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
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11834456-B2
Publication Date
2023-12-05
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 invention concerns 11,13-modified saxitoxin compounds defined as Formula (I), Formula (I-P), Formula Xe, Formula Xe-P, and Formula (Id), as pharmaceutically acceptable salt or salts thereof, hydrates, solvates, stereoisomers, tautomers, and mixtures. The compounds are characterized by structural selection rules for X2 and by constraints on R4, R4a, R7, R7a, R7b, and R8 within the defined formulas, with certain embodiments excluding compounds selected from Group A or Group B. Formula Xe adds PG1 and PG2 as nitrogen-protecting groups, and Formula (Id) introduces a multiring scaffold with protonated/amine functionality and n as 1 or 2.
The structural definition specifies that X2 is either —C(R4)(R4a)— or —N(R8)—, with R4 and R4a independently hydrogen or C1-6 alkyl, and R7 hydrogen or C1-6 alkyl. R7a and R7b are chosen from substituent sets that include 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), and cyano, with optional aryl substitution in aryloxy and aryl-C1-6 alkyl. R8 is defined to be hydrogen, C1-6 alkyl, carboxy-C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, or phenyl optionally substituted with specified groups.
The disclosure further includes pharmaceutical compositions containing the compound together with a pharmaceutically acceptable excipient, carrier, or diluent, as well as single unit dosage forms and kits. It also addresses related Formula Xe-P embodiments with nitrogen-protecting groups and a preparation concept for converting a Formula Xe protected compound to Formula I by deprotecting the nitrogen protecting groups, optionally isolating the resulting Formula I compound. The intended use is treatment of pain and other sodium-channel-modulated conditions linked to voltage-gated sodium channel function.
Claims Coverage
The consolidated claim coverage includes formula-defined compound families centered on the same compound class, with extensive substituent constraints, pharmaceutically acceptable salt and related forms, explicit Group A or Group B exclusions, a pharmaceutical composition, and treatment methods linked to voltage-gated sodium channel function.
Formula (I) compound with defined X2 and substitutions
A compound of Formula (I) as a pharmaceutically acceptable salt or salts thereof, wherein X2 is —C(R4)(R4a)— or —N(R8)—, each R4 and R4a is independently hydrogen or C1-6 alkyl, R7 is hydrogen or C1-6 alkyl, R7a is one R7b selected from the stated substituent sets, R8 is one of the stated groups, and the compound is not selected from Group A.
Formula Xe with PG1 and PG2 nitrogen-protecting groups and constrained substituents excluding Group B
A compound of Formula Xe or a salt or salts thereof, where PG1 is a nitrogen-protecting group, PG2 is a nitrogen-protecting group, X2 is —C(R4)(R4a)— or —N(R8)—, each R4 and R4a is independently hydrogen or C1-6 alkyl, R7 is hydrogen or C1-6 alkyl, R7a and R7b are selected from the stated substituent sets, R8 is one of the stated groups, and the compound is not selected from Group B.
Selected compound provided as pharmaceutically acceptable salts and alternative variants
A compound selected from the stated compound set, as a pharmaceutically acceptable salt or salts thereof, or a hydrate, solvate, stereoisomer, tautomer, or mixture thereof.
Pharmaceutical composition including the compound
A pharmaceutical composition comprising the compound in one or more of the stated forms together with a pharmaceutically acceptable excipient, carrier, or diluent.
Treatment or prophylaxis of conditions linked to voltage-gated sodium channel function
A method for treating a mammal condition linked to voltage-gated sodium channel function by administering a therapeutically or prophylactically effective amount of the pharmaceutical composition, including pain, cough, itch, and discomfort associated with dry eye syndrome.
The claims define voltage-gated sodium channel modulating 11,13-modified saxitoxin compound embodiments in pharmaceutically acceptable forms, with extensive structural constraints on Formula (I) and Formula Xe substituents. The Formula Xe claim additionally requires PG1 and PG2 to be nitrogen-protecting groups and excludes compounds in Group B, while the Formula (I) claim excludes compounds in Group A. The claim set further covers pharmaceutical compositions and methods for treating mammal conditions linked to voltage-gated sodium channel function.
Stated Advantages
The compounds are described as NaV-selective analgesics rather than broad NaV antagonism.
The disclosure emphasizes NaV-selective inhibition of voltage-gated sodium channel function.
The disclosure identifies the relevance of NaV isoforms to pain, including NaV1.3, NaV1.7, and NaV1.8.
Documented Applications
Treating pain and discomfort responsive to sodium channel modulation.
Treating pain, cough, itch, or discomfort associated with dry eye syndrome.
Treating pain selected from erythromelalgia, diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, arthritis, osteoarthritis, postherpetic neuralgia, cancer pain, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, postsurgical pain, subacute pain, chronic pain, dry eye syndrome, discomfort associated with dry eye syndrome, pain associated with acute corneal injuries or abrasions, acute ocular pain, chronic ocular pain, pain associated with corneal infections, Parkinson’s disease, ALS, and ocular surgery.
Treating pain and/or sodium-channel-modulated conditions by administering a therapeutically or prophylactically effective amount of the 11,13-modified saxitoxin compounds.
Treating a mammal condition linked to voltage-gated sodium channel function.
Interested in licensing this patent?