Combination therapy of tetracyclic quinolone analogs for treating cancer

Abstract

The present invention provides methods, compositions, and combinations for treating cancer via combined use of a compound of formula I or a pharmaceutically acceptable salt, ester, solvate and/or prodrug thereof, wherein A, Q, n, m, R7, R8, V, X1, X2, X3, X4, X5, X6, and X7 are as defined herein, and at least one therapeutically active agents selected from immunotherapeutics, anticancer agents, and anti-angiogenics.

1 . A pharmaceutical combination comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate and/or prodrug thereof; and at least one additional therapeutically active agent selected from one or more of the group consisting of immunotherapeutic agents, anticancer agents, and angiogenic agents; wherein: 
       
         
           
           
               
               
           
         
         X 2 , X 3 , X 4 , X 5 , X 6  and X 7  independently are NR 4 , CH 2 , CHQ or C(Q) 2 , provided that zero, one or two of X 2 , X 3 , X 4 , X 5 , X 6  and X 7  are NR 4 ; 
         A and V independently are H, halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 4 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         each Q is independently halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 3 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         in each —NR 1 R 2 , R 1  and R 2  together with N may form an optionally substituted azacyclic ring, optionally containing one additional heteroatom selected from N, O and S as a ring member; 
         R 1  is H or C1-C6 alkyl, optionally substituted with one or more halogens, or ═O; 
         R 2  is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; 
         R 3  is an optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl, or C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring; 
         each R 4  is independently H, or C1-C6 alkyl; 
         R 7  is H and R 8  is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; or in —NR 7 R 8 , R 7  and R 8  together with N may form an optionally substituted azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member; 
         m is 0, 1, 2, 3 or 4; 
         n is 0, 1, 2, 3, 4, or 5. 
       
     
     
         2 . The pharmaceutical combination of  claim 1 , wherein the compound of formula (I) is represented by formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         A and V independently are H, halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         each Q is independently halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         in each —NR 1 R 2 , R 1  and R 2  together with N may form an optionally substituted azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member; 
         R 1  is H or C1-C6 alkyl, optionally substituted with one or more halogens, or ═O; 
         R 2  is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; 
         R 3  is an optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl, or C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring; 
         each R 4  is independently H, or C1-C6 alkyl; 
         m is 0, 1, 2, 3 or 4; 
         n is 0, 1, 2, 3, 4 or 5; and 
         p is 0, 1, 2 or 3. 
       
     
     
         3 . The pharmaceutical combination of  claim 1 , wherein the compound of formula (I) is represented by formula (III): 
       
         
           
           
               
               
           
         
         wherein: 
         A and V independently are H, halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         each Q is independently halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         in each —NR 1 R 2 , R 1  and R 2  together with N may form an optionally substituted azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member; 
         R 1  is H or C1-C6 alkyl, optionally substituted with one or more halogens, or ═O; 
         R 2  is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; 
         R 3  is an optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl, or C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring; 
         each R 4  is independently H, or C1-C6 alkyl; 
         R 7  is H and R 8  is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; 
         m is 0, 1, 2, 3 or 4; and 
         n is 0, 1, 2, 3, 4 or 5. 
       
     
     
         4 . The pharmaceutical combination of  claim 3 , wherein the Compound is Compound A: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The pharmaceutical combination of  claim 1 , wherein the compound of formula (I) and the at least one additional therapeutically active agent are in single dosage form or in separate dosage forms. 
     
     
         6 . The pharmaceutical combination of  claim 5 , wherein the separate dosage forms are administered via same mode of administration or different modes of administration. 
     
     
         7 . The pharmaceutical combination of  claim 6 , wherein the separate dosage forms are co-administered via simultaneous administration, sequential administration, overlapping administration, interval administration, continuous administration, or a combination thereof. 
     
     
         8 . The pharmaceutical combination of  claim 1 , wherein the at least one additional therapeutically active agent comprises at least one immunotherapeutic agent. 
     
     
         9 . The pharmaceutical combination of  claim 8 , wherein the at least one immunotherapeutic agent is selected from one or more of the group consisting of: monoclonal antibody, an immune effector cell, adoptive cell transfer, an immunotoxin, a vaccine, or a cytokine. 
     
     
         10 . The pharmaceutical combination of  claim 8 , wherein the at least one immunotherapeutic agent is an antibody or an antigen-binding portion thereof that disrupts the interaction between Programmed Death-1 (PD-1) and Programmed Death Ligand-1 (PD-L1). 
     
