2-heteroaryl-5,11-dihydro-6n-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6-ones, their pharmaceutically acceptable salts, pharmaceutical composition having inhibitory activity against reverse transcriptase of hiv-1

 

(57) Abstract:

Describes the new 2-heteroaryl-5,11-dihydro-6N-dipyrido[3,2-b;2',3'-e] [l, 4] diazepin-6-ones, their pharmaceutically acceptable salts, pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1 of General formula I, where R1R2and AG are specified in paragraph 1 of the claims value, and their pharmaceutically acceptable salts. The compounds of formula I and their salts can be an active ingredient of the pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1. 2C. and 3 C.p. f-crystals, 2 PL.

The invention relates to new derivatives dipyridodiazepinone possessing biological activity, and more particularly to 2-heteroaryl-5,11-dihydro-6H-dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-Onam, their pharmaceutically acceptable salts and pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1.

Known derivatives of dipyrido-diazepinones, which can be an active ingredient of the pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1 (see sibirica-diazepinones, possessing inhibitory activity against reverse transcriptase of HIV-1.

This task is solved by the proposed 2-heteroaryl-5,11-dihydro-6H - dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-ones of General formula (I)

< / BR>
where R1means a hydrogen atom or alkyl with 1 to 3 carbon atoms;

R2means alkyl with 1 to 4 carbon atoms or cycloalkyl with 3-6 carbon atoms;

Ar denotes a group of formula (a) - (d)

< / BR>
where R3means hydrogen, methyl, ethyl, acetyl or aminocarbonyl, each of R4, R5and R6means hydrogen; or one of R4, R5and R6means methyl, acetyl, etoxycarbonyl, carboxypropyl, aminocarbonyl or cyano, and the other two Deputy both signify hydrogen; each of A, B, D, and E is retinovoy group, one of which may be substituted by alkyloxy with 1 to 3 carbon atoms,

or their pharmaceutically acceptable salts.

The first group preferred diazepinones General formula (I) include compounds in which

R1means a hydrogen atom, alkyl with 1 to 3 carbon atoms;

R2is alkyl with 1 to 3 carbon atoms or cycloalkyl with 3-4 carbon atoms;

The Ar group of formula (a) - (d), where R3Osnach and R6means methyl, acetyl, etoxycarbonyl, aminosulfonyl or cyano, and the other two Deputy both signify hydrogen; each of A, B, D, or E is retinovoy group, one of which may be substituted by alkyloxy with 1 to 3 carbon atoms, or their pharmaceutically acceptable salts.

The second group preferred diazepinones General formula (I) include compounds in which

R1means methyl;

R2means alkyl with 2 to 3 carbon atoms or cycloalkyl with 3-4 carbon atoms;

Ar denotes a group of formula (a), (b) or (C), where R3means hydrogen or methyl; each of R4, R5and R6means hydrogen; or one of R4, R5and R6means methyl, acetyl, etoxycarbonyl, aminocarbonyl or cyano, and the other two Deputy denote hydrogen; or

Ar denotes a group of formula (d) or (e), where R3means hydrogen or methyl; each of R4, R5and R6means hydrogen;

each of A, B, D, and E is retinovoy group, one of which may be substituted by alkyloxy with 1 to 3 carbon atoms, or their pharmaceutically acceptable salts.

The third group preferred diazepinones General form is up [3,2-b:2',3'-e] [1,4]diazepin-6-it;

11-cyclopropyl-5,11-dihydro-5-methyl-2-(3-pyrrolyl)-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-it;

11-cyclopropyl-5,11-dihydro-5-methyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-it; and

5,11-dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b:2',3'-e] [1,4]diazepin-6-it;

and their pharmaceutically acceptable salts.

Compounds of General formula (I) can represent an active ingredient of the pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1, which in addition to the pharmaceutically acceptable carrier contains a proposed connection in prophylactically or therapeutically effective amount.

The proposed connection can be obtained well-known methods. For example, the compound of General formula (II)

< / BR>
where R1and R2have the above meanings and R7is a leaving group, e.g. chlorine, bromine, iodine or triftormetilfullerenov, is subjected to the interaction with the connection of anti-formula (III)

Ar-SnBu3(III)

where Ar has the above meaning, in the presence of a catalyst, preferably a palladium catalyst such as tetrakis(triphenylphosphine)-palladium(O), teady (II).

The reaction is usually carried out in an atmosphere of inert gas, argon or nitrogen, or in an inert solvent, such as 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and the like, typically at a temperature between room temperature and the boiling point of the solvent. In some cases, there may be used compounds trimacinolone corresponding to the presence of TBT compounds of the formula (III).

Another way is that the compound of the above General formula (II) is subjected to interaction with tsinkorganicheskih compound of formula (IV),

Ar-ZnCl, (IV)

where Ar has the above meaning, which can be obtained by addition of zinc chloride to the organolithium compound of the formula (V),

Ar-Li, (V)

where Ar has the above meaning.

The reaction is usually carried out similarly to the above described method, i.e., in the atmosphere of inert gas, e.g. argon or nitrogen, and in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(O) tetrakis(triphenylarsine)palladium(O), tetrakis(tri-2-furifosmin)palladium(O) or chloride bis(triphenylphosphine)palladium(II). Usually an inert solvent, such as 1,4-dioxane, tetrahydrofuran, sulphuric ether and n is storytale.

The original compound of formula (II) can be obtained by cyclization of the appropriate amide of carboxylic acids of the formula (VI),

< / BR>
where R1, R2and R7have the above meaning and Hal means chlorine, bromine, fluorine or iodine.

The cyclization is usually carried out by transformation of compounds of formula VI in the alkali metal salts and the subsequent condensation at temperatures between 0oC and the boiling point of the reaction mixture. If R1means alkyl, metallation requires at least 1 mol metalliser agent. If, on the other hand, R1is hydrogen, it is necessary to use at least 2 mol of this agent. For metallation preferably used hydrides of lithium, sodium or potassium or alkali lithium, such as n-utillity.

The cyclization reaction is usually carried out in inert solvents, e.g. tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diglyme, triglyme, dimethylformamide, benzene or anisole. Cyclization also contributes to heating the amides of carboxylic acids of the formula (VI) in dipolar aprotic solvents, preferably in sulfolane or dimethyl sulfone. Shows the usefulness of the use of catalytic amounts of strong acids to note is econsultancy or p-acid, polyphosphoric acid, methanesulfonate or p-toluenesulfonic acid. The desired reaction temperature is between 110 and 220oC.

To obtain the compounds of formula II, where R7is triftormetilfullerenov (triflate"), you must first obtain a connection, where R7is a methoxy group. The resulting intermediate compound then subjected to demethylation in the processing of a suitable acid, such as concentrated Hydrobromic acid or trichromacy Bor. The resulting intermediate compound with a hydroxyl group is then subjected to transformation in triplet when processing anhydride of triftoratsetata, usually in the presence of a weak base, such as N,N-diisopropylethylamine or triethylamine.

Amides of carboxylic acids of the formula (VI) used as starting materials are produced, for example, when the aminating amides of 2-chloronicotinic acid of the formula (VII),

< / BR>
where R1, R7and Hal have the abovementioned meaning, with the primary amines of the formula (VIII)

H2N-R2, (VIII)

where R2have the above meaning.

The reaction can be also carried out the min or carbonates of sodium or potassium. The reaction can be carried out without solvent; some advantage, however, makes the use of inert organic solvents at temperatures between 0oC and 175oC, preferably at the boiling point. Suitable inert solvents which may be used include the excess primary amine of General formula VIII, ethers, open-chain or cyclic, such as tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diglyme; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene or pyridine; alcohols, such as methanol, ethanol, isopropanol; dipolar aprotic solvents, such as dimethylformamide; 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-tetrahydro-2(1H)-pyrimidinone and sulfolan.

Intermediate compounds of formula (VII), where R1means alkyl, can be obtained by alkylation of 2-chloronicotinic acid of formula (IX)

< / BR>
where R7and Hal have the abovementioned meaning, with a compound of formula (X)

R1X (X)

where R1means alkyl, and X is an appropriate leaving group, for example, X is a reactive residue of ester, halogen atom, the group OSO2OR1methansulfonate or econsultancy, as triethylamine, diazabicyclo, 4-(dimethylamino)pyridine, or hydroxides of alkaline or alkaline earth metals, such as caustic soda, caustic potash, calcium hydroxide, carbonates of alkaline or alkaline earth metals or bicarbonates, such as sodium carbonate or potassium or potassium bicarbonate.

Amides of 2-chloronicotinic acid of General formula (IX) can be obtained by condensation of the appropriately substituted acid chloride of 2-chloronicotinic acid with an appropriately substituted 3-amino-2-halogenopyrimidines in a well-known reaction conditions.

All other source materials required for the preparation of compounds of formula (II) are known from the literature, they can be purchased or can be obtained using methods known from the literature.

The compound of formula (II), where R2and R7have the above significance, and R1means alkyl, can be obtained by transformation of a compound of formula (XI)

< / BR>
R2and R7have the above value into the corresponding compound containing alkali or alkaline earth metal in position 5, and the subsequent reaction of the compounds with the alkaline metal connected with the tion of the compounds of formula (XI), its corresponding salt with the alkaline metal in the first stage, alkylation of compounds of formula (XI) can also be carried out by the reaction with the compound of the formula (X) in the presence of amines, such as triethylamine, diazabicyclo or 4-(dimethylamino)pyridine, or carbonates and bicarbonates of alkali metals, such as carbonates of sodium and potassium or sodium bicarbonate.

The transformation of compounds of formula (XI) in the corresponding connection with the alkaline or alkaline earth metal may be effected by the reaction of compounds of formula (XI) with a hydroxide of alkali or alkaline earth metal, such as lithium hydroxide, a hydrate of barium oxide, caustic soda or sodium hydroxide, alcoholate of an alkali metal such as sodium methylate or tert-butyl potassium, amidon alkali metal such as sodium amide or potassium amide, or alkali metal hydride such as sodium hydride or potassium hydride. The reaction is usually carried out in the presence of a suitable organic solvent at temperatures between -78oC and +60oC, preferably at room temperature. Inert organic solvents, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, toluene or pyridine, preferred, if the hydrides of alkali metals is zemelnogo metal, can also be applied aqueous mixture with an organic solvent such as methanol or tetrahydrofuran. For the conversion of the thus obtained substituted alkali or alkaline earth metal 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-it is in the compound of General formula (II), the solution of suspension of compounds containing alkali or alkaline earth metal, is subjected directly, i.e. without isolation, the reaction with the compound of the formula V at -20oC or at higher temperatures up to the boiling point of the solvent or reaction medium, any below. Substitution occurs almost exclusively on the nitrogen atom position 5 dehydrodimerization, even if R2in the original substance of the formula (XI) is a hydrogen atom, in the case when using one equivalent of base and one equivalent of the compound of formula (X).

Intermediate compounds of formula (XI) can be obtained by cyclization of the appropriately substituted compounds of formula (VI). This is the preferred method in cases when the ability to cyclization can be weakened if R1means alkyl.

The compound of formula (II), where R1and R7have the above significance, pin 6-she of the formula (II), where R2is hydrogen, the corresponding metal salt of the formula (XII)

< / BR>
where M represents alkali metal such as lithium, sodium, potassium, rubidium or cesium, or M represents a group MgHal+where Hal means chlorine atom, bromine or iodine, and subsequent alkylation with a compound of formula (XIII)

R2X, (XIII)

where R2and X have the above meaning.

The conversion of intermediate compounds of formula (II) into the corresponding compound containing an alkaline metal, formula (XII) can be carried out by the reaction of compounds of formula (II), where R2is hydrogen, alkyllithium (for example, with n-butyllithium or tert-butyllithium), in the presence of tetramethylethylenediamine, dialkylamino lithium (for example, diisopropylamide lithium, dicyclohexylamine lithium and isopropyl-cyclohexylamine lithium), with abilities (for example, phenyllithium), hydroxide of alkaline metal (for example, a hydroxide of lithium, sodium or potassium), alkali metal hydride (e.g. sodium hydride or potassium), with amidon alkali metal(for example, inorganic salts of sodium or potassium) or with a Grignard reagent (for example, methylmagnesium, ethylmagnesium or phenylmagnesium). One equina organic solvent at temperatures between -78oC and the boiling point of this reaction mixture. If for metallation use alkylate, ability, dialkylamide lithium or Grignard reagent, the preferred solvents are ethers, such as tetrahydrofuran, sulphuric ether or dioxane, in a mixture with aliphatic or aromatic hydrocarbons, such as hexane or benzene, and the process can be carried out at temperatures between -20 and +80oC. When the metallation is carried out using alkali metal hydride or alkali metal amide, in addition to the solvents mentioned previously, it is also possible to use xylene, toluene, acetonitrile, dimethylformamide and dimethylsulfoxide, when applied hydroxide of an alkali metal, it is also possible to use alcohols, such as ethanol, methanol, and aliphatic ketones, such as acetone, and mixtures of these solvents with water.

