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Metalloprotease inhibitors containing a heterocyclic moiety

Inactive Publication Date: 2008-09-11
ALANTOS PHARMA HLDG INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016]In particular, the heterocyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of MMP-13, MMP-8 and MMP-3 mediated degenerative diseases characterized by excessive extracellular matrix degradation and/or remodelling, such as cancer, and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis, parkinsons disease, chronic obstructive pulmonary disease and pain, such as inflammatory pain, bone pain and joint pain.
[0017]The present invention also provides heterocyclic metalloprotease inhibiting compounds that are useful as active ingredients in pharmaceutical compositions for treatment or prevention of metalloprotease—especially MMP-13—mediated diseases. The present invention also contemplates use of such compounds in pharmaceutical compositions for oral or parenteral administration, comprising one or more of the heterocyclic metalloprotease inhibiting compounds disclosed herein.
[0018]The present invention further provides methods of inhibiting metalloproteases, by administering formulations, including, but not limited to, oral, rectal, topical, intravenous, parenteral (including, but not

Problems solved by technology

The difficulty in developing effective MMP inhibiting compounds comprises several factors, including choice of selective versus broad-spectrum MMP inhibitors and rendering such compounds bioavailable via an oral route of administration.

Method used

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  • Metalloprotease inhibitors containing a heterocyclic moiety
  • Metalloprotease inhibitors containing a heterocyclic moiety
  • Metalloprotease inhibitors containing a heterocyclic moiety

Examples

Experimental program
Comparison scheme
Effect test

examples 3a to 3b

Preparative Examples 3a to 3b

[0138]Following a similar procedure as described in the Preparative Example 3, except using the aminoalcohols indicated in Table 1.3 below, the following compounds were prepared.

TABLE I.3Prep. Ex. #aminealcoholproductyield / MS3an.d.[MH]+ = 246 / 483b19%[MH]+ = 246 / 48

example 4

Preparative Example 4

[0139]

Step A

[0140]A suspension of the title compound from the Preparative Example 3, Step B (567 mg) and CuCN (230 mg) in dry N-methyl-pyrrolidin-2-one (15 mL) was degassed under Argon and heated under microwave irradiation to 200° C. for 2 h. The mixture was concentrated, diluted with 1N HCl (100 mL) and extracted with EtOAc (200 mL). The organic layers were washed with H2O (2×200 mL) and brine (200 mL), dried (MgSO4), filtered, absorbed on silica and purified by flash chromatography (cyclohexane / ethyl acetate 7:3 to 6:5) to give the title compound as a colourless solid. [MH]+=211.

Step B

[0141]To an ice cooled solution of the title compound from Step A above in dry MeOH (20 mL) were added di-tert-butyl dicarbonate (500 mg) and NiCl2.6H2O (20 mg), followed by the careful portionwise addition of NaBH4 (320 mg). The resulting black mixture was stirred for 20 min at 0-5° C. (ice bath), then the ice bath was removed and stirring at room temperature was continued over...

examples 4a to 4d

Preparative Examples 4a to 4d

[0143]Following a similar procedure as described in the Preparative Example 4, Step A except using the educt indicated in Table I.4 below, the following compounds were prepared.

TABLE I.4Prep. Ex. #eductproductyield / MS4an.d.[MH]+ = 1934b93%[MH]+ = 1934cn.d.[MH]+ = 1934d55%[MH]+ = 211

Preparative Examples 5a to 5f

[0144]Following a similar procedure as described in the Preparative Example 4, Step B except using the educt indicated in Table I.5 below, the following compounds were prepared.

TABLE 1.5Prep. Ex. #eductproductyield / MS5a32%(3 steps)[MNa]+ = 3195b56%[MNa]+ = 3195c28%(2 steps)[MNa]+ = 3195dn.d.[MNa]+ = 3255e58%[MNa]+ = 3015f64%[MNa]+ = 337

Preparative Examples 6a to 6h

[0145]Following a similar procedure as described in the Preparative Example 4, Step C except using the educt indicated in Table I.6 below, the following compounds were prepared.

TABLE I.6Prep. Ex. #eductproductyield / MS6aquant.[M-Cl]+ = 1976bquant.[M-Cl]+ = 1956cquant.[M-Cl]+ = 1976dquant.[...

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PUM

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Abstract

The present invention relates generally to pharmaceutical agents containing a heterocyclic moiety, and in particular, to heterocyclic metalloprotease inhibiting compounds. More particularly, the present invention provides a new class of heterocyclic MMP-13 inhibiting compounds with a benzoxazinone moiety, that exhibit an increased potency and selectivity in relation to currently known MMP-13 inhibitors.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 905,565, filed Mar. 7, 2007, which is hereby incorporated by reference.FIELD OF THE INVENTION[0002]The present invention relates generally to metalloprotease inhibiting compounds containing a heterocyclic moiety, and more particularly to MMP-13 inhibiting compounds with a benzoxazinone moiety.BACKGROUND OF THE INVENTION[0003]Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS=a disintegrin and metalloproteinase with thrombospondin motif) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction, and tissue remodelling. Over-expression of MMPs and aggrecanases or an imbalance between extracellular matrix synthesis and degradation has been suggested as factors in inflammatory, malignant and degenerative disease p...

Claims

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Application Information

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IPC IPC(8): A61K31/538C07D413/12A61P29/00A61P19/02
CPCC07D487/02C07D498/02C07D519/00A61P1/02A61P1/04A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/14A61P13/00A61P13/02A61P13/12A61P15/00A61P15/06A61P17/00A61P17/02A61P17/04A61P17/06A61P17/10A61P17/16A61P19/00A61P19/02A61P19/06A61P19/08A61P19/10A61P21/00A61P25/00A61P25/04A61P25/16A61P25/18A61P25/28A61P27/02A61P27/06A61P27/16A61P29/00A61P29/02A61P3/10A61P31/04A61P31/12A61P31/18A61P33/06A61P35/00A61P35/04A61P37/06A61P37/08A61P39/06A61P43/00A61P7/00A61P7/02A61P9/00A61P9/10A61P9/12A61P9/14
Inventor GEGE, CHRISTIANBLUHM, HARALDHOCHGURTEL, MATTHIASSCHNEIDER, MATTHIASCHEVRIER, CARINETAVERAS, ARTHUR
Owner ALANTOS PHARMA HLDG INC
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