     
         11 . The pharmaceutical combination of  claim 8 , wherein the at least one immunotherapeutic agent is selected from one or more of the group consisting of: an anti-PD-1 antibody, a PD-1 antagonist, an anti-PD-L1 antibody, a siRNA targeting expression of PD-1, a siRNA targeting the expression of PD-L1, and a peptide, fragment, dominant negative form, or soluble form of PD-1 or PD-L1. 
     
     
         12 . The pharmaceutical combination of  claim 11 , wherein the anti-PD-1 antibody is a monoclonal antibody. 
     
     
         13 . The pharmaceutical combination of  claim 11 , wherein the anti-PD-1 antibody is a humanized antibody. 
     
     
         14 . The pharmaceutical combination of  claim 8 , wherein the at least one immunotherapeutic agent is selected from one or more of the group consisting of a CTLA-4 antagonist, an anti-CTLA-4 antibody, a siRNA targeting the expression of CTLA-4, and a peptide, fragment, dominant negative, or soluble form of CTLA-4. 
     
     
         15 . The pharmaceutical combination of  claim 9 , wherein the monoclonal antibody is selected from one or more of the group consisting of anti-PD-1 antibody, nivolumab, pembrolizumab alemtuzumab, bevacizumab, brentuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, anti-B7-H4, anti-B7-H1, anti-LAG3, BTLA, anti-Tim3, anti-B7-DC, anti-CD160, MR antagonist antibodies, anti-4-1BB, anti-OX40, anti-CD27, and CD40 agonist antibodies. 
     
     
         16 . The pharmaceutical combination of  claim 15 , wherein the monoclonal antibody is selected from the group consisting of nivolumab and pembrolizumab. 
     
     
         17 . The pharmaceutical combination of  claim 16 , wherein the monoclonal antibody is nivolumab. 
     
     
         18 . The pharmaceutical combination of  claim 1 , wherein the at least one additional therapeutically active agent comprises at least one anticancer agent. 
     
     
         19 . The pharmaceutical combination of  claim 18 , wherein the at least one anticancer agent is selected from one or more of the group consisting of an alkylating agent, an anti-metabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an anti-tumor antibiotic, a tyrosine kinase inhibitor, an immunosuppressive macrolide, an Akt inhibitor, an HDAC inhibitor an Hsp90 inhibitor, an mTOR inhibitor, a PI3K/mTOR inhibitor, a PI3K inhibitor, a CDK (cyclin-dependent kinase) inhibitor, CHK (checkpoint kinase) inhibitor, and PARP (poly (DP-ribose)polymerase) inhibitors. 
     
     
         20 . The pharmaceutical combination of  claim 18 , wherein the at least one anticancer agent is a PI3K inhibitor. 
     
     
         21 . The pharmaceutical combination of  claim 19 , wherein the PI3K inhibitor is Idelalisib. 
     
     
         22 . The pharmaceutical combination of  claim 18 , wherein the at least one anticancer agent is a PARP inhibitor. 
     
     
         23 . The pharmaceutical combination of  claim 22 , wherein the PARP inhibitor is Olaparib. 
     
     
         24 . The pharmaceutical combination of  claim 1 , wherein the at least one additional therapeutically active agent comprises at least one anti-angiogenic agent. 
     
     
         25 . The pharmaceutical combination of  claim 25 , wherein the at least one anti-angiogenic is selected from one or more of the group consisting of 2-methoxyestradiol, AG3340, prinomastat, batimastat, BAY 12-9566, carboxyamidotriazole, CC-1088, dextromethorphan acetic acid, dimethylxanthenone acetic acid, EMD 121974, endostatin, IM-862, marimastat, matrix metalloproteinase, penicillamine, PTK787/ZK 222584, RPI.4610, squalamine, squalamine lactate, 3-[2,4-dimethylpyrrol-5-yl-methyl-idenyl]-2-indolinone (SU5416), (±)-thalidomide, S-thalidomide, R-thalidomide, 0-(chloroacetylcarbamoyl)fumagillol (TNP-470), combretastatin, paclitaxel, tamoxifen, COL-3, neovastat, BMS-275291, SU6668, 2-ME, interferon-alpha, anti-VEGF antibody, Medi-522 (Vitaxin II), CAI (inhibitor of calcium influx), celecoxib, Interleukin-12, IM862, amilloride, Angiostatin® protein, angiostatin K1-3, angiostatin K1-5, captopril, DL-alpha-difluoromethylornithine, DL-alpha-difluoromethylornithine HCl, His-Tag® Endostatin™ Protein, fumagillin, herbimycin A, 4-hydroxyphenylretinamide, gamma-interferon, juglone, laminin, laminin hexapeptide, laminin pentapeptide, lavendustin A, medroxyprogesterone, medroxyprogesterone acetate, minocycline, minocycline HCl, placental ribonuclease inhibitor, suramin, sodium salt Suramin, human platelet thrombospondin, tissue inhibitor of metalloproteinase 1, neutrophil granulocyte tissue inhibitor of metalloproteinase 1, or rheumatoid synovial fibroblast tissue inhibitor of metalloproteinase 2. 
     
