Novel compounds useful in pain management

Abstract

Compounds of general formula I are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.

1 . A compound according to formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 m and n is each and independently an integer of from 1-3, and one or more of the hydrogens in such an alkylene-chain may optionally be substituted by anyone of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; or  
 one or more of the methylene groups may optionally be substituted by a heteroatom such as O, N or S;  
 R 1  is selected from hydrogen, a branched or straight C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl, C 4 -C 8 (alkyl-cycloalkyl) wherein the alkyl is C 1 -C 2  alkyl and the cycloalkyl is C 3 -C 6  cycloalkyl;  
 R 2  is selected from any of  
 (i) hydrogen;  
 (ii) a straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl;  
 (iii) —[(CH 2 ) q -aryl];  
 (iv) —[(CH 2 ) r -heteroaryl] where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;  
 and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; and wherein q and r is each and independently an integer of from 0 to 3;  
 (v) C 3 -C 10  cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;  
 and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
 (vi) C 6 -C 10  aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;  
 (vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; or  
 R 1  and R 2  may optionally form a heterocyclic ring;  
 R 3  is selected from anyone of  
 (i) hydrogen;  
 (ii) a straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl;  
 (iii) —[(CH 2 ) q -aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;  
 (iv) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
 (v) C 3 -C 10  cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
 (vi) —[(C 3 -C 6  cycloalkyl)-(CH 2 ) q ] wherein q is an integer of from 1 to 3;  
 R 4  is selected from  
 (i) hydrogen;  
 (ii) a straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl;  
 (iii) —[(CH 2 ) q -aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;  
 (iv) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
 (v) C 3 -C 10  cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;  
 and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
 (vi) C 6 -C 10  aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;  
 (vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;  
 R 5  is selected from anyone of  
 (i) hydrogen;  
 (ii) a straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl;  
 (iii) —[(CH 2 ) q -aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;  
 (iv) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
 (v) C 3 -C 10  cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
                     
  wherein  
 R 7 , R 8 , R 9 , R 10  and R 11  is each and independently selected from 
 (a) hydrogen;  
 (b) a straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl;  
 (c) —[(CH 2 ) q -aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;  
 (d) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;  
 (e) C 3 -C 10  cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;  
 
 and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; 
 (f) C 6 -C 10  aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; or  
 
 R 4  and R 5  may optionally form a heterocyclic ring; 
 Y is each and independently selected from any of hydrogen, CH 3 ; —(CH 2 ) p1 CF 3 ; halogen; C 1 -C 3  alkoxy; hydroxy; —NO 2 ; —OCF 3 ; —CONR a R b ; —COOR a ; —COR a ; —CH 2 ) p2 NR a R b ; —(CH 2 ) p3 CH 3 , (CH 2 ) p4 SOR a R b ; —(CH 2 ) p5 SO 2 R a ; —(CH 2 ) p6 SO 2 NR a ; C 4 -C 8 (alkyl-cycloalkyl) wherein alkyl is C 1 -C 2  alkyl and cycloalkyl is C 3 -C 6  cycloalkyl; 1 or 2 heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O; and oxides such as N-oxides or sulfoxides; and wherein  
 R a  and R b  is each and independently selected from hydrogen, a branched or straight C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 3 -C 8  cycloalkyl; and wherein  
 p 1 , p 2 , p 3 , p 4 , p 5  and p 6  is each and independently 0, 1 or 2;  
 
 as well as pharmaceutically acceptable salts, isomers, hydrates, isoforms and prodrugs thereof.  
 
     
     
         2 . A compound according to formula I of  claim 1 , wherein 
         m=n=1 R 1  is selected from    (i) hydrogen;    (ii) a branched or straight C 1 -C 6  alkyl; or    (iii) C 3 -C 8  cycloalkyl;    R 2  is selected from any of    (i) hydrogen;    (ii) a straight or branched C 1 -C 6  alkyl;    (iii) —[(CH 2 ) q -aryl];    (iv) —[(CH 2 ) r -heteroaryl] where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;    and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in  claim 1;  and wherein q and r is each and independently an integer of from 0 to 3;    (v) C 3 -C 6  cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O;    and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;    (vi) C 6 -C 10  aryl, optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;     (vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;  or    R 1  and R 2  may optionally form a heterocyclic ring;    R 3  is selected from anyone of    (i) hydrogen;    (ii) a straight or branched C 1 -C 6  alkyl;    (iii) —[(CH 2 ) q -aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;     (iv) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in  claim 1;     (v) C 3 -C 10  cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in  claim 1;     (vi) —[(C 3 -C 6  cycloalkyl)-(CH 2 )q] wherein q is an integer of from 1 to 3;    R 4  is selected from    (i) hydrogen;    (ii) a straight or branched C 1 -C 6  alkyl;    (iii) —[(CH 2 ) q -aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;     (iv) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in  claim 1;     (v) C 6 -C 10  aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;     R 5  is selected from anyone of    (i) hydrogen;    (ii) a straight or branched C 1 -C 6  alkyl;    (iii) —[(CH 2 ) q -aryl] wherein q is 0 or 1, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;     (iv) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in  claim 1;     (v) C 3 -C 6  cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined  claim 1;                            wherein    R 7 , R 8 , R 9 , R 10  and R 11  is each and independently selected from 
 (a) hydrogen;  
 (b) a straight or branched C 1 -C 6  alkyl or C 2 -C 6  alkenyl;  
 (c) —[(CH 2 ) q -aryl] wherein q is an integer of from 0 to 3, and wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;   
 (d) heteoaryl-(C 5 -C 10  alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in  claim 1;   
 (e) C 3 -C 10  cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in  claim 1;   
 (f) C 6 -C 10  aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;  or  
   R 4  and R 5  may form a heterocyclic ring which may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1 .    
     
