Aminoethylaromatic compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor

Abstract

The present invention relates to aromatic compounds of the formula (I) and the physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D 3 receptor ligand.

1 . An aminoethylaromatic compound of the formula I 
       
         
           
           
               
               
           
         
         wherein 
         Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, wherein Ar may carry 1 radical R a  and wherein Ar may also carry 1 or 2 radicals R b ; 
         R a  being selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, fluorinated C 2 -C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, fluorinated C 1 -C 6 -alkyl, fluorinated C 3 -C 6 -cycloalkyl, fluorinated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, COOH, NR 4 R 5 , CH 2 NR 4 R 5 , ONR 4 R 5 , NHC(O)NR 4 R 5 , C(O)NR 4 R 5 , SO 2 NR 4 R 5 , C 1 -C 6 -alkylcarbonyl, fluorinated C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonylamino, fluorinated C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylcarbonyloxy, fluorinated C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylthio, fluorinated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, fluorinated C 1 -C 6 -alkylsulfinyl, fluorinated C 1 -C 6 -alkylsulfonyl, phenylsulfonyl, phenyl, phenoxy, benzyloxy and a 3- to 7-membered heterocyclic radical, wherein the five last mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen, cyano, OH, oxo, CN, and the radicals R a , 
         R b  being, independently from each other, selected from halogen, cyano, nitro, OH, methyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluormethoxy, difluoromethoxy and trifluoromethoxy,
 the radical R a  and one radical R b , if present and bound to two adjacent carbon atoms of phenyl, may form a 5- or 6-membered heterocyclic or carbocylic ring which is fused to the phenyl ring and which is unsubstituted or which may carry 1, 2 or 3 radicals selected from halogen, NO 2 , NH 2 , OH, CN, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, fluorinated C 1 -C 6 -alkyl, fluorinated C 3 -C 6 -cycloalkyl, fluorinated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl, C 1 -C 4 -alkoxy-C 2 -C 4 -alkyl, C 1 -C 6 -hydroxyalkoxy, C 1 -C 4 -alkoxy-C 2 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkylaminocarbonyl, di-C 1 -C 6 -alkylaminocarbonyl, fluorinated C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonylamino, fluorinated C 1 -C 6 -alkylcaarbonylamino, C 1 -C 6 -alkylcarbonyloxy, fluorinated C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylthio, fluorinated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, fluorinated C 1 -C 6 -alkylsulfinyl and fluorinated C 1 -C 6 -alkylsulfonyl, 
 
         X is N or CH; 
         E is NR 3 ; 
         R 1  is C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkylmethyl, C 3 -C 4 -alkenyl, fluorinated C 1 -C 4 -alkyl, fluorinated C 3 -C 4 -cycloalkyl, fluorinated C 3 -C 4 -cycloalkylmethyl, fluorinated C 3 -C 4 -alkenyl, formyl or C 1 -C 3 -alkylcarbonyl; 
         R 1a  is H, C 1 -C 4 -alkyl, C 3 -C 4 -cycloalkyl, C 3 -C 4 -cycloalkylmethyl, C 3 -C 4 -alkenyl, fluorinated C 1 -C 4 -alkyl, fluorinated C 3 -C 4 -cycloalkyl, fluorinated C 3 -C 4 -cycloalkylmethyl, fluorinated C 3 -C 4 -alkenyl, or R 1a  and R 2  together are (CH 2 ), with n being 2, 3 or 4, or R 1a  and R 2a  together are (CH 2 ) n  with n being 2, 3 or 4; 
         R 2 , R 2a  are independently of each other H, C 1 -C 4 -alkyl or fluorinated C 1 -C 4 -alkyl or R 2a  and R 2  together are (CH 2 ) m  with m being 1, 2, 3, 4 or 5; 
         R 3  is H or C 1 -C 4 -alkyl; 
         R 4 , R 5  independently of each other are selected from H, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkyl; 
         R 6 , R 7  independently of each other are selected from H, fluorine, C 1 -C 4 -alkyl and fluorinated C 1 -C 4 -alkyl or together form a moiety (CH 2 ) p  with p being 2, 3, 4 or 5;
 provided that for R 1  being C 1 -C 4 -alkyl, R 2 =R 2a  being H, E being NH, X being CH and Ar=substituted phenyl Ar carries at least one substituent R a  which is different from linear C 1 -C 3 -alkyl, OCH 3 , OCF 3 , CF 3 , SCH 3  or NHC(O)CH 3 . 
 and the physiologically tolerated acid addition salts of these compounds. 
 
