Derivatives of amino acids and their acid additive salt

 

(57) Abstract:

Usage: as an inhibitor of viral protease beginning. The essence of the invention: derivatives of amino acids f-ly 1, where R is benzyloxycarbonyl or 2-hinolincarbonova. Reagent 1: 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tertiary butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide. Reagent 2: N-(benzyloxycarbonyl)-alpha-asparagine. Reaction conditions: in the presence of hydroxybenzotriazole, N-ethylmorpholine and dicyclohexylcarbodiimide in dry tetrahydrofuran. 4 C.p. f-crystals, 1 table. Connection structure of f-crystals I:

The invention relates to derivatives of amino acids and their acid additive salts.

Derivatives of amino acids described in this invention have the following General formula I

I

where R benzyloxycarbonyl or 2-hinolincarbonova, and their pharmaceutically acceptable salts accession acids.

Compounds having formula I, and these acids and their salts are new and possess valuable pharmacological properties. In particular, they inhibit proteases of viral early and can be used for prevention or treatment of viral infections, in particular, diseases caused by the HIV virus and other pet is but additive salt, which are used as substances having a therapeutic effect. These compounds and their salts can be used to treat and prevent diseases, especially in the treatment or prevention of diseases caused by viral infection. Presents according to the invention compounds and their salts used for the preparation of medicaments for the treatment or prophylaxis of viral infections.

Acceptable for pharmaceutical use salt accession acid is a salt formed by reactions of these new compounds with inorganic acids, for example, kaleidotrope acids such as hydrochloric acid or Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and others, or with organic acids, such as, for example, acetic acid, citric acid, citric acid, maleic acid, fumaric acid, tartaric acid, tartaric acid, methanesulfonate, p-toluensulfonate and others.

According to the invention compounds having the formula I and their salts suitable for pharmaceutical use, can be obtained as follows:

a) interaction of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl formula III

< / BR>
where R has the meaning defined above, or its reactive derivative;

b) recovering compounds having the General formula IV

< / BR>
where R has the previously defined meaning, and separation of the desired 2(R)-hydroxy-isomer from the mixture, or

the interaction of 2-[3(S)-[(L-asparaginyl)amino] -2(R)-hydroxy-4-phenylbutyl] -N-tert. buildimage-(4aS, 8aS)-isoquinoline-3(S)-carboxamide having the formula V

< / BR>
c agent, forming benzyloxycarbonyloxy group or 2-hinolincarbonova group;

g) if necessary, carry out the conversion of the compounds having formula I, pharmaceutically acceptable salt, obtained by the interaction with acid.

The interaction of compounds having the formula II with the acid of formula III, according to the method (a) can be carried out using methods known from the chemistry of peptides. So, when using the acid of formula III, the reaction is preferably carried out in the presence of a condensing agent, such as hydroxybenzotriazole and dicyclohexylcarbodiimide. This reaction is carried out in an inert organic solvent such as ether (e.g. diethyl ether, tetrahydrofuran, and others) or in dimethylformamide at low C. Suitable reactive derivatives of acids of formula III used in this way are, for example, corresponding galodamadruga (e.g., acid chloride), acid anhydrides, mixed anhydrides, activated esters, etc. When using the reactive derivative, the reaction is usually carried out in inert organic solvents, such as golozhabernyi aliphatic hydrocarbons (e.g. dichloromethane) or an ether (e.g. diethyl ether, tetrahydrofuran, and others) and, favorably, in the presence of organic bases (for example, N-ethylmorpholine, diisopropylethylamine and others) at a low temperature, preferably from approximately -10oC to +5oC, especially at a temperature of about 0oC.

The reduction of compounds of formula IV (according to the method described in (b), can be carried out in accordance with methods known to restore the carbonyl group to hydroxyl. For example, the recovery is carried out using complex metal hydrides, such as alkali metal borohydride, especially sodium borohydride, in the presence of a suitable organic solvent, such as alkanol (aperature. The separation of the desired 2(R)-hydroxy-isomer from the mixture can be performed by known methods, for example, chromatography, etc.

