Arylsulfonamide derivatives as c-jun-n-terminal kinases (jnk's) inhibitors

Abstract

The present invention relates to sulfonamide derivatives of formula I notably for use as pharmaceutically active compounds, as well as to pharmaceutical formulations containing such sulfonamide derivatives. Said sulfonamide derivatives are useful in the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases. Furthermore, said sulfonamide derivatives are efficient modulators of the JNK pathway, they are in particular efficient and selective inhibitors of JNK2 and -3. The present invention is furthermore related to novel sulfonamide derivatives as well as to methods of their preparation. Ar 1 is a substituted or unsubstituted aryl or heteroaryl group; X is O or S, preferably O; Ar 2 a substituted or unsubstituted arylene or heteroarylene group; R 1 and R 2 are independently selected from the group consisting of hydrogen and a C 1 -C 6 -alkyl group;

1 . A sulfonamide according to formula I 
     
       
         
         
             
             
         
       
       a geometrical isomer thereof, an optically active form thereof, an enantiomer thereof, a diastereomer thereof, a mixture thereof, or a salt thereof 
       wherein: 
       Ar 1  is a substituted or unsubstituted aryl group; 
       X is O or S; 
       Ar 2  is a substituted or unsubstituted thienylene group; 
       R 1  and R 2  are independently selected from the group consisting of hydrogen and a C 1 -C 6 -alkyl group; 
       R a , R a′ , R b , R b′  are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; 
       or R a′  and R a  or R b′  together with the carbon atoms they are linked, form a substituted or unsubstituted 5-8-membered saturated, partially unsaturated or aromatic ring containing optionally one or more heteroatoms selected from O, N, S; 
       R 3  is selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl; 
       or R 3  and R a  or R a′  form, together with the N atom linked to R 3 , a 5-8-membered saturated ring, containing optionally at least one further heteroatom selected from O, N, S; 
       R 4  is selected from the group consisting of H and —C(H)R 5 R 6 ; 
       R 5  and R 6  are independently selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroarylC 1 -C 10 -alkyl; 
       m is an integer from 1 to 5; 
       n is an integer from 0 to 2; and 
       p is an integer from 1 to 10; 
       wherein the compound according to formula I is not: 
       N-[[5-[[[3-[[4-[(3-aminopropyl)amino]butyl]aminopropyl]amino]sulfonyl]-2-thienyl]methyl]-Benzamide, N-[[5-[[[3-[[4-[(3-aminopropyl)amino]butyl]amino]propyl]amino]sulfonyl]-2-thienyl]methyl]-4-chloro-Benzamide, or N,N′-[1,4-butanediylbis(imino-3,1-propanediyliminosulfonyl-5,2-thiophenediylmethylene)]bis[4-chloro-]Benzamide. 
     
   
   
       2 . The sulfonamide according to  claim 1 , wherein Ar 1  is phenyl, optionally substituted by a group selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, amino, acylamino, aminocarbonyl, C 1 -C 6 -alkoxycarbonyl, aryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfonyl and C 1 -C 6 -thioalkoxy. 
   
   
       3 . The sulfonamide according to  claim 1 , wherein Ar 1  is an unsubstituted or substituted phenyl. 
   
   
       4 . The sulfonamide according to  claim 1 , wherein Ar 2  is thienylene optionally substituted by a group selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, amino, acylamino, aminocarbonyl, C 1 -C 6 -alkoxycarbonyl, aryl, carboxyl, cyano, halogen, hydroxy, nitro, sulfonyl and C 1 -C 6 -thioalkoxy. 
   
   
       5 . The sulfonamide according to  claim 1 , wherein Ar 2  is an unsubstituted or substituted thienylene group. 
   
   
       6 . The sulfonamide according to  claim 1 , wherein Ar 1  is selected from the group consisting of halogenophenyl, nitrophenyl, hydroxyphenyl, alkoxy phenyl, and 3,4,-dihydroxyphenyl,
 X is O,   R 1  is hydrogen,   m is 1 and   Ar is thienylene.   
   
   
       7 . The sulfonamide according to  claim 1 , wherein: Ar 1  is 4-chlorophenyl; X is O; R 1  and R 2  are both hydrogen; m is 1; n is 0, 1 or 2; Ar 2  is a thienylene or phenylene group; R a , R a′ , R b , R b′  are hydrogen; R 3  is hydrogen, C 1 -C 6 -alkyl or aryl; R 4  is selected from the group consisting of H, C 1 -C 10 -alkyl, aryl C 1 -C 10 -alkyl, CH 2 —(C 3 -C 8 -cycloalkyl), CH 2 —(C 3 -C 8 -heterocycloalkyl), CH 2 -aryl and a CH 2 -heteroaryl group. 
   
   
       8 . The sulfonamide according to  claim 1 , wherein Ar 1  is a 4-chlorophenyl, X is O, R 1  and R 2  are hydrogen, m is 1; n is 0, 1 or 2; Ar 2  is a thienylene or phenylene group, R a  or R a′  forms a 5-6 membered ring with R 3 ; R 3  is hydrogen, C 1 -C 6 -alkyl or aryl; R 4  is selected from the group consisting of H, C 1 -C 10 -alkyl, aryl C 1 -C 10 -alkyl, CH 2 —C 3 -C 8 -cycloalkyl, CH 2 —C 3 -C 8 -heterocycloalkyl, aryl and a CH 2 -heteroaryl group. 
   
   
       9 . The sulfonamide according to  claim 1 , wherein Ar 1  is a 4-chlorophenyl; X is O; R 1  and R 2  are hydrogen; m is 1; n is 0, 1 or 2; Ar 2  is a thienylene or phenylene group; R a  forms a 5-6 membered ring with R a′ ; R 3  is hydrogen, C 1 -C 6 -alkyl or aryl; R 4  is selected from the group consisting of H, C 1 -C 10 -alkyl, aryl C 1 -C 10 -alkyl, CH 2 —C 3 -C 8 -cycloalkyl, CH 2 —C 3 -C 8 -heterocycloalkyl, aryl and CH 2 -heteroaryl group. 
   
   
       10 . A medicament comprising the sulfonamide according to  claim 1  and one or more pharmaceutically acceptable diluents or excipients. 
   
   
       11 . A method for treating at least one disorder in a person in need thereof comprising administering the sulfonamide according to formula I 
     
       
         
         
             
             
         
       
       wherein: 
       Ar 1  is a substituted or unsubstituted aryl group; 
       X is O or S; 
       Ar 2  is a substituted or unsubstituted thienylene group; 
       R 1  and R 2  are independently selected from the group consisting of hydrogen and a C 1 -C 6 -alkyl group; 
       R a , R a′ , R b , R b′  are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; 
       or R a′  and R a  or R b′  together with the carbon atoms they are linked, form a substituted or unsubstituted 5-8-membered saturated, partially unsaturated or aromatic ring containing optionally one or more heteroatoms selected from O, N, S; 
       R 3  is selected from the group consisting of H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S; aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl; 
       or R 3  and R a  or R a′  form, together with the N atom linked to R 3 , a 5-8-membered saturated ring, containing optionally at least one further heteroatom selected from O, N, S; 
       R 4  is selected from the group consisting of H and —C(H)R 5 R 6 ; 
       R 5  and R 6  are independently selected from the group consisting of H, C 1 -C 10 , alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3 heteroatoms selected from the group consisting of N, O, and S, aryl C 1 -C 10 -alkyl and heteroaryl C 1 -C 10 -alkyl; 
       m is an integer from 1 to 5; 
       n is an integer from 0 to 2; and 
       p is an integer from 1 to 10; 
       an isomer thereof, an optionally active form thereof, a diastereomer thereof, and a mixture thereof; 
       to the person in an amount sufficient to treat the at least one disorder, wherein the at least one disorder is selected from the group consisting of epilepsy, Huntington's disease, Parkinson's disease, retinal disease, spinal cord injury, Multiple Sclerosis, head trauma and ischemia; a cardiovascular disease; stroke; arterosclerosis; myocordial infarction; myocordial reperfusion injury; an ischemic condition; heart injury; renal injury; kidney injury; brain reperfusion injury and renal failure. 
     
