The method of producing aminocarbonylmethyl

 

(57) Abstract:

Usage: in chemistry derived carbamates, in particular in the method of producing aminocarbonylmethyl expressing cholinergic activity and capable of use as analgesic agents. The inventive method provides for receiving aminocarbonylmethyl f-ly I, in which Z is hydrogen or lower alkyl; R1is lower alkyl or halogenarenes; R2is lower alkyl or cycloalkyl, or 3S-CIS-isomers or 3R-TRANS-isomers or mixtures of these two isomers, including a racemic mixture, or their pharmaceutically acceptable acid additive salts. Synthesis of conducting the reaction of the compound f-ly III, where Z - see above in the case when (a) R1and R2- identical with the isocyanate f-ly: R1-NC(O), where R1- lower alkyl, at a molar ratio of isocyanate and compound f-ly III not less than 2 : 1, or in case b) R1and R2different, with isocyanate f-ly: R2-NC(O), where R2- see above, taken in an amount of about one equivalent relative to the compound f-III crystals with subsequent interaction of the obtained product with isocyanate f-ly: R1-NC(O). 3 table.

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with

The invention SUB> is lower alkyl, cycloalkyl or aryl; and

R2is lower alkyl or cycloalkyl;

which are used to mitigate various dysfunctions of memory, which are characterized by a cholinergic deficit such as disease Alzheimer and as analgesic agents.

Unless stated otherwise, the following definitions will be used throughout the patent description and claims.

The term "lower alkyl" denote linear or branched alkyl group containing from 1 to 7 carbon atoms. Examples of the above-mentioned lower Akilov include methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, secondary.-butyl, tration.-butyl and pentyl, hexyl, and heptyl linear and branched chain.

The term "cycloalkyl" will mean cycloalkyl group containing from 3 to 7 carbon atoms in the ring. The above cycloalkyl group may be substituted by 1 or 2 lower alkyl groups.

The term halogen will mean fluorine, chlorine, bromine or iodine.

The term "aryl" shall mean unsubstituted phenyl group or a phenyl group monosubstituted by lower alkyl, halogen, nitro, lower avania synthetic schemes above.

In the structural formula representing the compounds of the present invention, the bold lines , leaving 3A-carbon and 8A-carbon 1,2,3,3 and, 8,8 a-hexahydropyrazino(2,3-b)Indology ring system, mean that two deputies are above the mid-plane trehalase system, while the dashed lines indicate that two deputies are below the mid-plane trehalase system, and the wavy lines indicate that two deputies are either above or below above the mid-plane. Due to structural limitations, two Deputy in 3A and 8A positions must both be above the mid-plane, or both below the above the mid-plane. Thus, in formulas (I), (II) and (III) substituents in 3A and 8A-carbons are CIS, as they are on the same side trehalase system. In those cases, when the above-mentioned substituents are both above the mid-plane trehalase system configuration will be referred to as 3S-CIS, and in those cases when both Deputy are below the average plane of the ring, the configuration will be referred to as 3R-CIS. These two types of configurations are presented below.

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During the patent is to be the connection which 3S-CIS or 3R-Cys, or a racemic or other mixture of the two, then this formula will contain wavy line as shown below.

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The present invention includes both of the above CIS-isomer, namely 3S-CIS-isomer and 3R-CIS-isomer for the name or structural formula of each compound, although sometimes only one isomer is depicted in the patent description to save space. The present invention also includes all of the mixture 3S-CIS and 3R-CIS-isomers, including a racemic mixture (ratio 1: 1 3aS-CIS 3aR-CIS).

Synthetic scheme

Stage AND

On the basis of the compounds of formula II and using the synthetic scheme proposed by Julian and others (J. Chem. Soc, 1935, C. 563-566 and 755-757), it is possible to obtain the compound of formula III, as it is shown in the diagram below. About synthetic schemes, the reader is sent to the original articles.

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Stage

If you want to obtain the compound of formula I, in which R1is the same as R2the compound III provide an opportunity to interact with the isocyanate of formula R1NCO, where R1is lower alkyl or cycloalkyl. In a preferred embodiment, the molar ratio between the isocyanate is of the shavings of metal sodium in the reaction mixture in the presence of an appropriate solvent, such as tetrahydrofuran or dichloromethane, at a temperature of from about 20oC to the temperature of reflux distilled solvent.

