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Benzodioxane derivatives and their pharmaceutical use

A technology of alkyl and phenyl, which is applied in the field of benzodioxane derivatives and their pharmaceutical applications, can solve the problems associated with side effects, elevated blood pressure, heart rate, gastrointestinal secretion and anxiety, etc., to improve solubility and enhance Potency, effect of improving selectivity

Inactive Publication Date: 2019-03-01
ORION CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, use of nonselective alpha2 antagonists is associated with side effects such as increased blood pressure, heart rate, salivation, gastrointestinal secretion, and anxiety

Method used

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  • Benzodioxane derivatives and their pharmaceutical use
  • Benzodioxane derivatives and their pharmaceutical use
  • Benzodioxane derivatives and their pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0138] Preparation of Compounds of the Disclosure

[0139] General Method A

[0140] The 1-(piperidin-3-yl) derivative (1 equiv) was dissolved in acetonitrile or DMF (~1M) in a microtube. Add DIPEA (0-1.2 equiv), K 2 CO 3 (1.5-2.5 equiv) and benzodioxene derivative (1-1.2 equiv), and seal the vial. The reaction mixture was heated at 120°C for 3 hours. The solvent was removed under reduced pressure.

[0141] General Method B

[0142] To a solution of the appropriate 4-oxobutyrate derivative (1 equiv) and (S)-3-aminopiperidine derivative (1-1.1 equiv) in DCE (0.1-0.2M) was added at 0°C NaBH(OAc) 3 (1.2-2 equivalents), then stirred at room temperature for 6-18h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried and evaporated.

[0143] General Method C

[0144] To a solution of the appropriate 2-hydroxyacetamide (asetamide) derivative (1 equivalent) in DMF (0.1-0.28M) was added Et at 0 °C 3 N or DIPEA (2-3 eq) followed by...

Embodiment 1

[0157] Example 1: 1-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidine-3 -yl)-4,4-dimethylpyrrolidin-2-one

[0158] Step 1: Benzyl (S)-3-(4,4-dimethyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate

[0159] According to general method B using methyl 3,3-dimethyl-4-oxobutyrate (1.5 g, 10.4 mmol, Organic Syntheses 1993, 71, 189), benzyl (S)-3-aminopiperidine-1-carboxylate (2.68g, 11.4mmol) and NaBH(OAc) 3 (2.64g, 12.5mmol) and DCE (100ml) to prepare benzyl (S)-3-(4,4-dimethyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate. The product was purified by flash chromatography to afford 1 g of benzyl (S)-3-(4,4-dimethyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate.

[0160] LC-MS (ES+) [M+1]: 331.2.

[0161] Step 2: (S)-4,4-Dimethyl-1-(piperidin-3-yl)pyrrolidin-2-one

[0162] Benzyl (S)-3-(4,4-dimethyl-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.2 g, 3.6 mmol) from step 1 was used according to general procedure D ), 10% Pd / C (200mg) and EtOAc (50ml) to prepar...

Embodiment 2

[0167] Example 2: 1-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidine-3 -yl)-4,4-diphenylimidazolidin-2-one

[0168] Step 1: Benzyl (2-oxo-1,1-diphenylethyl)carbamate

[0169]Benzyl (2-hydroxy-1,1-diphenylethyl)carbamate (8.0 g, 23.05 mmol, European Journal of Organic Chemistry, 2008(2), 350) was stirred ice-cold in DCM (200 ml) A mixture of PCC (9.9 g, 46.10 mmol) and silica gel (10 g) was added to the solution and stirred at room temperature for 12 h. The reaction mixture was diluted with DCM and filtered through a pad of celite. Evaporation of the filtrate gave crude compound which was purified by flash column to give 4.0 g of product.

[0170] LC-MS (ES+) [M+1]: 346.1.

[0171] Step 2: (S)-tert-butyl 3-((2-(((benzyloxy)carbonyl)amino)-2,2-diphenylethyl)amino)-piperidine-1-carboxylate

[0172] (S)-tert-butyl 3-aminopiperidine-1-carboxylate (2.32 g, 11.59 mmol), (2-oxo-1,1-diphenylethyl) from step 1 was used according to general procedure B - Benzyl ca...

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Abstract

Compounds of formula (I): wherein Ra and Rb are as defined in the claims, exhibit alpha2C antagonistic activity and are thus useful as alpha2C antagonists.

Description

technical field [0001] The present disclosure relates to pharmacologically active 1-((2,3-dihydrobenzo[b][1,4]-dioxin-2-yl)methyl)piperidine derivatives or pharmaceutically acceptable derivatives thereof Salts and esters, as well as pharmaceutical compositions comprising them and their use as α2C antagonists. Background of the invention [0002] It is generally known and accepted in the art that compounds exhibiting alpha adrenergic activity are useful in the treatment of a variety of diseases and disorders of the peripheral and central nervous system (CNS). [0003] Alpha adrenergic receptors can be divided on a pharmacological basis into alpha 1 and alpha 2 adrenoceptors, both of which can be further divided into subtypes. Three genetically encoded subtypes, α2A, α2B, α2C adrenoceptors, have been identified in humans. A fourth pharmacologically defined subtype, the α2D adrenoceptor, is known in some other mammals and in rodents. It corresponds to the genetically defined...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D413/14C07D417/14C07D471/04C07D473/00C07D487/04C07D487/10C07D513/04A61K31/453A61K31/519A61K31/52A61P25/28
CPCA61P25/28A61P25/18A61P25/24A61P25/08A61P25/16C07D405/14C07D413/14C07D417/14C07D471/04C07D473/00C07D487/04C07D487/10C07D513/04A61K31/453A61K31/519A61K31/52
Inventor A·哈伊卡雷宁E·昆普莱宁A·波赫亚卡利奥J·皮斯蒂宁S·王
Owner ORION CORPORATION