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Pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its medical application

A technology of indolizine formylmethyl and methanesulfonamide, which is applied in the field of indolizine formylmethyl p-methylsulfonamide phenethylamine derivatives and their medical applications, and can solve the problem of restricting the wide application of Class III antiarrhythmic drugs and other problems to achieve the effect of overcoming side effects

Inactive Publication Date: 2013-10-23
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, research results in recent years have shown that although class III antiarrhythmic drugs have shown good antiarrhythmic effects in clinical practice, their arrhythmic side effects (mainly torsade de points, TdP) are still It is a very serious problem that limits the wide application of class III antiarrhythmic drugs in clinical practice
Dofetilide’s current clinical application has shown that it is relatively safe and effective, but animal experiments have shown that it has the above-mentioned side effects, so it has the potential to appear in clinical practice.

Method used

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  • Pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its medical application
  • Pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its medical application
  • Pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Preparation of 2-phenyl 3-bromoacetyl indolizine (compound 6)

[0044] a) Preparation of N-phenacylmethyl-2-methylpyridinium salt (compound 4)

[0045] 2-Methylpyridine (Compound 3) (4.7g, 0.05mol) and ω-bromoacetophenone (9.9g, 0.05mol) were heated to reflux in 200ml of ethyl acetate for 2 hours, cooled, and the white solid was collected by filtration. After washing with ethyl acetate, 12.1 g of a white solid product was obtained, with a yield of 83%, mp: 215-217°C.

[0046] b) Preparation of 2-phenylindolizine (compound 5)

[0047] Compound 4 (14.6g, 0.05mol) was dissolved in 150ml of water and 80ml of dichloromethane, adding K 2 CO 3 (13.8g, 0.1mol), stirred at room temperature for 1 hour, separated the organic layer, washed once with water, anhydrous MgSO 4 Dry and concentrate to obtain pale yellow crystals (6.9g, 72%), mp: 193-194°C.

[0048] c) Synthesis of 2-phenyl 3-bromoacetyl indolizine (compound 6)

[0049] 2-Phenylindolizine (compound 5) (1.9g, 0.01mol...

Embodiment 2

[0051] Preparation of β-(4-nitrophenyl)-ethylamine hydrobromide (hydrobromide of compound 10)

[0052] a) Preparation of 1-(4-nitrophenyl)-2-(N-acetylamino)ethane (compound 9)

[0053] In 100ml (0.796mol) of β-phenylethylamine (compound 7), add 76ml (0.804mol) of acetic anhydride dropwise under cooling in an ice bath, keep the temperature at 40-45°C, and stir for 2 hours after dropping.

[0054] In a mixture of 150ml (2.81mol) of concentrated sulfuric acid and 150ml (3.33mol) of nitric acid, add the above standby solution dropwise at 20°C, continue to react for 2h after dropping, pour into ice water, extract three times with ethyl acetate, and combine the ester layers , washed with water, anhydrous Na 2 SO 4 Dry, concentrate to dryness, recrystallize from acetone 2 water (recrystallize using a mixed solvent of acetone and water, volume ratio 2:1), and obtain 76g of white needle crystals, yield 46.0%, mp138-140℃.

[0055] b) Preparation of β-(4-nitrophenyl)-ethylamine hydrob...

Embodiment 3

[0058] Preparation of N-(2-phenyl-3-indolizine formylmethyl)-p-nitrophenylethylamine (compound 11)

[0059] 2g (0.012mol) p-nitrophenylethylamine (compound 10), 2g (0.014mol) potassium carbonate, 20ml acetonitrile, heated and stirred under reflux for 20 minutes, cooled to room temperature, slowly added dropwise 2.5g (0.008mol) dissolved in 20ml acetonitrile ) 2-phenyl-3-bromoacetylindolizine (compound 6), stirred and reacted for 2 hours, poured the reaction solution into a large amount of ice water, allowed to stand, and filtered with suction to obtain 3.5 g of a yellow solid (wet product). Developing agent: petroleum ether: ethyl acetate = 1:1, R f =0.33. IR(KBr,cm -1 ):3066,2911,1615,1511,1410,742,702; 1 H NMR (CDCl 3 ,300MHz)δ(ppm):2.79(t,2H,J=6.7Hz,- CH 2 CH 2 N),2.88(t,2H,J=6.7Hz,-CH 2 CH 2 N),3.41(s,2H,-CO CH 2 -),6.49(s,1H,ArH),6.92(t,1H,J=6.9Hz,ArH),7.20-7.55(m,10H,ArH and-NH-),8.12(d,2H,J=8.5 Hz,ArH),9.97(d,1H,J=7.1Hz,ArH);ESI-MS m / z:400.2[M+H] + ;Anal.C...

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Abstract

The invention provides a pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative having the structural general formula as shown in the specification and its officinal salt, wherein R1 represents CH3, COCH3, CH2C6H5, COC6H5, CH2C6H4-Cl-p, CH2C6H4CH3-p, CH2C6H4OCH3-p, CH2C6H3OCH2O-3, 4, CH2C6H3(OCH3)2-3, 4 or C6H11; R2 represents H or SO2CH3; and R3 represents SO2CH3. The invention also provides an application of the above pyrrocoline formylmethyl p-methane sulfonamide phenylethylamine derivative and its officinal salt in the preparation of medicines for treating cardiovascular disease. By the adoption of the medicine provided by the invention, side-effect generally existing in III antiarrhythmic drugs is overcome, patient compliance with drugs is raised, and the risk brought by drug interaction is reduced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a class of indolizine formylmethyl-p-methanesulfonamide phenethylamine derivatives and their medical application. Background technique [0002] Cardiovascular diseases, such as hypertension, coronary heart disease, and arrhythmia, have become major diseases that endanger human health. Severe arrhythmias such as tachyventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD) are important causes of cardiovascular death. [0003] Antiarrhythmic drugs currently in clinical use and development can be divided into four categories according to the Vanghan Williams classification: class I are sodium channel blockers; class II are beta blockers; class III are selective prolongation Myocardial action potential duration (APD) and effective refractory period (ERP) drugs; Class IV is calcium channel blockers. Class Ⅲ antiarrhythmic d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P9/06
Inventor 蔡进吉民
Owner SOUTHEAST UNIV
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