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Heterocyclic compound and its preparation method and use

A compound and cycloalkyl technology, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., can solve problems such as unsatisfactory activity and improve drug metabolism Kinetic properties, good physical and chemical properties, and the effect of improving safety

Active Publication Date: 2020-10-09
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the above two types of compounds have shown antiviral activity to varying degrees, their activity has not yet reached a satisfactory level.

Method used

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  • Heterocyclic compound and its preparation method and use
  • Heterocyclic compound and its preparation method and use
  • Heterocyclic compound and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0241] The present invention is further described below in conjunction with the examples, but the provision of these examples is not intended to limit the scope of the present invention.

[0242] Unless otherwise stated, commercially available anhydrous and HPLC grade solvents were used without further purification.

[0243] Recorded at ambient temperature with a Bruker instrument (400MHz) 1 H NMR spectrum using TMS as internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) are given in Hertz (Hz). 1 The splitting multiplicity of H NMR spectral peaks is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

[0244] LC-MS adopts Agilent 1200 liquid chromatograph coupled with Agilent 6120 Quadrupole mass spectrometer, and detects at 214nm and 254nm. The preparative liquid chromatography uses SHIMADZU CBM-20A and Agilent 1260 preparative liquid chromatograph, C18OBD 19×150mm5μM preparative column, dete...

Embodiment 1

[0246] Example 1 (4R)-6-((4-(4-((((((R)-1-(6-amino-9H-purin-9-yl)prop-2-yl)oxy)methyl Base) ((2-methylbenzyl)oxy)phosphono)oxy)phenyl)piperidin-1-yl)methyl)-4-(2-chloro-4-fluorophenyl)-2- (Thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 1)

[0247]

[0248] Step 1: Synthesis of tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (compound 1-2)

[0249] At room temperature, tert-butyl 4-(4-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (compound 1-1) (3.0g, 8.2mmol) was added Add 10% Pd / C (300mg) to tetrahydrofuran (10mL) and methanol (20mL), after the compound is completely dissolved, add 10% Pd / C (300mg) under the protection of nitrogen, complete the addition, replace with hydrogen, react at room temperature for 18h, filter, and post-process the filtrate to obtain The title compound (2.0 g). ESI-MS(m / z): 222.1[M-55+H] + .

[0250] Step 2: 4-(4-(((((R)-1-(6-amino-9H-purin-9-yl)prop-2-yl)oxy)methyl)(hydroxy)phosphono) Synthesis ...

Embodiment 2

[0260] Example 2 (4R)-6-((4-(4-((((((R)-1-(6-amino-9H-purin-9-yl)prop-2-yl)oxy)methyl base)(((S)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphono)oxy)phenyl)piperidin-1-yl)methyl)-4-( 2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 2)

[0261]

[0262] Compound 1-5 (30 mg, 0.04 mmol), L-ethyl lactate (8.0 mg, 0.07 mmol) and PyBOP (38 mg, 0.07 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature , after the dissolution was complete, N,N-diisopropylethylamine (19 mg, 0.14 mmol) was added dropwise. After the addition was complete, the reaction was carried out at room temperature for about 4 h, and the title compound (5.0 mg) was obtained after purification.

[0263] Its structure is characterized as follows:

[0264] 1 H NMR (400MHz, DMSO-d 6 )δ9.77(s, 1H), 8.13(s, 1H), 8.05(s, 1H), 8.03(d, J=23.26Hz, 1H), 7.95(d, J=3.13Hz, 1H), 7.44- 7.40(m, 2H), 7.27-7.16(m, 5H), 7.05-7.03(m, 2H), 6.06(s, 1H), 5.00-4.92(...

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Abstract

The present invention relates to a heterocyclic compound having anti-viral activity, a drug composition comprising same, a preparation method thereof, and an application thereof for the prevention or treatment of viral diseases including but not limited to viral hepatitis A, viral hepatitis B, viral hepatitis C, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).

Description

[0001] field of invention [0002] The present invention relates to a heterocyclic compound with antiviral activity, a pharmaceutical composition containing it, a preparation method thereof and its application in the prevention or treatment including but not limited to viral hepatitis A, viral hepatitis B, viral hepatitis C, Use in viral diseases of influenza, herpes and acquired immunodeficiency syndrome (AIDS). [0003] Background of the invention [0004] Viruses consist of a nucleic acid molecule (DNA or RNA) and protein or only protein (such as prions). Viruses can cause a variety of infectious diseases, common diseases caused by viruses include but are not limited to viral hepatitis A, viral hepatitis B, viral hepatitis C, influenza, herpes and acquired immunodeficiency syndrome (AIDS). [0005] Antiviral drugs currently in clinical use work by inhibiting virus attachment, uncoating, viral gene replication, maturation or release, or by affecting the host's immune system...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61P31/16A61P31/14A61K31/685A61K31/675A61P31/12A61P31/22A61P31/20
CPCA61K31/675A61K31/685A61P31/12A61P31/14A61P31/16A61P31/20A61P31/22C07F9/6561Y02A50/30
Inventor 蔡家强宋帅邓汉文曾宏宋宏梅唐祖建刘瑶田强黄海涛王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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