Crystalline form of eszopiclone, its composition, preparation and application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses crystalline form of S-zopicone with spectrum of powder X-ray diffraction with application of Cu-Ka radiation, with characteristic peaks, expressed under conditions 20 approximately at 11.08°, approximately 12.38°, approximately 15.86°, approximately 17.88°, approximately 19.98°C and approximately 20.58°, DSC-thermogram, on which peak is observed approximately at 207.7°C, and infrared spectrum of absorption (IR) with characteristic peaks approximately at 3078 cm-1, approximately 2942-2838 cm-1, approximately 2790 cm-1, approximately 1716 cm-1, approximately 1463 cm-1, approximately 1372 cm-1 and approximately 757 cm-1.

EFFECT: claimed are: method of preparation of crystalline form of eszopiclone, pharmaceutical preparation and its application in manufacturing medication for treatment of sleep disorder.

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TECHNICAL FIELD of INVENTION

The present invention relates to the field of medicine, in particular to crystalline forms of eszopiclone and their composition, process of preparation and medicinal application.

BACKGROUND of INVENTION

Zopiclone, a drug used to treat sleep disorders, has been developed by the company RHONE-PONLENC RORER PHARMACEUTICAL COMPANY LTD, FRANCE, in the mid 80-ies of the last century and put into mass production in more than 80 countries, as, for example, in Europe, under the trade name of IMOVANE (IMOVANE®). Sales of the drug reached 160 million US dollars in 1999, the drug has been used in China for about 10 years. Currently, there are many manufacturers of this drug, including Shanghai Huashi Pharmaceutical Co., Ltd., Qilu Pharmaceutical Co., Ltd., and Guangdong Shunfeng Pharmaceutical Co., Ltd. Formula zopiclone presented below:

S-zopiclone (eszopiclone) - one chiral programalso monomer zopiclone chemical name: (+)-(3)-(4-methylpiperazin-1-carboxylate)(6-(5-chloropyridin-2-yl)-7-carbonyl-6,7-dihydro-5-N-pyrrolo[3,4-b]pyrazin-5-yl ether). Since 1998, the drug was developed by company Sepracor Inc., and in October 2004 was approved by the Management under the control over quality of food and drugs on the I sale on the market. However, the racemic zopiclone there are a number of severe side effects, including a bitter taste in the mouth, caused by release of the drug in the saliva, dry mouth, drowsiness, and morning fatigue, headache, dizziness and impaired neuromotor functions. Compared to the racemic zopiclone S-isomer has a number of advantages and fewer side effects. As shown by pharmacodynamic studies, programalso enantiomer of zopiclone significantly contributes to its short term hypnotic effect, thus providing a better effect than racemic zopiclone. Meanwhile, it was shown that S-zopiclone has a much lower toxicity than the racemic zopiclone, as shown by a comparative study of acute toxicity. In contrast to racemic zopiclone S-isomer may have anticraving effect without affecting athletic coordination. It was noted that sopilko is stereoselective with respect to the benzodiazepine receptor, while the S-isomer has the ability to bind to the benzodiazepine receptor is approximately 50 times higher than the R-isomer.

It is known that such a connection, as, for example, the drug can exist in different crystalline forms, which is called polymorphism. In General, different crystal which forms of the same drug may have different physical properties and chemical resistance. It is very important in the production of pharmaceutical preparations to use the medicine as a bioactive component of the crystalline forms, which not only exerts its therapeutic effect, but also effectively reduces its toxicity and side effects. To this day among the data published preparative methods and applications of the composition of S-zopiclone was not provided descriptions of his particular crystalline form.

The ESSENCE of the INVENTION

The aim of the present invention is the provision of stable crystalline form of S-zopiclone.

Another objective of the present invention is the provision of a method of preparation of crystalline form of S-zopiclone.

Another objective of the present invention is the provision of a composition which is a crystalline form of S-zopiclone.

Another objective of the present invention is the provision of medical use of crystalline form of S-zopiclone.

According to one aspect of the present invention, presents the crystalline form of S-zopiclone identified range of powder x-ray diffraction, differential scanning calorimetry (DSC) and infrared absorption spectrum (IR), clearly shown on the relevant drawings. The relevant data are presented following the way:

The peak of the DSC thermograms is visible when 207,7°C.

Range of powder x-ray diffraction of the drug had characteristic peaks, expressed in terms of 2θ at the average values (θ reflection angle) approximately 11,08°, approximately 12,38°, approximately 15,86°, approximately 17,88°, approximately 19,98° and approximately 20,58°.

Its infrared absorption spectrum (IR) had characteristic peaks at approximately 3078 cm-1approximately 2942-2838 cm-1approximately 2790 cm-1approximately 1716 cm-1approximately 1463 cm-1approximately 1372 cm-1and approximately 757 cm-1preferably at approximately 3078 cm-1approximately 2942-2838 cm-1approximately 2790 cm-1approximately 1716 cm-1approximately 1577-1545 cm-1approximately 1463 cm-1approximately 1372 cm-1approximately 1007 cm-1approximately 849 cm-1and approximately 757 cm-1.

The crystalline form of S-zopiclone of the present invention is characterized by what is generally accepted as the spectrum of x-ray diffraction, differential scanning calorimetry (DSC) and infrared absorption spectrum (IR).

In General, the spectrum of the powder x-ray diffraction obtained from crystalline compounds is a characteristic d is I given crystal form, expressed in terms of 2θ, using Cu-Ka radiation.

DSK known to the skilled in the art, is used to measure the temperature of thermoperiod in the absorption and releasing of heat due to the change of crystal structure and melting of crystalline solids. Constant analysis showed that the difference between the temperature of thermoperiod and the melting point is typically in the range of about ±2°C, usually within about ±1°C. Therefore, the composition with specific DSC peak or melting point means that the difference between the DSC peak and the melting temperature is within ±2°C, which is considered an alternative method of determining the various crystalline form of S-zopiclone. Thus, a preliminary determination of the various crystalline forms of compounds can be carried out based on (at least partially) characterized by different transition temperature.

Infrared absorption spectrum (IR) is used to measure the absorption of infrared light caused by specific chemical bonds that relate to the infrared vibrational spectra of the molecules.

And DSC, and IR can provide us with information on the physico-chemical properties of the crystalline form of S-zopiclone.

preparation of S-zopiclone, which is used as the raw material for the manufacture of crystalline form of S-zopiclone according to the present invention, is as follows:

To connect racemic zopiclone and D-(+)-malic acid with a mixture of methanol and acetone to dissolve by stirring at a temperature of 20-30°C, cooled to 0-10°C. maintain this temperature for approximately onset 6 to 48 hours, continuing to mix, filter, washed with methanol and dried to obtain D-(+)-malic acid S-zopiclone. Next, the above obtained D-(+)-malic acid S-zopiclone is dissolved by water. The value of pH is 6-9, then the solution is extracted with ethyl acetate, dried, concentrated and filtered to obtain a filter cake. The filter cake is washed and dried to obtain S-zopiclone as raw materials.

Skilled in the art, it is difficult to predict whether they will be able crystalline form of this compound, which is closely connected with the conditions of its preparation. Process for the purification of S-zopiclone using ethyl acetate as solvent has several advantages: lower toxicity, easier handling, reduced costs and better results. Therefore, the inventors sufficiently explored different conditions of crystallization using ethyl acetate as solvent.

In accordance with one aspect of the present invention, a method of crystallization of S-zopiclone, the cat is which consists of the following steps:

(a). Dissolve S-zopiclone ethyl acetate temperature from 60°C to the reflux temperature. Used 10-80 ml of ethyl acetate per 1 g of S-zopiclone, preferably 25-50 ml of ethyl acetate, 1 g of S-zopiclone;

(b). Let the mixture cool at room temperature up to 30-50°C., preferably 35-45°C.; maintaining the temperature for 10 min to 12 hours, preferably 1-6 hours;

(c). Constantly be cooled to 10 - -10°C, preferably 5 - -5°C to maintain the temperature for 10 min to 12 hours, after 1-6 hours; and

(d). To separate a crystalline structure.

However, this method of crystallization can be performed using the device for mixing or without, preferably with a device for mixing.

In accordance with another aspect of the present invention, obtained the drug with a therapeutically effective amount of crystalline form of S-zopiclone according to this invention and a pharmaceutically acceptable carrier. Additionally, the drug forms a complex tool together with other active ingredients.

In accordance with another aspect of the present invention, a medical drug in this invention is formed in pharmaceutical drug single dose. Also pharmaceutical drug single dose of oznacza the t form dosage, for example, each tablet in tablet form, each capsule in capsule form, each bottle with liquids for oral administration and each bag with the pellets, etc.

In accordance with another aspect of the present invention, the drug may contain 0.1 to about 99.9 weight % of the crystalline form of S-zopiclone of the present invention along with a pharmaceutically acceptable carrier. Preferably, the weight percent of the crystalline form of S-sopelana of the present invention in the preparation is about 0.1-20 weight %, most preferably 1-10 weight %.

In General, the crystalline form of S-zopiclone of the present invention and a pharmaceutically acceptable carrier can be used to generate a medical preparation according to this invention by standard pharmaceutical technology, for example, by means of conventional mixing, granulating and tableting. Specialists in this field it is well known that the types and characteristics pharmaceutically acceptable carrier depends on the amount of active ingredient is mixed with a carrier, the chosen route of administration and other well-known factors. Specified pharmaceutically acceptable carrier according to the present invention includes various types of organic and inorganic N. the bearers, which can be administered in combination with a drug, for example, the media used for solid preparations, such as excipients, lubricants, binding components, razryhrytelya and covering substances can also be used pharmaceutically acceptable additives such as colorants and sweeteners. In accordance with one aspect of the present invention, pharmaceutically acceptable carriers are selected from the group consisting of sugars, such as maltose, glucose, fructose, dextran, sucrose, lactose, cyclodextrins (e.g., β-cyclodextrin, starch, cellulose and their derivatives; sugar alcohols such as mannitol, sorbitol and xylitol; inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; inorganic salts, such as sodium chloride, potassium chloride, sodium pyrosulphite, hydrosulfite sodium, sodium thiosulfate, calcium carbonate, bicarbonate calcium, carbonates and phosphates of alkali metals and their water solutions; amino acids such as glycine, methionine and cysteine hydrochloride; organic salts, such as Dunadry ADD, EDTA calcium-sodium, sodium lactate, stearate such as calcium stearate and magnesium stearate) and alginate; and other pharmaceutically acceptable carriers, such as mercaptoacetate acid, acetic KIS the PTA, vitamin C, derivatives of silicone, gelatin, polyvinylpyrrolidone, glycerol, tween-80, agar, surfactants, polyethylene glycol, phospholipids, kaolin and talc powder, etc.

In accordance with another aspect of the present invention, pharmaceutically acceptable formulation containing a crystalline form of S-zopiclone according to this invention, may be made in the form of any pharmaceutically acceptable dosage, which includes tablets, such as pills with sugar pills, tablets, film shell and tablets with intersolubility coating; capsules, such as hard capsules and soft capsules; liquid for oral administration, tablets to dissolve in the buccal pocket, granules, soluble granules, pills, powder, pastes, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops and dressings. Thus, the preparation of the present invention is preferably presented in oral form, for example, capsules, tablets, liquids for oral administration, granules, pills, powder and pellets, etc.; and injection, for example, powder injections, injectable solutions and the solutions for intravenous infusion, the most preferred form of tablets.

In accordance with another aspect of the present invention, oral drug Stabi who enoy crystalline form of S-zopiclone may contain conventional excipients, connecting components, obamaobama agents, diluents, tabletiruemye agents, lubricating agents, disintegrating agents, coloring agents, sweeteners and moisturizing ingredients and, optionally, the tablets can be coated.

Preferably, the excipient can be represented by lactose, D-mannitol, D-sorbitol, starch (for example, α-starch, amylopectin and dextrin), cellulose and their derivatives (for example, crystalline cellulose, hydroxypropylcellulose with a low degree of substitution and carboxymethylcellulose sodium, gum Arabic, light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminum silicate, etc.

Preferably, the lubricant can be represented by magnesium stearate, calcium stearate, talkboy powder and silica gel, etc.

Preferably, the connecting components can be represented by starch (for example, α-starch, dextrin and amylopectin), sucrose, trehalose, gelatin, gum Arabic, cellulosome and their derivatives (e.g. methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, hydroxypropylcellulose and hypromellose), D-mannitol and pyrrolidone, etc.

Preferably, razryhrytelya can be represented by lactose, starch,sodium carboximetilkrahmala, the cellulose and their derivatives (e.g. carboxymethylcellulose, carboxymethylcellulose calcium and hydroxypropylcellulose with a low degree of substitution) and light anhydrous silicic acid, etc

Preferably, the covering agent can be represented by hypromellose, hydroxypropylcellulose, ethylcellulose, carboxymethyl cellulose and polyvinyl alcohol, etc.

Preferably, the dyes can be represented by water-soluble food tartazine yellow dye (food dyes such as food red No. 2 and No. 3, food No. 4 and No. 5, food blue No. 1 and No. 2), water-insoluble precipitated dye (e.g., aluminum salt of water-soluble food tartazine yellow dye), natural dyes (e.g., β-carotene, chlorophyll and colcothar) etc.

Preferably, the sweetener can be represented by saccharin sodium, dicale glycyrrhizate, aspartame and stevia, etc.

In accordance with one aspect of the present invention, the medication may be injected in the traditional way the subject by any means, for example, orally, locally, parenteral or inhalation, preferably oral.

In accordance with one aspect of the present invention, when used for the treatment of sleep disorders, a single dose of a drug which contains 1-15 mg of crystalline form of S-zopiclone, preferably contains 3-12 mg of crystalline form of S-zopiclone.

In accordance with another aspect of the present invention, the use and dosage of the drug depends on the patient's condition, taking medication according to this invention, it can be taken once a day every day for 1-10 single doses at a time, for example, before bedtime, 1-10 bags, or 1-10 pills or 1-10 tablets.

Description of the DRAWINGS

Figure 1 represents a spectrum of x-ray diffraction of crystalline form of S-zopiclone according to this invention.

Figure 2 represents a graph of the DSC of the crystalline form of S-zopiclone of the present invention.

Figure 3 is an infrared absorption spectrum of crystalline form of S-zopiclone according to this invention.

Figure 4 represents a spectrum of x-ray diffraction of crystalline form of S-zopiclone according to this invention is exposed to high temperature (60°C) for 10 days.

Figure 5 represents a spectrum of x-ray diffraction of crystalline form of S-zopiclone according to this invention is exposed to high humidity (25°C, relative humidity of 92.5%) for 10 days.

6 represents a spectrum of x-ray diffraction of crystalline form of S-zopiclone according to this invention, exposed to intense with the ETA (4500±500Lx) for 10 days.

Fig.7 represents the range of x-ray diffraction of crystalline form of S-zopiclone according to this invention at a temperature of 40±2°C and relative humidity 75±5% within 6 months.

Fig represents a spectrum of x-ray diffraction of crystalline form of S-zopiclone according to this invention, exposed to room temperature for 36 months.

In accordance with one aspect of the present invention presents the use of the crystalline form of S-zopiclone according to this invention in the preparation of medicaments for the treatment of sleep disorders. Below are the results of pharmacodynamics.

Study 1. The results of the pharmacodynamics of crystalline form of S-zopiclone according to this invention

In contrast to patterns of drug benzodiazepine, S-zopiclone operates on a different binding site of the benzodiazepine receptor in complex GABAA receptor/Cl-channel.

The crystalline form of S-zopiclone according to this invention as the test drug was prepared in accordance with Example 1 of the present invention.

1. Pharmacodynamic study of crystalline form of S-zopiclone in laboratory conditions

The value of the IC50binding of S-zopiclone of the receptor benzodiazepine is 21±3 (nmol/l), where IC50means half the maximum overwhelming concentration is then, inversely proportional to the ability of the receptor binding. Thus, it indicates that the S-zopiclone has a strong ability of binding with the receptor. Studies have shown that although the chemical structure of S-zopiclone and differs from the structure of the drug benzodiazepine, both drugs have similar mechanisms of action binding receptor benzodiazepine, but have different binding sites.

2. Pharmacodynamic studies of crystalline form of S-zopiclone in vivo

Male rats, long-Evans (weighing 250-275 g) were selected and divided into 3 groups, they were fed for 12-hour cycle of day and night. After a week of feeding was carried out the experiment.

2.1 Analysis of spontaneous activity

To measure the total spontaneous activity was observed horizontal activity in rats with open circumstances. Accordingly, all animals were placed in 8 black rooms, protected from light, their spontaneous activity was observed using infrared sensors embedded in the walls at regular intervals, recording every 10 min for 120 minutes.

Animals were administered the crystalline form of S-zopiclone dosage of 10 mg/kg of body weight. 30-60 minutes after administration of the drug absorbing effect on locomotor ability reached a peak and disappeared is via 2 hours.

2.2 Labyrinth test

Introduction crystalline form of S-zopiclone at 10 mg/kg body weight had a significant effect on all outputs open and closed outputs. At the dosage of 5 mg/kg body weight and 10 mg/kg of body weight was observed that the crystalline form of S-zopiclone may significantly increase the time spent in the open passages.

As shown by the above results, the crystalline form of S-zopiclone had a significant effect not only for the treatment of sleep disorders, but also the treatment of anxiety, without affecting the ability to sporting coordinate.

Study 2. The study of the properties and durability of crystalline form of S-zopiclone

The product was presented to white or grayish/yellowish crystal or crystalline powder.

1. Solubility

Test the solubility was carried out using conventional solvents in accordance with the GENERAL method of NOTIFICATION in the Chinese Pharmacopoeia (2000 edition).

The crystalline form of S-zopiclone according to this invention as the test drug was prepared in accordance with Example 1 of the present invention.

Research method: the required amount of fine powder of crystalline form of S-zopiclone was accurately measured, it was added a certain amount of dissolved€;La with an accuracy of ±2%. At a temperature of 25±2°C, RA the solution was intensively shaken for 30 seconds, this procedure was repeated after 5-minute intervals. Within 30 minutes was observed solubility behavior. The results are presented in Table 1.

Table 1
The solubility of the crystalline form of S-zopiclone really sobraniia
SolventWeight of sample (mg)The required amount of solvent (ml)The required amount of solvent for dissolving 1 g of the sample (ml)Solubility
chloroform1000,66easily soluble
hydrochloric acid(0.1 mol/l)100,770instant
acetone102,0200poorly soluble
methanol105,0 500poorly soluble
the ethyl acetate106,0600poorly soluble
ethanol1015,01500very poorly soluble
anhydrous ether1090,09000very poorly soluble
water1020020000practically insoluble

Conclusions

The crystalline form of S-zopiclone according to this invention is readily soluble in chloroform, soluble in hydrochloric acid (0.1 mol/l), slightly soluble in acetone, ethyl acetate or methanol, very slightly soluble in ethanol and ether, and practically insoluble in water.

2. Resistance

The crystalline form of S-zopiclone according to this invention as the test drug was prepared in accordance with Example 1 of the present invention.

2.1 Test at high temperatures (60°C)

Crist is licenca the form of S-zopiclone according to this invention has been entered by the parties in an open and transparent colorless tube and placed in a thermostatic container (60°C) for 10 days. Samples were selected on 5-th and 10-th day, respectively, for measuring their resistance in accordance with the key concepts related to resilience. The results are presented in Table 3.

The results showed that the crystalline form of S-zopiclone remains stable after 10 days of exposure to high temperature (60°C), and its parameters are almost completely consistent with the parameters 0-day, including the nature, the melting temperature and the content of impurities such as levosimendan. Range of x-ray diffraction of crystalline form of S-zopiclone according to this invention, is exposed to a high temperature for 10 days, is presented in figure 4.

2.2 Test at high humidity (25°C, relative humidity: 92,5%)

The crystalline form of S-zopiclone for this invention was the parties entered into the open and colorless transparent tube and placed in a closed vessel (KNO3a saturated solution, relative humidity: 92,5%) for 10 days. Samples were selected on 5-th and 10-th day, respectively, for measuring their resistance in accordance with the key concepts related to resilience. Meanwhile, the weight of the test drug before and after the study was carefully measured. The results are presented in Table 2 and Table 3.

As shown by the results after 10 days of exposure to high humidity nab who was udalos a small increase in the mass of crystalline form of S-zopiclone, almost full compliance with the 0-th day. The results are presented in Table 2. Range of x-ray diffraction of crystalline form of S-zopiclone exposed to high humidity for 10 days, is presented in figure 5.

Table 2.
The increase in the mass of crystalline form of S-zopiclone-time studies at high humidity
Time0-dayDay 510th day
Weight1,0001 g1,0007 g1,0008 g
The increase in mass-0,07%0,08%

2.3 Test when exposed to intense light

The crystalline form of S-zopiclone on this invention was introduced into the open and colorless transparent tube and subject to direct exposure to intense light (4500±500 Lux) for 10 days. Samples were selected on 5-th and 10-th day, respectively, for measuring their resistance in accordance with the key concepts related to the strength of the Results presented in Table 3.

