Derivatives of r(-)-3-hinokitiol in the form of a mixture of their diastereomers or of an individual diastereomer or their salts

 

(57) Abstract:

Usage: in pharmacology, in particular as physiologically active substances. The inventive product is a derivative of R(-)-3-hinokitiol f-ly I (see drawing), where R is not - or branched lower alkyl, C3-C7-cyclo - C1-C2-alkyl; R1is hydrogen or is not - or branched lower alkyl or acyl f-ly: R2-C(O)-, where R2is hydrogen or is not - or branched lower alkyl; And - C5-C7- cycloalkyl, phenyl, thienyl, pyridyl; X is the anion of a non - organic or organic acid; Y and Z are both oxygen, or one oxygen or sulfur; m and m = 0 or 1; n = 1-3; p = p = 1, or p and p different of 0 or 1, and a and group 3-genociding ether are genialnom position. 1 C.p. f-crystals, 1 table.

The invention relates to new nitrogen-containing heterocyclic compounds having valuable properties, in particular the derivative of R(-)-3-hinokitiol General formula I

R1-N where R is an unbranched or branched lower alkyl, cycloalkenyl with 3-7 carbon atoms in cycloalkyl part and 1-2 carbon atoms in the alkyl part;

R1hydrogen, unbranched or branched lower alkyl or acyl of the formula R2
X is the anion of an organic or inorganic acid,

Y and Z both mean oxygen, or each of them means oxygen or sulfur;

m and m' are the same and mean the integer 0 or 1;

n is an integer 1, 2 or 3;

R and R' are the same and mean l or different and denote 0 and 1, and a and group 3-genociding ether are genialnom position, in the form of a mixture of their diastereomers, or an individual diastereoisomers or their salts, having, in particular, pharmacological activity, in particular activity antimuskarinovoe act occurs.

The new compounds of General formula I, where m and m' denote O, and A, Y, Z, R1n, p and R' have the above meanings, receive, for example, by interaction of R(-)-hinokitiol obtained, if necessary, in place of the compound of General formula II

R1-N where R1, Z, Y, A, n, p and p' have the abovementioned meanings and L is a suitable a group to delete.

Suitable groups are removed, for example, halogen atom, lower alkoxyl, fenoxaprop, imidazol-1-yl, ethylcarbonate group, mesilate-group, and (benzotriazol-1-yl)-oxy group, preferably a chlorine atom, ethoxy group, imidazol-1-yl.

The product yield of the reactions is lyst for example, a lump of metallic sodium, sodium hydrate, 5-dimethyl-aminopyridine, triethyl - amine, 1,8-diazabicyclo-[5,4,0]undec-7-ene or pyridine. The reaction is carried out in a medium of anhydrous inert solvent, for example dichloromethane, chloroform, benzene, toluene, ethyl acetate, tetrahydrofuran, dimethylformamide or mixtures thereof. Usually the reaction is carried out at a temperature of 0-100aboutC, preferably at 50aboutC.

Compounds of General formula I, where m and m' denote the I, R, X, R1, A, Y, Z, n, p and p' have the abovementioned meanings, are obtained by the interaction with the compound of General formula III

R1-N where R1, Y, Z, A, n, p and p' have the above meanings, with a suitable alkylating agent, for example, unbranched or branched lower alkylhalogenide, halide cycloalkyl with 1-2 carbon atoms in the alkyl part, alkylhalogenide, aralkylamines or dimethyl - sulfate, preferably the bromide, the bromide of cyclopropyl or dimethylsulfate. The reaction is carried out in a medium polar solvent, e.g. acetonitrile, methanol, ethanol, preferably acetonitrile, at 30-70aboutWith, preferably 50aboutC.

Compounds of General formula I, where m and m' denote 0, if n is by reaction with an inorganic or organic acid known method, e.g. by reaction of compounds in the form of a base with a solution or the corresponding acid in the environment suitable solvent. Especially preferred acid is, e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate or tartaric acid.

Radicals and complex 3-hinkleyville esters can be introduced into compounds of the formula I in any position of the ring, for free replacement. But they are always together on the same carbon atom than is obtained genialne substitution. The compounds of formula I according to the invention have a second center of chirality, which is the carbon atom, which is associated with genialny deputies and complex 3-genocidally ether, and so they can be in the form of a mixture of two diastereomers.