For the conversion of the thus obtained alkali metal salt in the compound of formula (II), where R2means alkyl, solution, suspensions compounds containing alkali metal, is subjected to reaction directly, i.e. without isolation of the reaction product with a compound of the above formula (XIII) at temperatures between -20 formula (I) can be optionally converted into their non-toxic, pharmaceutically acceptable salt, obtained as a result of the merger of acid or base by standard methods; for example, by dissolving the compounds of formula (I) in a suitable solvent and the processing solution of one or more molar equivalents of the desired acid or base in accordance with the necessity. The invention also includes such salts.

Examples of inorganic and organic acids, which can form as a result of the merger, non-toxic, pharmaceutically acceptable salts with the compound of the formula (I) are the following: hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonate, tartaric acid, fumaric acid, acetic acid and the like. Examples of inorganic and organic bases which can form as a result of the merger, non-toxic, pharmaceutically acceptable salts with the compound of the formula (I) are as follows: caustic soda, sodium hydroxide, a hydroxide of magnesium, ammonium, tromethamine and the like. The compounds of formula (I) can form salts when joining one molar equivalent of acid or base in accordance with the necessity.

As already in the HIV-1. The inhibition of reverse transcriptase of HIV-1, they ultimately inhibit or suppress the ability of the virus to integrate its genome into the genome of the potential cells of the host body, which, in turn, inhibits or suppresses viral replication. When injected into suitable dosage forms, either alone or in combination with other antiviral agents, immunomodulators, antibiotics, drugs that reduce the risk of infection or vaccines, these compounds are thus useful for the prevention or treatment of infection caused by HIV-1. Another aspect of the invention, therefore, is a method for the prevention or treatment of infection caused by HIV-1, which provides for the introduction of man exposed to infection or infected by HIV-1, prophylactically or therapeutically effective amount of the new compounds of formula 1, as described above.

Used herein, the terms "infection caused by HIV-1" means the replication of HIV-1 in humans.

Used herein, the term "treatment of infection caused by HIV-1" encompasses the full or partial inhibition or suppression of HIV-1 replication in humans, in which the replication of the virus which engages in a complete prevention of the implementation of the replication of the virus in the human body, who were exposed to HIV-1, but in which the replication of the virus has not yet begun to happen.

Compounds of the present invention are effective means to treat infections caused by HIV-1, because of their ability to partially or fully inhibit or suppress the replication of HIV-1 in infected humans.

When used for treatment of infection caused by HIV-1, the compounds of the present invention can be introduced either before or after the onset of clinical manifestations of infection caused by HIV-1, such as a complex of related to AIDS, ARC, or AIDS.

Compounds of the present invention is effective for prevention caused by HIV-1 infection in humans, due to the ability of these compounds to prevent the implementation of the replication of the virus in humans who were exposed to HIV-1, but in which the replication of the virus has not yet begun to happen.

The compounds of formula (I) can be administered in single or fractional doses by mouth, parenteral or topical way. Suitable ingestion dose for the compounds of formula (I) may be in the range of from 100 mg to 3 g per day. The preferred dose for ingestion connection 2 grams per day. In dosage forms for parenteral administration suitable unit dose may contain from 0.1 to 250 mg of these compounds, preferably from 1 mg to 200 mg, while, as for the topic of introducing prefer a finished dosage form that contains from 0.01 to 1% active ingredient. It should, however, note that the input dose will vary from patient to patient and the dosage for each individual patient will depend on the judgment of the Clinician, which will be used as a criterion to determine the appropriate dosage size and condition of the patient, and the response of the patient to the drug.

When the compounds of the present invention must be entered through the mouth, they can be introduced as a medicine in the form of pharmaceutical preparations which contain them in combination with a compatible pharmaceutical carrier. This carrier may be an inert organic or inorganic carrier suitable for administration through the mouth. Such carriers are, for example, water, gelatin, talc, starch, magnesium stearate, Arabic gum, vegetable oils, polyalkylene glycols, vaseline and the like media.

The pharmaceutical preparations can be przygotowany and the like, or liquid, for example, solutions, suspensions, emulsions and the like. The pharmaceutical preparations can be subjected to such a standard for their operations, as sterilization. Further, the pharmaceutical preparations may contain the usual ancillary medicinal substance, such as protecting tools, stabilizers, emulsifiers, chemicals, improves taste, moisturizing agents, buffers, salts for modifying the osmotic pressure and the like. Solid carriers which may be used include, for example, starch, lactose, mannitol, methylcellulose, microcrystalline cellulose, talc, silicon dioxide, secondary acidic calcium phosphate and high-molecular polymers (such as polyethylene glycol).

For parenteral administration, the compound of formula (I) may be introduced in an aqueous or nonaqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, protecting tools, buffers, or other soluble substances to give the same solution with the blood osmotic pressure, thickening agents, suspendresume agents or other pharmaceutically acceptable is likely, the polyethylene glycol, complexing agents (such as, for example, ethylenediaminetetraacetic acid), antioxidants (such as sodium bisulfite, sodium metabisulfite and ascorbic acid), high molecular polymers (such as liquid polyethylene oxides) to control viscosity and polyethylene derivatives of sorbitol anhydrides. If necessary, add also protecting means, such as benzoic acid, methyl or propyl ester of p-aminobenzoic acid, alkyldimethylbenzylammonium chloride and other Quaternary ammonium compounds.

The compounds of this invention can also be entered in the form of solutions for use through the nose and may contain in addition to the compounds of the present invention suitable buffers, regulators tone, means of protection from germs, antioxidants and increases the viscosity of funds in an aqueous solvent. Examples of agents used to increase the viscosity, are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, Polysorbate or glycerin. Added means of protection from germs may include alkyldimethylbenzylammonium chloride, thimerosal (utilitysimilar sodium), PI is t to be entered using the suppository.

The compounds of this invention can be administered either separately or in combination with other antiviral agents, immunomodulators, antibiotics, drugs that reduce the risk of infection or vaccines. For example, the compounds of this invention can be introduced in combination with one or more known nucleoside analogues reverse transcriptase inhibitors of HIV, such as azidothymidine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC), other non-nucleoside inhibitors of HIV reverse transcriptase or HIV protease inhibitors.

As established previously, the compounds provided by the invention, inhibit the enzymatic activity of the reverse transcriptase of HIV-1. Based on the testing of these compounds, as described below, you can see that they inhibit RNA-dependent DNA polymerase activity of the reverse transcriptase of HIV-1.

It is known (data not shown), they also inhibit DNA-dependent DNA polymerase activity of the reverse transcriptase of HIV-1.

When using analysis of reverse transcriptase (RT), described below, compounds may be tested for ability to inhibit RNA-dependent DNA polymerase activity of reverse track way. The results of this test are given in table. 1.

Analysis of the reverse transcriptase (RT).

Theory analysis:

Among enzymes, in favor of which encodes immune deficiency virus human (HIV-1) is a reverse transcriptase (1), so named because it transcribers copy of DNA to messenger RNA. This activity can be quantitatively measured in the analysis of free cells of the enzyme, which has been described previously (2) and is based on the observation that reverse transcriptase is able to use synthetic matrix [poly r(C) initiated by oligo d(G)] to play radioactively labeled, acid precipitable DNA strand, using3H-deoxyguanosine-5'-ripoff as substrate. The analysis, described below, uses the wild-type enzyme, which is the predominant form of the enzyme observed in patients infected with HIV-1. The use of a mutant reverse transcriptase inhibitors (Y181C and Y181L, prepared by site-specific mutagenesis, in which the tyrosine residue at codon 181 was replaced by residues of cysteine or leucine, respectively) and similar conditions of analysis allows you to assess the effectiveness of the compounds in the inhibition of these mutant enzymes.

oC, 225 rpm) (5) to which is added 100 μg/ml ampicillin for positive selection, inoculant when diluted 1:40 in the M9 medium, to which was added 10 μg/ml thiamine, 0.5% KAZ-amino acids, and 50 μg/ml of ampicillin (5). The culture is incubated (37oC, 225 rpm) until reaching an optical density of 0.3 - 0.4 at 540 nm. At this time add repressing inhibitor IPTG (isopropyl-b-D-thiogalactopyranoside) to a concentration of 0.5 mm and the mixture incubated for 2 hours Bacteria precipitated by centrifugation, re-suspended in a buffer of 50 mm Tris(hydroxymethyl)aminomethane, 0.6 mm ethylenediaminetetraacetic acid, 0,375 M sodium chloride and hydrolyzing with the addition of lysozyme (1 mg/ml) for 30 min in ice. Cells are dissolved on the addition of 0.2% nonidet P-40 and placed in 1M sodium chloride.

After removing insoluble residue by centrifugation, the protein is precipitated on the addition of 3 volumes of a saturated aqueous solution of ammonium sulfate. The enzyme is precipitated by centrifugation, re-suspended in the buffer for reverse transcriptase (50 mm Tris(hydroxymethyl)aminomethane, pH 7.5, stored at -70oC for further use.

b) the Composition of 2X concentrated source of the reaction mixture

The initial reagent Concentration 2X mix

1 M Tris(hydroxymethyl)aminomethane, pH 7.4 100 mm

1 M dithiothreitol - 40 mm

1M sodium chloride - 120 mm

1% nonidet P-40 - 0,1%

1 M magnesium chloride - 4 mm

[poly r(C)/oligo d(G)] (5:1) - 2 µg/ml

3H-deoxyguanosine-5'-triphosphate (81 microns) - 0.6 μm

Analysis methodology:

2X concentrated source, the reaction mixture was proportionally diluted and stored at -20oC. the Mixture is stable, it is thawed for use in each assay. Enzyme analysis was adapted to the system consisting of a tablet for micrometrology with 96 cells, and has been described previously (6). Tris(hydroxymethyl)aminomethan (50 mm, pH 7.4), solvent (solvent, diluted to match the dilution of the compound or compounds in the solvent is distributed in tablets for micrometrology with 96 cells (10 μl/cell; 3 cells/connection). Reverse transcriptase of HIV-1 thawed, diluted in 50 mm Tris(hydroxymethyl)aminomethane with a pH of 7.4 so that 15 ál of diluted enzyme contained 0.001 E (one unit means that amount of enzyme 0.12 - 0.5 M ethylenediaminetetraacetic acid added in the first three cells of the tablet for micrometrology. Ethylenediaminetetraacetic acid gelaterie present Mg++and prevents reverse transcription. This group serves as the background of the polymerization, the subtrahend from all steel groups. 25 ál 2X reaction mixture was added to all wells and subjected to incubation at room temperature for 60 minutes Analysis complete, precipitating DNA in each cell using 50 μl of 10% trichloroacetic acid (10% V/o) sodium pyrophosphate (1% V/o). Tablet for micrometrology subjected to incubation for 15 min at 4oC and the precipitate is placed on the N filter 30 of the glass fiber paper (Schleicher &Schuell) using for collecting semi-automatic device Skadron. The filters are then washed with an additional amount of trichloroacetic acid (5%) containing sodium pyrophosphate (1%), washed with aqueous ethanol (70%), dried and placed in scintillation tubes (6). In each tube was placed 2 ml of a mixture for scintillation and count on the counter beta-particles Beckmann. Calculation of percent inhibition is conducted according to the following formula:

< / BR>
Literature

1. Benn, S., et al., Science, 230:949, 1985.

2. Farmeri, W. G. et al., Science, 236:305,/P> 5. Maniatis, T., Fritsch, E. F., and J. Sambrook, eds. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, 1982.

6. Spira, T., et al., J. Of Clinical Microbiology, 25:97, 1987.

To confirm that the connection is active according to the analysis of the reverse transcriptase inhibitor capable of inhibiting HIV replication in a living system, obtained in accordance with the invention compounds were also tested in the analysis of culture (entities) T-lymphocytes man, described below. The results of this study are presented in table. 1.

Analysis of entities (culture T-lymphocytes person).

Theory analysis:

The formation of syncytial is characteristic of in vitro cultures of CD4+ T lymphocytes infected with HIV-1. In this analysis of T-lymphocytes processed by the connection, which is the putative inhibitor of replication, and then they infect HIV-1. After incubation the culture is tested for the formation of entities. The absence or reduction in the number of entities serves as a measure of the ability of these compounds to inhibit HIV replication.

Analysis method:

Target cells labeled c8166 are subcloned lymphoma cells human T-limfotsitov origin, get them with the initial density is surgical centre. Includes selected number of tested compound dissolved in dimethyl sulfoxide. After 24 h 50 - 100 doses that cause an effect in 50% of the test cultures, strain lymphotropism virus T-lymphocytes person (HTLV-IIIB) HIV-1 (2) inoculant in every culture. Control cultures get a connection or just a virus. 4 days after infection by virus culture visually investigated the frequency and distribution of virus-induced giant cell of entities. The percentage inhibition of the studied compound is determined by comparison with control values. Confirmation of the presence or absence of virus replication is carried out by collecting free from cell culture fluids from all experimental groups to determine the presence or absence of infectious progeny through the induction of the formation of entities in the secondary cultures of T-lymphocytes person after 3 days.

Literature

1. M. Somasundaran and H. L Robinson, Science, 242, 1554 (1988).

2. G. M. Shaw, R. H. Hahn, S. K. Arya, J. E. Groopman, R. C. Gallo, and F. Wong-Staal, Science, 226, 1165 (1984).

In order to assess the specificity of the activity of the enzyme connections offered by the present invention, some of the compounds were ispytatb of feline leukemia virus and DNA-alpha-polymerase of sweetbread. None of the tested thus compounds did not have any inhibitory activity against these enzymes. These results indicate that inhibitory activity against the enzymes in connection offered by this invention is directed quite specifically against reverse transcriptase of HIV-1.

