Substituted piperidines

Abstract

A novel class of substituted piperidines, pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment and/or prevention of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.

1 . A compound of the general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 m is 0, or, 2,  
 R 1  is  
 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, 
 which may optionally be substituted with one or more substituents selected from halogen, C 1-6 -alkoxy and hydroxy,  
 
 C 3-8 -cycloalkyl, C 5-8 -cycloalkenyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, di(C 3-8 -cycloalkyl)-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 5-8 -cycloalkenyl-C 1-6 -alkyl, C 5-8 -cycloalkenyl-C 2-6 -alkenyl, C 5-8 -cycloalkenyl-C 2-6 -alkynyl, 
 wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C 1-6 -alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl,  
 
 R 2  is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 alkyl,  
 X is —CH 2 —(CH 2 ) n —, —(CH 2 ) n —CH═CH—(CH 2 ) p —, —CH 2 —(CH 2 ) n —O—(CH 2 ) p —, —CH 2 —(CH 2 ) n —C(═O)—(CH 2 ) p   13  , —CH 2 —(CH 2 ) n —S—(CH 2 ) p —, —CH 2 —(CH 2 ) n —S(═O)—(CH 2 ) p — or —CH 2 —(CH 2 ) n —S(═O) 2 —(CH 2 ) p —,  
 n and p are independently 0, 1, 2, 3 or 4,  
 R 3  and R 4  are independently hydrogen, methyl or trifluoromethyl,  
 Y is  
 (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, oxo, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 5 R 6  and —O(C═O)NR 5 R 6 , 
 wherein R 5  and R 6  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 5  and R 6  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—,  
 aryl, aryloxy, aryl-C 1-6 -alkyl and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluorom ethyl, trifluorom ethoxy, —NR 7 R 8  and —O(C═O)NR 7 R 8 , 
 wherein R 7  and R 8  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 7  and R 8  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O— 
 
 
 (b) C 3-8 -cycloalkyl or C 5-8 -cycloalkenyl, which may optionally be substituted with one or more substituents selected from 
 C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,  
 aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 9 R 10  and —O(C═O)NR 9 R 10 , 
 wherein R 9  and R 10  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 9  and R 10  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 
 
 (c) C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, which may optionally be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 11 R 12  and —O(C═O)NR 11 R 12 , 
 wherein R 11  and R 12  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 11  and R 12  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 aryl, aryl-C 1-6 -alkyl and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 13 R 14  and —O(C═O)NR 13 R 14 , 
 wherein R 13  and R 14  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 13  and R 14  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O— 
 with the proviso that the compound must not be  
                                       
 as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.  
 
 
 
     
     
         2 . A compound according to  claim 1 , wherein m is 1.  
     
     
         3 . A compound according to  claim 2 , wherein R 3  and R 4  are both hydrogen.  
     
     
         4 . A compound according to  claim 1 , wherein R 1  is C 1-6 -alkyl which may optionally be substituted with one or more substituents selected from halogen, C 1-6 -alkoxy and hydroxy.  
     
     
         5 . A compound according to  claim 4 , wherein R 1  is C 1-6 -alkyl.  
     
     
         6 . A compound according to  claim 1 , wherein R 1  is di(C 3-8 -cycloalkyl)-C 1-6 -alkyl, wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C 1-6 -alkyl, halogen, trifluorom ethyl and 2,2,2-trifluoroethyl.  
     
     
         7 . A compound according to  claim 6 , wherein R 1  is dicyclopropylmethyl.  
     
     
         8 . A compound according to  claim 1 , wherein R 2  is C 1-6 -alkyl.  
     
     
         9 . A compound according to  claim 1 , wherein X is —CH 2 —(CH 2 ) n —, —(CH 2 ) n —CH═CH—(CH 2 ) p —, —CH 2 —(CH 2 ) n —O—(CH 2 ) p —, —CH 2 —(CH 2 ) n —C(═O)—(CH 2 ) p , —CH 2 —(CH 2 ) n —S—(CH 2 ) p —, wherein n and p are as defined in  claim 1 .  
     
     
         10 . A compound according to  claim 1 , wherein X is —CH 2 —(CH 2 ) n —, —CH═CH—, —CH 2 —(CH 2 ) n —O—, —CH 2 —(CH 2 ) n —C(═O)—, or —CH 2 —S—(CH 2 ) p —, wherein n is 0, 1, 2 or 3, and p is 0 or 1.  
     
     
         11 . A compound according to  claim 10 , wherein X is —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH═CH—,—CH 2 —O—, —(CH 2 ) 3 —O—, —(CH 2 ) 2 —C(═O)—, —CH 2 —S—CH 2 — or —CH 2 —S—.  
     
     
         12 . A compound according to  claim 11 , wherein X is —CH 2 —.  
     
     
         13 . A compound according to  claim 1 , wherein Y is C 1-6 -alkyl, C 3-8 -cycloalkyl, aryl or heteroaryl, which may optionally be substituted as defined in  claim 1 .  
     
     
         14 . A compound according to  claim 1 , wherein Y is C 1-6 -alkyl, cyclohexyl, phenyl, naphthyl, pyridyl, benzoxazolyl or benzothiophenyl, which may optionally be substituted as defined in  claim 1 .  
     
     
         15 . A compound according to  claim 14 , wherein Y is phenyl or naphthyl which may optionally be substituted with one or more substituents selected from trifluoromethyl, trifluoromethoxy, halogen, C 1-6 -alkyl, —NR 5 R 6 , —O(C═O)NR 5 R 6  and C 1-7 -alkanoyl, wherein R 5  and R 6  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 5  and R 6  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring, aryl-C 1-6 -alkoxy, aryloxy, aryl-C 1-6 -alkyl and aryl, which may optionally be substituted with halogen or C 1-6 -alkyl,  
       or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—.  
     
