10′,11′-modified saxitoxins useful for the treatment of pain
Inventors
Pajouhesh, Hassan • Miljanich, George • Mulcahy, John • Du Bois, Justin • AXTMAN, Matthew • Walker, James • Merit, Jeffrey E.
Assignees
Leland Stanford Junior University • SiteOne Therapeutics Inc
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Publication Number
US-10106549-B2
Publication Date
2018-10-23
Expiration Date
Abstract
Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating conditions associated with voltage-gated sodium channel function, for example conditions associated with pain. The compounds are 10′,11′-modified saxitoxins. The compounds are optionally additionally modified at carbon 13. In certain embodiments, the 10′,11′-modified saxitoxins are of Formula I: where R1, R2 and R3 are as described herein. Also provided herein are methods of treating pain in a mammal comprising administering an effective treatment amount of a 10′,11′ modified saxitoxin or composition to a mammal. In an embodiment, the mammal is a human.
Core Innovation
The invention relates to a compound according to Formula I, including a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form or polymorphic form thereof. The structural definition uses variables R1 and R2 to specify substituents and functional groups, together with further structural definitions for R3, R4, R5, and aryl/heteroaryl substituent variables R101, R102, and R103. The compound scope includes multiple provisos that restrict which combinations are permitted.
R1 and R2 include hydrogen, halogen, hydroxylalkyl, heteroalkyl, unsubstituted or substituted alkyl, aryl, heteroaryl, hydroxyl, O-(unsubstituted alkyl), carbonyl-associated substituents, and sulfur- and oxygen-containing alternatives such as —OSO3H and —OS(O)2-. The compound scope also includes the case where R1 and R2, together with the two carbon atoms to which they are attached, form a six to ten-membered unsubstituted carbocyclic ring. Additional provisions restrict combinations such as R1 being hydrogen with R2 being hydroxyl or —OSO3H, and require corresponding non-excluded selections for R3 or R4/R5.
The claims further provide narrower variants and related products by constraining particular parameters, such as setting R1 to hydrogen in a defined subset of Formula I compounds. The document also includes a pharmaceutical composition definition that uses the Formula I compound with a pharmaceutically acceptable excipient, carrier, or diluent. In addition, the document includes a preparation-related narrowing that deprotects a compound of Formula XXa to obtain the Formula I compound, optionally followed by isolating the resulting Formula I compound.
Claims Coverage
The provided independent claims define a Formula I compound family with multiple selectable substituent groups and several proviso exclusions, plus additional independent claim coverage for a pharmaceutical composition and a preparation approach. Across the independent claims in the provided set, the inventive features amount to three broad features.
Formula I compound family with substitution and provisos
A compound according to Formula I (or a pharmaceutically acceptable salt, stereoisomeric form, tautomeric form or polymorphic form thereof) in which R1 and R2 take defined substituent sets, optionally forming a six to ten-membered unsubstituted carbocyclic ring, with R3 defined as hydrogen or —C(O)NR4R5, R4 and R5 independently hydrogen or alkyl variants, and R101, R102, and R103 defined with additional proviso limitations excluding certain combinations.
Pharmaceutical composition with pharmaceutically acceptable excipient, carrier, or diluent
A pharmaceutical composition comprising the compound of claim 1 in combination with a pharmaceutically acceptable excipient, carrier, or diluent.
Deprotecting Formula XXa to obtain Formula I
A method for preparing a compound of Formula I by deprotecting a compound of Formula XXa, optionally followed by isolating the resulting Formula I compound.
The provided independent-claim set covers a broad but constrained Formula I compound family using R-group substitution definitions and multiple provisos, a pharmaceutical composition defined by formulation with pharmaceutically acceptable excipients, carriers, or diluents, and preparation coverage defined as deprotecting Formula XXa to yield Formula I, with optional isolation.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Pain treatment by modulating voltage-gated sodium channel activity, including sodium channel isoforms implicated in nociception.
Administering an effective amount of the compounds to a mammal, including humans, for pain treatment.
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