11,13-modified saxitoxins for the treatment of pain
Inventors
Mulcahy, John • Pajouhesh, Hassan • Miljanich, George • DELWIG, ANTON • BECKLEY, Jacob • SHIBUYA, Grant Masaaki • Du Bois, Justin
Assignees
Leland Stanford Junior University • SiteOne Therapeutics Inc
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Publication Number
US-11236097-B2
Publication Date
2022-02-01
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): where R4, R4a, R7, R7a, and X2 are as described herein.
Core Innovation
The disclosure provides compounds of Formula (I) and pharmaceutically acceptable salt(s), hydrate, solvate, stereoisomer, tautomer, or mixture thereof. The compounds are defined by structural variables including X2 as —N(R8)—, R4 and R4a independently hydrogen or C1-6 alkyl, R7 hydrogen or C1-6 alkyl, and R7a as aryl, heterocyclic, or biphenyl optionally substituted with 1, 2, 3, or 4 R7b.
Each R7b is independently selected from halo, C1-6 alkyl, halo-C1-6 alkyl, aryl-C1-6 alkyl, hydroxy, C1-6 alkoxy, halo-C1-6 alkoxy, aryloxy, nitro, C1-6 alkylthio, halo-C1-6 alkylthio, C1-6 alkylsulfinyl, halo-C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, halo-C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di-C1-6 alkylamino, —C(O)(heterocycloalkyl), or cyano, and R8 is C3-C8-cycloalkyl. Additional embodiments define Formula Xe as a nitrogen-protected precursor with PG1 and PG2 as nitrogen-protecting groups and the same X2, R4/R4a, R7, R7a, R7b, and R8 framework.
Related embodiments include Formula (Ic) and Formula (Id) variants, with further listed meanings for R8 and specified heterocycle options in R7a. A method of preparing a compound of Formula (I) is described by deprotecting a compound of Formula Xe or a salt thereof to yield Formula (I), followed by optional isolating of the Formula (I) compound.
The disclosure also links 11,13-modified saxitoxin compounds to voltage-gated sodium channel function and states that the compounds are for treating pain and other conditions associated with NaV channel involvement.
Claims Coverage
The consolidated set includes three independent claims: a compound of Formula (I), a compound of Formula Xe, and a method of preparing Formula (I) by deprotecting Formula Xe. Across these claims, the coverage centers on defined substituent-variable chemical structures, with X2 as —N(R8)—, R4/R4a and R7 constrained to hydrogen or C1-6 alkyl, R7a selected from aryl, heterocyclic, or biphenyl forms with optional R7b substitution, and R8 as C3-C8-cycloalkyl.
Formula (I) compound with defined X2 and substituent scope
A compound of Formula (I) wherein X2 is —N(R8)—; R4 and R4a are independently hydrogen or C1-6 alkyl; R7 is hydrogen or C1-6 alkyl; R7a is aryl, heterocyclic, or biphenyl optionally substituted with 1, 2, 3, or 4 R7b; each R7b is independently selected from the enumerated set including halo, C1-6 alkyl, halo-C1-6 alkyl, aryl-C1-6 alkyl, hydroxy, C1-6 alkoxy, halo-C1-6 alkoxy, aryloxy, nitro, C1-6 alkylthio, halo-C1-6 alkylthio, C1-6 alkylsulfinyl, halo-C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di-C1-6 alkylamino, —C(O)(heterocycloalkyl), or cyano; and R8 is C3-C8-cycloalkyl, including pharmaceutically acceptable salt(s), hydrate, solvate, stereoisomer, tautomer, or mixture thereof.
Formula Xe compound with nitrogen-protecting groups
A compound of Formula Xe or salt(s) thereof, where PG1 and PG2 are nitrogen-protecting groups; X2 is —N(R8)—; R4 and R4a are independently hydrogen or C1-6 alkyl; R7 is hydrogen or C1-6 alkyl; R7a is aryl, heterocyclic, or biphenyl optionally substituted with 1, 2, 3, or 4 R7b; each R7b is independently selected from the enumerated substituent set; and R8 is C3-C8-cycloalkyl.
Deprotecting a Formula Xe precursor to yield Formula (I)
A method of preparing a compound of Formula (I) comprising deprotecting a compound of Formula Xe or salt thereof, where PG1 and PG2 are nitrogen-protecting groups and X2 is —N(R8)— with the recited R4, R4a, R7, R7a, R7b, and R8 definitions, to yield a compound of Formula I, and optionally isolating the compound of Formula I.
The independent claims define Formula (I) compounds with constrained substituent patterns, corresponding Formula Xe precursor compounds with nitrogen-protecting groups, and a deprotection-based preparation method that yields Formula (I) with optional isolation.
Stated Advantages
Surprisingly improved potency for isoform NaV 1.7.
Improved selectivity versus undesired NaV isoforms compared with prior art compounds.
Treating pain and other conditions associated with voltage-gated sodium channel function, including conditions associated with dry eye syndrome.
Documented Applications
Treating a condition associated with voltage-gated sodium channel function in a mammal, including pain, cough, itch, or discomfort associated with dry eye syndrome.
Administration to a mammal, including a human, using a therapeutically or prophylactically effective amount in a pharmaceutical composition for conditions linked to voltage-gated sodium channel function.
Treating pain and voltage-gated sodium-channel modulated conditions using therapeutically or prophylactically effective amounts of 11,13-modified saxitoxin compounds.
Pharmaceutical compositions, single-unit dosage forms, and kits.
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