For carrying out the process according to (C) with a suitable reagent to obtain benzyloxycarbonyloxy group is a benzyl ether of Harborview acid. Suitable reagents for producing 2-hinolincarbonova groups are the corresponding acid and its reactive derivative such as the corresponding galoyanized (for example, the acid chloride of the acid, acid anhydride, mixed anhydrides, activated esters, etc. the Interaction of the compounds of formula V with the above reagents is carried out by the method described in stage (a).

The conversion of compounds of formula I, pharmaceutically acceptable salts of the acids according to the method (d), it is possible to carry out processing of these compounds by the conventional method, an inorganic acid, for example, kaleidotrope acid, such as hydrochloric or Hydrobromic acids, sulphuric acid, nitric acid, phosphoric acid, etc. or organic acid, such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric kislota the original substance in the method (a), is the new. It can be obtained for example, by the interaction of the compounds having General formula VI,

< / BR>
where R1the group protecting the amino group (for example, tert.butoxycarbonyl or benzyloxycarbonyl), and "X" chlorine atom or bromine, N-tert. -buildimage-(4aS,8aS)-isoquinoline-3(S)-carboxamide having the formula VII

< / BR>
and recovering the obtained compound of General formula VIII

< / BR>
where R1shall have the meaning given previously, the separation of the desired 2(R)-hydroxyether from the mixture and the removal of the group R1from the compounds having the General formula IX

< / BR>
in which R1has the previously defined meaning, with the formation of the compounds of formula II.

The interaction of the compounds of formula VI, preferably where one group R1means benzyloxycarbonyl, with the compound of the formula VII can be carried out in a known manner, for example, in an inert organic solvent such as galijasevic aliphatic hydrocarbon (e.g. dichloromethane and so on ) and in the presence of a base (for example, trialkylamine, such as triethylamine, and others) typically at room temperature.

The recovery of the compounds of formula VIII c polucheniyami earlier, according to method (b) of the present invention, which is the restoration of the compounds of formula IV and division 2(R)-hydroxy-isomer from the mixture obtained.

Cleavage of the group R1from the compounds of formula IX can also be carried out in a known manner, using a strong inorganic acid, such as galoidvodorodnykh acid or a strong organic acid (for example, triperoxonane acid and so on) it's best at a temperature of from about 0oC to room temperature. On the other hand, ameloblastoma group R1, tsepliaeva hydrogenations, can be subjected to cleavage using hydrogen in the presence of a noble metal as a catalyst (e.g. palladium catalyst such as palladium on coal) in an organic solvent or mixture of solvents in which the reaction conditions, inert (for example, alkanol, such as ethanol, isopropanol, or ester alkenylboronic acid, as, for example, ethyl acetate and others), usually at room temperature.

The following method for obtaining compounds of formula II includes first interaction of the compounds of General formula X

< / BR>
where R1previously defined, with a compound having a shape and others), dimethylformamide or similar solvent at elevated temperatures, better from approximately 60oC to about 120oC, followed by removal of the group R1in the reaction product (compound of formula (IX), as described earlier.

The compounds of formula IV used as starting materials for the production of (b) can be prepared upon removal aminosidine group, R1from compounds having the formula VIII, and the interaction of the reaction product with an acid of formula III or its reactive derivative. The interaction can be performed in a manner analogous to the previously described in (a).

The compound having the formula V used as starting substances in process (b) is new and is yet another object of the invention.

The compound of formula V can be obtained, for example, the removal of benzyloxycarbonyl group R from the compounds of formula I in which R is benzyloxycarbonyl or tert.butoxycarbonyl group, with the formation of compound I, but in which R is tertiary butoxycarbonyl group. This latter compound can be obtained, for example by reaction of compounds of formula II with N-(TRM previously described in connection with the removal of the group R1from compounds of formula VIII.

