N-//1-/4-/4-pertenece/butyl/-4-piperidinyl/-n-methyl - amino/-2-benzthiazole or their pharmaceutically acceptable salts accession acid, the method of production thereof, anti-arrhythmic composition iii class and how you can get

 

(57) Abstract:

The invention relates to new derivatives of 2-benzothiazole of the formula I, where one of the substituents R1and R2the hydroxy - group, while the other denotes hydrogen, or its pharmaceutically acceptable salt accession acid. Get the connection I N-alkylation of an intermediate of compound (II), where R1and R2same as above, with a reagent of formula III, in which W - tsepliaeva group. The compounds of formula I can be used as antiarrhythmics class III. 2 S. and 6 C.p. f-crystals, 1 PL.

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-

The invention relates to new compounds, namely 2-[[1-[4-(4-pertenece) butyl] -4 - piperidinyl]methylamino]-6-benzothiazolone and-5-benzothiazolone, to their pharmaceutically acceptable salts accession acid, and their use as antiarrhythmic drugs class III.

Sudden cardiac arrest is the leading cause of death in the industrialized countries of the West. In most cases, sudden death caused by arrhythmia, often ventricular fibrillation. (The main cause of arrhythmias is arteriosclerotic change of the coronary artery, which she arrhythmias could lead to saving the lives of many people, daily exposed to arrhythmias.

Arrhythmias are disorders of speed, regularity, and also the place of origin of the cardiac impulse, in addition, it can be pathological changes in the conductivity of cardiac tissue, which changes the normal sequence of activation processes of the Atria and ventricles. Arrhythmia can be roughly divided into three different types depending on the intensity of the arrhythmia. Weak form of arrhythmia is a beats, which is only a minor deviation from a normal heart rhythm. A more severe form of arrhythmia include tachycardia, from short to relatively long, which is characterized by a significant increase in the frequency of contractions of the heart muscle. During this tachycardia the heart contracts in a coordinated manner, however, excessive heart rate interferes with the efficient filling of the Atria and/or ventricles. In this regard, the amount of blood circulating in the body, severely impaired: this leads to the development of dangerous situations. The most pronounced and, of course, the most dangerous form of arrhythmia is a Phi is of the heart muscle due to repetitive excitation of cardiac fibers. Fibrillation or atrial flutter prevents coordinated contraction of the heart and can lead, in the absence of a medical emergency, to fatal consequences.

Arrhythmia can occur as a result of anomalies either in the process of generation of the pulse, or in the process of conduction of the impulse through the cardiac tissue. Most of the existing to date antiarrhythmic drugs has an impact on changes in the pulse generation. However, in the case of arrhythmias associated with impaired conduction of the impulse, often called circular arrhythmia, still requires the development of adequate treatment (The new England Journal of Medicine, 1991, 324 (12), 781-788). Although drug therapy of cardiac arrhythmias based on an integrated approach, taking into account different groups of factors, mainly, it is believed that for prevention or treatment of the above circular arrhythmias may be those acceptable antiarrhythmic agent that increases the refractory period. Such antiarrhythmic agent, which have the ability to increase the refractory period, are, according to the classification Vaughan-Williams (Vaughan - Williams), class III antiarrhythmic drugs (I. Clin. Pharmacology, 1984, 24, 129-147).

+2, associated with arrhythmias caused by abnormalities in the pulse generation (Cardiovasculas Research, 1993, 27, 349-357).

Unexpectedly, it was found that structurally related compounds of the present invention can be used as an antiarrhythmic agent of class III. The invention relates to new compounds of the formula I

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where one of the substituents R1and R2denotes a hydroxy-group, while the other one represents a hydrogen

and their pharmaceutically acceptable salts accession acid.

