Pyridine derivatives for the treatment of metabolic disorders related to insulin resistance or hyperglycemia
The present invention provides novel compounds represented by the general formula (I): their stereoisomers, pharmaceutically acceptable salts and their pharmaceutically acceptable solvates thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia. The invention also relates to a process for the manufacture of compounds of formula (I) and pharmaceutical compositions containing them.
1. A method for the treatment of a metabolic disorder related to insulin resistance or hyperglycemia, comprising:
administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, the formula (I) is represented by:
wherein:
Ar is a phenyl group substituted with heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl group may be unsubstituted or substituted;
B is —O—, —S—, or —NH—;
R 1 is hydrogen;
R 2 is S(O) 2 R 4 or C(O)(CH 2 ) n —C(O)OR 5 ;
R 3 is halogen, cyano, (CO)OR 6 , or C(O)NR 7 R 8 ;
R 4 is unsubstituted or substituted aryl;
R 5 is hydrogen, (C 1 -C 6 )alkyl, or unsubstituted or substituted aryl;
R 6 is hydrogen or (C 1 -C 4 )alkyl;
R 7 and R 8 are independently hydrogen or (C 1 -C 6 )alkyl; and
n is an integer from 1-3;
wherein the metabolic disorder related to inulin resistance or hyperglycemia is selected from type 2 diabetes, obesity, glucose intolerance, dyslipidemia and hyperinsulinemia.
2. The method according to claim 1 ;
wherein, in the compound of formula (I):
Ar is a phenyl group substituted with heterocyclyl, wherein the heterocyclyl group may be unsubstituted or substituted;
B is —O—;
R 1 is hydrogen;
R 2 is S(O) 2 R 4 ;
R 3 is halogen; and
R 4 is unsubstituted or substituted aryl.
3. The method according to claim 2 ;
wherein, in the compound of formula (I):
Ar is a phenyl group substituted with piperazinyl with the phenyl moiety coupled to B, wherein the piperazinyl group may be unsubstituted or substituted;
B is —O—;
R 1 is hydrogen;
R 2 is S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is 4-methylphenyl, 2-chloro-4-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, or 3,4-dichlorophenyl.
4. The method according to claim 3 ;
wherein, in the compound of formula (I):
Ar is 4-(4-acetyl-piperazin-1-yl)phenyl with the phenyl moiety coupled to B;
B is —O—;
R 1 is hydrogen;
R 2 is S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is 4-methylphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2-chloro-4-trifluoromethylphenyl.
5. The method according to claim 1 ;
wherein, in the compound of formula (I):
Ar is a phenyl group substituted with heteroaryl, wherein the heteroaryl group may be unsubstituted or substituted;
B is —O—;
R 1 is hydrogen;
R 2 is S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is unsubstituted or substituted aryl.
6. The method according to claim 5 ;
wherein in the compound of formula (I):
Ar is 6-(2-benzo[d]thiazol-2-yl)phenyl with the phenyl moiety coupled to B;
B is —O—;
R 1 is hydrogen;
R 2 is S(O) 2 R 4 ;
R 3 is chlorine; and
R 4 is 4-methoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2-chloro-4-trifluoromethylphenyl.
7. The method, according to claim 1 ;
wherein, in the compound of formula (I):
Ar is a phenyl group substituted with heterocyclyl with the phenyl moiety coupled to B; wherein the heterocyclyl group may be unsubstituted or substituted;
B is —O—;
R 1 is hydrogen;
R 2 is C(O)(CH 2 ) n —C(O)OR 5 ;
R 3 represents halogen, cyano, (CO)OR 6 , or C(O)NR 7 R 8 ;
R 5 is hydrogen, (C 1 -C 6 )alkyl, or unsubstituted or substituted aryl;
R 6 is hydrogen or (C 1 -C 4 )alkyl;
R 7 and R 8 are independently hydrogen or (C 1 -C 6 )alkyl; and
n is an integer from 1-3.
8. The method, according to claim 1 ;
wherein the compound of formula (I) is selected from:
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-2,4-dichlorobenzene-sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-4-methoxybenzene-sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-3,4-dimethoxy-benzene
sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-2,5-dimethoxy-benzene
sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-2-chloro-4-(trifluoromethyl)benzenesulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-3,4-dichlorobenzene-sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-4-(trifluoromethoxy)benzene-sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-4-methylbenzene-sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-2,4-difluorobenzene-sulfonamide,
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-4-fluorobenzene-sulfonamide,
2,4-Dichloro-N-(5-chloro-6-(4-(piperazin-1-yl)phenoxy)pyridin-3-yl)benzenesulfonamide,
N-(5-Chloro-6-(3-(4-methylpiperazin-1-yl)phenoxy)pyridin-3-yl)-2,4-difluorobenzene sulfonamide,
N-(5-Chloro-6-(3-(4-methylpiperazin-1-yl)phenoxy)pyridin-3-yl)-4-methoxybenzene-sulfonamide,
4-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-ylamino)-4-oxobutanoic acid,
N-(6-(2-(Benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-yl)-2,4-dichlorobenzene-sulfonamide,
N-(6-(2-(Benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-yl)-4-methoxybenzene-sulfonamide,
N-(6-(2-(Benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-yl)-3,4-dichloro-benzenesulfonamide, and
N-(6-(2-(Benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-yl)-2-chloro-4-(trifluoromethyl)benzenesulfonamide.
9. The method according to claim 1 ;
wherein the metabolic disorder related to insulin resistance or hyperglycemia is type 2 diabetes.
10. The method according to claim 1 ;
wherein the metabolic disorder related to insulin resistance or hyperglycemia is obesity.