selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, —(C 1 -C 8 )alkenyl, —(C 1 -C 8 )alkynyl, unsubstituted or substituted -ara(C 1 -C 6 )alkyl, unsubstituted or substituted -heteroara(C 1 -C 6 )alkyl, where the substituents on said substituted ara(C 1 -C 6 )alkyl and substituted heteroara(C 1 -C 6 )alkyl am selected from the group consisting of halogen, —CN, —NO 2 , —NH 2 , —OH, halo(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —SH, thio(C 1 -C 6 )alkyl, —SONH 2 , —SO 2 NH 2 , —SO—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —NHSO 2 (C 1 -C 6 )alkyl, and —NHSO 2 NH 2 ;
m is 1, 2 , 3 or 4;
n is 0, 1, 2, 3 or 4;
o is 0, 1, 2, 3 or 4;
p is 1, 2 , 3 or 4;
q is 0, 1, 2, 3 or 4; and
r is 0, 1, 2, 3 or 4.

2 . The method according to claim 1 wherein X is selected from the group consisting of —O—, —S—, and —S—S—.

3 . The method according to claim 2 wherein X is —O— and
(i) the sum of p+q+r is 1, the definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are all H, and the sum of m+n+o is 3 or greater;
(ii). the sum of p+q+r is 2, the sum of m+n+o is 2, and R 1 cannot be ethyl; or
(iii) the sum of p+q+r is 2, the definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are all H, and the sum of m+n+o is 3 or greater.

4 . The method according to claim 2 wherein X is —S— and
(i) the sum of p+q+r is 1, the definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are all H, and the sum of m+n+o is 5 or greater; or
(ii) the sum of p+q+r is 2, the definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are all H, and the sum of m+n+o is 4 or greater.

5 . The method according to claim 2 wherein X is —S—S and R1 is hydrogen, and wherein the sum of m+n+o is 2, 3 or 4 and/or the sum of p+q+r is 1, 2, 3 or 4.

6 . The method according to claim 1 wherein X is selected from the group consisting of —NR 14 —O—, —O—NR 14 —, and —NR 14 —NR 15 —.

7 . The method according to claim 6 wherein X is —NR 14 —O—, and R 1 and R 14 are hydrogen, and wherein the sum of m+n+o is 2, 3 or 4 and/or the sum of p+q+r is 1, 2 or 3.

8 . The method according to claim 6 wherein X is —O—NR 14 —, and R 1 and R 14 are hydrogen, and wherein the sum of m+n+o is 2, 3 or 4 and/or the sum of p+q+r is 1, 2, 3 or 4.

9 . The method according to claim 6 wherein X is —NR 14 —NR 15 —, R 1 , R 14 and R 15 are hydrogen, and wherein the sum of m+n+o is 2, 3 or 4 and/or the sum of p+q+r is 1, 2, 3 or 4.

10 . The method according to claim 2 , wherein each of R 2 through R 13 is independently selected from hydrogen and —(C 1 -C 8 )alkyl.

11 . The method according to anyone of claims 1 - 10 , wherein the compound of Formula I is the L-isomer substantially free of the D-isomer.

12 . The method according to claim 1 , wherein the compound of Formula I is (S)-2-amino-3-(3-aminopropoxy)propanoic acid.

13 . A method of treating an insulin resistance disorder in a subject in need thereof comprising administering to the individual an effective amount of a compound according to Formula I, or pharmaceutically acceptable salt thereof:

wherein:
X is selected from the group consisting of —O—, —S—, —NR 14 —O—, —NR 14 —, —NR 14 —NR 15 — and —S—S—;

R 1 is selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, —(C 1 -C 8 )alkenyl, —(C 1 -C 8 )alkynyl, unsubstituted or substituted -ara(C 1 -C 6 )alkyl, unsubstituted or substituted -heteroara(C 1 -C 6 )alkyl, where the substituents on said substituted ara(C 1 -C 6 )alkyl and substituted heteroara(C 1 -C 6 )alkyl are selected from the group consisting of halogen, —CN, —NO 2 , —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl)] 2 , —OH, halo(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —SH, thio(C 1 -C 6 )alkyl, —SONH 2 , —SO 2 NH 2 , —SO—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —NHSO 2 (C 1 -C 6 )alkyl, and —NHSO 2 NH 2 ;
R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 12 , and R 13 are independently selected from the group consisting of hydrogen and —(C 1 -C 6 )alkyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl and —OH, provided that both R 4 and R 5 cannot be —OH;
R 10 and R 11 are independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl and —OH, provided that both R 10 and R 11 cannot be —OH;
R 14 and R 15 are independently selected from the group consisting of hydrogen, —(C 1 -C 8 )alkyl, —(C 1 -C 8 )alkenyl, —(C 1 -C 8 )alkynyl, unsubstituted or substituted -ara(C 1 -C 6 )alkyl, unsubstituted or substituted -heteroara(C 1 -C 6 )alkyl, where the substituents on said substituted ara(C 1 -C 6 )alkyl and substituted heteroara(C 1 -C 6 )alkyl are selected from the group consisting of halogen, —CN, —NO 2 , —NH 2 , —OH, halo(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —SH, thio(C 1 -C 6 )alkyl, —SONH 2 , —SO 2 NH 2 , —SO—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —NHSO 2 (C 1 -C 6 )alkyl, and —NHSO 2 NH 2 ;
m is 1, 2 , 3 or 4;
n is 0, 1, 2, 3 or 4;
o is 0, 1, 2, 3 or 4;
p is 1, 2 , 3 or 4;
q is 0, 1, 2, 3 or 4; and
r is 0, 1, 2, 3 or 4.

14 . The method according to claim 13 , wherein the insulin resistance disorder is selected from the group consisting of diabetes, type 2 diabetes, pre-diabetes, obesity, metabolic syndrome, insulin resistance, insulin-resistance syndromes, syndrome X, high blood pressure, hypertension, high blood cholesterol, hyperlipidemia, dyslipidemia, atherosclerotic disease, hyperglycemia, hyperinsulinemia, hyperproins

Assignees

• Univ Temple

Inventors

• Merali Salim
• Barrero Carlos A
• Childers Wayne E
• Morton George C

Classifications

• C07C229/22 Primary

  the carbon skeleton being further substituted by oxygen atoms · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07C271/22 Primary

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• A61K31/197

  the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) · CPC title

• C07B2200/07

  Optical isomers · CPC title