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Novel aminodithioformate compounds, and preparation method and application thereof

A technology of carbadithiocarbamic acid and ester compounds, which is applied in the field of new carbadithiocarbamate compounds and their preparation, and can solve the problems of limited and no anti-tumor activity

Active Publication Date: 2015-08-05
北京天池凯源科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, some small molecule PKM2 agonists with good activity have been found, but very limited
Moreover, the reported PKM2 agonists only show good activity at the enzyme level, and have no significant anti-tumor activity at the cellular level.

Method used

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  • Novel aminodithioformate compounds, and preparation method and application thereof
  • Novel aminodithioformate compounds, and preparation method and application thereof
  • Novel aminodithioformate compounds, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Synthesis of 3-pyridinemethylcarbamodithioate-(2-benzoyl)ethyl ester (compound 1)

[0048]

[0049] Dissolve 3-aminomethylpyridine (541mg, 5mmol) in 25mL DCM, add TEA (506mg, 5mmol), stir at room temperature for 10min, add CS 2 (457mg, 6mmol), reacted at room temperature for 20min, added 3-chloropropiophenone (843mg, 5mmol), reacted for 5h at room temperature, directly spin-dried the solvent under reduced pressure, column chromatography (P:E=1:2), and obtained white Solid, 77.2% yield. Melting point: 82-84°C.

[0050] 1 H NMR (400MHz, DMSO) δ10.50 (s, 1H), 8.70-8.32 (m, 2H), 7.97 (d, J = 7.4Hz, 2H), 7.66 (ddd, J = 10.8, 8.5, 4.4Hz, 2H), 7.53(t, J=7.1Hz, 2H), 7.37(dd, J=7.7, 4.8Hz, 1H), 4.86(d, J=5.3Hz, 2H), 3.50(dt, J=11.8, 4.7 Hz,4H).

[0051] 13 C NMR (100MHz, DMSO) δ198.72, 197.82, 149.56, 148.90, 136.65, 135.96, 133.90, 133.40, 129.25, 128.37, 123.98, 47.58, 38.65, 29.32.

Embodiment 2

[0052] Example 2 Synthesis of 3-pyridinemethylcarbamodithioate-[2-(3,4-dichloro-benzoyl)]ethyl ester (compound 2)

[0053]

[0054] Dissolve 3,4-dichloroacetophenone (756mg, 4mmol) in 10mL DMF, add paraformaldehyde (240mg, 8mmol), catalyst CF 3 COOH (iPr) 2 NH (860mg, 4mmol), react at 80°C for 12h, cool to room temperature, add 50mL of water, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and perform column chromatography (P: E=20:1), the oily intermediate (2-1) was obtained with a yield of 27.5%. Dissolve 3-aminomethylpyridine (324mg, 3mmol) in 20mL DCM, add TEA (303mg, 3mmol), stir at room temperature for 5min, add CS 2 (274mg, 3.6mmol), reacted for 10min, added intermediate 2-1, reacted at room temperature for 5h, evaporated the solvent under reduced pressure, and column chromatography (P:E=2:1) ​​gave a white solid with a yield of 56.3%. Melting point: 139.3-140.2°C.

[0055] Intermediate 2-1

[0056...

Embodiment 3

[0062] Example 3 Synthesis of 3-pyridinemethylcarbamodithioate-[2-(4-fluoro-benzoyl)]ethyl ester (compound 3)

[0063]

[0064] Using 4-fluoroacetophenone as a raw material, the target compound was synthesized with reference to the synthetic route of Example 2. Intermediate 3-1 is an oily product with a yield of 46.1%; product 3 is a white solid with a yield of 35.4% and a melting point of 127.4-128.1°C.

[0065] Intermediate 3-1

[0066]

[0067] 1 H NMR (400MHz, CDCl 3 )δ8.11-7.83(m,2H),7.14(dt,J=10.6,9.6Hz,3H),6.58-6.23(m,1H),6.12-5.77(m,1H).

[0068] 13 C NMR (100MHz, CDCl 3 )δ188.31, 165.96, 163.43, 132.63, 132.60, 130.98, 130.34, 130.25, 129.29, 114.85, 114.64.

[0069] Product 3

[0070] 1 H NMR (400MHz, DMSO) δ10.60(t, J=5.5Hz, 1H), 8.81-8.35(m, 2H), 8.33-7.92(m, 2H), 7.93-7.56(m, 1H), 7.46- 7.17(m,3H),4.85(d,J=5.6Hz,2H),3.72-3.40(m,4H).

[0071] 13 C NMR (100MHz, DMSO) δ197.73, 197.32, 166.84, 164.34, 149.57, 148.85, 135.98, 133.44, 131.45, 131.36, 12...

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Abstract

The invention discloses novel aminodithioformate compounds, and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry. The structure of the compounds is disclosed as formula I. The research proves that the compounds are PKM2-targeted and are an excitant of PKM2, and also detects that the compounds can generate the antineoplastic action by preventing the PKM2 from entering the karyons. The compounds have favorable antineoplastic action, and have favorable selectivity for tumor cells. Therefore, the compounds can be used as an antineoplastic drug, and have wide application value.

Description

technical field [0001] The present invention relates to compounds and their preparation methods and applications, in particular to novel carbamodithiocarbamate compounds and their preparation methods and applications. These compounds are a new class of PKM2 agonists and can be used as antitumor drugs, belonging to Medicinal Chemistry field. Background technique [0002] Anticancer drug research has always been one of the hot spots 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 the current research on anti-tumor drugs is to find anti-tumor drugs with good curative effect and low side effects. Taking advantage of the difference between tumor cells and normal cells in the metabolic process, selectively interfering with the key links in the metabolic process of tumor cells, it is possible to achieve the purpose of i...

Claims

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Application Information

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IPC IPC(8): C07D213/40C07D405/12C07D213/50C07D409/12C07D401/12C07D417/12C07D471/04A61P35/00A61P3/08
CPCC07D213/40C07D213/50C07D401/12C07D405/12C07D409/12C07D417/12C07D471/04
Inventor 尹玉新张裕
Owner 北京天池凯源科技有限公司
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