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Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions

A technology for anabolism and metabolites, which can be used in the fields of active ingredients of heterocyclic compounds, resistance to vector-borne diseases, drug combinations, etc., and can solve problems such as non-maintenance

Inactive Publication Date: 2013-05-01
BAYER HEALTHCARE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

VEGFR-3 function is required for the formation of new lymphatic vessels but not for the maintenance of existing lymphatic vessels

Method used

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  • Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions
  • Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions
  • Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention diseases and conditions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0427] Example 1: Preparation of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid carboxamide

[0428]

[0429]To a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid carboxamide (177 mg, 0.68 mmol) in toluene (3 mL) was added 4-chloro-3-(trifluoromethyl ) phenylisocyanate (150mg, 0.68mmol). The mixture was stirred at room temperature for 72 hours. The reaction was concentrated under reduced pressure and the resulting residue was triturated with ether. The resulting solid was collected by filtration and dried under vacuum for 4 hours to obtain the title compound (155 mg, 0.32 mmol; 47% yield); 1H-NMR (DMSO-d6) 2.78 (d, J=4.9, 3H) , 7.03-7.08(m,1H), 7.16(dd,J=2.6,5.6,1H), 7.32(dd,J=2.7,11.6,1H), 7.39(d,J=2.5,1H), 7.60(s ,2H), 8.07–8.18(m,2H), 8.50(d,J=5.7,1H), 8.72(s,1H), 8.74-8.80(m,1H), 9.50(s,1H); MS (HPLC / ES)483.06m / z=(M+1).

Embodiment 2

[0430] Example 2: 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid formamide hydrochloride preparation

[0431] The free base form of the compound described in Example 1 (2.0 g) was dissolved in anhydrous THF (15 mL) and 4M HCl / dioxane (excess) was added. The solution was then concentrated under vacuum to yield 2.32 grams of an off-white solid. The crude salt was dissolved in hot ethanol (125 mL), activated carbon was added and the mixture was heated at reflux for 15 minutes. The hot suspension was filtered through a pad of Celite 521 and cooled to room temperature. The flask was placed in the refrigerator overnight. The crystalline solid was collected by suction filtration, washed with ethanol, then hexane and air dried. The mother liquor was concentrated and crystallization (in refrigerator) was performed overnight. A second crop of solids was collected and combined with the first crop. The colorless salt was dried in a vacu...

Embodiment 3

[0435] Example 3: 4{4-[3-(4-Chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid carboxamide methanesulfonate preparation of

[0436] The free base form of the compound described in Example 1 (2.25 g) was dissolved in ethanol (100 mL) and the methanesulfonic acid stock solution (excess) was added. The solution was then concentrated in vacuo to give a yellow oil. Ethanol was added and concentrated again to afford 2.41 g of an off-white solid. The crude salt was dissolved in hot ethanol (about 125 mL) and then cooled slowly to crystallize. After reaching room temperature, the flask was placed in the refrigerator overnight. The colorless crystalline material was collected by suction filtration; the resulting filter cake was washed with ethanol, then hexane and air dried to give 2.05 g of material which was dried in a vacuum oven at 60°C overnight.

[0437] Melting point: 231°C

[0438] Elemental analysis:

[0439]

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Abstract

Synthetic metabolites of compounds of Formula (I); salts thereof, prodrugs thereof, pharmaceutical compositions containing such synthetic metabolites, and use of such compound and compositions to treat diseases mediated by raf, VEGFR, PDGFR, p38 and flt-3. Described are M2, M3, M4, and M5 synthetic metabolites of compounds of formula I, wherein the structures of said compound of formula I and said M2, M3, M4, and M5 synthetic metabolites are defined as in the specification.

Description

technical field [0001] The present invention relates to novel compounds, pharmaceutical compositions comprising said compounds and the use of these compounds or compositions alone or in combination with anticancer agents for the treatment of abnormal VEGFR, PDGFR, raf, p38 and / or flt-3 Uses in diseases and disorders of kinase signaling. Background of the invention [0002] Activation of the ras signaling pathway indicates a cascade of events with profound effects on cell proliferation, differentiation and transformation. Raf kinases—downstream effectors of ras—are thought to be key mediators of these signals from cell surface receptors to the nucleus (Lowy, D.R.; Willumsen, B.M. Ann. Rev. Biochem. 1993, 62, 851; Bos, J.L. Cancer Res. 1989, 49, 4682). Inhibition of the effects of active ras by administering an inactivating antibody to raf kinase or by co-expressing dominant negative raf kinase or dominant negative MEK (a substrate of raf kinase) has been shown to inhibit th...

Claims

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Application Information

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IPC IPC(8): A61K31/44A61K31/4412C07D213/81A61P35/00
CPCC07D213/81A61K31/44C07D213/89A61K31/4412A61P35/00Y02A50/30
Inventor S·威廉
Owner BAYER HEALTHCARE LLC
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