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Stage

If you want to obtain the compound of formula I, in which R1different from R2then to compound III provide an opportunity to interact with the isocyanate of formula R2NCO, to obtain the compound of formula IV using essentially the same procedure described in stage except that the amount of isocyanate in the preferred embodiment is approximately 1 equivalent relative to the amount of compound III. Further, the compound IV provide an opportunity to interact with other isocyanate of formula R1NCO using the same procedure as described above to obtain compound I,

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The compounds of formula I, which is the subject of the present invention can be used in the treatment of various disorders of memory, which are characterized by cholinergic function, such as disease of Alzheimer.

This usage is confirmed by the ability of these compounds to inhibit the enzyme acetylcholinesterase and thus to increase the concentration of acetylcholine in the brain.

Analysis of the inhibition of the pigs. However, only the distribution of brain acetylcholinesterase (AChE) correlates with Central the cholinergic innervation. It's the same innervation, which should be mitigated with the disease of Alzheimer. Therefore, special inhibitors of brain AChE (as opposed to AChE serum) will give less side effects and, thus, lower toxicity than physostigmine (nonspecific inhibitor of AChE). The applicant determined the in vitro inhibition of the acetylcholinesterase activity in the striped bodies of the rat brain. The results of this analysis for the representative compounds, which are the subject of the present invention, and physostigmine (connection-prototype) are given in table. 1.

Inhibition of in vitro activity of acetylcholinesterase in striped bodies of rats

The acetylcholinesterase (AChE), which is sometimes called a real or specific cholinesterase found in nerve cells, skeletal muscle, smooth muscle, various glands and red blood cells. AChE can be distinguished from other cholinesterase using specificdate substrate and inhibitor and with the help of regional distribution. Its distribution in the brain correlate with cholinergic undervalue accepted what is the physiological role of AChE is the rapid hydrolysis and inactivation of acetylcholine. Inhibitors for AChE have a noticeable "holinoblokatorami" effects in organs with cholinergic induced effects and has been used for therapeutic purposes in the treatment of glaucoma, myasthenia gravis during pregnancy and paralytic ileus. However, recent studies have shown that inhibitors of AChE can also be used in the treatment of dementia of Alzheimer.

The procedure described below, are used in accordance with the present invention to analyze the activity of anti-cholinesterase. It is a modification of the procedure of Ellman and others (Biochem. Pharmacol. 7, S. 98 (1961)).

Procedure

A. Reagents

1. 0.05 M phosphate buffer, pH 7,2

(a) 6.85 g NaH2PO>4H2O/100 ml distilled H2O

(b) 13,40 g Na2HPO47H2O/100 ml distilled H2O

(c) add (a) (b) up until the pH reaches 7.2 for

(d) dilute 1:100

2. The Chromogen-substrate buffer

(a) to 9.9 mg of 5,5-dithiobisnitrobenzoic acid (DTNB) (0.25 mm)

(b) 99 mg S-acetylthiocholine chloride (5 mm)

(c) to a volume of 100 ml of 0.5 M phosphate buffer, pH 7,2 (reagent 1)

3. For most analyses wearable is so, that the final concentration at the stage of predictably varies from 10-3up to 10-6Meters Can be used in various concentrations depending on the strength of the drug.

C. exposure of the fabric

Male Wistar rats decapitat, the brain quickly removed, striped body cut off, weighed and subjected to homogenization in 19 volumes (approximately 7 mg protein/ml) in 0.05 M phosphate buffer, pH 7,2, using a homogenizer (Potter-Elvehjem. Portion 50 μl of homogenate added to 50 μl of media containing various concentrations of the test drug and pre-incubated for 10 min at room temperature.

C. Analysis

1. For the well-known definitions IC50use a Bichromatic Analyzer Abbott, AVA-100 to determine the activity of acetylcholinesterase.

Tools

Filter: 450-415

Temperature of incubation: 30oWITH

Decimal point: 0000

Analysis time: 5 min

Rotation of the Carousel: 3

The direction of reaction: reduction

the end

Cup with a syringe: dilution 1:101

After 10 min pre-incubation of tissue enzyme with the inhibitor sample is mixed with chromogenic buffer subset reactions and prints the results in units of the enzyme after 15 minutes

2. Enzyme activity can also be measured using a spectrophotometer Guildford 250. This procedure is used for more accurate kinetic measurements.

