Derivatives of benzodiazepine and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I): wherein R1 represents hydrogen, halogen atom, (C1-C7)-alkyl, hydroxy- or (C1-C7)-alkylthio-group; R2 represents -C(O)O-(C1-C7)-alkyl, 1,2,4-oxadiazole-3-yl or 1,2,4-oxadiazole-5-yl wherein their cyclic fragments are substituted with (C3-C7)-cycloalkyl; R3 represents hydrogen atom (C1-C7)-alkyl, -(CH2)n-(C3-C7)-cycloalkyl, -(CH2)n-halogen, -(CH2)n-pyridine-4-yl or -(CH2)n-phenyl wherein phenyl ring can be substituted with one or some substitutes chosen from the group comprising (C1-C7)-alkoxy-group, halogen atom, -SO2CH3, phenyl, -OCF3, nitro-group, -CF3, -NR2, or it means -(CH)n-indolyl optionally substituted with (C1-C7)-alkyl or (C1-C7)-alkoxy-group, or means pyrrolidinyl-5-oxo-group, -C(O)-NR2, -(CH2)n-OH, -(CH2)n-NR2 or -(CH2)n-benzo[1,3]dioxol; R represents hydrogen atom or (C1-C7)-alkyl; n = 0, 1, 2 or 3, and its pharmaceutically acceptable acid-additive salts with exception for the following compounds: 9H-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid ethyl ester. 10-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine, 3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d]benzodiazepine-10-carboxylic acid ethyl ester, 10-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine, 3-chloro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid ethyl ester, 3-chloro-1-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine and 3-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid ethyl ester. Also, invention relates to pharmaceutical composition comprising both new and above enumerated and excluded compounds. New compounds possess ability for selective binding with α5-subunit of gamma-aminobutyric acid receptor A and can be used in treatment, for example, Alzheimer's diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 1 tbl, 67 ex

 

The present invention relates to substituted derivative of imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine following formula,

where

R1means hydrogen, halogen, (ness.)alkyl, (ness.)alkoxy, hydroxy, cyano, trifluoromethyl, triptoreline or (ness.)alkylthio,

R2means - C(O)O-(ness.)alkyl, isoxazol, 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl, cyclic fragments which can be substituted by a group (ness.)alkyl, trifluoromethyl or cycloalkyl,

R3means hydrogen, (ness.)alkyl, -(CH2)n-cycloalkyl, -(CH2)n-halogen, -(CH2)n-pyridin-4-yl or -(CH2)n-phenyl, and the phenyl ring may be substituted by one or two substituents selected from the group comprising (ness.)alkoxy, halogen, -SO2CH3, phenyl, OCF3, nitro, CF3, -NR2or means -(CH2)n-indolyl, optionally substituted (ness.)the alkyl or (ness.)alkoxy, or means pyrrolidinyl-5-oxo, -C(O)-NR2, -(CH2)n-OH, -(CH2)n-NR2or -(CH2)n-benzo[1.3]dioxol,

R means hydrogen or (ness.)alkyl, and

n is 0, 1, 2 or 3, and

to their pharmaceutically acceptable acid additive salts,

with the exception of the following compounds:

ethyl ester N-imidazo[1,5-a][1,2,4]Tria is olo[3,4-d][1,4]benzodiazepine-10-carboxylic acid,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

ethyl ester of 3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

ethyl ester of 3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

3-chloro-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine and

ethyl ester of 3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid.

The above specific derivative imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine described previously (Heterocycles, t, No. 2 (1994)), however, the document notes that these compounds have unexpectedly low affinity to BzR (benzodiazepine receptor) and, therefore, do not have anti-fobia sedative effect. Now unexpectedly found that this class of compounds have a high affinity and selectivity for binding sites α5 subunit And of the GABA receptor, and these compounds can be used as amplifiers cognitive abilities or to treat disorders of cognition, such as Alzheimer's disease.

Receptors the main inhibitory neurotransmitter, gamma-aminobutyric acid (the AMC) divided into two main classes: (1) And GABA receptors, which are members of the subfamily of ligand-activated ion channels and (2) In the GABA receptors, which are members of the family of receptors coupled with G-proteins. As the receptor is heteropentameric membrane protein polymer containing mainly α, β and γ subunit.

To date, cloned and sequenced 21 subunit And receptor. To build And recombinant receptors, which most closely mimic the biochemical, electrophysiological and pharmacological functions of native And receptors isolated from the mammalian brain, we need three types of subunits (α, β and γ). There are good reasons to believe that the binding site of the benzodiazepine is between α and γ subunits. Among And recombinant receptors many features classic BzR mimics type I receptor α1β2γ2, while ion channels (α2β2γ2, α3β2γ2 and α5β2γ2 belong to BzR type II.

Set (McNamara, Skelton, Psychobiology, 21, 101-108)that the inverse agonist β-SMS benzodiazepine receptor enhances spatial learning in the water maze Morris. However, β-CCM and other conventional inverse agonists benzodiazepinovogo receptor cause convulsions or is the tsya proconvulsant, what prevents their use as agents that enhance cognitive ability. In addition, these compounds are not selective against subunits And receptor, while partially or fully reverse the agonist subunit α5 And of the GABA receptor, which almost has activity against binding sites α1 and/or α2 and/or α3 And of the GABA receptor, can be used to obtain a medication that can be used to enhance cognitive abilities, as a tool, with little or no possessing prostorovym action. In addition, you can use inverse agonists α5 And of the GABA receptor, which have some activity to sites link α1 and/or α2 and/or α3 And of the GABA receptor, but which are functionally selective in relation to α5 subunits. However, the preferred inverse agonists that are selective to α5 subunits And receptor GABA and relatively inactive for sites linking α1, α2 and α3 And of the GABA receptor.

Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts, the method of obtaining the above-mentioned compounds, pharmaceutical preparations containing these compounds, and their receipt and use of Viseu azannyh compounds in the treatment and prevention of diseases, first of all the diseases and conditions related to the aforementioned, or upon receipt of the appropriate drugs.

The most preferred indications in the present invention is Alzheimer's disease.

Common terms used in this description have the following meanings, regardless of whether these terms separately or in various combinations.

The term (ness.)alkyl means an alkyl group with straight or branched chain, containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. Preferred group (ness.)alkyl containing 1-4 carbon atoms.

The term (ness.)alkoxy means a group in which the alkyl residues have the meanings indicated above, attached via an oxygen atom.

The term halogen means chlorine, iodine, fluorine and bromine.

The term cycloalkyl means a cyclic alkyl radical containing from 3 to 7 carbon atoms in the cycle, such as cyclopropyl, cyclopentyl or cyclohexyl.

The term (ness.)alkylthio means the group-S-(C1-C7)alkyl,

The term "pharmaceutically acceptable acid additive salts" includes salts of inorganic or organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid is, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate, a pair of toluensulfonate etc.

Preferred are compounds that have a binding constant (Kibelow 15 nm, selective α5 subunits And receptor GABA and relatively inactive against binding sites α1, α2 and α3 And of the GABA receptor.

For use in respect of the above diseases preferred compounds of formula I in which R2means the group-C(O)O-(ness.)alkyl.

Preferred are compounds of this group, where R3means hydrogen, and R1means hydrogen, methoxy, methyl, -SCH3or halogen, for example, the following connections:

ethyl ester of 3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid, or

ethyl ester of 3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic sour the s.

Other preferred soedinenii this group are such compounds in which R3means-CH2HE, -(CH2)2-methylenedioxyphenyl, methyl, -CH2-indolyl, optionally substituted by a methoxy group, or-CH2is phenyl, substituted by a group-SO2CH3, phenyl, -OCF3, -N(CH2)2, NO2or methoxy, and R1means methoxy, chlorine or bromine, for example, the following connections:

ethyl ester of 3-methoxy-7-methyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-hydroxymethyl-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-(3-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-[(7-methoxy-1H-indol-3-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-bromo-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-bromo-7-(3-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-[2-benzo[1,3]dioxol-5-yl)ethyl]-3-chloro-N-imidazo[1,5-a][1,2,4]triaz the lo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-(4-methanesulfonylaminoethyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-[(biphenyl-4-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-(4-cryptomaterial)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][l,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-chloro-7-(4-nitrobenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-(4-dimethylaminobenzoyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid, or

ethyl ester of 3-bromo-7-(4-dimethylaminobenzoyl)-N-imidazo[1,5-a] [1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid.

Other preferred compounds for use in the treatment of the above diseases are such compounds in which R2means group 3-cyclopropyl-[1,2,4]oxadiazol-5-yl.

Examples of preferred compounds in this group are such compounds in which R3means hydrogen, and R1means hydrogen, methoxy, methyl, -SCH3or halogen, for example, the following connections:

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]b is enzodiazepin,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-bromo-N-imidazo[1, 5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methylsulfanyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

3-chloro-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine or

3-chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine.

Other preferred compounds from this group are those compounds in which R3means-CH2-indolyl or-CH2is phenyl, optionally substituted by a group-N(CH3)2, a R1means chlorine or bromine, for example, the following connections:

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-7-(4-dimethylaminobenzoyl)-3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

3-chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-(1H-indol-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine or

7-benzyl-3-chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine.

The proposed compounds of formula I and their pharmaceutically acceptable salts can be obtained well-known in the field of the methods is, for example, as described below, which includes

a) interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where the substituents R1-R3have the meanings indicated above, or

b) interaction of the compounds of formula

H2NNH2

with the formation of the compounds of formula

and the cyclization of this compound in the interaction with

R3(OC2H5)3VI

obtaining the compounds of formula

where the substituents R1-R3have the meanings indicated above, or

in) modificatio one or more substituents R1-R3in accordance with the values specified above, and

if necessary, the conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

According to option a) the compounds of formula I can be obtained as follows: the compound of formula II, for example, the ethyl ester of 6-chloro-8-methoxy-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid or ethyl ester of 6-chloro-8-methyl-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid or ethyl ester of 6-chloro-8-bromo-4H-2,5,10b-tratamento[e]azulene-3-carbon is acid Oh is treated with a compound of formula III, for example, formylhydrazine, acethydrazide, hydrazide indole-3-acetic acid, dimethylaminoacetonitrile or the like, the Reaction is carried out in the presence of N,N-dimethyl-para-toluidine or N-ethyldiethanolamine or even in the absence of grounds and refluxed in chlorobenzene or para-xylene in a few hours.

Under option b) the compounds of formula I can be obtained in the following way: the compound of formula IV, for example, the ethyl ester of 6,8-dibromo-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid or 6-bromo-3-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4H-2,5,10b-tratamento[e]azulene treated with anhydrous solution of hydrazine in a suitable solvent, for example, THF, and the resulting mixture is heated for several hours. After cooling and evaporation, the solid can be used directly in the next stage. Then, the resulting solid is treated with the appropriate compound of formula VI, for example, triethylorthoformate in alcohol, such as ethanol, and the mixture is refluxed for several hours.

