Substituted benzamides and methods of use thereof
Inventors
Chowdhury, Sultan • Dehnhardt, Christoph Martin • Focken, Thilo • GRIMWOOD, Michael Edward • Hemeon, Ivan William • MCKERRALL, Steven • Sutherlin, Daniel
Assignees
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Publication Number
US-11203572-B2
Publication Date
2021-12-21
Expiration Date
Abstract
The invention provides compounds having the general formula I: and pharmaceutically acceptable salts thereof, wherein the variables RA, RAA, subscript n, ring A, X2, L, subscript m, X1, ring B, R1, and RN have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
Core Innovation
The disclosed subject matter relates to compounds of formula I, including substituted aromatic and heteroaromatic cores linked to an amide/sulfonamide-like moiety and a benzamide scaffold with specified ring A, ring B, and a linker L. Representative embodiments include multiple substituted ring systems bearing fluoro, chloro, trifluoromethyl, difluoromethyl, methoxy, and cycloalkyl-type substituents, together with pharmaceutically acceptable salts, prodrug, metabolite, solvate, tautomer, stereoisomers, and isotopes.
The invention addresses treatment of pain and related conditions, with emphasis on sodium channel-mediated diseases including pain and pruritus. The disclosed compounds are described as selective inhibitors of NaV1.7 by voltage-dependent sodium channel inhibition, and the background frames the therapeutic problem as achieving isoform-selective blockers of voltage-gated sodium channels with improved therapeutic index.
The document also describes pharmaceutical compositions comprising a Formula I compound and pharmaceutically acceptable excipients, and therapeutic use extending to depression, cardiovascular diseases, respiratory diseases, psychiatric diseases, cancer, and pruritus. Scheme and examples are provided for specific Formula I embodiments, including substituted benzamide structures and prodrug or metabolite variants.
Claims Coverage
The consolidated independent claim coverage centers on a method of treating pain in a mammal by administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. The claim scope is defined by extensive structural constraints on ring A, ring B, linker L, X1 and X2, indices m and n, and multiple substituent options, with dependent scope further narrowing selected substituents and pain categories.
Method of treating pain with formula I compounds
A method of treating pain in a mammal by administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
Defined substituent and ring framework
Formula I includes defined selections for R1, RAA, RA, ring A, ring B, X1, X2, L, m, and n, with ring and substituent options spanning carbocyclyl, aryl, heteroaryl, heterocyclyl, and multiple optional substituent groups.
Linker L and X1/X2 selections
L is selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene, optionally substituted with from 1 to 3 substituents selected from O, C1-4 alkyl, halo, and C1-4 haloalkyl; X1 and X2 are each independently selected from absent, O, S(O), S(O)2, and N(RX), with the m-dependent presence constraint.
Optional selection of pain type
Dependent scope includes selected pain categories and combinations, including neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder pain, ulcerative colitis pain, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, and peripheral nerve injury.
Overall, the claim coverage is anchored in a pain-treatment method in mammals using therapeutically effective administration of a Formula I compound class. The inventive features are the formula-defined ring, linker, and substituent architecture, together with optional narrowing to specific pain categories.
Stated Advantages
Selectively inhibits NaV1.7 by voltage-dependent sodium channel inhibition.
The disclosure states an improved therapeutic index for treating sodium-channel mediated diseases.
Documented Applications
Treatment of pain in a mammal, including neuropathic pain, inflammatory pain, and many named pain subtypes.
Treatment of pruritus.
Treatment of depression.
Treatment of cardiovascular diseases.
Treatment of respiratory diseases.
Treatment of psychiatric diseases.
Treatment of cancer.
Use in pharmaceutical compositions comprising a compound of Formula I and pharmaceutically acceptable excipients.
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