Bicyclic and tricyclic pyrimidine tyrosine kinase inhibitors with antitubulin activity and methods of treating a patient
Inventors
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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-11618758-B2
Publication Date
2023-04-04
Expiration Date
2032-02-02
Abstract
Bicyclic and tricyclic pyrimidine tyrosine kinase inhibitors with antitubulin activity are provided in the present invention. The compositions of the present invention possess dual activity in a single agent of potent vascular endothelial growth factor receptor inhibitory activity as well as antitubulin activity. Water soluble salts of these compositions are also described. Methods of treating a patient having cancer, macular degeneration, and arthritis with the compositions and salts thereof of the present invention are disclosed.
Core Innovation
The present invention provides bicyclic and tricyclic pyrimidine tyrosine kinase inhibitors that also exhibit antitubulin activity. These compositions display dual activity within a single agent: specifically, potent vascular endothelial growth factor receptor (VEGFR) inhibitory activity along with antitubulin activity. The invention encompasses both these dual-acting molecules and their water-soluble salts.
This dual-functionality addresses several unmet needs in oncology and related fields. Traditional antitubulin agents, such as taxanes and Vinca alkaloids, face significant challenges, including multidrug resistance (notably P-glycoprotein (Pgp) and βIII-tubulin mediated resistance), poor water solubility, and limitations in combination therapy due to pharmacokinetic disadvantages. Furthermore, conventional VEGFR inhibitors are largely cytostatic and offer limited tumor eradication when used alone.
The compositions of the present invention, by combining VEGFR2 inhibition and antitubulin cytotoxicity in a single molecule, offer the potential to overcome both Pgp and βIII-tubulin resistance, circumvent solubility issues via water-soluble salt forms, and provide more efficient cancer treatment by temporally and spatially synchronizing antiangiogenic and cytotoxic actions. These agents are designed to treat cancer, macular degeneration, and arthritis by leveraging both antiangiogenic and cytotoxic mechanisms within one compound.
Claims Coverage
There are three independent claims in this patent, each focusing on a key inventive feature.
Compound of Formula 8
A compound of Formula 8, wherein R is selected from the group consisting of H, NH2, and a straight chain or branched chain alkyl group having from 1 to 10 carbon atoms; optionally comprising stereochemical conformations thereof; and optionally comprising a pharmaceutically acceptable salt thereof.
Pharmaceutical composition comprising a compound of Formula 8
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 8, as defined, which may optionally include stereochemical conformations and pharmaceutically acceptable salts thereof.
Pharmaceutical composition with compound of Formula 8 and carrier
A pharmaceutical composition containing a therapeutically effective amount of a compound of Formula 8 in combination with at least one pharmaceutically acceptable carrier.
The independent claims cover the novel compound of Formula 8, its use in pharmaceutical compositions, and pharmaceutical compositions that include a pharmaceutically acceptable carrier.
Stated Advantages
The compositions possess dual activity—potent VEGFR2 inhibition and antitubulin cytotoxicity—in a single agent.
They provide highly water-soluble salts, addressing solubility issues associated with other antimitotic agents.
The compositions are designed to overcome P-glycoprotein (Pgp) and βIII-tubulin mediated drug resistance.
Single-agent compositions mitigate pharmacokinetic disadvantages, overlapping toxicities, lack of patient compliance, and high costs seen with combination therapies involving separate VEGFR2 inhibitors and antitubulins.
These agents exhibit broad and potent cytotoxicity across a wide panel of tumor cell lines, including resistant types.
They synchronize cytostatic antiangiogenic and cytotoxic effects, enhancing efficiency of tumor treatment.
Documented Applications
Methods of treating a patient with cancer by administering an effective amount of the described compositions or salts thereof.
Methods of treating a patient with macular degeneration by administering the compositions or salts thereof.
Methods of treating a patient with arthritis using the compositions or their water-soluble salts.
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