       
     
     
         2 . The compounds of  claim 1 , wherein Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2, or 3 further heteroatoms, independently of each other, selected from O, S and N, as ring members, wherein Ar carries one radical R a  which is selected from the group consisting of C 2 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, fluorinated C 1 -C 6 -alkyl, fluorinated C 3 -C 6 -cycloalkyl, fluorinated C 1 -C 6 -alkoxy, NR 4 R 5 , 1-aziridinyl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, wherein the last four mentioned radicals may be fluorinated, a phenyl group and an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 further heteroatoms, independently of each other, selected from O, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 radicals selected from halogen and the radicals R a ; and wherein Ar may carry 1 or 2 further radicals R b , which are independently from each other selected from halogen, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy; and wherein R 4 , R 5 , independently of each other are selected from H, C 1 -C 3 -alkyl and fluorinated C 1 -C 3 -alkyl, provided that for R 2 =R 2a =H, E=NH, X=CH and Ar=substituted phenyl Ar carries at least one substituent R a  which is selected from secondary C 3 -C 6 -alkyl, fluorinated C 2 -C 6 -alkyl, fluorinated C 3 -C 6 -cycloalkyl, fluorinated C 2 -C 6 -alkoxy, NR 4 R 5 , 1-aziridinyl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, wherein the last for mentioned radicals may be fluorinated, a phenyl group and an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0, 1, 2 or 3 further heteroatoms, independently of each other, selected from O, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 radicals selected from Halogen and the radicals R a . 
     
     
         3 . The compound of  claim 1 , wherein Ar carries one radical R a  of the formula R a′   
       
         
           
           
               
               
           
         
         wherein 
         Y is N, CH or CF, 
         R a1  and R a2  are independently of each other selected from C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, fluorinanted C 1 -C 2 -alkyl, provided for Y being CH or CF one of the radicals R a1  or R a2  may also be hydrogen or fluorine, or 
         R a1  and R a2  together form a radical (CH 2 ) m  wherein 1 or 2 of the hydrogen atoms may be replaced by fluorine, hydroxy, oxo, C 1 -C 2 -alkyl or C 1 -C 2 -alkoxy, wherein one CH 2  moiety may be replaced by O, S, S═O, SO 2  or N—R c , R c  being hydrogen or C 1 -C 2 -alkyl and wherein m is 2, 3, 4, 5 or 6. 
       
     
     
         4 . The compound of  claim 3 , wherein the radical R a′  is selected from isopropyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl; (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, cyclopropyl, cyclobutyl, 1-fluorocyclopropyl, and 2-fluorocyclopropyl. 
     
     
         5 . The compound of  claim 3 , wherein the radical R a′  is selected from 4-morpholinyl, 4-thiomorpholinyl, 4-(1,1-dioxo)thiomorpholinyl, piperazin-1-yl, 4-methylpiperazin-1-yl, azetidin-1-yl, 2-methylazetidin-1-yl, (S)-2-methylazetidin-1-yl, (R)-2-methylazetidin-1-yl, 3-fluoroazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-hydroxyazetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, (S)-pyrrolidin-2-yl, (R)-pyrrolidin-2-yl, pyrrolidin-3-yl, (S)pyrrolidin-3-yl, (R)-pyrrolidin-3-yl, 2-fluoropyrrolidin-1-yl, (S)-2-fluoropyrrolidin-1-yl, (R)-2-fluoropyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, (S)-3-fluoropyrrolidin-1-yl, (R)-3-fluoropyrrolidin-1-yl, 2,2-difluoropyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, (S)-2-methylpyrrolidin-1-yl, (R)-2-methylpyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, (S)-3-methylpyrrolidin-1-yl, (R)-3-methylpyrrolidin-1-yl, 1-methylpyrrolidin-2-yl, (S)-1-methylpyrrolidin-2-yl, (R)-1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, (S)-1-methylpyrrolidin-3-yl, (R)-1-methylpyrrolidin-3-yl, 2,2-dimethylpyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 2-trifluoromethylpyrrolidin-1-yl, (S)-2-trifluoromethylpyrrolidin-1-yl, (R)-2-trifluoromethylpyrrolidin-1-yl, 3-trifluoromethylpyrrolidin-1-yl, (S)-3-tritluoromethylpyrrolidin-1-yl, (R)-3-trifluoromethylpyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-oxazolidin-3-yl, piperidin-1-yl, 2-methylpiperidin-1-yl, (S)-2-methylpiperidin-1-yl and (R)-2-methylpiperidin-1-yl. 
     
