Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases

a technology of macrophage migration inhibitory factor and substituted naphthyridine, which is applied in the direction of immunological disorders, metabolism disorders, extracellular fluid disorders, etc., can solve the problems of limited ability to evaluate the inhibition of mif to its cell surface receptor, inability to detect and treat macrophage migration inhibitors, and inability to detect macrophage migration inhibitors. the effect of intracellular activity

Inactive Publication Date: 2005-06-09
AVANIR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] As MIF has been identified in a variety of tissues and has been associated with numerous pathological events, there exists a need in the art to identify inhibitors of MIF. There is also a need for pharmaceutical compositions containing such inhibitors, as well as methods relating to the use thereof to treat, for example, immune related disorders or other MIF induced pathological events, such as tumor associated angiogenesis. The preferred embodiments can fulfill these needs, and provide other advantages as well.

Problems solved by technology

Hence, when its activities / gene expression are overinduced by the administration of excess exogenous glucocorticoids (for example when clinical indicated to suppress inflammation, immunity and the like), there is significant toxicity because MIF itself exacerbates the inflammatory / immune response.
Further, it remains unclear whether this enzymatic activity mediates the biological response to MIF and the activities of this protein in vitro and in vivo.
The ability to evaluate the inhibition of MIF to its cell surface receptor is also limited since no high affinity receptor is currently known.
Furthermore, inhibitors that act intracellularly are often toxic by virtue of their action on related targets or the activities of the target inside cells.
Small molecule inhibitors of the ligand receptor complex are difficult to identify let alone optimize and develop.

Method used

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  • Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases
  • Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases
  • Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases

Examples

Experimental program
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Effect test

example 1

Synthesis of 2-Benzylamino Nicotinic Acid (1)

[0275] Benzylamine (14 mL, 126.8 mmol) was added to a solution of chloronicotinic acid (10 g, 63.4 mmol) in pyridine and refluxed overnight. The pyridine was distilled and the residue was dissolved in 1N NaOH. The solution was diluted with water to adjust the pH to 10 to 11 and washed by dichloromethane. The aqueous phase was neutralized with cold aqueous 10% HCl solution to adjust the pH to 6 to 7. The solids formed were filtered, washed with cold water, and dried in a vacuum oven to yield 12.2 g (84%) of 2-benzylamino nicotinic acid (1) as white solids. MP: 148° C.; 1H-NMR (DMSO-d6): d 4.69 (d, J=3.6 Hz, 2H), 6.61 (dd, J=4.9, 7.7 Hz, 1H), 7.23 (m, 1H), 7.29 (m, 4H), 8.08 (dd, J=1.8, 7.0 Hz, 1H), 8.28 (dd, J=1.8, 7.0 Hz, 1H), 8.47 (br. s, 1H), 13.10 (s, 1H); EIMS: 229 (M+1), 251 (M+23).

Synthesis of 1-Benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (2)

[0276] Trichloromethyl chloroformate (2.5 mL, 21 mmol) was added slowly to a suspension...

example 2

[0457] Assays to evaluate the activity of potential MIF inhibitors are described in the following sections.

[0458] Macrophage Migration Assay

[0459] Macrophage migration is measured by using the agarose droplet assay and capillary method as described by Harrington and Stastny et al., J. Immunol. 110(3):752-759, 1973. Briefly, macrophage-containing samples are added to hematocrit tubes, 75 mm long with a 1.2 mm inner diameter. The tubes are heat-sealed and centrifuged at 100×G for 3 minutes, cut at the cell-fluid interface and imbedded in a drop of silicone grease in Sykes-Moore culture chambers. The culture chambers contain either a control protein (BSA) or samples. Migration areas are determined after 24 and 48 hours of incubation at 37° C. by tracing a projected image of the macrophage fans and measuring the areas of the migration by planimetry.

[0460] Alternatively, each well of a 96-well plate is pre-coated with one microliter of liquid 0.8% (w / v) Sea Plaque Agarose in water dis...

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Abstract

Inhibitors of MIF having a naphthyridine backbone are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. The inhibitors of MIF have the following structures:
including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, R, R1, R2, X, Y and Z are as defined herein. Compositions containing an inhibitor of MIF in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.

Description

RELATED APPLICATION [0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60 / 497,443, filed Aug. 22, 2003, the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] Inhibitors of macrophage migration inhibitory factor (MIF) having a naphthyridine backbone are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. BACKGROUND OF THE INVENTION [0003] The lymphokine, macrophage migration inhibitory factor (MIF), has been identified as a mediator of the function of macrophages in host defense and its expression correlates with delayed hypersensitivity, immunoregulation, inflammation, and cellular immunity. See Metz and Bucala, Adv. Immunol. 66:197-223, 1997. Macrophage migration inhibitory factors (MIFs), which are between 12-13 kilodaltons (kDa) in size, have been identified in several mammalian a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61P29/02A61P35/00A61P37/06C07D471/04
CPCA61P1/04A61P1/18A61P3/04A61P3/10A61P7/00A61P7/06A61P9/00A61P9/04A61P9/10A61P9/14A61P11/00A61P11/06A61P13/12A61P17/14A61P19/02A61P25/00A61P25/16A61P25/28A61P27/16A61P29/00A61P29/02A61P31/04A61P31/12A61P35/00A61P37/00A61P37/02A61P37/06A61P43/00C07D471/04
Inventor SIRCAR, JAGADISHK.C., SUNILYING, WENBINDAVIS, TIMOTHY
Owner AVANIR PHARMA
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