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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, respirator, drug composition, etc., can solve the problems of limited use of several pde4 inhibitors of the first-generation such as rolipram and piclamilas

Inactive Publication Date: 2013-03-28
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides novel compounds that act as inhibitors of the phosphodiesterase 4 (PDE4) enzyme. These compounds have been found to have useful therapeutic properties, and can be used in the treatment of various medical conditions. The invention also provides methods for preparing these compounds, as well as pharmaceutical compositions and uses of the compounds in therapy. The compounds are derived from a specific group of compounds, called 1-phenyl-2-pyridinyl alkyl alcohols, which have been found to have inhibitory activity against PDE4.

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
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Effect test

example 1

Synthesis of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzamido)acetoxy)ethyl)pyridine 1-oxide (5)

[0594]

Step 1: Synthesis of (S)-4-(2-(2-(tert-butoxycarbonylamino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (2)

[0595](S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (80 mg; 0.19 mmol) was dissolved in DMF (2 ml), then 2-(tert-butoxycarbonylamino)acetic acid (70 mg, 0.4 mmol), EDC (60 mg, 0.3 mmol), and DMAP (30 mg, 0.25 mmol) were added. The reaction was stirred at RT for 6 hours, then it was diluted with water and extracted with EtOAc. The organic phase was extracted with HCl 1M and with K2CO3 sat, dried over Na2SO4 and evaporated under vacuum to give 80 mg of the desired compound (Yield: 74%).

Step 2: Synthesis of (S)-4-(2-(2-aminoacetoxy)-2-(3(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl...

example 2

Synthesis of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(phenylsulfonyl)propanoyloxy)ethyl)pyridine 1-oxide (13)

[0603]

Synthesis of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(phenylsulfonyl)propanoyloxy)ethyl)pyridine 1-oxide (13)

[0604]((S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide) (150 mg, 0.357 mmol), EDC (103 mg, 0.535 mmol), 3-(phenylsulfonyl)propanoic acid (84 mg, 0.393 mmol), and DMAP (65.4 mg, 0.535 mmol) in DCM (30 ml) were stirred at RT for 4 hours. The reaction mixture was washed with HCl 1N (2×) and NaHCO3 sat. sol. (2×); the organic layer was dried over Na2SO4 and evaporated to dryness. The residue was purified by trituration with iPr2O (10 ml). Further triturations with petroleum ether (15 ml) and Et2O (20 ml) were performed to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(phenylsulfonyl)propanoyloxy)et...

example 3

Synthesis of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(4-(methylsulfonamido)benzylcarbamoyloxy)ethyl)pyridine 1-oxide (24)

[0608]

Step 1: Synthesis of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (20)

[0609](S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1.5 g, 3.57 mmol), and DMAP (0.436 g, 3.57 mmol) were dissolved in DCM (50 ml), and 4-nitrophenyl carbonochloridate (0.863 g, 4.28 mmol) was added portion wise. The mixture was stirred at RT overnight. After 18 hours, the solvent was evaporated and the crude purified by silica gel flash chromatography (petroleum ether:EtOAc 3:7) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)-ethyl)pyridine 1-oxide (1.609 g, 2.75 mmol, 77% yield, MS / ESI+ 585 [MH]+).

Step 2: Synthesis of (S)-3,5-dichloro-4-(2-(3-(cycl...

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Abstract

The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.

Description

CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority to European Patent Application No. 11182814.1, filed on Sep. 26, 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 derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.[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 oedema of airway walls, increased mucous production and inflammation.[0006]Drugs for treating respiratory diseases such as asthma and COPD are currently administered through inhalation. One of the advantages of th...

Claims

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Application Information

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IPC IPC(8): C07D213/89C07D413/12A61K31/5377C07D401/12A61K31/496C07D417/12A61K31/4439C07D409/12A61K31/4436A61K31/444A61K31/506A61K31/56A61P11/00A61P11/06A61K31/44
CPCC07D213/89C07D401/12C07D409/12C07D413/12C07D417/12A61K31/44A61K31/4439A61K31/496A61K31/5377A61P11/00A61P11/02A61P11/06C07D213/55C07D213/56C07D213/69A61M15/0045A61M15/009A61M16/14
Inventor ARMANI, ELISABETTAAMARI, GABRIELECAPALDI, CARMELIDAESPOSITO, ORIANAPERETTO, ILARIA
Owner CHIESI FARM SPA
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