Antifungal oxodihydropyridinecarbohydrazide derivative

Patent metadata

Field	Value
Publication number	US-9617216-B2
Application number	US-201415029638-A
Country	US
Kind code	B2
Filing date	Oct 21, 2014
Priority date	Oct 21, 2013
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The present invention relates to novel oxodihydropyridinecarbohydrazide derivatives with excellent antifungal activities, an antifungal composition containing the same, and its use for the prevention and treatment of fungal infectious diseases. The oxodihydropyridinecarbohydrazide derivatives of the present invention have excellent antifungal and fungicidal activities, and thus will be useful for the prevention and treatment of various fungal infections by Candida spp., Aspergillus spp., Cryptococcus neoformans and Trichophyton spp., etc. Additionally, the oxodihydropyridinecarbohydrazide derivatives of the present invention, unlike other fungicidal preparations, can be orally administered.

First claim

The invention claimed is:

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

wherein,
R 1 is hydrogen; or halogen,
R 2 is hydrogen; halogen; cyano; or C 1-4 haloalkyl,
R 3 is hydrogen; halogen; cyano; C 1-4 alkoxy; C 1-4 haloalkyl or C 1-4 haloalkylsulfonyl,
X is carbon; or nitrogen, wherein when X is carbon, then said X is unsubstituted or substituted with halogen,
R 4 is hydrogen; halogen; C 1-4 alkyl; or is connected to R 7 to form

R 5 is hydrogen; halogen; or C 1-4 haloalkylphenylamino,
R 6 is hydrogen; halogen; pyridinyl; or phenyl unsubstituted or substituted with halogen, cyano, and C 1-4 haloalkyl,
R 7 is phenoxyethyl substituted with one to three same or different halogen atoms; phenoxyethyl substituted with C 1-4 haloalkyl; ethyl substituted with halophenyl; C 1-4 alkoxyethyl; morpholinoethyl; C 1-4 haloalkylphenylpiperazinylethyl; halophenyl; C 1-4 haloalkylphenyl; cyclohexylmethyl; thiazolylmethyl; C 1-4 haloalkylpyridinylmethyl; C 1-4 alkyl; dimethylaminocarbonylmethyl; C 1-4 haloalkylphenylacetamido; or oxotrifluoromethylphenylethyl,
R 8 is hydrogen; or is connected to R 7 to form C 1-3 alkylene.

2. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is hydrogen; chloro; or fluoro.

3. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 2 is hydrogen; chloro; fluoro; cyano; or trifluoromethyl.

4. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is hydrogen; chloro; fluoro; cyano; methoxy; trifluoromethyl; or trifluoromethylsulfonyl.

5. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is hydrogen; fluoro; or methyl.

6. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 5 is hydrogen; chloro; or trifluoromethylphenylamino.

7. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 6 is hydrogen; chloro; pyridinyl; chlorophenyl; fluorophenyl; cyanophenyl; or trifluoromethylphenyl.

8. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 7 is phenoxyethyl substituted with dichloro, chloro, or fluoro; trifluoromethylphenoxyethyl; chlorophenethyl; fluorophenethyl; methoxyethyl; morpholinoethyl; trifluoromethylphenylpiperazinylethyl; chlorophenyl; fluorophenyl; trifluoromethylphenyl; cyclohexylmethyl; thiazolylmethyl; trifluoromethylpyridinylmethyl; methyl; dimethylaminocarbonylmethyl; fluoromethylphenylacetamido; or oxotrifluoromethylphenylethyl.

9. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein X is carbon, said X being substituted with fluoro.

10. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein X is nitrogen,
R 1 is hydrogen,
R 2 is hydrogen or fluoro,
R 3 is fluoro or methoxy,
R 4 is hydrogen; fluoro; or methyl,
R 5 is hydrogen,
R 6 is hydrogen; chlorophenyl; fluorophenyl; cyanophenyl; or trifluoromethylphenyl, and
R 7 is chlorophenyl; or methyl.

11. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein R 8 is hydrogen; or is connected to R 7 to form propylene.

12. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:
1) N′-(2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
2) N′-(3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
3) N′-(4-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
4) N′-(3-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
5) N′-(4-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
6) N′-(3-cyanophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
7) N′-(4-cyanophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
8) 1-methyl-6-oxo-N′-(3-(trifluoromethyl)phenyl)-1,6-dihydropyridine-3-carbohydrazide,
9) 1-methyl-6-oxo-N′-(4-(trifluoromethyl)phenyl)-1,6-dihydropyridine-3-carbohydrazide,
10) 1-methyl-6-oxo-N′-(4-(trifluoromethylsulfonyl)phenyl)-1,6-dihydropyridine-3-carbohydrazide,
11) N′-(2,4-difluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
12) N′-(3,4-difluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
13) N′-(3,5-difluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
14) N′-(3,4-dichlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
15) N′-(2,4-dichlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
16) N′-(4-chloro-3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
17) N′-(3-chloro-4-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
18) N′-(6-fluoropyridine-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
19) N′-(2,6-difluoropyridine-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
20) N′-(6-fluoro-2-methylpyridine-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
21) N′-(5-fluoro-6-methoxypyridine-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
22) 4-chloro-N′-(3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
23) 4-chloro-N′-(4-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
24) 5-chloro-N′-(3-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
25) 5-chloro-N′-(4-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
26) 5-chloro-N′-(3-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
27) 5-chloro-N′-(4-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
28) 5-chloro-N′-(3-cyanophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
29) 5-chloro-N′-(4-cyanophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
30) 5-chloro-N′-(2,4-difluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
31) 5-chloro-N′-(3,4-difluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
32) 5-chloro-N′-(3,5-difluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
33) 7-chloro-N′-(3-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carbohydrazide,
34) 7-chloro-N′-(4-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carbohydrazide,
35) N′-(3-fluorophenyl)-1-methyl-6-oxo-4-(4-(trifluoromethyl)phenylamino)-1,6-dihydropyridine-3-carbohydrazide,
36) N′-(4-fluorophenyl)-1-methyl-6-oxo-4-(4-(trifluoromethyl)phenylamino)-1,6-dihydropyridine-3-carbohydrazide,
37) N′-(5-fluoro-6-methoxypyridine-3-yl)-5-(4-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
38) 5-(4-chlorophenyl)-N′-(5-fluoro-6-methoxypyridine-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
39) N′-(5-fluoro-6-methoxypyridine-3-yl)-1-methyl-6-oxo-5-(4-(trifluoromethyl)phenyl)-1,6-dihydropyridine-3-carbohydrazide,
40) 5-(4-cyanophenyl)-N′-(5-fluoro-6-methoxypyridine-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
41) N′-(3-fluorophenyl)-1-methyl-6-oxo-5-(pyridine-2-yl)-1,6-dihydropyridine-3-carbohydrazide,
42) 1-(2-fluorophenyl)-N′-(3-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
43) N′,1-Bis(3-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
44) N′-(3-fluorophenyl)-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carbohydrazide,
45) N′-(4-fluorophenyl)-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,6-dihydropyridine-3-carbohyd

Assignees

• Dae Woong Pharma

Inventors

• Park Joon Seok
• Yoon Youn Jung
• Park Chang Min
• Na Yun Soo
• Cho Min Jae
• Lee Ho Bin
• Han Mi Ryeong
• Park Yeon Jung
• Kim Ji Duck

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/10

  Antimycotics · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D213/63 Primary

  One oxygen atom · CPC title