Sulfonylguanidine compounds and pharmaceutical uses thereof

Abstract

Sulfonylguanidine compounds corresponding to the tautomeric formulas I and Ia, a method for producing them, pharmaceutical compositions containing them, and methods of using them to prepare medicaments and for treating various medical conditions. The sulfonylguanidine compounds have an affinity for the gabapentin binding site and can be used to treat conditions such as pain, epilepsy, migraine and others.

What is claimed is:  
     
         1 . A method of treating a condition selected from: 
 the group consisting of pain, epilepsy and migraine; or    the group consisting of hyperalgesia, allodynia, inflammatory pain and post-operative pain; or    the group consisting of hot flashes, post-menopausal symptoms, amyotropic lateral sclerosis (ALS), reflex sympathetic dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired nystagmus, psychiatric or neuropathological disorders, painful diabetic neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease, neurodegenerative diseases, gastrointestinal lesions, erythromelalgic or post-poliomyelitic pain, and trigeminal or post-herpetic neuralgia; or 
 a method of providing anticonvulsant, analgesic or anxiolytic treatment;  
 said method comprising administering to a patient in need thereof a pharmaceutically effective amount of a sulfonylguanidine compound corresponding to at least one of the tautomeric formulas I and Ia,  
                     
 wherein  
   R 1  is aryl or heteroaryl, that may be unsubstituted or singly or multiply substituted;    R 2  is selected from the group consisting of: 
 C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, and singly or multiply substituted or unsubstituted;  
 C 3-8 -cycloalkyl that is saturated or unsaturated, and singly or multiply substituted or unsubstituted;  
 aryl or heteroaryl, that is unsubstituted or singly or multiply substituted;  
 aryl, C 3-9 -cycloalkyl and heteroaryl, that is bonded via saturated or unsaturated C 1-3 -alkyl, S(O) 2  or NH, and that is unsubstituted or singly or multiply substituted;  
 NR 4 R 5  
 where R 4 , R 5  are independently selected from the group consisting of H; C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, and singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, and singly or multiply substituted or unsubstituted; aryl or heteroaryl, that is unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, and unsubstituted or singly or multiply substituted; or  
 R 4  and R 5  together form —CH 2 CH 2 OCH 2 CH 2 —,  
 —CH 2 CH 2 N(R 7 ) CH 2 CH 2 —, where R 7  is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, and singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, and singly or multiply substituted or unsubstituted; aryl or heteroaryl, that is unsubstituted or singly or multiply substituted; or  
 aryl, C 3-9 -cycloalkyl or heteroaryl, that is bonded via saturated or unsaturated C 1-3 -alkyl, and that is unsubstituted or singly or multiply substituted; and  
 
 SO 2 R 6  
 where R 6  is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, and singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, and singly or multiply substituted or unsubstituted; aryl or heteroaryl, that is unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, that is bonded via saturated or unsaturated C 1-3 -alkyl, and that is unsubstituted or singly or multiply substituted;  
 
   R 3  is H or CH 3 ; or    R 2  and R 3  together form    —CH 2 (CH 2 ) n CH 2 —, where n=2 or 3, —CH 2 CH 2 OCH 2 CH 2 —, or —CH 2 CH 2 N(R 8 )CH 2 CH 2    where R 8  is C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, and singly or multiply substituted or unsubstituted;    optionally in the form of a racemate, a pure stereoisomer, enantiomer or diastereomer, or a mixture of stereoisomers, enantiomers or diastereomers; in the form of a free acid or free base or a physiologically compatible salt, or in the form of a solvate, or a hydrate; in both tautomeric forms corresponding to formulas I and Ia, or exclusively in one of the tautomeric forms corresponding to formula I or Ia, or in a mixture of the tautomeric forms corresponding to formulas I and Ia.      
     
     
         2 . A method according to  claim 1 , wherein said condition is selected from: 
 the group consisting of neuropathic, chronic or acute pain; or    the group consisting of thermal hyperalgesia, mechanical hyperalgesia and allodynia, and cold-induced allodynia, or the group consisting of bipolar disorders, anxiety, panic attacks, mood fluctuations, manic behavior, depression, and manic-depressive behavior; or    the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy.    
     
     
         3 . A method according to  claim 1 , wherein R 2  is selected from the group consisting of: 
 C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, and that is singly or multiply substituted or unsubstituted;    C 3-8 -cycloalkyl that is saturated or unsaturated, and singly or multiply substituted or unsubstituted;    aryl or heteroaryl, that is singly or multiply substituted or unsubstituted; and aryl, C 3-9 -cycloalkyl and heteroaryl, that is bonded via saturated or unsaturated C 1-3 -alkyl, and that is unsubstituted or singly or multiply substituted.    
     
     
         4 . A method according to  claim 1 , wherein R 2  is selected from the group consisting of aryl and heteroaryl bonded via saturated or unsaturated C 1-3 -alkyl group, and that may be unsubstituted or singly or multiply substituted.  
     
