Phosphatidylcholine transfer protein inhibitors
This invention relates to compounds of Formulas I, II, and III, and their use as inhibitors of phosphatidylcholine transfer protein (PC-TP). The invention further relates to pharmaceutical compositions and methods of treatment of disorders related to the inhibition of PC-TP using the compounds of Formulas I, II, and III. Such disorders include obesity and disorders associated with obesity.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof; wherein:
X is N, Y is N, and Z is CH;
X is N, Y is CH, and Z is N;
R′, R″, and R′″ are each independently selected from H and C 1-3 alkyl;
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, cyano, hydroxyl, carboxyl, carbamyl, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl;
R 6 and R 7 are each C 1-6 alkyl;
n is 0;
W is O;
each R 11 is independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, alkylamino, di-C 1-6 -alkylamino, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, di-C 1-6 alkylcarbonylamino, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl
provided that:
when the compound has Formula I, W is O, X is N, Y is N, and Z is CR 10 , then the following provisos apply:
(a) when R 6 and R 7 are each methyl, R 10 is H, and R 1 , R 2 , R 4 , and R 5 are H, then R 3 is not methoxy or chloro; and
(b) when R 6 and R 7 are each methyl and R 10 is H, then at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is other than H.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H and halogen.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each methyl.
4. The compound according to claim 1 , wherein the compound is a compound of Formula Ia:
or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , which is selected from:
2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;
2-chloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;
2,3-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;
3,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;
2,4-dichloro-N-((4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)(methyl)carbamoyl)benzamide;
2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)-N-methylsulfamoyl)phenylcarbamoyl)benzamide;
2,4-dichloro-N-(4-(N-(2,6-dimethylpyrimidin-4-yl)sulfamoyl)phenylcarbamoyl)benzamide; and
2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-N-methylbenzamide;
or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 , which is selected from:
2,4-dichloro-N-(2-(diethylamino)ethyl)-N-((4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)carbamoyl)benzamide; and
2,4-dichloro-N-((4-(N-(2-(diethylamino)ethyl)-N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)carbamoyl)benzamide;
or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 , which is 2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide; or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
9. A method of treating a disorder selected from obesity, type 2 diabetes, non-alcoholic fatty liver disease, asthma, hyperlipidemia, coronary artery disease, arthritis, gallstones, and atherosclerosis in a patient in need thereof, comprising administering to said patient a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition according to claim 8 , wherein the compound is selected from:
4-chloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide; and
2,4-dichloro-N-(3-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;
or a pharmaceutically acceptable salt thereof.
12. A method of treating obesity, type 2 diabetes, non-alcoholic fatty liver disease, asthma, hyperlipidemia, coronary artery disease, arthritis, gallstones, and atherosclerosis in a patient in need thereof, comprising administering to said patient a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is N, Y is N, and Z is CH; or
X is N, Y is CH, and Z is N; or
R′, R″, and R′″ are each independently selected from H and C 1-3 alkyl;
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, di-C 1-6 -alkylamino, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl;
R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, di-C 1-6 -alkylamino, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylthio, and C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl;
n is 0; and
W is O;
each R 11 is independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, alkylamino, di-C 1-6 -alkylamino, C 1-6 alkylcarbamyl, di-C 1-6 alkylcarbamyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, di-C 1-6 alkylcarbonylamino, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R′, R″, and R′″ are each independently selected from H and methyl; and
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H and halogen.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R′, R″, and R′″ are each independently selected from H and methyl; and
R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H and chloro.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula Ib:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 9 , wherein the compound is the compound of claim 7 , or a pharmaceutically acceptable salt thereof.
17. The method of claim 9 , wherein the disorder is obesity.
18. The method of claim 9 , wherein the disorder is type 2 diabetes.
19. The method of claim 9 , wherein the disorder is atherosclerosis.
20. The method of claim 9 , wherein the disorder is non-alcoholic fatty liver disease.
21. The method of claim 9 , wherein the disorder is asthma.