Pyrazole derivatives and use thereof as orexin receptor antagonists

Abstract

The present invention relates to the orexin receptor antagonists compounds of the general formula (I) as well as to their isomers, salts and solvates, to the pharmaceutical compositions containing them and to the therapeutic application thereof.

1 . Compounds of the general formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         Ar represents phenyl group or a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms, preferably nitrogen atom, oxygen atom or sulphur atom, where any of these rings may optionally be mono- or polysubstituted with halogen atom, C 1-4  alkyl group, C 1-4  alkoxy group, hydroxyl group, cyano group, trihalogenomethyl group, amino group or an amino group substituted with one or two C 1-4  alkyl group; 
         Y stands for —CH 2 — group, 
         X stands for sulphur atom, oxygen atom, —NH-group, —N(C 1-4  alkyl)group, —CH 2 -group, —(S═O)— or —SO 2 -group; or X and Y together represent a —CH═CH— group with cis or trans geometry, 
         A represents a moiety with a five- or six-membered aromatic ring which contains in ortho-, meta- or para-position two free valencies, and is optionally mono- or polysubstituted with halogen atom, C 1-4  alkyl group or C 1-4  alkoxy group; or with a partially or fully saturated five- or six-membered cycloalkyl ring optionally mono- or polysubstituted with halogen atom, C 1-4  alkyl group or C 1-4  alkoxy group; or with a heteroaromatic or partially or fully saturated heterocyclic ring wich contains 1-3 heteroatoms, preferably nitrogen, oxygen or sulphur atom, and is optionally mono- or polysubstituted with halogen atom, C 1-4  alkyl group or C 1-4  alkoxy group; 
         R 1  represents benzyl group, C 1-4 -alkyl-, C 1-4 -hydroxyalkyl-, C 3-8 -alkoxycarbonylalkyl-, C 2-7 -alkylcarbonyl-, C 2-7 -carboxyalkyl-, aminocarbonyl-(C 1-4 )-alkyl, C 1-3 -alkylaminocarbonyl-(C 1-4 -alkyl, amino-(C 1-4 -alkyl, C 1-3 -alkylamino-(C 1-4 -alkyl-, morpholino-(C 1-4 -alkyl-, or morpholinocarbonyl-(C 1-4 -alkyl group or a phenyl group, optionally substituted with one or more halogen atoms, 
         R 2  represents one of the following groups which is optionally substituted with one or more halogenatom, hydroxyl group, C 1-4  alkyl group, trihalogenomethyl-group, thio-C 1-4 -alkyl group, amino group, —(C═O)—NH—C 1-4 -alkyl or cycloalkyl group: phenyl group, phenylethyl group, naphthyl group, indanyl- or indenyl group, five- or six-membered heteroaromatic or partially or fully saturated cyclic group containing 1-3 identical or different heteroatoms, preferably nitrogen, oxygen or sulphur atom, a group containing a bicyclic heteroaromatic moiety or a partially or fully saturated bicyclic heteroring with 1 or 2 or 3 identical or different heteroatoms, preferably nitrogen, oxygen or sulphur atom; 
         R 3  stands for hydrogen atom or C 1-4  alkyl group, 
         R 2  and R 3  together with the nitrogen atom to which they are attached may represent a partly or fully saturated six-membered ring optionally substituted with a substituted phenyl or benzyl group. 
         R 5  stands for halogen atom, hydrogen atom, C 1-4  alkyl group, C 1-4  thioalkyl group, C 1-4  alkoxy group— 
         and their salts, isomers, and solvates. 
       
     
     
         2 . Compounds of the general formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         Ar represents phenyl group or a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms, preferably nitrogen atom, oxygen atom or sulphur atom, where any of these rings may optionally be mono- or polysubstituted with halogen atom, C 1-4  alkyl group, C 1-4  alkoxy group, hydroxyl group, cyano group, trihalogenomethyl group, amino group or an amino group substituted with one or two C 1-4  alkyl group; 
         Y stands for —CH 2 — group, 
         X stands for sulphur atom, oxygen atom, —NH-group, —N(C 1-4  alkyl)group, —CH 2 -group, —(S═O)— or —SO 2 -group; or X and Y together represent a —CH═CH— group with cis or trans geometry, 
         A represents a moiety with a five- or six-membered aromatic ring which contains in ortho-, meta- or para-position two free valencies, and is optionally mono- or polysubstituted with halogen atom, C 1-4  alkyl group or C 1-4  alkoxy group; or with a partially or fully saturated five- or six-membered cycloalkyl ring optionally mono- or polysubstituted with halogen atom, C 1-4  alkyl group or C 1-4  alkoxy group; or with a heteroaromatic or partially or fully saturated heterocyclic ring wich contains 1-3 heteroatoms, preferably nitrogen, oxygen or sulphur atom, and is optionally mono- or polysubstituted with halogen atom, C 1-4  alkyl group or C 1-4  alkoxy group; 
         R 1  represents benzyl group, C 1-4 -alkyl-, C 1-4 -hydroxyalkyl-, C 3-8 -alkoxycarbonylalkyl-, C 2-7 -alkylcarbonyl-, C 2-7 -carboxyalkyl-, aminocarbonyl-(C 1-4 )-alkyl, C 1-3 -alkylaminocarbonyl-(C 1-4 )-alkyl, amino-(C 1-4 )-alkyl, C 1-3 -alkylamino-(C 1-4 )-alkyl-, morpholino-(C 1-4 -alkyl-, or morpholinocarbonyl-(C 1-4 -alkyl group or a phenyl group, optionally substituted with one or more halogen atoms, 
         R 2  represents one of the following groups, optionally substituted with one or more halogen atom, C 1-4  alkyl group, trihalogenomethyl-group, thio-C 1-4 -alkyl group, amino group, —(C═O)—NH—C 1-4 -alkyl or cycloalkyl group: phenyl group, phenylethyl group, naphthyl group, indanyl- or indenyl group, five- or six-membered heteroaromatic or partially or fully saturated cyclic group containing 1-3 identical or different heteroatoms, preferably nitrogen, oxygen or sulphur atom, a group containing a bicyclic heteroaromatic moiety or a partially or fully saturated bicyclic heteroring with 1 or 2 or 3 identical or different heteroatoms, preferably nitrogen, oxygen or sulphur atom; 
         R 3  stands for hydrogen atom or C 1-4  alkyl group, 
         R 2  and R 3  together with the nitrogen atom to which they are attached may represent a partly or fully saturated six-membered ring optionally substituted with a substituted phenyl or benzyl group. 
         R 5  stands for halogen atom, hydrogen atom, C 1-4  alkyl group, C 1-4  thioalkyl group, C 1-4  alkoxy group— 
         and their salts, isomers, and solvates. 
       
     
     
         3 . Compounds of the general formula (I) according  claim 1 .
 wherein   Ar stands for phenyl group or a 6-membered heteroaromatic ring with 1 or 2 nitrogen atoms, where the aromatic rings may optionally be mono- or polysubstituted with halogen atom or C 1-4  alkoxy group,   Y stands for methylene group,   X stands for sulphur atom, oxygen atom, methylene group, —N(methyl)group;   A represents ortho-phenylene group or a heteroaromatic moiety containing in ortho-position two free valencies;   R 1  represents C 1-4 -alkyl-, C 1-5 -hydroxyalkyl-, C 3-8 -alkoxycarbonylmethyl, C 2-6 -carboxyalkyl- or methylaminocarbonyl group, or an alkylaminocarbonyl group substituted with one or two C 1-4 -alkyl group;   R 2  represents aromatic or partially saturated bicyclic group containing 0, 1, 2 or 3 heteroatoms, optionally substituted with one or more C 1-4 -alkyl group, halogen atom or amino group,   R 3  represents hydrogen atom,   R 5  represents halogen atom, C 1-4 -alkyl-, or C 1-4 -alkylthio group,   and their salts, isomers, and solvates.   
     
     
         4 . Compounds of the general formula (I) according  claim 1 .
 wherein   Ar represents a phenyl group, optionally substituted with halogen atom; or a 6-membered heteroaromatic ring with 1 or 2 nitrogen atoms, optionally substituted with halogen atom,   Y stands for methylene group,   X represents methylene group, sulphur atom, oxygen atom, or a nitrogen atom carrying a C 1-4 -alkyl group;   A represents ortho-phenylene group or a heteroaromatic moiety containing in ortho-position two free valencies;   R 1  represents a staight or branched C 1-4 -alkyl group, C 1-3 -hydroxyalkyl group or C 3-6 -alkoxycarbonylmethyl group;   R 2  represents an aromatic or partially saturated bicyclic moiety optionally substituted with C 1-4  alkyl group or halogen atom; or an aromatic or partially saturated bicyclic moiety containing 1-3 heteroatoms, favourably nitrogen, sulphur or oxygen atom,   R 3  represents hydrogen atom,   R 5  represents chloro atom, methyl group or thiomethyl group.   and their salts, isomers, and solvates.   
     
