Benzothiazole derivatives with actitvity 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 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,  
 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 ) 2 —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 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  
  b) —(CH 2 ) n -five membered aromatic or non aromatic heterocycle, with the exception of the 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-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  
  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  
  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  
  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 two hydrogen atoms;  
 R 5 , R 6  are independently from each other hydrogen or lower alkyl;  
 n is 0, 1, 2, 3 or 4;  
 m is 0 or 1;  
 o is 0, 1, 2, 3 or4;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of formula IA according to  claim 1 ,  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, lower alkyl, lower alkoxy, 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, halogen, —C(O)OH, —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;  
 R′ is  
  (a) phenyl, substituted by —C(O)H, or by the following groups 
 —(CH 2 ) n OH  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o -lower alkoxy,  
 —(CH 2 ) n N(R 5 )-lower alkenyl,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o -cycloalkyl,  
 —(CH 2 ) n N(R 5 )—(CH 2 ) o —S-lower alkyl,  
 —(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 —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 ,  
 —S(O) 2 -morpholin  
 
  or is phenyl, which is unsubstituted or substituted by 
 —(CH 2 ) 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  
 
  b) a five membered aromatic or non aromatic heterocycle, with the exception of the piperazinyl group, wherein the aromatic heterocycle is substituted 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  
  c) —N(R 5 )(CH 2 ) n+1 -phenyl, optionally substituted by lower alkoxy, —O(CH 2 ) n+1 -phenyl, or —N(R 5 )C(O)-phenyl; or  
  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  
  e) lower alkyl-lower alkoxy, —N(R 5 )(CH 2 ) n N(R 5 )(R 6 ), —(CH 2 ) n OH or —(HC═CH) n C(O)O-lower alkyl;  
 X is two hydrogen atoms;  
 R 5 , R 6  are independently from each other hydrogen or lower alkyl,  
 n is 0, 1, 2, 3 or4;  
 m is 0 or 1;  
 o is 0, 1, 2, 3 or 4;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . The compounds of formula IA in accordance with  claim 1 , wherein R 1  is methoxy, X is oxygen and R 2 /R 3  are hydrogen.  
     
     
         4 . The compound of formula IA in accordance with  claim 3 , wherein R′ is an unsubstituted or substituted five or six membered aromatic heterocycle.  
     
     
         5 . The compound of formula IA in accordance with  claim 4 , wherein the compound is 
 N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide;    5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide;    5-methyl-furan-2-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide;    N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide;    5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-pyridin-4-yl-benzothiazol-2-yl)-amide;    5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-pyridin-3-yl-benzothiazol-2-yl)-amide;    5-methyl-thiophene-2-carboxylic acid [4-methoxy-7-(2-methyl-pyridin-4-yl)-benzothiazol-2-yl]-amide; or    5-methyl-thiophene-2-carboxylic acid [7-(3-amino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide.    
     
     
         6 . The compound of formula IA in accordance with  claim 1 , wherein R′ is an unsubstituted or substituted five or six membered non aromatic heterocycle.  
     
     
         7 . The compound of formula IA in accordance with  claim 6 , wherein the compound is 
 morpholine-4-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide;    thiomorpholine-4-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide;    1-oxo-11 4-thiomorpholine-4-carboxylic acid (4-methoxy-7-phenyl-benzothiazol-2-yl)-amide;    morpholine-4-carboxylic acid {4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-amide;    morpholine-4-carboxylic acid [4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide;    morpholine-4-carboxylic acid {4-methoxy-7-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzothiazol-2-yl}-amide;    morpholine-4-carboxylic acid [4-methoxy-7-(2-piperidin-1-yl-thiazol-4-yl)-benzothiazol-2-yl]-amide;    morpholine-4-carboxylic acid [4-methoxy-7-(5-methyl-thiophen-2-yl)-benzothiazol-2-yl]-amide;    4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester;    1-acetyl-piperidine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide;    4-oxo-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide; or    1-oxo-1λ 4 -thiomorpholine-4-carboxylic acid (4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-amide.    
     