Sol receive at room temperature by known methods, which are also known to the person skilled in the art. It is possible to obtain salts of both inorganic and organic acids. Examples of such salts are hydrochloride, the hydrobromide is, sulfates, nitrates, citrates, acetates, maleate, succinate, methanesulfonate, para-toluensulfonate etc.

Scheme 1 depicts the methods of making compounds of formula I. the starting materials are known compounds or they can get well-known in the field of methods, for example, according to schemes 2, 3 and 4.

Scheme 1

The substituents shown in figure 1 have the meanings specified above.

According to scheme 1, the compound of the formula I can be obtained as described below. The corresponding compound of formula VII, where R1means substituted 2H-3,1-benzoxazin-2,4(1H)-dione, and (2,4-dimethoxyaniline)acetic acid (VIII) is suspended in para-xylene and heated in an argon atmosphere for approximately 2 hours After cooling to room temperature is the crystallization of the product. The resulting compound of formula IX is dissolved in toluene in the presence of N,N-dimethyl-para-toluidine. Then add phosphorus oxychloride, the solution is heated and after completion of the reaction is evaporated with toluene. Then, the resulting compound of formula X is dissolved in THF and added dropwise to the mixture cooled solution of Diisopropylamine lithium in THF and ethyl ether (E)-(dimethylaminomethylene)acetic acid or (S/2)-N'-(3-cyclopropyl[1,2,4]oxadiazol-5-almatygoroformleniya. The next phase obtained is the compound of formula XII dissolved in a mixture of CH 2Cl2and triperoxonane acid, and then treated with triftormetilfullerenov. The resulting compound of formula XIII is cleaned in the usual way. A mixture of this compound and N,N-dimethyl-para-toluidine are dissolved in chlorobenzene in an argon atmosphere and at room temperature add oxychloride or oxybromide phosphorus and the mixture is refluxed. The compound obtained of the formula XIV purify known methods. If the formula XIV hal means chlorine, the compound of the formula I get the reaction of the compounds of formula XIV, for example, the ethyl ester of 6-chloro-8-methoxy-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid, with the corresponding formylhydrazine formula III. The reaction is carried out in the presence of N,N-dimethyl-para-toluidine or N-ethyldiethanolamine or even in the absence of the base, and refluxed in chlorobenzene or para-xylene. If the formula XIV "hal" means bromine, such a connection, for example, the ethyl ester of 6,8-dibromo-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid, is treated with anhydrous solution of hydrazine and received in the form of a solid compound of formula V is directly used in the subsequent stage. Finally, the compound of the formula I are obtained when boiling under reflux a mixture of the compounds of formula V with triethylorthoformate in ethanol.

Getting the original Mat is rials

Scheme 2

In the diagram R' have the values specified above.

The original connection of the formula VII receive according to scheme 2. The compound of formula XV hydronaut in the usual way with the formation of the corresponding 2-aminobenzoic acid of formula XVI. Then, the compound obtained is dissolved in dioxane and treated with bis(trichloromethyl)carbonate by boiling under reflux.

Scheme 3

Figure 3 shows the derivation of the known starting materials. Methods of obtaining these compounds are also known or can be obtained by analogy with known methods. For example, N-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide get the reaction of N-phthaloylglycine in DMF) and 1,1'-carbonyldiimidazole then adding cyclopropanecarboxamide. Then, the resulting N-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide dissolved in 1,2-dichloroethane and add N-methylhydrazine. The obtained 4-(aminomethyl)-3-cyclopropyl-1,2,4-oxadiazol treated with diethylacetal N,N-dimethylformaldehyde and heated at approximately 130°To obtain the necessary source connection (E/Z)-N'-(3-cyclopropyl[1,2,4]oxadiazol-5-ylmethyl-N,N-dimethylformamide.

Scheme 4

Scheme 4 original connection ethyl ester (E)- (dimethylaminomethylene is about)acetic acid obtained when the interaction of glycine with diethylacetal N,N-dimethylformamide in ethanol.

As mentioned above, the compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. It was found that the compounds according to the invention are ligands And receptors GABA containing α5 subunit, and therefore, can be used for the treatment in those cases when it is necessary to stimulate cognitive abilities.

Compounds were tested by the following method

Obtain the membrane fraction and analysis of the receptor binding.

The affinity of compounds to the subtypes And receptor GABA was determined by competitive binding with [3H] - flumazenil (85 CI/mmol, firm Amersham) in SF9 cells expressing the receptor of the rat following composition: α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2.

Cellular precipitate suspended in Tris-buffered Krebs solution (buffer solution for analysis of binding ligands, 4.8 mm KCl, 1.2 mm CaCl2, 1.2 mm MgCl2, 120 mm Nad, 15 mm Tris, pH 7.5), homogenized in a blender transmitter station for about 15 sec on ice and centrifuged in a centrifuge UZ at 4°C for 30 min (100000 g, rotor: TFT 4594=300000.min). Cellular precipitate resuspendable in Tris-buffered Krebs solution and homogenized in a blender transmitter station for about 15 sec on ice. Prepared aliquot parts by volume of 1 ml, were determined by the contents of protein (Bradford) and received aliquot part of the membrane fractions were stored at -70° C.

Analysis of the binding of the radioactive ligand was performed in 200 ál of solution (in 96-well tablets)containing 100 ál of cells, [3H]flumazenil at a concentration of 1 nm in the analysis of binding subunits α1, α2, α3, and 0.5 nm for analysis of binding to subunits α5, and the analyzed compound at a concentration of 10-10-3×10-6M. Nonspecific binding was determined using 10-5M diazepam, which were generally less than 5% of the total binding. Samples were incubated until reaching equilibrium at 4°C for 1 h, collected on unifilter GF/C (Packard company) by filtration using the collector cells (Packard company), and then washed with ice-cold buffer solution for washing (50 mm Tris, pH 7.5). After drying was determined by the radioactivity on the filters in a liquid scintillation counter. Values of Kiwas calculated by the Excel-Fit (Microsoft) and used the average value of two measurements.

Compounds described in the examples were tested by the above method. Values of Kifor all compounds, determined according to the displacement of [3N]flumazenil from α5 subunit And receptor GABA rats was 100 nm or below. In a preferred embodiment, compounds according to the invention selectively contact α5 subunit compared to α1, α2 andα 3 subunits.

Data on activity of some preferred compounds listed in the following table.

Table
Example No.Ki[nm] α1Ki[nm] α2Ki[nm] α3Ki[nm] α5
130,657,639,21,3
6407,8361,5148, 8 persons10,8
1334,955,523,71,2
19480,9500,1482,314,5
20802,7283,9190,910,7
25for 95.3122,8107,45,9
37295,8266,1162,08,2
47694,5224,6100,313,1
501002,9409,4to 220.114.4V
5464,6148,0to 108.212,9
69359,8308,4158,17,
6167,353,018,91,3
6312,510,75,60,6

The compounds of formula I and their pharmaceutically acceptable acid salt additive, can be used as medicines, for example, in the form of drugs. The pharmaceutical preparations can be administered orally, for example in the form of tablets, pills in the shell, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can be performed rectally, for example in the form of suppositories, or parenterally, for example, and the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable acid salt additive can be mixed with pharmaceutically inert, inorganic or organic excipients for the production of pills, tablets in the shell, coated tablets and hard gelatin capsules. As such excipients, for example, tablets, coated tablets and hard gelatin capsules, you can use lactose, corn starch or its derivatives, talc, stearic acid or its salts and other Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like

<> Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like

Moreover, the pharmaceutical preparations can contain preservatives, solubilizing, stabilizing, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating the osmotic pressure, buffer substances, masking agents or antioxidants. In addition, they can contain other therapeutically valuable substances.

The dosage can vary within wide limits in accordance with the individual requirements in each particular case. Usually when administered orally is sufficient daily dose of from 10 to 1000 mg of the compounds of General formula I, although the upper limit can be exceeded if necessary.

The present invention is illustrated by the following examples without limiting its scope.

The intermediate connection And

(2,4-Dimethoxyaniline)acetic acid

This intermediate compound is known1and m is should get ways known in the art, for example, by the following method:

Glycine (100 g of 1.33 mol) was dissolved in 1N. NaOH (1.6 l) and treated with a solution of 2,4-dimethoxybenzaldehyde (200 g, of 1.20 mol) in Meon (800 ml). The resulting solution was first made over 10% Pd/C (40 g) in a hydrogen atmosphere at a pressure of 1.1 bar at room temperature (RT) for 2 hours, the Catalyst was separated by filtration and washed Meon (500 ml). The filtrate was concentrated to approximately 2 l, viparita all the Meon. The obtained alkaline aqueous solution was cooled with ice and acidified 3h. HCl (approximately 500 ml) to pH 4, which resulted in precipitation of the product. Solid white substance was separated by filtration and washed with ice water (200 ml). The wet crystals were dried at 60°S, first at 25 mbar during the night, and then at 0.1 mbar for 8 hours to receive 232 g (85%) of product containing as an impurity 3% NaCl. The product was used without additional purification, tPL115°C, m/z 225 (M).

Intermediate compound B

Ethyl ester of (E)-(dimethylaminomethylene)acetic acid

This intermediate compound is known and can be obtained

methods known in the art, for example, by the following method:

Method And

A mixture of glycine (69,8 g to 0.8 mole) and diethylacetal M,N-dimethylformamide (69,8 ml of 4.0 mol) was heated with reverse holodilniki and the formed ethanol was removed using traps Dean-stark. The product was distilled to yield 108,4 g (86%). tKip.120-122°/28 mbar.

Method B

The hydrochloride of the ethyl ester of glycine portions was dissolved in 10% aqueous solution of Na2CO3obtained solution was saturated with NaCl, filtered and the filtrate was extracted twice CH2Cl2(400 ml). The organic layer was dried, filtered and carefully evaporated. The residue was distilled at 45°C/18 mbar. It was obtained ethyl ester of glycine (32 g, 43%) as a colourless liquid.

Ethyl ester of glycine (35 g, 339 mmol) was dissolved in diethylacetal N,N-dimethylformamide (64 ml, 373 mmole) and heated to 130°C. Ethanol (approximately 20 ml) kept using traps Dean-stark. The residue was distilled at 110 C/18 mbar, the product was obtained as a yellowish liquid (52 g, 97%). m/z 159 (M+H).

The intermediate connection

(E/Z)-N'-(3-Cyclopropyl[1,2,4]oxadiazol-5-ylmethyl)-N,N-dimethylformamide

Stage 1

N-[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide

N-Phthaloylglycine (90,7 g, 442 mmole) portions (due to clumping) was dissolved in DMF (500 ml). Then portions was added 1,1'-carbonyldiimidazole evil (78,9 g, 486 mmol) (caution: selection FROM). The resulting suspension was heated at 80°C for 20 min, and then cooled to CT, was added cyclopropanecarboxamide and heated at 110°C for 2 hours the Solution was cooled to CT, poured into water(4 l), was stirred for 15 min, filtered, the product on the filter was washed with water (400 ml), and dried, yield 104 g (87%). tPL115°C, m/z 269 (M).

