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Aromatic heterocyclic derivatives and their application in medicine

A drug and pharmacy technology, applied in the field of medicine, which can solve the problems of limited dose and low therapeutic ratio.

Active Publication Date: 2019-03-01
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The primary problem is the low therapeutic ratio of these compounds, which severely limits the doses that can be administered

Method used

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  • Aromatic heterocyclic derivatives and their application in medicine
  • Aromatic heterocyclic derivatives and their application in medicine
  • Aromatic heterocyclic derivatives and their application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0476]Example 1: ((3R,5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy )phenyl)oxazole-4-carbonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl carbamate hydrochloride

[0477]

[0478] Step 1: Synthesis of compound (2S,4R)-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine hydrochloride

[0479] N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline methyl ester (210mg, 0.86mmol), p-toluenesulfonyl chloride (195mg, 1.03mmol), triethylamine (200mg, 2.14mmol ) and 4-dimethylaminopyridine (12mg, 0.086mmol) were dissolved in dichloromethane (10mL), reacted at room temperature for 10h, then stopped the reaction, added water (20mL), extracted with dichloromethane (10mL×3), combined the organic phases with Anhydrous Na 2 SO 4 Drying, removal of solvent, and the concentrated solution was subjected to column chromatography (eluent: Petroleumether / EtOAc (v / v)=4 / 1) to obtain 110 g of a colorless liquid: (2S,4S)-2-methoxycarbonyl-4 - tert-butyl p-toluenesulfonyloxyp...

Embodiment 2

[0509] Example 2: 4-(((2S,4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoro Methoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidin-2-yl)methoxy)benzoic acid hydrochloride

[0510]

[0511] Step 1: Compound 4-(((2S,4R)-1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy Synthesis of methyl)-4-(difluoromethoxy)phenyl)oxazole-4-carbonyl)-4-((methoxycarbonyl)amino)pyrrolidin-2-yl)methoxy)benzoate

[0512] The compound ((3R,5S)-1-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl carbamate (200 mg, 0.32 mmol) was dissolved in THF (10 mL), Add methyl 4-hydroxybenzoate (85mg, 0.55mmol) and triphenylphosphine (126mg, 0.48mmol), add diisopropyl azodicarboxylate (DIAD) (97mg, 0.48mmol) in an ice bath, and react at room temperature Stop the reaction after 12h, add saturated ammonium chloride aqueous solution (10mL), extract ...

Embodiment 3

[0523] Example 3: ((3R,5S)-1-(5-((S)-1-amino-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)oxazole-4-carbonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)methyl carbamate hydrochloride

[0524]

[0525] Step 1: Compound (S)-5-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(3-(cyclopropylmethoxy)-4-(di Synthesis of methyl fluoromethoxy)phenyl)oxazole-4-carboxylate

[0526] At room temperature, N,N'-carbonyldiimidazole (CDI) (1.20g, 7.5mmol) was dissolved in anhydrous THF (10mL), and compound (S)-2-((tert-butoxycarbonyl)amino) was added slowly -3-Methylbutanoic acid (1.4g, 6.3mmol), stirred at room temperature for 20min, added 2-(((3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)(methyl Thio)methylene)amino)methyl acetate (1.5g, 4.2mmol), at -78°C, slowly add a THF solution (1.0M, 13mL) of potassium hexamethyldisilazide dropwise, and react for 1.5 Stop after h, add water (25mL) to quench the reaction, then extract with ethyl acetate (25mL×3), combine the o...

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Abstract

The invention discloses an aromatic heterocyclic derivative and application of the derivative in medicines and particularly provides an aromatic heterocyclic compound or a stereoisomer, a geometric isomer, a tautomer, nitrogen oxide, hydrate, solvate, metabolite, a pharmaceutically acceptable salt or prodrug thereof and a drug composition containing the compound. The invention further discloses application of the compound or its drug composition in drug preparation, and the drug is used for the treatment of respiratory diseases, especially chronic obstructive pulmonary disease (COPD).

Description

field of invention [0001] The invention belongs to the technical field of medicine, and specifically relates to a class of aromatic heterocyclic compounds, a pharmaceutical composition containing the compound of the invention, and its application and application method. In particular, the compounds described in the present invention are PDE 4 inhibitors for the treatment of chronic obstructive pulmonary disease (COPD). Background of the invention [0002] Cyclic nucleotide phosphodiesterases (PDEs) are an important super-enzyme family, which can effectively control the concentration of cAMP and cGMP in cells by hydrolyzing cAMP and cGMP, thereby regulating the transmission of second messengers in vivo biochemical effect. PDEs are widely distributed in mammalian tissues, and their diversity leads to specific distribution of different PDE enzymes at the cellular and subcellular levels, which can selectively regulate a variety of cellular functions, and are good drug design an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/06C07D413/14A61K31/454A61K31/422A61P11/00A61P37/08A61P29/00A61P25/00A61P3/10A61P11/06A61P17/00A61P19/02A61P13/10A61P27/14A61P11/02A61P1/04A61P19/08
CPCC07D413/06C07D413/14
Inventor 余天柱钟雪张仕国雷健华何为刘兵张英俊张健存郑常春肖瑛闫兴国
Owner SUNSHINE LAKE PHARM CO LTD