Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor

A CH3, -5-N technology, applied in antiviral agents, medical preparations containing active ingredients, organic chemistry, etc.

Active Publication Date: 2014-09-24
HUAXIASHENGSHENG PHARMA BEIJING CO LTD
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of drug is prone to drug resistance, only one nucleotide mutation is needed to produce drug resistance, and it can produce cross-resistance with other NNRTIs

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor
  • Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor
  • Preparation and application of novel 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

[0013] Preparation of Example 13-oxo-4-(3,5-dimethyl)-phenylbutyric acid ethyl ester (compound 1)

[0014] Suspend the activated zinc powder (washed successively with 3N hydrochloric acid, distilled water, absolute ethanol, and absolute ether, and then vacuum-dry) in dry THF (125ml) and heat to reflux, drop 20 drops of ethyl bromoacetate , when the cloudy solution was gray-green (about 45 minutes), 3,5-dimethylbenzonitrile (1.305 g, 9.0 mmol) was added in one portion, and bromoacetic acid was slowly added dropwise in about 1 hour Ethyl ester (4.95ml, 45mmol), reflux for 10 minutes after the dropwise addition. Diluted with THF (125ml×3), added potassium carbonate aqueous solution (50%, 54ml) and stirred rapidly for 45 minutes, left to stand and separated to form two phases. The upper THF phase was poured out, and the remaining part was washed with THF (2×100 ml). The combined THF phases were added with hydrochloric acid (10%, 50 ml) and stirred at room temperature for 45 minut...

Embodiment 2

[0016] Preparation of Example 22-thio-6-(3,5-dimethyl)-benzyluracil (compound 2)

[0017]4.54g (197.5mmol) of sodium metal was dissolved in 108ml of absolute ethanol, 10.54g (136mmol) of thiourea and 2.10g (9.0mmol) of compound 1 were added, and the reaction mixture was heated to reflux for 6 hours. Rotate under reduced pressure at 40-50°C until almost completely dry, and dissolve the residue in water (80ml). Add concentrated hydrochloric acid (20ml) to precipitate a precipitate, add glacial acetic acid to adjust pH ≈ 4, filter the precipitate with a suction filter funnel, wash with 10% EtOH solution, and dry to obtain a white solid 2-thio-6-(3,5-di Methyl)-benzyluracil 2.098g (compound 2), two-step total yield 94.7%, mp 253~255°C.

[0018] MS(ESI+) m / z: 247.1[M+H] + , 269.1[M+Na] +

Embodiment 3

[0019] Preparation of Example 36-(3,5-dimethyl)-benzyluracil (compound 3)

[0020] 2-Thio-6-(3,5-dimethyl)-benzyluracil (2.098g, 8.53mmol) was dissolved in 10% chloroacetic acid (150ml), and heated to reflux for 24 hours. After cooling to room temperature, a white needle-like solid precipitated, which was filtered out with a suction filter funnel, washed with cold ethanol and cold ether in turn, and dried to obtain a white solid 6-(3,5-dimethyl)-benzyluracil 1.258g, yield 64.2%, mp 288-290°C.

[0021] MS(ESI+) m / z: 231.1[M+H] + , 253.1[M+Na] +

[0022] 1 H NMR (300MHz, DMSO-d 6 )δ: 11.69(s, 1H, N3-H), 10.93(s, 1H, N1-H), 6.92~6.90(m, 3H, Ph-H), 5.22(s, 1H, C5-H), 3.54 (s, 2H, CH 2 ), 2.25(s, 6H, Ph-CH 3 ).

[0023] 13 C NMR (75MHz, DMSO-d 6 )δ: 21.31 (CH 2 Ph), 37.90 (CH 2 Ph), 99.24(C-5), 156.18(C-6), 152.07(C-2), 164.57(C-4), 138.00, 136.38, 128.84, 127.19(C arom ).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

This application involves the use of non-nucleoside HIV-1 reverse transcriptase inhibitor 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) as the lead substance, which is combined into clinical The experimental drugs MKC-442 and TNK-651, based on the theory of bioelectron isosterism and hydrogen bonding, designed a new class of molecules with related structures. See general formula I, the definition of each group in the formula is as described in the claims. At the same time, it also relates to the evaluation of the reverse transcriptase activity of the compounds and the application of these compounds as HIV-1 reverse transcriptase inhibitors. The conformation of the synthesized new compound is more conducive to the combination with HIV-1 reverse transcriptase, which is more conducive to its inhibition of reverse transcriptase activity, and becomes a new type of HIV-1 reverse transcriptase inhibitor with high activity and low toxicity agent.

Description

1. Technical field [0001] This application involves the use of non-nucleoside HIV-1 reverse transcriptase inhibitor 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) as the lead substance, which is combined into clinical The experimental drugs MKC-442 and TNK-651, based on the theory of bioelectron isosterism and hydrogen bonding, designed a new class of molecules with related structures. The conformation of the synthesized new compound is more conducive to the combination with HIV-1 reverse transcriptase, which is more conducive to its inhibition of reverse transcriptase activity, and becomes a new type of HIV-1 reverse transcriptase inhibitor with high activity and low toxicity agent. Among them, the amino group at the 4-position of the compound can form more hydrogen bonds through tautomerism, which enhances the interaction with reverse transcriptase; increasing the volume of the substituent at the 5-position is more conducive to exerting its steric hindrance and m...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/553C07D239/47C07D239/545A61K31/513A61P31/18
Inventor 王孝伟张建芳刘俊义马丽英
Owner HUAXIASHENGSHENG PHARMA BEIJING CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap