Tricyclic compounds having cytostatic and/or cytotoxic 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-10208051-B2
Publication Date
2019-02-19
Expiration Date
2027-08-27
Abstract
The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.
Core Innovation
The invention provides tricyclic compounds that possess both cytostatic and cytotoxic activity in a single molecule by inhibiting receptor tyrosine kinase(s) (RTKs), dihydrofolate reductase (DHFR), thymidylate synthase (TS), and/or dihydroorotate dehydrogenase (DHODH). These compounds aim to offer anti-angiogenic and anti-tumor effects and are described by specific chemical formulas (formula I and formula II) with detailed substitution patterns and variations.
The underlying problem addressed is that current agents targeting angiogenesis, primarily RTK inhibitors, are only cytostatic and stop tumor growth without killing tumor cells. Existing treatments often require combination therapies of cytostatic and cytotoxic agents, which leads to issues such as difficulties in drug transport to targets, additive or synergistic toxicities, development of drug resistance, and increased cost and complexity.
By integrating both cytostatic (anti-angiogenic via RTK inhibition) and cytotoxic activities (via DHFR, TS, or DHODH inhibition) into a single compound, the invention circumvents drawbacks associated with multi-drug therapies. Methods of using such compounds for inhibiting these enzymes and treating tumor cells and proliferative diseases are provided, along with detailed synthetic methods and evidence of efficacy in vitro and in animal models.
Claims Coverage
There is one independent claim that is focused on the structural definition of a compound of formula II.
Tricyclic compound of formula II with specific substituents
The inventive feature is a compound of formula II, defined by: - B and C rings that may be completely or partially saturated or unsaturated with respect to certain bonds. - The C ring may contain an N or substituted N depending on its saturation level, where substitutions may be at R1, R2, and R3. - X and/or Y independently selected from N, NH, O, S, or C. - P defined as NR4, O, S, or CR4R5, with R4 and R5 as lower alkyl, alkene, or alkyne. - R1 and R2 independently selected from H, alkyl, cycloalkyl (6 or fewer carbons), alkene, alkyne, carbonyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl (including benzene, pyridine, biphenyl, bipyridine, quinazoline, isoquinoline, alkylaryl, alkylheteroaryl, substituted alkylaryl, substituted alkylheteroaryl, or a substituted or unsubstituted saturated heterocyclic having 6 or fewer atoms). - Z selected from S, O, NR5, CR6R7, S—C, C—S, O—CR6, CR6—O, NR6—C, C—NR6, CR6—NR7, or CR6R7, with R5, R6, R7 as H or lower alkyl, alkene, alkyne, or cycloalkyl having 6 or fewer carbon atoms. - Z may be attached to the C ring at positions 5, 6, 7, or 8, in same or different forms, and at multiple positions. Z may be omitted, and R3 may be directly attached to positions 5, 6, 7, or 8. - Stereoisomeric forms, including racemic and diastereoisomeric mixtures, are included when P=C and R6/R7 are different, leading to chirality. - R3 further defined as H, alkyl, cycloalkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, substituted saturated/unsaturated alkylheteroaryl/alkylheterocyclic, p-, m-, o-benzoyl-L-glutamate, or 2,5-/2,4-thienoyl-L-glutamate, and the benzene or thiophene ring may or may not have further substitutions, including mono-, bi-, or tricyclic aryl or heteroaryl, ring substitutions such as biphenyl, bipyridyl, phenyl-pyridyl or fused systems such as quinoline, naphthyl, and relevant substituted versions.
The claims cover a class of tricyclic compounds with a broad range of substituents as defined by formula II, with options for further specification and stereochemistry, focused on the structural characteristics enabling the dual cytostatic and cytotoxic activities.
Stated Advantages
Single compounds provide both cytostatic and cytotoxic activity, reducing the need for multiple drug combinations.
Circumvents drawbacks associated with drug transport to targets when using two or more separate agents.
Reduces or eliminates additive or synergistic toxicities seen with combined agents.
May lessen the resistance of cancer cells to a particular drug.
Reduces costs associated with the use of two or more drugs.
Documented Applications
Treatment of tumor cells in 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.
Treatment of other proliferative diseases and disorders such as macular degeneration and retinopathies.
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