Macrocyclic compound as well as preparation method and application thereof

A technology of macrocyclic compounds and nitrogen oxides, applied in organic chemistry, drug combination, pharmaceutical formulations, etc., can solve the problems that non-covalent compounds cannot overcome drug resistance, poor selectivity of T790M mutants, inevitable C797S drug resistance mutations, etc.

Pending Publication Date: 2022-02-18
BEIJING ADAMADLE BIOTECHNOLOGY LTD CO
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second-generation inhibitors, such as afatinib and dacomitinib, etc., have stronger binding activity to EGFR, but have poor selectivity for T790M mutants, and cannot reach effective concentrations in vivo at tolerable doses
[0005] The third-generation inhibitor osimertinib can be used not only as second-line treatment for patients with T790M mutation after first- and second-generation treatment, but also as first-line treatment for patients with EGFR-sensitive mutations who have not been treated with EGFR-TKIs. After 9.9-18.9 months of treatment with the EGFR inhibitor osimertinib, C797S (mutation of cysteine ​​to serine at position 797 of exon 20) drug resistance mutation will inevitably occur
[0008] In 2019, Boehringer In

Method used

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  • Macrocyclic compound as well as preparation method and application thereof
  • Macrocyclic compound as well as preparation method and application thereof
  • Macrocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0302] The synthesis of embodiment 1.(2-aminoethyl) (2-hydroxyethyl) tert-butyl carbamate

[0303]

[0304] The first step: 2,2,2-trifluoro-N-(2-((2-hydroxyethyl)amino)ethyl)acetamide

[0305]

[0306] At 0°C, add 2-(2-aminoethylamine)ethanol (10.0g, 96.0mmol), dry diethyl ether (30mL) and ethyl trifluoroacetate (13.6g, 96.0mmol) successively into a 100mL round bottom flask, The resulting mixture was stirred at room temperature for 2 h, a white precipitate formed. After filtration, the filter cake was washed twice with ether (20mL×2), and dried to obtain 2,2,2-trifluoro-N-(2-((2-hydroxyethyl)amino)ethyl)acetamide (14.6g, White solid), yield: 74.9%.

[0307] The second step: tert-butyl (2-hydroxyethyl)(2-(2,2,2-trifluoroacetylamino)ethyl)carbamate

[0308]

[0309] At room temperature, 2,2,2-trifluoro-N-(2-((2-hydroxyethyl)amino)ethyl)acetamide (13.4g, 0.066mol) was successively added to a dry 500mL round bottom flask, Tetrahydrofuran (200mL) and Boc 2 O (14.5g, 0...

Embodiment 2

[0315] The synthesis of embodiment 2.5-amino-4-methylpentan-1-alcohol

[0316]

[0317] The first step: tert-amyl (2,6-dimethylhept-5-en-1-yl)carbamate

[0318]

[0319] Dissolve 3,7-dimethyloct-6-enoic acid (3.5g, 20.56mmol) in toluene (300mL), heat up to 50°C, add triethylamine (2.5g, 24.67mmol), and then slowly add Diphenyl phosphate nitrogen (5.65g, 20.56mmol), heated to 70°C and stirred for 12h, added 2-methylbutan-2-ol (3.6g, 41.16mmol), heated to 110°C and stirred for 2h, then 2-Methylbutan-2-ol (3.6 g, 41.16 mmol) was added. The reaction mixture was stirred at 110 °C for 12 h. Concentrate under reduced pressure, add water (100 mL) to the obtained residue, extract with ethyl acetate (200 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The residue was purified by silica gel column chromatography with eluent system petroleum ether / ethyl acetate=6...

Embodiment 3

[0326] Example 3. Synthesis of (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl 4-toluenesulfonate

[0327]

[0328] The first step: (R)-(2-hydroxypropyl) tert-butyl carbamate

[0329]

[0330] At room temperature, (R)-1-aminopropan-2-ol (1.5g, 0.02mol) and DCM (20mL) were successively added to a 100mL round bottom flask, cooled to 0°C, and Boc 2 O (4.8g, 0.022mol) and triethylamine (4.0g, 0.04mol) were warmed up to room temperature and stirred for 2h. Add water (20 mL), extract with dichloromethane (20 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Removal system petroleum ether / ethyl acetate=5 / 1 was purified to obtain (R)-(2-hydroxypropyl)carbamate tert-butyl ester (2.4 g, white solid), yield: 68.6%.

[0331] The second step: (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl 4-toluenesulfonate

[0332]

[0333] At room temperature, successively add tert-butyl (...

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Abstract

The invention relates to a macrocyclic compound as well as a preparation method and application thereof, the macrocyclic compound has a structure as shown in a formula I, and A, B, D, R1, R2, R3, R4, R5, Z, X, m, n and p are defined in the specification. The macrocyclic compound disclosed by the invention not only can overcome EGFR C797S mutation, but also can overcome EGFR T790M mutation, and is relatively high in selectivity.

Description

technical field [0001] The present invention relates to macrocyclic compounds and their preparation methods and applications, in particular to compounds for inhibiting, regulating and / or regulating signal transduction of EGFR kinase, their preparation methods, pharmaceutical compositions containing them and their applications. Background technique [0002] Protein kinases are the enzymatic components of signaling pathways that catalyze the transfer of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and / or threonine residues of proteins. Compounds that inhibit protein kinase function are therefore valuable tools for assessing the physiological consequences of protein kinase activity. Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been the subject of extensive research and has been demonstrated in many diseases, including diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, It plays ...

Claims

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Application Information

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IPC IPC(8): C07D498/22C07D513/22C07D498/18A61K31/439A61K31/4545A61K31/496A61K31/5377A61K31/504A61K31/529A61K31/4995A61P35/00A61P35/02
CPCC07D498/22C07D513/22C07D498/18A61P35/00A61P35/02
Inventor 张培龙李功兰文丽薛宝玉
Owner BEIJING ADAMADLE BIOTECHNOLOGY LTD CO
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