Acid-additive salts of terbinafine and malic acid, method for their preparing and pharmaceutical composition for treatment of fungal infection

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a novel terbinafine salt of the formula (I):

with malic acid possessing an antimycotic activity and to a method for its preparing and pharmaceutical composition used in treatment of fungal infection. L-(-)-bimalate is the most preferable form of salt. Method for preparing salt involves interaction of compound of the formula (I) as a free base with the corresponding form of malic acid. Pharmaceutical composition comprises indicated salt in combination with at least one pharmaceutically acceptable carrier or excipient. Pharmaceutical composition can be prepared as a solution or lacquer for nails. Proposed salt shows improved pharmacokinetic properties that makes its to be preferable in preparing pharmaceutical compositions adopted for systemic and topical using.

EFFECT: improved preparing method, improved and valuable properties of salt and pharmaceutical composition.

8 cl, 6 dwg, 5 ex

 

The invention relates to acid additive salts allylamine antifungal agents.

The invention relates to salts of compounds of formula I

and malic acid,

i.e. to form an acid additive salt of (E)-N-methyl-6,6-dimethyl-N-(1-naphthylmethyl)hept-2-EN-4-inyl-1-amine and malic acid, which is hereinafter abbreviated referred to as "compounds of the invention".

Compounds according to the invention are new and with improved pharmaceutical properties of salts are known compounds of formula I.

The connection according to the invention is in racemic or enantiomeric form. The connection is in the form of an acid additive salt, a malate or bimala, preferably bemalt. The malic acid fragment preferably is a racemic (DL)-(±)- or L-(-)-enantiomeric, preferably L-(-)-enantiomeric form. Thus, preferred are (DL)-(±)and L-(-)-simulate, primarily L-(-)-simulat.

Compounds according to the invention have the polymorphism. Under the scope of the invention covered by the compounds according to the invention in any polymorphic form, for example in form a or form B of L-(-)-simulate, which are described below.

The object of the invention is also a method of obtaining the compounds according to the invention, which is, is the connection of the formula I in free base form is subjected to interaction with the appropriate form of malic acid and allocate the resulting salt from the reaction mixture.

The method according to the invention can be implemented in a conventional manner, for example by carrying out the reaction in an appropriate inert solvent, such as isopropanol, ethyl ester acetic acid, isopropylacetate, Cyclopentanone, n-butanol or ethyl formate.

The compound of formula I in the form of an acid additive salt, and its equivalents, and its use as antifungal agents, for example for the treatment of mycosis caused dermatophyte infection, described inter alia in EP 24687. This compound is sold under the generic name terbinafine in free base form or acid additive salts of hydrochloric acid under the brand name of Lamisil®. In the scientific literature, for example in EP 515310 A1, also described two forms of the compounds as salts, namely lactate and ascorbate used in pharmaceutical compositions intended for topical application to the skin.

Terbinafine is an effective antifungal agent in oral and local application. It is effective against a wide spectrum of fungal diseases, including fungal sinusitus infections and onychomycosis. Most preferably it is used to fight against dermatophytes, contagious fungi that infect the dead skin tissue or derivatives of the skin, such as the corneal layer, nails and hair. Taco is nail fungus affects the nail bed, protected solid outer layer of the nail. Thus, if the infection has penetrated under the nail, the nail provides the fungus with a protective environment that allows you to grow the fungus. The impact of these fungi can cause unsightly appearance of the nails, fungi seriously complicate foot care, have a negative impact on overall quality of life of patients and their health, reducing the health of the patient. If untreated, the fungus can lead to deformity of the nails of the toes and cause pain when walking. In addition, the fungus can cause cracks in the skin, which is favorable for the occurrence of bacterial infections. As a result of such infections in people suffering from diabetes can have serious complications, such as diabetic foot, including primary associated with disease complications, such as gangrene, which in the end may be dangerous to human life or result in the need for amputation. Other subgroups of patients with high risk include patients infected with human immunodeficiency virus (HIV), patients suffering from acquired immunodeficiency syndrome (AIDS), and patients with other types of immunosuppression (for example, recipients of grafts and patients undergoing prolonged therapy with COI is by whether corticosteroids). Onychomycosis is more common in people in old age (60 years, the incidence increases up to 30%). The most common are diseases such fungi as Microsporum, Trichophyton, such as Trichophyton rubrum or Trichophyton mentagrophytes, and Epidermophyton, such as Epidermophyton floccosum. In medicine it is widely known that onychomycosis is difficult diagnosis and treatment, especially in patients in old age.

Terbinafine may also be used for the treatment of onychomycosis of the nail toes and nails fingers (plicarum nails caused by dermatophytes. In particular, the terbinafine is allowed for the treatment of plicarum nails caused by Trichophyton. For example, it was found that treatment of the toes previously used standard drug by griseofulvina proved to be ineffective, because the treatment they require 1-2 years, as a rule, relapse and complete cure is unlikely.

In oral administration for the treatment of onychomycosis of terbinafine hydrochloride, normally injected once a day in tablet form with quick release, containing 250 mg of terbinafine. Such tablet, marketed under the trademark Lamisil®provides release 80% terbinafine for 30 min according to the standard studies of solubility in terms of the s in vitro, conducted, for example, by the method using a blade mixer at pH 3. The duration of treatment with terbinafine is 12 weeks. Its clinical effect is that to happen the growth of healthy nail, displacement and replacement with unsightly diseased nail, where debris and dead fungi. For the formation of a completely renovated nail takes approximately 10 months.

Although, as a rule, it is considered that the terbinafine is as safe as any permitted use of the drug, there is information about the side effects associated with its use. Identified a large number of side effects, such as headaches, gastrointestinal symptoms (including diarrhea, dyspepsia, abdominal pain, nausea and flatulence), anomalies detected during the study of the liver (e.g., enzyme abnormalities), dermatological symptoms such as itching, hives and rash, and taste disorders, such as loss of taste. Such adverse action, as a rule, are weak and short-lived. Other adverse effects include symptomatic of idiosyncratic hepatobiliary dysfunction, (e.g., cholestatic hepatitis), expressed skin reactions such as Stevens-Johnson, neutropenia and thrombocytopenia. Chrome is also adverse action can lead to visual impairment, such as changes of the crystalline lens and retina, as well as allergic reactions, including anaphylaxis, fatigue, vomiting, arthralgia, myalgia and hair loss. Terbinafine is a strong inhibitor of CYP2D6 and can lead to clinically relevant side effects when combined with the introduction of drugs, which represent substrates for this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, enkainid and propafenone. Below in the present description, all such manifestations in abbreviated form are called side effects.

Pharmacokinetic and biopharmaceutical properties terbinafine hydrochloride are well-known. It is known that it is well absorbed. Peak concentrations of the drug in plasma (below referred to asmaxcomprising approximately 1.3 µg/ml (accounting for approximately 20%of the variations are, for example, from 0.9 to 1.6 μg/ml)are achieved in humans after 1-2 h after administration of a single dose of terbinafine 250 mg, the Area under the curve when measuring dependence within 24 hours (below denoted as AUC) approximately 4,76 mcg·h/ml When introducing terbinafine with food high in fat value AUC increased by 42%. For patients with pacec the second failure (for example, with creatinine clearance ≥50 ml/min) or cirrhosis, the clearance of terbinafine is reduced by approximately 50%. In the steady state, for example, when the troughs and the peaks are constant after taking the drug for several days, Withmaxabove 25%, but AUC exceeds 2.5 times the corresponding parameters achieved by the introduction of a single dose. These data are consistent with an effective half-life of terbinafine, constituting approximately 36 hours

Pharmacokinetics and absorption properties are described, for example, J.Faergemann and others, Acta Derm. Venereol. (Stockh.) 77 (1997), cc.74-76. However, the region of absorption of terbinafine is unknown and there is no proven clinical conditions, the correlation caused by actions pharmacokinetic profile, so there is no rational background for development containing terbinafine pharmaceutical forms having improved therapeutic effect.

Despite the very important role terbinafine known cases of adverse side effects was an obstacle to its wider application or administration by mouth. Some problems identified in the case of oral administration of terbinafine hydrochloride, led inevitably to the limitations of therapy with the use of terbinafine for the treatment of is not very aresnic or non-hazardous medical conditions, for example plicarum of the feet (Tinea pedis).

With the invention it has been unexpectedly found that salts of the compounds of formula I and malic acids have particularly favorable pharmacokinetic properties and, in addition, it was found that they possess a unique combination of properties that are advantageous from the point of view of preparation of the composition, which makes them particularly preferred for the preparation of pharmaceutical compositions terbinafine adapted for systemic and local application.

So, when systemic use of malate, the compounds of formula I of the variability of pharmacokinetic parameters is significantly less than when using the known salts or free bases of the compounds, for example the hydrochloride.

This is proved, among other things, in pharmacological research on animals, which was conducted in seven dogs breed Beagle approximately 5 years of age, weighing approximately 10 kg, which was administered oral capsules, obtained by mixing the active substance, representing salt terbinafine [hydrochloride or L-(-)-simulat; equivalent to 62.5 mg of the compound in the form of the base in capsule], lactose mass ratio of 1:1 and filling the mixture of the corresponding hard gelatin capsules (size distribution of the particles which was the same for both salts).

It was found that the variability in the concentration of terbinafine in plasma between different animals (expressed as coefficient of variation [below in the present description designated as CV] area under the curve [AUC] with the introduction of L-(-)-simulate terbinafine (30%) is noticeably reduced compared to the variability in the introduction hydrochloride (39%). Obtained the average AUC values were, respectively, 392 and 348 ng·h/ml, was observed even a small increase in the absolute concentration in plasma when using simulate.

Obtained in this experiment, the average values Withmaxwas 134 and 146 ng/ml, respectively for L-(-)-simulate and hydrochloride, the CV values were, respectively, 26 and 47%, which further demonstrates the reduction of the variability of pharmacokinetic parameters using the malate.

Based on these data, it can be expected that the person will be similar to the reduced variability of pharmacokinetic parameters, and as a result, it is possible to achieve a more stable efficiency in the treatment with the use of terbinafine as antimycotic tools, even when used in very high doses, in particular, by oral administration, for example, in the treatment of onychomycosis oral.

In addition, the connection is possible according to the invention can be applied topically, such as a nail, as it follows from the results of the following analysis of the in vitro penetration/distribution:

Experience using nails of the toes of the corpse were performed in the camera Franz (figure 1), which was modified in order that it could fix the nail of the toe of the corpse of the person by means of two elastic rings made of silicone elastomer (polydimethylsiloxane (PDMS)), which has good bonding properties for the corresponding fastening solid nail, for measurement of radioactivity in the acceptor chamber used liquid scintillation counter (Sands (with the level of sensitivity of the order of picograms). Each experiment was carried out in three replications. 90 randomly selected nail maintained for 72 h in a solution containing 100 μl of labeled using14From terbinafine hydrochloride or L-(-)-simulate (form A) [solution 25 mkbk/ml; 1% active substance; 5% 1,2-propylene glycol; 2% Cetomacrogol-1000®(polyoxyethyleneglycol-1000-monoacetate); 25% 94%ethanol; 67% distilled water] (wt.%). The surface of each nail, which was subjected to composition, had a diameter of 9 mm (approximately 64 mm2). The exposure was carried out in a sealed (Luggage, which did not penetrate the air) and leaky (camera, in which both the cal air) conditions.

Bearing a radioactive label product was identified in the filled buffer receiving chamber after incubation for about 8 hours as measured using Sands, its concentration in the receiving chamber increases with increasing time of incubation and concentration of the applied composition. The experiment was carried out in parallel in 24 cameras to study entry. Each composition were tested in three replications.

The results are shown in figure 2: as in tight (black dots)and non - (black squares) conditions after 72 h was identified significant level of penetration (about 63 and 41 ng).

In addition, with the invention it has been unexpectedly found that the compounds according to the invention have the preferred properties from the point of view of preparation of the composition. So, they are more easily form crystals than a connection in the form of hydrochloride or free base. In addition, the crystals, for example, L-(-)-simulate can exist in different polymorphic forms. Polymorphs have different speeds of dissolution, the milling characteristics and stability, for example, in galenical forms, in which the pharmaceutical active substance is in solid form, such as tablets or suspension, and have different bioavailability. Unexpected cash is Chiyo polymorphism gives an advantage from the point of view of processing, for example, in the case of polymorph with considerable thermodynamic stability in compositions in which the compound is present in solid form, for example tablets or suspensions, or polymorph characterized by a particularly high rate of dissolution or solubilization, compositions containing the dissolved compound, such as lipsticks. Thus, the compounds according to the invention are more suitable for processing, for example, in the case of large-scale production of tablets; they also have the preferred properties of penetration/distribution and therefore they are easy to include in compositions for topical application, such as lipsticks. In addition, they have good solubility in water and in many organic solvents, which is a prerequisite for good biological availability: at 25°L-(-)-bimala has a solubility in water of up to about 12-14 mg/ml and >30 mg/ml in ethyl acetate compared to 6.7 mg/ml in water and 0.7 mg/ml in ethyl acetate for hydrochloride. In addition, compounds are hygroscopic, which allows you to create a stable composition with minimal risk to their inherent chemical decomposition.

Thus, these compounds have a unique combination of good characteristics from the point of view of education is otki, good solubility and lack of hygroscopicity, which makes them most suitable for the preparation of pharmaceutical compositions comprising terbinafine.

In addition, the objects of the invention are:

pharmaceutical composition comprising a compound according to the invention in combination with at least one pharmaceutically acceptable carrier or diluent,

pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, non-acid additive salts of malic acid, when it is obtained from the compounds according to the invention,

connection according to the invention, intended for use as pharmaceutical agents,

connection according to the invention intended for use in the preparation of medicines,

connection according to the invention when it is received as described above

the compound of formula I in free base form or salt, other than the acid additive salts of malic acid, when it is obtained from the compounds according to the invention,

- the use of compounds according to the invention for preparing a medicinal product intended for the treatment of, for example, by oral administration, diseases, such as fungal diseases, support the developing treatment using the compounds of formula I in free base form or in salt form,

a way of producing a pharmaceutical composition, providing a mixture of compounds according to the invention with at least one pharmaceutically acceptable carrier or diluent, and

a method of prophylaxis or therapeutic treatment of fungal diseases, such as fungal sinusitis or onychomycosis, namely, that the patient in need of such treatment is administered a therapeutically effective amount of the compounds according to the invention.

Pharmaceutical compositions containing a compound according to the invention preferably include the standard dose of the drug, for example, by filling the shells of capsules, such as soft or hard gelatin shells of capsules, or by tabletting, or using any other forming process. Thus, the invention proposed a standard dose of a medicinal product intended for administration once or twice a day, for example, depending on the particular purpose of therapy, the phase of therapy, etc. that contain respectively the half or full daily dose. Such compositions can be entered two or three times a week. Preferably the composition is administered once a day.

The number of compounds according to the invention, of course, may vary depending, for example, from the content of the other component is in, route of administration and the desired treatment. However, as a rule, the connection is present in an amount of from about 0.1 to about 35% based on the weight of the entire composition. The total daily dose of the active substance (in terms of number of compounds in free base form) is, for example, from about 50 to about 500 mg per day, for example, 250 mg / day or 400, 600, or 700 mg / day, which is convenient to introduce, for example, in divided doses up to 4 times a day. The standard dose of the drug include, for example, from about 12.5 to about 800 mg of the compounds according to the invention (in terms of number of compounds in free base form) in a mixture of at least one solid or liquid pharmaceutically acceptable carrier or diluent.

