Application of glutaric acid derivatives or their pharmaceutically acceptable salts as antiarrhythmic drug

FIELD: medicine.

SUBSTANCE: there is offered application of glutaric acid derivatives of general formula where R1 = imidazole, indole, R2 = COOH, H, or its pharmaceutically acceptable salt as an antiarrhythmic drug (versions), a medical product, a pharmaceutical composition and method of appropriate prescription. There is presented effectiveness of Nαglutaryl-L-histidine, Nαglutaryl-L-tryptophan in arrhythmia caused by adrenal heart rhythm disorder, in nicotine arrhythmia and acute occlusive myocardium disorder.

EFFECT: effective in arrhythmia.

5 cl, 6 tbl, 3 ex

 

The present invention relates to medicine and relates to the use of derivatives of glutaric acid, namely N-acyl derivatives of amino acids and their pharmaceutically acceptable salts as anti-arrhythmic drugs for the correction of disorders of cardiac rhythm.

Prior art

As you know, currently widely used in clinical practice means of complications are propranolol (inderal, obzidan) and amiodarone (cordarone).

Their main disadvantages are the lack of efficiency and low therapeutic range, which shows a high frequency of cardiac and non cardiac side effects [Mashkovsky PPM Medicines. Manual for doctors. Edition of 15. Publisher New Wave. 2005. C.390-392, 264-266].

The closest to the action, the analogue of the claimed compounds is dikalova salt N-succinyl-D,L-tryptophan, exhibiting anti-ischemic, cardiotonic and antiarrhythmic action research [Bulletin of experimental biology and medicine. 1998. So 125. No. 5. C.544-547].

The disadvantages of the known compounds are low antiarrhythmic activity with the inside, as well as the lack of breadth of therapeutic action.

In connection with the above is relevant poiskovik anti-arrhythmic drugs, able to demonstrate a high antiarrhythmic activity with the inside and with greater efficiency in the treatment of cardiac arrhythmias.

In the published international application WO 99/01103 described antiallergic and hypolipidemic action of N-acyl derivatives of biogenic amines, such as glutamylcysteine.

N-acyl derivatives of the amino acids histidine and tryptophan are disclosed in the published international application WO 2006/135280, which describes their use as anti-allergic and operagoers funds.

In publication EN 2005118635 describes N-acyl derivatives of amino acids, which have anti-allergic, anti-inflammatory and hypolipidemic effect and can be used for the treatment of allergic diseases: bronchial asthma, allergic rhinitis, allergic rhinitis, seasonal rhinitis, perennial rhinitis, atopic dermatitis, psoriasis, urticaria, allergic (including anaphylactic) reactions to insect bites and medications, cold Allergy, allergic conjunctivitis, chronic obstructive pulmonary diseases, namely chronic obstructive bronchitis, emphysema, obliterative bronchitis, cystic fibrosis and diseases associated with lipid metabolism, such as atherosclerosis, WA is a group of coronary heart disease and cerebral, myocardial infarction, stroke.

The authors of the present invention, it was found that some of the N-acyl derivatives of amino acids possess antiarrhythmic effect and can be used effectively in the treatment of cardiac arrhythmias.

The aim of the present invention is the use of derivatives of glutaric acid and their pharmaceutically acceptable salts as anti-arrhythmic drugs.

Brief description of the invention

The present invention relates to the use of derivatives of glutaric acid of General formula (I):

where

R1= imidazole, indole,

R2= COOH, H,

or their pharmaceutically acceptable salts as antiarrhythmic tools.

Further, the present invention relates to pharmaceutical compositions and agent with antiarrhythmic effect, containing an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salts, and, if necessary, pharmaceutically acceptable carrier.

Another object of the invention is a method of treating arrhythmia comprising introducing an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

A detailed description of the invention

Connected to the I General formula (I) shown in table 1.

Table 1
ConnectionNo. of connectionsR1R2
Nα-glutaryl-L-tryptophanII-COOH
Nα-glutaryl-L-histidineIII-COOH
GlutamylcysteineIVH

Compounds of General formula (I) can be obtained, for example, as described in EN 2005118635 by adding the anhydride glutaric or succinic acid in a water-immiscible organic solvent to aqueous solution of amino acids of General formula:

where R1is

or

This method allows you to use excess Alliluyeva agent, to achieve a complete acylation of the α-amino group of the amino acid and the yield of the target product approximately the 70%. To maintain the required pH using organic base is pyridine, which is not hydrolyzes anhydride and, in addition, as is known, is a catalyst for acylation. The use of pyridine avoids contamination of the final product inorganic salts, which, together with the reaction product remains in the aqueous layer. Used approaches can simplify the separation of the target product from the unreacted anhydride and the appropriate amino acids and select the target product by simple crystallization.

Compounds of General formula (I) can be also obtained in the form of pharmaceutically acceptable salts by reacting, for example, sodium hydroxide, potassium hydroxide, magnesium carbonate, lithium hydroxide, calcium carbonate routine methods widely described in the literature.

Compounds of General formula (I) possess antiarrhythmic activity and can be used to treat arrhythmias.

Compounds of General formula (I) are introduced in an effective amount that provides the desired therapeutic result.

For the treatment of arrhythmia compounds of General formula I can be administered orally and intravenously in the form of standard dosage forms containing non-toxic pharmaceutically acceptable carriers.

Compounds of General formula (I) can be entered n they in doses components from 0.01 to 10 mg/kg of body weight per day, preferably at doses from 0.05 to 5 mg/kg once or more than once a day.

It should be noted that the specific dose for each particular patient will depend on many factors, including the activity of this used compound, the age, body weight, sex, General health and diet of the patient, time and route of administration of drugs, the rate of its excretion from the body, specifically used a combination of drugs and the severity of the disease in the individual being treated.

The pharmaceutical compositions of the present invention contain a compound of General formula (I) in an amount effective to achieve the desired result, and can be entered as standard medicinal forms (for example, in solid, semisolid, or liquid form), containing compounds of the present invention as an active ingredient in a mixture with a carrier or excipient suitable for intravenous and oral administration. The active ingredient can be included in a composition together with commonly used non-toxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules, tablets or any other medicines.

As fillers there may be COI is used various substances, such as sugars, for example glucose, lactose or sucrose, mannitol or sorbitol, cellulose derivatives and/or calcium phosphates, for example tricalcium phosphate or acid phosphate of calcium, as a binder component can be used such as starch paste, for example corn, wheat, rice, potato starch, gelatin, tragakant, methylcellulose, hypromellose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone. If necessary, can be used loosening agents, such as the abovementioned starches and carboximetilkrahmal, Poperechnaya polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.

Can be used optional additives, such as agents that regulate fluidity, and lubricating agents, such as silica, talc, stearic acid and its salts, such as magnesium stearate or calcium stearate and/or propylene glycol.

The additives can also be used stabilizers, thickeners, dyes and fragrances.

In the preparation of standard dosage forms, the amount of active ingredient used in combination with a carrier, may vary depending on the recipient treated, the specific method of administration of the drug.

That is, for example, when using the compounds of General formula (I) in the form of solutions for injection, the concentration of active agent is from 0.01 to 5%. As diluents can be used with 0.9% sodium chloride solution, distilled water, a solution of novocaine injection, ringer's solution, glucose solution, specific additives to dissolve. When introduced into the body of the compounds of the present invention in the form of tablets, their number is 5.0-500 mg standard dosage form.

Dosage forms of the present invention receive by standard techniques, such as, for example, the processes of mixing, granulating, the formation of drops, dissolution and lyophilization.

A detailed study of pharmacological activity of the compounds of General formula (I) presents the following examples.

Results studies

pharmacological activity of the compounds of General formula (I)

Example 1. Antiarrhythmic activity of the compounds of General formula (I) and Pikalevo salt N-succinyl-D,L-tryptophan, as well as their impact on mortality in adrenaline arrhythmia in mice

Adrenal disorders of heart rhythm played on outbred white laboratory mice of both sexes weighing 18-22 g fibrillation in Experimental animals caused by the method described in the source E.N. Moore, Spear JF. Acute animal models for the study of antiarrhythmic drugs for the prevention of sudden coronary death.// Clin. Pharmacol. Antiarrhythmic Therapy. New-York. 1984. C. 31-46.

The results of comparative testing of the claimed compounds and Pikalevo salt N-succinyl-D,L-tryptophan are shown in table 2.

