Tetrahydro-Quinolinylurea Derivatives

Abstract

This invention relates to tetrahydro-quinolinylurea derivatives and salts thereof which are useful as active ingredients of pharmaceutical preparations. The tetrahydro-quinolinylurea derivative of the present invention has vanilloid receptor (VR1) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urological diseases or disorders, such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, and lower urinary tract symptoms; chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, and inflammatory disorders such as asthma and chronic obstructive pulmonary (or airways) disease (COPD).

1 - 13 . (canceled) 
   
   
       14 . A method for the treatment of an urological disorder or disease comprising the step of administering to a subject in need thereof a therapeutically effective amount of an urea derivative of formula (I) or a salt thereof: 
     
       
         
         
             
             
         
       
       wherein 
       m represents 0, 1, 2, or 3; 
       p represents 0, 1, 2, or 3; 
       —X— represents a bond, —O—, or —N(R 10 )—, wherein R 10  is hydrogen or C 1-6  alkyl, with the proviso that —X— represents a bond when m is 0; 
       R A  and R B  represent hydrogen, or 
       R A  and R B  together form a carbonyl-group with the carbon-atom to which they are connected; 
       R 1  represents aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, hydroxy, carboxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 3-8  cycloalkylamino, C 1-6  alkoxycarbonyl, phenyl (which phenyl is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6 alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl), benzyl (in which phenyl moiety is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6 alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl), sulfonamide, C 1-6  alkanoyl, C 1-6  alkanoylamino, carbamoyl, C 1-6  alkylcarbamoyl, cyano, C 1-6  alkyl (which alkyl is optionally substituted by cyano, nitro, hydroxy, carboxy, amino, C 1-6  alkoxycarbonyl or mono-, di-, or tri-halogen), C 1-6  alkoxy (which alkoxy is optionally substituted by mono-, di-, or tri-halogen), phenoxy (in which phenyl moiety is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl or C 1-6  alkyl), C 1-6  alkylthio (which alkylthio is optionally substituted b mono-, di-, or tri-halogen), C 3-8  cycloalkyl and heterocycle; and 
       R 2  represent C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, hydrogen, hydroxy, aryl, heteroaryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, arylsulfonyl, or heteroarylsulfonyl, wherein said alkyl, alkenyl or alkynyl are optionally substituted by mono-, di-, or tri-halogen, hydroxy, carboxyl, nitro, cyano, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 3-8 cycloalkyl, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(aryl)amino, N-(heteroaryl)amino, carbamoyl, N—(C 1-6 alkyl)aminocarbonyl, or N,N,-di(C 1-6 alkyl)aminocarbonyl, and said cycloalkyl, aryl, heteroaryl, aryl moiety of said arylsulfonyl, or heteroaryl moiety of said heteroarylsulfonyl are optionally substituted by mono-, di-, or tri-halogen, hydroxy, carboxyl, cyano, nitro, (C 1-6 alkoxy)carbonyl, C 3-8 cycloalkyl, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(aryl)amino, N-(heteroaryl)amino, carbamoyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkyl optionally substituted by mono-, di-, or tri-halogen, or C 1-6 alkoxy optionally substituted by mono-, di-, or tri-halogen. 
     
   
   
       15 . The method as claimed in  claim 14 , wherein said urological disorder or disease is overactive bladder, urinary incontinence, detrusor hyperflexia, detrusor instability, or benign prostatic hyperplasia. 
   
   
       16 - 17 . (canceled) 
   
   
       18 . A method for the treatment of a disorder or disease related to pain comprising the step of administering to a subject in need thereof a therapeutically effective amount of an urea derivative of formula (I) or a salt thereof: 
     
       
         
         
             
             
         
