Adamantane derivatives

Abstract

The invention provides adamantane derivatives of formula (I), a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy. In formula (I) D represents CH 2 or CH 2 CH 2 , E represents C(O)NH or NHC(O) and R 3 represents a group of formula (I).

1 . A compound of general formula 
       
         
           
           
               
               
           
         
         wherein D represents CH 2  or CH 2 CH 2 ; 
         E represents C(O)NH or NHC(O); 
         R 1  and R 2  each independently represent hydrogen, halogen, amino, nitro, C 1 -C 6  alkyl or trifluoromethyl, but R 1  and R 2  may not both simultaneously represent hydrogen; 
         R 3  represents a group of formula 
       
       
         
           
           
               
               
           
         
         R 4  represents a C 1 -C 6  alkyl group; 
         X represents an oxygen or sulphur atom or a group NR 13 , SO or SO 2 ; 
         R 5  represents hydrogen, or R 5  represents C 1 -C 6  alkyl or C 2 -C 6  alkenyl, each of which may be optionally substituted by at least one substituent selected from halogen, hydroxyl, (di)-C 1 -C 6 -alkylamino, —Y—R 6 , 
       
       
         
           
           
               
               
           
         
          a 5- or 6-membered heteroaromatic ring comprising from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur which heteroaromatic ring may itself be optionally substituted by at least one substituent selected from halogen, hydroxyl and C 1 -C 6  alkyl; 
         Y represents an oxygen or sulphur atom or a group NH, SO or SO 2 ; 
         R 6  represents a group —R 7 Z where R 7  represents a C 2 -C 6  alkyl group and Z represents an —OH, —CO 2 H, —NR 8 R 9 , —C(O)NR 10 R 11  or —N(R 12 )C(O)—C 1 -C 6  alkyl group, and, in the case where Y represents an oxygen or sulphur atom or a group NH, R 6  additionally represents hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkylcarbonyl, C 1 -C 6  alkoxycarbonyl, —C(O)NR 14 R 15 , —CH 2 OC(O)R 16 , —CH 2 OC(O)OR 17  or —C(O)OCH 2 OR 18 ; 
         R 8 , R 9 , R 10 , R 11  and R 12  each independently represent a hydrogen atom or a C 1 -C 6  alkyl group; 
         R 13  represents hydrogen, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkylmethyl, or R 13  represents a C 1 -C 6  alkyl group optionally substituted by at least one substituent selected from hydroxyl and C 1 -C 6  alkoxy; and 
         R 14 , R 15 , R 16 , R 17  and R 18  each independently represent C 1 -C 6  alkyl group; 
         with the proviso that when E is C(O)NH, X is O, NH or N(C 1 -C 6  alkyl), then R 5  is other than a hydrogen atom or an unsubstituted C 1 -C 6  alkyl group; 
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         2 . The compound according to  claim 1 , wherein D represents CH 2 . 
     
     
         3 . The compound according to  claim 1 , wherein E represents NHC(O). 
     
     
         4 . The compound according to  claim 1 , wherein R 1  and R 2  each independently represent a hydrogen, chlorine or bromine atom, or an amino, nitro, C 1 -C 3  alkyl or trifluoromethyl group. 
     
     
         5 . The compound according to  claim 1 , wherein X represents an oxygen atom or a group NR 13 . 
     
     
         6 . The compound according to  claim 5 , wherein R 13  represents hydrogen, —(CH 2 ) 2 OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclohexylmethyl. 
     
     
         7 . The compound according to  claim 1 , wherein R 5  represents a C 1 -C 6  alkyl group substituted by a single substituent —Y—R 6 . 
     
     
         8 . The compound according to  claim 1 , wherein Y represents an oxygen or sulphur atom or a group NH. 
     
     
         9 . The compound according to  claim 8 , wherein R 6  represents —(CH 2 ) 2 OH, —(CH 2 ) 3 OH, hydrogen, methyl, isopropyl, methylcarbonyl or t-butylcarbonyl. 
     
     
         10 . The compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to  claim 1  which is selected from: 
       2-Chloro-5-[[2-(2-hydroxy-ethylamino)-ethylamino]-methyl]-N-(tricyclo[3.3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide dihydrochloride, 
       2-Chloro-5-[[2-(2-hydroxyethoxy)ethylamino]methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[(3-hydroxy-2,2-dimethylpropylamino)methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[(5-hydroxypentylamino)methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[2-[(2-hydroxyethylthio)ethylamino]methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, acetate salt, 
       2-Chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       2-Chloro-5-[3-(methylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, acetate salt, 
       2-Chloro-5-[3-[(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       5-[3-[(2-Amino-2-methylpropyl)amino]propyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, dihyrdrochloride salt, 
       2-Chloro-5-[3-[(4-hydroxybutyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-hydroxy-2-methylpropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, acetate salt, 
       2-Chloro-5-[3-[[2-(methylamino)ethyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, dihydrochloride salt, 
       (S)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       (R)-2-Chloro-5-[3-[(2-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       (R)-2-Chloro-5-[3-[(2-hydroxy-1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       2-Chloro-5-[3-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       5-[3-[[2-(Acetylamino)ethyl]amino]propyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       2-Chloro-5-[3-[[2-(diethylamino)ethyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, dihydrochloride salt, 
       2-Chloro-5-[3-[(3-methoxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       2-Chloro-5-[3-[(3-hydroxy-3-methylbutyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       2-Chloro-5-[3-[(2-methoxyethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, hydrochloride salt, 
       2-Chloro-5-[[3-(methylamino)propoxy]methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)benzamide, 
       2-Chloro-5-[[2-[(2-hydroxyethyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt, 
       2-Chloro-5-[[2-[(3-hydroxypropyl)amino]ethoxy]methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, acetic acid salt, 
       2-Chloro-5-[[[3-[(1-methylethyl)amino]propyl]amino]methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       5-[[(3-Aminopropyl)amino]methyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[[[2-[(1-methylethyl)amino]ethyl]amino]methyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       3-[[3-[4-Chloro-3-[[(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)amino]-carbonyl]phenyl]propyl]amino]propanoic acid, 2,2-dimethylpropyl ester, trifluoroacetic acid salt, 
       5-(2-Aminoethyl)-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)benzamide, 
       2-Chloro-5-[3-[(2-hydroxyethyl)pentylamino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(methyl-2-propenylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[2-(dimethylamino)ethyl]methylamino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       5-[3-(Butylethylamino)propyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(methylpentylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[2-(diethylamino)ethyl]ethylamino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-hydroxyethyl)methylamino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(dipropylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-hydroxyethyl)(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       5-[3-[Butyl(2-hydroxyethyl)amino]propyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(diethylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(dimethylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       5-[3-(Butylmethylamino)propyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-hydroxyethyl)propylamino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[ethyl(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(dibutylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(ethylpropylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[methyl(1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[3-(dimethylamino)propyl]methylamino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[cyclohexyl(2-hydroxyethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(cyclohexylmethylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(cyclohexylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[1-(hydroxymethyl)-2,2-dimethylpropyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(cyclopropylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[2-(dimethylamino)ethyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(3-hydroxy-2,2-dimethylpropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(1,1-dimethylethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[3-(dimethylamino)propyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(cyclopentylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-5-[3-[(1,2,2-trimethylpropyl)amino]propyl]-benzamide, 
       5-[3-(Butylamino)propyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[1-(hydroxymethyl)-2-methylpropyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(1-methylpropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[2-(methylthio)ethyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-hydroxy-1,1-dimethylethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(cyclohexylmethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-(2-propenylamino)propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-fluoroethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[(2-methoxy-1-methylethyl)amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[3-(methylamino)propoxy]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)benzamide, dihydrochloride salt, 
       5-[[[(1-Aminocyclopropyl)methyl](2-hydroxyethyl)amino]methyl]-2-chloro-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       5-[[(2-Hydroxyethyl)[2-(methylamino)ethyl]amino]methyl]-2-methyl-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)-benzamide, 
       2-Chloro-5-[3-[[2-(1-methyl-1H-imidazol-4-yl)ethyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)benzamide, 
       2-Chloro-5-[3-[[2-(1H-imidazol-4-yl)ethyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)benzamide, and 
       2-Chloro-5-[3-[[3-(1H-imidazol-1-yl)propyl]amino]propyl]-N-(tricyclo[3.3.1.1 3,7 ]dec-1-ylmethyl)benzamide. 
     
     
         11 . A process for the preparation of a compound of formula (I) as defined in  claim 1  which comprises:
 (a) when X represents an oxygen or sulphur atom or a group NR 13 , reacting a compound of general formula   
       
         
           
           
               
               
           
         
          wherein L 1  represents a leaving group and D, E, R 1 , R 2  and R 4  are as defined in formula (I), with a compound of general formula 
       
       
         
           
           
               
               
           
         
          wherein X′ represents an oxygen or sulphur atom or a group NR 13 , and R 5  is as defined in formula (I), optionally in the presence of a suitable silver salt; or 
         (b) when X represents SO or SO 2 , reacting a corresponding compound of formula (I) in which X represents a sulphur atom with a suitable oxidising agent; or 
         (c) when X represents a group NR 13 , reacting a compound of general formula 
       
       
         
           
           
               
               
           
         
          wherein R 20  represents a bond or C 1 -C 5  alkyl group and D, E, R 1  and R 2  are as defined in formula (I), with a compound of general formula 
       
       
         
           
           
               
               
           
         
          wherein R 5  and R 13  are as defined in formula (I), in the presence of a reducing agent; 
       
       and optionally after (a), (b) or (c) converting the compound of formula (I) obtained to a pharmaceutically acceptable salt or solvate thereof. 
     
     
         12 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1  or  claim 10  in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         13 . A process for the preparation of a pharmaceutical composition as claimed in  claim 12  which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in  claim 1  or  claim 10  with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         14 - 19 . (canceled) 
     
     
         20 . A method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1  or  claim 10  to a patient in need thereof. 
     
     
         21 . A method of treating rheumatoid arthritis which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1  or  claim 10  to a patient in need thereof. 
     
     
         22 . A method of treating chronic obstructive pulmonary disease which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in  claim 1  or  claim 10  to a patient in need thereof.