Benzenesulfonamide compounds and their use as therapeutic agents

Patent metadata

Field	Value
Publication number	US-9630929-B2
Application number	US-201214355552-A
Country	US
Kind code	B2
Filing date	Oct 30, 2012
Priority date	Oct 31, 2011
Publication date	Apr 25, 2017
Grant date	Apr 25, 2017

Abstract

This invention is directed to benzensulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of sodium channel-mediated diseases or conditions, such as pain.

First claim

What is claimed is:

1. A compound of formula (I):

wherein:
k is 0, 1, 2, 3 or 4;
m is 1;
n is 0, 1, 2, 3, 4 or 5;
q is 0, 1, 2, 3, 4, 5 or 6;
R 1 is —N(R 10 )—, or —N(R 11 )—;
R 2 is C(R 9 );
R 3 is hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl;
or R 3 is a direct bond to R 4 ;
R 4 is H, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, haloalkyl, —C(O)R 10 , —C(O)N(R 10 ) 2 or —C(═NCN)N(R 10 ) 2 ;
or R 3 and R 4 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl;
each R 5 and each R 6 are independently hydrogen, alkyl, halo, haloalkyl, nitro, cyano, —OR 10 , —S(O) t R 10 (where t is 0, 1 or 2), —C(O)OR 10 ,—C(O)R 10 or —C(O)N(R 10 ) 2 ;
each R 7 is independently hydrogen, alkyl, halo, haloalkyl, —OR 10 , —S(O) t R 10 (where t is 0, 1 or 2), —C(O)OR 10 , —C(O)R 10 or —C(O)N(R 10 ) 2 ;
or any two R 7 's on the same carbon may form an oxo and the other R 7 's, if present, are independently hydrogen, alkyl, halo, haloalkyl, —OR 10 , —S(O) t R 10 (where t is 0, 1 or 2), —C(O)OR 10 , —C(O)R 10 or —C(O)N(R 10 ) 2 ;
or any two R 7 's on different carbons may form an optionally substituted straight or branched alkylene chain optionally containing one or more heteroatoms, and the other R 7 's, if present, are independently hydrogen, alkyl, halo, haloalkyl, —OR 10 , —S(O) t R 10 (where t is 0, 1 or 2), —C(O)OR 10 ,—C(O)R 10 or —C(O)N(R 10 ) 2 ,
each R 9 is independently hydrogen, alkyl, halo, haloalkyl, —OR 10 ,—N(R 10 ) 2 , —S(O) t R 10 (where t is 0, 1 or 2), —C(O)OR 10 , —C(O)R 10 or —C(O)N(R 10 ) 2 ;
each R 10 is independently hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and
each R 11 is independently —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —S(O) p R 10 (where p is 1 or 2) or —S(O) p N(R 10 ) 2 (where p is 1 or 2);
or an individual stereoisomer, enantiomer or tautomer thereof or a mixture thereof;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein:
R 3 is hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl;
or R 3 is a direct bond to R 4 ;
R 4 is optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —C(O)N(R 10 ) 2 or —C(═NCN)N(R 10 ) 2 ;
or R 3 and R 4 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl.

3. The compound of claim 2 wherein:
R 3 is hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl;
or R 3 is a direct bond to R 4 ;
R 4 is optionally substituted heterocyclyl, optionally substituted heteroaryl, —C(O)N(R 10 ) 2 or —C(═NCN)N(R 10 ) 2 ;
or R 3 and R 4 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl.

4. The compound of claim 3 wherein:
n is 0, 1, or 2;
q is 0, 1 or 2; and
each R 7 is independently hydrogen, alkyl, halo, haloalkyl, —OR 10 , —S(O) t R 10 (where t is 0, 1 or 2), —C(O)OR 10 , —C(O)R 10 or —C(O)N(R 10 ) 2 .

5. The compound of claim 4 wherein:
k is 0, 1 or 2;
R 3 is hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl;
or R 3 is a direct bond to R 4 ;
R 4 is —C(O)N(R 10 ) 2 , —C(═NCN)N(R 10 ) 2 , optionally substituted heterocyclyl or optionally substituted heteroaryl, where the heterocyclyl is N-heterocyclyl and the heteroaryl is N-heteroaryl;
or R 3 and R 4 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl; and
each R 9 is independently hydrogen, alkyl, halo or haloalkyl.

6. The compound of claim 4 wherein:
k is 0, 1 or 2;
R 1 is —N(R 10 )—;
R 3 is hydrogen, alkyl, haloalkyl, optionally substituted aryl or optionally substituted aralkyl;
or R 3 is a direct bond to R 4 ;
R 4 is —C(O)N(R 10 ) 2 , —C(═NCN)N(R 10 ) 2 , optionally substituted heterocyclyl or optionally substituted heteroaryl, where the heterocyclyl is N-heterocyclyl and the heteroaryl is N-heteroaryl;
or R 3 and R 4 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl; and
each R 9 is independently hydrogen, alkyl, halo, haloalkyl or —OR 10 .

7. The compound of claim 6 wherein:
R 3 is hydrogen or optionally substituted aralkyl;
or R 3 is a direct bond to R 4 ;
R 4 is an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;
each R 5 is independently hydrogen, halo or haloalkyl;
each R 6 is independently hydrogen, halo, haloalkyl or cyano; and
each R 7 is independently hydrogen, alkyl, halo or haloalkyl.

8. The compound of claim 7 wherein:
R 3 is hydrogen or a direct bond to R 4 ;
R 4 is an optionally substituted N-heteroaryl or an optionally substituted N-heterocyclyl;
each R 9 is independently hydrogen; and
each R 10 is independently hydrogen or alkyl.

9. The compound of claim 8 wherein:
R 3 is hydrogen or a direct bond to R 4 ;
R 4 is optionally substituted N-heteroaryl selected from optionally substituted thiadiazolyl,optionally substituted tetrazolyl, optionally substituted isoxazolyl, optionally substituted thiazolyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, or optionally substituted pyridazinyl;
or R 4 is optionally substituted 1,2,4-thiadiazol-5(4H)-ylidene.

10. The compound of claim 1 selected from:
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(pyridin-2-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-3-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)-1-methylpiperidin-3-yl)methoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide2,2,2-trifluoroacetate;
2,5-difluoro-4-((trans-4-(4-fluorophenyl)peperidin-3-yl)methoxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3yl)methoxy)-2,5-difluoro-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(2-methyl-2H-tetrazol-5-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(5-methylisoxazol-3-yl)benzenesulfonamide;
4-((trans-4-(4-chloropheny)piperidin-3-yl)methoxy)-N-(5-chlorothi azol-2-yl)-2,5-difluorobenzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(5-methylthiazol-2-yl)benzenesulfonamide;
4-((trans-4-(4-chlorophenyl)piperidin-3-yl)methoxy)-2,5-difluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide;

Assignees

• Xenon Pharmaceuticals Inc

Inventors

• Sun Shaoyi
• Zenova Alla Yurevna
• Chafeev Mikhail
• Jia Qi
• Zhang Zaihui
• Oballa Renata Marcella

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P35/00

  Antineoplastic agents · CPC title