Methods and compositions for studying, imaging, and treating pain

Patent metadata

Field	Value
Publication number	US-10513525-B2
Application number	US-201514923349-A
Country	US
Kind code	B2
Filing date	Oct 26, 2015
Priority date	May 7, 2009
Publication date	Dec 24, 2019
Grant date	Dec 24, 2019

Abstract

Saxitoxin analogue compounds, compositions, pharmaceutical compositions, methods of synthesis of saxitoxin analogues, methods of imaging, methods of treatment, including methods of treating pain, are provided. Saxitoxin (STX), gonyautoxin (GTX), and zetekitoxin, and variant STX compounds bind to sodium channels and are effective to reduce or block flow of sodium ions through such channels. Such channel block affects nerve and muscle action, and may be effective to reduce or block pain sensations, relax muscles, reduce muscle spasm, and reduce wrinkles. STX analogue binding to sodium channels may also be useful to locate, image, or mark sodium channels, and so be useful in studying sodium channels and sodium channel disorders, and in the diagnosis and treatment of patients suffering from sodium channel disorders. In embodiments, the variant STX compounds include conjugates having increased serum half-life as compared to STX when administered to a subject. Also provided are methods for alleviating pain in a subject in need of treatment.

First claim

What is claimed is:

1. A compound having structure A shown below, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the above:

wherein R1 is selected from the group consisting of: halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, perfluoroalkyl, cycloalkyl, (cycloalkyl)alkyl, substituted phenyl, (substituted phenyl)alkyl, aryl, heteroaryl, heterocyclic, heterocyclo, alkanoyl, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, heteroaryl(alkyl), nitro, oxa, oxo, sulfonyl, sulfonamido, sulfone, —OR A , ═O, —C(═O)R A , —OC(═O)OR A , —CO 2 R A , —CN, —SCN, —SR A , —SOR A , —SO 2 R A , —NO 2 , —N(R A ) 2 , —NHC(O)R A , and —C(R A ) 3 , wherein each occurrence of R A can be independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, haloalkyl, perhaloalkyl, cycloalkyl, (cycloalkyl)alkyl, substituted phenyl, (substituted phenyl)alkyl, aryl, heteroaryl, heterocyclic, heterocyclo, alkanoyl, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, heteroaryl(alkyl), nitro, oxa, oxo, sulfonyl, sulfonamido, and sulfone;
wherein R2 is hydrogen;
wherein R3 is hydrogen or alkyl;
wherein R4 is hydrogen or alkyl;
wherein R5 is hydrogen or —OSO 3 − ;
wherein R6 is hydrogen or —OSO 3 − ; and
wherein R7 is hydrogen,
with the proviso that the compound having structure A is not a compound selected from dcSTX, dcGTX2 and dcGTX3.

2. The compound of claim 1 having structure B shown below, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the above:

3. The compound of claim 1 having structure C shown below, a tautomer thereof, or a pharmaceutically acceptable salt of any of the above:

4. The compound of claim 1 linked to a label selected from the group consisting of: a radioisotope, a fluorescent moiety, a chemiluminescent moiety, an enzyme, an antibody, an antibody fragment, a magnetic particle, and a quantum dot.

5. A pharmaceutical composition comprising the compound of claim 1 , or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt of any of the above.

6. The compound of claim 1 , wherein said compound has a longer duration of action of anesthetic effect than saxitoxin.

7. The compound of claim 1 , wherein R1 is hydroxyl, alkoxyl, cyano, heteroaryl, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, —OR A , ═O, —OC(═O)OR A , —CN, —SCN, —SR A , —SOR A , —SO 2 R A , —NO 2 , —N(R A ) 2 , or —NHC(O)R A , wherein each occurrence of R A can be independently a group such as hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, haloalkyl, perhaloalkyl, cycloalkyl, (cycloalkyl)alkyl, substituted phenyl, (substituted phenyl)alkyl, aryl, heteroaryl, heterocyclic, heterocyclo, alkanoyl, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, heteroaryl(alkyl), nitro, oxa, oxo, sulfonyl, sulfonamido, or sulfone.

8. The compound of claim 1 , wherein R A is independently hydrogen, methyl, isopropyl, tetradecyl, or any one of the following:

Assignees

• Univ Leland Stanford Junior

Inventors

• Du Bois Justin
• Mulcahy John
• Andresen Brian
• Yeomans David C
• Biswal Sandip

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title