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

Small molecule compound serving as JAK kinase inhibitor, and application thereof

A technology of small molecular compounds and compounds, applied in anti-inflammatory agents, digestive system, organic chemistry, etc.

Active Publication Date: 2021-01-01
TECHNODERMA MEDICINES
View PDF7 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although some studies have reported that JAK1 inhibitors can specifically inhibit Th2 allergic inflammation, there are few reports on the effective inhibition of JAK1 and / or TYK2 inhibitors at the same time. Has broader promise, especially in inflammatory diseases whose pathogenesis involves autoimmune abnormalities
In addition, the pathogenesis of more inflammatory diseases, especially inflammatory skin diseases, may involve multiple JAKs, so it is of great significance to develop potent single or dual inhibitors of JAK1 and Tyk2, especially for topical treatment of skin diseases , strong inhibitors can bring good curative effect while avoiding the side effects caused by systemic drugs, but this will also require strong inhibitory activity to achieve

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
  • Small molecule compound serving as JAK kinase inhibitor, and application thereof
  • Small molecule compound serving as JAK kinase inhibitor, and application thereof
  • Small molecule compound serving as JAK kinase inhibitor, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1 The General Method for Synthesizing Compound 1 (TDM-180973)

[0076]

[0077] Step 1: Preparation of compound 1c (2-chloro-4-(1H-pyrrol-3-yl)pyrimidine)

[0078] Add compound 1a (2g, 13.43mmol) to 250mL three-necked flask, compound 1b (4.69g, 13.43mmol), tetrakis (triphenylphosphine) palladium (940mg, 1.08mmol), potassium carbonate (3.7g, 26.85mmol), Dioxane (120 mL) and water (120 mL). The reaction liquid was replaced with nitrogen several times, heated to 80°C for 45 minutes, LCMS [M+H] +=180, the detection reaction is complete. Post-processing: the reaction solution was concentrated and dried, and the obtained crude product was passed through the column [eluent: (EA / PE)=0-30%] to obtain the target compound (compound 1c, 1.13g, yield 46.86%) as a yellow solid, LCMS [M+1] + =180.

[0079] Step 2: Compound 1e (3-(3-(2-chloropyrimidin-4-yl)-1H-pyrrol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylic acid tert Butyl ester) preparation

[0080] To a solution ...

Embodiment 2

[0088] Example 2 The General Method of Synthetic Compound 2 (TDM-180975)

[0089]

[0090] Step 1: Preparation of compound 2b (3-methyl-5-nitropyridinemethylamide)

[0091] A mixed solution of compound 2a (3 g, 18.4 mmol) and concentrated sulfuric acid (18 ml) was heated to 80° C. and stirred for 25 minutes. LCMS[M+H] + =182, the detection reaction is complete. Post-treatment: Cool the reaction solution to room temperature, pour it into ice water (100ml), then adjust the pH to neutral with sodium carbonate, extract the mixture three times with ethyl acetate (3*100ml), combine the organic phases, and wash with saturated brine , dried over anhydrous sodium sulfate, suction filtered, concentrated and pulled to dryness to obtain the yellow target compound (compound 2b, 3.33g, yield 94.2%), LCMS [M+1] + =182.

[0092] Step 2: Preparation of compound 2c (5-amino-3-methylpicolylamide)

[0093] Add palladium carbon (10%, 300 mg) to compound 2b (3.14 g, 17.33 mmol) in methanol ...

Embodiment 3

[0097] Example 3 The General Method of Synthetic Compound 3 (TDM-180976)

[0098]

[0099] Step 1: Preparation of compound 3b (ethyl 3-methyl-5-nitrolinoleate)

[0100] Concentrated sulfuric acid (40ml) was slowly added to ethanol (160ml) solution at 0°C, then compound 3a (4g, 24.5mmol) was added in batches to the reaction solution, and the reaction solution was heated to reflux and stirred for 72 hours. LCMS[M+H] + =211, the detection reaction is complete. Post-treatment: Cool the reaction solution to room temperature and pour it into water (50ml), extract three times with ethyl acetate (3*50mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, suction filter, concentrate and extract Dry to obtain the yellow target compound (compound 3b, 3.73g, yield 72.56%), LCMS [M+1] + =211.

[0101] Step 2: Preparation of compound 3c (3-methyl-5-nitrolinoleic acid)

[0102] Add 1N sodium hydroxide (120ml, 120.16mmol) solution to compound 3b...

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 present invention provides a small molecule compound. The small molecule compound is a compound represented by a formula shown in the description, or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, and a pharmaceutically acceptable salt or prodrug thereof; and in the formula, R1 to R5 are each independently selected from C or N, and R is selected from a cycloalkyl group,a substituted cycloalkyl group, a heterocycloalkyl group, a substituted heterocycloalkyl group, an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group. The smallmolecule compound can inhibit JAK kinase, and is particularly used as a JAK1 / Tyk2 dual inhibitor and a Tyk2 specific inhibitor.

Description

technical field [0001] The present invention belongs to the field of small molecule compounds, in particular, relates to a compound that can be used to prevent or treat autoimmune diseases such as rheumatoid arthritis, ulcerative colitis and systemic lupus erythematosus, etc., or related inflammatory skin diseases such as Small molecule compounds for psoriasis, eczema, vitiligo and alopecia areata, etc. Background technique [0002] JAK (Janus kinase, Janus Kinase) is a family of intracellular non-receptor tyrosine protein kinases, including four members JAK1, JAK2, JAK3 and Tyk2. The JAK-STAT (Signal Transducer and Activator of Transcription proteins) signal transduction pathway is the main pathway for intracellular transduction of signals stimulated by the combination of inflammatory cytokines and receptors. Many evidences show that the JAK-STAT signaling pathway plays an indispensable driving role in the pathogenesis of many diseases, especially autoimmune diseases such ...

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
IPC IPC(8): C07D403/14C07D401/14A61K31/506A61P37/06A61P17/00A61P29/00A61P19/02A61P1/04A61P3/10A61P9/14A61P17/06A61P17/10
CPCC07D403/14C07D401/14A61P37/06A61P17/00A61P29/00A61P19/02A61P1/04A61P3/10A61P9/14A61P17/06A61P17/10C07B2200/07A61K31/506A61P37/00
Inventor 方文奎李冠群蔡雨婷潘翔朱文浩汪杨王增全
Owner TECHNODERMA MEDICINES
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