The results showed that the crystalline form of S-zopiclone remained stable after 10 days of exposure to intense light (4500±500 Lux), and its parameters are almost completely consistent with the parameters 0-day, including the nature, the melting temperature and the content of impurities such as levosimendan. Range of x-ray diffraction of crystalline form of S-zopiclone exposed to intense light (4500±500 Lux) for 10 days, presented on Fig.6.

Table 3
The results of a study of factors affecting the crystalline form of S-zopiclone
ConditionsTime (day)Appearance and colorThe melting temperature (°C)Admixture (%)Content (%)
LevosimendanOther impurities
High temperature (60°C)0Grayish/yellowish crystalline powder205,5-207,00,06 0,09100,06
5Grayish/yellowish crystalline powder206,0-207.00,080,11100,01
10Grayish/yellowish crystalline powder206,0-207.00,070,12100,12
High humidity (92.5%)0Grayish/yellowish crystalline powder205,5-207,00,060,09100,06
5Grayish/yellowish crystalline powder206,0-207,00,080,1199,86
10Grayish/yellowish crystalline powder206,0-207.00,070,1199.91 per
the effects of intense light 0Grayish/yellowish crystalline powder205,5-207.00,060,09100,06
5Grayish/yellowish crystalline powder205,5-207,00,080,1099,77
10Grayish/yellowish crystalline powder205,5-206,50,070,11100,02

2.4 Accelerated test

The crystalline form of S-zopiclone was packaged in packaging that is similar to the commercial, and placed in a thermostatic container (temperature: 40±2°C, relative humidity: 75±5%) at 6 months. Samples were selected on the 1st, 2nd, 3rd and 6th month, respectively, for measuring their resistance in accordance with the key concepts related to resilience. The results are presented in Table 4.

The results showed that the crystalline form of S-zopiclone remained stable after 6 months of accelerated tests. Its parameters are almost fully meets the parameters of the 0-th day, including Hara is Ter, the melting temperature and the content of impurities, such as levosimendan. Range of x-ray diffraction of crystalline form of S-zopiclone under conditions of temperature 40±2°C and relative humidity 75±5% for 6 months is presented in Fig.7.

Table 4
The results of accelerated tests crystalline form of S-zopiclone
Time (month)Appearance and colorThe melting temperature (°C)Admixture (%)Content (%)
LevosimendanOther impurities
0Grayish/yellowish crystalline powder205,5-207,00,060,09100,06
1Grayish/yellowish crystalline powder206,0-207,50,070,10100,13
2 Grayish/yellowish crystalline powder206,0-207,00,070,12100,02
3Grayish/yellowish crystalline powder206,0-207,00,050,1299.91 per
bGrayish/yellowish crystalline powder205,5-207,00,060,0999,73

2.5 Test during prolonged storage of the sample

The crystalline form of S-zopiclone was packaged in packaging that is similar to the commercial, and was stored at room temperature. Samples were taken at the 3rd, 6th, 9th, 12th, 18th, 24th, and 36th months, respectively to measure their resistance in accordance with the key concepts related to resilience. Data in comparison with the 0-th day is presented in Table 5.

As shown by the test results during long-term storage of a sample of the crystalline form of S-zopiclone remained steadfast, and its parameters are almost completely consistent with parameter 0-day, including the nature, the melting temperature and the content of impurities, such as levosimendan. Range of x-ray diffraction of crystalline form of S-zopiclone according to this invention at room temperature for 36 months presented on Fig.

Table 5
The test results during long-term storage of a sample of crystalline form of S-zopiclone
Time (Month)Appearance and colorThe melting temperature (°C)Admixture (%)Content (%)
LevosimendanOther impurities
0Grayish/yellowish crystalline powder205,5-207,00,060,09100,06
3Grayish/yellowish crystalline powder205,0-206,50,060,11100,3
6Grayish/yellowish crystalline powder coated examination bed with the 206,5-207,50,060,14100,21
9Grayish/yellowish crystalline powder206,0-207,50,040,14100,16
12Grayish/yellowish crystalline powder205,5-207,00,060,14100,08
18Grayish/yellowish crystalline powder206,0-207,50,070,17100,12
24Grayish/yellowish crystalline powder205,5-206,50,070,1899,80
36Grayish/yellowish crystalline powder206,0-207,00,070,20100,06

Conclusions:

In Zack is Uchenie the crystalline form of S-zopiclone on this invention was introduced into the open and colorless transparent tube and placed in a different environment for 10 days, including high temperature (60°C), relative humidity (92,5%) and exposure to intense light (4500±500 Lux). Moreover, after 6 months of accelerated studies of crystalline form of S-zopiclone, put up in packaging that is similar to the commercial, (temperature: 40±2°C, relative humidity: 75±5%), compared with the results of the 0-th day, we detected no significant changes in many parameters, including the nature, the melting temperature and the content of impurities such as levosimendan. The results of influencing factors showed that the crystalline form of S-zopiclone according to this invention should be stored in an airtight and dry place.

After 36 months of testing during long-term storage of a sample of the crystalline form of S-zopiclone, put up in packaging that is similar to the commercial, at room temperature, compared with the results of the 0-th day, there were no significant changes in parameters, including the nature, the melting temperature and the content of impurities such as levatation.

Under the terms of the above tests was not observed phenomenon of transformation of the crystals. Was thoroughly confirmed that the crystalline form of S-zopiclone of the present invention has a stable structure.

Study 3. Pharmacokinetic study of a single injection of crystalline form of S-zopiclone is durovym volunteers

1. Purpose

Disposable injection of different dosages of the drug to healthy volunteers were studied from the point of view of assessing its pharmacokinetic profile, as well as the rules for the distribution, metabolism and excretion in vivo. Because the crystalline form of S-zopiclone was developed for administration to a subject orally, also studied the influence of food intake on the absorption, distribution, metabolism and excretion of the drug.

2. Method.

Evaluation of pharmacokinetics: according to the results of phase I clinical test portability and pre-designed dose phase II clinical test, all volunteer test participants can tolerate high dose of 11.25 mg/kg MT (body mass index), three different groups according to the dosage were divided as follows: group low-dose group of moderate-dose and high-dose treatment group was 3, 6 and 12 mg/kg MT, respectively. Used triple-cross pattern of Latin squares. All subjects were randomly divided into three test groups, when carrying out each test, subjects were administered the test drug in different dosages. Thus, after 3 tests, each subject was entered tested the drug in high, moderate and low dosage in accordance with the model of Latin squares. The interval between the two is astami was 2 weeks.

Besides investigating the influence of food intake on the metabolism of the drug in vivo. 8 subjects were selectively divided into 2 groups. 2 tests, the subjects in each group received the drug in the same dosage (6 mg) on an empty stomach and after 5 min after the standard meals. The interval between the two tests was 2 weeks.

