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Pyrrolidinone derivatives

a technology of pyrrolidinethione and pyrrolidinone, which is applied in the field of pyrrolidinones and pyrrolidinethiones and analogs, can solve the problems of complex biological functions mediated by these proteins, and achieve the effects of reducing the extravasation and tissue infiltration, enhancing localized infiltration of monocytes, and reducing the number of t cells

Inactive Publication Date: 2005-01-06
JUSIBI
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Benefits of technology

It is well established that MCP-1 is a central factor in the immunoregulation of inflammatory responses. Numerous studies in animals have demonstrated the direct effect of MCP-1 on the infiltration of immune effector cells in vivo. For example, transgenic mice expressing MCP-1 in specific tissues exhibit an enhanced localized infiltration of monocytes in those tissues (Gu, L. et al (1997), J. Leuk. Biol. 62: 577; Gunn, M. et al (1997), J. Immunol. 158: 376). Injection of MCP-1 protein into animals has also been shown to induce the infiltration of basophils and T cells (Taub, D. et al (1995), J. Clin. Invest. 95: 1370; Conti, P. et al (1997), Int. Immunol. 9: 1563; Kuntsfeld, R. et al (1998), J. Invest. Dermatol. 111: 1040). Knockout mice lacking either MCP-1 (Lu, B. et al (1998), J. Exp. Med. 187: 601) or CCR2 (Kurihara, T. et al (1997), J. Exp. Med. 186: 1757; Kuziel, W. et al (1997), Proc. Nat. Acad. Sci. USA 94: 12053) exhibit a reduction in the extravasation and tissue infiltration of monocytes and macrophages in response to inflammatory stimuli. Neutralization of MCP-1 with monoclonal antibodies has been shown to inhibit the infiltration of monocytes (Ajuebor, M. et al (1998), J. Leuk. Biol. 63: 108) and T cells (Rand, M. et al (1996), Am. J. Pathol. 148: 855) in experimentally-induced models of inflammation in animals.
The immune response to pathogens initially involves presentation of antigen to CD4+ T cells followed by clonal expansion and differentiation of the T cells into Th1 and Th2 subpopulations (Paul, W. (1992), in Inflammation, J. Gallin, I. Goldstein, and R. Snyderman (eds), pp 775-790. Raven Press; Abbas, A. et al (1996), Nature 383: 787). The two T cell subsets produce different types of cytokines that

Problems solved by technology

Consequently, the biological functions mediated by these proteins are diverse and complex.

Method used

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  • Pyrrolidinone derivatives
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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 4-acetyl-5-cyclohexyl-3-hydroxy-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-one (compound 10).

To a stirring solution of p-toluidine (430 mg, 4.0 mmol) in 4 ml of acetic acid at room temperature, are added cyclohexane carboxaldehyde (450 mg, 4.0 mmol) and ethyl acetopyruvate (640 mg, 4.0 mmol). The reaction mixture is heated to 95° C., stirred for 120 minutes, cooled to room temperature and the solvent removed under reduced pressure. Diethyl ether (10 ml) is added to the residue and the mixture stirred for 30 minutes whereupon a white precipitate forms. The fmal compound is collected after filtration as a white crystalline solid mp 222° C. The filtrate may be concentrated to give additional compound.

1H NMR (300 MHz, CDCl3): δ 0.80-1.20 (m, 5H), δ 1.40-1.79 (m, 5H), δ 1.96 (m, 1H) δ 2.41 (s, 3H), δ 2.56 (s, 3H), 4.97 (d, 1H, J=0.9 Hz), 7.29 (m, 4H), 8.90 (s, br, 1H) ppm.

The racemic mixture can be resolved on a chiral HPLC column (Chiral Cel OD-H) using a mixture of...

example 2

Preparation of 1-(4-chlorophenyl)-5-cyclohexyl-3-hydroxy-4-[3-(4-hydroxyphenyl)propanoyl]-1,5-dihydro-2H-pyrrol-2-one (Compound 67)

To a stirring solution of 4-hydroxy benzyl acetone in 40 mL of dry DMF at room temperature, are added 0.96 g (40 mmol) of sodium hydride. The reaction mixture turns deep yellow and after 30 minutes diethyl oxalate (5.43 ml, 40 mmol) is added. The mixture is stirred overnight at room temperature, then quenched with HCl 10% and extracted with ethyl acetate. The organic layers are washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure. The formation of the desired ethyl 6-(4-hydroxyphenyl)-2,4-dioxohexanoate is checked by H1-NMR before being used further without purification.