     
         8 . The compound of formula IA in accordance with  claim 1 , wherein R′ is phenyl, unsubstituted or substituted by —CH 2 OH, —CH 2 NHCH 2 CH 2 OCH 3 , —CH 2 NHCH 2 CH 2 OH, —CH 2 NHCH 2 -pyridinyl, —CH 2 NH 2 , —CH 2 NHCH 2 CH 2 SCH 3 , —CH 2 N(CH 3 )CH 2 CH 2 SCH 3 , —CH 2 N(CH 3 )CH 2 CH 2 OCH 3 , —CH 2 N(CH 2  CH 3 )CH 2 CH 2 OCH 3 , —CH 2 NHCH 3 , —CH 2 SCH 2 CH 2 N(CH 3 ) 2 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 2 OCH 3  or —CH 2 N(CH 3 )C(O)OCH 3 .  
     
     
         9 . The compound of formula IA in accordance with  claim 8 , wherein the compound is 
 4-hydroxymethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    4-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    4-[(2-hydroxy-ethylamino)-methyl]-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-4-ylmethyl)-amino]-methyl}-benzamide;    N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-{[(pyridin-3-ylmethyl)-amino]-methyl}-benzamide;    4-aminomethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-[(2-methylsulfanyl-ethylamino)-methyl]-benzamide;    4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    N-[7-(2-amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide;    4-fluoro-N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide; or    4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide.    
     
     
         10 . The compound of formula IA in accordance with  claim 8 , wherein the compound is 
 4-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-benzamide;    4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-benzamide;    N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-trifluoromethyl-benzamide;    N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    4-chloro-3-{[ethyl-(2-methoxy-ethyl)-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminomethyl-benzamide;    4-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-methylaminomethyl-benzamide;    4-chloro-3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    4-chloro-3-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide; or    3-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide.    
     
     
         11 . The compound of formula IA in accordance with  claim 8 , wherein the compound is 
 3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    4-[(2-ethoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide;    4-(2-dimethylamino-ethylsulfanylmethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    4-{[(2-ethoxy-ethyl)-ethyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    4-{[(2-ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    4-(2-methoxy-ethoxymethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    4-methoxymethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide;    N-(4-methoxy-7-thiomorpholin-4-yl-benzothiazol-2-yl)-benzamide; or    [4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylcarbamoyl)-benzyl]-methyl-carbamic acid methyl ester.    
     
     
         12 . The compound of formula IA in accordance with  claim 1 , wherein R′ is phenyl, substituted by an unsubstituted or substituted —(CR 5 R 6 ) n -five to seven membered aromatic or non aromatic heterocycle.  
     
     
         13 . A compound of formula IA in accordance with  claim 12 , wherein the compound is 
 4-imidazol-1-ylmethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    (4-Hydroxy-piperidin-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    4-[1,4]diazepan-1-ylmethyl-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    4-(3(S)-dimethylamino-pyrrolidin-1-ylmethyl)-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-benzamide;    N-{4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-yl}-4-pyrrolidin-1-yl-methyl-benzamide;    N-(4-methoxy-7-thiophen-2-yl-benzothiazol-2-yl)-4-pyrrolidin-1-yl-methyl-benzamide;    N-[4-methoxy-7-(2-pyridin-2-yl-thiazol-4-yl)-benzothiazol-2-yl]-4-pyrrolidin-1-yl-methyl-benzamide;    4-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1-yl-methyl-benzamide;    N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3-pyrrolidin-1-yl-methyl-benzamide;    N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(2-methyl-imidazol-1-yl-methyl)-benzamide; and    N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-(4-methyl-piperazin-1-yl-methyl)-benzamide.    
     
     
         14 . A compounds of formula IA in accordance with  claim 1 , wherein R 4  is an unsubstituted or substituted seven membered aromatic or non aromatic heterocycle.