A kind of small molecular compound as jak kinase inhibitor and its use

A small molecule compound, compound technology, applied in the direction of anti-inflammatory agent, drug combination, organic chemistry, etc., to achieve good JAK kinase activity and effect

Active Publication Date: 2021-10-22
TECHNODERMA MEDICINES
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  • 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

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  • A kind of small molecular compound as jak kinase inhibitor and its use
  • A kind of small molecular compound as jak kinase inhibitor and its use
  • A kind of small molecular compound as jak kinase inhibitor and its use

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...

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PUM

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Abstract

The present invention provides a small molecular compound, which is a compound represented by the following formula, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, and pharmaceutically Acceptable salt or prodrug, wherein R 1 to R 5 Each is independently selected from C or N; and wherein R is selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. The small molecule compound of the present invention can inhibit JAK kinase, more particularly 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

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Application Information

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