     
         5 . A method according to  claim 4 , wherein said aryl or heteroaryl is bonded via a CH 2  group.  
     
     
         6 . A method according to  claim 4 , wherein said aryl or heteroaryl is singly or multiply substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OH, NO 2 , SH, NH 2 , C 1-4 -alkyl and O—C 1-4 -alkyl.  
     
     
         7 . A method according to  claim 4 , wherein R 2  is a heteroaryl group bonded via saturated or unsaturated C 1-3 -alkyl, and that may be unsubstituted or singly or multiply substituted.  
     
     
         8 . A method according to  claim 7 , wherein R 2  is selected from the group consisting of pyridinyl, thiophenyl, furanyl and pyrimidinyl, bonded via saturated or unsaturated C 1-3 -alkyl, and that may be unsubstituted or singly or multiply substituted.  
     
     
         9 . A method according to  claim 8 , wherein R 2  is pyridinyl.  
     
     
         10 . A method according to  claim 7 , wherein said aryl or heteroaryl is bonded via a —CH 2 — group and is singly substituted in the para position.  
     
     
         11 . A method according to  claim 1 , wherein said sulfonylguanidine compound is selected from the group consisting of: 
 N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (1)    N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide (2)    N-(aminomorpholin-4-yl-methylene)-4-methylbenzene-sulfonamide (3)    N-(aminocyclohexylaminomethylene)-4-methylbenzene-sulfonamide (4)    N-(aminophenylaminomethylene)-4-methylbenzene-sulfonamide (5)    N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonamide (6)    N-[amino-(naphthalin-2-yl-amino)-methylene]-4-methylbenzenesulfonamide (7)    N-[amino-(4-methylpiperazin-1-yl-amino)-methylene]-4-methylbenzenesulfonamide (8)    N-[amino-(1-pyridin-2-yl-hydrazino)-methylene]-4-methylbenzenesulfonamide (9)    N-[aminopropylaminomethylene]-4-methylbenzene-sulfonamide (10)    N-(aminobutylaminomethylene)-4-methylbenzene-sulfonamide (11)    N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide (12)    N-[aminobutylaminomethylene]-4-methylbenzene-sulfonamide (13)    N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide (14)    N-[amino-sec-butylaminomethylene]-4-methylbenzene-sulfonamide (15)    N-[amino-(N′-tosyl-2-yl-hydrazino)-4-methylbenzene-sulfonamide (16)    N-[amino-(2H-pyrazol-3-yl-amino)-methylene]-4-methylbenzenesulfonamide (17)    N-(aminopyrrolidin-1-yl-methylene)-4-methylbenzene-sulfonamide (18)    N-[amino-(naphthalin-1-yl-amino)-methylene]-4-methyl-benzenesulfonamide (19)    N-[amino-(morpholin-4-yl-amino)-methylene]-4-methyl-benzenesulfonamide (20)    N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (21)    N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (22)    N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (23)    N-[amino-(pyridin-3-yl-amino)-methylene]-4-methyl-benzenesulfonamide (24)    N-(aminopyrrolidin-1-yl-methylene)-4-chlorobenzene-sulfonamide (25)    N-(aminopyrrolidin-1-yl-methylene)-benzenesulfonamide (26)    N-(aminopyrrolidin-1-yl-methylene)-2-nitrobenzene-sulfonamide (27)    N-[amino-(morpholin-4-yl-amino)-methylene]-4-chlorobenzenesulfonamide (28)    N-[amino-(morpholin-4-yl-amino)-methylene]-benzenesulfonamide (29)    Naphthalene-1-sulfonic acid amino-(morpholin-4-yl-amino)-methylene amide (30)    N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-C-phenylmethanesulfonamide (31)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulfonamide (32)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzenesulfonamide (33)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesulfonamide (34)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfonamide (35)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide (36)    Naphthalene-2-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (37)    1-methyl-1H-imidazole-4-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (38)    N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-phenyl]-acetamide (39)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesulfonamide (40)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylbenzenesulfonamide (41)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfonamide (42)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesulfonamide (43)    Naphthalene-1-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (44)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesulfonamide (45)    Thiophene-2-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (46)    Quinoline-8-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (47)    5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (49)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfonamide (50)    N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (51)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfonamide (52)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (53)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesulfonamide (54)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfonamide (55)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (56)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfonamide (57)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfonamide (58)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesulfonamide (59)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (60)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (61)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (62), and    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (63),    optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in an arbitrary mixture ratio; in the represented form or in the form of their acids or their bases; or in the form of their salts, in particular the physiologically compatible salts, preferably the hydrochloride or sodium salt; or in the form of their solvates, in particular the hydrates; in both tautomeric forms according to formulas I and Ia, exclusively in one of the tautomeric forms according to formulas I or Ia or also in mixtures of both forms according to formulas I and Ia.    
     