Tools

Lamp Visible range

The filter is Not used

The wavelength of 412 nm

Slit width of 0.2 mm

Breeding Small hole

Calibrated absorption of 1.0 unit full scale

The speed of the chart paper 0.5 cm/min

Reagents added to the side of the template and sample cuvettes with gaps, as follows:

Template Sample

0,08 ml of 0.05 M phosphate buffer 0.8 ml of 0.05 M phosphate buffer

0.8 ml of the Chromogen-substrate buffer 0.8 ml Chromogen-substrate buffer

10 μl of enzyme (tissue homogenate)

First, determine eingeborenen enzyme activity (tissue homogenate). The test drugs are dissolved in appropriate solvents and add after appropriate dilution in buffer media. The reaction rate is determined by the slope of the recorded changes of absorption. Actual speed (moth-liter-min) can be calculated, as indicated in the following formula:

rate (mol/liter/min)/tilt(1,36 x 104).

The results are shown in table. 1.

Analysis on fear of the Dark

In this assay, mice are tested on their ability to remember the unpleasant effects within 24 hours the Mice are placed in a chamber which contains a dark room; highly incandescent light leads them into a dark room, where through the metal plate on the floor for them to apply the electrical section. The animal is removed from the apparatus for testing and feel, after 24 h, the ability to memorize electric discharge.

If scopolamine, known in this area antiholinergiceski agent used for memory loss, to apply to the animal before the first location of the animal in the chamber for testing, it will enter a dark part of the chamber shortly after placing it in the camera for testing 24 hours later. This action of scopolamine blocked active test compound, which leads to a longer interval before re-entry of the animal into a dark room.

These results for active compounds are expressed in percentage of animals in which the effect of scopolamine is blocked, as evidenced by the increase in the interval between the location in the camera to test and re-entrance into a dark room.

Resue prototype) are presented in table. 2.

The compounds I, which is the subject of the present invention can also be used as analgesic agents due to their ability to alleviate pain in mammals. The activity of these compounds is confirmed through testing on mice, in which pain is stimulated by the application of 2-phenyl-1,4-benzoquinone (PQW), standard test sedation (Proc. Soc. Exptl. Biol. Med, 95, S. 729 (1957)).

The suppression of pain in mice, caused by familienaam (PQW)

a 0.125% concentration of phenyl-para-benzoquinone in 5% aqueous ethanol solution was applied to mice (10 ml/kg, intraperitoneal). This causes specific "pain", which manifests itself in the form of inward rotation of one or more legs, curvature and rotation of the trunk, the tension of the abdominal wall, lordosis and bending of the back. Only 28 of male mice Charles river CD-I (18-30 g) were used for the analysis of reaction time. Animals get food and water freely during their detention in the cells before the test. Connection experience at a dose of 20 mg/kg (subcutaneously) and dose prepared using distilled water, and if the connection is not dissolved, then add one drop of Tween-80, surface-to aktivnaya (five in each group) at various times pre-treatment (for example, 15, 30, 45 and 60 min before injection of finishinga. Control animals (two per group) will receive an equal volume of media. After applying finishinga mice are placed individually in the chemical glasses 1 l and within 5 minutes to give an opportunity to "Relax". Then the mice were observed for 10 min and the number of attacks of pain recorded for each animal. The formula for calculating the inhibition percentage is:

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The time period with the maximum percentage of inhibition is considered as the peak time. Response to doses were maintained for interesting compounds or compounds which inhibit the attacks by 70% or more. The test reaction, the dosage is carried exactly the same as on the reaction time, except that they have 10 animals per group at peak times of activity of the drug.

Use fifty animals divided into four groups, which give the carrier. Mice in the General case is given four doses of the drug each time, twice the number of previous doses. ED50calculated using linear regression analysis on the computer.

The results of this analysis for several compounds which are the subject of this izobreteniya, which is the subject of the present invention can be applied to the patient, for example, by any known method, in particular, tematicheskie in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. Free main final products, although they are effective by themselves, can be used for the manufacture of various forms and applied in the form acceptable from a pharmaceutical point of view, attached salts of the acids with the aim of stability, convenience of crystallization, higher solubility, etc.

Acid, which is used to produce acceptable in the pharmaceutical point of view attached salts of acids in accordance with the present invention include inorganic acids such as hydrochloric, Hydrobromic, sulphuric, nitric, phosphoric and perchloric acid and organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids.

Active compounds that are the subject of the present invention can be applied tematicheskie, for example, with an inert diluent or entrances. Order tematicheskoe therapeutic application of the active compounds of the present invention may be incorporated with excipients and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gum, etc., These preparations should contain at least 0.5% of active compound, but this number can vary depending on the specific forms and can range from 4 to about 7 wt. form. The number of active compound in such compositions is such to provide the appropriate dose. Preferred compositions and spooling, which is the subject of the present invention, receive so that tematicheskie the form of a unit dose contains from 1.0 to 300 mg of active compound.

Tablets, pills, capsules, lozenges, etc. can also contain the following ingredients: binding material, such as microcrystalline cellulose, resin tragakant or gelatin; an excipient such as starch or lactose, loosening agent, such as aginova acid, primogel, corn starch, etc., lubricating agent such as magnesium stearate or sarotex; acenti slip such as colloidal silicon dioxide; and flavoring agents such as somatizers agent. When the form of a unit dose is a capsule, it may contain in addition to materials of the above type, a liquid carrier such as fatty oil. Other forms of unit doses may contain various other materials which modify the physical form of a unit dose, for example, in the form of a coating. Thus, tablets or pills may be coated with sugar, shellac or other "tookececmy" covering agents. A syrup may contain, in addition to the active compounds, sucrose as a flavoring agent and some preservative agents, colouring agents and flavouring agents. The materials used in the preparation of these various compositions should be pharmaceutically pure and non-toxic in the quantities used.

The purpose of parenteral therapeutic application of active compounds that are the subject of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but this number can vary from 0.5 to about 30 wt. The number of active compound in such compositions is such that it must be received at the appropriate dose. Preferred compositions and spooling of showing,5 to 100 mg of active compound.

The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; hepatoblastoma agents, such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the regulation of tone, such as sodium chloride or dextrose. Parenteral spooling can be introduced into the syringe or bubbles for multiple doses, made of glass or plastic.

Examples of compounds that are the subject of the present invention include those listed below, as well as their 3R-CIS isomers and mixtures 3S-CIS and 3R-CIS isomers, including racemic mixtures:

(3S-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a,8-trimethylpyrrole[2,3-b]indol-5-yl methyl[(methylamino)-carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and 8,8 and hexahydro-and 1,3,7,8-tetramethylspiro [2,3-b]indol-5-yl methyl[(methylamino)carbonyl]carbamate;

(3aS-CIS)-7-bromo-1,2,3,3 and, 8,8-hexahydro-1.3 a,8-trimethylpyrrole[2,3-b] indol-5-the propyl[(propylamino)carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[[(3-chlorophenyl)amino]carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl heptyl[(heptylamine)carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[(heptylamine)carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[(cyclohexylamino)carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl heptyl[(propylamino)carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[(phenylamino)carbonyl]carbamate;

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[[(4-were)amino]carbonyl]carbamate;

(3aR-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[[(3-chlorophenyl)amino]carbonyl]carbamate;

CIS-()-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole [2,3-b]indol-5-yl propyl[(propylamino)carbonyl]carbamate.

Example 1

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[(methylamino)carbonyl]carbamate

Degassed solution of physostigmine (3.0 g) in tetrahydrofuran (13 ml) processing is. The mixture was stirred at room temperature for 18 h and then was heated to 45oWith 3.5 hours At the end of the reaction period, the solution was concentrated to an oil foam and the crude product was subjected to purification using rapid chromatography on silikagelevye column. The resulting solid product (1.3 g) was subjected to recrystallization from dichloromethane (4 ml) and isopropyl simple ether (40 ml), to obtain crystals of 1.03 g, melting point 157-158oC.

