Method of producing atazanavir sulphate

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing HIV protease inhibitor atazanavir sulphate in form of Form A crystals, which involves reacting a solution of a free base of atazanavir in an organic solvent in which atazanavir sulphate is virtually insoluble, at temperature ranging from 35°C to 55°C with a first portion of concentrated sulphuric acid in an amount sufficient for reaction with less than approximately 15 wt % free base of atazanavir, addition of nucleating centres of Form A atazanavir sulphate crystals, addition of an additional amount of concentrated sulphuric acid in several steps, where the acid is added at increasing rate to form atazanavir sulphate crystals and drying the atazanavir sulphate to form Form A crystals. A method of producing atazanavir sulphate in form of Form C crystals is also proposed.

EFFECT: improved method.

20 cl, 11 dwg, 6 tbl, 5 ex

 

The technical field

This invention relates to a method for inhibiting HIV protease atazanavir bisulfate and its new forms.

The level of technology

U.S. patent No. 5849911, Fässler et al. reveals some azapeptide of HIV protease inhibitors (which includes atazanavir), having the structure:

where

R1indicates the lowest alkoxycarbonyl,

R2indicates secondary or tertiary alkyl or lower alkylthio - lower alkyl,

R3denotes phenyl, which is unsubstituted or substituted by one or more lower CNS radicals, or C4-C8-cycloalkyl,

R4denotes phenyl or cyclohexyl, each of which is substituted in the 4-position of the unsaturated heterocyclyl, which is attached via a carbon atom in the ring has 5 to 8 atoms in the ring, containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinil (-SO-) and sulfonyl (SO2-and is unsubstituted or substituted by lower alkyl or phenyl - lower alkyl,

R5regardless of R2has one of the meanings indicated for R2and

R6regardless of R1indicates the lowest alkoxycarbonyl or its salt, provided that there is at least one salt-forming group, which includes various groups in pharmaceutical preparations is automatic acceptable salts join acid.

There are several ways to get azapeptide, including obtaining compounds, where R1and R6and R2and R5indicate in each case two identical radicals, with diaminododecane formula:

condensed with an acid of the formula:

or its reactive derivative, where R'1and R'2and R2and R5have the value specified for R1and R6for R2and R5respectively.

Upon receipt of the above ATV diaminododecane (a) of the formula:

produced by combinations of epoxide:

with hydrazinecarboxamide:

in the presence of isopropyl alcohol to obtain the protected diamine:

which is treated with hydrochloric acid in the presence of a solvent, such as tetrahydrofuran, to obtain the diamine (a):

The diamine is isolated and used in the next stage of the combination, when it reacts with acid (b):

or its reactive ester, with the use of an agent combinations, such as O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethylpropylenediamine) (TPTU).

It was found that the free base of the diamine unstable and therefore should not be used to obtain the free base of atazanavir.

In U.S. patent No. 6087383, Singh et al. described bisulfate salt azapeptide inhibitor of HIV protease, known as atazanavir, which has the formula:

(also called atazanavir bisulfate or sulfate atazanavir).

In example 3, Singh et al. describe receiving atazanavir bisulfate in the form of crystals of Type-II, which are gidratirovannuyu hygroscopic and crystalline form and in the form of crystals of Type-I, which are anhydrous/desolvation crystalline form.

The invention

According to this invention provides new forms of atazanavir bisulfate, which include the Configuration and Shape of E3. It is preferable Configuration C. in Addition, in accordance with this invention provides a method for receiving atazanavir bisulfate in crystalline Form A (bulk drug) (called crystals of Type-I in example 3 of U.S. patent No. 6087383, Singh et al.). Crystalline form a obtained according to the invention has a desirable uniform distribution of particles sizes and nearly constant average particle size and is used to build the program Configuration, partially crystalline substance, which is used together with various excipients for preparation of medicines.

A method of obtaining a crystalline Form a of atazanavir bisulfate according to the invention uses a modified technique cubic crystallization, when sulfuric acid is added with increasing speed in accordance with a cubic equation (see below), and includes the stage of interaction of a solution of the free base of the ATV in an organic solvent (in which bisulfate salt ATV practically insoluble) with the first portion of concentrated sulfuric acid in a quantity sufficient to react with less than about 15%, preferably less than about 12 wt.% the free base of the ATV, add crystal nuclei Form a of atazanavir bisulfate to the reaction mixture, adding an additional quantity of concentrated sulfuric acid at numerous stages with increasing speed in accordance with a cubic equation for the formation of crystal Form A.

In addition, according to this invention provides a method for obtaining the shape of atazanavir, which is obtained from atazanavir bisulfate and includes atazanavir bisulfate and called Configuration C. Configuration can be obtained put the m suspension of crystals of Form a in water and drying. Or the same Configuration can be obtained by exposure of the crystals Form And under conditions of high relative humidity, the value of which more than approximately 95% RH (water vapor), for at least 24 h Configuration can also be obtained by wet granulation of atazanavir bisulfate or combination of atazanavir bisulfate and excipients and drying the wet granulate.

According to a preferred variant crystals Form And are mixed with excipients that are part of the drug, such as one or more bulk agents such as lactose, one or more disintegrants, such as crosspovidone, and subjected to wet granulation with obtaining Configuration in a mixture with excipients.

Further, according to this invention provides a new form of atazanavir bisulfate, namely, Form E3, which is electricalsignal form tiratanaloka of MES of atazanavir bisulfate.

Form E3 receive suspendirovanie free base atazanavir in ethanol, processing suspension of concentrated sulfuric acid, heating, introducing into the resulting solution embryos wet (ethanol) crystals E3, processing a mixture of heptane (or other solvent such as toluene or hexane), filtration and drying.

In addition, in accordance with this invention envisage the identified method of obtaining crystals of atazanavir bisulfate Form And, which includes the stage of obtaining triamine salt of the formula:

preferably, cleaners containing hydrochloride (3M) salt) and without releasing triamine salt interaction of this triamine salt with an active complex ether, preferably of the formula:

in the presence of a base and an organic solvent to obtain the free base of the ATV, which, without isolation, becomes atazanavir bisulfate by a modified cubic crystallization, as described in this application.

In addition, in accordance with this invention provides a new composition on the basis of atazanavir bisulfate, which includes atazanavir bisulfate in the form of crystalline Form a or Configuration and a pharmaceutically acceptable carrier for the active ingredient. Pharmaceutically acceptable carrier may include fillers, binder, disintegrant, lubricating agents and other conventional excipients.

According to the invention various forms of atazanavir bisulfate can be characterized by various methods that are well known in the art. These forms can be characterized using the method of crystallography single crystal, which is based on the measurement cell of the crystal Forms at a fixed temperature to define the Deposit. A detailed description of the unit cells shown in Stout & Jensen, X-Ray Structure Determination: A practical Guide, Macmillan Co., New York (1968), Chapter 3. Or a unique arrangement of atoms in space within the crystal lattice can be characterized according to the observed fractional atomic coordinates. Another method of characteristics crystal structure is powder crystallography, when experimental or observed diffraction profile is compared with the simulated profile characterizing pure powder material, both determined at the same temperature, but the measurement of the desired shape are characterized as a range of 2Θ values.

Can be used and other means of characterizing the shape, such as nuclear magnetic resonance in the solid state (SSNMR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). These settings can also be applied in combination to characterize the desired shape.

Crystals of Form a can be characterized by unit cell parameters, is equal to:

The size of the cell:

a=9,86(5) Ǻ

b=29,245(6) Ǻ

C=8,327(2) Ǻ

α=93,56(2)°

β=114,77(3)°

γ=80,49(3)°

Space group 1

Molecules/asymmetric unit 2,

this crystalline form is available at about 22°C.

Form a can be characterized by fractional is languid coordinates, listed in Table 3, and the crystal structure shown in figure 2.

Form a can be characterized simulated and observed powder crystallography, as shown in figure 1.

Form a can also be characterized by the method of differential scanning calorimetry (DSC) to obtain thermograms with the endotherm with an early peak at about 165,6°C, as shown in Figure 3.

Form a can be characterized by the curve of thermogravimetric analysis (TGA), which shows a slight weight loss at a temperature of about 100-150°C, as shown in Figure 4.

Form a can be characterized by chemical shifts in NMR in the solid state (SSNMR), as shown in Table 4, and the spectrum shown in Figure 5.

Form a can be characterized by fractional atomic coordinates listed in Table 5.

Form a salt can be characterized isotherms moisture - sorption with increasing weight, equal to about 0.1% in the range of RH from 25% to 75% at 25°C.

According to one aspect of the invention, the Configuration may be characterized by powder crystallography, as shown in Figure 5.

According to another aspect of the invention, the Configuration can be characterized by thermogram of differential scanning calorimetry, as shown in Fig.7, therm is the gram visible of the endotherm in the range of from about to 76.7°C to about 96,6°C and from about 156,8°C to about 165,9°C.

According to another aspect of the invention, the Configuration may be characterized by thermogravimetric curve analysis; where visible loss of weight, equal to about 2.4%to about 125°C and weight loss, equal to about 4.4%to about 190°C., as shown in Fig.

According to this invention Form E3 can be characterized by crystallographic parameters, as shown in Table 5, is equal to:

a=10,749(5) Ǻ

b=13,450(4) Ǻ

C=9,250(2) Ǻ

α=98,33(2)°

β=95,92(3)°

γ=102,83(3)°

Space group P1

Molecules/asymmetric unit 1,

this crystalline form is observed at about -23°C.

According to another aspect of the invention Form E3 can be characterized by fractional atomic coordinates listed in Table 6.

According to another aspect of the invention Form E3 can be characterized simulated and observed the diffraction patterns shown in Fig.9.

According to another aspect of the invention Form E3 can be characterized by thermogram of differential scanning calorimetry in which the endotherm typically range from about 89,4°C to about 96,6°C, as shown in figure 11.

According to another aspect of the invention Form E3 can be characterized by thermogravimetric curve analysis, in which losing weight is equal to when is Erno 14,7%, observed at about 150°C, as shown in Table 8.

According to another aspect of the invention Form E3 can be characterized by the crystal structure, as shown in Figure 10.

Brief description of figures

Figure 1 shows calculated (simulated) (22°C) and observed (experimental at room temperature) powder diffraction pattern (Cu Kαλ=1,5418 Å) of Form A.

Figure 2 shows the crystal structure of Form A.

Figure 3 represents thermogram of Form a, obtained by the method of differential scanning calorimetry (DSC).

Figure 4 shows a curve obtained by differential scanning calorimetry (DSC), for sample Forms A.

Figure 5 presents data13With NMR in the solid state to Form A.

6 represents the observed (experimental at room temperature) the diffraction pattern Configuration obtained by powder crystallography (Cuαλ=1,5418 Ǻ).

7 shows thermogram of the Configuration obtained by the method of differential scanning calorimetry.

On Fig presents the curve obtained by means of thermogravimetric analysis for Configuration C.

Figure 9 shows calculated (simulated) (22°C) and observed (experimental at room temperature) of the diffraction pattern of the Form E3 obtained by the method of Raskovoy crystallography.

Figure 10 shows the structure of a crystal Form E3 and

Figure 11 presents thermogram of Form E3 obtained by the method of differential scanning calorimetry, and thermogravimetric curve analysis to Form E3.

Detailed description of the invention

This invention provides, at least partially, in the form of atazanavir bisulfate, namely, form E3 and Configuration as new materials, in particular in pharmaceutically acceptable form. The term "pharmaceutically acceptable", as used herein, refers to those compounds, materials, compositions and/or dosage forms which are, from the point of view of sound medical judgment, suitable for contact with the tissues of humans and animals without signs of strong toxicity, irritation, allergic response, or other problem complications in reasonable relation to the benefit/risk. According to some preferred options crystalline form of the free base and its salts get in almost pure form. The term "almost pure"as used in this application, means a compound having a purity of more than about 90%, including, for example, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% and about 100%.

Used the term "poly the Orff" refers to crystalline forms, having the same chemical composition but different spatial arrangement of molecules, atoms and/or ions forming the crystal.

Used the term "MES" refers to a crystalline form of a molecule, atom and/or ion that contains molecules of the solvent or solvents that are introduced into the crystal structure. Solvent molecules in the MES can be streamlined and/or disordered. MES may contain stoichiometric or non-stoichiometric amount of solvent molecules. For example, the MES with non-stoichiometric amount of solvent molecules can be formed by partial loss of solvent from the MES.

Samples of the crystalline forms can be obtained from almost pure phase homogeneity, which indicates the presence of a dominant number one crystalline form and possibly minor amounts of one or more crystalline forms. The presence of more than one crystalline form in the sample can be determined by methods such as powder x-ray crystallography (PXRD) or nuclear magnetic resonance in the solid state (SSNMR). For example, the presence of extropian in the diffraction pattern, measured experimentally, and compared with the simulated diffraction pattern may be indicative of more than one crystal is practical form in the sample. Simulated the diffraction pattern can be calculated on the basis of data of a single crystal (see Smith D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns Lawrance Laboratory, Livermore, California, UCRL-7196 (April 1963). Crystalline form preferably has a purely homogeneous phase, as evidenced by less than 10%, preferably less than 5% and, more likely, less than 2% of the total area of the peaks in the experimental diffraction pattern arising from extrapola that are missing on the simulated diffraction pattern (PXRD). The preferred crystalline form, having almost pure homogeneous phase with less than 1% of the total area of the peaks on the experimental diffraction pattern (PXRD)arising from extrapola that are missing on the simulated diffraction pattern (PXRD).

Methods of obtaining crystalline forms known from the prior art. Crystalline forms may be obtained by different methods, including, for example, crystallization of the recrystallization from a suitable solvent, sublimation, growth from the melt, turning in a solid state from the other phase, crystallization from supercritical fluid and jet spray. Methods crystallization or recrystallization of the crystalline forms of a mixture of solvents include, for example, evaporation of the solvent, reducing the temperature of the mixture of solvents, the introduction of germ crystals in Herasymenko a mixture of compounds and/or salts in the solvent, drying of the mixture during freezing and adding antibacterially (protivozastoinoe) to the solvent mixture.

Crystals of drugs, including polymorphs, methods for their preparation and characterization of crystals of the drug are discussed in Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer, and J.G. Stowell, 2ndEdition, SSCI, West Lafayette, Indiana (1999).

In the case of the method of crystallization using a solvent, the choice of solvent or solvents usually dependent on one or more factors such as the solubility of the compounds, methods of crystallization, the vapor pressure of the solvent. You can use a combination of solvents, for example, the connection may be solubilisation in the first solvent to obtain a solution and then adding antibacterial to reduce the solubility of the compounds in solution and crystal formation. Protiwaritmical is a solvent in which the compound is poorly soluble. Suitable solvents to obtain crystals include polar and non-polar solvents.

One method of obtaining crystals of atazanavir bisulfate suspended and/or stirred in a suitable solvent to obtain a suspension, which can be heated to accelerate dissolution. The term "suspension" refers to a saturated solution of atazanavir bisulfate or its salt, which can be the t also contain additional number of atazanavir bisulfate or its salt to obtain a heterogeneous mixture of atazanavir bisulfate or its salt and a solvent at a given temperature. Suitable solvents in this case include, for example, polar aprotic solvents and proton polar solvents and mixtures of two or more of these solvents, as described in this application.

Germ crystals can be added to any mixture for acceleration of crystallization. Specialist it is clear that the introduction of the germ is used as a means of controlling the growth of a particular crystalline form or as a means of regulating the distribution of particles in the crystalline product. Accordingly, the calculation of the number of embryos depends on the size of available embryos and the desired size of the secondary particles of the product, as described, for example, in "Programmed cooling of batch crystallizers", J.W.Mullin and J.Nyvlt, Chemical Engineering Science (1971) 26: 369-377. In General, the germ of the small size necessary to effectively regulate the growth of crystals in the party. The germ of a small size can be obtained by passing through a sieve, grinding or micronization crystals of larger size or by microcrystallization solutions. You should pay attention to the grinding or micronization of the crystals did not lead to any change in the crystallization of the desired crystalline form (namely, change to obtain the amorphous form or another polymorpha).

The cooled mixture can be filtered under vacuum allocated solids may be washed with a suitable solvent, such as cold solvent recrystallization, and dried in a stream of nitrogen to produce the desired crystalline form. Selected solid product can be subjected to analysis using an appropriate method spectroscopy or analysis, such as SSNMR, DSC, PXRD, or the like, to confirm the formation of the preferred crystalline form of the product.

The resulting crystalline form is usually obtained more than about 70 wt.% the selected product, preferably more than 90% per weight of atazanavir bisulfate, originally used in the method of crystallization. The product can be minced or passed through a sieve with apertures for separating pieces of the product if necessary.

Crystalline forms may be obtained directly from the reaction medium in the final stages of receiving atazanavir bisulfate. This can be achieved, for example, when applied at the last stage of the method of the solvent or mixture of solvents, which can crystallize the atazanavir bisulfate. Otherwise, the crystal form can be obtained by distillation or addition of solvent. Suitable solvents for this purpose include any of the solvents described in this application, including proton polar solvents such as alcohols and aprotic polar solution is teli, such as ketones.

In General, the reaction mixture may be filtered to remove any unwanted impurities, inorganic salts, etc. with subsequent washing with a solvent used for the reaction or crystallization. The resulting solution can be concentrated to remove excess solvent or gaseous components. If using distillation, the final amount of the collected distillate may vary depending on process parameters, such as vessel size, degree of mixing, etc. In General, the reaction solution may be distilled to about {fraction (1/10)} of the initial solution before removing the solvent. You can go to sample and analyze to determine the extent of reaction and the wt.% product according to standard techniques. If desirable, additional can be added or removed from the reaction solvent to optimize the concentration. Preferably, the final concentration was approximately 50 wt.%, at this point usually results in suspension.

It may be preferable to add a solvent in the reaction vessel without distillation of the reaction mixture. Preferred solvents for this purpose are solvents that can eventually settle in the crystal lattice, as discussed above in connection with the exchange dissolve the firs. Although the concentration may vary depending on the desired degree of purity, separation and so on, the final concentration of free base I in the solution, preferably equal to from about 4% to about 7%. The reaction mixture can be stirred after adding the solvent and simultaneously heat. For example, you can stir the reaction mixture for about 1 h, heating it to about 70°C. the Hot mixture is filtered and washed with the reaction solvent added to the solvent or their mixture. For the onset of crystallization in any solution for crystallization can be added germ crystals.

Various forms described herein, can be distinguished from one another using various analysis methods known to the person skilled in the art. Such methods include, without limitation, the method of nuclear magnetic resonance in the solid state (SSNMR), method of powder x-ray crystallography (PXRD), differential scanning calorimetry (DSC) and/or method thermogravimetric analysis (TGA).

