7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo [1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one, analogs thereof, and salts thereof and methods for their use in therapy

Abstract

This disclosure relates to methods of treatment using compound (1) or analogs thereof, and pharmaceutically acceptable salts thereof. Also disclosed are compounds of formula (10): as defined in the specification, and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the same. Methods of treatment, such as for cancer, are provided that comprise administering the compounds and their salts to a subject in need of such treatment.

1 . A compound having formula (10) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein R 1  and R 2  are independently selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkylphenyl, C 1-4 alkylphenylketone, C 1-4 benzyl-piperazine, C 1-4 alkylthienyl, C 1-4 alkylpyridinyl, C 1-4 alkylisoxazolidinyl, C 1-4 alkylmorpholinyl, C 1-4 alkylthiazolyl, and C 1-4 alkylpyrazinyl wherein C 1-4 alkyl, C 1-4 alkylphenyl, C 1-4 alkylphenylketone, C 1-4 benzyl-piperazine, C 1-4 alkylthienyl, C 1-4 alkylpyridinyl, C 1-4 alkylisoxazolidinyl, C 1-4 alkylmorpholinyl, C 1-4 alkylthiazolyl, and C 1-4 alkylpyrazinyl are optionally substituted with C 1-4 alkyl, C 1-4 alkoxyl, hydroxyl, perhalogenated C 1-4 alkyl, or halogen, and wherein when R 1  represents CH 2 Ph, R 2  does not represent CH 2 -((2-CH 3 )-Ph). 
     
     
         2 . The compound of  claim 1 , wherein R 1  and/or R 2  is a benzyl optionally substituted with one or more of the following substituents on the benzyl ring: X, —CH 3 , —NO 2 , —OCH 3 , —CN, —CXH 2 , —CX 2 H, C 2 -C 4  alkyl, —CX 3 , —CH 2 (CX 3 ), —CH(CX 3 ) 2 , —C(CX 3 ) 3 , —C p X 2p+1 , —OCX 3 , —OC p H 2p+1 , —OC p X 2p+1 , OR m , SR m , NR m R n , NR m C(O)R n , SOR m , SO 2 R m , C(O)R m , and C(O)OR m ;
 where R m  and R n  are independently selected from hydrogen or a C 1 -C 4  alkyl; 
 where p is an integer from 2 to 20; and 
 X represents a halogen. 
 
     
     
         3 . The compound of  claim 1 , wherein R 1  is a hydrogen or an unsubstituted benzyl. 
     
     
         4 .- 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein the compound is represented by formula (40) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 wherein R a1 , R a2 , R a3 , R a4 , and R a5  are each independently selected from the group consisting of hydrogen, X, —CH 3 , —NO 2 , —OCH 3 , —CN, —CXH 2 , —CX 2 H, C 2 -C 4  alkyl, —CX 3 , —CH 2 (CX 3 ), —CH(CX 3 ) 2 , —C(CX 3 ) 3 , —C p X 2p+1 , —OCX 3 , —OC p H 2p+1 , —OC p X 2p+1 , OR m , SR m , NR m R n , NR m C(O)R n , SOR m , SO 2 R m , C(O)R m , and C(O)OR m ; 
 
       where R m  and R n  are independently selected from hydrogen or a C 1 -C 4  alkyl; 
       p is an integer from 2 to 20; and 
       X represents a halogen. 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 8 , wherein the compound is represented by formula (45) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1  having formula (50) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R b  is selected from the group consisting of X, —CH 3 , —NO 2 , —OCH 3 , —CN, —CXH 2 , —CX 2 H, C 2 -C 4  alkyl, —CX 3 , —CH 2 (CX 3 ), —CH(CX 3 ) 2 , —C(CX 3 ) 3 , —C p X 2p+1 , —OCX 3 , —OC p H 2p+1 , —OC p X 2p+1 , OR m , SR m , NR m R n , NR m C(O)R n , SOR m , SO 2 R m , C(O)R m , and C(O)OR m ; 
 R a1 , R a2 , R a4 , and R a5  are each independently selected from the group consisting of hydrogen, X, —CH 3 , —NO 2 , —OCH 3 , —CN, —CXH 2 , —CX 2 H, C 2 -C 4  alkyl, —CX 3 , —CH 2 (CX 3 ), —CH(CX 3 ) 2 , —C(CX 3 ) 3 , —C p X 2p+1 , —OCX 3 , —OC p H 2p+1 , —OC p X 2p+1 , OR m , SR m , NR m R n , NR m C(O)R n , SOR m , SO 2 R m , C(O)R m , and C(O)OR m ; 
 
       where R m  and R n  are independently selected from hydrogen or a C 1 -C 4  alkyl; 
       p is an integer from 2 to 20; 
       and X represents a halogen. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 13 , wherein the compound is represented by formula (55) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 .- 18 . (canceled) 
     
     
         19 . The compound of  claim 13 , wherein R b  is a CH 3  or a OCH 3  substituent. 
     
     
         20 . (canceled) 
     
     
         21 . A composition comprising a salt of a compound of  claim 1 . 
     
     
         22 . (canceled) 
     
     
         23 . The composition according to  claim 21 , wherein the salt is a di-salt. 
     
     
         24 . The composition according to  claim 23 , wherein the di-salt is a hydrochloride di-salt. 
     
     
         25 . (canceled) 
     
     
         26 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         27 . A method of treatment, comprising administering to a subject in need of such treatment a pharmaceutically acceptable amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         28 .- 119 . (canceled) 
     
     
         120 . A method of identifying whether a subject having cancer is likely to be responsive to administration of compound (1), comprising:
 (i) obtaining a biological sample from the subject;   (ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample;   (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard; and   (iv) determining whether the subject is likely to be responsive to administration of compound (1), based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.   
     
     
         121 . The method of  claim 120 , wherein the dopamine receptor is selected from DRD2, DRD2S, DRD2L, and DRD3. 
     
     
         122 . The method of  claim 120 , wherein the dopamine receptor is from the D2-like family of dopamine receptors. 
     
     
         123 . The method of  claim 120 , further comprising the step of administering an effective amount of compound (1) to the subject. 
     
     
         124 .- 138 . (canceled) 
     
     
         139 . A method of assessing the effectiveness of or monitoring a subject having cancer and undergoing administration of compound (1), comprising:
 (i) obtaining a biological sample from the subject;   (ii) measuring prolactin levels;   (iii) determining whether the subject is likely to be responsive to administration of compound (1), based on the levels measured relative to those for a pre-determined standard.   
     
     
         140 . (canceled) 
     
     
         141 . (canceled) 
     
     
         142 . The compound of  claim 10 , wherein R a1 , R a4 , R a5 , are each hydrogen; and R a2  and R a3  are each selected from fluorine or chlorine. 
     
     
         143 . The compound of  claim 10 , wherein R a1 , R a2 , R a4 , R a5 , are each hydrogen; and wherein R a3  is OCH 3 .