Novel thiophene derivatives which are HM74A agonists

Abstract

The invention is concerned with novel substituted thiophene derivatives of formula (I) wherein R 1 to R 8 , X, m and n are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds are HM74A agonists and can be used as medicaments.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 X is O, S, SO 2 , NR 9 , —C(O)NR 9 —, —NR 9 C(O)—, —CH 2 —, —C═C— or —C≡C—;  
 R 1  is hydrogen or lower-alkyl;  
 R 2  is hydrogen, halogen, lower-alkyl or fluoro-lower-alkyl;  
 R 3  is hydrogen, halogen, lower-alkyl or fluoro-lower-alkyl;  
 R 4 , R 5 , R 6  and R 7  independently from each other are hydrogen, halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl or fluoro-lower-alkoxy, or R 4  and R 5  are bound together to form a cycloalkyl together with the carbon atom to which they are attached and —R 4 —R 5 — is —(CH 2 ) 2-6 —, or R 6  and R 7  are bound together to form a cycloalkyl together with the carbon atom to which they are attached and —R 6 —R 7 — is —(CH 2 ) 2-6 —; or; 
 R 4  and R 6  are bound together to form a ring and —R 4 —R 6 — is —(CH 2 ) 2-6 —;  
 
 R 8  is aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl, lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl, R 10 R 11 NC(O), R 10 R 11 NC(O)-lower-alkyl, fluoro-lower-alkyl, R 10 R 11 N-lower-alkyl, lower-alkyl-SO 2 , lower-alkyl-SO 2 O, lower-alkyl-SO 2 —NR 10 , R 10 R 11 NSO 2 , cyano, NO 2 , cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl, fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl, phenyl and heteroaryl, which phenyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and lower-alkyl-C(O)N(R 10 );  
 R 9  is hydrogen, lower-alkyl or fluoro-lower-alkyl;  
 R 10  and R 11  independently from each other are hydrogen or lower-alkyl;  
 m is 0, 1, 2 or 3;  
 n is 0, 1, 2 or 3;  
 and pharmaceutically acceptable salts and pharmaceutically acceptable esters thereof, with the proviso that the compound of formula (I) is not 2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic acid methyl ester.  
 
   
   
       2 . The compound according to  claim 1 , wherein R 4 , R 5 , R 6  and R 7  independently from each other are hydrogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl or fluoro-lower-alkoxy, or R 4  and R 5  are bound together to form a cycloalkyl together with the carbon atom to which they are attached and —R 4 —R 5 — is —(CH 2 ) 2-6 —, or R 6  and R 7  are bound together to form a cycloalkyl together with the carbon atom to which they are attached and —R 6 —R 7 — is —(CH 2 ) 2-6 —; and R 8  is aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl, lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl, R 10 R 11 NC(O), R 10 R 11 NC(O)-lower-alkyl, fluoro-lower-alkyl, R 10 R 11 N-lower-alkyl, lower-alkyl-SO 2 , lower-alkyl-SO 2 O, lower-alkyl-SO 2 —NR 10 , R 10 R 11 NSO 2 , cyano, cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl, fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl, phenyl and heteroaryl, which phenyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and lower-alkyl-C(O)N(R 10 ), wherein R 10  and R 11  are as defined in  claim 1 .  
   
   
       3 . The compound according to  claim 1 , wherein X is O, —CH 2 — or NR 9  and R 9  is as defined in  claim 1 .  
   
   
       4 . The compound according to  claim 1 , wherein X is O or —CH 2 —.  
   
   
       5 . The compound according to  claim 1 , wherein X is O.  
   
   
       6 . The compound according to  claim 1 , wherein R 1  is hydrogen.  
   
   
       7 . The compound according to  claim 1 , wherein R 2  is hydrogen.  
   
   
       8 . The compound according to  claim 1 , wherein R 3  is hydrogen or lower-alkyl.  
   
   
       9 . The compound according to  claim 1 , wherein R 3  is hydrogen.  
   
   
       10 . The compound according to  claim 1 , wherein R 4 , R 5 , R 6  and R 7  independently from each other are hydrogen, halogen or lower-alkyl.  
   
   
       11 . The compound according to  claim 1 , wherein R 4 , R 5 , R 6  and R 7  independently from each other are hydrogen or lower-alkyl.  
   
   
       12 . The compound according to  claim 1 , wherein R 4 , R 5 , R 6  and R 7  independently from each other are hydrogen or methyl.  
   
   
       13 . The compound according to  claim 1 , wherein R 8  is aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, fluoro-lower-alkyl, cyano, NO 2 , cycloalkyl, pyrimidinyl, pyrazinyl, pyridinyl and phenyl, which phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and lower-alkyl-C(O)N(R 10 ), and R 10  is as defined in  claim 1 .  
   
   
       14 . The compound according to  claim 1 , wherein R 8  is aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, cycloalkyl and phenyl, which phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-C(O) and lower-alkyl-C(O)N(R 10 ).  
   
   
       15 . The compound according to  claim 1 , wherein R 8  is phenyl or pyridinyl, which phenyl or pyridinyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, cycloalkyl and phenyl, which phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen and lower-alkoxy.  
   
   
       16 . The compound according to  claim 1 , wherein R 8  is 4′-fluoro-biphenyl-4-yl, biphenyl-4-yl, 2′-methoxy-biphenyl-4-yl, 5-(4-fluoro-phenyl)-pyridin-2-yl, 2-chloro-phenyl, phenyl, 3,4-dichloro-phenyl, 4-cyclopentyl-phenyl, 4-tert-butyl-phenyl or 5-(2-fluoro-phenyl)-pyridin-2-yl.  
   
   
       17 . The compound according to  claim 1 , wherein R 8  is 4-pyrimidin-2-yl-phenyl, 4-pyrazin-2-yl-phenyl, 4-pyridin-2-yl-phenyl, 4-pyridin-3-yl-phenyl or biphenyl-3-yl.  
   
   
       18 . The compound according to  claim 1 , wherein m is 1, 2 or 3.  
   
   
       19 . The compound according to  claim 1 , wherein m is 1 or 3.  
   
   
       20 . The compound according to  claim 1 , wherein n is 0.  
   
   
       21 . The compound according to  claim 1 , wherein R 9  is hydrogen.  
   
   
       22 . The compound according to  claim 1 , wherein R 10  and R 11  are hydrogen.  
   
   
       23 . The compound according to  claim 1 , selected from the group consisting of 
 4-[2-(4′-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(2′-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3′-Chloro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(2′-Methyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3′-Acetylamino-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3′-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3′-Acetyl-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-(5-Phenyl-pentanoylamino)-thiophene-3-carboxylic acid,    4-{2-[5-(2-Methoxy-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid,    4-{2-[5-(4-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid,    4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,    4-[4-(3-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,    4-[4-(2-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,    4-[4-(3-Fluoro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid,    4-(4-Phenoxy-butyrylamino)-thiophene-3-carboxylic acid,    4-(2-Methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic acid,    4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-{2-[5-(2-Chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid,    4-[2-(4-Cyclohexyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Isopropyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-tert-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-sec-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid, and    4-{2-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid,    and pharmaceutically acceptable salts and esters thereof.    
   
   
       24 . The compound according to  claim 1 , selected from the group consisting of 
 4-[2-(4′-Fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid;    4-[2-(Biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid;    4-[2-(2′-Methoxy-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid;    4-{2-[5-(4-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid;    4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid;    4-(2-Methyl-4-phenoxy-butyrylamino)-thiophene-3-carboxylic acid;    4-[2-(3,4-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid;    4-[2-(4-Cyclopentyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid;    4-[2-(4-tert-Butyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid; and    4-{2-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid;    and pharmaceutically acceptable salts and esters thereof.    
   
   
       25 . The compound according to  claim 1 , selected from the group consisting of 
 4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Pyrazin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Pyridin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Pyridin-3-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Pyridin-4-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3,5-Dichloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Chloro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-(2-m-Tolyloxy-acetylamino)-thiophene-3-carboxylic acid,    4-[2-(3-Ethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Nitro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Ethoxy-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Ethynyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(Biphenyl-3-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Chloro-4-cyano-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Chloro-4-methyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Chloro-3-fluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Chloro-3-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(2-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Fluoro-5-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3,5-Difluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Trifluoromethoxy-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3,5-Bis-trifluoromethyl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3-Chloro-5-fluoro-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3,5-Dibromo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3,5-Dichloro-phenylamino)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(2-tert-Butyl-pyrimidin-5-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4′-Fluoro-biphenyl-4-yloxy)-acetylamino]-5-methyl-thiophene-3-carboxylic acid,    4-[2-(3,4-Dichloro-phenoxy)-propionylamino]-thiophene-3-carboxylic acid,    4-[2-(4′-Fluoro-biphenyl-4-yloxy)-propionylamino]-thiophene-3-carboxylic acid,    4-[2-(4-tert-Butyl-phenoxy)-propionylamino]-thiophene-3-carboxylic acid,    4-[2-Fluoro-2-(4′-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-tert-Butyl-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(3,4-Dichloro-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic acid, and    4-[2,2-Difluoro-2-(4′-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    and pharmaceutically acceptable salts and esters thereof.    
   
   
       26 . The compound according to  claim 1 , selected from the group consisting of 
 4-[2-(4-Pyrimidin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Pyrazin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Pyridin-2-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-Pyridin-4-yl-phenoxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(Biphenyl-3-yloxy)-acetylamino]-thiophene-3-carboxylic acid,    4-[2-(4-tert-Butyl-phenoxy)-2-fluoro-acetylamino]-thiophene-3-carboxylic acid, and    4-[2,2-Difluoro-2-(4′-fluoro-biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid    and pharmaceutically acceptable salts and esters thereof.    
   
   
       27 . A process for the manufacture of compounds of formula (I) according to  claim 1 , comprising the steps of: 
 a) reacting a compound of formula (II)                           with a compound of formula (III),                           wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, m and n are as defined in  claim 1  and R 12  is OH, Cl, Br, or a carboxylic acid moiety to form an anhydride; or    b) hydrolysis of a compound of formula (Ia)                           wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, m and n are as defined in  claim 1  and R 1  is lower-alkyl.    
   
   
       28 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1  or 2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic acid methyl ester, and a pharmaceutically acceptable carrier and/or adjuvant.  
   
   
       29 . A method for the treatment and/or prevention of diseases which are modulated by HM74A agonists, comprising the step of administering a therapeuctically effective amount of a compound according to  claim 1  or 2-methyl-4-[[(phenylmethoxy)carbonyl]amino]-3-thiophenecarboxylic acid methyl ester, to a human being or animal in need thereof.  
   
   
       30 . The method according to  claim 29 , wherein said disease is increased lipid levels, increased cholesterol levels, atherosclerotic diseases, dyslipidemia, low HDL-cholesterol, hypertriglyceridemia, thrombosis, angina pectoris, peripheral vascular disease, stroke, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, impaired or improvable cognitive function, sepsis, inflammatory diseases, asthma, colitis, pancreatitis or cholestasisfibrosis of the liver.