   
   
       12 . A method for treating at least one disorder in a mammal in need thereof, comprising administering the sulfonamide according to  claim 1  to the mammal in need thereof in an amount sufficient to treat the at least one disorder, wherein the at least one disorder is selected from the group consisting of Alzheimer's disease, an auto-immune disease, inflammatory bowel disease (IBD), rheumatoid arthritis, asthma, septic shock, transplant rejection, cancer, breast-cancer, colorectal-cancer, pancreatic cancer, ovarian cancer, prostate cancer, testicular cancer, hepatic cancer, kidney cancer, and lung cancer. 
   
   
       13 . A pharmaceutical composition comprising at least one sulfonamide according to  claim 1  and one or more of a pharmaceutically acceptable carrier, diluent or excipient. 
   
   
       14 . A process for the preparation of the sulfonamide according to  claim 1  wherein R 4  is not H, comprising reductively aminating a carbonyl group of formula VII with a compound of formula VI 
     
       
         
         
             
             
         
       
     
   
   
       15 . A process for the preparation of the sulfonamide according to  claim 1 , wherein R 4  is H, comprising deprotecting a compound of formula IV 
     
       
         
         
             
             
         
       
     
   
   
       16 . The process according to  claim 14 , wherein the compound of formula VI is obtained by deprotecting a compound of formula IV 
     
       
         
         
             
             
         
       
     
   
   
       17 . The process according to  claim 15 , wherein the compound of formula IV is obtained by reacting a compound of formula II with a compound of formula III 
     
       
         
         
             
             
         
       
     
   
   
       18 . A process for the preparation of the sulfonamide according to  claim 1 , comprising N-sulfonylating a compound of formula X with a sulfonylchloride of formula III 
     
       
         
         
             
             
         
       
     
   
   
       19 . The process according to  claim 18 , wherein the compound of formula X is obtained by deprotecting a compound of formula IX 
     
       
         
         
             
             
         
       
       wherein P is a protecting group. 
     
   
   
       20 . The process according to  claim 19 , wherein the compound of formula IX is obtained by reductively aminating a compound of formula VII with a compound of formula VIII 
     
       
         
         
             
             
         
       
       wherein P is a protecting group. 
     
   
   
       21 . A process for the preparation of the sulfonamide according to  claim 1 , comprising reductively aminating a carbonyl group of formula XIII with an amine of formula XIV 
     
       
         
         
             
             
         
       
     
   
   
       22 . The process according to  claim 21 , wherein the compound of formula XIII is obtained by oxidizing a compound of formula XII 
     
       
         
         
             
             
         
       
     
   
   
       23 . The process according to  claim 22 , wherein the compound of formula XII is obtained by sulfonylating a compound of formula XI 
     
       
         
         
             
             
         
       
     
   
   
       24 . A method for modulating a JNK pathway in a mammal comprising administering the sulfonamide according to  claim 1  to the mammal in an amount effective for modulating the JNK pathway. 
   
   
       25 . The method as claimed in  claim 24 , wherein the sulfonamide is administered in an amount effective for the prevention of one or more disorders associated with the abnormal expression or activity of JNK. 
   
   
       26 . The method as claimed in  claim 25 , wherein the sulfonamide is administered for the treatment or prevention of one or more disorders associated with the abnormal expression or activity of at least one of JNK2 or JNK3. 
   
   
       27 . The method as claimed in  claim 11 , wherein X is O.