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A kind of biphenyl derivative, its preparation method and its application in medicine

A technology of pharmacy and benzene ring, applied in the field of biphenyl derivatives and their preparation, can solve problems such as poor affinity

Active Publication Date: 2021-01-15
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, for airway obstructive diseases such as asthma and COPD, a better M receptor antagonist should have a higher affinity for M1 and M3 and a lower affinity for M2

Method used

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  • A kind of biphenyl derivative, its preparation method and its application in medicine
  • A kind of biphenyl derivative, its preparation method and its application in medicine
  • A kind of biphenyl derivative, its preparation method and its application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0268] Example 1: [1-[3-[5-[(4-carbamoyl-1-piperidinyl)methyl]indolin-1-yl]-3-oxo-propyl]-4 -piperidinyl]N-(2-phenylphenyl)carbamate (compound 1)

[0269] [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]indolin-1-yl]-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[0270]

[0271] The first step: [1-[3-(5-formylindolin-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl) Urethane (1B)

[0272] [1-[3-(5-formylindolin-1-yl)-3-oxo-propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[0273]

[0274] Take 4-piperidinyl N-(2-phenylphenyl)carbamate (1A) (prepared with reference to WO2012009166) (0.15g, 0.5mmol) and 1-acryloylindoline-5-aldehyde ( Intermediate 1) (0.10g, 0.5mmol) was placed in a 25mL round bottom flask, tetrahydrofuran (10mL) was added, and reacted at room temperature for 24 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (triethylam...

Embodiment 2

[0282] Example 2: [1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]di Indolin-1-yl]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (compound 2)

[0283] [1-[3-[5-[(2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]indoli n-1-yl]-3-oxo -propyl]-4-piperidyl]N-(2-phenylphenyl)carbamate

[0284]

[0285] [1-[3-(5-formaldehyde indolin-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (1B) (0.35g, 0.7mmol) and 3-ethyl-5,6-dihydro-4H-pyrrole[3,4-d]imidazole-2-carboxamide (Intermediate 2) (0.25g, 1.4mmol ) in a 50mL round-bottomed flask, add isopropanol (20mL), stir at 60°C for 30 minutes, concentrate under reduced pressure at 60°C for 1 hour, add isopropanol (20mL), anhydrous Sodium sulfate (0.20g, 1.4mmol) and acetic acid (0.24mL, 4.2mmol), after stirring evenly, add sodium triacetoxyborohydride (0.45g, 3.1mmol) at 0°C, rise to room temperature and react for 3 hours . After the reaction, the reaction solution w...

Embodiment 3

[0288] Example 3: [(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidinyl)methyl]benzoyl]-methyl-amino] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadieno[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate ( Compound 3)

[0289] [(3aS,5r,6aR)-2-[2-[[4-[(4-carbamoyl-1-piperidyl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6, 6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[0290]

[0291] The first step: [(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopentadien[c]pyrrol-5-yl]N-(2- Phenylphenyl) carbamate (3B)

[0292] [(3aS,5r,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[0293]

[0294] Take (3aS,5r,6aR)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadieno[c]pyrrole-2-carboxylic acid tert-butyl ester (3A ) (prepared with reference to CN102146084) (2.27g, 10mmol) and 2-phenylphenylisocyanate (1.95g, 10mmol) were placed in a 100mL round bottom flask, and tetrahydrofuran (40mL) and triethylamine (2.77mL, 20mmol) were added ...

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PUM

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Abstract

The present invention relates to a biphenyl derivative and a preparation method and a use thereof in medicine, in particular relates to a compound shown by general formula (I) or a stereomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, an eutectic or a prodrug thereof, and a preparation method and a use in the preparation of drugs for treating obstructive airways disorders, wherein the compound of formula (I) is as shown in the figure. The definitions of the substituents are the same as defined in the description.

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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IPC IPC(8): C07D487/04C07D401/14C07D401/12C07D471/10C07D211/46C07D211/78A61K31/4545A61K31/454A61K31/4725A61K31/4709A61P11/06
CPCA61K31/454A61K31/4545A61K31/4709A61K31/4725C07D211/46C07D211/78C07D401/12C07D401/14C07D471/10C07D487/04Y02P20/55
Inventor 郑苏欣张国彪张晓波王文晶李航杜勇邱关鹏魏用刚
Owner SICHUAN HAISCO PHARMA CO LTD
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