Papd5 and papd7 inhibitors for treating a hepatitis b infection

Abstract

The present invention relates to a method for identifying a compound that prevents, ameliorates and/or inhibits hepatitis B virus (HBV) infections. The compound (i) reduces the expression and/or activity of PAP associated domain containing 5 (PAPD5) and/or PAP associated domain containing 7 (PAPD7); and/or (ii) binds to PAPD5 and/or PAPD7 and inhibits 5 propagation of HBV; and is identified as a compound that prevents, ameliorates and/or inhibits HBV infections. An inhibitor of PAPD5 and/or PAPD7 for use in treating and/or preventing HBV infections; as well as a combined preparation comprising an inhibitor of PAPD5 and an inhibitor of PAPD7 for simultaneous or sequential use in the treatment or prevention of HBV infections is also provided. The present invention includes a 10-pharmaceutical composition for use in treatment and/or prevention of HBV infections, and a method for monitoring therapeutic success during treatment of HBV infections.

1 - 16 . (canceled) 
     
     
         17 . An inhibitor of PAPD5 and/or PAPD7 for use in treating a HBV infection, wherein said inhibitor is
 a. a small molecule that binds to PAPD5 and/or PAPD7; or   b. an antibody that specifically binds to PAPD5 and/or PAPD7.   
     
     
         18 . The inhibitor according to  claim 17 , which
 a. binds to PAPD5 and/or PAPD7 polypeptide; and/or   b. inhibits expression and/or activity of PAPD5 and/or PAPD7.   
     
     
         19 . The inhibitor according to  claim 17 , wherein the inhibitor reduces secretion of HBsAg and HBeAg. 
     
     
         20 . The inhibitor according to  claim 17 , wherein the inhibitor inhibits development of chronic HBV infection and/or reduces the infectiousness of a HBV infected person. 
     
     
         21 . The inhibitor according to  claim 17 , wherein the inhibitor is the compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is C 1-6 alkyl, C 3-7 cycloalkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, nitroC 1-6 alkyl, C 1-6 alkoxycarbonylC 1-6 alkyl, carboxyC 1-6 alkyl, di(C 1-6 alkoxycarbonyl)methylenyl, cyanoC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, phenylC 1-6 alkyl, C 1-6 alkylsufanylC 1-6 alkyl, C 1-6 alkylsufonylC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, C 1-6 alkylsufonylaminoC 1-6 alkyl, C 1-6 alkoxycarbonyl aminoC 1-6 alkyl, aminocarbonylC 1-6 alkyl, diC 1-6 alkylaminocarbonylC 1-6 alkyl, monocyclic heterocycloalkylC 1-6 alkyl or imidazolylC 1-6 alkyl; 
         R 2  is aryl or heteroaryl, said aryl or heteroaryl being unsubstituted, or substituted by one, two, three or four substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, halogen, haloC 1-6 alkyl, cyano, nitro, hydroxy, haloC 1-6 alkoxy, —O—C x H 2x —R 3 , —O—C y H 2 —NHR 6 , —NR 9 R 10 , —SO 2 —R 11 , —SO 2 —NR 12 R 13 , carboxy, C 1-6 alkoxycarbonyl, —C(═O)—NR 12 R 13 , aryl, heteroaryl, monocyclic heterocycloalkyl and —O-monocyclic heterocycloalkyl; wherein 
         monocyclic heterocycloalkyl is unsubstituted or substituted by C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylcarbonyl, C 1-6 alkylsufonyl or C 1-6 alkoxycarbonyl; 
         R 3  is hydrogen; C 3-7 cycloalkyl; haloC 3-7 cycloalkyl; hydroxy; hydroxyC 1-6 alkylC 3-7 cycloalkyl; C 1-6 alkoxy; monocyclic heterocycloalkyl; monocyclic heterocycloalkyl substituted by C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylsufonyl, C 3-7 cycloalkyl or C 1-6 alkoxycarbonyl; —C(═O)—R 4 ; C 1-6 alkylsulfinyl; —SO 2 —R 5 ; —C(NHR 7 )—C(═O)—R 8 ; carboxyC 1-6 alkoxy or aminocarbonylC 1-6 alkoxy; wherein 
         R 4  is hydroxy, C 1-6 alkoxy, amino, C 1-6 alkylamino, diC 1-6 alkylamino, tetrahydrofuranylamino, pyrrolidinyl or morpholinyl; 
         R 5  is C 1-6 alkyl, C 3-7 cycloalkyl, hydroxy, amino, C 1-6 alkylamino or diC 1-6 alkylamino; 
         R 7  is hydrogen or C 1-6 alkoxycarbonyl; 
         R 8  is hydroxy or C 1-6 alkoxy; 
         R 6  is hydrogen, C 1-6 alkylcarbonyl, haloC 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, 
         C 1-6 alkylsulfonyl, C 3-7 cycloalkylsulfonyl or C 1-6 alkoxyC 1-6 alkylsulfonyl; 
         R 9  and R 10  are independently selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl, C 3-7 cycloalkylcarbonyl and C 3-7 cycloalkylsulfonyl; or 
         R 9  and R 10  together with the nitrogen to which they are attached form monocyclic heterocycloalkyl; 
         R 11  is C 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl, haloC 3-7 cycloalkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, haloC 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkylC 1-6 alkyl, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl, diC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylcarbonylaminoC 1-6 alkyl, C 1-6 alkylsulfonylaminoC 1-6 alkyl, C 1-6 alkoxycarbonylaminoC 1-6 alkyl, C 1-6 alkylsulfenylC 1-6 alkyl, C 1-6 alkylsulfanylC 1-6 alkyl or C 1-6 alkylsulfonylC 1-6 alkyl; 
         R 12  and R 13  are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, haloC 1-6 alkyl, C 3-7 cycloalkyl and haloC 3-7 cycloalkyl; or 
         R 12  and R 13  together with the nitrogen to which they are attached form monocyclic heterocycloalkyl; 
         x is 1, 2, 3, 4, 5, 6, 7 or 8; 
         y is 1, 2, 3, 4, 5, 6, 7 or 8; 
         U, W and Z are independently selected from CH and N; 
         one of X and Y is N, and the other one is CH or N. 
       
     
     
         22 . The inhibitor for the use according to  claim 17 , wherein the inhibitor is an antibody that specifically binds to the amino acid stretch of any one of SEQ ID NOs: 7, 8 or 9. 
     
     
         23 . A pharmaceutical composition for use in the treatment of a HBV infection, wherein the pharmaceutical composition comprises
 a. the inhibitor for the use according to  claim 17 ; and   b. a pharmaceutically acceptable carrier.   
     
     
         24 . A method for monitoring the therapeutic success during the treatment of a HBV infection, wherein the method comprises:
 a. analyzing in a sample obtained from a test subject the amount and/or activity of PAPD5 and/or PAPD7;   b. comparing said amount and/or activity with reference data corresponding to the amount and/or activity of PAPD5 and/or PAPD7 of at least one reference subject; and   c. predicting therapeutic success based on the comparison step (b).   
     
     
         25 . A pharmaceutical composition for use in the treatment of a HBV infection, wherein the pharmaceutical composition comprises:
 a. the inhibitor according to  claim 21 ; and   b. a pharmaceutically acceptable carrier.   
     
     
         26 . A pharmaceutical composition for use in the treatment of a HBV infection, wherein the pharmaceutical composition comprises:
 a. the inhibitor according to  claim 21 ; and   b. a pharmaceutically acceptable carrier.