Substituted furo[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase inhibitors and microtubule targeting antitumor agents
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Publication Number
US-9777012-B2
Publication Date
2017-10-03
Expiration Date
Abstract
Compounds of Formula I: and compounds of Formula II: are provided. Pharmaceutical compositions comprising either the compound of Formula I or Formula II are disclosed. Methods of treating patients having cancer are provided by administering to the patient a therapeutically effective amount of one or more compounds having Formula I or Formula II to treat the patient. The compounds of Formula I or II are preferably conformationally restricted furo[2,3-d]pyrimidines having dual inhibition of microtubule assembly and receptor tyrosine kinases.
Core Innovation
The invention is directed to conformationally restricted furo[2,3-d]pyrimidine derivatives, including bicyclic compounds represented by Formula I and Formula II, with variable substituents defined by R and Ar. The disclosed compounds are presented as agents for inhibiting multi-targeted receptor tyrosine kinases and/or microtubules, and the document describes pharmaceutical compositions that include a therapeutically effective amount of a compound or a pharmaceutically acceptable salt together with pharmaceutically acceptable carriers, excipients, or adjuvants.
The document describes dual inhibition involving microtubule assembly inhibition through tubulin binding and multi-targeted receptor tyrosine kinases, including VEGFR-2, EGFR, and PDGFR-β. Molecular modeling and docking are used to support the conformational restriction approach and relate the compound frameworks to bioactive conformations and potency, including docking to the colchicine site of tubulin and ATP sites of receptor tyrosine kinases.
The patent reports comparative biological evaluation across multiple assays and models, including RTK inhibition measured by a phosphotyrosine ELISA cytoblot and cell proliferation and angiogenesis assays, along with antiproliferative activity measurements and drug-resistance assessments using resistant cell models and controls. Compound 10 is reported as showing an overall best balance, including potent EGFR and tubulin inhibition, direct colchicine-site binding, improved potency across an NCI-60 panel compared to compound 1, and improved performance in overcoming ABC/βIII tubulin and Pgp-mediated resistance.
Claims Coverage
The provided independent claims cover five inventive features: a Formula I compound, a Formula I pharmaceutical composition, a method of inhibiting multi-targeted receptor tyrosine kinases and/or microtubules using Formula I, a Formula II pharmaceutical composition, and a method of inhibiting multi-targeted receptor tyrosine kinases and/or microtubules using Formula II.
Formula I compound
A compound of Formula I, wherein R is selected from the group consisting of specified options.
Pharmaceutical composition for Formula I
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable carrier, excipient or adjuvant.
Inhibiting multi-targeted RTKs and/or microtubules with Formula I
A method of inhibiting multi-targeted receptor tyrosine kinases and/or microtubules in a patient by administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition for Formula II
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable carrier, excipient or adjuvant.
Inhibiting multi-targeted RTKs and/or microtubules with Formula II
A method of inhibiting multi-targeted receptor tyrosine kinases and/or microtubules in a patient by administering a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof.
Overall, the claims cover Formula I and Formula II bicyclic furo[2,3-d]pyrimidine compounds, corresponding pharmaceutical compositions, and patient methods for inhibiting multi-targeted receptor tyrosine kinases and/or microtubules through administration of the respective compounds or pharmaceutically acceptable salts.
Stated Advantages
Multi-targeted cancer treatment by combining dual inhibition of microtubule assembly (tubulin binding) and receptor tyrosine kinases (RTKs).
Potential circumvention of multi-drug resistance associated with P-glycoprotein.
Provides a best overall balance for compound 10, with potent EGFR and tubulin inhibition.
Direct colchicine-site binding is reported for compound 10.
Improved potency for compound 10 across an NCI-60 panel compared to compound 1.
Improved performance in overcoming ABC/βIII tubulin and Pgp-mediated resistance is reported for compound 10.
Documented Applications
Treating cancer in patients by administering Formula I and/or Formula II compounds, and pharmaceutically acceptable salts, via pharmaceutical compositions with therapeutically effective amounts.
Inhibiting multi-targeted receptor tyrosine kinases and/or microtubules in a patient using administered therapeutically effective amounts of Formula I or Formula II compounds, or pharmaceutically acceptable salts.
Assessment of RTK inhibition, including EGFR, VEGFR-2, and PDGFR-β, using phosphotyrosine ELISA cytoblot.
Cell proliferation and angiogenesis evaluation.
Tubulin-related activity evaluation, including microtubule depolymerization and colchicine binding/polymerization inhibition assays.
Antiproliferative activity and drug-resistance effects using resistant cell models and control paclitaxel.
GI50 evaluation across the NCI-60 panel for selected compounds including compounds 6, 7, and 10 versus compound 1.
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