Stage 2

4-(Aminomethyl)-3-cyclopropyl-1.2.4-oxadiazol

N-[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide (104 g, 387 mmol) was dissolved in 1,2-dichloroethane (500 ml), then was added N-methylhydrazine (22,4 ml, 426 mmol) and the solution boiled under reflux for 5 hours, the Suspension was cooled with ice, the precipitate (2-methyl-2,3-dihydrophenazine-1,4-dione) was separated by filtration and washed with 1,2-dichloroethane (100 ml). The filtrate was evaporated, the residue was distilled at 70°/0.4 mbar (with a bath temperature of 100 to 150° (C), the output is 39.3 g (73%). m/z 139 (M).

Stage 3

(E/Z)-N'-(3-Cyclopropyl[1,2,4]oxadiazol-5-ylmethyl)-N,N-dimethylfuran-amidin

4-(Aminomethyl)-3-cyclopropyl-1,2,4-oxadiazol (39,3 g, 282 mmole) was dissolved in diethylacetal N,N-dimethylformaldehyde (77 ml, 451 mmol) and was heated at 130°until complete evaporation of the resulting EtOH (refrigerator of Hickman). Excess reagent was removed by distillation in vacuum and then distilled product with a bath temperature of 140-150°C/0.1 mbar, the output of 49.3 g (90%). m/z 195(MH+).

Example 1

Ethyl ester of 3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d] [1,4]benzodiazepine-10-carboxylic acid

Stage 1

6-Methoxy-2H-3,1-benzoxazin-2,4(1H)-dione

This intermediate compound is known and it can p in order to obtain ways, known in the art, for example, by the following method:

2-Amino-5-methoxybenzoic acid (19.3 g, 115 mmol) was dissolved in dioxane (200 ml)was treated with bis(trichloromethyl)carbonate (11.3 g, 38 mmol) and boiled under reflux for 1 h, the Suspension was cooled to CT, the crystals were separated by filtration and washed with dioxane (20 ml). The mother liquor was evaporated, the residue was led from ethyl acetate, the yield of 20.9 g (94%). tPL244°C (decomp.), m/z 193 (M).

Stage 2

4-(2,4-Dimethoxybenzyl)-7-methoxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

6-Methoxy-2H-3,1-benzoxazin-2,4(1H)-dione (23 g, 119 mmol) and (2,4-dimethoxyaniline)acetic acid (27 g, 120 mmol) suspended in para-xylene (500 ml) and boiled under reflux (140° (C) in argon atmosphere for 2 hours, the Hot solution was cooled to CT, it was observed spontaneous crystallization of the product. The crystals were separated by filtration and washed para-xylene (50 ml), yield 39 g (92%). tPL196°C, m/z 356(M).

Stage 3

2-Chloro-4-(2,4-dimethoxybenzyl)-7-methoxy-3,4-dihydrobenzo-[e][1,4]diazepin-5-he

4-(2,4-Dimethoxybenzyl)-7-methoxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (23.7 g, 67 mmol) and N,N-dimethyl-para-toluidine (19.2 ml, 133 mmole) were mixed in toluene (200 ml) and was heated at 100°C. Then was added dropwise phosphorus oxychloride (6,7 ml, 73 mmol who) and was heated at 100° C for 2.5 hours the resulting solution was dark red color was evaporated to dryness, the residue was dissolved in THF (150 ml) and used directly in the next stage.

Stage 4

Ethyl ester of 5-(2,4-dimethoxybenzyl)-8-methoxy-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

Hexamethyldisilazane (48,5 ml, 66 mmol) was dissolved in THF (150 ml), cooled in an atmosphere of argon to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (145 ml, 233 mmole). After stirring at -70°C for 1 h was added a solution of ethyl ester of (E)-(dimethylamino-methylamino)acetic acid (21 g, 133 mmole) in THF (50 ml) and was stirred at -70°C for 1 h and Then at -70°C was added a solution of 2-chloro-4-(2,4-dimethoxybenzyl)-7-methoxy-3,4-dihydrobenzo[e][1,4]-diazepin-5-it (24,9 g, 66 mmol) in THF (150 ml)was heated to 10°C for approximately 1 h and again cooled to -30°C. and Then slowly cooling to -30°With added glacial acetic acid (38 ml, 664 mmole), turbid suspension was heated to 0°With added water (40 ml) and the resulting solution was boiled under reflux for 1 h, which resulted in the formation of a thick precipitate. The hot suspension was diluted with water (450 ml), cooled to 30°C, filtered, and the white crystals on the filter is washed with THF/water (1:1, 400 ml) and dried at 60°/25 mbar, Ihad 16.7 g (56%). tPL204°C, m/z 451 (M).

Stage 5

Ethyl ester 8-methoxy-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]-azulene-3-carboxylic acid

Ethyl ester of 5-(2,4-dimethoxybenzyl)-8-methoxy-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid (9.8 g, 22 mmole) suspended in CH2Cl2(50 ml), cooled in ice and slowly diluted triperoxonane acid (50 ml). The obtained clear solution was treated with 5°triftormetilfullerenov acid (3.8 ml, 44 mmole). The resulting red solution was stirred at RT for 2 h, evaporated to dryness, the residue was extracted with CH2Cl2(500 ml), then with two portions of 10% solution of NaHCO3(500 ml). The crude product (approximately 10 g) was treated with hot ethyl acetate (100 ml), cooled, and the white crystals were separated by filtration (5.6 g, 85%). tPL240°C, m/z 301 (M).

Stage 6

Ethyl ester of 6-chloro-8-methoxy-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

Ethyl ester 8-methoxy-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]-azulene-3-carboxylic acid (7.5 g, 25 mmol) and N,N-dimethyl-para-toluidine (10,8 ml, 75 mmol) were mixed in chlorobenzene (80 ml) in an argon atmosphere. Then at RT was added phosphorus oxychloride (3.4 ml, 37 mmol) and the mixture is boiled under reflux for 3.5 hours the resulting solution was cooled to CT, diluted in CH2Cl /acetone, 100:15, (300 ml) and directly purified rapid chromatography on silica gel (CH2Cl2/acetone, 100:15). The white product was recrystallized by dissolving in hot ethyl acetate (300 ml) and concentration before precipitation (approximately 100 ml), yield 7 g (88%). tPL186°C, m/z 301 (M).

Stage 7

Ethyl ester of 3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]-benzodiazepine-10-carboxylic acid

A mixture of ethyl ester of 6-chloro-8-methoxy-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid (0.1 g, 0.31 in mmole), formylhydrazine (41 mg, 0,69 mmole) and N-ethyldiethanolamine (0,054 ml, at 0.31 mmole) in chlorobenzene (1 ml) was boiled under reflux for 4 hours Then the reaction mixture was extracted with CH2Cl2water, the organic layer was dried and evaporated. The residue was purified rapid chromatography on silica gel (CH2Cl2/MeOH, 30:1). tPLl97°C, m/z 325 (M).

Example 2

Ethyl ester of 3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]-benzodiazepine-10-carboxylic acid

Stage 1

6-Methyl-2H-3,1-benzoxazin-2,4-(1H)-dione

This intermediate compound is known and can be obtained by methods known in the art, for example, by the following method:

A mixture of 2-amino-5-methylbenzoic acid (45,2 g to 0.30 mole) and ethylchloride (of 31.4 ml of 0.33 mol) in dioxane (250 ml) was heated with reverse what holodilniki over 4.5 hours After cooling, was added acetylchloride (50 ml) and boiled under reflux continued for a further 4 h After cooling, the mixture was evaporated and the resulting solid was treated with tert-butyllithium ether/heptane (1:1, 400 ml) by boiling under reflux for 1 h, the Solid was separated by filtration and washed with tert-butylmethylamine ether/heptane (1:1, 80 ml), the yield of 47.7 g (90%). m/z 177 (M).

Stage 2

4-(2,4-Dimethoxybenzyl)-7-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

A suspension of 6-methyl-2H-3,1-benzoxazin-2,4-(1H)-dione (18,3 g, 103 mmole) in para-xylene (125 ml)containing (2,4-dimethoxyaniline)acetic acid (25.6 g, 114 mmol)was heated under reflux (150° (C) for 2.5 hours After cooling to CT precipitate was separated by filtration and washed para-xylene (2×20 ml), the output of 34.1 g (97%). m/z 341 (MN+).

Stage 3

2-Chloro-4-(2,4-dimethoxybenzyl)-7-methyl-3,4-dihydrobenzo[e][1,4]diazepin-5-he

4-(2,4-Dimethoxybenzyl)-7-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (34,0 g, 100 mmol) and N,N-dimethyl-para-toluidine (28,9 ml, 200 mmol) were mixed in toluene (100 ml) and was heated to 100°C. Then was added dropwise phosphorus oxychloride (10.1 ml, 110 mmol) and was heated at 100°C for 2.5 hours the resulting solution was dark red directly used in the next stage.

Stage 4

E. the silt ester 5-(2,4-dimethoxybenzyl)-8-methyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

Hexamethyldisilazane (68,7 ml, 330 mmol) was dissolved in THF (350 ml), cooled in an atmosphere of argon to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (206 ml, 330 mmol). After stirring at -70°C for 1 h was added a solution of ethyl ester of (E)-(dimethylamino-methylamino)acetic acid (31,6 g, 200 mmol) in THF (30 ml), and stirred at -70°C for 1 h and Then at -70 C was added a solution of 2-chloro-4-(2,4-dimethoxybenzyl)-7-methyl-3,4-dihydrobenzo[e][1,4]-diazepin-5-it (35,9 g, 100 mmol) (obtained as described above), was heated at 10°C for 1 h and again cooled to -30°C. After 30 min at -30°With added acetic acid (57 ml), the suspension was heated to CT, was added water (57 ml) and the resulting mixture was boiled under reflux for 14 hours After cooling, the mixture was evaporated and then dissolved in dichloromethane (DHM) (300 ml). The resulting solution was washed with 1 M HCl (2×100 ml) and 10% sodium hydrogen carbonate solution (100 ml), dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: EtOAc), to yield 17.6 g (41%). m/z 436 (MH+).

Stage 5

Ethyl ester 8-methyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento-[e]azulene-3-carboxylic acid

Ethyl ester of 5-(2,4-dimethoxybenzyl)-8-methyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid (9.8 g, 23 mmole) suspended in CH 2Cl2(100 ml), cooled in ice and slowly diluted triperoxonane acid (30 ml). The resulting solution at 5°processed triftormetilfullerenov acid (3.0 ml, 34 mmole). The red solution was stirred at RT for 2 h Then the mixture was evaporated, the residue was dissolved in CH2Cl2(20 ml), washed with 10% sodium hydrogen carbonate solution (2x5 ml), the organic layer was dried (Na2SO4) and was evaporated. The product was obtained by rubbing with EtOAc, the output of 9.55 g (92%). m/z 283 (M-N-).