The compounds of formula I have basic properties and, consequently, can be converted into a therapeutically active non-toxic salt accession acid by treatment with appropriate acids such as inorganic acids: Solana by adding organic acids, such as acetic, prapanova, glycolic acid, 2-hydroxypropanoic, 2 - oxopropanoic, afandieva, prapadyeta, batandjieva, (Z)-2-Balenciaga, (E)-2-Balenciaga, 2-hydroxybutanoic, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoate and similar acids. On the other hand, the salt form can be treated with alkali to obtain the main form.

The term "salt accession acid" used in this context, also includes solvate, representing compounds of formula I can form a solvate, as well as solvate, all of which are within the scope of the invention. Examples of such solvate includes hydrates, alcoholate, etc.,

The compounds of formula I are 2-[[1-[4-(4-pertenece)butyl] -4-piperidinyl] -methylamino]-6-benzothiazole and 2-[[1-[4-pertenece)butyl]-4-piperidinyl] -methylamino] -5-benzothiazolyl, as well as their pharmaceutically acceptable salts accession acid.

Very interesting compounds were 2-[[1-[4-(4-pertenece)butyl] -4-piperidinyl]-methylamino - 6-be the essential connection is 2-[[1-[4-(4-pertenece)butyl] -4-piperidinyl] -methylamino]- 6-benzothiazolyl (Z)-2-butenedioate (1: 1).

The procedure for preparation of compounds of the present invention of formula I quite exhaustively described in U.S. patent US-4861785. In particular, the compounds of the present invention can be obtained by means known in the art N-alkylation of the intermediate compounds of formula II in which R1and R2match the definitions given for formula I, with the use of the reagent of formula III, in which the reaction is capable tsepliaeva group, such as halogen, for example chlorine.

.

Normal frequency of contractions of the heart muscle is regulated by the impulse arising in the sinus node. Further, the impulse from the sinus node spreads through the heart tissue, leading to a coordinated contraction of the ventricles and Atria.

Circulation arrhythmia occurs when the impulse from the sinus node activates not all heart, and leaves untouched land with low reactivity, after some time, this anomalous area is also activated, whereas the remaining part of the heart already vosstanovilas, but this normal plot re-enters the pulse of the anomalous zone, causing the beats. Such areas with low reactivity is also mentioned, for treatment or prevention of a circular adults should increase the refractory period of cardiac cells. Under refractory period, see the period during which the cardiac cell is not able to respond for a passing impulse. When the impulse arising in the anomalous zone, included in the normal area of cardiac tissue in the moment when heart cells are in a state in which the incoming pulse is not applied in the scatter signal is suppressed, which prevents the development of a circular arrhythmias.

Unexpected was found that the compounds of the invention have the ability to prolong the refractory period of cardiac cells and, therefore, can be used as antiarrhythmics class III. In addition, unlike the currently available antiarrhythmic drugs class III, the compounds of the invention are less arrhythmogenic activity, in particular compounds of the invention possess a less pronounced tendency to cause utter-ventricular fibrillation". Such state of "utter-ventricular fibrillation" occur when the refractory period is unnecessarily prolonged. Moreover, the compounds of formula I, Hara is the refractory period can be determined using electrophysiological method, measuring the increase in the duration of the action potential, which can be monitored both in vitro and in vivo, as determined on the electrocardiogram by extension Q interval, which represents the time interval between receipt of the signal to the ventricles and the attenuation of the signal. In the present description of the pharmacological example indicates the ability of the compounds of formula I significantly increase the duration of the action potential.

These compounds do not affect potassium channels. In addition, they induce a pronounced prolongation of the action potential in ventricular cells and essentially no effect on the duration of the action potential of Purkinje cells.

The claimed compounds are powerful inhibitors of lipid peroxidation and scavengers of reactive forms of oxygen. It is known that lipid peroxidation is involved in the development of ischemia.

For compounds of formula I shows that they have good bioavailability and slowly metabolized, which results in an increase in the length of their actions. In addition, the compounds of the invention practically does not cause Central effectsa as a means of dealing with the atrial and ventricular arrhythmias or fibrillyatsy.

