Small molecule compound

A technology of small molecule compounds and compounds, applied in the fields of drug combination, organic chemistry, digestive system, etc.

Pending Publication Date: 2019-12-31
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, but most of them focus on inhibiting JAK1 and JAK3, especially Tyk2 inhibitors have rarely been reported.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Embodiment 1, the general method of synthetic compound TDM-180712

[0082]

[0083] Step 1: Example 112b

[0084] The original compound 112a, methyl 1H-indole-3-carboxylate (554mg, 3.16mmol) and sodium hydride (183mg, 4.59mmol, 60%wt.) were added to the three-necked flask, pumped under the condition of the system water pump Gas was replaced with nitrogen three times. Under ice-bath conditions, anhydrous DMF (50 mL) was added via syringe with stirring, and then the mixture was stirred for 30 min. A solution of compound B0, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (600 mg, 2.87 mmol) in DMF (10 mL) was slowly injected into the reaction solution. The resulting reaction solution was refluxed at 100° C. for 4 hours. After the reaction was completed, it was poured into water (30 mL), extracted with ethyl acetate (60 mL x 3). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pr...

Embodiment 2

[0093] Embodiment 2, the general method of synthetic compound 125 (TDM-180725)

[0094]

[0095] Step 1: Example 125b

[0096] (1-(2-((1-Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-3-yl)carbamate tert-butyl ester

[0097] Add compound 125a (0.25g, 0.75mmol), THF (10mL) mixture of DIPEA (193mg, 1.5mmol) to inject t-BuOH (15mL) and DPPA (309mg , 1.13 mmol). The mixture was heated to 105°C and refluxed for 18 hours. Starting material remained by LCMS, then another batch of DIPEA (193 mg) and DPPA (309 mg) was added and the resulting mixture was stirred at 105 °C under Ar for 20 h. The reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate=0 / 100) to obtain compound 125b as a yellow solid (80 mg, yield <12.5%).

[0098] [Note: Response reproducibility is not good. ]

[0099] LCMS[M+1] + =406.2

[0100] Step 2: Example 125c

[0101] 1-(2-((1-Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-indol-3-amine

[0102] T...

example 3

[0109] Example 3: General method for the synthesis of compound 122 (TDM-180722)

[0110]

[0111] Step 1: Example 122c

[0112] At room temperature, to compound 122a (200mg, 0.96mmol) ie 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine, compound 122b (287mg, 0.96mmol) ie 4,4,5,5-Tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborinane, [1,1'-bis(diphenylphosphino)bis To a mixture of ferrocene]palladium dichloride (70.2 mg, 0.096 mmol) and sodium carbonate (210 mg, 1.92 mmol) were added 1,4-dioxane (20 mL) and water (3 mL). The mixture was then degassed under vacuum, and the mixture was heated to 105° C. and stirred for 3 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. It was purified by silica gel column (petroleum ether:ethyl acetate=25:75) to obtain red solid compound 122c (242 mg, yield 56.8%), namely N-(1-methyl-1H-pyrazol-4-yl )-4-(4-nitrophenyl)pyrimidin-2-amine. LCMS[M+1] + =297.

[0113] St...

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PUM

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Abstract

The invention provides a small molecular compound, The small molecular compound is characterized by having a structure as shown in the following molecular general formula, wherein X1 and X2 are selected from carbon or nitrogen, G1 is a carbon ring or a heterocyclic ring with aromaticity, any one or more hydrogen atoms on the G1 ring are substituted by R1, wherein R1 is selected from nitrogen-containing groups. The small molecule compound can be used as an efficient and specific JAK kinase inhibitor, especially a Tyk2 inhibitor, and/or a JAK1 inhibitor, and/or a JAK1/Tyk2 dual inhibitor, or a Tyk2/JAK1 dual inhibitor or a Tyk2/Jak2 dual inhibitor.

Description

technical field [0001] The present invention relates to the field of small molecular compounds, in particular to a compound that can be used to treat, prevent and alleviate autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, or related inflammatory skin diseases such as psoriasis and eczema , Vitiligo and other small molecule compounds. Background technique [0002] Protein kinases catalyze the phosphorylation of amino acids at specific sites in proteins. According to the phosphorylation of amino acids, they can be divided into tyrosine kinases, serine kinases, and arginine kinases. JAK is a family of intracellular non-receptor tyrosine kinases (Tyrosine Kinase), including four members JAK1, JAK2, JAK3 and Tyk2. JAK is mainly expressed in hematopoietic cells, leukocytes and intestinal epithelial cells, and is responsible for mediating the signal transmission of various cytokines involved in inflammatory responses. When cytokines bind to cell surface recep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07D403/12C07D401/14C07D405/14A61P37/02A61P17/00A61P19/02A61P29/00A61P1/04A61P17/06
CPCC07D403/14C07D403/12C07D401/14C07D405/14A61P37/02A61P17/00A61P19/02A61P29/00A61P1/04A61P17/06
Inventor 邢莉李冠群王晓磊蔡雨婷姜翔潘翔朱文浩汪杨王增全
Owner TECHNODERMA MEDICINES
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