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(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 acetylaminoisoindoline 1,3-dione, its preparation method and its compound

A technology of methanesulfonylethyl and methoxyphenyl, which can be used in pharmaceutical combinations, pharmaceutical formulations, organic active ingredients, etc., can solve problems such as lack of selectivity

Inactive Publication Date: 2010-05-12
AMGEN (EURO) GMBH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Currently used PDF4 inhibitors lack selectivity at acceptable therapeutic doses

Method used

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  • (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 acetylaminoisoindoline 1,3-dione, its preparation method and its compound
  • (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 acetylaminoisoindoline 1,3-dione, its preparation method and its compound
  • (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4 acetylaminoisoindoline 1,3-dione, its preparation method and its compound

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Experimental program
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preparation example Construction

[0077] Preparation and storage of anhydrous pharmaceutical compositions should preserve their anhydrous nature. Accordingly, it is preferred that anhydrous compositions be packaged using materials known to be water repellent so that they can be packaged in suitable prescribed kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, single-dose containers (eg, vials), blister packs, and split packs.

[0078] The present invention further includes pharmaceutical compositions and dosage forms containing one or more compounds that reduce the rate at which the active ingredient will decompose. These compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0079] As with the amount and type of excipients, the amount and specific type of active ingredient in the dosage form may vary depending on factors such as, but not limited to, the route of...

Embodiment 1

[0110] 5.1 Example 1: 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- Synthesis of Acetylaminoisoindoline-1,3-dione

[0111] 1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 ml) was heated to reflux for 15 hours. The solvent was removed in vacuo to give an oil. The resulting oil was separated by chromatography to give the product (1.0 g, 59% yield) as a yellow solid, mp: 144°C.

[0112]1 H NMR (CDCl 3 )δ1.47(t, J=7.0Hz, 3H, CH 3 ), 2.26(s, 3H, CH 3 ), 2.88 (s, 3H, CH 3 ), 3.75(dd, J=4.4, 14.3Hz, 1H, CHH), 3.85(s, 3H, CH3), 4.11(q, J=7Hz, 2H, CH2), 5.87(dd, J=4.3, 10.5Hz , 1H, NCH), 6.82-6.86(m, 1H, Ar), 7.09-7.11(m, 2H, Ar), 7.47(d, J=7Hz, 1H., Ar), 7.64(t, J=8Hz, 1H, Ar), 8.74 (d, J=8Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13 C NMR (CDCl 3 )δ14.61,24.85,41.54,48.44,54.34,55.85,64.43,111.37,112.34,l15.04,118.11,120.21,124.85,129.17,130.96,136.01,137.52,148.54,149...

Embodiment 2

[0114] 5.2 Example 2: (+) 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl Synthesis of ]-4-acetylaminoisoindoline-1,3-dione

[0115] Preparation of 3-aminophthalic acid

[0116] Palladium on carbon (10%, 2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) were added to a 2.5 L Parr hydrogenator under nitrogen atmosphere. Hydrogen was bubbled into the reaction vessel to a pressure of 55 psi. The mixture was shaken for 13 hours maintaining a hydrogen pressure between 50-55 psi. The hydrogen was vented and the mixture was purged 3 times with nitrogen. The suspension was filtered through a bed of Celite and washed with methanol. The filtrate was concentrated under vacuum. The resulting solid was reslurried with ether and isolated by vacuum filtration. The solid was vacuum dried to constant weight to obtain 54 g (84% yield) of 3-aminophthalic acid as a yellow solid.

[0117] 1 H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H...

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Abstract

Stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (-) isomer, and prodrugs, metabolites, polymorphs, salts,solvates, hydrates, and clathrates thereof are discused. Also discussed are methods of using and pharmaceutical compositions comprising the (+) enantiomer of 2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione are disclosed. The methods include methods of treating and / or preventing disorders ameliorated by the reduction of levels of TNF- alpha or the inhibition of PDE4.

Description

[0001] This application is a divisional application of the following applications: filing date: March 20, 2003; application number: 03811093.8 (PCT / US03 / 08738); title of invention: "(+)-2-[1-(3-ethoxy 1,3-dione-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of use and compositions thereof”. 1. Field of invention [0002] The present invention relates to the ( +) Methods of use of the enantiomers and compositions comprising the same. 2. Background of the invention [0003] Tumor necrosis factor-α (TNF-α) is a cytokine released primarily by mononuclear phagocytes in response to immune stimuli. TNF-α is able to promote most cellular processes such as differentiation, recruitment, proliferation and protein degradation. At low levels, TNF-α has a protective effect against infectious agents, tumors and tissue damage. But TNF-alpha also plays a role in many diseases. TNF-α, when administered to mammals or humans, induces or exacerbates infl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4035A61P35/00C07C317/28C07D209/48
CPCY02A50/30
Inventor P·H·谢菲尔G·W·穆勒H·-W·满C·葛
Owner AMGEN (EURO) GMBH
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