Benzyl sulfonamide derivatives useful as MOGAT-2 inhibitors
The present invention provides compounds of Formula below: and analogues thereof where the various substituent groups, R1, R2, R3, R4, R5 A, and X are described herein; or a pharmaceutical salt thereof; a method of treating a condition such as hypertriglyceridemia and a process for preparing the compounds.
1. A compound of the formula below:
wherein
R1 is selected from: —CH 3 and —CF 3 ;
R2 is selected from: H, —CH 3 , —CH 2 OCH 3 , and —CH 2 OCH 2 CH 3 ;
R3 is selected from: H, —C 1-2 alkyl, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 ;
R4 is selected from: H, halo, and —OCH 3 ;
R5 is selected from H and halo;
A is selected from: CH, CF, C—CN, and N;
X is selected from: CH, CF, COCH 3 , and N; and
provided that only one of X and A is N,
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R1 is —CH 3 .
3. A compound according to claim 1 wherein R1 is —CF 3 .
4. A compound according to claim 1 , wherein R2 is selected from: H, —CH 3 , —CH 2 OCH 3 .
5. A compound according to claim 4 wherein R2 is H.
6. A compound according to claim 1 wherein R3 is selected from: H, —CH 3 , —CH 2 OCH 3 , and —CH 2 OCH 2 CH 3 .
7. A compound according to claim 6 wherein R3 is selected from: H, —CH 2 OCH 3 , and —CH 2 OCH 2 CH 3 .
8. A compound according to claim 7 wherein R3 is —CH 2 OCH 3 .
9. A compound according to claim 1 wherein R4 is selected from: H and F.
10. A compound according to claim 9 wherein R4 is F.
11. A compound according to claim 1 wherein R5 is H.
12. A compound according to claim 1 wherein A is selected from CH or CF.
13. A compound according to claim 1 wherein A is N.
14. A compound according to claim 1 wherein X is CF or N.
15. A compound according to claim 1 wherein X is CH.
16. A compound of according to claim 1 wherein the pharmaceutically acceptable salt is a hydrogen chloride addition salt.
17. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
18. A compound of the formula below:
or a pharmaceutically acceptable salt thereof.
19. A compound which is N-[(1S)-2,2,2-Trifluoro-1-{4-[({(2S)-2-[(5-fluoropyridin-2-yl)oxy]-3-methoxypropyl}amino)methyl]phenyl}ethyl]methanesulfonamide hydrochloride.
20. A pharmaceutical composition comprising N-[(1S)-2,2,2-Trifluoro-1-{4-[({(2S)-2-[(5-fluoropyridin-2-yl)oxy]-3-ethoxypropyl}amino)methyl]phenyl}ethyl]methanesulfonamide, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
21. A compound which is N-[(1S)-2,2,2-Trifluoro-1-{4-[({(2S)-2-[(5-fluoropyridin-2-yl)oxy]-3-ethoxypropyl}amino)methyl]phenyl}ethyl]methanesulfonamide hydrochloride salt in crystalline form characterized by an X-ray powder diffraction pattern obtained from a CuKα source λ=1.54056 Å), which comprises peaks at:
a) 12.71°, 14.95°, 18.13°, 18.67°, 21.14° and 27.76°±/−0.2 in 2θ or
b) 5.46°, 11.10°, 12.71°, 13.97°, 14.95°, 18.13°, 18.67°, 21.14°, and 27.76°±/−0.2° in 2θ.
22. A composition comprising greater than 80% w/w N-[(1S)-2,2,2-Trifluoro-1-{4-[({(2S)-2-[(5-fluoropyridin-2-yl)oxy]-3-ethoxypropyl}amino)methyl]phenyl}ethyl]methanesulfonamide hydrochloride salt in crystalline form according to claim 21 .
23. A composition comprising greater than 95% w/w N-[(1S)-2,2,2-Trifluoro-1-{4-[({(2S)-2-[(5-fluoropyridin-2-yl)oxy]-3-ethoxypropyl}amino)methyl]phenyl}ethyl]methanesulfonamide hydrochloride salt in crystalline form according to claim 21 .
24. A pharmaceutical composition comprising N-[(1S)-2,2,2-Trifluoro-1-{4-[({(2S)-2-[(5-fluoropyridin-2-yl)oxy]-3-ethoxypropyl}amino)methyl]phenyl}ethyl]methanesulfonamide hydrochloride salt in crystalline form according to claim 21 and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
25. A method of treating a patient in need of treatment for hypertriglyceridemia, the method comprises administering to the patient an effective amount of a compound, according to claim 1 , or a pharmaceutically acceptable salt thereof.
26. A method of treating a patient in need of treatment for hypertriglyceridemia, the method comprises administering to the patient an effective amount of a compound according to claim 18 , or a pharmaceutically acceptable salt thereof.
27. A method of treating a patient in need of treatment for hypertriglyceridemia, the method comprises administering to the patient an effective amount of a pharmaceutical composition according to claim 24 .