Derivatives triazolo[1,4]diazepine and methods for their production

 

(57) Abstract:

Essence: derived triazolo-1,4-diazepino formulas I - III and their pharmaceutical salts, where R1and R2Is H or alkyl, R3- halogen, R4is lower alkyl, X is a group of the formula-OCO-, - NR5CO-, where R5- H or lower alkyl, -CO-, or other group, and Y - cycloalkyl, cycloalkenyl, quinil or other groups. Derivatives of diazepine I - III show the vast platelet activating factor action for an extended period of manifestation of this activity. 7 C. and 4 h.p. f-crystals, 1 tab., 3 Il.

The invention relates to new derivatives of 1,4-diazepine and their pharmacologically acceptable salts, methods for their production and pharmaceutical applications. Compounds and their salts have excellent therapeutic activity.

Recently, platelet activating factor (hereinafter abbreviated FOP) has attracted special attention, and now clarified its relationship with various diseases. It is believed that the FOP is involved not only in inflammatory processes, but also with coagulopathy consumption, endotoxic shock, asthma, ulcers and resistances during organ transplantation. In addition, attention has been drawn in cutestkidever, aimed at compounds with anti-VEILS activity. For example, in laid the patent application Japan N 63-33382 as compounds with anti-VEILS action proposed derivatives of 1,4-diazepine. However, satisfactory funds with anti-VEILS activity, suitable in particular for the treatment of allergic diseases such as asthma, hitherto not offered.

Accordingly, we have continued long-term studies of derivatives of 1,4-diazepine with not only a great anti-VEILS activity, but also increased the period of the activity.

We have conducted long-term intensive studies to achieve the above objectives, in which we found that this objective answer derivatives of 1,4-diazepine, which are defined below, or their pharmacologically acceptable salts. The present invention accomplished based on the above results.

The invention represents a triazole derivatives (1,4) diazepine General formula I

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or their pharmaceutically acceptable salts, in which R1and R2are the same or different and represent a hydrogen atom or lower alkyl,

R3represents a halogen atom,
formula: , where R5means a hydrogen atom or lower alkyl, or a group of the formula: , and Y means (C3-C6)cycloalkyl group, possibly substituted methyl group or a possibly substituted in the first position etinilnoy group; or (C3-C6)cycloalkyl(C1-C2)alkyl group; or (C3-C6)alkylamino group, possibly substituted phenyl group; or a group of the formula:

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where R7is hydrogen or methyl, r is 0 or 1; a group of the formula: NC(CH2)pwhere p is an integer from 1 to 5; or a group of the formula: ; or a group of the formula: A(CH2)qwhere A represents a group selected from peredelnoj group, tetrahydropyranyloxy group, morpholinopropan and imidazolidine group, and q is an integer from 0 to 2; or a group of the formula:

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where S is an integer from 1 to 2;

or phenylethylene group; or a group of the formula:

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or a group of the formula:

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or a group of the formula:

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where R8and R9the same or different and represent hydrogen or lower alkyl, or pyridylmethyl, or cyclohexyl, or R8and R9together with the nitrogen atom form piperidine, imidazoline or morpholino ring, and B represents fenelonov or (C1-C3< / BR>
where R10hydrogen or methyl;

or a group of the formula:

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or phenyl(C1-C2)alkyl group, possibly substituted in the phenyl ring by halogen;

or a group of the formula:

;

or a group of the formula:

;

or a group of the formula:

,

in which G is - CH=CH- , or-SCH2-;

or, when X represents a group of the formula:

where R6means lower alkyl, Y is (C2-C7)alkyl group,

or n means 0, when Y represents C3-C6)alkylamino group.

Preferred compounds of formula I and their pharmaceutically acceptable salts are compounds in which R3means chlorine, R1is hydrogen and R4methyl, and

when R2means hydrogen, then Y - X is the group

;

or group

;

or group

;

or group

;

or group

;

or group

;

or group

;

or when R2means methyl, Y - X means a group

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or group

or group , or

group

.

In addition, the invention is derived triazolo[1,4]diazepine General formula II:

,

or its pharmaceutically receiving ecstasy lower alkyl, X represents a group of the formula: or a group of the formula

Y represents a C3-C6)cycloalkyl(C1-C2) alkyl group, or (C3-C6)alkylamino group, or a group of the formula:

where R7is methyl,

or a group of the formula NC(CH2)pwhere P is an integer from 1 to 3, or a group of the formula A(CH2)qwhere A represents a group selected from peredelnoj, tetrahydropyranyloxy, morpholinos and morpholinosydnonimine group, q is an integer from 0 to 2, or (C2-C7)alkyl group, or phenyl(C1-C2)alkyl group, possibly substituted in the phenyl ring by halogen atom, nitro - or triptorelin group.

The invention presents derivative triazolo[1,4]diazepine General formula III:

< / BR>
or their pharmaceutically acceptable salts, where R1and R2are hydrogen atoms, R3represents a halogen atom, R4represents lower alkyl,

when n is 1, X represents a group , or Y represents a C3-C6)cycloalkyl group, or (C3-C6)alkyl group, or a group of the formula: NC(CH2)pwhere P is an integer from 1 to 3, or a group of the formula: A(CH2)qwhere A represents a group, the number from 0 to 3, or phenylethylene group, or (C2-C7)alkyl group, or phenyl(C1-C2)alkyl group, possibly substituted in the phenyl ring by halogen atom, or (C1-C2)alkoxy(C1-C2)alkyl group, or X represents a group-and Y - group , or when n is 0, Y represents a C3-C6)alkylamino group, (C1-C2)alkoxy(C1-C2)alkyl group, dimethylaminomethylene or thiophenesulfonyl group.

The invention discloses a method of using vysokorejtingovykh compounds and their salts. According to the invention the pharmaceutical composition comprises a pharmacologically effective amount of the compound or its salt according to the above definition, as well as pharmacologically acceptable carrier. A method of treating diseases against which effectively manifestation of anti-VEILS activity is the introduction of pharmacologically effective amounts of compounds of the invention or its salts. This disease is an allergic disease such as asthma.

Derivatives of 1,4-diazepine General formula (I) has good inhibitory PHAT efficiency and stability under high security.

is acceptable salts, possessing good anti-FAT effect. Another objective of the invention is to provide a method for obtaining such derivatives. Another object of the invention is to obtain containing such derivatives funds.

In the present invention preferred are compounds of the following chemical structure:

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where R1, R2, R3, R4and Y respectively agree to the above values;

< / BR>
where R1, R2, R3, R4and Y respectively agree to the above values;

< / BR>
where R1, R2, R3, R4, R5and Y respectively take values above.

As for the values of R1and R2in the compound group (I) of the invention, most preferably, if R1is a hydrogen atom and R2- lower alkyl, in particular methyl. The above reflects the following General formula:

< / BR>
where Randis lower alkyl.

The most preferred group of compounds in which Randis methyl, are compounds of the following General formula:

< / BR>
where Y, R3and R4take the above values, Z represents a group of formula or .

Used in the present invention, the pharmacologically acceptable salt is a conventional non-toxic salts, for example: inorganic salts such as chlorhidrate, bromhidrosis, sulfates, phosphates, etc., and organic salts such as acetates, maleate, succinate, methanesulfonate, etc. and salts of amino acids such as alginin, aspiratinuyu acid, glutamic acid, etc.

Compounds of the invention are of the molecule in the asymmetric carbon atom and can exist in different spatial isomers. In the practice of the invention, individual isomers and mixtures thereof are all covered by the scope of the invention. For example, the compound of formula (D), above, has an asymmetric carbon atom associated with Rand(if Rand- methyl), which has stereoisomers. The isomers can be separated conventional preparative methods.

In addition, certain compounds can form hydrates, which are also covered by the scope of the invention.

Compounds of the invention are synthesized by conventional methods, typical examples of which are shown below.

Preparative method 1

To obtain the compounds of formula (I), in which X, n, Y, R1, R2, R3and R4take, respectively, the above values.

The compound of formula (IV) is condensed with the compound of the formula (V) and obtain the connection formula (Ia), which is one of the target compounds.

The reaction is carried out in the usual way without solvent or in an inert under the reaction conditions solvent selected from chloroform, tetrahydrofuran, diethyl ether, acetone, benzene, toluene and dimethylformamide. The reaction temperature from room temperature up to 150oC, most preferably 100 - 130oC.

In the above reaction scheme, the compound of formula (V) used as starting product, synthesize, for example, according to the following reaction scheme:

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where Y, X and n respectively take values above and Hal represents a halogen atom.

In the above reaction scheme, the compound of General formula (VI) condense with galoidoproizvodnykh General formula (VII) and get a connection General formula (V).

The reaction is recommended in the presence of bases, including amines, such as triethylamine, pyridine, etc., hydrides of alkali metals such as sodium hydride, potassium hydride, etc., hydroxides Sels solvent or in a solvent. Examples of solvents include: ethers, such as tetrahydrofuran, dioxane, etc., galoidoproizvodnykh, such as methylene chloride, chloroform, etc., aromatic compounds such as benzene, toluene, xylene, etc., and other compounds such as dimethylformamide, dimethylsulfoxide, etc.

Preparative method 2

The synthesis of compounds in which X is represented by a formula and n = 1, carried out according to the following reaction scheme:

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or a reactive derivative of this acid (VIII)

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If more, then the carboxylic acid of General formula (VIII) or its reactive derivative condensed with the compound of General formula (IV) and get a connection General formula (IB), which is one of the target compounds.

The condensation is conducted in the usual way. Reactive derivatives of the acid include: galodamadruga acids, such as anhydrides, bromohydrin etc.; acid azides; N-hydroxybenzotriazole derived; active esters such as N-hydroxysuccinimide; symmetric acid anhydrides; mixed anhydrides with alkaline carbonates, p-toluensulfonate etc.

The reaction is performed by heating without solvent or in a solvent is chloride carbon dimethylformamide, etc., with the implementation of, for example, dehalogenase. The best results are achieved when carrying out the reaction in the presence of inorganic salts, such as sodium bicarbonate, potassium carbonate, caustic soda, etc., or organic bases such as triethylamine, pyridine, pyrimidine, diethylaniline etc.

When using the free acid the best results are achieved in the presence of a condensing means, such as 1,1'-carbonyldiimidazole, dicyclohexylcarbodiimide etc.

Preparative method 3

The synthesis of compounds in which X is represented by a formula and n = 1, carried out according to the following reaction scheme:

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where Y, R1, R2, R3, R4and R6take respectively the above meanings and Hal represents a halogen atom.

Galoidoproizvodnykh formula (IX) and the compound of General formula (IV) react with the formation of the target compounds of formula (Ic).

Reaction refers to the reaction of dehydrohalogenating and it is conducted in the usual way by heating without solvent or in a solvent that does not participate in the reaction and is selected, for example, from benzene, toluene, xylene, tetrahydrofuran, chloroform, look no further than the, is aka as sodium bicarbonate, potassium carbonate, sodium carbonate and caustic soda, or organic bases such as triethylamine, pyridine, pyrimidine, diethylaniline etc.

Preparative method 4

For the synthesis of compounds of formula (I), where n = 0, use the following reaction scheme:

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where Y, R1, R2, R3and R4take respectively the above meanings and Hal represents a halogen atom.

Galoidoproizvodnykh formula (X) is reacted with a compound of General formula (IV) with the formation of the target compounds of formula (Id).

Reaction refers to the reaction of dehalogenase and it is conducted in the usual way by heating without solvent or in a solvent that does not participate in the reaction and is selected from benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride and dimethylformamide. The best results are achieved when carrying out the reaction in the presence of inorganic salts, such as sodium bicarbonate, potassium carbonate, sodium carbonate and caustic soda, or organic bases such as triethylamine, pyridine, pyrimidine, diethylaniline etc.

The original compound of formula (IV) used in SUP>1, R2, R3and R4take, respectively, the above values.

According to the scheme given above tioned formula (XI) is subjected to hydrolysis to obtain compounds of General formula (IV).

The hydrolysis is conducted according to a conventional method in which the compound of General formula (IV) can be obtained by heating in the presence of, for example, sodium hydroxide, potassium hydroxide, ethoxide sodium, sodium methoxide, etc., In the reaction may be used a solvent such as methyl alcohol, ethyl alcohol, etc., tetrahydrofuran, dimethoxyethane or aqueous solvent.

In the case of the above-mentioned starting compound of the formula (IV) in which R1is hydrogen, R2is methyl and R4is methyl, preparative method thereof can be accounted for by the following specific scheme (see Fig. 1 to 3).

In Fig. 3 the sign "*" denotes asymmetric carbon atom and the formula (XX) is the corresponding enantiomer.

Below briefly illustrates each of the above stages.

(The first stage)

2-Bromopropionitrile formula (XIII) according to normal procedures condensed with the compound of General formula (XII) and get a connection General formula (XIV).

Or the reaction may be carried out in the presence of a base, including amine, such as triethylamine, pyridine, etc., hydroxide of alkali metal such as sodium hydroxide, potassium hydroxide, etc., or alkali metal hydride such as sodium hydride, potassium hydride, etc. in a solvent that does not participate in the reaction, such as, for example, dichloromethane, dichloroethane, tetrahydrofuran, toluene, benzene, xylene, dimethylformamide, etc.

(Second stage)

At this stage, through the connection of General formula (XIV) according to the usual method is passed ammonia gas and get a connection General formula (XV).

The reaction is recommended in the range of low temperatures, for example at 30 - 100oC.

The reaction is carried out without solvent or in a solvent that does not participate in the reaction and is selected from ethers, such as tetrahydrofuran, dioxane, etc., ethyl acetate, chloroform, methanol, ethanol, pyridine and dichloromethane.

(The third one hundred what elisala and the formation of compounds of General formula (XVI).

One technique is described in more detail. The compound is dissolved in an appropriate solvent that does not participate in the reaction, such as, for example, benzene, toluene, xylene, pyridine, etc., and to the solution is added an equivalent of an acid catalyst such as acetic acid, silica gel, etc., the Reaction system is heated with removal of water formed through the drying means or nozzles Dean-stark.

(Fourth stage)

At this stage, carry out the reaction between pentasulfide phosphorus and compound of General formula (XVI) to obtain the compounds of General formula (XVII).

The reaction is carried out in a solvent such as pyridine, dimethoxyethane, diglyme, tetrahydrofuran, toluene, benzene, xylene, etc., the Reagent can serve as azide from pentasulfide phosphorus reagent Lawson, (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide). In some cases, the reaction is carried out in the presence of a base such as sodium bicarbonate.

(Fifth stage)

At this stage, carry out the reaction acetohydrazide with the compound of General formula (XVII) with its cyclization and the formation of compounds of General formula (XVIII).

The reaction is performed by heating acetohydrazide in rest OUTSTA solvent. Or spend the reaction of hydrazine hydrate is added in a solvent such as methanol or ethanol, and the resulting hydrazide is introduced into reaction with ethyl ortho-acetate and get the target product. In one embodiment, can be carried out the reaction of the hydrazide with acetylchloride or acetic anhydride and then carry out the dehydration of the obtained product with obtaining the compounds of formula (XVIII).

(Sixth stage)

At this stage carried out in the usual manner by hydrolysis of compounds of General formula (XVIII) and get a connection General formula (XIX).

Carry out the reaction by known methods, for example by heating in the presence of potassium hydroxide, sodium hydroxide, ethoxide sodium, sodium methoxide, ethoxide potassium, potassium methoxide, etc., with the obtained compounds of General formula (XIX).

The reaction may be used a solvent including an alcohol solvent such as methyl alcohol or ethyl alcohol, tetrahydrofuran, dimethoxyethane or aqueous solvents.

A specific example of obtaining compounds of General formula (XIX) using the above set of transformations is illustrated in preparative example (see below), where R3the chlorine atom.

Connect the in to obtain the final compounds with good anti-VEILS activity. More specifically, the target compound, obtained on the basis of the intermediate compounds (i.e. compounds of General formula (I), where R1is a hydrogen atom and R2- methyl), exhibits unexpectedly high anti-VEILS activity in comparison with the known derivatives of 1,4-diazepine. In this sense, the compounds of General formula (IV) in which R1is a hydrogen atom and R2- lower alkyl, in particular methyl, are very valuable intermediate products.

Intermediate compounds have an asymmetric carbon atom, therefore exist as optical isomers. In the practice of the invention d1-isomers, if desired, can be separated into optically active products.

The separation can be carried out at the stage of obtaining compounds of General formula (XV) with application to separation optical separating means, such as (+) or (-)-tartaric acid, (+) or (-)-camphoric acid, (+) or (-)-dibenzoyltartaric acid, (+) or (-)-10-camphorsulfonic acid, (+) or (-)-mandelic acid, etc. Or at the stage of obtaining compounds of General formula (IV) or (XIX) separation may be effected by the optical separating means, such as Dibenzoyl-D-tartaric acid or XV), (XIX) or (IV) the use column for separating optical isomers, such as, for example, a column with a chiral polyamide on silica gel in HPLC (high performance liquid chromatography with elution with a mixture of tetrahydrofuran-hexane.

Other compounds, other than as described in the methods for their preparation, can be obtained in a similar way, but based on other original products.

Experimental example

Test linking PHAT-receptor with human platelets

(Methodology)

Platelets are selected in the usual way in healthy people and suspended to a concentration of 108platelets/460 μl in binding buffer (10 mm phosphate saline buffer (pH 7) with 0.1% (wt./about.) ABS (bovine serum albumin) and 0.9 mm CaCl2). Platelets (108in 460 μl buffer is transferred into polypropylene tubes and pre-incubated with the test compound (20 μl) after centrifugation for 6 min at 37oC. Then, in a test tube add 20 μl of a solution of a binding buffer with3N-VEILS (final concentration3N-VEILS of 0.6 nm) and incubated for 6 minutes. The binding reaction stopped by addition of 3 ml ice leaching solution (salt solution containing 0.1% (michelango filter using a scintillator with a liquid scintillation counter to measure the radioactivity of the filter.

The percentage of inhibition calculated by the following equation and subsequent interpolation of the results obtained gain values IR (inhibitory concentration).

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where binding of radioactivity binding in the absence of cold-FOP or test compounds;

nonspecific binding of radioactivity binding in the presence of 10-5M VEILS.

The results are shown in the table.

Nonspecific binding of radioactivity (dpm) after incubation with 10-5M VEILS.

The results are shown in the table.

The sign "*" denotes asymmetric carbon atom and the sign "(+)" and "(-)" indicates the specific direction of rotation.

From the table it is evident that the compounds of the invention possess anti-VEILS activity. Moreover, it was found that the compounds have increased and more prolonged anti-VEILS activity with greater safety compared with known compounds. Thus, the present invention has great advantages.

Accordingly, the compounds of the invention are effective for the treatment and prevention of diseases transmitted VEILS.

A typical illness is allergic diseases, asthma, thrombosis, cerebral apoplexy (cerebral hemorrhage, cerebral thrombosis), myocardial infarction (angina), syndrome of consumption coagulopathy person (CST), thrombophlebitis, glomerular hepatitis, anaphylactic shock, the shock from bleeding, etc., the compounds of the invention will be particularly useful as antiallergic agents and anti-asthmatic medications.

With the introduction of these compounds as anti-FAT means they can be used in oral dosage in the form of tablets, powders, granules, capsules, syrups, etc., Or they can be used in parenteral dosages in the form of suppositories, injections, external medicines or internal drip infusion. In the case of the invention compounds are recommended as oral contraceptives.

The dosage can depend on the type of disease, its severity and the age of the patient. In the case of oral administration of compounds used in a dosage of 0.001 - 10 mg/kg, preferably 0.01 to 0.5 mg/kg

Preparations for oral or parenteral administration can be manufactured by conventional pharmaceutically acceptable additives. To obtain solutions for injecr, buffer solutions, stabilizers and soljubilizatory. The mixture can be dried by freezing if necessary with getting injections for subcutaneous, intramuscular or intravenous injection or intravenous drip infusion.

Below presents data on acute toxicity, obtained when tested on rats of compound of example 77, LD50(mg/kg):

Oral - Intravenous

males

1000 - 2000 - 120 - 240

females

612 - 120 - 240

The following are typical examples of the invention, which should not be construed as limiting it.

Among the following examples: (A) examples 1 - 77 and preparative examples 1 to 29; (B) examples 78 - 104 and preparative examples 30 to 34; (C) examples 105 - 120 and preparative examples 35 to 43; (D) examples 121 - 137 and preparative examples 44 - 52.

It should be noted that the receipt of the parent compounds or substances described in preparative examples.

EXAMPLE 1

6-(2-Chlorophenyl)-3-(1-cyano-1-methylethanolamine)-11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
(1) Synthesis of 1-cyano-1-methylethylenediamine

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Under ice cooling to 0.85 grams (10 mmol) of cyanhydrin acetone at pyrid the Oia reaction the solvent is distilled off to obtain a residue, which is dissolved in chloroform and washed with 1 N. hydrochloric acid, saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The resulting product was then purified column chromatography on silica gel with elution with a mixture of ethyl acetate - n-hexane (1:49) and get with the quantitative yield of the target compound as a colorless solid.

