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Cyclohexene derivative or its pharmaceutically acceptable salt and application thereof

A technology of cyclohexene and derivatives, which is applied in the field of cyclohexene derivatives and can solve problems such as limited applications

Active Publication Date: 2013-07-31
GUANGZHOU HENOVCOM BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally, drug resistance occurs 2-3 days after the start of treatment, and it is only effective against influenza A, thus limiting its clinical application

Method used

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  • Cyclohexene derivative or its pharmaceutically acceptable salt and application thereof
  • Cyclohexene derivative or its pharmaceutically acceptable salt and application thereof
  • Cyclohexene derivative or its pharmaceutically acceptable salt and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1 Compound 3-1: (3R,4R,5S)-4-acetamido-5-amino-3-(3(S)-ethoxypiperidine)-1-cyclohexene-1-carboxy acid preparation.

[0124] 1. Preparation of intermediate 1.

[0125] Using shikimic acid as the starting material, the intermediate 1 ((3R,4R,5S)-3-acetoxy-4-acetamido-5-tert-butoxyamido-1-cyclohexyl was prepared after conversion Alkene-1-carboxylate ethyl ester), the reaction process is as follows:

[0126]

[0127] 2. Preparation of (3R,4R,5S)-4-acetamido-5-tert-butylcarboxamido-3-(3(S)-ethoxypiperidine)-1-cyclohexene-1-carboxylic acid .

[0128] Dissolve intermediate 1 (1 mmol) and tetrakistriphenylphosphine palladium (58 mg, 0.05 mmol) in 5 mL of DMF under nitrogen protection, add DIPEA (0.6 mL, 3 mmol), stir for 5 minutes, and then add 3S-ethoxypiperidine Pyridine in DMF. Stir at room temperature for 5 minutes, then heat the reaction at 80°C until the end (about 2h). After cooling to room temperature, 50 mL of ethyl acetate and 10 mL of saturated brine...

Embodiment 2

[0132] Example 2 Compound 5-1: Preparation of (3R,4R,5S)-4-acetamido-5-piperyl-3-S-ethoxypiperidine-1-cyclohexene-1-carboxylic acid.

[0133] Take the compound 3-1 prepared in Example 1, dissolve it in DMF solution, add 1H-pyrazole-1-carboxamidine and triethylamine, and stir at room temperature for 8 hours. After the solvent was distilled off under reduced pressure, it was redissolved in ethyl acetate, and the pH was adjusted to 2-3 with 1M HCl. The precipitate was filtered to obtain compound 5-1.

[0134] The characterization data of compound 5-1 is: ESI-MS m / z: 368(M+1). 1 H NMR (400MHz,MeOD)δ6.96(s,1H),4.51–4.32(m,2H),4.02–3.89(m,1H),3.85(br,1H),3.65-3.45(m,4H), 3.35(s,1H),3.00(dd,J=17.9,4.9Hz,1H),2.46(dd,J=17.5,10.5Hz,1H),2.26(d,J=38.9Hz,1H),2.08(d ,J=17.5Hz,3H),1.82(d,J=14.9Hz,1H),1.33-1.40(m,3H),1.20(t,J=6.9Hz,3H), 13 CNMR (126MHz, MeOD) δ175.56, 167.35, 158.85, 137.85, 127.35, 68.56, 65.53, 55.82, 54.75, 51.79, 50.56, 43.77, 31.45, 22.70, 18.70, 17.28, 15.60.

Embodiment 3

[0135] Example 3 Compound 3-2: (3R,4R,5S)-4-acetamido-5-amino-3-(3(S)-acetamidopiperidine)-1-cyclohexene-1-carboxy acid preparation.

[0136] 1. Preparation of Intermediate 1: Same as Example 1.

[0137] 2. (3R,4R,5S)-4-acetamido-5-tert-butylformylamino-3-(3(S)-acetamidopiperidine)-1-cyclohexene-1-carboxylic acid preparation.

[0138] Dissolve intermediate 1 and tetrakistriphenylphosphine palladium in DMF under nitrogen protection, add DIPEA, stir for 5 minutes, then add 3S-acetamidopiperidine in DMF, and heat the reaction until the end. Cool to room temperature, add ethyl acetate and saturated brine for extraction, and dry the organic phase over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and compound 2-2 was obtained after separation by column chromatography.

[0139] 3. Preparation of compound 3-1.

[0140] Compound 2-2 was dissolved in tetrahydrofuran, and the rest of the operations were the same as in Example 1 to obtain compound...

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Abstract

Belonging to the field of pharmaceutical chemistry, the invention discloses a cyclohexene derivative shown as formula I or its pharmaceutically acceptable salt. The cyclohexene derivative or its pharmaceutically acceptable salt has good inhibitory activity on influenza virus neuraminidase, and especially has high activity on the neuraminidase of oseltamivir resistant influenza virus strains.

Description

technical field [0001] The present invention relates to the technical field of medicinal chemistry, in particular to a cyclohexene derivative and its application. Background technique [0002] Influenza is a common respiratory disease that can debilitate the patient and cause various complications, sometimes requiring hospitalization and possibly death. It is highly contagious, and it is easy for the elderly and infirm with weaker resistance to infect each other , causing a certain range of popularity. Annual influenza epidemics cause 3 to 5 million severe cases and 300,000 to 500,000 deaths. People older than 65 years old and younger than two years old with poor immunity are high-risk groups that may develop severe illness and death. [0003] Influenza virus has a wide host range and segmented genome, and it is prone to gene mutation or gene reassortment to form new variants during its infection and replication process. This is the fundamental reason for the high variabil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/42C07D211/56C07D211/70C07D207/08C07D207/12C07D211/46C07D211/58C07D211/22C07D223/08A61K31/55A61K31/451A61K31/454A61K31/40A61P31/16
Inventor 张健存
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
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