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

Abstract

The present invention relates to compositions and methods for cancer treatment comprising compounds of Formulae I, II, and III. In some aspects, the invention relates to the treatment of B-cell Lymphoma or other hematopoietic cancers. In other aspects, the invention provides methods for treating particular types of hematopoietic cancers, such as, for example, B-cell lymphoma, using a combination of one or more compounds of Formulae I, II, and III. Combination therapy with, for example, 26S proteasome inhibitors, such as, for example, Bortezomib, are also included. In another aspect the present invention relates to autoimmune treatment with compounds of Formulae I, II, and III. In another aspect, this invention relates to methods for identifying compounds, for example, compounds of the BH3 mimic class, that have in vitro properties that predict in vivo efficacy against B-cell lymphoma tumors and other cancers as well as autoimmune disease.

What is claimed is: 
     
         1 . A method for treating cancer, comprising administering to a patient in need thereof a compound of Formula I in amounts sufficient to inhibit or reduce growth of the cancer in the patient, wherein Formula I is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer, solvate, 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; 
 R 1  is: when Z is C: hydrogen, alkoxy, perfluoroalkyl, F, Cl;
 when Z is N: 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 the group consisting of methylamino, methylene, o-fluoroaniline, aminoethylcarbamate, ethylamine, hydroxyethylamine, or amino-t-butylcarbamate. 
     
     
         3 . The method of  claim 1 , wherein R 1  is selected from the group consisting of methoxy, hydrogen, fluoro, trifluoromethyl, chloro, or trifluoromethyl. 
     
     
         4 . The method of  claim 1 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, or methyl. 
     
     
         5 . The method of  claim 1 , wherein the compound of Formula I is selected from the group consisting of:
 7-((4-methoxyphenyl)(morpholino)methyl)quinolin-8-ol (1);   7-((2,6-dimethylmorpholino)(pyridin-2-yl)methyl)quinolin-8-ol (2);   7-(morpholino(pyridin-2-yl)methyl)quinolin-8-ol (3);   7-((4-fluorophenyl)(4-methylpiperazin-1-yl)methyl)quinolin-8-ol (4);   7-(morpholino(4-(trifluoromethyl)phenyl)methyl)quinolin-8-ol (5);   7-((4-chlorophenyl)(piperidin-1-yl)methyl)quinolin-8-ol (6);   7-((4-fluorophenyl)(morpholino)methyl)quinolin-8-ol (7);   7-((4-methylpiperazin-1-yl)(pyridin-4-yl)methyl)quinolin-8-ol (8);   7-((4-(2-fluorophenyl)piperazin-1-yl)(pyridin-2-yl)methyl)quinolin-8-ol (9);   ethyl 4-((8-hydroxyquinolin-7-yl)(pyridin-2-yl)methyl)piperazine-1-carboxylate (10);   7-((4-fluorophenyl)(4-methylpiperazin-1-yl)methyl)quinolin-8-ol (11);   7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)quinolin-8-ol (12);   7-((4-(2-hydroxyethyl)piperazin-1-yl)(phenyl)methyl)quinolin-8-ol (13);   tert-butyl 4-((4-fluorophenyl)(8-hydroxyquinolin-7-yl)methyl)piperazine-1-carboxylate (14), or;   7-((4-methylpiperazin-1-yl)(pyridin-3-yl)methyl)quinolin-8-ol (15).   
     
     
         6 . A method for treating cancer, comprising administering to a patient in need thereof a compound of Formula II in amounts sufficient to inhibit or reduce growth of the cancer in the patient, wherein Formula II is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer, solvate, or a pharmaceutically acceptable salt thereof, wherein:
 R 4  is selected from hydrogen, substituted or unsubstituted C 1-6  alkyl, 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 ; and 
 R 5  is selected from hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted straight or branched C 1-10  alkyl, substituted or unsubstituted C 1-6  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  aminoalkyl, substituted or unsubstituted C 3-10  aminocycloalkyl, substituted or unsubstituted C 1-10  alkylamino, substituted or unsubstituted C 5-10  aryl, hydroxyl, alkoxy, aminocarbonyl (amido), aminosulfonyl (sulfonamide), halo, 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 . 
 
