发明名称 NOVEL BIFUNCTIONAL METNASE/INTNASE INHIBITORS AND RELATED COMPOSITIONS AND METHODS OF TREATMENT OF CANCER
摘要 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.
申请公布号 US2015087886(A1) 申请公布日期 2015.03.26
申请号 US201414510476 申请日期 2014.10.09
申请人 STC.UNM 发明人 Hromas Robert;Leitao Andrei;Oprea Tudor I.;Sklar Larry A.;Williamson Elizabeth A.;Wray Justin;Wang Wei
分类号 C07D215/56;C07D401/06;A61K31/475;A61N5/10;C07D401/12;A61K45/06;C07D401/10;A61K31/7048;A61K31/47;A61K31/496 主分类号 C07D215/56
代理机构 代理人
主权项 1. A compound of the formula: wherein: R1 is a C1-C6 hydrocarbon which is optionally substituted, a (CH2)j—C1-C6 ether or thioether group which is optionally substituted, a (CH2)j—C1-C6 acyl group which is optionally substituted, a (CH2)j—NR1R2 group wherein R1 and R2 are each independently H, or a C1-C6 alkyl group optionally substituted with halo or at least one hydroxyl group, an optionally substituted (CH2)n-amide group, an optionally substituted (CH2)n-thioamide group, an optionally substituted (CH2)n-aryl group or an optionally substituted (CH2)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; R2 is H, halo, or an optionally substituted C1-C6 hydrocarbon which is optionally substituted with a —C0-C6-hydrocarbon-NRcRd group, where Rc and Rd are each independently a —(CH2)i—W group where each i is independently 0, 1, 2, 3, 4, 5 or 6 and W is a halo group; R3 is H, halo, —N(H)Ra, —N(H)C(═O)Ra, —C(═O)Rb, agroup or a —C0-C6-hydrocarbon-NRcRd group which is optionally substituted and wherein R2 and R3 are not both H or halo; each of i, Rc and Rd is independently the same as described above; each RT is independently H or a C1-C3 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; Ra is where Rx is a C1-C6 hydrocarbon which is optionally substituted, an optionally substituted (CH2)j—C1-C6 ether or thioether group, an optionally substituted (CH2)j—C1-C6 acyl group, an optionally substituted (CH2)n-amide group, or an optionally substituted (CH2)n-thioamide group; Ry, and R, are each independently, an optionally substituted C1-C6 hydrocarbon, an optionally substituted (CH2)j—C1-C6 ether or thioether group, an optionally substituted (CH2)j—C1-C6 acyl group, a (CH2)j—NR1R2 group wherein R1 and R2 are each independently H, or a C1-C6 alkyl group optionally substituted with halo or at least one hydroxyl group, an optionally substituted (CH2)n-amide group, or an optionally substituted (CH2)n-thioamide group; Rb is an optionally substituted aryl, an optionally substituted (C0-C6 hydrocarbon)-aryl, an optionally substituted —O-aryl, an optionally substituted (C0-C6 hydrocarbon)-hetaryl, an optionally substituted —O-hetaryl wherein each Rb group is optionally substituted with one or more substituents, each of which is independently Ra as defined above, halo, C1-C6 hydrocarbon, —C1-C6 haloalkyl, —O—C1-C6 alkyl, —O—C1-C6 haloalkyl, oxo (═O), or —CO2Rm, where Rm is —H or —C1-C6 alkyl which is optionally substituted with at least one hydroxyl group, or Rb may be an optionally substituted C0-C6alkyl-W—X—Z group, where W is an optionally substituted carbocyclic aryl or heteroaryl group; X is absent, S, O or a —N(RN)— group where RN is H or a C1-C3 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 Ra′, halo, C1-C6 hydrocarbon, —C1-C6 haloalkyl, —O—C1-C6 alkyl, —O—C1-C6 haloalkyl, oxo (═O), or —CO2Rm, wherein Ra′ is where Rx′ is absent or Rx, and Ry and Rz are the same as described above, or a pharmaceutically acceptable salt, solvate or polymorph thereof.
地址 Albuquerque NM US