Compounds for the treatment of metabolic disorders
View Patent ↗Agents useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, polycystic ovary syndrome, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis are disclosed, compound of the formula (I): wherein n is 1 or 2; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0 or 1; t is 0 or 1; R 1 is alkyl having from 1 to 3 carbon atoms; R 2 is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms; R 3 and R 4 together are alkyl having two or three carbon atoms; or R 3 and R 4 are the same as each other and each is methyl or ethyl; R 5 is hydrogen or alkyl having from one to six carbon atoms. A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, hydroxy, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or A is cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or A is a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula (I) by a ring carbon. Alternatively, the agent can be a pharmaceutically acceptable salt of the compound of Formula (I).
1. A compound of the formula:
wherein
n is 1;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
q is 0 or 1;
t is 0;
R 1 is alkyl having from 1 to 3 carbon atoms;
R 2 is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms;
R 3 and R 4 together are alkyl having two or three carbon atoms; or R 3 and R 4 are the same as each other and each is methyl or ethyl;
R 5 is hydrogen or alkyl having from one to six carbon atoms;
A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, hydroxy, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or
cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or
a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula I by a ring carbon;
or a pharmaceutically acceptable salt of the compound.
2. The compound or salt of claim 1 , wherein q is 0; R 2 is hydrogen; R 5 is hydrogen, methyl or ethyl; m is 0, 2 or 4; and
A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, hydroxy, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy.
3. The compound or salt of claim 2 , wherein A is 2,6-dimethylphenyl.
4. The compound or salt of claim 3 , wherein R 3 and R 4 are the same as each other and each is methyl or ethyl.
5. The compound or salt of claim 4 wherein the compound is selected from the group consisting of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4,4-dimethoxybutanoic acid and 2-(3-(2,6-Dimethylbenzyloxy)phenyl)-2,2-dimethoxyacetic acid.
6. The compound or salt of claim 3 , wherein R 3 and R 4 together are alkyl having two or three carbon atoms.
7. The compound or salt of claim 6 , wherein the compound is selected from the group consisting of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4,4-(1,3-dioxolan-2-yl)butanoic acid and 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4,4-(1,3-dioxan-2-yl)butanoic acid.
8. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and from one milligram to four hundred milligrams of a biologically active agent,
wherein the agent is a compound of the formula:
wherein
n is 1;
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
q is 0 or 1;
t is 0;
R 1 is alkyl having from 1 to 3 carbon atoms;
R 2 is hydrogen, halo, alkyl having from 1 to 3 carbon atoms, or alkoxy having from 1 to 3 carbon atoms;
R 3 and R 4 together are alkyl having two or three carbon atoms; or R 3 and R 4 are the same as each other and each is methyl or ethyl;
R 5 is hydrogen or alkyl having from one to six carbon atoms;
A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, hydroxy, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or
cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or
a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula I by a ring carbon;
or a pharmaceutically acceptable salt of the compound.
9. The pharmaceutical composition of claim 8 , wherein q is 0; R 2 is hydrogen; R 5 is hydrogen, methyl or ethyl; m is 0, 2 or 4; and
A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, hydroxy, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy.
10. The pharmaceutical composition of claim 9 , wherein A is 2,6-dimethylphenyl.
11. The pharmaceutical composition of claim 10 , wherein R 3 and R 4 are the same as each other and each is methyl or ethyl.
12. The pharmaceutical composition of claim 11 wherein the compound is selected from the group consisting of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4,4-dimethoxybutanoic acid and 2-(3-(2,6-Dimethylbenzyloxy)phenyl)-2,2-dimethoxyacetic acid.
13. The pharmaceutical composition of claim 10 , wherein R 3 and R 4 together are alkyl having two or three carbon atoms.
14. The pharmaceutical composition of claim 13 , wherein the compound is selected from the group consisting of 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4,4-(1,3-dioxolan-2-yl)butanoic acid and 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4,4-(1,3-dioxan-2-yl)butanoic acid.
15. The pharmaceutical composition of claim 8 in oral dosage form.