Substituted pyrimidine compounds and methods of use and manufacture
Inventors
Gangjee, Aleem • Matherly, Larry H.
Assignees
Wayne State University • Duquesne University of the Holy Spirit
Publication Number
US-10167287-B2
Publication Date
2019-01-01
Expiration Date
2035-08-07
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Abstract
This invention provides substituted pyrimidine compounds having the formula: wherein X is absent, CH2, S, or O, and R is an alkyl group having from one to ten carbon atoms, and optionally salts, hydrates, or solvates thereof, that are useful in treating a patient having a disease or cancer. The compounds of this invention are useful as multi-enzyme antifolates selectively targeting the folate receptor (FR). Further, a method of making 5- and 6-substituted cyclopenta[d]pyrimidine for nonclassical and classical antifolates as TS and DHFR inhibitors is provided.
Core Innovation
This invention provides substituted pyrimidine compounds, specifically multi-enzyme antifolates that selectively target the folate receptor (FR). These compounds are of the general formula wherein X is absent, CH2, S, or O, and R is an alkyl group having from one to ten carbon atoms, and include their salts, hydrates, or solvates. The invention also includes methods for synthesizing 5- and 6-substituted cyclopenta[d]pyrimidines, which may serve as nonclassical or classical antifolates and act as inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DHFR).
The problem addressed by the invention is the dose-limiting toxicity of conventional antifolates that are taken up by the ubiquitously expressed reduced folate carrier (RFC). Because RFC is present in both normal tissues and tumors, current antifolate drugs lack tumor specificity, leading to toxic effects. Additionally, tumor resistance can develop through reliance on single-enzyme inhibition. Therefore, there is a need for antifolates that are selectively transported into tumor cells via transporters like folate receptor (FR) or proton-coupled folate transporter (PCFT), which have limited expression in normal tissues, and that inhibit multiple enzymes involved in purine and pyrimidine biosynthesis.
The compounds of this invention, including 5- and 6-substituted cyclopenta[d]pyrimidines, are designed with specific structural modifications, such as heteroatom replacements and varied linker lengths, to enable selective uptake by tumor-expressed FR and targeted inhibition of multiple folate-utilizing enzymes. The invention also describes novel methods for synthesizing such compounds, providing handles for further functionalization and versatility in drug design. These compounds and their pharmaceutical compositions offer utility in treating diseases, including cancer, by selectively targeting tumor cells.
Claims Coverage
The patent includes one independent claim detailing the inventive features related to a method of treating specific cancers with the described compounds.
Method of treating cancer with a specified pyrimidine compound
A method comprising administering to a patient having cancer selected from the group consisting of Malignant Pleural Mesothelioma and Non-Small Cell Lung Cancer an effective amount of a compound of a specified formula, wherein: - The compound is a substituted pyrimidine wherein X is absent, CH2, S, or O, and R is an alkyl group having from one to ten carbon atoms; - The method covers compounds optionally in the form of salts, hydrates, or solvates; - The method is limited to therapeutic treatment of said cancers by administration of these compounds.
The independent claim broadly covers the therapeutic application of specific substituted pyrimidine compounds for treating particular cancers by administering an effective amount of the compound to a patient.
Stated Advantages
The compounds are selectively taken up by tumor cells via folate receptor (FR) or proton-coupled folate transporter (PCFT), providing targeted therapy with potentially reduced toxicity to normal tissues.
The compounds are designed as multi-enzyme antifolates, inhibiting multiple enzymes in purine and pyrimidine biosynthesis pathways, thereby addressing tumor resistance issues.
The invention provides a novel and viable synthetic methodology for producing 5- and 6-substituted cyclopenta[d]pyrimidines, offering versatile handles for further pharmacological modification.
Documented Applications
Treatment of cancer, specifically including Malignant Pleural Mesothelioma and Non-Small Cell Lung Cancer, by administration of the disclosed compounds.
Use as multi-enzyme antifolates for inhibition of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) in cancer therapy.
Utility as pharmaceutical compositions comprising the compounds for administration via various routes for treating diseases, including cancer.
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