In the case of a mixture of diastereoisomers can be divided into pure individual components of the known methods of separation on the basis of their different physical and chemical properties, for example, by fractional crystallization or chromatography using an appropriate solvent mixtures.

Obtaining compounds of the formula I is illustrated by the following examples.

P R I m e R 1. Piperidin pyridinecarboxylic acid and 0.81 g of 1,1-carbonyldiimidazole in 12 ml of anhydrous dimethylformamide drops add to stir well the solution of 0.64 g of R(-)-hinokitiol and 0.15 g of an 80% aqueous solution of sodium hydride in anhydrous dimethylformamide. The reaction mixture of razmeri - live at room temperature overnight, then the dimethylformamide is removed in vacuo. The residue is distributed between water and ethyl acetate, organic layer washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue is subjected to chromatography on silica gel (eluent: a mixture of methylene chloride, methanol and ammonium hydroxide in the ratio of 90:10:1). The target product is obtained as a mixture of diastereoisomers in the ratio of 1:1. Output: 0,72, Etc., 177-179about(From simple diethyl ether). MS 329 m/e [M + H]

Column liquid chromatography under pressure (hereinafter: "CGH"):

The diastereoisomer A. trace 6.11. The diastereoisomer B= trace of 6.73.

[Eluent: acetonitrile and phosphate triethylamine in the ratio of 60:40 at 40aboutS]

Calculated With 69,49; N 7,37; N 8,53.

WITH19H24N2O3< / BR>
Found, 69,41; N 7,40; N 8,49.

Described in example 1 given the following connection:

Pyrrolidin-2-oxo-4-phenyl-4-[(R)-1-Aza - bicyclo(2.2.2)octyl]-carboxylate (compound 2).

Etc., 90-94aboutC (decomposition) (from simple diethyl ether). MS=315 m/e [M+H]

CGH: Diastereoisomer A, trace 8,67. The diastereoisomer In, mark the remaining 9.08.

[Eluent: acetonitrile, BR>WITH18H22N2O3.

Found, 68,71; N 7,12; N 8,90.

P R I m m e R 2. Pyrrolidin-2-oxo-3-phenyl-3-[(R)-1-azabicyclo(2.2.2)octyl]-Carbo-kilat (compound 3).

1 g (R)(-)-hinokitiol dissolved in 50 ml of benzene and within 30 minutes, heated under reflux to remove the water. Added 0.18 g lump of metal sodium and the resulting suspension is heated under reflux for 60 minutes, Add a solution of 1.6 g pyrrolidin-2-oxo-3-phenyl-3-ethylcarboxylate in 20 ml of dry benzene, and then the reaction mixture is heated under reflux for 6 hours, the Cooled solution is evaporated in vacuum to dryness, the residue absorbed by ethyl acetate and water and washed with water. The organic layer is dried over sodium sulfate and evaporated to dryness. Resulting yellow residue is subjected to chromatography on silica gel (eluent: a mixture of methylene chloride, methanol and ammonium hydroxide in the ratio of 90: 10:1, Rf 0,27). The target product is obtained as a mixture of diastereoisomers in the ratio of 1:1. Yield 0.64 g, so pl. 142-143aboutC.

MS 315 m/e [M + H]

CGH: diastereoisomer A. trace a 9.25. The diastereoisomer Century mark 11, 42.

[Eluent: acetonitrile, phosphate triethylamine and water in zootoxin the>
< / BR>
Found, 68,70; N 7,21; N 8,83.

Described in example 2 given the following compounds.

Piperidine-2,6-dioxo-3-phenyl-3-[(R)-1 - azabicyclo(2.2,2)octyl] -carboxylate (compound 4).

So pl. 160-163aboutC.

MS 343 m/e [M+H]

CGH: Diastereoisomer A, trace 8,63. The diastereoisomer, mark 9,04.

[Eluent: acetonitrile, phosphate triethylamine and water in the ratio of 40:40: 20 at a temperature of 40aboutS]

Calculated With 66,65; N 6,48; N 8,18.

WITH19H22N2O3.

Found, 66,57; N 6,51; N By 8.22. Piperidine-2-oxo-6-phenyl-[(R)-1-Aza-bicyclo(2,2,2)octyl]-carboxylate (compound 5).

So pl. 144-150aboutC (decomposition) (in the form of a hydrochloric salt, from simple diethyl ether).

