Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Non-nucleoside reverse transcriptase inhibitors

a reverse transcriptase inhibitor and non-nucleoside technology, applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems of mutant hiv strains that are resistant to known inhibitors, and are highly susceptible to debilitating and ultimately fatal opportunistic infections

Inactive Publication Date: 2013-11-07
MERCK CANADA INC
View PDF1 Cites 14 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about certain compounds that can inhibit the activity of HIV reverse transcriptase, prevent infection by HIV, treat infection with HIV, and delay the onset or progression of AIDS and ARC. These compounds include certain 3- (optionally substituted phenoxy)-1- ((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methylene-1,2-pyridinone compounds and their pharmaceutically acceptable salts. The invention also includes methods for making these compounds and using them for the aforementioned purposes.

Problems solved by technology

Affected individuals exhibit severe immunosuppression which makes them highly susceptible to debilitating and ultimately fatal opportunistic infections.
A particular problem is the development of mutant HIV strains that are resistant to the known inhibitors.

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
  • Non-nucleoside reverse transcriptase inhibitors
  • Non-nucleoside reverse transcriptase inhibitors
  • Non-nucleoside reverse transcriptase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)

[0493]

Step 1(a): 3-(3-bromo-5-chlorophenoxy)-2-chloro-4-(trifluoromethyl)pyridine (1-2)

[0494]

[0495]A mixture of the 3-bromo-5-chlorophenol (3.74 g; 18.0 mmol), 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (3.00 g; 15.0 mmol) and K2CO3 (2.49 g; 18.0 mmol) in NMP (15 mL) was heated to 120° C. for one hour, then cooled to room temperature. The mixture was then diluted with 250 mL EtOAc and washed with 3×250 mL 1:1 H2O:brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by ISCO CombiFlash (120 g column; load with toluene; 100:0 to 0:100 hexanes:CH2Cl2 over 40 minutes) provided title compound (1-2) as a white solid. Repurification of the mixed fractions provided additional title compound. 1H NMR (400 MHz, CDCl3): δ 8.55 (d, J=5.0 Hz, 1H); 7.64 (d, J=5.0 Hz, 1H); 7.30 (s, 1H); 6.88 (s, 1H); 6.77 (s, 1H).

Step ...

example 1a

3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile (1-1)

[0505]

Step 1A(a): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (1A-2)

[0506]

[0507]A mixture of the 3-chloro-1-iodophenol (208 g; 816.0 mmol), 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (155 g; 777.0 mmol) and K2CO3 (161 g; 1165.0 mmol) in NMP (1.5 L) was held at 60° C. for 2.5 hours, and then left at room temperature for 2 days. The mixture was then re-heated to 60° C. for 3 hours, then cooled to room temperature. The mixture was then diluted with 4 L EtOAc and washed with 2 L water+1 L brine. The combined organics were then washed 2× with 500 mL half brine then 500 mL brine, dried over MgSO4 and concentrated to afford crude 1A-2. 1H NMR (500 MHz, DMSO) δ 8.67 (d, J=5.0 Hz, 1H), 7.98 (d, J=5.0 Hz, 1H), 7.63-7.62 (m, 1H), 7.42-7.40 (m, 1H), 7.22 (t, J=2.1 Hz, 1H).

Step 1A(b): 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(triflu...

example 2

3-Chloro-5-({1-[(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile (2-1)

[0513]

[0514]The title compound was prepared using the procedure described in Example, wherein the iodomethane employed in Step 1(f) was replaced with iodoethane. 1H NMR (400 MHz, DMSO): δ 11.68 (s, 1H); 7.92 (d, J=7.3 Hz, 1H); 7.76 (s, 1H); 7.60 (s, 1H); 7.52 (s, 1H); 6.69 (d, J=7.3 Hz, 1H); 5.20 (s, 2H); 3.65-3.56 (m, 2H); 1.11 (t, J=7.1 Hz, 3H).

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

PropertyMeasurementUnit
purityaaaaaaaaaa
purityaaaaaaaaaa
room temperatureaaaaaaaaaa
Login to View More

Abstract

Heteroaromatic compounds of Formula I:are HIV reverse transcriptase inhibitors, wherein R1, R2, R3, R4 and R5 are defined herein. The compounds of Formula I and their pharmaceutically acceptable salts are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

Description

FIELD OF THE INVENTION[0001]The present invention is directed to certain 3-(optionally substituted aromatic and aliphatic hydrocarbyloxy)-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl])-pyridin-2(1H)-one compounds and their use for the inhibition of HIV reverse transcriptase, the prophylaxis of HIV infection and HIV replication, the treatment of HIV infection and HIV replication, the prophylaxis of AIDS, the treatment of AIDS, and the delay in the onset and / or progression of AIDS.BACKGROUND OF THE INVENTION[0002]The retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) and type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which makes them highly susceptible to debilit...

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 Applications(United States)
IPC IPC(8): C07D401/06A61K45/06A61K31/4439
CPCC07D401/06A61K31/4439A61K45/06A61P31/00A61P31/18
Inventor BURCH, JASONCOTE, BERNARDNGUYEN, NATALIELI, CHUN SINGST-ONGE, MIGUELGAUVREAU, DANNY
Owner MERCK CANADA INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com