US-12617812-B2 - Platinum(IV) complexes, methods of manufacture, compositions containing, and methods of use thereof

US12617812B2US 12617812 B2US12617812 B2US 12617812B2US-12617812-B2

Abstract

A platinum(IV) complex selected from the group consisting of Various methods contain steps for manufacturing the platinum(IV) complexes, and a pharmaceutical composition contains the platinum(IV) complex are also addressed.

Inventors

Guangyu Zhu
Zhiqin Deng

Assignees

CITY UNIVERSITY OF HONG KONG

Dates

Publication Date: 20260505
Application Date: 20220525

Claims (7)

1 . A platinum(IV) complex selected from a group consisting of
2 . A method for manufacturing the platinum(IV) complex of Formula II(a) of claim 1 , comprising the steps of: A) providing c,c,t-[Pt(DACH)(OH) 2 (ox)]; B) providing a NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxochroman-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)propanoic acid; and C) reacting c,c,t-[Pt(DACH)(OH) 2 (ox)] with the NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxochroman-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)propanoic acid to form the platinum(IV) complex of Formula II(a).
3 . A method for manufacturing the platinum(IV) complex of Formula II(b) of claim 1 , comprising the steps of: A) providing a platinum(IV) complex of Formula II(a); B) providing an NHS ester of 5,6-dimethylxanthenone-4-acetic acid; and C) reacting the platinum(IV) complex of Formula II(a) with the NHS ester of 5,6-dimethylxanthenone-4-acetic acid to form the platinum(IV) complex of Formula II(b).
4 . A method for manufacturing the platinum(IV) complex of Formula II(c) of claim 1 , comprising the steps of: A) providing diammine (cyclobutane-1,1 dicarboxylato) dihydroxido platinum(IV); B) providing a NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxochroman-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)propanoic acid; C) reacting diammine (cyclobutane-1,1 dicarboxylato) dihydroxido platinum(IV) with the NHS ester of 3-((4-(3-(7-(diethylamino)-2-oxochroman-3-yl)-3-oxoprop-1-en-1-yl)phenyl)(methyl)amino)propanoic acid to form the platinum(IV) complex of Formula II(c).
5 . A method for manufacturing the platinum(IV) complex of Formula II(d) of claim 1 , comprising the steps of: A) providing the platinum(IV) complex of Formula II(c); B) providing an NHS ester of 5,6-dimethylxanthenone-4-acetic acid; and C) reacting the platinum(IV) complex of Formula II(c) with the NHS ester of 5,6-dimethylxanthenone-4-acetic acid to form the platinum(IV) complex of Formula II(d).
6 . A pharmaceutical composition comprising a platinum(IV) complex according to claim 1 and a pharmaceutical-acceptable ingredient.
7 . The pharmaceutical composition according to claim 6 , wherein the pharmaceutical-acceptable ingredient is selected from a group consisting of an additional anti-cancer agent, an adjuvant, an antibody, a binder, a buffer, a diluent, a filler, a pharmaceutically-acceptable carrier, a preservative, a surfactant, a contrast media, a radioactive agent, a photodynamic therapy agent, a photothermal therapy agent, an ultrasonic therapy agent, and a combination thereof.

Description

FIELD OF THE INVENTION The present invention elates to platinum-based anti-cancer, anti-tumor, and anti-infection drugs. More specifically, the present invention relates to platinum-based anti-cancer chemotherapy drugs and anti-infection drugs. BACKGROUND Platinum-based anticancer drugs are the most widely used chemotherapy agents in current clinical practice. It is estimated that more than 50% of cancer patients receiving chemotherapy are treated with platinum drugs alone or in combination with other anticancer drugs. The therapeutic outcome of platinum drugs, however, is often limited by the serious side effects and drug resistance of cancer cells. For example, current chemotherapeutic agents may be activated in non-pathological tissue. While certain specific cytotoxic platinum complexes are also known for medical use (see, for example, US 2018/155382 A1, to Zhu, et. al., assigned to City University of Hong Kong, published on Jun. 7, 2018, the entirety of which is incorporated herein by reference), additional complexes are desirable. Some previous platinum anticancer complexes bind to the DNA of cancer cells and induce DNA damage to kill cancer cells. However, the therapeutic efficiency of these drugs is limited by factors such as low platinum-DNA binding efficiency, poor selectivity between cancer and normal cells, the resistance of cancer cells towards drugs (e.g., enhanced DNA repair ability), etc. Ultraviolet (UV) and visible light photo-activated drugs (herein including pro-drugs) are known and have shown activity against, for example, cancerous tumors. However, use of current photosensitizers in such photo-activated drugs suffers from significant problems, such as side-effects, phototoxicity and cytotoxicity in non-targeted tissue, drug resistance, oxygen-dependent reactions, the requirement that the cancer/tumor/infection to be close to the skin surface and/or other internal body cavity areas accessible to UV/visible light sources, etc. which may severely limit their use and/or effectiveness. It is known that bacteria can quickly develop and transfer drug resistance to conventional antibiotics. Furthermore, conventional antibacterial photodynamic therapy (APDT) agents strongly rely on intracellular drug accumulation for their antibacterial effects. Therefore, the bacterial cell wall and membrane are present significant barriers to the successful application of APDT and related drugs. Accordingly, given the current inherent limitations to current technologies, there remains a need to develop additional platinum therapies and drugs for the treatment of cancer, tumors and/or infections that can overcome these limitations. Furthermore, there is a great need to develop anticancer and antibacterial agents with both controllable activation properties as well as tumor-specific targeting. The need further exists for platinum complexes that may effectively overcome drug resistance through a distinct and controllable mechanism of action. The need further exists for photoactivatable complexes that may transform to strong oxidants to oxidize survival-related intracellular biomolecules and generate reactive oxygen species (ROS), lipid peroxide, etc. to disrupt intracellular redox balance to kill cancer cells or bacteria. SUMMARY OF THE INVENTION An embodiment of the present invention relates to a platinum(IV) complex of Formula I: where X, X′, Y, Y′, and Z are each independently an electron donor ligand, R1˜R5 are each independently a functional group, L is the linker unit, and n is selected from the group of 0, a positive charge, and a negative charge. An embodiment of the present invention relates to various methods for manufacturing embodiments of the platinum(IV) complex herein. An embodiment of the present invention relates to a method of treating cancer, a tumor, or an infection in a subject comprising the steps of administering to the subject an effective dose of the platinum(IV) complex herein, and administering to the subject near-infrared radiation (NIR). An embodiment of the present invention relates to a pharmaceutical composition containing the platinum(IV) complex described herein. Without intending to be limited by theory, it is believed that the present invention may provide one or more benefits such as, new and improved photo-oxidants and photo-oxidation; improved treatment for cancer, tumors and/or infections; reduced patient toxicity; improved therapy targeting; decreased phototoxicity as compared to UV treatments; enhanced anticancer and antibacterial treatments and compositions; controllable temporal and location-specific activation; reduced side effects, platinum complexes that overcome cisplatin resistance, platinum resistance, PDT resistance, etc.; and methods to disrupt intracellular redox balance to kill cancer cells or bacteria. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows an embodiment of synthesis steps for complex 4 (i.e., Formula II(c)) and complex 5 (i.e., Formula II(a)); FIG. 2