11,13-modified saxitoxins for the treatment of pain

Patent metadata

Field	Value
Publication number	US-10112953-B2
Application number	US-201615283187-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	Sep 30, 2015
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

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 R 1 , X 1 and X 3 are as described herein.

First claim

What is claimed is:

1. A Compound of Formula (I):

where
R 1 is H, OH, —OS(O) 3 − , —OS(O) 2 R 5 , —OC(O)R 6 , —NR 7 C(O)R 7a , —OC(O)NR 10 R 10a , —NR 11 R 11a , —NH 3 + , —NR 13 S(O) 2 R 13a , or —NR 14 C(O)NR 14a R 14b ;
X 1 is R 3 and X 2 is R 9 ; or
X 1 and X 2 together with the —NC(O)— to which they are attached form a 5 or 6-membered ring where X 1 , X 2 , and the one or two additional ring atoms are independently selected from —C(O)—, —O—, —S—, —NR 8 —, and —C(R 4 )(R 4a )— provided that only one is selected from —O—, —S—, and —NR 8 —; and where the 5 or 6-membered ring is optionally fused at two adjacent carbon atoms, or is optionally fused at one carbon atom and one nitrogen atom which are adjacent to each other, to a form a saturated or unsaturated 6-12 membered bicyclic ring; where the 1, 2, 3, 4, 5, or 6 additional bicyclic ring atoms are independently —CR 12 ═ or —C(R 12 ) 2 —; or
X 1 and X 2 together with the —NC(O)— to which they are attached form 1,3-dioxo-hexahydro-1H-4,7-methanoisoindolyl;
each R 4 and R 4a is independently H; C 1-6 alkyl; or when the 6-12 membered ring is fused at a —C(R 4 )(R 4a —, one or both of the R 4 and R 4a on the —C(R 4 )(R 4a )— form a single or double bond with an adjacent ring atom;
R 8 is hydrogen; C 1-6 alkyl; phenyl optionally substituted with 1, 2, or 3 groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, and cyano; or when the 6-12 membered ring is fused at an —NR 8 —, the R 8 forms a single bond with an adjacent ring atom;
each R 12 is independently hydrogen, halo, C 1-6 alkyl, halo-C 1-6 alkyl, or aryl;
R 3 is —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, or —C(O)phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 5 is H, C 1-6 alkyl, or aryl optionally substituted with 1, 2, 3, or 4 R 5a ;
each R 5a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di- C 1-6 alkylamino, phenyl, or cyano;
R 9 is C 1-6 alkyl, C 1-6 alkoxy, or phenyl where the phenyl is optionally substituted with one or two groups independently selected from halo, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and aryl;
R 6 is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 6a ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 6a ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 6a ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 6a ; biphenyl optionally substituted on either ring with 1, 2, or 3 R 6a ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 6a , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 7 is hydrogen or C 1-6 alkyl;
R 7 a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 7 b; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 7b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 7b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 7b ; biphenyl optionally substituted on either ring with 1, 2, or 3 R 7b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 7b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 10 is hydrogen or C 1-6 alkyl;
R 10a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 10b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 10b ; phenylcarbonyl where the phenyl is optionally substituted with 1, 2, or 3 R 10b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 10b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 10b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 10b , or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 10b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 11 is hydrogen or C 1-6 alkyl;
R 11a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 11b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 11b ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 11b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 11b ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 11b ; or cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl; and
each R 11b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, nitro, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 13 is hydrogen or C 1-6 alkyl;
R 13a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 13b ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 13b , heteroaryl optionally substituted with 1, 2, 3, or 4 R 13b ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 13b , biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 13b ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
each R 13b , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano;
R 14 is hydrogen or C 1-6 alkyl;
R 14a is hydrogen or C 1-6 alkyl;
R 14b ) is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 14c ; aralkyl where the aryl is optionally substituted with 1, 2, 3, or 4 R 14c ; heteroaryl optionally substituted with 1, 2, 3, or 4 R 14c ; heterocyclic optionally substituted with 1, 2, 3, or 4 R 14c ; biphenyl optionally substituted on either ring with 1, 2, 3, or 4 R 14c ; or cycloalkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl; and
each R 14c , when present, is independently halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, halo-C 1-6 alkylthio, C 1-6 alkylsulfinyl, halo-C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, halo-C 1-6 alkylsulfonyl, nitro, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, phenyl, or cyano; or

Assignees

• Siteone Therapeutics Inc
• Univ Leland Stanford Junior

Inventors

• Mulcahy John
• Pajouhesh Hassan
• Shibuya Grant Masaaki
• Delwig Anton
• Miljanich George
• Du Bois Justin

Classifications

• 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

• A61P43/00

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

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/06

  Antimigraine agents · CPC title