Derivatives of 2-n-1-benzopyran-2-it, showing anticalcium activity


The invention relates to new chemical compounds of the heterocyclic series, with pronounced anticalcium activity, which may find application in medical practice in the treatment and prevention of cardiovascular diseases and represent derivatives of 2-N-1-benzopyran-2-it General formula I

where R and R1have the meanings indicated in the claims. 7 tab., 1 Il.

The invention relates to new chemical compounds of the heterocyclic series, namely derivatives of 2-N-1-benzopyran-2-it General formula I

where R=CH3, R1=-NH-(CH2)2-Br(1); R=-CH3, R1=-NH-(CH2)3-Cl (2);

R=-CH3, R1=-O-(CH2)2-VG(3); R=-CH3, R1=-O-(CH2)3-Cl (4);

R=-H, R1=-O-(CH2)2-Br(5); R=-H, R1=-O-(CH2)3-Cl (6);

R=-O-(CH2)2-VG, R1=-N (7); R=-O-(CH2)3-Cl, R1=-H (8);

R=-H, R1=-O-(CH2)2HE (9); R=-H, R1=-O-(CH2)2-SH (10);

R=-H, R1=-O-(CH2)2-NH2( 2)2HE (13);

R=H, R1=-O-(CH2)2-O-(CH2)2HE (14);

which have varying degrees anticalcium activity and can find application in medical practice in the treatment of cardiovascular diseases.

In medical practice in the treatment of cardio-sosudistyh, amlodipine and others with short and prolonged anticalcium activity (Mashkovsky M. D. Medicines. - 2000. - T. 1. - S. 413-415; Kuleshova E. C. calcium Antagonists and their role in the treatment of diseases of the cardiovascular system. - 2002. - part 1 and 2).

However, the above drugs have a high incidence of side effects, in particular phenoptin to 10%, and nifedipine 30%, manifested in the form of swelling of the legs, hypotension, changes in heart rate, etc. in Addition, in recent years, noted that the use of short acting dihydropyridines, especially nifedipine, may increase the risk of development of malignant tumors, myocardial infarction and death in patients with arterial hypertension (Kuleshova E. C. calcium Antagonists and their role in the treatment of diseases of the cardiovascular system. - 2002. - part 1 and 2; Furberg, C. D., Psaty Century. M, Meyer J. V. Circulation. - 1995. - V. 92. - P. 1326-1331; Psaty C. M., Heckbert, S. R., Koepsell T. D. et al. JAMA. - 1995. - V. 274. - P. 620-625; Pahor m, Psaty, B. M., Alderman, M. H. et al. Lancet. - 2000. - Dec. 9. - 356 (9246):1970-4). In animal experiments has also been established embryotoxicity of diltiazem and most antagonists 1,4-dihydropyridine. When long-term therapy with diltiazem, nifedipine and felodipina in the early stages beremennost and all of 1,4-dihydropyridine derivatives of the first and second generation contraindicated in any pregnancy (Svensson A. Clin. Exp. Hypertension. - 1993. - V. 15. - R. 1353-1361; Lowe, S. A., Rubin, P. C. J. Hypertension. - 1992. - V. 10. - R. 201-207).

In connection with the foregoing synthesis and study of new antagonists of calcium ions from other groups of heterocyclic compounds (not 1,4-dihydropyridine derivative) is highly relevant for practical medicine, especially for clinical cardiology.

The closest structure, physico-chemical and pharmacological properties of the claimed group of compounds is 7,7'-Ethylenedioxy-2-N-1-benzopyran-2,2'-Dion-diamancel (15), previously synthesized and patented in Russia as an anti-ischemic agent (Abishev A. H., Denisenko, p. P., Pukhov, M. P. Patent of Russia №1836086; Abishev A. H., diyachuk, I. Patent of Russia №2155036; Abishev A. H., Aghayev, E. M., Marusenko O. C. Patent of Russia №2187303).

diamancel-7,7'-Ethylenedioxy-2-N-1-benzopyran-2,2' -dione (15)

This connection is approved by the State Pharmacological Committee of Ministry of health of Russia (minutes No. 10 dated 27.06.96), and the order of the Minister of health approved for use in medical practice in the form of tablets of 0.01 g [Ankerdine (diamancel) - forte] for the treatment of coronary heart disease in adults (order No. 202, 14.07.97).

Thus, in the process of wiring ujena substance - diamancel (15) with anticalcium activity and different from calcium antagonists phenylalkylamines and 1,4-dihydropyridine ranks higher activity (30 mg/day), therapeutic breadth (25000) and low toxicity (LD50= 2500 mg/kg).

