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 compound of the general formula (I):
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;
n is an integer from 1-3; and
a stereoisomer or pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein
Ar is a phenyl group substituted with heterocyclyl, wherein the heterocyclyl 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;
n is an integer from 1-3; and
a stereoisomer or pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 , wherein
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;
R 4 is unsubstituted or substituted aryl; and
a stereoisomer or pharmaceutically acceptable salt thereof.
4. A compound according to claim 2 , wherein
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;
R 4 is 4-methylphenyl, 2-chloro-4-trifluoromethylphenyl, 3-chloro-4-methylphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluoro-4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, or 4-cyanophenyl; and
a stereoisomer or pharmaceutically acceptable salt thereof.
5. A compound according to claim 4 , wherein
Ar is 4-(piperazin-1-yl)phenyl with the phenyl moiety coupled to B;
B is oxygen —O—;
R 1 is hydrogen;
R 2 is S(O) 2 R 4 ;
R 3 is chlorine;
R 4 is 2,4-dichlorophenyl; and
a stereoisomer or pharmaceutically acceptable salt thereof.
6. A compound according to claim 4 , wherein
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;
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; and
a stereoisomer or pharmaceutically acceptable salt thereof.
7. A compound according to claim 4 , wherein
Ar is 3-(4-methyl-piperazin-1yl)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;
R 4 is 4-methoxyphenyl or 2,4-difluorophenyl; and
a stereoisomer or pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 , wherein
Ar is a phenyl group substituted with heteroaryl, wherein the 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;
n is an integer from 1-3; and
a stereoisomer or pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 , wherein
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;
R 4 is unsubstituted or substituted aryl; and
a stereoisomer or pharmaceutically acceptable salt thereof.
10. A compound according to claim 9 , wherein
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;
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; and
a stereoisomer or pharmaceutically acceptable salt thereof.
11. A compound according to claim 9 , wherein
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;
R 4 is 4-methoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, or 2-chloro-4-trifluoromethylphenyl; and
a stereoisomer or pharmaceutically acceptable salt thereof.
12. A compound according to claim 2 , wherein
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;
n is an integer from 1-3; and
a stereoisomer or pharmaceutically acceptable salt thereof.
13. A compound according to claim 12 , wherein
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 C(O)(CH 2 ) 2 —C(O)OR 5 ;
R 3 is chlorine;
R 5 is hydrogen; and
a stereoisomer or pharmaceutically acceptable salt thereof.
14. A compound according to claim 1 , wherein the compound is:
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,
N-(6-(2-(Benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-yl)-2-chloro-4-(trifluoromethyl)benzene sulfonamide; and
a stereoisomer or pharmaceutically acceptable salt thereof.
15. A compound according to claim 1 , wherein the compound is:
N-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-yl)-2,4-dichlorobenzene-sulfonamide,
2,4-Dichloro-N-(5-chloro-6-(4-(piperazin-1-yl)phenoxy)pyridin-3-yl)benzenesulfonamide,
4-(6-(4-(4-Acetylpiperazin-1-yl)phenoxy)-5-chloropyridin-3-ylamino)-4-oxobutanoic acid; and
a stereoisomer or pharmaceutically acceptable salt thereof.
16. A process for the preparation of a compound of general formula (I):
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 3 is halogen, cyano, (CO)OR 6 , or C(O)NR 7 R 8 ;
R 6 is hydrogen or (C 1 -C 4 )alkyl;
R 7 and R 8 are independently hydrogen or (C 1 -C 6 )alkyl;
R 1 is H, R 2 is SO 2 R 4 , and R 4 is unsubstituted or substituted aryl, which comprises
a) reacting a compound of general formula (II):
wherein Hal is fluorine, chlorine, bromine or iodine and R 3 is as defined above, with a compound of formula (III): Ar—BH wherein Ar and B are as defined above, in presence of a base such as cesium carbonate, to obtain a compound of general formula (IV);
wherein Ar, B and R 3 are as defined above;
b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V);
wherein Ar, B and R 3 are as defined above;
c) reacting the amino compound of general formula (V) with Hal-SO 2 R 4 wherein Hal is fluorine, chlorine, bromine or iodine and R 4 is as defined above, in the presence of a base to obtain the compound of formula (I); and,
d) optionally, converting the resulting compound into a pharmaceutically acceptable salt.
17. A process for the preparation of a compound of general formula (I):
wherein
Ar is a phenyl group substituted with heterocyclyl or heteroaryl; wherein the heteroaryl or heterocyclyl group may be unsubstituted or substituted;
B is —O—, —S—, or —NH—;
R 3 is halogen, cyano, (CO)OR 6 , or C(O)NR 7 R 8 ;
R 6 is hydrogen or (C 1 -C 4 )alkyl;
R 7 and R 8 are independently hydrogen or (C 1 -C 6 )alkyl;
R 1 is H, R 2 is C(O)(CH 2 ), —C(O)OR 5 , wherein n is an integer from 1-3, and R 5 is hydrogen, (C 1 -C 6 )alkyl, or unsubstituted or substituted aryl, which comprises
a) reacting a compound of general formula (II):
wherein Hal is fluorine, chlorine, bromine or iodine and R 3 is as defined above, with a compound of formula (III): Ar—BH wherein Ar and B are as defined above, in presence of a base such as cesium carbonate, to obtain a compound of general formula (IV);
wherein Ar, B and R 3 are as defined above;
b) subjecting the nitro compound of formula (IV) above to reduction to obtain a corresponding amino compound of general formula (V);
wherein Ar, B and R 3 are as defined above;
c) refluxing the amino compound of general formula (V) above with an anhydride [(CH 2 ) n (CO) 2 O] to obtain an acid of formula (I) wherein R 2 is —C(O)(CH 2 ) n —C(O)OH and n is an integer from 1-3;
d) optionally, converting the acid of formula (I) to an ester of formula (I) wherein R 2 is —C(O)(CH 2 ) n —C(O)OR 5 , wherein n is an integer from 1-3, and R 5 is (C 1 -C 4 )alkyl or aryl; and,
e) optionally, converting the resulting acid or ester into a pharmaceutically acceptable salt.
18. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of general formula (I) according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
19. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of general formula (I) according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and at least one further pharmaceutically active compound, together with a pharmaceutically acceptable carrier or diluent.