(2) Synthesis of 6-(2-chlorophenyl)-3-(1-cyano-1-methylethanolamine)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine

< / BR>
In chloroform dissolve 0.5 g of 1-cyano-1-methylethylenediamine and 0.15 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4]diazepine, mix well, and then the solvent is distilled off. The resulting mixture was stirred in a bath at 120oC for 1 hour. After cooling and cleaning column chromatography on silica gel with elution with a mixture of chloroform - ethanol (99:1) to obtain 0.18 g of the desired product as an amorphous substance.

1H-NMR (90 MHz, CDCl3) : or 1.77 (6H, s), 1.8-to 2.2 (2H, m), 2,68 (3H, s), 3,1-3,6 (2H, m), 4,22 (1H, m), 4,50-4,88 (2H, m), 5,6 (1H, m), 7,35 (4H, m).

FABMS (M+H+) m/z: 481

EXAMPLE 2

6-(2-Chlorophenyl)-3-(3-cyanopropionic)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[ogladanie ice to 0.85 grams of 4-hydroxybutanal and 1.5 g of pyridine in chloroform (20 ml) added dropwise 1.5 g of phenylcarbamate, then stirred for 30 minutes. After completion of the reaction, the reaction mixture was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent is then evaporated and purification of the residue on a column of silica gel with elution with a mixture of ethyl acetate - n-hexane (3:17) to obtain 1.2 g of the target compound.

(2) Synthesis of 6-(2-chlorophenyl)-3-(3-cyanopropionic)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine

< / BR>
In chloroform dissolved 0.11 g of 1-cyanopiperidine and 0.13 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4] diazepine, mix well, and then the solvent is distilled off. The resulting mixture was stirred for 1 hour in a bath at 110oC, then cooled, and after purification by chromatography on a column of silica gel with elution with a mixture of chloroform - ethanol (49:1) to obtain 0.1 g of the target product.

1H-NMR (90 MHz, CDCl3) : 1,41-of 1.80 (m, 2H), 1,80-2,17 (m, 2H), 2,22-2,52 (m, 2H), and 2.6 (s, 3H), 2,80-USD 5.76 (m, 6H), 4,2 (t, J = 7 Hz, 2H), and 7.3 (m, 4H).

FABMS (M+H+) m/z: 481

EXAMPLE 3

3-(3-Butyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
(1) Synthesis of 3-bumply added 1.7 g of phenylcarbamate and stirred for 30 minutes. After completion of the reaction, the reaction mixture was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent is then distilled off and after cleaning column chromatography on silica gel with elution with a mixture of ethyl acetate - n-hexane (1:49) with a quantitative yield obtain the target compound as a colourless oil.

(2) Synthesis of 3-(3-butyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

< / BR>
In chloroform dissolve 0.1 g 3-butylperbenzoate and 0.18 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine mix well, and then the solvent is distilled off. The resulting mixture was stirred for 1 hour at 110oC. After cooling and cleaning column chromatography on silica gel with elution with a mixture of chloroform - ethanol (99:1) to obtain 0.17 g of the target product.

1H-NMR (90 MHz, CDCl3) : 1,60 - of 2.16 (m, 2H), was 1.94 (s, 3H), 2,5 ( LW. t, J = 2 Hz, 7 Hz, 2H), 2,66 (s, 3H), 2,86 - 5,74 (m, 6H), 4,17 (t, J = 7 Hz, 2H), 7,29 (m, 4H).

MS m/z (Pos. Gab): 466 (M + H+).

EXAMPLE 4

6-(2-Chlorophenyl)-3-(2-cyanoethylidene)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] the Rila and 1.2 g of triethylamine in dichloroethane (20 ml) added dropwise 1.4 g of phenylcarbamate and stirred for 30 minutes. After completion of the reaction the mixture was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After removal of the solvent and purification of column chromatography on silica gel with elution with a mixture of ethyl acetate - n-hexane (1:9) to obtain 1.3 g of the target compound.

(2) Synthesis of 6-(2-Chlorophenyl)-3-(2-cyanoethylidene)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine

< / BR>
In chloroform dissolve 0.09 g of N-(2-cyanoethyl)carbamate and 0.18 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4] diazepine, mix well, and then the solvent is distilled off. The resulting mixture was stirred for 1 hour at 140oC. After cooling, cleaning column chromatography on silica gel with elution with a mixture of chloroform - methanol (19:1) to obtain 0.12 g of the target product.

1H-NMR (90 MHz, CDCl3) : 1,45 - of 2.23 (m, 2H), and 2.6 (t, J = 7 Hz, 2H), 2,64 (s, 3H), 2,80 - 5,69 (m, 9H), 7,29 (m, 4H).

MS m/z (Pos. Fab): 466 (M + H)+.

EXAMPLE 5

6-(2-Chlorophenyl)-11-methyl-3-(2-PROPYNYL)-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
To a solution of 0.12 g of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]tcheremissine 1 hour at 60oC. At room temperature, add 60 mg of 3-bromopropene and the reaction mixture is stirred for 1 hour at 60oC. After cooling, the reaction mixture was added water, extracted with ethyl acetate and dried over magnesium sulfate. Removal of solvent and purification of column chromatography on silica gel with elution with a mixture of chloroform - methanol (98,5: 1,5) receive 20 mg of the target product.

1H-NMR (90 MHz, CDCl3) : 1,52 - 2,12 (m, 2H, in), 2.25 (t, J = 2 Hz, 1H), 2,16 - 2,84 (m, 2H), 2,66 (s, 2H), 3.45 points (d, J = 2 Hz, 2H). 3,74 (m, 2H,), 3,9 - 4,4, 5,20 - 5,76 ( 2m, 2H), 7,27 (m, 2H).

MS m/z: 407.

EXAMPLE 6

6-(2-Chlorophenyl)-11-methyl-3-cyclopropanecarbonyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 4 ml of N,N-dimethylformamide is dissolved 90 mg cyclopropanecarbonitrile and to the resulting solution was dropwise at -60oC add a solution of 150 mg of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4] diazepine in 6 ml N,N-dimethylformamide and 210 mg of triethylamine and the mixture is stirred for 30 minutes. After removal of the solvent added saturated aqueous sodium bicarbonate solution, extracted with chloroform and dried over magnesium sulfate. After filtration, removal of the solvent and purification poluchat 140 mg (yield 79%) of target compound.

1H-NMR (90 MHz, CDCl3) : 0,4 - 1,3 (m, 4H), 1,4 - 2,7 (m, 3H), to 2.67 (s, 3H), 2,8 - 5,8 (m, 6H), a 7.1 to 7.6 (m, 4H).

Ms m/z (Pos. Fab.): 438 (M + H)+.

EXAMPLE 7

6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 4 ml of N, N-dimethylformamide was dissolved 100 mg of 6-(2-chlorophenyl)-3-cyclopropanecarbonyl-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4]diazepine, to the resulting solution was added 54 mg of sodium hydride (55%) and 0.5 ml of the bromide and the mixture is stirred for 1 hour at room temperature. The reaction is stopped by addition of water and the solution neutralized with acetic acid. The solvent is then distilled off under reduced pressure and the resulting residue is extracted with 20 ml dichloromethane. The resulting solution was dried over anhydrous magnesium sulfate, the solvent is removed and after cleaning column chromatography on silica gel (400 mesh, 10 g) to obtain the title compound.

1H-NMR (90 MHz, CDCl3) : 0,55 - of 1.15 (m, 4H), 1,45 - of 2.50 (m, 3H), 2,1 (d, J = 6.8 Hz, 3H), of 2.66 (s, 3H), 2,8 - 4,8 (m, 3H), 4.26 deaths (K, J = 6,8 Hz, 1H), 4,8 - 5,2 (m, 1H), 7,05 - the 7.65 (m, 4H).

Ms m/z (Pos. Fab.): 452 (M + H)+.

EXAMPLE 8

6-(2-Chlorophenyl)-3-cynnamoyl-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5] and to the resulting solution was added dropwise 4 ml of a solution of 120 mg of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepine and 160 mg of triethylamine in N,N-dimethylformamide and the mixture is stirred. After removal of the solvent added saturated aqueous sodium bicarbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, the solvent is distilled off and after cleaning the residue column chromatography on silica gel with elution with a mixture of MeOH - CH2Cl2(1:99) to obtain 11 mg (68%) of the title compound.

MS m/z (Pos. Fab.): 500 (M + H)+.

EXAMPLE 9

6-(2-Chlorophenyl)-3-cyclobutanecarbonyl-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 8 ml of N,N-dimethylformamide was dissolved 50 mg cyclobutanecarbonyl acid, 70 mg of the monohydrate of 1-hydroxybenzotriazole and 150 mg of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4] diazepine under ice cooling was added 100 mg of N,N'-dicyclohexylcarbodiimide, then stirred for 10 minutes at the same temperature and day 4oC. Then, after stirring for another 1 hour at room temperature, the insoluble matter is filtered off and the solvent is distilled off. Add saturated aqueous sodium bicarbonate solution, then extracted with Chi balance column chromatography on silica gel with elution with a mixture of MeOH - CH2Cl2(1:99) to obtain 180 mg (98%) of target compound.

1H-NMR (90 MHz, CDCl3) : 1.4 to 2.5 (m, 9H), to 2.67 (s, 3H), 2,8 - 5,9 (m, 6H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. Fab.): 452 (M + H)+.

EXAMPLE 10

6-(2-Chlorophenyl)-3-diethylphosphino-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 5 ml of tetrahydrofuran and 1 ml of triethylamine dissolved 100 mg of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4] triazolo[4,3-a] [1,4]diazepine, to the resulting solution was added 100 mg of diethylphosphate and the mixture is stirred for 1 hour at room temperature. The reaction solution was added to saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure and purification of the obtained residue column chromatography on silica gel with elution with a mixture of CH3OH:CH2Cl2(5:95) to obtain 100 mg (72%) of target compound.

MS (FAB): 506 (M + H)+.

1H-NMR (90 MHz, ): of 1.28 (t, J = 8, 6H), 1,44 - of 2.20 (m, 2H), 2,69 (s, 3H), 3,7 - 4,6 (m, 9H), 5,33 - 5,72 (m, 1H), 7,12 - of 7.48 (m, 5H).

EXAMPLE 11

3-(3-Butyloxycarbonyl)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3, is tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4] diazepine in dimethylformamide (2 ml) was added 28 mg of sodium hydride (55%, and 0.2 ml of the bromide and stirred for 1 hour at room temperature.

To terminate the reaction, water is added and the solution is neutralized with acetic acid. The solvent is distilled off under reduced pressure and the resulting residue extracted with 10 ml of dihlormetilen and then 20 ml of dihlormetilen. The solution is dried over magnesium sulfate, the solvent is removed and after cleaning column chromatography on silica gel (400 mesh, 10 g) with elution with a mixture of methanol - dichloromethane (1:99) to obtain 24 mg of the target compound.

1H-NMR (90 MHz, CDCl3): to 7.4 (5H, Ar), 4,9 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,5 (1H, J = 18 Hz, N-CH2(C-2)), 4,2 (1H, m, C8(H) a 4.1 (2H, t, J = 8 Hz, O-CH2), 2,7 (3H, s), and 2.5 (2H, DV. t, J = 1.7 Hz, -CH2), and 2.1 (3H, d, J = 7 Hz, CH, CH3), 3 - 2 (5H, m).

EXAMPLE 12

6-(2-Chlorophenyl)-8,11-dimethyl-3-(3-cyanopropionic)-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
To a solution of 62 mg of 6-(2-chlorophenyl)-3-(3-cyanopropionic)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4] diazepine in 2 ml of dimethylformamide at room temperature is added 34 mg of sodium hydride (55%) and billaut water and neutralized with acetic acid. The solvent is distilled off under reduced pressure and the resulting residue extracted with 10 ml of dihlormetilen and then 20 ml of dihlormetilen. The solution is dried over magnesium sulfate, the solvent is removed and after cleaning column chromatography on silica gel (400 mesh, 10 g) with elution with a mixture of methanol - dichloromethane (1:99) to obtain 21 mg of the target compound.

1H-NMR (90 MHz, CDCl3): 7,4 (2H, Ar), 4,9 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,5 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,2 (1H, m, C8(H) a 4.1 (2H, t, J = 8 Hz, O-CH2), 2,7 (3H, s), 2,4 (3H, d, J = 7 Hz), 2,1 (3H, d, J = 7 Hz, CHCH3), 3 - 2 (6H, m).

EXAMPLE 13

6-(2-Chlorophenyl)-8,8-diethyl-3-(3-cyanopropionic)-11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4] triazolo[4,3-a] [1,4]diazepin

< / BR>
To a solution of 69 mg of 6-(2-chlorophenyl)-3-(3-cyanopropionic)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4] diazepine in 2 ml of dimethylformamide at room temperature, add 10 mg of sodium hydride (55%) and 0.03 ml of the bromide and stirred for 2 hours at room temperature.

Thin-layer chromatography revealed the presence of the parent compound and two new products, namely: monoethylamine and diethylpropion. So add 10 mg of sodium hydride is italist acetic acid. The solvent is distilled off under reduced pressure and the resulting residue extracted with 10 ml of dihlormetilen and then 20 ml of dihlormetilen. The solution is dried over magnesium sulfate, the solvent is removed and after cleaning column chromatography on silica gel (400 mesh, 13 g) with elution with a mixture of methanol - dichloromethane (1:99) to obtain 41 mg of the target compound.

1H-NMR (90 MHz, CDCl3): to 7.4 (5H, Ar), 4,9 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,5 (1H, J = 18 Hz, N-CH2(C-2)), 4,1 (2H, t, J = 8 Hz, O-CH2), 2,7 (3H, s, CH3), 2,0 - 2,7 (10H, m) and 1.3 (6H, t, J = 7 Hz, CH2CH3).

EXAMPLE 14

3-(3-Butyloxycarbonyl)-6-(2-chlorophenyl)-8,8-diethyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
Reproduced General method of example 12 using 65 g of 3-(3-butyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine. Received 23 mg of the target product.

1H-NMR (90 MHz, CDCl3): to 7.4 (5H, Ar), 4,9 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,5 (1H, J = 18 Hz, N-CH2(C-2)), 4,1 (2H, t, J = 8 Hz, O-CH2), 2,7 (3H, s, CH3), 2,0 - 2,7 (8H, m, CH2CH3and CH2CH3) and 1.3 (6H, t, J = 7 Hz, CH2CH3).

EXAMPLE 15

6-(2-Chlorophenyl)-3-(1-cyano-1-methylethanolamine)-7,11-d is in example 1 in N,N-dimethylformamide (3 ml) under cooling with ice added 0.24 g of sodium hydride (60%) and stirred for 30 minutes. Then to the solution was added 0,37 mg bromide, stirred for 30 minutes under ice cooling and for 1 hour at room temperature. After completion of the reaction, water is added, extracted with chloroform and dried with magnesium sulfate. Obtained after filtration and concentration the residue is purified column chromatography on silica gel with elution with a mixture of chloroform - methanol (99:1) and get to 0.19 g of the target compound.

1H-NMR (90 MHz, CDCl3) : of 1.76 (s, 6H), 1.8 - to 2.2 (m, 2H), 2,1 (d, 3H), of 2.66 (s, 3H), of 3.0 to - 3.9 (m, 2H), 4,24 (K, 1H), 4,3 - 4,9 (m, 2H), 7,35 (m, 4H).

FABMS (M + H+) m/z: 495.

EXAMPLES 16 - 71

According to the method of the above example, the following compounds.

EXAMPLE 16

6-(2-Chlorophenyl)-3-(1-cyano-1-methylethanolamine)-8,8,11-trimethyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,8 (s, 6H), and 2.8 (s, 3H), 3,1 (s, 3H), of 3.0 to - 3.9 (m, 4H), and 3.8 (s, 3H), 4,4 - 4,9 (m, 2H), and 7.4 (m, 4H).

EXAMPLE 17

6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 0,04 - 0,32 (m, 2H), of 0.36 to 0.60 (m, 2H), 0.70 to to 1.16 (m, 1H), 1,52 - 2,17 (m, 2H), 2,66 (s, 3H), 2,84 - to 5.85 (m, 7H), 3.04 from (LW. d, J = 6 Hz, 7 Hz, 2H), 7,32 is of IMT-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,12 - of 2.24 (m, 12H), is 2.37 (s, 1H), 2,80 - USD 5.76 (m, 7H), 7,29 (m, 4H).

FABMS (M + N+) m/z: 519.

EXAMPLE 19

6-(2-Chlorophenyl)-3-(5-cyanomethylaminopropyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,28 - of 2.16 (m, 8H), 2,32 (t, J = 7 Hz, 2H), 2,81 - of 5.68 (m, 9H), 7,29 (m, 4H).

FABMS (M + H+) m/z: 508.

EXAMPLE 20

6-(2-Chlorophenyl)-3-(4-cyanobenzeneboronic)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,55 - to 2.18 (m, 2H), to 2.67 (s, 3H), 3,8 - 5,7 (m, 6H), 7,32 (m, 4H), 7,47 (m, 4H), and 8.4 (ush., s, 1H).

FABMS (M + H+) m/z: 514.

EXAMPLE 21

6-(2-Chlorophenyl)-3-(3-cyanobenzeneboronic)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,43 - 2,17 (m, 2H), 2.63 in (s, 3H), 3.04 from - of 5.68 (m, 6H), 7,05 - 7,72 (m, 8H).

FABMS (M + H+) m/z: 514.

EXAMPLE 22

6-(2-Chlorophenyl)-3-(3-ethynyltestosterone)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,4 - 2,4 (m, 2H), 2,66 (s, 3H), 3,01 (s, 1H), 3,05 - 5,08 (m, morpholine-4-yl)carbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,32 is 2.44 (m, 2H), 2,66 (s, 3H), 2,92 to 5.8 (m, 6H), 3,21 (t, J = 6 Hz, 4H), 3,63 (t, J = 6 Hz, 4H), 7,29 (m, 4H).

FABMS (M + H+) m/z: 483.

EXAMPLE 24

6-(2-Chlorophenyl)-3-(1-ethynylcyclopentanol)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,40 is 2.44 (m, 10H), of 2.56 (s, 1H), to 2.67 (s, 3H), 2,9 - 5,8 (m, 6H), 7,29 (m, 4H).

FABMS (M + H+) m/z : 506.

EXAMPLE 25

6-(2-Chlorophenyl)-11-methyl-3-(phenylethylamine)- 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,67 - to 2.40 (m, 2H), 2,68 (s, 3H), 3.04 from - 5,80 (m, 6H), 7,12 - of 7.60 (m, 9H).

FABMS (M + H+) m/z: 498.

EXAMPLE 26

6-(2-Chlorophenyl)-3-(1,1-dimethyl-2-propenylboronic)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,40 - to 2.18 (m, 2H), by 1.68 (s, 6H), 2,53 (s, 1H), to 2.67 (s, 3H), 2,90 - USD 5.76 (m, 6H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 480.

EXAMPLE 27

6-(2-Chlorophenyl)-11-methyl-3-(1-methyl-2-propenylboronic)- 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,38 of - 2.32 (m, 2H), 1,5 (d, J = 7 Hz, 3H), of 2.45 (d, J = 2 Hz, 1H),>6-(2-Chlorophenyl)-11-methyl-3-(1-methyl-3-butyloxycarbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,3 (d, J = 7 Hz, 3H), are 1.5 - 2.6 (m, 5H), to 2.66 (s, 3H), 2,88 - 5,72 (m, 7H), 7,29 (m, 4H).

FABMS (M + H+) m/z: 480.

EXAMPLE 29

6-(2-Chlorophenyl)-11-methyl-3-(2-intenrational)- 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : of 1.13 (d, J = 7 Hz, 3H), 1,54 - of 2.36 (m, 2H), 2,25 (Tr. K, J = 2 Hz, 7 Hz, 2H), to 2.67 (s, 3H), 2,84 - USD 5.76 (m, 6H), of 4.66 (t, J = 2 Hz, 2H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 480.

EXAMPLE 30

6-(2-Chlorophenyl)-11-methyl-3-(3-intenrational)- 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,5 - 2,2 (m, 2H), 1,74 (t, J = 2 Hz, 3H), 2,42 (m, 2H), 2,66 (s, 3H), 2,9 - 5,7 (m, 6H), 4,11 (t, J = 7 Hz, 2H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 480.

EXAMPLE 31

6-(2-Chlorophenyl)-3-[2-(imidazol-1-yl)etoxycarbonyl] -11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,50 - 2,19 (m, 2H), 2,66 (s, 3H), 2,8 - 5,8 (m, 10H) 6,70 - 6,92 (m, 1H), 6,92 - 7,06 (m, 1H), 7,12 - rate of 7.54 (m, 1H), 7,30 (m, 4H).

FABMS (M + H+) m/z: 508.

EXAMPLE 32

6-(2-Chlorophenyl)-11-m is seen

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,40 - 2,12 (m, 6H), to 2.67 (s, 3H), 2,84 - of 5.68 (m, 11H), 7,29 (m, 4H).

FABMS (M + H+) m/z: 498.

EXAMPLE 33

6-(2-Chlorophenyl)-3-[5-hexyloxybenzoyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,20 of - 2.32 (m, 6H), was 1.94 (t, J = 2 Hz, 1H), 2,21 (LW. t, J = 2 Hz, 7 Hz, 2H), 2,66 (s, 3H), 2,84 - USD 5.76 (m, 6H), 7,28 (m, 4H).

FABMS (M + H+) m/z: 494.

EXAMPLE 34

6-(2-Chlorophenyl)-3-(3-cyano-1-oxopropyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,16 - of 2.38 (m, 2H), 2,42 - and 2.79 (m, 4H), to 2.67 (s, 3H), 3,20 - 5,72 (m, 6H), 7,31 (m, 4H).

FABMS (M + H+) m/z: 451.

EXAMPLE 35

6-(2-Chlorophenyl)-3-(2-cyano-1-oxoethyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,60 to 2.35 (m, 2H), 2,66 (s, 3H), 3,20 - USD 5.76 (m, 8H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 437.

EXAMPLE 36

6-(2-Chlorophenyl)-3-(3-cyanopropionic)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,41 - of 1.80 (m, 2H), 1,80 - 2,17 (m, 2H), 2,22 - 2,52 (m, 2H), 2,66 (s, 3H), 2,86 - USD 5.76 (m, 6H), 4,2 (t, J = 7 Hz, 2H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 450.

EXAMPLE 38

6-(2-Chlorophenyl)-11-methyl-3-(1-propolypeptide-4-yl)oxycarbonyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,4 - 2,9 (m, 11H), of 2.25 (t, 1H), and 2.7 (s, 3H), and 3.3 (d, 2H), 3,0 - 3,9 (m, 2H), 4,0 - 4,9 (m, 1 + 2H), 5,4 - 5,8 (m, 1H), and 7.4 (m, 4H).

MS m/z (Pos. FD): 535.

EXAMPLE 39

6-(2-Chlorophenyl)-3-cyclohexyloxycarbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,2 - 2,3 (m, 12H), and 2.7 (s, 3H), 3,0 - 4,0 (m, 2H), 4,0 - 4,8 (m, 1 + 1 + 2H), 5,4 - 5,8 (m, 1H), and 7.4 (m, 4H).

MS m/z (Pos. FAB): 496.

EXAMPLE 40

6-(2-Chlorophenyl)-3-cyclohexyloxycarbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : from 0.6 to 2.7 (m, 17H), and 2.7 (s, 3H), 3,0 - 4,0 (m, 2H), of 4.0 - 4.4 (m, 1 + 2H), 4,4 - 4,8 (m, 2H), 5,4 - 5,8 (m, 1H), and 7.4 (m, 4H).

MS m/z (Pos. FAB): 538.

EXAMPLE 41

6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 0,2 - 2,0 (m, 2H), 2,BR> 6-(2-Chlorophenyl)-3-cyclohexyloxycarbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 0,8 - 2,2 (m, 13H), and 2.7 (s, 3H), 3,0 - 4,0 (m, 2H), 3,7 - 4,0 (d, 2H), 4,1 - 4,8 (m, 1 + 2H), 5,4 - 5,8 (m, 1H), and 7.4 (m, 4H).

MS m/z (Pos. FAB): 510.

EXAMPLE 43

6-(2-Chlorophenyl)-11-methyl-3-(4-pyridylcarbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1.4 to 2.5 (m, 2H), to 2.67 (s, 3H), 3,10 - of 3.75 (m, 2H), 3.9 to about 5.8 (m, 4H), of 7.0 to 7.7 (m, 6H), and 8.4 to 8.8 (m, 2H).

MS m/z (Pos. FAB): 475.

EXAMPLE 44

6-(2-Chlorophenyl)-3-cyclohexyloxycarbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 0,6 - 2,4 (m, 13H), of 2.16 (d, J = 6,5 Hz, 2H), to 2.67 (s, 3H), 2,8 - 5,9 (m, 6H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 494 (M + H)+.

EXAMPLE 45

6-(2-Chlorophenyl)-3-cyclohexanecarbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 0,7 - 2,7 (m, 13H), to 2.67 (s, 3H), 2,8 - 5,8 (m, 6H), and 7.1 to 7.4 (m, 4H).

MS m/z (Pos. FAB): 480 (M + H)+.

EXAMPLE 46

6-(2-Chlorophenyl)-11-methyl-3-(3-pyridylcarbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4"ptx2">

MS m/z (Pos. FAB): 475 (M + H)+.

EXAMPLE 47

3-[4'-(Morpholine-4-ylsulphonyl)phenylenecarbonyl] -6-(2-chlorophenyl)- 11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,8 - 2,2 (m, 4H), 2.63 in (s, 3H), 2,80 - is 3.08 (m, 4H), 3,24 - 3,90 (m, 9H), 4,6 - 4,9 (m, 2H), 7,20 - 7,42 (m, 4H), 7,45 - to 7.68 (m, 4H), 7,75 (ush. band, 1H).

MS: m/z 638.

EXAMPLE 48

6-[4'-(N-Piperidinomethyl)phenylenecarbonyl] -6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,1 - 2,3 (m, 10H) of 2.64 (s, 3H), 2,75 - 3,10 (m, 4H), 3,3 - 4,3 (m, 2H), 4,60 to 4.92 (m, 2H), 7,15 - 7,40 (m, 4H), 7,42 - of 7.60 (m, 4H) 7,72 (ush. band, 1H).

MS: m/z 636.

EXAMPLE 49

3-[4'-(N-Imidazolylalkyl)phenylenecarbonyl] -6-(2-chlorophenyl)- 11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,6 - 2,4 (m, 4H), and 2.7 (s, 3H), 3.75 to 4,30 (m, 2H), 4,4 - 5,0 (m, 2H), 7,0 - 7,5 (m, 12H).

MS: m/z 619.

EXAMPLE 50

3-[4'-(Sulfamoyl)phenylenecarbonyl] -6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,4 - 2,2 (m, 4H), 2,62 (s, 3H), 3,6 - 4,4 (m, 2H), 5,1 - 5,5 (m, 2H), and 7.1 (s, 2H), 7.3 to delamination] -6-(2-chlorophenyl)- 11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,1 (t, 6H, J = 7.2 Hz), 1.7 to 2.3 (m, 4H), 2,62 (s, 3H), and 3.16 (K, 4H, J = 7,2 Hz), 3,4 - 4,2 (m, 2H), 3,55 - of 3.60 (m, 2H), 7.18 in - 7,40 (m, 4H), 7,54 (AB, 4H, J = 9 Hz), and 7.7 (s, 1H).

MS: m/z 624.

EXAMPLE 52

3-[4'-(N'-Cyclohexanesulfonyl)phenylenecarbonyl]-6-(2-chlorophenyl)- 11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 0,8 - 2,2 (m, 14H), of 2.64 (s, 3H), 2,8 - 4,3 (m, 3H), 4,6 - 4,3 (m, 3H), 4,6 - 4,9 (m, 2H), of 5.05 (d, 1H, J = 7,2 Hz), 7,2 - 7,4 (m, 4H), 7,56 (AB, 4H, J = 9 Hz), 7,76 (s, 1H).

MS: m/z 650.

EXAMPLE 53

3-[4'-(2"-Pyridylsulfonyl)phenylenecarbonyl] -6-(2-chlorophenyl)- 11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,6 - 2,2 (m, 4H), of 2.72 (s, 3H), 3,6 - 4,5 (m, 6H), 6,50 - 6,72 (m, 2H), of 7.0 to 7.7 (m, 11H), 8,11 - of 8.28 (m, 1H).

MS: m/z 659.

EXAMPLE 54

3-[3-(N-Piperidinomethyl)propylenecarbonate] -6-(2-chlorophenyl)- 11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5] thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : of 1.4 - 2.3 (m, 12H), and 2.7 (s, 3H), 2.95 and (t, 2H, J = 7,2 Hz), 3.1 to 3.4 (m, 4H), 3,5 - 4,2 (m, 2H), 4,22 (t, 2H, J = 7,2 Hz), 4,42 - 4,82 (m, 2H), 7,2 - 7,5 (m, 4H).

MS: m/z 603.

EXAMPLE 55

3-[3-(N-Morpholinomethyl)propylacetate the P>1H-NMR (90 MHz, CDCl3) : 1,6 - 2,4 (m, 6H), and 2.7 (s, 3H), 2,98 (t, 2H, J = 7,2 Hz), 3,6 - 3,9 (m, 4H), 2,8 - 4,4 (m, 2H), 4,22 (t, 2H, J = 7,2 Hz), 4,40 - 4,84 (m, 2H), 7,2 - 7,5 (m, 4H).

MS: m/z 605.

EXAMPLE 56

3-[4'-(N-Morpholinomethyl)phenoxycarbonyl] -6-(2-chlorophenyl)- 11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4] triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,6 - 2,4 (m, 4H), to 2.74 (s, 3H), 2,8 - 3,1 (m, 4H), 3,6 - 3,8 (m, 4H), 3,1 - 5,1 (m, 4H), 4.9 to about 7.6 (m, 8H).

MS: m/z 639.

EXAMPLE 57

6-(2-Chlorophenyl)-3-(2-cyanoethylidene)carbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,57 - 2,22 (m, 2H), 2,61 (t, J = 7 Hz, 2H), to 2.67 (s, 3H), equal to 2.94 (s, 3H), of 3.0 to 5.8 (m, 6H), 3.43 points (t, J = 7 Hz, 2H), 7,31 (m, 4H).

FABMS (M+ H+) m/z: 480.

EXAMPLE 58

6-(2-Chlorophenyl)-3-(1-ethinyl-1 cyclohexyloxy-1-carbonyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,04 to 2.35 (m, 12H), 2,59 (s, 1H), to 2.67 (s, 3H), 2,78 - 5,78 (m, 6H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 520.

EXAMPLE 59

6-(2-Chlorophenyl)-11-methyl-3-(1-phenyl-2-propenylboronic)- 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDClz: 528.

EXAMPLE 60

6-(2-Chlorophenyl)-3-(2-cyanoethoxy)carbonyl-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,40 - of 2.34 (m, 2H), 2,66 (s, 3H), and 2.7 ( t, J = 7 Hz, 2H), 2,79 - USD 5.76 (m, 6H), 4,28 (t, J = 7 Hz, 2H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 467.

EXAMPLE 61

6-(2-Chlorophenyl)-11-methyl-3-(2-PROPYNYL)aminocarbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,56 - of 2.08 (m, 2H), 2,19 (d, J = 2 Hz, 1H), 2,65 (s, 3H), 2,96 - 5,70 (LW. d, J = 2 Hz, 7 Hz, 6H), 3,98 (LW. d, J = 2 Hz, 7 Hz, 2H), a 4.83 (t, J = 7 Hz, 1H), 7,28 (m, 4H).

FABMS (M + H+) m/z: 451.

EXAMPLE 62

3-(2-Butyloxycarbonyl)-6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,43 - of 2.15 (m, 2H), 1,84 (t, J = 2 Hz, 3H), of 2.66 (s, 3H), 2,80 - 5,74 (m, 6H), with 4.64 (K, J = 2 Hz, 2H), and 7.3 (m, 4H).

FABMS (M + H+) m/z: 466.

EXAMPLE 63

6-(2-Chlorophenyl)-11-methyl-3-[2-(2-pyridyl)ethylaminomethyl] - 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,46 was 2.25 (m, 2H), 2,65 (s, 3H), was 2.76 - USD 5.76 (m, 6H), of 2.92 (t, J = 7 Hz, 2H), 3,42 - 3,68 (m, 2H), 5,95 - 6,24 (m, 1H), 6,93 - 7,39 (m, 6H), 7,4 - 7,66 (m, 1H), 8,25 - to 8.40 (m, 1H).


< / BR>
1H-NMR (90 MHz, CDCl3) : 1,54 - of 2.20 (m, 2H), 2,30 - of 2.58 (m, 6H), to 2.67 (s, 3H), 2,88 - 5,80 (m, 6H), 3,17 - of 3.42 (m, 2H), 3,55 - 3,74 (m, 4H), 5,03 - 5,19 (m, 1H), and 7.3 (m, 4H).

MS m/z: 525.

EXAMPLE 65

6-(2-Chlorophenyl)-3-[4-(morpholine-4-ylcarbonyl)-2-butyloxycarbonyl]- 11-methyl-2,3,4,5-tetrahydro - 8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,55 - of 2.28 (m, 2H), 2,66 (s, 3H), 2,87 - of 5.75 (m, 6H), 3,34 - of 3.54 (m, 4H), 3,54 - and 3.72 (m, 4H), and 4.75 (s, 4H), and 7.3 (m, 4H).

MS m/z: 594.

EXAMPLE 66

6-(2-Chlorophenyl)-11-methyl-3-[4-(pyridine-2-eletromechanical)- 2-butyloxycarbonyl] -2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,6 - 2,2 (m, 2H), and 2.7 (s, 3H), 3.00 and - of 5.75 (m, 6H), to 4.46 (d, J = 5 Hz, 2H), 4.72 in (s, 4H), 5,90 - of 6.20 (m, 1H), a 7.1 to 7.6 (m, 6H), 7,5 - 7,9 (m, 1H), 8,40 - to 8.70 (m, 1H).

MS m/z: 615.

EXAMPLE 67

6-(2-Chlorophenyl)-11-methyl-3-(4-intenrational)-2,3,4,5-tetrahydro - 8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,52 - of 2.08 (m, 4H), of 1.92 (t, J = 2 Hz, 1H), 2,08 - to 2.40 (m, 2H), 2,66 (s, 3H), 2,84 - 5,72 (m, 6H), 4,17 (t, J = 7 Hz, 2H), 7,29 (m, 4H).

MS m/z: 479.

EXAMPLE 68

6-(2-Chlorophenyl)-11-methyl-3-(2-propenylboronic)-2,3,1,68 - of 2.15 (m, 2H), 2,5 (t, J = 3 Hz, 1H), 2,62 (s, 3H), 2,85 - 5,79 (m, 6H) and 4.65 (d, J = 3 Hz, 2H), and 7.4 (m, 4H).

MS m/z: 451.

EXAMPLE 69

6-(2-Chlorophenyl)-11-methyl-3-[2-(pyridin-2-yl)etoxycarbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,64 - of 2.25 (m, 2H), 2,50 - 5,74 (m, 6H), 2,71 (s, 3H), 2,9 (t, J = 7 Hz, 2H), 3,91 (t, J = 7 Hz, 2H), 6,86 - 7,80 (m, 7H), at 8.36 - 8,76 (m, 1H).

MS m/z: 518.

EXAMPLE 70

6-(2-Chlorophenyl)-11-methyl-3-[(tetrahydropyran-2-yl)methoxycarbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,12 of - 2.32 (m, 8H), to 2.66 (s, 3H), 2,92 - 5,72 (m, 11H), and 7.3 (m, 4H).

MS m/z: 499.

EXAMPLE 71

6-(2-Chlorophenyl)-11-methyl-3-[2-(morpholine-2-yl)etoxycarbonyl)- 2,3,4,5-tetrahydro - 8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,54 - of 2.24 (m, 2H), 2,36 - of 2.64 (m, 6H), 2,68 (s, 3H), 3.04 from of 5.84 (m, 6H), 3,52 - of 3.80 (m, 4H), 4,24 (t, J = 7 Hz, 2H), 7,39 (m, 4H).

MS m/z: 526.

Preparative example 1

6-Acetyl-2-(2-bromopropionyl)-3-(2-chlorobenzoyl)-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine

< / BR>
To 600 g of 2-amino-3-(2-chlorobenzoyl)-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridine added 13.3 g of toluene and 3,66 liters of water, then add 301 g Hydra is billaut 170 g of sodium bicarbonate and 170 ml of 2-bromopropionitrile to complete the reaction. After cooling to room temperature, add 500 g of sodium bicarbonate and the organic phase is separated. The aqueous phase is extracted twice with ethyl acetate, the combined organic phase washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and after washing the obtained solid residue with ether to obtain 800 g of the target product.

1H-NMR (90 MHz, CDCl3) : of 1.7 - 2.4 (m, 2H), 1,99 (d, J = 2 Hz, 2H), of 2.06 and 2.12 (both s, total 3H), 3.25 to to 3.7 (m, 2H), to 4.41 (K, J = 7.2 Hz, 1H), 4,4 - 4,8 (m, 2H), 7 - 7.5 (m, 4H).

Preparative example 1

6-Acetyl-2-(2-aminodiphenylamine)-3-(2-chlorobenzoyl)-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine

< / BR>
(Method A)

In 0.72 liters of dichloroethane and 1.08 liters of ethyl acetate is dissolved 841 g of 6-acetyl-2-(2-bromopropionyl)-3-(2-chlorobenzoyl)-4,5,6,7 - tetrahydrothieno[2,3-c] pyridine and -10oC miss gaseous ammonia. The resulting mixture is heated in an autoclave for 1 hour at 100oC. After completion of the reaction the excess ammonia is removed and the reaction mixture is transferred under ice cooling, 3 N. hydrochloric acid. After extraction with ethyl acetate, the aqueous phase is neutralized with a saturated aqueous solution of sodium carbonate and then repeatedly extracted with chloroform and after removal of the solvent under reduced pressure get 636,8 g of the target product.

1H-NMR (90 MHz, CDCl3) : to 1.48 (d, J = 6.8 Hz, 3H), 1,6 - 2,3 (m, 4H), 2,07 and 2.12 (two s, total 3H), 3.25 to 4.00 points (m, 3H), 4,35 - of 4.75 (m, 2H), 7.0 and about 7.6 (m, 4H).

(Method B)

In 150 ml of chloroform at room temperature was dissolved 10 g of 2-amino-3-(2-chlorobenzoyl)-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and the resulting solution was gradually within one hour is added at room temperature and mixing 17 g of the hydrochloride of Albergaria. After completion of the reaction to the mixture is added 150 ml of water and stirred for 30 minutes. The aqueous phase is separated. The solution in chloroform with the purpose of extraction is treated with 150 ml of water. Both aqueous phases are combined, washed with chloroform, neutralized with sodium bicarbonate and extracted with chloroform. The solvent is removed under reduced pressure and get the 10.1 g of compound as yellow powder.

Preparative example 3

8-Acetyl-5-(2-chlorophenyl)-3-methyl-6,7,8,9-tetrahydro-1H, 3H-pyrido[4',3': 4,5]thieno[3,2-f][1,4]diazepin-2-he

< / BR>
2.3 liters of toluene, 637 ml of pyridine and 94,3 ml of acetic acid are dissolved 636,8 g of 6-acetyl-2-(2-aminodiphenylamine)-3-(2-chlorobenzoyl)-4,5,6,7 - tetrahydrothieno[2,3-c] pyridine and refluxed during the day and night, removing water from the reaction system. After the removal process is SS="ptx2">

1H-NMR (90 MHz, CDCl3) : 1.3 to 2.6 (m, 2H), 1,76 (d, J = 6.8 Hz, 3H), of 2.06 and 2.12 (two s, total 3H), 2,8 - 4,1 (m, 2H), a 3.87 (K, J = 6,8 Hz, 1H), 4,1 - 5,1 (m, 2H), and 7.1 - 7.5 (m, 4H), 9,0 - 9,5 (ush. s, 1H).

Preparative example 4

3-Methyl-5-(2-chlorophenyl)-8-diacetyl-6,7,8,9-tetrahydro-1H, 3H-pyrido[4', 3': 4,5]thieno[3,2-f][1,4]diazepin-2-tion

< / BR>
In 3 liters of dimethoxyethane dissolve 288 g of 3-methyl-5-(2-chlorophenyl)-8-acetyl-6,7,8,9-tetrahydro-1H, 3H-pyrido[4', 3': 4,5]thieno[3,2-f][1,4]diazepin-2-it, add 186 g of sodium bicarbonate and 364 g of pentasulfide phosphorus and refluxed for 3 hours. The reaction mixture was filtered through celite and the solvent is distilled off under reduced pressure. To the obtained residue, in small amounts, add methanol and dichloromethane for subsequent adsorption on silica gel and after drying and purification of column chromatography with elution with a mixture of dichloromethane - methanol (98:2) to obtain 300 g of target compound.

Preparative example 5

6-(2-Chlorophenyl)-3-diacetyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 70 ml of dioxane was dissolved to 4.81 g of 3-methyl-5-(2-chlorophenyl)-8-diacetyl-6,7,8,9-tetrahydro-1H, 3H-pyrido[4', 3': 4,5]thieno[3,2-f][1,4]diazepin-2-thione, to the resulting solution was added the t and purification of the obtained residue column chromatography with elution with a mixture of dichloromethane - ethanol (98:2) to obtain 750 g of target compound.