It should be noted that the representative fenilalkilaminov - phenoptin active in doses calculated 240-480 mg/day., 1,4-dihydropyridine - nifedipine - 30-60 mg/day. and benzodiazepines - diltiazem - 240-360 mg/day.

The aim of the present invention is to search for new compounds with number 2-N-1-benzopyran-2-it - analogues of diamancel with more pronounced anticalcium activity and security than the compounds used in medical practice, namely the fenilalkilaminov, 1,4-dihydropyridines and benzodiazepine.

This goal is achieved by the synthesis and study anticalcium properties not previously known compounds of a number of 2-N-1-benzopyran-2-it - analogues of diamancel (15),

To date, synthesized a large number of similar compounds, and for many of them physico-chemical and pharmacological properties. Therefore, this invention is illustrated by the following specific examples of synthesis and investigation of anticalcium activity nekotoryh>A. In a three-neck round bottom flask with a capacity of 300 ml, equipped with a mechanical stirrer, reflux with potassium chloride tube and addition funnel, was placed 150 ml of ethylene glycol (EG) or dimethylformamide (DMF), the corresponding sample 4-hydroxy-7-hydroxy-4-methyl-7-hydroxy-4-methyl-7-amino - or 4,6-dimethyl-7-amino-benzopyran-2-it, and potash. The reaction mixture is heated on an oil bath (80°C to 110°C) with constant stirring for 2 hours. After dissolution hanging compounds is added dropwise appropriate amount of 1,2-dibromoethane, 1-bromo-3-chloropropane*, 1-chloro-2-aminoethane or 1-chloro-2-mercaptoethane mixture and continue to heat with stirring for another 16 hours, then cooled to room temperature and add water. The formed crystals are filtered, washed thoroughly with water and the residue is recrystallized from various solvents. You get a private connection- 15, 16, 18, 21, 22, 24, 28, 30, physico-chemical properties of which are presented in table.1.

*Were synthesized bromo - or chloralhydrate containing in the side chain of 4 to 6 carbon atoms.

B. Uterine fluid is concentrated under vacuum and applied to a column (3&#nego with chloroform and chloroform, collecting fractions of 100 ml After concentration of fractions and recrystallization of the precipitated residues from the appropriate solvent receive connections 1-14 in individual form. Their physico-chemical indicators are also presented in table.1.

Example 2. General methods of synthesis of compounds combined 17, 19, 20, 23, 25-27,29, 31-36.

Century dvuhgolosy round bottom flask with a capacity of 250 ml, equipped with a mechanical stirrer, reflux with potassium chloride tube was placed 100 ml of DMF, the appropriate sample 4-hydroxy-7-hydroxy-4-methyl-7-amino-ethyl-, 4,6-dimethyl-7-amino - or 6-glucosyl-7-hydroxy-benzopyran-2-it, and potash. The reaction mixture is heated on an oil bath (80°C to 110°C) with constant stirring for 2 hours. After the dissolution of hanging connections add the appropriate attachment 7-(2'-bromatology)-, 4-methyl-7-(2'-bromatology) -, or 4-methyl-7-(2'-bromethalin)-benzopyran-2-she and the mixture continued to heat with stirring for another 5 hours, then cooled to room temperature and add water. The formed crystals are filtered, washed thoroughly with water and the residue is recrystallized from various solvents. Receive individual soedineniya in conditions when the interaction of the corresponding 7-(2'-acetyloxy)-, 7-(2’-sulfoxidation) -, or 7-(2'-aminoethoxy)-derived benzopyran-2-or 4-methyl-benzopyran-2-one with 7-(2'-bromatology) -, or 4-methyl-7-(2’ bromatology)-benzopyran-2-one. Their physico-chemical characteristics are presented in table.1.

Example 3. Definition anticalcium activity of the synthesized compounds.

Due to the fact that many calcium antagonists (AK) is most often used as antiarrhythmic means, in our work we used the number of arrhythmias of various origins. In particular, the primary screening of the studied groups of compounds were performed on mice using the model chloralkali arrhythmia. With the introduction of an excess of calcium chloride arrhythmia is manifested in the form of fibrillatio, utter ventricle with subsequent cardiac arrest. In this experiment, there was used a dose of calcium chloride 330 mg/kg, was administered intravenous (IV) causing 100% mortality of mice during the first 20-40 C. the Studied compounds were administered intraperitoneally for 2, 5 and 15 min before the intravenous introduction of calcium chloride. As Comparators used verapamil, diltiazem and nifedipine, while the recorded value ED50according to the test of survival of mice.

