Compositions useful as inhibitors of voltage-gated sodium channels
The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. 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.
1. A compound of formula II-A:
or a pharmaceutically acceptable salt thereof, wherein:
X is O, S, NR, C(O), or C(R) 2 ;
R 3 is independently selected from halogen, CN, CF 3 , NO 2 , or an optionally substituted group selected from C 1-6 aliphatic, C 1-6 cycloaliphatic, C 6-10 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —C(O)R′, —COOR′, —NRCOR′, —CON(R′) 2 , —S(O) 2 R′, or —S(O) 2 N(R′) 2 ;
R 5 is independently Q-R x ;
Q is a bond or is a C 1 - 6 aliphatic chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S, or NR;
each occurrence of R X is independently selected from R′, halogen, NO 2 , CN, OR′, SR′, N(R′) 2 , NR′C(O)R′, NR′C(O )N(R′) 2 , NR′CO 2 R′, C(O)R′, CO 2 R′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , SOR′, SO 2 R′, SO 2 N(R′) 2 , NR′SO 2 R′, NR′SO 2 N(R′) 2 , C(O)C(O)R′, or C(O)CH 2 C(O)R′;
each occurrence of R′ is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group; and
each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C 1-8 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′ taken together with the atom(s) to which they are bound, or two occurrences of R′ taken together with the atom(s) to which they are bound, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that:
when X is O and R 5 is OMe, then R 3 is not NO 2 .
2. The compound according to claim 1 , wherein X is O, S, NH, C(O), or CH 2 .
3. The compound according to claim 1 , wherein X is O.
4. The compound according to claim 1 , wherein each R 3 is independently selected from Cl, Br, F, CF 3 , methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CN, NO 2 , —COOH, —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —O(CH 2 ) 2 OCH 3 , —CONH 2 , —COO(C 1-6 alkyl), —OH, —OCF 3 , —SCF 3 , —OCH 3 , —CH 2 OH, —NHCOCH 3 , —SO 2 NH 2 , —SO 2 CH 3 , methylenedioxy, ethylenedioxy, or an optionally substituted group selected from pyrrolyl, thiadiazolyl, pyridyl, imidazolyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, 2-oxo-imidazolidyl, C 1-4 alkoxy, phenyl, phenylethyl, phenyloxy, phenyloxymethyl, phenylformyl, benzyl, benzylamino, or benzyloxy.
5. The compound according to claim 4 , wherein R 3 is methyl, ethyl, propyl, isopropyl, t-butyl, and sec-butyl.
6. The compound according to claim 1 , wherein each R 5 is independently selected from halogen, CN, NO 2 , or an optionally substituted group selected from C 1-4 aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —NRCOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .
7. The compound according to claim 6 , wherein each R 5 is independently selected from Cl, Br, F, CF 3 , methyl, ethyl, CN, —COOH, —N(CH 3 ) 2 , —N(Et) 2 , —N(iPr) 2 , —O(CH 2 ) 2 OCH 3 , —CONH 2 , —COOCH 3 , —OH, —CH 2 OH, —NHCOCH 3 , —SO 2 NH 2 , methylenedioxy, ethylenedioxy, piperidinyl, piperazinyl, morpholino, or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.
8. The compound according to claim 1 , wherein X is O or S; R 3 is selected from optionally substituted C 1-6 aliphatic or CF 3 ; and R 5 is selected from CN, CF 3 , —C(O)R′, —COOR′, —OR′, halogen, optionally substituted C 1-4 aliphatic, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl.
9. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
10. A compound of formula III-A:
or a pharmaceutically acceptable salt thereof, wherein:
R 3 and each occurrence of R 5 is independently Q-R X ;
y is 0-4;
Q is a bond or is a C 1-6 aliphatic chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S, or NR;
each occurrence of R X is independently selected from R′, halogen, NO 2 , CN, OR′, SR′, N(R′) 2 , NR′C(O)R′, NR′C(O)N(R′) 2 , NR′CO 2 R′, C(O)R′, CO 2 R′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , SOR′, SO 2 R′, SO 2 N(R′) 2 , NR′SO 2 R′, NR′SO 2 N(R′) 2 , C(O)C(O)R′, or C(O)CH 2 C(O)R′;
each occurrence of R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group;
each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C 1-8 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′ taken together with the atom(s) to which they are bound, or two occurrences of R′ taken together with the atom(s) to which they are bound, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
11. The compound according to claim 10 , wherein R 3 is selected from halogen, CN, NO 2 , or an optionally substituted group selected from C 1-6 aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —C(O)R′, —COOR′, —NRCOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .
12. The compound according to claim 10 , wherein R 3 is a C1-C6 alkyl group.
13. The compound according to claim 10 , wherein y is 0-4 and each R 5 group, when present, is independently selected from halogen, CN, NO 2 , or an optionally substituted group selected from C 1-4 aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —COOR′, —C(O)R′, —NRCOR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .
14. A compound selected from:
1
6
15
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26
36
48
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53
59
63
78
82
84
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91
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111
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128
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143
.
15. A method of modulating a sodium channel comprising the step of contacting said channel with a compound of formula II-A:
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is independently selected from halogen, CN, CF 3 , NO 2 , or an optionally substituted group selected from C 1-6 aliphatic, C 1-6 cycloaliphatic, C 6-10 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —OR′, —CH 2 OR′, —SR′, —CH 2 SR′, —C(O)R′, —COOR′, —NRCOR′, —CON(R′) 2 , —S(O) 2 R′, or —S(O) 2 N(R′) 2 ;
R 5 is independently Q-R x ;
Q is a bond or is a C 1-6 aliphatic chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S, or NR;
each occurrence of R x is independently selected from R′, halogen, NO 2 , CN, OR′, SR′, N(R′) 2 , NR′C(O)R′, NR′C(O)N(R′) 2 , NR′CO 2 R′, C(O)R′, CO 2 R′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , SOR′, SO 2 R′, SO 2 N(R′) 2 , NR′SO 2 R′, NR′SO 2 N(R′) 2 , C(O)C(O)R′, or C(O)CH 2 C(O)R′;
each occurrence of R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group; and
each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C 1-8 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′ taken together with the atom(s) to which they are bound, or two occurrences of R′ taken together with the atom(s) to which they are bound, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
16. A method of treating or lessening the severity in a subject of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, postherpetic neuralgia, comprising administering an effective amount of a compound according to claim 1 or a pharmaceutically acceptable composition comprising a compound to said subject in need thereof.
17. The method according to claim 16 , wherein said method is used for treating or lessening the severity of acute, chronic, neuropathic, or inflammatory pain.