IP Library › Granted Patent US 8,026,370

Granted Patent B2

US 8,026,370 · App. 11/667,006 · Granted Sep 27, 2011

Carboxylic acid derivative containing thiazole ring and pharmaceutical use thereof

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Quick Facts

Patent No.: US 8,026,370
App. No.: 11/667,006
Granted: Sep 27, 2011
Kind: B2

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Abstract

According to the present invention, a compound represented by the following formula (I) having a superior PPAR α agonist action and concurrently showing a hypolipidemic action can be provided, and further, a compound useful as a synthetic intermediate for the compound can be provided.

Claims (206)

1. A carboxylic acid derivative containing a thiazole ring represented by formula (I):

wherein R 1 and R 2 are the same or different and each is a hydrogen atom or an alkyl group, or R 1 and R 2 are bonded to each other to form a cycloalkyl group;

R 3 is a hydrogen atom or an alkyl group;

R 4 is a hydrogen atom, an alkyl group or an aryl group;

n is an integer of 1 to 5;

Y is an oxygen atom, a sulfur atom, —NR 5 —, —CONR 5 —, —NR 5 CO— or —NHCONR 5 —, wherein R 5 is a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group; and

Z is a cycloalkyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group or a heteroarylalkyl group,

wherein, in the aforementioned groups, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group, a heteroaryl group and a heteroarylalkyl group each optionally have substituent, or a pharmaceutically acceptable salt thereof.

2. The carboxylic acid derivative containing the thiazole ring of claim 1 , which is represented by formula (I′):

wherein R 1 , R 2 , R 3 , R 4 , n, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof.

3. The carboxylic acid derivative containing the thiazole ring of claim 1 , wherein, in the formula (I), n is an integer of 1 to 3, Y is an oxygen atom, a sulfur atom, —NR 6 —, —CONR 6 —, —NR 6 CO— or —NHCONR 6 —, wherein R 6 is a hydrogen atom, an alkyl group, a cycloalkylalkyl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group or a heteroarylalkyl group, wherein, in the aforementioned groups, an alkyl group, an arylalkyl group, an arylalkenyl group, an aryloxyalkyl group and a heteroarylalkyl group each optionally have substituent, and Z is an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted arylalkyl group or an optionally substituted heteroaryl group, or a pharmaceutically acceptable salt thereof.

4. The carboxylic acid derivative containing the thiazole ring of claim 1 , wherein, in the formula (I), Y is an oxygen atom, a sulfur atom or —NR 7 —, wherein R 7 is a hydrogen atom, an alkyl group or —CH 2 —W, wherein W is an aryl group or a heteroaryl group, wherein, in the aforementioned groups, an alkyl group, an aryl group and a heteroaryl group each optionally have, and Z is represented by a substituent selected from formula (II):

wherein R 8 , R 9 and R 10 are the same or different and each is a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a haloalkyloxy group, a cyano group, a nitro group, —NR 13 R 14 , —NR 15 COR 16 , —CONR 17 R 18 , wherein R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are the same or different and each is independently a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group, or R 13 and R 14 can be bonded to each other to form a heterocyclic ring wherein the heterocyclic ring comprises a total of 2 to 10 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and R 15 and R 16 can be bonded to each other to form a heterocyclic ring wherein the heterocyclic ring comprises a total of 2 to 10 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, —OR 19 , —COR 20 or —C≡R 21 , wherein R 19 , R 20 and R 21 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group;

R 11 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, a haloalkyl group, a cyano group or a nitro group;

R 12 is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group;

E 1 is an oxygen atom, a sulfur atom or —NR 22 —, wherein R 22 is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group or a heteroarylalkyl group,

wherein, in the aforementioned groups, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group and a heterocycle each optionally have substituent, or a pharmaceutically acceptable salt thereof.

5. The carboxylic acid derivative containing the thiazole ring of claim 1 , wherein, in the formula (I), Y is an oxygen atom, a sulfur atom or —NR 23 —, wherein R 23 is a hydrogen atom, an optionally substituted alkyl group, or a substituent selected from formula (III):

wherein R 24 and R 25 are the same or different and each is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylcarbonyl group, a heteroaryl group, a halogen atom, a haloalkyl group, a haloalkyloxy group, —NR 26 R 27 , —NR 28 COR 29 , —CONR 30 R 31 , wherein R 26 , R 27 , R 28 , R 29 , R 30 and R 31 are the same or different and each is independently a hydrogen atom, an alkyl group, an aryl group or a heteroaryl group, or R 26 and R 27 , and R 30 and R 31 are bonded to each other to form a heterocycle, or —OR 32 , wherein R 32 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group, wherein, in the aforementioned groups, an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroarylalkyl group and a heterocycle each optionally have substituent, and Z is a substituent selected from formula (IV):

wherein R 8 , R 9 and R 10 are as defined above, or a pharmaceutically acceptable salt thereof.

6. The carboxylic acid derivative containing the thiazole ring of claim 1 , which is selected from the group consisting of

(34) 2-[(4-[2-[(4′-fluorobiphenyl-4-yl)oxy]ethyl]-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(38) 2-[(4-{2-[(4′-chlorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(68) 2-[(4-{2-[(3′-fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(76) 2-[(4-{2-[(4′-fluorobiphenyl-4-yl)thio]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(79) 2-[(4-[2-[(3,4′-difluorobiphenyl-4-yl)oxy]ethyl]-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(100) 2-{[4-(2-{[5-(4-fluorophenyl)pyridin-2-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio-2-methylpropionic acid

(102) 2-methyl-2-({4-[2-({5-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(103) 2-methyl-2-({4-[2-({5-[3-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(104) 2-methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyridin-2-yl}oxy)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(106) 2-{[4-(2-{[5-(4-chlorophenyl)pyridin-2-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(107) 2-{[4-(2-{[5-(3-chlorophenyl)pyridin-2-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(108) 2-{[4-(2-{[5-(3,4-dichlorophenyl)pyridin-2-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(109) 2-{[4-(2-{[5-(3-chloro-4-fluorophenyl)pyridin-2-yl]oxy}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(152) 2-methyl-2-{[4-({[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}methyl)-1,3-thiazol-2-yl]thio}propionic acid

(162) 2-methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(220) 2-{[4-(2-{[6-(4-chloro-2-fluorophenyl)pyridazin-3-yl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(224) 2-({4-[2-({6-[2-fluoro-4-(trifluoromethyl)phenyl]pyridazin-3-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid

(226) 2-{[4-(2-{[5-(4-chlorophenyl)pyrazin-2-yl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(227) 2-[(4-{2-[[5-(4-chlorophenyl)pyrazin-2-yl](methyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(229) 2-methyl-2-({4-[2-(methyl{5-[4-(trifluoromethyl)phenyl]pyrazin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(231) 2-methyl-2-({4-[2-(methyl{5-[4-(trifluoromethoxy)phenyl]pyrazin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(232) 2-({4-[2-({5-[2-fluoro-4-(trifluoromethyl)phenyl]pyrazin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid

(243) 2-methyl-2-({4-[2-({5-[4-(trifluoromethyl)phenyl]pyridin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(260) 2-{[4-(2-{[6-(4-chlorophenyl)pyridin-3-yl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(261) 2-methyl-2-({4-[2-({6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid

(265) 2-[(4-{2-[(5-ethylpyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(267) 2-[(4-{2-[heptyl(5-propylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(319) 2-[(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(320) 2-({4-[2-(3-cyclohexyl-1-heptylureido)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid

(326) 2-{[4-(2-{(5-ethylpyrimidin-2-yl)[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(329) 2-[(4-{2-[(5-ethylpyrimidin-2-yl)(hexyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(346) 2-{[4-(2-{(5-ethylpyrimidin-2-yl)[(2E)-3-phenylprop-2-en-1-yl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid

(379) 2-[(4-{2-[(3-butoxypropyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(430) 2-methyl-2-[(4-{2-[[(1-phenyl-1H-pyrazol-4-yl)methyl](5-propylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]propionic acid

(442) 2-[(4-{2-[heptyl(5-morpholin-4-ylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(449) 2-[(4-{2-[(3-ethyl-1H-pyrazol-5-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid, and

(450) 2-[(4-{2-[heptyl(3-propyl-1H-pyrazol-5-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid,

or a pharmaceutically acceptable salt thereof.

7. The carboxylic acid derivative containing the thiazole ring of claim 1 , wherein, in the formula (I), Y is an oxygen atom and Z is an aryl group or a heteroaryl group, or a pharmaceutically acceptable salt thereof.

8. The carboxylic acid derivative containing the thiazole ring of claim 1 , wherein, in the formula (I), Y is an oxygen atom and Z is an aryl group, or a pharmaceutically acceptable salt thereof.

9. The carboxylic acid derivative containing the thiazole ring of claim 1 , which is selected from the group consisting of

(34) 2-[(4-{2-[(4′-fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(38) 2-[(4-{2-[(4′-chlorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(68) 2-[(4-{2-[(3′-fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(76) 2-[(4-{2-[(4′-fluorobiphenyl-4-yl)thio]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid

(79) 2-[(4-{2-[(3,4′-difluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid