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Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof

A solid, form technology that is used in the treatment of various diseases and/or conditions and can solve the problems of complex preparation and selection of pharmaceutical compounds

Inactive Publication Date: 2011-05-04
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Considering that changes in the solid form may affect various physical and chemical properties that may have advantages or disadvantages in processing, formulation, stability and bioavailability, and other important pharmaceutical properties, the solid form of the pharmaceutical compound Preparation and selection are complex

Method used

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  • Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
  • Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof
  • Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0229] 5.1. Example 1: 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl Synthesis of Aminoisoindoline-1,3-dione

[0230] 1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0g, 3.7mmol) and 3-acetamidophthalic anhydride (751mg, 3.66mmol) A stirred solution in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. The resulting oil was chromatographed to yield the product as a yellow solid (1.0 g, 59% yield): mp, 144°C; 1 H NMR (CDCl 3 )δ: 1.47(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, CH), 3.85(s, 3H, CH3), 4.11(q, J=7Hz, 2H, CH 2 ), 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 )δ:14.61,24.85,41.54,48.44,54.34,55.85,64.43,111.37,112.34,115.04,118.11,120.21,124.85,129.17,130.96,136.01,137.52,148.54,149.65,...

Embodiment 2

[0231] 5.2. Example 2: (+) 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-ethane Synthesis of Acylaminoisoindoline-1,3-dione

[0232] Preparation of 3-aminophthalic acid

[0233] 10% Pd / C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) were charged to a 2.5 L Parr hydrogenator under a nitrogen atmosphere. Fill the reaction vessel with hydrogen to 55 psi. The mixture was shaken for 13 hours while maintaining the hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged 3 times with nitrogen. The suspension was filtered through a bed of celite and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacuo to constant weight to provide 54 g (84% yield) of 3-aminophthalic acid as a yellow product. 1 H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (br, s, 2H); 13 C-NMR...

Embodiment 3

[0241] 5.3. Example 3: TNF-alpha Inhibition

[0242] TNF-α test induced by LPS in human whole blood

[0243]The ability of compounds to inhibit LPS-induced TNF-α production in human whole blood was measured essentially as in the LPS-induced TNF-α assay in human PBMC described below, except that freshly drawn whole blood was used instead of PBMC. (Muller et al., 1999, Bioorg. & Med. Chem. Lett., 9: 1625-1630.) To compound A, human whole blood LPS-induced TNF-αIC 50 = 294nM.

[0244] LPS-induced suppression of serum TNF-α in mice

[0245] Compounds were tested in this animal model according to previously described methods (Corral et al., 1996, MoI. Med., 2:506-515). For compound A, LPS-induced serum TNF-α inhibition in mice (ED 50 , mg / kg, orally)=0.05.

[0246] LPS-induced TNF-α production

[0247] Lipopolysaccharide (LPS) is an endotoxin produced by Gram-negative bacteria such as Escherichia coli (E. coli), which induces the production of many pro-inflammatory cytokine...

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Abstract

Solid forms comprising (+)-2-[l-(3-Ethoxy-4-methoxyphenyl)-2- methylsulfonylethyl]-4-acetylaminoisoindoline-l,3-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their use 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

1. Field of invention [0001] The present invention provides is containing (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonyl ethyl]-4-acetylaminoisoindoline - Solid forms of 1,3-diketones, compositions comprising such solid forms, methods of making such solid forms, and methods of using them for the treatment of various diseases and / or conditions. 2. Background of the invention [0002] Tumor necrosis factor alpha (TNF-α) is a cytokine released primarily by mononuclear phagocytes in response to immune stimuli. TNF-α can enhance most cellular physiological processes, such as differentiation, recruitment, proliferation and protein degradation. At low levels, TNF-α confers protection against infectious agents, tumors and tissue damage. However, TNF-alpha also plays a role in many diseases. When administered to a patient, TNF-[alpha] induces or exacerbates inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen d...

Claims

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Application Information

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IPC IPC(8): A61K31/4035
CPCA61K31/4035A61P1/04A61P1/16A61P11/00A61P11/06A61P13/08A61P13/10A61P15/00A61P17/00A61P17/02A61P17/04A61P17/06A61P19/02A61P19/08A61P19/10A61P21/00A61P25/00A61P25/16A61P25/24A61P27/02A61P29/00A61P31/04A61P31/08A61P31/18A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08A61P43/00A61P7/00Y02A50/30
Inventor 乔治·W·穆勒彼得·H·谢弗汉华·曼川胜·葛珍·徐
Owner CELGENE CORP
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