Quaternary ammonium derivative of lidocaine eliciting anti-arrhythmic activity and method for its preparing

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a new biologically active compound. Invention describes quaternary ammonium derivative of lidocaine of the formula:

eliciting anti-arrhythmic activity. Also, invention describes a method for preparing quaternary ammonium derivative of lidocaine of the formula (1). Method involves interaction of N-(2,6-dimethylphenylaminocarbonylmethyl)-morpholine with allyl bromide in isopropyl alcohol medium at temperature 58-62°C followed by cooling the reaction mixture to room temperature and isolation of N-allyl-(2,6-dimethylphenylaminocarbonylmethyl)-morpholinium bromide. Invention provides preparing new compound eliciting useful biological properties.

EFFECT: improved preparing method.

2 cl, 4 tbl, 4 ex

 

The invention relates to medicine and can be used in medical practice for correction of disorders of cardiac rhythm.

Known compound N-(2,4,6-trimethylphenylsulfonyl)-N-allylnormorphine bromide called quaternion exhibiting anti-ischemic and anti-arrhythmic effect in ischemic heart disease (RU 2105554, IPC 6 a 61 K 31/535, C 07 D 29/037, publ. 1997).

A disadvantage of the known solution is its high toxicity and low breadth of therapeutic action.

The technical result consists in the reduction of acute toxicity, increasing the breadth of therapeutic action and reducing mortality of laboratory animals under chronic stress.

The technical result is achieved Quaternary ammonium derivative of lidocaine - N-allyl-(2,6-dimethylaminocarbonylmethyl) morpholine bromide of formula (1):

possess antiarrhythmic activity.

The method of obtaining the compounds of formula (1) is that N-(2,6-dimethylaminocarbonylmethyl)morpholine is subjected to interaction with allyl bromide in the environment of isopropyl alcohol at a temperature of 58-62°C, followed by cooling the reaction mixture to room temperature and excretion of N-allyl-(2,6-dimethylaminoethyl-methyl)morpholine bromide.

JV the property according to the invention is illustrated by the following example.

Example. Synthesis of N-allyl-N-(2,6-dimethylaminocarbonylmethyl)morpholine bromide

To 100 g of N-(2,6-dimethylaminocarbonylmethyl)the research poured 130 ml of isopropyl alcohol, the solution gradually add 49 ml of allyl bromide. The mixture is heated to a temperature of 60°C, stirred for 5-6 hours, then cooled, the separated product is filtered off. Get to 133.5 g technical matter (89,72%), which is purified by recrystallization from isopropyl alcohol with the addition of activated charcoal. Get 109,5 g of white crystalline powder, easily soluble in alcohol, soluble in water, practically insoluble in ether and chloroform. T square 195-197°C.

Found %: 55,12 of 6.71 N N 7,42 About 8,53, Br 21,52

Calculated, %: C 55,29 N 6,82 N To 7.59 About 8,66, Br 21,64

C17H25N2O2Br, M.M. 369,29

The IR spectrum γ cm-1: 1550 (NHCO), 1670 (C=O), 3280 (NH)

The study of pharmacological activity 1

Unlike quaternion 1 differs less toxicity intraperitoneal, oral and intravenous routes of administration, as well as greater security, as illustrated by example 1.

Example 1. The acute toxicity of 1 and the nearest analogues

The acute toxicity of 1 was studied in experiments on mice (n=440, m=18-20 g) by intraperitoneal and oral routes of administration, cats (n=15, m=1.5-4.8 kg) by intravenous introduction the AI.

Figure LD50was calculated by the method of Miller and Tainter (kN. Belenky, M. elements of a quantitative evaluation of the pharmacological effect. - Riga: Academy of Sciences of the Latvian SSR, 1963. - 130 C.). To determine acute toxicity when administered intravenously (LD100) solutions in isotonic sodium chloride was administered to animals prior to the cardiac arrest. The results of the study of structural predecessor lidocaine quaternion, and 1 are shown in table 1.

In the data table clearly shows that the inventive compound is more toxic than structural predecessor lidocaine intraperitoneal injection and less toxic than the Quaternary derivative of trimekainom - quaternity. Oral introduction acute toxicity 1 was less than the same indicator of lidocaine and quaternion. Lethal intravenous dose of 1 for cats is also lower than that of quaternion and lidocaine.

Example 2. Antiarrhythmic activity of 1 and the nearest analogues with ventricular arrhythmias in the late stage of experimental myocardial infarction in dogs

Ventricular arrhythmias in the late stage of experimental myocardial infarction played in adult dogs of both sexes weighing 7,0-15,0 kg Violation of coronary blood flow in animals caused by the method described in the sources: Harris A.S. Delayed developmentof making emergency ectopic ventricular rhythm following experimental coronary occlusion. // Circulation Res. - 1950. - Vol.1. - N6. - P.1318-1328, Herzenstein AI, Kostin AV Antiarrhythmic action of trimekainom with ventricular fibrillation // Cardiology. - 1976. No. 1. - S-131.

The test results of the inventive compounds and analogs are given in table 2.

Study 1. 1 introduction in a dose of 4 mg/kg was possible to suppress the arrhythmia 100% of the experiments. The duration of the antiarrhythmic effect was at least 500 minutes of observation. Full antiarrhythmic effect developed after an average of 15 minutes after injection.

Thus, the strength and duration of antiarrhythmic effect 1 is not inferior quaternion and lidocaine. As well as Quaternary derivative of trimekainom (quaternion) 1 typical dwuhfaznosti occurrence antiarrhythmic actions.