Stage 6 and stage 7 (without isolating the ethyl ester of 6-chloro-8-methyl-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid)

Ethyl ester of 6-chloro-8-methyl-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid and ethyl ester of 3-methyl-N-imidazo[1,5-a][1,2,4]triazolo-[3,4-d][1,4]benzodiazepine-10-carboxylic acid

Ethyl ester 8-methyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]-azulene-3-carboxylic acid (9.5 g, 33 mmole) and N,N-dimethyl-para-toluidine (14.4 ml, 99 mmol) were mixed in chlorobenzene (100 ml) in an argon atmosphere. Then at RT was added phosphorus oxychloride (4.6 ml, 50 mmol) and the resulting mixture was boiled under reflux for 1.5 hours After cooling, the mixture was evaporated and used in the next stage. The mixture was dissolved in chlorobenzene (100 ml)was added N,N-ethyldiethanolamine (5.7 ml, 33 mmole) and formylhydrazine (4.4 g, 66 mmol) and the resulting mixture is boiling the or under reflux for 4 hours After cooling, the mixture was evaporated and dissolved in CH2Cl2(50 ml) and water (20 ml). The organic layer was separated, dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: EtOAc), to yield 2.85 g (28%). tPL236-238°C, m/z 310 (MN+).

Example 3

Ethyl ester of 3-isopropyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

Stage 1

6-Isopropyl-1H-benzo[d][1,3]oxazin-2,4-dione

A mixture of 2-amino-5-isopropylbenzoic acid (30 g, 16.7 mmole) and ethylchloride (1.75 ml, an 18.4 mmole) in dioxane (20 ml) was boiled under reflux for 2 hours, After cooling, to the mixture was added acetylchloride (1,4 ml) and boiled under reflux for a further 3 hours After cooling, the mixture was evaporated and the resulting solid was treated with tert-butyllithium ether/heptane (1:1, 20 ml) by boiling under reflux for 1 h, the Solid was separated by filtration and washed with tert-butylmethylamine ether/heptane (1:1, 10 ml), yield 3.1 g (89%). m/z 204 (M-N-).

Stage 2

4-(2,4-Dimethoxybenzyl)-7-isopropyl-3,4-dihydro-1H-benzo[e][1,4]-diazepan-2,5-dione

A suspension of 6-isopropyl-1H-benzo[(1][1,3]oxazin-2,4-dione (3.0 g, 15 mmol) in para-xylene (40 ml)containing (2,4-dimethoxyaniline)acetic acid (3.7 g, 16 mmol)were heated under reflux (150° (C) for 2.5 is. After cooling to CT precipitate was separated by filtration and washed para-xylene (2x20 ml), yield 4.9 g (90%). m/z 367 (M-N-).

Stage 3

2-Chloro-4-(2,4-dimethoxybenzyl)-7-isopropyl-3,4-dihydrobenzo[e][1,4]-diazepin-5-he

4-(2,4-Dimethoxybenzyl)-7-isopropyl-3,4-dihydro-1H-benzo[e][1,4]-diazepan-2,5-dione (1.5 g, 4.1 mmole) and N,N-dimethyl-para-toluidine (1,76 ml, 12.2 mmole) were mixed in toluene (8 ml) and heated to 100°C. Then was added dropwise phosphorus oxychloride (559 μl, 6.1 mmole) and heated at 100°C for 2.5 hours After cooling the mixture was evaporated, dissolved in THF (10 ml) and directly used in the next stage.

Stage 4

Ethyl ester of 5-(2,4-dimethoxybenzyl)-8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

Hexamethyldisilazane (2,8 ml of 13.4 mmole) was dissolved in THF (25 ml), cooled in an atmosphere of argon to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (8,4 ml of 13.4 mmole). After stirring at -70°C for 1 h was added a solution of ethyl ester of (E)-(dimethylamino-methylamino)acetic acid (1.28 g, 8.1 mmole) in THF (5 ml) and stirred at -70°C for 1 h and Then at -70°C was added a solution of 2-chloro-4-(2,4-dimethoxybenzyl)-7-isopropyl-3,4-dihydrobenzo[e][1,4]-diazepin-5-it (1,59 g, 4,1 mmole) (obtained as described above), were heated to 10 C for 1 h and again cooled is about -30° C. After 30 min at -30°With added acetic acid (3.0 ml), the suspension was heated to CT, was added water (3.0 ml) and the resulting mixture was boiled under reflux for 14 hours After cooling, the mixture was evaporated and then dissolved in DHM (30 ml). The resulting solution was washed with 1 M HCl (2×15 ml), a saturated solution of sodium bicarbonate (10 ml), dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: Eyes/hexane, 19:1), the output of 1.9 g (99%). m/z 464 (MH+).

Stage 5

Ethyl ester of 8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento-[e]azulene-3-carboxylic acid

Ethyl ester of 5-(2,4-dimethoxybenzyl)-8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid (410 mg, 0.9 mmole) suspended in CH2Cl2(3.0 ml), cooled in ice and slowly diluted triperoxonane acid (2.0 ml). The resulting solution was treated with 5°triftormetilfullerenov acid (1.0 ml, 1.3 mmole). The red solution was stirred at RT for 2 h Then the mixture was evaporated, the residue was dissolved in CH2Cl2(20 ml), washed with 10% sodium hydrogen carbonate solution (2×5 ml), the organic layer was dried (Na2SO4) and was evaporated. The product was obtained by rubbing with EtOAc, to yield 250 mg (90%). m/z 313 (MN).

Stage 6

Ethyl ester of 6-chloro-8-isopropyl-4H-2,5,10b-tratamento[e]azulene-3-carbon is th acid

Ethyl ester of 8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]-azulene-3-carboxylic acid (1.8 g, 5.6 mmole) and N,N-dimethyl-para-toluidine (2.4 ml and 16.9 mmole) were mixed in chlorobenzene (10 ml) in an argon atmosphere. Then at RT was added phosphorus oxychloride (771 μl, 8.4 mmole) and the resulting mixture was boiled under reflux for 2 hours After cooling, the mixture was evaporated and the product was purified by chromatography on silica gel (eluent: EtOAc), to yield 1.3 g (68%).

Stage 7

Ethyl ester of 3-isopropyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-[1,4]-benzodiazepine-10-carboxylic acid

A mixture of ethyl ester of 6-chloro-8-isopropyl-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid (50 mg, 0.15 mmole), formylhydrazine (10 mg, 0,17 mmole) and N,N-dimethyl-para-toluidine (24 μl, 0.17-mmole) in chlorobenzene (2 ml) was boiled under reflux for 10 hours Then the reaction mixture was evaporated and the product was purified preparative GHUR, the output of 8.7 mg (17%). tPL160-163°C, m/z 338 (M).

Example 4 (Method A)

Ethyl ester of 3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]-benzodiazepine-10-carboxylic acid

Stage 1

4-(2,4-Dimethoxybenzyl)-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

A suspension of 6-bromo-2H-3,1-benzoxazin-2,4(1H)-dione (22,0 g, 91 mmol) in para-xylene (200 ml)containing (2,4-dimethoxyaniline)acetic acid (22,5 g, 100 mmol)was heated under reflux (150° (C) those which begins 1 PM After cooling to CT precipitate was separated by filtration and washed para-xylene (100 ml), the output of 33.5 g (91%). m/z 403/405 (M).

Stage 2

2-Chloro-4-(2,4-dimethoxybenzyl)-7-bromo-3,4-dihydrobenzo[e][1,4]diazepin-5-he

4-(2,4-Dimethoxybenzyl)-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3.0 g, 7.4 mmole) and N,N-dimethyl-para-toluidine (2,1 ml of 14.8 mmole) were mixed in toluene (30 ml) and heated to 100°C. Then was added dropwise phosphorus oxychloride (745 μl, 8.1 mmole) and heated at 100°C for 2.5 hours the resulting solution was dark red was evaporated, the residue was dissolved in THF (10 ml) and directly used in the next stage.

Stage 3

Ethyl ester of 5-(2,4-dimethoxybenzyl)-8-bromo-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

Hexamethyldisilazane (5,1 ml, is 24.4 mmole) was dissolved in THF (30 ml), cooled in an atmosphere of argon to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (14,5 ml of 23.2 mmole). After stirring for 1 h at -70°solution was added ethyl ether (E)-(dimethylamino-methylamino)acetic acid (2,34 g of 14.8 mmole) in THF (10 ml) and stirred at -70°C for 1 h and Then at -70°C was added a solution of 2-chloro-4-(2,4-dimethoxybenzyl)-7-bromo-3,4-dihydrobenzo[e][1,4]-diazepin-5-she (3.1 g, 7,4 mmole) (obtained as described above) in THF (10 ml)was heated to 10°C for 1 h and was novoajdari to -30° C. After 30 min at -30°With added acetic acid (8.0 ml), the suspension was heated to CT, was added water (8.0 ml)and the resulting mixture is boiled under reflux for 2 hours After cooling, the mixture was evaporated and then dissolved in DHM (30 ml). The resulting solution was washed with 1 M HCl (g ml), saturated sodium hydrogen carbonate solution (10 ml), dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: EtOAc), to yield 0.9 g (24%). m/z 500/502 (M).

Stage 4

Ethyl ester of 8-bromo-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento-[e]azulene-3-carboxylic acid

Ethyl ester of 5-(2,4-dimethoxybenzyl)-8-bromo-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid (2.6 g, 5.2 mmole) suspended in CH2Cl2(15 ml), cooled in ice and slowly diluted triperoxonane acid (11.9 ml). The resulting solution at 5°processed triftormetilfullerenov acid (680 μl, of 7.8 mmole). The red solution was stirred at RT for 1.5 h Then the mixture was evaporated and dissolved in CH2Cl2(50 ml), washed with 10% sodium hydrogen carbonate solution (2×25 ml), the organic layer was dried (Na2SO4) and was evaporated. The product was obtained by rubbing with EtOAc, yield 1.8 g (100%). m/z 350/352 (M).

Stage 5 and 6

Ethyl ester of 6,8-dibromo-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid and ethyl ester of 8-bromo-6-hydrazino-N-2,5,10b-tratamento[e]azulene-3-carboxylic acid

Ethyl ester of 8-bromo-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]-azulene-3-carboxylic acid (0.2 g, 0.6 mmole) and N,N-dimethyl-para-toluidine (165 μl, 1.1 mmole) was mixed in toluene (5 ml)was treated with phosphorylation (180 mg, 0.6 mmole) and the resulting mixture was boiled under reflux for 5 hours After cooling, the mixture was evaporated, the residue was extracted with CH2Cl2(10 ml) and water (10 ml). The organic layer was separated, dried (Na2SO4) and was evaporated. The residue was dissolved in THF (10 ml)was treated with anhydrous solution of hydrazine (1 M in THF, 2.0 ml, 0.2 mmole) and the resulting mixture was boiled under reflux for 12 hours After cooling, the mixture was evaporated and the solid (m/z 364/366 (M)) is directly used in the next stage.

