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Immunomodulator

A technology of alkylene and alkyl, applied in the field of immunomodulator and its preparation of medicine

Active Publication Date: 2021-02-09
HITGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Despite the existence of multiple IL-17A antibodies, few studies have investigated small molecule-specific inhibitors of IL-17 with orally bioavailable

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] The preparation of embodiment 1 intermediate 1

[0115]

[0116] Step 1 Preparation of intermediate 1-1

[0117]

[0118] Dimethyl carbonate (17g, 189mmol) and THF (80mL) were added to a 250mL three-necked flask, added with stirring at room temperature, NaH (60% w / w, 3.18g, 79.4mmol), and protected by nitrogen replacement. A solution of 1-indanone (5 g, 37.8 mmol) in THF (40 mL) was added dropwise to the reaction solution using a dropping funnel. After the dropwise addition, the temperature was raised to reflux for 2 hours, and TLC showed that the reaction was complete. The reaction solution was poured into a mixture of 1M HCl and ice, extracted three times with ethyl acetate (100mL), the combined EA layers were dried, and spin-dried to obtain black oil 1-1 (crude product, 7.11g, yield: 99%) , used directly in the next reaction.

[0119] Step 2 Preparation of intermediate 1-2

[0120]

[0121] Intermediate 1-1 (7.11g, 37.8mmol) was added to a 250mL single-ne...

Embodiment 2

[0146] The preparation of embodiment 2 intermediate 2

[0147]

[0148] The preparation of step 1 intermediate 2-1

[0149]

[0150] Referring to the preparation method of Example 1, dimethyl carbonate (13.5g, 150mmol) and THF (80mL) were added to a 250mL three-necked flask, and NaH (60%w / w, 1.68g, 42mmol) was added under stirring at room temperature, nitrogen Displacement protection. A solution of 6-fluoro-1-indanone (3g, 20mmol) in THF (40mL) was added dropwise to the reaction solution using a dropping funnel. After the addition, the temperature was raised to reflux for 2 hours. TLC showed that the reaction was complete. The reaction solution was poured into a mixture of 1M HCl and ice, extracted three times with EA (100 mL), the combined EA layers were dried, and spin-dried to obtain a black oil 2-1 (4.12 g, crude product), which was directly used in the next reaction.

[0151] Step 2 Preparation of intermediate 2-2

[0152]

[0153] Intermediate 2-1 (4.12g, 20m...

Embodiment 3

[0178] The preparation of embodiment 3 intermediate 3

[0179]

[0180] Preparation of step 1 intermediate 3-1

[0181]

[0182] Referring to the preparation method of Example 1, add ethyl benzofuran-2-carboxylate (5.63g, 29.6mmol) into a 250mL single-necked bottle, add anhydrous THF (60mL) to dissolve, and cool to -78°C in a dry ice-ethanol bath. DIBAL (1M toluene solution, 74mL, 74mmol) was slowly added dropwise, and after the addition was completed, it was slowly raised to room temperature to react overnight, and TLC showed that the reaction was complete. The reaction solution was poured into 1M HCl, stirred at room temperature for 30 minutes, EA (100mL) was added to extract 3 times, the combined EA layers were dried and spin-dried to obtain light yellow oil 3-1 (4.5g, yield: 102.6%), MS m / z:149(M+1) + .

[0183] Step 2 Preparation of intermediate 3-2

[0184]

[0185] Add NBS (5.95g, 33.4mmol) and DCM (80mL) into a 250mL three-necked flask, cool to -30°C under...

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Abstract

The invention discloses an immunomodulator, and particularly relates to compounds for inhibiting IL-17A and application of the compounds serving as the immunomodulator in preparation of drugs. The invention discloses an application of a compound shown as a formula I or a stereoisomer thereof in preparing medicines for inhibiting IL-17A, and provides a new choice for clinically screening and / or preparing medicines for treating diseases related to IL-17A activity.

Description

technical field [0001] The invention relates to an immunomodulator and its use in the preparation of medicines. Background technique [0002] IL-17 (Interleukin-17) is a pro-inflammatory cytokine that plays a role in the induction of other inflammatory cytokines, chemokines and adhesion factors. The IL-17 family consists of cytokines involved in acute and chronic inflammatory responses, including IL-17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F . IL-17A is expressed by TH17 cells, which are involved in the pathogenesis of inflammatory and autoimmune diseases. Human IL-17A is a glycoprotein with a molecular weight of approximately 17,000 Daltons. IL-17A transmits signals into cells through the IL-17 receptor complex (IL-17RA and IL-17RC) (Wright, et al. Journal of immunology, 2008, 181:2799-2805). The main function of IL-17A is through the upregulation of pro-inflammatory and neutrophil migration cytokines and chemokines including IL-6, G-CSF, TNF-α, IL...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D405/14A61K31/5377A61K31/4184A61K31/506A61P35/00A61P29/00A61P37/02
CPCC07D413/14C07D405/14A61P35/00A61P29/00A61P37/02
Inventor 李进张登友刘利洪新福周贤思白晓光尚巳耘林燕萍陈欣
Owner HITGEN INC
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