Monocyclic, thieno, pyrido, and pyrrolo pyrimidine compounds and methods of use and manufacture of the same
Inventors
Assignees
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Publication Number
US-9994586-B2
Publication Date
2018-06-12
Expiration Date
Abstract
The present invention provides a compound of Formula XXVIII:werein R1is H or CH3, and optionally including a salt or a hydrate of said compound.
Core Innovation
The disclosure describes fluorinated 6-substituted pyrrolo[2,3-d]pyrimidine antifolates, related des-fluoro parents, and amide-bridged pyrrolo[2,3-d]pyrimidine antifolates. The compounds are discussed in relation to folate receptor (FRα/FRβ), the proton-coupled folate transporter (PCFT, SLC46A1), and the reduced folate carrier (RFC, SLC19A1), with structural simplicity for subsequent optimization toward FR/PCFT selectivity and multiple folate-enzyme inhibition.
Molecular modeling supports an intramolecular fluorine–NH interaction, described as a pseudo 6-membered ring, which improves binding in FRα and GARFTase. The disclosure also addresses FRα/PCFT/RFC-selective amide-bridged classical antifolates, DHFR inhibition in Pneumocystis jirovecii and human DHFR, and transporter-selective evaluation in transporter-expressing CHO lines and KB human tumor cells.
The patent further describes monocyclic pyrimidine analogs as colchicine-site tubulin destabilizers, including microtubule depolymerization and colchicine binding inhibition, and thieno[3,2-d]pyrimidine analogs with colchicine-site binding considerations through docking rationale on β-tubulin. It also includes pharmaceutical compositions comprising the described compounds with acceptable pharmaceutical carriers and methods for treating cancer patients by administering therapeutically effective amounts of the compounds.
Claims Coverage
Two independent claim scopes are identifiable from the provided claim text. They both define a compound of Formula XXVIII with R1 as H or CH3, and allow optional inclusion of a salt or a hydrate.
Formula XXVIII compound definition
A compound of Formula XXVIII wherein R1 is H or CH3.
Optional salt or hydrate inclusion
The compound optionally includes a salt or a hydrate of said compound.
Overall, the provided claim coverage is limited to a Formula XXVIII compound with R1 restricted to H or CH3, together with optional salt or hydrate forms.
Stated Advantages
Improved FR/PCFT potency for fluorinated antifolates 4–6.
Notably enhanced PCFT activity for compound 6.
Limited RFC activity for most fluorinated analogs.
Structural simplicity for further optimization toward FR/PCFT selectivity and multiple folate-enzyme inhibition.
Superior activity is reported for certain sulfur-containing analogs, with compound 10 highlighted as especially showing superior activity.
N-methyl is described as essential for compound 10 performance.
Provides DHFR inhibition in Pneumocystis jirovecii and human DHFR with selectivity ratios described in the document.
Reduced resistance/efflux mechanisms in prior lead compounds, including P-glycoprotein (Pgp) and βIII-tubulin resistance.
Documented Applications
Selective transport via folate receptors (FRα/FRβ) and proton-coupled folate transporter (PCFT) relative to the reduced folate carrier (RFC) for antifolate activity.
Inhibition of folate-related enzymes including GARFTase and related targets.
Colchicine-site tubulin destabilization through monocyclic pyrimidine analogs.
Treatment of conditions associated with Pneumocystis jirovecii dihydrofolate reductase and cancer.
Treating cancer patients by administering therapeutically effective amounts of the described compounds.
Biological evaluation of anticancer scaffold families including monocyclic pyrimidine tubulin inhibitors using proliferation inhibition, microtubule depolymerization, tubulin assembly inhibition, and colchicine binding inhibition.
Biological evaluation of FRα/PCFT/RFC-selective amide-bridged classical antifolates using transporter-expressing CHO cell lines and KB human tumor cells.
Antifolate/antitumor compound evaluation including DHFR inhibition in Pneumocystis jirovecii and associated context described as Pneumocystis jirovecii pneumonia (PCP).
Biological evaluation of tubulin inhibitors described in the document as involving microtubule depolymerization and antiproliferative effects, including resistance-related considerations via P-glycoprotein (Pgp) and βIII-tubulin.
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