Novel crystalline form of perindopril

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of perindopril of formula I: . Also proposed are methods for synthesis of amorphous and crystalline perindopril using starting substance in form of stereospecific amino acid, N-[(S)-carbethoxy-1-butyl]-(S)-alanine, which is protected by a trimethylsilyl group and converted to reactive acid chloride using thionyl chloride or its complex with 1-H-benzotriazole (1:1), which reacts with (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid, having a protected carboxy group. The invention also relates to a pharmaceutical composition based on the said crystalline form of perindopril.

EFFECT: novel form of perindopril is obtained, which can be used in medicine for treating cardiovascular diseases.

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The technical field to which the invention relates.

The present invention relates to a new method of synthesis of perindopril to the new amorphous form of perindopril and to a new crystalline form of perindopril.

The level of technology

Perindopril has the following structural formula I:

and is a (2S,3aS,7aS)-1[(2S)-2-[[(1S)-1-etoxycarbonyl)butyl]amino]propionyl]octahydro-1H-indole-2-carboxylic acid. Perindopril acts as a transport form ("prodrugs") perindoprilat decollate, which is its active form. After oral administration perindopril is rapidly absorbed in the body and the liver is the primary metabolism with the formation of perindoprilat and its active metabolites. He is an ACE inhibitor used in the treatment of cardiovascular diseases, particularly in the treatment of hypertension and congestive heart failure.

ACE inhibitors ("angiotensin converting enzyme") inhibit the conversion of angiotensin I to angiotensin II. They are hypotensive agents, also acting as a vasodilator.

Perindopril was first disclosed in EP 0049658 B1 and US 4508729. Described in the method of obtaining is quite complex and results in a mixture of stereoisomers, which should be once elati. N,N'-Dicyclohexylcarbodiimide is used as the condensing reagent. In the mentioned patent also disclosed perindopril in the form of pure (S) isomer and its sodium salt.

In DE 19721290 describes a method for ACE inhibitors, which substituted derivatives of alanine similarbut and activate with thionyl chloride to obtain similarbank derivatives of carboxylic acids, which enter into reaction with the appropriate amino acids having protected carboxypropyl. Appropriate inhibitors get by removal of the protective groups.

In WO 03/064388 described a method for the synthesis of perindopril, which is N-[(S)-carbethoxy-1-butyl]-(S)-alanine activate with thionyl chloride to obtain the corresponding intermediate - acid chloride of N-[(S)-carbethoxy-1-butyl]-(S)-alanine with protected group of NH, which is then injected into the reaction of (2S,3aS,7aS)-octahedron-2-carboxylic acid. The acid chloride receive through the use of thionyl chloride at ambient temperature or slightly higher temperature. Group NH protect using N-alkoxycarbonyl group, for example N-ethoxycarbonyl, N-methoxycarbonylamino or N-benzyloxycarbonyloxy group. The disadvantages of this synthesis are, on the one hand, the low stability of the N-alkoxycarbonyl groups in a very acidic when chlorination and, with each the second side, excessive stability of the N-benzyloxycarbonyloxy group, removal of which is necessary for catalytic hydrogenation.

Perindopril obtained by methods of the prior art, is a colorless or slightly yellow oily substance that hardens when cooled. To date perindopril not isolated in crystalline form. Disclosed crystalline form only molecular salt of perindopril - pharyngopalatine - EP 1296947 B1, EP 1294689 A1 and EP 1296948 B1.

Summary of the invention

In one embodiment, the present invention relates to a new crystalline form of perindopril, which is characterized by a powder x-ray that contains characteristic peaks at 2θ): 5,101, 8,615, 9,373, 11,090, 11,403, 15,230, 15,990, 17,215, 19,011, 19,506, 20,124 and 20,568.

In another embodiment, the present invention relates to amorphous perindopril.

Another variant of implementation relates to a process for the preparation of perindopril of formula I

includes the following stages:

(i) a secondary amino group stereospecific amino acid N-[(S)-carbethoxy-1-butyl]-(S)-alanine of the formula II:

protect trimethylsilyl groups with obtaining the compounds of formula III:

/p>

(ii) then, the compound (III) activated by reaction with an activating reagent selected from the group comprising thionyl chloride and thionyl chloride complex with 1-N-benzotriazole, to obtain the acid chloride of formula IV:

(iii) the acid chloride of the formula IV is administered in the reaction of (2S,3aS,7aS)-octahedron-2-carboxylic acid having a protected carboxypropyl formula V:

in which R denotes trimethylsilyloxy, tert-boutelou or benzyl group, and get protected derivative of perindopril of formula VI:

(iv) then the derivative of formula VI is converted into a perindopril of formula I by removal of all protective groups.

In another embodiment, the present invention relates to a method for producing an amorphous form of perindopril, such as described above, including additional stages:

(v) filtering the crude perindopril obtained at stage (iv) of the method proposed in the present invention, through a layer of silica gel and

(vi) evaporation in a vacuum all remaining traces of solvent.

In another embodiment, the present invention relates to a method for producing an amorphous form of perindopril, which includes stages (i)to(iv)described above, and the additional step of filtering the Oia protected derivative of perindopril of formula VI through the active layer of the basic aluminum oxide to conduct this stage catalytic hydrogenation.

In another embodiment, the present invention relates to a method of obtaining a new crystalline form of perindopril proposed in the present invention, which includes stages of dissolution of amorphous perindopril in lower simple dialkylated ether containing up to 8 carbon atoms, and crystallization of this new crystalline form of perindopril from the resulting solution.

In another embodiment, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a new crystalline form of perindopril in conjunction with one or more pharmaceutically acceptable carriers or inert fillers.

In another embodiment, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an amorphous form of perindopril in conjunction with one or more pharmaceutically acceptable carriers or inert fillers.

In another embodiment, the present invention relates to a new crystalline form of perindopril to obtain pharmaceutical compositions intended for use in the treatment of cardiovascular diseases.

