Benzothiazole derivatives with activity as adenosine receptor ligands

Abstract

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

1 . A method of treating a person having a disease state treatable by modulation of the adenosine A 2A  receptor comprising administering to a person in need of such treatment, an effective amount of a compound of the formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl, lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or trifluoromethyloxy; 
 R 2  and R 3  are each independently hydrogen, halogen, lower alkyl or lower alkyloxy; 
 R 4  is hydrogen, lower alkyl, lower alkenyl, halogen, —C(O)OH, —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, alkoxy 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 lower alkyl, halogen-lower alkyl, lower alkoxy, cyano, nitro, —C(O)H, —C(O)OH or by the following groups 
 —(CH 2 ) n —C(O)—N(R 5 )—(CH 2 ) o -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(R 5 )(R 6 ), 
 —(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 )—(CH 2 ) o NR 5 R 6 , 
 —(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, 
 —S(O) 2 —N(R 5 )(R 6 ), 
 —(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 further substituted by hydroxy, —N(R 5 )(R 6 ), lower alkoxy 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 further substituted by hydroxy, —N(R 5 )(R 6 ) or lower alkyl, 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 are unsubstituted or substituted by one or two substituents, selected from the group consisting of 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-Cl-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) —(CH 2 ) n+1 -phenyl, 
 —N(R 5 )(CH 2 ) n -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) —(CH 2 ) n —N(R 5 )(R 6 ), lower alkyl, —O—(CH 2 ) n -lower alkoxy, —(CH 2 ) n -lower alkoxy, lower alkoxy, cycloalkyl, —N(R 5 )(CH 2 ) n O-lower alkyl, —N(R 5 )(CH 2 ) n OH, —N(R 5 )(CH 2 ) n N(R 5 )(R 6 ), —C(O)O-lower alkyl, —(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  and R 6  are each independently 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, optionally 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. 
 
   
   
       2 . The method of  claim 1 , wherein the disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, hypoxia, ischaemia, seizure, substance abuse, ADHD, and diabetes mellitus. 
   
   
       3 . The method of  claim 2 , wherein the disease is Parkinson's disease. 
   
   
       4 . The method of  claim 1 , wherein the compound of formula I has the formula I-A 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, lower alkyl, lower alkoxy, benzyloxy, cycloalkyloxy, halogen, hydroxy or trifluoromethyloxy; 
 R 2  and R 3  are each independently 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 )—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, or [1,4]oxazepan-4-yl, 
 or is 
 a five or six membered aromatic or non aromatic heterocycle, which is optionally 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, optionally 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 )lower alkoxy, 
 —(CH 2 ) n O-halogen-lower alkyl, 
 —(CH 2 ) n O—(CH 2 ) n+1 O-lower alkyl, 
 —S(O) 2 ) n —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, or 
 —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 are optionally substituted by 2-oxo-pyrrolidin, piperidinyl, phenyl, —(CH 2 ) n OH, halogen, CF 3 , ═O, lower alkyl, cycloalkyl, —(CH 2 )—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-Cl-phenyl, piperazin-1-yl, morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo, pyrrolidin-1-yl or piperidin-1-yl or is benzopiperidin-1-yl or benzothien-2-yl, 
 or is 
 c) —N(R 5 )(CH 2 ) +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 nonaromatic 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  and R 6  are each independently 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, or 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. 
 
   
   
       5 . The method of  claim 4 , wherein
 R 1  is lower alkoxy;   R 2  and R 3  are hydrogen;   R 4  is a five or six membered aromatic or non aromatic heterocycle, which is optionally attached to the benzo group via the linker —(O) m —(CH 2 ) 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
 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 are optionally 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 )—O-lower alkyl, -or by tetrahydrofuran, substituted by 4-Cl-phenyl, piperazin-1-yl, morpholinyl, thiomorpholinyl, thiomorpholin-1-oxo, pyrrolidin-1-yl or piperidin-1-yl or is benzopiperidin-1-yl or benzothien-2-yl; 
   X is O;   R 5  and R 6  are each independently 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, or piperazinyl, unsubstituted or substituted by lower alkyl;   n is 0, 1, 2, 3 or 4; and   m is 0 or 1.   
   
   
       6 . The method of  claim 5 , wherein R 1  is methoxy, R 2  and R 3  are hydrogen, R 4  is morpholino, X is O, and R′ is 4-methyl-4-methoxy-morpholino. 
   
   
       7 . The method of  claim 6 , wherein the disease is Parkinson's disease.