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Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

A technology of medicinal salts and compounds, applied in the field of kynurenine-3-monooxygenase inhibitors

Inactive Publication Date: 2014-12-24
CHDI FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the relationship between KMO inhibition and AA (anthranilic acid) elevation may also have significant biological effects

Method used

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  • Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
  • Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof
  • Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0277] (+)-(1S,2S)-Cyclopropane-1,2-dicarboxylic acid monomethyl ester prepared as described in EP1475385, 2004

[0278]

[0279] Step 1, Method 1: Methyl (1S,2S)-2-(chlorocarbonyl)cyclopropane-1-carboxylate

[0280] DMF (0.16 mL, 2.08 mmol) was added dropwise to (+)-(1S,2S)-cyclopropane-1,2-dicarboxylic acid monomethyl ester (3.0 g, 20.8 mmol) under nitrogen atmosphere at room temperature A stirred solution in DCM (80 mL). Oxalyl chloride (5.45 mL, 62.4 mmol) was added dropwise to the reaction mixture over 30 minutes, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated and the resulting residue was co-evaporated with DCM (3 x 20 mL) to give the title compound (3.42 g, 98% yield) as a yellow oil which was used without further purification.

[0281] Step 2, Method 1: Methyl (1S,2S)-2-[(3,4-dichlorophenyl)carbonyl]cyclopropane-1-carboxylate

[0282] See eg, Naoaki et al, Bioorganic and Medicinal Chemistry Letters, 2005, 1...

Embodiment 2

[0307]

[0308] Step 1, 4-Bromo-2-chloro-1-cyclopropoxybenzene

[0309] Add bromocyclopropane (14.6g, 24.0mmol) in one portion to 4-bromo-2-chlorophenol (5.0g, 24.0mmol) and cesium bicarbonate (19.6g, 60.0mmol) in dimethylacetamide (80mL) in the stirred solution. The mixture was heated to 150°C and stirred at this temperature for 16 hours. Then, another portion of bromocyclopropane (14.6 g, 24.0 mmol) was added, and the mixture was stirred at 150° C. for another 24 hours. The reaction mixture was then cooled to room temperature, poured onto ice-water (200 mL), extracted with TBME (3 x 200 mL). The combined organic layers were washed with water (2 x 100 mL) followed by brine (50 mL). The organic layer was removed and dried (MgSO 4 ), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: heptane, then 33% heptane, 67% DCM) to afford the title compound (5.0 g, 84% yield) as a colorless oil. Tr=2.41min m / z (ES + )(M+H + )...

Embodiment 3

[0321]

[0322] Step 1, Sodium (1S,2S)-2-{[3-chloro-4-(propan-2-yloxy)phenyl]carbonyl}cyclopropane-1-carboxylate

[0323] (1S,2S)-2-{[3-Chloro-4-(propan-2-yloxy)phenyl]carbonyl}cyclopropane-1-carboxylic acid (0.14g, 0.51mmol) in NaOH (2M solution , 0.23mL, 0.46mmol) and stirred for 1 hour. Then, diethyl ether (2 mL) was added, and the organic layer was separated and discarded. The aqueous layer was concentrated to afford the title compound (0.097 g, 62% yield) as an off-white solid.

[0324] Sodium (1S,2S)-2-{[3-chloro-4-(propan-2-yloxy)phenyl]carbonyl}cyclopropane-1-carboxylate

[0325] δ H (500MHz,DMSO)7.88-7.97(2H,m)7.30(1H,d)4.78-4.89(1H,m)2.77-2.89(1H,m)1.64-1.74(1H,m)1.33(6H,d)1.14 -1.25(2H,m). Tr=4.03min m / z (ES + )(M+H + )283,285.

[0326] The following compounds were prepared essentially as described above.

[0327] Sodium (1S,2S)-2-{[3-chloro-4-(trifluoromethyl)phenyl]carbonyl}cyclopropane-1-carboxylate

[0328] δ H (500MHz, DMSO) 7.99-8.16 (3H, m) 2.86...

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Abstract

Certain compounds, or pharmaceutically acceptable salts or prodrugs thereof, pharmaceutical compositions comprising the same and methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one compound, or pharmaceutically acceptable salt or prodrug thereof described herein, effective to reduce signs or symptoms of the disease or disorder. These diseases include neurodegenerative disorders such as Huntington's disease. The application also provides a method for screening a compound capable of inhibiting KMO activity.

Description

technical field [0001] The present application provides some kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions and methods of use thereof. Background technique [0002] Kynurenine-3-monooxygenase (KMO) is an enzyme of the tryptophan degradation pathway that catalyzes the conversion of kynurenine (KYN) to 3-hydroxykynurenine (3-HK), the 3 -Hydroxykynurenine is further degraded to the excitotoxic NMDA receptor agonist QUIN (3-hydroxyanthranilic acid oxygenase). 3-OH-KYN and QUIN act synergistically, that is, 3-OH-KYN significantly enhances the excitotoxic effect of QUIN. Studies from several laboratories have provided evidence that metabolic deviation of the KYN pathway from the 3-OH-KYN / QUIN branch increases the neuroprotectant KYNA in the brain, which confers neuroprotection. In addition to having effects in the brain, inhibition of KMO is further expected to affect surrounding tissues. Therefore, inhibition of KMOs may be useful in the treatment of perip...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/19
CPCC07D307/94C07D309/10C07D215/18C07D311/58C07D317/46C07D317/60C07D319/18C07D233/64C07D235/26C07D403/10C07D405/08C07D405/10C07D405/12C07C317/44C07D413/08C07D413/10C07C323/62C07C229/22C07C229/46C07C229/48C07D257/04C07D203/08C07D263/58C07C235/82C07D207/08C07D271/07C07D207/337C07D295/155C07D305/06C07D305/08C07D307/54C07D307/80C07C2601/02C07C2602/50C07D311/20C07D203/10C07D307/79C07D413/12C07H15/20C07C69/757C07C62/38A61P25/00A61P25/28A61P43/00
Inventor L·M·托莱多-谢尔曼C·多明格斯M·普赖姆W·L·米切尔P·约翰逊N·温特
Owner CHDI FOUND
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