11,13-modified saxitoxins for the treatment of pain
Inventors
Pajouhesh, Hassan • Zhou, Xiang • Mulcahy, John
Assignees
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Publication Number
US-12162886-B2
Publication Date
2024-12-10
Expiration Date
Abstract
Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function where the compounds are 11,13-modified saxitoxins according to Formula (I): (Formula (I)); where R1, and R2 are as described herein.
Core Innovation
The invention relates to compounds defined by Formula (I) and Formula (X), including related compounds of Formula (I-P1), Formula (I-P), Formula (Ia), Formula (Ib), and Formula (X-3), with substituent variables constrained to defined chemical classes and structural options. The disclosed scope includes pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or combinations thereof, and in Formula (X) the compounds are described as protected-amine scaffolds with nitrogen-protecting groups PG1 and PG2.
The structural disclosure emphasizes aryl, heterocycle, and biphenyl options for R7a, with optional substitution by defined R7b groups, and further describes ring systems such as chromanyl, 2,3-dihydrobenzofuranyl, and other fused or ring systems. Additional scaffold features include X2 being halo, CN, or N3 in Formula (X), and Y being hydrogen or a Boc group in related embodiments.
The provided material also describes 11,13-modified saxitoxin derivatives represented by Formula (I) and Formula (X), with specific compounds and analogs identified by numbered examples. The disclosure frames the compounds for therapeutic use in pain and for affecting voltage-gated sodium channel function, and it includes pharmaceutical compositions and methods of use.
Claims Coverage
The consolidated claim coverage centers on two independent compound claims, Formula (I) and Formula (X), together with a method of treating selected pain conditions. Across these claims, the inventive features focus on the defined scaffold classes, the permitted substituent patterns, and the inclusion of pharmaceutically acceptable salt and stereochemical/tautomeric forms. In total, the merged claim set presents three main inventive features.
Compound of Formula (I) with constrained substituent classes
A compound of Formula (I) wherein substituent variables are defined by the listed substituent classes and ring options, and the compound is provided as a pharmaceutically acceptable salt or salts, a stereoisomer, a mixture of stereoisomers, a tautomer, or combinations thereof.
Protected-amine compound of Formula (X) with nitrogen-protecting groups
A compound of Formula (X) as a salt or salts thereof in which PG1 and PG2 are nitrogen-protecting groups; X2 is halo, CN, or N3; R2 is —NR7C(O)R7a; and R7, R7a, and R7b are defined with constrained substitution patterns, including aryl, heterocycle, or biphenyl optionally substituted with 1, 2, 3, or 4 R7b.
Method of treating specified pain conditions
A method of treating pain conditions associated with voltage-gated sodium channel function, with pain subtypes selected from erythromelalgia, diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, postherpetic neuralgia, cancer pain, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, and postsurgical pain.
The claim coverage is anchored on Formula (I) and Formula (X) compound definitions with extensive but explicit substituent constraints, together with salt and stereochemical/tautomeric variants. The claim set also recites a method of treating the listed pain conditions associated with voltage-gated sodium channel function.
Stated Advantages
Treating pain and related NaV-associated conditions using voltage-gated sodium channel (NaV) modulators.
Documented Applications
A pharmaceutical composition comprising the compound with a pharmaceutically acceptable carrier.
A method of treating pain conditions associated with voltage-gated sodium channel function, including the listed pain disorders and pain types.
Treating pain and/or affecting voltage-gated sodium channel function using the disclosed compounds, compositions, and kits.
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