MS 329 m/e [M + H]

CGH: diastereoisomer A, trace 22,40. The diastereoisomer, mark 24,06.

[Eluent: n-hexane, isopropanol and methanol in the ratio of 88:10:2, at a temperature of 25aboutS]

Calculated With 62,54; N 6,91; N 7,68.

WITH19H25ClN2O3< / BR>
Found, 62,28; N. Of 6.99; N 7,60.

Pyrrolidin-2-oxo-5-phenyl-5-[(R)-1-Aza - bicyclo(2.2.2)octyl]-carboxylate (compound 6).

So pl. 125-127aboutC (decomposition) (hydrochloric salt of simple di the/P> [Eluent: acetonitrile, a 0.01 molar phosphoric acid with 0.02% triethylamine (pH 3) and water in the ratio of 30:40:30 at a temperature of 40aboutS]

Calculated, 61,62; N Is 6.61; N 7,98.

WITH18H23ClN2O3< / BR>
Found, With 61,03; N 6,70; N Of 7.82.

Piperidine-1-acetyl-3-phenyl-3[(R)-1 - azabicyclo(2.2.2)octyl]-carboxylate (compound 7).

Thick oil.

MS 357 m/e [M+N).

CGH: diastereoisomer A, trace of 4.45. The diastereoisomer, a trace of 4.77.

[Eluent: acetonitrile, phosphoric acid and water in the ratio of 40:40:20 at a temperature of 40aboutS]

Calculated With 70,76; N A 7.92; N 7,86.

WITH21H28N2O3< / BR>
Found, 70,50; N. Of 7.97; N 7,72.

Piperidine-2-oxo-5-(pyridin-2-yl)-5- [(R)-1-azabicyclo(2.2.2)octyl]-carboxylate (compound 8).

So pl. 160-163aboutC.

MS 330 m/e [M+H]

CGH: diastereoisomer A, trace 6,93. The diastereoisomer, mark 7,51.

[Eluent: acetonitrile, phosphoric acid and water in the ratio 10:40:50, at a temperature of 40aboutS]

Calculated With 65,63; N? 7.04 Baby Mortality; N 12,76.

WITH18H23N3O3< / BR>
Found, 65,48; N 7,06; N 12,69.

Piperidine-2-thioxo-3-phenyl-3-[(R)-1 - azabicyclo(2.2.2)octyl]-carboxylate (compound 9).

So pl. 111-113Xan, methanol and isopropanol in the ratio of 85:7:8 at a temperature of 25aboutS]

Calculated, 66,24; E 7,02; N 8,13.

WITH19H24N2O2S.

Found, 65,88; N 6,95; N 8,00.

Piperidine-2-oxo-3-(thiophene-2-yl)-3- [(R)-1-azabicyclo(2.2.2)octyl]-carboxylate (compound 10).

So pl. 132aboutC.

MS 335 m/e [M+H]

CGH: diastereoisomer A, trace 20,40. The diastereoisomer, mark 22,00;

[Eluent: n-hexane, methanol and isopropanol in a ratio of 88:6:6, at a temperature of 30aboutS]

Calculated With 61,05; N 6,63; N Scored 8.38.

WITH17H22N32O3S.

Found, C 60,45; 6,67 N; N 8,17.

Piperidine-2-oxo-3-phenyl-3-[(R)-1-Aza - bicyclo(2.2.2)octyl]-carboxylate (compound 11).

So pl. 153-156aboutC (from petroleum ether).

MS 329 m/e [M+H]

CGH: diastereoisomer A, trace of 14.8. The diastereoisomer, mark of 16.5.

[Eluent: n-hexane, isopropanol and methanol in the ratio of 88:6:6 at a temperature of 25aboutS]

Calculated With 69,49; N 7,37; N 8,53.

WITH19H24N2O3.

Found, To 69.61; H 7,41; N 8,44.

Piperidine-2-oxo-5-phenyl-5-[(R)-1-Aza - bicyclo(2.2.2)octyl]-carboxylate (compound 12).

So pl. 181-184aboutC (from petroleum ether).

MS 329 is ethylamine (pH 3) and water in the ratio 15:50:35, at a temperature of 40aboutS]

Calculated With 69,49; N 7,37; N 8,53.

WITH19H24N2O3.

