Substituted aminothiazole derivatives, pharmaceutical compositions, and methods of use
View Patent ↗Substituted aminothiazole derivatives, methods of their preparation, pharmaceutical compositions comprising a substituted aminothiazole, and methods of use in treating human or animal disorders. The compounds may be useful as inhibitors of action of AgRP on a melanocortin receptor and thus may be useful for the management, treatment, control, or the adjunct treatment of diseases which may be responsive to the modulation of melanocortin receptors including obesity-related disorders.
1. A compound of the following formula or a pharmaceutically acceptable salt thereof:
wherein
n is 1, 2 or 3;
R 1 is selected from the group consisting of:
wherein
R 2 is selected from the group consisting of: —C 1-4 alkyl and -L 1 -C 1-4 alkyl, wherein L 1 is selected from the group consisting of —S—, and —SO 2 —,
R 3 is selected from the group consisting of: hydrogen and —C 1-4 alkyl,
R 4 is selected from the group consisting of: hydrogen and —C 1-4 alkyl,
wherein the alkyl groups in R 2 , R 3 , and R 4 are optionally substituted with one or more substituents independently selected from the group consisting of: fluoro and chloro;
L 2 is a direct bond;
R 5 is
wherein
each of R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 is independently R a , and
R 6 is selected from the group consisting of: hydrogen and methyl, wherein the methyl group is optionally substituted with one or more halogens;
wherein
R a is selected from the group consisting of: -hydrogen, -halogen, —C 1-6 alkyl, -phenyl, cycloalkyl, and —O—C 1-6 alkyl,
wherein the alkyl, cycloalkyl, and phenyl groups are each optionally substituted with one or more substituents independently selected from R b ; and
R b is selected from the group consisting of: halogen, —C 1-6 alkyl, and -halo-C 1-4 alkyl.
2. The compound of claim 1 , wherein n is 2; and
R 1 is
wherein
R 2 is selected from the group consisting of: —C 1-4 alkyl and -L 1 -C 1-4 alkyl, wherein L 1 is selected from the group consisting of —S—, and —SO 2 —,
R 3 is selected from the group consisting of: hydrogen and —C 1-4 alkyl, and
R 4 is selected from the group consisting of: hydrogen and —C 1-4 alkyl, wherein the alkyl groups in R 2 , R 3 , and R 4 are optionally substituted with one or more substituents independently selected from the group consisting of: fluoro and chloro.
3. The compound of claim 2 , wherein R 3 and R 4 are hydrogen, and R 2 is methyl.
4. The compound of claim 1 , wherein R 9 , R 10 , R 11 , R 12 , R 13 , R 16 , R 17 , R 18 and R 19 are hydrogen, and at least one of R 14 and R 15 is not hydrogen.
5. The compound of claim 4 , wherein R 14 is hydrogen, and
R 15 is selected from the group consisting of: -halogen, —C 1-6 alkyl, -phenyl, —C 5-6 cycloalkyl, and —O—C 1-6 alkyl,
wherein the alkyl, cycloalkyl, and phenyl groups are each optionally substituted one or more times with substituents independently selected from R b .
6. The compound of claim 5 , wherein R 15 is selected from the group consisting of: -methyl, -ethyl, -propyl, -isopropyl, and -tert-butyl.
7. The compound of claim 1 , wherein
n is 2;
R 1 is
wherein
R 2 is methyl; and
R 3 and R 4 are hydrogen;
L 2 is a direct bond; and
R 5 is
wherein
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 18 and R 19 are hydrogen, and R 15 is selected from the group consisting of: -methyl, -ethyl, -propyl, -isopropyl, and -tert-butyl.
8. The compound of claim 1 , wherein
n is 2;
R 1 is selected from the group consisting of:
wherein
R 2 is —C 1-4 alkyl,
R 3 is hydrogen or —C 1-4 alkyl, and
R 4 is hydrogen or —C 1-4 alkyl;
L 2 is a direct bond;
R 5 is
wherein
R 9 , R 10 , R 11 , R 12 , R 13 , R 16 , R 17 , R 18 and R 19 are hydrogen;
and at least one of R 14 and R 15 is not hydrogen; and
R 6 is hydrogen;
R a is selected from the group consisting of: -hydrogen, —C 1-6 alkyl, -phenyl, and -cyclohexyl,
wherein the alkyl, cyclohexyl, and phenyl groups are each optionally substituted with one or more substituents independently selected from R b ; and
R b is —C 1-6 alkyl.
9. The compound of claim 1 , wherein
n is 2;
R 1 is
wherein
R 2 ethyl or methyl, and
R 3 and R 4 are hydrogen;
L 2 is a direct bond;
R 5 is
wherein
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 16 , R 17 , R 18 and R 19 are hydrogen; and
R 15 is selected from the group consisting of: tert-butyl, isopropyl, and phenyl; and
R 6 is hydrogen.
10. The compound of claim 1 , wherein R 2 is methyl.
11. A compound, which is a compound selected from the group consisting of:
3-[[4-(trans-4-tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
3-[[4-(4-isopropyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
3-{(5-Methyl-thiophen-2-ylmethyl)-[4-(4-trifluoromethyl-cyclohexyl)-thiazol-2-yl]-amino}-propionic acid;
3-[[4-(4-Ethyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
3-{(5-Methyl-thiophen-2-ylmethyl)-[4-(4-propyl-cyclohexyl)-thiazol-2-yl]-amino}-propionic acid;
3-[[4-(4,4-difluoro-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
3-[[4-(4-tert-Butyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
3-[[4-(4-Methoxy-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
3-{(5-methyl-thiophen-2-ylmethyl)-[4-(trans-4-phenyl-cyclohexyl)-thiazol-2-yl]-amino}-propionate;
3-[[4-(4,4-Dimethyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
3-[(4-bicyclohexyl-4-yl-thiazol-2-yl)-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid; and
3-[{4-[4-(4-fluoro-phenyl)-cyclohexyl]-thiazol-2-yl}-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid;
or a pharmaceutically acceptable salt thereof.
12. 3-[[4-(trans-4-Tert-butyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.
14. A method of treatment of a disorder comprising: administering to a subject a therapeutically effective amount of a compound of claim 1 , wherein the disorder is selected from the group consisting of female sexual dysfunction, and male sexual dysfunction.
15. A method of treatment comprising: administering to a subject a therapeutically effective amount of a compound of claim 1 , wherein the compound is administered in an amount sufficient to induce weight loss, halt weight gain, or decrease the rate of weight gain in the subject.
16. A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.
17. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.