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1-Oxo- and 1,3-dioxoisoindolines and method of reducing inflammatory cytokine levels

a technology of inflammatory cytokine and oxo- and 1,3-dioxoisoindolines, which is applied in the field of 1oxoand 1, 3dioxoisoindolines and method of reducing inflammatory cytokine levels, can solve the problems of impaired t-cell mediated immunity and severe opportunistic infections of infected individuals

Inactive Publication Date: 2008-11-20
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds effectively reduce TNFα and other inflammatory cytokine levels, offering a broad therapeutic benefit for inflammatory, infectious, and malignant diseases, including rheumatoid arthritis, HIV / AIDS, and opportunistic infections, by inhibiting NFκB and increasing cAMP, thereby mitigating disease severity and progression.

Problems solved by technology

As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and / or unusual neoplasms.

Method used

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  • 1-Oxo- and 1,3-dioxoisoindolines and method of reducing inflammatory cytokine levels
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  • 1-Oxo- and 1,3-dioxoisoindolines and method of reducing inflammatory cytokine levels

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-(2,6-Dioxopiperid-3-yl)-4-methylisoindoline-1,3-dione

[0039]A stirred solution of 3-methylphthalic anhydride (2.96 g, 18.2 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (3.00 g, 18.2 mmol) and sodium acetate (1.57 g, 19.1 mmol) in acetic acid (30 mL) was heated at reflux for 23 hours. The solvent was removed in vacuo to give a solid which was stirred with water (40 mL) for 1 hour, filtered, washed with water (30 mL), and then heated with decolorizing charcoal (1 g) in acetone (2 L) at reflux temperature for 30 min. The suspension was filtered through a pad of Celite to give a clear solution. The solvent of filtrate was removed in vacuo to give 2-(2,6-dioxopiperid-3-yl)-4-methylisoindoline-1,3-dione as a white solid (4.08 g, 82% yield)—mp 290.0-292.0° C.; 1H NMR (DMSO-d6); δ 2.03-2.09 (m, 1H, CHH), 2.50-2.60 (m, 2H, CH2), 2.63 (s, 3H, CH3), 2.83-2.95 (m, 1H, CHH), 5.13 (dd, J=5.4, 12.3 Hz, 1H, NCH), 7.65-7.79 (m, 3H, Ar), 11.13 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 17.04, 21.99...

example 2

[0040]By substituting equivalent amounts of 3-ethylphthalic anhydride, 3-fluorophthalic anhydride, 3-chlorophthalic anhydride, 3-carbamoylphthalic anhydride, and 3-methoxyphthalic anhydride in the procedure of Example 1, there are respectively obtained 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-ethylisoindoline, 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline, 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-chloroisoindoline, 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-carbamoylisoindoline, 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-methoxyisoindoline.

example 3

[0041]By substituting equivalent amounts of 3-amino-3-methylpiperidine-2,6-dione hydrogen chloride for 3-aminopiperidine-2,6-dione hydrogen chloride in the procedure of Example 1, 1,3-dioxo-2-(2,6-dioxo-3-methylpiperidin-3-yl)-4-methylisoindoline is obtained.

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Abstract

1-Oxo- and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolines substituted in the 4- and / or 7-position of the isoindoline ring and optionally further substituted in the 3-position of the 2,6-dioxopiperidine ring reduce the levels of inflammatory cytokines such as TNFα in a mammal. A typical embodiment is 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline

Description

[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 078,180 filed on Mar. 16, 1998 entitled 1-Oxo- and 1,3-Dioxoisoindolines and Method of Reducing Inflammatory Cytokine Levels, hereby incorporated by reference into this application.BACKGROUND OF THE INVENTION[0002]Tumor necrosis factor-α, or TNFα, is a cytokine which is released primarily by mononuclear phagocytes in response to a number immunostimulators. It is a key proinflammatory cytokine in the inflammation cascade causing the production and / or release of other cytokines and agents. When administered to animals or humans, it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states. Excessive or unregulated TNFα production thus has been implicated in a number of disease conditions. These include endotoxemia and / or toxic shock syndrome {Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/454A61P29/00A61P35/00A61K31/4427A61K31/445A61P1/00A61P1/04A61P11/00A61P11/06A61P19/02A61P31/00A61P31/18A61P37/02A61P37/04A61P37/06A61P43/00C07D401/04
CPCA61K31/454C07D401/04A61P1/00A61P1/04A61P11/00A61P11/06A61P19/02A61P29/00A61P31/00A61P31/18A61P35/00A61P37/00A61P37/02A61P37/04A61P37/06A61P43/00Y02A50/30
Inventor MAN, HON-WAHMULLER, GEORGE W.
Owner CELGENE CORP