Peptidylarginine deiminase inhibitor and application thereof

An amino and alkyl technology, applied in the field of medicine, can solve the problem of the lack of varieties of PAD4 inhibitors

Active Publication Date: 2019-09-03
TRANSTHERA SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Currently, there are few varieties of PAD4 inhibitors under research. In order to better meet the huge clinical needs, we aim to develop PAD4 inhibitors with higher activity and better druggability

Method used

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  • Peptidylarginine deiminase inhibitor and application thereof
  • Peptidylarginine deiminase inhibitor and application thereof
  • Peptidylarginine deiminase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0398] Embodiment 1: Synthesis of intermediate 3-methoxy-4-(methylamino)-5-nitrobenzoic acid methyl ester

[0399]

[0400] Step 1: Synthesis of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate

[0401]

[0402] Methyl 4-hydroxy-3-methoxybenzoate (25.4g, 0.139mol) was dissolved in glacial acetic acid (100mL), and a mixed solution of nitric acid (10.2mL) and acetic acid (52mL) was slowly added dropwise under ice-cooling, about 1 The hour dropwise addition was completed. The reaction solution was slowly raised to room temperature and stirred for 4 hours. After filtering, the filter cake was washed successively with water, n-hexane and diethyl ether, and dried to obtain the product as a yellow solid (21.0 g, yield: 66%).

[0403] Step 2: Synthesis of methyl 4-chloro-3-methoxy-5-nitrobenzoate

[0404]

[0405] Dissolve methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (21g, 0.095mol) in DMF (200mL), cool to -20°C, slowly add oxalyl chloride (23.7mL) dropwise, dropwise The temperatur...

Embodiment 2

[0410] Example 2: Synthesis of intermediate 1-ethyl-1H-pyrrolo[3,2-b]pyridine-2-carbaldehyde

[0411]

[0412] Step 1: Synthesis of 1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine

[0413]

[0414] Under nitrogen protection, sodium hydride (mass fraction 60%, 0.8g, 20mmol, 2.0eq) was added in batches to anhydrous THF (30mL) at room temperature, and 1H-pyrrolo[3,2-b]pyridine (1.19 g, 10mmol, 1.0eq) was dissolved in anhydrous THF (10mL), slowly added dropwise to the system, after the drop was completed, the reaction was incubated for 30 minutes. Benzenesulfonyl chloride (3.5g, 20mmol, 2.0eq) was dissolved in THF (10mL), slowly added dropwise to the system, and the dropwise addition was completed in 15 minutes, and the reaction was carried out at room temperature for 4 hours. LC-MS detected that the reaction was complete, slowly added 0.1mol / L HCl aqueous solution (20mL) dropwise to quench the reaction, added water (30mL), extracted with EA (50mL×2), combined the organic phas...

Embodiment 3

[0426] Example 3: Synthesis of intermediate 5-ethyl-5H-pyrrolo[2,3-b]pyrazine-6-carbaldehyde

[0427]

[0428] Step 1: Synthesis of 3-((trimethylsilyl)ethynyl)pyrazin-2-amine

[0429]

[0430] Under nitrogen protection, 3-chloropyrazin-2-amine (12.9g, 0.1mol, 1.0eq) was dissolved in DMF (150mL), CuI (9.5g, 0.05mol, 0.5eq), tetrakis(triphenyl Phosphine) palladium (11.55g, 0.01mol, 0.1eq) and triethylamine (30.3g, 0.3mol, 3.0eq), cool down to 0°C, slowly add trimethylsilylacetylene (14.7g, 0.15mol, 1.5 eq), after the dropwise addition was completed, it was heated to 70° C. and stirred for 12 hours. TLC and LC-MS detected that the reaction was complete. Pour the reaction solution into water (300mL), add EA (500mL), filter with suction, wash the filter cake with EA (50mL×2), separate the filtrate, and wash the organic phase with saturated brine , dried, filtered with suction, the filtrate was concentrated, and the crude product was purified by silica gel column chromatogra...

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PUM

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to a peptidylarginine deiminase PAD4 inhibitor compound shown in a formula (I) or pharmaceutically acceptable salts,stereoisomers and tautomers thereof, as well as pharmaceutical compositions, pharmaceutical preparations and application thereof. X, Y, R1, R2, R3, R4, R5, R7, R8, R9, ring B and m are as defined in the specification. The compound has inhibitory effect on peptidylarginine deiminase PAD4, and can be used for treating various diseases, such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, multiple sclerosis, cystic fibrosis, cancer, cutaneous lupus erythematosus, asthma and psoriasis.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to a peptidyl arginine deiminase PAD4 inhibitor compound represented by general formula (I) and pharmaceutically acceptable salts, stereoisomers and tautomers thereof, As well as their pharmaceutical compositions, pharmaceutical preparations and uses. The compounds involved in the present invention have inhibitory effect on peptidyl arginine deiminase PAD4, and can be used to treat various diseases, such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, multiple Sexual sclerosis, cystic fibrosis, cancer, cutaneous lupus erythematosus, asthma, and psoriasis. Background technique [0002] PAD4 is a member of the peptidylarginine deiminase (peptidylarginine deiminase, PAD) family, has a homodimer structure, is Ca 2+ Dependent enzyme, each monomer contains 5 calcium ion binding sites, consists of 663 amino acid residues, molecul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D471/04C07D495/04C07D491/048A61K31/4545A61K31/454A61K31/55A61K31/4709A61K31/438A61K31/4184A61P29/00A61P19/02A61P1/04A61P25/00A61P35/00A61P11/06A61P17/06A61P17/00
CPCC07D487/04C07D471/04C07D495/04C07D491/048A61P29/00A61P19/02A61P1/04A61P25/00A61P35/00A61P11/06A61P17/06A61P17/00A61P27/00A61P37/00A61P11/00A61P25/28
Inventor 吴永谦李琳
Owner TRANSTHERA SCIENCES (NANJING) INC
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