Example 3. Activity 1 and quaternion on the model of aconitine arrhythmia in rats and mice

Arrhythmia reproduced by the method Wiesia and Nowlaeronee (1958) (book. Kaverin NV, Berdyaev HE, Kuduk H.E., Pashina O.E. guidelines for the study of the antiarrhythmic activity of new pharmacological substances // Guidance on experimental (preclinical) study of new pharmacological substances, Ed. Wpisane. - M., 2000. - S). Nitrate aconitine was administered to animals at a dose of 50 mg/kg the Results are shown in table 3.

This model provides is to judge the breadth of therapeutic action of the present compounds his closest analogues and structural predecessor. About the breadth of therapeutic action judged largest complications index, defined as the ratio LD50intraperitoneal way of introduction to the ED50on aconitine model arrhythmias.

The experiment shows that 1 effectively suppresses atrial fibrillation, caused by the intravenous injection of nitrate aconitine. The value of antiarrhythmic index, calculated for 1, is far superior to any quaternion and lidocaine, therefore, 1 has a greater breadth of therapeutic action than comparable counterparts, indicating its greater security at equivalent activity.

Example 4. Study of influence of 1, lidocaine and quaternion on experimental mortality in long introduction to the animals that are under stress

At the present time to assess the safety of long-term antiarrhythmic therapy method is used (Balashov VP, balikova L.A. Shuvalov E.N. and other New method for safety assessment of potential anti-arrhythmic drugs // bull. Exp. Biol. and the honey. - 2002. - T. No. 5. - S-600) simulation 6-hour immobilization stress in white mice daily for 6 weeks.

The results of study 1, lidocaine and quaternion presented in t is BL. All compounds were administered at a dose of constituting 5% of LD50intraperitoneal injection to mice. 1 at the dose of 4 mg/kg intraperitoneally, lidocaine 10 mg/kg, quaternity - 2 mg/kg

In the control immobilization resulted in the death of some animals, and mortality after 6 weeks was 30%. Lidocaine significantly increased the lethality of mice under stress. Quaternity found a trend towards improvement, and percentage of mortality with the introduction of 1 was the smallest of all the substances.

The data presented demonstrate that N-allyl-N-(2,6-dimethylaminocarbonylmethyl) morpholine bromide (1) exhibits a pronounced antiarrhythmic properties in models of ventricular and atrio-ventricular (acontinued) arrhythmias, comparable with properties closest analogue (quaternion) and superior to antiarrhythmic properties of structural predecessor (lidocaine).

The duration of effect 1 is the same figure quaternion and significantly exceeds the duration of effect of lidocaine. An important advantage of the claimed compounds is its large breadth of therapeutic action, as compared with the same period of lidocaine and quaternion. In addition, in conditions of long-term immobilization stress in a 6-week introduction, 1 in contrast to lidocaine does not increase mortality is ity of experimental animals.

Thus, modification morpholino analogue of lidocaine by attaching to the nitrogen atom of allyl groups (synthesis of N-allyl-N-(2,6-dimethylaminocarbonylmethyl) morpholine bromide) allows to obtain more effective and safe compound for the treatment of cardiac arrhythmias than its structural predecessor and the nearest equivalent.

Table 1.
Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and how to obtain it
The studied parametersLidocaineQuaternion1
LD50in b/W, mg/kg200±15***54±4**82±5*
(M±m)(173-227)(46-62)(76-94)
MouseN=80n=60n=100
LD50per os,297±14***450±26**630±26*
Mg/kg(271-324)(400-500)(578-689)
(M±m)
Mousen=80 n=60n=60
LD100/mg/kg128±7***47±4**90±4*
(M±m)
catsn=5n=6n=4
Note: * - differences when compared with quaternion significant at p<0,05; ** - differences when compared with lidocaine significant at p<0,05.

Table 2.
Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and how to obtain it
№ p/pTest connectionThe character of the original rhythmThe nature of the rhythm after administration of the substanceThe number of animalsThe effect, minThe effect duration, minSuppression of arrhythmia %
The frequency of heart. abbreviationsThe frequency of ectopic contractionsHRBSECExperience Full effect (%)
1.Lidocaine191±9143±24175±3062 (33)14-661±11
2.Quaternion206±10159±25188±6055 (100)16±4536±56100
3.1191±9143±24175±301010 (100)15±5500 minutes of nablyudeniya100

Table 3.
Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and how to obtain it
Trial medicationDose mg/kgnWith arrhythmia (%)The timing of HPDuration NR, minED50mg/kgAI
Control-191931±1290,0±8,0--
Lidocaine2,56668±2267,0±to 12.0
594135±1541,0±6,0of 8.47±1,923,5
1093186±3835,0±6,0
1590--
Quaternion0,555100±24136,0±26
1,564140±6057,0±8,02,09±0,5825,8
2,0116200±3564,0±13,0
4,060--
10,59889±21100,0±13
1,59696±3384,0±18,02,0±0,5843,5
2,093154±1345,0±13,
4,090--
Note: ED50- effective dose, HP - rhythm disturbances, AI - antiarrhythmic index.

Table 4.
Quaternary ammonium derivative of lidocaine with antiarrhythmic activity, and how to obtain it
GroupThe number of dead animals
Abs.%
Without immobilization (n=20)00
Immobilization (control; n=40)1230,0
+1 (n=40)1435,0
+ lidocaine (n=40)2152,5*
+ quaternion (n=40)1640,0
Note:*p<0,05 when compared to control.

1. Quaternary ammonium derivative of lidocaine formulas (1)

possess antiarrhythmic activity.

2. A method of obtaining a Quaternary ammonium derivative of lidocaine formula 1, wherein N-(2,6-dimethylaminocarbonylmethyl) morpholine is subjected to interaction with allyl bromide in the environment of isopropyl alcohol at a temperature of 58-62°C, followed by cooling the reaction mixture to room temperature and excretion of N-allyl-(2,6-dimethylaminocarbonylmethyl) morpholine bromide.



 

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