Test results

Compounds of General formula (I), administered orally in doses of 0.05 and 0.5 mg/kg, had pronounced antiarrhythmic effect: hindered the development of blockages holding and episodes of ventricular tachycardia. When this substance had a number of peculiarities of the influence on mortality of experimental animals. The compound Nα-glutaryl-L-histidine (0.05 and 0.5 mg/kg), and glutamylcysteine (at a dose of 0.05 mg/kg) effectively increased the life span of experimental animals, and the connection monosodium salt of Nα-glutaryl-L-tryptophan (0.05 and 0.5 mg/kg) statistically significantly reduced the mortality of experimental animals. Low mortality in the introduction connections monosodium salt of Nα-glutaryl-L-tryptophan combined with the elimination of ventricular ectopic complexes in all experimental animals.

Thus, the strength of antiarrhythmic action of compounds of General formula (I) exceed Pikalevo salt N-succinyl-D,L-tryptophan, also entered inside. Unlike Pikalevo salt N-succinyl-D,L-tryptophan soybean is inane General formula (I) significantly increase life expectancy and reduce the incidence of fatal outcomes in the inside in the studied doses.

Example 2. The activity of compound III (Nα-glutaryl-L-histidine) and Pikalevo salt N-succinyl-D,L-tryptophan on the model of aconitine arrhythmia in mice

Fibrillation was produced according to the method of SCI Valeeva and NV Kaverina (1958) [Kaverin NV, Berdyaev HE, Kuduk H.E., Pashina O.E. guidelines for the study of the antiarrhythmic activity of new pharmacological substances. Manual on experimental (preclinical) study of new pharmacological substances. Ed. by V.P. Fisenko. - M. 2000. C. 210]. Nitrate aconitine was administered to animals at a dose of 50 mcg/kg intravenously.

This model allows to judge the breadth of therapeutic action of the present compounds and Pikalevo salt N-succinyl-D,L-tryptophan. About the breadth of therapeutic action judged largest complications index (AAI), defined as the ratio LD50the oral way of introduction to the ED50on aconitine model arrhythmias. The results of the calculations are presented in table 3.

Table 3
Effective dose, LD50, AAI for compound III (Nα-glutaryl-L-histidine) and Pikalevo salt N-succinyl-D,L-tryptophan, calculated on aconitine model arrhythmias in mice
Trial medication Route of administrationED50mg/kgLD50mg/kg (per/os mouse)AAI (LD50/ED50)
Dikalova salt N-succinyl-D,L-tryptophanper/osNo*N-
Nα-glutaryl-L-histidine (compound III)per/os0,185±0,083450024324
Note: * ED50not defined, because at doses of 0.05-5 mg/kg arrhythmias develop in 71-100% of the animals used, and the dose of 50 mg/kg 50% of the animals die after administration of the substance.

The experiment shows that the compound III (Nα-glutaryl-L-histidine) with the inside effectively prevents atrial-ventricular fibrillation induced by the intravenous injection of nitrate aconitine. The value of the ED50calculated for compound III (Nα-glutaryl-L-histidine), indicates that the compound III (Nα-glutaryl-L-histidine) has a greater breadth of therapeutic action than dikalova salt N-succinyl-D,L-tryptophan, which the testimony is t greater safety first at equivalent activity.

Example 3. Study of the effect of compound III (Nα-glutaryl-L-histidine) and Pikalevo salt N-succinyl-D,L-tryptophan on the course of early occlusal arrhythmias in cats

At the present time to assess the effectiveness of therapy in terms of transient ischemic aristogenesis used the method described Storozhuk astray freight [Protivopellargnoe activity of some antiarrhythmic drugs with the maximum high ligation of the coronary artery and reperfusion in cats. Pharmacol. and toxicol. 1985. No. 3. P.47-49].

The results of the study of compound III (Nα-glutaryl-L-histidine), Pikalevo salt N-succinyl-D,L-tryptophan and classic antiaritmikov presented in table 4.

Table 4
Antiarrhythmic activity of compound III (Nα-glutaryl-L-histidine), Comparators and Pikalevo salt N-succinyl-D,L-tryptophan on the model of occlusive arrhythmias in cats
№ p/pThe test substance or the drug dose (mg/kg)nNumber of animals with ventricular fibrillationThe time of occurrence of arrhythmia, minKilled animals in the group
Control3123 (74%)18±57 (23%)
2Propranolol (1,0)72 (28%)*24±10
3The cordarone (1,0)104 (40%)*21±60
6Dikalova salt N-succinyl-D,L-tryptophan (0,05)63 (50%)19±30
7Dikalova salt N-succinyl-D,L-tryptophan (0,5)61 (17%)*210
8Nα-glutaryl-L-histidine (compound III) (0,05)82 (25%)*18±20
9Nα-glutaryl-L-histidine (link) - Rev. III) (0,5) 61 (17%)*180
Note: * - differences from the corresponding rate in the control significant at p<0,05.