     
         6 . The compound of  claim 2 , wherein the radical R a′  carries 1, 2, 3 or 4 fluorine atoms. 
     
     
         7 . The compound of  claim 1 , wherein Ar carries one radical R a , which is selected from CHF 2 , CH 2 F, OCHF 2  and OCH 2 F. 
     
     
         8 . The compound of  claim 1 , wherein Ar carries one radical R a , which is selected from 5- or 6-membered heteroaromatic radicals having as ring members 1 heteroatom selected from O, S and N and which may further have 1, 2 or 3 nitrogen atoms as ring members, and wherein the 5- or 6-membered heteroaromatic radical may carry 1, 2 or 3 substituents selected from halogen, NO 2 , NH 2 , OH, CN, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, fluorinated C 1 -C 6 -alkyl, fluorinated C 3 -C 6 -cycloalkyl, fluorinated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkyl, C 1 -C 4 -alkoxy-C 2 -C 4 -alkyl, C 1 -C 6 -hydroxyalkoxy, C 1 -C 4 -alkoxy-C 2 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkylaminocarbonyl, di-C 1 -C 6 -alkylaminocarbonyl, fluorinated C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonylamino, fluorinated C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylcarbonyloxy, fluorinated C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylthio, fluorinated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, fluorinated C 1 -C 6 -alkylsulfuriyl and fluorinated C 1 -C 6 -alkylsulfonyl. 
     
     
         9 . The compound of  claim 8 , wherein Ar carries one heteroaromatic radical R a ′ which is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl and tetrazolyl, where the heteroaromatic radical may be unsubstituted or may carry 1 to 3 substituents selected from halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluorinated C 1 -C 4 -alkyl and fluorinated C 1 -C 4 -alkoxy. 
     
     
         10 . The compound of  claim 1 , wherein Ar is phenyl. 
     
     
         11 . The compound of  claim 1 , wherein Ar is phenyl that carries a radical R a  in the 4-position of the phenyl ring. 
     
     
         12 . The compound of  claim 1 , wherein X is CH. 
     
     
         13 . The compound  claim 1 , wherein X is N. 
     
     
         14 . The compound  claim 1 , wherein R 1  is n-propyl, fluorinated C 2 -C 3 -alkyl or 1-propen-3-yl. 
     
     
         15 . The compound of  claim 1 , wherein R 1a  is hydrogen. 
     
     
         16 . The compound of  claim 1 , wherein R 2a  is hydrogen. 
     
     
         17 . The compound of  claim 16 , wherein both R 2a  and R 2  are hydrogen. 
     
     
         18 . The compound of  claim 1 , wherein one of the radicals R 2a  and R 2  is hydrogen while the other is methyl. 
     
     
         19 . The compound of  claim 1 , wherein R 1a  is n-propyl or 1-propen-3-yl. 
     
     
         20 . The compound of  claim 1 , wherein R 2  is hydrogen and R 2a  and R 1a  together are (CH 2 ) n  with n being 3 or 4. 
     
     
         21 . A pharmaceutical composition comprising at least one compound of the formula 1 or a pharmaceutically acceptable salt thereof of  claim 1 , optionally together with at least one physiologically acceptable carrier or auxiliary substance. 
     
     
         22 . A method for treating a medical disorder, wherein the medical disorder is a disease of the central nervous system, susceptible to treatment with a dopamine D3 receptor ligand, said method comprising administering an effective amount of at least one compound of the formula I or a pharmaceutically acceptable salt thereof of  claim 1  to a subject in need thereof. 
     
     
         23 .- 25 . (canceled)