Conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as anti-tumor agents
Inventors
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Assignees
Duquesne University of the Holy Spirit
Member
Nanomedicine Manufacturing Lab, Duquesne UniversityNANOMEDICINE MANUFACTURING LABORATORY
Nanomedicines produced at NML include colloidal nanosystems for molecular imaging (magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging), targeted and local drug delivery, and imaging-supported drug delivery and theranostic nanomedicines and biomaterials. These products can be delivered locally, parenterally, or implanted into body cavities or wounds. Nanotechnology-based therapeutics are typically presented with high costs and challenging quality control, representing critical barriers to future clinical translation. In contrast, the offeror NML efforts over the past decade produced cost-effective, robust, and scalable manufacturing methods for nanomedicines with a high level of quality control by utilizing Quality-by-Design (QbD) approaches. Specifically, the application of QbD to nanomedicine manufacturing and quality control led to several firsts: 1) the first imaging-supported pain nanomedicine for trauma and surgical pain; 2) the first oxygen carrier with embedded imaging agents for real-time in line tracking during organ/limb preservation; 3) the first successful longitudinal immunomonitoring in non-human primates and porcine models using clinical grade imagers; 4) demonstrated nerve injury recovery following trauma by local nanomedicine implantation in rodents. NML also designs and produces biocompatible and multi-drug delivery hydrogels and biomaterials for multitude of applications, from supporting neuroregeneration to local immunosuppression and wound healing. Furthermore, NML successfully scaled up their laboratory protocols to produce >2L of nanoparticles/batch and evaluate them in human limb trials for oxygen delivery. The work in these areas has been supported by USAF and CDMRP contracts, which are highly collaborative and involve partners across academia, industry and Government. NML is currently funded by CDMRP and ARPA H.
Founded in 1878, Duquesne University is consistently ranked among the nation's top Catholic universities for its award-winning faculty and horizon-expanding education. Research happens in all fields across the University, from the humanities and sciences to health-related fields and business. This research is supported by the federal and state governments, foundations, and corporate partners. Duquesne's Pittsburgh location connects researchers of all kinds to a knowledge economy powered by large tech, medical, energy, and industrial sectors.
NANOMEDICINE MANUFACTURING LABORATORY Nanomedicines produced at NML include colloidal nanosystems for molecular imaging (magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging), targeted and local drug delivery, and imaging-supported drug delivery and theranostic nanomedicines and biomaterials. These products can be delivered locally, parenterally, or implanted into body cavities or wounds. Nanotechnology-based therapeutics are typically presented with high costs and challenging quality control, representing critical barriers to future clinical translation. In contrast, the offeror NML efforts over the past decade produced cost-effective, robust, and scalable manufacturing methods for nanomedicines with a high level of quality control by utilizing Quality-by-Design (QbD) approaches. Specifically, the application of QbD to nanomedicine manufacturing and quality control led to several firsts: 1) the first imaging-supported pain nanomedicine for trauma and surgical pain; 2) the first oxygen carrier with embedded imaging agents for real-time in line tracking during organ/limb preservation; 3) the first successful longitudinal immunomonitoring in non-human primates and porcine models using clinical grade imagers; 4) demonstrated nerve injury recovery following trauma by local nanomedicine implantation in rodents. NML also designs and produces biocompatible and multi-drug delivery hydrogels and biomaterials for multitude of applications, from supporting neuroregeneration to local immunosuppression and wound healing. Furthermore, NML successfully scaled up their laboratory protocols to produce >2L of nanoparticles/batch and evaluate them in human limb trials for oxygen delivery. The work in these areas has been supported by USAF and CDMRP contracts, which are highly collaborative and involve partners across academia, industry and Government. NML is currently funded by CDMRP and ARPA H. Founded in 1878, Duquesne University is consistently ranked among the nation's top Catholic universities for its award-winning faculty and horizon-expanding education. Research happens in all fields across the University, from the humanities and sciences to health-related fields and business. This research is supported by the federal and state governments, foundations, and corporate partners. Duquesne's Pittsburgh location connects researchers of all kinds to a knowledge economy powered by large tech, medical, energy, and industrial sectors.
Publication Number
US-10189853-B2
Publication Date
2019-01-29
Expiration Date
2035-12-16
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.
Interested in licensing this patent?