Prodrugs of pyridone amides useful as modulators of sodium channels
The invention relates to prodrug compounds of formula I: wherein R 2 , R 3 , R 5 , R 7 and X are as defined herein. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain. The compounds of formula I possess advantageous solubility and physicochemical properties.
1. A compound of formula I:
wherein, independently for each occurrence:
R 2 and R 3 are independently hydrogen, halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
R 5 is hydrogen, halogen, OH, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 7 is hydrogen, halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
X is —PO(OH) 2 , —PO(OH)O − M + , —PO(O − ) 2 .2M + , or —PO(O − ) 2 .D 2+ ; M + is a pharmaceutically acceptable monovalent cation; and D 2+ is a pharmaceutically acceptable divalent cation;
provided that R 2 , R 3 , R 5 , and R 7 are not simultaneously hydrogen.
2. The compound according to claim 1 , wherein R 2 is hydrogen, Cl or CF 3 ; R 3 is hydrogen, Cl, CF 3 or CF 2 CF 3 ; R 5 is hydrogen, Cl, F, CH 3 , OCH 3 or OCF 3 ; and R 7 is hydrogen, fluorine or OCF 3 .
3. The compound according to claim 1 , wherein X is —PO(OH) 2 .
4. The compound according to claim 1 , wherein the compound has formula I-B:
wherein, independently for each occurrence:
R 3 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
R 5 is halogen, OH, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 7 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
X is —PO(OH) 2 , —PO(OH)O − M + , —PO(O − ) 2 .2M + , or —PO(O − ) 2 .D 2+ ; M + is a pharmaceutically acceptable monovalent cation; and D 2+ is a pharmaceutically acceptable divalent cation.
5. The compound according to claim 4 , wherein R 3 is CF 3 , Cl or CF 2 CF 3 ; R 5 is F, CH 3 or OCH 3 ; R 7 is F; and X is —PO(OH) 2 .
6. The compound according to claim 4 , wherein the compound is (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.
7. The compound according to claim 4 , wherein the compound is (4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.
8. The compound according to claim 4 , wherein the compound is (4-(4-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.
9. The compound according to claim 1 , wherein the compound has formula I-A
wherein, independently for each occurrence:
R 2 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
R 5 is halogen, OH, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 7 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
X is —PO(OH) 2 , —PO(OH)O − M + , —PO(O − ) 2 .2M + , or —PO(O − ) 2 .D 2+ ; M + is a pharmaceutically acceptable monovalent cation; and D 2+ is a pharmaceutically acceptable divalent cation.
10. The compound according to claim 9 , wherein the compound is (4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.
11. The compound according to claim 1 , wherein the compound has formula I-C
wherein, independently for each occurrence:
R 2 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
R 7 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
X is —PO(OH) 2 , —PO(OH)O − M + , —PO(O − ) 2 .2M + , or —PO(O − ) 2 .D 2+ ; M + is a pharmaceutically acceptable monovalent cation; and D 2+ is a pharmaceutically acceptable divalent cation.
12. The compound according to claim 11 , wherein the compound is (4-(2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.
13. The compound according to claim 1 , wherein the compound has formula I-G
wherein, independently for each occurrence:
R 2 and R 3 are independently halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen;
R 5 is halogen, OH, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;
R 7 is halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
X is —PO(OH) 2 , —PO(OH)O − M + , —PO(O − ) 2 .2M + , or —PO(O − ) 2 .D 2+ ; M + is a pharmaceutically acceptable monovalent cation; and D 2+ is a pharmaceutically acceptable divalent cation.
14. The compound according to claim 13 , wherein the compound is (4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.
15. An amorphous Form C of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, wherein said amorphous Form C is characterized by an X-ray powder diffraction pattern as measured b Cu K α radiation, substantially similar to FIG. 5 .
16. A crystalline Form B of (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate, wherein said crystalline Form B is characterized by an X-ray powder diffraction pattern (XRPD) comprising at least three approximate peak positions (degrees 2 theta +0.2) when measured usin Cu K α , radiation, selected from the group consisting of 4.4 15.2 16.4, 18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2, 24.8, 26.3, 29.6, 30.1 and 31.3, when the XRPD is collected from about 4 to about 40 degrees 2 theta (2 θ).
17. A process for preparing the crystalline Form B of claim 16 , comprising contacting (4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate with water, an organic solvent, a mixture of organic solvents or a mixture of an organic solvent and water at a suitable temperature, stirring for up to 4 weeks and isolating the solid.
18. A pharmaceutical composition comprising the compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
19. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject the compound according to claim 1 .
20. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia comprising administering to the subject an effective amount of the compound according to claim 1 .