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Phenylquinoline TRPV1 antagonist and its preparation method and application

A phenylquinoline and phenyl technology, applied in the field of medicinal chemistry, can solve the problems of loss of response to harmful stimuli, loss of pain, and burning sensation

Active Publication Date: 2020-12-08
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The natural product capsaicin, as the first discovered TRPV1 receptor agonist, has extremely high application research value, but the application of capsaicin will produce some side effects, such as local application of capsaicin will cause a burning sensation, and it will cause pain after a few days to a few weeks Loss and loss of response to various noxious stimuli

Method used

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  • Phenylquinoline TRPV1 antagonist and its preparation method and application
  • Phenylquinoline TRPV1 antagonist and its preparation method and application
  • Phenylquinoline TRPV1 antagonist and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Preparation of 2-phenylquinoline-3-carboxylic acid (iii)

[0104] Add KOH (0.56g, 10.02mmol) and absolute ethanol (10ml) into a 50ml single-necked bottle. After the KOH is completely dissolved, add isatin (i) (0.5g, 3.34mmol), stir at reflux at 80°C for 15min, and then add Acetophenone (ii) (0.82g, 6.8mmol), heat to reflux for 12h, remove the solvent under reduced pressure, add water (20ml) to dissolve, wash with saturated brine (20ml×3) take the water layer, adjust pH=2 with concentrated hydrochloric acid , and filtered to obtain 0.82 g of a light yellow solid, with a yield of 96.87%.

Embodiment 2

[0106]Preparation of N-phenyl-4-(2-phenylquinoline-4-carbonyl)piperazine-1-carboxamide (1)

[0107] (a) Preparation of isocyanatobenzene (v)

[0108] Dissolve aniline (1g, 10mmol) in DMSO (10ml), add N,N'-carbonyldiimidazole (2g, 12mmol) to the solution, stir at room temperature for 2h, add water (30ml) and ethyl acetate (30ml) , extraction and separation, the aqueous layer was washed with ethyl acetate (20ml×3), and after combining the organic layers for 24h, the solvent was evaporated under reduced pressure, and the solvent was evaporated under reduced pressure to obtain an oily substance;

[0109] (b) Preparation of N-phenylpiperazine-1-carboxamide (vii)

[0110] The product obtained in (a) was dissolved in dichloromethane (20ml), 1-Boc-piperazine (1.67g, 9mmol) was added, stirred at room temperature for 2h, and the solvent was evaporated under reduced pressure to obtain an oily substance. The matching ratio is petroleum ether: ethyl acetate = 4:1. The obtained product w...

Embodiment 3

[0115] Preparation of 4-(2-phenylquinoline-4-carbonyl)-N-(4-methylphenyl)piperazine-1-amide (2)

[0116] Referring to the preparation method of 1 in Example 2, compound 2 was obtained as a light yellow solid with a yield of 55.2%, mp: 105-109°C;

[0117] 1 H NMR (300MHz, DMSO-d 6 )δppm: 8.53(s, 1H, NH), 8.34(d, J=6.5Hz, 2H, Ar-H), 8.27-8.09(m, 2H, Ar-H), 7.86(t, J=7.3Hz, 2H, Ar-H), 7.76-7.46(m, 4H, Ar-H), 7.31(d, J=8.4Hz, 2H, Ar-H), 7.04(d, J=8.3Hz, 2H, Ar-H ), 3.97-3.60 (m, 4H, piperazine), 3.53-3.12 (m, 4H, piperazine), 2.22 (s, 3H, CH 3 ); 13 C NMR (75MHz, DMSO-d 6 )δppm:166.45,156.32,155.56,148.12,143.76,138.52,138.14,131.17,131.01,130.43,130.17,129.36,129.21,127.96,127.78,125.24,123.35,120.29,119.24,116.05,46.95,44.43,44.03,41.73 , 20.80; ESI-MS m / z: 451.5 ([M+H] + ).

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Abstract

The invention relates to a compound shown as a general formula (I) and salt thereof. The compound has a relatively strong analgesic effect; the activity of one part of compounds is much higher that ofcinchophen and BCTC and basically has no hepatotoxicity, gastric mucosa damages and body temperature increasing side effect; the invention further relates to a preparation method of the compounds andmedical preparations containing the compounds. By adopting the preparation method, a series of compounds shown as the general formula (I) and pharmaceutically acceptable salts thereof are synthesized. The general formula (I) is shown in the description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of TRPV1 antagonists. The invention also discloses a preparation method thereof, a pharmaceutical composition with the compounds as active components, and their application in treating pain. [0002] technical background [0003] Pain is one of the most common clinical symptoms. Due to the complexity of its pathological mechanism, pain has become a major unmet medical need. There are two main types of analgesic drugs currently used clinically: opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). [0004] Opioid analgesics produce analgesic effect by binding to opioid receptors and activating opioid receptors. These drugs usually work quickly and can significantly reduce or eliminate pain. However, the biggest side effect of this type of drug is that continuous repeated use will produce drug resistance and lead to addiction. Once the drug is stopped, withdrawal sy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/14C07D401/06A61K31/47A61K31/4709A61K31/496A61P29/00
CPCC07D215/14C07D401/06
Inventor 黄文龙钱海廖晨周嘉琪王娜思李慧兰刘春霞
Owner CHINA PHARM UNIV
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