Novel Substituted 4-Phenyl-4[H-Imidazol-2-YL]-Piperidine Derivatived And Their Use As Selective Non-Peptide Delta Opioid Agonists

Abstract

The present invention relates to novel 4-phenyl-4-[ 1 H-imidazol-2-yl]-piperidine derivatives according to Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. In particular are claimed compounds according to Formula (I) in which A=B is C═O or SO 2 , X is a covalent bond, R 1 is alkyloxy, alkyloxyalkyl, Ar or NR 9 R 10 , wherein R 9 and R 10 each independently are hydrogen or Ar; or A=B and R 1 together form a benzoxazolyl radical; p is zero, R 3 is benzyl optionally substituted with hydroxy, alkyl or alkyloxycarbonyl and R 4 and R 5 each are hydrogen. The invention also relates to processes for the preparation of the compounds according to the invention and their use in medicine, in particular as selective non-peptide δ-opioid agonists for use in the treatment of various pain conditions.

1 . A compound according to Formula (I)  
       
         
           
           
               
               
           
         
       
       the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof, wherein: 
 A=B is C═O, C═N—R 6  wherein R 6  is hydrogen or cyano, C═S, S═O, SO 2 , C═CR 7 R 8  wherein R 7  and R 8  each independently are hydrogen, nitro or alkyl, or A=B and R 1  together form an optionally substituted semi-aromatic or aromatic carbocyclic or heterocyclic radical Het 2  or Het 3 ;  
 X is a covalent bond, —CH 2 — or —CH 2 CH 2 —;  
 R 1  is hydrogen, alkyloxy, alkylcarbonyloxy, Ar-oxy, Het-oxy, Ar-carbonyloxy, Het-carbonyloxy, Ar-alkyloxy, Het-alkyloxy, alkyl, polyhaloalkyl, alkyloxyalkyl, Ar-alkyl, Het-alkyl, Ar, Het, thio, alkylthio, Ar-thio, Het-thio or NR 9 R 10  wherein R 9  and R 10  each independently are hydrogen, alkyl, Ar, Ar-alkyl, Het, Het-alkyl, alkyl-carbonyl, Ar-carbonyl, Het-carbonyl or alkyloxycarbonylalkyl; or A=B and R 1  together form an optionally substituted semi-aromatic or aromatic carbocyclic or heterocyclic radical Het 2  or Het 3 ;  
 R 2  is hydroxy, alkyloxy, alkylcarbonyloxy, phenyloxy, phenylcarbonyloxy, halo, cyano, alkyl, polyhaloalkyl, alkyloxyalkyl, formyl, carboxy, alkylcarbonyl, alkyloxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, phenyl, nitro, amino, mono- or dialkyl-amino, thio or alkylthio;  
 R 3  is alkyl, Ar, Ar-alkyl, Ar-alkenyl, Het, Het-alkyl or Het-alkenyl;  
 R 4 , R 5  each independently is hydrogen, alkyl, carboxy; aminocarbonyl, alkyloxycarbonyl, halo or hydroxyalkyl;  
 p is an integer equal to zero, 1, 2 or 3; 
 alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon (cycloalkyl) radical having from 3 to 7 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 7 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom may be optionally substituted with amino, nitro, thio, hydroxy, oxo, cyano, formyl or carboxy;  
 
 alkenyl is an alkyl radical having one or more double bonds;  
 Ar is a homocycle selected from the group of phenyl and naphthyl, each optionally substituted with one or more substituents, each substituent independently selected from the group of hydroxy, alkyloxy, phenyloxy, phenylcarbonyloxy, polyhaloalkyloxy, halo, cyano, alkyl, polyhaloalkyl, alkyloxyalkyl, formyl, haloformyl, carboxy, alkylcarbonyl, alkyloxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl, phenylalkyl, phenyl, nitro, amino, mono- or dialkyl-amino, thio, alkylthio or SO 2 —CH 3 ;  
 halo is a substituent selected from the group of fluoro, chloro, bromo and iodo;  
 polyhaloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 7 carbon atoms, wherein one or more carbon atoms is substituted with one or more halo-atoms;  
 Het is a heterocyclic radical selected from the group of Het 1 , Het 2  and Het 3 .  
 Het 1  is an aliphatic monocyclic heterocyclic radical selected from the group of pyrrolidinyl, dioxolyl, imidazolidinyl, pyrrazolidinyl, piperidinyl, dioxyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl and tetrahydrofuranyl;  
 Het 2  is a semi-aromatic monocyclic heterocyclic radical selected from the group of 2H-pyrrolyl, pyrrolinyl, imidazolinyl and pyrrazolinyl; and  
 Het 3  is an aromatic monocyclic heterocyclic radical selected from the group of pyrrolyl, pyrazonyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl; or an aromatic bicyclic heterocyclic radical selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothienyl; each monocyclic and bicyclic heterocyclic radical may optionally be substituted on a carbon and/or an heteroatom with halo, hydroxy, alkyloxy, alkyl, Ar, Ar-alkyl or pyridinyl.  
 
     
     
         2 . The compound according to  claim 1 , wherein R 1  is selected from the group of alkyloxy, Ar-alkyloxy, alkyl, polyhaloalkyl, alkyloxyalkyl, Ar-alkyl, Het-alkyl, Ar, piperazinyl, pyrrolyl, thiazolyl, pyrrolidinyl and NR 9 R 10  wherein R 9  and R 10  each independently are hydrogen, alkyl, Ar, Ar-alkyl, pyridinyl or alkyloxycarbonylalkyl.  
     
     
         3 . The compound according to  claim 1 , wherein A=B and R 1  together form a radical selected from the group of benzoxazolyl, thiazolyl, benzothiazolyl, benzimidazolyl and pyrimidinyl.  
     
     
         4 . The compound according to  claim 1 , wherein X is a covalent bond.  
     
     
         5 . The compound according to  claim 1 , wherein R 2  is alkyloxy or halo.  
     
     
         6 . The compound according to  claim 1 , wherein R 3  is selected from the group of phenylalkyl and naphthyl, each independently substituted with at least one substituent selected from the group of halo, alkyloxycarbonyl, hydroxy, alkyloxy and dialkylaminocarbonyl.  
     
     
         7 . The compound according to  claim 1 , wherein A=B is C═O or SO 2 , R 1  is alkyloxy, alkyloxyalkyl, Ar or NR 9 R 10 , wherein R 9  and R 10  each independently are hydrogen or Ar; or A=B and R 1 , together form a benzoxazolyl radical; p is zero, R 3  is benzyl optionally substituted with hydroxy or alkyloxycarbonyl, and R 4  and R 5  each are hydrogen.  
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         9 . A method of treating a human suffering from a pain condition selected from the group consisting of centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain; arthritis; psoriasis; asthma; inflammatory bowel disease; respiratory function disorder; functional diarrhea; non-ulcerogenic dyspepsia; incontinence; and irritable bowel syndrome (IBS), which comprises administering to the human in need of such a treatment a therapeutically effective amount of a compound according to  claim 1.