For a rough evaluation of the cytotoxicity of the compounds proposed by the invention, several such compounds have been tested in the analysis of bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazole (MTT), as described below. The results of this test are given in table. 1. Compounds having a relatively high concentration value for the manifestation of 50% cytotoxicity (CC50). are preferred.

The MTT assay.

Theory analysis:

Analysis of MTT (methyl 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl - tetrazole) is based on the splitting of the bromide of tetrazole metabolically active cells, resulting in a blue color, corresponding with high accuracy the quantity of matter. This analysis was described previously (1), but was optimized for the tests described here.

Analysis method:

In the analysis as a line of target cells by ispolzovaniem 10% fetal bovine serum. Cells (100 μl) is placed in a cell microbiological tablet at a concentration of 105cells per ml in the presence of varying concentrations of inhibitor. Cells are incubated at 37oC in humidified thermostat carbon dioxide in the atmosphere. After 5 days in each well was added 20 μl of MTT (5 mg/ml in RPMI 1640, treated with ultrasound, filtered through 0.2 micron filter and stored at 4oC). After 4 h of additional incubation at 37oC in each cell add 60 ál of Triton-X and carefully stir to help dissolve crystals. In each cell add 5 ál of absolute ethanol and the resulting mixture is incubated for 30 min at 60oC and immediately take readings from the display reader (Dynatech) at a wavelength of 570 nm.

The resulting data analyzed by the method of nonlinear regression to obtain the values of CC50.

Literature

1. Mosmann, Tim, J. Immunol. Methods 65:55, 1983.

2. Jacobs, J. P., J. Natl. Cancer Inst., 34:231, 1965.

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

Example 1.

5,11-Dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b:2',3'-e] [1,4]diazepin-6-he.

a) 4-(Tributylstannyl)pyrazole.

b) 5,11-Dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b:2', 3'-e][1,4]diazepin-6-he.

A mixture of 4-(tributylstannyl)pyrazole (0.270 g), 5,11-dihydro-11-ethyl-5-methyl-2-tripterocalyx-6H-dipyrido [3,2-b: 2', 3'-e] [1,4]diazepin-6-she (0.292 g), lithium chloride (0.157 g) chloride and bis(triphenylphosphine)palladium(II) (0.034 g) in dimethylformamide (2 ml) was heated in a sealed tube at 130oC for 15,5 hours the Mixture was cooled to room temperature and stirred for 2 hours with an aqueous solution of potassium fluoride. The mixture was diluted with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was separated on silica gel (ethyl acetate/hexane gradient) to obtain specified in the title compounds is="ptx2">

5,11-Dihydro-11-ethyl-2-(1-aripirazole-4-yl)-5-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he.

Specified in the title compound (foam, so pl. 60-62oC) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-tripterocalyx - 6H-dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-she and N-ethyl-4-moderate in the manner similar to that described in example 1.

Example 3.

5,11-Dihydro-11-ethyl-5-methyl-2-(1-methylpyrazole-4-yl)-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he.

Specified in the title compound (so pl. 65-67oC) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-tripterocalyx - 6H-dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-she and N-methyl-4-moderate in the manner similar to that described in example 1.

Example 4.

5,11-Dihydro-11-n-propyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b: 2', 3'-e] [1,4]diazepin-6-he.

Specified in the title compound (so pl. 291-292oC) was prepared from 5,11-dihydro-11-n-propyl-2-tripterocalyx-6H - dipyrido[3,2-b:2', 3'-e] [1,4]diazepin-6-she 4-(tributylstannyl)of pyrazole in the manner similar to that described in example 1.

Example 5.

5,11-Dihydro-5-methyl-11-n-propyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b:2', 3'-e][1,4]diazepin-6-he.

Specified in the title compound (so pl. 206-207

Example 6.

5,11-Dihydro-5-methyl-11-cyclopropyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he.

Specified in the title compound (so pl. 233-235oC) was prepared from 5,11-dihydro-5-methyl-11-cyclopropyl-2-tripterocalyx - 6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-she 4-(tributylstannyl)of pyrazole in the manner similar to that described in example 1.

Example 7.

2-(1-Carbuilders-3-yl)-5,11-dihydro-11-ethyl-5-methyl-6H - dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he

To a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H - dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-she (0.054 g) in chloroform (5 ml) were added triphosgene (0,050 g) and diisopropylethylamine (0.2 g). The mixture was stirred at room temperature for 4 days. Then was added a concentrated solution of the hydroxide of ammonium (10 drops) and the mixture was stirred 10 min. the Mixture was diluted with chloroform, washed with water, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was chromatographically on silica gel (ethyl acetate/ethanol) and has been specified in the title substance was subjected to crystallization from ethyl acetate/isopropyl ether, so pl. 175-180oC.

Example 8.

2-(1-Acetamidine (so pl. 186-188oC) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H - dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-it when heated in acetic anhydride at boiling for 1 h in the presence of potassium acetate.

Example 9.

5,11-Dihydro-11-ethyl-5-methyl-2-(3-pyrazolyl)-6H-dipyrido [3,2-b:2',3'-e] [1,41, diazepin-6-he.

A mixture of 5,11-dihydro-[1-(N,N-dimethylaminomethyl)pyrazole-5-yl]- 11-ethyl-5-methyl-6H-dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-she (0,051 g) and hydrazine hydrate (0,41 g) in ethanol (0.5 ml) was stirred at boiling for 3 days. The cooled mixture was diluted with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was separated using preparative chromatography plate (ethyl acetate/hexane) and received 0,020 g specified in the title compound in the form of foam.

Example 10.

5,11-Dihydro-11-ethyl-5-methyl-2-(3-methylpyrazole-4-yl)-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he.

Specified in the title compound (so pl. 113-115oC) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-tripterocalyx - 6H-dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-it 3-methyl-4-(tributylstannyl)of pyrazole in the manner similar to that described in example 1.

Example 1-Methylpyrrole-2-yl)tributylamine

1-Methylpyrrole (0.065 g) was added to a cooled (-35oC) mixed solution of utility (2.5 M of 0.32 ml) in anhydrous tetrahydrofuran (5 ml). Then was added N,N,N',N'-tetramethylethylenediamine (0,090 g) and the mixture was stirred 90 minutes at -10 to -15oC. and Then slowly added chloride, tributylamine (0.26 g) and the mixture was allowed to warm to room temperature, stirred 15 minutes, the Solvent drove and got (1-methylpyrrole-2-yl)tributylamine, suitable for use in the next reaction.

b) 5,11-Dihydro-11-ethyl-5-methyl-2-(1-methylpyrrole-2-yl)-6H-dipyrido [3,2-b:2',3'-e][1,4]diazepin-6-he.