     
     
         7 . The method of  claim 6 , wherein R 4  is selected from the group consisting of ethyl, phenyl, or pyridyl. 
     
     
         8 . The method of  claim 6 , wherein R 5  is selected from the group consisting of hydrogen, aminoacetyl, methylsulfonamidyl, methoxy, or isopropoxy. 
     
     
         9 . The method of  claim 6 , wherein the compound of Formula II is selected from the group consisting of:
 7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline (16);   7-((4-phenylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline (17);   7-((4-(pyridin-3-yl)piperazin-1-yl)(4-trifluoromethyl)phenyl)methyl)quinoline (18);   N-(7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)quinolin-8-yl)acetamide (19);   N-(7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)quinolin-8-yl)acetamide (20);   7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)-8-methoxyquinoline (21), and;   7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)-8-isopropoxyquinoline (22).   
     
     
         10 . A method for treating cancer, comprising administering to a patient in need thereof a compound of Formula III in amounts sufficient to inhibit or reduce growth of the cancer in the patient, wherein Formula III is: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer, solvate, or a pharmaceutically acceptable salt thereof, wherein:
 R 4  is selected from hydrogen, substituted or unsubstituted C 1-6  alkyl, 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 ; and 
 R 5  is selected from hydrogen, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted straight or branched C 1-10  alkyl, substituted or unsubstituted C 1-6  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  aminoalkyl, substituted or unsubstituted C 3-10  aminocycloalkyl, unsubstituted or substituted C 3 -C 10  heterocyclyl, substituted or unsubstituted C 1-10  alkylamino, substituted or unsubstituted C 5-10  aryl, hydroxyl, alkoxy, aminocarbonyl (amido), aminosulfonyl (sulfonamide), halo, 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 . 
 
     
     
         11 . The method of  claim 10 , wherein R 4  is ethyl. 
     
     
         12 . The method of  claim 10 , wherein R 5  is selected from the group consisting of methyl, piperidinyl, aminoacetyl, or isopropoxy. 
     
     
         13 . The method of  claim 10 , wherein the compound of Formula III selected from the group consisting of:
 7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)-6-methylquinolin-8-ol (23);   7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)-5-(piperidin-1-yl)quinolin-8-ol (24);   N-(7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)-8-hydroxyquinolin-5-yl)acetamide (25), and;   7-((4-ethylpiperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)-5-isopropoxyquinolin-8-ol (26).   
     
     
         14 . The method of any one of  claims 1 ,  6 , or  10 , wherein the cancer is a hematopoietic cancer. 
     
     
         15 . The method of  claim 14 , wherein the hematopoietic cancer is selected from 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. 
     
     
         16 . The method of  claim 14 , wherein the patient is also administered a 26S proteasome inhibitor. 
     
     
         17 . The method of  claim 16 , wherein the 26S proteasome inhibitor is bortezomib. 
     
     
         18 . The method of  claim 14 , wherein the patient is also administered any combination of dexamethasone derivative and/or thalidomide derivative compound. 
     
     
         19 . The method of  claim 18 , wherein the thalidomide derivative is revlamid. 
     
     
         20 . The method of  claim 14 , wherein the patient is also administered a chemotherapeutic agent that increases the level of Mcl-1 in the cancer cell. 
     
     
         21 . A method for treating an autoimmune disease, comprising administering to a patient in need thereof a compound of any one of  claim 1 ,  6 , or  10  in amounts sufficient to inhibit or reduce the autoimmune disease. 
     
     
         22 . The method of  claim 21  wherein the autoimmune disease is selected from type I diabetes, rheumatoid arthritis, osteo arthritis, psoriatic arthritis, psoriasis, neuromyaotonia, mayasthenia gravis, lupus erythematosus, endometriosis, Graves disease, granulomatosis, Crohn's disease, interstitial cystitis, uvitis, or multiple sclerosis. 
     
