Phosphatidylcholine transfer protein inhibitors

Patent metadata

Field	Value
Publication number	US-9556129-B2
Application number	US-201514812657-A
Country	US
Kind code	B2
Filing date	Jul 29, 2015
Priority date	Aug 17, 2009
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

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.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:
X is N, Y is CH, and Z is CH; or
X is CH, Y is N, and Z is CH; or
X is CH, Y is CH, and Z is N;
W is O;
R′, R″, and R′″ are each independently selected from H and C 1-4 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 alkynyl, 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 independently H and C 1-6 alkyl;
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, 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 alkylcarbonylamino, di-C 1-6 alkylcarbonylamino, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl; and
n is 0;

provided that when Z is CH, R 1 , R 2 , R 4 R 5 , R 6 and R 7 are each H, and either X is N, and Y is CH, or X is CH and Y is N, then R 3 is other than chloro.

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 independently C 1-6 alkyl.

4. The compound according to claim 1 , which is selected from:
2,4-dichloro-N-(4-(N-(4,6-dimethylpyridin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;
or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

6. 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.

7. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, said compound selected from compounds of Formula II:

wherein:
X is N, Y is CH, and Z is CH; or
X is CH, Y is N, and Z is CH; or
X is CH, Y is CH, and Z is N;
W is O;
R′, R″, and R′″ are each independently selected from H and C 1-4 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 alkynyl, 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 independently H and C 1-6 alkyl;
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, 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 alkylcarbonylamino, di-C 1-6 alkylcarbonylamino, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl; and
n is 0.

8. A method of treating obesity, type 2 diabetes, non-alcoholic fatty liver disease, asthma, hyperlipidemia, coronary artery disease, arthritis, gallstones, or atherosclerosis in a patient in need thereof, comprising administering a compound to said patient, said compound selected from compounds of Formula II:

wherein:
X is N, Y is CH, and Z is CH; or
X is CH, Y is N, and Z is CH; or
X is CH, Y is CH, and Z is N;
W is O;
R′, R″, and R′″ are each independently selected from H and C 1-4 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 alkynyl, 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 independently H and C 1-6 alkyl;
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, 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 alkylcarbonylamino, di-C 1-6 alkylcarbonylamino, C 1-6 alkylthio, C 1-6 alkylsulfinyl, and C 1-6 alkylsulfonyl;
n is 0.

9. The pharmaceutical composition of claim 7 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H and halogen.

10. The pharmaceutical composition according to claim 7 , wherein R 6 and R 7 are each independently C 1-6 alkyl.

11. The method of claim 8 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H and halogen.

12. The method of claim 8 , wherein R 6 and R 7 are each independently C 1-6 alkyl.

13. The method of claim 6 , wherein the disorder is obesity.

14. The method of claim 6 , wherein the disorder is type 2 diabetes.

15. The method of claim 6 , wherein the disorder is atherosclerosis.

16. The method of claim 6 , wherein the disorder is non-alcoholic fatty liver disease.

17. The method of claim 6 , wherein the disorder is asthma.

18. The method of claim 8 , wherein the disorder is obesity.

19. The method of claim 8 , wherein the disorder is type 2 diabetes.

20. The method of claim 8 , wherein the disorder is atherosclerosis.

21. The method of claim 8 , wherein the disorder is non-alcoholic fatty liver disease.

22. The method of claim 8 , wherein the disorder is asthma.

Assignees

• Brigham & Womens Hospital Inc

Inventors

• Cohen David
• Wagle Neil
• Cuny Gregory D
• Xian Jun
• Glicksman Marcie
• Stein Ross L
• Shishova Ekaterina Y

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title