1H-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1 antagonistic activity

Abstract

The present invention relates to a group of novel 1H-imidazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component. These 1H-imidazole derivatives are potent cannabinoid-CB1 receptor agonists, partial agonists or antagonists, useful for the treatment of psychiatric and neurological disorders, as well as and other diseases involving cannabinoid neurotransmission. The compounds have the general formula (I) wherein R and R1-R4 have the meanings given in the specification.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group C 1-3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono- or dialkyl (C 12 )-amido, (C 1-4 )-alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl, or R represents naphtyl, with the proviso that when R is 4-pyridinyl, R 4  represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or hydroxy group,  
 R 1  represents phenyl or pyridinyl, which groups may be substituted with 14 substituents Y, which can be the same or different, wherein Y has the above mentioned meaning, or R 1  represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, which groups may be substituted with 1-2 substituents Y, which can be the same or different or R 1  represents a five-membered aromatic heterocyclic ring having one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which five-membered aromatic heterocyclic ring may be substituted with 1-2 substituents Y, which can be the same or different or R 1  represents naphtyl,  
 R 2  represents H, branched or unbranched C 1-8  alkyl, C 3-8  cycloalkyl, Cm alkenyl, C 5-8  cycloalkenyl which groups may contain a sulfur, oxygen or nitrogen atom,  
 R 3  represents branched or unbranched C 2-8  alkyl, C 1  alkoxy, C 5-8  cycloalkyloxy, C 3-8  cycloalkyl, C 5-10  bicycloalkyl, C 6-10  tricycloalkyl, C 3-8  alkenyl, C 5-8  cycloalkenyl, which groups may optionally contain one or more heteroatoms from the group (O, N, S) and which groups may be substituted with a hydroxy group or 1-2 C 1-3  alkyl groups or 1-3 fluoro atoms, or R 3  represents a benzyl or phenethyl group which aromatic rings may be substituted with 1-5 substituents Z, which can be the same or different, from the group C 1-3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 12 )-amino, mono- or dialkyl (C 1-2 )-amido, (C 1-3 )-alkylsulfonyl, dimethyl-sulfamido, C 1-3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R 3  represents a phenyl or pyridinyl group, which groups are substituted with 1-4 substituents Z, wherein Z has the meaning as indicated above,  
 or R 3  represents a pyridinyl group, or R 3  represents a phenyl group, with the proviso that R 4  represents a halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl methanesulfonyl, methylsulfanyl or C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or hydroxy group, or R 3  represents a group NR 5 R 6  with the proviso that R 2  represents a hydrogen atom or a methyl group, wherein  
 R 5  and R 6  are the same or different and represent branched or unbranched C 1-4  alkyl, or R 5  and R 6 — together with the nitrogen atom to which they are bonded—form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms which heterocyclic group contains one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C 1-3  alkyl group or a hydroxy group, or R 2  and R 3 — together with the nitrogen atom to which they are bonded—form a saturated or unsaturated heterocyclic group having 4 to 10 ring atoms which heterocyclic group contains one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which heterocyclic group may be substituted with a C 1-3  alkyl group or a hydroxy group,  
 R 4  represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or a hydroxy group, and prodrugs, stereoisomers and salts thereof.  
 
     
     
         2 . Pharmaceutical compositions containing a pharmacologically active amount of at least one compound as claimed in 1 as an active component.  
     
     
         3 . Method of preparing pharmaceutical compositions as claimed in  claim 2  characterised in that a compound as claimed in  claim 1  is brought in a form suitable for administration.  
     
     
         4 . Process for the preparation of compounds having formula (I), characterised in that a compound is prepared wherein R, R 1 -R 3  have the meanings given in  claim 1  and R 4  represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro atoms, by reacting a compound having formula (II), (Ill) or (IV) with a compound of formula R 2 R 3 NH.  
     
     
         5 . Process for the preparation of compounds having formula (Ii)  
       
         
           
           
               
               
           
         
       
       wherein R 4  represents a C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro substituents, or wherein R 4  represents a halogen atom or a cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl or propionyl group, characterized in that a compound is prepared wherein R and R 1  have the meanings given in  claim 1  and R 7  represents a branched or unbranched alkyl group (C 1-4 ) or benzyl group, by reacting a compound having formula (II) wherein R 4  is a hydrogen atom with a compound having formula R 4 ′-X, wherein X represents a leaving group and R 4 ′ represents a C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro substituents, or wherein R 4 ′ represents a halogen atom or a cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl or propionyl group, in the presence of a strong non-nucleophilic base.  
     
     
         6 . Process for the preparation of a compound having formula (II)  
       
         
           
           
               
               
           
         
       
       wherein R 4  represents a branched or unbranched C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro substituents, characterized in that a compound is prepared wherein R, R 1  have the meanings given in  claim 1  and R 7  represents a branched or unbranched alkyl group (C 14 ) or benzyl group, by reacting a compound having formula (V) or its tautomer  
       
         
           
           
               
               
           
         
       
       wherein R and R 1  have the meanings given in  claim 1 , with a compound having formula (VI)  
       
         
           
           
               
               
           
         
       
       wherein R 4  represents a branched or unbranched C 1-4  alkyl group, which C 1-4  alkyl group may be substituted with 1-3 fluoro atoms and R 8  represents a so-called leaving group and R 7  represents a branched or unbranched alkyl group (C 1-4 ) or benzyl group.  
     
     
         7 . Compounds of formula (IX)  
       
         
           
           
               
               
           
         
       
       wherein R and R 4  have the meanings given in  claim 1  and wherein R 1  represents a phenyl or pyridinyl group, which groups are substituted with 14 substituents Y, which can be the same or different, or R 1  represents a pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl group, which groups are substituted with 1-2 substituents Y, which can be the same or different or R 1  represents a five-membered aromatic heterocyclic moiety having one or two heteroatoms from the group (N, O, S), which heteroatoms can be the same or different, which five-membered aromatic heterocyclic moiety may be substituted with 1-2 substituents Y, which can be the same or different or R 1  represents naphtyl and R 9  represents a hydroxy group, a branched or unbranched alkoxy (C 14 ) group, a benzyloxy group or a chloro substituent.  
     
     
         8 . Compounds of formula (X) and tautomers thereof.  
       
         
           
           
               
               
           
         
       
       wherein R represents a 4-chlorophenyl group, a. 4-bromophenyl group or a 4-(trifluoromethyl)phenyl group.  
     
     
         9 . Use of a compound as claimed in  claim 1  for the preparation of a pharmaceutical composition for the treatment of disorders involving cannabinoid neurotransmission.  
     
     
         10 . Use as claimed in  claim 9  characterised in that said disorders are psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders.