Solid benzazepin compound salts and their use in preparation of pharmaceutical compounds

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to compounds of general formula: , wherein R1 represents phenyl-С16-alkyl group or 1-naphthyl-С16-alkyl group; R2 biologically labile ether forming group in the form of pharmaceutically acceptable metal salt, which is selected from lithium, calcium, magnesium, and zinc slats; and also to a method for preparing above-defined compounds and to pharmaceutical composition containing salts according to this invention. These compounds are used in treatment cardiac diseases or hypertension, in improvement of gastrointestinal blood circulation, and in treatment and prevention of cardiac disturbances induced by adriamicyn and analogous antitumor agents.

EFFECT: increased assortment of pharmaceutically active compounds of benzazepin series.

15 cl, 2 tbl, 5 ex

 

This invention relates to new salts of the compounds of the formula

and their use in obtaining pharmaceutical compounds.

Benzazepine the above formula is known from EP 0733642, EP 0830863, WO 00/48601 and WO 01/03699. EP 0733642 relates to compounds of formula (I) and their physiologically acceptable salts, as such, and their use in heart failure. EP 0830863 WO 00/48601 and WO 01/03699 refer to the use of the above compounds to improve gastrointestinal blood flow in hypertension, in the treatment and prevention of heart disease induced by adriamycin and similar drugs, respectively.

Preferred benzazepine are compounds where R1represents phenylethylene group or 1-naphthylethylene group, R2and R3both represent hydrogen, and where R4represents biolabeling ester group. Suitable groups forming biolabels esters include (C1-C6)-alkyl groups, phenyl or phenyl- (C1-C6)-alkyl groups, which are optionally substituted in the phenyl ring (C1-C6)-alkyl or (C2-C6)-alkalinous circuit associated with two adjacent carbon atoms, dioxyalkylene groups that are not necessarily the Deputy is received in the dioxolane ring (C 1-C6)-alkyl or (C2-C6)-alkanolammonium groups, oxymethylene group which is optionally substituted C1-C6)-alkyl. When the group R4is a (C1-C6)-alkyl, it is preferably non-branched (C1-C4)-alkyl group. In the most preferred compounds, R4represents ethyl.

In the course of further pharmaceutical and clinical research found that the most preferred compounds, which are solid pins, have, therefore, a serious disadvantage.

To ensure a reproducible constant bioavailability of the active ingredient from a solid pharmaceutical dosage forms, it is important to use a homogeneous and reproducible modification of an active connection. Therefore, there are always some doubts about the reproducibility and constancy of the bioavailability of compounds from materials in the normal state are not homogeneous, such as a solid foam.

It is also clear that in an industrial scale is very hard to distinguish solid foam. In addition, the compound sparingly soluble in water and, therefore, very difficult to obtain the composition of the compounds that can be used for intravenous (IV) injection. Prior to this invention within ewenny composition could be obtained only from the respective decollate (see example II in EP 0733642). This means that for intravenous composition should be used in a different connection than for oral composition, undesirable for pharmaceutical compounds. Subsequent investigation found that the sodium and potassium salt of mono-acid is much more soluble in water, but these salts can be selected only in the form of a solid foam.

The objective of this invention is the provision of salt compounds of General formula (I), which must meet the following requirements:

A) simple, in industrial scale, the method of separating pure solid compounds by crystallization or precipitation;

B) a sufficiently high solubility in physiological fluids to obtain intravenous;

C) properties of solids, which provide a pharmaceutical composition with standard excipients and standard equipment;

D) preferably obtain without significant loss of chiral and chemical purity.

This task can be accomplished by obtaining metal salts of compounds of General formula (I), as mentioned above, where the metal ion is lithium ion or ion of the divalent metal. Preferred salts of divalent metals are salts of calcium, magnesium and zinc. Most preferred is calcium salt. Noida is but detected, what these salts, in contrast to the salts of sodium and potassium, mentioned in EP 0733642, have very desirable properties, as they may be isolated in solid (amorphous) form and dissolve in isotonic fluid with a pH of 7.4 in the amount of at least 10 times the amount of the corresponding acid. In addition, salts of divalent metals can be obtained without racemization.

The following aspect of the present invention proposes a method of obtaining metal salts, preferably Li+or salts of divalent Ca2+, Mg2+or Zn2+.

Unexpectedly, it was found that lithium salts and salts of divalent metals, the compounds of formula I are very readily soluble at room temperature in a polar aprotic solvent, such as cyclohexane, toluene, methyl tert-butyl ether and ethyl acetate.

Salts of this invention can be easily obtained by mixing a hydroxide or a suitable salt of the desired metal with a solution or suspension of the compounds of formula I in one of the above polar aprotic solvents. Alternatively, when the hydroxide or salt of the desired metal is insufficiently soluble to begin the interaction, can be added a small amount of water to the solution or suspension in an organic solvent and water can be removed AZ is Otradnoe distillation. In this case, should be selected nonpolar aprotic solvent which forms an azeotropic mixture with water. For metals, which are practically insoluble hydroxide, may be added to the metal in the form of atrata (for example, Mg(OEt)2) or in the form of a mixed hydroxide/carbonate (3Zn(OH)2·2ZnC3). The preferred solvent for the above-mentioned method is methyl tert-methyl ether or ethyl acetate. If the salt is obtained in solution, it can be allocated to the initial removal of water that can be carried out using azeotropic distillation, followed by mixing with the precipitator. The precipitator is a second liquid, which is added to the solution to reduce the solubility of the dissolved compounds, causing the precipitation/crystallization and maximize product yield. For the two fluids (the original solvent and added precipitator) complete Miscibility with one another in any ratio. This approach is also used to decrease the solubility of inorganic salts in aqueous solution by adding a miscible with water, an organic solvent (ALFASSI, Z. B. et al., 'alche J. 1984,30, 874-6; MYDLARZ, J. et al., J. Chem. Eng. Data 1989,34, 124-6; MULLIN, J. W. et al., Chem. Eng. Process. 1989,26, 93-9). Examples of the precipitator in the framework of this invention are linear hydrocarbons. Preferred is entrusted by the precipitators are linear C 4-C10the hydrocarbons. The preferred precipitant is n-hexane.

Since in almost all cases, the salt is isolated in the form of non-crystalline residue, which is homogeneous, it is sometimes desirable to carry out this stage of crystallization to increase the purity of the active compounds, which must meet stringent requirements. Unexpectedly, it was found that Sol S-α-methylbenzylamine the compounds of formula I is most suitable for the purification of these compounds, as specified salt is crystalline and can be easily recrystallized with a high yield of organic solvents, preferably alcohols, such as ethanol or isopropyl alcohol. Thus, this invention also relates to the salts of S-α-methylbenzylamine compounds of formula I. These salts are suitable as intermediates in the purification stages, since the S-α-methylbenzylamine proved too toxic for use.

These salts S-α-methylbenzylamine the compounds of formula I can be obtained by adding S-α-methylbenzylamine to a solution of the compounds of formula I in ethanol or isopropanol or other suitable alcohol. Salt crystallizes from this solution in the maturation and cooling (depending on concentration).

Pharmaceutically PR is acceptable salts of this invention can be obtained according to the methods of acquiring, known in the prior art. Can be used in conventional dosage forms, such as tablets, capsules or suppositories. Data pharmaceutical dosage forms can be obtained by known methods, such as direct compression, granulation, extrusion, molding using conventional solid excipients, such as fillers, such as cellulose, lactose and starch, binders, such as cellulose and polyvinylpyrrolidone (pvp), disintegrant, for example starches and cross-linked polyvinylpyrrolidone (pvp), slip agents (glidant), for example colloidal silicon dioxide, lubricants such as magnesium stearate or normal liquid and semi-solid excipients, such as polyethylene glycols, derivatives of castor oil, triglycerides and waxes. In addition, can be added preservatives, such as parabens, and emulsifiers, such as Polysorbate.

Pharmaceutically acceptable salts of this invention are suitable as drugs for large mammals, especially for humans, for the treatment of heart failure and for promotion of diuresis/natriyureza, especially for patients suffering from heart failure, to improve gastrointestinal blood flow in the treatment of hypertension and in the treatment and Professor the prevention of heart disease, caused by adriamycin and similar drugs. With this purpose, the compounds of this invention can be used in medical forms, which can be introduced parenterally, especially intravenously, orally or by suppository. Used doses may vary individually and depending on the nature of the condition to be treated, the specific applicable substance and method of administration. Medical form with the content of the active ingredient from 1 to 800 mg per dose mainly suitable for the introduction of large mammals, especially humans.

The following examples are given with the intent to further illustrate the invention in more detail and, therefore, these examples in any case do not imply limitation of the scope of the invention.

EXAMPLES.

Example 1.

The main method of obtaining metal salts of compounds of formula I.

Approximately 15 mmol of active substance in the acidic form is dissolved or suspended in 40 ml of weakly polar aprotic solvent. Add a solution of about 1.2 equivalent of reactant metal in the water or in the same solvent as an active ingredient. In some cases it is necessary to add water in order to begin the interaction. Water is removed by azeotropic distillation. When the reagent of the metal represents the t of a hydroxide or ethylate, the solvent is removed completely, followed by re-dissolution in 40-160 ml initial weakly polar aprotic solvent, followed by filtration to remove unreacted reagent metal, and optionally other salts formed. The filtered solution was added to hexane and, when a solid product is collected on the filter. During the formation of tar or oil a large part of the solvent is decanted and the remaining solvent is evaporated to obtain a solid foam.

td align="center"> I
Table I
Getting two different salts of the active substances
Connection*The metal saltThe reagent metal MSolventThe number M (g) (mmol)The quantity of solvent (ml)Quantity of hexane (ml)Output %Result
ICA2+Ca(OH)2MTBE0,67 (9,0)408095Solid powder
IMg2+Mg(OEt)2MTBE1,25 (10,9)40130103Solid powder
Zn2+3Zn(OH)2.2Zn(CO3)2MTBE1,05 (10,9)11523595Solid powder
ILi+LiOHMTBE0,4 (16,7)16013085Solid powder
IK+KOHMTBE1,02 (18,3)9523598Solid foam
INa+NaOHMTBE1,02 (17,8)9523589Solid foam
IICa2+Ca(OH)2EtOAc0,56 (7,6)7523587Solid powder
*The connection I = 1H-1-benzazepin-1-acetic acid, 3-[[[1-[(2R)-2-(etoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)-.

*Connection II = 1H-1-benzazepin-1-acetic acid, 3-[[[1-[2-(etoxycarbonyl)-4-(1-naphthalenyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-oxo-,[S-(R*,S*)]-.

Properties of the resulting salts are presented in table 2. The content of the compound was determined to be the HPLC method using a MACHEREY-NAGEL Nucleosil 100-5 C 18-HD column using a gradient starting with 5% and ending at 100%, with a phosphoric acid buffer with a pH of 5.1 as eluent a and eluent B, which represents acetonitrile, mixed with 10% eluent A). The metal content was determined using complexometric titration with a solution of Ethylenediamine-Tetra-acetic acid for calcium and atomic emission spectroscopy (AES) for all other metals.

Table 2
The properties of the salts obtained in accordance with table 1
Connection*The metal saltThe content of the compound (Rel. %)The metal content (%wt./wt.)Theoretical metal content (%wt./wt.)Solubility in polar aprotic organic solventsSolubility in water
ICA2+99,8the 3.83,6instantinstant
IMg2+99,62,42,2instantinstant
IZn2+99,97,05,8soluble instant
ILi+88,01,61,3instantsoluble
IK+78,47,56,8not solublesoluble
INa+84,74,34,1not solublesoluble
IICa2+The concentration is3,43,3instantinstant
*The connection I = 1H-1-benzazepin-1-acetic acid, 3-[[[1-[(2R)-2-(etoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)-.

*Connection II = 1H-1-benzazepin-1-acetic acid, 3-[[[1-[2-(etoxycarbonyl)-4-(1-naphthalenyl)bull]cyclopentyl]carbonyl]amino]-(2,3,4,5-tetrahydro-oxo-, [S-(R*,S*)]-.

The concentration is not defined.

Based on data from table 2 it becomes clear that salts of Li, Ca, Mg and Zn, which emit in the form of a solid powder soluble in polar aprotic solvents. Examples of these solvents include ethyl acetate, toluene, cyclohexane and methyl tert-butyl ether. These compounds are also soluble in polar aprotic races is varicela, such as THF, acetone, acetonitrile, DMF and DMSO. Set the content of the metal in the salt is slightly higher than theoretical content, but this is normal for these types of methods and analyses. During the formation of salt with a strongly basic by monovalent hydroxide degradation of the active substance, leading to low content of compounds in the final salt.

Example 2.

Getting salt S-α-methylbenzylamine 1H-1-benzazepin-1-acetic acid, 3-[[[1-[(2R)-2-(etoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)-.

18 g of 1H-1-benzazepin-1-acetic acid, 3-[[[1-[(2R)-2-(etoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)- dissolved in 90 ml of absolute ethanol. 4.1 g S-α-methylbenzylamine added at 20-25°C. Spontaneously formed crystalline suspension is heated to 40°C and stirred for one hour. After cooling to 0-5°and With additional stirring for 4 hours the crystals are collected by filtration, washed with 40 ml of chilled absolute ethanol and dried at 45°in a vacuum furnace. 19 g of salt S-α-methylbenzylamine 1H-1-benzazepin-1-acetic acid, 3-[[[1-[(2R)-2-(etoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)- receive as of the first portion.

Example 3.

Getting calcium is howling salt 1H-1-benzazepin-1-acetic acid, 3-[[[1-[(2R)-2-(etoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)-.

To a solution of 30 g of salt S-α-methylbenzylamine 1H-1-benzazepin-1-acetic acid, 3-[[[1-[(2R)-2-(etoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-, (3S)- in 120 ml of methyl tert-butyl ether (MTBE) was added 100 ml of 1M aqueous solution of hydrochloric acid, and the resulting mixture is stirred for 10 minutes. The layers are separated and the organic layer is washed at least three times with 15 ml of water up until the pH reaches values above 5. Add 95% Ca(OH)2in the amount of 2 g, and the mixture is heated to 55°With a reflux condenser. After 30 minutes the amount of suspension is slightly reduced, add 0,5 ml of water. The mixture is refluxed for 2 hours and water separator (trap Dean-stark). After 2 hours, the distillate is completely clean, and the reaction mixture was slightly cloudy. The mixture is cooled to 30-35°add within 30 minutes by running a filter to 240 ml of hexane. The solid product is separated by filtration and washed with 50 ml of hexane. After drying gain of 25.6 g not quite white free flowing powder.

1H-NMR: δ = 7,29 (1H, DD, J=2.2 and 8,1), 7,28 (1H, DDD, J=2,0, 6,6, 8,1), 7,25 (1H, DD, J=2.0 and 7,6), 7,19 (1H, DDD, J=2,2, 6,6, 7,6), 7,19 (2H, dddd, J=0,6, 1,7, 7,5, 7,8), 7,13 (1H, DD, J=1,3 and 5), 7,10 (2H, DDD, J=1,3, 2,1, 7,8), 4,39 (1H, d, J=16,9), 4,28 (1H, DD, J=8.1 and 11,7), 4,28 (1H, d, J=16,9), 4,07 (1H, DD, J=7.2 and 10,8), to 4.01 (1H, DD, J=7.1 and 10,8), to 3.33 (1H, DDD, J=8,0, 13,2, 13,7), 2,57 (1H, DDD, J=1,2, 7,1, 13,7), 2,52 (1H, DD, J=5.9 and 9,6), 2,49 (1H, DD, J=6,7 and 9.4), 2,31 (1H, dddd, J=3,3, 5,1, 9,2, 9,3), 2,29 (1H, dddd, J=7,1, 8,1, 13,1, 13,2), 2,03 (1H, dddd, J=1,2, 8,0, 11,7, 13,1), 2,0 (1H, DD, J=9.3 and 14,2), is 1.82 (1H, DD, J=3.3 and 14,2), is 1.82 (1H, DDD, J=5,9, 9,4, 13,6), 1,70 (1H, DDD, J=6,7, 9,6, 13,6), 2,02-1,42 (8H, m)to 1.21 (3H, DD, J=7,1 and 7,2).

Example 4.

Getting salt S-α-methylbenzylamine connection II = 1H-1-benzazepin-1-acetic acid, 3-[[[1-[2-(etoxycarbonyl)-4-(1-naphthalenyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-oxo-, [S-(R*,S*)]-.

21 g of compound (II) = 1H-1-benzazepin-1-acetic acid, 3-[[[1-[2-(etoxycarbonyl)-4-(1-naphthalenyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-oxo-, [S-(R*,S*)]is dissolved in 190 ml of MTBE. Add 45 ml of ethanol and 4.5 g S-α-methylbenzylamine. After storage for 4 days at 4°and stirring once a day the crystals are collected by filtration, washed with 80 ml of MTBE and dried at 45°in a vacuum furnace. 19 g of salt S-α-methylbenzylamine connection II = 1H-1-benzazepin-1-acetic acid, 3-[[[1-[2-(etoxycarbonyl)-4-(1-naphthalenyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-oxo-, [S-(R*,S*)]- get the first serving.

Example 5.

Getting the calcium salt of 1H-1-benzazepin-1-acetic acid, 3-[[[1-[2-(etoxycarbonyl)-4-(1-naphthalenyl)butyl]cyclopentyl]carbonyl]amino]2,3,4,5-tetrahydro-oxo-, [S-(R*,S*)]-.

To a heterogeneous mixture of 10 g of salt S-α-methylbenzylamine 1H-1-benzazepin-1-acetic acid, 3-[[[1-[2-(etoxycarbonyl)-4-(1-naphthalenyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-oxo-, [S-(R*,S*)]in 80 ml of methyl tert-butyl ether (MTBE) and 60 ml of water, added dropwise within 15 minutes with stirring to 4.4 ml 36% aqueous solution of hydrochloric acid, and the mixture was stirred for 1.5 hours at room temperature. The layers are separated and the organic layer washed twice with 50 ml water. The organic layer is concentrated to obtain oil, add 15 ml of ethyl acetate, and the resulting solution was again concentrated to obtain oil. Oil is again dissolved in 80 ml of ethyl acetate and add 2 ml of water. Add 95% Ca(OH)2in the amount of 0.56 g, and the mixture is refluxed for 4 hours with a water separator (the office of the Dean-stark). The solution is filtered and reduce its volume to 40 ml of the Solution is cooled to 30-35°add 30 minutes to 250 ml of cold hexane (10° (C) and stirred for an additional 30 minutes at 10°C. the Solid product is separated by filtration and washed twice with 10 ml of hexane. After drying in vacuum (18 hours, 50°C, 120 mbar) gain of 7.4 g of a free flowing powder.

1H-NMR: δ = to 7.99 (1H, broad doublet, J=8), 7,88 (1H, DD, J=1.5 and 8), 7,73 (1H, broad doublet, J=8), 7,56-7,44 (2H, m), 7,37 (1H, t, J=8), ˜of 7.36 (NH, d, J=8), 7,31 (1H, DD, J=1.5 and 8), 7,29 (1H, d, J=8), from 7.24 (1H, triple doublet, J=1,5, 8, 8), 7,21 (1H, DD, J=1.5 and 8), 7,13 (1H, triple doublet, J=1,5, 8, 8), 4,48 (1H, d, J=16), to 4.23 (1H, double triplet, J=8, 8, 12), 4,14-3,99 (3H, m), of 3.56 (1H, triple doublet, J=8, 13, 13), 3,02-2,96 (2H, m), 2,5-of 2.34(2H, m), 2,2-of 1.74 (8H, m), 1,6-of 1.24 (6H, m)of 1.20 (3H, t, J=6).

1. The compound of General formula

where R1is phenyl-(C1-C6)-alkyl group or 1-naphthyl-(C1-C6)-alkyl group;

R2represents biolabeling atheromatous group

in the form of a pharmaceutically acceptable metal salt, wherein the salt is selected from the group consisting of lithium salts, calcium salts, magnesium salts and zinc.

2. Salt compounds of General formula (I) as defined in claim 1, where R2has the same meaning as in claim 1, where R1is phenylethylene or 1-naphthylethylene group.

3. Salt compounds of General formula (I) as defined in claims 1 and 2, where R2is an ethyl group.

4. Calcium salt compound as defined in claims 1 to 3.

5. The method of obtaining salt according to claims 1 to 4, characterized in that the solution or suspension of the hydroxide of the specified metal is mixed with a solution or suspension of the compounds of formula (I) in weakly polar aprotic solvent to obtain a homogeneous solution of salt in the specified weakly polar and the roton solvent.

6. The method according to claim 5, where the specified weakly polar aprotic solvent is a methyl tert-butyl ether or ethyl acetate.

7. The method according to claim 5 or 6, where the salt is isolated in solid form by (i) optional azeotropic removal of water, followed (ii) by crystallization or precipitation of the salt by mixing the solution in a weakly polar aprotic solvent precipitator.

8. The method according to claim 7, where the specified precipitator is linear (C4-C10)-hydrocarbon.

9. The method of claim 8, where the specified precipitator is n-hexane.

10. The pharmaceutical composition active for the treatment of heart disease, to improve gastrointestinal blood circulation, for the treatment of hypertension and for the treatment and prevention of heart disease induced by adriamycin and similar antitumor drugs, containing at least one salt as defined in claims 1 to 4 as an active ingredient.

11. The method of obtaining the composition of claim 10, wherein the salt as defined in claims 1 to 4 are mixed with at least one excipient and the resulting mixture is transferred to a suitable introduction to the form.

12. The use of salt as defined in claims 1 to 4 to obtain a composition for the treatment of heart disease.

13. The use of salt as defined in claims 1 to 4 to obtain a composition for improving gastro-kiseon the th circulation.

14. The use of salt as defined in claims 1 to 4 to obtain a composition for the treatment of hypertension.

15. The use of salt as defined in claims 1 to 4 to obtain a composition for the treatment and prevention of heart disease induced by adriamycin and similar antitumor drugs.

Priority items:

16.01.2002 according to claims 1-15.



 

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Peptide compounds // 2281955

FIELD: chemistry of peptides, medicine, pharmacy.

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< / BR>
or

< / BR>
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

< / BR>
R1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2WITH6H3(OCH3)2]-; -N(CH2WITH6H5)-; -N(CH2WITH6H5)C(O)N(CH2WITH6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower thiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives

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1 tbl, 2 dwg

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EFFECT: expanded synthetic possibilities in furan series and increased choice of biologically active compounds.

16 cl, 85 tbl, 481 ex

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22 cl, 4 dwg, 2 tbl, 217 ex

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14 cl, 4 tbl, 19 ex

FIELD: medicine, experimental medicine.

SUBSTANCE: starting since the 7th to the 28th d after modeling a patient's limb's ischemia it is necessary to inject L-arginine intraperitoneally at the dosage ranged 30-200 mg/kg body weight. The innovation provides optimal dosages and the mode for injecting L-arginine as NO donator.

EFFECT: higher efficiency.

1 tbl

FIELD: medicine, surgery.

SUBSTANCE: it is necessary to obtain surgical access to femoral arteries and aorta to squeeze the latter with its branches to remove the main arteries and collaterals out of circulation. Then the interference on aorta and femoral arteries should be fulfilled followed by reconstruction of circulation along aorta and femoral arteries. Moreover, 12 h before the onset of surgical interference a patient should be intravenously injected with perfluorane at the dosage of 5 ml/kg body weight, moreover, a patient should inhale oxygen-enriched air mixture (for 40-50%) during 12 h. In the course of surgical interference it is necessary to additionally introduce oxygenated perfluorane intra-aortally - 70 ml and into common femoral arteries from both sides - per 50 ml. After operation patients should inhale the above-mentioned oxygen-enriched air mixture during 12 h. The innovation provides prophylaxis of post-ischemic syndrome in case of prolonged surgical interferences upon squeezed arteries.

EFFECT: higher efficiency of protection.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes acylated 6,7,8,9-tetrahydro-5H-benzocycloheptenylamines of the general formula (I): wherein R1 and R4 mean independently hydrogen atom (H), (C1-C10)-alkyl monosubstituted with fluorine atom (F); R2 and R3 mean independently H and (C1-C10)-alkyl; A means -CH, -CHOH; each among B, C and D means -CH2; R5 means possibly substituted phenyl or group Hetar. Also, invention describes method for synthesis of indicated compounds and a pharmaceutical preparation designated for stimulation of expression of endothelial NO-synthase. Nitrogen oxide (NO) released by endothelial tissue displays important significance in function of some main mechanisms of cardiovascular system. Nitrogen oxide exerts the vasodilating effect and inhibits platelets aggregation, adhesion of leukocytes to endothelial tissue and proliferation of smooth muscle cells in internal envelope of blood vessels.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparations.

16 cl, 1 tbl, 152 ex

FIELD: medicine, experimental cardiopharmacology.

SUBSTANCE: method involves modeling the endothelial dysfunction by every day intraperitoneal administration of L-nitroarginine methyl ester in rats (Wistar strain) in the dose 25 mg/kg for 7 days. On background of dysfunction modeling its correction is carried out by simultaneous intragastric administration of enalapril in the dose 0.5 mg/kg and by intraperitoneal administration of resveratrol in a single dose 2 mg/kg per 24 h. Degree of dysfunction development and activation of its correction are evaluated by the ratio endothelium-independent and endothelium-dependent vasodilation. Method provides possibility for study of endothelium-protective effects of resveratrol and activation of endothelial NO-synthase at stage of modeling endothelial dysfunction and their evaluation by the above given ratio endothelium-independent and endothelium-dependent vasodilation. Invention can be used in correction of endothelial dysfunction.

EFFECT: improved method of correction.

2 tbl, 1 ex

FIELD: medicine, medicine of catastrophes, toxicology, resuscitation.

SUBSTANCE: it is necessary to puncture any available artery, then centripetally under the pressure in flow mode one should introduce oxygenated blood substitute of gas-transport function - perfluorane at the dosage of about 10-30 ml/kg. Immediately after introducing perfluorane it is important to inject adrenaline intra-arterially. Then it is necessary to fulfill indirect cardiac massage, defibrillation, artificial pulmonary ventilation at oxygen supply and intravenous injection of infusion solutions. The innovation enables to reconstruct cardiac function in short terms and, thus, correspondingly, improve cerebral circulation due to providing direct supply of oxygenated blood substitute into the system of cerebral and coronary vessels and, also, maintain the functions reconstructed during the period of transporting a patient into medical center.

EFFECT: higher efficiency of reconstruction.

5 dwg, 1 ex

FIELD: medicine, bioactive agents.

SUBSTANCE: claimed agent for parantheral administration represents peptide complex containing 70-90 % of low molecular fraction comprising peptide components with molecular mass 72-678 Da, and peptide concentration of 2.5-2.9 mg/ml. Said agent is obtained from blood vessel of calf not older than 12 months or hog by extraction with acetic acid in presence of zinc chloride. Calf or hog blood vessels are frozen at not less -40°C, conditioned at -20-22°C for at least two months, and ground. Then 3 % acetic acid solution in volume ratio of 1:5 is added at 20±5°C. Extraction is carried out under continuous stirring to produce homogenous mixture. Then 1 % zinc chloride solution is added into mixture in volume ratio of 50:1; mixture is cooled under continuous stirring to 7-16°C; stirred during 1 h after each 4 h defecation for 48 hours. Extract is separated from ballast substances; acetone is added to extract in volume ratio of 1:5, followed by conditioning at 3-5°C for 4 hours. Obtained homogenized deposition is deposited again with acetone two time or more. Further active substance containing precipitate is washed on gravity filter with two-fold volumes of acetone cooled to 7-16°C to produce light-gray precipitate. Precipitate is passed through metal sieve, dried, dissolved in distilled water at room temperature and continuous stirring to produce polypeptide concentration of 2.5-2.9 mg/ml. Solution is centrifuged, filtered, subjected to ultrafiltration purification under back pressure of 1.0 kgf/cm2 or less trough materials with retentiveness of 15000 Da. Glycocol is added into ultrafiltrate up to finish concentration of 10-20 mg/mg at pH 5.6-6.6. Solution is subjected to sterilizing filtration under pressure of 2.0 kgf/cm2 or less, poured in 2 ml ampoules, and autoclaved for 8 min, at 120°C and atmospheric pressure of 1.1 kgf/cm2.

EFFECT: method of increased yield, non-toxic and apirogenic agent of improved purity.

2 cl, 4 ex, 3 tbl, 1 dwg

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

FIELD: organic chemistry, peptides, biochemistry.

SUBSTANCE: invention relates to compounds of the formula (I): , wherein R means hydrogen atom; R1 means carbocyclic aryl substituted optionally with halogen atom or (carbocyclic aryl or biaryl)-(lower)-alkyl substituted optionally with trifluoromethyl group or halogen atom; alk means (lower)-alkylene; R3 means hydrogen atom or acyl substituted optionally with alkoxy-group, morpholinyl, triazolyl or piperazinyl groups; R4 means hydrogen atom substituted optionally with methoxy-(lower)-alkyl or oxacycloalkyl group; R5 means hydrogen atom or (lower)-alkyl; R6 means (lower)-alkyl; R7 means (lower)-alkyl; or R6 and R7 in common with carbon atom to which they are bound mean 3-10-membered cycloalkylidene; X means -O-,-S(O)n-, -NHCO- wherein n = 0 or 2; -COOR2 means carboxyl or derivative of carboxyl group as a pharmaceutically acceptable ester wherein R2 is chosen from (lower)-alkyl, morpholine carbonylmethyl, dimethylaminocarbonylmethyl or diethylaminocarbonylmethyl, or its pharmaceutically acceptable salt. Proposed compounds are used as dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase and as inhibitor of endothelin-converting enzyme also.

EFFECT: valuable medicinal and biochemical properties of dipeptides.

8 cl, 7 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: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising the medicinal preparation "Noopept" as an active component. Pharmaceutical composition for preparing solid medicinal formulations of the preparation comprises "Noopept", microcrystalline cellulose, polyvinylpyrrolidone, stearic acid or stearate as tablets. The medicinal preparation "Noopept" representing N-phenylacetyl-L-prolylglycine ethyl ester elicits the nootropic and neuroprotective activity in broad ranges of doses. The composition comprises small amounts of special additives, tablet release active component easily and invention provides its high bioavailability. Tablets satisfy all requirements of the State Pharmacopoeia of XI edition.

EFFECT: improved and valuable pharmaceutical and medicinal properties of pharmaceutical composition.

7 cl, 1 tbl, 3 ex

FIELD: bioorganic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel aspartyl derivatives of histamine of the general formula (I): , wherein R means hydrogen atom (H), or , or that are able to modulate activity of enzymes of antioxidant protection - superoxide dismutase (SOD) and catalase. Also, invention relates to using the known compounds of the general formula (I) for the same designation wherein at the same values of X the value R represents acetyl group, and to their pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition possessing capacity to modulate activity of SOD and catalase and comprising the effective amount of compound of the general formula (I), and to a method for synthesis of compounds of the general formula (I). Method involves interaction of pentafluorophenyl ester Nα-Z-, β- or α-benzyl ester of aspartic acid with histamine followed by hydrogenolysis without isolation of intermediated protected derivatives of aspartyl histamine.

EFFECT: improved method of synthesis, valuable biochemical properties of derivatives.

12 cl, 3 tbl, 2 sch, 2 dwg, 8 ex

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