     
         5 . The following compounds according  claim 1 . and their salts, isomers, and solvates:
 2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulphanyl)-N-naphthalin-2-ylbenzamide;   2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-6-ylbenzamide hydrochloride;   2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulphanyl)-N-indan-5-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-2-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-naphthalin-2-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-2-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-6-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   N-(1-Bromoisoquinolin-3-yl)-2-(5-chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethylsulphanyl)benzamide;   2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-isoquinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-naphthalin-2-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-6-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyrazin-2-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-(1-methylisoquinolin-3-yl)benzamide;   2-(1-Ethyl-3-phenyl-5-chloro-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   2-(3-Phenyl-5-chloro-1-propyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   2-(1-Butyl-3-phenyl-5-chloro-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   Ethyl-{3-phenyl-5-chloro-4-[2-(quinolin-3-ylcarbamoyl)-phenylsulphanylmethyl]-1H-pyrazol-1-yl}-acetate;   2-[3-Phenyl-1-(2-hydroxyethyl)-5-chloro-1H-pyrazol-4-ylmethylsulphanyl]-N-quinolin-3-ylbenzamide;   2-(3-Phenyl-1,5-dimethyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   2-(3-Phenyl-1-methyl-5-methylsulphanyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;   3-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulphaniy)-thiophen-2-carboxylic acid naphthalin-2-ylamide;   2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;   2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy)-N-naphthalin-2-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-2-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;   2-[3-(4-Fluorophenyl)-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy]-N-quinolin-3-ylbenzamide;   2-[2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-yl)ethyl]-N-quinolin-3-ylbenzamide;   2-[3-(4-Fluorophenyl)-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy]-N-quinolin-3-ylbenzamide;   2-[2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-yl)ethyl]-N-quinolin-3-ylbenzamide;   2-[2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-yl)ethyl]-N-quinolin-3-ylbenzamide;   2-[(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethyl)methylamino]-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-(3,4-dichlorophenyl)benzamide;   2-[5-Chloro-1-methyl-3-(2-thienyl)-1H-pyrazol-4-ylmethoxy]-N-quinolin-3-ylbenzamide;   2-[(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethyl)methylamino]-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethoxy)-N-(6,7-difluoroquinolin-3-yl)benzamide;   2-(5-Chloro-1-methyl-3-pyridazin-3-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;   2-(5-Chloro-1-methyl-3-pyridazin-4-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide.   
     
     
         6 . Pharmaceutical composition, characterized in that it contains a compound of the general formula (I)—wherein the meanings of Ar, Y, X, A, R 1 , R 2 , R 3  and R 5  are as defined in  claim 1 . —or its salt, isomer or solvate. 
     
     
         7 . Pharmaceutical composition according to  claim 6 , characterized in that it contains a compound of the general formula (I) according to  claim 5 , or its salt, isomer or solvate. 
     
     
         8 . Pharmaceutical composition, characterized in that it contains a compound of the general formula (I)—wherein the meanings of Ar, Y, X, A, R 1 , R 2 , R 3  and R 5  are as defined in  claim 1 . —or its salt, isomer or solvate, and at least one excipient used in the pharmaceutical industry. 
     
     
         9 . Use of the compounds of the general formula (I)—wherein the meanings of Ar, Y, X, A, R 1 , R 2 , R 3  and R 5  are as defined in  claim 1 —to prepare medicines, pharmaceutical compositions, suitable to antagonize the orexin-1 receptors or the orexin-1 and orexin-2 receptors, and thus suitable to treat or prevent diseases connected with the activity of the orexine receptors. 
     
     
         10 . Process for the preparation of the compounds of the general formula (I) and their salts, isomers and solvates—wherein the meanings of Ar, Y, X, A, R 1 , R 2 , R 3  and R 5  are as defined above-characterized by—that
 a.) the acid of the general formula (II)— 
 
       
         
           
           
               
               
           
         
         wherein the meanings of Ar, Y, X, A, R 1  and R 5  are as defined in  claim 1 —is transformed into its active derivative and is reacted with the amine of the general formula (III)
   HNR 2 R 3   (III)
 
 
         wherein the meanings of R 2  and R 3  are as defined in  claim 1 —or 
         b.) a chloromethyl derivative of the general formula (VI)—wherein the meanings of Ar, R 1  and R 5   
       
       
         
           
           
               
               
           
         
         are as defined in  claim 1 —is reacted with an amide of the general formula (IX) 
       
       
         
           
           
               
               
           
         
         wherein the meanings of X, A, R 2  and R 3  are as defined in  claim 1 . 
         and if desired the resulting compound is liberated from its salt or transformed into its salt. 
       
     
     
         11 . Process a.) according to  claim 10 —characterized by—that the compound of the general formula (II) is activated by transforming it into its acid chloride by use of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride or benzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate and is reacted in this form with the amine of the general formula (II). 
     
     
         12 . Compounds of the general formula (IV) 
       
         
           
           
               
               
           
         
         wherein the meanings of Ar, R 1 , and R 5  are as defined in  claim 1 . 
       
     
     
         13 . Compounds of the general formula (V) 
       
         
           
           
               
               
           
         
         wherein the meanings of Ar, R 1 , and R 5  are as defined in  claim 1 . 
       
     
     
         14 . Compounds of the general formula (VI) 
       
         
           
           
               
               
           
         
         wherein the meanings of Ar, R 1 , and R 5  are as defined in  claim 1 . 
       
     
     
         15 . Compounds of the general formula (VII) 
       
         
           
           
               
               
           
         
         wherein the meanings of Ar, Y, X, A, R 1  and R 5  are as defined in  claim 1 . and R represents C 1-4 -alkyl group. 
       
     
     
         16 . Compounds of the general formula (X) 
       
         
           
           
               
               
           
         
         wherein the meanings of Ar, R 1  and R 5  are as defined in  claim 1 .