2-piperazine ethyl phenyl carbamate derivatives and pharmaceutical application thereof

A technology of phenyl carbamate and derivatives, applied in the field of 2-piperazine ethyl phenyl carbamate derivatives and their pharmaceutical uses, can solve problems such as poor water solubility, poor oral bioavailability, and unfavorable preparations , to achieve the effect of good water solubility

Active Publication Date: 2020-06-05
南京缘聚医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, ZL006-05 has poor water solubility and poor oral bioavailability (4.2%), which is not conducive to making preparations
Although ZL006-05 water-soluble prodrugs ZL006-0501 and ZL006-0502 have good water solubility of ZL006-05, the amount of ZL006-05 produced in vivo is very limited (see Table 2), suggesting that their main metabolites are not ZL006-05 , it is difficult to obtain satisfactory efficacy (see Table 3, Table 4)

Method used

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  • 2-piperazine ethyl phenyl carbamate derivatives and pharmaceutical application thereof
  • 2-piperazine ethyl phenyl carbamate derivatives and pharmaceutical application thereof
  • 2-piperazine ethyl phenyl carbamate derivatives and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Embodiment 1: the synthesis of target compound

[0018] synthetic route:

[0019]

[0020] 1.1 Synthesis of target compound 1

[0021] Synthesis of M-2: Take 3,5-dichlorosalicylaldehyde (1.9g, 10mmol), dissolve it in ethanol (10mL), add sodium borohydride (1.48g, 39.2mmol) in batches at 0°C, and react at room temperature for 2 Hours, the solvent was distilled off under reduced pressure, 30 mL of water was added, extracted three times with ethyl acetate (10 mL), the organic phase was washed with saturated aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate=10:1, V / V) gave product M-2 (1.7 g). The product is a white solid. 1 H NMR (400MHz, CDCl 3 )δ7.32(s,1H),7.31(s,1H),4.71(s,2H).

[0022] Synthesis of M-3: Take M-2 (1.4g, 7.2mmol), dissolve it in tetrahydrofuran (5mL), add phosphorus tribromide (2...

Embodiment 2

[0029] Embodiment 2 target compound water solubility test

[0030] At 25°C, the saturated aqueous solution (0.1mol / L sodium phosphate buffer solution) of the target compound was used to measure the main peak area by the high performance liquid phase method, and was compared with the high performance liquid phase main peak area of ​​the methanol solution of the target compound at 0.1 mg / mL. For comparison, calculate its solubility in water.

[0031] Table 1 Solubility of target compounds in water (25°C, mg / mL)

[0032]

[0033] The water solubility test of the target compound shows that the solubility of the target compound in weakly acidic (pH=5.0-6) aqueous solution is significantly higher than that of ZL006-05.

Embodiment 3

[0034] Example 3 Determination of target compound blood drug concentration and active metabolite ZL006-05 concentration in vivo

[0035] C57 mice were administered intravenously (i.v.2mg / kg) with the same mol dose of the compound (Example Compound 1: 2mg / kg, ZL006-0501: 2mg / kg, ZL006-05: 1.5mg / kg), 5min after administration, Blood was collected at 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, and 24h, the plasma was separated, and the concentration of the target compound and ZL006-05 in the plasma was determined by high performance liquid chromatography-mass spectrometry. The pharmacokinetic parameters of the target compound were calculated by DAS software, and the absolute bioavailability was calculated according to the ratio of the area under the drug-time curve for oral administration and intravenous administration.

[0036] Chromatographic conditions The chromatographic column is an Agilent Eclipse Plus C18 column (50mm×2.1mm, 1.8μm); the mobile phase is ultrapure water-acetonitr...

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PUM

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Abstract

The invention relates to a phenyl 2-piperazine ethyl carbamate derivative and a pharmaceutical application thereof. The structure of the phenyl 2-piperazine ethyl carbamate derivative accords with a general formula (I), wherein R is -H or-CH3. The drug has good water solubility, can rapidly release ZL006-05 in vivo, can maintain a high blood concentration of ZL006-05, and has a neuroprotective effect similar to that of ZL006-05 and a better nerve repair promoting effect. The derivative can be used for preparing medicines for treating cerebral apoplexy, neuropathic pain and other diseases.

Description

technical field [0001] The invention belongs to the field of pharmacy and provides a class of phenyl 2-piperazine ethyl carbamate derivatives and their medicinal application. Background technique [0002] Cerebral infarction seriously endangers human health. nNOS-PSD-95 uncoupler 4-N-(2-hydroxy-3,5-dichlorobenzyl)aminosalicylic acid (ZL006), can reduce NMDAR without affecting the physiological functions of NMDAR and nNOS The pathological release of NO mediated by glutamate has shown obvious neuroprotective effect on nerve cell damage under glutamate stimulation, improving neurological deficit symptoms and reducing infarct volume in middle cerebral artery occlusion (MCAO) reperfusion animals (Nature Medicine 2010, 16, 1439–1443). Invention patent PCT / CN2012 / 083455 discloses the 2-cannol ester of ZL006 (ZL006-05), which has better anti-stroke and neuropathic pain effects. [0003] [0004] However, ZL006-05 has poor water solubility and poor oral bioavailability (4.2%), ...

Claims

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Application Information

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IPC IPC(8): C07D295/13A61P25/00A61P25/04A61K31/625
CPCA61P25/00A61P25/04C07D295/13
Inventor 李飞李伦家
Owner 南京缘聚医药科技有限公司
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