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Isoxazolidine derivatives

a technology of isoxazolidine and derivatives, applied in the field of new antiinflammatory and antiallergic compounds, can solve the problems of limited duration of action, and achieve the effects of improving the development ability, pharmacokinetic or pharmacodynamic characteristics, and reducing the risk of side effects

Inactive Publication Date: 2012-09-20
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]It is another object of the present invention to provide novel anti-inflammatory and antiallergic compounds, with improved pharmacokinetic and pharmacodynamic characteristics.
[0018]These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I), described below, exhibit improved developability, and pharmacokinetic and pharmacodynamic characteristics, such as low systemic exposure, great selectivity, potency or duration of action.
[0024]Surprisingly, it has been found that the compounds of the present invention show improved developability, pharmacokinetic or pharmacodynamic characteristics, such as low systemic exposure, great selectivity, potency or duration of action.

Problems solved by technology

Moreover, the limited duration of action of ICS currently available in the clinical practice contributes to suboptimal management of the disease.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of acetic acid (8S,9S,10R,13S,14S,17R)-17-(2-acetoxy-acetyl)-10,13-dimethyl-3,11dioxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester (intermediate 2)

[0371]

[0372]To a suspension of acetic acid 2-((10R,13S,17R)-17-hydroxy-10,13-dimethyl-3,11-dioxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxo-ethyl ester (intermediate 1) (2 g, 4.99 mmol) and p-toluene sulphonic acid (PTSA) (200 mg, 1.051 mmol) in acetic acid (5 ml), at 0° C., trifluoroacetic anhydride (5 ml, 35.4 mmol) was slowly added over 10 minutes. After stirring at 0° C. for 20 minutes, the reaction mixture was stirred at RT for 3 hours.

[0373]The reaction mixture was poured in ice / water (130 ml), and the resulting mixture was extracted with DCM (2×100 ml) and AcOEt (2×100 ml). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash chromatography on silica gel, in gradient elutio...

example 2

Preparation of acetic acid 2-((6S,8S,9R,10S,11S,13S,14S)-6,9-difluoro-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15-decahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxo-ethyl ester (intermediate 5)

[0378]

[0379]To a solution of butyric acid (9R,10S,11S,13S,17R)-17-(2-acetoxy-acetyl)-9-chloro-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester (intermediate 4) (2.48 g, 4.88 mmol) in anhydrous DMF (60 ml), under nitrogen atmosphere, potassium acetate (3.83 g, 39.0 mmol) was added and the reaction mixture was stirred at 100° C. for 1.5 hours. The cooled reaction mixture was poured into ice and brine (200 ml), and the aqueous layer was extracted with AcOEt (3×150 ml). The combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated to afford 2.55 g of crude title compound which was used in the next step without further purification.

[0380]1H NMR (300 MHz, DMSO-d6): ppm 7.29 (dd, 1H)...

example 3

Preparation of (6S,8S,9R,10S,11S,13S,14S)-17-(2-(tert-butyldimethylsilyloxy)acetyl)-6,9-difluoro-11-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15-decahydro-3H-cyclopenta[a]phenanthren-3-one (intermediate 9)

[0386]

[0387]To a solution of 6 (300 mg, 0.793 mmol) in dry DMF (12 ml), imidazole (135 mg, 1.982 mmol) and pyridine (0.321 ml, 3.96 mmol) were added, followed by tert-butylchlorodimethylsilane (263 mg, 1.744 mmol). The reaction was stirred at room temperature for 2 hours. The conversion was complete. The reaction was diluted with AcOEt and washed with water, the aqueous layer was extracted twice with AcOEt, and then the combined extracts were dried over sodium sulphate and evaporated. The crude was purified via chromatographic column over silica gel (DCM, DCM / AcOEt 8:1) to give 365 mg (93% yield).

[0388]LC-MS (ESI POS): 493.1 (MH+)

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Abstract

Anti-inflammatory and antiallergic compounds of the glucocorticosteroid series, according to formula (I) according to formula (I) defined herein are useful for treating diseases of the respiratory tract characterized by airway obstruction.

Description

CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority to European Patent Application No. 11158230.0 filed on Mar. 15, 2011, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to novel anti-inflammatory and antiallergic compounds of the glucocorticosteroid series, methods of preparing such a compound, pharmaceutical compositions which contain such a compound them, combinations which contain such a compound, and therapeutic uses of such a compound. The present invention also relates to methods of treating and / or preventing certain diseases and conditions by administering such a compound. More particularly, the invention relates to glucocorticosteroids that are isoxazolidine derivatives.[0004]2. Discussion of the Background[0005]Corticosteroids are potent anti-inflammatory agents, able to decrease the number, activity and movement of inflammatory cells. They are...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/58A61P29/00A61M16/14A61P11/06A61M15/00A61M11/04C07J71/00A61P11/00
CPCA61K31/58C07J71/0068A61K45/06A61P11/00A61P11/06A61P11/08A61P29/00A61P37/08A61P5/44C07J71/00
Inventor GHIDINI, ELEONORARIZZI, ANDREA
Owner CHIESI FARM SPA
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