     
         26 . The pharmaceutical combination of  claim 1 , which is a pharmaceutical formulation further comprising a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier. 
     
     
         27 . The pharmaceutical combination of  claim 4 , wherein Compound A is present in an amount from about 1 mg to about 500 mg. 
     
     
         28 . The pharmaceutical combination of  claim 1 , wherein the compound is Compound A: 
       
         
           
           
               
               
           
         
       
       and wherein the at least one additional therapeutically active agent is selected from one or more of the group consisting of a PARP inhibitor and an anti-PD-1 antibody. 
     
     
         29 . The pharmaceutical combination of  claim 28 , wherein the PARP inhibitor is Olaparib. 
     
     
         30 . The pharmaceutical combination of  claim 28 , wherein the anti-PD-1 antibody is nivolumab. 
     
     
         31 . A method for treating or ameliorating cell proliferation disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I); 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, solvate and/or prodrug thereof; 
         wherein: 
         X 1  is CH or N; 
         X 2 , X 3 , X 4 , X 5 , X 6  and X 7  independently are NR 4 , CH 2 , CHQ or C(Q) 2 , provided that zero, one or two of X 2 , X 3 , X 4 , X 5 , X 6  and X 7  are NR 4 ; 
         A and V independently are H, halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         each Q is independently halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , or —R 3 ; 
         in each —NR 1 R 2 , R 1  and R 2  together with N may form an optionally substituted azacyclic ring, optionally containing one additional heteroatom selected from N, O and S as a ring member; 
         R 1  is H or C1-C6 alkyl, optionally substituted with one or more halogens, or ═O; 
         R 2  is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; 
         R 3  is an optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl, or C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring; 
         each R 4  is independently H, or C1-C6 alkyl; 
         R 7  is H and R 8  is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring; or in —NR 7 R 8 , R 7  and R 8  together with N may form an optionally substituted azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member; 
         m is 0, 1, 2, 3 or 4; 
         n is 0, 1, 2, 3, 4, or 5; 
         and administering radiotherapy or at least one additional therapeutically active agent before, during, or after the subject has been administered a compound of formula (I). 
       
     
     
         32 . The method of  claim 31 , wherein the cell proliferation disorder is cancer. 
     
     
         33 . The method of  claim 32 , wherein the cancer is selected from the group consisting of: heme cancer, colorectum cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, cancer of the lymph nodes, colon cancer, prostate cancer, brain cancer, cancer of the head and neck, bone cancer, Ewing's sarcoma, skin cancer, kidney cancer, and cancer of the heart. 
     
     
         34 . The method of  claim 32 , wherein the cancer is selected from the group consisting of wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, Ewing's sarcoma, head and neck cancer, and cervical cancer. 
     
     
         35 . The method of  claim 33 , wherein the heme cancer is selected from the group consisting of: leukemia, lymphoma, myeloma, and multiple myeloma. 
     
     
         36 . The method of  claim 32 , wherein the cancer is homologous recombination (HR) dependent double strand break (DSB) repair deficient cancer or non-homologous end joining (NHEJ) DSB repair deficient cancer. 
     
     
         37 . The method of  claim 33 , wherein the subject is human. 
     
     
         38 . The method of  claim 33 , wherein the one or more additional therapeutic agent is selected from one or more of the group consisting of immunotherapeutic agents, anticancer agents, and angiogenic agents. 
     
     
         39 . The method of  claim 31 , wherein the Compound is Compound A: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The method of  claim 39 , wherein the at least one additional therapeutically active agent is selected from one or more of the group consisting of a PARP inhibitor and an anti-PD-1 antibody. 
     
     
         41 . The method of  claim 40 , wherein the PARP inhibitor is Olaparib. 
     
     
         42 . The method of  claim 40 , wherein the anti-PD-1 antibody is nivolumab.