Analysis:

Calculated for C17H24N4O3: 61,43% C, 7,28% H, 16,85% n

Found: 61,31% C, 7,26% H, Ls 16.80% N

Example 2

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 7,8-tetramethylspiro [2,3-b] indol-5-yl methyl[(methylamino)carbonyl]carbamate

Degassed solution of 7-methyl eseroline (500 mg) in tetrahydrofuran (8 ml) was treated with shavings of sodium (3 mg) and methyl isocyanate (0.7 ml) at room temperature for 20 minutes the Reaction was observed on the plate for TLC (thin layer chromatography Tr). Shaving sodium was removed, and the solution was concentrated until dry. The residue was extracted in a simple ether (100 ml), and insoluble particles were separated by filtration. The crude product of simple ether was subjected ochistki product (400 mg) was dissolved in a simple ether (30 ml) and once filtered, and then concentrated again to oil. The oil was utverjdali isopropyl simple ether (1 ml). After recrystallization of the solid matter from isopropyl simple ether (4 ml) was obtained crystals (358 mg), melting point 147-149oC.

Analysis:

Calculated for C18H26N4O3: 62,41% C, 7,56% H, 16,17% n

Found: 62,40% C, to 7.59% H, 16,08% n

Example 3

Hemihydrate (3S-CIS)-7-bromo-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole [2,3-b]indol-5-yl methyl[(methylamino)carbonyl]carbamate

To a solution of 7-bromo of physostigmine (1,87 g) in tetrahydrofuran (20 ml) was downloaded methyl isocyanate (1.0 g) and a catalytic amount of sodium. The mixture was heated overnight to 50oC. the Reaction solution was concentrated to oil. The oil was subjected to purification using operational chromatography twice with silikagelevye columns. The most pure fractions were combined to obtain a colorless oil (650 mg). After crystallization from a small number of simple broadcast received 420 mg of crystals, melting point 105-108oC. This material, as it turned out, was the hemihydrate and clean that was installed using TLC using SiO2-plates.

Analysis:

Example 4

Oxalate (3S-CIS)-1,2,3,3 and 8,8 and hexahydro-1.3 a,8-trimethylpyrrole[2,3-b] indol-5-yl propyl[(propylamino)carbonyl]carbamate

The solution eseroline (1.7 g) and n-propyl isocyanate (1.5 g, 2.2 equivalents) in 50 ml of degassed dry tetrahydrofuran was treated with shavings of metal sodium (0.2 g) and stirred at ambient temperature. After 16 h, the solution was heated to reflux distilled for 4 h, and then concentrated. The residue was subjected to purification using operational chromatography to obtain the result of 2.1 g of oil. This oil was transferred into a simple ether and treated with oxalic acid (0.8 g) and concentrated. The residue was subjected to recrystallization from methanol/simple ether to obtain 1.9 g of crystals, melting point 125-127oC.

Analysis:

Calculated for C21H32N4O3C2H2O4: 57,72% C, 7,16% H, 11,71% n

Found: 57,72% C, 7,44% H, 11,76% n

Example 5

(3aS-CIS)-1,2,3,3 and, 8,8-hexahydro-1.3 a, 8-trimethylpyrrole[2,3-b] indol-5-yl methyl[[(3-chlorophenyl)amino]carbonyl]carbamate

Degassed solution of physostigmine (2,75 g) in tetrahydrofuran (30 ml) were loaded 3-chlorophenyl-isocyanate (1.65 g, 1.1 equivalent) and not the second ether and filtered. The solid was subjected to recrystallization from a mixture of dichloromethane/isopropyl simple ether (10 ml 10 ml) to obtain 3.4 g, melting point 144-146oC.

Analysis:

Calculated for C22H25ClN4O3: 61,61% C 5.88 per cent H, 13,06% n

Found: 61,31% C, 5,91% H, 12,94% N.

The method of producing aminocarbonylmethyl General formula I

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where Z is hydrogen or lower alkyl;

R1lower alkyl or halogenfree;

R2lower alkyl,

their 3aS-CIS-isomer, or 3aR-CIS-isomer, or mixtures of these two isomers, including a racemic mixture, or acceptable from a pharmaceutical point of view of acid additive salts, characterized in that conduct the interaction of compounds of General formula III

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where Z is the specified value,

in the case when R1and R2identical with the isocyanate of General formula

R1NCO,

where R1lower alkyl,

when the molar ratio of the isocyanate and the compound III is not less than 2:1, or in the case when R1and R2different, with the isocyanate of General formula

R2NCO,

where R2has the specified value,

taken in an amount of about one equivalent relative to coom General formula

R1NCO,

where R1has the specified value.

 

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0 (a)

N-O-R3(b) or

SN-R4(c);

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FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

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(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

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

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

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