Patent HU-E034919-T2 (HU)
Title: 2,4,5,6-Substituted 3,6-dihydropyrimidine derivatives as hepatitis B virus (HBV) polymerase inhibitors for the treatment of e.g. chronic hepatitis
Inventor: ZHANG YINGJUN
IPC: A61P31/12
Filed: 2013-08-23
Abstract: FIELD: chemistry. 
     SUBSTANCE: invention relates to new isomeric forms of the dihydropyrimidin derivative represented by formula (I) or (Ia), or a pharmaceutically acceptable salt thereof. In the formula (I) or (Ia)  
       
     each A is -O-; each R is -X-Z; X is - (CR 7 R 7a ) m -; Z has the formula (II) or (IIa)  
       
     where each B is - (CR 7 R 7a ) m -; each W is N; each Y is - (CR 7 R 7a ) m - or -O-, where m has the value 0 or 1; each R 1  is phenyl or phenyl substituted with one or more substituents, which are the same or different, representing H, F, Cl, Br, nitro or trifluoromethyl, for example 3,5-bis(trifluoromethyl)phenyl; each R 2  is H or C 1-4 alkyl; R 3  has one of the following formulas:  
       
       
     or  
     each R 10  is independently H, F, Cl, methyl, ethyl, cyano, hydroxy, nitro, amino, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, -(CR 7 R 7a ) m -C(=O)O-R 8a , -(CR 7 R 7a ) m -C(=O)N(R 8a ) 2  or trifluoromethylsulfonyl; each R 11  is independently H, methyl, ethyl, propyl, isopropyl, butyl, trifluoromethyl or -(CR 7 R 7a ) m -C(=O)O-R 8a ; each p is independently 0, 1, 2 or 3; each R 4  is H; each R 7a  and R 7  is independently H, methyl, ethyl, -(CH 2 ) m -OH -(CH 2 ) m -C(=O)O-R 8  or propyl; each R 8  and R 8a  is independently H, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, 1-methylpropyl, aminomethyl, 1-amino-2-methylpropyl, 1-aminoethyl, 2-aminoethyl, 1-aminobutyl, 1-aminopropyl, 2-aminopropyl, Boc-NH-methyl, 1-Boc-NH-2-methylpropyl, 1-Boc-NH-ethyl, 2-Boc-NH- ethyl, 1-Boc-NH-butyl, 1-Boc-NH-propyl, 2-Boc-NH-propyl, methoxy, ethoxy, -(CH 2 ) m -OH, -(CH 2 ) m -C(=O)O-(CH 2 ) m -H, -(CH 2 ) m -OC(=O)-(CH 2 ) m -H or tert-butyl; Boc is tert-butyloxycarbonyl; each R 9  is independently -(CR 7 R 7a ) t -OH, -(CR 7 R 7a ) m -C(=O)O-R 8 , -(CR 7 R 7a ) m -C(=O)O-(CR 7 R 7a ) m -OC(=O)O-R 8 , -(CR 7 R 7a ) m -C(=O)O-(CR 7 R 7a ) m -OC(=O)-R 8 , -(CR 7 R 7a ) m -C(=O)O-(CR 7 R 7a ) m -C(=O)O-R 8 , -(CR 7 R 7a ) t -OC(=O)-R 8 , triazolyl, tetrazolyl or -(CR 7 R 7a ) m -C(=O)N(R 8 ) 2 , provided that R 9  is -(CR 7 R 7a ) t -OH, R 3  is furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl or triazinyl; each n is independently 1 or 2; each t is independently 1, 2, 3 or 4; each m is independently 0, 1, 2, 3 or 4; and arbitrarily each C 1-4 alkyl, C 1-4 haloalkyl, amino-C 1-4- alkyl, C 1-4 alkoxy, furanil, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, thiazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl and triazinyl as described above, is independently substituted by one or more substituents that are the same or different, wherein the substituent is H, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, -(CR 7 R 7a ) m -C(=O)O-R 8a  or -(CR 7 R 7a ) m -C(=O)N(R 8a ) 2 . 
     EFFECT: compounds possess the properties of an inhibitor of hepatitis B virus activity and can be used in the treatment of diseases caused by hepatitis B infection, which is cirrhosis or hepatocellular carcinoma. 
     12 cl, 3 tbl, 159 ex