Pyrimidine compounds and pyrimido indole compounds and methods of use
Inventors
Assignees
Duquesne Unversity Of Holy Spirit • Duquesne University of the Holy Spirit
Publication Number
US-10233194-B2
Publication Date
2019-03-19
Expiration Date
2035-08-07
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Abstract
The present invention discloses a compound comprising the formula: wherein R is hydrogen or an alkyl group having from one to ten carbon atoms, or a compound of the formula wherein the S is replaced by CH2, and optionally comprising a pharmaceutically acceptable salt, hydrate, or solvate thereof. A method of treating a patient having cancer or a disease comprising administering to a patient an effective amount of the compound or pharmaceutically acceptable salt, hydrate, or solvate thereof.
Core Innovation
The present invention discloses substituted pyrimidine compounds and pyrimido indole compounds, including their pharmaceutically acceptable salts, hydrates, or solvates. These compounds are useful for treating patients having cancer or certain diseases by administering an effective amount of the compound or its salt, hydrate, or solvate. The invention also provides methods for such treatment, as well as pharmaceutical compositions containing these compounds.
The invention addresses the challenge of drug resistance encountered in cancer treatment. Microtubule binding agents, commonly used in chemotherapy, can become less effective due to the expression of the β-III tubulin isotype and P-glycoprotein (P-gp) in tumors, which contribute to clinical resistance by lowering intracellular drug accumulation. Moreover, current inhibitors for targets such as VEGFR-2, PDGFR-β, human thymidylate synthase (hTS), and dihydrofolate reductase (DHFR) have limitations including lack of selectivity and adverse effects.
To solve these problems, the invention introduces novel compounds that function as anti-tubulin agents, DHFR inhibitors, and single agent combination chemotherapeutic agents inhibiting VEGFR-2, PDGFR-β, and hTS. The invention further provides methods and compositions that harness these compounds' ability to overcome resistance mediated by P-gp and β-III tubulin overexpression. In particular, certain embodiments feature structures that are designed to address species selectivity and reduce undesirable interactions, allowing for effective treatment against multidrug-resistant cancers and opportunistic infections.
Claims Coverage
The patent contains two independent claims covering distinct inventive features: the novel compound itself and a pharmaceutical composition containing the compound.
Novel pyrimidine or pyrimido indole compound
A compound comprising the specific formula as described, in which R is hydrogen or an alkyl group having from one to ten carbon atoms, or where the S is replaced by CH₂, and optionally comprising a pharmaceutically acceptable salt, hydrate, or solvate thereof.
Pharmaceutical composition containing the novel compound
A pharmaceutical composition comprising a therapeutically effective amount of the described compound (where R is hydrogen or an alkyl group having from one to ten carbon atoms, or where S is replaced by CH₂), and optionally comprising a pharmaceutically acceptable salt, hydrate, or solvate thereof.
The inventive features define the scope of protection for both the novel class of pyrimidine or pyrimido indole compounds and the related pharmaceutical compositions for therapeutic use.
Stated Advantages
The compounds circumvent resistance mediated by P-glycoprotein (P-gp) and β-III tubulin, maintaining activity in multidrug-resistant cancer cell lines.
Certain compounds show improved potency and selectivity for targeted enzymes, such as dihydrofolate reductase from Pneumocystis jirovecii, over human DHFR.
Single agent combination chemotherapeutic potential enables simultaneous inhibition of multiple targets (VEGFR-2, PDGFR-β, hTS), addressing cytotoxic and antiangiogenic mechanisms.
Reduction in the need for co-administered drugs (e.g., sulfonamide or leucovorin) due to enhanced potency and selectivity.
Potential for decreased drug–drug interactions, toxicity, and improved patient compliance due to single agent design.
Documented Applications
Treatment of patients having cancer by administering an effective amount of the disclosed compound or its salt, hydrate, or solvate.
Use as anti-tubulin agents to inhibit microtubule polymerization and disrupt mitosis in cancer cells.
Use as dihydrofolate reductase (DHFR) inhibitors, including selective inhibition of Pneumocystis jirovecii DHFR for treatment of opportunistic infections.
Use as single agent combination chemotherapeutic agents inhibiting VEGFR-2, PDGFR-β, and human thymidylate synthase (hTS), thereby providing both antiangiogenic and cytotoxic effects.
Treatment of multidrug resistant cancer and overcoming resistance due to P-gp or β-III tubulin overexpression.
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