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Inhibitors of copper-containing amine oxidases

A technology of amine oxidase and compounds, applied in the field of enzyme inhibitors, can solve problems such as not showing activity

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

[0009] Takahashi, H. et al. reported a large number of N-alkylaminoephedrines in Yakugaku Zasshi 101 (12): 1154-1156 (1981), including N-(isopropylidene amino)-ephedrine (or R, S Synthesis of -(+)-(2-hydroxyl-1-methyl-2-phenylethyl)methylhydrazone-2-propenxin): These hydrazone compounds were synthesized to evaluate their effects on the bronchial musculature and were found not to exhibit any appreciable activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1 (1R, 2S)-2-(1-methylhydrazino)-1-phenyl-1-hydrogen maleate (1)

[0117] In an ice bath with vigorous stirring, to a suspension of (1R,2S)-2-methylamino-1-phenyl-1-propanol hydrochloride (2.02g, 10mmol) in water (50ml) was added dropwise NaNO 2 (1.38g, 20mmol) in water (10ml), followed by the dropwise addition of AcOH (0.30g, 5mmol). The mixture was stirred at room temperature for 8 hours, then extracted with EtOAc (4 x 50ml). dry (Na 2 SO 4 ) through the combined organic phases, and evaporated under reduced pressure to obtain 1.86 g of oily product of N-nitroso derivatives, which were directly used in subsequent steps without further purification.

[0118] To the stirred LiAlH 4 (1R, 2S)-2-methylamino-N-nitroso-1-phenyl-1-propanol (1.86 g, 9.6 mmol) was added dropwise to a suspension of (0.73 g, 19.2 mmol) in THF (50 ml). ) in THF (20ml), the mixture was stirred and refluxed for 3 hours. with H 2 A mixture of O (1.5ml) and THF (20...

Embodiment 2

[0119] Embodiment 2 (1R * , 2S * )-2-(1-methylhydrazino)-1-phenyl-1-propanol hydrochloride (2)

[0120] Add (1R * , 2S * )-2-Methylamino-1-phenyl-1-propanol (0.86g, 5.3mmol) in ether (5ml). The resulting reaction mixture was stirred at room temperature for 30 minutes and evaporated to dryness. To the residue was added 5% hydrochloric acid (30ml), and the mixture was stirred at ambient temperature for 1 hour. with Et 2 O (2×30ml) washed the mixture with Na 2 CO 3 Basified and extracted with EtOAc (3 x 50ml). The combined EtOAc extracts were dried and evaporated to give a solid residue which was dissolved in methanol (5ml) and converted to the crystalline salt with 22% ethanolic hydrochloric acid (2ml) and diethyl ether salt. The crystals were filtered off and recrystallized from methanol / ether. 1 H-NMR (400MHz, D 2 O) δ (ppm): 1.20 (3H, d, J = 6.8Hz, CHCH 3 ), 3.09 (3H, s, NCH 3 ), 3.67 (1H, m, NCH), 5.41 (1H, br s, OCH), 7.47 (5H, m, C 5 h ...

Embodiment 3

[0121] Embodiment 3 (1R * , 2S * )-2-(1-methylhydrazino)-1-phenyl-1-propanol hydrochloride (2)

[0122] Add dropwise (1R * , 2S * )-2-(1-methylhydrazino)-N-nitroso-1-phenyl-1-propanol (1.94g, 10mmol, prepared according to Example 1 from (1R * , 2S * )-2-Methylamino-1-phenyl-1-propanol hydrochloride) in AcOH (18ml). The temperature of the reaction mixture was maintained at 20-25°C during the addition by external cooling. After the addition was complete, the mixture was stirred at 50 °C for 1 hour, then filtered with suction, and the zinc residue was washed with H 2 A mixture of O (15ml) and AcOH (5ml) was washed. The filtrate and washings were combined and concentrated in vacuo to about 10 mL. Under ice-cooling, the solution was basified with NaOH solution, and then washed with Et 2 O (4 x 50ml) extraction. The combined ether extracts were dried and evaporated to give a yellow oil which was dissolved in methanol (5ml) and converted to the crystal...

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PUM

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Abstract

The present invention is directed to 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 have general formula: or a pharmaceutically acceptable solvate, hydrate, or salt thereof, wherein R<1> to R<8> and X are as defined herein.

Description

field of invention [0001] The invention belongs to the field of medicinal chemistry, and relates to a hydrazine-based compound and its use as an inhibitor of copper-containing amine oxidase (E.C. 1.4.3.6) and enzymes apparently equivalent thereto. The compounds of the present invention have medical applications, such as the treatment of various diseases including but not limited to various inflammations. In particular, these compounds can be used to treat acute and chronic inflammatory conditions or diseases, such as chronic arthritis, enteritis and chronic skin diseases, as well as diseases related to carbohydrate metabolism and aberrations in adipocyte differentiation or function and smooth muscle cell function related diseases. Background of the invention [0002] VAP-1 is a human endothelial cell adhesion molecule, which has a variety of unique properties different from other inflammation-related adhesion molecules. This molecule has a specific and constrained expressi...

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
CPCA61K31/472A61K31/14A61K31/131A61K31/445A61K31/15A61K31/40A61P1/04A61P1/16A61P11/06A61P17/00A61P19/02A61P25/00A61P29/00A61P3/00A61P3/10A61P3/08A61P37/00A61P43/00A61P9/00A61P9/10
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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