Preparative example 6

6-(2-Chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5] thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 1 liter of methanol is dissolved 281 g of 6-(2-chlorophenyl)-8,11-dimethyl-3-diacetyl-2,3,4,5-tetrahydro-8H-pyrido[4',3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4] diazepine, to the resulting solution was added 0,81 liters of 4n. sodium hydroxide and heated to boiling under reflux. After cooling, the reaction mixture podsalvage and extracted with chloroform, after which the solvent is distilled off under reduced pressure. Purification of the obtained residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (95:5) to obtain 142 g of target compound.

1H-NMR (90 MHz, CDCl3) : 1,1 - 2,3 (m, 3H), 2,1 (d, J = 6.8 Hz, 3H), 2,45 - 3,3 (m, 2H), 2,66 (s, 3H), 3,85 - 4,10 (m, 2H), 4.26 deaths (K, J = 6,8 Hz, 1H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 384 (M + H)+.

Preparative example 7

(-)-6-(2-Chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 980 ml of ethanol under heating dissolve 86 g ()-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5] thieno[3,2-f][1,2,4] triazolo[4,3-a][1,4]diazepine and 45,86 g DIB ether, after the action of dilute aqueous sodium bicarbonate solution and twice by extraction with dichloromethane was transferred to the free state. The organic phase is washed with saturated saline, dried over anhydrous magnesium sulfate and after removal of the solvent under reduced pressure to obtain 11 g of the target compound.

In addition, the filtrate from which the filter was separated tartrate, is subjected to the above-described processing is obtained 11.3 g of the target compound.

[]2D6- 23,5o(c = 1, EtOH).

Preparative example 8

(+)-6-(2-Chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
By the method of preparative example 7, but using Dibenzoyl-1-tartaric acid to obtain the target compound.

[]2D6+17,56o(c = 0,02, EtOH).

EXAMPLE 72

(+)-6-(2-Chlorophenyl)-3-(1-cyano-1-methylethanolamine)-8,11-dimethyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a] [1,4]diazepin

< / BR>
In dichloromethane was dissolved 5 g of (-)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine, to the solution add 5 Ksenia reaction, the obtained residue is purified column chromatography with elution with a mixture of chloroform - methanol (99:1) and obtain 2.7 g of the target compound.

1H-NMR (90 MHz, CDCl3) : of 1.76 (s, 6H), 1.8 - to 2.2 (m, 2H), 2,1 (d, 3H), of 2.66 (s, 3H), of 3.0 to - 3.9 (m, 2H), 4,24 (K, 1H), 4,3 - 4,9 (m, 2H), 7,35 (m, 4H).

FABMS (M + N)+481.

[]2D6+17,56o(c = 0,02, EtOH).

EXAMPLE 73

(+)-3-(3-Butyloxycarbonyl)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In dichloromethane was dissolved 5 g of (-)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4] diazepine, to the solution was added 5 g of 3-butylperbenzoate and the mixture is heated 4 hours at 110oC distillation of the solvent. After completion of the reaction, the obtained residue is purified column chromatography with elution with a mixture of dichloromethane - methanol (99:1) and obtain 1.6 g of the target compound.

1H-NMR (90 MHz, CDCl3) : to 7.4 (5H, Ar), 4,9 (d, 1H, J = 18 Hz,N-CH2(C-2)), 4,5 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,2 (1H, m, C8(H) a 4.1 (2H, t, J = 8 Hz, O-CH2), 2,7 (3H, s), and 2.5 (2H, DV. t, J = 1 Hz, 7 Hz, -CH2), and 2.1 (3H, d, J = 7 Hz, CHCH3), 3,0 - 2,0 (5H, m).

[]2D4+17o(c = 1, CHCl3).

EXAMPLE 74

(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-PIR-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4] diazepine, to the solution was added 1.42 g of triethylamine and under ice cooling are added dropwise 1.44 g cyclopropanecarbonitrile. After completion of the reaction, the reaction mixture was washed with saturated aqueous sodium bicarbonate, then saturated saline, dried over anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure. Purification of the obtained residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (98:2) and get to 4.2 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 0,55 - of 1.15 (m, 4H), 1,45 - of 2.50 (m, 3H), 2,1 (d, J = 6.8 Hz, 3H), of 2.66 (s, 3H), 2,8 - 4,8 (m, 3H), 4.26 deaths (K, J = 6,8 Hz, 1H), 4,8 - 5,2 (m, 1H), 7,05 - the 7.65 (m, 4H ).

MS m/z (Pos. Fab): 452 (M + H)+.

[]2D6+equal to 4.97o(c = 1, EtOH).

[]2D6+14,91o(c = 1, CHCl3).

Other methods of producing compounds in the above examples is shown below.

Preparative example 9

1-(Cyano-1-methylethanolamine)-4-hydroxypiperidine

< / BR>
A mixture of 50 g of 1-cyano-1-methylethylenediamine and 25 g of 4-hydroxypiperidine heated at 130o. After completion of the reaction the resulting product is distilled to colonnaden.

1H-NMR (90 MHz, CDCl3) : 1,26 - 2,10 (m, 5H), 1.8 m (s, 6H), 2,96 - to 3.35 (m, 2H), 3,60 - to 4.15 (m, 3H).

Preparative example 10

1-(cyano-1-methylethanolamine)-4-piperidone

< / BR>
To a solution 4,15 ml oxalicacid in dichloromethane (50 ml) at -78oC added dropwise 5,06 ml of dimethyl sulfoxide and then of 5.05 g of 1-(1-cyano-1-methylethanolamine)-4-hydroxypiperidine. After stirring at the same temperature for 1 hour add 16,57 ml of triethylamine and stirring is continued for 1 hour at room temperature. The reaction mixture is filtered, washed with water, dried over anhydrous magnesium sulfate, the solvent is distilled and purification of the residue column chromatography on silica gel with elution with a mixture of ethyl acetate - n-hexane (1:9) gain of 3.9 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 1,8 (s, 6H), 2,48 (t, J = 7 Hz, 4H), 3,74 (t, J = 7 Hz, 4H).

Preparative example 11

2-Amino-3-(2-chlorobenzoyl)-6-(1-cyano-1-methylethanolamine)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

< / BR>
To a mixture of 3.9 g of the compound of preparative example 10, 0.6 g of sulfur, and 3.3 g of 2-carcinogenecity and 20 ml of N,N-dimethylformamide are added at 40oC 1.6 ml of triethylamine and everything is stirred for 3 hours at 60oC. Upon termination of the reaction the solvent l3) : 1,60 - of 1.95 (m, 2H), of 1.75 (s, 6H), 3,4 (m, 2H), 4,32 (m, 2H), and 7.1 - 7.5 (m, 6H).

Preparative example 12

2-(2-Bromopropylamine-3-(2-chlorobenzoyl)-6-(1-cyano-1-methylethanolamine)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

< / BR>
To a mixture of 5 g of the compound of preparative example 11, 2.1 g of hydroxycarbonate sodium, 50 ml of water and 200 ml of toluene are added at 60oC dropwise 4.6 g of 2-bromopropionitrile. After completion of the reaction, add ethyl acetate, the aqueous phase is separated, the organic phase is washed with saturated saline, dried over anhydrous magnesium sulfate and after removal of the solvent receive 6 g of target compound.

1H-NMR (90 MHz, CDCl3) : of 1.76 (s, 6H), of 1.88 (m, 2H), 2.0 (d, J = 7 Hz, 3H), 3,24 - of 3.60 (m, 2H), 4,20 - and 4.68 (m, 2H), 4,62 (K, J = 7 Hz, 1H), 7,0 - 7,5 (m, 4H).

Preparative example 13

2-(2-Aminodiphenylamine)-3-(2-chlorobenzoyl)-6-(1-cyano-1-methylethanolamine) -5,6,7,8-tetrahydrothieno[2,3-c]pyridine

< / BR>
In 50 ml of ethyl acetate was dissolved 6 g of the compound of preparative example 12, and the solution is saturated for 2 hours at -20oC ammonia and then heated for 5 hours at 100oC in a sealed tube. After completion of the reaction the reaction product is extracted with 2n. hydrochloric acid, the resulting aqueous phase is neutralized with bicarbonate is that magnesium and removal of the solvent obtain 0.7 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 1,51 (d, J = 7 Hz, 3H), 1,50 - 2,04 (m, 2H), 1,78 (s, 6H), 3,28 - of 3.60 (m, 2H), 3,62 - of 3.96 (m, 1H), 4,5 (m, 2H), 7,20 - rate of 7.54 (m, 4H).

Preparative example 14

3-Methyl-5-(2-chlorophenyl)-8-(1-cyano-1-methylethanolamine) -6,7,8,9-tetrahydro-1H,3H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepin-2 - he

< / BR>
A mixture of 0.4 g of the compound of preparative example 13, 0.7 g of pentasulfide phosphorus, 0.4 g of sodium bicarbonate and 40 ml of 1,2-dimethoxyethane refluxed for 2 hours. After completion of the reaction the solvent is distilled off, the residue is added methanol, the insoluble substance is filtered off, the filtrate is concentrated. Purification of the residue column chromatography on silica gel with elution with a mixture of chloroform - methanol (99:1) to obtain 0.3 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 1,5 - 2,0 (m, 2H), 1,76 (s, 6H), of 1.92 (d, J = 7 Hz, 3H), 3,0 - 4,0 (m, 2H), 4,0 - 4,3 (m, 1H), 4,3 - 5,0 (m, 2H), a 7.1 to 7.6 (m, 4H).

EXAMPLE 75

3-(1-Cyano-1-methylethanolamine)-(2-chlorophenyl)-8,11-dimethyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
In 20 ml of 1,4-dioxane was dissolved 0.3 g of the compound of preparative example 14 and 0.3 g acetohydrazide and refluxed for 3 hours. Upon completion of the reaction the solvent is distilled off and cleaning Asia.

1H-NMR (90 MHz, CDCl3) : of 1.76 (s, 6H), 1.8 - to 2.2 (m, 2H), 2,10 (d, 3H), of 2.66 (s, 3H), of 3.0 to - 3.9 (m, 2H), 4,24 (K, 1H), 4,3 - 4,9 (m, 2H), 7,35 (m, 4H).

Preparative example 15

N-(3-Butyloxycarbonyl)-4-hydroxypiperidine

< / BR>
3-Butylperbenzoate (10 g) and 5.8 g of 4-hydroxypiperidine heated without solvent for 30 minutes at 100oC. After completion of the reaction, the purification column chromatography on silica gel with elution by the mixture hexane - ethyl acetate (1:1 to 1:2) to obtain 10.6 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 1,16 - 2,10 (m, 5H) to 1.98 (t, J = 2 Hz, 1H), 1,42 (LW. t, J = 2 Hz, 7 Hz, 2H), 2,9 - 3,5 (m, 2H), 3,6 - 4,1 (m, 3H), 4,15 (t, J = 7 Hz, 2H).

Preparative example 16

N-(3-Butyloxycarbonyl)-4-piperidone

< / BR>
Mix 25 ml of oxalicacid and 500 ml of dichloromethane and the mixture is gradually added dropwise in a stream of nitrogen at a temperature of from -50oC to -70oC added 41 ml of dimethyl sulfoxide, after which the reaction mixture is added dropwise a solution of N-(3-butyloxycarbonyl)-5-hydroxypiperidine (10.3 g) in 50 ml of dichloromethane. Finally, are added dropwise to 120 ml of triethylamine and the temperature is slowly increased to room. The reaction mixture is transferred into a saturated saline solution, extracted three times with dichloromethane and dried over betwo the raffia on silica gel with elution by the mixture hexane - the ethyl acetate (3:1) get a 8.9 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 2,0 (t, J = 2 Hz, 1H), 2,3 - 2,8 (m, 6H), 3,76 (t, J = 7 Hz, 4H), is 4.21 (t, J = 7 Hz, 2H).

Preparative example 17

2-Amino-3-(2-chlorobenzoyl)-6-(3-butyloxycarbonyl)-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine

< / BR>
In 25 ml of dimethylformamide is dissolved with 7.4 g of N-(3-butyloxycarbonyl)-4-piperidone, 1,21 g of sulfur and 61.5 g of 2-carcinogenecity, then add 3.5 ml of triethylamine and stirred for 1 hour at 60oC. after the reaction, the purification of the product column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 11.2 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 1,64 - 1,90 (m, 2H), 1,96 (t, J = 2 Hz, 1H), 2,3 - 2,7 (t, J = 2 Hz, 7 Hz, 2H), 3,4 (t, J = 7 Hz, 2H), 4,14 (t, J = 7 Hz, 2H), a 4.3 to 4.5 (m, 2H), 7,0 - 7,5 (m, 6H).

Preparative example 18

2-(2-Bromopropionyl)-3-(2-chlorobenzoyl)-6-(3-butyloxycarbonyl) -4,5,6,7-tetrahydrothieno[2,3-c]pyridine

< / BR>
In 20 ml of dioxane was dissolved 1.35 g of 2-amino-(2-chlorophenyl)-6-(3-butyloxycarbonyl)-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine, the solution was added 0.33 g of pyridine, and then at 0oC added dropwise 0.9 g of 2-bromopropionitrile. Upon completion of the reaction, the reaction mixture is transferred into the water, e is the research Institute and after purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - hexane (1:1 - 1:0) to obtain 1.19 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 2,02 (t, J = 7 Hz, 3H), 1.7 to 2.2 (m, 3H), 3,5 (LW. t, J = 2 Hz, 7 Hz, 2H), 3,44 (t, J = 7 Hz, 2H), 4,16 (t, J = 7 Hz, 2H), 4,4 - 4,8 (m, 3H), 7,0 - 7,5 (m, 5H).

Preparative example 19

2-(2-Aminodiphenylamine)-3-(2-chlorobenzoyl)-6-(3-butyloxycarbonyl) -4,5,6,7-tetrahydrothieno[2,3-c]pyridine

< / BR>
In 36 ml of ethyl acetate is dissolved to 1.16 g of 2-(2-bromopropionyl)-3-(2-chlorobenzoyl)-6-(3-butyloxycarbonyl)-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine, the solution when cooled saturated with gaseous ammonia, and then heated at 100oC in a sealed tube. Upon completion of the reaction product is cooled, add 50 ml of ethyl acetate, washed with 1N. hydrochloric acid, the aqueous phase is neutralized with an aqueous solution of sodium carbonate and extracted with chloroform. The organic phase is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and after purification of the residue column chromatography on silica gel with elution with dichloromethane obtain 0.36 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 1,5 (t, J = 7 Hz, 3H), 1,6 - 1,8 (ush. s, 2H), 1,8 - 2,1 (m, 3H), 2,52 (LW. t, J = 2 Hz, 7 Hz, 2H), 3,44 (t, J = 7 Hz, 2H), 3,76 (K, J = 7 Hz, 1H), 4,16 (t, J = 7 Hz, 2H), 4,50 with 4.64 (m, 2H), and 7.1 to 7.7 (m, 5H).

prohibited[3,2-f][1,4]diazepin-2-he

< / BR>
In 10 ml of toluene and 0.8 ml of pyridine is dissolved 0.36 g of 2-(2-aminodiphenylamine)-3-(2-chlorobenzoyl)-6-(3-butyloxycarbonyl)-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine, the solution is added to 0.18 ml of acetic acid and refluxed with removal of water. After completion of the reaction, the toluene is distilled off under reduced pressure, warded off the reaction mixture dichloromethane, then washed with water and dried over anhydrous magnesium sulfate. Distillation under reduced pressure of the solvent and purification of residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (100:0 to 97:3) receive 0,22 g of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,76 (d, J = 7 Hz, 3H), 1,6 - 2,2 (m, 3H), 2,5 (LW. t, J = 2 Hz, 7 Hz, 2H), 2,9 - 4,0 (m, 2H), 3,86 (K, J = 7 Hz, 1H), 4,17 (t, J = 7 Hz, 2H), 4,3 - 4,9 (m, 2H), 7.0 and about 7.6 (m, 5H).

Preparative example 21

3-Methyl-5-(2-chlorophenyl)-8-(3-butyloxycarbonyl)-6,7,8,9 - tetrahydro-1H,3H-pyrido[4',3':4,5]thieno[3,2-f][1,4]diazepin-2-tion

< / BR>
In 10 ml of dimethoxyethane dissolving 0.21 g of 3-methyl-5-(2-chlorophenyl)-8-(3-butyloxycarbonyl)-6,7,8,9 - tetrahydro-1H,3H-pyrido[4',3':4,5]thieno[3,2-f] [1,4] diazepin-2-it, to the solution was added 0.11 g of sodium bicarbonate and 0.22 g of pentasulfide phosphorus and everything is heated 3 hours at 80oyagel and the solvent evaporated to dryness. Column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 0.15 g of purified target compound.

1H-NMR (90 MHz, CDCl3) : 1,12 - 2,00 (m, 2H), 1,73 (d, J = 7 Hz, 3H), 2,12 (t, J = 2 Hz, 1H), 2,4 (LW. t, J = 2 Hz, 7 Hz, 2H), 2,64 - of 3.80 (m, 2H), 4,01 (K, J = 7 Hz, 1H), was 4.02 (t, J = 7 Hz, 2H), 4,10 was 4.76 (m, 2H), 7,28 (m, 2H).

EXAMPLE 76

3-(3-Butyloxycarbonyl)-6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,4]triazolo[4,3-a][1,4]diazepin

< / BR>
To 150 mg of 3-methyl-5-(2-chlorophenyl)-8-(3-butyloxycarbonyl)-6,7,8,9 - tetrahydro-1H, 3H-pyrido[4', 3':4,5]thieno[3,2-f][1,4]diazepin-2-thione was added 100 mg acetohydrazide, then add 2 ml of dioxane and all heated 3 hours at 130oC distillation of the solvent. After completion of the reaction, the purification of the obtained residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (98:2) to obtain 80 mg of the target compound.

1H-NMR (90 MHz, CDCl3) : 7,5 (4H, Ar), 4,9 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,5 (1H, d, J = 18 Hz, N-CH2(C-2)), 4,2 (1H, m, C8(H) a 4.1 (2H, t, J = 8 Hz, O-CH2), 2,7 (3H, s), and 2.5 (2H, DV. t, J = 1 Hz, 7 Hz, -CH2), and 2.1 (3H, d, J = 7 Hz, CHCH), 3 - 2 (5H, m).

Preparative example 22

1-Cyclopropanecarbonyl-4-hydroxypiperidine

< / BR>
In 400 ml of dichloro billaut a solution of 20.7 g of cyclopropanecarbonitrile in 100 ml of dichloromethane. Upon completion of the reaction, the reaction mixture is extracted with chloroform in the absence of salt, dried over magnesium sulfate and the solvent is distilled off under reduced pressure. Purification of the obtained residue column chromatography on silica gel with elution with dichloromethane obtain 32 g (96%) of target compound.

1H-NMR (90 MHz, CDCl3) : 0,55 - of 1.55 (m, 4H), 1,15 - of 2.15 (m, 5H), 2,4 (ush. s, 1H), 2,80 - 3,55 (m, 2H), 3,65 - 4,30 (m, 3H).

Preparative example 23

1-Cyclopropanecarbonyl-4-piperidone

< / BR>
In 500 ml of dichloroethane dissolve 66 g oxalicacid to the solution at -67oC added dropwise 61 g of dimethyl sulfoxide, then at the same temperature was added a solution of 44 g of 1-cyclopropanecarbonyl-4-hydroxypiperidine dropwise and, finally, when -67oC add 131 g of triethylamine, after which the temperature was raised to room temperature. The resulting salt is filtered off, the filtrate is concentrated, the concentrate water is added, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. In addition, the aqueous phase is extracted with chloroform and the extract was dried. The solvent is distilled off under reduced pressure and purification of the obtained residue column chromatography on silica gel with elution with a mixture etelaat (m, 1H), 2.49 USD (t, J = 6,1 Hz, 4H), 3,91 (t, J = 6,1 Hz, 4H).

Preparative example 24

2-Amino-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine

< / BR>
In 330 ml of N,N-dimethylformamide is dissolved 33 g of 1-cyclopropanecarbonyl-4-piperidone, 6.3 g of sulfur and 25.5 g of 2-carcinogenecity and then at 60oC add 20 g of triethylamine. Upon completion of the reaction the solvent is distilled off under reduced pressure, to the residue for crystallization add the methanol, the crystals are filtered and washed with methanol receive of 49.4 g (69%) of target compound.

1H-NMR (90 MHz, CDCl3) : 0,55 - of 1.15 (m, 4H), 1,4 - 2,0 (m, 3H), 3,35 of 3.75 (m, 2H), 4,3 - 4,7 (m, 2H), of 7.0 to 7.7 (m, 4H).