After a single injection of the test drug samples were collected venous blood with 6 ml of anticoagulant heparin at 0 (immediately before drug administration), 15 min, 30-th min, 45 min, 60-th min, 1,5 hour, 2nd hour, 3rd hour, 4 hour, 6 hour, 8 hour, 12 hour, 16 hour and 24-th hour, respectively, for determining the concentration of S-zopiclone. To obtain a curve of the ratio of the concentration-time drug concentration in the plasma of each subject was determined by HPLC at different times. Were counted in the main pharmacokinetic parameters of subjects, including the average concentration of urine (SCM), Cmax(concentration), Tmax(time), CKM 0~∝, CKM0-tAnd t1/2and so on

3. The selection of subjects

The number of: (a predefined number, and analyzed the number) 10 people in the group.

Criteria of inclusion and exclusion: age 19-45 years and body mass index (BMI) 19-29 kg/m2.

When selecting the physical health of the subjects was confirmed in accordance with their history what s disease, medical examination, ECG and laboratory tests. Moreover, the study must be signed an informed consent form (FIS).

4. Characteristics, application and dosage drug test

The crystalline form of S-zopiclone was prepared in tablets with sheath (3 mg S-zopiclone/tablet) in accordance with Example 1 and Example 9, was once administered orally.

5. The duration of treatment

After a single oral administration were observed for twenty-four hours.

6. Evaluation criteria

Pharmacokinetic indices: to obtain a curve of the ratio of the concentration-time drug concentration was determined immediately before administration and at various intervals after administration of the drug. Were counted in the main pharmacokinetic parameters, including Cmax, TmaxSCM0~∝, CKM0-tAnd t1/2and so on

Indexes security: when selecting and 24 hours after administration of the drug was measured by several indicators, including life indicators, conducted a medical examination, ECG and clinical analyses. During the study adverse events was recorded in a timely manner.

7. Statistical method

Pharmacokinetics: for calculation of the main pharmacokinetic parameters were used software to provide the tion for statistical analysis R.

Security: significant clinical safety indicators presented in the table according to their type and frequency.

8. Results and conclusions

The subjects were strictly followed the study Protocol, not deviating from it and not breaking it, not combining drugs. Non-medical reason one of the subjects did not pass the last 3rd blood sample after 8 hours after administration of the drug at a dose of 12 mg/kg of MT.

Pharmacokinetic results.

Pharmacokinetic parameters of subjects after a single injection of crystalline form of S-zopiclone is shown in Table 6.

Table 6
Pharmacokinetic parameters of subjects after a single injection of crystalline form of S-zopiclone
Pharmacokinetic parametersPharmacokinetic study of disposable oral drugPharmacokinetic study before and after a meal
3 mg6 mg12 mg6 mg (fasting)6 mg (after a meal)
Cmax(µg/l)33,96±8,6360,94±11,44182,72±67,4460,69±11,4362,60±18,95
Tmax(h)1,50±0,6b1,28±0,431,58±0,401,31±0,441,75±0,89
CKM0-∞(µg/h/l)259,66±92,58404,21±73,321291,26±426,68335,73±145,57284,00±88,36
t1/2(h)6,98±0,99to 8.20±6,14of 8.06±2,827,17±2,696,75±1,49
The plasma clearance (l/h)to 14.10±4,515,80±3,010,90±5,0016,00±3,321,4±7,4

Results safety:

As adverse reactions were recorded, bitter taste in the mouth and the majority of the subjects (25%-40%), other undesirable reaction was dizziness and headache. The results showed, compared with the group who AMI low and moderate dosages, more species and more frequent cases of adverse reactions was evident in the group with high dose (12 mg/kg / MT). Two subjects in group a dosage of 12 mg/kg MT fell into a state of delirium, including talkative, hyperactive, and unconsciousness. But these adverse reactions were mild and of short duration. Within 12 hours after drug administration, all adverse reactions disappeared without special treatment.

Conclusions:

Tablets crystalline form of S-zopiclone can rapidly absorbed after oral administration of the drug. Dosage and concentration of the drug in plasma within 3-12 mg had a good linear relationship. Common adverse reactions included bitter taste in the mouth and dizziness, indicating that the crystalline form of S-zopiclone according to this invention has a good safety record for clinical use.

The crystal form is of type solid particles with the atoms (or ions and molecules), organized steric periodically. In General, crystalline organic forms of the drug are related to the molecular lattice, which can form different crystalline forms depending on various process conditions. Moreover, different crystalline forms of the same drug can often lead to significant the major differences in many physico-chemical properties (for example, appearance, solubility, melting point and density), the dissolution and bioavailability of the drug, thus affecting the stability and bioavailability of the drug. To date, researchers preformism drugs have become an integral and important aspect for research and development, review and approval of the drug, production, quality control and research before creating the formula to choose the form and dosage for the new drug.

The crystalline form of S-zopiclone according to this invention has the following advantages:

1. She may have a better therapeutic effect for the treatment of sleep disorders, to help relieve anxiety without affecting sports coordination.

2. It can be immediately absorbed after oral administration. In the framework of the effective dose, the concentration of drug in the blood and dosage have good linear correlation that makes the product safer for clinical use.

3. In terms of the above studies were not studied the phenomenon of crystalline transformation. There is evidence that the crystalline form of S-zopiclone of this study had stable structure.

4. It has good fluidity and compressibility (i.e. it is easily pressed into a tablet). Full ACC is DTIE pharmacodynamic and pharmacokinetic requirements for clinical use to a large extent contributes to the practical production.

EXAMPLES

The following examples illustrate the present invention but do not limit the invention in any way.

An example of the preparatory process for the preparation of S-zopiclone as raw materials

A 3-liter reaction flask was added racemic zopiclone (100 g), D-(+)-malic acid (34 g), methanol (100 ml) and acetone (1500 ml) to dissolve, stirring for 2 hours at room temperature. The resulting solution was allowed to cool to 6°C. after 24 hours at 6°C, the solution was stirring his for 1 hour, was filtered twice with methanol (total volume 100 ml) and dried to obtain D-(+)-malic acid S-zopiclone (52,5 g).

The above D-(+)-malic acid S-zopiclone (52,5 g) was dissolved with water (1000 ml), then added potassium bicarbonate (8%) to establish the level of pH 8; the precipitate was becoming solid. Then a solution of 4 times were extracted with ethyl acetate (total volume 1000 ml). Then the ethyl acetate layer was dried with anhydrous sodium sulfate (as desiccant) for 5 hours, filtered, and removed the desiccant. The solution was concentrated by distillation, and then was filtered 3 times washed with ethyl acetate (total volume 1000 ml) and dried to obtain S-zopiclone (33,2 g) as raw materials.

Example 1 - preparation of a crystalline form of S-zopiclone

500-milliliters vessel was added S-zopiclone (10.0 g). DL the gradual dissolution of solids added, mixed and heated in ethyl acetate (350 ml). The resulting solution was heated in a vessel under reflux for 10 minutes and allowed to cool at room temperature to approximately 40°C. After 2 hours of stirring at about 40°C. the solution was cooled to approximately 0°C, stirring his for 1 hour at a temperature of approximately 0°C, was filtered by suction and dried in vacuo to obtain the crystalline form of S-zopiclone (8,9 g).

Defined by the following data:

Range of powder x-ray diffraction showed characteristic peaks, which manifested itself in terms of 2θ at approximately 11,08°C, approximately 12,38°C, approximately 15,86°C, approximately 17,88°C, approximately 19,98°C and approximately 20,58°C.

The peak on the DSC thermogram was about when 207,7°C.

Infrared absorption spectrum (IR) showed characteristic peaks at approximately 3078 cm-1approximately 2942-2838 cm-1approximately 2790 cm-1approximately 1715 cm-1approximately 1463 cm-1approximately 1372 cm-1and approximately 757 cm-1.

Example 2 - preparation of crystalline form of S-zopiclone

500-milliliters vessel was added 3-zopiclone (10.0 g). For the gradual dissolution of the solids was added, mixed and heated in ethyl acetate (250 ml). The resulting solution is heated is Ali in the vessel under reflux for 10 minutes and allowed to cool at room temperature to about 45°C. After 10 minutes of stirring at approximately 45°C. the solution was cooled to about 1°C, stirring his for 2 hours at a temperature of approximately 1°C, was filtered by suction and dried in vacuo to obtain the crystalline form of S-zopiclone (9.0 g).

Defined by the following data:

Range of powder x-ray diffraction showed the characteristic peaks that appeared in conditions 29 at approximately of 11.15°, approximately 12,38°, approximately 15,92°, approximately 17,79°, approximately 19.93 per° and about to 20.52°.

The peak on the DSC thermogram was about when 208,4°C.

Infrared absorption spectrum (IR) showed characteristic peaks at approximately 3081 cm-1approximately 2941-2838 cm-1approximately 2791 cm-1approximately 1716 cm-1approximately 1463 cm-1approximately 1372 cm-1and approximately 758 cm-1.

Example 3 - preparation of crystalline form of S-zopiclone

In 1000 milliliters vessel was added 3-zopiclone (10.0 g). For the gradual dissolution of the solids was added, mixed and heated in ethyl acetate (500 ml). The resulting solution was heated in a vessel under reflux for 10 minutes and allowed to cool at room temperature to about 35°C. After 7 hours of stirring at about 35°C. the solution was cooled to PR is approximately 3°C, was stirring his for 5 hours at a temperature of approximately 3°C, was filtered by suction and dried in vacuo to obtain the crystalline form of S-zopiclone (8.7 g).

Defined by the following data:

Range of powder x-ray diffraction showed characteristic peaks, which manifested itself in terms of 2θ at approximately 11,08°, approximately 12,42°, approximately $ 15.87 with°, approximately 17,81°, approximately 19,90° and approximately 20,55°.

The peak on the DSC thermogram was about when 207,3°C.

Infrared absorption spectrum (IR) showed characteristic peaks at approximately 3077 cm-1approximately 2942-2839 cm-1approximately 2791 cm-1approximately 1714 cm-1approximately 1463 cm-1approximately 1372 cm-1and approximately 757 cm-1.

Example 4 - preparation of crystalline form of S-zopiclone

In 250 milliliters vessel was added S-zopiclone (10.0 g). For the gradual dissolution of the solids was added, mixed and heated in ethyl acetate (100 ml). The resulting solution was heated in a vessel under reflux for 10 minutes and allowed to cool at room temperature to approximately 50°C. After 4 hours of stirring at about 50°C. the solution was cooled to about 8°C, stirring his for 7 hours at a temperature of approximately 8°C, AHP crystal growth is literaly suction and dried in vacuo to obtain the crystalline form of S-zopiclone (9.2 grams).

Defined by the following data:

Range of powder x-ray diffraction showed characteristic peaks, which manifested itself in terms of 2θ at approximately 11,08°, approximately 12,38°, approximately 15,86°, approximately 17,85°, approximately 19,90° and approximately 20,58°.

The peak on the DSC thermogram was about when 207,2°C.

Infrared absorption spectrum (IR) showed characteristic peaks at approximately 3077 cm-1approximately 2941-2837 cm-1approximately 2792 cm-1approximately 1715 cm-1approximately 1463 cm-1approximately 1372 cm-1and approximately 758 cm-1.

Example 5 - preparation of crystalline form of S-zopiclone

In 1000 milliliters vessel was added 3-zopiclone (10.0 g). For the gradual dissolution of the solids was added, mixed and heated in ethyl acetate (800 ml). The resulting solution was heated in a vessel under reflux for 10 minutes and allowed to cool at room temperature to about 30°C. After 10 hours of stirring at about 30°C. the solution was cooled to approximately -5°C, stirring his for 50 minutes at a temperature of approximately -5°C., was filtered by suction and dried in vacuo to obtain the crystalline form of S-zopiclone (8,4 g).

Defined by the following data:

Spectrum powder rentgenovsk the th diffraction showed characteristic peaks, which manifested itself in terms of 2θ at approximately 11,08°, approximately 12,35°, approximately 15,86°, approximately 17,88°, approximately 19,94° and approximately 20,58°.

The peak on the DSC thermogram was about when 208,1°C.

Infrared absorption spectrum (IR) showed characteristic peaks at approximately 3077 cm-1approximately 2943-2839 cm-1approximately 2791 cm-1approximately 1715 cm-1approximately 1463 cm-1approximately 1371 cm-1and approximately 757 cm-1.

Example 6 - preparation of crystalline form of S-zopiclone

In 1000 milliliters vessel was added S-zopiclone (10.0 g). For the gradual dissolution of the solids was added, mixed and heated in ethyl acetate (750 ml). The resulting solution was heated in a vessel under reflux for 10 minutes and allowed to cool at room temperature to about 45°C. After 10 hours of stirring at approximately 45°C. the solution was cooled to approximately 0°C, stirring his for 2 hours at a temperature of approximately 0°C, was filtered by suction and dried in vacuo to obtain the crystalline form of S-zopiclone (8.8 g).

Defined by the following data:

Range of powder x-ray diffraction showed characteristic peaks, which manifested itself in terms of 2θ at approximately 11,08°, priblizitelen the 12,38°, approximately 15,86°, approximately 17,86°, approximately 19,98° and approximately 20,58°.

The peak on the DSC thermogram was about when 207,5°C.

Infrared absorption spectrum (IR) showed characteristic peaks at approximately 3078 cm-1approximately 2942-2838 cm-1approximately 2790 cm-1approximately 1717 cm-1approximately 1463 cm-1approximately 1371 cm-1and approximately 759 cm-1.

Example 7 - preparation of crystalline form of S-zopiclone

500-milliliters vessel was added S-zopiclone (10.0 g). For the gradual dissolution of the solids was added, mixed and heated in ethyl acetate (400 ml). The resulting solution was heated in a vessel under reflux for 10 minutes and allowed to cool at room temperature to about 35°C. After 12 hours of stirring at about 35°C. the solution was cooled to approximately -10°C, stirring his for 10 minutes at a temperature of approximately -10°C, was filtered by suction and dried in vacuo to obtain the crystalline form of S-zopiclone (8.3 g).

Defined by the following data:

Range of powder x-ray diffraction showed characteristic peaks, which manifested itself in terms of 2θ at approximately 11,08°, approximately 12,34°, approximately 15,92°, approximately 17,88°, approximately 19,98° and CA is approximately 20,58°.

The peak on the DSC thermogram was about when 207,7°C.

Infrared absorption spectrum (IR) showed characteristic peaks at approximately 3078 cm-1approximately 2941-2837 cm-1approximately 2790 cm-1approximately 1715 cm-1approximately 1464 cm-1approximately 1372 cm-1and approximately 757 cm-1.

Example 8 - preparation of crystalline form of S-zopiclone

In 1000 milliliters vessel was added 3-zopiclone (10.0 g). For the gradual dissolution of the solids was added, mixed and heated in ethyl acetate (700 ml). The resulting solution was heated in a vessel under reflux for 10 minutes and allowed to cool at room temperature to about 38°C. After 12 hours of stirring at approximately 38°C. the solution was cooled to approximately 10°C, stirring his for 12 hours at a temperature of approximately 10°C, was filtered by suction and dried in vacuo to obtain the crystalline form of S-zopiclone in (8.9 g). Defined by the following data:

Range of powder x-ray diffraction showed characteristic peaks, which manifested itself in terms of 2θ at approximately 11,08°, approximately 12,41°, approximately 15,86°, approximately 17,81°, approximately 19,98° and approximately 20,58°.

The peak on the DSC thermogram was about when 207,6°C. the Infrared spectrum of the absorption (IR) showed characteristic peaks at approximately 3081 cm -1approximately 2943-2838 cm-1approximately 2790 cm-1approximately 1715 cm-1approximately 1466 cm-1approximately 1372 cm-1and approximately 757 cm-1.

Example 9 - preparation of tablets crystalline form of S-zopiclone

The formula

ComponentsWeight (g)
The crystalline form of S-zopiclone30,00
Lactose500,00
Corn starch100,00
Pre klasterizovannykh starch50,00
Povidone K3010,00
Sodium carboximetilkrahmal30,00
Micropowder silica gel3,00
Magnesium stearate4,00
The povidone K30 aqueous solution (8%)The required number
Covering substance Opadry II (Opadry)20,00

It was made ten thousand tablets, each tablet contains 3 mg of the crystalline form of S-zopiclone according to this invention.

Special stages are the following:

the crystalline form of S-zopiclone, lactose, corn starch, pre-klasterizovannykh starch, povidone K, sodium carboximetilkrahmal and micropowder silica gel pass through a sieve of 100 mesh, respectively, for further use. The crystalline form of S-zopiclone weighed according to the number specified in the formula, and uniformly mixed with other assistive technology, exponentially increasing in equal amounts. A mixture of 3 times pass through a sieve of 100 mesh. The required amount of povidone K aqueous solution (8%) was added to the obtained powder to obtain a soft material. Soft material was granulated, and passing it through a sieve of 20 mesh. Moistened granules were dried at 50-60°C and pass through a 20 mesh to achieve the same granules. Added micropowder silica gel and well mixed. Then added magnesium stearate and well mixed. The angle of repose was measured value is less than 30°. The drug was tested, was determined as the weight of the tablet, then the tablet was made using 6 mm flat punch press for further coverage.

P is obtained simple tablets were coated with a substance Opadry® II. In accordance with the usual formula Opadry® II (soluble in the stomach), was prepared solution for applying membranes using water as solvent. The solid content of the solution for the shell was 18%. The temperature of the incoming air: 80°C, the temperature of the moving layer: 38-40°C spray pressure: 3.5 bar, the rotation speed of the vessel for the application of sheath: 23 revolutions per minute, a feed rate of material: 2-3 g/min. Formed membrane shell possessed great strength, great power clutch, full coverage and uniform color.

Tablets were given to patients in approximately 1 hour before bedtime, disposable oral administration at a dose of 1-4 tablets.

Example 10 - preparation of capsules of crystalline form of S-zopiclone

The formula

ComponentsWeight (g)
The crystalline form of S-zopiclone30,00
Lactose500,00
Corn starch100,00
Pre klasterizovannykh starch50,00
Povidone K3010,00
Sodium carboximetilkrahmal30,00
Micropowder silica gel3,00
Magnesium stearate4,00
The povidone K30 aqueous solution (8%)The required number

It was made ten thousand capsules, each capsule contains 3 mg of the crystalline form of S-zopiclone according to this invention.

Special stages are the following:

the crystalline form of S-zopiclone, lactose, corn starch, pre-klasterizovannykh starch, povidone K, sodium carboximetilkrahmal and micropowder silica gel pass through a sieve of 100 mesh, respectively, for further use. The crystalline form of S-zopiclone weighed according to the number specified in the formula, and uniformly mixed with other assistive technology, exponentially increasing in equal amounts. A mixture of 3 times pass through a sieve of 100 mesh. The required amount of povidone K aqueous solution (8%) was added to the obtained powder to obtain a soft material. Soft material was granulated, and passing it through a sieve of 20 mesh. Moistened granules were dried at 50-60°C and miss chere is C 20 mesh to achieve the same granules. Added micropowder silica gel and well mixed. Then added magnesium stearate and well mixed. The angle of repose was measured value is less than 30°. After checking the composition of the drug was determined by its capacity.

Capsules were made location in capsules No. 3.

Capsules were given to the patient within 1 hour before bedtime, disposable oral administration at dosage 1-4 capsules.

1. The crystalline form of S-zopiclone spectrum of powder x-ray diffraction using Cu-Ka radiation with characteristic peaks expressed in terms of 2θ at approximately 11,08°, approximately 12,38°, approximately 15,86°, approximately 17,88°, approximately 19,98° and approximately 20,58°C; DSC-tomography, in which the peak is at approximately 207,7°C, and an infrared absorption spectrum (IR) with characteristic peaks at approximately 3078 cm-1approximately 2942-2838 cm-1approximately 2790 cm-1approximately 1716 cm-1approximately 1463 cm-1approximately 1372 cm-1and approximately 757 cm-1.

2. The method of preparation of the crystalline form of S-zopiclone according to claim 1, characterized in that it comprises the following steps:
(a) the dissolution of S-zopiclone in ethyl acetate to a temperature of from 60°C. to reflux temperature, and use 10-80 ml of ethyl acetate per 1 g of S-zopiclone;
(b cooling solution at room temperature up to 30-50°C, holding at that temperature for from 10 min to 12 h;
(c) cooling to a temperature of from 10 to -10°C, holding at this temperature for 10 min to 12 h; and
(d) separating the crystalline form.

3. The method according to claim 2, characterized in that in stage (a) is used 25-50 ml of ethyl acetate per 1 g of S-zopiclone; the step (b) is cooled at room temperature up to 35-45°C, and holding at that temperature lasts for 1-6 h; step (C) is cooled to a temperature of from 5 to -5°C and holding at this temperature lasts for 1-6 hours

4. Pharmaceutical preparation for the treatment of sleep disorders, containing a crystalline form of S-zopiclone of claim 1 and a pharmaceutically acceptable carrier.

5. The pharmaceutical preparation according to claim 4, characterized in that a single dose of the pharmaceutical preparation contains 1-15 mg of crystalline form of S-zopiclone.

