antitumor agents; anticancer agents; structurally related to the leptomycin family; Leptolstatin
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Publication Number
US-7795457-B2
Publication Date
2010-09-14
Expiration Date
Abstract
Carbamate compounds having a structure represented by formula I (where R1, R2, R3, R4, R5 and R6 are as defined herein) are useful as anti-tumor agents.
Core Innovation
The invention relates to compounds having a structure represented by formula I, or pharmaceutically acceptable salts thereof, with defined substituent groups R1–R9 and a ring-size variable n selected from 2, 3, 4, 5, or 6. The compounds are described in a leptomycin-family context and preserve the Michael acceptor pharmacophore of leptomycin B, while converting the C24 carboxylic acid functionality into a C24 alcohol in disclosed examples.
The compounds inhibit CRM1 (exportin-1) by forming an adduct with a cysteine residue in the CRM1 export machinery, thereby blocking nuclear export. The biological effects include p53 accumulation, cell cycle arrest and/or apoptosis, and the described target proteins include p53, p73, STAT1, ADAR1, Rev, actin, and Bcr-Abl.
The document further frames the intended therapeutic effect as treatment of hyperproliferative diseases, including cancer, and describes combination therapy with imatinib (Gleevec) for Bcr-Abl-positive cells. It also includes pharmaceutical formulation aspects such as formulations with excipients, microcapsules, or nanoparticles.
Claims Coverage
The provided independent claim covers a formula I compound or pharmaceutically acceptable salt thereof, defined by extensive substituent limitations and a proviso for R5, with n restricted to 2–6. The claim set also includes dependent refinements to selected substituents, specific illustrated compounds including formula A-4, and a pharmaceutical formulation comprising an excipient.
Formula I compound scaffold with defined substituents
A compound having a structure represented by formula I or a pharmaceutically acceptable salt thereof, with R1, R2, R3, R4 and R5 independently defined; R5 can also be C(=O)NH2; R6, R7, R8 and R9 are defined with allowed functional-group and ring substituent options; and n is independently 2, 3, 4, 5, or 6.
Specific substituent selection for NR4R5
A compound in which the NR4R5 substituent is selected from the group of alternative chemical substituents depicted for NR4R5.
Trifluoromethyl-substituted pyridyl moiety with R6 fixed to H
A compound in which the NR5R6 group includes a trifluoromethyl-substituted pyridyl moiety and where R6 is H.
Selection from illustrated compounds corresponding to the scaffold
A compound selected from a group of specific illustrated compounds corresponding to the scaffold, including illustrated members referenced as A-1, A-2, A-4, A-15, A-16, A-17, A-19, and A-21.
Compound corresponding to formula A-4
A compound with a chemical structure corresponding to formula A-4.
Pharmaceutical formulation with excipient
A pharmaceutical formulation that includes a compound as defined in claim 1 together with an excipient.
The claim coverage is concentrated on a formula I compound class with detailed substituent definitions and a defined n range, plus refinement to specific illustrated structures and a pharmaceutical formulation comprising the compound and an excipient.
Stated Advantages
Inhibition of CRM1-mediated nuclear export.
Induction of apoptosis.
Cell-cycle arrest.
p53 nuclear accumulation.
Antiproliferative activity across multiple tumor cell lines.
Potential therapeutic use across hyperproliferative diseases, including possible synergy with imatinib (Gleevec).
Documented Applications
Treatment of hyperproliferative diseases, including cancer.
Inhibiting target-cell proliferation.
Inhibiting CRM1-mediated nuclear protein export.
Use in contexts involving p53/p73 nuclear accumulation.
Use affecting pathways associated with Bcr-Abl, STAT1, ADAR1, and Rev.
Combination or potential synergy with imatinib (Gleevec).
Pharmaceutical formulations comprising the compound and an excipient, including mentions of microcapsules and nanoparticles.
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