Compounds were injected intravenously in doses: compound III (Nα-glutaryl-L-histidine) and dikalova salt N-succinyl-D,L-tryptophan - 0.05 and 0.5 mg/kg, cordarone and propranolol - 1.0 mg/kg

In the control ligation of the coronary artery in cats accompanied by the development of ventricular arrhythmias in 74% of the experiments. Dikalova salt N-succinyl-D,L-tryptophan has not demonstrated reliable antiarrhythmic effect at the dose of 0.05 mg/kg, while compound III (Nα-glutaryl-L-histidine) intravenously in the dose had reliable activity. At a dose of 0.5 mg/kg compound III (Nα-glutaryl-L-histidine) and dikalova salt N-succinyl-D,L-tryptophan found similar therapeutic activity.

The data presented demonstrate that in terms of modeling acute occlusive myocardial damage in cats compound III (Nα-glutaryl-L-histidine) prophylactic intravenous injection is more effective in a wider range of doses than dikalova salt N-succinyl-D,L-tryptophan.

Compound III (Nα-glutaryl-L-is histidin) and dikalova salt N-succinyl-D,L-tryptophan prevented experimental mortality of animals on this model, the control comprised 23%.

Thus, the study of the compounds of General formula (I) on different models of oral and intravenous improves the efficiency and safety of antiarrhythmic therapy. An advantage of the claimed compounds is the large breadth of therapeutic action.

Examples of dosage forms

A. Preformed shape

Tablet form is received, using the following ingredients:

The compound corresponding to General formula (I) or its pharmaceutically acceptable salt1-150 mg
Potato starch20-50 mg
Magnesium stearate3 mg
Aerosil1 mg
Lactoseup to 300 mg

The components are mixed and pressed to form tablets weighing 300 mg each.

B. injection

An example of the composition of the solution for injection:

The compound corresponding to General formula (I) or its pharmaceutically acceptable Sol is 0.2-20 mg
Water for injection2 ml

1. The use of compounds of General formula (I)

where R1=imidazole, indole,
R2=COOH, N,
or its pharmaceutically acceptable salt as antiarrhythmic tools.

2. The use of compounds of General formula (I)

where R1=imidazole, indole,
R2=COOH, N,
or its pharmaceutically acceptable salt to obtain drugs with antiarrhythmic activity.

3. Pharmaceutical composition having antiarrhythmic activity containing a compound of General formula (I)

where R1=imidazole, indole,
R2=COOH, N,
or its pharmaceutically acceptable salt in an effective amount and a pharmaceutically acceptable carrier.

4. Drug, possess antiarrhythmic activity, containing the compound of General formula (I)

where R1=imidazole, indole,
R2=COOH, N,
or its pharmaceutically acceptable salt.

5. A method of treating arrhythmia comprising the administration to a mammal an effective amount of compounds of General formula (I)

where R1R2=COOH, N,
or its pharmaceutically acceptable salt.



 

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The invention relates to medicine, proctology, to methods of treatment of ulcerative colitis

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted 3-sulphur-indoles with formula I: or their pharmaceutically acceptable salts, or their solvates where: R1 represents NR4COR6, NHSO2R5, NHCOR6, 5-6-member heteroaryl, containing 1-2 heteroatoms, independently chosen from N, S and O; R2 represents H, C1-7alkyl; R3 represents quinolyl, phenyl, where the latter is substituted with a halogen, C1-6alkoxy, SO2R4; R4 represents C1-6alkyl; R5 and R6 independently represent C1-6alkyl, phenyl, imidazolyl, all of which can be substituted with NR14R15; R14, R15 each independently represents H, C1-C6alkyl; under the condition that, if R1 represents NHSO2R5, then R3 represents phenyl.

EFFECT: compounds can be used in making medicine for treating asthma, rhinitis or chronic obstructive pulmonary disease (COPD).

10 cl, 37 ex

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