6. The pharmaceutical preparation according to claim 5, characterized in that a single dose of the pharmaceutical preparation contains 3-12 mg of crystalline form of S-zopiclone.

7. The use of crystalline form of S-zopiclone of claim 1 in the manufacture of medicaments for the treatment of sleep disorders.

8. The use of a pharmaceutical preparation according to any one of claims 4 to 6 in the manufacture of medicaments for the treatment of sleep disorders.



 

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21 cl, 4 tbl, 13 ex

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19 cl, 4 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is the use of 7-chlor-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one or a pharmaceutically acceptable salt thereof for treating various types of insomnia (terminal one, insomnia in an individual under min. 65 years, for the relief of wakefulness after the beginning of a sleep, for the prolongation of total sleep time after the beginning of a sleep - versions), pharmaceutical compositions for the appropriate application (versions) and methods of treating the various types of insomnia (versions).

EFFECT: invention is effective in treating insomnia, maintaining the sleep, terminal insomnia, including in the aged; the compound has a short half-life, ie 3-4 hours (so it causes no residual sedative action), and improves the daily activity in the aged suffering diurnal drowsiness.

61 cl, 29 dwg, 10 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2,6-di-fluoro-butylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H, or to its pharmaceutically acceptable salt.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

14 cl, 15 ex, 8 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2-fluoro-butyl-6-isopropylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

16 cl, 12 ex, 6 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a dietary and pharmaceutical composition containing ligustilide to be applied in a method of treating or preventing depression, generalised anxiety disorders, dysphoria, obsessive-compulsive behaviour, and affective disorders, as well as to a non-therapeutic application of the dietary composition containing ligustilide.

EFFECT: higher efficacy of the applied derivatives.

6 cl, 17 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted quinoxaline-type piperidine compounds of formula or to a pharmaceutically acceptable derivative thereof, wherein: Y1 represents O; Q is specified in condensed benzo or pyridino; each R2 is independently specified in: (a) -halogen or -CN; (b) -(C1-C6)alkyl; a is an integer specified in 0, 1 or 2; a dash line in a 6-member ring containing a nitrogen atom which is condensed with Q group means the presence or absence of a bond, and when the dash line means the absence of the bond, then R3, and one R4 are absent; R3 is specified in: (a) -H; each R4 is independently specified in: (a) -H; or (b) - halogen or CN; or (c) -X, -(C1-C6)alkyl-X, -(5- or 6-member)heterocyclyl-X or -(5- or 6-member)heterocyclyl-(C1-C6)alkyl-X; or (d) -C(=Y)X, -C(=Y)T3, -C(=Y)YX, - C(=Y)YT3, -C(-Y)N(T1)(T2), -C(=Y)N(R9)CN, -C(=Y)N(R9)X, -C(=Y)N(R9)YH, -C(=Y)N(R9)YX, -C(=Y)N(R9)YCH2X, -C(-Y)N(R9)YCH2CH2X or -C(=Y)N(R9)S(K))2T3; or (e) -N(R9)X, -N(R9)-CH2X, -N(R9)-CH2CH2X, -N(R9)CH2N(R9)C(=N(R12))N(R12)2, -N(R9)-CH2CH2N(R9)C(=N(RI2))N(R12)2, -N(T1)(T2), -N(T3)C(=Y)T3, -N(T3)C(=Y)YT3, -N(T3)C(=Y)N(T1)(T2), -N(T3)S(=O)2T3 or -N(T3)S(=O)2N(T1)(T2); X represents: (a) -H, -( C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkoxy, -(C3-C7)cycloalkyl, -(5- or 6-member)heterocycle or -(7-10-member)bicycloheterocycle each of which is unsubstituted or substituted with 1, 2 or 3 of optionally substituted R8 groups; or (b) -phenyl, -naphthalenyl, or -(5- or 6-member)heteroaryl each of which is unsubstituted or substituted with 1 or 2 of independently specified in R7 groups; each Y is independently specified in O; A and B are independently specified in: (a) -H; or (c) A-B together can form a (C2-C6)bridge each can optionally contain -HC=CH- or -O- in a (C2-C6)bridge; wherein the 6-member ring containing a nitrogen atom which is condensed with Q group can be found in the endo- or exo- configuration in relation to the A-B bridge; or (d) A-B together can form the -CH2-N(Ra)-CH2- bridge wherein the 6-member ring containing a nitrogen atom is condensed with Q group, and can be found in the endo- or exo- configuration in relation to the A-B bridge; Ra is specified in -H or -(C1-C6)alkyl; Z represents -[(C1-C10)alkyl optionally substituted with R1]h-, wherein h is equal to 0 or 1; each R1 is independently specified in: (b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl3 -(C3-C7)cycloalkoxy, -(C6-C14)bicycloalkyl, -(C8-C10)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C7-C14)bicycloalkenyl, -(3-7-member)heterocyclyl each of which is unsubtituted or substituted with 1, 2 or 3 of independently specified in R8 groups;

or or (d) -phenyl, -naphthalenyl each of which is unsubstituted or substituted with R7 group; each R6 is optionally specified in -H; each R7 is independently specified in -(C1-C4)alkyl, -OR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, -halogen, -N(R9)2, -C(=O)OR9; each R8 is independently specified in -(C1-C4alkyl, tetrzolyl, imidazolyl, furanyl, -(C1-C6)alkylCOOR9, -OR9, -SR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, =O, -halogen, -N(R9)(C1-C6)alkylCOOR9, -N(R9)2, -N(R9)S(=O)2R12, -N(R9)C(=O)R12, -N(R9)C(=O)OR12, -C(=O)R9, -C(=O)N(T1)(T2), -C(=O)OR9, -OC(=O)R9, or -S(=O)2R9; each R9 is independently specified in -H, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -phenyl, -benzyl, -(5- to 6-member)heterocycle, -C(halogen)3; -CH(halogen)2 or -CH2(halogen); if h is equal to O, then R11 can be specified in -H, -C(=O)OR9 or -C(=O)N(R6)2 or R11 can be -(C1-C4)alkyl; if h is equal to 1, then R11 can be specified in -H; each R12 is independently specified in -H or -(C1-C4)alkyl; m is equal to an integer specified in 3, 4, 5, 6, 7, 8 or 9; each e and f is equal to an integer independently specified in 0 or 1, provided 2≤(e+f)≤5; each j and k is equal to an integer independently specified in 0 or 1, provided 1≤(j+k)≤4; each p is equal to an integer independently specified in 0 or 1; each T1, T2, and T3 is independently specified in -H or -(C1-C10)alkyl which is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups, or T1 and T2 together can form 5- to 8-member ring wherein the number of ring atoms contains a nitrogen atom wherein T1 and T2 are bound; the above 5- to 8-member ring is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups and optionally any carbon atom in the above 5- to 8-member ring is independently substituted with O or N(R6); each halogen is independently specified in -F, -CI, -Br or -I.

EFFECT: invention refers to the intermediate compounds of formula

, , for preparing the above compounds of formula (II), compositions containing the above compounds and to a method of treating or preventing a diseased state, such as a pain.

36 cl, 58 ex, 2 tbl

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