Aminodithioformate compounds, preparation method therefor and use of aminodithioformate compounds in preparation of antitumor drugs

A technology of aminodithiocarboxylate and ester compounds, which can be used in antitumor drugs, active ingredients of heterocyclic compounds, drug combinations, etc., can solve the problem of unsatisfactory pyruvate kinase subtype selectivity, low activity, and unclear tumors question

Active Publication Date: 2017-10-03
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the Warburg effect was discovered as early as the early 20th century, how this effect occurs and what significance it has on the occurrence and development of tumors has been unclear.
[0007] Although several inhibitors of PKM2 have been discovered so far, their activity is low and their selectivity over other pyruvate kinase subtypes is not ideal

Method used

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  • Aminodithioformate compounds, preparation method therefor and use of aminodithioformate compounds in preparation of antitumor drugs
  • Aminodithioformate compounds, preparation method therefor and use of aminodithioformate compounds in preparation of antitumor drugs
  • Aminodithioformate compounds, preparation method therefor and use of aminodithioformate compounds in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1: Preparation of 2-chloromethyl-3-methyl-1,4-naphthoquinone (1)

[0089] Dissolve menadione (1g, 5.81mmol) in glacial acetic acid (10ml), add 36% formaldehyde aqueous solution (3ml), add hydrogen chloride gas under ice bath, stir for 30min, until the solution turns red, stir at room temperature React overnight. The solution turned dark brown, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, and separated and purified with a silica gel column (eluted with petroleum ether / ethyl acetate) to obtain a yellow solid 1. 960mg, yield 75.0%, 1 H NMR(400MHz, CDCl 3 )δ8.13-8.18(m,2H,ArH),7.76-7.78(m,2H,ArH),4.64(s,2H,CH 2 S),2.35(s,3H,C=CCH 3 ).

Embodiment 2

[0090] Example 2: Preparation of 3-methyl-1,4-diox-1,4-dihydronaphthalene-2-methyl diethylaminodithioformic acid (2)

[0091] Dissolve diethylamine (123μL, 1.2mmol) in acetonitrile (10ml), add carbon disulfide (72μL, 1.2mmol), stir the reaction at room temperature for 30min, add 2-chloromethyl-3-methyl-1,4- Naphthoquinone (220mg, 1mmol), stir the reaction at room temperature, TLC detects the disappearance of the raw material point, terminate the reaction, spin down the solvent under reduced pressure, add a small amount of water, extract with ethyl acetate, combine the ester layers, wash with saturated brine, and anhydrous sodium sulfate Dry, separate and purify with silica gel column (petroleum ether / ethyl acetate elution) to obtain a yellow solid 2,298mg, yield 89.6%, mp 155-156°C. 1 H NMR(400MHz, CDCl 3 )δ8.11-8.14(m,2H,ArH),7.73-7.74(m,2H,ArH),4.65(s,2H,CH 2 S),4.06(q,2H,NCH 2 ),3.73(q,2H,NCH 2 ),2.37(s,3H,C=CCH 3 ),1.30(t,6H,2CH 2 CH 3 ). 13 C NMR(100MHz, CDCl 3 )δ194.49,184.8...

Embodiment 3

[0092] Example 3: Preparation of 3-methyl-1,4-diox-1,4-dihydronaphthalene-2-methyl dipropylaminodithioformic acid (3)

[0093] Using the synthetic method of compound 2 above, using 2-chloromethyl-3-methyl-1,4-naphthoquinone and dipropylamine as the reactants to obtain a yellow solid 3 with a yield of 86.0%, mp 80-81°C. 1 H NMR(400MHz, CDCl 3 )δ8.10-8.14(m,2H,ArH),7.72-7.74(m,2H,ArH),4.63(s,2H,CH 2 S),3.93(t,2H,NCH 2 ),3.61(t,2H,NCH 2 ),2.35(s,3H,C=CCH 3 ),1.70-1.82(m,4H,2CH 2 CH 3 ),0.92-0.98(m,6H,2CH 2 CH 3 ). 13 C NMR(100MHz, CDCl 3 )δ195.02,184.79,183.89,146.48,141.64,133.62,132.19,131.93,126.49,57.25,54.43,33.92,20.70,19.62,13.66,11.18.HR-MS(ESI + )m / z:362.1249[M+H] + .Found:362.1244[M+H] + .

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Abstract

The invention discloses a series of aminodithioformate compounds, a preparation method therefor and use of aminodithioformate compounds in preparation of antitumor drugs. Through carrying out activity screening on a micromolecular compound library, a novel structure type of PKM2 inhibitors are discovered from the micromolecular compound library, and a series of aminodithioformate compounds with a structure represented by a general formula I shown in the description are designed and synthesized according to the inhibitors. Proven by enzyme activity tests, the compounds have remarkable superior PKM2 inhibiting activity and selectivity to those of currently available PKM2 inhibitors. Through separately carrying out killing effect test on pyruvate kinase M2 and M2 subtypes and four kinds of tumor cell lines, i.e., MCF-7, HCT116, Hela and H1299 by using the compounds disclosed by the invention, activity tests prove that the compounds have a remarkable tumor cell proliferation inhibiting action.

Description

Technical field [0001] The present invention relates to a novel amino dithioformate compound, its pharmaceutically acceptable salt, and a pharmaceutical composition containing the compound. The invention also relates to the use of such compounds in the preparation of anti-tumor drugs which have the effect of selectively antagonizing pyruvate kinase M2 subtype and inducing tumor cell apoptosis. It also relates to the preparation methods of these compounds. The invention belongs to the technical field of drug synthesis. Background technique [0002] Anti-tumor drug research has always been one of the hotspots in drug research all over the world. At present, there are many effective anti-tumor drugs, but there are few anti-tumor drugs with good efficacy and low side effects. Therefore, the key problem to be solved in current anti-tumor drug research is to find anti-tumor drugs with good curative effects and low side effects. Taking advantage of the difference between tumor cells...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C333/20C07D295/21C07D265/30C07D277/04C07D295/32C07D213/75C07C333/22A61K31/325A61K31/54A61K31/535A61K31/426A61K31/40A61K31/4453A61K31/495A61K31/4402A61K31/4406A61K31/4409A61K31/4545A61K31/4025A61K31/427A61P35/00
CPCC07C333/20C07C333/22C07D213/75C07D265/30C07D277/04C07D295/21C07D295/32
Inventor 尹玉新宁显玲齐海龙
Owner PEKING UNIV
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