Cyclopenta[d]pyrimidines and substituted cyclopenta[d]pyrimidines as antitubulin and microtubule targeting agents, monocyclic pyrimidines as tubulin inhibitors, and pyrrolopyrimidines as targeted antifolates and tubulin and multiple receptor tyrosine kinase inhibition and antitumor agents
Inventors
Assignees
Duquesne University of the Holy Spirit
Publication Number
US-10239880-B2
Publication Date
2019-03-26
Expiration Date
2036-04-15
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Abstract
The present invention provides a compound of Formula I, and salts thereof, and a pharmaceutical composition comprising a compound of Formula I: wherein R1 is selected from the group consisting of and R2 is an alkyl group having from one to ten carbon atoms, or wherein R2 is selected from the group consisting of R1 is an alkyl group having from one to ten carbon atoms; and R is H, or an alkyl group having from one to ten carbon atoms, and R3 is H, an alkyl group having from one to ten carbon atoms, or a halogen. Preferably the compound of Formula V includes wherein R3 is a halogen, and most preferably wherein the halogen is chlorine. Methods of treating a patient with cancer with these compounds are also provided.
Core Innovation
The present invention provides new pyrimidine-based compounds, including cyclopenta[d]pyrimidines, substituted cyclopenta[d]pyrimidines, monocyclic pyrimidines, and pyrrolopyrimidines, and their pharmaceutically acceptable salts, as anti-cancer agents. These compounds are characterized by specific chemical formulas (Formula I–VII), defined substituents at key positions, and include embodiments with preferred substituents such as alkyl, halogen (with preference for chlorine), and methyl groups. The invention also encompasses pharmaceutical compositions containing these compounds.
The problem addressed is the need for single-agent therapeutics in cancer treatment that combine both cytotoxic and targeted antiangiogenic activities. Existing cytotoxic and targeted agents, when combined as separate drugs, can interact unpredictably and present challenges in synchronizing mechanisms of action and drug delivery. Additionally, there is a lack of effective colchicine site microtubule inhibitors in clinical practice and the prevalence of drug resistance due to factors like P-glycoprotein and β-III tubulin. The invention aims to overcome these limitations by providing compounds capable of dual inhibition: disrupting microtubules (antitubulin activity) and inhibiting multiple receptor tyrosine kinases (RTKs).
These compounds are shown preclinically to induce microtubule depolymerization and inhibit RTKs such as VEGFR-2, EGFR, and PDGFR-β, with potencies comparable to known clinical drugs. They are also effective in cell lines overexpressing P-glycoprotein and βIII-tubulin, overcoming resistance pathways. Embodiments are disclosed for treating cancer in a patient by administering a therapeutically effective amount of one or more of the claimed compounds or their pharmaceutical compositions.
Claims Coverage
There are two primary independent inventive features covered by the claims: (1) the compound of Formula I and its salts defined by specific substituents, and (2) a pharmaceutical composition comprising a compound of Formula I or its salt with a pharmaceutically acceptable excipient.
Compound of Formula I and its salts with defined substituents
The invention provides a compound of Formula I and its salts, wherein: - R1 is selected from specified groups, - R2 is an alkyl group having from one to ten carbon atoms or other defined groups, - R3 is H, an alkyl group having from one to ten carbon atoms, or a halogen, - R is H or an alkyl group having from one to ten carbon atoms. There are specific preferences where R1 or R2 is methyl, and R3 is a halogen (most preferably chlorine), covering multiple specific embodiments and isomers as explicitly listed in the claims.
Pharmaceutical composition comprising a compound of Formula I or its salt
The invention further claims a pharmaceutical composition comprising: - A compound of Formula I or a pharmaceutically acceptable salt thereof, - At least one pharmaceutically acceptable excipient or carrier. The composition may incorporate any of the claimed versions of Formula I and its salts, with substituents as described above.
The claims broadly protect new cyclopenta[d]pyrimidine-based compounds with specific substituents and their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds.
Stated Advantages
The compounds possess intrinsic dual action as both antitubulin (microtubule-depolymerizing) agents and receptor tyrosine kinase (RTK) inhibitors, synchronizing two drug mechanisms in a single agent.
Compared to combination chemotherapy, the single-agent compounds potentially simplify pharmacokinetics and avoid challenges of separate drug interactions.
The compounds are effective against cell lines overexpressing P-glycoprotein and βIII-tubulin, thereby overcoming established multidrug resistance pathways.
In preclinical models, certain compounds demonstrate statistically significant antitumor effects with acceptable toxicity profiles, distinguishing them from existing therapies.
Water-soluble salts of these compounds can be formulated into oral dosage forms, providing orally administered active antitumor agents.
Documented Applications
Methods of treating a patient with cancer by administering a therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, or VII, or their pharmaceutical compositions.
Treatment of leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, cervical cancer, renal cancer, prostate cancer, breast cancer, and brain cancer.
Use as antitumor agents targeting microtubule dynamics and multiple receptor tyrosine kinases, potentially including resistant tumor types overexpressing P-glycoprotein and/or βIII-tubulin.
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