     
         3 . A compound according to  claim 2 , wherein 
         m=n=1 R 1  is selected from    (i) a straight or branched C 1 -C 6  alkyl; or    (ii) C 3 -C 8  cycloalkyl;    R 2  is selected from    (i) methyl; or    (ii) phenyl optionally substituted by 1 or 2 substituents Y wherein each Y is as defined in  claim 1;     R 3  is selected from    (i) —CH 2 -phenyl, optionally substituted by 1 or 2 subtituents Y where Y is as defined in  claim 1;     (ii) —CH 2 -cyclohexyl or —CH 2 -cyclopentyl;    R 4  is selected from    (i) hydrogen; or    (ii) methyl;    R 5  is selected from    (i) hydrogen;    (ii) methyl; or                          R 4  and R 5  together form a heterocyclic ring, optionally substituted by 1 or 2 substituents Y, where Y is as defined in  claim 1 .    
     
     
         4 . A compound according to  claim 1 , which compound is anyone selected from  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to any of the preceding claims, in form of its hydrochloride, sulfate, tartrate or citrate salts.  
     
     
         6 . A compound according to any of claims  1 - 5  for use in therapy.  
     
     
         7 . A compound according to  claim 6 , wherein the therapy is pain management.  
     
     
         8 . A compound according to  claim 6 , wherein the therapy is directed towards gastrointestinal disorders.  
     
     
         9 . A compound according to  claim 6 , wherein the therapy is directed towards spinal injuries.  
     
     
         10 . A compound according to  claim 6 , wherein the therapy is directed to disorders of the sympathetic nervous system.  
     
     
         11 . Use of a compound according to formula I of  claim 1  for the manufacture of a medicament for use in the treatment of pain.  
     
     
         12 . Use of a compound according to formula I of  claim 1  for the manufacture of a medicament for use in the treatment of gastrointestinal disorders.  
     
     
         13 . Use of a compound according to formula I of  claim 1  for the manufacture of a medicament for use in the treatment of spinal injuries.  
     
     
         14 . A compound according to any of claims  1 - 10 , further characterised in that it is isotopically labelled.  
     
     
         15 . Use of a compound according to  claim 14  as a diagnostic agent.  
     
     
         16 . An isotopically labelled compound of the formula I of  claim 1 .  
     
     
         17 . A diagnostic agent comprising a compound of the formula I of  claim 1 .  
     
     
         18 . A pharmaceutical composition comprising a compound of the formula I according to  claim 1  as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.  
     
     
         19 . A process for the preparation of a compound of the formula I according to  claim 1 , whereby 
 A)    (i) bis-amino xylylene of the formula                           is converted into mono-(diBoc)-guanidinomethyl of the formula (II)                           which thereafter is reacted with an aldehyde, providing a secondary amine of the general formula IV                           wherein R 3  is as defined in formula I of  claim 1;     (ii) compound IV is subjected to an urea formation, providing a compound of the formula (VI)                           which finally is deprotected, providing a compound of the general formula VII                           wherein    R 1 , R 2  and R 3  are as defined in formula I of  claim 1;  or    B)    (i) a compound of the formula (VIII).                           wherein X is CN and Y is CHO, is subjected to a reductive amination using a primary amine R 3 NH 2  wherein R 3  is as defined in formula I of  claim 1 , providing a compound of the formula (IX)                           wherein R 3  is as defined in formula I of  claim 1 , which thereafter is subjected to an urea reaction by using a chloroformate of the formula (V)                           which finally is reduced, providing a compound of the formula (XI)                          (ii) compound (VIII) wherein X is CH 2 Br and Y is CN, is reacted with an amine R 4 R 5 NH wherein R 4  and R 5  are as defined in formula I of  claim 1 , providing a compound of the formula (XII)                           which is reduced and reacted with an aldehyde R 3 CHO wherein R3 is as defined in formula I of  claim 1 , and finally subjected to an urea action with a chloroformate (V) as in step (i), providing a compound of the formula (XV)                           is wherein R 1 , R 2 , R 3 , R 4  and R 5  are as defined in formula I of  claim 1 .    
     
     
         20 . A method for the treatment of pain, whereby an effective amount of a compound of the formula I according to  claim 1  is administered to a subject in need of pain management.  
     
     
         21 . A method for the treatment of gastrointestinal disorders, whereby an effective amount of a compound of the formula I according to  claim 1 , is administered to a subject suffering from said gastrointestinal disorder.  
     
     
         22 . A method for the treatment of spinal injuries, whereby an effective amount of a compound of the formula I according to  claim 1 , is administered to a subject suffering from said spinal injury.