Specialist it is clear that x-ray diffraction pattern can be obtained by measurement error, which depends on the measurement conditions. In particular, it is well known that the intensity in the diffraction pattern can fluctuate depending on the measurement conditions and forms is whether the morphology of the crystal. Further, it should be understood that the relative intensity can also vary depending on the experimental conditions and, accordingly, the precise order of intensity should not be taken into account. Additionally, the error in the measurement of the diffraction angle in the case of conventional x-ray diffraction is usually approximately 0.2% or less, preferably, about 0.1% (as defined below), and such degree of a measurement error should be taken into account as relevant to the aforementioned angles of diffraction. Accordingly, it should be borne in mind that the crystalline form according to the invention is not limited to crystalline forms, which provide the x-ray diffraction pattern identical to the pattern shown in the attached figures in this application. Any crystalline forms, which provide the x-ray diffraction patterns virtually identical to that shown in the attached figures, are included in the scope of this invention. The ability to evaluate the practical identity of the x-ray diffraction patterns is within the competence of the specialist in this field.

The term "Form"used in the manner and Form E3 refers to a homogeneous crystal structure.

The term "Configuration"is used in relation to Configuration, refers to the characteristic of rentgenovskoi the diffraction pattern.

The term of atazanavir bisulfate" refers to atazanavir bisulfate, and sulfate atazanavir.

When carrying out the method of producing crystals Form And bisulfate atazanavir according to the invention apply the modified method cubic crystallization, when the free base of the ATV is dissolved in an organic solvent in which the atazanavir bisulfate practically insoluble, including acetone, a mixture of acetone and N-methylpyrrolidone, ethanol, a mixture of ethanol and acetone and the like, to obtain the solution in which the concentration of the free base of atazanavir is from about 6.5 to about 9.7 wt.%, preferably, from about 6.9 to about 8.1 wt.%.

The solution of the free base of the ATV heated at a temperature in the range of from about 35°to about 55°C., preferably from about 40°to about 50°C and subjected to the interaction with so many of concentrated sulfuric acid (containing from about 95 to about 100% H2SO4), which is sufficient for the reaction with less than 15%, preferably from about 5 to less than about 12%, more preferably from about 8 to about 10 wt.% the free base of the ATV. Thus, the original solution of the free base of the first ATV will work with less than 15%, prepact the tion, from about 5 to less than about 12 wt.% used sulfuric acid. During the reaction, the reaction mixture was support at a temperature in the range from about 35 to about 55°C., preferably from about 40°to about 50°C.

The reaction continued for a period of time of about 12 to about 60 minutes, preferably from about 15 to about 30 minutes

The reaction mixture was added germ crystals of Form a of atazanavir bisulfate in an amount in the range of about 0.1 to about 80%, preferably from about 3 to about 8% based on the weight of the free base of the ATV remaining in the reaction mixture, maintaining the temperature of the reaction mixture equal to from about 35 to about 55°C., preferably from about 40°to about 50°C.

The reaction is continued until the onset of crystallization. Then injected sulfuric acid in several stages with increasing speed according to the cubic equation, described below, receiving atazanavir bisulfate, which is in the process of drying forms a crystal Form A.

The particle size of the crystals and the morphology of the obtained atazanavir bisulfate depend on the speed of adding sulfuric acid, which determines the rate of crystallization. It was found that the modified methodology cubic crystallization (who islot added with increasing speed according to a cubic equation) allows the formation of relatively large, more well-defined crystals of atazanavir bisulfate along with a more narrow range of particle sizes and fewer small particles than in the case of crystallization by adding a constant speed. It was shown that the slow initial rate filing acid facilitates the growth of crystals without secondary education embryos. Thus, since the surface area increases with increasing particle size, the germ layer capable of withstanding the increasing speed of adding acid without inducing secondary education embryos. Slow initial rate of addition allows the crystals become larger, thus increasing their average size. Cubic crystallization leads to the formation of more dense residue on the filter that helps to remove liquid from the precipitate and washing, as well as the formation of the product, which is easier to drying with a smaller amount of solid lumps than during crystallization at constant speed add.

The method used cubic crystallization is carried out at a controlled temperature according to the publication Mullin "Crystallization, 3rdEd.", 1993, Butterworth - Heineman Pubs. and is determined by the following equation:

where Tmax= temperature of crystallization,

Tmin= temperature of okoncane the crystallization

time = the time of crystallization,

timeall= total time of crystallization.

As crystallization of atazanavir bisulfate is governed by the speed of adding sulfuric acid, variable temperature in equation (1) is replaced by the volume of acid. In this equation the variable denoting the minimum amount, missing:

where Vtime= volume of sulfuric acid added during the passage of crystallization,

Vall= total acid of 90% of the download,

time = the time of crystallization,

timeall= total time of crystallization.

Equation (2) is called "cubic equation".

By adjusting the crystallization rate using this equation, can be adjusted within acceptable limits, the formation of embryos, as the system is maintained at a constant low level of saturation.

Crystals Form And are identified by the methods of x-ray powder crystallography and crystal structure, as shown in figures 1 and 2, respectively.

Crystalline form a of atazanavir bisulfate or configuration, and the Form E3, obtained as described above, represent the end of atazanavir bisulfate and can be used as medicinal products for administration to patients.

In soo is conformity with the method according to the invention, a Configuration can be obtained by the action of water on the crystal Form And followed by drying.

According to another method according to the invention, a Configuration can be obtained by exposure of the crystals Form And under conditions of high relative humidity, the value of which exceeds about 95%, preferably, it is equal to from about 95 to about 100% RH (water vapor) for at least 24 hours, preferably from about 24 to about 48 hours

According to another variant of the invention the Configuration To get wet granulation Form a of atazanavir bisulfate obtaining granules of atazanavir bisulfate and then the granules are dried.

During the process of pelletizing of atazanavir bisulfate granularit in water and dried at a temperature in the range from about 40°to about 80°C., preferably in the range from about 50°to about 60°C. the Stage of drying, preferably for about 2 hours to about 20 hours, preferably for from about 8 hours to about 10 hours

The configuration can also be obtained by wet granulation of Form a of atazanavir bisulfate in the presence of conventional pharmaceutical additives, for example, one or more bulk agents, preferably lactose, one or more disintegrants, preferably, crosspovidone, and drying, as described above, to obtain the Configuration in a mixture with excipients.

It is the Configuration, Shape And or the Orme E3, preferably the Configuration used in the composition for injection in the treatment of diseases caused by viruses, as described below.

The configuration is characterized by x-ray powder crystallography, as shown in Figure 3.

Form E3 is obtained by suspension of the free base of atazanavir in ethanol, processing suspension of concentrated sulfuric acid at a molar ratio of acid: free base in the range from about 1:1 to about 1.1:1, heating the resulting solution at a temperature of from about 30°to about 40°C., injection of embryos wet (ethanol) crystals E3 sulfate atazanavir, processing a mixture of heptane (or other solvent such as hexane or toluene), filtration and drying of the form E3 of atazanavir bisulfate (tritanomaly MES).

Stage of nucleation involves the use of a certain number of embryos to effect the formation of crystals E3, for example, the molar ratio of embryos Form E3 bisulfate atazanavir free base is between approximately 0.02:1 to about 0.04 to:1.

Form E3 identified by x-ray powder crystallography, as shown in Fig.7, and the crystal structure, as shown in Fig.6.

According to this invention atazanavir in the form of its free base is obtained by treatment is otci solution protected triamine salt of the formula

(where PG denotes a protective group, such as trebuetsyasistemnye (Boc) or TRIFLUOROACETYL, preferably Boc), acid, preferably hydrochloric (when using Boc) or base (when used TRIFLUOROACETYL) in the presence of an organic solvent, such as methylene chloride, tetrahydrofuran or methanol, and the solvent preferably is methylene chloride, at a temperature ranging from about 25°to about 50°C., preferably from about 30°to about 40°C with the formation of triamines acid salt, preferably a salt, of the formula:

and without allocation triamine salt, interaction of this salt with the active ester of the acid of the formula:

preferably, the active ester of the formula:

in the presence of a base, such as K2HPO4diisopropylethylamine, N-methylmorpholine, sodium carbonate or potassium carbonate, preferably K2HPO4in the presence of an organic solvent, such as methylene chloride, a mixture of ethyl acetate and butyl acetate, acetonitrile or ethyl acetate, preferably methylene chloride, at a temperature ranging from about 25°to about 50°C., preferably from about 30°to about 40°C. to obtain the free the warping of atazanavir.

Protected source triamine get the reaction of the epoxide:

where PG denotes, preferably. Boc, such as N-(trebuetsyasistemnye)-2-(S)-amino-1-phenyl-3(R)-3,4-epoxybutane, hydrazinecarboxamide:

where PG, preferably, represents Boc, in the presence of isopropyl alcohol or another alcohol, such as ethanol or butanol.

The atazanavir bisulfate suitable for introduction warm-blooded animal, especially a human, for the treatment or prevention of a disease that responds to inhibition of retroviral proteases, especially retroviral aspartate proteases, such as HIV-1 or HIV-2 gag-protease, for example, retroviral diseases such as AIDS or its preliminary stages.

The atazanavir bisulfate, especially the Configuration, Shape or Form E3, preferably, the Configuration or Shape And can be used in the treatment of diseases caused by viruses, especially retroviruses, especially SPEED and or its preliminary stages, when a therapeutically effective amount of a Configuration of atazanavir bisulfate. Form a or Form E3 is introduced at a dose which is effective in the treatment of specified diseases, especially in warm-blooded animal, such as man, which is due to the presence of one of the mentioned diseases, especially AIDS is a or its preliminary stages, requires such treatment. The preferred dose, you need to put in warm-blooded animals, for example humans weighing approximately 70 kg is from about 3 mg to about 1.5 g, preferably from approximately 10 mg to approximately 1.25 g, for example, from about 50 mg to about 600 mg per day, divided preferably 1 to 4 single doses which may be, for example, are the same. Usually children get half the dose for adults. Medicine, preferably, be administered orally.

