Preparation and applications of phenylquinolinone-based and flavone-based derivative

A technology of benzoquinolinone and benzoquinolinone thiazine, which is applied in the field of preparation of phenylquinolinone and flavonoid derivatives, and can solve the problems of nerve cell toxicity and nerve cell apoptosis

Active Publication Date: 2019-01-01
HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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Method used

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  • Preparation and applications of phenylquinolinone-based and flavone-based derivative
  • Preparation and applications of phenylquinolinone-based and flavone-based derivative
  • Preparation and applications of phenylquinolinone-based and flavone-based derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Synthesis of I-1 and I-2 in class I compounds (quinolinones).

[0066] Step 1: 4-(3-chloropropoxy)benzoic acid (Intermediate 1).

[0067] Ethyl p-hydroxybenzoate II-1 (12 g, 72 mmol), 1,3-bromochloropropane (14.2 mL, 144 mmol) and K 2 CO 3 (20 g, 144 mmol) was dissolved in 100 mL of acetonitrile and heated to reflux for 12 h. Suction filtration to remove excess K 2 CO 3 , the solvent was distilled off under reduced pressure to obtain a colorless oily liquid. Directly add 15 mL of 6 N NaOH solution and 30 mL of CH 3 OH, reflux for 1 h. After the reaction solution became clear, it was cooled and acidified with 2 N hydrochloric acid to pH = 2. A large amount of white solid was precipitated, filtered with suction, washed with water, and dried to obtain 14.5 g of white solid powder. Yield 94%; 1 H NMR (500 MHz, CDCl 3 ): δ 8.08 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 3.77 (t, J = 6.5 Hz, 2H),2.30-2.25 (m, 2H); ESI-...

Embodiment 2

[0076] Example 2: Synthesis of I-3~I-6 in class I compounds (quinolinones).

[0077] Step 1: 2-(4-(3-chloropropoxy)phenyl)-1-methylquinoline-4(1 H )-ketone (intermediate 5a).

[0078] Intermediate 4 (276 mg, 0.88 mmol) was dissolved in 5 mL DMF, 42 mg NaH (60%, 1.05 mmol) was added, stirred at room temperature for 30 min, then methyl iodide (138 mg, 0.97 mmol) was added, and the temperature was raised To 35°C, react for 30min. Pour the reaction solution into 50 mL H 2 O, extracted with EtOAc, washed with water, washed with saturated NaCl, anhydrous NaCl 2 SO 4 dry. After recovering the solvent, it was separated by column chromatography (petroleum ether: EtOAc=10: 1) to obtain 250 mg of white solid. Yield 87%; 1 H NMR (500MHz, CDCl 3 ): δ 8.17 (d, J = 8.0 Hz, 1H), 8.10-8.08 (m, 3H), 7.71 (d, J = 8.0,1H), 7.48 (t, J = 7.5 Hz, 1H), 7.14 (s, 1H), 7.05 (d, J = 9.0 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 4.12 (s, 3H), 3.79 (t, J = 6.5 Hz, 2H), 2.31-2.26 (m, 2H); ESI-...

Embodiment 3

[0089] Example 3: Synthesis of I-7 and I-8 in class I compounds (quinolinones).

[0090] Step 1: 4-(3-chloropropoxy)acetophenone (intermediate 6).

[0091] p-Hydroxyacetophenone (5.0 g, 36.7 mmol), 1,3-bromochloropropane (7.3 mL, 73.5 mmol) and K 2 CO 3 (10 g, 73.5 mmol) was dissolved in 30 mL of acetonitrile, heated to reflux for 10 h. Suction filtration to remove excess K 2 CO 3 , the solvent was distilled off under reduced pressure, and separated by column chromatography (petroleum ether: EtOAc=10: 1) to obtain 7.6 g of a colorless liquid. Yield 98%; 1 H NMR (500MHz, CDCl 3 ): δ 7.95 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 4.20 (t, J =6.0 Hz, 2H), 3.77 (t, J = 6.0 Hz, 2H), 2.56 (s, 3H), 2.29-2.24 (m, 2H); ESI-MS: m / z =213 [M+H] + .

[0092] Step 2, 2-bromo-1-(4-(3-chloropropoxy)phenyl)ethanone (intermediate 7).

[0093] Intermediate 6 (2.12 g, 10 mmol) was dissolved in 20 mL of ether, and Br was slowly added dropwise at 0°C 2 (0.51 mL, 10 mmol), ...

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Abstract

The present invention relates to a phenylquinolinone-based and flavone-based derivative and a preparation method thereof, wherein the derivative is a histamine H3 receptor antagonist, can protect andrestore the normal function of central nervous system, especially can be used in neurodegenerative diseases and ischemic brain injury, and has great clinical application value.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to the preparation of phenylquinolinones and flavonoid derivatives, the active ingredient of which is a histamine H3 receptor antagonist, which can protect and restore the normal function of the central nervous system and prevent neurodegeneration Diseases, ischemic-ischemic encephalopathy, Parkinson's syndrome, narcolepsy, epilepsy and gradual freezing disease. The phenylquinolinone and flavonoid derivatives also include their pharmaceutically acceptable salts, complexes, solvates and the like. Background technique [0002] Histamine H 3 Receptors exist in the cerebral cortex, striatum, hippocampus, olfactory bulb, substria terminal nucleus, thalamus, lower brainstem spinal nucleus, cerebellum, etc. Histamine H 3 Receptors are self-receptors of neuronal synapses. Exciting the receptors will inhibit the release of histamine or other neurotransmitters, and antagonizing the recepto...

Claims

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Application Information

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IPC IPC(8): C07D215/233C07D311/30A61K31/47A61K31/352A61P25/16A61P25/28A61P25/08A61P25/00
CPCC07D215/233C07D311/30A61K31/352A61K31/47A61K31/4709A61P25/00A61P25/08A61P25/16A61P25/28C07D311/60C07D311/62
Inventor 盛荣楼金芳严洪兵胡永洲唐黎张冯敏
Owner HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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