In another embodiment, the present invention con is seeking to use amorphous form of perindopril to obtain pharmaceutical compositions designed for use in the treatment of cardiovascular diseases.

In another embodiment, the present invention relates to a method for treatment of cardiovascular diseases, including the introduction needs it to the patient a therapeutically effective amount of new crystalline forms of perindopril.

In another embodiment, the present invention relates to a method for treatment of cardiovascular diseases, including the introduction needs it to the patient a therapeutically effective amount of an amorphous form of perindopril.

Description of the drawings

Figure 1 - the mass spectrum of the new crystalline form of perindopril (obtained by the method of the CDF MS ER+ - TOF mass spectrometry with ionization by elektrorazpredelenie).

Figure 2 - IR spectrum of the new crystalline form of perindopril.

Figure 3 radiograph of a new crystalline form of perindopril.

4 is the NMR spectrum of the new crystalline form of perindopril.

Detailed description of the invention

In one embodiment, the present invention relates to a process for the preparation of perindopril of formula I

includes the following stages:

(i) a secondary amino group stereospecific amino acid N-[(S)-carbethoxy-1-butyl]-(S)-alanine of the formula II:

protect trimethylsilyl groups with obtaining the compounds of formula III:

(ii) then, the compound (III) activated by reaction with an activating reagent selected from the group comprising thionyl chloride and thionyl chloride complex with 1-N-benzotriazole, to obtain the acid chloride of formula IV:

(iii) the acid chloride of the formula IV is administered in the reaction of (2S,3aS,7aS)-octahedron-2-carboxylic acid having a protected carboxypropyl formula V:

in which R denotes trimethylsilyloxy, tert-boutelou or benzyl group, and get protected derivative of perindopril of formula VI:

(iv) then the derivative of formula VI is converted into a perindopril of formula I by removal of all protective groups.

Advantages of the method of obtaining perindopril proposed in the present invention include the use of fully protected reagents and the use of very reactive reagent for the activation of such form that the reaction can be conducted under mild conditions. The formation of decomposition products and epimeres is very small. Therefore, the outputs are high enough. All raw materials and reagents are commercially available and their possible industrial production.

p> In a preferred embodiment, the method proposed in the present invention may include the additional step of allocating perindopril in which impurities are removed from the final reaction mixture by extraction with an aqueous solution, and the organic phase containing perindopril, dried by evaporation of the solvent in vacuo.

In the field of peptide chemistry (G.A.Grant, Synthetic Peptides, W.H.Freeman and Co. New York, 1992, p.81) it is well known that the combination of two amino acids all other reactive side groups must be protected with appropriate protective groups, which prevent side reactions. At the end of the synthesis of the protective group must be removed without damaging the new connection. Protection of the side groups is particularly important in the case of activation of the carboxyl group with thionyl chloride, which is highly reactive. Therefore, if at the stage (ii) of the method as the activating reagent using thionyl chloride, the reaction must be performed at low temperatures, ideally at a temperature below -10°C.

An alternative to the use of thionyl chloride as the activating reagent is the use of the reactive complex of thionyl chloride with 1-N-benzotriazole, which is an excellent reagent to obtain the acid anhydrides or chlorides founded the th in mild reaction conditions, since the reaction is not exothermic. The reagent in the mixing ratio of 1:1 (S.S.Chaudari et al., Synlett 1999, 11, 1763), also can be prepared in advance in the form of a solution in methylene chloride, because it is stable and does not have the aggressiveness characteristic of thionyl chloride. Adverse reactions, particularly chlorination in the α-position relative to a carbonyl group, significantly reduced.

The removal of the protective group of the protected perindopril of formula VI in stage (iv) may be conducted by various methods depending on the type of the protective group.

Trimethylsilyl protective group can be removed by hydrolysis in water, for example Trimethylsilyl protective group can be removed by reaction with water at the stage of allocation of perindopril after completion of the synthesis.

Tert-butylene and benzyl groups you want to delete on a separate stage, for example, through the use of strong acid or catalytic hydrogenation. All traces of sulfur from the crude product, including protected derivative of perindopril of formula VI, you must remove to catalytic hydrogenation, in order to avoid deactivation of the catalyst. For this significant stage filtration through a suitable layer. One example of a suitable layer is the active primary aluminium oxide. Prepact the positive activity of such a layer is 2-3. A suitable thickness of such layer is preferably equal to about 2-4 cm, 3 see for example

According to the invention unexpectedly found that very pure perindopril can be obtained by filtration of the final product stage (iv) of the method proposed in the present invention is carried out as already described. Stage filtering can be performed by dissolving the crude substance in methylene chloride and passing the solution through a layer of silica gel, for example Merck 60, the degree of granulation of 0.2-0,0063. Silica gel can be dampened with a mixture of methylene chloride/ethanol 94/6 (about./about.) and eluted with the same mixture. Received perindopril is in the form of a viscous oil, which in turn colorless, amorphous solid by evaporation of traces of residual solvent under high vacuum. Amorphous chemical compounds characterized by the absence of diffraction peaks in x-ray powder.

In addition, it was found that amorphous perindopril alternative can be obtained by the method proposed in the present invention, by carrying out an additional stage of filtration protected derivative of perindopril of formula VI through the layer of active basic alumina prior to carrying out catalytic hydrogenation.

This is the first disclosure of the existence or releasing avrprog the perindopril. Amorphous perindopril proposed in the present invention does not detect the diffraction peaks in x-ray powder.

Solid amorphous perindopril obtained according to the present invention, can be converted into the molecular salt with tert-butylamine by crystallization in a suitable solvent, methylene chloride, ether, tert-butyllithium ether, ethyl acetate, butyl acetate, 2-pentanone, cyclohexane, methylcyclohexane or similar solvents.

According to the invention unexpectedly found that amorphous perindopril, dissolved in a lower dialkylated simple ether containing up to 8 carbon atoms (for example, diethyl ether), crystallizes in the form of colourless crystals which melt at 110-114°C. This new crystalline form of perindopril were characterized by IR spectroscopy, MS, NMR, x-ray spectra. A new crystalline form of perindopril proposed in the present invention, soluble in water; at 20°C in 100 ml water dissolve 20, It is not hygroscopic and therefore suitable for inclusion in pharmaceutical compositions.

In another embodiment, the present invention relates to a method for producing an amorphous form of perindopril, including additional stages:

(v) filtering the crude perindopril obtained at stage (iv) of the method, proposed in the present invention, through a layer of silica gel and

(vi) evaporation in a vacuum all remaining traces of solvent.

In another embodiment, the present invention relates to a method for producing an amorphous form of perindopril of formula I, comprising the following stages:

(i) a secondary amino group stereospecific amino acid N-[(S)-carbethoxy-1-butyl]-(S)-alanine of the formula II protects trimethylsilyl groups with obtaining the compounds of formula III,

(ii) then, the compound (III) activated by reaction with an activating reagent selected from the group comprising thionyl chloride and thionyl chloride complex with 1-N-benzotriazole, to obtain the acid chloride of formula IV,

(iii) the acid chloride of the formula IV is administered in the reaction of (2S,3aS,7aS)-octahedron-2-carboxylic acid having a protected carboxypropyl formula V in which R denotes trimethylsilyloxy group, and get protected derivative of perindopril of formula VI,

(iv) then the derivative of formula VI is converted into a perindopril of formula I by removal trimethylsilyl groups at the stage of removal of impurities by extraction of the aqueous solution,

(v) the organic phase containing perindopril, dried by evaporation of the solvent in vacuum,

(vi) the crude perindopril dissolved in methylene chloride and filter the Ute through a layer of silica gel,

(vii) the fraction containing perindopril, is evaporated in a high vacuum.

In another embodiment, the present invention relates to a method for producing an amorphous form of perindopril of formula I, comprising the following stages:

(i) a secondary amino group stereospecific amino acid N-[(S)-carbethoxy-1-butyl]-(S)-alanine of the formula II protects trimethylsilyl groups with obtaining the compounds of formula III,

(ii) then, the compound (III) activated by reaction with an activating reagent selected from the group comprising thionyl chloride and thionyl chloride complex with 1-N-benzotriazole, to obtain the acid chloride of formula IV,

(iii) the acid chloride of the formula IV is administered in the reaction of (2S,3aS,7aS)-octahedron-2-carboxylic acid having a protected carboxypropyl formula V in which R is a benzyl group, and get protected derivative of perindopril of formula VI,

(iv) impurities are removed from the final reaction mixture by extraction with an aqueous solution,

(v) the organic phase is filtered through a layer of aluminum oxide,

(vi) the fraction containing the derivative of formula VI, is evaporated in vacuum,

(vii) then the derivative of formula VI is converted into a perindopril of formula I by removal of all protective groups by catalytic

hydrogenation,

(viii) remove the catalyst filter is receiving,

(ix) the solvent is evaporated in vacuum.

Another object of the present invention is a method of obtaining a new crystalline form of perindopril characterised by the fact that amorphous perindopril dissolved in the lower dialkylated simple ether (e.g. diethyl ether), and then give him secretariats. The crystallization is preferably carried out at a temperature in the range from 0 to 35°C, more preferably from 5 to 25°C. the Best results are obtained when the crystallization is carried out in two stages - first at a higher temperature (e.g., 15-30°C., more preferably 20-25°C), and then at a lower temperature, such as from 0 to 10°C, preferably 2-5°C). For example, the first stage of crystallization can be performed for 3 h at room temperature and then for 6 h at +5°C.

Another variant of implementation of the present invention relates to an amorphous form of perindopril obtained using any method of obtaining amorphous perindopril proposed in the present invention.

Another variant of implementation of the present invention relates to an amorphous form of perindopril obtained using any method of obtaining amorphous perindopril proposed in the present invention.

Another variant of implementation of the present invention relates to a new crystal is practical form of perindopril, obtained by the method of obtaining a crystalline form of perindopril proposed in the present invention.

Another variant of implementation of the present invention relates to a new crystalline form of perindopril obtained by the method of obtaining a crystalline form of perindopril proposed in the present invention.

The pharmaceutical composition proposed in the present invention, on the one hand, may include amorphous perindopril or its salt, or its derivative in combination with one or more pharmaceutically acceptable carriers or inert fillers. Alternatively, the pharmaceutical composition proposed in the present invention may include perindopril in new crystalline form disclosed in the present invention, or its salt or its derivative (preferably tert-butylamine salt) in combination with one or more pharmaceutically acceptable carriers or inert fillers.

Pharmaceutically acceptable inert fillers can be selected from the group comprising binders, diluents, agents, providing raspadaemost, stabilizing agents, preservatives, lubricants, fragrances, flavorings, sweeteners and other inert fillers known in the field of pharmaceutical technology. But Italy and inert fillers preferably can be selected from the group including hydroxypropylcellulose, lactose, microcrystalline cellulose, calcium carbonate, starch, colloidal silicon dioxide, sodium salt starch glycolate, talc, magnesium stearate, polyvinylpyrrolidone.

The pharmaceutical composition proposed in the present invention, optional can be combined products, in addition to perindopril containing one or more additional pharmaceutically active components. Preferably, the additional pharmaceutically active component was a diuretic, for example indapamide.

Suitable pharmaceutical compositions are solid dosage forms such as tablets with immediate or delayed release of active component, effervescent tablets or dispergirujutsja tablets and capsules.

The pharmaceutical compositions can be obtained by methods known in the field of pharmaceutical technology.

In another embodiment, the present invention relates to a new crystalline form of perindopril to obtain pharmaceutical compositions intended for use in the treatment of cardiovascular diseases such as hypertension and heart failure.

In another embodiment, the present invention Rel is referring to the use of the amorphous form of perindopril to obtain pharmaceutical compositions designed for use in the treatment of cardiovascular diseases such as hypertension and heart failure.

