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Complement factor B inhibitor as well as pharmaceutical composition, preparation method and application thereof

A compound and solvate technology, applied in the field of complement factor B inhibitors and their pharmaceutical compositions, can solve the problems of heavy burden on patients, no specific therapeutic drugs, and difficult to cure with diversity, and achieve good regulation/inhibition effect, performance good effect

Pending Publication Date: 2022-02-18
SHANGHAI MEIYUE BIOTECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Inflammatory and immune-related diseases are diverse and difficult to cure; the only drug on the market for PNH diseases is eculizumab, but due to the price, it has brought a heavy burden to patients; at the same time, many patients have been treated with eculizumab Anemia still occurs after zizumab treatment, and many patients still need continuous blood transfusion; in addition, eculizumab needs to be administered intravenously
And some diseases have no specific treatment drugs so far, such as IgAN, etc.
There are unmet clinical needs in these areas that require the development of new small molecule drugs for medical treatment

Method used

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  • Complement factor B inhibitor as well as pharmaceutical composition, preparation method and application thereof
  • Complement factor B inhibitor as well as pharmaceutical composition, preparation method and application thereof
  • Complement factor B inhibitor as well as pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] Intermediate 1:

[0177]

[0178] In a 3L three-necked flask, sequentially add tetrahydrofuran (150mL) and 4-bromoxynil (50g), and slowly add isopropylmagnesium chloride lithium chloride complex (1.3M, 210mL) to the reaction system under nitrogen protection , the reaction was carried out at room temperature for 2 hours. Then the reaction system was diluted by adding anhydrous tetrahydrofuran (500mL) and cooled to -5°C, 4-methoxypyridine (25mL) was added, and benzyl chloroformate (35mL) was slowly added dropwise (maintaining the system temperature below 0°C), After the addition was complete, the reaction was stirred at 0°C for 2 hours, then warmed to room temperature and continued for 16 hours at room temperature. After the reaction, add 6M hydrochloric acid (150mL) and stir for half an hour and dilute with water (1000mL), extract twice with ethyl acetate (500mL), wash the combined extracts with saturated brine (50mL), and dry over anhydrous sodium sulfate And filte...

Embodiment 2

[0214] Intermediate 1:

[0215]

[0216] In a 250mL single-necked bottle, add dichloromethane (50mL), 5-methoxy-7-methyl-1H-indole (3g), Boc anhydride (5.68g), 4-dimethylaminopyridine (227mg) in sequence and triethylamine (2.26 g), the reaction was carried out at room temperature for 16 hours. After the reaction, the reaction solution was quenched by adding saturated ammonium chloride solution (5 mL), extracted three times with dichloromethane (20 mL), the combined organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain Intermediate 1 (4.6 g, yield: 94%). MS m / z(ESI):262.0[M+1].

[0217] Intermediate 2:

[0218]

[0219] In a 250 mL single-necked bottle, dichloromethane (80 mL), N-methylformanilide (3.8 g) and oxalyl chloride (3.6 g) were added in sequence, and the reaction was stirred at room tempera...

Embodiment 3

[0221] Intermediate 1:

[0222]

[0223] In a 100mL single-necked bottle, add 1-(vinyloxy)butane (10mL), triethylamine (300mg), o-phenanthroline (54mg), palladium acetate (67mg) and benzyl (2S, 4S)- 2-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (Example 1, Intermediate 5) (500 mg), the reaction mixture was heated to 90 °C under nitrogen protection and at this temperature Stir for 16 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain Intermediate 1 (360 mg, yield: 63%). MS m / z(ESI):384.8[M+23].

[0224] Intermediate 2:

[0225]

[0226] Under ice bath and nitrogen protection, a solution of trifluoroacetic acid (228mg) in dichloromethane (2mL) was added to a solution of diethylzinc (1M, 2mL) in dichloromethane (4mL); the reaction was carried out under ice bath After one hour, the reaction system was added dichlorom...

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PUM

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Abstract

The invention provides a heterocyclic compound containing piperidine as shown in a formula (I). The compounds are used for treating diseases and diseases related to complement alternative pathway activation, such as paroxysmal nocturnal hemoglobinuria (PNH), IgA nephropathy (IgAN) including C3 glomerulopathy (C3G), membranous nephropathy (MN) and other glomerular diseases, atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), diabetic retinopathy (DR), and other diseases associated with abnormal activation of the alternative complement pathway by inhibiting / regulating a complement factor B.

Description

[0001] This application claims to enjoy the patent application number 202010790872.8 submitted by the applicant to the State Intellectual Property Office of China on August 7, 2020, and the invention name is "complement factor B inhibitor and its pharmaceutical composition, preparation method and use". Application priority. The entirety of this prior application is incorporated by reference into the present application. technical field [0002] The invention belongs to the field of medicine, and in particular relates to a complement factor B inhibitor and its pharmaceutical composition, preparation method and application. Background technique [0003] Complement is a class of soluble pattern recognition molecules in the immune system that can perform multiple effector functions. Under natural conditions, complement components exist in the form of inactive zymogens, and a variety of specific and non-specific immunological mechanisms decompose these inactive zymogens to produ...

Claims

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Application Information

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IPC IPC(8): C07D491/107C07D401/06C07D471/08C07D451/06C07D405/14C07D491/048C07D491/052C07D495/04C07D491/06C07D471/04C07F9/38C07D209/08A61K31/438A61K31/454A61K31/439A61K31/435A61K31/436A61K31/4355A61K31/4725A61K31/4545A61K31/675A61P13/12A61P27/02A61P9/10A61P7/06A61P25/00A61P29/00A61P19/02A61P21/00A61P21/04A61P9/00A61P11/00A61P7/00
CPCC07D491/107C07D401/06C07D471/08C07D451/06C07D405/14C07D491/048C07D491/052C07D495/04C07D491/06C07D471/04C07F9/3834C07D209/08A61P13/12A61P27/02A61P9/10A61P7/06A61P25/00A61P29/00A61P19/02A61P21/00A61P21/04A61P9/00A61P11/00A61P7/00C07D401/14Y02P20/55Y02A50/30C07F5/025C07F9/65583C07D221/22C07D453/06C07D401/04A61K31/454A61P13/02A61P37/00
Inventor 栾林波陈永凯王朝东
Owner SHANGHAI MEIYUE BIOTECH DEV
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