11,13-modified saxitoxins for the treatment of pain
AssigneesSiteone Therapeutics, Inc., The Board of Trustees of the Leland Stanford Junior University
InventorsJohn Mulcahy, Hassan Pajouhesh, George Miljanich, Anton Delwig, Jacob Beckley, Grant Masaaki Shibuya, Justin Du Bois
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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.
Claims29
A Compound of Formula (I):
- wherein
- X2 is —N(R8)—;
- R4 and R4a are independently hydrogen or C1-6alkyl;
- R7 is hydrogen or C1-6alkyl;
- R7a is aryl optionally substituted with 1, 2, 3, or 4 R7b;
- heterocyclic optionally substituted with 1, 2, 3, or 4 R7b;
- or biphenyl optionally substituted with 1, 2, 3, or 4 R7b;
- each R7b, when present, is independently halo, C1-6alkyl, halo-C1-6alkyl, aryl-C1-6alkyl, hydroxy, C1-6alkoxy, halo-C1-6alkoxy, aryloxy, nitro, C1-6alkylthio, halo-C1-6alkylthio, C1-6alkylsulfinyl, halo-C1-6alkylsulfinyl, C1-6alkylsulfonyl, halo-C1-6alkylsulfonyl, amino, C1-6alkylamino, di-C1-6alkylamino, —C(O)(heterocycloalkyl), or cyano;
- where the aryl in aryloxy and aryl-C1-6alkyl are optionally substituted with 1, 2, or 3 groups independently selected from C1-6alkyl, halo, and halo-C1-6alkyl;
- and
- R8 is C3-C8-cycloalkyl;
- or
- as a pharmaceutically acceptable salt or salts thereof;
- or a hydrate, solvate, stereoisomer, tautomer, or mixture thereof.
A compound of Formula Xe
- or salt(s) thereof, where
- PG1 is a nitrogen-protecting group;
- PG2 is a nitrogen-protecting group;
- X2 is —N(R8)—;
- R4 and R4a are independently hydrogen or C1-6alkyl;
- R7 is hydrogen or C1-6alkyl;
- R7a is aryl optionally substituted with 1, 2, 3, or 4 R7b;
- heterocyclic optionally substituted with 1, 2, 3, or 4 R7b;
- or biphenyl optionally substituted with 1, 2, 3, or 4 R7b;
- each R7b, when present, is independently halo, C1-6alkyl, halo-C1-6alkyl, aryl-C1-6alkyl, hydroxy, C1-6alkoxy, halo-C1-6alkoxy, aryloxy, nitro, C1-6alkylthio, halo-C1-6alkylthio, C1-6alkylsulfinyl, halo-C1-6alkylsulfinyl, C1-6alkylsulfonyl, halo-C1-6alkylsulfonyl, amino, C1-6alkylamino, di-C1-6alkylamino, —C(O)(heterocycloalkyl), or cyano;
- where the aryl in aryloxy and aryl-C1-6alkyl are optionally substituted with 1, 2, or 3 groups independently selected from C1-6alkyl, halo, and halo-C1-6alkyl;
- and
- R8 is C3-C8-cycloalkyl.
A method of preparing a compound of Formula (I) comprising
- a) deprotecting a compound of Formula Xe
- or salt thereof, where
- PG1 is a nitrogen-protecting group;
- PG2 is a nitrogen-protecting group;
- X2 is —N(R8)—;
- R4 and R4a are independently hydrogen or C1-6alkyl;
- R7 is hydrogen or C1-6alkyl;
- R7a is aryl optionally substituted with 1, 2, 3, or 4 R7b;
- heterocyclic optionally substituted with 1, 2, 3, or 4 R7b;
- or biphenyl optionally substituted with 1, 2, 3, or 4 R7b;
- each R7b, when present, is independently halo, C1-6alkyl, halo-C1-6alkyl, aryl-C1-6alkyl, hydroxy, C1-6alkoxy, halo-C1-6alkoxy, aryloxy, nitro, C1-6alkylthio, halo-C1-6alkylthio, C1-6alkylsulfinyl, halo-C1-6alkylsulfinyl, C1-6alkylsulfonyl, halo-C1-6alkylsulfonyl, amino, C1-6alkylamino, di-C1-6alkylamino, —C(O)(heterocycloalkyl), or cyano;
- where the aryl in aryloxy and aryl-C1-6alkyl are optionally substituted with 1, 2, or 3 groups independently selected from C1-6alkyl, halo, and halo-C1-6alkyl;
- and
- R8 is C3-C8-cycloalkyl;
- to yield a compound of Formula I;
- and
- b) optionally isolating the compound of Formula I.
Dependencies are inferred from the claim text.