Bromo-phenyl substituted thiazolyl dihydropyrimidines

Abstract

This invention relates to a bromo-phenyl substituted thiazolyl dihydropyrimidine, its preparation method and use as a medicament for treating and preventing hepatitis B infections. The invention also relates to a composition comprising the dihydropyrimidine, one or more antiviral agents and, optionally, an immunomodulator for treating and preventing HBV infections.

What is claimed is: 
     
       1. A compound having formula (I) or its isomer (Ia): 
       
         
           
           
               
               
           
         
         or an enantiomer or a salt thereof, wherein R 1  is o-bromine, R 2  is p-fluorine, R 3  is a C 1 -C 4  alkyl, R 6  is thiazolyl-2-yl, X is methylene, and Z is morpholinyl. 
       
     
     
       2. The compound of  claim 1  or the enantiomer or the salt thereof, wherein R 1  is o-bromine, R 2  is p-fluorine, R 3  is methyl or ethyl, R 6  is thiazolyl-2-yl, X is methylene, and Z is morpholinyl. 
     
     
       3. A compound having one of the following structures or an enantiomer, tautomer or salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
       4. A compound having one of the following structures or a levo isomer, tautomer or salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
       5. The compound according to  claim 1  or the enantiomer or the salt thereof, wherein the salt is an inorganic acid salt or an organic acid salt. 
     
     
       6. The compound according to  claim 5  or the enantiomer or the salt thereof, wherein the inorganic acid salt is a hydrochloric acid salt, a hydrobromic acid salt, a phosphoric acid salt or a sulfuric acid salt. 
     
     
       7. The compound according to  claim 5  or the enantiomer or the salt thereof, wherein the organic acid salt is a carboxylate or a sulfonate. 
     
     
       8. The compound according to  claim 7  or the enantiomer or the salt thereof, wherein the carboxylate is acetate, maleate, fumarate, malate, citrate, tartarate, lactate or benzoate. 
     
     
       9. The compound according to  claim 7  or the enantiomer or the salt thereof, wherein the sulfonate is methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate or naphthalenedisulfonate. 
     
     
       10. A method of preparing the compound of  claim 1 , wherein the method is characterized by:
 (a) reacting a benzaldehyde having formula (II) with a β-ketoester having formula (III) to produce a benzylidene compound having formula (IV): 
 
       
         
           
           
               
               
           
         
       
       and
 (b) reacting the benzylidene compound having formula (IV) with an amidine having formula (V): 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof
 wherein R 1  is o-bromine, R 2  is p-fluorine, R 3  is a C 1 -C 4  alkyl, R 6  is thiazolyl-2-yl, X is methylene, and Z is morpholinyl. 
 
     
     
       11. A method of preparing the compound of  claim 1 , wherein the method is characterized by reacting a compound having formula (III) with an aldehyde having formula (II) and an amidine having formula (V) or a salt thereof in one step, 
       
         
           
           
               
               
           
         
         wherein R 1  is o-bromine, R 2  is p-fluorine, R 3  is a C 1 -C 4  alkyl, R 6  is thiazolyl-2-yl, X is methylene, and Z is morpholinyl. 
       
     
     
       12. A method of preparing the compound of  claim 1 , wherein X of formula (I) is methylene and the method is characterized by reacting the compound having formula (VI) with morpholine (VII) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein Y is a nucleophilic substituent, and R 1  is o-bromine, R 2  is p-fluorine, R 3  is a C 1 -C 4  alkyl, and R 6  is thiazolyl-2-yl. 
       
     
     
       13. A method of preparing the compound of  claim 1 , which is characterized by the step of reacting a compound having formula (II) with an aldehyde having formula (X) and an amidine having formula (V) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is o-bromine, R 2  is p-fluorine, R 3  is a C 1 -C 4  alkyl, R 6  is thiazolyl-2-yl, X is methylene, and Z is morpholinyl. 
       
     
     
       14. A composition comprising the following components:
 A) at least one compound according to  claim 1 ; 
 B) at least an HBV antiviral agent which is different from component A; and, when appropriate, 
 C) at least an immunomodulator or an interferon. 
 
     
     
       15. The composition of  claim 14 , wherein the component B is an HBV polymerase inhibitor, lamivudine or a phenylpropenamide compound having the following formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 each of R 1  and R 2  is independently C 1-4  alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and/or oxygen; and 
 each of R 3  to R 12  is independently hydrogen, halogen, C 1 -C 4 -alkyl, optionally substituted C 1 -C 4 -alkoxy, nitro, cyano or trifluoromethyl; and 
 X is halogen or optionally substituted C 1-4  alkyl. 
 
     
     
       16. The composition of  claim 15 , wherein the component B is the phenylpropenamide compound having the following structure: 
       
         
           
           
               
               
           
         
       
     
     
       17. A medicament comprising at least one composition of  claim 14 , and, when appropriate, one or more active pharmaceutical agents. 
     
     
       18. A method for treating hepatitis B infection or a disease caused by hepatitis B infection, which comprises administering the composition of  claim 14  to a patient having the disease. 
     
     
       19. The method of  claim 18 , wherein the method is for treating the disease caused by hepatitis B infection selected from hepatitis, cirrhosis or hepatocellular carcinoma. 
     
     
       20. A method for treating hepatitis B infection or a disease caused by hepatitis B infection, which comprises administering the compound of  claim 1  to a patient having the disease. 
     
     
       21. The method of  claim 20 , wherein the method is for treating the disease caused by hepatitis B infection selected from hepatitis, cirrhosis or hepatocellular carcinoma. 
     
     
       22. A pharmaceutical composition comprising at least one compound according to  claim 1 , and, when appropriate, a pharmaceutically acceptable carrier.