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

Dhfr inhibitors, compositions, and methods related thereto

A compound, R12 technology, applied in DHFR inhibitors, compositions and related fields, can solve side effects and other problems

Inactive Publication Date: 2020-06-02
VYERA PHARMA LLC
View PDF12 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, clinically relevant doses of pyrimethamine produce plasma concentrations that effectively inhibit hDHFR, leading to many of the observed mechanistic side effects of pyrimethamine
Furthermore, the relatively high IC of pyrimethamine against tgDHFR 50 Requires high plasma concentrations for efficacy, which may lead to additional off-target induced side effects

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
  • Dhfr inhibitors, compositions, and methods related thereto
  • Dhfr inhibitors, compositions, and methods related thereto
  • Dhfr inhibitors, compositions, and methods related thereto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0238] Example 1: General method

[0239] for 1 H NMR, NMR spectra were recorded on Varian 400 MHz. Quadrupole operating in ES(+) ionization mode on Shimadzu LCMS 2010 (column: sepaxODS 50 x 2.0mm, 5um) or Agilent 1200HPLC, 1956MSD (column: Shim-pack XR-ODS 30 x 3.0mm, 2.2um) LCMS was performed on a mass spectrometer.

[0240] LC / MS method A: run at 40°C on a Shimadzu LC-20AB with MS 2010 detector using a Luna-C18(1) column (2.0*30mm, 3um). Mobile phase A was 0.037% (v / v) TFA in water and mobile phase B was 0.018% (v / v) TFA in acetonitrile. The flow rate was 0.8 mL / minute from 0.01 to 1.51 minutes and then 1.2 mL / minute from 1.52 to 2.00 minutes. The gradient was from 90% mobile phase A to 10% mobile phase A over 1.15 minutes, then held at 10% mobile phase A until 1.65 minutes, then back to 90% mobile phase A at 1.66 minutes, and held at 90% until 2.0 minutes % mobile phase A. UV detection was at 220 nm and MS was measured in positive ion mode.

[0241] LC / MS method B...

Embodiment 2

[0244] Embodiment 2: synthetic method A

[0245]

[0246] Piperazine intermediate 1001 is generally commercially available or can be prepared by various literature methods (i.e., Rong Gao and Daniel J. Canney. A versatile and practical microwave-assisted synthesis of sterically hindered N-arylpiperazines, J. Org. Chem. , 2010, 75(21), 7451-53). For example, aniline or aminoheteroaryl starter 1002 can be reacted with bis(2-chloroethyl)amine and sulfolane at 140°C to give intermediate 1001. (Lokesh Ravilla et al., An efficient scale up process for synthesis of N-arylpiperazines Tetrahefron Letters, 2015, 56(30), 4541-44). Alternatively, protected piperazines can be reacted with bromoaryl or bromoheteroaryl compounds 1003 under Buchwald conditions to afford the desired intermediate 1001.

[0247] Using KF as a basic catalyst and heating in DMSO, 1001 undergoes a nucleophilic substitution reaction with 5-bromopyrimidine-2,4(1H,3H)-dione 1004 to give 5-piperazinylpyrimidine ...

Embodiment 3

[0293] Embodiment 3: synthetic method B

[0294] According to Synthetic Method B, the compounds of the present invention can be prepared by Suzuki or Stille coupling reactions as shown below.

[0295]

[0296] Alternatively, the bromophenyl derivative 1010 can also be converted to the boronic acid ester 1011 shown below, which can then be reacted under Suzuki reaction conditions with a variety of aryl or heteroaryl halides, as shown below with 4 -Chloro-2-methylpyrimidine reaction is exemplified to give the final target as 1012.

[0297]

[0298] Synthesis method B is exemplified by the synthesis of 5-(4-(3-(2-methylpyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine (compound 69):

[0299]

[0300] 5-(4-(3-bromophenyl)piperazin-1-yl)pyrimidine-2,4-diamine (compound 1010) (1.0g, 2.8mmol, 1.0 equivalent), (2-methylpyrimidine- 5-yl)boronic acid (394.9mg, 2.8mmol, 1.0eq), Cs 2 CO 3 (1.4g, 4.3mmol, 1.5 equivalents), Pd(PPh 3 ) 4 (165.4mg, 143.2umol, 0.05 e...

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

The invention relates to inhibitors of dihydrofolate reductase and pharmaceutical preparations thereof. The invention further relates to methods of treatment of parasitic infections, such as T. gondii, T. cruzi, P. falciparum, T. brucei, or L. major infections, using novel inhibitors of the invention.

Description

[0001] related application [0002] This application claims the benefit of priority from U.S. Provisional Patent Application No. 62 / 542,018, filed August 7, 2017, which is hereby incorporated by reference in its entirety. [0003] Background of the invention [0004] Parasitic protozoan infection is a big problem concerning human health. Toxoplasmosis is a parasitic infection caused by Toxoplasmagondii (T. gondii). Although toxoplasmosis is often asymptomatic, people infected with toxoplasmosis may experience severe symptoms, including seizures, poor coordination, lung damage, eye damage, and brain damage; and infection in immunocompromised patients It is often fatal if not treated. Other parasitic protozoan infections include leishmaniasis / leishmaniosis, which is caused by Leishmania major (L. major), Leishmania tropicala (L. tropica), Leishmania brasiliensis Protozoa of the genus Leishmania including Leishmania brasiliensis (L.brasiliensis) and Leishmania donovani (Leishma...

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(China)
IPC IPC(8): C07D401/04C07D401/14C07D403/04C07D403/14C07D405/14C07D409/14C07D413/14C07D417/14A61K31/506A61P33/02A61P33/06
CPCA61P33/02A61P33/06C07D239/50C07D401/12C07D401/14C07D403/12C07D403/14C07D405/12C07D405/14C07D417/12
Inventor A·T·霍普S·B·托马斯M·威尔士
Owner VYERA PHARMA LLC
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