Substituted pyrrolo,-furano, and cyclopentylpyrimidines having antimitotic and/or antitumor activity and methods of use thereof

Inventors

Gangjee, Aleem

Assignees

Duquesne University of the Holy Spirit

Publication Number

US-11840539-B2

Publication Date

2023-12-12

Expiration Date

2028-07-10

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Abstract

The present invention provides substituted pyrrolo-, furano-, and cyclopentylpyrimidine bicyclic pharmaceutical compositions comprising compounds of Formula IV, and pharmaceutically acceptable salts, solvates, and hydrates thereof, having antimitotic activity, anti-multidrug resistance activity, such as for example P-glycoprotein inhibition, and antitumor activity, and which inhibit paclitaxel sensitive and resistant tumor cells. Also provided are methods of utilizing these compounds and pharmaceutical compositions for treating tumor cells and inhibiting mitosis of cancerous cells.

Core Innovation

The invention provides substituted pyrrolo-, furano-, and cyclopentylpyrimidine bicyclic pharmaceutical compositions comprising compounds of Formula IV, along with their pharmaceutically acceptable salts, solvates, and hydrates. These compounds are characterized by possessing antimitotic activity, anti-multidrug resistance activity (such as P-glycoprotein inhibition), and broad antitumor activity, and are effective against both paclitaxel-sensitive and paclitaxel-resistant tumor cells.

The problem addressed by the invention arises from the limitations of existing antimitotic and antitumor agents, particularly the challenge of multidrug resistance (MDR) in cancer therapy. Many current chemotherapeutic agents, including vinca alkaloids, taxanes (like paclitaxel), and colchicine, encounter treatment failures due to the development or inherent presence of resistance, often mediated by P-glycoprotein (Pgp) efflux transporters. These resistances significantly restrict the effectiveness of conventional cancer therapies, necessitating the development of compounds that can target both microtubule dynamics and overcome MDR in tumor cells.

The core innovation of the present invention is the provision of single molecules, exemplified by bicyclic heteroaromatic structures such as those of Formula III and IV, that combine antimitotic, anti-multidrug resistance (such as Pgp inhibition), and antitumor properties. These compounds can be formulated into water-soluble acid salts suitable for oral administration, thus overcoming issues of solubility that limit prior art drugs. The invention also provides methods for using these compounds to treat tumor cells and inhibit cancer cell mitosis, including in cases refractory to other treatments due to multidrug resistance.

Claims Coverage

There is one independent claim focusing on the pharmaceutical composition containing a compound of Formula IV or its pharmaceutically acceptable salt.

Pharmaceutical composition comprising a compound of Formula IV

The main inventive feature is a pharmaceutical composition that includes a compound of Formula IV, or a pharmaceutically acceptable salt thereof. - The structure of Formula IV is defined in the specification, including the possible substituents for R1, R2, R3, R4, R5, R6, X, and Y, with specific stated alternatives and configurations. - The composition may additionally include at least one pharmaceutically acceptable carrier, according to dependent claims. - Preferred embodiments specify substituents such as R1 as a methoxyphenyl group, X as NR4 where R4 is H, R6 as an alkyl aryl group with a —CH2— alkyl and phenyl aryl, and a double bond between positions 6 and 7 of the five-membered ring.

The independent claim broadly covers pharmaceutical compositions containing defined bicyclic pyrimidine derivatives (Formula IV) or their pharmaceutically acceptable salts, including specific substituent preferences and the inclusion of suitable carriers.

Stated Advantages

The compounds exhibit antimitotic, anti-multidrug resistance (Pgp inhibition), and antitumor activity in a single molecule, potentially circumventing the drawbacks of using multiple drugs such as drug transport issues, additive or synergistic toxicities, drug resistance, and higher treatment costs.

The compounds are effective inhibitors of both paclitaxel-sensitive and paclitaxel-resistant tumor cells.

Water-soluble acid salts of the compounds can be formulated for oral administration, addressing water solubility problems found in prior antimitotic agents.

Compounds retain cytotoxicity toward multidrug-resistant tumor cells, with efficacy not diminished by Pgp-mediated resistance.

Documented Applications

Treatment of cancer in patients by administering a therapeutically effective amount of a compound of Formula III or IV, or their pharmaceutically acceptable salts, prodrugs, solvates, or hydrates.

Inhibition of mitosis of cancerous cells by subjecting one or more live cancerous cells to a mitotic inhibitory amount of a compound of Formula III or IV, or their respective pharmaceutically acceptable salt, prodrug, solvate, or hydrate.

Treatment of proliferative diseases and/or disorders such as leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.

Use in combination with additional chemotherapeutic agents, such as paclitaxel, docetaxel, vinca alkaloids, colchicine, colcemid, cisplatin, and nocadazol, to enhance effectiveness by reversing multidrug resistance and restoring tumor sensitivity to antimitotic agents.

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