Preparative example 25

2-(2-Bromopropionyl)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl - 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

< / BR>
To 21,83 g 2-amino-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl)-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine add 450 ml of toluene and 150 ml of water, then add to 10.16 g of sodium bicarbonate and heated to 50 - 60oC add 9.5 g of 2-bromopropionitrile. To complete the reaction optionally add an aqueous solution of sodium hydrogen carbonate (10.6 g of sodium bicarbonate in 150 ml of water) and 5 ml of 2-bromopropionitrile. what'or, dried over anhydrous magnesium sulfate and after removal of the solvent under reduced pressure gain of 29.9 g (quantitative yield) of the target compound.

1H-NMR (90 MHz, CDCl3) : 0,55 - 1,20 (m, 4H), 1,6 - 2,2 (m, 3H), 1,99 (d, J = 7.2 Hz, 3H), 3,35 - of 3.80 (m, 2H), 4,45 - 4,85 (m, 2H), br4.61 (K, J = 7.2 Hz, 1H), 7.0 and about 7.6 (m, 4H).

Preparative example 26

2-(2-Aminodiphenylamine)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine

< / BR>
In 65 ml of 1,2-dichloroethane and 65 ml of ethyl acetate is dissolved 23,04 g 2-(2-bromopropionyl)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7 - tetrahydrothieno[2,3-c]pyridine and the resulting solution is passed ammonia gas for 1 hour at -15oC, after which the solution is placed in a sealed vial and heated for 2 hours at 100oC. To complete the reaction through the solution again passed for 30 minutes at -15oC ammonia, after which the sealed ampoule is heated for another 1.5 hours at 110oC. After cooling with ice, the reaction mixture was transferred into a cooled ice 2 N. hydrochloric acid, add ethyl acetate and the aqueous phase is separated. To the aqueous phase added under ice cooling sodium carbonate establishing pH 8, then extracted with chloroform in demineralized conditions. The extract was washed with saturated is yhod 64%) of target compound.

1H-NMR (90 MHz, CDCl3) : 0,45 - of 1.20 (m, 4H), to 1.48 (d, J = 7.2 Hz, 3H), 1,4 - 2,4 (m, 3H), 3,35 - of 3.85 (m, 2H), 3,74 (K, J = 7.2 Hz, 1H), 4,45 - 4,85 (m, 2H), of 7.0 to 7.7 (m, 4H).

Preparative example 27

5-(2-Chlorophenyl)-8-cyclopropanecarbonyl-3-methyl-6,7,8,9 - tetrahydro-1H, 3H-pyrido[4',3':4,5]thieno[3,2-f][1,4]diazepin-2-he

< / BR>
In 260 ml of toluene and 90 ml of pyridine is dissolved to 12.95 g of 2-(2-aminodiphenylamine)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7 - tetrahydrothieno[2,3-c] pyridine, the solution was added to 5.4 g of acetic acid and refluxed for 5 hours. After removal of the solvent added benzene and filtering the formed crystals get 2,96 g of target compound. Column chromatography of the mother liquor on silica gel with elution with a mixture of ethyl acetate-hexane (4:6) gain of 3.84 g of the target compound.

1H-NMR (90 MHz, CDCl3) : from 0.50 to 1.25 (m, 4H), 1.3 to 2.3 (m, 3H), of 1.75 (d, J = 6.5 Hz, 3H), 2,80 - a 5.25 (m, 5H), 7,00 - the 7.65 (m, 4H).

Preparative example 28

5-(2-Chlorophenyl)-8-cyclopropanecarbonyl-3-methyl-6,7,8,9 - tetrahydro-1H, 3H-pyrido[4',3':4,5]thieno[3,2-f][1,4]-diazepin-2-tion

< / BR>
In 60 ml of 1,2-dimethoxyethane suspended of 2.92 g of 5-(2-chlorophenyl)-8-cyclopropanecarbonyl-3-methyl-6,7,8,9 - tetrahydro-1H, 3H-pyrido[4', 3': 4,5]thieno[3,2-f] [1,4] diazepin-2-it, the suspension before clonney the mixture is filtered through celite, the filter cake is thoroughly washed with a 30% mixture of methanol - dichloromethane and the washing liquor is combined with the filtrate. The combined filtrate is concentrated and purification of the concentrate by column chromatography on silica gel with elution with dichloromethane gain of 1.03 g of target compound (yield 33%).

1H-NMR (90 MHz, 10% CD3OD - CDCl3) : 0,80 - of 1.55 (m, 4H), 1.60 - to a 2.75 (m, 3H), 2.0 (d, J = 6,1 Hz, 3H), 3,2 - a 5.2 and 5.6 to 6.2 (both m, total 5H), 7,2 - 7,8 (m, 4H).

MS m/z (Pos. FAB): 446 (M+H)+.

Preparative example 29

6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 40 ml of dioxane was dissolved 1 g of 5-(2-chlorophenyl)-8-cyclopropanecarbonyl-3-methyl-6,7,8,9 - tetrahydro-1H, 3H-pyrido[4', 3': 4,5]thieno[3,2-f][1,4] diazepin-2-thione, to the solution was added 0.17 g acetohydrazide and everything is stirred for 10 hours at 90oC and 1 hour at 120oC. Optionally added 0.17 g acetohydrazide and to complete the reaction is stirred for further 1 hour at 120oC. After removal of the solvent and purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 280 mg (yield 27: target connection.

1H-NMR (90 MHz, CDC is about 2H), 7,00 - the 7.65 (m, 4H).

EXAMPLE 77

6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3': 4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 10 ml of dichloromethane was dissolved 100 mg of 6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4] triazolo [4,3-a][1,4]diazepine, to the solution was added 10 ml of 4n. hydrochloric acid, then added with stirring 1 ml of an aqueous solution containing 30 mg of sodium nitrite. To ice the solution was added sodium carbonate establishing pH 8, then extracted with dichloromethane, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, concentrated and purification of the concentrate by column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) get to 69.9 mg (72%) of target compound.

1H-NMR (90 MHz, CDCl3) : 0,55 - of 1.15 (m, 4H), 1,45 - 2,5 (m, 3H), 2,1 (d, J = 6.8 Hz, 3H), of 2.66 (s, 3H), 2,8 - 4,8 (m, 3H), 4.26 deaths (K, J = 6,8 Hz, 1H), 4,8 - 5,2 (m, 1H), 7,05 - the 7.65 (m, 4H).

MS m/z (Pos. FAB: 452 (M + H)+.

EXAMPLE 78

3-[2-(Tetrahydropyran-4-yl)oxyethyl] oxycarbonyl-6-(2-chlorophenyl)- 11-methyl-2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H S is hexadecacarbonyl-11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 0,6 - 2,3 (m, 15H), and 2.7 (s, 3H), 3,0 - 4,0 (m, 2H), of 4.0 - 4.4 (m, 1 + 2H), 4,4 - 4,8 (m, 2H), 5,4 - 5,8 (m, 1H), and 7.4 (m, 4H).

MS m/z (Pos. FAB: 524.

EXAMPLE 80

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,20 of - 2.32 (m, 6H), was 1.94 (t, J = 2 Hz, 1H), 2,21 (LW. t, J = 2 Hz, 7 Hz, 2H), 2,66 (s, 3H), 2,84 - USD 5.76 (m, 6H), 4,08 (t, J = 7 Hz, 2H), 7,28 (m, 4H).

MS m/z (Pos. FAB: 495 (M+H)+.

EXAMPLE 81

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,40 - of 2.21 (m, 6H), is 2.37 (t, J = 7 Hz, 2H), to 2.67 (s, 3H), 2,92 - 5,80 (m, 6H), 4,11 (t, J = 7 Hz, 2H), 7,31 (m, 4H).

MS m/z (Pos. FAB): 494 (M + H+).

Example 82

6-(2-Chlorophenyl)-3-(1-cyanoethoxy)carbonyl-11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,7 (t, J = 7 Hz, 3H), of 1.75 (m, 1H), 2,15 (m, 1H), 2,69 (s, 3H), of 3.25 (m, 1H), 3,85 (m, 1H), 4,2 (m, 1H), 4.53-in (m, 1H), around 4.85 (m, 1H), 5,43 (m, 1H), 5,65 (m, 1H), 7.23 percent - of 7.65 (m, 4H).

MS m/z (Pos. FAB): 467 (M+).

EXAMPLE 83

6-(2-Chlorophenyl)-3-cyclobutanecarbonyl-11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1.5 to 2.5 (m, 8H), and 2.7 (s, 3H), 3,0 - 4,0 (m, 2H), 4,0 - 4,9 (m, 1 + 1 + 2H), 5,4 - 5,8 (m, 1H), and 7.4 (m, 4H).

MS m/z (Pos. FAB): 468

EXAMPLE 84

6-(2-Chlorophenyl)-3-(2-methyl-3-cyanopropionic)carbonyl-11-methyl - 2,3,4,5-tetrahydro-8H-Piri (m, 1H), 2,12 (s, 1H), and 2.7 (s, 3H), of 3.25 (m, 1H), 3,9 (m, 1H), 4,08 (s, 2H), 4,22 (m, 1H), 4,55 (m, 1H), 4,56 (m, 1H), 5,62 (m, 1H), 7,30 was 7.45 (m, 4H).

MS m/z (Pos. FAB): 495 (M+).

EXAMPLE 85

6-(2-Chlorophenyl)-11-methyl-3-(2-methylcyclohexanecarboxylic)- 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
6-(2-Chlorophenyl)-11-methyl-3-(3-methylcyclohexanecarboxylic)- 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
6-(2-Chlorophenyl)-11-methyl-3-(4-methylcyclohexanecarboxylic)- 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
The above compounds have the same values in the NMR spectra, are shown below.

1H-NMR (90 MHz, CDCl3) : 0,7 - 1,0 (d, 3H), 1,0 - 2,2 (m, 11H), and 2.7 (s, 3H), 3,0 - 4,0 (m, 2H), 4,0 - 4,9 (m, 1 + 1 + 2H), 5.3 to about 5.8 (m, 1H), and 7.4 (m, 4H).

MS m/z (Pos. FAB): 510.

Preparative example 30

3-Cyclopropylamino acid

< / BR>
It is 5.06 g of ethyl ester of 3-cyclopropylamino acid was added 100 ml of methanol, 100 ml of tetrahydrofuran and 2 g of 10% palladium on coal (containing 50% water), and then during the day hydronaut at normal temperature and normal pressure. The catalyst is filtered off, the solvent is distilled off, the residue is added 20 ml of methanol, 20 the solvent, water is added and washed with ethyl acetate. To the obtained aqueous phase added under ice cooling an aqueous solution of hydrochloric acid to pH 3 and then extracted with chloroform without adding salt and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent evaporated and purification of the residue column chromatography on silica gel with elution with dichloromethane obtain 1.8 g of the target compound.

1H-NMR (90 MHz, CDCl3) : 0,65 - 1,10 (m, 2H), 1,10 - of 1.85 (m, 5H), 2,33 (t, J = 7.2 Hz, 2H), 8,9 (ush. s, 1H).

EXAMPLE 86

6-(2-Chlorophenyl)-3-(3-cyclopropyl)propionyl 11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
In 8 ml of N,N-dimethylformamide was dissolved 50 mg of 3-cyclopropylamino acid, 120 mg of 6-(2-chlorophenyl)-11-methyl-2,3,4,5-tetrahydro-8H-pyrido[4',3': 4,5] thieno [3,2-f] [1,2,4] triazolo[4,3-a][1,4]diazepine and 60 g of the monohydrate of 1-hydroxybenzotriazole and to the resulting mixture while cooling with ice, add 80 mg of N,N'-dicyclohexylcarbodiimide. After stirring for 10 minutes, the mixture continued to stir the day at 4oC. and Then stirred for 1 hour at room temperature, the solvent is distilled off, the residue from the distillation add saturated aqueous solution of sodium bicarbonate, extracted with chloroform and dried by Geografia on silica gel with elution with a mixture of dichloromethane - methanol (1:99) to obtain 110 mg of the target compound.

1H-NMR (90 MHz, CDCl3) : 0,70 - of 1.05 (m, 3H), of 1.05 to 2.40 (m, 6H), and 2.27 (t, J = 7 Hz, 2H), to 2.67 (s, 3H), 2,8 - 5,9 (m, 6H), 7,10 - of 7.55 (m, 4H).

MS m/z (Pos. FAB)

EXAMPLE 87

6-(2-Chlorophenyl)-3-cynnamoyl-11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
In 8 ml of N,N-dimethylformamide is dissolved 80 mg of cinnamoroll, to the solution was added 4 ml of a solution of 120 mg of 6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine and 160 mg of triethylamine in N,N-dimethylformamide (-60oC, dropwise) and all mixed in the same conditions for 30 minutes. After removal of the solvent added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent evaporated and purification of the residue column chromatography on silica gel with elution with a mixture of methanol - dichloromethane (1:99) to obtain 110 mg (68%) of the title compound.

1H-NMR (CDCl3) : 1,2 - 2,6 (m, 2H), 2,48 (s, 3H), 2,8 - 5,9 (m, 6H), 6,74 (t, J = 15.1 Hz, 1H), and 7.1 to 7.7 (m, 9H), to 7.64 (t, J = 15.1 Hz, 1H).

MS m/z (Pos. FAB): 500 (M + H)+.

EXAMPLE 88

6-(2-Chlorophenyl)-11-methyl-3-(2-methylcyclopropyl)- 2,3,4,5-cut 50 mg 2-methylcyclopropane acid, 130 mg of 6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4]triazolo [4,3-a][1,4]diazepine and 70 mg of the monohydrate of 1-hydroxybenzotriazole, to the solution under cooling with ice add 90 mg of N,N'-dicyclohexylcarbodiimide and everything is stirred for 10 minutes. Stirring is continued day 4oC and 1 hour at room temperature. After removal of the solvent added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent is distilled off and after purification of the obtained residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 120 mg (76%) of target compound.

1H-NMR (CDCl3) : 0,40 - 0,72 (m, 1H), 0,72 of 1.00 (m, 1H), 1.26 in (s, 3H), 1,4 - 2,4 (m, 2H), 2,68 (s, 3H), 2,9 - 5,9 (m, 6H), and 7.1 to 7.7 (m, 4H).

MS m/z (Pos. FAB): 452 (M + H)+.

EXAMPLE 89

6-(2-Chlorophenyl)-11-methyl-3-phenylacetyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
In 4 ml of N,N-dimethylformamide is dissolved 120 mg of 6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a] [1,4] diazepine and 160 mg of triethylamine and the resulting solution is added dropwise at -60oC add to RESTC distilled off, to the residue is added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent evaporated and purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 110 mg (69%) of target compound.

1H-NMR (CDCl3) : 1,0 - 2,6 (m, 2H), 2,61, and 2,66 (both s, total 3H), of 2.8 to 6.0 (m, 6H), 3,69, and of 3.77 (both ears. with only 2H), 6,8 - in 7.7 (m, 9H).

MS m/z (Pos. FAB): 488 (M + H)+.

EXAMPLE 90

6-(2-Chlorophenyl)-11-methyl-3-(3-methylcrotonyl)- 2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
In 4 ml of N,N-dimethylformamide is dissolved 120 mg of 6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a] [1,4] diazepine and 160 mg triethylamine and the resulting solution was added at -60oC to a solution of acid chloride of 3-methylcrotonate acid (50 mg) in 5 ml of N, N-dimethylformamide. After completion of the reaction the solvent is distilled off, the residue is added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent evaporated and purification of the obtained residue and a column of chromatographie the>SUP>1H-NMR (CDCl3) : 1,0 - 2,5 (m, 8H), and 2.7 (s, 3H), 2,8 - 5,9 (m, 6H), 6.73 x (ush. s, 1H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 452 (M + H)+.

EXAMPLE 91

6-(2-Chlorophenyl)-11-methyl-3-((TRANS)-2-phenylcyclopropanecarboxylic)- 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a] [1,4]diazepin

< / BR>
In 12 ml of N,N-dimethylformamide is dissolved 70 mg of TRANS-2-phenyl-1-cyclopropanecarbonyl acid, 120 mg of 6-(2-chlorophenyl)-11-methyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine and 60 mg of the monohydrate of 1-hydroxybenzotriazole and to the resulting solution under ice cooling was added 80 mg of N,N'-dicyclohexylcarbodiimide. After stirring for 10 minutes the mixture is stirred for a day at 4oC and 1 hour at room temperature. The solvent is distilled off, the residue is added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. Sulfate is filtered off, the solvent evaporated and purification of the obtained residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 160 mg of the target compound.

1H-NMR (CDCl3) : 1,4 - 2,8 (m, 6H), to 2.66 (s, 3H), 2,8 - 5,8 (m, 6H), about 6.5 to 7.7 (m, 6H).

MS m/z (Pos. FAB): 514 (M + H)+.


< / BR>
1H-NMR (CDCl3) : of 1.7 - 2.5 (m, 2H), and 2.14 (d, J = 4 Hz, 3H), of 2.72 (s, 3H), 2,8 - 5,9 (m, 6H), 6.87 in (K, J = 4 Hz, 1H), of 7.0 to 7.7 (m, 9H).

MS m/z (Pos. FAB)

EXAMPLE 93

6-(2-Chlorophenyl)-11-methyl-3-(4-pyridylthio)acetyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (CD3OD-CDCl3) : 1,4 - 2,6 (m, 2H), 2,68 (s, 3H), 2,8 - 5,9 (m, 6H), 3,82 (ush. s, 2H), 7,05 and 7.6 (m, 6H), to 8.1 and 8.6 (m, 2H).

MS m/z (Pos. FAB): 521 (M + H)+.

EXAMPLE 94

6-(2-Chlorophenyl)-11-methyl-3-(3-phenylpropionyl)-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 1,0 - 2,3 (m, 4H), to 2.66 (s, 3H), 2,65 is 3.15 (m, 2H), 2,8 - 5,9 (m, 6H), 6,65 - the 7.65 (m, 9H).

MS m/z (Pos. FAB): 502 (M + H)+.

EXAMPLE 95

6-(2-Chlorophenyl)-11-methyl-3-[3-(3-pyridyl)acryloyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 1.5 to 2.5 (m, 2H), 2,68 (s, 3H), of 3.0 to 5.8 (m, 6H), 6,83 (ush. d, J = 15,5 Hz, 1H), 7,15 - of 7.90 (m, 6H), and 7.6 (d, J = 15,5 Hz, 1H), 8,3 - 8,5 (m, 1H), 8,64 (ush. s, 1H).

MS m/z (Pos. FAB): 501 (M + H)+.

EXAMPLE 96

6-(2-Chlorophenyl)-3-(3-cyclohexylpropionic)-11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 0,6 - 2,5 (m, 15H), 2,28 (ush. t, J = 8 Hz, 2H), 2,66 (s, 3H), who yl)acetyl-11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 1,0 - 2,4 (m, 2H), 2,66 (s, 3H), 2,8 - 5,9 (m, 6H), 3,65 (ush. s, 2H), 6,65 - of 7.60 (m, 8H).

MS m/z (Pos. FAB): 506 (M + H)+.

EXAMPLE 98

6-(2-Chlorophenyl)-3-(4-cyanobutane)-11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : of 1.4 - 2.3 (m, 4H), 2,30 - to 2.65 (m, 4H), to 2.67 (s, 3H), 2,8 - 5,8 (m, 6H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 465 (M + H)+.

Preparative example 31

Ethyl ester tetrahydropyran-4,a-acetic acid

< / BR>
Under ice cooling to a solution 6,72 g (30 mmol) of diethylphosphonoacetate in 100 ml of dimethylformamide added 1.2 g (30 mmol) of sodium hydride and stirred for 10 minutes. Then to the mixture while cooling with ice, add 2.5 g (25 mmol) of tetrahydro-4H-Piran-4-it, the temperature was raised to room temperature and the stirring is continued for 2 hours at 80oC. After the reaction add ethyl acetate, washed with saturated saline and dried over magnesium sulfate. The solution is concentrated under reduced pressure and purification of the residue column chromatography on silica gel with elution by the mixture hexane - ethyl acetate (9:1) gain of 4.2 g of the desired product as a pale yellow oily substance.

1H-NMR (CDClthe first example 32

Ethyl ester of 4-tetrahydropyranyloxy acid

< / BR>
In 50 ml of methanol was dissolved 2 g of ethyl ether tetrahydropyran-4,a-acetic acid, to the solution was added 10% palladium on coal and the mixture hydronaut 3 hours. After filtration of the catalyst and concentration under reduced pressure the reaction mixture obtain 1.6 g of the target product.

1H-NMR (CDCl3) : 1,1 - 2,3 (m, 7H), 1,3 (t, J = 7.2 Hz, 3H), 3,2 - 3,6 (Tr. d, J = 12,6 Hz, 2.9 Hz, 2H), 3,8 - 4,3 (m, 2H), 4,1 (K, J = 7.2 Hz, 2H).

Preparative example 33

4-Tetrahydropyranyloxy acid

< / BR>
To 0.9 g of ethyl ester of 4-tetrahydropyranyloxy acid, add 20 ml of methanol, 10 ml water and 1 g of sodium hydroxide and stirred for 1 hour at 80oC. the Solvent is distilled off, to the residue water is added, after washing with ethyl acetate, acidified with aqueous hydrochloric acid solution to pH 3, extracted with chloroform without adding salt and dried over anhydrous magnesium sulfate. The solution is filtered and, after removal of the solvent obtain 0.87 g of the crude target product.

