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Compound having selective inhibitory activity against human fatty acid amide hydrolase and use thereof for treating pains

A fatty amide, inhibitory activity technology, used in organic chemistry, non-central analgesics, drug combinations, etc.

Pending Publication Date: 2018-11-30
李敬敬
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although there are no FAAH inhibitors on the market, there are several drugs in the clinical and preclinical biological activity testing stage

Method used

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  • Compound having selective inhibitory activity against human fatty acid amide hydrolase and use thereof for treating pains
  • Compound having selective inhibitory activity against human fatty acid amide hydrolase and use thereof for treating pains
  • Compound having selective inhibitory activity against human fatty acid amide hydrolase and use thereof for treating pains

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Synthesis of 2-(8-(benzyloxy)-7-(morpholin-4-yl)quinolin-2-yl)oxazole

[0027] 1. Synthesis of 7-bromo-N-(2,2-dimethoxyethyl)-8-hydroxyquinoline-2-carboxamide:

[0028]

[0029] To a suspension of 7-bromo-8-hydroxyquinoline-2-carboxylic acid (compound 1) (77.74 g, 290 mmol) in ethyl acetate (200 mL) was added thionyl chloride (41.40 g, 348 mmol) at room temperature , and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with tetrahydrofuran (50 mL), and then 2,2-dimethoxyethane-1-amine (42.69 g, 406 mmol) and triethylamine (110 mL, 789 mmol) were added dropwise at room temperature solution in tetrahydrofuran (250 mL). The reaction mixture was then stirred at 40°C for 1 hour, cooled to room temperature, added with 300 mL of water and extracted with ethyl acetate. The organic layer was washed successively with 2mol / L hydrochloric acid, 10% potassium carbonate aqueous solution and water. The solvent was concentrate...

Embodiment 2

[0042] Example 2: Synthesis of 2-(8-(benzyloxy)-7-(2-phenoxy-morpholin-4-yl)quinolin-2-yl)oxazole

[0043]

[0044] Palladium acetate (2.40 g), sodium p-toluenesulfonate (3.90 g), sodium tert-amylate (11.8 g) were added to a suspension of 2-phenoxy-morpholine (52 mmol) in toluene under an argon atmosphere. solution in toluene (37 mL), diadamantanebutylphosphine (7.70 g), and stirred at room temperature for 1 hour. In the reaction suspension, compound 5 (19.10 g, 50.10 mmol) and toluene (33 mL) were added under ice-water bath conditions, and then heated to reflux for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and 2mol / L hydrochloric acid (37.5 mL) was added. The formed precipitate was collected by filtration to give 20.75 g of light brown crystals of 2-(8-(benzyloxy)-7-(2-phenoxy-morpholin-4-yl)quinolin-2-yl)oxazole, Yield 88%. LC-MS (ESI, pos, ion) m / z: 480[M+H].

Embodiment 3

[0045] Example 3: Synthesis of 2-(8-(benzyloxy)-7-(2,3-diphenoxy-morpholin-4-yl)quinolin-2-yl)oxazole

[0046]

[0047] Under an argon atmosphere, to a suspension of 2,3-diphenoxy-morpholine (52 mmol) in toluene was added palladium acetate (2.40 g), sodium p-toluenesulfonate (3.90 g), sodium tert-amylate ( 11.8 g) in toluene (37 mL), diadamantanebutylphosphine (7.70 g), and stirred at room temperature for 1 hour. In the reaction suspension, compound 5 (19.10 g, 50.10 mmol) and toluene (33 mL) were added under ice-water bath conditions, and then heated to reflux for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and 2mol / L hydrochloric acid (37.5 mL) was added. The formed precipitate was collected by filtration to give 22.91 g of light brown crystals of 2-(8-(benzyloxy)-7-(2,3-diphenoxy-morpholin-4-yl)quinolin-2-yl) Oxazole, 80% yield. LC-MS (ESI, pos, ion) m / z: 572[M+H].

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Abstract

The present invention discloses a compound having selective inhibitory activity against human fatty acid amide hydrolase and a use thereof for treating pains. The compound has the structural formula as follows: wherein R1, R2, R3 and R4 are each independently selected from -H or -OPh. The tested compound has very good inhibitory activity against the human and rat fatty acid amide hydrolase. From an example 1 to an example 4, the IC50 value of the hFAAH is within a range from 4 nM to 13 nM; the IC50 value of the rFAAH is within a range from 84 nM to 133 nM; and the compound has the selective inhibitory activity against the human fatty acid amide hydrolase. The compound can be used for treating the pains; and the pains can be postoperative pains, chronic pains, cancer pains, pains caused bycancer chemotherapy, neuralgia, nociceptive pains and inflammatory pains.

Description

technical field [0001] The invention belongs to the combination of the fields of medicinal chemistry, pharmaceutical analysis, pharmaceutical preparations and pharmaceutical activity testing, and relates to a compound with selective inhibitory activity on human fatty amidohydrolase and its use for treating pain, and the pain is postoperative pain , chronic pain, cancer pain, pain caused by cancer chemotherapy, neuralgia, nociceptive pain, inflammatory pain. Background technique [0002] Pain is an unpleasant sensory and emotional experience caused by noxious stimuli. Pain has been listed as the fifth vital sign after breathing, pulse, blood pressure, and body temperature. At present, most hospitals have set up separate pain departments to alleviate the suffering of patients, and pain is also an important item of neurology. [0003] Fatty acid amide hydrolase (FAAH) is an endomembrane amide signaling family protease, and it is the main catalytic hydrolysis metabolic enzyme ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04C07D413/14A61P29/00
CPCA61P29/00C07D413/04C07D413/14
Inventor 李敬敬
Owner 李敬敬
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