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Macrolides with anti-inflammatory activity

An aromatic heterocycle, selected technology, applied in the field of substituted macrolides

Inactive Publication Date: 2008-03-12
GLAXO GROUP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The pathogenesis is not fully understood, but oxidant-antioxidant imbalance is strongly associated with the development of these diseases

Method used

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  • Macrolides with anti-inflammatory activity
  • Macrolides with anti-inflammatory activity
  • Macrolides with anti-inflammatory activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0296] Example 1: 11,12-Carbonate-11,12-dideoxy-4"-O-(3-diethylamino-propionyl)-Aqi Mycin

[0297]

[0298] The 11,12-carbonate-11,12-dideoxy-4"-O-acryloyl-azithromycin (0.5g, 0.6mmol) obtained as described in the international patent application WO 03 / 042228, intermediate 50 and diethyl The amine (0.72 mL, 7 mmol) was dissolved in anhydrous methanol (60 mL), and the mixture was stirred overnight at 40° C. The methanol was removed by evaporation under reduced pressure, and the crude product was purified by column chromatography (DCM / MeOH / NH 4 OH=90:9:0.5) to obtain the title compound.

[0299] MS(ES+)m / z: [MH] + =902.46

[0300] 13 C-NMR(125MHz, CDCl 3 )δ: 177.1, 172.1, 153.3, 102.8, 95.3, 85.9, 85.1, 79.0, 78.0, 76.3, 73.3, 73.0, 70.7, 68.2, 67.7, 65.5, 62.9, 61.2, 49.5, 48.2, 46.7, 45.3, 43.0, 41.9 , 40.4, 35.3, 34.4, 29.3, 26.8, 26.2, 22.1, 22.0, 21.6, 21.2, 17.8, 14.9, 14.2, 10.5, 10.4, 5.5.

Embodiment 2

[0301] Example 2: 4″-O-(3-Diethylamino-propionyl)-8a-aza-8a-homoerythromycin A

[0302]

[0303] 4"-O-acryloyl-8a-aza-8a-homoerythromycin A (0.34g, 0.42mmol) obtained as described in Example 59 of International Patent Application WO 02 / 32917 (incorporated by reference) and two Ethylamine (0.56mL, 5.4mmol) was dissolved in anhydrous methanol (50mL), and the mixture was stirred overnight at 40°C. The methanol was removed by evaporation under reduced pressure, and the crude product was purified by column chromatography (DCM / MeOH / NH 4 OH=90:9:1.5) to obtain the title compound.

[0304] MS(ES+)m / z: [MH] + =876.48

[0305] 13 C-NMR (125MHz, DMSO) δ: 177.2, 174.6, 171.8, 102.2, 93.9, 82.1, 77.9, 76.5, 75.7, 74.6, 73.2, 72.5, 70.7, 70.4, 65.8, 64.7, 62.1, 48.7, 48.2, 45.9, 44.8, 42.2, 40.7, 40.2, 34.2, 32.7, 30.3, 27.2, 23.5, 21.5, 21.4, 20.5, 17.6, 17.2, 14.4, 11.5, 11.3, 9.2, 8.8.

Embodiment 3

[0306] Example 3: 4"-O-(3-Diethylamino-propionyl)-6-O-methyl-8a-aza-8a-homomycin A

[0307]

[0308] Diethylamine (80μl, 0.95mol) was added to the 4″-O-acryl-6-O-methyl-8a-aza-8a-high obtained as described in Example 9 of International Patent Application WO 02 / 32917 In a solution of erythromycin A (0.15g, 0.19mmol) in isopropanol (2mL), the reaction mixture was stirred in a tube overnight at 70°C. The isopropanol was removed by evaporation, and the residue was purified by an SP column (DCM / MeOH / NH 4 OH=90:9:0.5) to obtain the title compound (34mg).

[0309] MS(ES)m / z: [MH] + = 890 (95%).

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Abstract

The present invention relates to novel semisynthetic macrolides with anti-inflammatory activity. More specifically, the present invention relates to 14- and 15-membered macrolides substituted at the 4" position, their pharmaceutically acceptable derivatives, their preparation methods and intermediates, pharmaceutical compositions containing them and Their activity and use in the treatment of inflammatory diseases and conditions in humans and animals, especially those associated with excessive secretion of TNF-alpha, IL-1, IL-8, IL-2 or IL-5; and / or for use as Activity and uses of inhibitors of lymphocyte hyperproliferation and / or granulocyte degranulation.

Description

[0001] This application claims the priority of U.S. Provisional Application No. 60 / 643,841 filed on January 13, 2005 and U.S. Provisional Application 60 / 715,828 filed on September 9, 2005, the entire contents of which are hereby incorporated by reference. Invention field [0002] The present invention relates to substituted macrolides with anti-inflammatory activity, and pharmaceutically acceptable derivatives thereof and methods of use. [0003] technical problem [0004] The purpose of the present invention is to solve the technical problems brought about by providing new targeted anti-inflammatory drugs. More specifically, the present invention provides anti-inflammatory agents in which the active substance is neither a steroid nor an NSAID. The compound of the present invention can overcome the above-mentioned problems by virtue of its anti-inflammatory activity and accumulation ability in various immune cells recruited to the site of inflammation. Background of the invention ...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H17/08A61K31/7052A61K31/7048A61P29/00
CPCC07H17/08C07H17/00A61P1/00A61P1/04A61P11/00A61P11/02A61P11/06A61P17/06A61P17/10A61P19/02A61P27/02A61P29/00A61P37/00A61P37/02A61P43/00A61P7/00A61P7/10A61K31/7048C07D413/14
Inventor 奥格珍·卡利克马丁纳·博斯纳尼古拉·马杰诺维克杜布拉夫科·杰利克苏利曼·阿利霍齐克范杰·维拉佐里卡·马鲁西克-伊斯图克维斯纳·伊拉科维克贝里斯拉夫·博斯恩杰克博斯卡·赫瓦西克玛丽杰·托马斯科维克维斯纳·穆尼克瓦妮莎·艾维蒂克安滕·赫坦克戈兰·克拉戈尔玛丽杰·勒杰克
Owner GLAXO GROUP LTD
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