Educt of the formula III and their reactive derivatives, as well as compounds of formulas VI, VII and X, as described above, because they are new and not similar known compounds can be obtained in a manner analogous to obtain the known compounds, or by the method described in the following examples or the like.

Moreover, the reagents used in the method (b), are for the most part known compounds.

As mentioned above, the compounds of formula I and their pharmaceutically acceptable salts inhibit proteases of viral early and therefore suitable for the treatment and prevention of viral infections, particularly infections caused by HIV virus and other retronym viruses.

Inhibition of protease of the HIV virus outside the body by joints, which are presented in the invention can be demonstrated by the following test:

The HIV protease was expressed in E. coli and partially purified from soluble extracts of bacteria by fractionation with ammonium sulfate (0-30%). The protease activity was analyzed using as a substrate the protected Hexapeptide succinyl-Ser-Leu-Asn-Tyr-Pro-Ile image the substrate. Cleavage of the substrate was evaluated by quantification of the formed H-Pro-Ile of isobutyramide using spectrophotometric analysis of N-terminal Proline.

1.25 mm of substrate was dissolved in 125 mm citrate buffer (pH 5.5) containing 0.125 mg/ml Tween 20. To 80 μl of the above buffer substrate was added 10 μl of a solution of tested compound at various concentrations (dissolved in methanol or in dimethyl sulfoxide and diluted with water containing 0.1% Tween 20) and 10 ál of protease. The digestion was performed at 37oC within the prescribed time, then the process was stopped by adding 1 ml of color reagent [30 μg/ml of isatin and 1.5 mg/ml of 2-(4-chlorobenzoyl) benzoic acid in 10% acetone in ethanol (ratio of volume/volume)] the Solution was heated on a water bath, then pigmented residue was subjected to re-dissolved in 1 ml of 1% pyragollole with 33% water content in acetone (ratio of weight/volume/volume). The optical density of the solution was measured by spectrophotometry at 599 nm. The formation of H-Pro-Ile of isobutylamine in the presence of investigated compounds were compared with the control, the concentration of the tested compound that gives 50% inhibition of the deposits.

Antiviral activity of compounds in vitro formula I can be demonstrated on the example of the analysis described below:

Activity against the HIV virus

In this sample were used HTLV-III (strain RF) grown in cells S (CD4+human T-lymphoblastoid origin), using medium RPM1 1640 c bicarbonate buffer, antibiotics and 10% serum bovine embryo.

Suspension cells were infected with virus in number, ten TCD50the adsorption was carried out at a temperature of 37oC for 90 min, the Cells were washed with medium 3 times. The test was carried out in 6-ml test tubes with tissue culture, each vial contained 2 x 105infected cells in 1.5 ml medium. The analyzed compounds were dissolved in water and ether medium or in dimethyl sulfoxide, depending on the solubility and added 15 μl of a solution of a substance. Cultures were incubated at 37oC for 72 h in a humid atmosphere containing 5% carbon dioxide. Then the culture was centrifuged, and the aliquot sample of the supernatant liquid was transferred to a soluble state by Nonidet P40 and was exposed to the sample antigen, which was the primary anticavity with concresive was determined by spectrophotometry and deposited on the chart depending on the concentration of the analyzed substance. The concentration at which observed a 50% protection was determined by the index (I50).

Test for cytotoxicity, based on the absorption of the dye and the metabolism or the introduction of labeled radioactive isotope amino acids, is a series of experiments, along with the above breakdown, to determine the antiviral selectivity.

The results obtained when carrying out the above studies using compounds having formula I, as analyzed compounds are combined in the table.

Compounds described by formula I, and their pharmaceutically acceptable salts, can be used as drugs. Pharmaceuticals should be prepared for internal use, for example, orally (in the form of tablets, wafers, pills, soft and hard gelatin capsules, solutions, emulsions or suspensions), nasal (in the form of nasal sprays) or rectal (in the form of suppositories). In addition, the obtained preparations suitable for parenteral use, for example, intramuscular or intravenous (in the form of solutions for injection).