A mixture of (1-methylpyrrole-2-yl)anti obtained above, 5,11-dihydro-11-ethyl-5-methyl-2-tripterocalyx-6H-dipyrido [3,2-b: 2', 3'-e] [1,4] diazepin-6-she (0.20 g), chloride bis(triphenylphosphine)palladium(II) (0,010 g), lithium chloride (0,100 g) and anhydrous dimethylformamide (5 ml) was stirred at 90oC within 15 minutes After cooling to room temperature the mixture was diluted with water, was extracted with methylene chloride, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was first chromatographically on a column of silica gel in ethyl acetate/hexano (1:4), and then ethyl acetate/hexano (1: 1)and the plate (ethyl acetate/hexane, 1:1) received 0.025 g specified in the title compound in the form of foam, so pl. > 60oC.

Example 12.

5,11-Dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido [3,2-b:2',3'-e] [1,4]diazepin-6-he.

a) 3-Bromo-1-(triisopropylsilyl)pyrrole.

N-Bromosuccinimide (6.4 g) was added in one portion to a stirred solution of 1-(triisopropylsilyl)pyrrole (8.00 g) in anhydrous tetrahydrofuran (80 ml) at -78oC. the Mixture was stirred at this temperature for 2 hours, and then the mixture was allowed to warm to room temperature over night. The solvent was removed and to the residue was added water and the product was extracted with methylene chloride, the extract was dried (anhydrous sodium sulfate), filtered and evaporated. The residue was chromatographically on silica gel (hexano) and concentrated, received 10,00 g 3-bromo-1-(triisopropylsilyl)pyrrole as a colorless oil.

b) [1-(Triisopropylsilyl)pyrrol-3-yl] tributylamine was obtained in the manner similar to that described in example 16.

in) 5,11-Dihydro-11-ethyl-5-methyl-2-[1-(triisopropylsilyl)pyrrol - 3-yl]-6H-dipyrido[3,2-b: 2', 3'-e] [1,4]diazepin-6-it was obtained by the method similar to that described in example 16.

g) 5,11-Dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido solution of 5,11-dihydro-11-ethyl-5-methyl-2-[1-(triisopropylsilyl) pyrrol-3-yl] -6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-she (0.17 g) in anhydrous tetrahydrofuran (10 ml). After stirring the mixture for 1 h, the latter is diluted with ethyl ether, washed with water, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was chromatographically on silica gel (ethyl acetate/hexano, 1:1), and then subjected to crystallization from chloroform/hexanol and received 0.083 g specified in the title compound, so pl. 173-174oC.

Example 13.

5,11-Dihydro-11-ethyl-5-methyl-2-(2-pyrrolyl)-6H-dipyrido [3,2-b:2',3'-e] [1,4]diazepin-6-he.

a) (1-(tert-butoxycarbonyl)pyrrol-2-yl)tributylamine.

Diisopropylamide lithium in anhydrous tetrahydrofuran (1.2 M, or 0.83 ml) was slowly added to a cooled (-78oC) solution of 1-(tert-butoxycarbonyl)pyrrole (0,67 g) in absolute tetrahydrofuran (5 ml). After stirring for 3 h was slowly added to the presence of TBT chloride (0.65 g), then the mixture was allowed to warm to room temperature over night. The solvent was removed and received (1-(tert-butoxycarbonyl)pyrrol-2-yl) tributylamine, suitable for use in the next reaction.

b) a Mixture of 5,11-dihydro-11-ethyl-5-methyl-2-tripterocalyx - 6H-dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-she (0.2 g), (1-(tert-butoxycarbonyl)pyrrol-2-yl)inputs of TBT poluchil within 4 hours The solvent is then drove away, and the residue was dissolved in methylene chloride, washed with water, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was chromatographically on silica gel (ethyl acetate/hexano, 1:1), and then subjected to crystallization from ethyl acetate/hexanol. Tert-butoxycarbonyl group was removed by stirring the product of condensation of 30 min in the air, saturated with hydrogen chloride. The solvent is kept off, and the residue was purified using preparative chromatography plate (ethyl acetate/hexano, 1:4), received 0.022 g specified in the title compound in the form of foam, so pl. > 60oC.

Example 14.

2-(1-Acetylpyrrole-2-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he

Sodium hydride (0,013 g, 60% suspension in oil) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(2-pyrrolyl)-6H-dipyrido [3,2-b:2',3'-e][1,4] -diazepin-6-she (0.100 g) in anhydrous dimethylformamide (3 ml) and stirred 30 minutes After cooling to 0oC was added acetyl chloride (0.025 g) and the reaction mixture was allowed to warm to room temperature over night. Was added water and the product was extracted with methylene chloride, dried (anhydrous sodium sulfate), filtered and evaporated.organizations from ethyl acetate/petroleum ether received 0.018 g specified in the title compound, so pl. 106-108oC.

Example 15.

2-(2-Acetylpyrrole-3-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he, so pl. >80oC.

Phosphorus oxychloride (0.054 g) was added to a cooled (10oC) anhydrous N, N-dimethylacetamide (0.031 g), the mixture was stirred 15 min after removal of the cooling bath. Then was added dichloroethane (2 ml) and the resulting mixture was cooled to 5oC. 5,11-Dihydro-11-ethyl - 5-methyl-2-(3-pyrrolyl)-6H-dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-he (0.10 g) in dichloromethane (5 ml) was added within 10 min, bath cooling was removed and the mixture was heated at boiling for 3 hours After cooling to room temperature the mixture was poured into excess aqueous sodium acetate and stirred for 2 hours the Product was extracted with methylene chloride, was dried (anhydrous sodium sulfate), filtered and evaporated. The residue was purified using preparative chromatography plate (in the air) and got 0.014 r specified in the title compound in the form of foam, so pl. >80oC. Was selected 0.038 g of 2-(2-acetylpyrrole-4-yl)-5,11-dihydro-11-ethyl - 5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-she (example 17), so pl. 219-220oC.

Example 16.

5,11-Dihydro-2-[2-(etoxycarbonyl)pyrrol-4-yl] -11-ethyl-5-matiru 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido [3,2-b:2',3'-e][1,4] -diazepin-6-she (0.052 g) in diglyme (2.5 ml), the resulting mixture was stirred at 100oC for 2 h, the Reaction mixture was then poured on ice, the product was extracted with methylene chloride, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was chromatographically on silica gel (ethyl acetate/methylene chloride, 1:9) and received 0,070 g of 5,11-dihydro-11-ethyl-5-methyl-2-[2-(trichloroacetyl)pyrrol-4-yl] -6H - dipyrido[3,2-b: 2', 3'-e]-[1,4] diazepin-6-it.

b) the Product of (0,065 g) from example 16A was added to absolute ethanol (6 ml) and triethylamine (0.035 g), the mixture was stirred at 90oC for 10 h Treatment, according to example 16A, followed by crystallization from ethyl acetate/hexanol led to 0,048 g of compound indicated in the title, so pl. 209-210oC.

Example 17.

2-(2-Acetylpyrrole-4-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he

The connection specified in the title, (so pl. 219-220oC) was isolated from the reaction mixture as described in example 20.

Example 18.

2-(2-Canberra-3-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he.

A solution of 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido [3,2-b: 2', 3'-e] [1,4] diazepin-6-she (0.093 g) in dimethylformamide (1 ml) and acetonitrile (1 mi was allowed to warm to room temperature and stirred 2 h, then was poured into water, extracted with methylene chloride, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was purified using preparative chromatography plate (in the air) and received two pure substances. Crystallization of each of these pure substances from ethyl acetate/petroleum ether resulted in 0,038 g of compound indicated in the title, so pl. 262-263oC, and 0,038 g 2-(2-Canberra-4-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4]diazepin-6-it, so pl. 268-269oC.

Example 19.

2-(2-Canberra-4-yl)-5.11-dihydro-11-ethyl-5-methyl-6H-dipyrido [3,2-b: 2'.3'-e][1,4]diazepin-6-he.

Specified in the title compound (so pl. 268-269oC) was isolated from the reaction mixture as described in example 18.

Example 20.

5,11-Dihydro-11-ethyl-5-methyl-2-(1-methylpyrrole-3-yl)-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he.

Sodium hydride (0.008 g, 60% suspension in oil) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-she (0,065 g) in anhydrous dimethylformamide (3 ml) and stirred 30 minutes was Added methyl iodide (0.2 ml) and the reaction mixture was stirred for another 2 hours water was Added and the product was extracted with methylene chloride, dried (basetsana, 1:1) and then purified using preparative chromatography plate (ethyl acetate/hexano, 1: 1), received 0,040 g of compound indicated in the title, so pl. 187-188oC.

Example 21.

2-(2-Carboxyphenyl-4-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he.

The mixture 0,092 g of 5,11-dihydro-11-ethyl-5-methyl-2-[2-(trichloroacetyl) pyrrol-4-yl] -6H-dipyrido[3,2-b: 2',3'-e][1,4]diazepin-6-she (example 21A), potassium carbonate (0.55 g) and water (2.5 ml) was stirred at 95oC for 1.5 h the Mixture was cooled, acidified and washed with methylene chloride. The aqueous phase was filtered and received 0,016 g of compound indicated in the title, which was recrystallized from acetic acid/hexanol, so pl. 256-257oC.

Example 22.

2-(2-Carbonyliron-4-yl)-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-he.

A solution of 0.100 g of 5,11-dihydro-11-ethyl-5-methyl-2-[2-(trichloroacetyl) pyrrol-4-yl] -6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-she (example 21A) in anhydrous tetrahydrofuran (15 ml) was cooled to -15oC and passed through a solution of gaseous ammonia for 15 minutes the Mixture was then tightly closed and stirred at room temperature for 3 hours After removal of the solvent was added water and the mixture promiseland/ethanol, received 0,056 g specified in the title compound, so pl. 284-285oC.

Example 23.

5,11-Dihydro-5-ethyl-11-methyl-2-(2-pyrrolyl)-6H-dipyrido [3,2-b:2',3'-e] [1.4]diazepin-6-he.

A mixture of 2-chloro-5,11-dihydro-5-ethyl-11-methyl-6H-dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-she (0.21 g), (tert-butoxycarbonyl)pyrrole (0.25 g), potassium acetate (0.20 g), chloride bis(triphenylphosphine)palladium(II) (0,030 g) and 1-methyl-2-pyrrolidinone (2.5 ml) was heated in a sealed tube at 140oC for 14 hours After removal of solvent was added water and the product was extracted with methylene chloride, dried (anhydrous sodium sulfate), filtered and evaporated. The residue was chromatographically on silica gel (ethyl acetate/methylene chloride, 1:9) and further purified using preparative chromatography plate (ethyl acetate/methylene chloride, 1:9), was obtained after recrystallization from ethyl acetate/hexanol 0,020 g specified in the title compound, so pl. 161-162oC.

Example 24.

5,11-Dihydro-5,11-dimethyl-2-(2-pyrrolyl)-6H-dipyrido [3,2-b: 2', 3'-e] [1,4]diazepin-6-he.

Specified in the title compound (so pl. 158-160oC) was obtained from 2-chloro-5,11-dihydro-5,11-dimethyl-6H-dipyrido [3,2-b:2',3'-e][1,4]diazepin-6-she (tert-butoxycarbonyl)Pirro-5-methyl-2-(3-percell)-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he.

Specified in the title compound (so pl. 254-255oC) was obtained from 11-cyclopropyl-5,11-dihydro-5-methyl-2-tripterocalyx - 6H-dipyrido[3,2-b: 2', 3'-e] [1,4]diazepin-6-it [1-(triisopropylsilyl)pyrrol-3-yl] presence of TBT in the manner similar to that described in examples 17 and 16.

Compounds of the following examples were obtained by the method similar to those described above, or using appropriate modifications of this method.

Example 26.

5,11-Dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6H-dipyrido [3,2-b:2',3'-e] [1,4]diazepin-6-he's so square 213-214oC.

Example 27.

5,11-Dihydro-11-ethyl-2-(5-methoxyindol-2-yl)-5-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4]diazepin-6-he's so square 234,5-235,5oC.

Example 28.

5,11-Dihydro-11-ethyl-2-(indol-3-yl)-5-methyl-6H-dipyrido [3,2-b:2',3'-e] [1,4]diazepin-6-he's so square 241-241.5oC.

The following examples illustrate the possible formulations of pharmaceutical compositions.

Example 29.

Capsules or tablets (see table).

The compound obtained in example 12, making a powder mixture of the pre-mixed excipients, as described above, except for the lubricant. Then bring masiva the P> Example 30.

Parenteral solutions.

Ingredients - Number

Connection example 12 500 mg

Tartaric acid 1.5 grams

Benzyl alcohol is 0.1% by weight

Water for injection as required to 100 ml

Excipients are mixed with water, and then add the connection in example 12. Stirring is continued to obtain a clear solution. Bring the pH of the solution to 3.0, then filtered in a suitable vials or ampoules and sterilized in the autoclave.

