Compounds and methods for inhibiting MRP1

Abstract

The present invention relates to a compound of formula (I), which are useful for inhibiting resistant neoplasms where the resistance is conferred in part or in total by MRP1.

We claim:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       where: 
 het is a five (5) membered heteroaryl ring containing N and a second heteroatom selected from N, O, or S; 
 wherein the non-fused carbon atom of the heteroaryl ring is optionally substituted with C 1 -C 6  alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, an amino acid ester, CH 2 OH, CH 2 O-heterocycle, halo, CH 2 N 3 , CH 2 SR 1 , CH 2 NR 4 R 5 , OR 1 , SR 12 , S(CH 2 ) n -phenyl, or NR 4 R 5 ; provided that when het is pyrazole or imidazole, the saturated nitrogen of the het ring is optionally substituted with C 1 -C 4  alkyl;  
 
 R is (CH 2 ) m′ CHR 1 NHR 2 , O(CH 2 ) 2 NHR 2 , (CH 2 ) m′ COR 3 , NHR 2 , and (CH 2 ) m′ CHR 1 NR 4 R 5 ;  
 R′ is hydrogen, hydroxy, or O(C 1 -C 6  alkyl optionally substituted with phenyl or C 3 -C 7  cycloalkyl);  
 m and m′ are independently at each occurrence 0, 1, or 2;  
 R 1  is independently at each occurrence hydrogen or C 1 -C 6  alkyl;  
 R 2  is hydrogen, COR 6 , CH 2 R 6 , SO 2 R 7 , or a moiety of the formula  
                     
 R 3  is hydrogen, hydroxy, C 1 -C 6  alkoxy, an amino acid ester, an amino acid, or NR 4 R 5 ;  
 R 4  is hydrogen or C 1 -C 6  alkyl;  
 R 5  is hydrogen, C 1 -C 6  alkyl, C 6 -C 10  bicycloalkyl, (C 1 -C 4  alkyl)-phenyl, (C 1 -C 4  alkyl)-CO 2 R 1 , CH 2 CO 2 R 1 , aryl, substituted aryl, (CH 2 ) n CHR 8 NHC(O)OC(CH 3 ) 3 , (CH 2 ) n NH 2 , (CH 2 ) 2 NHCOR 6 , (CH 2 ) 2 OR 1 , (CH 2 ) q -heterocycle, (CH 2 ) q -substituted heterocycle, or R 4  and R 5 , together with the nitrogen to which they are attached, combine to form a pyrrolidin-1-yl, piperidin-1-yl, hexamethyleneimin-1-yl, or morpholin-4-yl ring;  
 n is 1, 2, 3, or 4;  
 q is 0, 1, 2, or 3;  
 R 6  is C 1 -C 6  alkyl, substituted C 3 -C 6  cycloalkyl, aryl, substituted aryl, tert-butoxy, (CH 2 ) q -heterocycle, (CH 2 ) q -substituted heterocycle, (CH 2 ) n S(O) r R 1 , C(CH 3 ) 2 CH 2 N(R 1 ), (CH 2 ) n CHR 8 NHC(O)OC(CH 3 ) 3 , (CH 2 ) n CHR 8 NH 2 , (CH 2 ) 2 NH-aryl, or NHR 7 ;  
 R 6′  is C 1 -C 6  alkyl, substituted C 3 -C 6  cycloalkyl, aryl, substituted aryl, (CH 2 ) q -heterocycle, (CH 2 ) q -substituted heterocycle, (CH 2 ) n S(O) r R 1 , C(CH 3 ) 2 CH 2 N(R 1 ) 2 , (CH 2 ) n CHR 8 NH—C(O)OC(CH 3 ) 3 , (CH 2 ), CHR 8 NH 2 , or (CH 2 ) 2 NH-aryl;  
 r is 0, 1, or 2;  
 R 7  is C 1 -C 6  alkyl, phenyl, or substituted phenyl;  
 R 8  is hydrogen or CO 2 R 1 ; and  
 R 9 , R 10 , and R 11  are independently at each occurrence hydrogen, halo, CO 2 R 1 , aryl, substituted aryl, thiophene, C 1 -C 4  alkoxy, (C 1 -C 3  alkyl)phenyl, or C 2 -C 6  alkenyl; R 12  is C 1 -C 6  alkyl, (C 1 -C 4  alkyl)-phenyl, aryl, substituted aryl, heterocycle or substituted heterocycle; or  
 a pharmaceutical salt thereof; provided that if R 9  and R 10  are hydrogen and R 11  is chloro, then het is not  
                     
 
     
     
         2 . The compound according to  claim 1  where m is 0 and R is at the meta position.  
     