In the industrial production of tablets, wafers, pills and etnicheskie fillers. As such fillers can be used lactose, corn starch or derivatives thereof, talc, stearic acid and its salts.

A suitable vehicle for soft gelatin capsules are vegetable oils, waxes, fats, semi-solid or liquid polyols etc., for solutions and syrups are water, polyols, sucrose, invert sugar, glucose, etc. for solution for injection water, alcohols, polyols, glycerol, vegetable oils, etc. for suppositories natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.,

Moreover, the pharmaceutical preparations may include preservatives, solvents, substances that increase the viscosity stabilizing agents, anticoagulants, wetting agents, emulsifiers, sweeteners, colorants, flavouring agents, salts for modifying the osmotic pressure, buffers, covering substances (shell) or antioxidants. In addition, may include other substances that have therapeutic value.

According to the invention compounds having the formula I, and their pharmaceutically acceptable salts accession acids, can be used for the treatment and prevention of viral diseases, moved individually in each case. Usually in the case of oral administration enough following a daily dose of from about 3 mg to about 3 g, preferably from about 10 mg to about 1 g (for example, approximately 300 mg per person), preferably separated by a reception at day 1-3 times, with each dose, generally the same. However, it should be noted that the upper limit may be exceeded when indicated.

Example 1. A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert. -buildimage-(4aS, 8aS)- isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in a mixture of ice and salt. Added 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide, and the mixture was stirred for 16 hours Then the mixture was diluted with ethyl ether, acetic acid and filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate and sodium chloride solution. The solvent was removed by evaporation, and the residue was subjected to chromatography on silica gel using a mixture of dichloromethane and methanol (9:1) for elution, getting 434 mg of 2-[3(S)-[N-(benzyloxycarbonyl)-L-asparaginyl]amino] -2(R)-hydroxy-4 - phenylbutyl-N-tertiary, buildimage-(4aS,8aS)-isoquinoline-3(S)-carboxamide is: (d4CH3OH, 400 MHz): 7,33 (5H, m, CH2O) to 7.25 (2H, m), 7,18 (2H, m); to 7.09 (1H, m), of 5.05 (2H, s, PhO), 4,42 (1H, dd, AsnJ 7,8, 6,1), 4,22 (1H, m, -CH2CH(OH)- J 10,7, about 4, about 4), 3,85 (1H, m, -CH(OH)CH2-J 8,0, 6,2, about 4), to 3.02 (1H, dd, Ph(H)CHJ -13,9, about 4), to 3.02 (1H, dd, 1eqJ -12,0, a little), 2,69 (1H, dd, PhCH (CH)-J -13,9, 10,7), 2,63 (1H, dd, -CH(OH)CHN-J -12,6, 8,0), 2,62 (1H, dd, H3axJ about 11 or less, to 2.57 (1H, dd, Asn1J-15.2 m, 6,1), of 2.38 (1H, dd, Asn2J-15.2 m, 7,8), 2,19 (1H, dd, -CH(OH)(H)N-J -12,6, 6,2), 2,17 (1H, dd, 1axJ -12,0, 3,2), 2,07 (1H, m, H4axJ is-12.7, about 11, about 11.5), of 1.78 (1H, m, H4a J4a-4axabout 11.5, J4a-4eqlittle, J4a-8abit), and 1.63 (1H, m, H8a J8a-1ax3,2, J8a-1eqlittle, J8a-4aa little) to 1.35 (1H, m, H4eqJ is-12.7, little, little), 1,30 (N, s, t-butyl), 2,0 1,2 (8H, m).