Compounds according to the invention can be activated by a method similar to the method of introduction of the standard drugs used for such indications.

They can be mixed with normal acceptable with chemotherapeutic perspective carriers or diluents and optionally with other excipients and enter, for example, orally, for example in the form of such compositions, such as tablets and capsules. The preferred composition is in the form of tablets contains the compound according to the invention, the substance which assists the pressing, is the such as microcrystalline cellulose, Supplement to ensure Shine tablets, such as anhydrous calcium phosphate, baking powder, such as glycolate, starch sodium, and a lubricant such as magnesium stearate. The preferred composition is in the form of a capsule contains a compound according to the invention, an inert diluent and described above anhydrous baking powder and lubricant.

Alternatively, the compound can be applied topically, for example in the form of compositions, such as lotions, solutions, ointments or creams, for example, nail Polish, or parenteral or intravenous. The concentration of the active ingredient, of course, may vary, for example, depending on the compounds according to the invention, the desired treatment and the applied nature of the form or composition. In General, satisfactory results are obtained, for example, when using the compositions for topical application having a concentration of active ingredient from about 0.1 to about 10 wt.%, preferably from about 0.5 to about 2 wt.%, most preferably about 1 wt.%.

Thus, in the present invention proposed new songs terbinafine containing compounds according to the invention, which allow to eliminate or significantly reduce encountered still problems treatment using terbinafi the and. In particular, they may contain terbinafine in fairly high and constant concentrations, which allows easy introduction by mouth once a day, at the same time provides better safety and tolerability from the point of view of reducing side effects.

Thus, the present invention can reduce the number of treatments terbinafine necessary for effective therapy, by reducing the duration of treatment with terbinafine and improve the overall security profile. In addition, it allows for a more precise standardization, and optimization of the design requirements necessary daily doses for individual patients undergoing therapeutic treatment with terbinafine, as well as for groups of patients undergoing the same therapy. More accurate standardization of therapeutic regimens designed for individual patients, can reduce the magnitude of the doses for specific groups of patients, and to reduce the requirements for modes that must be followed, which leads to a considerable reduction in the cost of treatment.

Additional pharmacokinetic characteristics of the pharmaceutical compositions containing compounds according to the invention, it is possible to define elati using standard pharmacological experiments (biological availability) in humans and animals. For example, one such standard pharmacological experiments can be performed on healthy non-Smoking volunteers, men or women, aged 18-45 years, with a weight that differs by no more than 20% of their ideal body weight. The experience may include a crossover single dose. Patients are home within 24-hours blood Samples are taken through 1, 2, 4, 8, 16, 32 and 72 h after injection of the pharmaceutical composition containing the compound according to the invention, and analyze the content of terbinafine. The concentration of terbinafine in blood or plasma, you can define a standard method, for example, using analytical methods GHWR/UV or LC-MS. Safety assessed after 1 week on the basis of the results of the standard survey related symptoms side effects. Preferably the daily dose of salt terbinafine 400, 600, or 700 to 800 mg in terms of the number of terbinafine in the form of a Foundation. At this dose the safety of terbinafine in a short period of treatment is high. Oral compositions according to the invention preferably provide value Withmaxmaking 100-250%, for example 100-150%, compared to a tablet with quick release, containing 250 mg of terbinafine hydrochloride, for example, with the introduction of a single dose and/or at a constant Leche is NII, for example, with the introduction of once a day for 7 days.

Pharmacokinetic studies of the effects of the concentration of the drug to the skin and nails can be done according to the same methods described above for standard pharmacological experiments. For example, clinical experience may be conducted using daily doses of the compositions containing the compound according to the invention, when processing for 3 weeks.

Tablets containing compounds according to the invention can be applied in the same testimony, and tablets with quick release on the basis of terbinafine hydrochloride. The applicability of the compounds according to the invention can be assessed in standard clinical tests or standard models with animals. For example, we can estimate the dose of the compositions containing the compound according to the invention, which provide levels (AUC) of terbinafine in plasma, equivalent to AUC levels in the plasma, providing the same therapeutic effect as well-known oral dosage forms of terbinafine hydrochloride, for example, in the form of tablets. Pharmaceutical compositions containing a compound according to the invention, in particular, have a surprisingly high tolerance from the viewpoint of the above side effects, they cause less side effects when combined with the introduction of CYP2D6 substrates such as nortriptyline, the desipramine, perphenazine, metoprolol, enkainid and propafenone.

In patients with onychomycosis of the toenails feet, the diagnosis of which was confirmed by microscopy and analysis of culture, it is possible to carry out a randomized, double-conducted blind study using positive control and monitoring using a placebo. The treatment is carried out for 12 weeks. To assess the absence of side effects in clinical trials should be carried out on several hundred patients. However, therapeutic efficacy can be assessed on the basis of test results of 25 patients older than 12 years. Safety is evaluated on the basis of the questionnaire about side effects related to the clinical aspects and vital signs. The efficiency is determined using microscopy, cultivation procedures and visual assessment of signs and symptoms. Compounds according to the invention is effective against the above fungi, especially Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum. In the group of patients includes patients with predisposing factors such as poor circulation, peripheral neuropathy, diabetes, damage due to repeated small injuries, and limited disturbance of the immune system, and AIDS. Patients have (I) distal the first lateral subungual onychomycosis, beginning in hyponymy and extending proximally in the bed and nail matrix, (II) proximal subungual onychomycosis, in which the fungus affects the cuticle or eponychium, reaching a matrix, then it is concluded in the substance of the nail plate, (III) the total dystrophic onychomycosis and (IV) superficial white onychomycosis. If necessary, the concentration of terbinafine in plasma is possible to define a common method or in accordance with the present description. The concentration of terbinafine in the nail can be estimated by cutting the nail and its subsequent analysis.

Description of the drawings

The drawings show:

figure 1: schematic diagram of the camera Franz,

figure 2: results of analysis of penetration/distribution: the number detected in the receiving chamber (ng), depending on the time (in h) in practice, using a 1%solution (L)-(-)-simulate terbinafine:

black squares: untight conditions;

black dots: in airtight conditions

figure 3: picture of the x-ray diffraction on the powder for the polymorphic forms And L-(-)-simulate terbinafine (examples 1 and 3),

figure 4: picture of the x-ray diffraction on the powder for the polymorphic form B of L-(-)-simulate terbinafine (example 2),

figure 5: picture of the x-ray diffraction on the powder for D-(+)-simulate terbinafine (primer),

6: picture of the x-ray diffraction on the powder for DL-(±)-simulate terbinafine (example 5).

Refer to figure 3-6: cps - signal intensity (number of pulses per second); Deg - diffraction angle (in degrees).

The invention is illustrated in more detail in the examples below. All temperatures are given in degrees Celsius, tPLdenotes the melting temperature.

Example 1: L-(-)-bimala terbinafine (polymorphic form A)

15,54 g (53,32 mmole) of terbinafine in the form of a base and 6,79 g (50,65 mmole) of L-(-)-malic acid is dissolved in 125 ml of ethyl acetate at 60°C. the Solution is cooled to 0°With slow crystallization. After maturation for 2 days at 4° deposited only a small number of crystals. After that, the mixture was stirred at 0°C. After stirring for 8 h thick suspension is diluted with 50 ml ethyl acetate. The mixture is filtered. Filtering is slow. The filter cake was washed with 60 ml of ethyl acetate at 0°and dried at 50°C/10 mbar for 20 h In the result mentioned in the title compound in the form of A (thin white powder; tPL˜96°C; solubility at 25°From: in ethanol, the mixture ethane/water 2:8.about. and in ethyl acetate >30 mg/ml; water ˜12 mg/ml

Elementary analysis:

Calculated: 70,57%; 7,34% N; 3,29% N; 18,80%

About arozena: 70,35%; 7,39% N; 3,13% N; 18,94%

Picture of x-ray diffraction on the powder is shown in figure 3.

Example 2: L-(-)-bimala terbinafine (polymorphic form B)

to 200.0 g (686,2 mmole) of terbinafine in the form of a base and 92,02 g L-(-)-malic acid is dissolved in 1500 ml of ethyl acetate at 60°C. Then clear the solution is allowed to cool slowly. At a temperature of 32°add 29,2 g of seed crystals of form B of L-(-)-simulate terbinafine (obtained according to the method described below) and the suspension is stirred at room temperature (20-25°C) for 20 hours and Then the mixture is cooled for 2 h to 3°C and stirred for 4 h at the same temperature. The resulting precipitate filtered. The crystals are dried at 50°and a pressure of 10 mbar for 20 h In the result mentioned in the title compound in the form B (white powder; tPL˜96°C; solubility at 25°With water: 15 mg/ml; [α]20=+7.2V°s at 365 nm in methanol) (to control the magnitude of the positive rotation of 100 mg of the obtained salt is dissolved in 2 ml of methylene chloride, add 3 ml of 0,2n. NaOH and measure the angle of rotation for the aqueous phase containing the free L-(-)-malic acid: α20=-0,134°at 546 nm).

Elementary analysis:

Calculated: 70,57%; 7,34% N; 3,29% N; 18,80%

Found: 70,54%; 7,37% N; 3,26% N; 18,75%

Picture of x-ray diffraction l is whose on the powder is shown in figure 4.

Seed crystals of form B was obtained as follows:

19,57 g terbinafine-shaped base and 8,55 g L-(-)-malic acid are dissolved in 160 ml of ethyl acetate at 50°C, then the solution is cooled for 1 h to 25°C and seeded with 5 mg of crystals of L-(-)-simulate terbinafine (form A), obtained according to the method described in example 1; the resulting mixture is allowed to stand without stirring overnight (18 h), then slowly stirred at room temperature; the resulting gelatinous mixture is heated to 50°C, the resulting clear solution is cooled to 25°C and re-inoculant 10 mg of crystals of L-(-)-simulate terbinafine (form A); then the mixture is allowed to stand for 3 days at room temperature without stirring. Then the resulting mixture is again gently mixed, after which there is a slow crystallization. After additional stirring for 24 h at room temperature the mixture is stirred for 3 h at 3°C, filtered and dried. The result is L-(-)-bimala terbinafine in form B.

Example 3: L-(-)-bimala terbinafine (polymorphic form A)

400,0 g terbinafine-shaped base (1,3725 mol) and 180,34 g L-(-)-malic acid (1,3450 mole) is dissolved in 3200 ml of isopropanol at 35°C. the Solution is cooled to 25°C for 45 min and inoculated 5,72 g L-(-)-Bima is ATA terbinafine in the form of A (obtained according to the method described in example 1). After stirring at room temperature for 27 h thick suspension was filtered. Filtering is slow. The crystals are washed with 500 ml of isopropanol and dried at 50°C/15 mbar for 24 hours of the result is specified in the title compound in the form of A (thin white powder; tPL˜96°C; solubility at 25°C in ethanol >50 mg/ml in ethyl acetate >30 mg/ml in water: ˜12 mg/ml).

Elementary analysis:

Calculated: 70,57%; 7,34% N; 3,29% N; 18,80%

Found: 70,47%; 7,12% N; 3,40% N; 18,60%

Picture of x-ray diffraction on the powder is shown in figure 3.

Example 4: D-(+)-bimala terbinafine

to 8.70 g (29,8 mmole) of terbinafine in the form of a base and of 4.00 g (29,8 mmole) of D-(+)-malic acid is dissolved in 100 ml of ethyl acetate at 50°C. a Clear solution is allowed to cool slowly and at 25°C add 254 mg of seed crystals of D-(+)-simulate terbinafine (obtained according to the method described below). Slow crystallization and the mixture is stirred at room temperature (20-25° (C) for 63 hours a Thick slurry is subjected to filtration. Filtration is very slow. The filter cake was washed with 20 ml of ethyl acetate and dried for 20 h at 50°C/10 mbar. The result is specified in the header connection (tPL˜96°C; solubility PR is 25° C in water: ˜7 mg/ml, glut, [α]20=-7,0°C at 365 nm in methanol) (for the control value of the negative rotation 100 mg of the obtained salt is dissolved in 2 ml of methylene chloride, add 3 ml of 0.2 N. NaOH and measure the angle of rotation for the aqueous phase containing free D-(+)-malic acid: α20=+0,137° at 546 nm).

Elementary analysis:

Calculated: 70.57%; 7,34% N; 3,29% N; 18,80%

Found: 70,42%; 7,45% N; 3,20% N; 18,92%

Picture of x-ray diffraction on the powder is shown in figure 5.

The seed crystals was obtained as follows:

4.35 g of terbinafine in the form of a base and 2.00 g of D-(+)-malic acid is dissolved in 35 ml of isopropanol at 80°C. the Solution is cooled for 30 min to 25°C and is made of 20 mg DL-(±)-malate terbinafine (obtained according to the method described in example 3). Then there is a very slow crystallization. After stirring for two days at room temperature, is deposited only a small amount of crystals. The suspension is filtered and the filter cake washed with 5 ml of isopropanol. The crystals are dried at 50°C/10 mbar for 20 h In the result of crystalline D-(+)-bimala terbinafine.

Example 5: DL-(±)-bimala terbinafine

The suspension containing an 8.70 g of terbinafine in the form of a base or 29.8 mmole) and of 4.00 g of DL-malic acid (29,8 mmole) at listello 70 ml isopropanol, heated to 80°C and get a clear solution. The solution is allowed to cool slowly. At 25°C add 10 mg of L-(-)-simulate terbinafine (polymorphic form a, obtained according to the method described in example 1). The mixture is stirred for 7 h at room temperature. The formed precipitate is filtered and the filter cake washed with 30 ml of isopropanol. The crystals are dried at 50°C/10 mbar for 20 h In the result mentioned in the title compound (white powder, tPL˜107°C; solubility at 25°C: ethanol >50 mg/ml in ethyl acetate ˜17 mg/ml in water: ˜7 mg/ml).

Elementary analysis:

Calculated: 70,57%; 7,34% N; 3,29% N; 18,80%

Found: 70,49%; Of 7.36 N; 3,16% N; 18,82%

Picture of x-ray diffraction on the powder is shown in Fig.6.

1. Salt of the compounds of formula I

and malic acid.

2. The compound according to claim 1 in the form of L-(-)-simulate.

3. A method of obtaining a compound according to claim 1, characterized in that the compound of formula I in free base form is subjected to interaction with the appropriate form of malic acid and allocate the resulting salt from the reaction mixture.

4. Pharmaceutical composition for treating a fungal infection that contains the compound according to claim 1 in combination with at least one pharmaceutically acceptable wear elem or diluent.

5. The pharmaceutical composition according to claim 4, which is the composition in the form of a solution.

6. The pharmaceutical composition according to claim 4 or 5, which is the composition in the form of nail Polish.

7. The compound according to claim 1, having antimycotic activity.

8. The compound according to claim 1, intended for the preparation of drugs having antimycotic activity.



 

Same patents:

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to derivatives of allylamines, namely, to a method for preparing terbinafine or its hydrochloride. Method involves interaction of N-methyl-naphth-1-yl-methylamine taken in excess with 1-halogen-6,6-dimethylheptene-2-ene-4-ine in water or inorganic base an aqueous solution followed by, if necessary, treatment of prepared product with hydrochloric acid. As a rule, as the parent reagent both 1-bromo-6,6-dimethylhept-2-ene-4-ine and 1-chloro-6,6-dimethylhept-2-ene-4-ine is used. Usually 5-50% mole excess of N-methyl-naphth-1-yl-methylamine is used in case using inorganic base. Method provides enhancing yield of the end compound, to simplify the process and to expand the raw base by using the more low-priced 1-chloro-6,6-dimethylhept-2-ene-4-ine as an alkylating agent.

EFFECT: improved preparing method.

3 cl, 3 ex

The invention relates to a new method of obtaining (E)-N-methyl-N-(1-naphthylmethyl)-6,6-dimethylheptyl-2-EN-4-inyl-1-amine of the formula (I) or its acid salt additive

The invention relates to new compounds of the formula I or II or compounds selected from the following group, with activity against receptor calcium, pharmaceutical compositions and methods of treating diseases caused by abnormal mineral homeostasis, hyperparathyroidism, hypercalcemia, malignant tumors, osteoporosis, hypertension and renal osteodystrophies

The invention relates to medicinal chemistry, to methods for obtaining compounds of compounds possessing the ability to inhibit holinesterzy and thereby improve the functioning of the brain in older people

FIELD: medicine.

SUBSTANCE: method involves applying traditional conservative therapy comprising hemosorption, hemodialysis, plasmapheresis during the first decompression hours. Perfluorane is additionally introduced as single dose of 6 ml/kg of body mass. Then, hyperbaric oxygenation is immediately carried out and the conservative therapy is continued.

EFFECT: enhanced effectiveness in saturating blood with oxygen the general blood circulation and microcirculation flow; increased oxygen delivery to ischemic tissues; reduced endotoxicosis phenomena.

FIELD: medicine, cardiosurgery.

SUBSTANCE: the present innovation deals with complex procedures for carrying out open-heart operations associated with high blood losses and considerable requirement for blood-substitution therapy. It is necessary to carry out preoperational autoblood sampling in cardiosurgical patients due to a single exfusion of 5-10% volume of patient's circulating blood and its conservation, moreover, 1-2 d before autoblood sampling it is necessary to conduct total hypoxic sample, detect the values of oxygen balance and lactate concentration in blood serum and at its values being SpO2>85%, SvO2>60%, O2EI<30 and the absence of lactate concentration growth at the background of 40-min-long respiration with hypoxic gaseous mixture with 10%-content of oxygen one should consider tolerance to hypoxia to be high and sample autoblood at the quantity of 10% against total volume of circulating blood; at physiological ability of a patient to breathe for 40 min with hypoxic gaseous mixture with 12%-content of oxygen it is possible to consider tolerance to hypoxia to be average and sample autoblood at the quantity being not more than 7% against the volume of circulating blood, and at physiological ability of a patient to breathe with hypoxic gaseous mixture only at the content of oxygen being under 14% tolerance to hypoxia should be stated to be low and, thus, one should sample not more than 5% against the volume of circulating blood. The innovation decreases postoperational complications, increases efficiency of hemotransfusional therapy due to individualized approach for detecting optimal quantity of autoblood sampled.

EFFECT: higher efficiency of sampling.

3 ex

FIELD: abdominal surgery, pulmonology, and immunology.

SUBSTANCE: abdominal cavity is first treated by hyperthermal perfusion with solution containing electrolytes, proteins, and dextrans at 41-42°C in solution and pressure 25-40 mm Hg, where solution is introduced at velocity 1.5-2 L/min. Exhausted solution is passed through filter sorbent and cleaned solution is reused for treatment of abdominal cavity. Exhausted solution cleaning procedure and reuse of cleaned solution is repeatedly performed during 20-30 min, whereupon abdominal cavity is subjected to treatment for 7-10 min by high-frequency insufflation with therapeutical aerosol and, 4-24 h later, above insufflation is performed for 10-15 min. In sum, patient is subjected to 2-4 sessions of combined treatment by hyperthermal perfusion and high-frequency insufflation with therapeutical aerosol and 4-8 sessions of high-frequency insufflation with therapeutical aerosol.

EFFECT: achieved cleaning of inclined sectors of peritoneum and pockets thereof, which contributes to reduction of postoperative complications.

3 ex

FIELD: medicine.

SUBSTANCE: method involves intraperitoneal treatment with Furacilini solution. Intravenous injection of 0.4% sodium hypochlorite solution is administered after the operation at a dose of 1/10 of circulating blood volume. 10-12 h later, it is administered for the second time at the same dose. Ultraviolet blood irradiation is applied at the next day after the operation in treating 1.5-2.0 ml of blood per 1 kg of patient body weight with irradiation power of 150 W/m. The treatment is applied every other day not less than 3-4 times.

EFFECT: increased blood thyroxin concentration.

1 tbl

FIELD: veterinary science, surgery.

SUBSTANCE: method involves applying the application of mixture comprising glue base with ligfol and Novocain on infected surface taken in the ratio, wt.-%: ligfol, 70; Novocain, 30. Method allows decreasing time for treatment of suppurative wounds by 1.5-2 times, economy of dressing material and time that improved labor conditions of veterinary expert. Invention can be used in treatment of suppurative wounds both aerobic and anaerobic etiology.

EFFECT: improved treatment method.

1 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with ways for purifying blood plasma in burnt patients followed by applying the plasma obtained either while carrying out the next plasmapheresis or as independent transfusion medium. For this purpose, it is necessary to carry out plasmapheresis in burnt patients. Heparin should be added into plasma removed during plasmapheresis and, additionally, hemodesis, followed by incubation at +4° C for about 5-18 h, then it should be centrifuged for depositing cryoprecipitate. The innovation suggested enables to alter conditions of cryoprecipitation so, that it is possible to increase precipitation of fibrinogen and fibrin-monomeric complexes, the quantity of which is sharply observed in burnt patients.

EFFECT: higher efficiency of purification.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves making surgical intervention after Widman with patient blood taken in the amount of 10-20 ml before placing flap. The blood is centrifuged during 11-13 min at 2400-2800 rpm and divided into 3 fractions like erythrocytes, plasma of high blood platelets content and plasma of low blood platelets content as a result of the treatment. The plasma of high blood platelets content is taken from laboratory glass and mixed with beta-tribasic calcium phosphate powder in proportion of 1:3. Then, the produced mixture is placed into defect zone and the flaps are fixed with sutures.

EFFECT: no additional surgical intervention needed; excluded allergic responses.

FIELD: medicine, surgery.

SUBSTANCE: method involves using dimexide 100% solution in 2% Novocain taken in the ratio 1:1 that is used as a compress for 30 min. Invention promotes to enhancing the effectiveness of preoperational treatment in simultaneous effect on pain endings. Invention can be used in carrying out preoperational treatment of skin.

EFFECT: improved treatment method.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with preventing hemodynamic complications at restoring circulation in a prolongly ischemized limb, or due to premeditated tourniquet application during operative interference. For this purpose, 5-12 min before the onset of circulatory restoration it is necessary to start intravenous injection of antihistamine and glucocorticosteroid preparations, followed by drop-by-drop infusion of inhibitors of proteolytic enzymes which should be continued after tourniquet removal, as well. The method provides tourniquet shock and tourniquet shock-associated complications along with developing the chance for increasing the duration period of operation.

EFFECT: higher efficiency of prophylaxis.

3 ex

FIELD: medicine, proctology.

SUBSTANCE: the present innovation deals with introducing a sclerosing preparation consisting of equal parts of 96% alcohol and 2% lidocain at the quantity of 2-4 ml, for all fissures it is necessary to inject 10 ml 0.5%-novocain solution and 2 ml solcoseryl or actovegin, then one should change the direction to move a needle towards coccyx towards sphincter's external diameter to introduce 5 ml 0.5%-Novocain solution and, not shifting a needle, one should introduce a sclerosing preparation. The innovation enables to conduct simultaneously the following procedures: anesthesia, the rupture of adhesions, blocking painful and sensitive branches of pudendal nerve that innervate ulcerous area that leads then to decreased pain syndrome, decreased sphincter's spasm and better ulcer's healing.

EFFECT: higher efficiency of sclerotherapy.

2 dwg, 2 ex

FIELD: medicine, pharmaceutical industry.

SUBSTANCE: invention relates to composition for peroral administration based on paracetamole remantadine, ascorbic acid rutine, loratadine and calcium gluconate. Claimed agent contains two different capsules or tablets which after administration provide therapeutic effect. Agent has febrifuge, antiviral, anti-inflammation, anti-allergic, etc. action, stimulates secretion of interferon-alpha and interferon-beta, and makes it possible to reduce time of influenza and viral infection treatment by 2-3 days.

EFFECT: stable pharmaceutical composition of prolonged storage time useful in large scale production.

10 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel O-substituted derivatives of 6-methyltramadol of the general formula (I) being optionally as their racemates, their pure stereoisomers but primarily as enantiomers or diastereomers, or as mixtures of stereomers being primarily as enantiomers or disatereomers in any their ratio in the mixture as a presented formulation or as their physiologically compatible salts. In the general formula (I) the value R means hydrogen atom (H), (C1-C3)-alkyl that can be saturated or unsaturated, branched or a direct, unsubstituted or substituted with -O-(C1-C3)-alkyl-group or OH-group, -CH2-(C4-C6)-cycloalkyl, (C4-C6)-cycloalkyl or thienyl group. Also, the invention relates to a method for synthesis of compounds of the general formula (I) by interaction of 2-dimethylaminomethyl-6-methylcyclohexanone of the formula (I) with metal-organic compound of the formula (III) wherein Z means Li; R has values given in the formula (I). The synthesized compounds of the formula (I) if necessary are converted to their physiologically compatible salts and/or racemates that are subjected for cleaving. Also, invention relates to a pharmaceutical composition.

EFFECT: improve method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 sch, 2 tbl, 30 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: it is necessary to carry out complex therapy including introduction of lidase, tactivin, dexason, coffeinum, nootropil, halidor, emoxipin, proserinum, actovegin, vinpocetine, cerebrum compositum, mildronate, dibasol, Magne-B6 and gliatilin at certain dosages and ways of injection, in combination with hirudotherapy, electrostimulation of optic nerve, electrophoresis with lekosym and magnetostimulation in superciliary, frontal, parietal and occipital areas. The suggested innovation improves acuity due to improved microcirculatory and metabolic processes in encephalon and optic analyzer.

EFFECT: higher efficiency of therapy.

1 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to using substituted derivative of 6-dimethylaminomethyl-1-phenylcyclohexane of the formula (I) for preparing a medicinal agent designated for treatment of more frequent urge for urination and enuresis, respectively. Proposed medicinal agent possesses less adverse effects and/or analgesic effects.

EFFECT: improved and valuable medicinal properties of compounds.

12 cl, 2 tbl, 3 ex

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