Pyrimidine compounds and pyrimido indole compounds and methods of use
Inventors
Assignees
Duquesne University of the Holy Spirit
Publication Number
US-11111252-B2
Publication Date
2021-09-07
Expiration Date
2035-08-07
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention discloses a compound of the formula:and optionally comprising a pharmaceutically acceptable salt or hydrate 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 or hydrate thereof.
Core Innovation
The present invention provides substituted pyrimidine compounds and pyrimido indole compounds, optionally including pharmaceutically acceptable salts or hydrates, that are useful for treating a patient having cancer or a disease. These compounds are designed to function as anti-tubulin agents, dihydrofolate reductase (DHFR) inhibitors, and as single agent combination chemotherapeutic agents inhibiting VEGFR-2, PDGFR-β, and human thymidylate synthase (hTS). The compounds can be administered in a pharmaceutical composition, and methods of treating diseases using these compounds are disclosed.
The invention addresses the problem that many clinically used microtubule-binding anti-tubulin agents are rendered less effective due to resistance mechanisms such as the expression of β-III tubulin isotype and P-glycoprotein (P-gp) in tumors. These factors contribute to multidrug resistance, decreasing the efficacy of existing cancer chemotherapies. Additionally, current DHFR inhibitors lack selectivity and can cause toxicity, and separate administration of cytostatic and cytotoxic agents leads to pharmacokinetic challenges.
The core innovation comprises novel compounds with specific substitutions on pyrimidine and pyrimido indole scaffolds to overcome the limitations of current therapies. These compounds exhibit anti-tubulin activity (including against drug-resistant cell lines), selective DHFR inhibition for targeting opportunistic infections, and dual inhibition of RTKs and hTS for single agent combination chemotherapy. Pharmaceutical compositions and methods of use in treating cancer or diseases with these compounds are also described.
Claims Coverage
The patent contains three independent claims introducing two inventive features.
Pyrimidine compound of specified formula
A compound of the following formula: - The chemical structure is specified in the claims (see formula provided in the claim text). - The compound optionally comprises a pharmaceutically acceptable salt or hydrate. - The invention is defined by the presence of the specified core pyrimidine structure.
Pharmaceutical composition comprising the specified pyrimidine compound
A pharmaceutical composition containing a therapeutically effective amount of the compound of the specified formula: - The composition may further comprise at least one pharmaceutical carrier. - The structure of the compound corresponds to the core formula disclosed in the claims.
The claims focus on the structural definition of the pyrimidine compound and its use in pharmaceutical compositions with optional carriers.
Stated Advantages
The compounds are useful as anti-tubulin agents, dihydrofolate reductase inhibitors, and single agent combination chemotherapeutic agents that can inhibit VEGFR-2, PDGFR-β, and human thymidylate synthase (hTS).
The compounds can overcome resistance mediated by P-glycoprotein (P-gp) and βIII-tubulin, making them effective in multidrug resistant cancer cell lines.
These agents can function both as cytostatic (antiangiogenic) and cytotoxic (antifolate) agents, providing combination chemotherapy potential in a single agent and potentially improving pharmacokinetics and reducing drug-drug interactions.
Compounds exhibit greater selectivity for pjDHFR over hDHFR compared to existing drugs, potentially reducing toxicity.
Documented Applications
Treating a patient having cancer or a disease by administering an effective amount of the compound or its pharmaceutical composition.
Use as anti-tubulin agents for cancer chemotherapy, including against multidrug resistant cancer cell lines.
Treatment of opportunistic infections in immunocompromised patients via dihydrofolate reductase (DHFR) inhibition.
Use as single agent combination chemotherapeutic agents inhibiting VEGFR-2, PDGFR-β, and human thymidylate synthase (hTS).
Interested in licensing this patent?