11,13-modified saxitoxins for the treatment of pain

Inventors

Mulcahy, John • Pajouhesh, Hassan • SHIBUYA, Grant Masaaki • DELWIG, ANTON • Miljanich, George • Du Bois, Justin

Assignees

Leland Stanford Junior University • SiteOne Therapeutics Inc

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 R1, X1 and X3 are as described herein.

Core Innovation

The invention provides compounds of Formula (I), including Formula (Ia) and Formula (Ib), with defined substituent options and ring-formation rules. The variables include R1, X1, X2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14, together with stereoisomer, tautomer, and mixture options, and pharmaceutically acceptable salts and hydrate/solvate forms.

X1 is defined as R3 and X2 is defined as R9, or X1 and X2 together with a −NC(O)− linkage form a 5- or 6-membered ring. The 5- or 6-membered ring is optionally fused at adjacent carbon atoms, or fused at adjacent carbon and nitrogen atoms, to form a saturated or unsaturated 6-12 membered bicyclic ring, with additional bicyclic ring atoms selected from −CR12− or −C(R12)2−.

The specification also includes a specific ring-system alternative, where X1 and X2 together with the −NC(O)− linkage form 1,3-dioxo-hexahydro-1H-4,7-methanoisoindolyl. Related claim content also defines a Formula Xe compound with PG1 and PG2 as specified nitrogen-protecting groups, and a method of preparing a compound of Formula (I) by deprotecting a compound of Formula Xe.

Claims Coverage

The consolidated claim coverage includes three independent claim directions: a compound of Formula (I), a compound of Formula Xe, and a preparation method converting Formula Xe to Formula (I), plus a therapeutic method claim. The claim set emphasizes scaffold definition, ring-formation and fusion constraints, nitrogen-protecting groups, and pharmacologically relevant coverage tied to voltage-gated sodium channel function.

Overall, the claims center on a broadly defined Formula (I) chemical scaffold with detailed ring-formation and substituent constraints, a protected-nitrogen Formula Xe precursor, a deprotection preparation method, and a therapeutic method linked to voltage-gated sodium channel function.

Stated Advantages

Documented Applications