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Quinoline derivatives and their use as mycobacterial inhibitors

一种化合物、药用酸的技术，应用在喹啉衍生物及其作为分枝杆菌抑制剂的应用领域，能够解决昂贵、药物有毒性、边缘等问题

Inactive Publication Date: 2005-09-21
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs are often toxic, expensive and marginally effective

Method used

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  • Quinoline derivatives and their use as mycobacterial inhibitors
  • Quinoline derivatives and their use as mycobacterial inhibitors
  • Quinoline derivatives and their use as mycobacterial inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0121] Preparation of intermediate compound 1

[0122]

[0123] Phenylpropionyl chloride (0.488mol) was added dropwise to 4-bromoaniline (0.407mol) at room temperature in Et 3 N (70ml) and CH 2 Cl 2 (700ml), and the mixture was stirred at room temperature overnight. This mixture was poured into water and concentrated NH 4 OH, and CH 2 Cl 2 extraction. The organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was crystallized from ether. The residue (119.67 g) was placed in CH 2 Cl 2 medium and washed with HCl 1N. The organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. Yield: 107.67 g of intermediate compound 1.

[0124] Preparation of intermediate compound 9

[0125]

[0126] Thus, using the same procedure as intermediate compound 1, but employing 4-methylphenylpropionyl chloride, intermediate compound 9 was prepared.

Embodiment A2

[0128] Preparation of intermediate compound 2

[0129]

[0130] This reaction was performed 2 times. POCl at 10°C 3 (1.225mol) was added dropwise to DMF (0.525mol). Intermediate compound 1 (prepared according to Al) (0.175 mol) was then added at room temperature. The mixture was stirred overnight at 80 °C, poured onto ice, and washed with CH 2 Cl 2 extraction. The organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated. The product was used without further purification. Yield: (77.62 g; Yield = 67%).

[0131] Preparation of intermediate compound 10

[0132]

[0133] Therefore, according to the same method as intermediate compound 2, intermediate compound 10 was prepared from intermediate compound 9 (prepared according to A1).

Embodiment A3

[0135] Preparation of intermediate compound 3

[0136]

[0137] Intermediate compound 2 (prepared according to A2) (0.233 mol) in CH 3 A solution of ONa (30%) in methanol (222.32ml) and a mixture in methanol (776ml) were stirred and refluxed overnight, then poured onto ice and washed with CH 2 Cl 2 extraction. The organic layer was separated and dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: CH 2 Cl 2 / cyclohexane 20 / 80, then 100 / 0; 20-45 μm). Pure fractions were collected and the solvent was evaporated. Yield: 25 g of intermediate compound 3 (yield = 33%; mp. 84°C) as a white powder.

[0138] Preparation of intermediate compound 11

[0139]

[0140] Thus, according to the same method as intermediate compound 3, intermediate compound 11 was prepared from intermediate compound 10 (prepared according to A2).

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PUM

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Abstract

The present invention relates to novel substituted quinoline derivatives according to the general Formula (Ia) or the general Formula (Ib), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. The claimed compounds are useful for the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum. In particular, compounds are claimed in which, independently from each other, R<1> is bromo, p=1, R<2> is alkyloxy, R<3> is optionally substituted naphthyl or phenyl, q=1, R<4> and R<5> each independently are hydrogen, methyl or ethyl, R<6> is hydrogen, r is equal to 0 or 1 and R<7> is hydrogen. Also claimed is a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of the claimed compounds, the use of the claimed compounds or compositions for the manufacture of a medicament for the treatment of mycobacterial diseases and a process for preparing the claimed compounds.

Description

[0001] The present invention relates to novel substituted quinoline derivatives useful in the treatment of mycobacterial diseases, in particular caused by pathogenic mycobacteria such as Mycobacterium tuberculosis, M. bovis, Diseases caused by Mycobacterium avium (M.avium) and Mycobacterium marinum (M.marinum). Background of the invention [0002] Mycobacterium tuberculosis is the causative agent of tuberculosis (TB) - a serious and potentially fatal infection with worldwide distribution. The World Health Organization estimates that more than eight million people are infected with TB each year, and two million people die from tuberculosis each year. Worldwide TB cases have increased by 20% in the last 10 years, placing an enormous burden on most poor countries. If these trends continue, TB incidence will increase by 41% over the next 20 years. In the 50 years since the introduction of effective chemotherapy, TB has been second to AIDS as the leading inf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/47A61K31/4706A61K31/496A61K31/5377A61K31/541A61P31/06C07D215/22C07D215/227C07D215/36C07D215/48C07D401/06C07D401/12C07D405/04C07D405/06C07D409/04C07D409/06C07D413/02C07D417/02C07D471/04C07D521/00
CPCC07D405/06C07D401/12C07D471/04C07D409/04C07D231/12C07D401/06C07D249/08C07D215/36C07D405/04C07D233/56C07D215/227C07D409/06C07D215/48A61P31/00A61P31/04A61P31/06C07D215/22
Inventor 杰罗姆·埃米尔·乔治斯J·F·E·范格斯特尔M·G·韦内H·J·J·普瓦内特L·F·B·德克拉纳D·F·J·韦尼耶F·C·奥德斯
Owner JANSSEN PHARMA NV
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