1H-NMR (CDCl3) : 1,0 - 2,4 (m, 5H), 2,28 (ush. d, J = 6,5 Hz, 2H), 3,37 (Tr. d, J = 11.5 Hz, 2.9 Hz, 2H), 3.7 to 4.1 (m, 2H), 7,85 (ush. s, 1H).

EXAMPLE 99

6-(2-Chlorophenyl)-11-methyl-3-(tetrahydro the (CD3OD-CDCl3) : 0,9 - 2,4 (m, 9H), to 2.67 (s, 3H), 2,8 - 5,9 (m, 10H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 496 (M+H)+.

Preparative example 34

Tetrahydropyran-4,aacetic acid

< / BR>
To 0.8 g of ethyl ether tetrahydropyran-4,a-acetic acid, add 20 ml of methanol, 10 ml water and 1 g of sodium hydroxide and the mixture is stirred for 2 hours at 80oC. After removal of the solvent to the mixture add water and washed with ethyl acetate. The aqueous phase is acidified with hydrochloric acid to acid reaction, and then extracted with ethyl acetate under conditions precluding the formation of salts, and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent is distilled off and after purification of the obtained residue column chromatography on silica gel with elution with dichloromethane obtain 0.17 g (25%) of the target product.

1H-NMR (CD3OD-CDCl3) : 2,34 (ush. t, J = 5.4 Hz, 2H), 2,98 (ush. t, J = 5.4 Hz, 2H), 3,50 - 3,95 (m, 4H), 5,66 (ush. s, 1H), 8,45 (ush. s, 1H).

EXAMPLE 100

6-(2-Chlorophenyl)-11-methyl-3-(tetrahydropyran-4,a-acetyl)-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 1.4 to 2.5 (m, 2H), 2,10 - to 2.41 (m, 2H), 2,41 is 2.80 (m, 2H), to 2.67 (s, 3H), 2,8 - 5,9 (m, 6H), 3,45 - 3,90 (m, 4H), 5,72 (ush. s, 1H), 7,15 - to 7.50 (m, 6H).


< / BR>
1H-NMR (CDCl3) : 0,40 - of 1.15 (m, 4H), 1,2 - 2,6 (m, 3H), of 2.66 (s, 3H), of 2.8 to 6.0 (m, 6H), 6,13 (d, J = 21,6 Hz, 1H), 6,25 (LW. d, J = 21,6 Hz, 14.4 Hz, 1H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 464 (M+H)+.

EXAMPLE 102

6-(2-Chlorophenyl)-3-[(TRANS)-3-cyclopropylamino] -8,11-methyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,4]diazepin

< / BR>
(1) preparation of ethyl ester of TRANS-3-cyclopropylamino acid

< / BR>
In 300 ml of N,N-dimethylformamide is dissolved 38,38 g ethyl ester diethylphosphonate acid, to the solution is added at 0oC 6.85 g of sodium hydride (60%), stirred for 30 minutes at room temperature and at 0oC added dropwise 10 g of cyclopropylamine. After stirring 2 hours at room temperature, add ice water, then extracted with ether, washed with water and dried over anhydrous magnesium sulfate. The solution is filtered and purification of the concentrated residue column chromatography on silica gel with elution with a mixture of ethyl acetate - hexane (2:98) receive 11,18 g (60%) of the title compound in the form of the TRANS-isomer.

1H-NMR (CDCl3) : 0,4 - 1,1 (m, 4H), of 1.26 (t, J = 7.2 Hz, 3H), 1,3 - 1,8 (m, 1H), 4,13 (K, J = 7.2 Hz, 2H), of 5.82 (d, J = 15,5 Hz, 1H), 6,37 (LW. d, J = 15,5 Hz, 10.1 Hz, 1H).

1H-NMR (CDCl3) : 0,3 - 1,2 (m, 4H), 1.2 to 1.9 (m, 1H), of 5.83 (d, J = 15.1 Hz, 1H), 6,47 (LW. d, J = 15.1 Hz, 6.5 Hz, 1H), 9,06 (ush. s, 1H).

(3) 6-(2-Chlorophenyl)-3-[(TRANS)-3-cyclopropylamino] -8,11-dimethyl - 2,3,4,5-tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a] [1,4]diazepin

< / BR>
In 12 ml of N,N-dimethylformamide is dissolved 90 mg of TRANS-3-cyclopropylamino acid, 120 mg of the monohydrate of 1-hydroxybenzotriazole and 240 mg of 6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4', 3': 4,5]thieno[3,2-f] [1,2,4]triazolo [4,3-a][1,4]diazepine, to the obtained solution under cooling with ice add 160 mg of 1,3-dicyclohexylcarbodiimide, and then stirred for 9 hours at 4oC and 1 hour at room temperature. After concentrating add saturated aqueous solution of sodium bicarbonate, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the filtrate Loretan (1:99) to obtain 240 mg (yield 80%) of target compound.

1H-NMR (CDCl3) : 0,4 - 1,1 (m, 4H), 1,35 - 2,00 (m, 2H), 2,0 - 2,6 (m, 1H), 2,09 (d, J = 6.8 Hz, 3H), 2,65 (s, 3H), 2,8 - 4,1 (m, 2H), 4,1 - to 5.3 (m, 2H), 4.26 deaths (K, J = 6,8 Hz, 1H), 6,15 (LW. d, J = 19,8 Hz, 1H), of 6.31 (LW. d, J = 19,8 Hz, 15.1 Hz, 1H), 7,10 - of 7.55 (m, 4H).

MS m/z (Pos. FAB): 478 (M + N)+.

EXAMPLE 103

6-(2-Chlorophenyl)-3-cyclobutanecarbonyl-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepin

< / BR>
In 8 ml of N,N-dimethylformamide is dissolved 40 mg cyclobutanecarbonyl acid and 120 mg of 6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4', 3': 4,5] thieno[3,2-f] [1,2,4] triazolo [4,3-a][1,4]diazepine and to the obtained solution under cooling with ice, add 80 mg of 1,3-dicyclohexylcarbodiimide, and then stirred for 9 hours at 4oC and 1 hour at room temperature. After concentrating add saturated aqueous solution of sodium bicarbonate, then extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, concentrated and purification of the concentrate by column chromatography on silica gel with elution with a mixture of methanol - dichloromethane (1: 99) to obtain 120 mg (yield 82%) of target compound.

1H-NMR (CDCl3) : 1,2 - 2,8 (m, 8H), is 2.09 (d, J = 6.8 Hz, 3H), 2,65 (s, 3H), 2,85 - of 3.80 (m, 3H), 3,8 - 4,6 (m, 2H), 4,25 (K, J = 6,8 Hz, 1H), 4,8 - 5,3 (m, 1H), 7.0 and about 7.6 (m, 4H).


< / BR>
In 8 ml of N, N-dimethylformamide was dissolved 50 mg cyclopentanecarbonyl acid and 120 mg of 6-(2-chlorophenyl)-8,11-dimethyl-2,3,4,5 - tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo [4,3-a][1,4]diazepine and to the obtained solution under cooling with ice, add 80 mg of 1,3-dicyclohexylcarbodiimide, and then stirred for 9 hours at 4oC and then for 1 hour at room temperature. After concentrating add saturated aqueous solution of sodium bicarbonate, then extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, concentrated and purification of the concentrate by column chromatography on silica gel with elution with a mixture of methanol - dichloromethane (1:99) to obtain 110 mg (73%) of target compound.

1H-NMR (CDCl3) : 1,1 - 2,1 (m, 8H), 2,1 (d, J = 6.8 Hz, 3H), 2,1 - 3,1 (m, 1H), 2,66 (s, 3H), 3,1 - 4,0 (m, 2H), 4,0 - to 5.3 (m, 2H), 4.26 deaths (K, J = 6,8 Hz, 1H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 480 (M+H)+.

Preparative example 35

N-(Benzyloxycarbonyl)-3-pyrrolidino

< / BR>
In 500 ml of chloroform was dissolved 30 g of 3-pyrrolidinone, to the solution was added 53 ml of triethylamine and then at room temperature dropwise gradually added 52 ml of benzyloxycarbonylamino. Upon completion of the reaction, the reaction mixture is transferred howl chromatography on silica gel with elution by the mixture of hexanitrate get 70,67 g of the target product.

1H-NMR (90 MHz, CDCl3) : a 1.7 - 2.1 (m, 2H), 2,8 - 3,2 (m, 3H), of 3.2 to 3.7 (m, 4H), of 4.2 to 4.5 (m, 1H), 5,1 (s, 2H), and 7.3 (s, 5H).

Preparative example 36

N-(Benzyloxycarbonyl)-3-pyrrolidone

< / BR>
To a solution of 150 ml of acid chloride oxalic acid in 2 liters of dihlormetilen slowly in the current of argon at a temperature of from -70oC to -50oC add 245 ml of dimethylsulfoxide, and then added dropwise a solution of 70,67 g of N-(benzyloxycarbonyl)-3-pyrrolidinone and after adding dropwise 720 ml of triethylamine, the temperature of the mixture was raised to room temperature. After the reaction, the reaction mixture was poured into water, extracted with dihlormetilen, after which the solvent is distilled off under reduced pressure. Purification of the residue column chromatography with elution by the mixture hexane - ethyl acetate receive 65,55 g of the target product.

1H-NMR (90 MHz, CDCl3) : 2,6 (t, J = 7.5 Hz, 2H), 3,7 - 4,0 (m, 4H), 5,12 (s, 2H), and 7.3 (s, 5H).

Preparative example 37

2-Amino-3-(2-chlorobenzoyl)-5-benzyloxycarbonyl-4,6 - dihydrothieno[2,3-c] pyrrol

< / BR>
In 300 ml of dimethylformamide is dissolved compound of preparative example 36 (66,55 g), to 54.3 g of 2-carcinogenecity and 9.9 g of sulfur, to the solution was added 45 ml of triethylamine and the mixture is heated 2 hours at 60o

1H-NMR (90 MHz, CDCl3) : 3,4 - 3,9 (m, 2H), 4,3 - 4,6 (m, 2H), 4,98 and 5,02 (both s, total 2H), 7.0 and about 7.6 (m, 11H).

Preparative example 38

2 Bromoacetamide-3-(2-chlorobenzoyl)-5-benzyloxycarbonyl-4,6-dihydrothieno [2,3-c]pyrrol

< / BR>
To a mixture of 600 ml of toluene and 150 ml of water is added to 68.4 g of compound of preparative example 37, then add a 33.5 g of sodium bicarbonate, then at 60oC added dropwise 25 ml of bromoacetamide. Upon completion of the reaction, the reaction mixture was poured into dihlormetilen, washed with water, the solvent is distilled off under reduced pressure and the resulting residue is used without further purification in subsequent reactions.

1H-NMR (90 MHz, CDCl3) : 3,50 - 3,95 (m, 2H), 4,08 (s, 2H), 4,3 - 4,7 (m, 2H), 5.03 and 5,07 (both s, total 2H), 7.0 and about 7.6 (m, 10H).

Preparative example 39

2 Aminoethylamino-3-(2-chlorobenzoyl)-5-benzyloxycarbonyl - 4,6-dihydrothieno [2,3-c]pyrrol

< / BR>
The compound of preparative example 38 was dissolved in 3.5 liters of ethyl acetate and the solution is saturated with 8 hours of gaseous ammonia. Insoluble inorganic substance is filtered, the resulting filtrate is dispersed under reduced pressure to remove the solvent and filtration is) : 3,3 - of 3.9 (m, 4H), 4,4 - 4,7 (m, 2H), 5.02 and 5,06 (both s, total 2H), 7,0 - 7,5 (m, 11H).

Preparative example 40

5-(2-Chlorophenyl)-7-benzyloxycarbonyl - 6,8-dihydro-1H, 3H-pyrrolo[4',3': 4,5]thieno[3,2-f][1,4]diazepin-2-he

< / BR>
In a mixture of 250 ml of benzene and 500 ml of pyridine is dissolved of 38.5 g of compound of preparative example 39, to the solution was added 5.2 ml of acetic acid and the mixture is heated at 120oC with removal from the system generated water. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and purification of the residue column chromatography with elution by the mixture hexane - ethyl acetate to obtain 21 g of the target product.

1H-NMR (90 MHz, CDCl3) : 3,6 - 3,9 (m, 2H), 4,42 (s, 2H), 4,3 - 4,7 (m, 2H), is 5.06 (s, 2H), 7,0 - 7,5 (m, 10H).

Preparative example 41

5-(2-Chlorophenyl)-7-benzyloxycarbonyl - 6,8-dihydro-1H, 3H-pyrrolo[4',3': 4,5]thieno[3,2-f][1,4]diazepin-2-tion

< / BR>
In 300 ml of toluene is dissolved to 13.7 g of the compound of preparative example 40, to the solution is added a reagent Ronson [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide] and all are heated for 15 minutes at 80oC. Upon termination of the reaction the solvent is distilled off under reduced pressure and purification of the residue column chromatography with elution by the mixture hexane - ethyl acetate pasego 2H), the 6.9 to 7.5 (m, 10H).

Preparative example 42

3-Benzyloxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin

< / BR>
To 10.2 g of the compound of preparative example 41 add 250 ml of methanol, then add to 4.8 mg of hydrazine monohydrate and everything is stirred for 1 hour at room temperature. At the end of the reaction the precipitate hydrazide filtered off, add 200 ml of triethyl ortho-acetate and heated for 40 minutes at 80oC. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure and purification of the concentrate by column chromatography with elution with a mixture of benzene - acetate receive 7,39 g of target compound.

1H-NMR (90 MHz, CDCl3) : 2,7 (s, 3H), 3,6 - 3,9 (m, 2H), 4,6 - 4,8 (m, 2H), 4,8 - 5,0 (m, 2H), of 5.05 and 5,09 (both s, total 2H), 7,0 - 7,5 (m, 9H).

Preparative example 43

3H-5-(2-Chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4', 3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
To 3 ml of dihlormetilen add to 0.23 g of compound of preparative example 42, then add 0.7 ml of attributively and stirred at room temperature. Upon completion of the reaction, add the methanol, the solvent is distilled off under reduced pressure and purification of the residue number of the Oia.

1H-NMR (90 MHz, CDCl3) : 2,7 (s, 3H), 3,6 - 3,9 (m, 2H), 4,5 - 4,7 (m, 2H), 4,8 - 5,1 (m, 2H), 7.0 and about 7.6 (m, 4H).

EXAMPLE 105

3-(2'-Cyanoethyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : to 2.67 (t, J = 7 Hz, 1H), 2,75 (t, J = 7 Hz, 1H), 2,75 (s, 3H), 3,64 - 3,90 (m, 2H), 4,25 (t, J = 7 Hz, 1H), or 4.31 (t, J = 7 Hz, 1H), with 4.64 - 4,82 (m, 2H), 4.80 to 5,12 (m, 2H), 7,26 - 7,46 (m, 4H).

MS m/z: 453.

EXAMPLE 106

3-(3'-Butenyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 2,0 (t, J = 7 Hz, 1H), 2,46 (LW. t, J = 7 Hz, 2 Hz, 1H), to 2.55 (s, 3H), of 2.75 (s, 3H), 3,60 of 3.75 (m, 2H), 4,14 (t, J = 7 Hz, 1H), 4,2 (t, J = 7 Hz, 1H), 4,60 - 4,85 (m, 2H), 4.75 V - 5,10 (m, 2H), 7,10 - rate of 7.54 (m, 4H).

MS m/z: 452.

EXAMPLE 107

3-[2-(Morpholine-4-yl)ethyl] oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4', 3': 4,5] thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4] diazepin

< / BR>
1H-NMR (CDCl3) : 2,20 - to 2.85 (m, 6H), was 2.76 (s, 3H), of 3.5 - 3.9 (m, 6H), 4,2 (t, J = 7 Hz, 1H), 4,28 (t, J = 7 Hz, 1H), 4,55 - 4,80 (m, 2H), 4.80 to further 5.15 (m, 2H), 7,20 - of 7.55 (m, 4H).

MS m/z: 513.

EXAMPLE 108

3-(3-Pyridylethyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDC40 - 8,56 (m, 1H).

MS m/z: 505.

EXAMPLE 109

3-(Tetrahydropyran-4-yl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4', 3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : of 1.4 - 2.3 (m, 4H), to 2.74 (s, 3H), 3,32 - of 4.05 (m, 7H), 4,60 - 5,08 (m, 4H), 7,20 - 7,56 (m, 4H).

MS m/z: 484.

EXAMPLE 110

3-(3'-buten-2-yl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : and 1.54 (d, J = 7 Hz, 3H), 2,48 (d, J = 2 Hz, 1H), 2,72 (s, 3H), 3,60 - 3,86 (m, 2H), 4,60 - 4,82 (m, 2H), 4,78 - 5,10 (m, 2H), 5,18 - 5,46 (m, 1H), 7,12 - rate of 7.54 (m, 4H).

MS m/z: 452.

EXAMPLE 111

3-(3'-Morpholino-3'-oxopropyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H,7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4] diazepin

< / BR>
1H-NMR (CDCl3) : 2,50 - and 2.83 (m, 2H), 2,72 (s, 3H), 3,32 - of 3.85 (m, 10H), 4,34 (t, J = 7 Hz, 1H), 4,4 (t, J = 7 Hz, 1H), to 4.52 - 4,80 (m, 2H), 4.72 in - 5,10 (m, 2H), 7,20 - 7,52 (m, 4H).

EXAMPLE 112

3-Cyclohexyloxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 0,68 is 1.96 (m, 11H), a 2.75 (s, 3H), 3,56 - 4,00 (m, 4H), 4,65 - 4,80 (m, 2H), 4,82 - by 5.18 (m, 2H), 7,20 - 7,58 (m, 4H).

MS m/z: 496.

EXAMPLE 113

3-Benzylaminocarbonyl-5-(2- (CDCl3) : of 2.68 (s, 3H), 3,60 - of 3.94 (m, 2H), 4,36 (d, J = 5.4 Hz, 2H), 4,50 - 5,08 (m, 4H),? 7.04 baby mortality is 7.50 (m, 10H).

MS m/z: 489.

EXAMPLE 114

3-(n-Hexyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 0,75 was 1.04 (m, 3H), 1,1 - 1,8 (m, 8H), of 2.72 (s, 3H), 3,54 - a-3.84 (m, 2H), was 4.02 (t, J = 7 Hz, 1H), 4,08 (t, J = 7 Hz, 1H), 4,58 - 4,80 (m, 2H), 4,78 - 5,10 (m, 2H), 7,20 - of 7.48 (m, 4H).

MS m/z: 484.

EXAMPLE 115

3-Ventilatsioonil-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : of 2.72 (s, 3H), of 2.86 (t, J = 7 Hz, 1H), equal to 2.94 (t, J = 7 Hz, 1H), 3,55 - a-3.84 (m, 2H), 4,24 (t, J = 7 Hz, 1H), 4,3 (t, J = 7 Hz, 1H), 4,50 - of 4.75 (m, 2H), 4,78 - 5,10 (m, 2H), 6,98 is 7.50 (m, 9H).

MS m/z: 504.

EXAMPLE 116

3-(4'-Chlorobenzyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : of 2.72 (s, 3H), 3,60 - to 3.92 (m, 2H), 4,6 - 4,8 (m, 2H), 4.80 to 5,04 (m, 2H), to 5.08 (s, 2H), 7,26 (AVK, J = 6 Hz, 4H), 7,10 - 7,46 (m, 4H).

MS m/z: 524.

EXAMPLE 117

3-(1'-Cyano-1'-methylethyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4', 3': 4,5] thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4] diazepin

< / BR>
1H-NMR (CDCl3) : of 1.52 (s, 3H), 1.8 m (c, 3H), 2,72 (c, 3H), 2,72 (c, 3H), 3.50 dicarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : of 2.72 (s, 3H), 3,66 - 3,88 (m, 2H), 4,67 - 4,82 (m, 2H), 4,82 - 5,08 (m, 2H), 5,18 (d, J = 2,8 Hz), 7,20 - 7,72 (m, 6H), of 7.96 - 8,24 (m, 2H).

MS m/z: 535.

EXAMPLE 119

3-(4'-Trifloromethyl)oxycarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4', 3': 4,5] thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4] diazepin

< / BR>
1H-NMR (CDCl3) : was 2.76 (s, 3H), 3,70 - to 3.92 (m, 2H), 4,70 - a 4.86 (m, 2H), 4,88 - 5,10 (m, 2H), with 5.22 (s, 2H), 7,25 - of 7.60 (m, 4H), 7,56 (AB, J = 7 Hz, 4H).

MS m/z: 558.

