Selective efflux inhibitors and related pharmaceutical compositions and methods of treatment

Abstract

The present invention provides novel compounds which inhibit cancer-associated transporter proteins, methods of treating or preventing the onset of a cancer-associated transporter protein-mediated disease by administering such compounds, and pharmaceutical compositions comprising such compounds. In one embodiment, the invention provides novel pyrazolo[1,5-a]pyrimidine efflux inhibitors that are selective toward ABCG2 over ABCB1.

1 . A compound of formula (I), or an enantiomer, diastereomer, tautomer, or pharmaceutically-acceptable salt or hydrate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkylene, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; 
         R 2  and R 4  are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxyl, acyl, amino, amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkylene, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl; 
         R 3  is selected from the group consisting of hydrogen, halogen, hydroxy, carboxyl, acyl, amino, amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkylene, or substituted or unsubstituted alkynyl; and wherein 
         R a , R b , R c , and R d  are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxyl, oxo, acyl, amino, amide, substituted or unsubstituted alkyl, substituted or unsubstituted alkylene, or substituted or unsubstituted alkynyl, or one or more of R a , R b , R c , and R d , together with the carbon ring atom to which it is bound, forms carbonyl. 
       
     
     
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         25 . A method of treating a patient who suffers from a cancer which contains ABCG2 resistant cancer cells, the method comprising administering to the patient in need a pharmaceutically effective amount of a compound of  claim 1 . 
     
     
         26 . The method of treatment of  claim 25 , wherein a pharmaceutically-effective amount of an additional anti-cancer agent is co-administered to the patient. 
     
     
         27 . The method of  claim 26 , wherein said additional anti-cancer agent is an antimetabolite, or a topoisomerase I and/or topoisomerase II inhibitor. 
     
     
         28 . The method of  claim 26  wherein said additional anti-cancer agent is Ara C, etoposide, doxorubicin, taxol, hydroxyurea, vincristine, cytoxan (cyclophosphamide), mitomycin C, adriamycin, topotecan, campothecin, irinotecan, gemcitabine, campothecin, cisplatin and mixtures thereof. 
     
     
         29 . The method of  claim 26  wherein said additional anti-cancer agent is adriamycin, anastrozole, arsenic trioxide, asparaginase, azacytidine, BCG Live, bevacizumab, bexarotene capsules, bexarotene gel, bleomycin, bortezombi, busulfan intravenous, busulfan oral, calusterone, campothecin, capecitabine, carboplatin, carmustine, carmustine with polifeprosan 20 implant, celecoxib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, cytoxan, cytarabine liposomal, dacarbazine, dactinomycin, actinomycin D, dalteparin sodium, darbepoetin alfa, dasatinib, daunorubicin liposomal, daunorubicin, daunomycin, decitabine, denileukin, denileukin diftitox, dexrazoxane, dexrazoxane, docetaxel, doxorubicin, doxorubicin liposomal, dromostanolone propionate, eculizuniab, Elliott's B Solution, epirubicin, epirubicin hcl, epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide VP-16, exemestane, fentanyl citrate, filgrastim, floxuridine (intraarterial), fludarabine, fluorouracil 5-FU, fulvestrant, gefitinib, gemcitabine, gemcitabine hcl, gemicitabine, gemtuzumab ozogamicin, goserelin acetate, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, interferon alfa-2b, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine CCNU, meclorethamine, nitrogen mustard, megestrol acetate, melphalan L-PAM, mercaptopurine 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, paclitaxel protein-bound particles, palifermin, pamidronate, panitumumab, pegademase, pegaspargase, pegfilgrastim, peginterferon alfa-2b, pemetrexed disodium, pentostatin, pipobroman, plicamycin, mithramycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide VM-26, testolactone, thalidomide, thioguanine 6-TG, thiotepa, topotecan, topotecan hcl, toremifene, tositumomab, tositumomab/z-131 tositumomab, trastuzumab, tretinoin ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zoledronate, zoledronic acid and mixtures thereof. 
     
     
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         33 . The method of treatment of  claim 26 , wherein the patient's cancer is non-responsive to chemotherapy. 
     
     
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         40 . The method of  claim 25  wherein said compound is according to the chemical structure: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt or hydrate thereof. 
     
     
         41 . The method according to  claim 25  wherein said cancer is a drug resistant or multiple drug resistant cancer. 
     
     
         42 . The method according to  claim 25  wherein said cancer is metastatic cancer. 
     
     
         43 . The method according to  claim 25  wherein said cancer is 
     
     
         44 . The method according to  claim 25  wherein said cancer is a leukemia or related hematopoietic cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, brain/CNS cancer, head and neck cancer, throat cancer, melanoma and non-melanoma skin cancer, Ewing's sarcoma, osteosarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, mouth cancer, pharynx cancer, oesophageal cancer, larynx cancer, kidney cancer, lymphoma or undifferentiated high-grade sarcoma. 
     
     
         45 . The method according to  claim 25  wherein said cancer is T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML, Ewing's sarcoma, osteosarcoma and undifferentiated high-grade sarcomas. 
     
     
         46 . The method according to  claim 25  wherein said cancer is T-ALL, Hodgkin's disease, non-Hodgkin's lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B lymphoma, Large B lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia. 
     
     
         47 . The method according to  claim 40  wherein said cancer is a leukemia or related hematopoietic cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, brain/CNS cancer, head and neck cancer, throat cancer, melanoma and non-melanoma skin cancer, Ewing's sarcoma, osteosarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, mouth cancer, pharynx cancer, oesophageal cancer, larynx cancer, kidney cancer, lymphoma or undifferentiated high-grade sarcoma. 
     
     
         48 . The method according to  claim 40  wherein said cancer is T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML, Ewing's sarcoma, osteosarcoma and undifferentiated high-grade sarcomas. 
     
     
         49 . The method according to  claim 40  wherein said cancer is T-ALL, Hodgkin's disease, non-Hodgkin's lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B lymphoma, Large B lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia.