Nebivolol and pharmaceutically acceptable salts thereof, method of producing said salts and nebivolol pharmaceutical compositions

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

EFFECT: invention also relates to a pharmaceutical composition with antihypertensive action without using a wetting agent, and to a tablet containing this pharmaceutical composition.

21 cl, 20 tbl, 21 ex

 

The SCOPE of the INVENTION

This invention relates to an improved method for the synthesis of pharmaceutically active derivative 2,2'-aminobutanol, then there are 2N-1-benzopyran-2-methanol, α,α'-iminobis-(methylene)bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]]then there nebivolol or its pharmaceutically acceptable salts, or rather cleaners containing hydrochloride salt (I)

Nebivolol is used to treat and prevent disorders of the coronary vessels.

This invention also relates to pharmaceutical compositions and method of producing solid oral dosage forms of nebivolol hydrochloride of the formula (I), without the use of wetting agent, and optionally with the use of linking and/or dezintegriruetsja agent.

This invention, moreover, represents a new polymorphic form of nebivolol hydrochloride.

Background of the INVENTION

For the treatment of high blood pressure, combat angina, arrhythmia, post-myocardial infection, heart failure, migraine or essential tremor applied beta-blockers.

Nebivolol is a highly selective beta-1 blocker, which, as it turned out, suitable for controlling hypertension. Hypertension (high blood pressure) represents a significant health risk, affects more than 500 mill the ones people worldwide and requires long-term therapy to control.

Chemically nebivolol is a derivative of 2,2'-aminobutanol, then there are 2N-1-benzopyran-2-methanol, α,α'-[iminobis-(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]]. In the European patent EP 744946 B1 discloses nebivolol, which is a mixture of equal amounts of 2 enantiomers having respectively SRRR - RSSS-configuration.

Ways to get nebivolol disclosed in European patents EP 0145067 and EP 0334429. European patent EP 0145067 B1 describes a method of conversion of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) in a mixture of isomers of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII). This reaction entails the use of sodium hydride as the base, which is extremely dangerous. In addition, the purity of the product, that is 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII), obtained with the use of sodium hydride, is low and, as it turned out, approximately 62-65%, which is unacceptable. A mixture of oxirane represented by the formula (VII), divide column chromatography, as shown in the Diagram (I), to obtain the A-isomer (VII) (i.e VII-A) of the first fraction and In-isomer (VII) (i.e VII-B) from the second fraction.

A-isomer (VII) is then treated with benzylamine to get Antilibanus And-isomer (VII) (i.e., the intermediate compound I), which reacts with In-isomer of prisutstvie oxalic acid to obtain the oxalate salt Antilibanus nebivolol (VIII-a), as shown in Scheme II.

In addition, oxalate salt (VIII-a), as found, should be treated with alkali to obtain the free base Antilibanus nebivolol (VIII).

Thus, as can be seen from Scheme II, the reaction between the intermediate compound I and (VII-B) includes a purification column chromatography and subsequent treatment with oxalic acid for the formation of oxalate salt. Treatment oxalic acid leads to the separation of unwanted (RSRR+SRSS) of diastereomers from desirable (RSSS+SRRR) isomers, due to differences in the solubilities of desirable and undesirable isomers. In addition, the salt of oxalic acid must be converted into the free base Antilibanus nebivolol treatment with alkali. Many steps in the described method makes it cumbersome, leading to increased energy consumption and cycle time of the production of the active pharmaceutical ingredient. In addition, the purity free base Antilibanus nebivolol, as found, is relatively low.

European patent EP 334429 B1 discloses an independent method of obtaining a specific RSSS isomer of nebivolol. Referred to the independent way of obtaining RSSS nebivolol includes the use of hazardous chemicals, such as chloride tonila, sodium hydride and Diisobutyl aluminum hydride (DEEB IS G), expensive optically active reagents, such as (+)-1,2,3,4,4A,9,10,10A-octahydro-1,4A-dimethyl-7-(1-methylethyl-1-penetrometer-[(+)-dehydroabietylamine], and application conditions, such as column chromatography and low temperatures. Mentioned means also includes a large number of stages, thereby increasing energy costs, labor and time required to complete a series, which makes the method expensive commercial.

In addition, European patent EP 744946 B1 discloses a method of producing nebivolol hydrochloride from a mixture containing the desired (RSSS+SRRR) base nebivolol contaminated unwanted (RSRR+SRSS) diastereomers, with the use of ethanol as a reactant and as a solvent recrystallization. The main disadvantage of this method is that as the starting material can be applied to the base of nebivolol with impurities of different isomers, which thus leads to a very low yield (6,6%) of the desired isomers (with SRRR - RSSS-configuration) of nebivolol hydrochloride. In addition, ethanol is a solvent that can be used only in controlled amounts due to strict regulatory requirements, and therefore its use on an industrial scale is limited.

Thus, there is a need for the development of the synthesis method, see the C desired diastereomers higher purity reducing unwanted isomeric impurities and eliminate the use of hazardous sodium hydride, at the same time reducing the steps of the method for the synthesis of nebivolol.

Discovered that the method for the synthesis of nebivolol in this invention not only improves the purity of the desirable mixture of diastereomers with the minimum number of stages of the method, but also eliminates the use of hazardous chemicals in the way.

Nebivolol is mainly used for the treatment and prevention of disorders of the coronary vessels. It is taken once or twice a day depending on the needs of the patient.

In the European patent EP 0744946 disclosed pharmaceutical compositions nebivolol where the medicine is a micronized form with the addition of one or more wetting agents, in particular, polysorbates as adjuvants. This patent emphasizes the need micronisation and subsequent hydration, because oral introduction of nebivolol hydrochloride prevents low solubility, if it is in normal crystalline form. To achieve good solubility of the active ingredient must be sufficiently hydrated.

Micronization of nebivolol hydrochloride required in EP 0744946 B1 to obtain pharmaceutical compositions, unnecessarily increases the cycle time of the production process. Also experiencing excessive energy consumption, for example, by grinding and sieving, h is about increasing the cost of the final product. In addition, as shown by a comparison of the solubility of the tablets, including crystalline nebivolol and micronized nebivolol, the dissolution rate of the tablets, including crystalline nebivolol (Example 6 of EP 744946), is less than 50% in 45 minutes.

European patent EP 0145067 B1 represents pharmaceutical composition derivatives of 2,2'-aminobutanol for different dosage forms, i.e. oral drops, injectable solution, oral solution, film-coated tablets, etc. In the European patent EP 0145067 B1 discloses the use of dodecyl sodium sulfate in obtaining tablets with a film coating. Dodecyl sodium sulphate, i.e. sodium lauryl sulfate (Wade, A. and Weller, P.J., Handbook of Pharmaceutical Excipients, 2nded., 1994, page 448), is a moisturizing agent in the core composition (tablets film-coated).

In the international application WO 2002/087508 disclosed nitrosated and nitrosylating nebivolol, its metabolites and pharmaceutical composition using the same components. It is shown that the bioavailability of the composition can be increased by micronization formulations using conventional techniques such as grinding, milling, drying, when spraying and the like, in the presence of an acceptable excipients or agents such as phospholipids or surfactants.

Thus, the literature shows that pop the TCI to use natural crystalline form of nebivolol lead to low dissolution rate and low bioavailability. Attempts combination of crystalline form with moisturizing agent is also largely unsuccessful. To achieve the proper rate of dissolution or bioavailability of nebivolol hydrochloride required micronized nebivolol. The micronisation process is costly, takes time and requires the use of a moisturizing agent.

Wetting agent is a surfactant, a substance capable of lowering the surface tension of the liquid in which it is dissolved. The effect of the surfactant through the membrane of the intestine is more complex. It is shown that most of the surfactants interact with absorbent membranes (Bermejo, D.M. and Ruiz-Garcia, A., Business Briefing: Pharmatech 2003; pages 1-7). The increased permeability and local damage is closely related complications interaction of surfactants with the wall of the intestine (Swenson, E.S., Milisen, W.B., Curatolo, W., Pharm. Res. 1994 Aug; 11(8), pages 1132-42). Entered the surfactants can facilitate the penetration or absorption of potentially toxic or pathogenic compounds, which, in turn, can lead to adverse effects on other organs (Lieberman, N., Rieger, M.M. and Banker, G.S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nded, Vol.1, page 261). The surfactant may facilitate the penetration and permeation of another substance, which thus enters the systemic circulation (Lieberman, H.A., Rieger, M.M. and Banker, G.S., Eds., Parmaceutical Dosage Forms: Disperse Systems, 2nded., Vol.1, page 264).

Polysorbate 60 or 80 affects the integrity of the intestinal mucosa (Lieberman, H.A., Rieger, M.M. and Banker, G.S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nded., Vol.1, page 261). Polysorbate 80 may enhance absorption of fat-soluble substances (www.lactose.co.uk/milkallergy/foodadditives400.html).

Treatment of hypertension is a long-term therapy, so the application oblajalsya agents in formulations nebivolol must consciously avoid. Large doses of Polysorbate 80 as a wetting agent in pharmaceutical formulations cause abdominal cramps, diarrhea (http://www.jtbker.com/msds/englishhtml/t7683.htm). In addition, it was found that Polysorbate 80 contained in the pharmaceutical compositions, caused allergies in different patients (http://www.hci.utah.edu/patientdocs/ hci/drugd/docetaxel.htm). You should also avoid the use of Polysorbate 20 and Polysorbate 40 in the formulations because they are forbidden in some countries (http://www. lactose.co.uk/milkallergy/foodadditives400.html).

Thus, a need exists for compositions of nebivolol that are safe, effective and, at the same time, effective for the production of indicators of cost and time.

The authors of this invention have found that the pharmaceutical compositions according to this invention, prepared with the use of nebivolol as the active ingredient and without applying moisturizer Agay is the showed excellent solubility characteristics, which, as also was found to be comparable with the formulation, commercially available.

In addition, unexpectedly found that nebivolol hydrochloride can be developed not only without the use of a moisturizing agent, but not necessarily without the use of binding or dezintegriruetsja agent without slowing down the dissolution characteristics of the drug.

The PURPOSE of THIS INVENTION

Thus, the purpose of this invention is to provide an improved method for the synthesis of pharmaceutically active derivative 2.2 aminobutanol, then there are 2N-1-benzopyran-2-methanol, α,α'-iminobis-(methylene)bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]]then there are grounds nebivolol or cleaners containing hydrochloride salt of formula (I) above.

The next objective of this invention is the provision of a simple and economical method for the synthesis of the base of nebivolol or cleaners containing hydrochloride salt, which includes minimalne the number of steps and which does not apply to hazardous chemicals.

Another purpose of this invention to provide pharmaceutical compositions comprising the active ingredient of nebivolol hydrochloride and one or more adjuvants, without the inclusion of wetting agent to achieve the desired solubility profile.

The purpose of this invention is to develop a str is about producing solid dosage forms, such as tablets or capsules simple and effective method.

Another aim of this invention is the preparation of solid dosage forms of nebivolol hydrochloride and one or more adjuvants, without the use of wetting agent, optionally without the use of a binding agent and optionally without the use of dezintegriruetsja agent.

Another purpose of this invention is the provision of a new polymorphic form of nebivolol and its pharmaceutically acceptable salts, in particular cleaners containing hydrochloride salt, and the way it was received.

Another aim of this invention is to provide use of the pharmaceutical composition of nebivolol hydrochloride according to this invention, prepared without use of a moisturizing agent, for the treatment of hypertension.

A BRIEF DESCRIPTION of the INVENTION

Thus, according to the first aspect of the present invention provides an improved method for the synthesis of pharmaceutically active derivative 2.2 aminobutanol, then there are 2N-1-benzopyran-2-methanol, α,α'-iminobis-(methylene)bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]]then there nebivolol or its galgenwaard, rather cleaners containing hydrochloride salt of nebivolol, as shown in Figure (I),

where

- 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) turns in sessomaru of oxiranes, represented by formula (VII)in the presence of tertiary butoxide potassium as the basis, and

- the reaction between Antilibanus A-isomer (VII) (i.e., the intermediate compound (I) and b-isomer (VII-B) and the reaction product is performed in the presence of an organic solvent under controlled time and temperature conditions, which leads to the formation of the free base Antilibanus nebivolol (IX).

According to the second aspect of the present invention provides nebivolol synthesized by the method according to this invention.

According to further aspect of the present invention are provided pharmaceutical compositions of nebivolol, including nebivolol or its pharmaceutically acceptable salts formed without the use of wetting agents.

In addition, this invention also represents a solid dosage form of nebivolol hydrochloride and one or more adjuvants without the use of wetting agent, optionally without the use of a binding agent and/or dezintegriruetsja agent and the method of its receipt.

According to further aspect of the present invention provides a method of obtaining a pharmaceutical composition according to this invention.

Another aspect of the present invention is a new polymorphic form of nebivolol and its Pharma is efticiency acceptable salts.

In the following embodiment of this invention the preferred specific surface area of nebivolol hydrochloride is from 0.2×103m2/kg up to 1,95×103m2/kg.

A DETAILED DESCRIPTION of the INVENTION

Thus, this invention represents an improved method of obtaining 2N-1-benzopyran-2-methanol, α,α'-iminobis-(methylene)bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]]then there nebivolol formula (IX), or its pharmaceutically acceptable salts, such as cleaners containing hydrochloride salt, as shown in the formula (I)

According to this invention nebivolol get the synthesis shown in Scheme III:

The stages of reaction to get nebivolol in this invention, from compound (II)according to the above Scheme III, is now described below.

5-fluoro-2-hydroxyacetophenone (II) tertiary treated with piperonyl potassium and diethyl oxalate to obtain 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (III) according to Reaction 1, as shown below, in a known manner (Japan patent No. 2218675).

Spend the reaction of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (III) with 10% palladium on coal in acetic acid as solvent, in an atmosphere of hydrogen to obtain 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV), as shown in Reaction 2 below, in a known manner (U.S. patent No. 4654362).

6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) is transformed into amide (V-A)using amine RR'NH and acid-activating agent, as shown in Reaction 3(a),

where R and R' is independently H, alkyl or phenyl, optionally associated with a heteroatom such as O, N or S, or is not associated with the heteroatom. Alkyl represents a C1-C6alkyl straight or branched chain.

In Reaction 3(a) education amide (V-A) of the acid (IV) amine RR'NH can be selected from the group of primary or secondary amines. Primary amine selected from aliphatic or aromatic primary amine, whereas secondary amine selected from cyclic or acyclic secondary amines, secondary amines, where the substituents on the nitrogen atom is independently an aliphatic or aromatic or a combination.

Preferably can be used secondary amines. More preferably used secondary amines, which are cyclic.

Amines can be selected from the group including dimethylamine, diethylamine, N-methylphenylamine, pyrrolidine, piperidine, N,O-dimethylhydroxylamine and morpholine. The preferred amine is piperidine.

The activating agent, according to which eacli 3 (a), selected from the group including thionyl chloride, ethylchloride, acetic anhydride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole and hariharan. Preferred activating agents are thionyl chloride and ethylchloride.

In a preferred embodiment, 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) make 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid piperidine amide (V) using thionyl chloride and piperidine in toluene as a solvent, as shown in the following Reaction 3.

The restoration of the amide (V-A) to obtain 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde formula (VI) is performed with the use of alkoxy-metal hydride, where the alkoxy group is substituted or unsubstituted-O(C1-C4)alkyl, and replacement, if it is,- O(C1-C4)alkyl, and the metal portion includes a metal selected from the group including Li or Na.

Restorative alkoxy metal hydride agent selected from the group consisting of sodium bis-(2-methoxyethoxy)aluminum hydride, lithium diethoxyaniline digital and lithium tri-tert-butoxy aluminum hydride.

The preferred reducing agent is the atrium bis-(2-methoxyethoxy)aluminum hydride.

6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid piperidine amide (V) restore using Vitride®, i.e. sodium bis-(2-methoxyethoxy)aluminum hydride in toluene to obtain 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI), as shown in Reaction 4.

Spend the reaction of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI) with trimethyl-sulfoxonium iodide in the presence of a base, tertiary butoxide potassium and dissolved dimethyl sulfoxide to obtain a mixture of isomers of oxiranes represented by the formula (VII), which can be optionally distilled, as shown in Reaction 5.

Thus, the invention in the above reaction avoids the use of sodium hydride as a base. Due to specified replacement of the aforementioned grounds, the purity of the reaction product, i.e. oxirane (VII), is significantly higher. The purity of oxirane obtained with the use of tertiary butoxide potassium as the base, is about 75% to distillation of the product, to compare the purity of the product prior to distillation, obtained in performance of this invention, using a base of sodium hydride according to the method described in European patent EP 0145067 B1, was 60-65%. The advantage of this method p. the present invention is that avoids the use of hazardous sodium hydride, and also increases the purity of oxirane.

A mixture of oxirane divided column chromatography by elution first pure fractions (A-isomer, i.e VII-A), namely (S)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran according to European patent EP 0145067. And then the second elution fraction (In-isomer, i.e VII-B) received (C)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran according to European patent EP 0145067.

Chromatographic separation of the two isomers a and b perform (EP 0145067) (Scheme I) using silica gel as the stationary phase, whereas allanton is a mixture of hexanol and ethyl acetate. If you have a large amount of material for cleaning, the cleaning column chromatography can be performed simultaneously on multiple columns (more than one column). Column chromatography first gives the isomer And isomer Century on the Basis of the purity of the fractions from the column, they can be mixed together and used in further reactions.

Carry out the reaction of (S)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII-A) with benzylamine in isopropyl alcohol to obtain (S)-6-fluoro-3,4-dihydro-alpha-[[(phenylmethyl)amino]-methyl]-2H-1-benzopyran-2-methanol (intermediate compound (I) in a known manner (U.S. patent No. 4654362), as shown in Reaction 6.

Carry out the reaction of (S)-6-perdiguero-α-[[(phenylmethyl)amino]-methyl]-2H-1-benzopyran-2-methanol (intermediate compound (I) with (In)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyrano (VII-B) in the presence of an organic solvent and emit at a temperature of from -5 to -25°C., maintaining the reaction mass at a temperature allocate more than 2 hours, to obtain Antilibanus nebivolol, as shown in Reaction 7.

In this invention the reaction between Antilibanus A-isomer (VII) (i.e., intermediate compound (I) and b-isomer (VII-B) is performed in an organic solvent and emit at a temperature of from -5 to -25°C, which leads directly to the formation of free base Antilibanus nebivolol (IX)containing only the desired isomer (with SRRR - RSSS-configuration). The present invention is observed that the selection, if it is performed at low temperature, in particular at temperatures from -5 to -25°C, gives essentially pure desired stereoisomers (purity, HPLC (high performance liquid chromatography) >90,0%), which can then optionally be cleaned in an alcohol solvent such as methanol, ethanol, to obtain the desired stereoisomer in shape with a high degree of purity (HPLC purity >98.5 per cent), for comparison, in the method described in the previous bronetehniki, received the desired isomer oxalate salt Antilibanus nebivolol with much less purity (HPLC purity <60,0%), even after repeated cleaning.

The organic solvent used in the Reaction 7, selected from the group comprising alcohols, esters, ketones and acetonitrile.

In one embodiment of this invention, the alcohol is selected from the group comprising methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, Isobutanol. In a preferred embodiment, use methanol. In another embodiment, the esters selected from the group comprising ethyl acetate, n-butyl acetate. In the following embodiment, ketones selected from the group comprising acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK).

The selection is performed in the temperature range from -5 to -25°C, preferably in the range from -10 to -20°C., and more preferably in the range from -10 to -15°C.

The reaction mass was kept at a temperature selection for 2-40 hours, preferably for 4-30 hours, more preferably within 8-20 hours and most preferably for about 10 to 15 hours.

Thus, the method according to this invention has the following advantages:

(i) avoids the use of column chromatography,

(ii) avoids obtain the oxalate salt and phase recrystallization and/p>

(iii) avoids the subsequent conversion of oxalate salt free benzylidene the basis of nebivolol by treatment with alkali.

Therefore, compared with the methods known from the prior art, the method according to this invention leads to a reduction in the number of stages of the method, thereby making it more economical and time efficient.

Further, the hydrogenation reaction is carried out with the use of 10% palladium on coal for dibenzylamine Antilibanus the base of nebivolol (VIII) to obtain the base of nebivolol (IX) in a known manner (U.S. patent No. 4654362), as shown in Reaction 8.

Nebivolol can be transformed into the form of its pharmaceutically acceptable acid additive salts by treatment with appropriate acids. Appropriate acids comprise, for example, inorganic acids such as halogenation acid, for example, chloromethane, Hydrobromic, sulphuric acid, nitric acid, phosphoric acid; or organic acids, for example, acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, tanginoa, proportionaly, batandjieva, (Z)-2-batandjieva, (E)-2-batandjieva, 2-hydroxybutanone, 2,3-dihydroxy-batandjieva, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzosulfimide is, 4-methylbenzol-sulfonic, cyclohexane-sulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid. In a preferred embodiment, the acid additive salt is hydrochloride.

With the help of an organic solvent and chloroethanol acid (Reaction 9) the basis of nebivolol (IX) make nebivolol hydrochloride (I). In this invention have observed that the receipt of nebivolol hydrochloride in alcohols/esters/ketones gives the minimum quantitative yield as compared with other organic solvents. This method of turning the base of nebivolol in cleaners containing hydrochloride salt of nebivolol in the presence of an alcohol as solvent gives the minimum quantitative yield of product. Thus, the method according to this invention it is possible to obtain a high yield of nebivolol hydrochloride, containing only the desired mixture of isomers.

Solvents for the conversion of nebivolol hydrochloride or even for further purification can be selected from the group comprising alcohols, esters, ketones, halogenated solvents, acetonitrile and water, or a mixture thereof. In one embodiment of the present invention, the alcohol used for the conversion, you can select from a group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutane is l, etc. In another embodiment, the ester can be selected from the group comprising ethyl acetate, n-butyl acetate, etc. In another embodiment, the ketone can be selected from acetone or isobutyl ketone (MIBK). In the following embodiment, halogenated solvents such as methylene dichloride, can be applied for turning the base of nebivolol in nebivolol hydrochloride.

Also nebivolol hydrochloride can be obtained by reaction of the base of nebivolol and alcohol hydrogen chloride, such as HCl in methanol, HCl in ethanol, HCl in n-propanol, HCl in isopropanol, HCl in n-butanol.

Also the same can be achieved by skipping model HC1 gas through a solution of the base of the nebivolol, you can use the above-mentioned solvent.

Form T1 nebivolol hydrochloride

This invention also introduces a new amorphous form of nebivolol and its pharmaceutically acceptable salts, denoted by the form T1.

Polymorphism is the occurrence of individual crystalline forms of the same compounds with the same molecular formula, but each polymorph may have different physical properties. One connection can give different polymorphic forms, physical properties, which can be individual and different, such as different solubility profiles, different point temperature the tour melting and different peaks of x-ray diffraction. Due to different solubility profiles of polymorphic forms, identification of pharmaceutical polymorph very important for obtaining pharmaceutical dosage forms with predictable solubility profiles.

The expression "amorphous" in this description refers to a physical condition, non-crystalline, and may be confirmed by x-ray diffraction, infrared spectroscopy and other resources, including examination with a polarizing microscope and differential scanning calorimetry, but not limited to them.

The expression "pharmaceutically acceptable salt" in this description refers to salts, known as non-toxic and is generally used in the pharmaceutical literature. Typical inorganic acids used for the formation of such salts include chloroethanol, Hydrobromic, iodomethane, nitric, sulfuric, phosphoric, hypophosphorous etc. you Can also use salt, derivatives of organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate and hydroxyalkanoate acids, aromatic acids, aliphatic and aromatic sulfonic acids. Thus, such pharmaceutically acceptable salts include the acetate, phenyl acetate, triptorelin, acrylate ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymet, malonate, mesilate, nitrate, oxalate, phthalate, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, bansilalpet, R-bromophenylacetate, chlorobenzenesulfonate, econsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, xylenesulfonate, tartaric etc. Preferred cleaners containing hydrochloride salt is salt.

In one particular preferred embodiment, the invention is cleaners containing hydrochloride salt nebivolol in amorphous form.

Specified amorphous form can be obtained by methods such as drying method, spray drying method, freeze, etc.

In a preferred embodiment, the specified form will receive the usual method of drying when spraying with the use of dryers with spray LabPlant SPD-005®. Nebivolol hydrochloride is dissolved in alcohol, such as methanol, by heating for the teachings transparent solution or set the pH of the solution base nebivolol/suspension in alcohol below 2.0 with aqueous HCl/HCl alcohol/gaseous HCl, which is then dried, when spraying for 2-5 hours, and then allocate nebivolol hydrochloride form T1.

The expression "selection" enables filtering, drying, or any other techniques known to experts in this field. The alcohol to form T1 nebivolol hydrochloride selected from the group comprising methanol, ethanol, propanol, isopropanol, n-butanol and the like, and mixtures thereof.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Figure 1: this figure shows a graph of the x-ray diffraction partially amorphous form T1 nebivolol hydrochloride obtained according to this invention.

Figure 2: this figure shows a graph of the x-ray diffraction of the crystalline form of nebivolol hydrochloride, obtained in a known manner (European patent EP 0145067).

Figure 3: this figure shows the comparative and the superposition graph of x-ray diffraction of the form T1 and crystalline forms of nebivolol hydrochloride obtained according to this invention.

Figure 4: This picture is a microscopic image of the crystal nebivolol hydrochloride, obtained through a microscope AXIOLAB.

Figure 5: This picture is a microscopic image of the dried when spraying nebivolol hydrochloride, obtained through a microscope AXIOLAB.

Fig.6: Graph C the dependence of the average values of plasma concentrations experienced nebivolol from time compared with the control formulation.

Characteristics of the form T1 nebivolol hydrochloride

Form T1 nebivolol hydrochloride of the formula (I) characterized by the following data.

Form T1 nebivolol hydrochloride is characterized by the graph of x-ray diffraction on the powder (XRPD), as shown in figure 1, and can be differentiated from the crystalline form angles of x-ray diffraction on the powder (°2θ)d-value and relative intensities as set forth in Table 1.

Table 1
Form T1Crystalline form
The diffraction angle ±0,2° (°2θ)The lattice parameter (D) (Å)Relative intensity (%)The diffraction angle ±0,2° (°2θ)The lattice parameter (D) (Å)Relative intensity (%)
5,4316,2627,425,7015,5016,73
of 11.15to 7.9338,76 11,437,7313,77
12,686,97to 6.5811,67EUR 7.5713,25
13,206,7018,15br12.627,01is 11.39
14.24 from6,2116,2713,15of 6.73to 24.02
of 14.576,0712,9814,56between 6.0813,16
15,915,5610,79trend of 15.875,5811,95
16,915,2422,1716,155,4830,72
17.11 per bbl5,1828,8816,546,65
18,244,8624,5017,205,1515,41
18,904,697,8618,194,8726,89

/tr>
Form T1Crystalline form
The diffraction angle ±0,2° (°2θ)The lattice parameter (D) (Å)Relative intensity (%)The diffraction angle ±0,2° (°2θ)The lattice parameter (D) (Å)Relative intensity (%)
19,774,4922,4918,93to 4.6826,43
21,184,198,5920,194,3921,31
21,824,0750,8220,58or 4.311,92
22,513,9473,2121,144,2039,13
23,85to 3.7382,0821,844,0614,09
24,39of 3.64100,0022,253,9949,17
25,173,5328.34 points22,753,9023,75
27,293,266,4023,323,813,45
28,693,114,9424,053,708,56
35,59 2,526,4024,543,6215,30
24,773,5927,45
25,413,50100,00
25,903,438,83
26,233,394,18
26,603,348,15
26,883,31of 7.69
27,71 3,211,79
28,623,11and 5.30
28,863,095,71
29,153,063,85
29,812,9913,19
30,462,93to 3.67
30,892,892,16
31,562,8313,74
32,092,7815,18

Form T1Crystalline form
The diffraction angle ±0,2° (°2θ)The lattice parameter (D) (Å)Relative intensity (%)The diffraction angle ±0,2° (°2θ)The lattice parameter (D) (Å)Relative intensity (%)
32,812,72or 4.31
33,322,683,50
33,632,66the 5.25
34,282,611,74
34,712,582,87
35,042,562,97
35,452,536,77
35,63of 2.51of 5.89
36,892,432,95
37,172,414,25
38,542,3 3,82
to 39.342,280,94

Form T1 nebivolol hydrochloride is different from the crystalline form according to the following criteria:

the absence of peaks at about 11,67±0,2; 16,54±0,2; 22,75±0,2; 25,41±0,2; 29,81±0,2; 31,56±0,2; 32,09±0,2 °2θ;

visible presence of peaks at 5,4330±0,2; 11,1544±0.2 and 19,7730±0,2 °2θ.

The pharmaceutical composition

This invention also provides a method of producing solid dosage forms, preferably tablets or capsules nebivolol hydrochloride (I) and one or more adjuvants without the use of a moisturizing agent. In addition, this invention also represents a solid dosage form of nebivolol hydrochloride and one or more adjuvants without the use of wetting agent, optionally without the use of a binding agent and optionally without the use of dezintegriruetsja agent, and the method of its receipt.

The pharmaceutical compositions according to this invention has preferably the form of tablets or capsules. The active ingredient used in this pharmaceutical composition is nebivolol hydrochloride, which does not need to be sifted through a sieve with 100 CTE is steamy one linear inch.

Solid dosage form of tablets or capsules according to this invention was produced using the active ingredient, that is, nebivolol hydrochloride, and pharmaceutically acceptable excipients selected from the group comprising diluents, dezintegriruetsja agents, binding agents, lubricating agents, agents promoting sliding, and other pharmaceutically acceptable excipients or adjuvants, but not moisturizing agent.

The diluents can be selected from the group comprising lactose, starch, dibasic anhydride calcium phosphate, rejonowy calcium phosphate, kaolin, sucrose, mannitol, precipitated calcium carbonate, sorbitol, maltodextrin, cellulose derivatives, including powdered cellulose, microcrystalline cellulose, and other materials well-known specialist in this field.

Binding agents can be selected from the group comprising polyvinylpyrrolidone or hypromellose, gum Arabic, alginic acid, hydroxypropylcellulose, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, reptitiously starch and other materials known to a person skilled in the field.

Dezintegriruetsja agents can be selected from the group comprising starch, sodium starch glycolate, or croscarmellose sodium, kresovi is he, argininemia acid, carboxymethylcellulose sodium, guar gum, and other materials well-known specialist in this field.

Lubricating agents can be selected from the group comprising stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenomonas castor oil, silica, colloidal silica, corn starch, calcium silicate, magnesium silicate, silicon hydrogel and other materials well-known specialist in this field.

The agents contributing to the slide, can be selected from the group comprising colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials well-known specialist in this field.

Other pharmaceutical solvents selected from the group including methanol, acetone and purified water.

The preferred specific surface area of nebivolol hydrochloride according to this invention is from 0.2×103m2/kg up to 1,95×103m2/kg.

The composition according to this invention includes the ingredients in the following proportions. The number of nebivolol or its pharmaceutically acceptable salt may come from the need for a human dose.

Table 2
No.Ingredient according to this inventionMinimum (%)Maximum (%)
1Nebivolol or its pharmaceutically acceptable salt0,510,00
2Thinner78,0093,05
3Binding agent (optional)0,55,00
4Disintegrity agent (optional)0,510,00
5Lubricating agent0,253,00
6Agent promoting slide0,253,00

Solid dosage form according to this invention, containing nebivolol or its pharmaceutically acceptable salt, receive according to the following steps:

(I) and. preparing a powder mixture, passing the lacto is zu, starch and croscarmellose sodium through a sieve with a number of openings per linear inch, #60, and then mixing it;

b) prepare a solution of nebivolol or its pharmaceutically acceptable salt and hydroxypropylmethylcellulose or povidone in methanol or acceptable solvent and water;

C) adsorb the solution obtained in the above step (b) to the dry mixture of diluents stage 1 (a);

d) dried product of the above step (C) and granularit water;

e) dry the wet granules at 60°C and sieved dry granules through a sieve with a number of openings per linear inch #30;

f) lubricate the granules of step (e) croscarmellose sodium, colloidal silicon dioxide, microcrystalline cellulose and magnesium stearate and mixed in the mixer;

g) press the granules obtained in step (IV), into tablets or filled with granules capsules.

OR

(I) to Nebivolol or its pharmaceutically acceptable salt, lactose, starch and croscarmellose sodium is passed through a sieve with a number of openings per linear inch, #60 and mix properly.

(II) Prepare a solution of a binding agent with the use of hydroxypropylmethylcellulose or povidone in water or anhydrous granular solvents.

(III) Granularit powder mixture of step (I)or (I') with a solution of a binding agent, prepared in stage II, m is xere with high speed and dry the granules in the dryer fluidized bed.

(IV) Lubricate the granules of step (III) croscarmellose sodium, colloidal silicon dioxide, microcrystalline cellulose and magnesium stearate and mixed in a container mixer.

(V) Pressed pellets obtained in step (IV), into tablets or filled with granules capsules.

Thus, when using the above simple and less expensive method of dissolution reaches at least 75% in 45 minutes without the use of a moisturizing agent, as shown in the relevant examples.

Throughout this description and the claims should be understood that the words "include" and "include" and their forms, such as "contains", "containing", "includes", "including"should be interpreted non-exceptionally, unless the context requires otherwise. That is, the use of such words may imply the inclusion of another element or elements that are not explicitly specified.

Details of the present invention, its objectives and advantages are explained in detail below in illustrative examples, not limiting. Examples only explain but not limit the idea of the present invention, and it is obvious that various modifications or changes in stages, methods, and compositions performed by professionals in this area without deviation from the scope of this invention should be covered by the scope and nature on the frame of the approach and scope of the invention.

EXAMPLES

Example 1

Getting 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid piperidine amide (V)

To 40 g of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) add 120 ml of toluene and 0.8 ml of dimethyl formamide with stirring at room temperature. Add thionyl chloride (32 g), the reaction mixture is heated to 60-70°C and maintained for 30 minutes. Thionyl chloride and the toluene is distilled off under reduced pressure. Then to the reaction mixture add 160 ml of toluene and cooled. Slowly add 88 ml of piperidine at room temperature and shaken for 30 minutes. The reaction mixture is acidified with diluted HCl. The aqueous layer was extracted with toluene, the combined organic layers washed with diluted HCl and then with water. The organic solvent is removed under reduced pressure to obtain 40 g of the compounds in the form of solids.

Alternatively, you can also apply the following methodology. To 100 g of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV) add 1500 ml of methylene chloride and 70 g of triethylamine at 20-40°C. the Reaction mixture is cooled to a temperature of from 0 to -5°C and slowly for 30-45 minutes add 57 g ethylchloride. The reaction mixture was kept at 0 to -5°C for 1 hour. Then add 55 g of piperidine for 30-45 minutes, supporting a temperature of 0 to -5°is. Until completion of the reaction the reaction mixture was kept at 0-5°C for 1.5 hours. Add 1 l of water at 0-5°C and adjust pH to a value of 2.0 with concentrated chloroethanol acid at 15-20°C. Shaken for 0.5 hours and the layers separated. The layer of methylene chloride was washed with 2 l of water, then completely distilled off the methylene chloride under vacuum at temperatures up to 45°C. Add 200 ml of hexane and completely distilled off. Again, add 200 ml of hexane, shake for at 20-40°C for 0.5 hour and cooled to 0-5°C. is maintained at 0-5°C for 1 hour, filtered and washed with 100 ml of chilled hexane at 0-5°C to obtain 110 g of dry weight (dried at 55-60°C in hot air for 6 hours) the specified connection in the form of solids.

Example 2

Getting 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (VI)

To 40 g of the amide (V) add 400 ml of toluene. To the reaction mixture is slowly poured the solution of Vitride®(a mixture of 44 g of Vitride®in toluene) at 10-15°C. To the reaction mixture is added methanol, and then acidified with diluted HCl. The reaction mixture is extracted with toluene and evaporated under reduced pressure to obtain 26 g of the specified connection.

Example 3

Getting 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII)

To 234 ml of dimethyl sulfoxide added 32 g of trimethyl sulfoxonium iodide. To the reaction mixture dobavlyautsya piperonyl potassium (16 g) and shaken for 1 hour at 20-40°C. The reaction mixture is cooled and poured a solution of the compound obtained in Example 2 in dimethyl-sulfoxide (26 ml), maintained at a temperature of 20-40°C for 1.5 hours. The reaction mixture is quenched in cold water. The aqueous layer was extracted with ethyl acetate, washed with water, evaporated under reduced pressure followed by distillation of the product to obtain 19.6 g of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII) in the form of a mixture of a and b in the form of oil.

A mixture of isomer A (VII-A) and isomer B (VII-B) divide column chromatography on silica gel as stationary phase and a mixture of hexane and ethyl acetate as eluant. of 6.75 g of a mixture of isomers a and b elute with hexane : ethyl acetate (in the ratio 97:3) to complete separation of isomer A. Then the column elute with hexane: ethyl acetate (ratio 90:10) to obtain isomer Century Eluate isomer a and isomer In evaporated to obtain 2.6 g of isomer A (VII-A) in the form of oil and 1.4 g of isomer B (VII-B), respectively.

The purity of the obtained product is 78-82%.

Example 4

Obtain (S)-6-perdiguero-α-[[(phenylmethyl)amino]-methyl]-2H-1-benzopyran-2-methanol (intermediate compound (I)

10,65 g of isomer A (VII-A) are added to 31,9575 ml of isopropyl alcohol followed by the addition 7,13 g benzylamine. The reaction mixture is heated under reflux for 2 hours and cooled to 0-5°C. the Precipitate is filtered icesat isopropyl alcohol (27 ml) to obtain charged 8.52 g of the specified connection.

Example 5

Getting Antilibanus the base of nebivolol (VIII)

To 50 ml of methanol, add 10 g of isomer B (VII-B) and 14,70 g And Amin (intermediate compound (I) and heated to 65-70°C. the Reaction mass is maintained at the same temperature for 15 hours. Then the mass is cooled to 50-55°C and add 30 ml of methanol. Then the mass is cooled to -10 to -15°C and shaken at the same temperature for 12 hours. The material is filtered, washed with 5 ml of methanol at -10 to -15°C., filtered and dried at 40-45°C for 8 hours to obtain 11.5g the specified connection.

Example 6

Getting the base of nebivolol (IX)

In hydrogenator put benzylidene the basis of nebivolol (VIII) (5,85 g) with 2-methoxy ethanol (117 ml) and 0,351 g of palladium on coal (10%). Apply pressure 160-170 pounds per square inch with gaseous hydrogen and heated to 70-75°C. Conditions of temperature and pressure was incubated for 3 hours until the reaction is completed. The reaction mass is then cooled to room temperature and filtered through (18 g) layer with upward flow of the second phase to separate the catalyst.

The filtrate is evaporated to obtain precipitation, precipitation isolated in methanol (38 ml) at 0-5°C. the Precipitate is dried to obtain 4.0 g of the base of nebivolol.

Example 7

Receiving nebivolol HCl (I) using methanol as the reaction solvent and purification of nebivolol is HCl (I)

To 10 g of the base of nebivolol (IX) add 70 ml of methanol and 3.5 g chloroethanol acid, the reaction mixture is shaken for 4 hours at 28-32°C. the Material was filtered and washed with chilled methanol. Then filtered to dryness. Wet material dephlegmator in 300 ml of methanol for 30 minutes, and then filtered through a layer with upward flow of the second phase. The methanol is completely evaporated, to the residue was added 100 ml of isopropyl alcohol, and then shaken for 30 minutes at 60-65°C. is Cooled to 25-30°C. the Material was again shaken at 28-32°C for 3 hours. The material is filtered, washed 20,0 ml of isopropyl alcohol and dried at 60-65°C for 8 hours to obtain 10.5 g of nebivolol hydrochloride (I). The range of the melting temperature - 223-227°C. Yield (%) - 96,33%. Purity HPLC - 99.89 per cent.

Example 8

Receiving nebivolol HCl (I) using isopropyl alcohol as the reaction solvent and purification of nebivolol HCl (I)

To 10 g of the base of nebivolol (IX) add 70 ml of isopropyl alcohol and 3.5 g chloroethanol acid, the reaction mixture is shaken for 4 hours at 28-32°C. the Material was filtered, washed with 10.0 ml of isopropyl alcohol and filtered to dryness. Wet material dephlegmator in 300 ml of methanol for 30 minutes, and then filtered through a layer with upward flow of the second phase. The methanol is completely distilled off and to the residue was added 100 ml of isopropyl alcohol and then vesbaltarve the t for 30 minutes at 60-65°C. Cooled down to 28-32°C. the Material is shaken at 28-32°C for 3 hours, filtered, washed 20,0 ml of isopropyl alcohol and dried at 60-65°C for 8 hours to obtain 10.6 g of nebivolol hydrochloride (I).

The range of the melting temperature - 223-227°C.

Output (%) - 97,24%.

Purity HPLC - a 99.16%.

Example 9

Receiving nebivolol HCl (I) from the base of nebivolol (IX) using ethanol as reaction solvent and purification of nebivolol HCl (I)

To 10 g of the base of nebivolol (IX) add 70 ml of ethanol and 3.5 g chloroethanol acid and the reaction mixture is shaken for 4 hours at 28-32°C. the Material was filtered, washed with 10.0 ml of ethanol and filtered to dryness. Wet material dephlegmator in 300 ml of methanol for 30 minutes, and then filtered through a layer with upward flow of the second phase. The methanol is completely distilled off and to the residue was added 100 ml of isopropyl alcohol and then shaken for 30 minutes at 60-65°C., Cooled down to 28-32°C, the material is shaken at 28-32°C for 3 hours, filtered and washed 20,0 ml of isopropyl alcohol and finally dried at 60-65°C. to obtain 10.5 g of nebivolol hydrochloride (I). Then the material is sieved through a sieve with a number of openings per linear inch #100.

The range of the melting temperature - 223-227°C.

Output (%) - 96,33%.

Purity HPLC - 99,45%.

Example 10

Receiving nebivolol hydrochloride (I) of Antilibanus the base of nebivolol (VIII)

Purity HPLC - 99,99%.

Example 11

The Form T1

By 2100 ml of methanol add 60,0 nebivolol hydrochloride at room temperature. The reaction mass is heated to 50-60°C. to obtain a clear solution. A clear solution is dried in the spray 3.5 hours with a feed rate of 10-12 ml/minute, the temperature at the inlet of the feed - 65-110°C and the temperature on the exit hole of 65-75°C. Then the product is dried at 60-65°C in accordance with the s 10,0 hours to obtain 38.0 g of the form T1.

Example 12

The form T1

By 2100 ml of methanol add 60,0 base nebivolol at room temperature. the pH of the reaction mass to regulate values lower than 2.0, the addition of concentrated HCl (16,20 g) and stirred to obtain a clear solution. Then the clear solution is dried when spraying for 3.5 hours with a feed rate of 10-12 ml/minute, the temperature at the inlet of the feed - 65-110°C and the temperature on the exit hole of 65-75°C. Then the product is dried at 60-65°C for 10,0 hours to obtain 38.0 g of the form T1. Data of x-ray diffraction on the powder shown in Table 1.

Preparation of SOLID DOSAGE FORMS

The ingredients used in the preparation of solid dosage forms containing nebivolol hydrochloride according to this invention are given below together with a method of obtaining. In all subsequent examples, the dissolution of the obtained tablets define in a paddle apparatus. The rotation speed is 50±2 rpm, the solvent medium is a 0,1 N HCl, maintained at a fixed temperature of 37°C (pH of 1.2, simulated gastric fluid). The total amount of solvent liquid 500 ml

Example 13

Obtaining tablets

For the manufacture of solid dosage forms in the following examples use the material, the floor is obtained in Example 8, that is, nebivolol hydrochloride.

Table 3
Composition tablets
IngredientsAmount mg/tabletMass percentage
Nebivolol hydrochloride equivalent to 5 mg of nebivololthe 5.452,72
Lactose125,0562,53
Starch*30,0015,00
Croscarmellose sodium12,006,00
The hypromellose (receiver array 6 cps)3,001,50
Microcrystalline cellulose (Avicel PH 102)23,0011,50
Magnesium stearate1,000,50
Colloidal silicon dioxide0,500,25
*8% (2.4 mg/tablet) additional starch added to compensate for water loss during drying.

The method

Nebivolol hydrochloride of 5.45 mg (2,72% weight/weight) sieved through a sieve with a number of openings per linear inch, #60, through the same sieve sift 125,05 mg lactose (62,53% weight/weight), 5,00 mg croscarmellose sodium (2.5% weight/weight) and 30,00 mg of starch (15,00% weight/weight). The sifted materials are mixed together. 3 mg (1,50% weight/weight) hydroxypropylmethylcellulose (6 cps) is dissolved in 30 ml of purified water (preheated to 70°C) and used as a solution for granulation to obtain granules of the above mixture until you get a mass of the desired consistency. This requires 25 ml of additional purified water. The wet mass is passed through a sieve with a number of openings per linear inch #08, and the wet granules are dried in a centrifugal drier at 70°C until the weight loss at drying will not be 1,28%. Dry granules are passed through a sieve with a number of openings per linear inch #20 and mix with compression mixture comprising 23,0 mg (11,50% W/W) microcrystalline cellulose (Avicel PH 102), 0.5 mg (0.25% W/W) colloidal silicon dioxide, 7,0 mg (3,50% weight/weight) croscarmellose sodium and 1.0 mg (0,50% weight/weight) of magnesium stearate, previously sifted through a sieve with a number of openings per linear inch, #60. Obtained in this mod is the way the mixture is pressed in 200 mg tablets on a tablet press using 7,93 mm (10/32 inch) round shallow punches with beveled edge.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (simulated gastric fluid)

Dissolving tablets prepared according to Example 13, are presented in Table 4.

Table 4
The product containing 5 mg uncoated tablet% drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1Nebivolol hydrochloride, Nebilet®[control]84,193,7to 97.198,3
2Nebivolol hydrochloride [experience]81,9087,2090,1092,70

The control Nebilet®is a tablet nebivolol hydrochloride manufacturer - Janssen Pharmaceuticals. The rate of dissolution that the notches of this invention, as found, is more than 75% in 45 minutes. Thus, the dissolution of the tablets of this invention is acceptable.

Example 14

Obtaining tablets

For the manufacture of solid dosage forms in the following examples use the material obtained in Example 8, that is, nebivolol hydrochloride.

11,50
Table 5
Composition tablets
IngredientsAmount mg/tabletMass percentage
Nebivolol hydrochloride (equivalent to 5 mg of nebivolol)the 5.452,72
Lactose125,0562,53
Starch*30,0015,00
Croscamellose sodium12,006,00
Polyvinylpyrrolidone3,001,50
Microcrystalline cellulose (Avicel PH 102)23,00
Magnesium stearate1,000,50
Colloidal silicon dioxide0,500,25
*8% (2.4 mg/tablet) additional starch added to compensate for water loss during drying.

The method

Nebivolol hydrochloride of 5.45 mg (2,72% weight/weight) sieved through a sieve with a number of openings per linear inch, #60, through the same sieve sift 125,05 mg lactose (62,53% weight/weight), 5,00 mg croscarmellose sodium (2.5% weight/weight) and 30,00 mg of starch (15,00% weight/weight). The sifted materials are mixed together. 3 mg (1,50% W/W) polyvinylpyrrolidone K-30 was dissolved in 30 ml of purified water, preheated to 70°C, and used as a solution for granulation in the manufacture of pellets of the above-mentioned mixture, until you get the mass of the desired consistency. This requires 25 ml of additional purified water. The wet mass is passed through a sieve with a number of openings per linear inch #08, and the wet granules are dried in a centrifugal drier at 70°C until the mass loss during drying will not make the amount of 1, 258%. Dry granules are passed through a sieve with a number of openings per linear inch #20 and mix with compression mixture comprising 23,0 mg (11,50% weight/weight) m is crocrystalline cellulose (Avicel PH 102), 0.5 mg (0.25% W/W) colloidal silicon dioxide, 7,0 mg (3.5% weight/weight) croscarmellose sodium and 1.0 mg (0,50% weight/weight) of magnesium stearate, previously sifted through a sieve with a number of openings per linear inch, #60. Thus obtained mixture is pressed in 200 mg tablets on a tablet press using 7,93 mm (10/32 inch) round shallow punches with beveled edge.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (simulated gastric fluid)

Dissolving tablets prepared according to Example 14, are presented in Table 6.

td align="center"> 2
Table 6
The product containing 5 mg uncoated tablet% drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1Nebivolol hydrochloride, Nebilet®[control]84,193,7to 97.198,3
Nebivolol hydrochloride [experience]89,0095,0097,20for 98.00

Standard, i.e. Nebilet®is a tablet nebivolol hydrochloride manufacturer - Janssen Pharmaceuticals. The dissolution rate of the tablets according to this invention, as explained, is more than 75% in 45 minutes. Thus, the dissolution of the tablets of this invention is acceptable.

Example 15

Obtaining tablets

For the manufacture of solid dosage forms in the following examples used the material obtained in Example 7, that is, nebivolol hydrochloride.

Receiving tablets by the wet granulation (the drug adsorbed on the filler)

The ingredients used to produce tablets containing nebivolol hydrochloride, according to this invention adsorption of drugs on the fillers and the subsequent wet granulation are shown below along with the method to obtain these pills.

Step A: compound for adsorption of drugs on the fillers.

Table 7
IngredientsQuantity (mg/tablet Mass percentage
Nebivolol hydrochloride equivalent to 5 mg of nebivolol (crystalline)the 5.452,86
Lactose144,6275,99
Starch*34,5018,13
Croscarmellose sodiumof 5.753,02
Methanol-
*8% more starch was added to compensate for water loss during drying.

The method

Nebivolol hydrochloride of 5.45 mg (2.86 per cent weight/weight) (2% extra to compensate for loss) add to 2780 ml of methanol under agitation (1% weight/volume solution of the drug in methanol), miss 144,62 mg lactose (75,99% weight/weight), 28,75 mg croscarmellose sodium (3,02% weight/weight) and of 34.5 mg of starch (18,13% weight/weight) through a sieve with a number of openings per linear inch, #60. The sifted materials are mixed together. This combined mixture into the bowl of fluidization, and the solution adsorb drugs in it by using a fluidized bed processor (the way the upper rasbridge the project).

Stage: Receiving tablets by the wet granulation

The ingredients used to produce tablets containing nebivolol hydrochloride, according to this invention by the wet granulation below along with the method to obtain these pills.

Table 8
IngredientsQuantity (mg/tabletMass percentage
Nebivolol hydrochloride adsorbed on the mixture in the stage And190,32582,75
The hypromellose (HPMC 6 cps)3,451,50
Croscarmellose sodium8,053,50
Microcrystalline cellulose (Avicel PH 102)26,4511,50
Magnesium stearate1,150,50
Colloidal silicon dioxide0,5750,25

The method

of 3.45 mg (1,50% weight/the EU) hydroxypropylmethylcellulose (6 cps) is dissolved in 35 ml of purified water, pre-heated to 70°C., then cooled and used as a solution for granulation to obtain granules by mixing the mixture, adsorption of nebivolol hydrochloride, to obtain the mass, the desired consistency. Need 25 ml addition of purified water. The wet mass is dried in a centrifugal drier at 70°C before drying by 1.48%. The dried granules are sieved through a sieve with a number of openings per linear inch #20 and mixed with lubricating agents, including 26,45 mg (11,50% W/W) microcrystalline cellulose (Avicel PH 102), 0,575 mg (0.25% W/W) colloidal silicon dioxide, 8,05 mg (3,50% weight/weight) croscarmellose sodium, and 1.15 mg (0,50% weight/weight) of magnesium stearate, previously sifted through a sieve with a number of openings per linear inch, #60. The final mixture thus obtained, pressed into tablets with an average weight of 230 mg per tablet press using 8.73 mm (11/32 inch) round shallow punches with beveled edge.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (simulated gastric fluid)

The dissolution of the tablets obtained according to Example 15, are presented in Table 9.

Table 9
The product containing 5 mg uncovered that the letku % drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1Nebivolol hydrochloride, Nebilet®[control]84,193,7to 97.198,3
2Nebivolol hydrochloride [experience]86,990,192,693,2

Example 16

Obtaining tablets

For the manufacture of solid dosage forms in the following examples use the material obtained in Example 8, that is, nebivolol hydrochloride.

Table 10
Composition tablets
IngredientQuantity (mg/tabletMass percentage
Nebivolol Hydra is chloride the 5.452,73
Lactose158,0579,03
Croscarmellose sodium126,00
Microcrystalline cellulose2311,50
Colloidal silicon dioxide0,50,25
Magnesium stearate10,50

The method

Through a sieve with a number of openings per linear inch, #60 sift nebivolol hydrochloride of 5.45 mg (2,72% weight/weight), lactose 158,05 mg (79,03% weight/weight) and croscarmellose sodium 5,00 mg (2.5% weight/weight). The sifted materials are mixed together. Add 35 ml of purified water as a solution for granulation for producing pellets of the above mixture to obtain a mass of the desired consistency. The wet mass is passed through a sieve with a number of openings per linear inch #08, the wet granules are dried in a centrifugal drier at 70°C before drying 0.65%. Dry granules are passed through a sieve with a number of openings per linear inch #20 and mixed with the mixture for extrusion, including 23,0 mg (11,50% in the C/W) microcrystalline cellulose, 0.5 mg (0.25% weight/weight) colloidal dioxide flint, 7,0 mg (3.5% weight/weight) croscarmellose sodium and 1.0 mg (0,50% weight/weight) of magnesium stearate, previously sifted through a sieve with a number of openings per linear inch, #60. The final mixture, thus obtained, is pressed into 200 mg tablets on a tablet press using 7,93 mm (10/32 inch) round shallow punches with beveled edge.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (simulated gastric fluid)

Dissolving tablets prepared according to Example 16, are presented in Table 11.

Table 11
The product containing 5 mg uncoated tablet% drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1Nebivolol hydrochloride; Nebilet®[control]84,193,7to 97.19,3
2Nebivolol hydrochloride [experience]to 92.194,795,896,3

The control Nebilet®is a tablet nebivolol hydrochloride manufacturer - Janssen Pharmaceuticals. Found that the dissolution rate of the tablets prepared according to this invention, is more than 75% in 45 minutes. Thus, the dissolution of the tablets of this invention is acceptable.

Example 17

Obtaining tablets

For the manufacture of solid dosage forms in the following examples use the material obtained in Example 7, that is, nebivolol hydrochloride.

Table 12
Composition tablets
IngredientQuantity (mg/tabletMass percentage
Nebivolol hydrochloridethe 5.452,41
Lactose179,12579,07
Croscarmellose sodium 13,86,09
Microcrystalline cellulose26,4511,68
Colloidal silicon dioxide0,5750,25
Magnesium stearate1,150,51

The method

Nebivolol hydrochloride of 5.45 mg (2.41 per cent weight/weight) are added to a methanol under agitation (1% weight/volume solution of the drug in methanol). Miss 179,125 mg (79,07% weight/weight) of lactose through a sieve with a number of openings per linear inch, #60. This mixture in the bowl of fluidization, and the solution adsorb drugs in it by using a fluidized bed apparatus (the way the upper spray).

Receiving tablets by the wet granulation

The ingredients used in the preparation of tablets containing nebivolol hydrochloride, according to this invention by the wet granulation below along with the method to obtain these pills.

The method

Purified water is used as a binder for granulation in the preparation of granules by mixing with the mixture, adsorption of nebivolol hydrochloride, to obtain the mass of the desired consistency. The wet mass is dried in a centrifugal drier, the ri 70°C before drying 0.71%. The dried granules are sieved through a sieve with a number of openings per linear inch #20 and mixed with lubricating agents, including 26,45 mg (11,67% W/W) microcrystalline cellulose, 0,575 mg (0.25% W/W) colloidal silicon dioxide, to 13.8 mg (6,09% weight/weight) croscarmellose sodium, and 1.15 mg (0.51 percent weight/weight) of magnesium stearate, previously sifted through a sieve with a number of openings per linear inch, #60. Thus obtained mixture is pressed into tablets with an average weight 226,55 mg per tablet press using 8.73 mm (11/32 inch) round shallow punches with beveled edge.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (simulated gastric fluid)

The dissolution of the tablets obtained according to Example 17, are presented in Table 13.

Table 13
The product containing 5 mg uncoated tablet% drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1 Nebivolol hydrochloride; Nebilet®[control]84,193,7to 97.198,3
2Nebivolol hydrochloride [experience]95,595,495,495,7

Example 18

Obtaining tablets

For the manufacture of solid dosage forms in the following examples use the material obtained in Example 8, that is, nebivolol hydrochloride.

Table 14
Composition tablets
IngredientQuantity (mg/tabletMass percentage
Nebivolol hydrochloride5,4502,73
Lactose170,05085,03
Microcrystalline cellulose23,00011,50
Colloidal silicon dioxide 0,25
Magnesium stearate1,0000,50

The method

the 5.45 mg (2,73% weight/weight) of nebivolol hydrochloride and 170,05 mg (85,03% weight/weight) of lactose are passed through a sieve with a number of openings per linear inch, #60. The sifted materials are mixed together. To obtain the mass of the desired consistency using 35 ml of purified water as a solution for granulation to obtain granules of the above mixture. The wet mass is passed through a sieve with a number of openings per linear inch #08, the wet granules are dried in a centrifugal drier at 70°C before drying by 0.39%. Dry granules are passed through a sieve with a number of openings per linear inch #20 and mixed with the mixture for extrusion, including 23,0 mg (11,5% W/W) microcrystalline cellulose, 0.5 mg (0.25% W/W) colloidal silicon dioxide and 1.0 mg (0,50% weight/weight) of magnesium stearate, previously sifted through a sieve with a number of openings per linear inch, #60. The final mixture, thus obtained, is pressed into 200 mg tablets on a tablet press using 7,93 mm (10/32 inch) round shallow punches with beveled edge.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (simulated gastric fluid)

The dissolution of the tablet is to, obtained according to Example 18, are presented in Table 15.

Table 15
The product containing 5 mg uncoated tablet% drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1Nebivolol hydrochloride; Nebilet®[control]84,193,7to 97.198,3
2Nebivolol hydrochloride [experience]to 89.5a 94.296,2to 97.1

The control Nebilet®is a tablet nebivolol hydrochloride manufacturer - Janssen Pharmaceuticals. Found that the dissolution rate of the tablets prepared according to this invention, is more than 75% in 45 minutes. Thus, the dissolution of the tablets of this invention are the two shall be acceptable.

Example 19

Obtaining tablets

For the manufacture of solid dosage forms in the following examples use the material obtained in Example 8, that is, nebivolol hydrochloride.

Table 16
Composition tablets
IngredientQuantity (mg/tabletMass percentage
Nebivolol hydrochloride5,4502,56
Lactose179,12584,20
Microcrystalline cellulose26,45012,43
Colloidal silicon dioxide0,5750,27
Magnesium stearate1,1500,54

The method

the 5.45 mg (2,56% weight/weight) of nebivolol hydrochloride are added to a methanol under agitation (1% weight/volume solution of the drug in methanol). Through a sieve with a number of openings per linear inch #number is 60179 miss 125 mg of lactose (84,20% weight/weight). E is the mixture in the bowl of fluidization, and the solution adsorb drugs in it by using a fluidized bed apparatus (the way the upper spray).

Receiving tablets by the wet granulation

The ingredients used to produce tablets containing nebivolol hydrochloride, according to this invention by the wet granulation below along with the method to obtain these pills.

The method

To obtain the mass of the desired consistency, use 50 ml of purified water as a solution for granulation in the preparation of granules by mixing with the mixture, adsorption of nebivolol hydrochloride. The wet mass is dried in a centrifugal drier at 70°C before drying by 1.12%. The dried granules are sieved through a sieve with a number of openings per linear inch #20 and mixed with lubricating agents, including 26,45 mg (12,43% W/W) microcrystalline cellulose, 0,575 mg (0.27% weight/weight) colloidal silicon dioxide, and 1.15 mg (0.54 percent weight/weight) of magnesium stearate, previously sifted through a sieve with a number of openings per linear inch, #60. The final mixture thus obtained, pressed into tablets with an average weight 212,75 mg per tablet press using 8.73 mm (11/32 inch) round shallow punches with beveled edge.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (modeling the data of gastric fluid)

Dissolving tablets prepared according to Example 19, are presented in Table 17.

Table 17
The product containing 5 mg uncoated tablet% drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1Nebivolol hydrochloride; Nebilet®[control]84,193,7to 97.198,3
2Nebivolol hydrochloride [experience]85,093,996,597,9

The control Nebilet®is a tablet nebivolol hydrochloride manufacturer - Janssen Pharmaceuticals. Found that the dissolution rate of the tablets prepared according to this invention, is more than 75% in 45 minutes. Thus, the dissolution of tablets filed with the invention is acceptable.

Example 20

Obtaining tablets

For the manufacture of solid dosage forms in the following examples use the material obtained in Example 10, i.e. nebivolol hydrochloride.

Table 18
Composition tablets
IngredientQuantity (mg/tabletMass percentage
Lactose monohydrate (Pharmatose 200 M)143,47562,38
Corn starch34,5015,00
Croscarmellose sodium (AC-DI-SOL)6,903,00
Nebivolol hydrochloridethe 5.452,37
Methanol
Hypromellose (6 cps)3,451,50
Purified water
The AOC is carmellose sodium (AC-DI-SOL) 6,903,00
Microcrystalline cellulose (Avicel PH 102)26,45
Silica colloidal anhydrous0,5750,25
Magnesium stearate2,301,00

The method

440 mg of methanol and 10 mg of water prepare a solution of 5.45 mg (2,37% weight/weight) of nebivolol hydrochloride and 3.45 mg (1.5% weight/weight) hypromellose. Through a sieve with a number of openings per linear inch #40 sift 143,475 mg (62,38% W/W) lactose, 34,50 mg (15% weight/weight) of corn starch (8% add extras to compensate for the loss and 3.45 mg (3% weight/weight) croscarmellose sodium. The sifted material is placed in the container for a product in a fluidized bed apparatus (FBP). The solution of nebivolol hydrochloride - hypromellose adsorb in the mixture, the fluid in the container of the apparatus of the fluidized bed by way of the upper spray. After complete adsorption solution medicines and binding agent mixture is dried. The mixture is then granularit with 28 mg of water. The wet granules are dried in a fluidized bed apparatus at 60°C. the Dried granules are sieved through a sieve with a number of openings per linear inch #30 and mesilat with 26,45 mg (11,5% W/W) microcrystalline cellulose, of 3.45 mg (3% weight/weight) croscarmellose sodium, 0,575 mg (0.25% W/W) colloidal silicon dioxide, previously sifted through a sieve with a number of openings per linear inch #40 and pre-sifted 2.30 mg (1% weight/weight) stearate. The final mixture thus obtained, pressed into tablets with an average weight of 230 mg per tablet press using 9.0 mm round concave punches with beveled edge and a groove on one side.

The dissolution profile of nebivolol hydrochloride according to this invention at a pH of 1.2 (simulated gastric fluid)

The dissolution of the tablets obtained according to Example 20, are presented in Table 19.

Table 19
The product containing 5 mg uncoated tablet% drug release at different time intervals
No.Dosage form15 minutes30 minutes45 minutes60 minutes
1Nebivolol hydrochloride; Nebilet®[control]84,20 90,0091,4092,10
2Nebivolol hydrochloride [experience]88,7093,6094,1094,70

Example 21

Comparative data bioavailability of the tablets nebivolol in this invention (test formulation) compared with tablet nebilet (the control formulation)

Pharmacokinetics

In the study of bioequivalence register and randomizer 24 healthy volunteers to receive experienced (nebivolol 5 mg, Torrent pharmaceuticals Ltd., India) or control (Nebilet®5 mg, Berlin-Chemie AG, Germany) formulations. Levels of nebivolol in plasma was measured using a validated method of liquid chromatography - mass spectrometry/mass spectrometry (LCMS/MS).

Average plasma concentrations of nebivolol after oral dose of 1 tablet (5 mg nebivolol) experimental formulations or 1 tablet (5 mg nebivolol) control formulations are shown in Figure VI.

Estimate pharmacokinetic parameters. For experienced nebivolol and control formulations valuemaxreached 2,605±0,66 ng/ml and 2,574±0,78 ng/ml, respectively. Large differences in the values of tmaxfor the test and control formulations were observed. OBS is give the value of AUC (0-t)(the value of the area under the curve "concentration - time") for the test and control formulations were 17,33±29,54 NGas/ml and 17,71±30,77 NGas/ml, respectively. The observed value of AUC(0-∞)for the test and control formulations were 29,69±62,72 NGas/ml and 21,86±41,96 NGas/ml, respectively.

Interval 90%confidence calculated by the values of ANOVA-log method (analysis of variance) for the primary parameter, inside individual ratio (Experiment/Control) AUC(0-t)AUC(0-∞)and Cmaxnebivolol, was 0.93-1.04 million, of 0.95-1.17 and 0,95-1,10.

Security

The drug was well tolerated. During the experience, none of the volunteers reported no adverse events. The results of laboratory studies found no adverse effects or adverse reactions for the drug.

CONCLUSION

The aforementioned pharmacokinetic parameters nebivolol experienced (nebivolol 5 mg, Torrent pharmaceuticals Ltd., India) and control (Nebilet®5 mg, Berlin-Chemie AG, Germany) formulations were bio-equivalent with respect to nebivolol, as shown in Table 20.

Table 20
FormulationThe average value of Cmax(ng/ml)The average is the value AUC (0-t)(ng/ml·h)The average AUC(0-∞)(ng/ml·h)
Nebivolol 5 mg Torrent pharmaceuticals Ltd., India2,605±0,6617,33±29,5429,69±62,72
Nebilet®5 mg Berlin-Chemie AG, Germany2,574±0,7817,714±30,7721,86±41,96
Withmaxpeak plasma concentrations achieved after drug administration.
AUC - area under the curve

1. An improved method of obtaining 2N-1-benzopyran-2-methanol, α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]]then there are grounds nebivolol formula (IX), or cleaners containing hydrochloride salt

at which perform the following steps:
(a) carry out the reaction of (S)-6-perdiguero-α-[[(phenylmethyl)amino]-methyl]-2H-1-benzopyran-2-methanol, that is, the intermediate compound I

the intermediate connection I
with (In)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyrano formula (VII-B)

in the presence of acceptable organic solvent such as mentioned here, selected from the group vkluchaya the alcohol, ether and ketone, and allocated at a temperature of from -5 to -25°C, and then maintain the reaction mass at a temperature selection for 2 to 40 hours to obtain Antilibanus nebivolol formula (VIII)

(b) dibenzyline Antilibanus nebivolol formula (VIII)obtained in the above step (a), to the base of nebivolol formula (IX) using 10% palladium on coal in a known manner,

(C) turn the base nebivolol formula (IX)obtained in the above step (b)to get nebivolol hydrochloride of the formula (I) with acceptable organic solvent such as mentioned herein, selected from the group comprising alcohol, ether, ketone, halogenated solvent, acetonitrile, water or mixtures thereof, and using chloroethanol acid

(d) allocate the reaction product of the above step (C).

2. The method of obtaining Antilibanus nebivolol formula (VIII), which carried out the reaction of (S)-6-perdiguero-α-[[(phenylmethyl)amino]-methyl]2N-1-benzopyran-2-methanol, that is, the intermediate compound I

the intermediate connection I
with (In)-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyrano formula (VII-B)

in the presence of acceptable organic solvent is such as mentioned here, selected from the group comprising alcohol, ether and ketone, and allocated at a temperature of from -5 to -25°C, and then maintain the reaction mass at a temperature selection for 2-40 hours to obtain Antilibanus nebivolol formula (VIII).

3. The method according to claim 1, characterized in that the alcohol is chosen from the group comprising methanol, ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, Isobutanol.

4. The method according to claim 1, wherein the alcohol is methanol.

5. The method according to claim 1, characterized in that the ester is chosen from the group comprising ethyl acetate, n-butyl acetate.

6. The method according to claim 1, characterized in that the ketone is chosen from the group comprising acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK).

7. The method according to claim 1, wherein the selection in step (a) is performed at a temperature of -10 to -15°C.

8. The method according to claim 1, characterized in that the reaction mass in step (a) is maintained at a temperature selection for 10-15 hours

9. The method according to claim 1, characterized in that the alcohol is chosen from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, etc.

10. The method according to claim 1, wherein the alcohol is methanol.

11. The method according to claim 1, wherein the alcohol is isopropyl alcohol.

12. The method according to claim 1, wherein the alcohol is ethanol.

13. The method according to claim 1, characterized those who, that nebivolol hydrochloride obtained in step (C)is diastereoisomers pure mixture of RSSS and SRRR isomers.

14. The method according to item 13, wherein the purity diastereoisomers clean mixture is more than 99,0%.

15. The method according to item 13, wherein the purity diastereoisomers clean mixture is > 99.5%.

16. The method according to item 13, wherein the purity diastereoisomers clean mixture is more than 99.8 per cent.

17. Pharmaceutical composition having an antihypertensive action, including nebivolol hydrochloride and a pharmaceutically acceptable carrier, characterized in that the pharmaceutical composition does not contain any wetting agent and optionally contains a binding agent and/or disintegrity agent, and the surface area of nebivolol hydrochloride is 0.2·103up to 1,95·103m2/kg.

18. The pharmaceutical composition according to 17, where this pharmaceutical composition is a tablet or capsule.

19. Tablet p with mainly the following composition:

Nebivolol hydrochloride2,37% wt./weight.
Lactose monohydrate62,38% wt./weight.
Corn starch15,00% wt./weight.
Croscarmellose sodium6.00% per weight./weight.
Hypromellose (6 cps)1.50% of the weight./weight.
Microcrystalline cellulose11,50% wt./weight.
Silica colloidal anhydrous0.25% weight./weight.
Magnesium stearate1,00% wt./weight.

20. The pharmaceutical composition according to 17, where nebivolol hydrochloride contains from 0.5 to 10% wt./weight.; diluent contains from 78 to 93,05% wt./weight.; lubricating agent contains from 0.25 to 3 wt%./weight.; substances promoting sliding, contains 0.25 to 3 wt%./weight.; optional linking agent contains from 0.5 to 5% wt./weight. and/or dezintegriruetsja agent contains from 0.5 to 10% wt./weight.

21. The pharmaceutical composition according to 17, characterized in that it has a solubility of more than 75% in 45 minutes



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to 2,4-pyrimidindiamins, such as N4-(4-Chlorine-3-methoxyphenyl)-5-fluorine-N2-[3-(N-ethylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-(3-Chlorine-4-methjopxycarbonylmethylenoxyphenyl)-5-fluorine- N2-[3-(N-methylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-[3-Chlorine-4-(N-methylamino)carbonylmethylenoxyphenyl]-5-fluorine-N2-[3-(]N methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin, N4-[3-Chlorine-4-(2-hydroxyethylenoxy)phenyl]-5-fluorine-N2-[3-(N- methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin and other compounds given in item 1 of claimed invention as Syk-kinase inhibitors, as well as to based on them pharmaceutical composition and their application.

EFFECT: claimed compounds can be applied for treatment of autoimmune diseases, systemic http://lingvo.yandex.ru/?text=lupus%20erythematosus, rheumatoid arthritis, etc.

12 cl, 27 dwg, 11 tbl, 1797 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new compounds with formula (I), their esters, carbamates and pharmaceutically used salts, which can be used as inhibitors of p38 kinase, which means they can be used for curing diseases and conditions for which p38 is the mediator. In formula (I): Q represents -C(R1R2R3); R1 is chosen from hydrogen, C1-C8 alkyl, hydroxyC1-C8alkyl, and C1-C8alkoxy C1-C8alkyl; R2 and R3 are chosen: (i) independently from: (a) hydrogen, under the condition that, if R1 represents hydrogen, then only one of R2 and R3 can be chosen from hydrogen; (b) C1-C8alkyl; C1-C8alkyl, substituted with one or two radicals halogen, -OR8, -S(O)pR10;(c) -OR8; or (ii) R2 and R3 together with the carbon atom to which they are bonded, form optionally substituted C3-C7cycloalkyl or substituted heterocyclic ring system; R4 and R5 are independently chosen from halogen; R8 and R9 are independently chosen from hydrogen, C1-C8alkyl; R10 represents C1-C8alkyl; m equals 0, n equals 0; and p equals 2; where the term "substituted cycloalkyl" stands for a cycloalkyl group, containing one or two substitutes, which are independently chosen from a group, consisting of -Y-ORs, -Y-S(O)0-2RS, C(=O)ORs, where Y is absent; Rs is independently chosen from hydrogen, C1-C8alkyl, except when the said substitute represents -Y-S(O)1-2Rs, then RS represents hydrogen; the term "heterocyclic ring system" stands for a saturated non-aromatic monocyclic fragment, consisting of 5 to 6 atoms, which are part of the ring system, from which one atom, which is part of the ring system, is a heteroatom, chosen from N, O, and the rest of the atoms in the ring system are carbon atoms; the term "substituted heterocyclic ring system" stands for a heterocyclic fragment mentioned above, containing one substitute, chosen from the group, -Y-Rs, -Y-ORs, -Y-C(O)2Rs, -Y-S(O)0-2Rs, where Y is absent or represents a C1-C4alkylene group, Rs represents the same as was defined above for the substituted cycloalkyl group.

EFFECT: used for treating diseases and conditions.

13 cl, 2 dwg, 5 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel amidomethyl-substituted derivatives of 2-(4-sulfonylamino)-3-hydroxy3,4-dihydro-2N-chromen-6-yl of the general formula (I) where R1 is C1-C4alkyl, R2 is C1-C4alkyl, R3 is phenyl optionally once or twice substituted or substituted by halogen, C1-C4alkyl, C1-C4alkoxy group or trifluoromethyl, naphthyl or biphenyl, R4 is hydrogen, C1-C6alkyl or C3-C7cycloalkyl-C1-C4alkyl, R5 is hydrogen, and R6 is C1-C6 alkyl, phenyl-C1-C4alkyl, phenyl group optionally substituted by halogen, furyl-C1-C4alkyl or tetrahydronaphthyl, or R5 and R6 together with nitrogen atom linking them form piperazine ring optionally substituted by phenyl.

EFFECT: also invention claims method of obtaining claimed compounds, and intermediary products used in method implementation, as well as medicines containing compounds of the formula (I) with antiarrhythmic effect, and application of these medicines.

11 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds N-(2-furylalkyl)-NHR carbamides with formula 1: , exhibiting growth-regulating and immuno-modeling activity, and method of producing them. The method involves reacting furfuryl idenacetone with urea in hydroamination conditions in an autoclave, in the presence of skeletal nickel catalyst and an organic solvent at 70-90°C temperature, and ratio of substrate to reagent equal to 1:1 or 2:1.

EFFECT: invention can be used in agriculture.

2 cl, 9 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: in novel tocopherol-modified therapeutic drug compounds of formula 1 T-L-D, T is tocopherol, L is succinate, and D is camptotecin or its derivative, where all three fragments are bound covalently. Invention also relates to emulsions based on said compounds, formulations of micelles, including said compounds, methods of treating cell proliferative disease using said compounds and formulations, as well as to said compounds application for production of medication for treatment of cell proliferative disease.

EFFECT: increase of composition and treatment method efficiency.

18 cl, 17 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to 5-substituted alkylaminopyrazole derivatives of formula I , wherein R1 is CN; W is C-halogen; R1 is halogen; R3 is C1-C3-haloalkyl, C1-C3-haloalkoxy; R4 is hydrogen, C1-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, COR8; A is C1-C12-alkylene; R5 is hydrogen, C3-C6-alkenyl, -(CH )qR7 or NR10R11; R5 is C1-C6-haloalkyl; as well as method for animal exogenous and endogenous pest controlling; pesticide composition and application of said compounds for production of veterinary drug. 5-Substituted alkylaminopyrazole derivatives are useful in pest controlling, including insects, arachnids and helminthes, such as nematodes.

EFFECT: new pesticide derivatives.

9 cl, 12 tbl, 20 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivative of aminobenzopyrane of the formula (2): Method involves reduction of nitro-group in derivative of 2,2-dimethyl-2H-1-benzopyrane of the formula (1): with hydrazine in the presence of a metallic catalyst. Invention provides high selectivity of the process with respect to olefin bonds and simple treatment that results to small waste and doesn't effect on reactor.

EFFECT: improved method of synthesis.

2 tbl

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: improved treatment method, valuable medicinal properties of compounds and composition.

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention concerns to applying RARγ agonist for preparing a medicinal agent comprising one or some such agonists and designated for treatment of emphysema wherein RARγ agonist is taken among compounds of the formula (I):

wherein R1 means residue of the formula:

or , or , or ; R2 means (C2-C8)-alkanoyl, (C2-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or group -OCH2R3 wherein R3 means hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl; each among R4-R9 means independently of one another hydrogen atom or (C1-C6)-alkyl; or R8 and R9 mean in common (CRaRb)n wherein Ra and Rb mean independently of one another hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3; R4-R7 have above given values; R10 means carboxyl, (C1-C6)-alkoxycarbonyl or mono- or di-(C1-C6)-alkylcarbamoyl; and their pharmaceutically acceptable salts; or among compounds of the formula (VI):

wherein R1 means C(O)R6 or CH2OH (wherein R6 means hydroxy-group or (C1-C6)-alkoxy-group); R2 means hydrogen atom, (C1-C15)-alkyl, (C1-C6)-alkoxy-group or cycloaliphatic group; R3 means hydrogen atom, hydroxy-group, (C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, (C1-C10)-alkoxy-group or cycloaliphatic group; R4 and R5 mean independently of one another hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; or among compound of the formula (VIII):

. Invention provides applying agonists eliciting the selective effect with respect to RARγ, for preparing a medicinal agent comprising one or some such agonists designated for emphysema treatment.

EFFECT: valuable medicinal properties of compounds.

4 cl, 5 tbl, 3 ex

The invention relates to a derivative chromane formula I

in which R1denotes acyl with 1 to 6 carbon atoms, R2, R3, R4represent hydrogen, X represents N,N or O, as well as their enantiomers and their salts, and methods for their preparation

The invention relates to new derivatives aminomethylpropanol acid formula 1

< / BR>
where Z represents (CH2)n, O or S; n is 0, 1 or 2; X represents 1-3 substituent, independently selected from hydrogen, halogen, (C1-6)alkyloxy,(C3-6)cycloalkane, (C6-12)aryloxy, (C6-12)aryl, teinila, CN, СООR6and (C1-4)alkyl, optionally substituted with halogen, or 2 substituent in adjacent positions together represent a condensed (C5-6)aryl group, or O-(CH2)m-O, where m is 1 or 2; Y is 1-3 selected from hydrogen, halogen, (C1-4)alkyloxy and (C1-4)alkyl, optionally substituted with halogen; R1represents COOR7; R2and R6are (C1-4)alkyl; R3, R4and R5independently represent hydrogen; R7, R8and R9independently represent hydrogen or (C1-4)alkyl; or pharmaceutically acceptable salts, and pharmaceutical compositions on their basis, with effect on the Central nervous system

The invention relates to new derivatives chromane General formula I,

,

where R is hydrogen, halide or NR1R1group; R1means hydrogen or alkyl group with 1-10 carbon atoms; R2means R1or NR1R1; R3means hydrogen or CO2R1; Ar1means a phenyl group or a 5-or 6-membered heterocyclic ring containing as the heteroatom atom N; m = 1, 2, or 3; n = 1, when this symbol is the group -(CO)nand n is 0, 1 or 2, when this symbol is the group (X); X is alkyl group with 1-4 carbon atoms; R4means hydroxyl or CNS group with 1-10 carbon atoms; and their pharmaceutically acceptable salts, having agonistic activity against beta-3-adrenergic receptor

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula I

< / BR>
in which X denotes O or S;

R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;

R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;

Y represents halogen;

R4and R5represent hydrogen;

Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;

R6and R7each denotes hydrogen or R6and R7together represent a bond;

Z denotes either (I) the divalent group-CHR9- in which the R11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-CHR12-CHR13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,

as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them

New salt // 2193560
The invention relates to a new salt - acid tartrate (R)-3-N,N-dicycloverine-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide, in particular its (2R, 3R)-tartrate and especially acid monohydrate (2R,3R)-tartrate of (R)-3-N,N-dicycloverine-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide, as well as to a method for the specified tartrate salts and pharmaceutical compositions based on it for the treatment and prevention of disorders of the Central nervous system and related medical abuses associated with the activity of the antagonist 5-HT1A-receptor

The invention relates to new compounds 2,4-xylidide and m-phenetidine 2-acetylaminofluorene-3-carboxylic acid of General formula 1

,

where Ia) R=2,4-(CH3)2WITH6H3; IB) R=m-C2H5OS6H4that possess anticoagulant activity and can be used in medicine

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

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