Benzothiazole derivatives with activity as adenosine receptor ligands

Abstract

The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.

1 . A compound of formula IA  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, lower alkyl, lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or trifluoromethyloxy;  
 R 2 , R 3  are independently from each other hydrogen, halogen, lower alkyl or lower alkyloxy;  
 R 4  is hydrogen, lower alkyl, lower alkenyl, halogen, —C(O)-lower alkyl, —C(O)-halogen-lower alkyl, —CH(OH)-halogen-lower alkyl, —C(O)O-lower alkyl, —NHC(O)-lower alkyl, —(CH 2 ) n —OH, or is phenyl, which is optionally attached to the benzo group via the linker —(O) m —(CH 2 ) n — and is unsubstituted or substituted by N(R 5 )(R 6 ), halogen or nitro, or is 2,3-dihydro-1H-indolyl, azepan-1-yl, [1,4]oxazepan-4-yl, or is a five or six membered aromatic or non aromatic heterocycle, which may be attached to the benzo group via the linker —(O) m —(CH 2 ) n  or —N═C(CH 3 )— and is unsubstituted or substituted by one or two group(s) R 7 , wherein R 7  is defined below;  
 R′ is 
 (a) phenyl, unsubstituted or substituted by halogen-lower alkyl, —C(O)H or by the following groups  
 —(CH 2 ) n —C(O)—N(R 5 )—(CH 2 ) n lower alkoxy,  
 —(CH 2 ) n O-halogen-lower alkyl,  
 —(CH 2 ) n O—(CH 2 ) n+1 O-lower alkyl,  
 —S(O) 2 —N(R 5 )—(CH 2 ) n O-lower alkyl,  
 —(CH 2 ) n OR 5 ,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o -lower alkoxy,  
 —(CH 2 ) n N[(CH 2 ) o -lower alkoxy] 2 ,  
 —(CH 2 ) n N[S(O) 2 CH 3 ] 2 ,  
 —(CH 2 ) n N[R 5 ][S(O) 2 CH 3 ],  
 —(CH 2 ) n N(R 5 )-lower alkenyl,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o -cycloalkyl,  
 —(CH 2 ) n N(R 5 )—C(O)O-lower alkyl,  
 —(CH 2 ) n —S—(CH 2 ) n —N(R 5 )(R 6 ),  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o —S-lower alkyl,  
 —(CH 2 ) n N(R 5 )—S(O) 2 CH 3    
 —(CH 2 ) n N(R 5 )—(CH 2 ) o -phenyl,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o OH,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o CH(OH)—CF 3 ,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o —CF 3 ,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o —O—CH(OH)—C 6 H 3 (OCH 3 ) 2 ,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o —O—C(O)—C 6 H 3 (OCH 3 ) 2 ,  
 N(R 5 )—C(O)-morpholin,  
 N(R 5 )—C(O)—N(R 5 )-phenyl, substituted by alkoxy,  
 —S(O) 2 -morpholin,  
 or is phenyl, which is unsubstituted or substituted by —(CR 5 R 6 ) n -five to seven membered aromatic or non aromatic heterocycle, and wherein the heterocycle is unsubstituted or substituted by hydroxy, —N(R 5 )(R 6 ) or lower alkyl, or by —(CH 2 ) n N(R 5 )(CH 2 ) o -five or six membered aromatic or non aromatic heterocycle and wherein the heterocycle is unsubstituted or substituted by hydroxy, —N(R 5 )(R 6 ) or lower alkyl,  
 or is —N(R 5 )-phenyl, which is unsubstituted or substituted by lower alkoxy, or is  
 b) —(CH 2 ) n -five or six membered aromatic or non aromatic heterocycle, with the exception of the piperazinyl group in case if n=0, which rings may be unsubstituted  
 
 or substituted by 2-oxo-pyrrolidin, piperidinyl, phenyl, —(CH 2 ) n OH, halogen, CF 3 , ═O, lower alkyl, cycloalkyl, —(CH 2 ) n —O-lower alkyl, —(CH 2 ) n NH 2 , —(CH 2 ) n CN, —C(O)O-lower alkyl, —CH 2 —O—S(O) 2 CH 3 , —C(O)-lower alkyl, —C(O)—(CH 2 ) n -lower alkoxy, 
 —CH 2 —N(R 6 )C 6 H 4 F, —CH 2 —N(R 6 )C(O)O-lower alkyl,  
 —N(R 6 )—C(O)—N(R 5 )—(CH 2 ) n —O-lower alkyl, -or by tetrahydrofuran, substituted by 4-C 1 -phenyl, or by piperazin-1-yl, morpholinyl, thiomorpholinyl,  
 thiomorpholin-1-oxo, pyrrolidin-1-yl or by piperidin-1-yl or is benzopiperidin-1-yl or benzothien-2-yl, or  
 is  
 c) —N(R 5 )(CH 2 ) n+1 -phenyl, unsubstituted or substituted by lower alkoxy,  
 —O(CH 2 ) n -phenyl, or  
 —N(R 5 )C(O)-phenyl, or  
 is  
 d) —N(R 5 )(CH 2 ) n -5- or 6 membered aromatic or non aromatic heterocycle, unsubstituted or substituted by lower alkyl, —(CH 2 ) n -5- or 6 membered aromatic or non aromatic heterocycle  
 or is  
 e) —O—(CH 2 ) n -lower alkoxy, lower alkyl-lower alkoxy, —N(R 5 )(CH 2 ) n N(R 5 )(R 6 ), —(CH 2 ) n OH, —(HC═CH) n C(O)O-lower alkyl, octahydro-quinoline, 3,4-dihydro-1H-isoquinoline, 2,3-benzo-1,4-dioxa-8-aza-spiro[4,5]decane or 1,4-dioxa-8-aza-spiro[4,5]decane.  
 
 X is O, S or two hydrogen atoms;  
 R 5 , R 6  are independently from each other hydrogen or lower alkyl,  
 R 7  is lower alkyl, lower alkoxy, —C(O)-lower alkyl, —C(O)O-benzyl, —C(O)O-lower alkyl, —(CH 2 ) n NR 5 R 6 , pyridinyl, unsubstituted or substituted by lower alkyl, or is —CH 2 N(R 5 )—C(O)O-lower alkyl, —NH—C(phenyl) 3 , pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, unsubstituted or substituted by lower alkyl;  
 n is 0, 1, 2, 3 or 4;  
 m is 0 or 1;  
 o is 0, 1, 2, 3 or 4;  
 or a pharmaceutically acceptable salt thereof.