Used as starting material 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl] -N-tertiary, buildimage-(4aS,8aS)-isoquinoline-3(S)-carboxamide received as follows:

(i) Suspension from 12,676 g (71.6 mmol) of 1,2,3,4-tetrahydro-3(S)-ethinlestradiol acid (Chem. Pharm. Bull. 1983, , 312) in 200 ml of 90% acetic acid was hydrogenosomal at 80oC and a pressure of 140 ATM over 5% rhodium on coal within 24 hours the Mixture was cooled to room temperature, and the catalyst was then filtered. The filtrate was evaporated to obtain a gum which was dissolved in 10 ml ethyl acetate. adosados liquid was removed by decantation, and the residue was extracted with hot ethyl acetate. This hot solution was poured into an intensively stirred mixture of 150 ml of diethyl ether and diisopropyl ether (1:1) to obtain a light grey solid, which was filtered off, washed with diethyl ether, and dried. Thus received 5,209 g of a mixture of decahydroquinoline-3(S)-carboxylic acid, which consisted largely (about 65%) 4aS,8aS isomers together with 4R,8aR isomers (about 25%), and about 10% TRANS-isomers; MS: m/e 184 [M+H]+.

(ii) 9,036 mg (49,4 mmole) of the preceding mixture decahydroquinoline-3(S)-carboxylic acid was dissolved in 50 ml (50 mmol) of 1M sodium hydroxide solution; the resulting solution was cooled to 0oC. 7,40 ml (51,87 mmole) of benzylchloride and 58.7 ml (58,7 mmol) of 1M sodium hydroxide solution was added dropwise over 1 hour, maintaining the temperature at 0-5oC cooling. Then the mixture was stirred a further 2 hours, during this time the temperature of the mixture was brought to room temperature. Added 100 ml of diethyl ether and the mixture was filtered, resulting in a received insoluble R,R-isomer, which was separated. The aqueous layer of the filtrate was separarely and brought to a pH of 1.5 to 2 by adding kazetta. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate and mariveles to get the oil. This oil was dissolved in 35 ml of ethyl acetate with addition to 2.85 ml (25 mmol) of cyclohexylamine. A white precipitate was collected by filtration, obtaining (after several fractional precrystallization from methanol/ethyl acetate) of 2.38 g cyclohexylamine salt of 2-(benzyloxycarbonyl)-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxylic acid; MS: m/e 318 [M+H]+.

(iii) 2,334 g cyclohexylamine salt of 2-(benzyloxycarbonyl)-decahydro-(4S, 8aS)-isoquinoline-3(S)-carboxylic acid was divided between 50 ml of ethyl acetate and 50 ml of 10% citric acid solution. The organic phase is separated, washed with water, filtered and evaporated to obtain of 1.87 g of 2-(benzyloxycarbonyl)-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxylic acid as a colourless resin; MS: m/e 318 [M+H]+.

(iv) the Solution 0,634 g (2.0 mmole) of 2-(benzyloxycarbonyl)-decahydro-(4S, 8aS)-isoquinoline-3(S)-carboxylic acid in 6 ml of dimethoxyethane processed to 0.23 g (2.0 mmole) of N-hydroxysuccinimide and 0,412 g (2.0 mmole) dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 18 hours the Mixture was filtered, and the filtrate was evaporated to obtain 0,879 g of the ester of N-Wali in 5 ml of dichloroethane, was cooled to 0oC and treated 0,219 g (3.0 mmole) of the tertiary butylamine. The mixture was stirred at 0oC for 2 h, then for 4.5 h at room temperature. The mixture is then washed with 2M hydrochloric acid, sodium carbonate solution and sodium chloride solution, dried with anhydrous magnesium sulfate and evaporated. The precipitate was dissolved in 20 ml diethyl ether and was filtered. The filtrate was evaporated to obtain 0,712 g of 2-(benzyloxycarbonyl)-N-tertiary, buildimage-(4S, 8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 373 [M+H]+.

