Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof

Abstract

The present invention provides a pharmaceutical composition containing the following compound having antiviral action:P is hydrogen or a group to form a prodrug;A1 is CR1AR1B, S or O;A2 is CR2AR2B, S or O;A3 is CR3AR3B, S or O;A4 is each independently CR4AR4B, S or O;the number of hetero atoms among atoms constituting the ring which consists of A1, A2, A3, A4, nitrogen atom adjacent to A1 and carbon atom adjacent to A4, is 1 or 2;R1A and R1B are each independently hydrogen, halogen, alkyl, or the like;R2A and R2B are each independently hydrogen, halogen, alkyl, or the like;R3A and R3B are each independently hydrogen, halogen, alkyl, or the like;R4A and R4B are each independently hydrogen, halogen, alkyl, or the like;R3A and R3B may be taken together with an adjacent carbon atom to form non-aromatic carbocycle or non-aromatic heterocycle;R1 is fluorine;m is any integer of 1 to 2; andn is any integer of 1 to 2.

1 . A pharmaceutical composition comprising a compound represented by the following formula (I) or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         wherein 
         P is hydrogen or a group to form a prodrug; 
         A 1  is CR 1A R 1B , S or O; 
         A 2  is CR 2A R 2B , S or O; 
         A 3  is CR 3A R 3B , S or O; 
         A 4  is each independently CR 4A R 4B , S or O; 
         the number of hetero atoms among atoms constituting the ring which consists of A 1 , A 2 , A 3 , A 4 , nitrogen atom adjacent to A 1  and carbon atom adjacent to A 4 , is 1 or 2; 
         R 1A  and R 1B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 2A  and R 2B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 3A  and R 3B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 4A  and R 4B  are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl; 
         R 3A  and R 3B  may be taken together with an adjacent carbon atom to form non-aromatic carbocycle or non-aromatic heterocycle; 
         n is any integer of 1 to 2; and 
         the group represented by formula: 
       
       
         
           
           
               
               
           
         
         is a group represented by formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , comprising the compound or its pharmaceutically acceptable salt, wherein the group represented by formula: 
       
         
           
           
               
               
           
         
         is a group represented by formula: 
       
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 . 
       
     
     
         3 . The pharmaceutical composition according to  claim 1 , comprising a compound represented by the following formula or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 . 
       
     
     
         4 . The pharmaceutical composition according to  claim 1 , comprising a compound represented by the following formula or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 . 
       
     
     
         5 . The pharmaceutical composition according to  claim 1 , comprising a compound represented by the following formula or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
         wherein each definition has the same meaning as described in  claim 1 . 
       
     
     
         6 . The pharmaceutical composition according to any one of  claims 1  to  5 , comprising a compound or its pharmaceutically acceptable salt,
 wherein the group to form a prodrug is a group selected from the following formula a) to ac):
   —C(═O)—P R0 ,  a)
 
   —C(═O)—P R1 ,  b)
 
   —C(═O)-L-P R1 ,  c)
 
   —C(═O)-L-O—P R1 ,  d)
 
   —C(═O)-L-O-L-O—P R1 ,  e)
 
   —C(═O)-L-O—C(═O)—P R1 ,  f)
 
   —C(═O)—O—P R2 ,  g)
 
   —C(═O)—N(—K)(P R2 ),  h)
 
   —C(═O)—O-L-O—P R2 ,  i)
 
   —C(P R3 ) 2 —O—P R4 ,  j)
 
   —C(P R3 ) 2 —O-L-O—P R4 ,  k)
 
   —C(P R3 ) 2 —O—C(═O)—P R4 ,  l)
 
   —C(P R3 ) 2 —O—C(═O)—O—P R4 ,  m)
 
   —C(P R3 ) 2 —O—C(═O)—N(—K)—P R4 ,  n)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-O—P R4 ,  o)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-N(P R4 ) 2 ,  p)
 
   —C(P R3 ) 2 —O—C(═O)—N(—K)-L-O—P R4 ,  q)
 
   —C(P R3 ) 2 —O—C(═O)—N(—K)-L-N(P R4 ) 2 ,  r)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-O-L-O—P R4 ,  s)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-N(—K)—C(═O)—P R4 ,  t)
 
   —C(P R3 ) 2 —O—P(═O)(—P R5 ) 2 ,  u)
 
   —C(P R3 ) 2 —P R6 ,  v)
 
   —C(═N+(P R7 ) 2 )(—N(P R7 ) 2 ),  w)
 
   —C(P R3 ) 2 —C(P R3 ) 2 —C(═O)—O—P R2 ,  x)
 
   —(P R3 ) 2 —N(—K)—C(═O)—O—P R2 ,  y)
 
   —P(═O)(—P R8 )(—P R9 ),  z)
 
   —S(═O) 2 —P R10 ,  aa)
 
   —P R11 , and  ab)
 