To a stirring solution of p-chloraniline (320 mg, 2.5 mmol) in 2.5 mL of acetic acid at room temperature, are added cyclohexane carboxaldehyde (0.30 mL, 2.5 mmol) and ethyl 6-(4-hydroxyphenyl)-2,4-dioxohexanoate (618 mg, 2.5 m...

example 3

Preparation of 4-acetyl-5-cyclohexyl-3-amino-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-one (compound 61).

A reaction mixture of 4-acetyl-5-cyclohexyl-3-hydroxy-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-one (139 mg, 0.44 mmol) and ammonium formate (342 mg, 4.44 mmol) in ethanol (0.2M, 2.2 ml) is heated at reflux for 16 hours. The solvent is removed in vacuo to give a white residue. Water is added to the residue to dissolve some of the white solid leaving a sandy-coloured precipitate. This mixture is then filtered, washed with a small amount of diethyl ether and dried under high vacuum at room temperature to give a pale brown solid.

1H NMR (400 MHz, CDCl3): δ 10.07 (s, br, 1H), 7.36 (d, 2H), 7.22 (d,2H), 6.41 (s, br, 1H), 4.83 (d, 1H), 2.36 (s, 3H), 2.19 (s, 3H), 1.80-0.96 (m, 9H).

EXAMPLE 4

Preparation and enantiomeric resolution of 4-acetyl-1-(4-chloro-2-fluorophenyl)-5-cyclohexyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one.

A. Preparation of 4-acetyl-1-(4-chloro-2-fluorophenyl)-5-c...

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Abstract

The present invention provides pharmaceutical compositions and novel compounds useful in the treatment of conditions mediated by CCR2, MCP-1 or the interaction thereof. The compounds of the present invention are pyrrolidinones and pyrrolidine-thiones.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to the field of pharmaceutical compounds in particular pyrrolidinones and pyrrolidine-thiones and analogs thereof. The invention further concerns processes for preparing these pharmaceutical compounds, compositions containing them and their use for the treatment and prevention of disease. 2. Summary of the Related Art Chemokines (chemotactic cytokines) are a large class of proteins that share structural homology and possess chemotactic activity for a variety of cell types (Luster, A. (1998), N. Eng. J. Med. 338:436; Kim, C. and Broxmeyer, H. (1999), J. Leuk. Biol. 65: 6.). They are divided into four groups based on the number and positioning of the first two cysteines of their sequence. The two major groups are the CC or beta chemokines (having two adjacent cysteines) and the CXC or alpha chemokines (X representing a single amino acid in between the cysteines). Examples of the former group include MIP-1...

Claims

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Application Information

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IPC IPC(8): A61K31/4015A61K31/402A61K31/4025A61K31/40A61K31/422A61K31/4439A61P1/04A61P1/16A61P7/02A61P9/10A61P9/14A61P11/00A61P11/02A61P11/06A61P13/12A61P15/00A61P17/00A61P17/04A61P17/06A61P19/02A61P21/02A61P25/00A61P25/28A61P27/02A61P27/16A61P29/00A61P31/04A61P31/18A61P35/00A61P37/02A61P37/08A61P39/02C07D207/24C07D207/26C07D207/273C07D207/36C07D207/38C07D401/04C07D405/04C07D405/08C07D409/04C07D409/06C07D413/06
CPCA61K31/4015A61K31/4439C07D207/24C07D207/273C07D413/06C07D401/04C07D405/04C07D409/04C07D409/06C07D207/36A61P1/04A61P1/16A61P11/00A61P11/02A61P11/06A61P13/12A61P15/00A61P17/00A61P17/04A61P17/06A61P19/02A61P21/02A61P25/00A61P25/28A61P27/02A61P27/16A61P29/00A61P31/04A61P31/18A61P35/00A61P37/02A61P37/08A61P39/02A61P7/02A61P9/10A61P9/14A61K31/40
Inventor ZOU, DONGDASSE, OLIVIEREVANS, JANELLEHIGGINS, PAULKINTIGH, JEREMYKNERR, LAURENTKONDRU, RAMASCHWARTZ, ERICZHAI, HAI-XIAO
Owner JUSIBI
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