In another embodiment, the present invention relates to a method for treatment of cardiovascular diseases such as hypertension and heart failure, including the introduction needs it to the patient a therapeutically effective amount of new crystalline forms of perindopril.

In another embodiment, the present invention relates to a method for treatment of cardiovascular diseases such as hypertension and heart failure, including the introduction of a therapeutically effective amount of an amorphous form of perindopril.

A therapeutically effective amount of perindopril is a number that is appropriate for dosage forms that are suitable for the treatment of cardiovascular diseases such as hypertension and heart failure. Usually pharmaceutically effective amount is from 1 to 15 mg perindopril, preferably from 2 to 8 mg

The present invention is illustrated by, but is not limited to the following examples.

Examples

Example 1

Getting pharyngopalatine

Stage I: Getting Siciliano (2S,3aS,7aS)-octahedron-2-carboxylic acid

To a suspension of 2.0 g (0,0077 mol) of (2S,3aS,7aS)-octahedron-2-carboxylic acid in 24 ml of methylene chloride at room temperature under stirring add to 0.98 ml of trimethylchlorosilane (0,0077 mol) and 1.08 ml (0,0077 mol) of triethylamine. The mixture is stirred at room temperature for 75 minutes

Stage II: Getting similarvideo N-[(S)-carbethoxy-1-butyl]-(S)-alanine

To a solution of 1.68 g (0,0077 mol) of N-[(S)-carbethoxy-1-butyl]-(S)-alanine in 30 ml of methylene chloride, cooled to -15°C., was added under stirring to 1.96 ml (0,0155 mol) of trimethylchlorosilane and 2.15 ml (0,00155 mol) of triethylamine. The solution was kept at -15°C for 2.5 h and stirred periodically.

Stage III: Getting perindopril

The complex of thionyl chloride with 1-N-benzotriazole (1:1)obtained from 0,92 g of 1-N-benzotriazole (0,0077 mol) and 0.56 ml of thionyl chloride (0,0077 mol), diluted with 5 ml of methylene chloride, with stirring, is added to the solution obtained in phase II. The mixture is additionally stirred for 30 minutes

To this solution under stirring was added Siciliano (2S,3aS,7aS)-octahedron-2-carboxylic acid, obtained in stage I. the resulting solution was first stirred while heating solution from -15 to +20°C. and then stirring is continued for another 24 h For the reaction can be monitored by analytical HPLC (high-performance liquids is Naya chromatography), as described in example 5.

After completion of the reaction was added water (30 ml), the pH value of the suspension is brought up to 4.38±0,1 using 6 M NaOH (2.7 ml). Then add 8 g of NaCl and mix thoroughly. Organic and aqueous layers separated. Methylenchloride phase is washed with 10% NaCl solution. The combined solution with NaCl at pH of 4.4 extracted twice with 15 ml of methylene chloride. United methylenechloride extracts dried over MgSO4and evaporated in vacuum at 40-50°C. Receive 5.10 g of yellow solids, containing perindopril.

Stage IV: Cleaning perindopril

Dry matter obtained in stage III, dissolved in methylene chloride (12 ml) and applied to a column filled with 50 g of silica gel (Merck 60, a grain size of 0.2-0,0063 mm), which is moistened with a mixture of methylene chloride/ethanol 94/6 (about./vol.). 1-N-Benzotriazol and perindopril separately elute from this column this solvent.

For flow separation by TLC (thin layer chromatography) is monitored as described in example 5. After evaporation of the solution perindopril get 2,48 g (87,5%) solid amorphous substance.

Stage V: Getting pharyngopalatine

Amorphous perindopril obtained at stage IV, dissolved in a mixture of methylcyclohexane/ethanol (20 ml + 2 ml) at 70°C and discolor with 0.5 g of activated charcoal. To a solution of arr the keys of 0.68 ml of tert-butylamine in 3 ml of methylcyclohexane and 1 ml ethanol. Half of the solvent is evaporated in vacuum at 70°C. After crystallization at -15°C overnight get 2.0 g of perindoprilat (72,6% of theoretical yield). According to the HPLC purity is about 99-99,5% (range). Melting point equal 124-135°C.

Example 2

Getting pharyngopalatine

Stage I: Getting similarvideo N-[(S)-carbethoxy-1-butyl]-(S)-alanine

1.88 g (0,00866 mol) of N-[(S)-Carbethoxy-1-butyl]-(S)-alanine is suspended in 30 ml of methylene chloride. The solution is cooled to -15°C and then with stirring, was added 2.2 ml of trimethylchlorosilane (0,0173 mol) and 2,40 ml of triethylamine (0,0173 mol). The solution was kept at -15°C for 90 minutes

To this solution under stirring was added 0.63 ml (0,00866 mol) of thionyl chloride in 6 ml of methylene chloride. The solution was kept at -15°C and stirred periodically.

Stage II: Retrieving and clearing perindopril

To the solution obtained in stage I, with stirring, was added 2.24 g (0,00866 mol) of benzyl ester of (2S,3aS,7aS)-octahedron-2-carboxylic acid in 10 ml of methylene chloride. The solution was kept at -15°C for 22 h, then with stirring, add 2 ml of triethylamine and stirring is continued for a further 11 h at 20°C. the Reaction mixture was extracted with 25 ml of 9% NaCl, 2×25 ml saturated solution of NaHCO3and dried over MgSO4. The resulting solution was filter is jut through the layer (3 cm) aluminum oxide (basic, activity 2-3). The solvent is evaporated in vacuum (3.13 g, oil).

The oil obtained is dissolved in methanol (50 ml) and add 1.0 g of palladium on activated charcoal (10%), and then hydronaut hydrogen at 35-40°C for 8 hours the Catalyst is filtered off, washed with methanol and the solvent is evaporated in vacuum at 40-50°C. Receive 2,32 g (72.7% yield) of dry white matter.

Stage III: Getting pharyngopalatine

Perindopril obtained at stage II, crystallized from 2-pentanone (30 ml) after addition of 0.7 ml of tert-butylamine in 3 ml of 2-pentanone. The solution was incubated for 1-2 h at room temperature and overnight at -15°C. Gain of 2.33 g (83.8 percent) of white crystals having a melting temperature of 120-130°C.

Example 3

Getting pharyngopalatine

Stage I: Getting Siciliano (2S,3aS,7aS)-octahedron-2-carboxylic acid

of 2.92 g of Perchlorate (2S,3aS,7aS)-octahedron-2-carboxylic acid (0,00812 mol, which corresponds 2,10 g of the free acid) are suspended in 26 ml of methylene chloride. To the solution was added to 1.03 ml (0,00812 mol) of trimethylchlorosilane and 2.25 ml (0,01624 mol) of triethylamine. The mixture is stirred at 20°C for 2 hours

Stage II: Getting similarvideo N-[(S)-carbethoxy-1-butyl]-(S)-alanine

1,76 g (0,00812 mol) of N-[(S)-Carbethoxy-1-butyl]-(S)-alanine suspended in 26 ml of methylene chloride and ohlajdauche -15°C. To this solution under stirring add 2,05 ml (0,01624 mol) of trimethylchlorosilane and 2.25 ml (0,01624 mol) of triethylamine. The solution was kept at -15°C for 5 min and periodically stirred.

Stage III: Getting perindopril

To the solution obtained in phase II, add a 0.59 ml (0,00812 mol) of thionyl chloride in 5 ml of methylene chloride. The solution was kept at -15°C for 45 min and periodically stirred. Then under stirring was added a solution of sicilianos (2S,3aS,7aS)-octahedron-2-carboxylic acid, obtained in stage I. the resulting solution was incubated overnight (at least 15 h) at -15°C. Then add 2 ml of triethylamine and the mixture is stirred at room temperature for a further 14 hours

To the reaction mixture was added 25 ml of water and the pH value was adjusted to 4.1±0,1 by addition of 6 M NaOH solution. 3 g of NaCl Dissolved in the aqueous phase, and then vigorously stirred. The resulting phases are separated and methylenchloride phase extracted twice more with 25 ml of a 9% aqueous solution of NaCl. The pH of the combined solution of NaCl was adjusted to 4.4±0.1, and then the solution in NaCl re-extracted 3 times with 20 ml of methylene chloride. Received methylenechloride extracts washed with 30 ml of 9% solution of NaCl and then combine with the primary methylenchloride faction. Methylenchloride fraction dried over MgSO4

Stage IV: Getting pharyngopalatine

Perindopril obtained at stage III, dissolved in ethyl acetate (25 ml) at 60-70°C. To the solution was added to 0.72 ml of tert-butylamine and 1 g of activated charcoal. The solution is carefully filtered and perindoprilat crystallized at -15°C during the night. Gain of 2.38 g of crystals (79,7%)having a melting point of 118 to 130°C.

Example 4

Obtaining crystalline perindopril

Stage I: Getting perindopril

Synthesis of perindopril carried out according to the method described in example 3, using the following reagents:

a) To obtain Siciliano (2S,3aS,7aS)-actor-2-carboxylic acid used 3.80 g (2S,3aS,7aS)-actor-2-carboxylic acid (0,01467 mol) in 45 ml of methylene chloride, to 1.86 ml (0,01467 mol) of trimethylchlorosilane and 2,04 ml (0,01467 mol) of triethylamine.

b) To obtain similarvideo N-[(S)-carbethoxy-1-butyl]-(S)-alanine: use 3,18 g (0,01467 mol) of N-[(S)-carbethoxy-1-butyl]-(S)-alanine, 3,71 ml (0,02934 mol) of trimethylchlorosilane and 4,07 ml (0,02934 mol) of triethylamine.

in) To activate similarvideo N-[(S)-carbethoxy-1-butyl]-(S)-alanine use of 1.07 ml (0,01467 mol) of thionyl chloride.

5,77 g of Solid crude perindopril receive according to the method described in example 3.

Stage II: Cleaning pairing is prila

The crude perindopril obtained at stage I, is dissolved in 15 ml of methylene chloride and passed through a column containing 30 g of silica gel (Merck 60, a grain size of 0.2-0,063 mm)moistened with a mixture of methylene chloride/ethanol 94/6 (about./vol.). Eluent containing perindopril, is evaporated in vacuum at 50°C and obtain 4.09 g of perindopril (75,9%).

Stage III: Obtaining crystalline perindopril

Perindopril obtained at stage II, dissolved in ethyl ether and crystallized at room temperature for 3 h, and then at +5°C for 5 hours Get 3,20 g of perindopril in a new crystalline form (78,2% of theoretical yield). Melting point equal 110-114°C.

The solution is characterized using IR spectroscopy, NMR, MS.

Powder x-ray of a new crystalline form of perindopril removed by using a Siemens diffractometer D 5000 using the technique of reflection under the following conditions: radiation CuKαthe range from 2 to 37°, the step of 0.04°, integration time: 1s. In the diffraction pattern (figure 3) presents the intensity and relative intensity (expressed through the angle 2θ or distance d:

td align="left"> the relative intensity, %
the angle 2θinterplanar distance d×10-10mthe intensity of the pulse, with-1
of $ 3,65624,1502772,02,4
5,10117,3109635,01,2
6,37813,846873042100
6,88412,83052165of 5.4
7,36211,998041545,1
7,84211,2649067,02,2
8,61510,2549643414,3

15,990
the angle 2θinterplanar distance d×10-10mthe intensity of the pulse, with-1the relative intensity, %
9,3739,4278144414,6
9719 9,093251414,6
11,0907,9716361220,1
11,4037,7538651416,9
12,2407,2254040313,2
12,5247,0622056718,6
12,8406,88883354the 11.6
13,2946,654382718,9
13,8006,4116940013,1
14,0826,2839263620,9
14,5726,0738147715,7
15,2305,8126684827,9
5,5382970023,0
17,2155,14680140346,1
17,9584,9354576425,1
18,6404,7563332810,8
19,0114,6644077225,4
19,5064,5471989129,3
20,1244,4087464321,1
20,5684,3145385027,9
21,5724,1159946615,3
22,0254,0323547215,5
22,9833,8665049216,2
23,9333,7149960720,0
23,3473,6527842213,9
25,3213,5144632810,8
25,5203,4875231910,5
26,1053,4106332710,7
29,8853,3134844714,7
27,6123,227832668,7
28,5603,122832688,8
28,7563,1019730910,2
29,4283,032662678,8
30,3032,94702277 9,1
30,5932,919832809,2
31,4132,845372618,6

Example 5

The tracking system reaction (HPLC):

Column: HD-Sil (ORPEGEN) 18-5s-100, 5 μm, 250×4.6 mm

Mobile phase: A) 25% acetonitrile/75% buffer pH 2

C) 70% acetonitrile/30% buffer pH 2.

The composition of the buffer: 0,92 g heptanesulfonate sodium, 1 ml of triethylamine in 1000 ml of solution, the pH value of 2.0 installed using perchloric acid.

Gradient: 100% a 1 min, then to 100% b for 25 min

Flow rate: 1.25 ml/min

Detection: UV at a wavelength of 200 nm.

Tracking system by passage through a column of silica gel or Al2O3(TLC):

Plate: silica gel Merck 60;

Mobile phase: methylene chloride/ethanol 90/10 (vol./about.)

Detection: the reagent Dragendorff.

The Rf values:

perindopril 0,44

1-N-benzotriazol 0,66

the triethylamine·HCl 0,20.

Example 6

Characterization of a new crystalline form of perindopril and new amorphous form of perindopril

MS removed spectrometer Auto Spec Micromass by the method of the CDF MS ER+.

Infrared spectra are removed on the spectrophotometer, Bio-Rad FTS-60. The samples examined in KBr.

1H-NMR spectrum of the s remove the instrument Varian NMR, 300 MHz, solvent D2O, external standard TMSPO=0.

Example 7

The composition of the mixture to obtain 1000 tablets containing 4 mg of active substance per tablet:

Perindopril obtained in example 43,34 g
Tert-butylamine0.66 g
Hydroxypropylcellulose2 g
Starch10 g
Lactose100 g
Magnesium stearate3 g
Talc3 g

Tert-butylamine dissolved in a solvent suitable for the preparation of granules, add crystalline perindopril obtained in example 4, and stirring is continued until the dissolution of perindopril. With stirring, add the remaining ingredients and mix granularit.

1. A new crystalline form of perindopril of formula I:

which is characterized by a powder x-ray that contains characteristic peaks at 2θ): 5,101, 8,615, 9,373, 11,090, 11,403, 15,230, 15,990, 17,215, 19,011, 19,506, 20,124 and 20,568.

2. New kristallicheskie the form of perindopril according to claim 1, characterised by the following powder x-ray taken using a diffractometer (cathode CuKα), are presented in units of angle 2θ, with the following interplanar distances d and the corresponding intensities and relative intensities:

the angle 2θinterplanar distance d×10-10mthe intensity of the pulse, c-1the relative intensity, %
of $ 3,65624,1502772,02,4
5,10117,3109635,01,2
6,37813,846873042100
6,88412,83052165of 5.4
7,36211,998041545,1
7,84211,2649067,02,2
8,615 10,2549643414,3
9,3739,4278144414,6
9,7199,093251414,6
11,0907,9716361220,1
11,4037,7538651416,9
12,2407,2254040313,2
12,5247,0622056718,6
12,8406,88883354the 11.6
13,2946,654382718,9
13,8006,4116940013,1
14,0826,2839263620,9
14,52 6,0738147715,7
15,2305,8126684827,9
15,9905,5382970023,0
17,2155,14680140346,1
17,9584,9354576425,1
18,6404,7563332810,8
19,0114,6644077225,4
19,5064,5471989129,3
20,1244,4087464321,1
20,5684,3145385027,9
21,5724,1159946615,3
22,0254,0323547215,5
22,9833,8665049216,2
23,9333,7149960720,0
23,3473,6527842213,9
25,3213,5144632810,8
25,5203,4875231910,5
26,1053,4106332710,7
29,8853,3134844714,7
27,6123,227832668,7
28,5603,122832688,8
28,7563,1019730910,2
29,4283,032662678,8
30,3032,947022779,1
30,5932,919832809,2
31,4132,845372618,6

3. The method of obtaining amorphous perindopril of formula I

includes the following stages:
(i) a secondary amino group stereospecific amino acid N-[(S)-carbethoxy-1-butyl]-(S)-alanine of the formula II:

protect trimethylsilyl groups with obtaining the compounds of formula III:

(ii) then, the compound (III) activated by reaction with an activating reagent selected from the group comprising thionyl chloride and thionyl chloride complex with 1-N-benzotriazole, to obtain the acid chloride of formula IV:

(iii) the acid chloride of the formula IV is administered in the reaction of (2S,3aS,7aS)-octahedron-2-carboxylic acid having a protected carboxypropyl formula V:

in which R denotes trimate the silyl group, and get protected derivative of perindopril of formula VI:

(iv) then the derivative of formula VI is converted into a perindopril of formula I by removal trimethylsilyl groups at the stage of removal of impurities by extraction with an aqueous solution,
(v) the organic phase containing perindopril, dried by evaporation of the solvent in vacuum, (vi) crude perindopril dissolved in methylene chloride and filtered by passing the resulting solution through a layer of silica gel, (vii) a fraction containing perindopril, evaporated in high vacuum.