The data presented in the table.2, showing the doses were given some protection from excess calcium ions. ED50for some of the studied compounds were, for example, AK-5 less than 0.01 mg/kg, AK-3, AK-15 0.1 mg/kg, AK-13 1.0 mg/kg, AK-17 10.0 mg/kg, and others have Also been identified LD50the studied compounds, however, draws attention to the fact that most of the considered compounds were not toxic.

The mapping is shown in table.2 indicators (ED50/LD50show that the breadth of therapeutic action of many of the synthesized analogues of diamancel (15) significant and superior to that of known calcium antagonists. In addition, table.2 data also shows that on chloralkali model arrhythmia protective index number of substances (AK-6, 20, 22, 25 and others) superior to that of the famous AK - verapamil and diltiazem. The greatest activity of the actions noted in connection AK-22.

Analysis of the data shows that, regardless of their origin and method of synthesis of 4 - or 7-monosubstituted, 4,7-disubstituted or dimeric derivatives of 2-N-1-benzopyran-2-it is connected in the provisions -7,7' various alkyl or aminoalkyl radicals, has been virtually non-toxic. 5 and 7-alkyl - or alkylhalogenide 2-N-1-benzopyran-2-it and is their most effective compounds were carried out in other models of experimental arrhythmias, due to various pharmacological preparations, but in comparison, mostly with verapamil.

Thus, it was shown that the insertion of intact mice pituitrin (1 mg/kg) causes arrhythmia and conduction disturbance in 100% of cases (see tab.3). Verapamil (10 mg/kg), introduced for 30 minutes before/injection of pituitrin, did not eliminate the arrhythmia, but was controlled conduction disorders in 50% of animals, while the number of new synthesized compounds AK-26 and 34 (1 mg/kg) and verapamil, warned violations conductivity at 60% and 30% of mice, and, in addition, 35% and 20% of cases were cut short by the development of arrhythmia.

In Genesis strofantino arrhythmias are the processes of disturbance of permeability of cell membranes for ions To+and CA2+. With the introduction of strofantina at a dose of 0.06 mg/kg in 100% of mice observed arrhythmia, 80% conduction disorders and celebrated the death of 30% of the animals (see table.4). Verapamil (10 mg/kg), introduced for 30 minutes before/injection strofantina, warned the death of animals, the appearance of arrhythmias and conduction disturbance. Almost all of the investigated compounds were warned the death of animals, and had an effect similar to verapamil, but in a smaller dose.

From the data presented in table.2-4, it follows that antiarrhythmic active, the rich are the most active among them are compounds containing between two benzopyranones cycles not more than two oxymethylene groups.

Based on the above data, it can be concluded that the biological activity of the synthesized derivatives of 2-N-1-benzopyran-2-it greatly depends on the structure and arrangement of the side chains (alkyl, oxyalkylene halogenoalkane).

An important role plays also the presence in the structure of 2-N-1-benzopyran-2-she conjugate systems-CH=CH --PYRANOVA cycle, but the latter, apparently, is not the decisive factor, as unsubstituted 2-N-1-benzopyran-2-he and his 3-carboxy - 4-hydroxy-derivatives containing in their molecules the system is less active than the other studied compounds of this series.

Thus, the obtained results show that the investigated derivatives of 2-N-1-benzopyran-2-it, i.e. analogs of diamancel, its mechanism of action can be classified as new generations of antagonists of calcium ions, which later was confirmed by us using different methods.

1. The data presented in the table.5, show that the most significant inhibition include

2. Selective effect of derivatives of 2-N-1-benzopyran-2-it, in particular diamancel (AK-15) and its analogues on a pool of calcium ions in nerve Terminalia we installed using pyroantimonate a method of identifying granules of calcium. The results showed that an excess of calcium ions, resulting in nerve Terminalia under the action of convulsive agent norbornane, is eliminated by the introduction of diamancel (see drawing).

Thus, for the first time established that the studied group of compounds as antagonists of calcium ions, actively not only affect the conductivity of the potential dependent calcium channel L-type, but also show a pronounced sensitivity in relation to the channels of the N - and T-type well represented in the Central nervous system and ganglia.

3. The ability of some of the studied derivatives of 2-N-1-benzopyran-2-she (AK-15, 18, 20, 31, 33, 36 and others) to inhibit current of calcium ions across the membranes was also installed during the registration of the kinetics of calcium channels in isolated neurons of the mollusk.

When performing work of this section the object of the study were selected neurons gastropod mollusc of the great pond snail (Lymnaea stagnalis), as membrane ion is s essentially similar to those observed in neurons in other animals, including mammals. The possibility of separating the isolated nerve cells, their large size, long functioning in the experiments (up to 1.5 h), allow to study in detail the mechanisms of generation of electrical potentials and electrical phenomena at the level of the potential-dependent ion channels of excitable membranes under the action of pharmacological agents.

