Monocyclic thieno, pyrido, and pyrrolo pyrimidine compounds and methods of use and manufacture of same
Inventors
Assignees
Duquesne University of the Holy Spirit
Publication Number
US-11078214-B2
Publication Date
2021-08-03
Expiration Date
2036-08-17
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Abstract
The present invention provides a compound of Formula XXVII: wherein X is CH2 or O, and R1 is H or CH3; or a salt or a hydrate of the compound, and further provides a pharmaceutical composition comprising the compound of Formula XXVII and one or more acceptable pharmaceutical carriers. A method of treating a patient having cancer comprising administering a therapeutically effective amount of a compound of Formula XXVII, or a pharmaceutical composition comprising a compound of Formula XXVII and one or more acceptable pharmaceutical carriers to the patient is disclosed.
Core Innovation
The present invention provides monocyclic thieno, pyrido, and pyrrolo pyrimidine compounds with specific substitutions, as represented by various formulae such as Formula XXVI and Formula XXVII, as well as their salts and hydrates. These compounds are formulated into pharmaceutical compositions by combining a therapeutically effective amount of one or more compounds with pharmaceutically acceptable carriers. Such compositions are suitable for administration via multiple routes, including oral, parenteral, rectal, buccal, and others.
This invention addresses the problem of treating life-threatening opportunistic infections, such as Pneumocystis jirovecii pneumonia (PCP) common in immunodeficient patients, and also tackles unmet needs in cancer treatment. Resistance to current therapies, toxicity, and a lack of selectivity in clinically used agents such as trimethoprim-sulfamethoxazole and non-selective dihydrofolate reductase (DHFR) inhibitors have resulted in a significant demand for more effective and selective therapies. Existing regimens have limitations due to side effects, incomplete efficacy, and the emergence of drug-resistant strains.
The disclosed compounds demonstrate selectivity and potency as inhibitors of pathogen DHFR, notably pjDHFR, as well as antitumor activities. The invention describes both single therapeutic agents and compositions, including methods for treating cancer by administering these agents. The compounds are developed for optimized selectivity and potency in targeting pathogen enzymes over human homologs, and for circumventing the resistance mechanisms and toxicities that limit current drug options in the treatment of cancer and opportunistic infections.
Claims Coverage
The patent includes five independent claims, each directed to unique inventive features pertaining to specific compounds and pharmaceutical compositions based on specified chemical formulae.
Compound of Formula XXVI
A compound of Formula XXVI, wherein X is O or S; R1 is H or CH3; and R2 is H or CH3, and the compound may also be in the form of a salt or a hydrate.
Pharmaceutical composition comprising compound of Formula XXVI
A pharmaceutical composition that contains a therapeutically effective amount of a compound of Formula XXVI, optionally including at least one pharmaceutically acceptable carrier.
Compound of Formula XXVII
A compound of Formula XXVII, wherein X is CH2 or O, and R1 is H or CH3, and the compound may also be in the form of a salt or a hydrate.
Pharmaceutical composition comprising compound of Formula XXVII
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula XXVII, optionally including at least one pharmaceutically acceptable carrier.
Pharmaceutical composition comprising compound of Formula XXIX
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula XXIX, wherein R1 is H or CH3; R2 is SCH3 or OCH3; and R3 is H or CH3, optionally with at least one pharmaceutically acceptable carrier.
Pharmaceutical composition comprising compound of Formula XXX
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula XXX, wherein X is CH2 or O and R1 is H or CH3, and optionally at least one pharmaceutically acceptable carrier.
The inventive features cover specific chemical compounds of defined structure and their use in pharmaceutical compositions, specifying composition ingredients and optional pharmaceutical carriers, directly addressing the preparation and therapeutic use of these novel agents.
Stated Advantages
The invention provides highly selective and potent inhibitors of pathogen dihydrofolate reductase (DHFR), notably pjDHFR, with improved selectivity over human DHFR.
The invention offers pharmaceutical compositions with compounds that potentially overcome resistance and reduce toxicity compared to existing therapies.
The compounds and compositions enable the treatment of cancer with therapeutically effective agents tailored for enhanced selectivity and minimized side effects.
Documented Applications
Use of the compounds and compositions in the treatment of cancer by administering a therapeutically effective amount to a patient.
Use of the compounds as selective and potent inhibitors of pathogen DHFR for addressing opportunistic infections, such as Pneumocystis jirovecii pneumonia, particularly in immunocompromised patients.
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