4. The method of obtaining amorphous perindopril of formula I

includes the following stages:
(i) a secondary amino group stereospecific amino acid N-[(S)-carbethoxy-1-butyl]-(S)-alanine of the formula II:

protect trimethylsilyl groups with obtaining the compounds of formula III:

(ii) then, the compound (III) activated by reaction with an activating reagent selected from the group comprising thionyl chloride and thionyl chloride complex with 1-N-benzotriazole, to obtain the acid chloride of formula IV:

(iii) the acid chloride of the formula IV is administered in the reaction of (2S, 3aS, 7aS)-octahedron-2-carboxylic acid, having the Conn is strong carboxypropyl formula V:

in which R denotes a benzyl group, and get protected derivative of perindopril of formula VI:

(iv) from the resulting reaction mixture to remove impurities by extraction of the aqueous solution,
(v) the organic phase is filtered by passing through a layer of aluminum oxide, (vi) the fraction containing the derivative of formula VI, is evaporated in vacuum, (vii) then the derivative of formula VI is converted into a perindopril of formula I by removal of all protective groups by catalytic hydrogenation, (viii) the catalyst is filtered off and (ix) the solvent evaporated in vacuum.

5. The way to get a new crystalline form of perindopril according to claim 1 or 2, comprising the stage of dissolution of amorphous perindopril in simple diethyl ether and crystallization of a new crystalline form of perindopril from the resulting solution.

6. The pharmaceutical composition intended for the treatment of cardiovascular diseases, containing a therapeutically effective amount of a new crystalline form of perindopril according to claim 1 or 2 in combination with one or more pharmaceutically acceptable carriers or inert fillers.

7. The pharmaceutical composition according to claim 6, in which the pharmaceutical composition comprises one or more complement the selected pharmaceutically active components, moreover, the additional pharmaceutically active component is a diuretic.

8. The pharmaceutical composition according to claim 7, in which the diuretic is indapamide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to an agent which has antiviral activity towards influenza A virus, which is a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylindoles of general formula (I) , where X denotes - H; n=1, 2; R3 denotes C1-C5alkyl; Alk denotes C1-C6alkyl; R1 and R2 are independently selected from C1-C4-alkyl, mainly CH3, or its pharmaceutically acceptable salts.

EFFECT: obtaining an agent which has antiviral activity towards influenza A virus.

2 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline form of B (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone hydrochloride, as well as to synthesis method thereof by passing HCl gas through a solution of (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone, separating the formed residue from the reaction mixture and drying.

EFFECT: end product can be used in medicine as a medicinal agent which has antagonistic effect on 5-HT2A receptor.

4 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new 3-amino-1-arylpropylindoles of formula I: or to its pharmaceutically acceptable salts, where: p is equal to 1 or 2; Ar means: indolyl, 2,3-dihydroindolyl, indazolyl, benzimidazolyl, benzofuranyl, and each can be substituted; R1 means: phenyl, naphthyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isoxazolyl, pyrazolyl, quinolinyl, aryl-C1-6alkyl where each can be substituted; C3-6cycloalkyl; branched C1-6alkyl; R2 and R3 each independently stands for: H, C1-6alkyl; OH-C1-6alkyl; benzyl; or R2 and R3 together with nitrogen atom whereto attached can form optionally substituted tetra-heptamerous ring, optionally with additional heteroatom chosen from N, O; Ra means H, C1-6alkyl; Rb means H, C1-6alkyl; OH; Rc and Rd each independently means H, C1-6alkyl; Or one of R2 and R3 together with one of Ra and Rb and atoms whereto attached can form penta- or hexamerous ring, optionally with additional heteroatom chosen from O, N; or one of R2 and R3 together with one of Rc and Rd together with atoms whereto attached, can form tetra-hexamerous ring, optinally with additional heteroatom chosen from O, N; Rc means H, C1-6alkyl; provided when p =1, Ra, Rb, Rc and Rd mean H, Ar means indole-1-yl and R1 means C6H5, then R2 and R3 do not mean CH3 and do not form hexamerous ring, and when Ar means indole-3-yl, p =1, Ra, Rb, Rc and Rd means H and R1 means C6H5-, 3-OCH3C6H5- then R2 and R3 do not mean simultaneously H, and when p =1, Ra, Rb, Rc and Rd mean H, Ar means indolyl and R1 means thienyl, pyridinyl, quinolinyl, then one of R2 and R3 means H, and another means C1-6alkyl where possible substitutes are presented in cl.1 of.

EFFECT: compounds express activity of double inhibition serotonin reuptake, possibility to use thereof in making a pharmaceutical composition and a medical product.

32 cl, 7 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of obtaining silodosin of formula: (3). Method involves mixing a new compound 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indol-1-yl}propylbenzoate with oxalic acid to obtain a corresponding oxalate with subsequent hydrolysis thereof, resulting in formation of a new compound 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino]propyl]-2,3-dihydro-1H-indole-7-carbonitrile and hydrolysis thereof to obtain the target compound. Methods of obtaining new intermediate compounds are described.

EFFECT: improved method of producing indoline.

12 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing compounds of formula (I) , with ACE inhibitory activity, and to pharmaceutically acceptable salts thereof, in which the carboxyl group of an amino acid of formula (II) is activated with a uronium salt of formula (III) in the presence of an aprotonic solvent, and the activated amino acid is reacted with a corresponding amine from the HR3 family. Substitutes R1-R3, R6-R9, B are given in the formula of invention.

EFFECT: end product with high output and high purity.

17 cl, 1 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new indole-alanine derivatives of formula I: , where: R1 is phenyl, naphthyl, where phenyl is substituted with one or two halogen atoms, C1-6 alkyls, C1-6 alkoxy or phenyl C1-6 alkyls; and R2 is H, C1-6 alkyl; in free form, in hydrate form or in form of a pharmaceutically acceptable salt. Formula I compounds exhibit selective agonist activity towards S1P4 receptor, at least ten times more selective towards one or more of S1P1, S1P2, S1P3 or S1P5 receptors.

EFFECT: possibility of using derivatives in a pharmaceutical composition.

7 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the selective method for preparation of "АХЭ" inhibitor - perindopril with usage as initial reagent of the sterospecific amino acid N-/1-(S)-ethoxycarbonylbutyl/-(S)-alanine which is activated by tetramethyl-uronium salts in the presence of tertiary organic base and following interreaction with (2S,3aS,7aS)-octahydroindolo-2-carbonic acid or its ester. After completing of the reaction the protective group is removed by the hydrogenation, interphase hydrogenation or extraction.

EFFECT: obtaining of perindopril with usage of tetramethyl-uronium salts as reagents of coupling reaction.

5 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel malononitryl derivatives of formula (I), which can be applied to fight pest insects. In formula (I) R1 represents hydrogen atom; R2 represents hydrogen atom; R represents hydrogen atom; R4 represents C1-C5-alkyl group substituted with at least one halogen atom, C2-C5-alkenyl group; R5 represents hydrogen atom, halogen atom, C1-C5-alkyl group; at least one of X1, X2 and X3 values represents CR6, the other represent nitrogen atoms; R represents hydrogen atom, halogen atom, cyanogroup, nitrogroup, formyl group, C1-C5-alkyl group optionally substituted with at least one halogen atom, C1-C5-alkyltiogroup, substituted with at least one halogen atom, C2-C6-alkylcarbonyl group substituted with at east one halogen atom, C2-C5-alkoxycarbonyl group or group (CH2)mQ, where m = 0, and Q stands for phenyl; and in case when one of R5 and R6 is bonded with two atoms in adjacent positions or two R6 are bonded with two atoms in adjacent positions, they can be bonded to each other in end positions with formation of C2-C6-alkandiyl group, or C4-C6-alkenediyl group. Invention also relates to composition and method used to fight pest-insects.

EFFECT: obtaining novel malononitryl derivatives of formula (I), which can be applied to fight pest-insects.

11 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula (I) , where R1 and R2 are independently chosen from hydrogen, halogen, nitro, alkyl, alkylaryl and XYR5; X and Y are independently chosen from O and (CR6R7)n; R3 represents hydrogen, alkyl or M; M represents an ion, chosen from aluminium, calcium, lithium, magnesium, potassium, sodium, zinc or their mixture; Z represents CR4; R4 is chosen from hydrogen, halogen, alkyl, alkylaryl and XYR5; R5 is chosen from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently chosen from hydrogen and alkyl; n is an integer from 1 to 6; at least one of R1 and R2 represents XYR5, and at least one of X and Y represents (CR6R7)n. The invention also pertains to the method of increasing concentration of D-serine and/or reducing concentration of toxic products of D-serine oxidation under the effect of DAAO in mammals, involving introduction into a subject of a therapeutically effective amount of a formula I compound, to the method of treating schizophrenia, treating or preventing loss of memory and/or cognitive ability, to the method of improving learning ability, method of treating neuropathic pain, as well as to a pharmaceutical composition, with DAAO inhibitory activity, based on these compounds.

EFFECT: obtained are new compounds and a pharmaceutical composition based on these compounds.

27 cl, 4 tbl, 72 ex

FIELD: medicine.

SUBSTANCE: therapeutic course involves examination that implies photography of eye-ground vessels and measurement of diametre of retinal vessels on an empty stomach of the patient prior to and after administration of a medicine. Observed increase in diametre of supero-temporal branch of central retinal artery at a distance of one vertical diametre of disk of optic nerve from an edge of disk of optic nerve by 10% and more from the initial one ensures to diagnose efficiency of the administered medicine. The absence of increase in diametre of supero-temporal branch of central retinal artery by 10% and more in administration of the same dosage of the medicine enables to diagnose development of tolerance.

EFFECT: method extends range of means to determine antihypertensive drug tolerance.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

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

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

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns normalisation of thromboplastin formation in patients suffering from arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated static and dynamic physical exercises, and also introduction of pioglitazone in a dose 30 mg once in the morning and a lisinopril in a dose 10 mg once a day in the morning during 1.5 months.

EFFECT: complex of specific medical agents and physical activity combined with empirically specified duration of treatment provides normalisation of thromboplastin formation that in turn reduces risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and cardiology, and concerns correction of blood microvesicle level in arterial hypertension. That is ensured by introduction of lisinopril in a dose 10 mg once in the morning and amlodipine in a dose 5 mg once in the morning within at least 5 weeks. Introduction of specific preparations throughout empirically specified time of treatment ensures complete normalisation of blood microvesicle level.

EFFECT: invention allows reducing risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns correction of blood microvesicle level in arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated physical exercises, and introduction of Fosinopril in a dose 10 mg once in the morning and pioglitazone in a dose 30 mg once in the morning. Therapeutic course is at least 7 weeks.

EFFECT: complex of drug-free modalities and specific pharmacological preparations combined with empirically specified time of treatment provides maintained optimum microvesicle level that in turn allows considerably reducing risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely haematology, cardiology and endocrinology and concerns correction of blood microvesicle level in arterial hypertension (AH) and pancreatic diabetes type II (PD II). That is ensured by integrated therapy involving graduated physical exercises, as well as introduction of lisinopril in a dose 10 mg once in the morning, amlodipine in a dose 5 mg once in the morning and pioglitazone in a dose 30 mg once in the morning for therapeutic course at least 7 weeks.

EFFECT: complex of specific medical preparations and physical exercises combined with empirically specified duration of treatment provides effective correction of blood microvesicle level and, thereby, reduced risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely haematology and endocrinology, and concerns normalisation of thrombocyte sensitivity to aggregation inducers in patients suffering from arterial hypertension with impaired glucose tolerance. That is ensured by integrated therapy including graduated physical exercises, and introduction of lisinopril in a dose 10 mg once a day in the morning and pioglitazone in a dose 30 mg once a day in the morning. Therapeutic course lasts for at least 6 weeks. The method enables complete normalisation of thrombocyte sensitivity to aggregation inducers owing to potentiation of therapeutic effect of certain components of integrated therapy.

EFFECT: that in turn allows reducing risk of thrombotic complications in given group of patients.

1 ex, 3 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

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