Conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as anti-tumor agents
Inventors
Assignees
Duquesne University of the Holy Spirit
Publication Number
US-10189853-B2
Publication Date
2019-01-29
Expiration Date
2035-12-16
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Abstract
The present invention provides conformationally restricted 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidine compounds and pharmaceutical compositions comprising these compounds. Preferably, the compounds exhibit dual inhibition of microtubule assembly and receptor tyrosine kinases. Methods of treating cancer comprising administering a therapeutically effective amount of at least one conformationally restricted 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidine compound to a patient is disclosed.
Core Innovation
The invention provides conformationally restricted 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidine compounds, their pharmaceutical compositions, and methods of using these compounds. These compounds are designed to exhibit dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), addressing the need for agents that can act simultaneously at multiple targets relevant to cancer treatment. The compounds are structurally defined by introducing conformational restrictions, either by incorporating bulky groups or by locking bonds into rings, to achieve optimized bioactive conformations for their dual inhibitory activities.
The problem being addressed is the need for more effective cancer therapeutics that can overcome the limitations of existing treatments, such as pathway redundancy, tumor heterogeneity, and multidrug resistance, which can limit the efficacy of monotherapies and combination therapies using separate drugs. Existing microtubule targeting agents and RTK inhibitors act on separate mechanisms and may face resistance mechanisms including P-glycoprotein (Pgp) and βIII tubulin-mediated drug resistance. There is a lack of approved colchicine site agents for anticancer therapy despite their potential to overcome such resistance.
This invention discloses compounds that, through conformational restriction strategies, can efficiently inhibit both microtubule assembly and multiple RTKs, such as EGFR, VEGFR2, and PDGFR-β. Specific embodiments include compounds of Formula I and Formula II, which show potent in vitro and in vivo antitumor activity, effectively inhibit tumor cell proliferation, and maintain or improve inhibitory activity even in drug-resistant cancer cell models. The invention also includes pharmaceutical compositions containing these compounds and methods of treating cancer and other proliferative diseases by administering a therapeutically effective amount to patients.
Claims Coverage
There are three independent claims, each covering a distinct inventive feature related to chemical compounds and their therapeutic use.
Compound of Formula II or pharmaceutically acceptable salt thereof
A compound as represented by Formula II, or a pharmaceutically acceptable salt thereof, where the substituent Ar is selected from a specified group provided in the patent. This feature focuses on conformationally restricted bicyclic furo[2,3-d]pyrimidine compounds with defined substitutions, which possess dual activities against receptor tyrosine kinases and microtubules.
Method of treating cancer using compound of Formula II
A method for treating a patient having cancer by administering a therapeutically effective amount of at least one compound of Formula II, or a pharmaceutically acceptable salt thereof. The compound is as described and claimed in terms of its specific chemical structure and activity.
Method of treating cancer using compound of Formula I
A method for treating a patient having cancer by administering a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof. The structural details of Formula I are provided in the specification, and the method is directed at using these conformationally restricted compounds with dual inhibitory activity.
The claims broadly cover the conformationally restricted bicyclic furo[2,3-d]pyrimidine compounds of specified formulas and their pharmaceutically acceptable salts, as well as methods for treating cancer by administering these compounds.
Stated Advantages
The compounds exhibit dual inhibition of microtubule assembly and receptor tyrosine kinases, allowing for single-agent combination chemotherapy potential.
The conformational restriction in the compounds can increase potency against both tubulin and EGFR without loss of activity against VEGFR2 and PDGFR-β.
Many of the compounds are effective in overcoming multidrug resistance mechanisms, including P-glycoprotein (Pgp)- and βIII tubulin-mediated resistance.
These compounds can act simultaneously at two or more distinct cancer targets, potentially preventing or delaying emergence of resistance, and avoiding drug-drug interactions, pharmacokinetic problems, and overlapping toxicities associated with using multiple agents.
Documented Applications
Treatment of cancer in patients, including administration to humans or animals diagnosed with cancer.
Use as dual multi-targeted receptor tyrosine kinase inhibitors and antimitotic agents in cancer chemotherapy.
Treatment of proliferative diseases and/or disorders, including leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.
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