The configuration, Shape or Form E3 of atazanavir bisulfate used for the above-described pharmaceutical purposes. Suitable compositions containing the Configuration or Shape And or Form E3 for oral administration include tablets, powders, capsules and elixirs. About 10-600 mg of the active ingredient is mixed with a physiologically acceptable carrier, means for delivering, excipient, binder, preservative, stabilizer, flavoring agent, etc. and receive a unit dosage form, as it is called in pharmacy practice.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, granulating the resulting mixture, if desired, and after the addition of appropriate excipients, if desired or necessary, pererabotki the mixture into tablets, core, coated tablets, capsules or powders for oral administration. You can also enter the active ingredients in polymeric carriers, which allow the active ingredients to diffuse or be released in measurable quantities.

Bulk agents or fillers contained in the pharmaceutical composition according to the invention in amounts in the range of about 0 to about 95 wt.% and, preferably, from about 10 to about 85 wt.% in the calculation of the composition. Examples of bulk agents or fillers suitable for use include, but are not limited to, derivatives of cellulose, such as microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, gelatinizing starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dexterity, maltodextrin, compressible sugar, and other known bulk agents or fillers and/or a mixture of two or more of these components, preferably lactose.

A binder may be contained in the pharmaceutical compositions according to the invention in an amount that ranges from about 0 to about 20 wt.%, preferably, from about 1 to about 10 wt.% in the calculation of the composition. Examples of St is based, suitable for use include, but are not limited to, hydroxypropylcellulose, corn starch, gelatinizing starch, modified corn starch, polyvinylpyrrolidone (PVP) (molecular weight ranging from about 5,000 to about 80,000, is preferably amounts to about 40,000), hypromellose (receiver array), lactose, resin acacia, ethylcellulose, cellulose acetate, and a wax binder, such as Carnauba wax, paraffin, spermaceti, polyethylene or microcrystalline wax, and other conventional binder and/or a mixture of two or more binders, preferably, hydroxypropylcellulose.

Disintegrant can be contained in the pharmaceutical composition according to the invention in an amount that ranges from about 0 to about 20% by weight, preferably from about 0.25 to about 15% by weight based on the composition. Examples of disintegrants suitable for use include, but are not limited to, sodium salt croscarmellose, crosspovidone, potato starch, gelatinizing starch, corn starch, sodium salt starch glycolate, microcrystalline cellulose or other known disintegrant, preferably, sodium salt croscarmellose.

The lubricating agent may be contained in the pharmaceutical composition and the gain in the quantity, in the range of about 0.1 to about 4% by weight, preferably from about 0.2 to about 2% by weight based on the composition. Examples of lubricating agents to obtain tablets, suitable for use include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, Carnauba wax, stearic acid, palmitic acid, sodium fumarate or hydrogenated vegetable fats and oils or other known lubricating agents and/or mixtures of two or more lubricating agents, preferably magnesium stearate.

Capsules are hard gelatin capsules and also soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Hard gelatin capsules may include the active ingredient in the form of granules, for example, with fillers such as lactose, binders, such as starches, crosspovidone, and/or additives promoting sliding, such as talc or magnesium stearate, and, if desired, stabilizers. In soft gelatin capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, may also be added stabilizers and/or antibacterial agents.

With ewusie following examples represent preferred variants of the invention.

Example 1.

1-[4-(piridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)-L-trelayne]amino}-4(S)-hydroxy-6-phenyl-2-azahexane the bisulfate (Form A) (Form a of atazanavir bisulfate).

A.

1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis[trebuetsyasistemnye)amino]-4(S)-hydroxy-6-phenyl-2-azahexane · 3HCl (tiamina·3HCl salt).

In a three-neck round bottom flask with a volume of 1000 ml with a mechanical stirrer, a tube for input of nitrogen and the temperature sensor was added to the protected triamine 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis[trebuetsyasistemnye)-amino]-4(S)-hydroxy-6-phenyl-2-azahexane:

(100 g, 0,178 mol) and CH2Cl2(500 ml, 5 ml/g of protected analogue) (obtained as described Z.Xu et al., Process Research and Development for an Efficient Synthesis of the IV Protease Inhibitor BMS-232,632, Organic Process Research and Development, 6, 323-328 (2002)) and the resulting suspension was stirred, maintaining the temperature equal to from about 5°to about 22°C.

To the reaction mixture was added concentrated hydrochloric acid (68 ml of 0.82 mol, 4.6 EQ.) with such a speed that the temperature of the reaction mixture remained at from 5°C to 30°C. the Reaction mixture was heated to 30-40°C. and stirred until completion of the reaction according to GHUR.

Was added water (70-210 ml, 0.7 to 2.1 ml/g of protected analogue) and stirred the reaction mixture for 15 min and gave the phases to separate. Ver the tion layer (enriched triamine ·3HCl salt) water oil were placed in a funnel.

Century

(Active ester of N-methoxycarbonyl-L-trelayne)

In a three-neck round bottom flask with a volume of 3000 ml, equipped with a mechanical stirrer, funnel, tube for input of nitrogen and the temperature sensor was added N-methoxycarbonyl-L-Treacy (77,2 g, 0,408 mol, 2,30 equiv.) 1-hydroxy - benzothiazole (NOVT) (60,8 g, 0,450 mol, 2,53 EQ.) and N-ethyl-N'-dimethylaminopropylamine (EDAC) (82,0 g, 0,430 mol, 2,42 EQ.) with the subsequent introduction of CH2Cl2(880 ml of 8.8 ml/g of protected analogue) and the resulting mixture was stirred at room temperature (18-25°C) to complete the formation of the active ester according to GHUR.

C. 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)-L-trelayne]amino}-4(S)-hydroxy-6-phenyl-2-azahexane (free base of the ATV).

Anhydrous dibasic potassium phosphate (K2HPO4, 226 g of 1.30 mol, 7,30 EQ. on the protected triamine) was dissolved in 1130 ml of water (11.3 ml/g of protected amine, 5 ml/g K2HPO4).

To a solution of the active ester obtained in section b, was added a solution of K2HPO4. To stir a mixture of the active ester/water solution K2HPO4was slowly added an aqueous solution of cleaners containing hydrochloride salt of the section And for 1.5-2.0 hours, while continuing stirring and maintaining the temperature in the flask from 5 to 20°C. After completion of the new the solution cleaners containing hydrochloride salt of the partition And the reaction mixture (reaction mix) were heated to 30-40°C. and stirred until the reaction mix according to GHUR.

The product mix was cooled to 15-20°C. and lower, enriched with organic product layer was separated from the upper aqueous layer.

The organic phase is enriched in the product, washed with 1 M NaH2PO4(880 ml, pH of 1.5 to 8.8 ml/g of protected analogue, 5 mol. EQ. on the protected triamine), the phases were allowed to separate and remove the spent aqueous layer.

Washed enriched product organic layer was mixed with 0,5N NaOH (800 ml, 8 ml/g of protected analogue) up until GHUR enriched organic phase shows that the concentration of active esters is 0.3 I.I. each. The phases were allowed to separate and the spent aqueous layer was removed.

Enriched organic phase is washed with 5% NaH2PO4(450 ml 4,5 ml/g of protected analogue, the pH of 4.3), the phases were allowed to separate and the spent aqueous layer was removed.

Enriched organic phase is washed with 10 wt./vol.% NaCl (475 ml of 4.75 ml/g of protected analogue), and spent the aqueous layer was removed.

The concentration of the free base in solution was 120-150 mg/ml and output (calculated) was 95-100 mol.%.

D. Exchange of solvent: CH2Cl2a mixture of acetone/N-organic.

To the enriched solution of the free base of the partition in a three-neck round-bottom flask with a volume of 3000 ml, equipped with a mechanical stirrer, a temperature sensor and a condenser, add the Yali N-organic (148 ml, 1.25 ml/g of free base on the basis of quantitative analysis in progress). The solution was concentrated to about 360 ml (2.5 to 3.5 ml/g of free base of the section) at a temperature in the jacket is 70°C or less; to the concentrated solution was added 500 ml of acetone (4-5 ml/g of free base of the section) and drove the mixture to obtain a volume equal to 400 ml or less.

The addition of acetone and the distillation was repeated until such time as the analysis of the process showed that the content of CH2Cl2reached the target value. At the time of crystallization of the amount of CH2Cl2in the enriched organic solvent was 0,77 about/about %. To the concentrated solution of the free base of acetone was added to a solution of 16 ml/g of free base. The bath temperature was maintained equal to 40-50°C to prevent crystallization of the free base. The solution was filtered through a filter of 10 μm or less porosity, maintaining the temperature is 40-50°C. the Filter was washed with acetone (125 ml, 1.0 ml/g of free base) and the wash water was added to the solution enriched free base in acetone/N-organic, which is used in the next stage.

E. 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)-L-trelayne]amino}-4(S)-hydroxy-6-phenyl-2-azahexane the bisulfate.

Approximately the 10% (2 g) with a total load of concentrated sulfuric acid (19 g, of 1.10 EQ.) added beneath the surface to a solution of free base in acetone/N-organic section D, maintaining the temperature at 40-50°C.

In the reaction mixture was added to the embryos with 5.0 wt.% (free base in solution) bisulfate. The resulting mixture was stirred at 40-50°C for at least 30 min, at this time, the bisulfate began to crystallize, as evidenced by the increase in turbidity of the mixture. The remaining sulfuric acid (17.8 g) was added over approximately 5 h in five stages according to the Protocol defined by a cubic equation, with maintained temperature is 40-50°C.

The speed of adding at each stage was determined according to the cubic equation above, the magnitude of this velocity are given in table 1.

Table 1
Stageml/kg/hml (H2SO4)/hg (H2SO4)/hDuration (min)
1to 4.620,5791,06560
26,93 0,8681,59760
316,552,0733,81460
430,263,7906,97460
548,476,07111,17123

When you are finished adding H2SO4the suspension was cooled to 20-25°C. under stirring for at least 1 h, the Suspension was stirred at 20-25°C for at least 1 hour Bisulfate was filtered to Shine and uterine fluid was returned to the cycle that is necessary to complete the transfer. The filter cake was washed with acetone (5-10 ml/g of free base; 1200 ml of acetone). The bisulfate was dried at NMT 55°C under vacuum to achieve LOD<1% to obtain a crystalline product.

The crystalline product was analyzed by PXRD, DSC and TGA, and received SSNMR spectra, it was found that the obtained (nonsolvated) crystals Form And bisulfate, specified in the header (see Figure 1-5).

Table 2
Data obtained from crystallography to Form A.
T°Ca (Ǻ)b (Ǻ)C (Ǻ)α°β°γ°V (Å)Z'sgdcalcR
+229,861 (5)29,245 (6)8,327 (2)93,56 (2)114,77 (3)80,49 (3)2150 (2)2P11,2400,06
T = temperature (°C) the crystallography
Z' = number of drug molecules in the asymmetric unit.

Table 3
Fractional parameters and their estimated standard deviations for Form A.
Atom xzIn (A2)
S10.3230(4)0.5467(1)0.5608(5)8.0(1)
O1000.431(1)0.5060(3)0.649(1)11.1(3)
O1020.335(1)0.5498(4)0.383(1)12.0(4)
O1030.360(1)0.5877(4)0.655(2)12.0(4)
O1040.176(1)0.5384(4)0.528(1)11.8(4)
S510.6177(4)0.4505(1)0.4003(5)7.2(1)
O1500.596(1)0.4430(4)0.564(1)12.5(4)
O1520.518(1)/td> 0.4921(4)0.317(1)13.8(4)
O1530.588(1)0.4121(3)0.289(2)12.2(4)
O1540.768(1)0.4587(4)0.454(1)12.1(4)
O40.6985(7)0.1753(3)0.6456(9)5.7(2)
O70.1687(8)0.1941(3)0.3411(9)6.5(2)
O11-0.0352(7)0.2482(3)0.0308(8)5.7(2)
O140.2280(7)0.1769(3)-0.233(1)6.1(2)
O150.0399(8)0.1335(3)-0.330(1)6.4(2)
O17.6169(7) 0.2821(3)0.963(1)7.1(2)
AtomXZB (A2)
O180.3750(7)0.2905(3)0.9136(9)6.2(2)
N20.5015(9)0.2182(3)0.902(1)4.5(2)
N50.4642(8)0.1647(3)0.6001(9)4.2(2)
N90.2317(9)0.2788(3)0.256(1)5.1(2)
N100.1820(9)0.2760(3)0.069(1)4.6(2)
N13-0.0148(8)0.2083(3)-0.280(1)4.6(2)
N39-0.087(1) 0.5265(3)0.272(1)6.1(3)
C10.491(1)0.2627(4)0.924(1)5.5(3)
C30.6381(9)0.1908(3)0.892(1)4.0(2)
C40.600(1)0.1764(4)0.702(1)4.6(3)
C60.420(1)0.1551(4)0.403(1)5.1(3)
C70.295(1)0.1936(4)0.297(1)5.1(3)
C80.357(1)0.2400(4)0.346(2)5.4(3)
C110.051(1)0.2592(4)-0.028(1)4.9(3)
C120.024(1)0.251(4) -0.223(1)4.5(3)
C140.094(1)0.1732(4)-0.280(1)4.7(3)
C160.146(2)0.0943(5)-0.342(2)10.9(5)
C190.616(1)0.3313(4)0.996(2)8.1(4)
C200.701(1)0.1485(4)1.025(1)5.8(3)
C210.842(1)0.1219(5)1.007(2)7.9(4)
C220.583(2)0.1160(5)0.997(2)8.0(4)
C230.748(2)0.1713(5)1.215(1)8.2(4)
C240.365(1)0.1079(4) 0.356(2)6.6(4)
C250.484(1)0.0691(4)0.470(1)6.5(3)
C260.643(2)0.0684(5)0.520(2)8.4(5)
C270.753(2)0.0293(6)0.622(2)11.4(6)
C280.709(3)-0.0044(7)0.691(3)15.0(9)
C290.553(2)-0.0032(5)0.644(2)14.2(7)
C300.441(2)0.0343(5)0.534(2)10.8(4)
C310.291(1)0.3229(4)0.311(2)5.7(3)
C320.177(1)0.3650(4)/td> 0.259(1)5.4(3)
C330.224(1)0.4064(4)0.262(2)6.3(3)
C340.122(1)0.4487(5)0.233(2)6.9(4)
C35-0.031(1)0.4469(4)0.189(1)4.8(3)
C36-0.081(1)0.4043(4)0.180(1)5.6(3)
C370.019(1)0.3629(4)0.218(1)5.4(3)
C38-0.136(1)0.4918(4)0.170(1)5.3(3)
C40-0.170(1)0.5683(4)0.279(2)7.8(4)
C41-0.318(2)0.5736(5) 0.158(2)9.1(5)
C42-0.376(2)0.5403(5)0.035(2)9.0(5)
C43-0.283(1)0.4964(5)0.039(2)8.1(4)
C44-0.096(1)0.2937(4)-0.345(1)6.2(3)
C45-0.258(1)0.2901(5)-0.366(2)8.5(4)
C46-0.085(2)0.2890(6)-0.530(2)10.8(5)
AtomxzIn (A2)
C47-0.057(2)0.3393(5)-0.265(2)8.9(5)
O540.2347(7)0.8167(3) 0.8392(8)5.3(2)
O570.7713(8)0.7950(3)1.0561(9)5.9(2)
O610.9725(7)0.7436(3)0.9141(8)5.3(2)
O640.7062(7)0.8164(3)0.427(1)5.9(2)
O650.8911(8)0.8598(2)0.535(1)6.1(2)
O670.3150(8)0.7090(3)1.184(1)6.4(2)
O680.5587(9)0.6986(3)1.377(1)6.6(2)
N520.4313(9)0.7713(3)1.271(1)4.9(2)
N550.4709(8)0.8265(3) 1.0332(9)4.2(2)
N600.7555(8)0.7179(3)0.728(1)4.6(2)
Note # 630.9491(8)0.7852(3)0.601(1)4.4(2)
N891.026(1)0.4719(3)With 0.711(1)6.0(3)
C510.442(1)0.7247(4)1.282(1)5.4(3)
C530.296(1)0.7996(4)1.141(1)5.1(3)
C540.3347(9)0.8159(3)0.989(1)4.1(3)
C560.519(1)0.8353(4)0.887(1)4.7(3)
C570.644(1)0.7959(4) 0.886(1)4.5(3)
C580.587(1)0.7494(4)0.854(1)5.2(3)
C610.884(1)0.7334(4)0.766(1)4.2(3)
C620.914(1)0.7392(4)0.603(1)4.4(3)
C640.839(1)0.8196(4)0.513(1)4.6(3)
C660.785(2)0.8996(5)0.433(3)12.1(7)
C690.323(1)0.6588(4)1.202(2)8.8(5)
C700.237(1)0.8409(4)Of 1,232(1)5.6(3)
C710.092(1)0.8701(5)1.080(2) 7.6(4)
C720.352(1)0.8744(4)1.328(2)7.1(4)
C730.187(1)0.8195(6)1.362(1)8.9(4)
C740.570(1)0.8825(4)0.907(2)6.4(3)
C750.450(1)0.9206(4)0.919(1)6.3(3)
C760.296(2)0.9236(5)0.813(2)8.1(4)
C770.188(2)0.9614(6)0.826(2)11.2(5)
C780.244(2)0.9942(6)0.960(2)15.2(7)
C790.405(3)0.9935(6)1.062(2) 13.9(7)
C800.504(2)0.9552(4)1.043(2)9.3(5)
C810.644(1)0.6672(4)0.832(2)6.2(3)
C820.762(1)0.6266(3)0.839(1)4.7(3)
C830.723(1)0.5934(4)0.696(2)6.1(3)
C840.822(1)0.5547(4)0.695(2)5.9(3)
C850.967(1)0.5478(4)0.828(1)5.0(3)
C861.009(1)0.5783(4)0.971(2)6.6(4)
C870.908(1)0.6184(4)0.971(2) 6.4(4)
C881.076(1)0.5070(4)0.827(1)5.5(3)
C901111(1)0.4326(4)0.690(2)7.4(4)
AtomxzIn (A2)
C911.258(2)0.4262(5)0.792(2)7.8(4)
C921.324(2)0.4578(5)0.918(2)8.7(5)
C931.230(1)0.4994(5)0.936(2)6.9(4)
C941.038(1)0.7005(4)0.584(1)4.8(3)
C951.196(1)0.7055(4)0.717(2)6.7(4)
S1.021(2)0.7049(5)0.392(2)8.9(4)
S0.998(1)0.6536(4)0.614(2)7.6(4)
N590.7084(8)0.7114(3)0.866(1)5.1(2)
N0.0470.5230.3836.0*
N0.9310.4770.6465.8*
N'0.4910.4710.6003.8*
N"0.4400.5120.3224.6*

Most of the hydrogens have been omitted, included only the hydrogens on the N9 and acid.

Anisotropic refined atoms are given in the form of the isotropic equivalent to setting samewe the Oia, defined as (4/3)* [A2*B(1,1)+b2*B(2,2)+C2*B(3,3)+ab(cos gamma)*B(1,2)x+ac(cos beta)*B(1,3)+bc(cos alpha)*B(2,3)].

Form And was characterized by a thermogram of differential scanning calorimetry, which had the endotherm typically in the range of from about 165,6°C to about 200,9°C, as shown in Figure 3.

Form And was characterized by thermogravimetric curve analysis, indicating a negligible weight loss up to about 100-150°C. the Crystals obtained cubic crystallization, when H2SO4added with increasing speed in accordance with a cubic equation, described above, were more and more clearly defined, was characterized by a more narrow range of particle sizes and fewer small particles than the crystals obtained at a constant speed of adding acid by crystallization.

The filter cake obtained according to the method of cubic crystallization, was pressed to a lesser extent than deposits obtained at a constant speed add that contributed to the effective sludge dewatering and washing, as well as obtaining a homogeneous product.

Table 4
Chemical shifts (13With SSNMR for the Form And measured in relation to TMS (tetramer is lilana).
δ/ppm
26,9
27,5
33,9
37,7
49,2
53,5
62,7
63,3
66,0
69,2
69,5
122,6
123,7
125,3
126,1
uniforms, 127.6
128,5
129,4
RB 131.1
RUR 134.4
138,8
139,7
140,6
143,2
143,9
149,9
150,3
other 153.9
159,3
172,0

Example 2.

The configuration of atazanavir bisulfate.

Method A.

Crystals of Form a of atazanavir bisulfate (obtained as described in Example 1) (25,33 g) suspended in 200 ml of water and stirred the mixture mechanically with obtaining a thick gel, which was dried.

The dried mixture was kneaded with a spatula, receiving Configuration C. X-ray powder diffraction pattern Configuration shown in Fig.6.

Method C.

Crystals of Form a of atazanavir bisulfate were subjected to wet granulation, using enough water (about 40% wt./weight), in a suitable mixer-granulator. The wet weight of Vassilev the stove. The obtained product was sifted through a suitable sieve. X-ray diffraction pattern of the obtained product complies with the Configuration, as shown in Fig.6.

The configuration was characterized by a thermogram of differential scanning calorimetry shown in Fig.7, with endothermy usually in the range of from about 76,7 to about 96,6°C and from about 156,8 to about 165,9°C.

The configuration was characterized by thermogravimetric curve analysis, indicating the loss of weight, equal to about 2.4% at about 125°C and is equal to about 4.4% at about 190°C, as shown in Fig.

Example 3.

Form E3 (tritanomaly MES) of atazanavir bisulfate.

Free base of atazanavir (obtained as described in Example 1, section (C) (3.0 g, 4.26 deaths mmol) suspended in dry ethanol fortress 200 (20,25 ml, 6.75 ml/g of free base) in a three-neck round-bottom flask with a volume of 100 ml, equipped with a mechanical stirrer, a temperature sensor and a funnel to balance the pressure.

In the suspension of the free base of the ATV at 20-25°C was added concentrated H2SO4(0.25 ml, and 0.46 g, 4,69 mmol, 1.1 EQ.). The resulting solution (KF 0.2 to 1.0% water) was filtered to Shine (paper Whatman #1), the filter was washed with 2.25 ml of absolute ethanol and the washing solution was added to the filtered solution. Rest the R was heated to 37°C and was added to the embryos, 10 mg of amorphous atazanavir bisulfate obtained from crystals Form E3 (exposure crystals Form E3 at room temperature), and the mixture was stirred for 15 minutes After 1 h was added hexane (380 ml of 8.25 ml/g of free base). Obtained crystallizing the mixture was stirred 8 h at 15-25°C. the Crystalline bisulfate ATV was filtered on a Buechner funnel. The filter residue was washed 184 ml (4 ml/g of free base) a mixture of 1:1 ethanol:heptane. Then the residue was washed 46 ml (1 ml/g of free base) of heptane. The obtained product was dried under vacuum at 40-50°C to achieve LOD=0,97%. The product yield was 47.7 g (0,0594 mol, of 74.3 mol.%), the product was a Form E3 of atazanavir bisulfate (tritanomaly MES) with GHUR HI=100,0 (see figures 9 and 10).

Table 5
Crystallographic parameters of the Form E3.
T°Ca (Ǻ)b (Ǻ)C (Ǻ)α°β°γ°V(Å)Z'sgdcalcR
+2310,749 (5)13,450 (4)9,250 (2)98,33 (3)95,92 (3)102,82 (3)1277 (2)1P11,2230,06
T = temperature (°C) the crystallography
Z' = number of drug molecules in the asymmetric unit.

Table 6
Fractional parameters and their standard deviations for Form E3.
AtomxZIn (A2)Accommodation, if not equal to 1
S990.5568(1)0.0760(1)0.5936(1)3.45(2)
O10.4200(5)0.5541(4)0.8496(5) 6.9(1)
O20.2889(5)0.6016(4)1.0066(6)8.1(1)
O40.7004(4)0.4509(3)1.0233(4)4.23(8)
O80.2913(4)0.2932(3)1.1074(4)4.23(8)
Ø120.1057(4)0.1088(3)0.9299(4)4.16(8)
O15'0.329(1)-0.0602(9)1.064(1)4.8(3)*.3
O15"0.324(2)-0.156(1)1.003(2)3.2(3)*.17
O150.3312(7)-0.1150(6) 1.0380(8)4.9(1)*.53
O160.1810(5)-0.1433(3)1.1819(4)5.7(1)
O860.391(1)0.6646(7)0.6196(9)11.5(4)
O890.3714(7)0.5646(5)0.3408(6)6.5(2)
O900.7502(4)0.2721(3)0.8957(5)4.99(9)
O950.4984(4)0.0446(3)0.7188(4)4.50(8)
O960.6644(4)0.0315(3)0.5660(4)4.83(8)
O970.4651(4) 0.0667(3)0.4636(4)5.08(9)
O980.6112(5)0.1957(3)0.6332(5)5.9(1)
N20.4938(5)0.6229(3)1.0921(5)4.8(1)
N50.5365(4)0.4385(3)1.1609(4)3.16(8)
N100.2952(4)0.2239(3)0.8056(4)3.17(8)
N110.2716(4)0.1163(3)0.7961(4)3.08(8)

td align="justify"> 0.0496(9)
AtomxzIn (A2)RA is operating, if not equal to 1
N140.1336(5)-0.0874(4)0.9743(5)4.9(1)
N38-0.2764(4)0.0574(3)0.2878(4)3.24(8)
C10.4011(6)0.5893(4)0.9712(7)5.3(1)
C30.6225(5)0.6026(4)1.0813(5)3.9(1)
C40.6231(5)0.4896(3)1.0873(5)3.19(9)
C60.5220(5)0.3284(3)1.1691(5)3.14(9)
C8 0.4026(5)0.2632(3)1.0653(5)3.21(9)
C90.4165(5)0.2747(4)0.9050(5)3.6(1)
C120.1740(5)0.0661(4)0.8596(5)3.4(1)
C130.1592(5)-0.0523(4)0.8367(5)3.8(1)
C150.2248(6)-0.1124(5)1.0627(6)4.6(1)
C170.2720(9)-0.1732(6)1.2842(7)7.3(2)
C180.1818(9)0.5715(9) 0.894(1)11.2(3)
C190.7292(7)0.6818(4)1.1928(7)5.8(2)
C20Annual production of 0.725(1)0.7914(6)1.169(1)10.7(3)
C210.8613(9)0.6645(8)1.165(1)10.5(3)
C220.710(1)0.6694(7)1.3507(8)10.2(3)
C230.5158(5)0.3135(4)1.3298(5)3.8(1)
C240.6305(6)0.3765(4)1.4359(5)4.0(1)
C250.7519(7)0.3708(6)1.4192(7)6.1(2)
SB0.8581(7)0.4279(7)1.5213(9)7.9(2)
On 270.8398(8)0.4935(6)1.6375(8)8.6(2)
S0.715(1)0.5002(6)1.6576(7)8.0(2)
S0.6112(8)0.4430(5)1.5589(6)6.0(2)
C300.3043(5)0.2519(4)0.6582(5)3.6(1)
A310.1813(5) 0.2051(4)0.5532(5)3.4(1)
C32)0.0645(5)0.2123(4)0.5934(5)3.9(1)
S-0.0489(5)0.1725(4)0.4957(5)3.8(1)
S-0.0441(5)0.1243(4)0.3503(5)3.16(9)
S0.0756(5)0.1176(4)0.3097(5)3.9(1)
C360.1867(5)0.1568(4)0.4095(5)3.9(1)
S-0.1615(5)0.0853(4)0.2417(4)3.1(9)
S-0.3885(5)0.0247(4)0.1969(5)3.9(1)
C40-0.3891(5)0.0200(4)0.0470(5)4.2(1)
C41-0.2737(6)0.0469(4)-0.0057(5)4.1(1)
S-0.1596(5)0.0781(4)0.0890(5)3.7(1)
S0.0488(6)-0.1114(4)0.7094(6)4.6(1)
S-0.0819(7)-0.0958(6)0.7378(9)6.8(2)
C45-0.2266(5)0.6929(9)7.8(2)
S0.0797(8)-0.0738(5)0.5667(7)6.2(2)
S0.569(1)0.7880(9)Annual production of 0.725(1)6.3(3)
AtomXzIn (A2)Accommodation, if not equal to 1
C850.448(1)0.7726(9)0.673(2)8.4(4)
C870.204(1)0.449(1)0.405(2)10.6(4)
C880.240(1)0.517(1) 0.316(1)8.6(3)
C910.8826(7)0.2919(5)0.8896(8)5.8(2)
C920.9613(7)0.3439(6)1.035(1)7.8(2)
H381-0.2750.0530.4033.2
H8910.3970.6020.4466.6
H9810.6580.2190.7176.6

Most of the hydrogens have been omitted; included only the hydrogens on the N9 and acid.

Anisotropic refined atoms are given in the form of the isotropic equivalent parameter substitution, defined as (4/3)* [A2*B(1,1)+b2*B(2,2)+C2*B(3,3)+ab(os gamma)*B(1,2)x+ac(cos beta)*B(1,3)+bc(cos alpha)*B(2,3)].

Form E3 was characterized by a thermogram of differential scanning calorimetry with endothermal usually in the range of from about 89,4 to about 96,6°C, as shown in figure 11.

Form E3 was characterized by thermogravimetric curve analysis with weight loss, equal to about 14.7% at a temperature of about 150°C, as shown in figure 11.

Example 4.

Capsules Configuration of atazanavir bisulfate was obtained from the following compositions, as described below.

IngredientSourceandthe composition at granular. (wt%/weight.)Capsule 50 mg (mg/capsule)Capsule 100 mg (mg/capsule)Capsule 200 mg (mg/capsule)
The atazanavir bisulfate63,256,84b113,67b227,34b
Lactose monohydrate, NF30,427,33c54,69c109,35c
Crosspovidone, NF6,05,3910,79 21,58
Magnesium stearate, NF0,40,36d0,72d1,44d
Purified water, USP, and water for injection, USPq.s.eq.s.eq.s.eq.s.e
Capsule size #4-1 of each.--
Capsule size #2--1 of each.-
Capsule size #0---1 of each.
Total weight100,0to 89.9179,9359,7
andOriginal composition by granulation of atazanavir bisulfate for capsules (55.5% of the weight./weight. in the form of free base) was used to obtain 50 mg, 100 mg and 200 mg capsules.
bThis quantity is expressed for atazanavir bisulfate with a 100% activity, it is equal to 55.5% of the weight./weight. for the free base.
withThe amount of lactose hydrate varies depending on the purity of atazanavir bisulfate and the number of used stearate.
dThe number of used stearate varies from 0.4 wt%./weight. to 0.8 wt%./weight.
eUsed only when receiving and removed during drying.

Original composition by obtaining granules of atazanavir bisulfate was prepared as follows, when it was formed Configuration C.

Form a of atazanavir bisulfate, lactose hydrate and part of crosspovidone (3 wt.% of the total number of crosspovidone) were mixed in a planetary mixer. The resulting mixture was subjected to wet granulation with purified water to make the Shape And Configuration C. the Wet granulate was dried in tray dryer, and crushed in a hammer mill. The remaining crosspovidone was added to crushed the granulate and the mixture was stirred in the mixer PKV. Added magnesium stearate and the mixture was stirred to obtain a homogenous product.

Example 5.

The powder Form And atazanavir bisulfate for oral administration were received from the following composition.

IngredientAmount (% weight./weight.)
Form a of atazanavir bisulfate3,79
Aspartame NF10,00
Sucrose, NF81,21
Flavoring Orange vanilla5,00

Form a of atazanavir bisulfate was mixed with aspartame, a flavoring agent Orange vanilla and sucrose in a suitable mixer. The mixture was ground in a hammer mill, then were mixed to obtain a homogeneous mixture. The product was placed in a bottle of high-density polyethylene.

1. The way to get atazanavir sulfate in the form of crystals of Form a, which includes the interaction of a solution of the free base of the ATV in an organic solvent, in which the sulfate atazanavir practically insoluble at a temperature of from 35 to 55°C with the first portion of concentrated sulfuric acid in a quantity sufficient to react with less than about 15 wt.% the free base of the ATV, adding germ crystals of Form a of atazanavir sulfate to the reaction mixture as crystals of atazanavir sulfate, adding additional quantities of concentrated sulfuric acid in several stages, where the acid is added with increasing speed, with the formation of crystals of atazanavir sulfate and the drying of atazanavir sulfate with the formation of crystal Form A.

2. The method according to claim 1, characterized in that the solution of the free base of the ATV initially reacts with approximately 5-15% of sulfuric acid based on the entire quantity of sulphuric acid.

3. The method according to claim 1, characterized in that the solution of the free base of the ATV initially reacts with approximately 8-12% of sulfuric acid based on the entire quantity of sulphuric acid.

4. The method according to claim 1, characterized in that the reaction mixture of the free base of the ATV and sulfuric acid is administered from about 0.1 to about 80 wt.% crystals Form And calculated on the weight of the free base of the ATV.

5. The method according to claim 1, characterized in that the reaction mixture containing the germ of the crystals are heated at a temperature in the range from about 35 to 55°C.

6. The method according to claim 1, characterized in that the organic solvent for the free base of the ATV is an acetone, a mixture of acetone with N-methylpyrrolidone is, ethanol or a mixture of ethanol with acetone.

7. The way to get atazanavir sulfate Form, which includes an excerpt of crystals of Form a of atazanavir sulfate in high humidity conditions, is equal to at least about 95%, for at least 24 hours

8. The way to get atazanavir sulfate Forms, including:
a) interaction of a solution of the free base of the ATV in an organic solvent, in which the sulfate atazanavir practically insoluble at a temperature of from 35 to 55°C with the first portion of concentrated sulfuric acid in a quantity sufficient to react with less than about 15 wt.% the free base of the ATV, adding germ crystals of Form a of atazanavir sulfate to the reaction mixture as crystals of atazanavir sulfate, adding additional quantities of concentrated sulfuric acid in several stages, where the acid is added with increasing speed, with the formation of crystals of atazanavir sulfate and the drying of atazanavir sulfate with the formation of crystals of Form a;
b) the suspension of crystals of atazanavir sulfate Forms in water and drying the suspension with the formation of Form C.

9. The way to get atazanavir sulfate Forms, including:
a) interaction of a solution of the free base of the ATV in an organic solvent, to the torus atazanavir sulfate is practically insoluble, at a temperature of from 35 to 55°C with the first portion of concentrated sulfuric acid in a quantity sufficient to react with less than about 15 wt.% the free base of the ATV, adding germ crystals of Form a of atazanavir sulfate to the reaction mixture as crystals of atazanavir sulfate, adding additional quantities of concentrated sulfuric acid in several stages, where the acid is added with increasing speed, with the formation of crystals of atazanavir sulfate and the drying of atazanavir sulfate with the formation of crystals of Form a;
b) exposure of crystals of Form a of atazanavir sulfate in conditions of relative humidity, the value of which more than 95% for at least 24 h, with the formation of Form C.

10. The way to get atazanavir sulfate Forms, including:
a) interaction of a solution of the free base of the ATV in an organic solvent, in which the sulfate atazanavir practically insoluble at a temperature of from 35 to 55°C with the first portion of concentrated sulfuric acid in a quantity sufficient to react with less than about 15 wt.% the free base of the ATV, adding germ crystals of Form a of atazanavir sulfate to the reaction mixture as crystals of atazanavir sulfate, adding an additional amount to zentrierung sulfuric acid in several stages, where acid is added with increasing speed, with the formation of crystals of atazanavir sulfate and the drying of atazanavir sulfate with the formation of crystals of Form a;
b) wet granulating atazanavir sulfate and drying the wet granulate with the formation of Form C.

11. The method according to one of claims 1 or 8-10, wherein sulfuric acid is added at an increasing rate according to the following equation:

where Vtime= volume of sulfuric acid added during the passage of crystallization,
Vall= total acid of 90% of the boot
time = the time of crystallization,
timeall= total time of crystallization.

12. The way to get atazanavir sulfate:

in the form of crystals of Form a, which includes obtaining triamine salt of the formula:

interaction triamine salt without highlighting it with the active ester of the acid of the formula:

and base in the presence of an organic solvent to obtain a solution of the free base of atazanavir:

and converting the free base to the corresponding sulfate salt, while sulfuric acid is added at an increasing rate according to the following ur is the ranking:

where Vtime= volume of sulfuric acid added during the passage of crystallization,
Vall= total acid of 90% of the boot
time = the time of crystallization,
timeall= total time of crystallization.

13. The method according to item 12, wherein tiamina cleaners containing hydrochloride salt is a salt of:

14. The method according to item 12, wherein the active ester acid has the formula:

15. The method according to item 12, wherein the base is a hydroxide of an alkali metal, a hydroxide of alkaline-earth metal, a carbonate of an alkali metal, a carbonate of alkaline-earth metal phosphate, alkali metal phosphate, alkaline earth metal or organic base.

16. The method according to item 12, wherein the base is an NaOH, KOH, Mg(OH)2, K2HPO4, MgCO3, Na2CO3, K2CO3, triethylamine, diisopropylethylamine or N-methylmorpholine and an organic solvent is methylene chloride, ethyl acetate, dichloroethane, tetrahydrofuran, acetonitrile or N,N-dimethylformamide.

17. The method according to item 12, wherein tiamina salt and an active ester react at a temperature in the range from about 30 to about 40°C.

18 the Method according to 17, characterized in that tiamina salt and an active ester react in the presence of K2HPO4as the base and methylene chloride as solvent.

19. The method according to item 12, characterized in that it includes a step of introducing germs crystals of atazanavir sulfate in a mixture of free base, acetone and N-methylpyrrolidone.

20. The way to get atazanavir sulfate in the form of crystals of form a:

which includes obtaining hydrochloride analogue of the formula:

interaction hydrochloride analogue with an active ester of the formula:

and K2HPO4in the presence of methylene chloride with the formation of a solution of the free base of the formula:

in methylene chloride and converting the free base to the corresponding sulfate salt by cubic crystallization, and sulfuric acid is added at an increasing rate according to the following equation:

where Vtime= volume of sulfuric acid added during the passage of crystallization,
Vall= total acid of 90% of the boot
time = the time of crystallization,
timeall= total time of crystallization.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention claims novel compounds with inhibition effect on HCV (hepatitis C virus) protease, and methods of obtaining the claimed compounds.

