Pharmaceutical compounds

a technology of benzofused and heterocyclic compounds, applied in the field of pharmaceutical compounds, can solve the problems of limited oral bioavailability and short duration of action, and achieve the effects of prolonging the duration of action, enhancing primary pharmacological properties, and improving bioavailability

Inactive Publication Date: 2011-04-14
ORION CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] Due to slow elimination via glucuronidation, the COMT inhibitors of the present invention have an improved bioavailability and / or a prolonged duration of action. Additionally, the compounds of the present invention possess enhanced primary pharmacological properties, i.e. COMT inhibiting activity. Furthermore, the compounds do not uncouple oxidative phosphorylation and thus possess a desirable safety profile.

Problems solved by technology

However, the commercially available COMT inhibitors are associated with a rather short duration of action and their oral bioavailability is limited.

Method used

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  • Pharmaceutical compounds
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Examples

Experimental program
Comparison scheme
Effect test

example 1

2-(4-Chloro-phenyl)-5,6-dihydroxy-4-nitro-2,3-dihydro-isoindol-1-one

2-(4-Chloro-phenyl)-5,6-dimethoxy-2,3-dihydro-isoindol-1-one

[0070] A solution of 2-bromomethyl-4,5-dimethoxy-benzoic acid methyl ester (2.9 g), 4-chloroaniline (1.28 g) and triethylamine (1.4 ml) was refluxed in toluene for six hours. The reaction mixture was stirred in an ice bath, filtered and washed with 1 M hydrochloric acid and water.

[0071] Yield: 0.74 g

[0072]1H NMR (DMSO-d6): δ=3.85 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 4.89 (s, 2H, CH2), 7.23 (s, 1H, ArH), 7.24 (s, 1H, ArH), 7.48 (d, 2H, J=8.9 Hz), 7.91 (d, 2H, J=8.9 Hz).

2-(4-Chloro-phenyl)-5,6-dihydroxy-2,3-dihydro-isoindol-1-one

[0073] 2-(4-Chloro-phenyl)-5,6-dimethoxy-2,3-dihydro-isoindol-1-one (0.74 g) was demethylated with 4 eq of boron tribromide as described in Example 8.

[0074] Yield: 0.79 g (raw material used as such in the next step)

[0075]1H NMR (DMSO-d6): δ=4.80 (s, 2H, CH2), 6.77 (s, 1H, ArH), 6.82 (s, 1H, ArH), 7.48 (d, 2H, J=9.1 Hz), 7.91 (d,...

example 2

5,6-Dihydroxy-7-nitro-3H-isobenzofuran-1-one

5,6-Dihydroxy-7-nitro-3H-isobenzofuran-1-one

[0088] To a solution of 5,6-dihydroxy-3H-isobenzofuran-1-one (0.4 g) in sulfuric acid at −30° C. was added 5 M nitric acid in sulfuric acid (0.55 ml). The reaction mixture was let to warm up to room temperature and then poured into ice water. The product was filtered and recrystallized from acetic acid.

[0089] Yield: 0.2 g

[0090]1H NMR (DMSO-d6): δ=5.26 (s, 2H, CH2), 7.14 (s, 1H, ArH), 10.6 (b, 1H, OH), 11.75 (b, 1H, OH).

example 3

7-Nitro-2-pyridin-4-yl-benzothiazole-5,6-diol, methane sulfonate

5,6-Dimethoxy-2-pyridin-4-yl-benzothiazole

[0091] A solution of 3,4-dimethoxyaniline (6 g) and sulfur (5 g) were refluxed in 4-picolin (15 ml) for five hours. The cool reaction mixture was poured into methanol, kept over ice bath for minutes and filtered. The product was washed with methanol and carbon disulfide.

[0092] Yield: 6.14 g

[0093]1H NMR (DMSO-d6): δ=3.88 (s, 3H, CH3O), 3.89 (s, 3H, CH3O), 7.67 (s, 1H, ArH), 7.76 (s, 1H, ArH), 7.94 (d, 2H, J=6.4 Hz), 8.75 (d, 2H, J=6.4 Hz).

5,6-Dimethoxy-4-nitro-2-pyridin-4-yl-benzothiazole

[0094] To a solution of 5,6-dimethoxy-2-pyridin-4-yl-benzothiazole (1.1 g) in sulfuric acid (10 ml) was added potassium nitrate (0.5 g). After 60 minutes in room temperature the mixture was poured into ice water and filtered. Recrystallization from acetone yielded the pure product.

[0095] Yield: 0.8 g

[0096]1H NMR (DMSO-d6): δ=4.05 (s, 3H, CH3O), 4.07 (s, 3H, CH3O), 8.07 (d, 2H, J=6 Hz), 8....

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Abstract

Compounds of formula (I), wherein R1-R4, X, Y and Z are as defined in claims, exhibit COMT enzyme inhibiting activity and are thus useful as COMT inhibitors.

Description

FIELD OF THE INVENTION [0001] The present invention relates to pharmacologically active benzofused five-membered heterocycles, or pharmaceutically acceptable salts and esters thereof, as well as to pharmaceutical compositions containing them and to their use as inhibitors of catechol-O-methyltransferase (COMT) enzyme. BACKGROUND OF THE INVENTION [0002] It is generally known and accepted in the art that COMT inhibitors are useful in the treatment of Parkinson's disease. COMT inhibitors have been shown to be effective in clinical use for the treatment of Parkinson's disease as an adjunct to levodopa therapy. In order to achieve a steady plasma concentration of levodopa, it is desirable that the COMT inhibitor has a good bioavailability and a long duration of action. However, the commercially available COMT inhibitors are associated with a rather short duration of action and their oral bioavailability is limited. [0003] COMT inhibitors have also been indicated to be useful in the treat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377A61K31/4535A61K31/4439A61K31/428A61K31/4035A61K31/381A61K31/343C07D413/02C07D409/02C07D417/02C07D275/04C07D209/46C07D333/52C07D307/87
CPCC07D209/46C07D275/04C07D277/64C07D277/66C07D277/84C07D417/04C07D307/89C07D333/62C07D333/68C07D333/70C07D409/06C07D307/88A61P25/16A61P43/00A61K31/404A61K31/425A61K31/343
Inventor AHLMARK, MARKOBACKSTROM, REIJOLUIRO, ANNEPYSTYNEN, JARMOTIAINEN, EIJA
Owner ORION CORPORATION
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