Unlock instant, AI-driven research and patent intelligence for your innovation.

Prodrugs and medical uses thereof

A use and compound technology, applied in the field of prodrug and its application in medicine, can solve the problems of low maximum tolerated dose, poor water solubility, low bystander effect, etc.

Pending Publication Date: 2021-01-12
CONVERT PHARM SA
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the HAPs may exhibit unfavorable drug characteristics such as poor water solubility, low maximum tolerated dose, low bystander effect, non-mechanistic activation of human aerobic reductase and / or not orally bioavailable

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Prodrugs and medical uses thereof
  • Prodrugs and medical uses thereof
  • Prodrugs and medical uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Example 1: Production of Cpd.11Ms and major cytotoxic metabolites.

[0142] Materials and methods

[0143] Synthesis and metabolism of Cpd.11Ms

[0144] According to the method described in WO2014031012, intermediate compound 2 (3-fluoro-4-(methylsulfonyl)benzaldehyde), compound 3 (3-fluoro-4 -(methylsulfonyl)benzoic acid) and compound 4 (5-fluoro-4-(methylsulfonyl)-2-nitrobenzoic acid). Compounds 1-4 are also commercially available. Acid chloride compound 5 was obtained by suspending compound 4 in dichloromethane and acetonitrile to provide a homogeneous solution before adding DMF and oxalyl chloride. After removal of solvent and excess oxalyl chloride, the resulting crude acid chloride compound 5 was dissolved in dichloromethane and THF, cooled to -10 °C, and then a solution of 1-ethylpiperazine in dichloromethane was added. The reaction mixture was stirred at ambient temperature and the resulting precipitate was collected by filtration and dried to give the cru...

Embodiment 2

[0162] Example 2: In vitro validation of Cpd.11Ms and Cpd.11c and Cpd.11d as anticancer agents active under hypoxic conditions.

[0163] Cancer cell line-based analysis using Cpd.11Ms

[0164] Tested cancer cell lines used for in vitro and / or in vivo studies and showing results are available through ATCC or DSMZ (Leibniz-Institut-German Institute for Microbiology) and are grouped by cancer type, see Table I.

[0165] Table I

[0166]

[0167]

[0168] Only in vitro hypoxia-based cytotoxicity assays have been performed on other cancer cell lines, demonstrating the sensitivity of Cpd.11d, covering these and other cancer subtypes: For breast cancer, EFM-192A (luminal B), EVSA- T(PR+ / ER) and JIMT-1(HER 2+); for lung cancer, several other NSCLC or SCLC cell lines; for pancreatic cancer, carcinoma (DAN-G,YAPC), adenocarcinoma ( HUP-T4). All cell lines were maintained in cell culture flasks and used complete media according to the supplier's instructions.

[0169] Cell-base...

Embodiment 3

[0186] Example 3: Efficacy of Cpd.11Ms in animal models of lung cancer, pancreatic cancer and breast cancer.

[0187] Materials and methods

[0188] animal model

[0189] All animal models were xenograft models established in BALB / c nude mice (6-8 weeks old, 17-23 g, maintained on standard conditions and diet), following protocols approved by the Institutional Animal Care and Use Committee. Cpd.11Ms was formulated using 2% DMSO (DMSO aqueous solution for injection, starting from the main formulation of Cpd.11Ms (100-60 mg / ml, 2% DMSO aqueous solution for injection)).

[0190] After tumor cell inoculation, animals were checked daily for morbidity and mortality. Before treatment initiation, all animals were weighed and tumor volumes were measured with calipers. When the average tumor size reaches about 250mm 3 , start treatment. Each treatment / control group consisted of 10 randomly assigned mice, which were injected daily for 5 days. The day of tumor cell inoculation is ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
purityaaaaaaaaaa
Login to View More

Abstract

The invention relates to nitrogen mustards bearing substituted piperazine carboxamide and their corresponding pharmaceutically acceptable salts as cytotoxic agents that target tumours and methods of use thereof, alone or in combination with other cancer treatments.

Description

technical field [0001] The present invention relates to nitrogen mustard substituted piperazine carboxamides and their corresponding pharmaceutically acceptable salts as tumor-targeting cytotoxic agents, and methods for their use alone or in combination with other cancer therapies. Background technique [0002] The use of tumor-selective prodrugs (i.e., therapeutically inactive compounds that can be selectively converted to therapeutically active compounds by cellular metabolism and / or in the tumor microenvironment) is an important strategy in targeting cancer-specific (e.g., hypoxic) approach that has been applied in cell-targeted cancer therapy. In particular, hypoxia-activated prodrugs (HAPs), which become cytotoxic agents only in hypoxic tumor compartments, are considered promising antineoplastic agents, especially in the setting of poor prognosis, drug combinations, and / or in response to standard-of-care treatments. In the case of drug resistance (Hunter F et al., 2016...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/166A61K31/277A61K31/495A61P35/00
CPCA61K31/166A61K31/277A61K31/495A61P35/00A61P35/04A61K45/06
Inventor 阿恩·海耶里克苏菲·德舒梅克索菲·蒂奥洛伊多米尼克·瑟萨戈菲力浦·朗班
Owner CONVERT PHARM SA