Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as PARP inhibitors
Inventors
Zhou, Changyou • Ren, Bo • Wang, Hexiang
Assignees
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Publication Number
US-10501467-B2
Publication Date
2019-12-10
Expiration Date
Abstract
Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.
Core Innovation
The invention relates to an oral dosage form comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit PARP, together with a pharmaceutically acceptable carrier. The disclosure describes fused tetra- or penta-cyclic dihydrodiazepinocarbazolones as PARP inhibitors and defines the compounds by extensive structural variables, including X selected from C, N, O, or S and integer parameters m, n, and t.
The structural framework specifies allowed substituent groups for R1, R2, and R3-R8, including hydrogen, halogen, CN, NO2, OR9, NR9R10, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl options, with optional substitution by R12. The definitions further include constraints on R9, R10, R11, R12, and R13, and on when certain substituents are absent or when oxo is present, together with ring-forming rules for 3- to 8-membered saturated, partially or fully unsaturated rings having 0, 1 or 2 heteroatoms selected from —NR13—, —O—, —S—, —SO— or —SO2—.
The disclosure also describes methods of inhibiting PARP and treating PARP-responsive diseases, including combination-use concepts with DNA-damaging cytotoxic agents, radiation, and radiation and/or chemotherapy. It further states diseases involving PARP and DNA repair, including conditions with DNA strand breaks, single-strand breaks, double-strand breaks, DNA repair defects, and PARP-responsive diseases.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to an oral dosage form comprising a Formula (I) compound, or a stereoisomer or pharmaceutically acceptable salt thereof, in an amount effective to inhibit PARP, together with a pharmaceutically acceptable carrier. The claim is defined by detailed structural variables and conditional ring/substituent rules, and the inventive features are merged across the provided claim summaries.
Oral dosage form with Formula (I) PARP inhibitor
An oral dosage form comprising a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit PARP, together with a pharmaceutically acceptable carrier.
Defined structural variables for Formula (I)
The compound is defined by X selected from C, N, O, or S; m and n each being 0, 1, 2, or 3; t being 0, 1, 2, or 3; and extensive substituent definitions for R1, R2, R3-R8, R9-R11, R12, and R13 with optional ring formation and allowed heteroatom-containing ring patterns.
Conditional substituent absence and oxo rules
The claim includes conditional presence/absence rules tied to X and oxo, including rules for R5, R6, R3, R4, R7, and R8 when X is O, N, S, or C and when one of the paired substituents is oxo.
Overall, the claim coverage is anchored on an oral dosage form containing a structurally defined Formula (I) compound, or stereoisomer or pharmaceutically acceptable salt, administered in an amount effective to inhibit PARP, with the scope tightly limited by substituent selections, ring sizes, heteroatom content, and conditional absence/presence rules.
Stated Advantages
Provides an oral dosage form in an amount effective to inhibit PARP.
Inhibits PARP.
Provides treatment of PARP-responsive diseases, including multiple cancers listed in the partial content.
Allows oral dosing as an oral dosage form.
Oral delivery of a PARP-inhibiting compound.
Documented Applications
Methods of inhibiting PARP by contacting PARP with the compounds.
Methods of treating PARP-responsive diseases, including ovarian cancer, breast cancer, colon cancer, leukemia, glioblastoma, lymphomas, melanomas, cervical carcinomas, cancer, ischemia-reperfusion injury, stroke/neural trauma, inflammatory diseases, immunological disorders, and degenerative disease.
Combination use with DNA-damaging cytotoxic agents and radiation for treating PARP-responsive diseases.
In vitro PARP inhibition assays and an in vivo mouse cancer model are described in connection with PARP inhibition and cancer relevance.
Oral dosage form use for delivering a compound that inhibits PARP.
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