Substituted pyrrolo, -furano, and cyclopentylpyrimidines having antimitotic and/or antitumor activity and methods of use thereof
Inventors
Assignees
Duquesne University of the Holy Spirit
Publication Number
US-10072019-B2
Publication Date
2018-09-11
Expiration Date
2028-07-10
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Abstract
The present invention provides substituted pyrrolo-, furano-, and cyclopentylpyrimidine bicyclic compounds of Formula III, and 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 compounds of Formula III and Formula IV, and their pharmaceutically acceptable salts, solvates, and hydrates. These compounds exhibit antimitotic activity, anti-multidrug resistance activity (such as P-glycoprotein inhibition), and antitumor activity, including effectiveness against paclitaxel sensitive and resistant tumor cells. Methods for using these compounds and compositions for treating tumor cells and inhibiting mitosis of cancerous cells are also provided.
The problem addressed by the invention arises from the limitations of existing antimitotic agents, including the development of multidrug resistance (MDR), often due to P-glycoprotein (Pgp) mediated drug efflux. This resistance leads to treatment failures in cancer chemotherapy, as many tumor types either inherently express or acquire MDR after exposure to chemotherapy, decreasing the efficacy of standard antitumor agents.
The invention solves this problem by providing single bicyclic heteroaromatic compounds having combinatorial chemotherapeutic properties: antimitotic activity, ability to inhibit MDR (including Pgp inhibition), and antitumor activity within a single molecule. These compounds can be used alone or in combination with chemotherapeutic agents, increasing the breadth of cell types and tumors that may be targeted, including cancer cells resistant to commonly used drugs such as paclitaxel.
Claims Coverage
There are two independent claims, each defining a main inventive feature regarding novel compound structures and pharmaceutical compositions.
Compound of Formula III with specified substitutions
A compound of Formula III, wherein the five membered ring may be saturated or unsaturated, and wherein: - R1 and R2 may be the same or different and comprise one of hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, aromatic, or heteroaromatic, each optionally further substituted with groups such as straight or branched alkyl, alkenyl, alkynyl, cyclic or alicyclic group, heterocyclic group, alkoxy, aryloxy, alkyloxyaryloxy, aryl, amine, halogen, phenol, naphthalene, piperidine, pyrrole, ketone, methylalkyl ketone, trifluoromethyl ketone, and optionally attached by a CH2 bridge, and optionally being partially or completely saturated or unsaturated when not represented by a halogen. - R3, R4, R5, R6, X, and Y are defined structures with permitted variations as described in the claim, including certain moieties that may be the same. - The claim expressly encompasses pharmaceutically acceptable salts, solvates, or hydrates of the compound.
Pharmaceutical composition comprising a compound of Formula III and pharmaceutically acceptable forms
A pharmaceutical composition comprising: - A compound of Formula III defined as above, and - Pharmaceutically acceptable salts, solvates, or hydrates thereof.
The inventive features primarily cover the specific novel chemical structures of substituted pyrrolo-, furano-, and cyclopentylpyrimidines, particularly those of Formula III and their variations, and claim their use in pharmaceutical compositions.
Stated Advantages
The compounds combine antimitotic, anti-multidrug resistance, and antitumor activities within a single molecule, circumventing the drawbacks of using multiple drugs.
The compounds inhibit both paclitaxel sensitive and resistant tumor cells and are not affected by P-glycoprotein mediated resistance, addressing the problem of multidrug resistance.
The present invention's salts are generally completely water soluble, overcoming water solubility problems associated with many existing antimitotic agents.
The compounds can be formulated into orally administered active antitumor agents due to their water solubility.
Documented Applications
Treating tumor cells and inhibiting mitosis of cancerous cells in conditions including leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.
Use as antimitotic agents in pharmaceutical compositions for the reversal of multidrug resistance, including in combination with other chemotherapeutic agents.
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