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 inhibitor and antitumor agents
Inventors
Assignees
Duquesne University of the Holy Spirit
Publication Number
US-11124520-B2
Publication Date
2021-09-21
Expiration Date
2036-04-15
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Abstract
The present invention provides a compound of Formula III, and salts thereof, and a pharmaceutical composition comprising a compound of Formula III: wherein R1 is selected from the group consisting of: wherein R2 is H or an alkyl group having from one to ten carbon atoms; R3 is H or an alkyl group having from one to ten carbon atoms; and R4 is H or an alkyl group having from one to ten carbon atoms. Methods of treating a patient with cancer with these compounds are also provided.
Core Innovation
The present invention provides compounds of Formula III, their salts, and pharmaceutical compositions comprising these compounds. The invention further discloses the preparation and use of these compounds for treating a patient with cancer. These compounds are described as having specific structural variations, where R1 is selected from certain groups, and R2, R3, and R4 are H or alkyl groups having from one to ten carbon atoms.
The problem addressed by this invention is the limitation of current cancer therapies that often require combinations of targeted therapies and cytotoxic agents, which can create challenges due to biological redundancy, lack of synchronization in drug mechanisms, and pharmacokinetic difficulties. Agents that disrupt microtubule dynamics, especially those binding at the colchicine site on tubulin, are effective in cancer therapy; however, resistance mechanisms such as P-glycoprotein and β-III tubulin expression limit their efficacy. Furthermore, the need for improved anticancer agents that can both target microtubules and inhibit receptor tyrosine kinases (RTKs) is identified.
The invention solves this problem by introducing a new class of compounds, including cyclopenta[d]pyrimidines, substituted cyclopenta[d]pyrimidines, monocyclic pyrimidines, and pyrrolopyrimidines. These compounds are designed to have dual activity as antitubulin agents (targeting the colchicine site) and as inhibitors of multiple RTKs, providing both cytotoxic and targeted antiangiogenic effects. The compounds are shown to initiate microtubule depolymerization and inhibit RTKs involved in angiogenesis, offering synchronized mechanisms of anticancer action in a single chemical entity.
Claims Coverage
The patent includes five independent inventive features regarding novel compounds, their preferred substituents, pharmaceutical compositions, and specific variations as described in the claims.
Compound of Formula III and its salts
A compound defined as Formula III, in which R1 is selected from specified groups, R2 is H or an alkyl group having from one to ten carbon atoms, R3 is H or an alkyl group having from one to ten carbon atoms, and R4 is H or an alkyl group having from one to ten carbon atoms, including the salts of such compounds.
Preferred compound of Formula III with R3 as methyl
A compound of Formula III and its salts wherein R3 is a methyl group, representing a preferred subset of the compounds.
Pharmaceutical composition comprising a compound of Formula III
A pharmaceutical composition containing a compound of Formula III and a pharmaceutically acceptable salt thereof, enabling formulation for cancer treatment.
Pharmaceutical composition with a compound of Formula III where R3 is methyl
A pharmaceutical composition comprising a compound of Formula III, and a pharmaceutically acceptable salt thereof, wherein R3 is a methyl group.
Compound of Formula IV and its salts
A compound of Formula IV and its salts, defined by R being selected from specified groups as represented in the patent.
The inventive features cover novel compounds of Formula III and IV (and their salts), with specific focus on preferred substituents, as well as pharmaceutical compositions comprising these compounds, particularly emphasizing compounds where R3 is a methyl group.
Stated Advantages
The compounds provide dual activity as antitubulin agents and receptor tyrosine kinase inhibitors, enabling synchronized mechanisms of anti-cancer action within a single agent.
Single agents acting on multiple targets retain the advantages of combination therapies while avoiding synchronization and pharmacokinetic challenges associated with separate drugs.
Compounds may overcome drug resistance mechanisms, including P-glycoprotein and β-III tubulin mediated resistance.
Water-soluble salts of the compounds can be formulated for oral administration, providing orally administered active antitumor agents.
Documented Applications
Methods of treating a patient with cancer using the compounds, salts, or pharmaceutical compositions described in the invention.
Treatment of various cancers, including without limitation 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.
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