     
         3 . The compound according to  claim 2  where R is (CH 2 ) m′ CHR 1 NHR 2  and m′ is 0 and R 1  is methyl.  
     
     
         4 . The compound according to  claim 3  where R 2  is 3,4,5-trimethoxybenzyl.  
     
     
         5 . The compound according to  claim 2  where R is (CH 2 ) m′ COR 3  and m′ is 0 or 1.  
     
     
         6 . The compound according to  claim 5  where R 3  is (3,4,5-trimethoxyphenyl)amino, (4-aminosulfonylphenyl)amino, or (6-methoxyquinolin-8-yl)amino.  
     
     
         7 . The compound according to  claim 2  where R is (CH 2 ) m′ CHR 1 NR 4 R 5  and m′ is 0, and R 1  and R 4  is hydrogen.  
     
     
         8 . The compound according to  claim 7  where R 5  is 5-methylisoxazol-3-yl, 3,5-dimethoxy-4-hydroxybenzyl, or 3,4,5-trimethoxybenzyl.  
     
     
         9 . A method of inhibiting MRP1 in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I, as defined in  claim 1 , or a pharmaceutical salt thereof.  
     
     
         10 . The method according to  claim 9  where the mammal is a human.  
     
     
         11 . The method according to  claim 10  where the compound of formula I is a compound where m is 0 and R is at the meta position.  
     
     
         12 . The method according to  claim 11  where the compound of formula I is a compound where R is (CH 2 ) m′ CHR 1 NHR 2  and m′ is 0 and R 1  is methyl.  
     
     
         13 . The method according to  claim 12  where the compound of formula I is a compound where R 2  is 3,4,5-trimethoxybenzyl.  
     
     
         14 . The method according to  claim 11  where the compound of formula I is a compound where R is (CH 2 ) m′ COR 3  and m′ is 0 or 1.  
     
     
         15 . The method according to  claim 14  where the compound of formula I is a compound where R 3  is (3,4,5-trimethoxyphenyl)amino, (4-aminosulfonylphenyl)amino, or (6-methoxyquinolin-8-yl)amino.  
     
     
         16 . The method according to  claim 11  where the compound of formula I is a compound where R is (CH 2 ) m′ CHR 1 NR 4 R 5  and m′ is 0, and R 1  and R 4  is hydrogen.  
     
     
         17 . The method according to  claim 16  where the compound of formula I is a compound where R 5  is 5-methylisoxazol-3-yl, 3,5-dimethoxy-4-hydroxybenzyl, or 3,4,5-trimethoxybenzyl.  
     
     
         18 . A method of inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance, in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I, as defined in  claim 1 , or a pharmaceutical salt thereof; in combination with an effective amount of one or more oncolytic agents.  
     
     
         19 . The method according to  claim 18  where the mammal is a human.  
     
     
         20 . The method according to  claim 19  where the oncolytic(s) is selected from: doxorubicin, daunorubicin, epirubicin, vincristine, and etoposide.  
     
     
         21 . The method according to  claim 19  where the neoplasm is of the Wilm's type, bladder, bone, breast, lung (small-cell), testis, or thyroid or the neoplasm is associated with acute lymphoblastic and myeloblastic leukemia, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma.  
     
     
         22 . The method according to  claim 19  where the compound of formula I is a compound where m is 0 and R is at the meta position.  
     
     
         23 . The method according to  claim 22  where the compound of formula I is a compound where R is CHR 1 NHR 2  and R 1  is methyl.  
     
     
         24 . The method according to  claim 23  where the compound of formula I is a compound where R 2  is 3,4,5-trimethoxybenzyl.  
     
     
         25 . The method according to  claim 22  where the compound of formula I is a compound where R is COR 3  or (CH 2 )COR 3 .  
     
     
         26 . The method according to  claim 25  where the compound of formula I is a compound where R 3  is (3,4,5-trimethoxyphenyl)amino, (4-aminosulfonylphenyl)amino, or (6-methoxyquinolin-8-yl)amino.  
     
     
         27 . The method according to  claim 22  where the compound of formula I is a compound where R is (CH 2 )NR 4 R 5  and R 4  is hydrogen.  
     
     
         28 . The method according to  claim 27  where the compound of formula I is a compound where R 5  is 5-methylisoxazol-3-oyl, 3,5-dimethoxy-4-hydroxybenzyl, or 3,4,5-trimethoxybenzyl.  
     
