Antitumor drug for intermittent administration of fgfr inhibitor

Abstract

The problem to be solved by the present invention is to provide a potent and highly selective novel FGFR inhibitor, and an antitumor agent having reduced side effects, such as increased blood phosphorus levels, while maintaining the antitumor effect of the FGFR inhibitor. The present invention provides an antitumor agent comprising a 3,5-disubstituted benzene alkynyl compound represented by Formula (I) or a salt thereof that is used so that the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered on an administration schedule of at least twice a week and a dosing interval of at least one day.

1 . An antitumor agent comprising a 3,5-disubstituted benzene alkynyl compound or a salt thereof that is used so that the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered on an administration schedule of at least twice a week and a dosing interval of at least one day, the 3,5-disubstituted benzene alkynyl compound being represented by Formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is the same or different, and each represents C 1 -C 6  alkyl; 
         X 1  and X 2  independently represent N or CH; 
         Y is a group represented by Formula (A): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkylene group, 
         
         a group represented by Formula (B): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 3 -C 10  cycloalkylene group, or 
         
         a group represented by Formula (C): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 6 -C 12  arylene group; 
         
         R 2  is hydrogen, C 2 -C 6  alkynyl, —C(═O)OR x , —C(═O)N(R x )(R y ), hydroxy-C 1 -C 6  alkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 2 -C 9  heteroaryl optionally having R 3 ; and 
         R 3  is C 1 -C 6  alkyl or di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl; 
         Z is —C(R 4 )═C(R 5 )(R 6 ) or —C≡C—R 7 ; 
         R 4 , R 5 , and R 6  are the same or different, and each represents hydrogen, halogen, C 1 -C 6  alkyl optionally having R 8 , or a group represented by Formula (D): 
       
       
         
           
           
               
               
           
         
         
           wherein the monovalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkyl group, 
         
         R 7  is hydrogen, C 1 -C 6  alkyl, or hydroxy-C 1 -C 6  alkyl; 
         R 8  is —OR x  or —N(R x )(R y ); 
         R 9  is C 1 -C 6  alkyl, halogen, or —OR x ; 
         R x  and R y  are the same or different, and each represents hydrogen, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 1 -C 6  alkoxy-C 1 -C 6  alkyl; 
         l is an integer of 0 to 3; 
         m is an integer of 1 to 3; and 
         n is an integer of 0 to 2. 
       
     
     
         2 . The antitumor agent according to  claim 1 , wherein the 3,5-disubstituted benzene alkynyl compound is (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one. 
     
     
         3 . The antitumor agent according to  claim 1 , wherein the administration schedule is based on a 1-week cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered at least twice every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         4 . The antitumor agent according to  claim 1 , wherein the administration schedule is based on a 14-day cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered 4 to 7 times every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         5 . The antitumor agent according to  claim 1 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 4, Day 8, and Day 11. 
     
     
         6 . The antitumor agent according to  claim 1 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, and Day 13. 
     
     
         7 . A method for treating a cancer patient, the method comprising administering a 3,5-disubstituted benzene alkynyl compound or a salt thereof on an administration schedule of at least twice a week and a dosing interval of at least one day, the 3,5-disubstituted benzene alkynyl compound being represented by Formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is the same or different, and each represents C 1 -C 6  alkyl; 
         X 1  and X 2  independently represent N or CH; 
         Y is a group represented by Formula (A): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkylene group, 
         
         a group represented by Formula (B): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 3 -C 10  cycloalkylene group, or 
         
         a group represented by Formula (C): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 6 -C 12  arylene group; 
         
         R 2  is hydrogen, C 2 -C 6  alkynyl, —C(═O)OR x , —C(═O)N(R x )(R y ), hydroxy-C 1 -C 6  alkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 2 -C 9  heteroaryl optionally having R 3 ; and 
         R 3  is C 1 -C 6  alkyl or di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl; 
         Z is —C(R 4 )═C(R 5 )(R 6 ) or —C≡C—R 7 ; 
         R 4 , R 5 , and R 6  are the same or different, and each represents hydrogen, halogen, C 1 -C 6  alkyl optionally having R 8 , or a group represented by Formula (D): 
       
       
         
           
           
               
               
           
         
         
           wherein the monovalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkyl group, 
         
         R 7  is hydrogen, C 1 -C 6  alkyl, or hydroxy-C 1 -C 6  alkyl; 
         R 8  is —OR x  or —N(R x )(R y ); 
         R 9  is C 1 -C 6  alkyl, halogen, or —OR x ; 
         R x  and R y  are the same or different, and each represents hydrogen, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 1 -C 6  alkoxy-C 1 -C 6  alkyl; 
         l is an integer of 0 to 3; 
         m is an integer of 1 to 3; and 
         n is an integer of 0 to 2. 
       
     
     
         8 . The method according to  claim 7 , wherein the 3,5-disubstituted benzene alkynyl compound is (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one. 
     
     
         9 . The method according to  claim 7 , wherein the administration schedule is based on a 1-week cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered at least twice every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         10 . The method according to  claim 7 , wherein the administration schedule is based on a 14-day cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered 4 to 7 times every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         11 . The method according to  claim 7 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 4, Day 8, and Day 11. 
     
     
         12 . The method according to  claim 7 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, and Day 13. 
     