Stage 7

Ethyl ester of 3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]-benzodiazepine-10-carboxylic acid

A mixture of ethyl ester of 8-bromo-6-hydrazino-4H-2,5,10b-tratamento[e]-azulene-3-carboxylic acid (0.4 g, 0.6 mmole) and triethylorthoformate (285 μl, 1.7 mmole) in ethanol (16 ml) was boiled under reflux for 18 hours, After cooling the mixture was evaporated. The product was purified by chromatography on silica gel (eluent: EtOAc), the output of 4.6 mg (5%). tPL198-200°C, m/z 374/376 (M).

Example 4 (Method B)

Ethyl ester of 6-chloro-8-bromo-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

Ethyl ester of 8-bromo-6-the CSR-5,b-dihydro-4H-2,5,10b-tratamento[e]-azulene-3-carboxylic acid (2.3 g, 6.4 mmole) and N,N-dimethyl-para-toluidine (2.8 ml, and 19.3 mmole) were mixed in chlorobenzene (25 ml) in an argon atmosphere. Then at RT was added phosphorus oxychloride (882 μl, 0.96 mmole) and the resulting mixture was boiled under reflux for 2 hours After cooling, the mixture was evaporated and purified by chromatography on silica gel (eluent: EtOAc), to yield 14 g (59%). m/z 368/370 (M).

Example 5

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4-d]benzodiazepine

Stage 1

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-methoxy-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

Hexamethyldisilazane (29 ml, 139 mmol) was dissolved in THF (250 ml), cooled to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (88 ml). After stirring for 15 min at -70° (C) was added over 15 min a solution of (E/Z)-N'-(3-cyclopropyl[1,2,4]-oxadiazol-5-ylmethyl)-N,N-dimethylformamidine (16.4 g, 840 mmol) in THF (50 ml). The resulting orange solution was stirred at -70°C for 15 min and then for 15 min was added to a solution of the crude 2-chloro-4-(2,4-dimethoxybenzyl)-7-methoxy-3,4-dihydrobenzo[e][1,4]diazepin-5-she (13.5 g, 42 mmole) in toluene and stirred at -70°C for 30 minutes the Reaction was stopped by adding acetic acid (30 ml) at -70°and the mixture was heated to CT. Then added water (30 ml), the resulting solution is slightly red boiled under reflux for 2 h, and then was evaporated. The residue was dissolved in CH2Cl2(200 ml), was extracted with 1N. HCl and 10% solution of NaHCO3. After concentration the product was led directly from the CH2Cl2exit 11 g (53%). tPL> 240°C, m/z 487 (M).

Stage 2

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methoxy-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-methoxy-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (5 g, 10.3 mmole) was dissolved in CH2Cl2(30 ml), cooled to 0°and then added triperoxonane acid (30 ml) and triftormetilfullerenov acid (2 ml, 22.9 mmole). The mixture was stirred at RT for 4 h, evaporated, the residue was dissolved in CH2Cl2(100 ml) and was extracted with a 10% solution of NaHCO3. The product was obtained after evaporation CH2Cl2, exit 3 g (86%). tPL245°C, m/z 337 (M).

Stage 3

[3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methoxy-4H-2,5,10b-tratamento[e]azulene-6-yl]hydrazine

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methoxy-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (1 g, 3 mmole) and N,N-dimethyl-para-toluidine (0,856 ml, 5.9 mmole) were mixed in toluene (25 ml)was treated with phosphorylation (0.935 g, 3.3 mmole) and boiled under reflux for 15 hours, the Toluene evaporated, the residue was extracted with CH2Cl2(50 ml) and water (50 ml). Organic is the cue layer was dried, was evaporated, and was again dissolved in THF (50 ml) and treated with 1 M solution of anhydrous hydrazine in THF (10 ml, 10 mmol) by boiling under reflux overnight. The mixture was evaporated and purified by chromatography on silica gel (eluent: CH2Cl2/Meon, 10:1), the product was obtained in the form of a solid light brown color (0.4 g, 38%). m/z 352 (MN+).

Stage 4

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

A mixture of (3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methoxy-4H-2,5,10b-tratamento[e]azulene-6-yl]hydrazine (0.1 g, 2.8 mmole) and triethylorthoformate (0,142 ml of 0.85 mmole) in ethanol (8 ml) was boiled under reflux for 14 hours the resulting solution was cooled with ice, the white crystals were separated by filtration, yield 80 mg (78%). tPL252°m/z 361 (M).

Example 6

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methyl-N-imidazo[1,5-a][1,2,4]-triazolo[4,3-d][1,4]benzodiazepine

Stage 1

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-methyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

4-(2,4-Dimethoxybenzyl)-7-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (5.0 g, 14.7 mmole) and N,N-dimethyl-para-toluidine (6.4 ml, 44,0 mmole) were mixed in toluene (50 ml) and was heated to 100°C. Then was added dropwise phosphorus oxychloride (4.0 ml, 44,0 mmole) and heated at 100°C for another 2 h Polioksidony the mixture was evaporated, was dissolved in THF (2.0 ml) and used directly in the next stage.

Hexamethyldisilazane (10.1 ml, 48.5 mmole) was dissolved in THF (60 ml), cooled in an atmosphere of argon to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (30,3 ml, 48.5 mmole). After stirring at -70°C for 1 h was added a solution of (E/Z)-N'-(3-cyclopropyl[1,2,4]oxa-diazol-5-ylmethyl)-N,N-dimethylformamidine (5.7 g, of 29.4 mmole) in THF (2 ml) and stirred at -70°C for 1 h and Then at -70°C was added a solution of 2-chloro-4-(2,4-dimethoxybenzyl)-7-methyl-3,4-dihydrobenzo[e][1,4]-diazepin-5-it (5,28 g, 14.7 mmole) (obtained as described above), was heated at 10°C for 1 h and again cooled to -30°C. After 30 min at -30°With added acetic acid (17 ml) and the suspension was heated to CT. Then added water (17 ml) and the resulting mixture was stirred at RT for 12 h the Mixture was evaporated and was again dissolved in EtOAc (100 ml). The resulting solution was washed with 1 M HCl (2×50 ml) and a saturated solution of NaHCO3(10 ml), dried (Na2SO4) and was evaporated. The product was purified by filtration through a layer of silica gel (eluent: EtOAc/hexane, 9:1). yield 4.8 g (69%), m/z 471 (M).

Stage 2

3-(3-Cyclopropyl-[1.2.4]oxadiazol-5-yl)-8-methyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-methyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-about the (17.5 g, 37.1 mmole) suspended in CH2Cl2(100 ml), cooled in ice and slowly diluted triperoxonane acid (to 85.2 ml). The resulting solution was treated with 5°triftormetilfullerenov acid (4.9 ml, 55.7 mmole). The red solution was stirred at RT for 4 h Then the mixture was evaporated, the residue was dissolved in CH2Cl2(100 ml), washed with 10% sodium hydrogen carbonate solution (2×50 ml), the organic layer was dried (Na2SO4) and was evaporated. The product was dissolved in EtOAc (100 ml)and then slowly added hexane (100 ml). The obtained solid twice with 20 ml washed with EtOAc/hexane, 1:1, the yield 9.3 g (78%). m/z 321 (M).

Stage 3

6-Chloro-3-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-thiomethyl-4H-2,5,10b-tratamento[e]azulene

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (9.3 g, of 28.8 mmole) and N,N-dimethyl-para-toluidine (12.5 ml, 86,5 mmole) were mixed in chlorobenzene (100 ml) in an argon atmosphere. Then at RT was added phosphorus oxychloride (4.0 ml, 43,2 mmole) and the resulting mixture was boiled under reflux for 2 hours After cooling, the mixture was evaporated, then was extracted with CH2Cl2(100 ml) and water (50 ml). The organic layer was separated, dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: CH2Cl2/acetone 30:1), yield 3.8 g (39%). m/z 340 (H +).

Stage 4

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methyl-N-imidazo[1,5-a][1,2,4]-triazolo[4,3-d[1,4]benzodiazepine

A mixture of 6-chloro-3-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-thiomethyl-4H-2,5,10b-tratamento[e]azulene (3.0 g, 8.8 mmole), formylhydrazine (1.1 g of 17.7 mmole) and N,N-ethyldiethanolamine (1.5 ml, 8.8 mmole) in chlorobenzene (30 ml) was boiled under reflux for 2.5 hours, After cooling the mixture was evaporated, then was extracted with CH2Cl2(100 ml) and water (50 ml). The organic layer was separated, dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: CH2Cl2/acetone 30:1), yield 2.4 g (80%). tPL253-256°C, m/z 346 (MN+).

Example 7

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-bromo-N-imidazo[1,5-a][1,2,4]-triazolo[4,3-d][1,4]benzodiazepine

Stage 1 and 2

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-bromo-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-4-(2,4-Dimethoxybenzyl)-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (5.0 g, 12.3 mmole) and N,N-dimethyl-para-toluidine (5,3 ml, 37,0 mmole) mixed in toluene (20 ml) and heated to 100°C. Then was added dropwise phosphorus oxychloride (3.4 ml, 37,0 mmole) and heated at 100 C for another 2 hours After cooling, the mixture was evaporated, dissolved in THF (20 ml) and used directly in the next stage.

Hexamethyldisilazane (8.5 ml, 40,7 mmole) solution of the Li in THF (60 ml), cooled in an atmosphere of argon to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (25,5 ml, 40,7 mmole). After stirring at -70°C for 1 h, to the mixture was added a solution of (E/Z)-N'-(3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-N,N-dimethylformamidine (4.8 g, 24.7 mmole) in THF (2 ml) and stirred at -70°C for 1 h and Then at -70°C was added a solution of 2-chloro-4-(2,4-dimethoxybenzyl)-7-bromo-3,4-dihydrobenzo-[e][1,4]diazepin-5-it (5,26 g, 12.4 mmole) (obtained as described above), were heated to 10°C for 1 h and again cooled to -30°C. After 30 min at -30°With added acetic acid (14 ml) and the suspension was heated to CT. Then added water (14 ml) and the resulting mixture was stirred at RT for 1.5 h the Mixture was evaporated and was again dissolved in EtOAc (100 ml). The resulting solution was washed with 1 M HCl (2×50 ml) and a saturated solution of NaHCO3(10 ml), dried (Na2SO4) and was evaporated. The product was purified by filtration through a layer of silica gel (eluent: EtOAc/hexane, 9:1), yield 2.0 g (31%). m/z 536/538 (M).

Stage 3

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-bromo-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-bromo-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (1.1 g, 2.0 mmole) suspended in CH2Cl2(6 ml), cooled in ice and slowly diluted triperoxonane acid (4,7 ml). Receiving the hydrated solution was treated with 5 triftormetilfullerenov acid (266 μl, 3.0 mmole). The red solution was stirred at RT for 1.5 h Then the mixture was evaporated, dissolved in CH2Cl2(10 ml) and washed with saturated solution of sodium bicarbonate (2×10 ml), the organic layer was dried (Na2SO4) and was evaporated. The product is triturated with EtOAc, the output 772 mg (100%). m/z 385/387 (M-N-).

