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 process for preparing 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 0-6 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;
provided that R 2 , R 3 , R 5 , and R 7 are not simultaneously hydrogen;
comprising:
transforming a compound of formula B:
to a compound of formula I, wherein X is P(O)(OH) 2 ; and
optionally, treating the compound of formula I, wherein X is P(O)(OH) 2 , with M + OH − or D 2+ (OH − ) 2 to afford the compound of formula I, wherein X is P(O)(OH)(O − )—M + , P(O)(O − ) 2 ·D 2+ , or P(O)(O − ) 2 ·D 2+ .
2. The process according to claim 1 , further comprising treating a compound of formula A:
with chloromethyl chloroformate to afford the compound of formula B.
3. The process according to claim 1 , wherein said transforming the compound of formula B to the compound of formula I, wherein X is P(O)(OH) 2 , comprises treating the compound of formula B with K(PG 1 ) 2 PO 4 to afford a compound of formula C:
and
deprotecting the compound of formula C to afford the compound of formula I, wherein X is P(O)(OH) 2 .
4. The process according to claim 2 , wherein said transforming the compound of formula B to the compound of formula I, wherein X is P(O)(OH) 2 , comprises treating the compound of formula B with K(PG 1 ) 2 PO 4 to afford a compound of formula C:
and
deprotecting the compound of formula C to afford the compound of formula I, wherein X is P(O)(OH) 2 .
5. The process according to claim 3 , wherein PG 1 is tert-butyl.
6. The process according to claim 4 , wherein PG 1 is tert-butyl.
7. The process according to claim 3 , wherein:
R 2 is H;
R 3 is CF 3 ;
R 5 is CH 3 ;
R 7 is F; and
X is —PO(OH) 2 .
8. The process according to claim 3 , wherein:
R 2 is H;
R 3 is CF 2 CF 3 ;
R 5 is OCH 3 ;
R 7 is F; and
X is —PO(OH) 2 .
9. The process according to claim 3 , wherein:
R 2 is H;
R 3 is Cl;
R 5 is CH 3 ;
R 7 is F; and
X is —PO(OH) 2 .
10. The process according to claim 3 , wherein:
R 2 is CF 3 ;
R 3 is H;
R 5 is CH 3 ;
R 7 is F; and
X is —PO(OH) 2 .
11. The process according to claim 3 , wherein:
R 2 is CF 3 ;
R 3 is H;
R 5 is H;
R 7 is F; and
X is —PO(OH) 2 .
12. The process according to claim 3 , wherein:
R 2 is Cl;
R 3 is Cl;
R 5 is OCH 3 ;
R 7 is F; and
X is —PO(OH) 2 .
13. A compound of formula B:
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—; and
R 7 is hydrogen, 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—.
14. The compound according to claim 13 , wherein the compound is selected from the group consisting of:
15. The compound according to claim 13 , wherein the compound is:
16. The compound according to claim 13 , wherein the compound is:
17. A compound of formula C:
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 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—; and
PG 1 is a protecting group.
18. The compound according to claim 17 , wherein the compound is selected from the group consisting of:
19. The compound according to claim 17 , wherein the compound is:
20. The compound according to claim 17 , wherein the compound is: