Novel bifunctional metnase/intnase inhibitors and related compositions and methods of treatment of cancer

Abstract

This invention relates to novel cancer treatment compositions and associated therapeutic methods. More particularly, this invention relates in part to small chemical bifunctional inhibitors of DNA replication and repair proteins Metnase and/or Intnase (also termed Gypsy Integrase, Gypsy Integrease-1, Gypsy Retransposon Integrase 1, or GIN-1) that simultaneously damage DNA, and to a therapeutic method that utilizes the inhibitors to increase the effectiveness of cancer treatment protocols, including radiation therapy. In preferred embodiments, compounds, compositions and methods of treatment of the invention are used to treat a patient suffering from leukemia (e.g. acute myeloid leukemia (AML) and related cancers. In certain aspects of such treatments, compounds, compositions and methods of treatment of the invention are administered as a monotherapy (in some cases, to patients who have exhibited resistance to Topo IIalpha inhibitors such as VP-16), or are co-administered with a Topo IIalpha inhibitor or other anti-cancer agents as otherwise described herein or in combination with radiation therapy.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is a C 1 -C 6  hydrocarbon which is optionally substituted, a (CH 2 ) j —C 1 -C 6  ether or thioether group which is optionally substituted, a (CH 2 ) j —C 1 -C 6  acyl group which is optionally substituted, a (CH 2 ) j —NR 1 R 2  group wherein R 1  and R 2  are each independently H, or a C 1 -C 6  alkyl group optionally substituted with halo or at least one hydroxyl group, an optionally substituted (CH 2 ) n -amide group, an optionally substituted (CH 2 ) n -thioamide group, an optionally substituted (CH 2 ) n -aryl group or an optionally substituted (CH 2 ) n -heterocyclic group; 
         Each j is independently 0, 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3; 
         Each n is independently 0, 1, 2, 3, 4, 5, or 6, preferably 0, 1, 2, or 3; 
         R 2  is H, halo, or an optionally substituted C 1 -C 6  hydrocarbon which is optionally substituted with a —C 0 -C 6 -hydrocarbon-NR c R d  group, where R c  and R d  are each independently a —(CH 2 ) i —W group where each i is independently 0, 1, 2, 3, 4, 5 or 6 and W is a halo group; 
         R 3  is H, halo, —N(H)R a , —N(H)C(═O)R a , —C(═O)R b , a 
       
       
         
           
           
               
               
           
         
       
       group or a —C 0 -C 6 -hydrocarbon-NR c R d  group which is optionally substituted and wherein R 2  and R 3  are not both H or halo;
 each of i, R c  and R d  is independently the same as described above; 
 each R T  is independently H or a C 1 -C 3  alkyl group which is optionally substituted with one or two hydroxyl groups; 
 each q is independently 0 or 1; 
 each v is independently 0 or 1; 
    is a first cyclic hydrocarbon group which is optionally substituted; 
    is a second cyclic hydrocarbon group which is optionally substituted; 
 R a  is 
 
       
         
           
           
               
               
           
         
         where R x  is a C 1 -C 6  hydrocarbon which is optionally substituted, an optionally substituted (CH 2 ) j —C 1 -C 6  ether or thioether group, an optionally substituted (CH 2 ) j —C 1 -C 6  acyl group, an optionally substituted (CH 2 ) n -amide group, or an optionally substituted (CH 2 ) n -thioamide group; 
         R y , and R, are each independently, an optionally substituted C 1 -C 6  hydrocarbon, an optionally substituted (CH 2 ) j —C 1 -C 6  ether or thioether group, an optionally substituted (CH 2 ) j —C 1 -C 6  acyl group, a (CH 2 ) j —NR 1 R 2  group wherein R 1  and R 2  are each independently H, or a C 1 -C 6  alkyl group optionally substituted with halo or at least one hydroxyl group, an optionally substituted (CH 2 ) n -amide group, or an optionally substituted (CH 2 ) n -thioamide group; 
         R b  is an optionally substituted aryl, an optionally substituted (C 0 -C 6  hydrocarbon)-aryl, an optionally substituted —O-aryl, an optionally substituted (C 0 -C 6  hydrocarbon)-hetaryl, an optionally substituted —O-hetaryl wherein each R b  group is optionally substituted with one or more substituents, each of which is independently R a  as defined above, halo, C 1 -C 6  hydrocarbon, —C 1 -C 6  haloalkyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, oxo (═O), or —CO 2 R m , where R m  is —H or —C 1 -C 6  alkyl which is optionally substituted with at least one hydroxyl group, or R b  may be an optionally substituted C 0 -C 6 alkyl-W—X—Z group, 
         where W is an optionally substituted carbocyclic aryl or heteroaryl group; 
         X is absent, S, O or a —N(R N )— group where R N  is H or a C 1 -C 3  alkyl group which is optionally substituted with one or two hydroxyl groups; and Z is absent, a carbocyclic aryl or heteroaryl group each of which group is further optionally substituted with one or more substituents, each of which substituent is independently R a′ , halo, C 1 -C 6  hydrocarbon, —C 1 -C 6  haloalkyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, oxo (═O), or —CO 2 R m , wherein R a′  is 
       
       
         
           
           
               
               
           
         
         where Rx′ is absent or R x , and Ry and Rz are the same as described above, or a pharmaceutically acceptable salt, solvate or polymorph thereof. 
       
     
     
         2 . The compound according to  claim 1  wherein said chemical compound is according to the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1  wherein R 1  is H or a C 1 -C 6  alkyl group;
 R 2  is H, halo or an optionally substituted phenyl group which is substituted in the meta or para position with a —(CH 2 ) i —NR c R d  group, where R c  and R d  are each independently a —(CH 2 ) i —W group where each i is independently 1, 2 or 3 and W is Cl. 
 
     
     
         4 . The compound according to  claim 1  wherein
 R 3  is H, halo, —N(H)R a , —N(H)C(═O)R a , or —C(═O)R b , a 
 
       
         
           
           
               
               
           
         
         group, a 
       
       
         
           
           
               
               
           
         
         group or a 
       
       
         
           
           
               
               
           
         
         Where   is a non-aromatic heterocyclic group which is optionally substituted;   is a phenyl group or an indole group; 
         Each i is independently 0, 1, 2, 3, 4, 5 or 6; 
         q is 0 or 1; 
         Each v is independently 0 or 1; 
         and R c  and R d  are each independently a C 1 -C 3  alkyl group which is substituted with at least one chloro group, and 
         where R b  is an carbocyclic aryl group which is substituted in the meta- or para-position by a R a  group where R x  is a —(CH 2 ) i — group, and each of R y  and R z  is a —CH 2 CH 2 Cl group. 
       
     
     
         5 . The compound according  claim 1  wherein R c  and R d  are each a —CH 2 CH 2 Cl group. 
     
     
         6 . The compound according to  claim 1  wherein R 3  is 
       
         
           
           
               
               
           
         
         i is 0, 1 or 2; 
         v is 0 or 1; 
         HET is a non-aromatic heterocyclic group; and 
         Aryl is a phenyl or indole group. 
       
     
     
         7 . The compound according to  claim 1  wherein R 1  is a C 3  alkyl group. 
     
     
         8 . The compound according to  claim 7  wherein said C 3  alkyl group is an isopropyl group or cyclopropyl group. 
     
     
         9 . The compound according to  claim 1  wherein R 2  or R 3  comprises at least one —(CH 2 ) i —NR c R d  group where Rc and Rd are each a —CH 2 CH 2 Cl group. 
     
     
         10 . The compound according to  claim 1  wherein R 1  is a cyclopropyl group. 
     
     
         11 . The compound according to  claim 1  wherein R 2  is H or halo when R 3  is an optionally substituted phenyl group substituted in the meta or para position with a —(CH 2 ) i —W group where i is 1, 2 or 3 and W is a Cl group. 
     
     
         12 . The compound according to  claim 11  wherein R 2  is F. 
     
     
         13 . The compound according to  claim 1  wherein R 3  is H or halo when R 2  is an optionally substituted phenyl group substituted in the meta or para position with a —(CH 2 ) i —W group where i is 1, 2 or 3 and W is a Cl group. 
     
     
         14 . The compound of  claim 1 , wherein R 1  is a C 1 -C 6  hydrocarbon, R 2  is H or halo and R 3  is other than H or halo. 
     
     
         15 . The compound of  claim 1 , wherein R 1  is a C 1 -C 6  alkyl, R 2  is H and R 3  is other than H or halo. 
     
     
         16 . The compound of  claim 1 , wherein R 1  is a C 1 -C 6  alkyl, R 2  is halo and R 3  is other than H or halo. 
     
     
         17 . The compound of  claim 1 , wherein R 1  is a C 1 -C 6  alkyl, R 2  is H or halo, and R 3  is —N(H)C(═O)R a . 
     
     
         18 . The compound of  claim 1 , wherein R 1  is a C 1 -C 6  alkyl, R 2  is H or halo, and R 3  is —N(H)R a  or —N(H)C(═O)R a , and R x , R y , and R z  are a C 1 -C 6  linear branched or cyclic alkyl group which is optionally substituted with halo. 
     
     
         19 . The compound of  claim 1 , wherein R 1  is a C 1 -C 6  alkyl, R 2  is H or halo, R 3  is —C(═O)R b , R b  is aryl which is substituted by R a , and R x , R y , and R z  are a C 1 -C 6  linear branched or cyclic alkyl group which is optionally substituted with halo. 
     
     
         20 . The compound of  claim 1 , wherein R 1  is H or a C 1 -C 6  alkyl, alkenyl, or alkynyl group which is optionally substituted with at least one hydroxyl or halogen group;
 R 2  is H or halo;   R 3  is H, —N(H)R a , —N(H)C(═O)R a , or —C(═O)R b ;   R x , R y , and R z  are each, independently, a C 1 -C 6  alkyl, alkenyl, or alkynyl group which is optionally substituted with at least one hydroxyl or halo; and wherein   R b  is aryl which is substituted by R a .   
     
     
         21 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . A compound of  claim 1  according to any of  FIGS. 12-16  hereof. 
     
     
         23 . A compound of  claim 1  according to any of  FIGS. 17-19  hereof. 
     
     
         24 . A compound of  claim 1  according to any of the chemical structures: 
       
         
           
           
               
               
           
         
       
     
     
         25 . A compound of  claim 1  according to any of the chemical structures: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A compound of  claim 1  according to any of the chemical structures: 
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound of  claim 1  according to the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         28 . A compound of  claim 1  according to the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         29 . A compound of  claim 1  according to the chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         30 . A method of treating cancer in a patient comprising administering to said patient an effective amount of at least one bifunctional inhibitor of Metnase and/or Intnase in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in combination with a second agent useful in treating cancer. 
     
     
         31 . The method according to  claim 30 , wherein said patient is also administered an effective amount of second agent useful in treating cancer. 
     
     
         32 . The method according to  claim 30 , wherein said patient is also treated with radiation therapy. 
     
     
         33 . The method of treating cancer in a patient comprising to said patient an effective amount of at least one bifunctional inhibitor of Metnase and/or Intnase in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in combination with a second agent useful in treating cancer, wherein said bifunctional inhibitor is a compound according to  claim 1  or a pharmaceutically acceptable salt, solvate or polymorph thereof. 
     
     
         34 . The method according to  claim 30 , wherein said cancer is selected from the group consisting of prostate cancer, metastatic prostate cancer, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, kidney cancer and lymphoma. 
     
     
         35 . (canceled) 
     
     
         36 . The method according to  claim 30 , wherein said second agent is selected from the group consisting of of antimetabolites, inhibitors of topoisomerase I and II, alkylating agents, microtubule inhibitors and mixtures thereof. 
     
     
         37 . The method according to  claim 30 , wherein the patient is co-administered etoposide (VP-16), raltegravir, or elvitegravir. 
     
     
         38 . The method according to  claim 30  wherein said second agent is selected from the group consisting of adriamyucin, aldesleukin; alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; Asparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfan oral; calusterone; capecitabine; carboplatin; carmustine; carmustine with Polifeprosan 20 Implant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; Dromostanolone propionate; Elliott's B Solution; epirubicin; Epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; Filgrastim; floxuridine (intraarterial); fludarabine; fluorouracil (5-FU); fulvestrant; gemcitabine, gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); meclorethamine (nitrogen mustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin; paclitaxel; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; talbuvidine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); uracil mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; and mixtures thereof. 
     
     
         39 . The method according to  claim 30  wherein said second agent is etoposide (VP-16), gemcitabine, 5-fluoruracil (5FU), cisplatin or a mixture thereof. 
     
     
         40 . A method of potentiating the effects of an anticancer agent in a therapeutic treatment of cancer in a patient, comprising co-administering to said patient along with said anticancer agent an effective amount of a bifunctional inhibitor of Metnase and Intnase. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . The method according to  claim 30  wherein said patient is other than an HIV positive, AIDS or ARC patient. 
     
     
         45 . The method according to  claim 44 , wherein said patient is a patient to whom HIV integrase inhibitors are contraindicated. 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . A method of treatment comprising administering to a patient suffering from a drug resistant cancer a compound of  claim 1 , optionally in combination with a second anticancer agent. 
     
     
         49 . The method of treatment according to  claim 48  further combined with radiation therapy. 
     
     
         50 . A pharmaceutical composition comprising an effective amount of a bifunctional inhibitor of Metnase and/or Intnase and at least one pharmaceutically acceptable carrier, additive, or excipient. 
     
     
         51 . The pharmaceutical composition comprising an effective amount of a bifunctional inhibitor of Metnase and/or Intnase and at least one pharmaceutically acceptable carrier, additive, or excipient, wherein the composition comprises an effective amount of a compound according to  claim 1 , optionally in combination with an additional agent useful in treating cancer. 
     
     
         52 - 66 . (canceled)