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Spiro-containing derivative with beta2 receptor agonist and M receptor antagonist activity and medical application of the spiro-containing derivative

A stereoisomer and pharmaceutical technology, applied in the field of spirocycle-containing derivatives with β2 receptor agonistic and M receptor antagonistic activities and their application in medicine

Inactive Publication Date: 2020-10-09
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although compound preparations have better therapeutic effects than single preparations, there are higher requirements for preparation preparation

Method used

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  • Spiro-containing derivative with beta2 receptor agonist and M receptor antagonist activity and medical application of the spiro-containing derivative
  • Spiro-containing derivative with beta2 receptor agonist and M receptor antagonist activity and medical application of the spiro-containing derivative
  • Spiro-containing derivative with beta2 receptor agonist and M receptor antagonist activity and medical application of the spiro-containing derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0229] [6-[3-[5-[[[(2R)-2-Hydroxy-2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]benzene Triazol-1-yl]propylamino]spiro[3.3]heptane-2-yl]-2-hydroxyl-2,2-bis(2-thienyl)acetate ditrifluoroacetate (compound 1 )

[0230] [6-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]benzotriazol-1-yl ]propylamino]spiro[3.3]heptan-2-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate ditrifluoroacetate

[0231]

[0232] The first step: [6-[tert-butoxycarbonyl(methyl)amino]spiro[3.3]heptane-2-yl]-2-hydroxyl-2,2-bis(2-thienyl)acetate ( 1b)

[0233] [6-[tert-butoxycarbonyl(methyl)amino]spiro[3.3]heptan-2-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate

[0234]

[0235] Dissolve tert-butyl N-(2-hydroxyspiro[3.3]heptan-6-yl)-N-methylcarbamate (1a) (0.5 g, 2.07 mmol) in toluene (20 mL), add Sodium hydride (0.311g, 7.77mmol) was stirred for 30min, methyl 2-hydroxy-2,2-bis(2-thienyl)acetate (0.66g, 2.59mmol) was added, and the temperature was raised to 115°C for 10 hours....

Embodiment 2

[0254] [2-[2-[5-[[[(2R)-2-Hydroxy-2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]benzene Triazol-1-yl]ethyl]-2-azaspiro[3.5]non-7-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate ditrifluoroacetic acid Salt (compound 2)

[0255] [2-[2-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]benzotriazol-1-yl ]ethyl]-2-azaspiro[3.5]nonan-7-yl]2-hydroxy-2,2-bis(2-thienyl)acetate ditrifluoroacetate

[0256]

[0257] The first step: tert-butyl 7-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-2-azaspiro[3,5]nonane-2-carboxylate (2b)

[0258] Tert-butyl 7-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-2-azaspiro[3.5]nonane-2-carboxylate

[0259]

[0260] Dissolve tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (1.5g, 6.26mmol) in toluene (60mL), add sodium hydride (0.180g, 7.52mmol), and stir for 30 After 10 minutes, methyl 2-hydroxy-2,2-bis(2-thienyl)acetate (1.75 g, 6.89 mmol) was added, and the temperature was raised to 115° C. for 10 hours. The reaction w...

Embodiment 3

[0279] [2-[3-[5-[[[(2R)-2-Hydroxy-2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]benzene Triazol-1-yl]propyl]-2-azaspiro[3.5]non-7-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate ditrifluoroacetic acid Salt (compound 3)

[0280] [2-[3-[5-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]benzotriazol-1-yl ]propyl]-2-azaspiro[3.5]nonan-7-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate ditrifluoroacetate

[0281]

[0282] The first step: [2-[3-(5-formylbenzotriazol-1-yl)propyl]-2-azaspiro[3.5]non-7-yl]-2-hydroxyl-2,2 -Bis(2-thienyl)acetate (3a)

[0283] [2-[3-(5-formylbenzotriazol-1-yl)propyl]-2-azaspiro[3.5]nonan-7-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate

[0284]

[0285] 2-Azaspiro[3.5]nonan-7-yl-2-hydroxy-2,2-bis(2-thienyl)acetate (2c) (0.1 g, 0.275 mmol) was dissolved in 10 ml of acetonitrile, Add 4-(5-formylbenzotriazol-1-yl)propyl methanesulfonate (see WO2017114377 for the synthesis method) (0.077g, 0.275mmol) and diisopropylethylamine (0.071g, 0.5...

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PUM

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Abstract

The present invention relates to a compound represented by a general formula (I), or a stereoisomer, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a co-crystal or a prodrug thereof, as well as a preparation method and applications of the compound in preparation of drugs for treatment of airway obstructive diseases, the compound represented by the general formula (I) is shown in the specification, and definitions of substituents are consistent with those in the specification.

Description

technical field [0001] The invention relates to a nitrogen-containing heterospirocyclic derivative and its preparation method and application in medicine, in particular to a kind of derivative with muscarinic receptor antagonism and β 2 - Novel nitrogen-containing heterospirocyclic derivatives or stereoisomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof with dual activity of adrenergic receptor agonism, and drugs thereof Composition and its application 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. Bronchodilators widely used in clinical practice include muscarinic receptor antagonists and beta 2 - Adrenoceptor agonists. Muscarinic receptor antagonists exert their bronchodilation effects by reducing vagal cholinergic levels in airway smooth muscle. Inhaled muscarinic receptor ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14C07D491/08A61K31/4709A61K31/55A61P11/00A61P11/06A61P11/08
CPCA61P11/00A61P11/06A61P11/08C07D409/14C07D491/08
Inventor 张晨廖雨亭卢泳华高秋严庞科
Owner SICHUAN HAISCO PHARMA CO LTD
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