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Publication Number
US-8003687-B2
Publication Date
2011-08-23
Expiration Date
Abstract
Esters of compounds in the leptomycin family, having a structure according to formula I where R, R10, R11, R12, R13, and R14 are as defined herein, exhibit anti-tumor properties.
Core Innovation
The invention relates to leptomycin-family ester compounds having a structure according to Formula I, where the ester group is defined by R and where R, R1, R2, and n satisfy specified structural options. The compounds are provided as pharmaceutically acceptable solvates, hydrates, and prodrug forms, so that the overall compound family includes the ester derivatives in multiple acceptable forms.
The described problem is hyperproliferative disease, including cancer, where inhibition of proliferation of target cells is needed. The compounds are described as inhibiting proliferation of target cells by contacting a patient’s cells with a therapeutically effective amount of the leptomycin-family ester compound.
The document further characterizes representative compounds within the Formula I ester family, including a comparative LMB methyl ester. It reports preparation embodiments for the leptomycin-family ester compounds and evaluates cytotoxicity by measuring IC50 values across multiple tumor cell lines, with activity generally comparable to LMB within about an order of magnitude.
Claims Coverage
The independent claim covers a leptomycin-family ester compound defined by a structure according to Formula I together with pharmaceutically acceptable forms, with three main structural inventive aspects (definition of R, definition of R1, and definition of R2 with n). The dependent claims further refine this structural scope and add method and formulation contexts tied to inhibiting CRM1-mediated nuclear export and pharmaceutical composition requirements.
Leptomycin-family ester compound of Formula I with defined R, R1, R2, and n
A compound having a structure according to formula I and a pharmaceutically acceptable thereof, wherein R is CH2R1; R1 is aryl, heteroaryl, or C(∼O)OR2; and R2 is C2–C4 alkyl, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, with n being 1, 2, 3, or 4.
Alternative Formula restrictions (formula 1/2/3)
The compound is specified as having a structure corresponding to formula 1, 2, or 3.
Inhibiting target cell proliferation and CRM1-mediated nuclear export by administration
A method for inhibiting the proliferation of tumor cell lines and/or inhibiting CRM1-mediated nuclear export of a protein by administering to a patient a therapeutically effective amount of a compound according to claim 1.
Human patient administration
The method is performed on a human patient.
Pharmaceutical composition with an excipient
A pharmaceutical composition that includes a compound according to claim 1 together with an excipient.
Across the independent and dependent claims, the coverage centers on leptomycin-family ester compounds defined by Formula I with specified structural substitutions (R, R1, R2, n), with dependent claims narrowing the ester structure to specified formula alternatives and extending coverage to therapeutic administration for inhibiting tumor cell proliferation and CRM1-mediated nuclear export, specifying human patients and including pharmaceutical compositions with an excipient.
Stated Advantages
Inhibits the proliferation of tumor cell lines.
Inhibits CRM1-mediated nuclear export of a protein.
Leads to apoptosis and nuclear accumulation of proteins including p53, p73, Bcr-Abl, STAT1, ADAR1, Rev, and actin.
Cytotoxicity activity generally comparable to LMB (within about an order of magnitude).
Documented Applications
Inhibition of proliferation of tumor cell lines by contacting cells in a patient with a therapeutically effective amount of a leptomycin-family ester compound.
Treatment of hyperproliferative disease in mammalian patients using a leptomycin-family ester compound.
Use as a medicament for inhibiting CRM1-mediated nuclear export of a protein and inhibiting tumor cell proliferation via administration.
Formulation as a pharmaceutical composition for medicament use, including the compound with an excipient.
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