On the basis of their pharmacological properties, the compounds of formula I can be used as drugs for the treatment of people suffering from arrhythmia, especially the circular arrhythmia. Mentioned use as a drug, i.e., the claimed method of treatment comprises the administration to a patient with arrhythmia, in particular with a circular fibrillation, a therapeutically effective amount of compounds of formula I.

The described compounds can be prepared in the form of various pharmaceutical forms for administration. Mentioned pharmaceutical forms are also new and therefore represent another aspect of the invention. As suitable compounds can lead to all songs, usually used for making drugs systemic or local action. To prepare the pharmaceutical compositions of the invention are combined in the form of a substantially homogeneous mixture of an effective amount of the compounds according to the invention may be in the form of salt accession acid with a pharmaceutically acceptable carrier, these media can be used in a wide range of forms depending on the form of predpochtitel unit dosage forms, suitable in particular for oral, rectal or subcutaneous administration, and for parenteral injection. In particular, in the manufacture of oral dosage compositions can be used in conventional pharmaceutical environment, namely, in the case of oral liquid forms, such as suspensions, syrups, elexir and solutions, such as water, glycols, oils, alcohols, etc. and, in the case of the preparation of powders, pills, capsules and tablets - solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja tools, etc. due To ease of administration, tablets and capsules represent the most convenient oral dosage form, for the manufacture of which, seems obvious, use solid pharmaceutical carrier. In the case of the preparation of compositions intended for parenteral administration used the media usually includes sterile water, at least for the most part, though other ingredients, such, in particular, that improve the solubility may also be acceptable. So, can be prepared injectable forms, which contain as filler salt solution, a glucose solution of iaenii, including as a suitable liquid carrier suspendresume agents and related tools. In a series of the described compositions are also solid form, which are made so that immediately before their application can be translated into liquid form.

In the compositions suitable for percutaneous administration, the filler may optionally include a means to enhance penetration, and/or a suitable wetting agent which can be mixed with acceptable additives of any nature in minor proportions, so that these additives could not have a significant harmful impact on the skin. Suitable compositions for the local way of introduction can be marked all the songs that are commonly used for the manufacture of preparations for local application, i.e., creams, dressings, pastes, various types of ointments, powders, etc.

Turned out to be particularly convenient to prepare the above-mentioned pharmaceutical compositions in the form of dosage units, which favorably distinguishes them from the point of view of ease of injection and normirovannoi dosages. Forms, including dosage units, in the context of the present description refers to physically discrete units suitable for the e amount of the active ingredient, which, as calculated, are able to exert the desired therapeutic effect in combination with a suitable for the case of pharmaceutical filler. Examples of such dosage unit forms include tablets (including scored tablets or coated), capsules, pills, sachets of powder, waffle form, injectable solutions or suspensions, etc., and parts thereof.

Every average person in the treatment of arrhythmias can easily determine the effective use daily amounts on the basis of the results presented here test. In General, it is assumed that the value of the effective daily dose ranges from 0.01 to 20 mg/kg body weight, more preferably from 0.1 to 10 mg/kg of body weight. It may be also acceptable to specify the required dose in two, three, four or more doses a day at appropriate intervals between such curiosly. Mentioned subdata can be prepared as unit dosage forms containing, for example, 1 to 1000 mg, and mostly 5 to 200 mg of active ingredient per unit dosage form.

More exact dosage and frequency of injection are determined by the particular use of a compound of formula I, osobennostyu patients, and other factors, things to consider when treatment and which are well known to every person skilled in the art. In addition, it is obvious that the said effective daily amounts may be reduced or increased depending on patient response to treatment and/or evaluation of the selected physician for specific drug therapy of the present invention. The effective daily dosage varies within the above range, so its value can be considered as a rough indication, but in no way from the point of view of limiting the scope or method of application of the present invention.