Found, 69,80; N 7,30; N 8,46.

P R I m e R 3. Azepin-2-oxo-6-phenyl-6-[(R)-1-azabicyclo(2.2.2)octyl]-carboxylate.

A suspension of 0.95 g of R(-)-3-hinokitiol and 0.17 g of sodium in anhydrous tetrahydrofuran for 30 min heated under reflux, then cooled. Enter a solution of 1.6 g of azepin-2-oxo-6-phenyl-6-ethylcarboxylate and 1.1 g of 1,1-carbonyldiimidazole in 30 ml of anhydrous tetrahydrofuran, and the resulting reaction mixture for 4 h heated under reflux. After cooling, add a few drops of glacial acetic acid and the reaction mixture is evaporated to dryness. By flash-chromatography on silica gel using as eluent a mixture of methylene chloride, methanol and ammonium hydroxide in the ratio 95:5:0.5 to share a couple of diastereoisomers in pure top (Rf 0.3) and clean the bottom (Rf 0.25 in) components. Components evaporated to dryness, whereupon receive individual diastereomers a and b in the form of a white solid (after processing simple diethyl ether).

The diastereoisomer A (compound 13).

So pl. 171-175aboutC (decomposition) (from simple IER is monia and water in the ratio of 30:40: 30, when 40aboutS]

Calculated, 70,15; N. Of 7.65; N 8,18.

WITH20H26N2O3.

Found, With 70,01; N To 7.67; N 8,24.

The diastereoisomer (compound 14).

So pl. 156-159aboutC (decomposition) (from simple diethyl ether).

MS 343 m/e [M + H]

CGH: track 5,63.

[Eluent: acetonitrile, phosphate triethylamine and water in the ratio of 30:40: 30 40aboutS]

Calculated, 70,15; N. Of 7.65; N 8,18.

WITH20H26N2O3.

Found, 70,24; N To 7.61; N By 8.22.

P R I m e R 4. Piperidine-1-methyl-2-oxo-3-phenyl-3-[(R)-1-azabicyclo(2.2.2(octyl] -carboxylate (compound 15).

0.4 g of sodium and 7 ml of methanol served in 400 ml of anhydrous heptane. When the sodium is dissolved, is distilled with excess methanol and add to 2.54 g of R(-)-3-Hinoki - dinola and to 4.98 g piperidine-1-methyl-2-oxo-3-phenyl-3-ethylcarboxylate. The reaction mixture is heated and about 300 ml for 3 h and distilled. After cooling drops add 40 ml of chloride - hydrogen acid (2 N), separated the organic layer is neutralized 10% sodium hydroxide, extracted with ethyl acetate and evaporated. Get a crude target product as a clear oil, which was subjected to purification by khromatograficheskii 90:10:1. Yield: 2.8 g, so pl. 58-64aboutC (decomposition) (in the form of dried hydrochloric salt).

MS 343 m/e [M + H]

CGH: diastereoisomer A, trace 13,53. The diastereoisomer, a trace of 14.76.

[Eluent: n-hexane, isopropanol and methanol in the ratio of 90:4:6, 25aboutS]

Calculated With 63,39; N 7,18; N 7,39.

WITH20H27ClN2O3.

Found, With 63,20; N 7,22; N 7,29.

P R I m e R 5. Piperidine-2-oxo-3-cyclohexyl-3-[(R)-1-azabicyclo(2.2.2)octyl]-CT - boxylic (compound 16).

1 g of potassium salts piperidine-2-oxo-3-cyclohexyl-3-carboxylic acid are added in several portions to the cooled solution of 10 ml of thionyl chloride in 10 ml of anhydrous benzene. The suspension is stirred at room temperature overnight, then evaporated to dryness. The resulting crude residue is suspended in 20 ml of anhydrous tetrahydrofuran, then with stirring added 0.96 g of R(-)-3-hinokitiol. The reaction mixture was stirred at room temperature for 4 h, then evaporated to dryness. The resulting crude residue was subjected to purification by chromatography column on silica gel using as eluent a mixture of methylene chloride, methanol and ammonium hydroxide in the ratio of 90:10:1 (Rf 0,22). Obtain 0.6 g of pure C is olistostromes salt).

MS 335 m/e [M + H]

CGH: diastereoisomer A, trace 8,73. The diastereoisomer, mark 10,28.

