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Inhibitors of copper-containing amine oxidases

A technology of compounds and uses, applied in the field of medicinal chemistry, which can solve problems such as not mentioned

Inactive Publication Date: 2003-10-22
BIOTIE THERAPIES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reference does not mention the 1,3,4-oxadiazines corresponding to the reported hydrazones

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 19

[0130] Example 19-Benzyl-2-methyl-5-oxa-1,2,9-triazaspiro[5.5]undecane dihydrochloride

[0131] The title compound was synthesized using one of the following three synthetic methods.

[0132] Method 1a: To 2-(N 1 -Methylhydrazino) ethanol (0.30g, 3.3mmol) in anhydrous toluene (10ml) solution was added 1-benzylpiperidin-4-one (0.63g, 3.3mmol), and the resulting reaction mixture was heated at room temperature Let stand for 24 hours. The toluene solution was decanted from the separated aqueous layer and evaporated to dryness. Anhydrous toluene (10ml) was added and the evaporation was repeated. The resulting pale yellow oil was dissolved in ethanol (2ml) and converted to the crystalline dihydrochloride by using 22% hydrogen chloride in ethanol (1ml) and diethyl ether. The crystals were filtered off and recrystallized from ethanol / ether. 13 C-NMR (500 MHz, solid state): δ 26.61 (broad peak), 33.81, 44.1, 52.2, 57.93, 83.44 (C-2), 128.42, 130.0, 133.04....

Embodiment 29

[0135] Example 29-Benzyl-2-methyl-4-phenyl-5-oxa-1,2,9-triazaspiro[5.5]undecane dihydrochloride

[0136] The title compound was synthesized using one of the following two synthetic methods.

[0137] Method 2a: To 2-(N 1-Methylhydrazino)-1-phenylethanol (0.50g, 3mmol) in anhydrous toluene (25ml) solution was added 1-benzylpiperidin-4-one (0.57g, 3mmol), and catalytic amount (1 drops) of glacial acetic acid. The resulting reaction mixture was allowed to stand at room temperature for 24 hours, then evaporated to dryness. Anhydrous toluene (10ml) was added and the evaporation was repeated. The resulting pale yellow oil was dissolved in ethanol (2ml) and converted to the crystalline dihydrochloride by using 22% hydrogen chloride in ethanol (1ml) and diethyl ether. The crystals were filtered off and recrystallized from ethanol / ether. 13 C-NMR (500 MHz, solid state): δ 26.61 (broad peak), 33.81, 44.1, 52.2, 57.93, 83.44 (C-2), 128.42, 130.0, 133.04.

[...

Embodiment 3

[0139] Example 3 (3S, 4R)-9-benzyl-2,3-dimethyl-4-phenyl-5-oxa-1,2,9-triazaspiro[5.5]undecane disalt salt

[0140] The title compound was synthesized using one of the following two synthetic methods.

[0141] Method 3a: To a solution of (1R,2S)-N-aminoephedrine (0.30g, 1.7mmol) in anhydrous benzene (30ml) was added 1-benzylpiperidin-4-one (0.31g, 1.6mmol). The resulting reaction mixture was allowed to stand at room temperature for 6 hours, then evaporated to dryness. The resulting residue was dissolved in 5 ml of 22% hydrogen chloride in ethanol, after a few minutes the solution was evaporated to dryness and the residue was recrystallized from an ethanol / ether mixture. 13 C-NMR (500 MHz, solid state): δ4.97, 28.42, 41.01, 46.9, 49.5, 59.57, 71.69, 83.87 (C-2), 129.67.

[0142] Method 3b: Add 1-benzylpiperidin-4-one (0.31g, 1.6mmol) to a solution of (1R,2S)-N-aminoephedrine (0.30g, 1.7mmol) in anhydrous benzene (30ml), A few drops of 22% hydrogen ...

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PUM

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Abstract

The present invention is directed to 1,3,4-hydrazino compounds that functions as inhibitors of copper-containing amine oxidases commonly known as semicarbazidesensitive amine oxidases (SSAO), including the human SSAO known as Vascular Adhesion Protein-1 (VAP-1). These SSAO inhibitors have therapeutic utility as drugs to treat conditions and diseases including, but not limited to, a number of inflammatory conditions and diseases (in particular chronic inflammatory conditions such as chronic arthritis, inflammatory bowel diseases, and chronic skin dermatorses), diseases related to carbohydrate metabolism and to aberrations in adipocyte differentiation or function and smooth muscle cell function, and vascular diseases. The compounds, their tautomers, isomers, hydrazine alcohol degradation product, and a pharmaceutically acceptable solvate, hydrate, or salt thereof, have general formula (I), wherein R<1> to R<8> are as defined herein.

Description

field of invention [0001] The invention belongs to the field of medicinal chemistry and relates to 1,3,4-oxadiazine compounds and their use as inhibitors of copper-containing amine oxidase (E.C. 1.4.3.6) and enzymes apparently equivalent thereto. The compounds of the present invention are useful in the treatment of various diseases, including but not limited to various inflammatory symptoms and diseases (especially chronic inflammatory symptoms or diseases, such as chronic arthritis, enteritis and chronic skin diseases), and carbohydrate metabolism. Medical use of drugs for diseases and diseases related to adipocyte differentiation or function and smooth muscle cell function aberrations. Background of the invention [0002] VAP-1 is a human endothelial cell adhesion molecule with a number of unique properties different from other inflammation-related adhesion molecules, which will be described below. VAP-1 has a specific and restricted expression pattern and mediates the bi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/16A61K31/00A61K31/131A61K31/14A61K31/15A61K31/40A61K31/445A61K31/472A61K31/5395A61P1/04A61P1/16A61P3/00A61P3/10A61P9/00A61P9/10A61P11/06A61P17/00A61P19/02A61P25/00A61P29/00A61P37/00A61P43/00C07B61/00C07D273/04C07D498/04C07D498/10
CPCA61K31/472A61K31/14A61K31/131A61K31/445A61K31/40A61K31/15A61P1/04A61P1/16A61P11/06A61P17/00A61P19/02A61P25/00A61P29/00A61P3/00A61P3/10A61P3/08A61P37/00A61P43/00A61P9/00A61P9/10
Inventor D·J·史密斯M·亚尔卡宁F·费勒普L·拉扎Z·斯扎康伊G·贝尔纳斯
Owner BIOTIE THERAPIES LTD
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