Pharmaceutical compound used as JAK kinase inhibitor

A drug compound and compound technology, which can be used in drug combinations, antipyretics, anti-inflammatory agents, etc., can solve problems such as few reports of Tyk2, and achieve the best therapeutic effect, good JAK kinase activity and the effect of

Active Publication Date: 2020-11-20
TECHNODERMA MEDICINES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, many pharmaceutical companies have developed new drugs targeting JAK family members, bu

Method used

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  • Pharmaceutical compound used as JAK kinase inhibitor
  • Pharmaceutical compound used as JAK kinase inhibitor
  • Pharmaceutical compound used as JAK kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 General method for synthesis of compound 1 (TDM-180944)

[0049]

[0050] Step 1: Preparation of compound 1 (TDM-180944)

[0051] To a solution of compound 1a (60 mg, 0.225 mmol) in pyridine (5 mL) was added compound 1b (65.8 mg, 0.315 mmol) at room temperature, and the mixture was heated to 70° C. and stirred for 6 h. Then the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane: 10% methanol in dichloromethane = 70:30) and formic acid preparation to obtain yellow solid compound 1, TDM-180944, namely 1- (2-Fluorophenyl)-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)methanesulfonamide (34.5mg , 34.97% yield).

[0052] 1 H NMR(400MHz, DMSO-d 6 )δ10.34(s,1H),9.45(s,1H),8.45(d,J=5.2Hz,1H), 8.10(d,J=8.6Hz,2H),7.93(s,1H),7.55( s, 1H), 7.45–7.30 (m, 4H), 7.25–7.17 (m, 3H), 4.60 (s, 2H), 3.84 (s, 3H). LCMS[M+1] + = 439.2.

Embodiment 2

[0053] Example 2 General method for synthesis of compound 2 (TDM-180945)

[0054] Prepare compound 2 in a similar manner to Example 1: TDM-180945, namely 1-(3-fluorophenyl)-N-(4-(2-(((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl ) Methanesulfonamide (26.1 mg, 19.8% yield).

[0055] 1 H NMR(400MHz, DMSO-d 6 )δ10.25(s,1H),9.45(s,1H),8.45(d,J=5.2Hz,1H), 8.12(d,J=8.6Hz,2H),7.93(s,1H),7.56( s, 1H), 7.40 (dd, J = 14.3, 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.26-7.15 (m, 2H), 7.11 (d, J = 7.3 Hz, 2H ), 4.63 (s, 2H), 3.84 (s, 3H). LCMS[M+1] + = 439.2.

Embodiment 3

[0056] Example 3 General method for synthesis of compound 3 (TDM-180958)

[0057]

[0058] Step 1: Preparation of compound 3c (3-cyanobenzylaminothiocarbamate)

[0059] Compound 3b (690 mg, 9.08 mmol) was added to the ethanol (13 mL) solution of compound 3a (1.78 g, 9.08 mmol), the reaction solution was heated to 80° C. and stirred for 1 hour, LCMS [M+H] + =192, the detection reaction is complete. Post-treatment: the reaction solution was concentrated to dryness to obtain the white target compound (compound 3c, 1.7 g, yield 97.7%), LCMS [M+1] + =192.

[0060] Step 2: Preparation of compound 3d ((3-cyanophenyl)methanesulfonyl chloride)

[0061] To the N-chlorosuccinimide (4.85g, 36.32mmol) in acetonitrile (20mL) was added 2N hydrochloric acid solution (2.5mL) and compound 3c (1.74g, 9.08mmol), the reaction solution was stirred at room temperature for 30 minutes . Post-treatment: After the reaction was completed, the acetonitrile was concentrated and removed, water (15 mL) was added, ...

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Abstract

The invention provides a pharmaceutical compound. The pharmaceutical compound is a compound shown in the following structural formula or a stereoisomer, a geometrical isomer, a tautomer, a racemate, ahydrate, a solvate, a metabolite and a pharmaceutically acceptable salt or prodrug thereof shown in the specification, wherein R represents 1 to 3 substituents on a benzene ring, and each of the 1 to3 substituents is independently selected from halogen or cyano. The pharmaceutical compound provided by the invention can inhibit JAK kinase, and more particularly can be used as a JAK1/Tyk2 dual inhibitor and a Tyk2 specific inhibitor. More specifically, the pharmaceutical compound provided by the invention can be used for preventing or treating autoimmune diseases such as rheumatoid arthritis,ankylosing spondylitis, ulcerative colitis, systemic lupus erythematosus, type I diabetes, sicca syndrome, vasculitis, alopecia areata, psoriasis, leucoderma and the like, or other inflammatory skin diseases such as atopic dermatitis, eczema, acne and hidradenitis suppurativa.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical compounds. Specifically, it relates to a method that can be used to prevent or treat autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, systemic lupus erythematosus, Dermatomyositis, multiple sclerosis, type I diabetes, psoriasis, vitiligo, Sjogren’s syndrome, etc., or other inflammatory skin diseases such as atopic dermatitis, eczema, lichen planus, lichen lustre, atrophic lichen sclerosus, lipid membrane Pharmaceutical compounds for inflammation, acne, hidradenitis suppurativa, etc., specifically, relates to a compound that is a JAK kinase inhibitor. Background technique [0002] Protein kinases catalyze the phosphorylation of amino acids at specific sites of proteins, and can be divided into tyrosine, serine and arginine kinases according to the phosphorylation of amino acids. JAK is a family of intracellular non-receptor tyrosine pro...

Claims

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Application Information

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IPC IPC(8): C07D403/12A61K31/506A61P29/00A61P37/02A61P3/10A61P17/10A61P17/00A61P9/10A61P1/04
CPCC07D403/12A61P29/00A61P37/02A61P3/10A61P17/10A61P17/00A61P9/10A61P1/04
Inventor 邢莉方文奎李冠群蔡雨婷王晓磊潘翔朱文浩汪杨王增全
Owner TECHNODERMA MEDICINES
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