EFFECT: pharmaceutical compositions including these compounds, and methods of compound application in treatment of HCV protease related diseases.

23 cl, 5 tbl, 39 ex

FIELD: organic chemistry of natural compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein each R1, R2 and R3 means independently hydrogen atom or (C1-C4)-alkyl; R4 means (C1-C12)-alkyl optionally comprising from one to three substitutes chosen from group including hydroxy-group, (C1-C12)-alkoxycarbonyl, carbamoyl, (C2-C7)-alkenyl, (C6-C10)-aryl optionally comprising from one to three substitutes chosen from group including halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-, (C1-C12)-alkylcarbonylamino-group, (C6-C10)-aryl-(C1-C12)-alkyl wherein aryl group comprises optionally from one to three substitutes chosen from group comprising halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-group, heterocyclyl-(C1-C12)-alkyl; R5 means hydroxy-, (C3-C7)-cycloalkylamino-group optionally substituted with phenyl, (C6-C10)-arylamino-, (C6-C10)-aryl-(C1-C4)-alkylamino-group optionally comprising from one to three substitutes chosen from group comprising sulfamoyl, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-group, heterocyclyl or benzyl, (C1-C4)-alkoxy-, benzhydrazino-group, heterocyclyl optionally comprising from one to three substitutes chosen from group including benzyl, benzhydryl, heterocyclylamino-group wherein heterocyclyl means saturated, unsaturated or aromatic monovalent cyclic radical comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or to their combination; n means a whole number 0, 1 or 2. Compounds of the formula (I) elicit anti-proliferative activity that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 1 tbl, 69 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-acylated pseudodipeptides comprising acidic group in neutral or charged form by one end of pseudodipeptide and accessory functionalized branching by the opposite end and corresponding to the general formula (I): wherein each R1 and R2 means acyl group of saturated or unsaturated, linear or branched carboxylic acid comprising from 2 to 24 carbon atoms, unsubstituted or comprising a substitute or substitutes chosen from hydroxyl, alkoxy- and acyloxy-groups; coefficient n has values from 0 to 3; coefficients p and q have values from 1 to 3; coefficient m has values from 1 to 3 except for a case when X means carboxyl or one of its derivative, and in this case it means values form 0 to 3; Y means oxygen atom (O) or -NH; X and Z mean accessory functionalized branching or acidic group in neutral or charged form chosen from the following groups: carboxyl, carboxy-(C1-C5)-alkoxy-, carboxy-(C1-C5)-alkylthio-, phosphono-(C1-C5)-alkoxy-, dihydroxyphosphoryloxy-, hydroxysulfonyloxy-, (carboxy-(C1-C5)-alkyl)aminocarbonyl, (dicarboxy-(C1-C5)-alkyl)aminocarbonyl, (ammonio-(C1-C5)-aminocarbonyl, carboxy-(amino-(C1-C5)-alkyl)aminocarbonyl under condition that at least one substitute among X and Z means an accessory functionalized branching, and their enantiomers and diastereoisomers. Proposed compounds show immunomolulating properties as adjuvants and these compounds can be grafted to antigen to modulate the immune response or can be grafted to pharmacophore to improve the therapeutic effect or its directed delivery.

EFFECT: improved preparing methods, improved and valuable medicinal properties of substances and compositions.

48 cl, 3 tbl, 112 dwg, 5 ex

Caspase inhibitors // 2274642

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds that represent inhibitors of caspases, in particular, inhibitors of interleukin-1β-converting enzyme and their pharmaceutical compositions. Proposed compounds can be used successfully as agents directed against diseases mediated by interleukin-1, apoptosis and factor inducing interferon-γ or by interferon-γ.

EFFECT: valuable medicinal and biochemical inhibitors.

35 cl

FIELD: organic chemistry and drugs.

SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.

EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg

The invention relates to new compounds which are inhibitors of interleukin-1-converting enzyme (IAP), is characterized by a specific structural formula; to pharmaceutical compositions having the ability to inhibit interleukin-1-converting enzymes, method of treatment and prophylaxis of diseases selected from the group consisting of IL-1-mediated autoimmune inflammatory, neurodegenerative diseases, as well as the selection method of the IAP inhibitor

The invention relates to new compounds of General formula I

< / BR>
where a is Gly; the remainder of the formula II

< / BR>
m= 0 or 1; n= 2 or 3; R1and R2each independently of the other represents H, R1and R2both together represent also

< / BR>
or

< / BR>
where IS -(CO)-(CH2)q-(CO)rwhere q=1, 2, or 3, r=0 or 1, or-CO-CH=CH-CO-; X IS H, Cl or1-C6alkyl; and if the mean remains optically active amino acids and derivatives of amino acids, are included as D-and L-forms, and their salts, process for the preparation of compounds of formula I and their salts; pharmaceutical composition having the ability to inhibit integrin containing in its structure at least one compound of the formula I and/or one of its physiologically acceptable salts

The invention relates to an inhibitor of serine proteases having piperidine side chain; to pharmaceutical compositions containing this inhibitor; and using the indicated inhibitor for the manufacture of a medicine for the treatment and prevention of diseases associated with the action of thrombin

The invention relates to arylpiperazines General formula I

< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

The invention relates to benzylchloride formula I or its salts, where R1- (C1-C6)alkyl, (C1-C4)cianelli, (C1-C4)hydroxyalkyl, (C3-C6)cycloalkyl, (C1-C6)halogenated, benzyl which may be substituted with halogen, thiazolyl; R2and R3independently - H, (C1-C4)alkyl, or R1and R2together with the sulfur atom and the carbon form a 3-8-membered ring; R4- H, halogen; And - hydrazinoacetate or hydrosonography group of formula A1 or A2; R9- H, halogen, NO2, CN, (C1-C4)alkyl, (C1-C4)halogenated, (C1-C4)alkoxy, (C1-C4)halogenoalkane, (C1-C4)alkylthio, (C1-C4)allogenicity, (C2-C4)alkylsulfonyl, (C1-C4)halogenated.sulphonated, phenyl which may be substituted with halogen, phenoxy, which may be substituted with halogen; R10- H; R11, R12, R13independently - H, (C1-C6)alkyl, (C1-C4)halogenated, (C2-C10)alkoxyalkyl, (C3-C8)alkoxyalkyl, (C2-C6)alkylthiol, (C1-C4)cianelli, benzyl which may be substituted with halogen, (C1-C4)halogenation, (C1-C4)alkyl, -COR14, -COOR15THAT IS SOP(R16R17, -SO2R20-C(R21)= HR22; or R12and R13together can form a group of the formula = CR23R24; R14- (C1-C20)alkyl, (C1-C8)halogenated, (C2-C12)alkoxyalkyl,oxyalkyl, phenyl; R16- H, (C1-C4)alkyl; R17- H, (C1-C6)alkyl, phenyl which may be substituted; R20- (C1-C4)halogenated, (C2-C4)dialkylamino; R21- (C1-C6)alkyl; R22- acyl, (C2-C6)alkoxycarbonyl; R23, R24independently - H, halogen, (C1-C6)alkyl, -NR25R26; R25and R26independently - H, (C1-C4)alkoxy, (C2-C12)alkoxyalkyl; Q1and Q2is nitrogen or CR9m = 1 to 3, n = 0, 1, 2

FIELD: chemistry.

SUBSTANCE: invention relates to production of bis(4-alkylaminopyridine-1) alkanes of formula I where R1 -s linear or branched alkyl, cycloalkyl or arylalkyl groups having from 4 to 18 carbons, preferably from 8 to 12 carbons, ideally - normal octyl, R2 - linear or branched alkylene groups having from 4 to 18 carbons, preferably from 8 to 14 carbons, ideally - 1,10 decandyl, X1, X2 - halogenanions (identical or diverse): fluoride-, chloride-, bromide-, iodideanions, ideally - chlorideanions through interreacting of 4-alkylaminopyridine of formula II with disubstituted alkylene of formula III X1-R2-X2 in a solvent at increased temperature with mole ratio of formula II compound to formula III compound equals 2:1, the process is carried out in anoxic environment, acetic acid or its mixture with water is used as a solvent, meanwhile the compound of formula II is treated with the compound of formula III in gradual and continuous way or portionwise, ensuring the reaction at temperature ranging from 90° to 130°C, ideally from 100 to 105°C.

EFFECT: preparation of bis(4-alkylaminopyridine-1) alkanes of high quality with higher yield at essential saving of expandable materials.

6 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of bis-(4-alkylaminopiridinium-1)alkanes of formula (1) where X stands for lipophilic anion from the following group: triiodide I3, iodate IO3, perchlorate ClO4; Y stands for either linear or branched alkylene group, which contains 4 to 18 carbon atoms; R stands for either linear or branched alkyl, cycloalkyl or arylalkyl group, which contains 5 to 18 carbon atoms, to methods of preparation thereof and application thereof as antibacterial and antiviral substances.

EFFECT: new substances show useful biological properties.

10 cl, 6 ex

The invention relates to imidazopyridine, in particular, there are some derivatives of 4-substituted-1-/2-methylimidazo [4,5-C]pyrid-1-yl)-benzene and alkylbenzene

The invention relates to compounds of the formula

< / BR>
and their pharmaceutically acceptable salts, in which:

R represents phenyl, substituted with 1-2 substituents, each independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl

The invention relates to chemical compounds with valuable properties, in particular derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula

< / BR>
(I) where a lower alkylene;

R is a hydrogen atom or a group

A< / BR>
or their salts
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