Synthesys of hydrated 4-amino-5-chloro-2-methoxy-n-(1-aza-bicyclo[3,3,1]non-4-yl)benzamide hydrocloride polymorph

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to new crystalline form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, including 2 moles water to 1 mole (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, the form II content being equal 75% and more; the above form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3,3,1]non-4-yl)benzamide hydrochloride has one or more optional properties, as follows: a) form II infrared spectrum include characteristic peak at 835±1.5 cm-1; b) X-ray pattern obtained on the above form powder is essentially corresponds to image Fig. 21; and c) water content rates 8.3% to 9.8%. The invention relates also to the form II ofhydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride production methods, to the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, and the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride identification method, as well as to pharmaceutical composition and treatment method for gastrointestinal motility impairment related disorders.

EFFECT: composition has improved properties for medical applications.

22 cl, 1 ex, 11 tbl, 22 dwg

 

According to the present invention, a method of preparing form II hydrate renzapride hydrochloride. In addition, the present invention provides for obtaining crystalline form II hydrate renzapride hydrochloride when its content in the amount of 75% or higher and its application in medicine.

In the application EP-A-94742 described substituted azabicyclic compound, (+)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3,3,1]non-4-yl)benzamide, known under the generic name renzapride (also known as the free base renzapride). Substituted azabicyclic compounds used for the treatment of disorders associated with impairment of gastrointestinal motility, in particular delays gastric emptying, dyspepsia, flatulence, esophageal reflux and peptic ulcers, in the treatment of vomiting and disorders of the Central nervous system.

In addition, according to the present invention it was found that the hydrate of renzapride hydrochloride is also effective in the treatment of irritable bowel syndrome (spastic colitis) (IBS), constipation, gastroparesis, abdominal pain and discomfort.

Hydrochloric salt renzapride (renzapride hydrochloride) is preferred over the free base, thanks to its higher stability.

In the application EP-A-0239321 described hydrated form of hydrochl the reed renzapride, which has a higher technological properties and stability compared with the anhydrous hydrochloride renzapride.

In the application EP-A-94742 describes the General operation of obtaining substituted azabicyclic connections.

Agonistic activity of hydrate of renzapride hydrochloride in relation to 5-HT4receptors, as well as its antagonistic activity against 5-HT2Band 5-HT3receptors make it an ideal candidate for use as a drug. It should be understood that the compounds used as medicines, must have certain characteristics. In addition to their biological activity such compounds should exhibit additional characteristics, such as good solubility, stability, ease of preparation of compositions comprising these compounds, etc.

The inventors have identified a new crystalline form of a hydrate of renzapride hydrochloride having improved properties for use as a drug. This new crystal form was called form II.

Accordingly, according to the first aspect of the present invention provides a method of preparing form II hydrate renzapride hydrochloride, including the keeping of renzapride in solution with the water holding and mixing it with water, the solvent, then adding to the solution renzapride of concentrated hydrochloric acid and release form II hydrate renzapride hydrochloride by filtration. Mixed with water, the solvents suitable for the purposes of the present invention may constitute one or more of the following solvents: tetrahydrofuran (THF), acetone and/or alcohol. The alcohols preferably may represent one or more of the following alcohols: methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, preferably ethanol.

The solution containing the water/mixed with water, the solvent preferably contains from 3 to 15% water, more preferably from 5 to 10% water, most preferably 8% or more water.

Keeping renzapride in a solution containing water/mixed water solvent, preferably performed with agitation, preferably with stirring. The curing solution renzapride can be produced at 20-25°C. However, the solution renzapride can be heated to ensure dissolution of renzapride in a solution containing water/mixed water solvent. Preferably the solution renzapride first incubated at 20-25°With, for example, within 15-30 minutes, and then aged by heating, for example by boiling with reverse, chilling the nick, to ensure dissolution.

After keeping renzapride in a solution containing water/mixed water solvent, the solution may be filtered to separate any powdered material.

Preferably the addition of hydrochloric acid to the solution renzapride carried out at 60-70°C. Then the temperature of the reaction mixture may be lowered to room temperature, more preferably up to 20-25°and then curing may be performed during one or more intervals of time ranging from 1 to 2 hours. Additionally, the reaction mixture may be maintained within one or more time intervals lasting 1 to 2 hours at 0-5°C.

If necessary, the selected form II hydrate renzapride hydrochloride may be dried under vacuum to reduce the amount of solvent, for example ethanol, to <3%, and the obtained solid substance may be treated with water, preferably purified water, in a confined space to bring the amount of the solvent (for example, the amount of ethanol in the product to values that are acceptable for commercial use, while maintaining the form II of the final product.

Preferably selected form II renzapride hydrochloride may be treated with water without drying in a vacuum; PR is doctitle form II renzapride hydrochloride can be processed with purified water in a confined space to bring the quantity of solvent for example, the amount of ethanol in the product concentration approximately equal to 3 wt.%, to values that are acceptable for commercial use. For the purposes of the present invention is acceptable for commercial use, is 1 wt.%, solvent or less, preferably 0.1 wt.% solvent or less.

Renzapride can be prepared in accordance with the Protocol described in EP-A-94742 and/or GB 0321091.1. In the framework of the present invention, the term "renzapride" refers to the free base, whose structure is shown below:

and the term "renzapride hydrochloride" refers to the hydrochloric salt of renzapride whose structure is depicted below:

Renzapride preferably obtained by condensation of substituted phenyl (11) with the amine (14), which takes place with the formation of condensation products of (8). In particular, substituted phenyl (11) can be activated, for example, converted into the acid chloride of acid (13) (acid chloride)

and the acid chloride (13) of the compound (11) can be condensed with the amine (14) with the formation of condensation products of (8)

with the subsequent removal of the protection connection (8), leading to renzapride

Methods for obtaining compounds (11) and (14) described in EP-A-94742 and GB 0321091.1.

Renzapride can be directly used in the method, which applies to the first aspect of the present invention, to obtain form II hydrate renzapride hydrochloride. Thus, according to the first aspect of the present invention provides easy, one-step method of preparation of form II hydrate renzapride hydrochloride from renzapride.

According to the second aspect of the present invention, a method of preparing form II hydrate renzapride hydrochloride from renzapride hydrochloride, and the method includes the formation of a saturated solution of renzapride hydrochloride in the solvent system comprising an organic solvent and from 3 to 30% of water, and the allocation of the specified solution form II hydrate renzapride hydrochloride. In a preferred implementation of the second aspect of the present invention form II hydrate renzapride hydrochloride can be isolated by crystallization.

Initiating the crystallization of form II hydrate renzapride hydrochloride may be performed using methods known in the present technical field. Preferably the form II hydrate renzapride hydrochloride is crystallized from the solvent system by cooling a saturated solution of hydrate of renzapride hydrochlori the a to 10° C or lower, preferably to 0°With or below, more preferably -5°With or below. Cooling a saturated solution of hydrate of renzapride hydrochloride may be accompanied by stirring to achieve complete crystallization of the hydrate of renzapride hydrochloride or until the desired stage of crystallization of the hydrate of renzapride hydrochloride.

For acceleration of crystallization may need the addition of miscible organic solvent, in which the hydrate of renzapride hydrochloride insoluble (in the framework of the present invention the solvent is named miscible non-solvent). In alternative to the saturated solution of hydrate of renzapride hydrochloride can be added seed crystals of form II hydrate renzapride hydrochloride. The addition of such seed crystals can be produced separately, simultaneously with or after cooling and/or mixing and/or adding mixed herstories.

For the preparation of a saturated solution of renzapride hydrochloride may be necessary to heat the solution. Preferably the mixture of renzapride hydrochloride and solvent is heated under reflux to boiling. For assistance in obtaining saturated solution may be produced by stirring or shaking.

Dazeley of the present invention, the solvent system can include one or more solvents, mix with water and is able to solubilize renzapride hydrochloride. Preferably the solvent is one or more of the following solvents: ethanol, acetone, isopropyl alcohol, tert-butyl methyl ether (TBAE) or THF, more preferably ethanol.

The recrystallization of hydrate of renzapride hydrochloride held with the formation of form II hydrate renzapride hydrochloride, preferably produced in an aqueous solution of ethanol, more preferably 20% aqueous solution of ethanol.

The selection of form II hydrate renzapride hydrochloride can be produced by means of filtration. Any remaining solvent in the selected product can be removed by washing the crystalline solid with an organic solvent. Preferably the solvent for washing has a higher volatility than the residual solvent, and can be easily removed from the product. Examples of such solvents suitable for the purposes of the present invention include THF, n-heptane or toluene. Alternatively, the isolated product may be washed with cold organic solvent comprising from 4% to 25% water, more preferably 8% or more of water, such as an 8% aqueous ethanol.

To remove any residual solvent, the product can be dried. Before occhialino in the drying process does not reduce the percentage of water content in the product. However, if the decrease of the percentage of water occurs, the product should be rehydration with the formation of form II hydrate renzapride hydrochloride. Methods of drying of the product include drying in the fluidized bed and dried in air in an oven in a vacuum or without him. Preferably the drying is carried out in an inert atmosphere such as nitrogen atmosphere.

Further, the remaining solvent can be removed by suspensionen product in an organic solvent. In this case suspendisse the solvent should also be more volatile than the residual solvent, so that it can be easily removed from the product. Examples of suitable suspendida solvents include TREE.

According to a third aspect of the present invention, a method of preparing form II hydrate renzapride hydrochloride, including the suspension of renzapride hydrochloride in an organic solvent comprising from 4% to 25% water, and the allocation of form II hydrate renzapride hydrochloride from the specified suspension.

Preferably the organic solvent miscible with water and can represent one or more of the following solvents: ethanol, acetone, isopropyl alcohol, TREE or THF. More preferably the solvent is an ethanol.

Prepare the organic solvent is, preferably containing from 6 to 10% water, more preferably 8% or more water. In a particularly preferred example of implementation of the organic solvent is an ethanol containing 8% of water.

Renzapride hydrochloride according to the second and third aspects of the present invention can be obtained in accordance with the method described in EP 0239321. In accordance with the second and third aspects of the present invention renzapride hydrochloride can be obtained in hydrated or non hydrated form.

In particular, renzapride (in the form of its free base) is dissolved in a suitable solvent, preferably ethanol, and to it add a solution of hydrochloric acid in a suitable solvent, preferably ethanol, by precipitation of the product.

A fourth aspect of the present invention relates to crystalline form II hydrate renzapride hydrochloride, comprising two moles of water per one mole of renzapride hydrochloride when the content of form II, equal to 75% or more.

It is preferable to provide the content of form II hydrate renzapride hydrochloride at the level of 80% or more, more preferably 90% or more, most preferably 95% or more.

Form II hydrate renzapride hydrochloride get in the form of a dihydrate. It contains about the 8.3 to 9.8 percent water, preferably from 8.5 to 9.6% of water, more preferably 9.0% of water. Despite the lack of a scientific theory, it was hypothesized and confirmed by research, that the water is not freely associated with molecules of renzapride, and is trapped within the crystal structure of its molecules.

Getting renzapride form II hydrate renzapride hydrochloride provides a number of advantages in properties compared with the properties of amorphous hydrate of renzapride hydrochloride. Advantages in the properties of the specified crystal form include the best resistance against the atmospheric water or moisture, the greater the tendency to separation by filtration and superior properties when dried. For specialists in the art it should be clear that the properties of the form II hydrate renzapride hydrochloride doing particularly preferred use of this form in medicine. In particular, the form II hydrate renzapride hydrochloride exhibits good stability with respect to moisture and, therefore, during prolonged storage, it is not subject to destruction. In particular, during long-term storage form II hydrate renzapride hydrochloride water content stored in the medication does not undergo significant changes.

It was observed that the form II hydrate renzapride Hydra is chloride has a narrow distribution of particle sizes. This ensures the preparation of this form hydrate renzapride hydrochloride, which allows to obtain homogeneous compositions based on mixtures, especially at low dosages of the drug. In addition, when mixing material can be avoided screening form II hydrate renzapride hydrochloride, which allows to make the composition more effectively. In addition, the form II hydrate renzapride hydrochloride exhibits a greater tendency to separation by filtration compared to the amorphous form.

Furthermore, the preparation of form II hydrate renzapride hydrochloride allows to obtain a homogeneous mixture, without resorting to grinding, filtering, etc. It increases the effectiveness of treatment renzapride and making songs out of it. In addition, the increased stability of form II hydrate renzapride hydrochloride in relation to the water allows you to more effectively carry out the drying of the active ingredients, which facilitates the manufacture of the compositions in the form of, for example, capsules or tablets.

Thus, the form II is particularly preferred for the preparation of medicaments, including renzapride, because of the narrow distribution of particle size it allows you to use the form II for the manufacture of capsules or tablets containing low concentrations of the drug, without resorting to grinding or thin is omolu.

Form II hydrate renzapride hydrochloride shows stability when exposed to moisture. Thus, this form can be stored for a long time. In addition, this material behaves in a predictable manner when dispensing and manufacturing.

The superior properties of the form II hydrate renzapride hydrochloride mean that the introduction of form II hydrate renzapride hydrochloride in dosage form, such as a pill that is more effective from the point of view of time, energy and cost in comparison with an amorphous hydrate of renzapride hydrochloride. In addition, as the form II hydrate renzapride hydrochloride and manufactured on the basis of the composition can be stored for a long time due to good moisture resistance form II hydrate renzapride hydrochloride.

Form II hydrate renzapride hydrochloride can be characterized by an infrared spectrum, which contains diagnostic peak at 835±1.5 cm-1.

Thus, according to the present invention, a method of identification form II hydrate renzapride hydrochloride in the sample, characterized by carrying out infrared spectroscopy of a sample of a hydrate of renzapride hydrochloride and detection of diagnostic peak at 835±1.5 cm-1(as shown, for example, on Fig).

The fifth aspect of the brew is his invention relates to pharmaceutical compositions, comprising form II hydrate renzapride hydrochloride, determined as described in the fourth aspect of the present invention, and a pharmaceutical excipient.

Suitable carriers and/or diluents are well known in the art and include pharmaceutical purity starch, mannitol, lactose, magnesium stearate, saccharin sodium, talc, cellulose, glucose, sucrose (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably sterile). The composition may be a mixed formulation, prepared on the basis of the composition, or may be combined formulation intended for simultaneous, separate or sequential use (including the introduction).

The connection offered in accordance with the present invention for use in accordance with the above indications may be entered in any conventional manner, for example orally (including inhalation), parenteral, mucosal (i.e. transbukkalno, sublingual, nazalnam), vaginal, rectal or transdermal way of introduction, the composition modify accordingly.

Form II hydrate renzapride hydrochloride, proposed in accordance with the present invention, can be prepared in the form of a composition with the replacement of the slow release. Composition with delayed release includes the form II hydrate renzapride hydrochloride in combination with slow release component. This composition allows the target release form II hydrate renzapride hydrochloride in the lower part of the gastrointestinal tract, for example in the small intestine, large intestine, colon and/or rectum. Composition with delayed release may include a form II hydrate renzapride hydrochloride and intersolubility floor or the floor, the solubility of which depends on pH, such as phthalates, cellulose acetate or other phthalates (for example, polyvinyl acetate phthalate, methacrylates (Eudragit (Eudragits))). In an alternative embodiment, the composition with delayed release can provide controlled release in the small intestine and/or colon, subject to the application of methacrylate coatings that are sensitive to changes in pH, introduction to polymeric microspheres that are sensitive to changes in pH, or the application of polymers exposed to destruction by hydrolysis. Composition with delayed release may include hydrophobic or gelling fillers or coatings. In addition, the release in the colon can be implemented at the expense of coatings that can be digested bacterial enzyme is mi, such as amylose or pectin, due polymers, pH-sensitive, with the help of hydrogel tubes, swelling over time (Pulsincap), using hydrogel coatings, collapsing over time, and/or using coatings containing acrylic acid associated with atheromatosis connections.

For oral administration, the compound can be introduced in the form of compositions, which may be liquid or solid, for example to represent the solutions, syrups, suspensions, emulsions, tablets, capsules, pellets, dry powders and/or granules.

Liquid composition usually consists of a suspension or solution of the compound or physiologically acceptable salt in a suitable aqueous or non-aqueous liquid medium (media), for example water, ethanol, glycerin, glycol or oil. The composition may also contain suspendisse agent, preservative, flavoring or coloring matter.

The composition is in the form of tablets can be prepared using any suitable pharmaceutical carrier (s), usually used for preparation of solid dosage forms. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, and microcrystalline cellulose.

The composition is in the form of a capsule may be prepared using conventional techniques incaps the population. For example, powders, granules or pills containing the active ingredient, can be prepared using standard carriers and then they can be filled capsule, for example, hard gelatin capsule, capsule, made of GPS (receiver array, hypromellose), soft gelatin capsule, etc.; alternatively, a dispersion or suspension can be prepared using any acceptable pharmaceutical carrier (carriers), such as aqueous solutions of mucilage (gum), various types of cellulose, silicates or oils and then a soft gelatin capsule fill obtained dispersion or suspension.

Compositions intended for oral administration can be formulated in such a way as to protect the active ingredient from destruction during the passage of the composition through the digestive tract, for example, by applying an external coating to the drug, in tablet or capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous or non-aqueous media or in the oil that is acceptable for parenteral administration, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. In alternative variations which the solution can be lyophilized (subjected to freeze-drying), and then restored by adding a suitable solvent just before the introduction.

Compositions for nasal or oral administration can be easily prepared in the form of aerosols, drops, gels and powders. Aerosol compositions usually contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually present in the amount of one or more doses in a sterile form in a sealed container, which can take the form of a cartridge or auxiliary reservoir to the spray device. Alternatively, the sealed container may be a disposable dispenser, in particular a nasal inhaler single dose or aerosol dispenser equipped with a metering valve and intended for disposal after use, the contents of the container. If the dosage form produces an aerosol dispenser, it contains a pharmaceutically acceptable gas propellant. Aerosol dosage forms can be made in the form of a pump spray.

Compositions suitable for transbukkalno or sublingual administration, include tablets, cakes and mints, which introduce the active ingredient and a carrier, such as sugar and gum Arabic, tragakant, or is Athyn and glycerin.

Compositions for rectal or vaginal injection is usually used in the form of suppositories (containing normal suppozitornyj base, such as cocoa butter), pessaries, vaginal tablets, pen or clysters.

Compositions suitable for transdermal administration, include ointments, gels and patches, and injections, including powder injection.

Typically, the composition is a standard dosage form such as tablet, capsule or ampoule.

Depending on the method of administration of the composition may contain from 0.1 to 99 wt.%, preferably from 0.1 to 60 wt.%, more preferably from 0.2 to 20 wt.% and most preferably from 0.25 to 12 wt.% form II hydrate renzapride hydrochloride.

The sixth aspect of the present invention relates to the form II hydrate renzapride hydrochloride, designated the fourth aspect of the present invention, or pharmaceutical compositions based on it-defined fifth aspect of the present invention, intended for the treatment and/or prevention of disorders related to the deterioration of gastrointestinal motility and/or abdominal pain.

In the framework of the present invention, the term "gastrointestinal tract includes the esophagus, stomach, small intestine and large intestine (including the colon and rectum). In the General case, the form II hydrate renzapride Hydra is chloride can be used to treat disorders, associated with worsening of gastrointestinal motility. These violations include one or more violations of the group, including irritable bowel syndrome, slow or delayed gastric emptying, dyspepsia, gastro-esophageal reflux, gastric ulcer and duodenal ulcer, flatulence, loose stools, constipation, diabetic neuropathy, functional abdominal bloating, gastroparesis, or abdominal pain. Form II hydrate renzapride hydrochloride can also be used for treatment of symptoms associated with disorders, including abdominal pain and/or discomfort, abdominal bloating, abnormality of stool consistency, the anomaly frequency of stools, feeling of incomplete evacuation, sensation of urgency evacuation and passage of the mucous membrane. It can also be used to treat vomiting and/or treatment of disorders of the Central nervous system, in particular psychosis. Preferably the form II hydrate renzapride hydrochloride used to treat irritable bowel syndrome, more preferably for the treatment of shut-predominance, Varano-predominance or alternating (with mixed symptoms of irritable bowel syndrome.

Dose form II hydrate renzapride hydrochloride, is effective for treatment of the above violations, C is dependent on the nature and severity of the violation, and weight of the patient who needs treatment. However, the standard dose for an adult patient weighing 70 kg is usually from 0.01 to 100 mg, for example from 0.1 to 50 mg, preferably from 0.5 to 16 mg compounds are proposed in accordance with the present invention, in the day. The standard dose, you can enter one or more times per day, for example 2, 3 or 4 times a day, usually 1-3 times per day, more preferably 1 or 2 times a day. It should be understood that the above dose range is a guide for the introduction of form II hydrate renzapride hydrochloride adult patient. The amount of substance introduced, for example, a child or infant, can be defined by a practicing physician or a specialist, well versed in the art, and may be less than or equal to the number entered to the adult patient. Preferably the standard dose is administered in the form of capsules or tablets.

The seventh aspect of the present invention relates to a method of treatment of disorders related to the deterioration of gastro-intestinal motility, comprising introducing to a subject in need of such treatment, form II hydrate renzapride hydrochloride described fourth aspect of the present invention, or the pharmaceutical composition described in the fifth aspect of the present invention.

All preferred prize is Aki each of the aspects of the present invention is applicable to other aspects of the invention mutatis mutandis.

The invention can be implemented in various ways; for illustration of the present invention will be described some examples of its implementation with reference to the accompanying drawings.

Figure 1 shows the range of13With NMR form II hydrate renzapride hydrochloride, which is in a solid state;

Figure 2 shows the range of13With NMR of amorphous hydrate of renzapride hydrochloride, which is in a solid state;

Figure 3 shows the sorption schedule DVS (Dynamic Vapour Sorption - graph of the dynamics of sorption from the vapor phase) form II hydrate renzapride hydrochloride;

Figure 4 shows the sorption schedule DVS Form II hydrate renzapride hydrochloride;

Figure 5 shows the sorption schedule DVS Form II hydrate renzapride hydrochloride;

Figure 6 shows the isothermal chart form II hydrate renzapride hydrochloride;

7 shows the sorption DVS graphics and isothermal chart Form II hydrate renzapride hydrochloride;

On Fig shown sorption schedule DVS Form II hydrate renzapride hydrochloride;

Figure 9 shows the isothermal chart Form II hydrate renzapride hydrochloride;

Figure 10 shows the sorption schedule DVS amorphous hydrate of renzapride hydrochloride;

Figure 11 shows the isothermal chart of the amorphous hydrate of renzapride hydrochloride;

On Fig is provided to the IR spectrum of form II hydrate renzapride hydrochloride;

On Fig presents an enlarged image of a part of the infrared spectrum of form II hydrate renzapride hydrochloride;

On Fig shows the IR spectrum of form II hydrate renzapride hydrochloride;

On Fig presents an enlarged image of a part of the infrared spectrum of form II hydrate renzapride hydrochloride;

On Fig presents an enlarged image of a part of the infrared spectrum of form II hydrate renzapride hydrochloride;

On Fig presents the IR spectrum of form II hydrate renzapride hydrochloride;

On Fig presents an enlarged image of a part of the infrared spectrum of form II hydrate renzapride hydrochloride;

On Fig presents the IR spectrum of form II hydrate renzapride hydrochloride;

On Fig presents an enlarged image of a part of the infrared spectrum of form II hydrate renzapride hydrochloride;

On Fig represented by x ray powder form II hydrate renzapride hydrochloride;

On Fig presents thermal analysis of form II hydrate renzapride hydrochloride.

The present invention will be further illustrated by means of one or more of the following non-restrictive examples.

EXAMPLES

Production of form II and amorphous hydrate of renzapride hydrochloride

Production of form II hydrate renzapride hydrochloride

Renzapride and hydrochloride renzapride can be obtained from the compliance with the methods, described in EP-A-0094742, EP-A-0239321 and GB 0321091.1

Preferred methods of cooking salt

The free base renzapride (1 wt. part) was suspensively in 8% aqueous ethanol (5 volumes; obtained from 0,4 about. water and 4.6 about. absolute ethanol) and stirred at 20-25°C for 15-30 minutes. The mixture was heated under reflux to boiling and boil until dissolved (estimated time up to 70 minutes), then cooled to 60-65°; for the Department of any powdered material was passed through a pre-heated feed line and filter (1 micron). The feed line and the filter was washed with hot (60 to 65°) 8% aqueous ethanol (1 volume received from 0,08 about. water and 0.92 about. absolute ethanol). Then a solution of the free base was treated with conc. hydrochloric acid (to 1.05 mol. equiv.) maintaining an internal temperature in the range of 60-70°C. the resulting mixture was cooled to 20-25°C and held at this temperature for 1-2 hours. The obtained suspension is then cooled to 0.5°C and kept at this temperature for a further 1-2 hours. Separated the sample suspension was filtered and recorded the IR spectrum of the substance to ensure that it is form II. The suspension may be kept for several periods equal to 1-2 hours, in order to provide to the Department that the material is a form II.

The product was isolated by filtration, the filter residue was washed with cooled displacement (0-5° (C) 8% aqueous ethanol (1 volume received from 0,08 about. water and 0.92 about. absolute ethanol) and then pulled (solvent) on the filter within 3-4 hours. The solid is transferred to trays and left in an enclosed space in the presence of purified water up until the content of ethanol was 1 wt.% or less.

The technique of recrystallization

Hydrochloride renzapride (1 wt. part) was treated with 20% aqueous ethanol (3 volumes; obtained from 0,6 about. water and 2.4 about. absolute ethanol). Stir the mixture was heated under reflux to boiling and boil until dissolved (estimated time up to 70 minutes), then cooled to 60-65°With; to separate the powdered material was passed through a pre-heated feed line and filter (1 micron). The feed line and the filter was washed with hot (60 to 65°) ethanol (about 4,5.), supporting the execution of all operations temperature in the range of 60-65°C.

The resulting mixture was cooled to 20-25°C and held at this temperature for 1-2 hours. The obtained suspension was then cooled to 0-5°C and kept at this temperature for a further 1-2 hours. Separated the sample suspension was filtered and recorded the IR spectrum of the substance to ensure that it forms the II. The suspension may be kept for several time intervals equal to 1-2 hours in order to ensure that before the separation of that material is a form II.

The product was isolated by filtration, the filter residue was washed with cooled displacement (0-5° (C) 8% aqueous ethanol (1 volume received from 0,08 about. water and 0.92 about. absolute ethanol) and then pulled (solvent) on the filter within 3-4 hours. The solid is transferred to trays and left in an enclosed space in the presence of purified water up until the content of ethanol was 1 wt.% or less.

Method for producing mist

Hydrochloride renzapride (1 wt. part) was treated with 8% aqueous solution of ethanol (5 vol.), the suspension was stirred and cooled to 0-5°With; as soon as the temperature has reached this range was stirred at 0-5°C for 2-3 hours. Separated the sample suspension was filtered and recorded the IR spectrum of the solid substance to ensure that it is form II. The suspension may be kept for several periods equal to 1-2 hours to ensure that before the separation of that material is a form II.

The product was isolated by filtration, the filter residue was washed with cooled displacement (0-5° (C) 8% aqueous ethanol (1 volume received from 0,08 about. water and 0.92 about. absolute ethanol) and ZAT is pulled (solvent) on the filter within 3-4 hours. The solid is transferred to trays and left in an enclosed space in the presence of purified water up until the content of ethanol was 1 wt.% or less.

Preparation of amorphous hydrate of renzapride hydrochloride

Amorphous hydrate of renzapride hydrochloride is prepared in accordance with the methods described in EP-A-0094742 and EP-A-0239321. From the point of view of the present invention, the term "amorphous" refers to a sample of a hydrate of renzapride hydrochloride, including both non-crystalline and crystalline material, and the crystalline material may be present in the form of a mixture of one or more forms.

Comparison of form II hydrate renzapride hydrochloride and amorphous hydrate of renzapride hydrochloride

13With NMR in the solid phase

Spectra13With NMR in the solid phase were obtained for the form II hydrate renzapride hydrochloride and amorphous hydrate of renzapride hydrochloride; spectra are presented in figure 1 and 2 respectively.

The spectra obtained for samples form II hydrate renzapride hydrochloride differed from the spectra obtained for the amorphous hydrate of renzapride hydrochloride. Relaxation properties of form II hydrate renzapride hydrochloride (define conditions detection signal) also differed from the corresponding properties of amorphous hydrate of renshape is as hydrochloride. Therefore, the conditions of the experiments were optimized for each sample.

In the following table 1 presents the signals observed for the form II hydrate renzapride hydrochloride. In addition, given the alleged assignment of the peaks.

Table 1
Data13With NMR in the solid state to form II hydrate renzapride hydrochloride
Signal amplitude (ppm)The expected retirement of atoms
19.233, 21.856, 28.413, 30.307and
46.141, 51.823, 53.329b
55.855
99.373d
109.184e
130.992f
149.352g
158.483h
164.700i
Not different from the backgroundj

This molecule must give seven high frequency (90+ ppm (ppm, ppm) signals (ignoring the fine structure), but were registered only six. The missing signal due to the carbon atom attached to chlorine. The interaction of these nuclei leads to broadened signal (and prob the tenderly, multiplet), which probably is responsible for the signals on the line scan between 100 and 130 ppm. A similar interaction slightly sirivat signals of carbon atoms linked with nitrogen (for example, the signal at the ˜149 ppm, presumably represents the signal of the aromatic fragment C-NH2).

A tentative assignment of the remaining signals is as follows: three-CH2-s+CH - group, between 15 and 30 ppm, three-CH2-N S+>CH-N - group, between 43 and 53 ppm, OMe - at 55-58 ppm, amide carbon - in 164-168 ppm, aromatic group-O - when 156-159 ppm, aromatic C-C - if ˜ 131 ppm and CH in ortho-position to the OMe - probably represents the line at 99 ppm, and the second group SN - when 109-112 ppm. The remaining potesenie signals of low intensity represent the sidebands of the signals of the rotation, which can not be seen.

Comparison of the NMR spectra obtained for the solid phase, to form II hydrate renzapride hydrochloride and amorphous hydrate of renzapride hydrochloride

In the arrangement of the signals observed in the region from 60 to 15 ppm in the spectra obtained for the form II hydrate renzapride hydrochloride and amorphous hydrate of renzapride hydrochloride, there are differences. In addition, in the spectrum obtained for the amorphous hydrate of renzapride hydrochloride, has split the signal p and 131,8 ppm, due to OMe. The specified signal when 131,8 ppm, apparently, is an unresolved pair of signals. Furthermore, the lack of resolution of low-frequency signals in the spectrum of the amorphous hydrate of renzapride hydrochloride, apparently caused by the presence of additional lines.

The dynamics of sorption from the vapor phase

The method

Each sample was placed in a holder for the sample and loaded into the system for DVS. Read the original mass. Then, for drying the sample, it was kept in an atmosphere with a relative humidity (RH) of 0% and read the testimony of dry mass. Then the sample was subjected to cyclical effects of adsorption/desorption, increasing humidity RH 0 to 90% with an interval of 10% RH. Data on the change in mass was adjusted to the exponential dependence, which was used for the automatic determination of the end point of each stage, which then initiated the following increase/decrease relative humidity.

For curves DVS speed lines represent the level of relative humidity (RH) in the chamber. Curved lines represent the change in sample mass. Control of RH carried out automatically; the values of RH was changed as soon as the rate of change of the mass of the sample was decreased to small values.

Form II hydrate renzapride hydrochloride

Schedule sorption isotherms for the form II shows would be the three initial moisture absorption (approximately 9 wt.%) at 10% RH, then there is only a very small change in mass of the sample, which indicates that the form II is a very stable material whose properties do not change under the action of moisture.

Graphics DVS and isotherms obtained for form II, shown in figure 3-9.

Sample behavior of the form II hydrate renzapride hydrochloride indicates that the form II is a very stable material whose properties do not change under the action of moisture.

Data DVS does not give grounds to assume that there is a certain balance between form II hydrate renzapride hydrochloride and other forms. When comparing these three cycles between observed only a very slight change in mass (i.e. they are very similar, as can be seen from the graphs of the isotherm).

In addition, it was observed only a very slight change in mass upon reaching the camera relative humidity RH 90%, the sample has absorbed about 9.5 wt.%, moisture, which indicates the resistance of the material against moisture, which remained constant throughout the three cycles. The increase in mass observed for the form II hydrate renzapride hydrochloride, consistent with the formation of the dihydrate. When humidity RH greater than 10%for all analyzed materials were observed very stable profile in relation to the influence of the moisture. When humidity RH greater than 10%, the weight of the dihydrate is changed very slightly.

Amorphous hydrate of renzapride hydrochloride

Schedule DVS and isothermal chart obtained for amorphous hydrate of renzapride hydrochloride, shown in figure 10 and 11.

From the graph DVS obtained for amorphous hydrate of renzapride hydrochloride (figure 10), shows that in the conditions of 10% RH (Relative Humidity, RH) environment, the moisture absorption is approximately 6 wt.%, then there is a more gradual absorption of up to 50% RH. After that, with increasing RH is lower moisture absorption. As the reduction from 90% to 10% RH there is a gradual decrease of the mass.

Profiles of adsorption/desorption for the second and third cycle are identical, while the desorption cycle is identical to the first cycle. The absorption at RH factor of 105 to 40%, higher than the absorption observed in the first cycle, in this case again the greatest weight loss occurs when going from 10 to 0% RH.

For isothermal diagram (11) clearly shows the difference between the first and subsequent cycles of adsorption. The desorption cycles are identical for all three cycles.

The data presented in figure 10 and 11 show that there is a clear difference in the properties of the samples before and after the first cycle of adsorption. Also there is a significant difference between the first cycle and the sorption and desorption. The lack of reproducibility of this cycle due to likely changes in material forms, and no hysteresis associated with other physical properties. Complete absorption of moisture by the change in RH from 0 to 90% approximately 12 wt.%, higher than the stoichiometric quantity required for the formation of the dihydrate.

After completion of the first cycle, the profile of adsorption/desorption becomes reproducible, indicating that the material is stable when interacting with moisture.

Thus, it is seen that the behavior of the amorphous hydrate of renzapride hydrochloride differs from the behavior of the dihydrate.

Own rate of dissolution

The method

Samples were prepared in the form of discs. Each disk was prepared by pressing the sample for 5 minutes under a pressure of 2 tons. Each disc was placed in the system for static dissolution, in which one side of the disk was exposed to the solvent environment. From each batch of material was prepared six disks for duplicate definitions of self-dissolution rate (IDR) at pH of 2.2, 4.0 and 7.0. Dissolved samples (0.8 ml) were removed at intervals of 5 minutes for 60 minutes and analyzed.

To find the amount of solute per unit area, the amount of released drug (mg) divided n is the surface area of the disc (0.5 cm 2). The average of duplicate determinations were plotted on a graph as a function of time (minutes). IDR (mg·cm-2·min-1) set the gradient (determined by the method of linear regression) of the linear portion of the profile of the release. If the transition in the solution is considered independent of pH, was determined independent of the pH rate IDR. Independent of the pH rate IDR was calculated by averaging the data for each time point for all studied pH values, and then calculate a linear regression of at least the first 5 experimental points. All values IDR misspelled covering the upper and lower limits of the 95% confidence interval of the linear regression.

For the linear regression analysis data IDR used all experimental points, since the release profiles were linear.

Table 2: IDR for Form II and amorphous hydrate of renzapride hydrochloride (mg/min/cm2)

SamplepH 2.2pH 4.0pH 7.0Independently
Form II5.5±0.25.7±0.25.9±0.35.7±0.3
Amorphous6.6±0.26.7±0.16.9±0.16.8±0.3

Features : the IKI own dissolution rate of the material form II differs from similar characteristics of amorphous material.

Characterization of form II hydrate renzapride hydrochloride

The analysis of the moisture in the form II hydrate renzapride hydrochloride

The water content of 11 different samples of form II hydrate renzapride hydrochloride was determined by Karl Fischer analysis, resulting in good reproducibility was found that it is about to 9.0 wt.%, water, which corresponds to the presence in the crystal structure of two molecules of water. It was found that the reproducibility of the water content in form II hydrate renzapride hydrochloride does not depend on the method of preparation of form II, or volumes of synthesis. The present invention provided with the opportunity of a reproduced control the amount of water present in the form II hydrate renzapride hydrochloride, which is very convenient to control the amount approved pharmaceutical ingredient during storage, handling, manufacture of compositions and manufacturing of the product.

The moisture content (by Karl Fischer)

Form IIto 9.0 wt.% ±0,31 (SD; n=11)

Infrared (IR) analysis

IR spectra were recorded for a number of samples of the form II, made in accordance with the method proposed by the present invention. On Fig-20 image is received IR spectra of form II hydrate renzapride hydrochloride. In the following table 3 shows the observed peaks.

Table 3: Representative data of X for samples of forms II hydrate renzapride hydrochloride

Form II*
3434,0 (br, m)
3358,5 (s, st)
2951,2 (br, w)
2591,5 (s, w)
2585,4 (br, m)
2511,7 (br, m)
1592,9 (s, st)
1540,8 (s, st)
1463,9 (s, st)
1454,9 (s, st)
1419,6 (s, w)
1316,4 (s, m)
1249,8 (s, m)
1209,9 (s, st)
1143,8 (s, w)
1130,0 (s, w)
1086,1 (s, m)
992,5 (s, m)
950,6 (s, w)
891,4 (s, w)
834,1 (s, m)
771,2 (s, w)
671,8 (s, m)
650,5 (s, w)
*Values are given in wavelengths (cm-1). Description peaks: s = sharp, br = broadened; the relative intensities are indicated as follows: st = strong, m = medium, w = weak.

All the samples studied form II hydrate renzapride hydrochloride show the characteristic peak at 835±1.5 cm-1. This peak can be used to establish the presence of form II hydrate renzapride hydrochloride. It should be understood that the exact position of this peak varies depending on the method of preparation of the sample applied to the device and so on, so table 4 shows the values for the characteristic peak observed for different samples form II hydrate renzapride hydrochloride.

The range for the control of the peak in the IR spectrum of form II hydrate renzapride hydrochloride was calculated on the basis of the values listed below

835,06
Table 4
The values observed for the characteristic peaks located at 835±1.5 cm-1
Sample of form IIThe control peak (cm-1)
1834,11
2834,11
3
4834,31
5834,31
6834,91
7834,01, 835,29 and 834,12 when repeat measurements
8834,31
9835,28
10835,28
11835,28
12836,28

The presence of the characteristic peak at 835±1.5 cm-1the IR spectrum of form II hydrate renzapride hydrochloride is safe to assume that the it is form II hydrate renzapride hydrochloride.

X-ray diffraction analysis of the powders form II hydrate renzapride hydrochloride (XRPD)

Form II hydrate renzapride hydrochloride were analyzed using x-ray diffraction analysis of the powders.

Radiograph obtained during the x-ray diffraction analysis of the powders (XRPD) of form II hydrate renzapride hydrochloride, shown in Fig. The presence of certain peaks in the XRPD indicates the crystalline structure of form II hydrate renzapride hydrochloride.

The stability of form II hydrate renzapride hydrochloride

Samples of form II hydrate renzapride hydrochloride kept under the following conditions: 25°C/60% relative humidity.

Table 5
The stability of form II hydrate renzapride hydrochloride
t=0 monthst=6 monthst=12 monthst=18 monthst=24 months
A stability test
1. DescriptionWhite homogeneous substanceWhite homogeneous substanceWhite homogeneous substanceWhite homogeneous substanceWhite homogeneous substance
2. Water content (by Karl Fischer)of 8.9 wt.%8.6 wt.%8.8 wt.%8.8 wt.%8.8 wt.%

Form II hydrate renzapride hydrochloride exhibits good resistance to moisture during storage.

The particle size distributions

The particle size distributions (PDS) renzapride was measured in accordance with the method, described in detail below.

Material parametersrenzapride: R.I.=1,5. Absorption=0,1
Model: universal (high) - high
sensitivity
The measurement parametersThe measuring time of 4 seconds
Background time 8 seconds
Limits dimmable: 3<Alemania<20 (included air filter)
The parameters of selection
sampleScirocco 2000
the speed of a vibratory load 40%
Air pressure 3.5 bar
One measurement for each load were performed three times
Table 6
The particle size distributions of the form II hydrate renzapride hydrochloride, manufactured in batches of 5 kg
d (0,1)/ μmd(0,5)/ μMd(0,9)/μMVariation*
Form II11,547,1109,02,1
* Variance = (d(0,9)-d(0,1))/d(0,5)

Fo the mA II has a narrow particle size distributions with dispersion equal to 2.1.

Photomicroscope

A small amount of sample was dispersible in silicone oil (glass slide) and on top of it put the cover glass. Images of specimens were fixed (minimum increase of two) using calibrated software, suitable for receiving images.

Form II hydrate renzapride hydrochloride consists of cubic/rhombohedral crystals of the correct form, which are preferred for the preparation of solid dosage forms.

Thermochemical analysis

The curve obtained when carrying out the TGA (TGA) (thermogravimetric analysis) form II, shown in Fig.

TGA curve for form II hydrate renzapride hydrochloride contains endothermic line (endotherm) at 150-180°C. apparently indicated endothermic line associated with the phase change digidratirovannogo material originating after the loss of water during analysis.

On thermogravimetric curve has a large endothermic peak (with Tmaxapproximately at 100° (C)caused by the loss of two moles of water. For endothermic peak followed by two exothermic peak at Tmax170 and 240°C. Thus, the material forms II loses water, turning into digidratirovannogo form, which then, when the temperature is e, approximately equal 150-170°undergoes phase transformation and then when 240°s melts and finally decomposes at elevated temperature.

Investigation of the solubility

Investigation of the solubility of form II hydrate renzapride hydrochloride in various mixtures of water/solvent is performed in accordance with the following standard procedure.

Approximately 50-100 mg of form II hydrate renzapride hydrochloride were placed in a glass vial with a capacity of 10 cm3and he added : 5 cm3suitable solvent. The suspension was stirred for 24 hours at 20°C. After the specified time, the suspension was filtered and analyzed transparent solutions using liquid chromatography high pressure (HPLC).

The results shown below.

Table 7
Investigation of the solubility of form II hydrate renzapride hydrochloride
A mixture of water/solventSolubility (mg/ml)
1% water in ethanol9,0
5% water in ethanolof 17.5
10% water in ethanolof 21.2
1% water in isopropanol (IPA)1,1
5% water in isopropanol2,8
10% water in isopropanol4,6
1% water in acetone0
5% water in acetone0,9
10% water in acetone6,7
1% water in tetrahydrofuran (THF)0
5% water in tetrahydrofuran0,4
10% water in tetrahydrofuran8,9

Removing the ethanol by suspensionen in solvent

Residual solvent can be removed from the form II suspensionen in the solvent. To study the influence of solvent on the ethanol content was prepared by several suspensions in the following solvents: wet water-containing acetone, THF (tetrahydrofuran), TREE (tert-butyl-methyl ether) and toluene. Applied following the standard procedure.

100 mg of form II was stirred at room temperature in 1 cm3(10 vol.) solvent for 24 hours. After the specified time, the solid was filtered and analyzed for solvent content and physical form.

The results are given in tables 8 and 9.

Table 8
Removing the ethanol by suspendirovanie in solvent
SolventContent is the solvent The ethanol content
5% water in THFNot foundNot found
Wet TBEETraces (0.1 wt.%)Not found
Wet tolueneNot foundNot found

The results show that the extraction of ethanol by suspension in solvents such as acetone, tetrahydrofuran (THF), toluene and TREE, may be carried to such an extent that its residual concentration not determined by NMR analysis (estimated to be <0.1% definition). The shape of the material isolated from suspensions was determined using IR spectroscopy, as a result it was found that in all cases the material is a form II.

Table 9
Form, selected after suspending in a solvent
SolventThe selected form
5% water in acetoneForm II
5% water in THFForm II
Wet TBEEForm II
Wet tolueneForm II

Research of processes of crystallization and drying of form II

DL the extraction of residual ethanol, the material was dried in vacuum at temperatures up to 80° C. Then, do not contain ethanol" solid substance was subjected to re-hydration for the finished material.

To explore the impact of drying on various forms of hydrate of renzapride hydrochloride samples weighing 1 g were prepared by crystallization from ethanol containing 1% of water, ethanol containing 5% water, isopropyl alcohol containing 1% of water and isopropyl alcohol containing 5% water. It should be understood that the following methodology recrystallization allows you to turn the hydrate of renzapride hydrochloride in form II hydrate renzapride hydrochloride. Used the following methodology.

1 g of the hydrate of renzapride hydrochloride was dissolved in the minimum amount of boiling solvent, and then left to cool for approximately 1 hour at room temperature, and then kept at a temperature equal to 5°C for 18 hours. A solid substance was separated by filtration and analyzed by NMR, IR and techniques KF (KF) (Karl Fischer). The results obtained are indicated in the following tables 10 and 11.

Table 10
The analysis of the original sample
SolventWater contentRemoving the*(mg)The solvent content#wt.%Water (KF)# wt.%Form (according to IR)#
Ethanol1%599lower than the 5.371,73±0,29Other
5%7140,16of 9.21±0,42Form II
IPS1%5659,070,99±0,05Other
5%6980,658,96±0,34Form II
*Weight of the crude is not included correction for solvent or water.
#after drying in vacuum (17 mbar) at 30°C for 4 hours.

Table 11
After further drying
SolventWater contentThe solvent content*wt.%Water (KF)*wt.%
Ethanol1%0,16and1,08±0,5
5%0,020,99±0,4
IPS1%1,200,61±0,02
5% 0,150,57±0,1
andObviously, the solvent is represented IPS, presumably due to drying samples in an oven with the material obtained in the IPS.
#After drying in vacuum (17 mbar) at 30°C for 4 hours + 15 hours at 60°C.

Initial analysis of the samples revealed that the form II (containing about 9% water) receive crystallization or from ethanol containing 5% water, or isopropyl alcohol containing 5% water.

The selected material originally contained relatively low concentrations of residual solvent, 0,16% ethanol and 0.65% isopropyl alcohol, respectively. These solvent concentration is much lower than the concentration found in the material, selected either from ethanol containing 1% water, or isopropyl alcohol containing 1% of water, and isopropyl alcohol containing 1% of water, which accounted for 5.4 and 9.1%, respectively. This suggests that the material dihydrate form II has no tendency to retain solvent, and therefore more exposed to drying than the material obtained from solvents containing low concentrations of water (<4%).

Further drying of the samples shows that after heating at 60°With vacuum (17 mbar) of all the samples are removed and the solvent and the water.

A brief description of the characteristics of recip is the R sample form II

The obtained characteristics of form II hydrate renzapride hydrochloride indicate that this form is a material with a crystalline structure which allows to obtain a radiograph with a clear picture and clear the infrared spectrum, and also has a well-defined water content. The water content does not change when changing the relative humidity of the environment in a wide range, which is confirmed by DVS definitions. This allows you to store the material for a long period of time. Form II has a fairly narrow range of size distribution of particles with satisfactorily mixed homogeneity. Microscopic examination showed that the different batches of the product contains the correct form crystals, which are ideal for the manufacture of solid dosage forms. The behavior of the form II under dispersion and preparation is quite predictable. The IR spectrum of form II contains the characteristic peak at 835±1.5 cm-1(sharp), which can be used to determine the presence of the specified form.

1. Method of preparation of form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride, including maintaining specified connection in a solution containing water and miscible with water, the solvent, and then adding to the resulting is astory of concentrated hydrochloric acid and the selection by filtering form II hydrate (± )-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride, characterized by one or more properties selected from the group consisting of:

a) infrared spectrum of the specified Shape that contains the characteristic peak at 835±1.5 cm-1;

(b) radiograph obtained for powder specified form, essentially corresponds depicted on Fig; and

c) the water content is from 8.3 to 9.8%.

2. The method according to claim 1, characterized in that mix with water, the solvent is one or more of the following solvents: tetrahydrofuran (THF), acetone and/or alcohol.

3. The method according to claim 2, characterized in that the alcohol is one or more of the following alcohols: methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.

4. The method according to any one of claims 1 to 3, characterized in that the solution containing the water/mixed water solvent contains from 3 to 15% water.

5. The method according to any one of claims 1 to 3, characterized in that (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide obtained by removing protection from the compounds (8)

6. Method of preparation of form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-yl)benzamide hydrochloride, moreover, this method involves the formation of a saturated solution of (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride in the solvent system comprising an organic solvent and from 3 to 30% of water, and the allocation of the specified solution form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride, characterized by one or more properties selected from the group consisting of:

a) infrared spectrum of the specified Shape that contains the characteristic peak at 835±1.5 cm-1;

(b) radiograph obtained for powder specified form, essentially corresponds depicted on Fig; and

c) the water content is from 8.3 to 9.8%.

7. The method according to claim 6, wherein the form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride emit through crystallization.

8. The method according to any of PP or 7, characterized in that the solvent system includes one or more solvents, miscible with water and capable of solubilisate (to increase solubility) (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride.

9. The method according to claim 8, characterized in that the solvent is one or more of the following solvents: ethanol, ACE is she, isopropyl alcohol, tert-butyl methyl ether (TBAE) or THF.

10. The method according to claim 7, characterized in that the crystallization of the hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride is carried out in an aqueous solution of ethanol.

11. Method of preparation of form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride, including suspending (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride in an organic solvent comprising from 4% to 25% water, and the allocation of the specified suspension form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride, characterized by one or more properties selected from the group consisting of:

a) infrared spectrum of the specified shape that contains the characteristic peak at 835±1.5 cm-1;

(b) radiograph obtained for powder specified form, essentially corresponds depicted on Fig; and

c) the water content is from 8.3 to 9.8%.

12. The method according to claim 11, characterized in that the organic solvent is one or more of the following solvents: ethanol, acetone, isopropyl alcohol, TREE or THF.

13. The method according to claim 11 or 12, characterized in that the organic solvent preferably VK is uchet from 6 to 10% water.

14. Form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride obtained in accordance with any of claims 1 to 13.

15. Crystalline form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride, comprising two moles of water to one mole of (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride when the content of form II, equal to 75% or more; however, this form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride has one or more properties selected from the group consisting of:

a) infrared spectrum of the specified shape that contains the characteristic peak at 835±1.5 cm-1;

(b) radiograph obtained for powder specified form, essentially corresponds depicted on Fig; and

c) the water content is from 8.3 to 9.8%.

16. Crystalline form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride 15 containing from 8.3 to 9.8% of water.

17. Crystalline form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride according to item 15 or 16, the infrared spectrum contains the characteristic peak at 835±1.5 cm-1.

18. The method of identification form II hydrate ( )-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride in the sample, characterized by carrying out infrared spectroscopy of a sample of the hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride and detection of diagnostic peak at 835±1.5 cm-1.

19. Pharmaceutical composition for treatment and/or prevention of disorders related to the deterioration of gastro-intestinal motility, comprising form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride as defined according to any one of p-17, and a pharmaceutical excipient.

20. A method of treating disorders related to the deterioration of gastro-intestinal motility, comprising introducing to a subject in need of such treatment, the crystalline form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride as defined according to any one of p-17, or pharmaceutical composition as defined by claim 19.

21. The method according to claim 20, whereby crystalline form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride defined p-17, or a pharmaceutical composition according to claim 19, used for the treatment and/or prevention of one or more violations of the group, including irritable bowel syndrome, slow elizabethanne gastric emptying, dyspepsia, gastro-esophageal reflux, gastric ulcer and duodenal ulcer, flatulence, loose stools, constipation, diabetic nephropathy, functional abdominal bloating, abdominal pain and/or discomfort, abdominal bloating, abnormality of stool consistency, the anomaly frequency of stools, feeling of incomplete evacuation, sensation of urgency evacuation, passage of mucous membranes, vomiting, gastroparesis and/or treatment of disorders of the Central nervous system.

22. The method according to claim 20, whereby crystalline form II hydrate (±)-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride according to any one of p-17 or a pharmaceutical composition according to claim 19, used for the treatment of shut-predominance, Varano-predominance or alternating (with mixed symptoms of irritable bowel syndrome.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new N,N'-substituted 3,7-diazabicyclo[3.3.1]nonanes of the general formula 1: (HY), where HY is hereinafter a pharmacologically acceptable acid; E is , R1 is H, low-grade alkyl, C1-C10alkoxy; R2 is generally represented by the general formulae (1.1a) , (1.2a) , (1.3a) , (1.4a) , where L is CHR11, ; R11 is H, NH2; R15 is H, low-grade alkyl, C1-C10alkoxy; R19, R19', R20 and R20' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R24 and R25 can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R3 and R3' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R4 and R4' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; X is a group of the general formula: (CH2)m-Z, where m=0, while Z is acetyl, or X is a valence link. Compounds I are capable of AMPA receptor activity modulation and hence can be applied in pharmaceutical compositions.

EFFECT: obtaining compound capable of AMPA receptor activity modulation.

12 cl, 2 dgw, 2 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1,4-diazabicycloalkane of the formula (IV): or its pharmaceutically acceptable addition salt wherein Ar represents carbocyclic aromatic (aryl) group or heterocyclic aromatic (heteroaryl) group that represents 5-6-membered ring comprising one nitrogen, sulfur or oxygen atom as a heteroatom and wherein aromatic group can be substituted with one substitute chosen from group consisting of (C1-C6)-alkoxy, halogen atom, -CF3, phenyl and benzyl. Also, invention relates to a pharmaceutical composition possessing inhibitory effect on nicotine acetylcholine receptors and containing the effective amount of compound of the formula (IV) or its pharmaceutically acceptable addition salt in combination with at least one pharmaceutically acceptable carrier or diluting agent. Invention provides derivatives of 1,4-diazabicycloalkane possessing inhibitory activity with respect to nicotine acetylcholine receptors.

EFFECT: valuable medicinal and pharmacological properties of compounds.

10 cl, 3 ex

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

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

8 cl, 11 tbl, 463 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel chemical compound, namely, to biologically active compound of the formula (I): possessing anti-arrhythmic activity and representing 5'-bromolappaconitine hydrobromide. Toxicity of this compound is by 4.8-fold less toxic as compared with analog used in medicinal practice and representing lappaconitine hydrobromide. Proposed compound possesses the expressed anti-arrhythmic activity in models with calcium chloride and adrenaline arrhythmia and provides the complete blocking both types of arrhythmia after administration of the dose that is 10-fold less of the therapeutic dose of lappaconitine hydrobromide.

EFFECT: improved and valuable medicinal properties of compound.

2 cl, 2 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a whitening composition comprising: (a) monomeric ligand or catalyst with transient metal of ligand of the formula (I): wherein R represents hydrogen atom; R1 and R2 are chosen independently from (C1-C4)-alkyl, pyridine-2-yl-methyl and (C2-C4)-alkylmethyl; X represents -C=O; R3 and R4 are similar and represent -(CH2)nC(O)O-(C1-C4)-alkyl; n = 0-4, and (b) equilibrating carriers and additional components. This composition is useful for catalytic whitening substrates with atmosphere oxygen. Also, invention describes a method for whitening the substrate involving applying step of the whitening composition on substrate in aqueous medium.

EFFECT: valuable properties of substances, improved whitening method.

11 cl, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: compounds of formula I are disclosed, wherein R1, R2, R3, R4, R5, R6, R7, R41, R42, R43, R44, R45, R46, A, and B are as described in description.

EFFECT: new compounds with increased electrophysiological activity useful in treatment of cardiac arrhythmias.

132 cl, 1 tbl, 37 ex

The invention relates to metallogenica derivative containing four nitrogen atom of the macrocycle, fused with the pyridine cycle, methods for their preparation and their use in medicine to obtain an image

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine area. Perform digestion on birch buds alcohol in several stages. At the first stage presoak 100 g of birch buds with the maintenance of essential oils of 5-8% in a tightly closed glass container in 300 ml of alcohol-rectificate of 95-96.2% strength and condition for 14-16 hours. At the second stage in the obtained solution at the first stage add as the catalyst potable water in amount of 300-306 ml at temperature of 45°C and condition within 2.5-4 hours up to obtaining of white cream colour by the solution and depression of alcohol strength to 45%. At the third stage add 0.5 litres of alcohol of 95-96.2% strength in a solution, condition the solution in a dark place at temperature of 24-26°C within two weeks in a hermetically sealed container up to obtaining of brownish-green colour. At the fourth stage add 180-200 ml of potable water with temperature 36°C and 180-200 ml of alcohol of 95-96.2% strength before depression of alcohol strength to 62.5% and digest within two weeks up to obtaining of dark brown colour.

EFFECT: decrease of toxicity of the product.

2 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine. A soft drink on the basis of herbs consists of the concentrated vegetative extract obtained from an admixture of herbs, chosen of Sida sps., Boerhaavia diffusa, Vitis vinifera, Tinospora cordifolia and Withania somnifera, along with green palm sugar, the agent causing a fermentation, and carbonised water, in which proportion Sida sps.: Boerhaavia diffusa: Vitis vinifera: Tinospora cordifolia: Withania somnifera in a powdery admixture makes (15-20 : (5-10 : (15-20 : (5-10 : (5-10); Proportion of wt/wt: green palm sugar: the concentrated vegetative extract makes from 1 : 3 to 1 : 4; wt/wt, a proportion of carbonised water: the admixture of the concentrated vegetative extract, green palm sugar and the agent causing a fermentation, makes from 1 : 3 to 1 : 5. Perform: (a) obtaining of parts of Sida sps., Boerhaavia diffusa, Vitis vinifera, Tinospora cordifolia and Withania somnifera; (b) crushing of parts of plants and their mixing with obtaining of a powdery admixture; (c) water addition to a powdery admixture from a stage (b) for obtaining of a water extract; (d) concentration of a water extract from the stage (c); (e) filtration of the concentrated extract from the stage (d); (f) admixture of green palm sugar to the filtered extract from the stage (e); (g) addition of Sacromyces strain and the agent causing fermentation, to the admixture from the stage (f); (h) fermentation of the admixture from the stage (g) during the period of time from 3 till 6 days; (i) filtration of the fermented admixture from the stage (h); (j) concentration of the fermented filtrate from the stage (i) with obtaining of the basic solution and (k) mixing of the basic solution (j) with the carbonised water in wt/wt proportion from 1 : 3 to 1 : 5 with obtaining of a soft drink on the basis of herbs.

EFFECT: creation of a soft drink on the basis of herbs.

11 cl, 5 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: application of N-dismetilklosapine is proposed for production of a medicine, increasing the muscarine receptor activity level, for facilitation of condition or treatment of schizofrenia. N-dismetil - klosapine is klosapine metabolite, applied for schizophrenia treatment. It is stated, that N-dismetilklosapine differs from klosapine with prepotent activation of muscarine receptors, including influence on M3- and M5- muscarine receptors (klosapin does not affect the latter), the capability of penetration into the central nervous system through the hematoencephalic barrier.

EFFECT: creation of medication, increasing muscarine receptor activity level, for facilitation of condition or treatment of schizophrenia.

10 cl, 3 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention concerns formulation for mucous membrane of oral cavity, containing effective number of substituted imidazol derivative of (1) formula along with additives, usually used in formulations for mucous membrane of oral cavity. Invention provides high security of administration.

EFFECT: provision of high security of medication administration.

22 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to pyperidine derivatives of formula (I) , where R represents galogen or C1-4alkyl; R1 represents C1-4alkyl; R2 or R3 independently represent hydrogen or C1-4alkyl; R4 represents trifluorinemethyl or galogen; R5 represents hydrogen, C1-4alkyl or C3-7cycloalkyl; R6 represents hydrogen, R7 represents radical of formula (W), or R7 represents radical of formula (W) and R7 represents hydrogen; X represents CH2, NR5 or O; Y represents nitrogen, and Z represents nitrogen; or Y represents CH, and Z represents nitrogen; A represents C(O), m is zero or whole number from 1 to 3; t is whole number from 1 to 3; and p and q are whole number from 1 to 2; or to their pharmaceutically acceptable salts and solvates. Claimed invention also relates to method of obtaining said derivatives and to their application for treating condition with tachyquininamia.

EFFECT: obtaining pyperidine derivatives, which can be used for treating tachyquininamia.

14 cl, 29 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to derivatives of 4-pyrrolidine phenyl benzole ether of formula where X-Y stands for -CH2-O-; R1, R1.1 and R1.2 independently on each other are selected from group, including H, haloid, haloid (C1-C6)alkyl, R21, R22 and R23 independently on each other stand for H; R24 stands for H; R3 stands for H; R4 stands for -CONHR5, -CN or -NHR6; R5 stands for H, (C1-C6)alkyl; R6 stands for -CO-H, -CO-(C1-C6)alkyl, -CO-NH2, -SO2-(C1-C6)alkyl; as well as its individual isomers and racemic and non-racemic mixtures. Compounds 1 inhibit monoaminooxidase B, which allows to apply them in pharmaceutical composition and for production of medications, intended for treatment and prevention of Alzheimer's disease and senile dementia.

EFFECT: invention ensures enhancing efficiency of composition and method of treatment.

15 cl, 7 dwg, 21 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to novel pyrrolidone derivatives of formula I where Q stands for =N- or =C(R24)-; X-Y stands for -CH2-CH2-, -CH=CH-, -CH2-O-; R1, R1.1 and R1.2 independent on each other stand for halogen, C1-C6alkyl, halogen(C1-C6)alkyl, cyano, C1-C6alkoxy, halogen(C1-C6)alkoxy; R21, R22 and R23 independent on each other stand for H and halogen; R24 stands for H, CH3, halogen; R3 stands for -C(O)N(H)CH3, -CH2CN; R4 stands for H; as well as its individual isomers, racemic or non-racemic mixtures of isomers. Compounds inhibit monoaminooxidase, which allows to use them in pharmaceutical compositions for treatment and prevention of Alzheimer's disease and senile dementia.

EFFECT: invention ensures enhancing efficiency of composition and method of treatment.

19 cl, 5 dwg, 49 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is applied for treatment of depressions and depressive disorders or other emotional insanities affected with depressants, such as anxiety, panic disorder, bipolar depressions, somatic disorders and premenstrual syndrome, including early stages thereof. Medical product and food substance based on extracted prickly pear blossom or leaves are offered.

EFFECT: compositions of medical products and food substance based on extracted prickly pear blossom or leaves, extends range of therapeutic action without by-action.

13 cl, 4 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns application of alpha-aminoamides of formula for production of medical product for headache treatment including cerebrum vasorelaxation mechanism and treatment method of specified states.

EFFECT: high efficiency and absence of by-effects.

13 cl, 1 tbl, 3 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: compound of formula [I]: is described, where the ring A represents halogen substituted benzene ring; the ring B represents benzene ring substituted with two lower, 1 to 4 carbon atoms, alcoxy-groups; the ring C represents benzene ring or five-member aromatic heterocyclic ring, that may be optionally substituted with substitute as follows: carboxyl group, C1-4-alkyl group, C2-7-alkanoiloxy-C1-6-alkyl group, phenyl-C1-4-alkyl group, phenyl group, optionally substituted with carboxyl group, or oxo-group; R1 represents C1-6-alkyl group, optionally substituted with hydroxyl group, that optionally substituted with C2-20-alkanoil or C1-7-alkyl group; X1a represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X1b represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X2 represents bound, -O- or -S- ; X3 represents bound or group, formed by one hydrogen atom elimination from either straight or branched chain C1-7-alkyl, or C2-6-alkenyl group, that optionally substituted with hydroxyl or oxo-group; and Y represents optionally etherified carboxyl group; or its salt. Benzoxazepin derivatives production method, medicine based on them, and their application are also described.

EFFECT: novel compounds have high lipids-decreasing effect and are helpful as hyperlipidemia prevention and treatment medicine.

20 cl, 168 ex

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