[Bounty: n-hexane, isopropanol and methanol in the ratio of 88:6:6, 25aboutS]

Calculated With 61,52; N 8,42; N 7,55.

WITH19H31ClN2O3.

Found, 61,41; N. Of 8.50; N 7,50.

P R I m e R 6. The bromide of azepin-2-oxo-6-phenyl-6-[(R)-1-azabicyclo(2.2.2)octyl] carboxylate (compound 17).

A solution of 0.5 g of azepin-2-oxo-6-phenyl-6-[(R)-1-azabicyclo(2.2.2)octyl]-carboxylate and 1.53 ml of methyl (2-molar solution in simple diethyl ether) in 7 ml of acetonitrile was stirred at room temperature for 2 days. The resulting solution was evaporated to dryness and by lyophilization obtain 0.55 g of the pure desired product in the form of a thick transparent oil. So pl. 60-68aboutC (decomposition) (after lyophilization).

CGH: diastereoisomer A, trace of 3.80.

[Eluent: acetonitrile, a 0.01-molar phosphoric acid with 0.02% triethylamine and water in the ratio of 30:40:30, at a temperature of 40aboutS]

Calculated With 57,67; N. Of 6.68; N 6,40.

WITH21H29BrN2O3.

Found, With 57,00; N 6,89; N 6,15.

Described in example 6 method from the corresponding intermediate compounds can be still is the carboxylate (compound 18).

So pl. 65-70aboutC (decomposition) (after lyophilization).

CGH: a mixture of diastereomers, mark 10,10.

[Eluent: acetonitrile, a 0.01-molar phosphoric acid with 0.02% triethylamine (pH 3) and water in a ratio of 20:60:20, 40aboutS]

Calculated With 59,61; N 6,74; N 6,05.

WITH23H31BrN2O3.

Found, 59,48; N 6,79; N 6,00.

The methyl piperidine-2-oxo-5-phenyl-5-[(R)-1-azabicyclo(2.2.2)octyl]-Carbo-celata. (compound 19).

So pl. 112aboutC (decomposition).

CGH: diastereoisomer A, trace cent to 8.85. The diastereoisomer, mark 9,34.

[Eluent: acetonitrile, phosphate triethylamine and water in the ratio 15:50: 35 40aboutS]

Calculated With 56,74; N To 6.43; N 6,62.

WITH20H27BrN2O3.

Found, 56,80; N 6,38; N 6,68.

Pharmacology

Antimuskarinovoe act occurs activity and selectivity.

Antimuskarinovoe act occurs the activity and selectivity were determined by in vitro experiments on the binding of receptors on the two types of tissue containing muscarinic receptors M1m M2, namely the cerebral cortex and heart, and functional experiments on isolated intestine and left presence Guinea pigs.

Experiments in vitro binding of Rezin of homogenized cortex, conducted in the following way.

For the experiment used the cerebral cortex of male rats weighing 220-250, the Process of homogenization was carried out in the environment sodium-magnesium with HEPES pH 7.4 (100 mmol NaCl, 10 mmol magnesium chloride and 20 mmol HEPES) filtering the suspension through double-layered cheesecloth. Curves on the activity of the investigated compounds were indirectly by the results of the control experiment with 0.5 nmol3N-pirenzepine marking muscarinic receptors in the cerebral cortex. 1 ml of a homogeneous mass incubated at a temperature of 30aboutC for 45 min in the presence of the marker ligand and cold ligands in different quantities, these conditions were reached equilibrium, as in the corresponding parallel experiments. The incubation was finished by centrifugation (12,000 rpm for 3 min). For removal of free radioactivity centrifugal washed twice with 1.5 ml of saline solution. Cut off the ends of the tubes containing centrifugal, was added 200 μl of tissue solubilizer and left to stand over night. Then add 4 ml of scintillation fluid (dimerum in toluene in a volume ratio of 1:10) and measured the radioactivity.

Experiments were performed three or four times and incubation contained 1 µm atropine sulphate. Nonspecific relationship averaged less than 30% of the Value D (dissociation constant) was determined by analysis of nonlinear regression, according to Ginzel, "Pharmacokinetics During Drug Development: Data Analysis and Evaluation Techniques", edited by G. Balzer and J. M. fan of Rossum, page 207, ed. G. Fischer, New York, 1982.

Antimuskarinovoe act occurs, the activity of M2was determined by analysis of displacement 3H-NMS from the homogenized heart in accordance with the described method.

The research results are summarized in the table.

These tables show that the new compounds are more selective than trading product pirenzepine (5,II-dihydro-II-[(4-methyl-I-piperazinyl)-acetyl]-6N-pyrido[2,3-b][1,4] benzodiazepine-6-one), published in the Rote Liste 1986, ed. Editio offices, DE, page 57, and the drug is No 59123).

New connections are classified srednetonnazhnyh substances.

1. Derivatives of R(-)-3-hinokitiol General formula

< / BR>
where R is an unbranched or branched lower alkyl, C3- C7-cyclo-C1-C2-alkylaryl;

R1hydrogen, unbranched or branched lower alkyl or acyl General formula R2CO., where R2hydrogen or an unbranched or branched missisquoi acid,

Y and Z are both oxygen or one oxygen or sulphur,

m and m are the same and mean the integer 0 or 1; n is 1,2 or 3;

p and p are the same and are 1 or different and denote 0 and 1,

and And and group 3-genociding ether are genialnom position

in the form of a mixture of their diastereomers, or an individual diastereoisomers or their salts.

2. Derivatives of R(-)-3-hinokitiol General formula

< / BR>
where R is an unbranched or branched lower alkyl, C3- C7-cyclo-C1C2-alkylaryl;

R1hydrogen, unbranched or branched lower alkyl or acyl General formula R2CO., where R2hydrogen or an unbranched or branched lower alkyl;

A C5C7cycloalkyl, phenyl, thienyl, pyridyl;

X is the anion of an organic or inorganic acid;

Y and Z are both oxygen or one oxygen or sulfur;

m and m are the same and denote 0 or 1;

n is 1,2 or 3;

p and p are the same and are 1 or different and denote 0 and 1,

where A and group 3-genociding ether are genialnom position, in the form of a mixture of their diastereomers, or an individual diastereoisomers or their pharmacologically-tolerated salts with antimouse

 

Same patents:

The invention relates to new chemical compound, particularly to a 10-methoxy-5-methyl-6-(1', 1'-dioxido-2' -meta-chlorvinyls-3'-hydroxy-4' -methoxy-benzo[b] thiophene-7-yl)-5H-3,4,6,7-tetrahydro[4,3,2-Q]-[3]benzazocine formula

(I) with an antidepressant

The invention relates to color components for selenocysteine negative photographic material, namely the new 1-(2,4,6-trichlorophenyl)-3-[2-chloro-5-(3-octadecylamino)aniline]- 4-(1-decyl-3,5-dimethylpyrazol-4-ylazo)pyrazolin-5-ONU formula I

CH= NNH< / BR>
This connection can be used as Magenta masking components (H-688)

The invention relates to derivatives of 2,4-bis-(pyridine)hintline, which can find application in agriculture for cotton defoliation

The invention relates to a series of racemic and optically active derivatives of pyrido[1,2-a] pyrazine, which are used as antidepressants and anxiolytics, as well as intermediates of these derivatives

The invention relates to the derivatives of pyrimidine, herbicide compositions and chemical method of weed control with their use

The invention relates to tetrahydropyrimidine derivative of formula (1) or their pharmaceutically acceptable salts, suitable as 3-HT3-capetronic antagonists:

(1) where Неt is a heterocyclic group, possibly substituted by 1-3 substituents selected from lower alkyl, lower alkenyl, lower quinil, group cycloalkyl-lower alkyl, arylalkyl, lower alkoxycarbonyl, halogen atom;

X represents a single bond attached to the carbon atom of the heterocyclic group

The invention relates to medicine and can be used to treat diseases caused by dopamine deficiency

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, cardiology, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I)

wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

41 cl, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with preventing hemodynamic complications at restoring circulation in a prolongly ischemized limb, or due to premeditated tourniquet application during operative interference. For this purpose, 5-12 min before the onset of circulatory restoration it is necessary to start intravenous injection of antihistamine and glucocorticosteroid preparations, followed by drop-by-drop infusion of inhibitors of proteolytic enzymes which should be continued after tourniquet removal, as well. The method provides tourniquet shock and tourniquet shock-associated complications along with developing the chance for increasing the duration period of operation.

EFFECT: higher efficiency of prophylaxis.

3 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

Up!