For measurement of transmembrane ion currents were applied method intracellular perfusion of isolated neurons and fixation of the membrane potential (MP). This method allows the complete replacement of the intracellular environment in isolated cells by dialysis through the damaged area of the surface of the membrane, to control and to arbitrarily change all concentration gradients at the membrane of the isolated cells, acting drugs in different concentrations on both sides of the membrane, as well as to measure the transmembrane ionic currents in terms of potential fixation without the use of microelectrodes.

For differentiation of ion currents applied environment with different ionic composition, and used the phenomenon of different potential dependence of ion currents. All tested compounds were added to the exterior (PE is stabilnymi their parameters, which was taken as the initial value (before the action of the substance), occurred after 3-5 min after complete replacement of the respective solutions. On the screen of the oscilloscope in the time of submitting the test pulse appeared isolated current with a characteristic phase of inactivation.

In our research it was found that all the compounds in the extracellular application reduced the amplitude of both incoming and outgoing ion currents. This effect was dose-dependent. With increasing concentrations of the studied substances was observed in a stronger inhibition of isolated transmembrane ion currents.

The results obtained are presented in table.6 and 7.

To confirm the relative electoral impact of the investigated compounds on the incoming calcium currents, we have obtained the calculated values of effective concentration 50% suppression (EC50) transmembrane ion currents.

By comparing the values of EC50showed that for 50% suppression of the calcium current is needed lowest concentrations of these substances. Based on these data, we obtained the ranks of the activity of the studied compounds in respect of each ion current.

The degree of suppression of the calcium t;AK-33>AK-18.

The same character location is observed with respect to sodium current.

The literature data (Krutetskiy H. I., lonskij A. C. Biophysics of membranes. - S. Petersburg. - 1994. - 206 S.; Kosterin S. A. Transport of calcium in smooth muscle. - Kiev. - “Naukova Dumka”. - 1990. - 216 C.) suggest that the potential-dependent channels of various types have similar molecular structure. This, in our opinion, and explains a similar trend in the effect of the studied substances, however, the calculation of the effective concentration 50% suppression demonstrates that 50% inhibition of sodium current was observed at concentrations greater than those for calcium 8.5 or more times. These data allow us to conclude that the investigated compounds exhibit more selective activity against incoming calcium current in comparison with the rest of the current (incoming sodium and facing potassium). This is not a quorum in relation to compounds of AC-18, AC-31, which have the difference EU50between calcium and sodium currents is 1.02 and 1.59, respectively.

Thus, the most probable realization of actions of the investigated compounds can be considered a direct blockade at the entrance gate of slow calcium channels, competition Uuuu normal passage through them of CA2+, nonspecific properties to stabilize the cell membrane.

Also, you cannot deny the possibility that the interaction of the investigated substances gate mechanisms channels as the reduction of ion currents is also possible due to the decrease in time of the open state of the individual channels or reduce the frequency of opening. About this may reflect the fact that changes in the kinetics of calcium transmembrane ionic current under the influence of the connection AK-20. Because the rate of activation or inactivation of ion currents is determined primarily by the degree of functional activity of the respective gate structures (activation m-gate or inactivation h-gate) ion channels, then there is the possibility of interaction of this compound directly from the portal particles of calcium channels. Under the influence of the other studied compounds, the kinetics of the studied transmembrane ion currents remained practically unchanged over the entire range of concentrations (see table.6 and 7).

Despite such a complex and ambiguous nature of the relationship between the transmembrane ion currents, however, we can conclude that the leading mechanism of action of the compounds studied is the blockades is subject to the group of calcium antagonists of the new generation.

Thus, on the basis of experimental data, we have confirmed the fact of opening a completely independent class of antagonists of calcium ions of a new generation of a number of derivatives of 2-N-1-benzopyran-2-it, actively influencing the conductivity of the potential dependent calcium channels not only L-type, widely represented in the muscles of the heart and blood vessels, but also N - and T-type most widely distributed in the Central nervous system and ganglia. It should be emphasized that the known antagonists of calcium ions phenylaniline, 1,4-dihydropyridine and benzo-diazepinones series such a broad spectrum of activity does not possess.

where R=CH3, R1=-NH-(CH2)2-Br (1);

R=-CH3, R1=-NH-(CH2)3-Cl (2);

R=-O-(CH2)2-Br, R1=-H (7);

R=-O-(CH2)3-CL, R1=-H (8);

R=-H, R1=-O-(CH2)2-SH (10);

R=-H, R1=-O-(CH2)2-NH2(11);

R=-CH3, R1=-O-(CH2)2-NH2(12);

R=-H, R1=-O-(CH2)2-O-(CH2)2-OH (14);



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