Example 31.

Solutions for introduction through the nose.

Ingredients - Number

Connection example 12 to 100 mg

Citric acid - 1.92 g

Chloride, alkyldimethylbenzylammonium is 0.025% by weight

Ethylenediaminetetraacetic acid - 0.1% by weight

Polyvinyl alcohol - 10% by weight

Water - as required to 100 ml

Excipients are mixed with water and then add the compound from example 12, the stirring is continued to obtain a clear solution. Bring the pH to 4.0 and then filtered in a suitable vials or ampoules.

1. 2-Heteroaryl-5,11-dihydro-6N-dipyrido[3,2-b:2',3'-e] [1,4]diazepin-6-ones of General formula I

< / BR>
where R1means a hydrogen atom sludge and carbon;

Ar denotes a group of formula (a) - (d)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R3means hydrogen, methyl, ethyl, acetyl or aminocarbonyl;

each of R4, R4and R6means hydrogen or one of R4, R5and R6means methyl, acetyl, etoxycarbonyl, carboxypropyl, aminocarbonyl or cyano, and the other two Deputy both signify hydrogen;

each of a, b, D, and E is retinovoy group, one of which may be substituted by alkyloxy with 1 to 3 carbon atoms,

or their pharmaceutically acceptable salts.

2. 2-Heteroaryl-5,11-dihydro-6N-dipyrido-[3,2-b: 2', 3'-e] [1,4] diazepin-6-ones of General formula I on p. 1, where R1means a hydrogen atom, alkyl with 1 to 3 carbon atoms, R2means alkyl with 1 to 3 carbon atoms or cycloalkyl with 3 to 4 carbon atoms, Ar denotes a group of formula (a) - (d), where R3means hydrogen, methyl or ethyl; each of R4, R5and R6means hydrogen or one of R4, R5and R6means methyl, acetyl, etoxycarbonyl, aminocarbonyl or cyano, and the other two Deputy both signify hydrogen, each of a, b, D or E is retinovoy group, one of which may be substituted by alkyloxy 1 [3,2-b:2',3'-e][1,4]diazepin-6-ones of General formula I on p. 1, where R1means methyl, R2means alkyl with 2 to 3 carbon atoms or cycloalkyl with 3 to 4 carbon atoms, Ar denotes a group of formula (a), (b) or (C), where R3means hydrogen or methyl, each of R4, R5and R6means hydrogen or one of R4, R5and R6means methyl, acetyl, etoxycarbonyl, aminocarbonyl or cyano, and the other two Deputy both signify hydrogen or Ar stands for a group of the formula (r) or (l), where R3means hydrogen or methyl, each of R4, R5and R6means hydrogen, each of a, b, D, and E is retinovoy group, one of which may be substituted by alkyloxy with 1 to 3 carbon atoms, or their pharmaceutically acceptable salts.

4. 2-Heteroaryl-5,11-dihydro-6N-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-ones of General formula I, selected from the group consisting of 5,11-dihydro-11-ethyl-5-methyl-2-(3-pyrrolyl)-6N-dipyrido[3,2-b: 2', 3'-e][1,4]diazepin-6-ons; 11-cyclopropyl-5,11-dihydro-5-methyl-2-(3-pyrrolyl)-6N-dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-ons; 11-cyclopropyl-5,11-dihydro-5-methyl-2-(4-pyrazolyl)-6N-dipyrido[3,2-b: 2',3'-e][1,4]diazepin-6-ones and 5,11-dihydro-11-ethyl-5-methyl-2-(4-pyrazolyl)-6N-dipyrido[3,2-b: 2',3'-e][1,4]diazepin-6-ones, and their pharmaceutically acceptable salts.

5. containing a pharmaceutically acceptable carrier and an active ingredient, characterized in that the active substance it contains a compound of General formula I on PP.1 - 4 in prophylactically or therapeutically effective amount.

Priority signs:

18.02.94 - R1and R2are specified in the claims values, Ar denotes a group of formula (a), (b) and (C), where R3means hydrogen, methyl, ethyl, acetyl, each of R4, R5and R6means hydrogen or one of R4, R5and R6means methyl, acetyl, etoxycarbonyl, aminocarbonyl or cyano, and the other two Deputy both signify hydrogen; p. 5 claims, in which the active substance has radicals with the above values;

14.12.94 - Ar means a group of formula (a), (b) and (C), where R3means aminocarbonyl, one of R4, R5and R6means carboxypropyl, and the other two Deputy both denote hydrogen or a group of formula (d) and (e), where a, b, D, E, R3and R4are specified in the claims values, p. 5 claims, in which the active substance has radicals with the above values.

 

Same patents:

The invention relates to a new series of tetracyclic compounds having two or three nitrogen atoms included in the ring, which have significant anti-allergic and anti-asthma activity, provides methods and compositions for their use, as well as technologies of their production

The invention relates to new heterocyclic compounds having valuable biological properties, in particular to derive dipyrido-diazepine General formula (I)

(I) where Z is oxygen, sulfur, group NCN иNOR9where R9lower alkyl;

R1hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkenylacyl, lower alkoxyl, lower alkanoyl, lower dialkylaminoalkyl, lower alkoxyalkyl, lower alkylthiomethyl, benzyl;

R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

R3hydrogen, hydroxyl, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, pyrrolidin-1-yl, pyrrolin-1 - yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine;

R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R8hydrogen, lower alkyl; and when Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl; R3, R4, R5, R6, R7and R8a hydrogen atom or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7the halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of zamestitelei R3, R5and R6is hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R83, R4and R5means butyl, and the other substituents R6, R7and R8mean hydrogen, and R6, R7and R8independently of one another denote hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8means butyl, and the other substituents R3, R4and R5mean hydrogen, R1does not mean hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl and lower alkylthiomethyl, and their hydrates and pharmacologically tolerable salts have valuable biological properties, particularly an inhibitory effect on reverse transcriptase of the virus HIV-1, so that they can be used for prevention or treatment of AIDS

The invention relates to a method for producing a dosage form of carbamazepine for oral dosage forms with delayed release of active substances

The invention relates to new trehlitrovy complexes, processes for their preparation and their use as pharmaceuticals, in particular for the treatment of cancer
The invention relates to medical practice

The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, possibly substituted C1-C8-alkyl; R3- peloid in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt

The invention relates to medicine and can be used to prevent or reduce the intensity of side effects and complications of dialysis used to treat patients with renal insufficiency

The invention relates to new derivatives benzazepine, which are used as antagonists Organisatorische, to their pharmaceutically acceptable salts, to pharmaceutical compositions containing these compounds as active ingredients and intermediate products for the synthesis of these compounds

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

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

17 cl, 70 ex

Up!