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Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

a technology of pyridinyl alkyl alcohol and phosphodiesterase, which is applied in the direction of biocide, drug composition, immunological disorders, etc., can solve the problems of limited use of several pde4 inhibitors of the first-generation such as rolipram and piclamilast, and achieve the effect of reducing side effects, appropriate development profile and high affinity for pde4 enzym

Inactive Publication Date: 2013-01-03
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new PDE4 inhibitors that have a great affinity for the PDE4 enzyme and are well-developed for use as inhalant treatments with minimal side effects.

Problems solved by technology

However, corticosteroids do not reduce the inflammatory response in COPD as they do in asthma.
However, the usefulness of several PDE4 inhibitors of the first-generation such as rolipram and piclamilast has been limited due to their undesirable side effects.

Method used

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  • Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors
  • Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors
  • Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 17

(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-methoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide 164)

[0488]

Step 1: 4-((S)-2-((S)-2-acetoxy-2-phenylacetoxy)-2-(3-(cyclopropyl-methoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (161)

[0489]A mixture of (S)-2-acetoxy-2-phenylacetic acid (0.924 g, 4.76 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.0 g, 2.380 mmol), EDC (0.684 g, 3.57 mmol), and DMAP (0.436 g, 3.57 mmol) in DCM (150 ml) was stirred at RT for 24 hours. More (S)-2-acetoxy-2-phenylacetic acid (0.350 g, 1.802 mmol), EDC (0.456 g, 2.380 mmol), and DMAP (0.300 g, 2.456 mmol) were added and the stirring was continued for 3 hours to complete conversion. The reaction mixture was washed twice with aqueous 1N HCl and then with aqueous 1M K2CO3; the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was triturated with iPrOH (30 ml) and filtered to afford the desired product (1....

example 18

Synthesis of (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (170)

[0495]

Step 1: Synthesis of 2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (166)

[0496]3,5-dichloro-4-methylpyridine (160) (54 g, 331 mmol) was dissolved in dry THF (480 mL) under anargon atmosphere and it was cooled at −78° C. in dry-ice / acetone bath. LHMDS 1N THF solution (331 ml, 331 mmol) was added drop-wise by keeping the temperature at −78°. The mixture was stirred at −78° for 1 hour. After that, a solution of 3,4-dimethoxybenzaldehyde (50 g, 301 mmol) in dry THF (120 ml) was added drop-wise by keeping the temperature at −78° C. When the addition was completed, the mixture was allowed to warm at RT.

[0497]The reaction was poured in ice and water (1 L), and the mixture was stirred until a copious precipitate formed. The solid was filtered, and dissolved in ethyl acetate (500 ml), dried over Na2SO4 and the solvent evaporated under vacuum. The crude was crystallized in CHCl3 / he...

example 36

Synthesis of 3,5-dichloro-4-(2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-hydroxyethyl)pyridine 1-oxide (172)

[0506]

Step 1: Synthesis of 2-(3,5-dichloropyridin-4-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethanol (171)

[0507]3,5-dichloro-4-methylpyridine (166) (4.37 g, 0.016 mol) was dissolved in dry THF (40 mL) under an argon atmosphere and it was cooled at −78° C. in dry-ice / acetone bath. LHMDS IN THF solution (28 ml, 28 mmol) was added drop-wise by keeping the temperature at −78°. The mixture was stirred at −78° for 1 hour. After that, a solution of 2,3-difluoro-3,4-benzodioxolocarboxaldheyde (5 g, 0.026 mol) in dry THF (10 ml) was added drop-wise by keeping the temperature at −78° C. When the addition was completed, the mixture was allowed to warm at RT. The reaction was poured in ice and water, and the aqueous phase extracted with ethyl acetate (3×). The combined organic phases were dried over Na2SO4 and the solvent evaporated under vacuum. The crude was crystallized in petroleum ...

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Abstract

Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme and the treatment of certain conditions such as COPD.

Description

CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority to European Patent Application No. 11168853.7, filed on Jun. 6, 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 inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the present invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them, and therapeutic uses of such compounds and compositions.[0004]2. Discussion of the Background[0005]Airway obstruction characterizes a number of severe respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include edema of airway walls, increased mucous production and inflammation.[0006]Drugs for treating respiratory diseases such as asthma and COPD are currently administered t...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D417/12C07D413/12A61K31/5377A61P17/00A61K31/541A61K31/496C07D401/14C07D417/14A61P11/00A61K31/4439A61K31/4545
CPCC07D213/89C07D401/12C07D401/14C07D405/06C07D405/14C07D413/12C07D417/12C07D417/14C07D498/04A61K45/06A61K31/4425A61K31/4439A61K31/444A61K31/4545A61K31/496A61K31/5377A61K31/538A61K31/541C07D213/30A61K31/517A61K31/635C07D471/04A61P11/00A61P11/02A61P11/06A61P17/00A61P37/08A61P43/00A61K31/44
Inventor ARMANI, ELISABETTAAMARI, GABRIELECARZANIGA, LAURACAPALDI, CARMELIDAESPOSITO, ORIANAVILLETTI, GINODE FANTI, RENATO
Owner CHIESI FARM SPA
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