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Azacycle-containing compound and preparation method and usage thereof

A compound, cycloalkyl technology, applied in the field of medicine, can solve the problems of repeated disease, prolonged disease cure time, and patient response differences

Active Publication Date: 2019-08-13
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, PPIs are widely used in the treatment of gastric acid-related diseases, but this type of drug still has certain limitations:
[0004] ① Long onset time: PPI needs to be catalytically converted into an active form under acidic conditions in order to play a role;
[0005] ②There is a limitation on the time of taking the medicine: since PPIs are only combined with the active proton pump, they need to be taken 60 minutes before meals to ensure that the blood drug concentration reaches the highest value when the proton pump is activated;
[0006] ③ There is nocturnal acid breakthrough: the half-life of existing PPI is generally within 2 hours, and it can only be combined with the activated proton pump. At night, due to the excitement of the vagus nerve, the secretion of gastric acid increases, and the proton pump is renewed and activated, so every night from 10:00 to the next morning Between 8 o'clock, there will be more than one hour when the pH value in the stomach is less than 4, that is, nocturnal acid breakthrough (NAB), which will lead to difficult healing of ulcers, difficulty in eradicating Helicobacter pylori, prolonging the healing time of the disease, and may cause illness repeatedly;
[0007] ④ There are differences in patient responses: PPIs mainly rely on CYP2C19 enzyme metabolism, and CYP2C19 enzymes have genetic polymorphisms in the population, and it is difficult to control the difference in curative effect between patients with different genotypes;

Method used

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  • Azacycle-containing compound and preparation method and usage thereof
  • Azacycle-containing compound and preparation method and usage thereof
  • Azacycle-containing compound and preparation method and usage thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] The preparation of embodiment 1 compound 101

[0135]

[0136] Compound 101a (10g, 65.4mmol), 2-fluoroiodobenzene (29g, 130.7mmol), cuprous iodide (24.8g, 130.7mmol), tripotassium phosphate (27.7g, 130.7mmol) and N,N'- Dimethylethylenediamine (5.8 g, 65.4 mmol) was added into toluene (200 mL), and refluxed under argon atmosphere for 24 h. The reaction solution was cooled and filtered, the filtrate was washed with water (100 mL×2), and the aqueous layer was extracted with ethyl acetate (200 mL×1). The organic phase was washed with saturated brine (200mL×1), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to column chromatography (petroleum ether / ethyl acetate=30 / 1 to 20 / 1) to obtain compound 101b (yellow solid). MS m / z(ESI):248.2[M+H].

[0137] Compound 101b (1.7g, 6.88mmol) was added in dichloromethane (30mL), cooled to -78°C, and N-bromosuccinimide (1.22g, 6.88mmol) was slowly added dropwise in dichloromethane (20mL ) s...

Embodiment 2

[0145] The preparation of embodiment 2 compound 114

[0146]

[0147] Compound 114a (476mg, 3.0mmol) and o-fluorobenzoyl chloride (426mg, 3.0mmol) were dissolved in dry toluene (6mL) under argon atmosphere, then trimethyl phosphite (372mg, 3mmol) was added dropwise in dry toluene (9mL) solution, react at room temperature for 2h. The reaction solution was concentrated, and the residue was subjected to column chromatography (petroleum ether / ethyl acetate=3 / 2) to obtain compound 114b (370 mg, yellow solid). MS m / z(ESI):375.1[M+1].

[0148] Compound 114b (800mg, 2.14mmol) and benzylhydrazine dihydrochloride (625mg, 3.2mmol, 1.5eq.) were suspended in toluene (3mL), refluxed for 2h, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (Petroleum ether / ethyl acetate=5 / 1) to obtain compound 114c (633 mg, yellow oil). MS m / z(ESI):369.2[M+1].

[0149] Compound 114c (920 mg, 2.5 mmol) was dissolved in 10 mL of acetonitrile, 40 mL ...

Embodiment 3

[0154] The preparation of embodiment 3 compound 104d

[0155]

[0156] Compound 104a (500g, 2.70mol) was dissolved in N,N-dimethylformamide dimethyl acetal (3.5L), refluxed for 3h, the reaction solution was evaporated to remove the solvent under reduced pressure, and the residue was added with n-hexane (500mL) and stirred , filtered, washed with cyclohexane (3 L), and dried in vacuo at 40° C. to give compound 104b (yellow solid). MS m / z(ESI): 241.3[M+1]. 1 H NMR (400MHz, CDCl 3 )δ7.31(s,1H),4.55(d,J=17.3Hz,2H),3.83(d,J=20.4Hz,2H),3.07(d,J=23.4Hz,6H),1.49(d, J=6.1Hz,9H)

[0157] Compound 104b (335g, 1.40mmol) was dissolved in toluene (1.675L), and hydrazine hydrate (81mL, 1.67mol) was added dropwise at 45°C, kept at 45°C for overnight reaction, a large amount of solid precipitated, filtered, and washed with cyclohexane (1.5L) , dried in vacuo at 50°C to give compound 104c (yellow solid). 1 H NMR (400MHz, CDCl 3 )δ7.24(s,1H),6.66(s,1H),6.16(s,1H),3.62(d,J=11.0Hz,2H),3.2...

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Abstract

The invention discloses a compound or its salt shown in the formula (I) and usage of the compound as a potassium competitive acid blocker or a gastric acid secretion inhibitor. The compound has a proton pump (H+ / K+)-ATPase inhibitory effect and can be used for preventing, treating and inhibiting diseases related to gastric acid secretion, such as peptic ulcer, zollinger-ellison syndromes, gastritis, erosive esophagitis, reflux esophagitis and symptomatic gastroesophageal reflux diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a nitrogen-containing heterocyclic compound, a preparation method thereof, and an application thereof as a potassium ion competitive acid blocker. Background technique [0002] At present, the main drugs for the treatment of upper gastrointestinal acid-related diseases are proton pump inhibitors (PPIs), ie, prazoles. PPI is a kind of prodrug, the molecular prototype is inactive, under acid catalysis, Smiles rearrangement can occur and be transformed into a spiro ring intermediate, and further form sulfenic acid or sulfenamide compound, both of which are active forms of the drug. with proton pump (H + / K + -ATPase) cysteine ​​C813 and / or C822 forms a disulfide bond, covalently binds, and irreversibly inhibits the activity of the proton pump, thereby inhibiting gastric acid secretion. [0003] At present, PPIs are widely used in the treatment of gastric acid-related...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/407A61K31/4162A61K31/4184A61K31/4178A61K31/4439A61K31/423A61K31/4196A61K31/497A61K31/5377A61K31/506A61K31/454A61P1/04A61P1/00A61P1/14A61P29/00A61P35/00A61P31/04A61P9/00A61P17/02A61P11/06A61P11/00A61P23/00
CPCA61P1/00A61P1/04A61P1/14A61P9/00A61P11/00A61P11/06A61P17/02A61P23/00A61P29/00A61P31/04A61P35/00C07D487/04C07D519/00A61K31/4035A61K31/407A61K31/4162A61K31/4178A61K31/4184A61K31/4196A61K31/423A61K31/4439A61K31/454A61K31/497A61K31/506A61K31/5377C07D209/52C07D405/02C07D409/02Y02P20/55
Inventor 陈庆财赵俊赵小伟陈祥峰宗在伟陆慧
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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