Stage 4

6-Chloro-3-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-bromo-4H-2,5,10b-tratamento[e]azulene

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-bromo-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (1.1 g, a 20.3 mmole) and N,N-dimethyl-para-toluidine (881 μl, 6.1 mmole) were mixed in chlorobenzene (8 ml) in an argon atmosphere. Then at RT was added phosphorus oxychloride (279 μl, 3.1 mmole) and the resulting mixture was boiled under reflux for 2.5 hours, After cooling the mixture was evaporated, then was extracted with CH2Cl2(50 ml) and water (25 ml). The organic layer was separated, dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: CH2Cl2/acetone 30:1), yield 550 mg (67%). m/z 403/405 (M-N-).

Stage 5

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-bromo-N-imidazo[1,5-a][1,2,4]-triazolo[4,3-d][1,4]benzodiazepine

A mixture of 6-chloro-3-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-bromo-4H-2,5,10b-tratamento[e]azulene (150,0 mg, 0.37 mmole), formylhydrazine (245,0 mg, 0,41 mmole) and N,N-dimethyl-para-toluidine (59 μl, of 0.41 mmole) in chlorobenzene (6 ml) boiling whom or under reflux for 3 hours After cooling, the mixture was evaporated. The product was purified by chromatography on silica gel (eluent: CH2Cl2/acetone 30:1), yield 94 mg (62%). tPL259-261°C, m/z 410/412 (M).

Example 8

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methylsulfanyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

Stage 1

6-Methylsulfanyl-1H-benzo[d][1,3]oxazin-2,4-dione

This intermediate compound is known and can be obtained by methods known in the art, for example, by the following method:

A mixture of 2-amino-5-methylbenzoic acid (4.9 g, to 26.7 mmole) and ethylchloride (2,9 ml of 30.0 mmole) in dioxane (25 ml) was boiled under reflux for 2 hours, After cooling, was added acetylchloride (2.3 ml) and boiled under reflux for a further 3 hours After cooling, the mixture was evaporated and the resulting solid was treated with tert-butyllithium ether/heptane (1:1, 20 ml) by boiling under reflux for 1 h, the Solid was separated by filtration and washed with tert-butylmethylamine ether/heptane (1:1, 10 ml), yield 4.8 g (85%). m/z 208 (M-N-).

Stage 2

4-(2,4-Dimethoxybenzyl)-7-methylsulfanyl-3,4-dihydro-1H-benzo[e][1,4]-diazepan-2,5-dione

A suspension of 6-methylsulfanyl-1H-benzo[e][1,3]oxazin-2,4-dione(4.8 g, 23 mmole) in para-xylene (50 ml)containing (2,4-dimethoxyaniline)acetic acid (5.6 g, 25 mmol), Ki is atili under reflux (150° (C) within 3 hours After cooling to CT precipitate was separated by filtration and washed twice para-xylene (2×20 ml), yield 7.5 g (89%). m/z 373 (MH+).

Stage 3

2-Chloro-4-(2,4-dimethoxybenzyl)-7-methylsulfanyl-3,4-dihydrobenzo-[e][1,4]diazepin-5-he

4-(2,4-Dimethoxybenzyl)-7-methylsulfanyl-3,4-dihydro-1H-benzo[e][1,4]-diazepan-2,5-dione (630 mg, 1.7 mmole) and N,N-dimethyl-para-toluidine (489 μl, 3.4 mmole) were mixed in toluene (5 ml) and heated to 100°C. Then was added dropwise phosphorus oxychloride (170 μl, 1.9 mmole) and heated at 100°for a further 1 h the resulting solution dark red directly used in the next stage.

Stage 4

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-methylsulfanyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

Hexamethyldisilazane (1.2 ml, 5.6 mmole) was dissolved in THF (10 ml), cooled in an atmosphere of argon to -70°and was slowly treated with a 1.6 m solution of n-utility in hexane (3.5 ml, 5.6 mmole). After stirring at -70°C for 1 h, to the mixture was added a solution of (E/Z)-N'-(3-cyclopropyl[1,2,4]oxadiazol-5-ylmethyl)-N,N-dimethylformamidine (0.66 g, 3.3 mmole) in THF (30 ml) and was stirred at -70°C for 1 h and Then at -70°C was added a solution of 2-chloro-4-(2,4-dimethoxybenzyl)-7-methylsulfanyl-3,4-dihydrobenzo[e][1,4]diazepin-5-it (of 0.67 g, 1.7 mmole) (obtained as described above), were heated to 1° C for 1 h and again cooled to -30°C. After 30 min at -30°With added acetic acid (4 ml), the suspension was heated to CT, was added water (4 ml) and the resulting mixture was boiled under reflux for 6 hours After cooling, the mixture was evaporated, and the residue was dissolved in CH2Cl2(20 ml). The resulting solution was washed with 1 M HCl (2×30 ml) and saturated sodium hydrogen carbonate solution (30 ml), dried (Na2SO4) and was evaporated. The product was purified by chromatography on silica gel (eluent: EtOAc), the output of 0.29 g (34%). m/z 504 (MH+).

Stage 5

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxybenzyl)-8-methylsulfanyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (280 mg, 0.6 mmole) suspended in CH2Cl2(5 ml), cooled in ice and slowly diluted triperoxonane acid (1.3 ml). The resulting solution was treated with 5°triftormetilfullerenov acid (74 μl, 0.8 mmole). The red solution was stirred at RT for 1.5 h Then the mixture was evaporated, the residue was dissolved in CH2Cl2(10 ml), washed with a saturated solution of sodium bicarbonate (10 ml), the organic layer was dried (Na2SO4) and was evaporated. The product was obtained by rubbing with EtOAc, to yield 160 mg (81%). m/z 354 (MN+).

Stage 6 and 7

6-Bromo-3-(-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4H-2,5,10b-tratamento[e]azulene and [3-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4H-2,5,10b-tratamento[e]azulene-6-yl]hydrazine

3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (160 mg, 0.45 mmole) and N,N-dimethyl-para-toluidine (131 μl, 0.9 mmole) was mixed in toluene (5 ml)was treated with phosphorylation (143 mg, 0.5 mmole) and boiled under reflux for 5 hours After cooling, the mixture was evaporated and the residue was extracted with CH2Cl2(10 ml) and water (10 ml). The organic layer was separated, dried (Na2SO4) and was evaporated. The residue was re-dissolved in THF (10 ml)was treated with anhydrous solution of hydrazine (1 M in THF, 1.6 ml, 0.16 mmole) and the resulting mixture was boiled under reflux for 12 hours After cooling, the mixture was evaporated and the solid (m/z 368 (MH+used directly in the next stage.

Stage 8

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methylsulfanyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

A mixture of [3-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-methylsulfanyl-4H-2,5,10b-tratamento[e]azulene-6-yl]hydrazine (210 mg, 0.57 mmole) and triethylorthoformate (285 μl, 1.7 mmole) in ethanol (8 ml) was boiled under reflux for 3 hours After cooling, the mixture was evaporated. The product was purified by chromatography on silica gel (eluent: EtOAc), to yield 43 mg (20%). tPL164-166°C. m/z 377 (M).

Example 9

Ethyl ester N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid/p>

Synthesis indicated in the title compound, solid, light brown, tPL263-264°described in Heterocycles, so 39, №2 (1994).

Example 10

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

Synthesis indicated in the title compound, solid, light brown, tPL298-300°described in Heterocycles, t, No. 2 (1994).

Example 11

Ethyl ester of 3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

Synthesis indicated in the title compound, solid, light brown, tPL233-234°C, described in Heterocycles, t, No. 2 (1994).

Example 12

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

Synthesis indicated in the title compound, solid, light brown, tPL253-254°described in Heterocycles, t, No. 2 (1994).

Example 13

Ethyl ester of 3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

Synthesis indicated in the title compound, solid, light brown, tPL226-227 of the°C, described in Heterocycles, t, No. 2 (1994).

Example 14

3-Chloro-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

Synthesis indicated in the title compound, solid, light brown, t PL298-300°described in Heterocycles, t, No. 2 (1994).

Example 15

7-Chloromethyl-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in the same way as described in example 2 (stage 4), using 2-chloro-1,1,1-trimethoxymethane. Yield 53%. tPL220°C, m/z 409 (M).

Example 16

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methoxy-7-methyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in the same way as described in example 2 (stage 4), when using triethylorthoformate. Yield 48%. tPL222°C, m/z 376 (MH+).

Example 17

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-7-ethyl-3-methoxy-N-imidazo[1,5-a][1,2,4][triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in the same way as described in example 2 (stage 4), when using triethylorthoformate. Yield 47%. tPL240°C, m/z 390 (MH+).

Example 18

Ethyl ester of 3-methoxy-7-benzyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using phenylacetic acid hydrazide. Yield 92%. tPL198°C, m/z 415 (M).

Example 19

Ethyl ester of 3-methoxy-7-methyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in the ore 1 (stage 7), when using acetylhydrazide. Yield 98%. tPL210°C, m/z 339 (M).

Example 20

Ethyl ester of 3-methoxy-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide indole-3-acetic acid. Yield 92%. tPLl98°C, m/z 415 (M).

Example 21

Ethyl ester of 3-methoxy-7-[(dimethylamino)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrochloride dimethylaminoacetonitrile. Yield 38%. tPL189°C, m/z 383 (MH+).

Example 22

Ethyl ester of 7-(2-hydroxyethyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), using 3-hydroxypropionitrile, m/z 383 (MH+).

Example 23

Ethyl ester of 7-[(2R)-5-oxo-2-pyrrolidinyl]-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), using (S)-5-oxo-2-pyrrolidinecarboxylic. tPL160°C, m/z 408 (M).

Example 24

Ethyl ester of 7-(carbarnoyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]be zodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), using 2-hydrazino-2-oxoacetate. tPL256°C, m/z 368 (M).

Example 25

Ethyl ester of 7-hydroxymethyl-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide hydroxyoctanoic acid, tPL255°m/z 355 (M).

Example 26

Ethyl ester of 7-(3,4-dimethoxybenzyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using the hydrazide of 3,4-dimethoxyphenylacetic acid, tPL196°C, m/z 476 (MH+).

Example 27

Ethyl ester of 3-methoxy-7-(3-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using the hydrazide 3-methoxyphenylacetic acid. tPL209°C, m/z 446 (MN+).

Example 28

Ethyl ester of 3-chloro-7-benzyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using phenylacetic acid hydrazide, tPL188°C, m/z 420 (MH+).

Example 29

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide indole-3-acetic acid. tPL242°C, m/z 459 (MN+).

Example 30

Ethyl ester of 7-(carbarnoyl)-3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide examinados acid. tPL> 250°m/z 373 (MH+).

Example 31

Ethyl ester of 3-methoxy-7-[(3-methyl-1H-indol-2-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (2-methyl-1H-indol-3-yl)acetic acid. tPL220°C, m/z 203 (M).