     
         16 . A compound according to  claim 15 , wherein Y is phenyl or naphthyl which may optionally be substituted with one or more substituents selected from 
 trifluoromethyl, trifluoromethoxy, halogen, C 1-6 -alkyl, —NR 5 R 6 , —O(C═O)NR 5 R 6  and C 1-7 -alkanoyl, wherein R 5  and R 6  independently are hydrogen or C 1-6 -alkyl,    phenyl-C 1-6 -alkoxy, phenyl-C 1-6 -alkyl, phenyloxy and phenyl, which may optionally be substituted with halogen or C 1-6 -alkyl,    or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—.    
     
     
         17 . A compound according to  claim 16 , wherein Y is phenyl, which is substituted with phenyl.  
     
     
         18 . Use of a compound according to any one of the preceding  claims 1  to  17  as a pharmaceutical composition.  
     
     
         19 . A composition comprising, as an active ingredient, at least one compound according to  claim 1  together with one or more pharmaceutically acceptable carriers or excipients.  
     
     
         20 . A composition according to  claim 19  in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the  claims 1  to  17 .  
     
     
         21 . Use of a compound of the general formula (I′):  
       
         
           
           
               
               
           
         
       
       wherein 
 m is 0, or, 2,  
 R 1  is  
 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, 
 which may optionally be substituted with one or more substituents selected from halogen, C 1-6 -alkoxy and hydroxy,  
 
 C 3-8 -cycloalkyl, C 5-8 -cycloalkenyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, di(C 3-8 -cycloalkyl)-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 2-6 -alkenyl, C 3-8 -cycloalkyl-C 2-6 -alkynyl, C 5-8 -cycloalkenyl-C 1-6 -alkyl, C 5-8 -cycloalkenyl-C 2-6 -alkenyl, C 5-8 -cycloalkenyl-C 2-6 -alkynyl, 
 wherein the cyclic moieties may optionally be substituted with one or more substituents selected from C 1-6 -alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl,  
 
 R 2  is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl or C 3-8 -cycloalkyl-C 1-6 alkyl,  
 X is —CH 2 —(CH 2 ) n —, —(CH 2 ) n —CH═CH—(CH 2 ) p —, —CH 2 —(CH 2 ) n —O—(CH 2 ) p —, —CH 2 —(CH 2 ) n —C(═O)—(CH 2 ) p   13  , —CH 2 —(CH 2 ) n —S—(CH 2 ) p —, —CH 2 —(CH 2 ) n —S(═O)—(CH 2 ) p — or —CH 2 —(CH 2 ) n —S(═O) 2 —(CH 2 ) p —,  
 n and p are independently 0, 1, 2, 3 or 4,  
 R 3  and R 4  are independently hydrogen, methyl or trifluoromethyl,  
 Y is  
 (a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, oxo, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 5 R 6  and —O(C═O)NR 5 R 6 , 
 wherein R 5  and R 6  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 5  and R 6  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—,  
 aryl, aryloxy, aryl-C 1-6 -alkyl and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluorom ethyl, trifluorom ethoxy, —NR 7 R 8  and —O(C═O)NR 7 R 8 , 
 wherein R 7  and R 8  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 7  and R 8  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O— 
 
 
 (b) C 3-8 -cycloalkyl or C 5-8 -cycloalkenyl, which may optionally be substituted with one or more substituents selected from 
 C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,  
 aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 9 R 10  and —O(C═O)NR 9 R 10 , 
 wherein R 9  and R 10  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 9  and R 10  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 
 
 (c) C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, which may optionally be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 11 R 12  and —O(C═O)NR 11 R 12 , 
 wherein R 11  and R 12  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 11  and R 12  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 aryl, aryl-C 1-6 -alkyl and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from 
 halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 13 R 14  and —O(C═O)NR 13 R 14 , 
 wherein R 13  and R 14  independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 13  and R 14  together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,  
 
 or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O— 
 as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of disorders and diseases related to the histamine H3 receptor.  
 
 
 
     
     
         22 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders in which an inhibition of the H3 histamine receptor has a beneficial effect.  
     
     
         23 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition having histamine H3 antagonistic activity or histamine H3 inverse agonistic activity.  
     
     
         24 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the reduction of weight.  
     
     
         25 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the treatment and/or prevention of overweight or obesity.  
     
     
         26 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the suppression of appetite or for satiety induction.  
     
     
         27 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the prevention and/or treatment of disorders and diseases related to overweight or obesity.  
     
     
         28 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the prevention and/or treatment of eating disorders such as bulimia and binge eating.  
     
     
         29 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.  
     
     
         30 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.  
     
     
         31 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to Type 2 diabetes.  
     
     
         32 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.  
     
     
         33 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the treatment and/or prevention of diseases and disorders in which a stimulation of the H3 histamine receptor has a beneficial effect.  
     
     
         34 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition having histamine H3 agonistic activity.  
     
     
         35 . Use of a compound as defined in  claim 21  for the preparation of a pharmaceutical composition for the treatment and/or prevention of allergic rhinitis, ulcer or anorexia.  
     
     
         36 . A method for the treatment of treatment and/or prevention of disorders or diseases related to the H3 histamine receptor the method comprising administering to a subject in need thereof an effective amount of a compound as defined in  claim 21 .  
     
     
         37 . The method according to  claim 36  wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.