Methods and compositions useful for treating diseases involving bcl-2 family proteins with isoquinoline and quinoline derivatives

Abstract

The present invention relates to a compositions for and methods for cancer treatment, for example, hematopoietic cancers (e.g. B-cell Lymphoma). In other aspects, the invention provides methods for treating particular types of hematopoietic cancers, such as B-cell lymphoma, using a combination of one or more of the disclosed compounds and, for example, 26S proteasome inhibitors, such as, for example, Bortezomib. In another aspect the present invention relates to autoimmune treatment with the disclosed compounds. In another aspect, this invention relates to methods for identifying compounds, for example, compounds of the BH3 mimic class, that have unique in vitro properties that predict in vivo efficacy against B-cell lymphoma tumors and other cancers as well as autoimmune disease.

1 . A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, tautomer thereof, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
 X is O, C, or N, with C or N optionally substituted with hydrogen, substituted or unsubstituted C 1-6  alkyl, hydroxyl-substituted alkyl, substituted or unsubstituted C 5-10  aryl, or substituted carbonyl group; 
 Y is CH or N; 
 
       Z is C or N;
 Z′ is CH or N; 
 when Z is C, R 1  is hydrogen, alkoxy, perfluoroalkyl, F, Cl; 
 
       when Z is N, R 1  is null; and 
       R 2  and R 3  are independently selected from hydrogen or substituted or unsubstituted C 1-6  alkyl. 
     
     
         2 . The method of  claim 1 , wherein X is selected from NEt, NCO 2 tBu, and O. 
     
     
         3 . The method of  claim 1 , wherein Y is CH. 
     
     
         4 . The method of  claim 1 , wherein Z is C. 
     
     
         5 . The method of  claim 1 , wherein Z′ is CH. 
     
     
         6 . The method of  claim 1 , wherein R 1  is selected from methoxy, fluoro, and trifluoromethyl. 
     
     
         7 . The method of  claim 1 , wherein the compound of Formula I is selected from:
 6-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)isoquinolin-5-ol (1);   tert-butyl4-((4-fluorophenyl)(5-hydroxyisoquinolin-6-yl)methyl)piperazine-1-carboxylate (2);   6-((4-ethylpiperazin-1-yl)(4-methoxyphenyl)methyl)isoquinolin-5-ol (3);   6-((4-ethylpiperazin-1-yl)(4-fluorophenyl)methyl)isoquinolin-5-ol (4);   6-(morpholino(4-(trifluoromethyl)phenyl)methyl)isoquinolin-5-ol (5);   6-((4-fluorophenyl)(morpholino)methyl)isoquinolin-5-ol (6), and   6-((4-methoxyphenyl)(morpholino)methyl)isoquinolin-5-ol (7).   
     
     
         8 . A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, tautomer thereof, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: 
         X is selected from O, C, or N, with C or N optionally substituted with hydrogen, substituted or unsubstituted C 1-6  alkyl, hydroxyl-substituted alkyl, substituted or unsubstituted C 5-10  aryl, or substituted carbonyl group; 
         R 3  is selected from substituted or unsubstituted C 1-6  alkyl, C 1-6  perfluoroalkyl, substituted or unsubstituted straight or branched C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, substituted or unsubstituted C 3-10  cycloalkyl, substituted or unsubstituted C 5-8  cycloalkenyl, substituted or unsubstituted C 1-10  alkylamino; and 
         R 4  is selected from hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, C 1-6  perfluoroalkyl, substituted or unsubstituted straight or branched C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, substituted or unsubstituted C 3-10  cycloalkyl, substituted or unsubstituted C 5-8  cycloalkenyl, substituted or unsubstituted C 1-10  alkylamino, or substituted or unsubstituted C 5-10  aryl, or substituted or unsubstituted saturated or unsaturated 3-11 member heteroaryl or heteroarylalkyl containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, S, or S(O) 2 . 
       
     
     
         9 . The method of  claim 8 , wherein X is selected from NEt and 0. 
     
     
         10 . The method of  claim 8 , wherein R 3  is methyl. 
     
     
         11 . The method of  claim 8 , wherein R 4  is trifluoromethyl. 
     
     
         12 . The method of  claim 8 , wherein the compound of Formula II is selected from
 7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)-8-methoxyquinoline (8);   7-((4-ethylpiperazin-1-yl)(4-fluorophenyl)methyl)-8-methoxyquinoline (9), and   4-((4-fluorophenyl)(8-methoxyquinolin-7-yl)methyl)morpholine (10).   
     
