Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
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-11091500-B2
Publication Date
2021-08-17
Expiration Date
2027-08-27
Abstract
The present invention provides tricyclic compounds, and pharmaceutically acceptable salts thereof, having antimitotic activity, anti-multidrug resistance activity, for example P-glycoprotein inhibition, and antitumor activity, and which inhibit paclitaxel sensitive and resistant tumor cells. Also provided are methods of utilizing these compounds for treating tumor cells and inhibiting mitosis of cancerous cells.
Core Innovation
The present invention provides tricyclic compounds, and pharmaceutically acceptable salts thereof, exhibiting antimitotic activity, anti-multidrug resistance activity, including inhibition of P-glycoprotein, and antitumor activity. These compounds are effective in inhibiting both paclitaxel-sensitive and resistant tumor cells and can be used as single-agent therapies or in combination with other chemotherapeutic drugs to treat cancer.
The invention addresses the problem of chemotherapy failure due to multidrug resistance (MDR), often caused by the overexpression of efflux transporters such as P-glycoprotein (Pgp) in tumors. Existing antimitotic agents, while effective, frequently face limitations including drug resistance, additive toxicities, solubility issues, and limited selectivity, highlighting the need for new agents with combined antimitotic, anti-MDR, and antitumor activities in a single molecular structure.
Through the design of novel tricyclic heteroaromatic compounds represented by Formula I and Formula II, the invention delivers single molecules that combine the desired biological activities and overcome significant drawbacks of current chemotherapeutic regimens. These compounds can be further formulated as water-soluble acid salts, making them amenable for oral dosage forms, and are shown to effectively inhibit the mitosis and growth of diverse cancer cell lines, including those resistant due to P-glycoprotein expression.
Claims Coverage
The patent contains one independent claim focusing on the medicinal use of specific tricyclic compounds with defined structural features and properties.
Method of treating a patient diagnosed with cancer using a compound of Formula I
The inventive feature is administering to a patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, where: - The compound is a tricyclic compound as defined by Formula I in the specification. - The structure permits both B and C rings to be completely or partially saturated or unsaturated with respect to specified bonds, and accommodates different substitutions at positions on the C ring. - R1 and R2 are independently hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, aromatic, or heteroaromatic and their substituted analogs, with explicit rules for possible substituents. - R3 and R4 are each independently defined with various options, including hydrogen, halogen, alkyl, NH2, NHR7, NR7R8, OH, OR, SH, SR, and, for R4, also NR6R7, SR6, OR6, and CHR6R7 under further restrictions. - X is selected from NH, NR5, oxygen, sulfur, CR5, or CR5R10, where R5 and R10 are further specified. - Y is selected from nitrogen, oxygen, sulfur, or CR6 with associated restrictions described in the claim. - The claim covers all stereoisomers, racemic and/or diastereoisomeric mixtures, and includes pharmaceutically acceptable salts, prodrugs, solvates, or hydrates of the compound.
The claim coverage is centered on the medicinal application of a structurally defined class of tricyclic compounds for treating cancer, specifying in detail the molecular variations, allowable substituents, and the inclusion of all relevant chemical forms.
Stated Advantages
Provides single compounds with combined antimitotic, anti-multidrug resistance, and antitumor activity, overcoming the need to use multiple drugs and circumventing associated drawbacks such as drug transport issues, increased toxicity, drug resistance, and higher costs.
Effectively inhibits mitosis of various tumor cells, including those that are sensitive or resistant to paclitaxel and those expressing P-glycoprotein-related multidrug resistance.
Water-soluble acid salts of the compounds can be prepared, facilitating oral dosage formulations and overcoming water solubility problems associated with existing antimitotic agents.
The compounds demonstrate cytotoxic activity toward a wide range of human cancer cell lines and maintain efficacy against P-glycoprotein overexpressing resistant tumor cells.
Documented Applications
Treating cancer in patients, including cancers such as leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.
Inhibiting mitosis of live cancerous cells through the administration of a mitotic inhibitory amount of the described tricyclic compounds or their pharmaceutically acceptable derivatives.
Formulating oral pharmaceutical compositions of the compounds as water-soluble salts to provide orally administered active antitumor agents.
Using the compounds as part of combination therapy with other chemotherapeutic agents, such as paclitaxel, docetaxel, vinca alkaloids, colchicines, colcemid, cisplatin, and nocadazol, to enhance therapeutic efficacy and reverse multidrug resistance.
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