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Cyclopropyl substituted thiophene naphthene amine type compound and application thereof

A technology of thiophenecycloalkylamine and cyclopropyl, applied in the field of medicinal chemistry, can solve the problems of drug resistance of neuraminidase inhibitors, easy to produce drug-resistant strains, and drugs without new structures

Inactive Publication Date: 2017-08-04
GUANGZHOU MEDICAL UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, this class of drugs has the following obvious disadvantages (Schnell JR, Chou JJ.Nature.2008, 451(7178):591-5): (1) it is ineffective against influenza B virus; (2) there are obvious side effects, causing obvious Gastrointestinal adverse reactions; central nervous system side effects, mainly manifested as insomnia, distraction and nervousness; (3) drug-resistant strains are prone to occur during treatment
Although it has been decades since the two single-skeleton drugs were launched, no drugs with new structures have emerged, and most of the inhibitors in research drugs still use adamantane as the backbone.
In addition, due to the continuous outbreak of influenza virus, neuraminidase inhibitor drugs are gradually developing drug resistance

Method used

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  • Cyclopropyl substituted thiophene naphthene amine type compound and application thereof
  • Cyclopropyl substituted thiophene naphthene amine type compound and application thereof
  • Cyclopropyl substituted thiophene naphthene amine type compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: 4-cyclopropyl-5-(((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-amino)methyl ) Preparation of thiophene-2-acetonitrile hydrochloride

[0053]

[0054] Compound 1 (1.4 g, 3 mmol), CuCN (550 mg, 6 mmol) and 25 mL of DMF were added to a 50 mL sealed reaction tube under nitrogen protection. Heated to 150°C and reacted overnight with electromagnetic stirring. Cool to room temperature, add 100 mL of water to quench the reaction, extract with ethyl acetate (50 mL×3), combine the organic phases, wash with water and saturated brine successively, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and pass the residue through a silica gel column Purified by chromatography (petroleum ether / ethyl acetate=40:1-15:1) to obtain 4-cyclopropyl-5-(((1R,2R,3R,5S)-2,6,6-trimethyldi Cyclo[3.1.1]heptane-3-amino)methyl)thiophene-2-acetonitrile colorless oil 462 mg, yield 37.2%.

[0055] Add the 4-cyclopropyl-5-(((1R,2R,3R,5S)-2,6,6-trimeth...

Embodiment 2

[0057] Example 2: (1R,2R,3R,5S)-N-((3-cyclopropyl-5-(methylsulfonyl)thiophen-2-yl)methyl)-2,6,6-trimethyl Preparation of bicyclo[3.1.1]heptane-3-amine hydrochloride

[0058]

[0059] Add compound 1 (407mg, 0.87mmol), sodium methanesulfinate, ketone iodide (184mg, 0.96mmol), L-proline (111mg, 0.96mmol), potassium carbonate (133mg, 0.96mmol) into a 50mL glass sealed tube mmol) and DMSO 20 mL. Under the protection of nitrogen, react at 80°C for 12h. Cool to room temperature, add 100mL ethyl acetate to dilute, wash with water, extract the aqueous layer with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=30:1-6:1) to obtain a white foamy solid (380 mg, 93%). The white foamy solid was de-Boc-protected with saturated hydrochloric acid ethyl acetate solution and salted, filtered and vacuum-dried...

Embodiment 3

[0061] Example 3: (1R,2R,3R,5S)-N-((3-cyclopropyl-5-(benzenesulfonyl)thiophen-2-yl)methyl)-2,6,6-trimethyl Preparation of bicyclo[3.1.1]heptane-3-amine hydrochloride

[0062]

[0063] The preparation method is the same as in Example 2, except that the sodium methanesulfinate in Example 2 is replaced by sodium phenylsulfinate. Yield 36%.

[0064] 1 H NMR (400MHz, DMSO-d 6 )δ:9.74(s,1H),9.27(s,1H),7.98(d,J=7.6Hz2H),7.77–7.62(m,3H),7.48(s,1H),4.58–4.38(m,2H ),3.45(s,1H),2.36(t,J=11.2Hz,1H),2.30–2.20(m,1H),2.16–2.04(m,2H),1.98-1.90(m,2H),1.77( t,J=5.2Hz,1H),1.36(d,J=10.0Hz,1H),1.19(s,3H),1.09(d,J=7.2Hz,3H),0.97(d,J=8.4Hz, 2H),0.88(s,3H),0.82–0.74(m,2H). 13 C NMR (126MHz, DMSO-d 6 )δ147.7, 142.6, 141.7, 136.8, 134.4, 131.7, 130.3, 127.4, 56.4, 47.4, 41.2, 40.8, 38.8, 32.3, 31.2, 27.7, 23.6, 21.0, 10.0, 9.3, 9.2. HRMS (m / z): [M+H] + calculated for C 24 h 33 ClNO 2 S 2 , 430.1869; found, 430.1867.

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Abstract

The invention discloses a cyclopropyl substituted thiophene naphthene amine type compound with a structure I as shown in the description, or pharmaceutically acceptable salts, stereisomers or prodrug molecules of the compound. The novel compound has a relatively good anti-influenza virus function, and has a relatively good inhibition function on influenza viruses with drug resistance to amantadine. The novel compound can be used for preventing and treating infection of influenza viruses.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a cyclopropyl-substituted thiophene cycloalkylamine compound and its application. Background technique [0002] Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease that seriously endangers human health. It is caused by influenza virus and has the characteristics of high prevalence, widespread prevalence and rapid transmission. There have been many worldwide influenza pandemics in history, among which the Spanish flu epidemic in 1918 was the most serious, and more than 20 million people were killed by influenza. In 2009, the "swine flu" that broke out in Mexico seriously threatened human life around the world. In recent years, H7H9 and H5N6 avian flu have also broken out continuously, causing great losses to human life and social economy. [0003] At present, the main means of preventing and treating influenza are M2 ion channel protein i...

Claims

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Application Information

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IPC IPC(8): C07D333/28C07D333/38C07D333/34C07D333/20C07D333/32C07D409/04A61K31/381A61K31/4025A61P31/16
CPCC07D333/20C07D333/28C07D333/32C07D333/34C07D333/38C07D409/04
Inventor 胡文辉余细勇赵昕吴波杨子峰曾少高
Owner GUANGZHOU MEDICAL UNIV
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