       
       wherein 
       m represents 0, 1, 2, or 3; 
       p represents 0, 1, 2, or 3; 
       —X— represents a bond, —O—, or —N(R 10 )—, wherein R 10  is hydrogen or C 1-6  alkyl, with the proviso that —X— represents a bond when m is 0; 
       R A  and R B  represent hydrogen, or 
       R A  and R B  together form a carbonyl-group with the carbon-atom to which they are connected; 
       R 1  represents aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6 alkyl)amino, C 3-8  cycloalkylamino, C 1-6  alkoxycarbonyl, phenyl (which phenyl is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, C 3-8  cycloalkylamino or C 1-6 alkoxycarbonyl), benzyl (in which phenyl moiety is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl), sulfonamide, C 1-6  alkanoyl, C 1-6  alkanoylamino, carbamoyl, C 1-6  alkylcarbamoyl, cyano, C 1-6  alkyl (which alkyl is optionally substituted by cyano, nitro, hydroxy, carboxy, amino, C 1-6  alkoxycarbonyl or mono-, di-, or tri-halogen), C 1-6  alkoxy (which alkoxy is optionally substituted by mono-, di-, or tri-halogen), phenoxy (in which phenyl moiety is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6 alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl or C 1-6  alkyl), C 1-6  alkylthio (which alkylthio is optionally substituted by mono-, di-, or tri-halogen), C 3-8  cycloalkyl, and heterocycle; and 
       R 2  represent C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, hydrogen, hydroxy, aryl, heteroaryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, arylsulfonyl, or heteroarylsulfonyl, wherein said alkyl, alkenyl or alkynyl are optionally substituted by mono-, di-, or tri-halogen, hydroxy, carboxyl, nitro, cyano, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 3-8 cycloalkyl, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(aryl)amino, N-(heteroaryl)amino, carbamoyl, N—(C 1-6 alkyl)aminocarbonyl, or N,N,-di(C 1-6 alkyl)aminocarbonyl, and said cycloalkyl, aryl, heteroaryl, aryl moiety of said arylsulfonyl, or heteroaryl moiety of said heteroarylsulfonyl are optionally substituted by mono-, di-, or tri-halogen, hydroxy, carboxyl, cyano, nitro, (C 1-6 alkoxy)carbonyl, C 3-8 cycloalkyl, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(aryl)amino, N-(heteroaryl)amino, carbamoyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkyl optionally substituted by mono-, di-, or tri-halogen, or C 1-6 alkoxy optionally substituted by mono-, di-, or tri-halogen. 
     
   
   
       19 . The method as claimed in  claim 18 , wherein said disorder or disease related to pain is neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, or stroke. 
   
   
       20 . A method for the treatment and/or prevention of an inflammatory disorder or disease comprising the step of administering to a subject in need thereof a therapeutically effective amount of an urea derivative of formula (I) or a salt thereof: 
     
       
         
         
             
             
         
       
       wherein 
       m represents 0, 1, 2, or 3; 
       p represents 0, 1, 2, or 3; 
       —X— represents a bond, —O—, or —N(R 10 —, wherein R 10  is hydrogen or C 1-6  alkyl, with the proviso that —X— represents a bond when m is 0; 
       R A  and R B  represent hydrogen, or 
       R A  and R B  together form a carbonyl-group with the carbon-atom to which they are connected; 
       R 1  represents aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6 alkyl)amino, C 3-8  cycloalkylamino, C 1-6  alkoxycarbonyl, phenyl (which phenyl is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl), benzyl (in which phenyl moiety is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl), sulfonamide, C 1-6  alkanoyl, C 1-6  alkanoylamino, carbamoyl, C 1-6 alkylcarbamoyl, cyano, C 1-6  alkyl (which alkyl is optionally substituted by cyano, nitro, hydroxy, carboxy, amino, C 1-6  alkoxycarbonyl or mono-, di-, or tri-halogen), C 1-6  alkoxy (which alkoxy is optionally substituted by mono-, di-, or tri-halogen), phenoxy (in which phenyl moiety is optionally substituted by halogen, nitro, hydroxy, carboxy, amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, C 3-8  cycloalkylamino, or C 1-6  alkoxycarbonyl or C 1-6  alkyl), C 1-6  alkylthio (which alkylthio is optionally substituted by mono-, di-, or tri-halogen), C 3-8  cycloalkyl, and heterocycle; and 
       R 2  represent C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, hydrogen, hydroxy, aryl, heteroaryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, arylsulfonyl, or heteroarylsulfonyl, wherein said alkyl, alkenyl or alkynyl are optionally substituted by mono-, di-, or tri-halogen, hydroxy, carboxyl, nitro, cyano, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 3-8 cycloalkyl, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(aryl)amino, N-(heteroaryl)amino, carbamoyl, N—(C 1-6 alkyl)aminocarbonyl, or N,N,-di(C 1-6 alkyl)aminocarbonyl, and said cycloalkyl, aryl, heteroaryl, aryl moiety of said arylsulfonyl, or heteroaryl moiety of said heteroarylsulfonyl are optionally substituted by mono-, di-, or tri-halogen, hydroxy, carboxyl, cyano, nitro, (C 1-6 alkoxy)carbonyl, C 3-8 cycloalkyl, amino, N—(C 1-6 alkyl)amino, N,N-di(C 1-6 alkyl)amino, N-(aryl)amino, N-(heteroaryl)amino, carbamoyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkyl optionally substituted by mono-, di-, or tri-halogen, or C 1-6 alkoxy optionally substituted by mono-, di-, or tri-halogen. 
     
   
   
       21 . The method as claimed in  claim 20 , wherein said inflammatory disorder or disease is asthma or COPD. 
   
   
       22 - 27 . (canceled)