     
         13 . The method of  claim 1 , wherein the cancer is a hematopoietic cancer. 
     
     
         14 . The method of  claim 13 , wherein the hematopoietic cancer is multiple myeloma, acute myelogenous leukemia; Hodgkin's lymphomas; Non-Hodgkin's Lymphoma; any other B-cell lymphomas; chronic lymphocytic leukemia; acute lymphoblastic leukemia; Chronic myelogenous leukemia; Acute monocytic leukemia; Small lymphocytic, consistent CLL; Follicular, predominantly small cleaved cell; Follicular, mixed small cleaved and large cell; Intermediate grade Follicular, large cell; Diffuse, small cleaved cell; Diffuse, mixed small cleaved and large cell; Diffuse, large cell (cleaved and non-cleaved); High grade; Large cell, immunoblastic; Lymphoblastic; Small non-cleaved cell; Burkitt's lymphoma; Non-Burkitt's lymphoma; Indolent NHL; B-cell CLL/small lymphocytic lymphoma; Marginal zone lymphoma; MALT; Splenic marginal 27. 27; zone lymphoma; Nodal marginal zone lymphoma; Lymphomplasmacytoid lymphoma/immunocytoma; Follicle center lymphoma, follicular type Grade I (0-5 centroblasts/hpf) or Grade II (6-15 centroblasts/hpf) or Grade III (>15 centroblasts/hpf); Aggressive NHL; Diffuse, large cell lymphoma; cancer is Mediastinal large cell lymphoma; Primary effusion lymphoma; Mantle cell lymphoma; Burkitt's lymphoma/high-grade Burkitt's-like; Precursor B-cell leukemia/lymphoma; Precursor T-cell leukemia/lymphoma; skin cancer; prostate cancer; gastric cancer; cancer is colon cancer; rectal cancer; liver cancer; cervical cancer; renal cancer; bladder cancer; nasopharyngeal cancer; esophagus cancer; pituitary gland tumor; thyroid cancer; melanoma; small-cell lung cancer; non-small cell lung cancer, or pancreatic cancer. 
     
     
         15 . The method of  claim 1 , wherein the patient is also administered a 26S proteasome inhibitor. 
     
     
         16 . The method of  claim 15 , wherein the 26S proteasome inhibitor is bortezomib. 
     
     
         17 . The method of  claim 1 , wherein the patient is also administered any combination of dexamethasone derivative and/or thalidomide derivative compound. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the patient is also administered a chemotherapeutic agent that increases the level of Mcl-1 in the cancer cell. 
     
     
         20 . A method for treating an autoimmune disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, tautomer thereof, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: 
         X is O, C, or N, with C or N optionally substituted with hydrogen, substituted or unsubstituted C 1-6  alkyl, hydroxyl-substituted alkyl, substituted or unsubstituted C 5-10  aryl, or substituted carbonyl group; 
         Y is CH or N; 
         Z is C or N; 
         Z′ is CH or N; 
         when Z is C, R 1  is hydrogen, alkoxy, perfluoroalkyl, F, Cl; 
         when Z is N, R 1  is null; and R 2  and R 3  are independently selected from hydrogen or substituted or unsubstituted C 1-6  alkyl. 
       
     
     
         21 . A method for treating an autoimmune disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof, tautomer thereof, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from O, C, or N, with C or N optionally substituted with hydrogen, substituted or unsubstituted C 1-6  alkyl, hydroxyl-substituted alkyl, substituted or unsubstituted C 5-10  aryl, or substituted carbonyl group; 
 R 3  is selected from substituted or unsubstituted C 1-6  alkyl, C 1-6  perfluoroalkyl, substituted or unsubstituted straight or branched C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, substituted or unsubstituted C 3-10  cycloalkyl, substituted or unsubstituted C 5-8  cycloalkenyl, substituted or unsubstituted C 1-10  alkylamino; and
 R 4  is selected from hydrogen, halogen, substituted or unsubstituted C 1-6  alkyl, C 1-6  perfluoroalkyl, substituted or unsubstituted straight or branched C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, substituted or unsubstituted C 3-10  cycloalkyl, substituted or unsubstituted C 5-8  cycloalkenyl, substituted or unsubstituted C 1-10  alkylamino, or substituted or unsubstituted C 5-10  aryl, or substituted or unsubstituted saturated or unsaturated 3-11 member heteroaryl or heteroarylalkyl containing 1, 2, 3, or 4 heteroatoms selected independently from N, O, S, or S(O) 2 . 
 
 
     
     
         22 - 45 . (canceled)