Amidopyridinol derivative or pharmaceutically acceptable salt thereof and pharmaceutical composition comprising same as active component

Patent metadata

Field	Value
Publication number	US-9802897-B2
Application number	US-201414784957-A
Country	US
Kind code	B2
Filing date	Apr 21, 2014
Priority date	Apr 19, 2013
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

An amidopyridinol derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including the amidopyridinol derivative as an active component represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof have an antiangiogenic effect in a chorioallantoic membrane model, and thus are useful as an agent for preventing or treating diseases associated with angiogenesis, and also have a colitis-inhibitory effect in a model of inflammatory bowel diseases, and thus are useful as an agent for preventing or treating inflammatory bowel diseases. Upon inoculation of lung cancer cells in a chorioallantoic membrane model, the amidopyridinol derivative of Chemical Formula 1 or the pharmaceutically acceptable salt thereof inhibits angiogenesis and tumor growth that are caused by tumorigenesis, and also inhibits the activity of cathepsin S that plays an important role in metastasis and invasion of cancer, and thus is useful as an inhibitor of cancer growth and metastasis.

First claim

The invention claimed is:

1. A compound represented by Chemical Formula 1 below or a pharmaceutically acceptable salt thereof:

wherein, in Chemical Formula 1 above,
R 1 ,R 2 , and R 4 are identical to or different from each other, and are each independently one selected from hydrogen, C1-C4 alkyl, and C1-C4 alkoxy, wherein hydrogen is not simultaneously selected by R 1 , R 2 , and R 4 ,
R 3 is one selected from benzyloxy and hydroxy, and
R 5 is one selected from C1-C15 alkyl substituted or not substituted with one or two substituents selected from halogen, hydroxy, C1-C12 alkoxy, phenoxy, C1-C12 alkylamino, C6-C14 aryl, and C1-C4 alkyl; C6-C14 aryl substituted or not substituted with one or two substituents selected from halogen, hydroxy, C1-C12 alkoxy, C1-C12 alkylamino, and C1-C4 alkyl; C2-C12 alkenyl substituted or not substituted with C6-C14 aryl; C3-C8 cycloalkyl; a 5- to 6-membered monocyclic heterocyclic compound containing one or two heteroatoms from N, S, or O; a heterocyclic compound containing a double ring structure having the 5- to 6-membered monocyclic heterocyclic compound and a phenyl; and naphthalene.

2. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein in the compound of Chemical Formula 1,
R 1 ,R 2 , and R 4 are each independently one selected from hydrogen, C1-C4 alkyland C1-C4 alkoxy, wherein hydrogen is not simultaneously selected by R 1 , R 2 , and R 4 ,
R 3 is one selected from benzyloxy and hydroxy, and
R 5 is selected from C1-C15 alkyl substituted or not substituted with one selected from halogen and C1-C4 alkyl; phenyl substituted with or not substituted with one selected from halogen, hydroxy, C1-C4 alkoxy, and C1-C4 alkyl; C1-C4 alkyl substituted with phenyl or halophenylene; cinnamyl; phenoxymethylene; C3-C8 cycloalkyl; benzodioxole; naphthalene; and thiophene.

3. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is one selected from a N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)amide and a N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)amide.

4. The compound or the pharmaceutically acceptable salt thereof of claim 3 , wherein the N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)amide is one selected from N -(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)acetamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl) dodecanamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-4-chlorobutanamide, N-(5-benzyloxy-3 ,4,6-trimethylpyridine-2-yl)isobutyrylamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-3-methylbutanamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)pivalamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)cyclopentanecarboxamide N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)cyclohexanecarboxamide N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-penylacetamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-3-phenylpropanamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl) benzamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-4-fluorobenzamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-4-methoxybenzamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-4-(tert-butyl)benzamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)benzo[d][1,3]dioxo 1 -5-carboxamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-1-naphthamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)thiophene-2-carboxamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-ethylbutanamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-phenoxyacetamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-phenylbutanamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2,4,6-trimethylbenzamide, 3-benzyloxy-N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)benzamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-3,5,5-trimethylhexanamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-(4-chlorophenyl)acetamide, N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2,2-dichloroacetamide, and N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)cinnamide.

5. The compound or the pharmaceutically acceptable salt thereof of claim 3 , wherein the N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)amide is one selected from N -(5-hydroxy-3,4,6-trimethylpyridine-2-yl)acetamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)dodecanamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-4-chlorobutanamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)isobutyrylamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-3-methylbutanamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)pivalamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)cyclopentanecarboxamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)cyclohexanecarboxamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-2-penylacetamide, N-(5-hydroxy-3,4,6trimethylpyridine-2-yl)-3-phenylpropanamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)benzamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-4-fluorobenzamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-4-methoxybenzamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-4-(tert-butyl)benzamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)benzo[d][1 ,3]dioxo 1 -5-carboxamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-1-naphthamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)thiophene-2-carboxamide, 2-ethyl-N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)butanamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-2-phenoxyacetamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-2-phenylbutanamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-2,4,6-trimethylbenzamide, 3-hydroxy-N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)benzamide, N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)-3,5,5-trimethylhexanamide, 2-(4-chlorophenyl)-N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)acetamide, 2,2- dichloro-N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)acetamide, and N-(5-hydroxy-3,4,6-trimethylpyridine-2-yl)cinnamide.

6. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the pharmaceutically acceptable salt is an organic acid selected from oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid, or is in a form of acid addition formed by an inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.

7. A method of treating an inflammatory bowel disease in a subject in need thereof, comprising:
administering an effective amount of a compound represented by Chemical Formula 2 or a pharmaceutically acceptable salt thereof to the subject,

wherein, in Chemical Formula 2 above,
R 1 , R 2 , and R 4 are identical to or different from each other, and are each independently one selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and halogen,
R 3 is one selected from C1-C4 alkoxy, benzyloxy, and hydroxyl, and,
R 5 is one selected from C1-C15 alkyl substituted or not substituted with one or two substituents selected from halogen, hydroxy, C1-C12 alkoxy, phenoxy, C1-C12 alkylamino, C6-C14aryl, and C1-C4 alkyl; C6-C14 aryl substituted or not substituted with one or two substituents selected from halogen, hydroxy, C1-C12 alkoxy, C1-C12 alkylamino, and C1-C4alkyl; C2-C12 alkenyl substituted or not substituted with C6-C14 aryl; C3-C8 cycloalkyl; a 5- to 6-membered monocyclic heterocyclic compound containing one or two heteroatoms selected from N, S or O; a heterocyclic compound containing a double ring structure having the 5- to 6-membered monocyclic heterocyclic compound and a phenyl; and naphthalene.

8. The method of claim 7 , wherein the inflammatory bowel disease is one selected from ulcerative colitis, Crohn's disease, intestinal Behcet's disease, hemorrhagic rectal ulcer, and

Assignees

• Univ Yeungnam Res Cooperation Foundation

Inventors

• Jeong Byeong Seon
• Kim Jung Ae
• Nam Tae Gyu
• Lee Hyun Ji
• Kim Dong Guk
• Kang You Ra
• Been Jae Hui
• Jin You Jin
• Regmi Sushil Chandra
• Gautam Jaya

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title