Programalso isomer of 6-(5-chloro-2-pyridyl)-(4-methyl-1 - piperazinil)-5-carbonyloxy-7-oxo-6,7-dihydro-5h-pyrrolo- (3,4-b)pyrazine and its pharmaceutically acceptable acid additive salt, method of production thereof and pharmaceutical composition based on them


(57) Abstract:

Programalso isomer of 6-(5-chloro-2-pyridyl)-(4-methyl-1-piperazinil)-5-carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin and its pharmaceutically acceptable acid additive salt, possessing anxiolytic, hypnotic and anticonvulsive activity, which allows their use in medicine and pharmacy, is produced by cleavage of the corresponding racemate using D(+)-0,0'-dibenzoyltartaric acid in an organic solvent. The pharmaceutical composition contains an active product that is listed above in an effective amount and a pharmaceutically acceptable additive. 3 S. p. f-crystals, 1 table.

The invention relates to optically active derivative 5H-pyrrolo-[3,4-b] pyrazine and its pharmaceutically acceptable acid salt additive, the way they are received and farbkomposition based on them.

Known derived 5H-pyrrolo-[3,4-b] pyrazine, in particular 6-(5-chloro-2-pyridyl)-(4-methyl-1-piperazinil)-5-carbonyloxy-7-oxo - 6,7-dihydro-5H-pyrrole[3,4-b]pyrazin known as zopiclone and featured as a hypnotic agent [1].

In connection with the presence of one asymmetric carbon atom in position -5 cycle 5H-pyrrol[3,4-b]p isomers.

It was found that programalso isomer of zopiclone exhibits unexpected properties not derived from properties of racemic zopiclone.

Therefore, an object of the invention is programalso isomer of zopiclone, method thereof and pharmaceutical composition based on it.

It is known that racemic product often active one of the two enantiomers, and this activity may be due to the increased toxicity, while the other enantiomer is less active or even inactive and less toxic. For such products increased activity does not compensate for the disadvantages of increased toxicity.

In the case of zopiclone unexpectedly discovered that programalso isomer not only more active about 2 times than the racemate, but less toxic than the toxicity of the racemate, and that levogyrate isomer at the same time practically inactive, but more toxic than the racemate.

For example, in experiments on mice with oral use of zopiclone toxicity manifests (DL50), close to 850 mg/kg, whereas programalso isomer toxicity has close to 1.5 g/kg, and levogyrate isomer shows the value of DL50agreement between 300 and 900 m is tranquilizing and anticonvulsive.

As for strength, the main tests for anxiolytic and sedative actions zopiclone, such as a test of the affinity to the Central benzodiazepine receptors according to the method of J. C. Blanchard and L. Julon J. of Npurochemistry 40, 601, (1983), developed on the basis of works Sguires and Braestrug, Nature, 266, 732 - 734 (1977), test for antagonistic activity against seizures induced by pentetrazole, according to the methodology Everett and Bixhards, J. Pharmacol 81, 402, (1944) or the test reflex rolling the mouse according to the method Zbinden and Randall, Advances in Pharmacol, 5, 213 - 291, (1967), showed that programalso isomer approximately 2-fold more active, whereas levogyrate isomer practically inactive.

According to the invention programalso isomer of zopiclone may be obtained from the corresponding racemate with conventional methods such as chromatography chiral phase splitting optically active salt or stereoselective enzymatic catalysis using a suitable microorganism or asymmetric synthesis.

More specifically, programalso isomer of zopiclone may be obtained by splitting zopiclone with optically active acids, acting in a suitable organic solvent.

As a researcher who GTC.

Usually work in an organic solvent, selected from among aliphatic halogenated hydrocarbons such as dichloromethane and NITRILES, such as acetonitrile, taken alone or in mixtures.

By doing so, salt programalso isomer precipitates and levogyrate isomer is extracted from the mother of crystallization solutions.

Programalso isomer of zopiclone is released from its salt by a base such as sodium hydroxide.

Programalso isomer of zopiclone may be used to treat conditions associated with dysfunction of the Central nervous system.

Programalso isomer of zopiclone is used, for example, as a sedative, tranquilizing and anticonvulsive tool.

However programalso isomer of zopiclone more useful for humans as a hypnotic.

Programalso isomer of zopiclone, acting on various parameters of sleep, increases its duration, and improves quality, reduces the number of night and early awakenings.

The invention relates to pharmaceutical compositions containing programalso isomer of zopiclone or one of its salts is s can be used orally, rectal or parenteral.

As pharmaceutically acceptable salts can be called salts of mineral acids, such as chlorhidrate, sulfates, nitrates, phosphates, or organic, such as acetates, propionate, succinate, benzoate, fumarate, tartratami, theophyllinate, salicylate, phenolphthalein, methylene-bis-beta-xinafoate), or substituted derivatives of these acids.

Solid compositions for oral administration can be produced in the form of tablets, pills, powders and granules.

In these compositions, the active product according to the invention is mixed with one or more diluents such as sucrose, lactose or starch. These compositions may also include other substances other than diluents, for example, binders, such as magnesium stearate.

Liquid compositions for oral administration can be produced in the form of emulsions, solutions, suspensions, syrups and elixirs containing inert diluents, such as water or hydrocarbon oil. These compositions can also comprise substances other than diluents, for example wetting, sweetening and flavouring.

