Permanently charged sodium and calcium channel blockers as anti-inflammatory agents
AssigneesChildren's Medical Center Corporation, President and Fellows of Harvard College, The General Hospital Corporation
InventorsClifford J. Woolf, Bruce P. Bean
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Abstract
The invention provides compounds, compositions, methods, and kits for the treatment or neurogenic inflammation.
Claims44
A method for treating neurogenic inflammation in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound that is capable of (i) entering a nociceptor through a channel-forming receptor present in said nociceptor when said receptor is activated and (ii) inhibiting a voltage-gated ion channel present in said nociceptor, wherein said compound does not substantially inhibit said channel when applied to the extracellular face of said channel and when said receptor is not activated.
A kit comprising:
- a) a compound that is capable of (i) entering a nociceptor through a channel-forming receptor present in said nociceptor when said receptor is activated and (ii) inhibiting a voltage-gated ion channel present in said nociceptor, wherein said compound does not substantially inhibit said channel when applied to the extracellular face of said channel and when said receptor is not activated;
- and
- b) instructions for administering said compound to a patient to treat neurogenic inflammation.
A compound according to Formula (XI):
- wherein
- each R11A, R11B, and R11C is selected, independently, from H or C1-4 alkyl, and X′ is any pharmaceutically acceptable anion.
A compound according to Formula (XII),
- wherein
- each of R12A, R12B, R12C, and R12D is, independently, selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 heteroalkyl, C7-14 alkaryl, C3-10 alkcycloalkyl, and C3-10 alkheterocyclyl;
- or R12A and R12B together complete a heterocyclic ring having at least one nitrogen atom;
- n is an integer between 1-5;
- each of R12E and R12F is, independently, selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 heteroalkyl, C7-14 alkaryl, C3-10 alkcycloalkyl, or C3-10 alkheterocyclyl;
- and
- X is any pharmaceutically acceptable anion.
A compound having a structure according to:
- wherein
- each R13A-R13J and R13O-R13T is selected, independently, from H, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 heteroalkyl, C7-14 alkaryl, C3-10 alkcycloalkyl, and C3-10 alkheterocyclyl, OR13AA, NR13ABR13AC, NR13ADC(O)R13AE, S(O)R13AF, SO2R13AGR13AH, SO2NR13AIR13AJ, SO3R13AK, CO2R13AL, C(O)R13AM, and C(O)NR13ANR13AO;
- each of R13AA-R13AO is, independently, selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C2-4 heteroalkyl;
- each R13K, R13L, R13M, and R13N is, independently, H or C1-4 alkyl, or R13K and R13L, or R13M and R13N, combine to form C═O, or R13K and R13M combine to form C═C;
- R13Y is H or C1-4 alkyl;
- R13Z and R13Z′ are, independently, selected from H, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 heteroalkyl, C7-14 alkaryl, C3-10 alkcycloalkyl, and C3-10 alkheterocyclyl;
- and
- X′ is any pharmaceutically acceptable anion.
A compound having a structure according to
- wherein
- n is an integer between 0-5;
- R14A is heterocyclyl,
- each of R14B, R14C, R14D), and R14E is, independently, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 heteroalkyl, C7-14 alkaryl, C3-10 alkcycloalkyl, and C3-10 alkheterocyclyl;
- and
- R14F is selected from H, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 heteroalkyl, C7-14 alkaryl, C3-10 alkcycloalkyl, and C3-10 alkheterocyclyl, OR14G, NR14HR14I, NR14JC(O)R14K, S(O)R14L, SO2R14MR14N, SO2NR14OR14P, SO3R14Q, CO2R14R, C(O)R14S, and C(O)NR14TR14V;
- and each of R14G-R13AO is, independently, selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C2-4 heteroalkyl.
A pharmaceutical composition, comprising a quarternary amine derivative or other charged derivative of any of compounds (1)-(563).
Dependencies are inferred from the claim text.