Experimental part

A. obtain the final compounds

Example 1. A mixture of 4.04 g of 1-(4-chloroethoxy)-4-fervently, to 5.58 g of 2-[methyl-(4-piperidinyl) amino] -5-benzothiazole, 2,12 g of sodium carbonate and 40 ml of N, N-dimethylacetamide is stirred at 60oC for 17 hours After cooling to room temperature the reaction mixture is diluted with 120 ml of water. The mixture is extracted twice with methylbenzol. The combined extracts dried, filtered and evaporated. The residue is cleaned with the use of column chromatography (silica gel; CHCl3CH3OH 96:4). The eluate, soderjashie room temperature, the salt is filtered off (the filtrate is removed), washed with 2-propanol and dried under vacuum overnight at 40oC, and then for 2.5 h under vacuum at 60othat leads to receiving the first fraction of 7.8 parts (71,4%) of product. Evaporation of the filtrate results in additional 2.2 parts (20,1) of product, total yield: 10 parts(91,5%) 2-[[1-[4-(4-pertenece)butyl]-4 - piperidinyl] methylamine]-5-benzothiazolone (Z)-2-butenedioate (1:1); so pl. 187,8oC (Conn. 1).

Example 2. A mixture of 3.05 g of 1-(4-chloroethoxy)-4-fervently, 4,19 g 2-[methyl-(piperidinyl)amino] -6-benzothiazole, 1.6 g of sodium carbonate, 30 ml of N, N-dimethylacetamide is stirred for 20 h in an oil bath at 60oC. After cooling, add 120 ml of water and twice extracted with a mixture of methylbenzol. The United extracts washed with water and NaCl solution, dried, filtered and evaporated. The residue is subjected to cleaning with the use of chromatography on a column (silica gel; CHCl3/CH3OH 96:4). The eluate containing the pure fractions are evaporated and the resulting residue is converted into the salt of (Z)-2-butenedioate in 2-propanol. The salt is filtered off (the filtrate is removed and dried, thus obtaining a fraction of 4.6 parts (45,1%) of product; so pl. to 107.7oC. the Eluate containing me (the filtrate is removed and dried, receiving a second fraction of 2.3 parts (22,5%) of product; so pl. 108,4oC. the combined filtrates are evaporated and the resulting residue is stirred in trichlormethane. The mixture is treated with a solution of NaHCO3at pH 7.5 - 8. After stirring the separated organic layer is dried, filtered and evaporated. The residue is converted into the salt of (Z)-2-butenedioate in 2-propanol. The salt is filtered off and dried, obtaining a third faction in 1.26 parts (12,3%) of product; so pl. USD 114.9oC. Total yield: 8,16 parts(79,9%) 2-[[1-/4-(4-pertenece)-butyl] -4-piperidinyl]methylamino]-6 - benzothiazole (Z)-2-butenedioate (1:2) monohydrate (Conn. 2).

In a similar way we obtain 2-[[1-[4-pertenece)butyl]- 4-piperidinyl]methylamino]-6-benzothiazolyl (Z)-2-butenedioate (1:2); so pl. 107,8oC (Conn. 3).

Example 3. A mixture of 2-(methyl-4-piperidinylidene)-6-benzothiazolyl of dihydrobromide (0,056 mol) and sodium carbonate (0,142 mol) in N,N-dimethylacetamide (500 ml) is stirred for 1 h at 60oC. Add a solution of 1-(4-chloroethoxy)-4-fervently (0.061 mol) in N,N-dimethylacetamide (15 ml), after which the reaction mixture is stirred over night at 60oC. the Cooled reaction mixture is poured into ice water. Then this mixture is extracted with toluene. Selected cromatografierea on a column of silica gel (eluent: CH1Cl2/CH3OH 97/3). Collect pure fractions of them and evaporated the solvent. The residue is converted into the salt of (Z)-2-butenedioic acid (1:1) in 2-propanol. The precipitate is filtered off and dried, obtaining 18 g(58,9%) 2-[[1-[4-(4-pertenece)butyl]-4-piperidinyl]methylamino]-6 - benzothiazole (Z)-2-butenedioate (1:1); so pl. 180,7oC (Conn. 4).

