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

a technology of phosphodiesterase and derivatives, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of limited use of several pde4 inhibitors of the first-generation such as rolipram and piclamilast, and poor selectivity of compounds, so as to achieve good persistency in the lung and short systemic duration

Inactive Publication Date: 2011-06-16
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

It is another object of the present invention to provide novel compounds which are useful as PDE4 inhibitors with an improved selectivity toward LPDE4.
As a matter of fact, it has now been found that providing a PDE4 inhibitor with an additional moiety interacting with the active site of the PDE4, there is an improvement in the selectivity of the inhibitors towards LPDE4.
The PDE4 inhibitors of the present invention efficaciously act upon inhalation administration and could be characterized by a good persistency in the lung and a short systemic duration.

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.
However, even these compounds are not provided with a good selectivity towards LPDE4.

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 1

Preparation of 3,5-dichloro-4-methylpyridine (Intermediate (4) of scheme 1)

Diisopropylamine (70 mL, 500 mmol) was dissolved in dry tetrahydrofuran (THF) (500 mL), the solution was cooled to −10° C. and buthyl lithium (2.5 N in hexane, 210 mL, 525 mmol) was added dropwise under stirring. After 30 minutes the solution was cooled to −20° C. and 3,5-dicholopyridine (66.6 g, 450 mmol) in tetrahydrofuran (200 mL) was added dropwise. The solution was stirred at −10° C. for 30 minutes, cooled to −70° C. and added dropwise with iodomethane (50 mL, 1.6 mol) in tetrahydrofuran (100 mL). The reaction mixture was allowed to warm to room temperature, quenched with water (100 mL) and extracted with diethyl ether (3×100 mL); the combined organic layers were dried over sodium sulphate (5 g) and evaporated to dryness. The crude product was crystallized twice from aqueous ethanol than from hexane to afford 3,5-dichloro-4-methylpyridine (49.9 g, 306 mmol, 68% yield) as a white solid.

MS / ESI+162-164-166 ...

example 2

Preparation of 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone (Intermediate (1) of scheme 1)

A solution of 3,5-dichloro-4-methyl-pyridine (2.06 g, 12.7 mmol) in dry tetrahydrofuran (30 ml) was cooled down to −78° C., then a 1.8 M solution of lithium diisopropylamide in tetrahydrofuran (7.4 ml, 13.3 mmol) was added dropwise under stirring, keeping the temperature below −70° C. The resulting solution was stirred for 30 min., then a solution of 3,4-dimethoxy-benzoyl chloride (2.55 g, 12.7 mmol) in dry tetrahydrofuran (20 ml) was added dropwise, maintaining the temperature below −70° C. After stirring for 15 minutes, ice (20 g) was added, followed by further 500 ml of water. The mixture was extracted with ethyl acetate (2×50 ml), the combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give an oil that was purified by flash chromatography (Eluent: ethyl acetate / petroleum ether from 10 / 90 to 30 / 70 v:v). 2.1 grams (6.4 mmol, 52% ...

example 3

Preparation of 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanol (Intermediate (2) of scheme 1)

Route A.

Sodium boron hydride NaBH4 (45.2 mg, 2.5 eq.) is added to a suspension of 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone (150 mg, 1 eq.) in CH3OH (5 ml), at room temperature under nitrogen atmosphere. The mixture is stirred at room temperature overnight, then the reaction is quenched with water and extracted with EtOAc. The organic layer is dried over Na2SO4 and the solvent is evaporated. The crude is purified by flash chromatography on silica gel in gradient elution from petroleum ether / EtOAc 9 / 1 v / v to petroleum ether / EtOAc 7 / 3 v / v, to obtain 75 mg of the title compound (50% yield).

MS / ESI+ 328-330-332[MH]+

The following intermediates were prepared using said route with suitable solvents:

TABLE 2Inter-mediatesR1R2R3Analytical2Mecyclopentyl3,5-MS / ESI+dichloro328-330-332 [MH]+2aMecyclo-3,5-MS / ESI+propylmethyldichloro368-370-372 [MH]+2bdifluoromethylcyclo-...

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Abstract

Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme.

Description

CROSS REFERENCES TO RELATED APPLICATIONSThis application claims priority to European Patent Application No. 07114019.8 filed on Aug. 8, 2007, and which is incorporated herein by reference in their entireties.BACKGROUND OF THE INVENTION1. Field of the InventionThe present 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.2. Discussion of the BackgroundAirway 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.Drugs for treating respiratory diseases such as asthma and COPD are currently administered through inhalation. One of the advantages of the inhalatory route...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/58C07D213/89A61K31/44A61P11/00A61P29/00C07D401/12A61K31/4545A61K31/444A61K31/4439C07D413/12A61K31/5377C07D405/12A61K31/4433A61K31/538C07J43/00
CPCC07D213/61C07D473/08C07D401/12C07D417/12C07D473/04C07D213/79C07D213/30A61K45/06A61K31/538A61K31/5377A61K31/522A61K31/4709A61K31/4545A61K31/444A61K31/4439A61K31/4433A61K31/44C07D405/12C07D213/80C07D213/38A61K31/455C07D213/89A61P11/00A61P11/06A61P11/08A61P29/00A61P43/00
Inventor DELCANALE, MAURIZIOARMANI, ELISABETTAAMARI, GABRIELE
Owner CHIESI FARM SPA
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