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Benzylisoquinoline compound, preparation method and application

A technology of benzylisoquinolines and compounds, applied in the fields of active ingredients of heterocyclic compounds, organic chemistry, drug combination, etc., can solve severe allergies and other problems, and achieve the effect of short duration of muscle relaxation and rapid disappearance of muscle relaxation

Inactive Publication Date: 2018-07-06
SICHUAN DAOZHEN TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] It can be seen that the current muscle relaxation drug reversal technology requires the external administration of a large number of molecules that are not related to the therapeutic effect to release the muscle relaxation effect. Some of these relatively large doses of rescue agents have been reported to have certain side effects on the body, such as severe allergies (LMenéndez- Ozcoidi, Anaesthesia, 2011, 66(3):217-9)

Method used

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  • Benzylisoquinoline compound, preparation method and application
  • Benzylisoquinoline compound, preparation method and application
  • Benzylisoquinoline compound, preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0043]

[0044] Put 715 mg of labdansu (CAS: 1699-51-0) and 334 mg of methyl 3-bromopropionate in 30 mL of acetonitrile, stir at 55°C for 24 hours, evaporate the acetonitrile to dryness under reduced pressure, and perform column chromatography (dichloromethane / methanol) =10 / 1) to obtain 590mg of N-methyl-N-propionic acid methyl ester labdansin quaternary ammonium salt, add 2N aqueous sodium hydroxide solution 20mL, hydrolyze at room temperature for 2 hours, adjust the Ph value to 9 with hydrobromic acid aqueous solution, reduce The solvent was evaporated to dryness under pressure, and the crude product was subjected to column chromatography (dichloromethane / methanol=10 / 1) to obtain 280 mg of N-methyl-N-propionyllaudansin quaternary ammonium bromide sodium salt, namely Fragment a.

[0045] Put 715 mg of labdansu (CAS: 1699-51-0) and 334 mg of 5-bromopentanol in 30 mL of acetonitrile, stir at 55°C for 24 hours, evaporate the acetonitrile to dryness under reduced pressure, and ...

Embodiment 2

[0049]

[0050] According to the method described in Example 1, using (S)-laudansu (CAS: 2688-77-9) as a starting material, the S, S type isomer of the compound of formula (I) can be obtained.

[0051] HNMR(d-DMSO): 1.21~1.27(2H,m), 1.56~1.73(4H,m), 2.72(2H,t,J=8Hz), 2.88~3.68(46H,m), 4.19(2H,t , J=8Hz), 4.91~4.97(2H,m), 5.87(2H,s), 6.05~6.89(10H,m).

Embodiment 3

[0053] Some of the compounds described in the examples were subjected to rabbit plasma decomposition experiments in vitro. Add DMSO solution (10 μL) containing 200 μg of drug to 4 mL of rabbit plasma to make the plasma drug concentration 50 μg / mL, incubate at 37 °C immediately after mixing, and take 200 μL of drug-containing plasma at 2 min, 5 min, 10 min, and 20 min respectively , add 600 μ L of methanol, after centrifugation, take the supernatant liquid for measurement, and measure the drug content by HPLC, the specific measurement conditions are: 4.6X50mm, 5 μm C18 column, 0.04% trifluoroacetic acid aqueous solution is A mobile phase, 0.02% trifluoroacetic acid acetonitrile solution is B mobile phase, flow rate 1.5mL / min, column temperature 45°C, gradient elution (B: 10% / 2.5min→80% / 1.5min→10% / 2min), diode array detector. The obtained drug concentration is measured, compared with the initial drug concentration at the time of injection, and the remaining percentage of the dru...

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Abstract

The structural formula is shown in the description, wherein Ar1, Ar2, Ar3 and Ar4 are non-substituted or substituted aryl groups; R is H or C1-5 alkyl group; R1, R2, R3 and R4 can be independent H orC1-5 alkyl groups; in addition, R1 and R2 can form C2-5 ene groups commonly, and R3 and R4 can form C2-5 ene groups commonly; B1 is C1-9 substituted or non-substituted, saturated or unsaturated alkylene groups, and the skeleton of B1 can contain heteroatoms such as O; B2 is C1-8 substituted or non-substituted, saturated or unsaturated alkylene groups, and the skeleton of B2 can contain heteroatomssuch as O; X is O or CH2 or NR5, wherein R5 is H or C1-5 alkyl groups; Y is O or CH2 or C(O)O; S is pharmaceutically-acceptable anions such as bromide ions, sulfonate ions. A stereoisomer with a structure shown in a formula (I), a stereoisomer mixture or pharmaceutically-acceptable salts and a pharmaceutical composition formed by the pharmaceutically-acceptable salts and pharmaceutically-acceptable carriers can generate a neuromuscular junction blocking effect and can be applied in the field of preparation of medicines for muscular relaxation.

Description

technical field [0001] The invention relates to a class of benzylisoquinoline compounds, a preparation method and use. Background technique [0002] Neuromuscular junction blockers, also known as muscle relaxants, are essential drugs during surgery. This type of drug relaxes the skeletal muscle of the patient during the operation, which is convenient for tracheal intubation, myometriotomy and other surgical operations. It is difficult to carry out the above operation under the condition of poor muscle relaxation. The use of neuromuscular junction blockers has a long history. Starting from the first clinical use of tubocura, various compounds with different structures have been used and eliminated clinically. At present, according to the structure type of drugs, there are three main types of muscle relaxants in clinical use: succinylcholine, aminosteroids and benzylisoquinolines. According to the mechanism of action, succinylcholine belongs to depolarizing muscle relaxants...

Claims

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Application Information

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IPC IPC(8): C07D217/20C07D217/18C07D221/20A61K31/47A61K31/4747A61P21/02
CPCY02P20/55C07D217/20C07D217/18C07D221/20
Inventor 不公告发明人
Owner SICHUAN DAOZHEN TECH CO LTD
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