Substituted bicyclic pyrimidine compounds with tubulin and multiple receptor inhibition
Inventors
Assignees
Duquesne University of the Holy Spirit
Publication Number
US-11572363-B2
Publication Date
2023-02-07
Expiration Date
2035-04-03
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Abstract
This invention provides substituted bicyclic pyrimidine compounds of the following formula: or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of a straight or a branched chain alkyl group having from 1 to 10 carbon atoms, wherein the alkyl group is partially or completely saturated. Methods of treating a patient diagnosed with cancer are disclosed comprising administering to the patient a therapeutically effective amount of the substituted bicyclic pyrimidine compounds, or a pharmaceutically acceptable salt thereof.
Core Innovation
This invention provides substituted bicyclic pyrimidine compounds, specifically including 7-Benzyl-4-chloro-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine and related analogs, as single agents that possess both cytotoxic and antiangiogenic properties. The cytotoxic activity is achieved through tubulin inhibition, while the antiangiogenic activity is mediated by inhibition of receptor tyrosine kinases (RTKs) such as VEGFR2, PDGFRβ, and EGFR. These compounds and their pharmaceutically acceptable salts, solvates, or hydrates are further incorporated into pharmaceutical compositions.
The problem addressed by the invention is the limited effectiveness of current cancer therapies due to tumor resistance mechanisms, such as expression of P-glycoprotein and βIII-tubulin, and the pharmacokinetic challenges, drug-drug interactions, and overlapping toxicities arising from the administration of multiple cancer drugs. Existing antitumor agents that interfere with microtubules are important but face barriers from resistance, while antiangiogenic agents typically provide only cytostatic effects.
The innovation combines both cytotoxic and multi-target antiangiogenic activity in a single compound, allowing these agents to overcome tumor resistance associated with both P-glycoprotein and βIII-tubulin. The patent also describes methods of treating patients diagnosed with cancer by administering therapeutically effective amounts of the disclosed compounds or pharmaceutical compositions, aiming to provide effective tumor size reduction, cytotoxicity, antiangiogenic effects, and minimize toxicity and resistance compared to combination therapies.
Claims Coverage
There are three independent inventive features described in the patent claims.
7-Benzyl-4-chloro-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine compound
A compound that is 7-Benzyl-4-chloro-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine, or a pharmaceutically acceptable salt thereof. - The inventive feature centers on this specific substituted bicyclic pyrimidine as a chemical entity. - The claim covers both the base compound and its pharmaceutically acceptable salts.
Method of treating cancer with substituted bicyclic pyrimidine compounds
A method of treating a patient diagnosed with cancer comprising administering to the patient a therapeutically effective amount of a compound of the formula: - The formula includes bicyclic pyrimidine derivatives where R is H or a straight or branched chain alkyl group having from 1 to 10 carbon atoms, either partially or completely saturated. - The method encompasses administering these compounds, or their pharmaceutically acceptable salts, for the treatment of cancer.
Method of treating cancer with selected substituted bicyclic pyrimidine analogs
A method of treating a patient diagnosed with cancer comprising administering to the patient a therapeutically effective amount of selected compounds: - The compounds covered are 7-Benzyl-4-chloro-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine and 7-Benzyl-N-(4-methoxyphenyl)-N,2,5-trimethyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof. - The inventive feature is the use of these specific analogs (and their salts) in a method for treating cancer.
The inventive features cover the substituted bicyclic pyrimidine compounds and methods of treating cancer using these specific compounds and analogs, emphasizing both the chemical entities and their therapeutic applications.
Stated Advantages
The compounds act as single agents with both antiangiogenic and cytotoxic activities.
They circumvent pharmacokinetic problems associated with delivering multiple cancer agents.
These compounds avoid drug-drug interactions that can occur with combination therapies.
They alleviate toxicity by allowing therapy at lower doses and are devoid of overlapping toxicities.
These agents delay or prevent tumor cell resistance, overcoming mechanisms such as P-glycoprotein and βIII-tubulin expression.
Documented Applications
Treatment of patients diagnosed with cancer by administering a therapeutically effective amount of substituted bicyclic pyrimidine compounds or their pharmaceutically acceptable salts, hydrates, and solvates.
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