(v) the Solution 0,689 g (of 1.85 mmole) of 2-(benzyloxycarbonyl)-N-tertiary, buildimage-(4S,8aS)-isoquinoline-3(S)-carboxamide in 20 ml of ethanol was hydrogenosomal in the presence of 0.01 g of 10% palladium on coal at room temperature and at atmospheric pressure for 18 hours, the Catalyst was removed by filtration and the solvent was removed by evaporation to obtain a quantitative yield of N-tertiary, buildimage-(4aS,8aS)-isoquinoline-3(S)-carboxamide in the form of pure oil; MS: m/e 239 [M+H]+that was used in the next stage without further purification.

(vi) a Solution of 440 mg of N-tertiary, buildimage-(4S,8aS)-isoquinoline-3(S)-carboxamide and 549 mg of 3(S)-benzylated 54 mg of 3(S)-(benzyloxyphenyl)-1,2(S)-epoxy-4-phenylbutane, the solution was stirred at 20oC for 16 hours the Solvent was removed by evaporation, and the residue was subjected to chromatography on silica gel using a mixture of diethyl ether:n-hexane:methanol (47,5:47,5:5) for the elution to obtain 771 mg of 2-[3(S)-(benzyloxycarbonyl)-2(R)-hydroxy-4-phenylbutyl] -N-tertiary, buildimage-(4S, 8aS)-isoquinoline-3(S)-carboxamide as white solid precipitate; MS: m/e 536 [M+H]+.

(vii) a Solution of 747 mg of 2-[3(S)-(benzyloxycarbonyl)-2(R)-hydroxy-4-phenylbutyl] -N-tert.-booth - indikacije-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 40 ml of ethanol was hydrogenosomal 10% palladium on coal at 20oC, atmospheric pressure for 5 hours, the Catalyst was removed by filtration, and the filtrate was evaporated to obtain 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert. -buildimage-(4aS - 8aS)- isoquinoline-3(S)-carboxamide as a pale yellow solid, which was used in the following stage without further purification.

Example 2. A solution of 154 mg of 2-[3(S)-[(L-asparaginyl)-amino]-2(R)-hydroxy-4-phenylbutyl] -N-tration on buildimage-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg gialdino acid in 6 ml of dry tetrahydrofuran was cooled in a mixture of ice and salt. Added 41 mg of hydroxybenzotriazole, 35 mg of N-the volume and was filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate and sodium chloride solution, and then evaporated. The precipitate was chromatographically on silica gel using dichloromethane and methanol (9:1) for elution to obtain 50 mg of N-tertiary, buildimage-2-[2(R)-hydroxy-4-phenyl-3-(S)-[[N-(2-hinolincarbonova) - L-asparaginyl]-amino]-butyl]-(4S,8aS)-isoquinoline-3(S)-carboxamide as a white precipitate; MS: m/e 671 [M+H]+; NMR: (d4CH3OH, 400 MHz):

charged 8.52 (1H, m), 8,18 (1H, m), 8,14 (1H, m), 8,02 (1H, m), to 7.84 (1H, m), 7,69 (1H, m), 7,18 (2H, m), 6.90 to (2H, m), 6,72 (1H, m), is 4.93 (1H, dd, AsnaCH J 6,6, 6,8), 4,27 (1H, m, -CH2CH(OH)-J 3,8, 3,8, 11,0), the 3.89 (1H, m, (OH)CH2-J 7,2, 6,4, 3,8), 3,06 (1H, dd, H1eqJ -12,0, 3,0), to 3.02 (1H, dd, Ph(H)CH-J -14,0, 3,8), 2,77 (1H, dd, Asn1J -15,6, 6,6), 2,68 (1H, dd, Asn2J -15,6, 6,8), 2,68 (1H, dd, PhCH (CH)-J -14,0, 11,0), some of 2.68 (1H, dd, -CH(OH)-J 12,0, 7,2), 2,63 (1H, dd, H3axJ 11,0, 2,2), 2,22 (1H, dd, -CH(OH)CH()N-J -12,0, 6,4), to 2.18 (1H, dd, H1axJ -12,0, 2,2), to 2.06 (1H, m, H4axJ -11,0, 11,0, 11,0), of 1.78 (1H, m, 4a J4a-4ax11,0, J4a-4eqabout 4, J4a-8aabout 4), of 1.65 (1H, m, 8a J8a-1ax2,2, J8a-1eq3,0, J8a-4aabout 4), to 1.37 (1H, m, H4eqJ -11,0, 2,2, about 4), 1,30 (N, s, t-butyl), a 2.0 a 1.2 (8H, m).

Used as source 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl] -N-tertiary, buildimage-(4aS, 8aS)-isoquinoline-3(S)-carboxamide received by the following method:

RAS is Rho-(4S,8aS)-isoquinoline-3(S)-carboxamide in 20 ml of ethanol was first made at room temperature and atmospheric pressure for 18 hours over 10% palladium on coal. The catalyst was filtered, and the filtrate was evaporated under reduced pressure to obtain 154 mg of 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl] -N-tertiary - th buildimage-(4S,8aS)-isoquinoline-3(S)-carboxamide, which was used in the next stage without further purification.

Example 3. A solution of 287 mg of N-(2-hinolincarbonova)-L-asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl] -N-tertiary, buildimage-(4aS, 8aS)-isoquinoline-3(S)-carboxamide [obtained by the method described in example 1 (i)-(vii)] in 3 ml of tetrahydrofuran was cooled to -10oC and added 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-she and 220 mg of dicyclohexylcarbodiimide. The mixture was stirred at -10oC for 2 h and at 20oC for 16 h, then was diluted with ethyl acetate and was filtered. The filtrate was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and then evaporated. The residue was subjected to chromatography on silica gel using 4% (by volume) methanol in dichloromethane for the elution to obtain 537 mg of N-tertiary, buildimage-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-hinolincarbonova)-- L-asparaginyl] amino] butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, which was identical to the product received in the first paragraph is the one and crystallization from methanol/ethyl acetate was received para-toluensulfonate N-tert. -buildimage-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-chinoline - bonil)-L-asparaginyl] amino] butyl] -(4aS, 8aS)-isoquinoline-3(S)-carboxy - Mead in the form of a white solid with a melting point of 246 248oC (decomposition).

N-(2-hinolincarbonova)-L-asparagine is used as starting material was prepared as follows:

A mixture of 540 mg of ester amide of succinic acid and gialdino acid and 300 mg of L-asparagine monohydrate in 2 ml of dimethylformamide was stirred at 20oC for 96 hours. The solvent was removed by evaporation to yield a white solid residue, which was intensively stirred in 10 ml of dichloromethane, was filtered and washed with dichloromethane. Thus received 431 mg of N-(2-hinolincarbonova)-L-asparagine in the form of a white solid; MS: m/e 288 [M+H]+.

The following example illustrates the preparation of a pharmaceutical preparation containing the compound of formula I or its pharmaceutically acceptable salt as an active ingredient.

Example A. an Aqueous solution of the active ingredient was sterile filtered, mixed while heating with a sterile gelatin solution, which contains phenol as a preservative with the use of such quantities g of phenol and distilled water up to 1 ml The mixture was poured in test tubes with a capacity of 1.0 ml in terms of antiseptics.

1. Derivatives of amino acids of General formula

< / BR>
where R benzyloxycarbonyl or 2-hinolincarbonova,

and their acid additive salt.

2. N-tert-Butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)- [[N-(2-hinolincarbonova(-L-asparaginyl] amino]butyl]-(4aS, 8aS)-isoquinoline-3 (S)-carboxamide.

3. 2-[3(S)-Amino-2(R)-hydroxy-4-phenylbutyl] N - tert-buildimage-(4aS, 8aS)-isoquinoline-3(S)- -carboxamide.

4. 2-[3(R)-[(L-Asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl] -N-tert-butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide.

 

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The invention relates to new derivatives of benzimidazole, possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

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(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine and relates to means for the prevention and treatment of diabetic complications, angiopathy, neuropathy, katakey

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

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