     
         13 . A 3,5-disubstituted benzene alkynyl compound or a salt thereof for treatment of a cancer patient administered on an administration schedule of at least twice a week and a dosing interval of at least one day, the 3,5-disubstituted benzene alkynyl compound being represented by Formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is the same or different, and each represents C 1 -C 6  alkyl; 
         X 1  and X 2  independently represent N or CH; 
         Y is a group represented by Formula (A): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkylene group, 
         
         a group represented by Formula (B): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 3 -C 10  cycloalkylene group, or 
         
         a group represented by Formula (C): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 6 -C 12  arylene group; 
         
         R 2  is hydrogen, C 2 -C 6  alkynyl, —C(═O)OR x , —C(═O)N(R x )(R y ), hydroxy-C 1 -C 6  alkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 2 -C 9  heteroaryl optionally having R 3 ; and 
         R 3  is C 1 -C 6  alkyl or di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl; 
         Z is —C(R 4 )═C(R 5 )(R 6 ) or —C≡C—R 7 ; 
         R 4 , R 5 , and R 6  are the same or different, and each represents hydrogen, halogen, C 1 -C 6  alkyl optionally having R 8 , or a group represented by Formula (D): 
       
       
         
           
           
               
               
           
         
         
           wherein the monovalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkyl group, 
         
         R 7  is hydrogen, C 1 -C 6  alkyl, or hydroxy-C 1 -C 6  alkyl; 
         R 8  is —OR x  or —N(R x )(R y ); 
         R 9  is C 1 -C 6  alkyl, halogen, or —OR x ; 
         R x  and R y  are the same or different, and each represents hydrogen, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 1 -C 6  alkoxy-C 1 -C 6  alkyl; 
         l is an integer of 0 to 3; 
         m is an integer of 1 to 3; and 
         n is an integer of 0 to 2. 
       
     
     
         14 . The compound or a salt thereof according to  claim 13 , wherein the 3,5-disubstituted benzene alkynyl compound is (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one. 
     
     
         15 . The compound or a salt thereof according to  claim 13 , wherein the administration schedule is based on a 1-week cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered at least twice every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         16 . The compound or a salt thereof according to  claim 13 , wherein the administration schedule is based on a 14-day cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered 4 to 7 times every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         17 . The compound or a salt thereof according to  claim 13 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 4, Day 8, and Day 11. 
     
     
         18 . The compound or a salt thereof according  claim 13 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, and Day 13. 
     
     
         19 . Use of a 3,5-disubstituted benzene alkynyl compound or a salt thereof for producing an antitumor agent that is used so that the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered on an administration schedule of at least twice a week and a dosing interval of at least one day, the 3,5-disubstituted benzene alkynyl compound being represented by Formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is the same or different, and each represents C 1 -C 6  alkyl; 
         X 1  and X 2  independently represent N or CH; 
         Y is a group represented by Formula (A): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkylene group, 
         
         a group represented by Formula (B): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 3 -C 10  cycloalkylene group, or 
         
         a group represented by Formula (C): 
       
       
         
           
           
               
               
           
         
         
           wherein the divalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a C 6 -C 12  arylene group; 
         
         R 2  is hydrogen, C 2 -C 6  alkynyl, —C(═O)OR x , —C(═O)N(R x )(R y ), hydroxy-C 1 -C 6  alkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 2 -C 9  heteroaryl optionally having R 3 ; and 
         R 3  is C 1 -C 6  alkyl or di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl; 
         Z is —C(R 4 )═C(R 5 )(R 6 ) or —C≡C—R 7 ; 
         R 4 , R 5 , and R 6  are the same or different, and each represents hydrogen, halogen, C 1 -C 6  alkyl optionally having R 8 , or a group represented by Formula (D): 
       
       
         
           
           
               
               
           
         
         
           wherein the monovalent moiety represented by 
         
       
       
         
           
           
               
               
           
         
         
           is a nitrogen-containing C 3 -C 10  heterocycloalkyl group, 
         
         R 7  is hydrogen, C 1 -C 6  alkyl, or hydroxy-C 1 -C 6  alkyl; 
         R 8  is —OR x  or —N(R x )(R y ); 
         R 9  is C 1 -C 6  alkyl, halogen, or —OR x ; 
         R x  and R y  are the same or different, and each represents hydrogen, C 1 -C 6  alkyl, C 3 -C 10  cycloalkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, or C 1 -C 6  alkoxy-C 1 -C 6  alkyl; 
         l is an integer of 0 to 3; 
         m is an integer of 1 to 3; and 
         n is an integer of 0 to 2. 
       
     
     
         20 . The use according to  claim 19 , wherein the 3,5-disubstituted benzene alkynyl compound is (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one. 
     
     
         21 . The use according to  claim 19 , wherein the administration schedule is based on a 1-week cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered at least twice every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         22 . The use according to  claim 19 , wherein the administration schedule is based on a 14-day cycle, in which the 3,5-disubstituted benzene alkynyl compound or a salt thereof is administered 4 to 7 times every one to three days per cycle, and this cycle is performed once or repeated twice or more. 
     
     
         23 . The use according to  claim 19 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 4, Day 8, and Day 11. 
     
     
         24 . The use according to  claim 19 , wherein the administration schedule is based on a 14-day cycle, in which among 14 days contained in one cycle, (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one or a salt thereof is administered on Day 1, Day 3, Day 5, Day 7, Day 9, Day 11, and Day 13.