     
         23 . A method for inhibiting or reducing malignant neoplasm growth comprising administering a compound of any one of  claim 1 ,  6 , or  10  in an amount effective to inhibit or reduce the growth. 
     
     
         24 . The method of  claim 23 , wherein the neoplasm is a hematopoietic neoplasm. 
     
     
         25 . A method of predicting sensitivity of a cancer cell to a therapeutic agent comprising contacting the cell or cellular component thereof with a compound of any one of  claim 1 ,  6 , or  10  and detecting apoptosis of the cell, wherein the presence of apoptosis indicates that the cell is sensitive to the therapeutic agent. 
     
     
         26 . A method of predicting sensitivity of a cancer cell to a therapeutic agent comprising contacting mitochondria from the cell with a compound of any one of  claim 1 ,  6 , or  10 , and detecting cytochrome C release from the mitochondria, wherein the cytochrome C release indicates the cell is sensitive to the therapeutic agent. 
     
     
         27 . A method of selecting a therapeutic agent for a subject comprising the steps:
 a) obtaining a cancer cell or cellular component thereof from the subject;   b) contacting the cancer cell or cellular component with a compound of any one of  claim 1 ,  6 , or  10 ;   c) determining whether or not said compound of any one of  claim 1 ,  6 , or  10  induces apoptosis in the cancer cell or triggers an apoptotic signal in the cellular component to produce a control Mcl-1 response;   d) contacting the cancer cell or cellular component with the agent   e) determining whether or not the agent induces apoptosis in the cancer cell or triggers an apoptotic signal in the cellular component to produce a test Mcl-1 response; and   f) comparing the test Mcl-1 response to the control Mcl-1 response wherein a similarity of the test Mcl-1 response compared to the control Mcl-1 response indicates that the agent is therapeutic for the subject.   
     
     
         28 . The method of  claim 27 , wherein the cell is permeabilized prior to contacting the cell with the therapeutic agent or compounds of any one of  claim 1 ,  6 , or  10 . 
     
     
         29 . The method of  claim 27 , further comprising contacting the permeabilized cell with a potentiometric dye. 
     
     
         30 . The method of  claim 29 , wherein the potentiometric dye is JC-1 or dihydrorhodamine 123. 
     
     
         31 . The method of  claim 27 , wherein the Mcl-1 response is measured by detecting a change in emission of the potentiometric dye. 
     
     
         32 . A method of predicting sensitivity of a cancer cell to a therapeutic agent by comparing the therapeutic response of the therapeutic agent to a control response derived by treating the cancer cell or mitochondria from the cancer cell with a compound of any one of  claim 1 ,  6 , or  10  wherein a similarity of the therapeutic response in the cancer cell compared to the control response indicates that the cancer cell is sensitive to the therapeutic agent. 
     
     
         33 . The method of  claim 32 , wherein the cell is permeabilized prior to contacting the cell with the therapeutic agent or a compound of any one of  claim 1 ,  6 , or  10 . 
     
     
         34 . The method of  claim 33 , further comprising contacting the permeabilized cell with a potentiometric dye. 
     
     
         35 . The method of  claim 34 , wherein the potentiometric dye is JC-1 or dihydrorhodamine 123. 
     
     
         36 . The method of  claim 32 , wherein the Mcl-1 response is measured by detecting a change in emission of the potentiometric dye. 
     
     
         37 . A method of selectively inhibiting of Mcl-1 over Bcl-xL, comprising contacting a cell with a compound of any one of  claim 1 ,  6 , or  10 . 
     
     
         38 . The method of  claim 37 , wherein the cell is a cancer cell. 
     
     
         39 . The method of  claim 38 , wherein the cell is a human cell. 
     
     
         40 . The method of any one of  claim 37 ,  38 , or  39 , wherein the compound is in an amount sufficient to inhibit or reduce growth of a cancer in a patient.