   —C(P R3 ) 2 —C(P R3 ) 2 —O—P R2 ,  ac)
 
 
 wherein L is straight or branched alkylene, or straight or branched alkenylene; 
 K is hydrogen, or alkyl optionally substituted by substituent group A; 
 P R0  is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A; 
 P R1  is carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, or alkylsulfanyl optionally substituted by substituent group A; 
 P R2  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A or trialkylsilyl; 
 P R3  is each independently hydrogen or alkyl; 
 P R4  is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A, or trialkylsilyl; 
 P R5  is each independently hydroxy or OBn; 
 P R6  is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A; 
 P R7  is each independently alkyl optionally substituted by substituent group A; 
 P R8  is alkyloxy optionally substituted by substituent group A; 
 P R9  is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A, or heterocyclylamino optionally substituted by substituent group A; 
 P R8  and P R9  may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A; 
 P R10  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, or heterocyclylalkyl optionally substituted by substituent group A; 
 P R11  is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A; 
 Substituent group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl group, heterocyclyl group, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho. 
 
     
     
         7 . The pharmaceutical composition according to  claim 6 , comprising a compound or its pharmaceutically acceptable salt,
 wherein the group to form a prodrug is a group selected from the following formula:
   —C(═O)—P R0 ,  a)
 
   —C(═O)—P R1 ,  b)
 
   —C(═O)—O—P R2 ,  g)
 
   —C(═O)—N(—K)(P R2 ),  h)
 
   —C(═O)—O-L-O—P R2 ,  i)
 
   —C(P R3 ) 2 —O—C(═O)—P R4 ,  l)
 
   —C(P R3 ) 2 —O—C(═O)—O—P R4 ,  m)
 
   —C(P R3 ) 2 —O—C(═O)—O-L-O—P R4 ,  o)
 
   —C(P R3 ) 2 —P R6 ,  v)
 
   —C(P R3 ) 2 —C(P R3 ) 2 —C(═O)—O—P R2 ,  x)
 
   —C(P R3 ) 2 —N(—K)—C(═O)—O—P R2 , and  y)
 
   —P(═O)(—P R8 )(—P R9 ),  z)
 
   wherein L is straight or branched alkylene;   K is hydrogen or alkyl optionally substituted by substituent group A;   P R0  is alkyl optionally substituted by substituent group A;   P R1  is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;   P R2  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, or heterocyclylalkyl optionally substituted by substituent group A;   P R3  is each independently hydrogen or alkyl;   P R4  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;   P R6  is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;   P R8  is alkyloxy optionally substituted by substituent group A;   P R9  is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A, or heterocyclylamino optionally substituted by substituent group A; and   P R8  and P R9  may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A,   Substituent group A; oxo, alkyl, alkylamino, carbocyclyl group, heterocyclyl group, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkylsilyl.   
     
     
         8 . The pharmaceutical composition according to  claim 6 , comprising a compound or its pharmaceutically acceptable salt,
 wherein the group to form a prodrug is a following formula:
   —C(P R3 ) 2 —O—C(═O)—O—P R4 ,  m)
 
   P R3  is each independently hydrogen or alkyl;   P R4  is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;   Substituent group A; oxo, alkyl, alkylamino, carbocyclyl group, heterocyclyl group, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkylsilyl.   
     
     
         9 . A pharmaceutical composition comprising a compound represented by the following formula or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A pharmaceutical composition comprising a compound represented by the following formula or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition comprising a compound represented by the following formula or its pharmaceutically acceptable salt: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The pharmaceutical composition according to any one of  claims 1  to  11 , which is an antiviral agent. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , which is a cap-dependent endonuclease inhibitor. 
     
     
         14 . The pharmaceutical composition according to any one of  claims 1  to  11 , which is used for shortening the duration infected with influenza. 
     
     
         15 . The pharmaceutical composition according to any one of  claims 1  to  11 , which is used for reducing the influenza virus. 
     
     
         16 . A crystal of the compound of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The crystal according to  claim 16 , wherein the crystal has two or more peaks in diffraction angles (2θ) selected from 8.6±0.2°, 14.1±0.2°, 17.4±0.2°, 20.0±0.2°, 24.0±0.2°, 26.3±0.2°, 29.6±0.2° and 35.4±0.2° in an X-ray powder diffraction spectrum. 
     
     
         18 . The crystal according to  claim 15 , wherein the crystal has peaks in diffraction angles (2θ) of: 8.6±0.2°, 14.1±0.2°, 17.4±0.2°, 20.0±0.2°, 24.0±0.2°, 26.3±0.2°, 29.6±0.2° and 35.4±0.2° in an X-ray powder diffraction spectrum. 
     
     
         19 . The crystal according to  claim 16 , wherein an X-ray powder diffraction spectrum of the crystal is substantially identical with  FIG. 3 . 
     
     
         20 . The pharmaceutical composition comprising the crystal according to any one of  claims 16  to  19 . 
     
     
         21 . The pharmaceutical composition according to  claim 20 , which is an antiviral agent. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , which is a cap-dependent endonuclease inhibitor. 
     
     
         23 . The pharmaceutical composition comprising the crystal according to any one of  claims 16  to  19 , which is used for shortening the duration infected with influenza. 
     
     
         24 . The pharmaceutical composition comprising the crystal according to any one of  claims 16  to  19 , which is used for reducing the influenza virus.