Example 32

Ethyl ester of 3-methoxy-7-[(5-methyl-1H-indol-2-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (5-methyl-1H-indol-3-yl)acetic acid. tPL> 250°C, m/z 468 (M).

Example 33

Ethyl ester of 7-(2-Chlorobenzyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (2-chlorophenyl)acetic acid. tPL15° C, m/z 449 (M).

Example 34

Ethyl ester of 3-methoxy-7-(2-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (2-methoxyphenyl) acetic acid, tPL80°C, m/z 445 (M).

Example 35

Ethyl ester of 7-(diethylcarbamoyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), using N,N-diethyl-2-hydrazino-2-oxoacetate. tPL75°C, m/z 425 (MH+).

Example 36

Ethyl ester of 3-methoxy-7-(2-trifloromethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (2-triptoreline)acetic acid. tPL225°C, m/z 483 (M).

Example 37

Ethyl ester of 3-methoxy-7-[(7-methoxy-1H-indol-3-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (5-methoxy-1H-indol-3-yl)acetic acid. tPL> 250°C, m/z 485 (MH+).

Example 38

Ethyl ester of 7-[(3-benzo[1,3]dioxol-5-ylmethyl)-3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzo who azepin-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide benzo[1,3]dioxol-5-luxusni acid, m/z 463 (M).

Example 39

Ethyl ester of 3-methoxy-7-(4-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (4-methoxyphenyl)acetic acid. tPL179°C, m/z 445 (M).

Example 40

Ethyl ester of 3-methoxy-7-(3-trifloromethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (3-triptoreline)acetic acid. tPL89°C, m/z 483 (M).

Example 41

Ethyl ester of 3-chloro-7-(4-trifloromethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (4-triptoreline)acetic acid. tPL217°C, m/z 487 (M).

Example 42

Ethyl ester of 3-chloro-7-(4-dimethylaminobenzoyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (4-dimethylaminophenyl)acetic acid. tPL206° C, m/z 463 (MH+).

Example 43

Ethyl ester of 3-chloro-7-(2,4-dimethoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (2,4-acid)acetic acid. tPL160°C, m/z 479 (M).

Example 44

Ethyl ester of 3-chloro-7-(4-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), when using hydrazide (4-methoxyphenyl)acetic acid, m/z 499 (M).

Example 45

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-7-benzyl-3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d[1,4]benzodiazepine

The product was obtained in the same way as described in example 7 (stage 5), when using phenylacetic acid hydrazide. tPL233-235°C, m/z 500/502 (M).

Example 46

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-7-(1H-indol-3-ylmethyl)-3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in the same way as described in example 7 (stage 5), when using hydrazide indole-3-acetic acid. tPL265°C (decomp.), m/z 539/541 (M).

Example 47

Ethyl ester of 3-bromo-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in the example 4 (method B), when using hydrazide indole-3-acetic acid. tPL258°C (decomp.), m/z 503/505 (M).

Example 48

Ethyl ester of 3-bromo-7-benzyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 4 (method B), using hydrazide indole-3-acetic acid. tPL190-192°C (decomp.), m/z 464/466 (M).

Example 49

Ethyl ester of 7-(benzo[1,3]dioxol-5-yl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), and using 3,4-methylenedioxybenzene. tPL247°C, m/z 446 (MN+).

Example 50

Ethyl ester of 3-bromo-7-(3-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 4 (method B), using the hydrazide 3-methoxyphenylacetic acid. tPL111-113°C, m/z 494/496 (M).

Example 51

Ethyl ester of 3-bromo-7-(3,4-dimethoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 4 (method B), using the hydrazide of 3,4-dimethoxyphenylacetic acid, tPL224-226°C, m/z 524/526 (M).

Example 52

Ethyl ester of 7-[(2-benzo[1,3]dioxol-5-yl)ethyl]-3-chloro-N and is idazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 4 (method B), using the hydrazide 3-(3,4-methylenedioxyphenyl)propio new acid. tPL208°With m/z of 476.9 (M).

Example 53

Ethyl ester of 7-(4-methanesulfonylaminoethyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product in the form of a white foam was obtained similarly as described in example 4 (method B), using hydrazide 4-methanesulfonyl-acetic acid, m/z 494 (MH ).

Example 54

Ethyl ester of 3-methoxy-7-[(biphenyl-4-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product in the form of a white foam was obtained similarly as described in example 4 (method B), using hydrazide 4-biphenylacetic acid, m/z 492 (MH+).

Example 55

Ethyl ester of 7-(4-dimethylaminobenzoyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 4 (method B), using hydrazide 4-dimethylaminobenzylidene acid. tPL210°C, m/z 459 (MN+).

Example 56

Ethyl ester of 3-methoxy-7-(4-cryptomaterial)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 4 (method B), when used and hydrazide 4-triftormetilfullerenov acid. tPL225°m/z 500 (MH+).

Example 57

Ethyl ester of 3-chloro-7-(4-nitrobenzyl)-N-imidazo[1,5-a][1,2,4]triazolo-[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product in the form of a white foam was obtained similarly as described in example 4 (method B), using hydrazide 4-nitrophenylarsonic acid, m/z 462 (M).

Example 58

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-7-(4-dimethylaminobenzoyl)-3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in the same way as described in example 7 (stage 5), when using hydrazide 4-dimethylaminobenzylidene acid. tPL140°C (decomp.), m/z 543/545 (M).

Example 59

Ethyl ester of 3-bromo-7-(4-dimethylaminobenzoyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 4 (method B), using hydrazide 4-dimethylaminobenzylidene acid, tPL240°C (decomp.), m/z 507/509 (M).

Example 60

3-Chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

Stage 1

Amide 8-chloro-5-(2,4-dimethoxybenzyl)-6-oxo-5,6-dihydro-4H-2.5.10b-tratamento[e]azulene-3-carboxylic acid

Ethyl ester of 3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid (example 13) (7,1 g, 15.7 mmole) suspended in dioxane (60 ml) and added formamid (2.8 ml, 71.3 mmole). Then slowly added 5.4 M solution of sodium methylate in methanol (2.9 ml of 15.5 mmole) and the mixture was stirred at RT over night. The resulting white suspension was diluted with water (70 ml) and stirred at RT for 1 h, the Dioxane was removed under reduced pressure, the suspension was stirred for 1 h in ice, the resulting crystals were separated by filtration, washed with water and dried at 60 C/0.1 mbar, the product was obtained as white crystals (6 g, 89%). tPL>220°C, m/z 427 (MN+).

Stage 2

8-Chloro-5-(2,4-dimethoxybenzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carbonitril

Amide 8-chloro-5-(2,4-dimethoxybenzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid (5.9 g, of 13.8 mmole) and phosphorus oxychloride (1.4 ml, 15.2 mmole) were mixed in dioxane (55 ml) and boiled under reflux during the night. The resulting yellow solution was evaporated, the residue was purified by chromatography on silica gel (eluent: CH2Cl2/acetone 20:1), the product was obtained as white foam (3.5 g, 61%). m/z 408 (MH+).

Stage 3

8-Chloro-5-(2,4-dimethoxybenzyl)-N-hydroxy-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxamide

8-Chloro-5-(2,4-dimethoxybenzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carbonitrile (2 g, 4.9 mmole) and hydroxylamine hydrochloride (1 g, of 14.6 mmole) suspended in DMF (10 ml) and m is Glenna was treated with 5.4 M solution of sodium methylate in methanol (2.7 ml, of 14.6 mmole). The yellow suspension was stirred overnight, then cooled with ice, diluted with water (20 ml) and stirred under ice cooling for 1 h, the precipitate was separated by filtration and washed with cold water (5 ml), the product was obtained as white crystals (1.9 g, 89%). m/z 442 (MH+).

Stage 4

8-Chloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-5-(2,4-dimethoxybenzyl)-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

8-Chloro-5-(2,4-dimethoxybenzyl)-N-hydroxy-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxamide (1.9 g, 4.3 mmole), magnesium oxide (0.156 g, 3.9 mmole) and cyclopropanecarbonitrile (0.5 ml, 5.3 mmole) in dioxane was heated under reflux overnight. The dioxane was evaporated, the residue was dissolved in DMF (20 ml) and boiled under reflux for 1 h DMF was evaporated, the residue was extracted with CH2Cl2and water. Extract the organic solvent was concentrated and added ethyl acetate, the product crystallized in the form of a solid white color (0.8 g, 39%). tPL198-205°C, m/z 492 (MH+).

Stage 5

8-Chloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he

8-Chloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-5-(2,4-dimethoxybenzyl)-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (2 g, 4 mmole) was dissolved in CH2Cl2(8 ml) and triperoxonane acid (8 ml), ohlord is whether ice, slowly processed triftormetilfullerenov acid (0.7 ml, 8 mmol) and was stirred without cooling for 2 hours the Solvent was evaporated, the residue was extracted with CH2Cl2and water. The product was obtained from the extract of the organic solvent in the form of a white foam (0.84 g, 62%). m/z 342 (MH+).

Stage 6

6,8-Dichloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-tratamento[e]azulene

8-Chloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-tratamento[e]azulene-6-he (0.84 g, 2.5 mmole) suspended in chlorobenzene (8 ml)was added N,N-dimethyl-para-toluidine (1.1 ml, 7.4 mmole) and phosphorus oxychloride (0,34 ml, 3.7 mmole) and the mixture is boiled under reflux during the night. The resulting solution was evaporated, the residue was purified by chromatography on silica gel (eluent: CH2Cl2/acetone, 10:1). The product was obtained in a solid white color (0.56 g, 63%). tPL200°C, m/z 359 (M).

Stage 7

3-Chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepin

6,8-Dichloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-4H-2,5,10b-tratamento[e]azulene (70 mg, 0,194 mmole), formylhydrazine (23 mg, of 0.39 mmole) and N-ethyldiethanolamine (of 0.066 ml to 0.39 mmole) was mixed in chlorobenzene and the mixture is boiled under reflux for 3.5 hours, the Solvent was evaporated, the residue was extracted with CH2Cl2water and is imali chromatography on silica gel (eluent: CH 2Cl2/2-propanol, 20:1). The product was obtained in a solid white color (36 mg, 50%). tPL>230°C, m/z 365 (M).

Example 61

3-Chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained as white foam, m/z 499 (MN+)similar to that described in example 60, using hydrazide indole-3-acetic acid.

Example 62

3-Chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-(4-dimethylaminobenzoyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-(1][1,4]benzodiazepine

The product was obtained in a solid white color, m/z 495 (MN+)similar to that described in example 60, using hydrazide (4-dimethylaminophenyl)acetic acid.

Example 63

7-Benzyl-3-chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in a solid white color, m/z 456 (MH+)similar to that described in example 60, using phenylacetic acid hydrazide.

Example 64

3-Chloro-7-cyclopropylmethyl-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in a solid white color, m/z 420 (M), in the same way as described in example 60, using hydrazide cyclopropylacetic acid.

