11,13-modified saxitoxins for the treatment of pain

Patent metadata

Field	Value
Publication number	US-11279706-B2
Application number	US-201816499201-A
Country	US
Kind code	B2
Filing date	Mar 29, 2018
Priority date	Mar 29, 2017
Publication date	Mar 22, 2022
Grant date	Mar 22, 2022

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 X2 are as described herein.

First claim

What is claimed is:

1. A compound of Formula (I):

where
R 1 is H, OH, —OSO 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 , —NR 14 C(O)NR 14a R 14b , or heterocycloalkyl;
X 1 is absent;
X 2 is —OH, —OR 4 , or —NR 2 R 3 ;
R 2 is hydrogen or C 1 -C 3 -alkyl; and R 3 is hydrogen, —OH, C 1-6 alkoxy, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, or heterocycloalkyl; or
R 2 and R 3 together with the nitrogen to which they are attached form a five or six membered heterocyclic ring optionally substituted with one, two, or three groups independently selected from halo, hydroxy, C 1-6 alkyl, and C 1-6 alkoxycarbonyl;
R 4 is C 1 -C 6 -alkyl or aryl-C 1-3 -alkyl;
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 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, 4, 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, 3, or 4 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 7a is C 1-6 alkyl; aryl optionally substituted with 1, 2, 3, or 4 R 7b ; 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, 3, or 4 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, 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 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, 3, or 4 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, 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, 3, or 4 groups independently selected from C 1-6 alkyl and halo-C 1-6 alkyl;
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, 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 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;
as a pharmaceutically acceptable salt or salts thereof; or a hydrate, solvate, stereoisomer, tautomer, or mixture thereof.

2. The compound of claim 1 where the compound is according to Formula (Ib):

as a pharmaceutically acceptable salt or salts thereof, or a hydrate, solvate, stereoisomer, tautomer, or mixture thereof.

3. The compound of claim 1 where X 2 is —OH.

4. The compound of claim 1 where X 2 is —NR 2 R 3 .

5. The compound of claim 1 where R 2 and R 3 are each hydrogen; or R 2 is hydrogen and R 3 is C 1 -C 6 -alkyl; or R 2 is hydrogen and R 3 is —OH; or R 2 is hydrogen and R 3 is C 1-6 alkoxy; or R 2 is C 1 -C 3 -alkyl and R 3 is C 1 -C 6 -alkyl.

6. The compound of claim 1 where
R 5 is aryl optionally substituted with 1, 2, 3, or 4 R 5a ;
R 6 is aryl optionally substituted with 1, 2, 3, or 4 R 6a ; heterocyclic optionally substituted with 1, 2, 3, or 4 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;
R 7a is aryl optionally substituted with 1, 2, 3, or 4 R 7b ; heterocyclic optionally substituted with 1, 2, 3, or 4

Assignees

• Siteone Therapeutics Inc
• Univ Leland Stanford Junior

Inventors

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

Classifications

• A61P29/00

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• C07D487/14 Primary

  Ortho-condensed systems · CPC title