B. Pharmacological examples

Example 4. The testing procedure used in this example, described in the literature (Archives of Pharmacology, 1985, 329, 316 - 325).

Guinea pigs of both sexes weighing 250 - 500 g stun and bleed. Then quickly cut them to the heart and cut the papillary muscles. Drugs are placed in the chamber for tissue volume of 2.5 ml and store them in Tired-solvent (Tyrode-solution) at the 35oC. Internal circulation support due to the constant passing a gaseous mixture consisting of 95% O2and 5% CO2. Drugs are subjected to electrical stimulation by means of two platinum electrodes placed close to the base of muscles, with a frequency of 1 Hz (pulse duration 1 MS). Transmembrane potentials measured in conventional glass microelectrodes filled with 3 mol/l KCl. In a bath containing the body, as indiff the amplifier, having capacitance with a compensating value and a high impedance at the input to the screen standing next to the oscilloscope.

After a period of equilibration, 90 min, the perfusion solution in the bath is replaced by a solution containing the analyzed compound. Biological samples for 45 min, incubated with a solution containing the analyzed connection (active concentrations shown in the table). The action potential measured at 20%, 50% and 90% repolarization (APD20, APD50, APD90). Repolarization is a process in which cells, reaching maximum values are returned to the membrane resting potential.

Example 5. The testing procedure used in this example, described in the literature (Journal of Cardiovascular Pharmacology, 1992, p. 682).

In a series of studies with shot the dogs, which before the experiment with the target compound was induced myocardial infarction by blockage of the main coronary arteries, the connection 4 when administered intravenously at doses of 0.32 mg/kg and of 0.48 mg/kg, reduced 4 out of 5 animals the frequency of occurrence during programmed electrical stimulation of the heart of sustainable tajika(16% after intravenous dose of 0.32 mg/kg) with a relatively small increase in QTc-interval (+4% after a dose of 0.32 mg/kg).

Example 6. Nine dogs was induced by chronic blockade of the atrioventricular node, and then in the area of the epicardium at the apex of the left ventricle and at the base of the right ventricle were placed electrodes. After 14 to 80 days the dog under anesthesia were again subjected to treatment involving the induction of bradycardia (called the siege atrioventricular node), the procedure of programmed electrical stimulation (8 regular pulses combined in the group with short-long-short intervals) and the presence of the tested compound. Registered as a monophasic action potential in the left and right ventricles, and the ECG. Arrhythmia type "Torsade de pointes ventricular" is defined as ventricular tachycardia characterized by a frequency of 5 punches that ends spontaneously or requires electro-therapy and which can be induced with a frequency of 3 times using the same Protocol. Under the same conditions, the point of utter-ventricular fibrillation is not detected in the presence of compounds 4, the input/doses of 0.32 mg/kg and of 0.48 mg/kg Only when the dose is increased ( 0,63 mg/kg, in/in) in 33% of the studied dogs can be induced arit is available at the present time, the means of class III.

B. Examples of songs

"Active ingredient" (A. I. ), which is used in all the examples, refers to the compound of formula (1) or its pharmaceutically acceptable salt add acid, or their stereoisomers.

Example 7. Oral drops.

500 g of A. I. dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60 - 80oC. After cooling to a temperature of about 30 - 40oC in the reaction mixture was added 35 l of polyethylene glycol and its well mixed. Then add a solution of 1750 g of sodium saccharin in 2.5 l of purified water, while in the process of mixing add 2.5 l of cocoa as corrigenda and q glycol.S. to a final volume of 50 l, which gives the solution used oral drops, containing 10 mg/ml A. I., the resulting solution fill the appropriate containers.

Example 8. Oral solution.