     
         29 . A pharmaceutical formulation comprising a compound of formula I, as defined in  claim 1 , or a pharmaceutical salt thereof; in combination with one or more pharmaceutical carriers, diluents, or excipients therefor.  
     
     
         30 . A pharmaceutical formulation comprising: 
 (a) a compound of formula I, as defined in  claim 1 , or a pharmaceutical salt thereof;    (b) one or more oncolytic agents; and    (c) one or more pharmaceutical carriers, diluents, or excipients therefor.    
     
     
         31 . The formulation according to  claim 30  where the oncolytic(s) is selected from: doxorubicin, daunorubicin, epirubicin, vincristine, and etoposide.  
     
     
         32 . A use of a compound of formula I, as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance in a mammal.  
     
     
         33 . A use of a compound of formula I, as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting MRP1.  
     
     
         34 . A use of a compound of formula I, as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting MRP1 conferred MDR in a resistant neoplasm, or a neoplasm susceptible to resistance in a mammal.  
     
     
         35 . A use of a compound of formula I, as defined in  claim 1 , in therapy.  
     
     
         36 . A pharmaceutical composition for inhibiting MRP1 in a mammal which comprises an effective amount of a compound of formula I, as defined in  claim 1 , or a pharmaceutical salt thereof.  
     
     
         37 . The composition according to  claim 36  where the mammal is a human.  
     
     
         38 . The composition according to  claim 37  where the compound of formula I is a compound where m is 0 and R is at the meta position.  
     
     
         39 . The composition according to  claim 38  where the compound of formula I is a compound where R is (CH 2 ) m′ CHR 1 NHR 2  and m′ is 0 and R 1  is methyl.  
     
     
         40 . The composition according to  claim 39  where the compound of formula I is a compound where R 2  is 3,4,5-trimethoxybenzyl.  
     
     
         41 . The composition according to  claim 38  where the compound of formula I is a compound where R is (CH 2 ) m′ COR 3  and m′ is 0 or 1.  
     
     
         42 . The composition according to  claim 41  where the compound of formula I is a compound where R 3  is (3,4,5-trimethoxyphenyl)amino, (4-aminosulfonylphenyl)amino, or (6-methoxyquinolin-8-yl)amino.  
     
     
         43 . The composition according to  claim 38  where the compound of formula I is a compound where R is (CH 2 ) m′ CHR 1 NR 4 R 5  and m′ is 0, and R 1  and R 4  is hydrogen.  
     
     
         44 . The composition according to  claim 43  where the compound of formula I is a compound where R 5  is 5-methylisoxazol-3-yl, 3,5-dimethoxy-4-hydroxybenzyl, or 3,4,5-trimethoxybenzyl.  
     
     
         45 . A pharmaceutical composition for inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance, in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I, as defined in  claim 1 , or a pharmaceutical salt thereof; in combination with an effective amount of one or more oncolytic agents.  
     
     
         46 . The composition according to  claim 45  where the mammal is a human.  
     
     
         47 . The composition according to  claim 46  where the oncolytic(s) is selected from: doxorubicin, daunorubicin, epirubicin, vincristine, and etoposide.  
     
     
         48 . The composition according to  claim 46  where the neoplasm is of the Wilm's type, bladder, bone, breast, lung (small-cell), testis, or thyroid or the neoplasm is associated with acute lymphoblastic and myeloblastic leukemia, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma.  
     
     
         49 . The composition according to  claim 46  where the compound of formula I is a compound where m is 0 and R is at the meta position.  
     
     
         50 . The composition according to  claim 49  where the compound of formula I is a compound where R is CHR 1 NHR 2  and R 1  is methyl.  
     
     
         51 . The composition according to  claim 50  where the compound of formula I is a compound where R 2  is 3,4,5-trimethoxybenzyl.  
     
     
         52 . The composition according to  claim 49  where the compound of formula I is a compound where R is COR 3  or (CH 2 )COR 3 .  
     
     
         53 . The composition according to  claim 52  where the compound of formula I is a compound where R 3  is (3,4,5-trimethoxyphenyl)amino, (4-aminosulfonylphenyl)amino, or (6-methoxyquinolin-8-yl)amino.  
     
     
         54 . The composition according to  claim 49  where the compound of formula I is a compound where R is (CH 2 )NR 4 R 5  and R 4  is hydrogen.  
     
     
         55 . The composition according to  claim 54  where the compound of formula I is a compound where R 5  is 5-methylisoxazol-3-oyl, 3,5-dimethoxy-4-hydroxybenzyl, or 3,4,5-trimethoxybenzyl.