N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 proteins as well as composition and application thereof

A technology of benzenesulfonylbenzamide and bcl-2, applied in the field of medicine, can solve problems such as poor patient compliance, poor absorption, distribution, metabolism and/or excretion, and limited application range

Active Publication Date: 2018-10-16
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Poor absorption, distribution, metabolism and / or excretion (ADME) properties are known to be a major reason for failure of many drug candidates in clinical trials
Many currently marketed drugs also limit their application range due to poor ADME properties
The rapid metabolism of drugs will cause many drugs that can treat diseases with high efficiency to be eliminated from the body too quickly, making it difficult to become a drug
Although frequent or high-dose medication may solve the problem of rapid drug clearance, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and increased treatment costs
In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites

Method used

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  • N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 proteins as well as composition and application thereof
  • N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 proteins as well as composition and application thereof
  • N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 proteins as well as composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0085] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found in, eg, Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

[0086] The reaction can be monitored according to any suitable method known in the art. For example, spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g. 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectroscopy (MS)) or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) Product formation was monitored.

[0087] Pharmaceutical compositions, prep...

Embodiment 1

[0119] Example 1 Preparation of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-d 2}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H- Pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, namely compound T-1, has the following molecular formula:

[0120]

[0121] Synthesize using the following route:

[0122]

[0123] Step 1 Synthesis of Compound 5.

[0124] Under nitrogen protection, sodium hydride (1.9g, 79.3mmol) and dimethyl carbonate (14.3g, 158.6mmol) were added to anhydrous THF (15ml) solution and heated, and 3,3-dimethylcyclohexane was added dropwise at reflux The THF solution of the ketone (5.0 g, 39.6 mmol) continued to reflux for 4 h after the dropwise addition was completed. Cool to room temperature, add methanol to quench the reaction, then add water and dichloromethane for extraction, collect the organic phase, and separate and purify by column chromatography to obtain 4.2 g of a colorless liquid product with...

Embodiment 2

[0143] Example 2 Preparation of 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-d 2}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl-d 2 )amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, namely compound T-2, the molecular formula is as follows:

[0144]

[0145] Adopt the following synthetic route:

[0146]

[0147] Step 1 Synthesis of compound 15.

[0148] At 0°C, the LiAlD 4 (0.4g, 10.08mmol) was slowly added dropwise to a solution of compound 14 (1.0g, 9.00mmol) in tetrahydrofuran (20ml), and the reaction was continued for 1h after the addition was complete. The reaction was quenched by adding 1M hydrochloric acid (10ml), extracted with dichloromethane (40ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 0.72g of a light yellow solid with a yield of 68.6%. LC-MS(APCI):m / z=118.29(M+1) + .

[0149] Step 2 Synthesis of compound 16.

[0150] 4-Fluoro...

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Abstract

The invention relates to a compound capable of inhibiting the activity of Bcl-2 anti-apoptosis protein as well as a preparation and application thereof, in particular to an N-benzenesulfonyl benzamidecompound for inhibiting Bcl-2 proteins as shown in formula (I), or a medicine composition of a crystal form, a precursor, a pharmaceutically-acceptable salt, a three-dimensional isomer, a solvent composition or a hydrate of the N-benzenesulfonyl benzamide compound. The compound and the composition containing the compound have excellent rejection capability for Bcl-2 proteins, have better pharmacokinetics parameter characteristics, can increase the medicine concentration of the compound in animal bodies, and can improve the drug curative effect and safety. (The formula (I) is shown in the description).

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to N-benzenesulfonylbenzamide compounds with excellent inhibitory effect on Bcl-2 protein, pharmaceutical compositions containing them, and their preparation methods and applications. Background technique [0002] Designing and synthesizing new anti-tumor drugs against tumor-specific targets has become the focus of targeted anti-tumor therapy. Recent studies have shown that the mechanism of apoptosis (programmed death) is involved in the occurrence, development and regression of tumors. Apoptosis is highly conserved, and similar molecular mechanisms of apoptosis exist in different species of organisms. The known apoptosis signaling pathways include two pathways, endogenous and exogenous. The mitochondrial apoptotic pathway is an endogenous pathway, and the apoptosis pathway mediated by death receptors is an exogenous pathway. In the endogenous pathway of apoptosis, the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/496A61P35/00A61P35/02C07B59/00
CPCA61P35/00A61P35/02C07B59/002C07D471/04C07B2200/05A61K31/496
Inventor 王义汉刘志强
Owner SHENZHEN TARGETRX INC
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