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution dissolve 10 g of 2,3 - dihydroxybutanedioate acid and then 20 g of A. I. the Last of these solutions combine with the remaining part of the original solution and add a mixture of 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of tarbiyaviy. The latter solution is combined with the first, add q water. S. up to a final volume of 20 l, which gives an oral solution comprising 5 mg of active ingredient applied to a teaspoon (5 ml). The resulting solution is poured into suitable containers.

Example 9. The capsule.

Well mix 20 g A. I., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate. After that, the obtained mixture is introduced into 1000 suitable for this purpose, hard gelatin capsules, each containing 20 mg of active ingredient.

Example 10. The tablets are film-coated.

A mixture of 100 g A. I., 500 g of lactose and 200 g starch is mixed well and thereafter humidified with a solution containing 5 g sodium dodecyl sulfate and 100 g of polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried and again sieved. Then add 100 g microcrystalline cellulose and 15 g of recovered vegetable oil. After that, mix well all the weight and is pressed into tablets with the receipt of a 10,000 tablets each containing 10 mg of active ingredient.

Coating

Example 11. The solution for injection.

1.8 g of methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate dissolved in about 0.5 l of boiling water intended for injection. After cooling to approximately the 50oC added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of A. I. Then the solution is cooled to room temperature and injected into the water for injection q.S. to a final volume of 1 l, giving a solution containing 4 mg/ml A. I. the Solution is sterilized by filtration (U.S. Pharmacopoeia (U. S. P.) XVII, S. 811) and fill them sterile containers.

Example 12. Suppositories.

3 g A. I. dissolved in a solution containing 3 g of 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol 400. Podvergautsya type q.S. to the final mass of 300 g of the resulting mixture is combined with the first solution. Thus prepared mixture is poured into molds at 37 - 38oC that gives 100 suppositories each containing 30 mg/ml A. I.

Example 13. The solution for injection.

60 g A. I. and 12 g of benzyl alcohol mix well and add sesame oil q.S. to a final volume of 1 l, which yields a solution containing 60 mg/ml A. I. the Solution is sterilized and injected into sterile containers.

1. N-//1-/4-/4-pertenece/butyl/-4-piperidinyl/-N-methylamino/- 2-benzthiazole having the formula I

< / BR>
where one of the substituents R1and R2represents a hydroxy-group, while the other denotes hydrogen,

or its pharmaceutically acceptable salt accession acid.

2. Connection on p. 1, which is a 2-//1-/4-(4-pertenece)butyl/-4-piperidinyl/methylamine/-5-benzthiazole or its pharmaceutically acceptable salt accession acid.

3. Connection on p. 1, which is a 2-//1-/4-(4-pertenece)butyl/-4-piperidinyl/methylamine/-6-benzthiazole or its pharmaceutically acceptable salt of the added acid.

4. Connection on p. 1, 1 : 1).

5. Antiarrhythmic composition III class, including pharmaceutically acceptable excipient and, as active ingredient a therapeutically effective amount of a compound according to any one of paragraphs.1 to 4.

6. The method of obtaining anti-arrhythmic composition class III under item 5, characterized in that it comprises thoroughly mixing a therapeutically effective amount of compound on the PP.1 - 4 with a pharmaceutically acceptable filler.

7. The compound according to any one of paragraphs.1 - 4, designed for use as antiarrhythmic drugs class III.

8. The method of obtaining N-//1-/4-/4-pertenece/butyl/-4-piperidinyl/-N-methylamino/2 benzthiazole under item 1, characterized in that the implement N-alkylation of the intermediate compounds of formula II, in the case when one of the two substituents R1and R2represents a hydroxy-group, and the other is hydrogen with a reagent of formula III, in which W denotes tsepliaeva reactionary group

< / BR>
and if necessary, converting the compounds of formula I in a therapeutically active non-toxic salt accession acid, or conversely, converting the said compound in the form of salt accession acid free basis is

 

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FIELD: organic chemistry, biochemistry.

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EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

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