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A compound, alkyl technology, applied in 1 field, can solve the problem of not understanding the signal transduction pathway and so on

Inactive Publication Date: 2006-05-17
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although many of the signaling pathways required for cytokine biosynthesis are still not understood, it appears that many of the substrates of p38 described above are clearly involved

Method used

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[0257] A series of 2(1H)-quinolones were prepared as described in Scheme 6. The starting material 1-scheme can be prepared from commercially available 1,3-dibromo-5-methoxy-2-methylbenzene by known literature methods such as those disclosed in International Publication No. WO 02 / 058695 A1 6.

[0258] Intermediate 4-Scheme 6 was prepared by two different methods. In the first approach, coupling bromide 1-Scheme 6 with a malonate or monomalonate in the presence of sodium hydride in THF prepared after the desired saponification and decarboxylation Desired compound 2-Scheme 6. Other suitable bases include, but are not limited to, lithium hydride, potassium hydride, sodium ethoxide, butyllithium, which can also be used in suitable organic solvents including, but not limited to, DMF, diethyl ether, dioxane, and ethanol. Carboxylic acid 2-Scheme 6 can then be converted to the corresponding activated carboxylate. Acid chlorides can be prepared, for example, using oxalyl chloride o...

Embodiment 1

[0421] 7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]phthalazin-2(1H)-one

[0422]

[0423] 1a) 4,6-dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine

[0424]

[0425] The preparation of the title compound was synthesized as described in WO 02 / 058695, the disclosure of which is incorporated herein by reference in its entirety.

[0426] 1b) tert-butyl 3-[4,6-dibromo-2-(2-chlorophenyl)-3-pyridyl]propionate

[0427]

[0428]Under nitrogen at -10°, a hexane solution of n-butyllithium (1.6 molarity (hereinafter "M"), 3.75 milliliters (hereinafter "ml"), 6.0 millimoles (hereinafter "mmol")) was added Into a solution of di-isopropylamine (0.84ml, 6.0mmol) in dry THF (15ml). After 5 minutes (hereinafter "min"), the solution was cooled to -70° and tert-butyl acetate (0.5 ml, 3.71 mmol) was added dropwise. After stirring at -70°C for 10 minutes, 4,6-dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine (0.405 grams (hereinafter "g"), 0.92 mmol was added under nitrogen ) i...

Embodiment 2

[0446] 7-Bromo-1,5-bis(2-chlorophenyl)[1,6]phthalazin-2(1H)-one

[0447]

[0448] Tetrachloride of 7-bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]phthalazin-2(1H)-one (30mg, 0.067mmol) The carbon (5ml) solution was treated with NBS (15mg) and AIBN (1.1mg) and heated at reflux for 1.5h. DBU (10 μl) was added, the mixture was cooled and dichloromethane (5 ml) was added followed by 8% sodium bicarbonate (10 ml). The mixture was passed through a hydrophobic frit and evaporated in vacuo to give the product as an off-white solid.

[0449] NMR (400MHz, CDCl 3 )δ 7.75-7.69 (1H, m), 7.60-7.33 (8H, m), 6.75 (1H, d), 6.65 (1H, s)

[0450] LC / MS R t 3.50 minutes m / z 445 / 447 / 449 [MH + ]

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Abstract

New substituted 1,5,7-trisubstituted-1,8-naphthyridine-2(1H)-one compounds; 1,5,7-trisubstituted-1,6-naphthyridine-2 -(1H)-one compounds and 1,5,7-trisubstituted quinolin-2(1H)-one compounds, their preparation methods, their use in the treatment of CSBP / p38 kinase-mediated diseases, and for A pharmaceutical composition for the treatment.

Description

technical field [0001] The present invention relates to a group of novel 1,5,7-trisubstituted-1,8-naphthyridine-2(1H)-one compounds; 1,5,7 trisubstituted-1,6-diazepines Naphthalene-2-(1H)-one compounds and 1,5,7-trisubstituted quinolin-2(1H)-one compounds, processes for their preparation, their use in the treatment of CSBP / p38 kinase-mediated diseases and Pharmaceutical compositions for such therapies. Background technique [0002] Intracellular signaling is the way cells respond to extracellular stimuli. Protein kinases and phosphatases and phospholipases are the major machinery for further transmission of signals within the cell independent of the nature of the cell surface receptors (e.g. tyrosine kinase proteins or coupled seven-transmembrane G-proteins) [Marshall, J.C. Cell , 80, 179-278 (1995)]. Protein kinases can be divided into 5 types, of which there are mainly 2 classes, namely tyrosine kinases and serine / threonine kinases, depending on whether the enzyme makes...

Claims

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Application Information

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IPC IPC(8): A61K31/4375A61P29/00A61P31/12C07D471/04
CPCY02A50/30
Inventor 杰弗里·C·贝姆詹姆斯·F·卡拉汉拉尔夫·F·霍尔林熹晨凯瑟琳·L·威多森
Owner SMITHKLINE BECKMAN CORP
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