Imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine derivatives as modulators of gaba a receptor

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine of the formula (I): , wherein R1 means halogen atom or (lower)alkyl; R2 means hydrogen atom, (lower)alkyl, (C3-C7)-cycloalkyl, -(CH2)m-phenyl wherein phenyl ring can be substituted with (lower)alkoxy-group or it means -(CH2)m-indolyl; R3 means -C(O)O-(lower)alkyl, -C(O)OH or five-membered heteroaromatic group comprising nitrogen and oxygen atoms as heteroatoms and wherein rings can be substituted with (lower)alkyl or (C3-C7)-cycloalkyl; n means 0, 1 or 2; m means 0, 1 or 2, and their pharmaceutically acceptable acid-additive salts. Compounds of this class elicit the high degree and selectivity to binding sites of GABA A α5-receptor and can be used in treatment of the conception enhancer or disorders of cognitive ability similar with Alzheimer's disease.

EFFECT: valuable medicinal properties of derivatives.

10 cl, 6 sch, 41 ex

 

The present invention relates to substituted derivative of imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine the following formula

in which R1denotes a halogen atom or a lower alkyl, respectively (ness.)alkyl;

R2denotes a hydrogen atom, (ness.)alkyl, cycloalkyl, -(CH2)m-phenyl, in which phenyl ring may be substituted (ness.)alkoxy, or represents -(CH2)m-indolyl;

R3denotes-C(O)O-(ness.)alkyl, -C(O)HE or five-membered heteroaromatic group, ring which may be substituted (ness.)the alkyl or cycloalkyl;

n denotes 0, 1 or 2;

m denotes 0, 1 or 2,

and their pharmaceutically acceptable acid additive salts.

It was found that compounds of this class show a high affinity and selectivity for binding site α5 GABA receptor and can be used for the treatment of cognition enhancer or disorders of cognitive ability that is similar to Alzheimer's disease.

Receptors for the main inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA receptors And that are members of the superfamily that controls ion channels undergo ligand, and (2) the GABA receptors, which are members of the family of receptors linked to the s and G-protein. The GABA receptor complex And, representing the membrane-associated heteropentameric protein polymer consists mainly of α-, β- and γ-subunits.

Recently been cloned and sequenced all 21 subunit of the GABA receptor A. For constructing recombinant GABA receptors And that best meet the biochemical, electrophysiological and pharmacological functions of native GABA receptors And obtained from the brain cells of mammals, requires subunit of the three types (α, β and γ). This is clear evidence that the binding site of the benzodiazepine is between αand γ-subunits. Among the recombinant GABA receptors And design α1β2γ2 Minitrue many of the effects of subtypes of classical type-I BzR, while ion channels α2β2γ2, α3β2γ2 and α5β2γ2 is defined as type-II BzR.

McNamara and Skelton in Psychobiology, 21:101-108, showed that an inverse agonist β-SMS benzodiazepine receptor enhances spatial orientation waterways Morris. However, β-SMS and other normal inverse agonists of the benzodiazepine receptor are proconvulsant or convulsant that prevents their use as substances that enhance cognitive abilities. In addition, these compounds are not electively against the subunits of the GABA receptor And, while partially or completely inverse agonists α5 GABA receptor And that almost do not show activity against the binding sites α1 and/or α2, and/or α3 GABA receptor And can be used for the preparation of a medicinal product which may be beneficial for improving cognitive sposobnostey, with low or beskonkursnoy activity. You can also use inverse agonists α5 GABA And who show some activity against the binding sites α1 and/or α2, and/or α3 GABA receptor but which are functionally selective for subunits containing α5. However, the preferred inverse agonists that are selective for subunits α5 GABA and almost show no activity for binding sites α1, α2 and α3 GABA receptor A.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, obtaining the above-mentioned compounds containing medicines and their preparation, as well as the application of the above compounds in the treatment or prophylaxis of diseases, in particular diseases and disorders of the above type, or in the preparation of the drugs.

The most preferred indications in accordance with the present invention are what I disorder cognitive abilities, similar to Alzheimer's disease.

In the present description used General concepts, in respect of which, regardless of whether there considering the notion alone or in combination, the following definitions apply :

Used in the present description the term "(ness.)alkyl" means remotemachine or branched alkyl group containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or the like,

Preferred (ness.)alkyl groups are groups containing from 1 to 4 carbon atoms.

The term "(ness.)alkoxy" means a group in which the alkyl residue has the values indicated above and which is attached via an oxygen atom.

The term "halogen atom" denotes an atom of chlorine, iodine, fluorine or bromine.

The concept of "cycloalkyl" denotes a cyclic alkyl ring containing from 3 to 7 carbon ring atoms, such as cyclopropyl, cyclopentyl or cyclohexyl.

The term "five-membered heteroaromatic group" refers to, for example, 1,2,4-oxadiazolyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, isothiazolin, isoxazolyl, etc. are Preferred 1,2,4-oxadiazolidine and isoxazolidine group.

The term "pharmaceutically acceptable acid additive salts" embraces salts Neorganicheskie and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid, etc.

Preferred examples are compounds that have activity binding (Kibelow 15 nm and selective to the sub α5 GABA and almost show no activity for the binding sites of the receptor α1, α2 and α3 GABA A.

Preferred compounds of formula I are those in which R3denotes the group-C(O)O-(ness.)alkyl. Preferred examples are compounds of this series, in which R1denotes a hydrogen atom, and R2has the above values, for example the following compounds:

ethyl ester 9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid and

ethyl ester 6-methyl-9H-imidazo[1,5-is]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid.

Other preferred compounds of formula I are those in which R3denotes the group-C(O)O-(ness.)alkyl, R2has the above significance, and R1denotes a halogen atom, for example, the following connections:

ethyl ester of 3-fluoro-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 3-fluoro-6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 3-fluoro-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid, ethyl ester 6-cyclopropyl-3-fluoro-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid and

ethyl ester of 3-bromo-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d] [1]benzazepine-10-carboxylic acid.

Other preferred compounds of formula I are those in which R3refers to a group of 1,2,4-oxadiazolyl or isoxazolyl, R2means (ness.)alkyl, n denotes 0 or 1, and R1denotes a halogen atom, for example, the following connections:

10-(3-cyclopropyl - 1,2,4-oxadiazol-5-yl)-6-methyl-9H-imidazo[1,5-a]pyrimido[5.4-d][1]benzazepine and 2-bromo-11-methyl-7-(5-methylisoxazol-3-yl)-8H-4b,6,10,12-tetraethylene[e,g]azulene.

The proposed compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods in the art are known, for example, by the means described the who:

a) reaction of compounds of formula

with phosphorus oxychloride to obtain the compounds of formula

in which the substituents R1and R2and n have the meanings mentioned above,

and the reaction of this compound with

obtaining the compounds of formula

and cyclization of this compound with Meso2N obtaining the compounds of formula

in which R1-R3and n have the meanings stated above, or

b) reaction of compounds of formula

in which the substituents R1and R2and n have the meanings indicated in claim 1 of the claims, with

obtaining the compounds of formula I, or

C) modifying one or more substituents R1-R3within the definitions given above and, if necessary, conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

The salt formation is carried out at room temperature in accordance with methods which are known and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acid is Tami. Examples of such salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleate, succinate, methanesulfonate, p-toluensulfonate etc.

Method of producing compounds of the formula I and/or their intermediate products is presented in more detail in the following schemes 1, 1a, 2, 3, 4, 5 and 6. Starting materials of the formulae IV, VI, XVI, XX and XXIV are known compounds or can be obtained in accordance with methods known in the art.

Scheme 1

Deputies described in scheme 1 above.

Scheme 1A

Obtaining compounds of formula I in accordance with the stage 7 in figure 1

The substituents shown in scheme 1A, described above.

Oxychloride of phosphorus can be replaced by the following equivalent connections:

in accordance with the following links:

J.Heterocycl. Chem., 1978, 15, 577-58

J.Org. Chem., 1976, 41, 2724-2727

J.Org. Chem., 1976, 41, 2720-2724 or

Synthesis, 1987, 162.

In accordance with schemes 1 and 1a, the compound of the formula I can be obtained in the following way. On the basis of the appropriately substituted Anthranilic acid (VI), under standard conditions get ether (VII). The processing of this product is the appropriate base and ethylsuccinate receive the product (VIII), and the use of which was followed by the intramolecular cyclization reaction of Dickman with getting beta keeeping products (IX). These last carbalicious in acidic or basic conditions to receive appropriately substituted benzazepines (X). In the processing of these products dimethylphosphoramidocyanidate formed enaminone products (XI), which then in turn 5,7-dihydro-6N-pyrimido[5,4-d][1]benzazepin-6-ones (II) processing appropriately substituted amidine (sometimes in the form of salts) in the presence of sodium methoxide. Next, the obtained compound was dissolved in phosphorus oxychloride and the solution is heated, and then vypaivajut further solution of this product is injected into a cold solution of either 1) ethylisothiocyanate and tert-butoxide potassium, or 2) diisopropylamide lithium and ether (E)-(dimethylaminomethylene)acetic acid and implement additional step cyclization with the addition of acetic acid followed by heating. The final products of formula I is purified in the usual way.

Scheme 2

An alternative method to obtain intermediates of formula VII

This method is also described in J.Heterocycl. Chem., 1965, 2, 459.

Scheme 3

The substituents shown in scheme 3, above.

The mixture α-tetralone of formula XVI, hydroxylamine, sodium acetate and water/ethanol is treated with boiling reverse x is Hladilnika for about 20 min and then cooled to 0° Poluchenii product is introduced into a solution of polyphosphoric acid at about 120°and heat up. Next lactam is dissolved in BuOH and water, and then add the potassium permanganate, after which the uranyl nitrate magnesium. This reaction is carried out at room temperature for approximately 48 hours After this implementation stages 5, 6 and 7 in scheme 1 to obtain the compound of formula 1A.

Scheme 4

The substituents shown in scheme 4 described above. These intermediates are described in more detail in the working examples.

Scheme 5

In accordance with scheme 5 get the connection formula IVb, which is used to produce compounds of the formula I, in which R3means isoxazoline group. This reaction is presented in scheme 6.

In accordance with scheme 5 described in more detail following the reaction stage.

Stage 1: ethyl ester of 5-methylisoxazol-3-carboxylic acid

To a solution of ethyl-2,4-dioxooleana in ethanol injected gidroxinimesoulid and sodium bicarbonate. Next, the reaction mixture was refluxed for 1 h After cooling, the mixture is evaporated, leaving a clear liquid, which distil with obtaining specified in the title compound.

Stage 2: (5-methylisoxazol-3-yl)who ethanol

In the solution of the ethyl ester of 5-methylisoxazol-3-carboxylic acid in ethanol at 0°in an argon atmosphere for 30 min portions add NaBH4. The reaction mixture is allowed to warm to CT. After 3 h the reaction mixture was diluted with HCl, and then, after cooling to room temperature, the mixture was washed with diethyl ether, the combined extracts dried and evaporated.

Stage 3: 3-methyl bromide-5-methylisoxazol

In the solution PBr3and pyridine in toluene at -10°injected With a solution of hydroxymethyl-3-methyl-5-isoxazol in pyridine. Next, the reaction mixture is stirred at -10°C for 1 h and stirred for approximately 14 h at RT. Then the reaction mixture was diluted with water and extracted with diethyl ether. After that, the combined extracts dried and evaporated. The residue is purified by chromatography.

Stage 4: 3-azidomethyl-5-methylisoxazol

To a solution of 3-methyl bromide-5-methylisoxazole in acetone at RT enter NaN3. Next, the reaction mixture is stirred for about 48 hours Then the reaction mixture was poured into water and extracted with EtOAc, dried and evaporated.

Stage 5: (5-methylisoxazol-3-yl)methylamine

To a solution of 3-azidomethyl-5-methylisoxazole in isopropanol at RT with intensive stirring enter triethylamine, 1,3-propanedithiol and natrojarosite. Next, the mixture is stirred at RT. By prosect and approximately 19 h add another 0.5 EQ. NaBH4and when CT is stirred for another 7 hours thereafter under vacuum, the solvent is evaporated and then the residue is dissolved in 10%aqueous citric acid and washed. The aqueous layer was alkalinized water NaOH to pH 12, saturated with NaCl and extracted with DHM. United DHM extracts are dried and concentrated.

Stage 6: N,N-dimethyl-N'-(5-methylisoxazol-3-ylmethyl)formamide

A solution of (5-methylisoxazol-3-yl)methylamine in N,N-dimethylformamidine maintained at the boiling point under reflux for 3 hours After cooling to room temperature the solvent is evaporated, leaving the compound of formula IVa.

Then the compound of formula IVa can be attached to the compound of formula III in accordance with schemes 1A and 6.

Scheme 6

R1, R2and n described above.

As mentioned above, the compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. It was found that the compounds of the present invention are ligands for GABA receptors containing subunits α5 and, therefore, effective in the treatment when it is necessary to improve cognitive ability.

Compounds investigated in accordance with the method described in the present description below.

Preparation of membranes and is ity binding

The affinity of compounds to the subunits of the GABA receptor And was determined by competition binding of [3N]flumazenil ([3H]Ro 15-1788) (85 Ci/mmol; firm Amersham) with SF9 cells expressing the receptor composition α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2 in rats.

Sediment cells suspended in Tris-buffered Krebs (4.8 mm KCl, 1.2 mm CaCl2, 1.2 mm MgCl2, 120 mm NaCl, 15 mm Tris buffer to experience binding pH 7.5), using Polytron homogenized for about 15 s on ice and centrifuged at 4°C for 30 min in a centrifuge UZ (100000 g, the rotor TFT 4594, the rotation speed of 300,000 rpm). Sediment cells again suspended in Tris-buffered Krebs and using Polytron homogenized on ice for about 15 C. Prepared aliquots of 1 ml were determined protein (Bradford method) and the resulting aliquots of membranes were stored at -70°C.

Experiments on the binding of radioligand performed in a volume of 200 ál (96-well plates)which contained 100 μl of cells, [3H]Ro 15-1788 in a concentration of 1 nm for α1, α2, α3 subunits and 0.5 nm for α5 subunits and the test compound in the range from 10-10up to 3×10-6M using 10-5M diazepam was determined nonspecific binding, which usually amounted to less than 5% of the total binding. Samples were incubated at 4°there are over 1 h to achieve equilibrium and cells were harvested monofilter GF/C (Packard company) by filtration using a Packard harvester and washing with ice buffer for washing (50 mm Tris, pH 7.5). After drying with acquired scintillation counter was determined preserved on filter radioactivity. The value of Kiwas calculated using Excel-Fit (firm Micposoft) and found the average of the two definitions.

According to the method described above, the tested compounds are presented in the examples, and have established that the value of Kiupon substitution of [3H]Ro 15-1788 from α5 subunit of the GABA receptor And rats for all connections is 100 nm or less. In a preferred embodiment, compounds according to the invention associated with α5 subunit selectivity than with α1, α2 subunits. For α5 subunit affinity less than 15 nm.

For particularly preferred compounds have received the following specific data.

Example No.Ki(nm)
13.7
25.5
38.9
47.6
613.8
84.6
98.0
1011.2
117.8
2212.5
293.8

The compounds of formula I and their pharmaceutically PR is acceptable acid additive salts can be used as medicines, for example, in the form of pharmaceutical preparations. Such pharmaceutical preparations can be introduced into the body orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

The compounds of formula I and their pharmaceutically acceptable acid salt additive can be combined with pharmaceutically inert inorganic or organic excipients for the manufacture of tablets, coated tablets, dragées and hard gelatin capsules. As such fillers can be used lactose, corn starch or its derivatives, talc, stearic acid and its salts, etc., for example for the manufacture of tablets, coated tablets and hard gelatin capsules. Acceptable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc

Acceptable excipients for preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

Acceptable preparation of solutions for injection fillers are, for example, water, alcohols, polyols, glycerol, rastitel the e oils etc.

Acceptable for the manufacture of suppositories fillers are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols etc

Moreover, the pharmaceutical preparations can include preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. However, they can also contain other has a therapeutic effect of the substance.

The dose can be varied within wide intervals, and in each case it is, of course, must fit individual needs. Usually in the case of oral administration the appropriate daily dose for the patient can be from about 10 to 1000 mg of the compounds of General formula I, although, when necessary, can also exceed the upper limit.

The present invention is illustrated, without limiting its scope, the following examples. The temperature in all cases specified in degrees Celsius.

Example 1

Ethyl ester N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) Ethyl ester of 2-aminobenzoic acid (atlanta.net), the compound of formula VII

Obtained in accordance with scheme 1, step 1, according to the literature Bamberger, Goldberger, J.Liebigs Ann. Chem., 1899, 362, 305).

Ethanol (500 ml) was cooled in ice and saturated with gaseous HCl. Then added 2-aminobenzoic acid (50 g) and the resulting mixture was boiled under reflux for 13 hours Then the hot solution was poured into 1.5 l of a mixture of water with ice, and then the solution was filtered and neutralized with sodium bicarbonate. After this, the solution evaporated, and then was extracted with diethyl ether (3 portions of 200 ml) and the combined extracts were dried and evaporated to a liquid residue, which was distilled to obtain the product (49 g, 82%yield) as a clear liquid; m/z 165 (M).

b) Ethyl ester of 2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]benzoic acid (compound of formula (VIII)

Obtained in accordance with scheme 1, step 2.

In a mixed solution of ethylanthranilate (50.0 g) in dry toluene (250 ml) at 0°With added calcium carbonate (60,6 g), and then the solution ethylsuccinate (59,8 g) in dry toluene (400 ml) and the reaction mixture was allowed to warm to CT within 30 minutes Then the resulting mixture was boiled under reflux for 1 h, and then the hot suspension was filtered. After this, the solution evaporated to a residue in the form of a white solid, which was recrystallized from EtOH to obtain the product (82,1 g, 93%yield) as white crystals, m/z 293 (M).

b) Ethyl ester of 2,3-dihydro-5-hydroc and-2-oxo-1H-benzazepin-4-carboxylic acid (compound of formula (IX)

Obtained in accordance with scheme 1, stage 3. In the suspension KN in oil (20%, 39,6 g) in an argon atmosphere was introduced toluene (60 ml). This suspension is cooled to 10°C, for 30 min (10-20° (C) was added the product from step 2 in the form of a solution in toluene (90 ml) followed by addition of dry DMF (12 ml). After cessation of hydrogen evolution resulting mixture was stirred at 70°C for 2 hours After cooling with stirring was added acetic acid (15 ml) followed by addition of water (120 ml). Next, the mixture was filtered and the obtained solid was dried in a vacuum drying Cabinet at 60°pressure 10 mbar during 30 minutes and Then the solid product (7.98 g) was recrystallized from ethanol to obtain white needle crystals (6.7 g, 84%yield), m/z 247(M).

g) 3,4-Dihydro-1H-1-benzazepin-2,5-dione (compound of formula (X)

Obtained in accordance with scheme 1, stage 4.

The product from step 3 (17.0 g) was dissolved in DMSO (610 ml)and then added water (30 ml) and the resulting mixture was stirred at 150°C for 1 h Then was added water (30 ml) and continued to stand at 150°C for 2 h and Then added to another aliquot of water (30 ml) and the mixture was stirred at 150°for another 2 hours and 20 minutes After cooling the mixture was poured into water (600 ml) and then the mixture was extracted with DHM (3 servings 250 ml), the combined extrac the s were washed with water (250 ml), then was dried and evaporated to a residue in the form of not quite white, orange solid. By recrystallization from EtOH were not quite white solid (6.0 g, 50%yield), m/z 175 (M).

d) 4-[(Dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione (compound of the formula (XI)

Obtained in accordance with scheme 1, step 5.

A mixture of the product from step 4 (3.1 g) and N,N-dimethylformamidine (21.1 ml) at 115-120°kept within 1 h After cooling, the solid was filtered and washed with diethyl ether, dried in a vacuum oven for 3 h at 50°under the pressure of 1 mm Hg to a residue in the form of a light orange solid (2.0 g, 58%yield), m/z (ISP)231 (MN).

e) 5,7-Dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he (compound of formula II

Obtained in accordance with scheme 1, step 6.

In a mixture of the product from step 5 (4.6 g) with Meon (160 ml)containing sodium methoxide (2,34 g)was added to formamidine HCl (2.4 g) and the resulting mixture at room temperature was stirred for 4 h Then was added water (80 ml), the resulting mixture was extracted with DHM (5 50 ml) and the combined extracts were dried over Na2SO4. After evaporation the residue was recrystallized from DHM/Meon with obtaining off-white crystals (2.2 g, 52%yield), m/z 211 (M).

W) Ethyl ester 9H-imidazo[1,5-a]pyrimido[5-d][1]benzazepine-10-carboxylic acid (compound of formula (I)

Obtained in accordance with scheme 1, step 7.

Into a solution of the product from step 6 (2.2 g) in CHCl3(15 ml) were administered N,N-dimethyl-p-toluidine (10.3 ml) and phosphorus oxychloride (1,59 ml) and the resulting mixture was boiled under reflux for 1 h After cooling, the mixture was poured into a solution Manso3(8,2 g) in water (40 ml) and the resulting mixture was extracted with DHM (4 servings 20 ml), and then the combined extracts were washed with water (40 ml), dried and evaporated to obtain imidocloprid. In the solution ethylisothiocyanate (1.19 g) in dry DMF (20 ml) was administered tert-piperonyl potassium (1.26 g) and the resulting solution at -50°added to a solution of imidocloprid (obtained by the above) in dry DMF (5 ml). After 10 min the reaction mixture was allowed to warm to room temperature (40 min)and then was added acetic acid (0.5 ml), then cooled with ice water (200 ml). The mixture was extracted with DHM (4 servings 40 ml) and the combined extracts were washed with water (50 ml), then dried over Na2SO4and evaporated. Chromatography of the residue on silica gel, elwira EtOAc/hexane, the product (770 mg, 24%yield) was obtained as white crystals, tPL: 285-287°C, m/z 306 (M).

Alternative sequence of reactions according to scheme 1

A mixture of the product from step 6 (1 mmol) and N,N-dimethyl-p-toluidine (2 mmole) were mixed in that is male (5 ml) and heated to 100° Statem was added dropwise phosphorus oxychloride (1.1 mmole) and exposure at 100°and was continued for 1 h Then the resulting mixture person to distil under reduced pressure and the residue was dissolved in THF (2 ml). In the solution hexamethyldisilazane (3.3 mmole) in THF (2 ml) in an argon atmosphere at -75°slowly added BuLi (1.6 M in hexano, 3.3 mmole). After stirring for 1 h at -75°solution was added ethyl ether (E)-(dimethylaminomethylene)acetic acid (2.0 mmole) in THF (1.0 ml), and then stirring was continued at -75°C for 1 h Then at -75°solution was added the appropriate imidocloprid (obtained by the above), then when -75°With was stirred for 1 h, and then was added acetic acid (20 mmol), the mixture was allowed to warm to 0°C, followed by addition of water (0.5 ml) and the mixture is boiled under reflux for 1 h After cooling, the mixture was extracted with DHM (2 portions of 10 ml) and the combined extracts were washed with water (10 ml)and then evaporated. The resulting residue was purified by chromatography on silica gel or preparative HPLC.

The experiments of examples 2 through 7 were carried out in accordance with scheme 1 and example 1.

Example 2

Ethyl ester of 6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-propyl-6H-pyrimido[54-d][1]benzazepin-6-he

Obtained similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and butyronitrile. Yield: 84%. White solid, m/z 253 (M).

b) Ethyl ester of 6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 5,7-dihydro-2-propyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 180°m/z (ISP) 349 (MH).

Example 3

Ethyl ester of 6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and sibutraminehydrochlo. Yield: 87%. White solid, m/z 253 (M).

b) Ethyl ester of 6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1] benzazepine-10-carboxylic acid

From 5,7-dihydro-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 190°m/z (ISP) 349 (MH).

Example 4

Ethyl ester of 6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 2-Cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and cyclopropanecarboxaldehyde. Yield: 62%. White solid, m/z (ISP) 252 (is N).

b) Ethyl ester of 6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

2-cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 110°m/z (ISP) 347 (MH).

Example 5

Ethyl ester of 6-(1,1-dimethylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 2-(1,1-Dimethylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and 2,2-dimethylpropyleneurea. Yield: 90%. White solid, m/z 267(M).

b) Ethyl ester of 6-(1,1-dimethylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 2-(1,1-dimethylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 250°C, m/z (ISP) 363 (MH).

Example 6

Ethyl ester of 6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and 2-(4-methoxyphenyl)acetamidomalonate. Yield: 31%.

White solid, m/z (ISP) 332 (MN).

b) Ethyl ester of 6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic key is lots

From 5,7-dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 200°m/z (ISP) 427 (M).

Example 7

Ethyl ester of 6-(1H-indol-3-ylmethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-(1H-indol-3-ylmethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and 2-(1H-indol-3-yl)acetamidine. Yield: 80%.

White solid, m/z 340 (M).

b) Ethyl ester of 6-(1H-indol-3-ylmethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d] [1]benzazepine-10-carboxylic acid

From 5,7-dihydro-2-(1H-indol-3-ylmethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 120°m/z (ISP) 436 (M).

Example 8

Ethyl ester of 3-fluoro-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1] benzazepine-10-carboxylic acid

a) Ethyl ester of 2-amino-5-fermenting acid (compound of formula (VII)

Received in accordance with schemes 1 or 2.

Light yellow liquid, tKip: 68-70°under residual pressure of 0.4 mbar.

b) Ethyl ester of 2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]-5-fermenting acid (compound of formula (VIII)

Obtained from the ethyl ester of 2-amino-5-fermenting acid in accordance with scheme 1, step 2. Yield: 100%.

White solid,m/z 311 (M).

b) Ethyl ester of 7-fluoro-2,3-dihydro-5-hydroxy-2-oxo-1H-benzazepin-4-carboxylic acid (compound of formula (IX)

Obtained from the ethyl ester of 2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]-5-fermenting acid in accordance with scheme 1, stage 3. Yield: 69%.

White solid, m/z 265 (M).

g) 7-Fluoro-3,4-dihydro-1H-1-benzazepin-2,5-dione (compound of formula (X)

Obtained from the ethyl ester of 7-fluoro-2,3-dihydro-5-hydroxy-2-oxo-1H-benzazepin-4-carboxylic acid in accordance with scheme 1 stage 4. Yield: 67%.

White solid, m/z 193 (M).

d) 4-[(Dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dione (compound of the formula (XI)

Obtained from 7-fluoro-3,4-dihydro-1H-1-benzazepin-2,5-dione in accordance with scheme 1, step 5. Yield: 75%.

Light orange solid, m/z 248 (M).

e) 10-Fluoro-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-he (the compound of formula (II)

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dione and acetamidomalonate. Yield: 50%.

White solid, m/z (ISP) 244 (MN).

W) Ethyl ester of 3-fluoro-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (compound of formula (I)

Obtained from 10-fluoro-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 230°m/z 338 (M).

Example 9

Atila the initial ester 3-fluoro-6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Fluoro-5,7-dihydro-2-propyl-6H-pyrimido[5,4-d[1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dionaea of butyronitrile. Yield: 50%.

White solid, m/z (ISP) 272 (MN).

b) Ethyl ester of 3-fluoro-6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-fluoro-5,7-dihydro-2-propyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 200°C, m/z (ISP) 367 (MH).

Example 10

Ethyl ester of 3-fluoro-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Fluoro-5,7-dihydro-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dione and sibutraminehydrochlo. Yield: 60%.

White solid, m/z (ISP) 272 (MN).

b) Ethyl ester of 3-fluoro-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-fluoro-5,7-dihydro-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 185°C, m/z (ISP) 367 (MH).

Example 11

Ethyl ester of 6-cyclopropyl-3-fluoro-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 2-Cyclopropyl-10-fluoro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(Dima is ylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dione and cyclopropanecarboxaldehyde. Yield: 88%.

White solid, m/z (ISP) 270 (MN).

b) Ethyl ester of 6-cyclopropyl-3-fluoro-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

2-cyclopropyl-10-fluoro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 220°C, m/z (ISP) 365 (MN).

Example 12

Ethyl ester of 3-fluoro-6-(1,1-dimethylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

(1,1-Dimethylethyl)-10-fluoro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dione and 2,2-dimethylpropyleneurea. Yield: 54%.

White solid, m/z (ISP) 286 (MN).

b) Ethyl ester of 3-fluoro-6-(1,1-dimethylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 2-(1,1-dimethylethyl)-10-fluoro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 233°m/z (ISP) 381 (MH).

Example 13

Ethyl ester of 3-fluoro-6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Fluoro-5,7-dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dione and 2-(4-methoxyphenyl)acetamidomalonate. Yield: 89%.

The white solid is emesto, m/z (ISP) 350 (MN).

b) Ethyl ester of 3-fluoro-6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-fluoro-5,7-dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 185°m/z (ISP) 445 (MH).

Example 14

Ethyl ester of 3-fluoro-6-(1H-indol-3-ylmethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Fluoro-5,7-dihydro-2-(1H-indol-3-ylmethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepin-2,5-dione and 2-(1H-indol-3-yl)acetamidine. Yield: 87%.

White solid, m/z (ISP) 359 (MN).

b) Ethyl ester of 3-fluoro-6-(1H-indol-3-ylmethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-fluoro-5,7-dihydro-2-(1H-indol-3-ylmethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 230°m/z (ISP) 454 (MH).

Example 15

Ethyl ester of 3-chloro-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) Ethyl ester of 2-amino-5-chlorbenzoyl acid (compound of formula (VII)

From ethylanthranilate and sodium hypochlorite (in accordance with M.Okabe and R-C Sun, Tetrahedron, 1995, 51, 1861) with a not quite white solids, tPL: 80°C, m/z 199.

b) Ethyl ester of 5-chloro--[(4-ethoxy-1,4-DIOXOLANYL)amino)]benzoic acid (compound of formula (VIII)

From the ethyl ester of 2-amino-5-chlorbenzoyl acid in accordance with scheme 1, step 2. Yield: 100%.

White solid, m/z 327 (M).

b) Ethyl ester of 7-chloro-2,3-dihydro-5-hydroxy-2-oxo-1H-benzazepin-4-carboxylic acid (compound of formula (IX)

From the ethyl ester of 5-chloro-2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]benzoic acid in accordance with scheme 1, stage 3. Yield: 81%.

White solid, m/z 281 (M).

d) 7-Chloro-3,4-dihydro-1H-1-benzazepin-2,5-dione (compound of formula (X)

From the ethyl ester of 7-chloro-2,3-dihydro-5-hydroxy-2-oxo-1H-benzazepin-4-carboxylic acid in accordance with scheme 1, stage 4. Yield: 48%.

White solid, m/z 209 (M).

d) 7-Chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione (compound of the formula (XI)

From 7-chloro-3,4-dihydro-1H-1-benzazepin-2,5-dione in accordance with scheme 1, step 5. Yield: 79%.

Light orange solid, m/z 264 (M).

e) 10-Chloro-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-he (the compound of formula (II)

Similar to the scheme 1 - 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and acetamidomalonate. Yield: 58%.

White solid, m/z 259 (M).

W) Ethyl ester of 3-chloro-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (compound of formula (I)

From 10-chloro-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-it under the about scheme 1, stage 7.

White solid, tPL: 202-204°m/z (ISP) 355 (MN).

Example 16

Ethyl ester of 3-chloro-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Chloro-5,7-dihydro-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similar to the scheme 1-7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and sibutraminehydrochlo. Yield: 87%.

White solid, m/z (ISP) 288 (MN).

b) 3-Chloro-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 10-chloro-5,7-dihydro-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 192°C, m/z (ISP) 383 (MH).

Example 17

Ethyl ester of 3-chloro-6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Chloro-2-cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similar to the scheme 1 - 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and cyclopropanecarboxaldehyde. Yield: 83%.

White solid, m/z (ISP) 286 (MN).

b) Ethyl ester of 3-chloro-6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 10-chloro-2-cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 230°m/z (ISP) 381 (MH).

Example 1

Ethyl ester of 3-chloro-6-(1,1-dimethylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Chloro-2-(1,1-dimethylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similar to the scheme 1 - 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and 2,2-dimethylpropyleneurea. Yield: 88%.

Not quite white solid, m/z (ISP) 302 (MN).

b) Ethyl ester of 3-chloro-6-(1,1-dimethylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 10-chloro-2-(1,1-dimethylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 180°C, m/z (ISP) 397 (MH).

Example 19

Ethyl ester of 3-chloro-6-[(4-methoxyphenyl)methyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Chloro-5,7-dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similar to the scheme 1 - 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and 2-(4-methoxyphenyl)acetamidomalonate. Yield: 87%.

White solid, m/z (ISP) 366 (MN).

b) Ethyl ester of 3-chloro-6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 10-chloro-5,7-dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 192°C, m/z (ISP) 461 (MH).

Primer

Ethyl ester of 3-chloro-6-(1H-indol-3-ylmethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Chloro-5,7-dihydro-2-(1H-indol-3-ylmethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similar to the scheme 1 - 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and 2-(1H-indol-3-yl)acetamidine. Yield: 46%.

White solid, m/z 374 (M).

b) Ethyl ester of 3-chloro-6-(1H-indol-3-ylmethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 10-chloro-5,7-dihydro-2-(1H-indol-3-ylmethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 120°m/z (ISP) 470 (MH).

Example 21

Ethyl ester of 3-bromo-N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) Ethyl ester of 2-amino-5-bromobenzoyl acid (compound of formula (VII)

As in scheme 1, step 1, from 2-amino-5-bromobenzoyl acid, ethanol and gaseous HCl at boiling under reflux for 16 h with getting not quite white solids, tPL: 83°C.

b) Ethyl ester of 5-bromo-2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]benzoic acid (compound of formula (VIII)

From the ethyl ester of 2-amino-5-bromobenzoyl acid in accordance with scheme 1, step 2. Yield: 79%.

White solid, m/z (ISP) 371/373 (MN).

b) Ethyl ester of 7-bromo-2,3-dihydro-5-hydroxy-2-oxo-1H-benzazepin-4-arbonboy acid (compound of formula (IX)

From the ethyl ester of 5-bromo-2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]benzoic acid in accordance with scheme 1, stage 3. Yield: 71%.

White solid, m/z (ISP) 325/327 (MN).

g) 7-Bromo-3,4-dihydro-1H-1-benzazepin-2,5-dione (compound of formula (X)

From the ethyl ester of 7-bromo-2,3-dihydro-5-hydroxy-2-oxo-1H-benzazepin-4-carboxylic acid in accordance with scheme 1, stage 4. Yield: 65%. White solid, m/z (ISP) 253/255 (MN).

d) 7-Bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione (compound of the formula (XI)

From 7-bromo-3,4-dihydro-1H-1-benzazepin-2,5-dione in accordance with scheme 1, step 5. Yield: 90%.

Light orange solid, m/z (ISP) 309/311 (MN).

e) 10-Bromo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he (the compound of formula (II)

Similarly to scheme 1 from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and formamidines. Yield: 83%.

White solid, m/z (ISP) 289/291 (MN).

W) Ethyl ester of 3-bromo-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-bromo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 210°m/z (ISP) 385/387 (MN).

Example 22

Ethyl ester of 3-bromo-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Bromo-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and acetamidomalonate. Yield: 87%.

White solid, m/z (ISP) 303/305 (MN).

b) Ethyl ester of 3-bromo-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-bromo-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 130°m/z (ISP) 399/401 (MN).

Example 23

Ethyl ester of 3-bromo-6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Bromo-5,7-dihydro-2-cyclopropyl-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and cyclopropanecarboxaldehyde. Yield: 99%.

White solid, m/z (ISP) 330/332 (MN).

b) Ethyl ester of 3-bromo-6-cyclopropyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-bromo-5,7-dihydro-2-cyclopropyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 230°C, m/z (ISP) 425/427 (MN).

Example 24

Ethyl ester of 3-bromo-6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 10-Bromo-5,7-dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and 2-(4-methoxyphenyl)acetamidomalonate. Yield: 99%.

White solid, m/z ISP) 410/412 (MN).

b) Ethyl ester of 3-bromo-6-[(4-methoxyphenyl)methyl]-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

10-bromo-5,7-dihydro-2-[(4-methoxyphenyl)methyl]-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 180°C, m/z (ISP) 505/507 (MN).

Example 25

Ethyl ester of 3,6-dimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) Ethyl ester of 2-amino-5-methylbenzoic acid (compound of formula (VII)

As in scheme 1, stage 1 (in accordance with S.P.Acharya and J.B.Hynes, J.Heterocyclic Chem., 1975, 12, 1283), the product obtained from 2-amino-5-methylbenzoic acid, ethanol and gaseous HCl. Yield: 80%.

White solid, m/z (ISP) 178 (M-N).

b) Ethyl ester of 2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]-5-methylbenzoic acid (compound of formula (VIII)

From the ethyl ester of 2-amino-5-methylbenzoic acid in accordance with scheme 1, step 2. Yield: 87%.

White solid, m/z (ISP) 308 (MN).

b) Ethyl ester of 2,3-dihydro-5-hydroxy-7-methyl-2-oxo-1H-benzazepin-4-carboxylic acid (compound of formula (IX)

From the ethyl ester of 2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]-5-methylbenzoic acid in accordance with scheme 1, stage 3. Yield: 41%.

White solid, m/z (ISP) 262 (MN).

g) 3,4-Dihydro-7-methyl-1H-1-benzazepin-2,5-dione (compound of formula (X)

From the ethyl ester of 2,3-dihydro-5-hydroxy-7-meth is l-2-oxo-1H-benzazepin-4-carboxylic acid in accordance with scheme 1, stage 4. Yield: 98%. White solid, m/z (ISP) 190 (MN).

d) 4-[(Dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepin-2,5-dione (compound of the formula (XI)

From 3,4-dihydro-7-methyl-1H-1-benzazepin-2,5-dione in accordance with scheme 1, step 5. Yield: 74%.

Light brown solid, m/z (ISP) 245 (MN).

e) 5,7-Dihydro-2,10-dimethyl-6H-pyrimido[5,4-d][1]benzazepin-6-he (the compound of formula (II)

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepin-2,5-dione and acetamidomalonate. Yield: 98%.

White solid, m/z (ISP) 240 (MN).

W) Ethyl ester of 3,6-dimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (compound of formula (I)

From 5,7-dihydro-2,10-dimethyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 200°m/z (ISP) 335 (MN).

Example 26

Ethyl ester of 3-methyl-6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-10-methyl-2-propyl-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepin-2,5-dione and butyronitrile. Yield: 90%. White solid, m/z (ISP) 268 (MN).

b) Ethyl ester of 3-methyl-6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 5,7-dihydro-10-methyl-2-propyl-6H-pyrimido[5,4-d][1]benzazepin-6-she's back in the availa able scientific C with scheme 1, stage 7.

White solid, tPL: 250°C, m/z (ISP) 363 (MH).

Example 27

Ethyl ester of 3-methyl-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-10-methyl-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepin-2,5-dione and sibutraminehydrochlo. Yield: 91%.