Use the 64

3-Chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-(3,4-dimethoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained as a colourless resin, m/z 515 (M), in the same way as described in example 60, using the hydrazide of 3,4-dimethoxyphenylacetic acid.

Example 65

3-Chloro-10-(5-cyclo propyl-1,2,4-oxadiazol-3-yl)-7-(5-methyl-lH-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained in the form of a solid brown, m/z 509 (M), in the same way as described in example 60, using hydrazide (5-methyl-1H-indol-3-yl)acetic acid.

Example 66

3-Chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-(3-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine

The product was obtained as white foam, m/z 485 (M), in the same way as described in example 60, using the hydrazide 3-methoxyphenylacetic acid.

Example 67

Ethyl ester of 3-hydroxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]-benzodiazepine-10-carboxylic acid

Stage 1

6-Hydroxy-1H-benzo[d][1,3]oxazin-2,4-dione

5-Hydroxyanthranilic acid (9.5 g, 62 mmole) suspended in dioxane (50 ml)was added bis(trichloromethyl)carbonate (6 g, 20 mmol) (discounttires reaction) and the resulting suspension was heated under reflux for 1 h Then the mixture was cooled to CT, solid substances which has been separated by filtration and washed with dioxane, the product was obtained as a crystalline substance brown (10.1 g, 90%). tPL236°C (decomp.).

Stage 2

6-(tert-Butyldiphenylsilyl)-1H-benzo[d][1,3]oxazin-2,4-dione

6-Hydroxy-1H-benzo[d][1,3]oxazin-2,4-dione (9.7 g, 54 mmole), tert-butyldiphenylchlorosilane (15.2 ml, 59 mmol) and imidazole (4 g, 59 mmol) was stirred in DMF (100 ml) at RT for 24 h Then the reaction mixture was extracted with ethyl acetate (400 ml) and water (300 ml). The product obtained from a solution in an organic solvent, was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 2:1), and then was led from hot ethyl acetate/hexane, the product was obtained as white crystals (13 g, 58%) tPL185°C.

Stage 3

7-(tert-Butyldiphenylsilyl)-4-(2,4-dimethoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

The product was obtained in the same way as described in example 1 (stage 2), the crude product was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 1:1), the product was obtained in the form of a white foam, yield 80%, 580 (M).

Stage 4

Ethyl ester of 8-(tert-butyldiphenylsilyl)-5-(2,4-dimethoxy-benzyl)-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 3 and 4), the crude product was purified by chromatography on silica gel (eluent: Huck is an/ethyl acetate, 1:2), the product was obtained as yellow foam, yield 54%, 675 (M).

Stage 5

Ethyl ester of 8-(tert-butyldiphenylsilyl)-6-oxo-5,6-dihydro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 5), but the reaction was conducted for 1 h, the crude product was purified by chromatography on silica gel (eluent: dichloromethane/2-propanol, 30:1), the product was obtained in the form of a white foam, yield 65%. 526 (MN+).

Stage 6

Ethyl ester of 8-(tert-butyldiphenylsilyl)-6-chloro-4H-2,5,10b-tratamento[e]azulene-3-carboxylic acid

The product was obtained in the same way as described in example 1 (step 6), the crude product was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 1:1), the product was obtained in the form of a white foam, yield 10%. 543 (M).

Stage 7

Ethyl ester of 3-(tert-butyldiphenylsilyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the same way as described in example 1 (stage 7), the crude product was purified by chromatography on silica gel in ethyl acetate, the product was obtained as white crystals, yield 46%. tPL233°C.

Stage 8

Ethyl ester of 3-hydroxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]-benzodiazepine-10-carboxylic acid

Ethyl ester of 3-(tert-butyldiphenylsilyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid (155 mg, of 0.28 mmole) was stirred in 1 M solution of tetrabutylammonium fluoride (1 ml) for 30 minutes the Mixture was extracted with dichloromethane and water. After purification by chromatography on silica gel (eluent: DHM/Meon, 40:3), the product was obtained as white crystals (55 mg, 62%). tPL>250°C, 310 (M-N)-.

Example 69

Ethyl ester of 3-chloro-7-(pyridine-4-ylmethyl)-N-imidazo[1,5-a][1,2,4]-triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

The product was obtained in the form of a solid light brown color, tPL213°C, m/z 421 (MH ), in the same way as described in example 4 (method B), using hydrazide dihydrochloride 4-peridiocally acid.

References

1. Hunkeler W., Kyburz E, EP 150040

2. Rogers-Evans, M., Spurr-P., EP 787729

3. Zhang P., Zhang W., Liu R., Harris C., Skolnik P., Cook, J.M., J. Med. Chem., 38,1679-1688 (1995).

4. Gerecke, M., E. Kyburz, R. Borer, W. Gassner, Heterocycles, 39, 693-721 (1994).

Example

Tablets of the following composition was obtained in the usual way:

mg tablet
The active ingredient5
Lactose45
Corn starch15
Microcrystalline cellulose34
Magnesium stearate1
Mac is and tablets 100

Example B

Capsules were obtained of the following composition:

mg capsule
The active ingredient10
Lactose155
Corn starch30
Talc5
Weight of filler capsules200

The active ingredient, lactose and corn starch were first mixed in a mixer and then in a device for grinding. The mixture was transferred to a stirrer, was added to the powder and thoroughly mixed. Then the mixture was placed in a hard gelatin capsule.

The example In

Suppositories received the following composition:

mg suppositories
The active ingredient15
The weight of the suppository1285
The total mass1300

The weight of the suppository was melted in a glass or steel vessel, thoroughly mixed and cooled to 45°C. Then was added finely ground active substance and stirred until full dispersion. The mixture was placed in a mold for suppositories required size, cooled, suppositories is animali of the mold and each suppository is individually Packed in waxed paper or foil.

1. Derivative of benzodiazepine General formula (I)

where R1means hydrogen, halogen, C1-C7alkyl, C1-C7alkoxy, hydroxy or1-C7alkylthio,

R2means-C(O)O-(C1-C7)alkyl, 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl, cyclic fragments are replaced With3-C7cycloalkyl,

R3means hydrogen, C1-C7alkyl, -(CH2)n-(C3-C7)cycloalkyl, -(CH2)n-halogen, -(CH2)n-pyridin-4-yl or -(CH2)n-phenyl, and the phenyl ring may be substituted by one or two substituents selected from the group comprising From1-C7alkoxy, halogen, -SO2CH3, phenyl, OCF3, nitro, CF3, -NR2or means -(CH2)n-indolyl, optionally substituted C1-C7the alkyl or C1-C7alkoxy, or means pyrrolidinyl-5-oxo, -C(O)-NR2, -(CH2)n-OH, -(CH2)n-NR2or -(CH2)n-benzo[1,3]dioxol,

R means hydrogen or C1-C7alkyl, and

n is 0, 1, 2 or 3,

and its pharmaceutically acceptable acid salt additive, except for the following connections:

ethyl ester N-imidazo[1,5-a][1,2,triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

ethyl ester of 3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

ethyl ester of 3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

3-chloro-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine and

ethyl ester of 3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid.

2. The compound of General formula I according to claim 1

where R1means hydrogen, halogen, C1-C7alkyl, C1-C7alkoxy or1-C7alkylthio,

R2means-C(O)O-(C1-C7)alkyl, 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl, cyclic fragments are replaced With3-C7cycloalkyl,

R3means hydrogen, C1-C7alkyl, -(CH2)n-halogen, -(CH2)n-phenyl, and the phenyl ring may be substituted by one or two substituents selected from the group comprising From1-C7alkoxy, halogen, CF3, -NR2or means -(CH2)n-indolyl, neobythites is but replaced With 1-C7the alkyl or C1-C7alkoxy, or means pyrrolidinyl-5-oxo, -C(O)-NR2, -(CH2)n-OH, -(CH2)n-NR2or benzo[1,3]dioxol,

R means hydrogen or C1-C7alkyl, and

n is 0, 1, 2 or 3,

and its pharmaceutically acceptable acid salt additive, except for the following connections:

ethyl ester N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

ethyl ester of 3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

ethyl ester of 3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

3-chloro-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine and

ethyl ester of 3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid.

3. The compound of formula I according to claim 1, where R2means-C(O)O-(C1-C7)alkyl.

4. The compound of formula I according to claim 3, where R3means hydrogen, a R1means hydrogen, methoxy, methyl, -SCH3or halogen.

5. The compound of formula I according to claim 4, which oznacza the t

ethyl ester of 3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid.

6. The compound of formula I according to claim 3, where R3means-CH2HE, -(CH2)2-methylenedioxyphenyl, methyl, -CH2-indolyl, optionally substituted by a methoxy group, or means-CH2is phenyl, substituted by a group of series-SO2CH3, phenyl, -OCF3, -N(CH3)2, NO2or methoxy, and R1means methoxy, chlorine or bromine.

7. The compound of formula I according to claim 6, which means

ethyl ester of 3-methoxy-7-methyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-hydroxymethyl-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-(3-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-[(7-methoxy-1H-indol-3-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid

ethyl ester of 3-bromo-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-carboneau acid,

ethyl ester of 3-bromo-7-(3-methoxybenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-[2-benzo[1,3]dioxol-5-yl)ethyl]-3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-(4-methanesulfonylaminoethyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-[(biphenyl-4-yl)methyl]-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-methoxy-7-(4-cryptomaterial)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-chloro-7-(4-nitrobenzyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 7-(4-dimethylaminobenzoyl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid, or

ethyl ester of 3-bromo-7-(4-dimethylaminobenzoyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid.

8. The compound of formula I according to claim 1, where R2means group 3-cyclopropyl-[1,2,4]oxadiazol-5-yl.

9. The compound of formula I of claim 8, where R3means hydrogen, and R1means hydrogen, methoxy, methyl, -SCH3or halogen.

10. The compound of formula I according to claim 9, which means

10-(3-cyclopropyl-1,2,4-oxadiazol the-5-yl)-3-methoxy-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-methylsulfanyl-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

3-chloro-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine or

3-chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine.

11. The compound of formula I of claim 8, where R3means-CH2-indolyl or-CH2is phenyl, optionally substituted-N(CH3)2and R1means chlorine or bromine.

12. The compound of formula I according to claim 11, which means

10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-7-(4-dimethylaminobenzoyl)-3-bromo-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,

3-chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-7-(1H-indol-3-ylmethyl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine or

7-benzyl-3-chloro-10-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine.

13. Pharmaceutical to the position, having the ability to selectively contact α5 subunit And receptor gamma-aminobutyric acid containing one or more compounds of formula I on PP. 1-12 or a compound selected from the group including

ethyl ester N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-fluoro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid,

ethyl ester of 3-chloro-N-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid and

ethyl ester of 3-methyl-N-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylic acid,

and pharmaceutically acceptable excipients.



 

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EFFECT: valuable properties of compound.

1 ex

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20 cl, 5 tbl, 149 ex

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
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7 cl, 3 tbl, 30 ex

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1 ex, 1 tbl

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12 cl, 3 tbl, 5 ex

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 104 ex

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