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Compounds containing conjugated allene structure, and pharmaceutical compositions and application thereof

A compound, C1-C4 technology, applied in the prevention or treatment of diseases related to abnormal B cell activity, in the field of B cell activation inhibitors, can solve the problems of uncertain properties, unknown biological activities and pharmacological properties, etc.

Inactive Publication Date: 2018-03-06
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, unlike compounds containing conjugated alkenes or conjugated alkyne structural fragments, the biological activity and pharmacological properties of compounds containing conjugated allene structural fragments are unknown, and the properties of all aspects are uncertain.

Method used

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  • Compounds containing conjugated allene structure, and pharmaceutical compositions and application thereof
  • Compounds containing conjugated allene structure, and pharmaceutical compositions and application thereof
  • Compounds containing conjugated allene structure, and pharmaceutical compositions and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0159] The synthesis of preparation embodiment 1 boric acid, borate:

[0160] Method 1: Synthesis of N-(2-pyridyl)4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolyl)-benzamide (C007)

[0161]

[0162] Step 1, synthesis of p-bromobenzoyl chloride: in a 250mL glass flask, add p-bromobenzoic acid (3g, 15mmol), N,N-dimethylformamide (DMF, 0.4mL) and dichloromethane (CH 2 Cl 2 , 50mL). The reaction solution was cooled to zero with an ice-water bath, and thionyl chloride (SOCl 2 , 1.32 mL, 18 mmol). The reaction was warmed to room temperature and stirred overnight. Evaporated to dryness by rotary evaporation, the obtained crude product was purified by co-evaporation with toluene (30 mL×2), and a colorless liquid was obtained which was directly used in the next reaction.

[0163] Step 2, synthesis of N-(2-pyridyl)-p-bromobenzamide (C004): put all the colorless liquid obtained in the previous step into a 250 mL glass flask, and dissolve it in dry tetrahydrofuran (THF, 20 mL). This so...

preparation Embodiment 2

[0183] Preparation Example 2 Synthesis of the key intermediate N-Cbz-(S)-3-(1-bromo,8-aminoimidazo[1,5-a]pyrazinyl)-substituted-2-pyrrolidine (S8)

[0184]

[0185] 2-(3-Chloropyrazin-2-yl)methanamine(S4)

[0186] Step 1, synthesis of 2-(3-chloropyrazinyl) methyl bromide (S2): 2-chloro-3-methylpyrazine (S1, 7.72g, 60mmol) and N-bromosuccinimide ( NBS, 14.87g, 84mmol) dissolved in carbon tetrachloride (CCl 4 , 100mL). One-time addition of benzoyl peroxide (Bz 2 o 2 , 1.45g, 6mmol), the reaction solution was refluxed overnight. Then, the reaction solution was cooled to room temperature, the solid was removed by filtration, and the solid was washed with carbon tetrachloride to obtain CCl 4 solution. The carbon tetrachloride solutions were combined and concentrated to obtain 13.27 g of a mixture containing S2, which was directly used in the next reaction without purification.

[0187]Step 2, Synthesis of 2-(3-chloropyrazinyl)methyl-substituted-2-isoindole-1,3-dione (S3):...

Embodiment 1

[0200] Embodiment 1: synthetic compound (S)-N-(pyridin-2-yl) para-position (3-(1-(2,3-butenoyl) pyrrolidin-2-yl)-8-aminoimidazole[ 1,5-a]pyrazin-1-yl)benzamide (1)

[0201]

[0202] Step 1: Synthesis of (S)-2-((1-(4-(pyridin-2-ylcarbamoyl)phenyl)-8-amino)imidazo[1,5-a]pyrazin-2-yl ) benzyl pyrrolidin-1-ylcarboxylate (C018)

[0203] In a 100mL glass bottle, add 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolyl)-benzoic acid 2-pyridylamineamide (213mg, 0.66 mmol), S8 (137 mg, 0.33 mmol) and 1,2-dimethoxyethane (4 mL). Aqueous sodium carbonate solution (2M, 2 mL) was added to the above solution, and the solution was deoxygenated. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (24 mg) was added to the reaction flask and oxygen was removed again. The reaction solution was refluxed overnight, cooled to room temperature, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried,...

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Abstract

The invention relates to compounds containing conjugated allene structure, and pharmaceutical compositions and application thereof, specifically to compounds as shown in a general formula (I) which are described in the specification or salts thereof, pharmaceutical compositions of the compounds, and application of the compounds as BTK inhibitors and / or B-cell activation inhibitors to prevention ortreatment of abnormal B-cell active activity or diseases related to BTK. The compounds have good lethal effect on cancer cells of lymphoma, breast cancer, liver cancer, intestinal cancer, stomach cancer, lung cancer, cervical cancer and the like, which proves that the compounds have potential of treating related cancers and autoimmune diseases.

Description

technical field [0001] The present invention relates to compounds containing conjugated allene structural fragments and uses thereof, in particular, to a class of small molecular compounds having conjugated allene structures or salts thereof, pharmaceutical compositions thereof, and their use as B cell activation inhibitors , for preventing or treating diseases related to abnormal activity of B cells. Background technique [0002] The chemical structures of carbonyl-conjugated alkenes and carbonyl-conjugated alkynes can form covalent bonds with amino acid residues such as cysteine ​​and lysine in proteins, and are widely used in the design and development of irreversible small molecule drugs. Small-molecule drugs containing carbonyl-conjugated olefins are widely used clinically. For example, the following seven drugs approved for marketing all contain carbonyl-conjugated olefin fragments. The EGFR kinase inhibitors afatinib and osimertinib are both approved by the US Food a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/519A61K31/4985A61P35/00A61P37/00A61P29/00A61P7/02
CPCC07D487/04C07D519/00
Inventor 赵玉军陈德恒严子琴郭德祥
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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