White solid, m/z (ISP) 268 (MN).

b) Ethyl ester of 3-methyl-6-(1-methylethyl)-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 5,7-dihydro-10-methyl-2-(1-methylethyl)-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 190°C, m/z (ISP) 363 (MH).

Example 28

Ethyl ester of 6-cyclopropyl-3-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 2-Cyclopropyl-5,7-dihydro-10-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepin-2,5-dione and cyclopropanecarboxaldehyde. Yield: 88%.

White solid, m/z (ISP) 266 (MN).

b) Ethyl ester of 6-cyclopropyl-3-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1] benzazepine-10-carboxylic acid

2-cyclopropyl-5,7-dihydro-10-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 250°m/z (ISP) 361 (MN).

In accordance with scheme 3 receive the following connections.

An alternative method for example 1

Ethyl ester 9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 3,4-Dihydro-1(2H)naphtalene-(E and Z)-oxime (compound of formula XVII, stage 1)

The mixture α-tetralone (13.4 ml), hydroxylaminopurine (7,86 g), sodium acetate (4,39 g), water (80 ml) and ethanol (80 ml) was boiled under reflux for 20 minutes Then using a bath of ice/Meon the mixture was cooled to 0°and after 1 h the solid was filtered, washed with water/EtOH (1:1, 100 ml), and then the solid was dried under high vacuum to obtain the product as white crystals (7,6 g, 47%yield), m/z 161 (M).

b) 1,3,4,5-Tetrahydro-2H-1-benzazepin-2-on (compound of formula XVIII, phase 1')

This reaction can be repeated as reported in literature (W-Y. Chen and N.W.Gilman, Heterocycles, 1983, 663-666).

Trichloroacetic acid (502 g) was melted on a water bath and then added α-tetralone (50 g). In this solution for 90 min was added sodium azide (33,4 g) with intermittent cooling on ice and heat to melt the solvent. Next, the resulting mixture was stirred at RT for 2 hours and Then the resulting mixture was stirred at 70°C for 16 hours After cooling, the mixture was put into water (1 l)and then was added solid sodium bicarbonate (400 g). this mixture was filtered and the filtrate was extracted with DHM (4 servings 150 ml), then the combined extracts were dried and evaporated, and the obtained solid was recrystallized from EtOH emitting product (26,4 g, 48%yield) as white crystals, m/z 161 (M).

b') 1,3,4,5-Tetrahydro-2H-1-benzazepin-2-on (compound of formula XVIII, stage 2)

Within 20 min the product from step 1 (108,6 g) at 120°was introduced into a solution of polyphosphoric acid, and then the obtained mixture was stirred for 30 min at 120°C. After cooling the mixture was poured into a mixture of ice water (1 l), and after 1 h the precipitate was filtered and then dried under high vacuum at 70°With obtaining the product as white crystals (94,8 g, 87%yield), m/z 161 (M).

b) 3,4-Dihydro-1H-1-benzazepin-2,5-dione (compound of formula IXX, stage 3)

Lactam (82,4 g) was dissolved in BuOH (1 l) was added water (3 l). Next was added potassium permanganate (315 g), after which the uranyl nitrate magnesium (510 g) and the mixture was stirred in a water bath at RT for 48 hours Then the mixture was acidified with HCl (3 M, 745 ml), then sodium bisulfite was added until until the solution became yellow-orange. This mixture was extracted with DHM (3 servings 1 l) and the combined extracts were washed with water (1 l)and then dried and evaporated to obtain a brown solid. This is the last recrystallized from EtOAc to obtain beige crystals (30,9 g, 34%is ihod).

g) 4-[(Dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione (compound of formula XI, stage 4)

As stated in relation to the compounds of formula XI at stage 5 in figure 1.

e) 5,7-Dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-he (compound of formula II, stage 5)

Similarly to scheme 1, step 6, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and formalinized.

e) Ethyl ester 9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (compound of formula I, example 1, step 6)

Into a solution of the product from step 5 (2.2 g) in CHCl3(15 ml) were administered N,N-dimethyl-p-toluidine (10.3 ml) and POCl3(1,59 ml) and the resulting mixture was boiled under reflux for 1 h After cooling, the mixture was poured into a solution of NaHCO3(8,2 g) in water (40 ml), the resulting mixture was extracted with DHM (4 servings 20 ml) and then the combined extracts were washed with water (40 ml), dried and evaporated to obtain imidocloprid. In the solution ethylisothiocyanate (1.19 g) in dry DMF (20 ml) was added tert-butoxide potassium (1.26 g) and at -50°With the resulting solution was introduced into a solution of imidocloprid (obtained similarly to the above) in dry DMF (5 ml). After 10 min the reaction mixture was allowed to warm to room temperature (40 min)and then was added acetic acid (0.5 ml), then cooled with ice water (200 ml). The mixture extragere is whether DHM (4 servings 40 ml) and the combined extracts were washed with water (50 ml), and then was dried over MgSO4and evaporated. Chromatography of the residue on silica gel, elwira EtOAc/hexane, in the form of white crystals were obtained product (770 mg, 24%yield), m/z 306 (M).

Example 29

Ethyl ester 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and acetamidomalonate. Yield: 44%. White solid, m/z 225 (M).

b) Ethyl ester of 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 253-254°m/z 320 (M).

Example 30

Ethyl ester of 6-phenyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-phenyl-6H-pyrimido[5,4-d[1]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepin-2,5-dione and benzenedimethanamine. Yield: 83%. White solid, m/z 287 (M).

b) Ethyl ester of 6-phenyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 5,7-dihydro-2-phenyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 244-246°C, m/z 382 (M).

Example 31

6-Methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]is encasedin-10-carboxylic acid

To a solution of ethyl ester 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (1.6 g, 5 mmol) in EtOH (20 ml) was administered sodium hydroxide (0,22 g, 5.5 mmole) and water (3.5 ml) and the resulting mixture was boiled under reflux for 20 minutes Then the mixture was cooled to 0°and then added hydrochloric acid (4 N., of 1.32 ml) and the mixture was cooled in an ice bath within 1 h of the Formed solid substance was filtered, and then dried under vacuum to residue in the form of off-white crystals of the product (1.1 g, 77%yield), tPL: 285-287°C, m/z 292 (M).

Example 32

10-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepin

To a suspension of 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (1.0 g, 3.4 mmole) in DMF (15 ml) was administered 1,1'-carbonyldiimidazole (0,61 g, 3,76 mmole), after which N-hydroxycyclohexanecarboxylate and the prepared solution was kept at 85°C for 1.5 h and Then was added acetic acid (3.4 ml) and the resulting mixture was stirred at 130°C for 40 minutes After cooling the mixture was evaporated and dissolved in DHM (15 ml). Received DHM the extract was washed with sodium bicarbonate (saturated solution, 40 ml), and then the aqueous phase was washed DHM (20 ml). Next United DHM layers were dried over MgSO4and evaporated. The residue was recrystallized from et is Lacetti/hexane emitting product (720 mg, 59%yield) as white crystals, tPL: 216-218°C, m/z 356 (M).

Example 33

Ethyl ester of 2,3,6-trimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 4-[(Dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepin-2,5-dione (compound of the formula (XI)

From 3,4-dihydro-7,8-dimethyl-1H-benzazepin-2,5-dione (compound of formula (X) in accordance with scheme 1, step 5. Yield: 84%.

White solid, m/z 258 (M).

b) 5,7-Dihydro-2,9,10-trimethyl-6H-pyrimido[5,4-d]benzazepin-6-he (the compound of formula (II)

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepin-2,5-dione and acetamidomalonate. Yield: 88%.

White solid, m/z 253 (M).

b) Ethyl ester of 2,3,6-trimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1] benzazepine-10-carboxylic acid (compound of formula (I)

From 5,7-dihydro-2,9,10-trimethyl-6H-pyrimido[5,4-d]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 210°C, m/z 348 (M).