Compositions for parenteral administration can preview the media can be used propylene glycol, the polyethylene glycol, vegetable oils, in particular olive oil, and organic esters, for example ethyl oleate. These compositions can contain auxiliary funds, in particular wetting agents, emulsifying agents and dispersing agents. Sterilization can be done in different ways, for example using a bacteriological filter, by the introduction of the sterilizing additives, by irradiation or heating. They can be prepared in the form of sterile compositions which can be dissolved at the time of admission in sterile water or other sterile spray environment.

Compositions for rectal prepared in the form of suppositories which may contain, in addition to the active product, excipients such as cocoa butter.

When treating people the doses depend on the desired effect and the duration of treatment, they are usually 2.5 to 15 mg per day orally for an adult.

The following examples, which may not be limited to, illustrate the invention.

Example 1. To a solution of 22,56 g D (+)-0,0'-dibenzoyltartaric acid in the form of a monohydrate (0.06 mol) in 300 cm3add a solution of dichloromethane zopiclone 23,28 g (0,06 mo is ocistnou salt is recrystallized in 2000 cm3acetonitrile, the result of 21.3 g of crystalline product with a yield of 46% and a melting point of 160-165oC (decomposition), torque capacity is equal to []2D0=83]2D0=102]2D0=135 3(c = 1.0, acetone).

Royal solutions from crystallization of salt of zopiclone with D(+)-0,0'-dibenzoyltartaric acid concentrated to dryness under reduced pressure and get 22,05 g of salt, torque capacity which is equal to []2D0=-21]2D0=138 3(c = 1.0, acetone).

Example 2. The usual method to prepare tablets with a dose of 3 g of active product having the following composition, g:

Programalso isomer of zopiclone - 0.003

Starch - 0,100

Precipitated silica - 0,035

Magnesium stearate - 0,005

Description of tests.

1. Oral toxicity in mice.

In this test determines the maximum dose of a compound that when administered orally to mice causes death in 50% of mice. Explore from 2 to 4 doses, using 5 mice for each dosage.

2. Affinity to the Central benzodiazepine receptor sites.

This method is based is provided the compounds of the specific fixation of the ligand with the benzodiazepine receptors, namely titrovannam by flunitrazepam. If the investigational compound has affinity to benzodiazepine sites of receptor-specific fixation of the ligand decreases. The experiment is carried out as follows.

The homogenate was washed all of the cerebral cortex of male rats (CD, COBS, Charles River, France) mixed with Tris-HCl buffer (50 mm) at pH of 7.4, so that the final concentration of protein in the mixture was 0.1 mg per 1 cm3. Add the studied compound in different concentrations and tretirovanie flunitrazepam (to a final concentration of 1.5 nm). In the presence of diazepam (10 μm) determine nonspecific fixation. After 120 min incubation at 0oC filter each sample through a glass fiber filter (filter Whatman GF/B) and a liquid scintillation counter to determine the level of radioactivity, detained on the filter. Thus, define IR50, i.e. the concentration of tested compound that inhibits 50 % of specific fixation of the ligand.

3. Antagonistic activity against seizures induced in mice by pentetrazole.

The method used is based on data from the work of Everett city hall (Everett and Richards, J. Pharmacol., 1944, 81, 402). Males or cavasola in cells divided into 15 compartments to 13 cm3each, and cover them by a transparent layer of rhodoid. Mice observed within 30 minutes it is Considered that the mouse was able to prevent the occurrence of seizures, if within the specified period (30 min) is not observed occurrence of seizures (tonic or clinical). Pentetrazol injected at a dose of 150 mg/kg 25 cm3saline solution. The investigated compound is administered orally for 45 min before observation. For studies of the effects of each dose using 5 mice. Next, calculate the ED50the compounds, which is the dose that, exerting the greatest effect, suppresses seizures caused by pentetrazole 50% of the investigated animals.

4. Activity in mice in the test on the rectifier reflex.

The principle of the method consists in studying the effect of compounds on natural rectifier reflex. Use of male or female mice CD1, COBS, Charles River, France) weighing 18 - 24 g each. Media (control) or investigational compound administered orally (150 cm3/kg) at the moment "t" before the beginning of the observation period; for each of the investigated dose used in 5 animals. Each animal is carefully laid on his back, Scheie 20 C. Compute the value of the ED50, i.e., the dose of a compound that causes loss rectifier reflex in 50% of test mice.

The research results presented in the table.

1. Programalso isomer of 6-(5-chloro-2-pyridyl)-(4-methyl-1 - piperazinil)-5-carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo-[3,4-b] pyrazine and its pharmaceutically acceptable kislotalimonnaya salt.

2. A method of obtaining a clockwise rotating isomer under item 1, characterized in that racemic 6-(5-chloro-2-pyridyl)-(4-methyl-1-piperazinil)-5 - carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo-(3,4-b)piperazine split with D(+)- 0,0'-dibenzoyltartaric acid in the organic solution, secrete salt programalso isomer and is separated from its salts programalso isomer of 6-(5-chloro-2-pyridyl)-(4 - methyl-1-piperazinil) -5-carbonyloxy-7-oxo-6,7-dihydro-5H - pyrrolo-(3,4-b)pyrazine, which is then optionally transferred to pharmaceutically acceptable acid additive salt.

3. Pharmaceutical composition having anxiolytic activity, hypnotic and anticonvulsive containing the active product and pharmaceutically acceptable additives, characterized in that it contains as an act


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eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex