Method for improving leptin resistance

Patent metadata

Field	Value
Publication number	US-9931351-B2
Application number	US-201414916085-A
Country	US
Kind code	B2
Filing date	Sep 3, 2014
Priority date	Sep 4, 2013
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

The present invention provides a compound of formula (I) which improves leptin resistance, a pharmaceutical composition comprising the compound, a method for manufacturing a pharmaceutical for improving leptin resistance comprising using the compound, use of the compound for manufacturing a pharmaceutical for improving leptin resistance, and a method for improving leptin resistance comprising administering the compound or the pharmaceutical composition. The improvement of leptin resistance can lead treatment and/or prevention of a disorder associated with leptin resistance, including, particularly, metabolic disorder, obesity, hyperphagia, steatosis, diabetes, and dyslipidemia.

First claim

The invention claimed is:

1. A method of reducing a body weight of a subject suffering from leptin resistance comprising administering to the subject an effective amount of a compound of formula (I):

wherein: R 1 is phenyl or sulfur-containing heteroaryl, wherein the sulfur-containing heteroaryl is an aromatic group of from 3 to 12 carbon atoms and 1 to 4 sulfur atoms within the ring, and the phenyl or sulfur-containing heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, alkoxy, hydroxy- or carboxy-substituted alkoxy, alkylthio, CHO, C(O)-alkyl, C(O)-alkylene-carboxyl, C(O)-alkylene-carboxy ester, cyano, and oxo, and R 2 is hydrogen, or an oxide, ester, pharmaceutically acceptable salt, or solvate thereof.

2. The method according to claim 1 , wherein the subject is a human, a dog or a cat.

3. The method according to claim 1 , wherein R 1 is, thiophenyl, benzothiophenyl, dibenzothiophenyl, or thianthrenyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, and alkyl.

4. The method according to claim 1 , wherein R 1 is benzothiophenyl, dibenzothiophenyl, or thianthrenyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halo and alkyl.

5. The method according to claim 1 , wherein R 1 is benzothiophenyl or dibenzothiophenyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halo and alkyl.

6. The method according to claim 1 , wherein R 1 is dibenzothiophenyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halo and alkyl.

7. The method according to claim 1 , wherein R 1 is phenyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, alkoxy, hydroxy- or carboxy-substituted alkoxy, alkylthio, CHO, C(O)-alkyl, C(O)-alkylene-carboxyl, C(O)-alkylene-carboxy ester, and cyano.

8. The method according to claim 1 , wherein R 1 is phenyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, alkoxy, and alkylthio.

9. The method according to claim 1 , wherein R 1 is phenyl which may be substituted with 1 to 3 substituents independently selected from the group consisting of halo and alkyl.

10. The method according to claim 1 , wherein the compound is selected from the group consisting of
4-amino-3-(6-phenylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-(6-p-tolylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-(6-m-tolylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-(6-o-tolylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
3-[6-(2-acetylphenyl)pyridine-3-ylazo]-4-aminonaphthalene-1-sulfonic acid,
3-[6-(3-acetylphenyl)pyridine-3-ylazo]-4-aminonaphthalene-1-sulfonic acid,
3-[6-(4-acetylphenyl)pyridine-3-ylazo]-4-aminonaphthalenesulfonic acid,
4-amino-3-[6-(2,4-dichlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-trifluoromethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-trifluoromethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-chlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(3-chlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-chlorophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-methoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-methoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-isopropoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-isopropoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(3-methoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2,3-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2,5-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(3,5-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(3-trifluoromethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
methyl 4-{4-[5-(1-amino-4-sulfonaphthalene-2-ylazo)pyridine-2-yl]phenyl}-4-oxobutyrate,
4-amino-3-[6-(3-cyanophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-cyanophenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(3,5-bistrifluoromethylphenyl)pyridine-3-ylazo]naphthalenesulfonic acid,
4-amino-3-[6-(2-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(5-fluoro-2-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-fluoro-6-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-fluoro-2-propoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(5-fluoro-2-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-fluoro-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-butoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-hexyloxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(4-butylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-hydroxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-{6-[2-(6-hydroxyhexyloxy)phenyl]pyridine-3-ylazo}naphthalene-1-sulfonic acid,
4-{2-[5-(1-amino-4-sulfonaphthalene-2-ylazo)pyridine-2-yl]phenoxy}butyric acid,
4-amino-3-{6-[2-(3-hydroxypropoxy)phenyl]pyridine-3-ylazo}naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-isobutoxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(5-chloro-2-hydroxyphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(2,6-dimethylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(3-formyl-2-isopropoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-(6-thiophene-2-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-(6-thiophene-3-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-(6-dibenzothiophene-4-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-(6-benzo[b]thiophene-3-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-(6-dibenzothiophene-4-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid potassium salt
4-amino-3-[6-(5,5-dioxo-5H-5λ6-dibenzothiophene-4-yl)pyridine-3-ylazo]naphthalene-1-sulfonic acid,
4-amino-3-(6-thianthrene-1-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid,
4-amino-3-[6-(2-butoxy-3-ethoxy-5-formylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid, and
4-amino-3-[6-(2-ethoxy-3-formyl-5-methylphenyl)pyridine-3-ylazo]naphthalene-1-sulfonic acid.

11. The method according to claim 1 , wherein the compound is 4-amino-3[6-(4-fluoro-2-methylphenyppyridine-3-ylazo]naphthalene-1-sulfonic acid.

12. The method according to claim 1 , wherein the compound is 4-amino-3-(6-dibenzothiophene-4-ylpyridine-3-ylazo)naphthalene-1-sulfonic acid.

13. A method of treating a disorder associated with leptin resistance selected from a metabolic disorder, obesity, hyperphagia, steatosis, diabetes, and dyslipidemia in a subject suffering from leptin resistance by reducing the body weight of the subject in accordance with the me

Assignees

• Univ Kyoto

Inventors

• Kakizuka Akira
• Ebihara Ken
• Abe Megumi
• Ebihara Chihiro

Classifications

• A61P43/00

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title