Example 34

Ethyl ester of 2,3-dimethyl-6-propyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-9,10-dimethyl-2-propyl-6H-pyrimido[5,4-d]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepin-2,5-dione and butyronitrile. Yield: 67%. White solid, m/z (ISP) 282 (MN).

b) Ethyl ester of 2,3-dimethyl-6-p is sawdust-9H-imidazo[1,5-a]pyrimido[5,4-d][1] benzazepine-10-carboxylic acid

From 5,7-dihydro-9,10-dimethyl-2-propyl-6H-pyrimido[5,4-d]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 213°C, m/z 376 (M).

Example 35

Ethyl ester of 6-[(4-methoxyphenyl)methyl]-2,3-dimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-[(4-methoxyphenyl)methyl]-9,10-dimethyl-6H-pyrimido[5,4-d]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepin-2,5-dione and 2-(4-methoxyphenyl)acetamidomalonate. Yield: 79%.

White solid, m/z (ISP) 360 (MN).

b) Ethyl ester of 6-[(4-methoxyphenyl)methyl]-2,3-dimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

From 5,7-dihydro-2-[(4-methoxyphenyl)methyl]-9,10-dimethyl-6H-pyrimido[5,4-d]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 150°m/z (ISP) 455 (MH).

Example 36

Ethyl ester of 6-(1H-indol-3-ylmethyl)-2,3-dimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid

a) 5,7-Dihydro-2-[1H-indol-3-ylmethyl]-9,10-dimethyl-6H-pyrimido[5,4-d]benzazepin-6-he

Similarly to scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepin-2,5-dione and 2-(1H-indol-3-yl)acetamidine. Yield: 72%.

White solid, m/z 368 (M).

b) Ethyl ester of 6-(1H-indol-3-ylmethyl)-2,3-dimethyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic what sloty

From 5,7-dihydro-2-[1H-indol-3-ylmethyl]-9,10-dimethyl-6H-pyrimido[5,4-d]benzazepin-6-it in accordance with scheme 1, step 7.

White solid, tPL: 135°C, m/z (ISP) 464 (MH).

Example 37

2-Bromo-11-methyl-7-(5-methylisoxazol-3-yl)-8H-4b,6,10,12-tetraethylene[e,g]azulene

a) Ethyl ester 5-methylisoxazol-3-karbonovoi acid

To a solution of ethyl-2,4-dioxooleana (20 g, 126 mmol) in ethanol (85 ml) was introduced gidroxinimesoulid (8.8 g, 126 mmol) and sodium bicarbonate (10.6 g, 0,126 mmole). Next, the reaction mixture is boiled under reflux for 1 h After cooling, the mixture is evaporated to a residue in the form of a transparent liquid that person to distil from the receipt of the balance in the form of a colourless liquid (13.3 g, 68%yield) specified in the title compound; m/z (EI) 156,0 (MN).

b) (5-Methylisoxazol-3-yl)methanol

In the solution of the ethyl ester of 5-methylisoxazol-3-carboxylic acid (13.3 g, 86 mmol) in ethanol (175 ml) in an argon atmosphere at 0°C for 30 min in individual portions was added NaBH4(8.8 g, 231 mmol). The reaction mixture was allowed to warm up to CT. After 3 h the reaction mixture was diluted with HCl (1 M, 100 ml), and then, after cooling to room temperature, the mixture was washed with diethyl ether (2 servings 250 ml), the combined extracts were dried and evaporated to obtain a residue in the form of a colorless oil specified in the title with the organisations (8,1 g, 84%yield), m/z (EI) level 113.0 (M).

C) 3-methyl bromide-5-methylisoxazol

In the solution PBr3(1.45 g, 25 mmol) and pyridine (0.5 ml) in toluene (12 ml) at -10°injected with a solution of hydroxymethyl-3-methyl-5-isoxazol (2.8 g, 25 mmol) in pyridine (0.2 ml). Next, the reaction mixture was stirred at -10°C for 1 h, then was stirred for 14 h at RT. Then the reaction mixture was diluted with water (50 ml) and was extracted with diethyl ether (2 portions of 50 ml). Then the combined extracts were dried and evaporated. The residue was purified by chromatography on silica gel, elwira EtOAc/hexane in a ratio of 1:9, and got mentioned in the title compound as a colourless liquid (1.7 g, 39%yield), m/z (EI) 175,0/177,0 (M).

g) 3-Azidomethyl-5-methylisoxazol

To a solution of 3-methyl bromide-5-methylisoxazole (150 mg, 0.9 mmole) in acetone (1 ml) at RT was administered NaN3(166 mg, of 0.26 mmole). Next, the reaction mixture was stirred for 48 hours Then the reaction mixture was poured into water (10 ml) and was extracted with EtOAc (3 portions of 10 ml), dried and evaporated. The product was chromatographically on silica gel, elwira EtOAc/hexane in a ratio of 1:1, receipt of the balance in the form of a colourless liquid specified in the title compound (87 mg, 74%yield), m/z 138,0 (M).

d) (5-Methylisoxazol-3-yl)methylamine

To a solution of 3-azidomethyl-5-methylisoxazole (6.2 g, 44,55 mmole) in isopropanol (100 ml) at RT with intense the main mixing was introduced triethylamine (12,4 ml, 89,0 mmole), 1,3-propanedithiol (0.45 ml, 4.5 mmole) and borohydride sodium (1.7 g, 44.5 mmole). Next, the mixture was stirred at RT. After 19 h added another 0.5 EQ. NaBH4(850 mg, 44.5 mmole) and stirred at RT for a further 7 hours and Then under vacuum, the solvent evaporated, then the residue was dissolved in 10%aqueous citric acid (10 ml) and washed with diethyl ether/hexane, 1:1 (3 servings 150 ml). The aqueous layer was podslushivaet 6 N. aqueous NaOH to pH 12, saturated NaCl and was extracted with DHM (4 servings 200 ml). United DHM extracts were dried and concentrated to obtain the residue in the form of a colourless liquid specified in the title compound (4.4 g, 87%yield), m/z 112,0 (M).

e) N,N-Dimethyl-N'-(5-methylisoxazol-3-ylmethyl)formamide

A solution of S-(5-methylisoxazol-3-yl)methylamine (150 mg, 1.3 mmole) in N,N-dimethylformamidine (2 ml, 14.4 mmole) was boiled under reflux for 3 hours After cooling to room temperature the solvent is evaporated to obtain a residue as a yellow oil specified in the title compound (220 mg, 98%yield), m/z 168,2 (MN).

W) 2-Bromo-11-methyl-7-(5-methylisoxazol-3-yl)-8H-4b,6,10,2-tetraethylene[e, g]azulene

10-bromo-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-it in accordance with scheme 1, step 7, using N,N-dimethyl-N'-(5-methylisoxazol-3-ylmethyl)formamidine instead of the ethyl ester of (E)-(is metilnikotinamida)acetic acid.

Transparent resin, m/z (ISP) 407/409 (MN).

Alternative ways without the cleansing of the intermediate product

Ethyl ester of 2-[(4-ethoxy-1,4-DIOXOLANYL)amino)]benzoic acid (compound of formula (VIII)

In a mixed solution of ethylanthranilate (5.0 g) in dry toluene (25 ml) at 0°were injected With calcium carbonate (6,1 g), after which the solution ethylsuccinate (6.0 g) in dry toluene (40 ml) and within 30 min the reaction mixture was allowed to warm up to CT. Next, the resulting mixture was boiled under reflux for 1 h, and then the hot suspension was filtered. After this, the solution evaporated to a white solid residue with getting the product in the form of white crystals (8,9 g, 100%yield), m/z 293 (M).

Ethyl ester of 2,3-dihydro-5-hydroxy-2-oxo-1H-benzazepin-4-carboxylic acid (compound of formula (IX)

To a suspension of NaH in oil (0.5 g) in an argon atmosphere was introduced THF (30 ml). In this suspension at RT in the form of a solution in THF (5 ml) for 5 min was added the product from step 2. After cessation of hydrogen evolution resulting mixture was stirred at 70°within 15 minutes After cooling with stirring was added acetic acid (1 ml) followed by addition of water (120 ml). Next, the mixture was filtered and the obtained solid substance within 1 h and dried in a vacuum drying Cabinet at 60°under the residual pressure of 10 mbar floor with the rising white solid (0.8 g, 99%yield), m/z 247 (M).