EXAMPLE 120

3-(2'-Cyanoethyl)aminocarbonyl-5-(2-chlorophenyl)-10-methyl - 2,4-dihydro-2H, 7H-pyrrolo[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (CDCl3) : 2,6 (t, J = 7 Hz, 2H), and 2.7 (s, 3H), 3,4 (t, J = 7 Hz, 1H), 3.46 in (t, J = 7 Hz, 1H), 4,58 - 4,80 (m, 2H), 4,8 - 5,1 (m, 2H), and 5.30 - to 5.58 (m, 1H), 7,2 - 7,5 (m, 4H).

MS m/z: 452.

Preparative example 44

1-Benzyloxycarbonyl-4-(2-hydroxyethyl)piperidine

< / BR>
In 480 ml water dissolve 50 g of 4-piperidinemethanol and 49.2 g of sodium bicarbonate to the solution under ice cooling are added dropwise to 55.2 ml benzyloxycarbonylamino, then stirred under the same conditions for 1 hour. Then the reaction mixture is extracted with chloroform, dried over anhydrous magnesium sulfate, the sulfate otherthrow is a mixture of ethyl acetate: hexane (30:70) to obtain 66 g (65%) of the title compound.

1H-NMR (CDCl3) : 0,75 - of 1.85 (m, 7H), of 2.5 - 3.0 (m, 2H), 3,4 - 3,8 (m, 2H), 3,9 - 4,3 (m, 2H), 5,11 (s, 2H), and 7.1 to 7.4 (m, 5H).

Preparative example 45

1-Benzyloxycarbonyl-4-(formylmethyl)piperidine

R

In one liter of dichloromethane is dissolved 159 g of acid chloride of oxalic acid to the solution at -67oC added dropwise 195,8 g of dimethyl sulfoxide and stirred for 30 minutes. Then when -67oC added dropwise 66 g of 1-benzyloxycarbonyl-4-(2-hydroxyethyl)piperidine in 200 ml of dichloromethane and, finally, at the same temperature are added dropwise 380 g of triethylamine, and then stirred for 1 hour. After removal of the solvent added ethyl acetate, the insoluble matter is filtered off, the filtrate is washed with water, dried over anhydrous magnesium sulfate, filtered and the solvent is distilled off. Purification of the residue column chromatography on silica gel with elution with a mixture of ethyl acetate: hexane (20:80) to obtain 55 g (84%) of the title compound.

1H-NMR (90 MHz: CDCl3) : 0,80 - of 1.85 (m, 4H), 1.85 to of 2.45 (m, 1H), 2,36 (LW. d, J = 6,1 Hz, 1.8 Hz, 2H), about 2.5 - 3.0 (m, 2H), 3,90 is 4.35 (m, 2H), 5,07 (s, 2H), and 7.1 - 7.5 (m, 5H), 9,67 (t, J = 1.8 Hz, 1H).

Preparative example 46

2-Amino-5-[4-(1-benzyloxycarbonyl)PI(formylmethyl)piperidine, of 6.75 g of sulfur and 38,87 g of 2-carcinogenecity, to the suspension at 40oC gain of 7.75 g of triethylamine and stirred for 1.5 hours. After removal of the solvent added ethyl acetate, washed with water and then saturated saline, dried over magnesium sulfate, filtered and the solvent is distilled off. Purification of the residue column chromatography on silica gel with elution with a mixture of ethyl acetate: hexane (30:70) get to 67.9 g (yield 76%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,15 - 2,10 (m, 4H), 3,40 - of 4.05 (m, 3H), 3.95 to of 4.35 (m, 2H), is 5.06 (s, 2H), 6,04 (ush. s, 1H), 6,94 (ush. s, 2H), 7,10 - of 7.55 (m, 9H).

Preparative example 47

2-[4-(1-Benzyloxycarbonyl)piperidin]-5-(bromoacetamide)-4- (2-chlorobenzoyl)thiophene

< / BR>
To the compound of preparative example 46 (67,9 g) add 1.5 liters of toluene, 350 ml of water and 27 g of sodium bicarbonate, then at 60oC add 48,61 g bromohydrin bromoxynil acid. Upon completion of the reaction, add ethyl acetate, the organic phase is separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The solution is filtered and, after removal of the solvent receive the title compound.

1H-NMR (90 MHz, CDCl3) : 1,1 - 2,2 (m, 4H), 2,55 was 3.05 (m, 3H), 4,07 (s, 2H), 4,00 is 4.45 (m, 2H), is 5.06 (s, 2H), 6,36 carbonyl)piperidin] -3- (2-chlorobenzoyl)thiophene

< / BR>
The entire amount of the compound of preparative example 47 add 2 liters of ethyl acetate, the solution under stirring at room temperature for 3 hours pass gaseous ammonia, after which the stirring is continued for another 12 hours. After passing within 30 minutes of gaseous nitrogen the organic phase is separated with the exception of salt, the resulting aqueous phase is extracted with the exception of salt. Both organic phases are dried over anhydrous magnesium sulfate, the solution is filtered and, after removal of the solvent receive the title compound.

1H-NMR (90 MHz, CDCl3) : 1,10 - of 2.15 (m, 4H), 2,50 was 3.05 (m, 3H), br4.61 (ush. s, 2H), 3,9 - 4,4 (m, 2H), is 5.06 (s, 2H), 6,32 (ush. s, 1H), a 7.1 to 7.6 (m, 9H).

Preparative example 49

2-[4-(1-Benzyloxycarbonyl)piperidin] -4-(2-chlorophenyl)thieno [3,2-f][1,4] diazepin-7-he

< / BR>
The entire amount of the compound of preparative example 48 add 600 ml of benzene, 1.5 liters of pyridine and 9.6 g of acetic acid, after which the mixture is boiled to remove from the system water. After removal of the solvent cleaning residue column chromatography on silica gel with elution with a mixture of ethyl acetate: hexane (60:40) get 61,21 g of the title compound (total yield at all three stages 77%). at 7.55 (m, 9H), 8,93 (ush. s, 1H).

Preparative example 50

2-[4-(1-Benzyloxycarbonyl)piperidin] -4-(2-chlorophenyl)thieno [3,2-f][1,4] diazepin-7-tion

< / BR>
The mixture 61,21 g of compound of preparative example 49, 13,53 g of sodium bicarbonate and 27,54 g pentasulfide phosphorus suspended in 1 liter of 1,2-dimethoxyethane and stirred for 1.5 hours at 80oC. the Reaction mixture was filtered through zletovo membrane formed filtervalue cake washed with a mixture of chloroform with methanol (7:3), the washing liquor is combined with the filtrate, the solvent is distilled and purification of the residue column chromatography with elution with dichloromethane containing 2 to 8% methanol, receive and 62.6 g (99%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,15 - 2,10 (m, 4H), 2,5 - 3,1 (m, 3H), 3.95 to of 4.45 (m, 2H), a 4.83 (ush. s, 2H), 5,07 (ush. s, 2H), 6,18 (ush. s, 1H), 7.0 and about 7.6 (m, 9H).

Preparative example 51

2-[4-(1-Benzyloxycarbonyl)piperidin] -4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
3.5 liters of methanol are suspended and 62.6 g of compound of preparative example 50, the suspension type of 33.5 g of hydrazine monohydrate, and then stirred for 1 hour at room temperature and 1 hour at 80oC. After removal of the solvent by distillation and purification OS(33%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,2 - 2,2 (m, 4H), 2,60 was 3.05 (m, 3H), to 2.67 (s, 2H), of 4.0 - 4.4 (m, 2H), 4,88 (ush. s, 2H), 5,07 (ush. s, 2H), 6,34 (ush. s, 1H), and 7.1 - 7.5 (m, 9H).

Preparative example 52

4-(2-Chlorophenyl)-9-methyl-2-(4-piperidyl)-6H-thieno [3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 140 ml of dichloromethane is dissolved of 6.65 g of the compound of preparative example 51, to the solution in a stream of nitrogen add 17 ml of trimethylsilylmethyl and stirred for 25 minutes in a stream of nitrogen. After cooling, add 40 ml of methanol, the solvent is then evaporated and purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol - triethylamine (of 94.5: 5:0.5) with the gain of 4.45 g (90%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,10 - 2,05 (m, 4H), 2,35 - 3,20 (m, 5H), and 2.6 (s, 3H), 4,77 (ush. s, 2H), 6,37 (ush. s, 1H), 7,2 - 7,6 (m, 4H).

MS m/z (Pos. FAB): 398 (M + H)+.

EXAMPLE 121

4-(2-Chlorophenyl)-9-methyl-2-[4-(1-phenylpropionitrile)] -6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
A mixture of 50 mg phenylpropiolic acid, 110 mg of the derivative of piperidine preparative example 52 and 50 mg of 1-hydroxybenzotriazole are dissolved in 8 ml of N, N-dimethylformamide, to the solution under ice cooling was added 70 mg of N, N'-dicyclohexylcarbodiimide, then mix chicken aqueous solution of sodium bicarbonate, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent evaporated and purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 130 mg (89%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,4 - 2,4 (m, 4H), 2,55 - to 3.50 (m, 3H), 2,68 (s, 3H), 4,35 - of 4.90 (m, 2H), 4,88 (ush. s, 2H), 6,37 (ush. s, 1H), 7,05 - the 7.65 (m, 8H).

MS m/z (Pos. FAB): 526 (M + H)+.

EXAMPLE 122

4-(2-Chlorophenyl)-2-[4-{ 1-(3-cyanopropionic)piperidyl} ]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
To 1 g of methyl ester of 3-cyanopropionic acid, add 10 ml of methanol, 1 ml water and 1.34 g of potassium carbonate and stirred for 2 hours at 60oC. After removal of the solvent added chloroform, insoluble matter is filtered off and washed with chloroform. The crystals add the methanol, the insoluble matter is filtered off and after removal of the solvent gain of 1.31 g of potassium salt of 3-cyanopropionic acid in a mixture with an inorganic salt.

In 10 ml of N,N-dimethylformamide was dissolved 100 mg viseporodicnog mixture of 150 mg of the derivative of piperidine preparative example 52 and the monohydrate of 1-hydroxybenzotriazole (80 mg), followed by cooling ice is the temperature value. After removal of the solvent added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent evaporated and purification of the residue on a column of silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 140 mg (yield 78%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,1 - 2,3 (m, 4H), to 2.67 (s, 3H), 2,4 - 3,4 (m, 3H), 3,5 - 4,2 (m, 2H), 4,4 - 5,9 (m, 1H), 4,88 (ush. s, 2H), 6.35mm (ush. s, 1H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 479 (M + H)+.

EXAMPLE 123

4-(2-Chlorophenyl)-9-methyl-2-[4-(1-morpholinobutyrophenone)] -6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 4 ml of N,N-dimethylformamide was dissolved 150 mg of the derivative of piperidine preparative example 52 and 150 mg of triethylamine and the resulting solution at -60oC added dropwise to a solution of 60 mg of chloroacetanilide in 4 ml of N,N-dimethylformamide. Upon completion of the reaction, add saturated aqueous solution of sodium bicarbonate, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the filtrate is distilled only the chloroform, the residue is added 40 mg of the research and 100 mg of potassium carbonate and stirred for 1.5 hours at 60oC. After removal of the solvent dobavlena and purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (98:2) to obtain 130 mg of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,20 was 2.25 (m, 4H), 2,30 - to 2.65 (m, 4H), 2,68 (s, 3H), 2,65 is 3.40 (m, 5H), 3.5 to 3.8 (m, 4H), 3,95 is 4.36 (m, 1H), 4,36 - of 4.90 (m, 1H), 4,89 (s, 2H), 6.35mm (ush. s, 1H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 525 (M + H)+.

EXAMPLE 124

4-(2-Chlorophenyl)-9-methyl-2-[4-{ 1-(4-pentanoyl)piperidyl} ] -6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 10 ml of N,N-dimethylformamide is dissolved 40 mg of 4-pentenovoi acid, 150 mg of the derivative of piperidine preparative example 52 and 60 mg of the monohydrate of 1-hydroxybenzotriazole, and then while cooling with ice, add 80 mg of N, N'-dicyclohexylcarbodiimide and stirred for a day at 4oC and 6 hours at room temperature. After removal of the solvent added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent evaporated and purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 140 mg (78%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1.3 to 2.3 (m, 5H), 2,3 - 2,7 (m, 4H), 2.5 and 3.4 (m, 3H), to 2.67 (s, 3H), 3,65 - to 4.15 (m, 1H), 4,4 - 5,0 (m, 1H), 4,88 (ush. s, 2H), 6.35mm (ush. s, 1H), 7,05 - of 7.60 (m, 4H).

MS m/z (Pos. FAB): 478 (M + H)+
< / BR>
Reproduced by the method of example 121, but using 4-bromoferrocene acid.

1H-NMR (90 MHz, CDCl3) : 1,15 - of 2.20 (m, 4H), 2,49 - 3,30 (m, 5H), 2,87 (s, 3H), 3,55 - 4,10 (m, 1H), 4,45 - 5,00 (m, 1H), 4,88 (ush. s, 2H), 6,34 (ush. s, 1H), 6,60 - 7,11 (m, 4H), 7,11 - of 7.60 (m, 4H).

MS m/z (Pos. FAB): 596(M + H)+, Cl = 35, Br = 81].

EXAMPLE 126

4-(2-Chlorophenyl)-2-[4-(1-cyanoacetylene)] -9-methyl-6H-thieno [3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
Reproduced by the method of example 121, but using tsianuksusnogo acid.

1H-NMR (90 MHz, CDCl3) : 1,4 - 2,4 (m, 4H), 2,45 - 3,55 (m, 3H), to 2.67 (s, 3H), 3,47 (s, 2H), 3,55 - 4,00 (m, 1H), 4,4 - 4,9 (m, 1H), 4,87 (ush. s, 2H), 6,37 (ush. s, 1H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 465 (M + H)+.

EXAMPLE 127

4-(2-Chlorophenyl)-9-methyl-2-[4-[{ 4-(2-thienyl)propionyl} piperidyl] ]-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
Reproduced by the method of example 121, but using 4-(2-thienyl)butane acid.

1H-NMR (90 MHz, CDCl3) : 1,1 - 2,2 (m, 6H), 2,40 - of 3.32 (m, 3H), to 2.67 (s, 3H), 3,32 is 4.45 (m, 4H), 4,45 - of 5.05 (m, 2H), 4,88 (ush. s, 2H), 6,32 (ush. s, 1H), 6,95 - of 7.60 (m, 7H).

MS m/z (Pos. FAB): 550 (M + H)+.

EXAMPLE 128

4-(2-Chlorophenyl)-2-[4-(1-cyclopropanecarbonitrile)] -9-methyl-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
Mina and to the resulting solution at -60oC added dropwise a solution of 650 mg of 3-bromopropionitrile in 10 ml of N, N-dimethylformamide. After removal of the solvent added saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered, the solvent is distilled off and after cleaning the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 400 mg (49%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 0,60 - of 1.15 (m, 4H), 1,20 was 2.25 (m, 5H), 2,4 - 3,5 (m, 3H), 2,68 (s, 3H), 3,7 - 5,0 (m, 2H), 4,89 (ush. s, 2H), 6,36 (ush. s, 1H), and 7.1 - 7.5 (m, 4H).

EXAMPLE 129

4-(2-Chlorophenyl)-9-methyl-2-[4-(1-pentanoyl)piperidyl] -6H-thieno [3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
Reproduced by the method of example 121, but using the acid chloride of valerianic acid.

1H-NMR (90 MHz, CDCl3) : of 0.91 (t, J = 6.5 Hz, 3H), 1,1 - 2,3 (m, 3H), 2,31 (t, J = 7.2 Hz, 2H), to 2.67 (s, 3H), 2.5 and 3.4 (m, 3H), 3,7 - 4,2 (m, 1H), 4,45 - 5,00 (m, 1H), 4,88 (ush. s, 2H), 6.35mm (ush. s, 2H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 482 (M + N)+.

EXAMPLE 130

4-(2-Chlorophenyl)-9-methyl-2-[4-(1-octanol)piperidyl] -6H-thieno [3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
Reproduced by the method of example 121, but using octanoylthio.

< (m, 1H), 4,88 (ush. s, 2H), 6.35mm (ush. s, 2H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 524 (M + H)+.

EXAMPLE 131

4-(2-Chlorophenyl)-2-[4-(1-methoxyacetanilide]-9-methyl-6H-thieno [3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
The compound synthesized according to the method of example 121, but using the acid chloride methoxybutanol acid.

1H-NMR (90 MHz, CDCl3) : of 1.4 - 2.3 (m, 4H), 2,4 - 3,2 (m, 3H), 2,68 (s, 3H), 3,39 (s, 3H), 3,7 - 4,2 (m, 1H), 4,06 (s, 2H), 4,4 - 4,9 (m, 1H), 4,89 (m, 1H), 6,36 (ush. s, 1H), 7,10 - of 7.55 (m, 4H).

MS m/z (Pos. FAB): 470 (M + H)+.

Preparative example 53

2-Morpholinobutyrophenone

< / BR>
In 40 ml of dichloroethane was dissolved 2 g of 4-(2-hydroxyethyl)the research and 3.6 g of pyridine, and then to the solution under ice cooling are added dropwise 5,97 g phenylcarbamate and stirred under the same conditions for 30 minutes. Add saturated aqueous sodium hydrogen carbonate solution, the organic phase is separated, the aqueous phase is extracted and the extract combined with the organic phase then washed with saturated saline and dried over anhydrous magnesium sulfate, the Solution is filtered, the solvent evaporated and purification of the residue column chromatography on silica gel with elution with a mixture of ethyl acetate - hexane (3:70) receive 3,39 g (89%) title aegc, 2H), 6,95 is 7.50 (m, 4H).

EXAMPLE 132

4-(2-Chlorophenyl)-9-methyl-2-[4-(2-morpholinoethoxy)piperidyl] - 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 6 ml of chloroform was dissolved 170 mg of the derivative of piperidine preparative example 52 and 290 mg of 2-morpholinobutyrophenone and the resulting solution was evaporated under stirring at 80oC to dryness. Again add chloroform and evaporation to dryness was repeated twice or thrice, seeking the completeness of the reaction. The resulting product is subjected to column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (97:3), to the obtained fractions add dichloromethane, of which decantation to separate insoluble substances. After distillation of dichloromethane again in a small amount of add dichloromethane and again separate the insoluble matter, and then in the distillation of dichloromethane obtain 170 mg of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,2 - 2,2 (m, 4H), of 2.25 - 3.15 in (m, 7H), of 2.54 (t, J = 6,1 Hz, 2H), 2,68 (s, 3H), 3,55 (m, 4H), 3.95 to of 4.45 (m, 2H), 4,18 (t, J = 6,1 Hz, 2H), 4,89 (ush. s, 2H), 6,36 (ush. s, 1H), 7,10 - of 7.55 (m, 4H).

MS m/z (Pos. FAB): 555 (M + H)+.

Preparative example 54

2-Cyanoethylidene

< / BR>
The compound synthesized by the method of the R>
4-(2-Chlorophenyl)-2-[4-{ 1-(2-cyanoethylidene)piperidyl}]- 9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 5 ml of chloroform was dissolved 150 mg of the derivative of piperidine preparative example 52 and 180 mg of 2-cyanoacrylate and the resulting solution was evaporated to dryness with stirring by heating from room temperature to 110oC. Operation with the addition of chloroform and evaporation to dryness with stirring repeat until the reaction is completed. Purification of the obtained product column chromatography on silica gel with elution with dichloromethane receive 90 mg of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,3 - 2,2 (m, 4H), 2,5 - 3,2 (m, 3H), 2,68 (s, 3H), 2,69 (t, J = 6,1 Hz, 2H), 3,90 is 4.45 (m, 2H), 4,25 (t, J = 6,1 Hz, 2H), 4,88 (ush. s, 2H), 6,36 (ush. s, 1H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 495 (M + H)+.

EXAMPLE 134

4-(2-Chlorophenyl)-2-[4-(1-cyanomethylation)piperidyl] -9-methyl - 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,1 - 2,4 (m, 4H), 2,6 - 3,3 (m, 3H), 2,68 (s, 3H), 3.9 to 4.5 (m, 2H), 4,89 (ush. s, 2H), 6,36 (ush. s, 1H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 481 (M + H)+.

EXAMPLE 135

4-(2-Chlorophenyl)-2-[4-{ 1-(3-cyanopropionic)piperidyl} ] - 9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]J = 5.8 Hz, 2H), 4,48 (ush. s, 2H), 6.35mm (ush. s, 1H), 7,10 - of 7.55 (m, 4H).

MS m/z (Pos. FAB): 509 (M + H)+.

EXAMPLE 136

2-[4-{ 1-(3-Butyloxycarbonyl)piperidin} ] -4-(2-chlorophenyl)- 9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,2 - 2,2 (m, 4H), to 1.96 (t, J = 2,9 Hz, 1H), 2,30 is 3.15 (m, 3H), of 2.51 (Tr. d, J = 6,8 Hz, 2.9 Hz, 2H), 2,68 (s, 3H), 3.9 to 4.5 (m, 2H), 4,15 (t, J = 6,8 Hz, 2H), 4,89 (ush. s, 2H), 6.35mm (ush. s, 1H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 494 (M + H)+.

EXAMPLE 137

2-[4-(1-Butoxycarbonyl)piperidin] -4-(2-Chlorophenyl)- 9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : to 0.92 (t, J = 6,1 Hz, 3H), 1,1 - 2,2 (m, 8H), 2,68 (s, 3H), 2,50 is 3.15 (m, 3H), 3,9 - 4,4 (t, J = 6.5 Hz, 2H), 4,88 (ush. s, 2H), 6.35mm (ush. s, 1H), 7,10 - of 7.55 (m, 4H).

MS m/z (Pos. FAB): 498 (M + H)+.

Preparative example 55

2-Bromacil tert-butyldimethylsilyloxy ether

< / BR>
In 40 ml of N,N-dimethylformamide was dissolved 2 g of ethylenepropylene and 2.4 g of imidazole and to the resulting solution at room temperature was added 2.65 g of tert-butyldimethylsilyloxy. After the reaction add benzene, and then washed with water and aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and, after removal of the solvent obtain 3.6 g (yield 94%) C, 2H).

Preparative example 56

1-(2-Hydroxyethyl)imidazole

< / BR>
In 70 ml of N,N-dimethylformamide is dissolved of 3.56 g of 2-bromacil tert-butyldimethylsilyl ether and of 1.97 g of imidazole, and then to the solution was added 4 g of potassium carbonate and stirred for 2 hours and 40 minutes at 90oC. After removal of the solvent added ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solution is filtered and, after removal of the solvent, the obtained residue is dissolved in tetrahydrofuran and the resulting solution was added and 12.6 ml of tetrabutylammonium (1 M solution in tetrahydrofuran) and stirred at room temperature. Upon completion of the reaction the solvent is distilled and purification of the residue column chromatography on silica gel with elution with dichloromethane get 0,59 g (35%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 3,28 (ush. s, 1H), 3,6 - 4,2 (m, 4H), 6,84 (ush. s, 1H), 7,28 (ush. s, 1H).

Preparative example 57

< / BR>
The compound synthesized from the compound of preparative example 56 by the method of preparative example 53.

EXAMPLE 138

4-(2-Chlorophenyl)-2-[4-[1-{ 2-(1-imidazolyl)ethoxycarbonyl} piperidyl] ]- 9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
S="ptx2">

MS m/z (Pos. FAB): 536 (M + H)+.

EXAMPLE 139

4-(2-Chlorophenyl)-9-methyl-2-[4-{ 1-tetrahydropyran-4-yl-oxycarbonyl) piperidyl}]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,0 - 2,2 (m, 8H), 2,5 - 3,2 (m, 3H), 2,68 (s, 3H), 3.25 to to 3.67 (m, 2H), 3,67 - 4,00 (m, 2H), 4,00 - 4,39 (m, 2H), 4,50 - of 5.05 (m, 1H), 4,88 (s, 2H), 6.35mm (ush. s, 1H), 7,05 - of 7.55 (m, 4H).

MS m/z (Pos. FAB): 526 (M + H)+.

Preparative example 58

Phenyl 3-phenylpropylamine

< / BR>
The connection is obtained with the yield of 70% by the method of preparative example 53.

1H-NMR (90 MHz, CDCl3) : 1,80 - of 2.25 (m, 2H), 2,74 (LW. d, J = 9 Hz, 6.5 Hz, 2H), 4,23 (d, J = 6,5 Hz, 2H), 6,95 - of 7.55 (m, 10H).

EXAMPLE 140

4-(2-Chlorophenyl)-9-methyl-2-[{ 1-(3-phenylpropionylamino)piperidyl} ] - 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,0 - 2,2 (m, 6H), 2,4 - 3,2 (m, 5H), 2,68 (s, 3H), 3,8 - 4,4 (m, 2H), 4,07 (t, J = 6.5 Hz, 2H), 4,87 (ush. s, 2H), 6,36 (ush. s, 1H), between 6.7 to 7.6 (m, 9H).

MS m/z (Pos. FAB): 560 (M + H)+.

EXAMPLE 141

4-(2-Chlorophenyl)-9-methyl-2-[4-{1-(2-morpholinosydnonimine)piperidyl} ]- 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 4 ml of chloroform was dissolved 170 mg of the derivative of piperidine preparative example 52 and 210 mg of 4-[2-(vinyloxycarbonyl)ethyl]the research and receive oraut twice with the completion of the reaction. The reaction product is subjected to column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (95:5). To the fractions obtained in small quantity, add dichloromethane and insoluble products can be removed by decanting. After distillation of dichloromethane again add a small amount of dichloromethane and again remove insoluble matter by filtration. After distillation of dichloromethane obtain 160 mg of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,00 - of 2.25 (m, 4H), 2,25 - 3,10 (m, 9H), to 2.67 (s, 3H), 3,1 - 3,5 (m, 2H), 3,50 - of 3.85 (m, 4H), 3,85 - 4,20 (m, 3H), 4,88 (ush. s, 2H), 6.35mm (ush. s, 1H), a 7.1 to 7.6 (m, 4H).

MS m/z (Pos. FAB): 554 (M + H)+.

Preparative example 59

4-(Vinyloxycarbonyl)morpholine

< / BR>
The compound synthesized by the method of preparative example 53 and purified column chromatography on silica gel with elution with a mixture of ethyl acetate - hexane (5:95).

1H-NMR (90 MHz, CDCl3) : 3,4 - 3,9 (m, 8H), and 6.9 - 7.5 (m, 5H).

EXAMPLE 142

4-(2-Chlorophenyl)-9-methyl-2-[4-(1-morpholinosydnonimine)] - 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
To 180 mg of the derivative of piperidine preparative example 52 and 250 mg of 4-(vinyloxycarbonyl)the research add 5 ml of chloroform, after which the rate will eraut column chromatography on silica gel with elution with dichloromethane and get to 38.8 mg of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,2 - 2,4 (m, 4H), 2,6 - 3,2 (m, 3H), 2,68 (s, 3H), 3.00 and is - 3.45 (m, 4H), 3,45 - 3,95 (m, 6H), 4,88 (ush. s, 2H), 6,36 (ush. s, 1H), 7,05 is 7.50 (m, 4H).

Preparative example 60

2-Ethoxyethyl-p-toluensulfonate

< / BR>
In 40 ml of pyridine was dissolved 2 g of 2-ethoxyethanol, to the solution under ice cooling is added to 5.66 g of p-toluensulfonate, after which the temperature was raised. Add ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate. The solution is filtered, the solvent is distilled off and after cleaning the residue column chromatography on silica gel with elution with a mixture of ethyl acetate - hexane (5: 95) get of 3.69 g (56%) of the title compound.

1H-NMR (90 MHz, CDCl3) : of 1.12 (t, J = 7.2 Hz, 3H), 2,42 (s, 3H), 3.42 points (K, J = 7.2 Hz, 2H), 3,4 - 3,7 (m, 2H), 4,0 - 4,2 (m, 2H), 7,26 (ush. d, J = 8,3 Hz, 2H), 7,73 (ush. d, J = 8,3 Hz, 2H).

EXAMPLE 143

4-(2-Chlorophenyl)-2-[4-{ 1-(2-ethoxyethyl)piperidyl} ] -9-methyl - 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 5 ml of N,N-dimethylformamide was dissolved 150 mg of the derivative of piperidine preparative example 52 and 140 mg of 2-ethoxyethyl p-toluensulfonate, to the solution was added 100 mg of potassium carbonate, and then stirred for 2 hours at 90oC. After the distillation gut, the solvent is distilled and purification of the residue column chromatography on silica gel with elution with a mixture of dichloromethane - methanol to obtain 130 mg (68%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,2 (t, J = 7.2 Hz, 3H), 1.5 and 2.4 (m, 6H), 2,4 - 3,0 (m, 1H), 2,64 (t, J = 6,1 Hz, 2H), 2,71 (s, 2H), 2,80 - of 3.25 (m, 2H), 3,51 (K, J = 7.2 Hz, 2H) and 3.59 (t, J = 6,1 Hz, 2H), 4.95 points (ush. s, 2H), 6,44 (ush. s, 1H), 7,2 - 7,6 (m, 4H).

MS m/z (Pos. FAB): 470 (M + H)+.

Preparative example 61

< / BR>
The compound obtained by the method of preparative example 60 with the release of 70%.

1H-NMR (90 MHz, CDCl3) : 1,95 (t, J = 2,9 Hz, 1H), and 2.27 (s, 3H), 2,53 (Tr. d, J = 7,2 Hz, 2.9 Hz, 2H), 4,06 (t, J = 7.2 Hz, 2H), 7,25 (ush. d, J = 8,3 Hz, 2H), 7,73 (ush. d, J = 8,3 Hz, 2H).

EXAMPLE 144

2-[4-{ 1-(3-Butenyl)piperidyl}]-4-(2-chlorophenyl)-9-methyl - 6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,4 - 3,0 (m, 11H), of 1.97 (t, J = 2.5 Hz, 1H), 2,68 (s, 3H), 2,8 - 3,2 (m, 2H), 4,88 (ush. s, 2H), 6.35mm (ush. s, 1H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 450 (M + H)+.

EXAMPLE 145

4-(2-Chlorophenyl)-4-[1-(dimethylaminomethyl)piperidin] -9-methyl - 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
In 3 ml of N,N-dimethylformamide was dissolved 100 mg of the derivative of piperidine preparative example 52 and 80 mg of triethylamine and the resulting solution was Koo parent compound remains unreacted in large quantities, at room temperature add triethylamine and dimethylsulphamoyl to the disappearance of the parent compounds. After removal of the solvent added a saturated solution of sodium bicarbonate, extracted with chloroform and dried over anhydrous magnesium sulfate. The solution is filtered and after purification column chromatography on silica gel with elution with a mixture of dichloromethane - methanol (99:1) to obtain 90 mg (71%) of the title compound.

1H-NMR (90 MHz, CDCl3) : 1,5 - 2,2 (m, 4H), 2,5 - 3,1 (m, 3H), 2,68 (s, 3H), and 2.8 (s, 6H), 3,55 - 3,90 (m, 2H), 4,89 (ush. s, 2H), 6,32 (ush. s, 1H), and 7.1 - 7.5 (m, 4H).

MS m/z (Pos. FAB): 505 (M+N)+.

EXAMPLE 146

4-(2-Chlorophenyl)-9-methyl-2-[4-{ 1-(2-thiophenesulfonyl)piperidyl}]- 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin

< / BR>
1H-NMR (90 MHz, CDCl3) : 1,5 - 2,3 (m, 4H), 2,30 - 2,95 (m, 1H), 2,44 (Tr. d, J = 12,2 Hz, 3.6 Hz, 2H), to 2.67 (s, 3H), 3,65 - to 4.15 (m, 2H), 4,88 (ush. s, 2H), 6,33 (ush. s, 1H), 6,8 - in 7.7 (m, 7H).

MS m/z (Pos. FAB).

1. Derivatives triazolo [1,4] diazepine General formula I

< / BR>
or their pharmaceutically acceptable salt,

where R1and R2- same or different, a hydrogen atom or lower alkyl;

R3is a halogen atom;

R4is lower alkyl;

n = 1, when X is a group of the formula

< / BR>
group foreclosurea group, possibly substituted methyl group or a possibly substituted in the first position etinilnoy group, or WITH3- C6-cycloalkyl-C1- C2is an alkyl group or3- C6-Alchemilla group, possibly substituted phenyl group, the group of the formula

where R7is hydrogen or methyl;

r = 0 or 1,

a group of the formula

NC(CH2)p,

where p is an integer from 1 to 5;

or a group of the formula

< / BR>
or a group of the formula

A(CH2)q,

where a is a group selected from peredelnoj group, tetrahydropyranyloxy group, morpholinopropan and imidazolidine group;

q is an integer from 0 to 2;

or a group of the formula

< / BR>
where s is an integer from 1 to 2,

or phenylethylene group, or a group of the formula

< / BR>
or a group of the formula

or a group of the formula

< / BR>
where R8and R9- same or different hydrogen or lower alkyl, or pyridylmethyl, or cyclohexyl, or R8and R9together with the nitrogen atom form piperidine, imidazoline or morpholino ring;

In - fenelonov or1- C3-Allenova group,

or a group of the formula

< / BR>
or a group of the formula

< / BR>
or a group of the formula
< / BR>
or a group of the formula

< / BR>
or a group of the formula

< / BR>
where G is CH=CH - or-S2-;

or, when X represents a group of the formula

< / BR>
where R6is lower alkyl;

Y - C2- C7is an alkyl group,

or n = 0, when Y3- C6-Alchemilla group.

2. Connection on p. 1 or their pharmaceutically acceptable salts, in which R1is hydrogen, R2is methyl and Y3- C6-cycloalkyl.

3. Connection on p. 1 or their pharmaceutically acceptable salts, in which Y is a group of the formula

< / BR>
where R7is hydrogen or methyl, WITH3- C6-Alchemilla group or3- C6-cycloalkyl-C1- C2is an alkyl group.

4. Connection on p. 1 or their pharmaceutically acceptable salts, in which R3is chlorine, R1is hydrogen and R4is methyl and when R2is hydrogen, then Y-X

< / BR>
or group

< / BR>
or group

< / BR>
or group

< / BR>
or group

< / BR>
or group

< / BR>
or group

< / BR>
or when R2is methyl, then Y - X

< / BR>
or group

< / BR>
or group

< / BR>
ilieski acceptable salt,

where R1and R2- hydrogen atoms;

R3is a halogen atom;

R4is lower alkyl;

X is a group of the formula

< / BR>
or a group of the formula

< / BR>
Y - C3- C6-cycloalkyl-C1- C2is an alkyl group, or3- C6-Alchemilla group, or a group of the formula

< / BR>
where R7is methyl,

or a group of the formula

NC(CH2)p,

where p is an integer from 1 to 3,

or a group of the formula

A(CH2)q,

A group selected from peredelnoj, tetrahydropyranyloxy, morpholino or morpholinosydnonimine groups;

q is an integer from 0 to 2,

or2- C7is an alkyl group or phenyl-C1- C2is an alkyl group, possibly substituted in the phenyl ring by halogen atom, nitro - or triptorelin group.

6. Derivatives triazolo [1,4] diazepine General formula III

< / BR>
or their pharmaceutically acceptable salt,

where R1and R2- hydrogen atoms;

R3is a halogen atom;

R4is lower alkyl;

when n = 1, X - band

< / BR>
or

< / BR>
Y - C3- C6-cycloalkyl group or3- C6is an alkyl group,

or a group of the formula

NC(CH2
q is an integer from 0 to 3,

or phenylethylene group, or WITH2- C7is an alkyl group, or phenyl-C1- C2is an alkyl group, possibly substituted in the phenyl ring by halogen atom, or WITH1- C2-alkoxy-C1- C2is an alkyl group, or X is a group

< / BR>
Y - group

< / BR>
or when n = 0, Y3- C6-Alchemilla group1- C2-alkoxy-C1- C2is an alkyl group, dimethylaminomethylene or thiophenesulfonyl group.

7. Compounds of General formula I on p. 1 formula, showing PHAT-inhibitory activity.

8. The method of obtaining derivatives triazolo [1,4]diazepine General formula Ia

< / BR>
where X is the group

< / BR>
or group

< / BR>
R1, R2, R3, R4, R5and Y have the meanings given in paragraph 1,

characterized in that the derived triazolo [1,4] diazepine General formula IV

< / BR>
where R1, R2, R3and R4have the meanings given in paragraph 1,

subjected to interaction with the compound of General formula V

< / BR>
where X and Y have the indicated value is R2, R3, R4and Y have the meanings given in paragraph 1,

characterized in that the derived triazolo [1,4] diazepine formula IV is subjected to interaction with the compound of the formula VIII

< / BR>
where Y has the value

or its reactive derivative.

10. The method of obtaining derivatives triazolo [1,4] diazepine General formula Ic

< / BR>
where R1, R2, R3, R4and R6matter, Opredelenie in paragraph 1;

Y - C2- C7-Alchemilla group,

characterized in that the derived triazolo [1,4] diazepine General formula IV is subjected to interaction with the compound of General formula IX

< / BR>
where R5and Y have the above meanings;

Hal is a halogen atom.

11. The method of obtaining derivatives of triazole [1,4] diazepine General formula Id

< / BR>
where R1, R2, R3and R4have the meanings given in paragraph 1;

Y - C3- C6-Alchemilla group,

characterized in that the derived triazolo [1,4] diazepine General formula IV is subjected to interaction with the compound of General formula X

Y - Hal,

where Y and Hal have the specified values.

Priority points:

31.10.88 on PP.1, 2, 7 - 11;

16.12.88 on p. 1

 

Same patents:

The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
where X is-CH=CH -, or S; R1- lower alkyl or trifluoromethyl; R2is chlorine or fluorine; R3is a radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC -, where n is an integer of 0,1 or 2; s is 0 or 1; R4is phenyl or mono-, di - or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms O or S and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine; R5is phenyl or pyridyl radical, provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center, their enantiomers and racemates and pharmaceutically-acceptable salts accession acids exhibiting the properties of antagonists of platelet activating factor (PAF) and, respectively, with angioprotective, immunological, is omposition based on them

The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General formula I:

I,

where X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula R4-(CH2)nC or R5-O-CH2-C_C-, where n is the integer 0, 1 or 2;

R4phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms 0 or S, and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine,

R5phenyl or pyridylethyl provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5attached via a carbon to oxygen connection with RAG-antagonistic properties

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to derivatives of 2, 3, 4, 5-tetrahydro - 1,4-benzothiazepine, containing pharmaceutical compositions, and methods for their preparation and to their use in the treatment of seizures and/or neurological disorders such as epilepsy, and/or as neuroprogenitors means to prevent such painful conditions as paralysis

The invention relates to compounds of formula (1)

< / BR>
in which

R1is a hydrogen atom;

R2is a hydrogen atom, (C3-C12) alkenylboronic, (C3-C12)cycloalkylcarbonyl, (C3-C12)cycloalkylcarbonyl, (C3-C12)alkylcarboxylic, (C3-C12)cycloalkyl (C1-C12)alkylcarboxylic, pyridyloxy, morpholinoethoxy or tetrahydropyranyloxy, halogen(C1-C6)alkylsulfonate, (C1-C6)alkylsilane;

R3is a hydrogen atom or halogen;

R4is a hydrogen atom or a (C1-C6)alkyl, or geometric, optical or stereoisomers, or pharmaceutically acceptable additive salts, which are useful for the treatment of various memory disorders characterized by a decrease cholinergic function such as Alzheimer's disease

The invention relates to novel 4,5-dihydro-1H-2,4-allowin the benzodiazepines and benzodiazipine appropriate diamines and aminoamides, to methods for their preparation and to methods and compositions for treating arrhythmia in mammals with said 4,5-dihydro-1H-2,4-ariovich of benzodiazepines and benzodiazipines

The invention relates to veterinary medicine, in particular, to methods of treatment of endometritis in cows using medicinal product prepared from peracetic acid-desoxin, in combination with the organic active substances

The invention relates to a derivative of galantamine, in particular a derivative of galantamine General formula (II)

< / BR>
in which R1represents hydrogen, (C1-C12)alkylsulphonyl, (C1-C12)alkoxycarbonyl, mono-(C1-C12)alkylaminocarbonyl or di-(C1-C12)alkylaminocarbonyl; R2represents a mono-(C1-C18)alkylaminocarbonyl or di-(C1-C8)alkylaminocarbonyl group; R3represents hydrogen or halogen; or pharmaceutically acceptable acid additive salts

The invention relates to medicine, in particular to Oncology, and for the treatment of metastatic tumors

The invention relates to Oncology, in particular, gynecology, and can be used in therapy of patients with endometrial cancer

The invention relates to medicine, namely to funds with anti-anxiety action

The invention relates to new derivatives of N-acyl-2,3-benzodiazepine General formula [I]

< / BR>
in which R is C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkylamino, di(C1-4alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s), or R is a benzoyl, cyclopropanecarbonyl, C1-5-carbarnoyl or phenylcarbamoyl group, or R is absent when the N(3) and C(4) atoms there is a double bond, R1represents a hydrogen atom, or R1no, when between N(3) and C(4) atoms there is a double bond, R2represents C1-3alkyl, or R1and R2together represent a methylene group, and between the N(3) and C(4) atoms, no double bond, R3means a hydrogen atom or a C1-4-aliphatic acyl group, R4represents a hydrogen atom, a C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkyl-amino-, di (C1-4alkyl) amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen (s), and benzoyl, Palmitoyl, cyclo who can present valence bonds, provided that, when both of the substituent R3and R4represent hydrogen atoms between the N(3) and C(4) atoms, no double bonds, as well as the stereoisomers of these compounds along with acidic salts accession (when possible) and pharmaceutical compositions containing 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

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: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

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, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

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