Biphenyl derivative, preparation method thereof, and application of biphenyl derivative to medicine

A pharmacy and prodrug technology, applied in the field of biphenyl derivatives and their preparation, can solve the problems of inappropriate use of patients, insufficient treatment, aggravation and the like

Inactive Publication Date: 2019-12-20
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, ipratropium bromide and oxitropium bromide are short-acting drugs, which need to be administered multiple times a day, which brings inconvenience to patients, and may lead to poor compliance due to frequent administration, thereby risking insufficient treatment
Aclidinium, given twice daily, may cause serious adverse reactions, including paradoxical bronchospasm, new or worsening narrow-angle glaucoma, new or worsening urinary retention, and should not be used in patients younger than 18 years of age
Some M receptor antagonists are administered by inhalation, and some drugs enter the circulatory system, causing systemic side effects such as dry mouth, gastrointestinal symptoms, urinary retention, and urinary tract infections.

Method used

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  • Biphenyl derivative, preparation method thereof, and application of biphenyl derivative to medicine
  • Biphenyl derivative, preparation method thereof, and application of biphenyl derivative to medicine
  • Biphenyl derivative, preparation method thereof, and application of biphenyl derivative to medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0189] Example 1: [1-[3-[4-[(2-carbamoyl-3-methyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]- N-Methyl-anilino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate; bistrifluoroacetate (compound 1)

[0190] [1-[3-[4-[(2-carbamoyl-3-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]-N-methyl-anilino]-3- oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; ditrifluoroacetic acidate

[0191]

[0192] Take [1-[3-(4-formyl-N-methyl-aniline)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (1A) (0.49g, 1.0mmol) and 1-methyl-5,6-dihydro-4H-pyrrole [3,4-d] imidazole-2-carboxamide (1B) (0.33g, 2.0mmol) dissolved Add methanol (30 mL), heat to 60°C, stir until the solution is clear, cool to room temperature, add sodium triacetoxyborohydride (0.63 g, 3 mmol), and react at room temperature for 3 hours. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL), extracted with dichloromethane (60 mL×2), dried over an...

Embodiment 2

[0194] Example 2: [1-[2-[[4-[[4-(difluoromethyl)-1-piperidinyl]methyl]benzoyl]-methyl-amino]ethyl 1]-4 -piperidinyl]N-(2-phenylphenyl)carbamate; bistrifluoroacetate (compound 2)

[0195] [1-[2-[[4-[[4-(difluoromethyl)-1-piperidyl]methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate; ditrifluoroacetic acidate

[0196]

[0197] [1-[2-[(4-Formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (2A) (prepared with reference to WO2012009166, Example 3) (0.486g, 1.00mmol) was dissolved in dichloromethane (10ml), and 4-difluoromethylpiperidine trifluoroacetate 2A (0.257g, 1.50mmol) was added (according to patent WO2010138490) and triethylamine (0.087g), after stirring at room temperature for 1 hour, acetic acid (0.636g, 3.0mmol) was added. After stirring at room temperature for 3 hours, sodium triacetoxyborohydride (0.496 g, 2.34 mmol) was added, and the reaction was terminated after stirring overnight at room temperature. Concentrate...

Embodiment 3

[0200] Example 3: [1-[2-[[4-[(4 fluoro-1-piperidinyl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N- (2-Phenylphenyl)carbamate (compound 3)

[0201] [1-[2-[[4-[(4-fluoro-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[0202]

[0203] [1-[2-[(4-Formylbenzoyl)-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (2A) (0.486g, 1.00mmol) was dissolved in dichloromethane (10ml), 4-fluoropiperidine hydrochloride (3A) (0.155g, 1.50mmol) (prepared according to US20110207704) and triethylamine (0.121g) were added, After reacting at room temperature for 1 hour, acetic acid (0.132 g, 2.20 mmol) was added. After stirring at room temperature for 3 hours, sodium triacetoxyborohydride (0.636 g, 3.00 mmol) was added, and the reaction was terminated after stirring overnight at room temperature. Concentrate under reduced pressure to remove most of the reaction solvent, slowly add saturated aqueous sodium bicarbonate solution (50 mL) ...

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Abstract

The invention relates to a biphenyl derivative, a preparation method thereof, and application of the biphenyl derivative to medicine. The biphenyl derivative is a compound shown in a general formula (I) or (II), or a stereoisomer, a hydrate, a metabolic product, a solvate, a pharmacologically acceptable salt, an eutectic crystal or a prodrug of the compound, and the preparation method, and application of the compound to preparation of drugs for treating airway obstructive diseases are disclosed, wherein the compound shown in the general formula (I) or (II) is shown as followings (please see the specifications for the formula (I) and (II)), and the definition of each substituent group is consistent with the specifications.

Description

technical field [0001] The present invention relates to a biphenyl derivative and its preparation method and application in medicine, in particular to a novel piperidine derivative with muscarinic receptor antagonistic activity or its stereoisomer, hydrate and solvate , metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, pharmaceutical compositions thereof, preparation methods and applications in medicine. Background technique [0002] Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Muscarinic receptor (M receptor) antagonists exert their bronchodilation effect by reducing vagal cholinergic levels in airway smooth muscle. Inhaled M-receptor antagonists are preferred over oral administration based on therapeutic efficacy and side effects. Inhaled M receptor antagonists currently used clinically include ipratropium bromide, oxitropium bromide, glycopyrronium ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10C07D211/44C07D401/14C07D211/62C07D487/04C07D401/12A61K31/438A61K31/407A61K31/496A61K31/4709A61K31/4545A61K31/454A61K31/4523A61P11/06A61P11/00
CPCA61P11/00A61P11/06C07D211/44C07D211/62C07D401/12C07D401/14C07D471/10C07D487/04
Inventor 郑苏欣张国彪张晓波王文晶杜勇李航赵剑飞
Owner SICHUAN HAISCO PHARMA CO LTD
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