     
         12 . A method according to  claim 1 , wherein the sulfonylguanidine compound is present entirely or substantially in the tautomeric form corresponding to formula I.  
     
     
         13 . A method according to  claim 1 , wherein the sulfonylguanidine compound is present entirely or substantially in the tautomeric form corresponding to formula Ia.  
     
     
         14 . A method according to  claim 1 , wherein the sulfonylguanidine compound is present as a pure diastereomer, a pure enantiomer, a non-equimolar mixture of the diastereomers or enantiomers, or exclusively in one of the tautomeric forms corresponding to formulas I and Ia.  
     
     
         15 . A method according to  claim 1 , wherein the sulfonylguanidine compound is present as a racemate or an equimolar mixture of diastereomers or enantiomers, or in a mixture of the tautomeric forms corresponding to formulas I and Ia.  
     
     
         16 . A sulfonylguanidine compound selected from the group consisting of: 
 N-{amino-[pyridin-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (1)    N-[amino-(benzylaminomethylene)]-4-methylbenzene-sulfonamide (2)    N-[(amino-4-methoxybenzylamino)-methylene]-4-methylbenzene-sulfonamide (6)    N-[aminophenethylaminomethylene]-4-methylbenzene-sulfonamide (14)    N-{amino-[(pyridin-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (21)    N-{amino-[(pyridin-4-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (22)    N-{amino-[(pyridin-3-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (23)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-bromobenzenesulfonamide (32)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3,4-dichlorobenzenesulfonamide (33)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesulfonamide (34)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-iodobenzenesulfonamide (35)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-benzenesulfonamide (36)    Naphthalene-2-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (37)    1-methyl-1H-imidazole-4-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (38)    N-[4-({amino-[(pyridin-2-yl-methyl)-amino]-methylene}-sulfamoyl)-phenyl]-acetamide (39)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-fluorobenzenesulfonamide (40)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-2,4,6-trimethylbenzenesulfonamide (41)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfonamide (42)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-methoxybenzenesulfonamide (43)    Naphthalene-1-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (44)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-3-methylbenzenesulfonamide (45)    Thiophene-2-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (46)    Quinoline-8-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (47)    5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid amino-[(pyridin-2-yl-methyl)-amino]-methylene amide (48)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (49)    N-{amino[(pyridin-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfonamide (50)    N-{amino[(pyrimidin-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (51)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfonamide (52)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (53)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesulfonamide (54)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfonamide (55)    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (56)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-butylbenzenesulfonamide (57)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-propylbenzenesulfonamide (58)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-isopropylbenzenesulfonamide (59)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-tert.-butylbenzenesulfonamide (60)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (61)    N-{amino[(thiophen-2-yl-methyl)-amino]-methylene}-4-methylbenzenesulfonamide (62), and    N-{amino[(furan-2-yl-methyl)-amino]-methylene}-4-chlorobenzenesulfonamide (63),    optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in an arbitrary mixture ratio; in the represented form or in the form of their acids or their bases; or in the form of their salts, in particular the physiologically compatible salts, preferably the hydrochloride or sodium salt; or in the form of their solvates, in particular the hydrates; in both tautomeric forms according to formulas I and Ia, exclusively in one of the tautomeric forms according to formulas I or Ia or also in mixtures of both forms according to formulas I and Ia.    
     
     
         17 . A compound according to  claim 16 , wherein the sulfonylguanidine compound is present entirely or substantially entirely in the tautomeric form corresponding to formula I.  
     
     
         18 . A compound according to  claim 16 , wherein the sulfonylguanidine compound is present entirely or substantially entirely in the tautomeric form corresponding to formula Ia.  
     
     
         19 . A pharmaceutical composition comprising a pharmaceutically active sulfonylguanidine compound according to  claim 16 , and at least one pharmaceutical carrier, additive or auxiliary substance.  
     
     
         20 . A pharmaceutical composition according to  claim 19 , further comprising a further pharmaceutically active compound.  
     
     
         21 . A pharmaceutical composition according to  claim 19 , wherein the sulfonylguanidine compound is present as a pure diastereomer, a pure enantiomer, a non-equimolar mixture of the diastereomers or enantiomers, or exclusively in one of the tautomeric forms corresponding to formulas I and Ia.  
     
     
         22 . A pharmaceutical composition according to  claim 19 , wherein the sulfonylguanidine compound is present as a racemate or an equimolar mixture of diastereomers or enantiomers, or in a mixture of the tautomeric forms corresponding to formulas I and Ia.  
     
     
         23 . A pharmaceutical composition according to  claim 19 , wherein the sulfonylguanidine compound is present as pure diastereomer or enantiomer, or as a non-equimolar mixture of diastereomers or enantiomers.  
     
     
         24 . A pharmaceutical composition according to  claim 19 , wherein the sulfonylguanidine compound is present as as a racemate or as an equimolar mixture of diastereomers or enantiomers.