3,4-Dihydro-1H-1-benzazepin-2,5-dione (compound of formula (X)

The product from step 3 (0.8 g) was dissolved in DMF (30 ml)and then added NaCl (0.28 g) and water (0,11 ml) and the resulting mixture was boiled under reflux for 3 hours Then, after cooling, the mixture was extracted with DHM (3 servings 5 ml), the combined extracts were washed with water (10 ml), then dried and evaporated to a residue in the form of not quite white, orange solid. By recrystallization from EtOH were not quite white solid (0.54 g, 95%yield), m/z 175 (M).

The production of intermediate products in accordance with scheme 4

Ethyl ester of 4-(2-nitrophenyl)-4-trimethylsilylacetamide acid (compound of formula XXI)

In the suspension svezheraspilennaya iodide zinc (5,28 g of 16.5 mmole) in dry DHM (2 ml) at room temperature in an argon atmosphere for 5 min was introduced a solution of 2-nitrobenzaldehyde (5.0 g, 33,0 mmole) and (1 amoxilcomprare)trimethylsilane (7.50 g, 43,0 mmole) in dry DHM (20 ml). After 1.5 h the reaction mixture was added hydrochloric acid (1 M, 50 ml) and the resulting mixture was extracted with DHM (3 portions of 50 ml). The combined organic extracts were dried over sodium sulfate and evaporated to a residue in the form of oil. Purification by chromatography on silica gel, elwira hexane/ethyl acetate (9:1), in the form of colorless was mallapally specified in the title compound (8,3 g, 77%yield); m/z 324 (M). As a side reaction product was isolated by ethyl ester of 4-hydroxy-4-(2-nitrophenyl)butyric acid [output: 10%, m/z 254 (MN)].

Ethyl ester of 4-(2-nitrophenyl)-4-oxomalonate acid (compound of formula XXII)

In the solution of the ethyl ester of 4-(2-nitrophenyl)-4-trimethylsilylacetamide acid (530 mg, 1.6 mmole) in dry DHM (5 ml) in an argon atmosphere was introduced PQQ (pyridineboronic) (878 mg, 4.1 mmole) and the resulting mixture was intensively stirred for 20 hours Then was added silica gel (5 g) and the mixture was filtered. Next, the filtrate evaporated and the residue was purified by chromatography on silica gel, elwira with ethyl acetate/hexane (3:1) to give a colourless liquid specified in the title compound (375 mg, 92%yield); m/z 252 (MN).

Ethyl ester of 4-(2-AMINOPHENYL)-4-oxomalonate acid (compound of formula XXIII)

Method 1

A solution of ethyl ester of 4-(2-nitrophenyl)-4-oxomalonate acid (200 mg, 0.8 mmole) in dry Meon (5 ml) in the presence of Pd/C (20 mg) was first made (1 ATA) for 3 hours the mixture was filtered and the filtrate evaporated. Purification by filtration through silica gel, elwira DHM, in the form of a colorless oil was obtained is listed in the title compound (140 mg, 80%yield); m/z 222 (MN).

Method 2

In the solution of the ethyl ester of 4-hydroxy-4-(2-nitrophenyl)butyric acid (200 mg, 0.9 mmole) in dry DHM (10 ml) was injected 4-metil Holin-N-oxide (157,4 mg, 1.3 mmole) and perruthenate of tetrapropylammonium (31.5 mg, and 0.09 mmole) and the resulting mixture was stirred at room temperature for 1 h Then the mixture was filtered and washed with diethyl ether. Purification of the obtained residue by filtration through silica gel, elwira DHM, in the form of a colorless oil was obtained is listed in the title compound (107 mg, 54%yield); m/z 222 (MN).

Method 3

In the solution of the ethyl ester of 4-(2-AMINOPHENYL)-4-trimethylsilylacetamide acid (200 mg, 0.7 mmole) in dry DHM (10 ml) was injected 4-methylmorpholin-N-oxide (157,4 mg, 1.3 mmole) and perruthenate of tetrapropylammonium (31.5 mg, and 0.09 mmole) and the resulting mixture was stirred at room temperature for 1 h Then the mixture was filtered and washed with diethyl ether. Purification of the obtained residue by filtration through silica gel, elwira DHM, in the form of a colorless oil was obtained is listed in the title compound (84 mg, 54%yield); m/z 222 (MN).

Ethyl ester of 4-(2-AMINOPHENYL)-4-trimethylsilylacetamide acid (compound of formula XXVI)

A solution of ethyl ester of 4-(2-nitrophenyl)-4-trimethylsilylacetamide acid (200 mg, 0.6 mmole) in dry EtOAc (5 ml) was first made (1 at) in the presence of Pd/C (20 mg) during the night. Then the mixture was filtered and evaporated. The obtained residue was dissolved in dry Meon (5 ml) and additionally was first made (1 at) in the presence of Pd/C (20 mg) for 1 h Yes is it the mixture was filtered and the filtrate evaporated. Purification of the obtained residue by filtration through silica gel, elwira hexane/ethyl acetate (8:1), in the form of a colorless oil was obtained is listed in the title compound (130 mg, 72%yield); m/z 295 (M).

Ethyl ester of 4-(2-AMINOPHENYL)-4-hydroxybutiric acid (compound of formula XXV)

Method 1

A solution of ethyl ester of 4-hydroxy-4-(2-nitrophenyl)butyric acid (200 mg, 0.8 mmole) in dry Meon (5 ml) was first made (1 at) in the presence of Pd/C (20 mg) for 5 h the mixture was filtered and the filtrate evaporated. Purification of the obtained residue by filtration through silica gel, elwira with ethyl acetate/hexane (3:1), in the form of a colorless oil was obtained is listed in the title compound (100 mg, 57%yield); m/z 224 (M).

Method 2

A solution of ethyl ester of 4-(2-nitrophenyl)-4-trimethylsilylacetamide acid (200 mg, 0.6 mmole) in dry Meon (5 ml) with few drops of ethyl acetate was first made (1 at) in the presence of Pd/C (20 mg) for 20 h the mixture was filtered and the filtrate evaporated. Purification of the obtained residue by filtration through silica gel, elwira DHM/ethyl acetate (8:1), in the form of a colorless oil was obtained is listed in the title compound (115 mg, 84%yield); m/z 224 (M).

3,4-Dihydro-1H-1-benzazepin-2,5-dione (compound of formula (X)

To a suspension of sodium hydride (10 mg, 0.43 mmole) in dry THF (1 ml) in an argon atmosphere at -40°introduced the ethyl ester of 4-(AMINOPHENYL)-4-oxomalonate acid (80 mg, of 0.36 mmole). After the reaction mixture was allowed to warm up to CT for 3 h, and then it was put into water (20 ml). The mixture was extracted with DHM (3 servings 15 ml)then the combined extracts were dried (sodium sulfate) and evaporated to a residue in the form of not-quite-white solid. By recrystallization from EtOAc was obtained a white solid product (51 mg, 81%yield), m/z 175 (M).

Example

The usual way to produce tablets of the following composition:

mg tablet
The active ingredient5
Lactose45
Corn starch15
Microcrystalline cellulose34
Magnesium stearate1
Weight tablets 100

Example B

Make capsules with the contents of the following composition:

mg/capsule
The active ingredient10
Lactose155
Corn starch30
Talc5
The mass of the filled capsules 200

Active ingredient, is actos and corn starch are mixed first in the mixer, and then in the grinding device. The mixture back into the mixer, add talc and carefully peremeshivayte mixture in the packing device is filled hard gelatin capsules.

The example In

Make suppositories of the following composition,

mg/supposit:
The active ingredient15
The basis for suppository1285
Just 1300

In a glass or steel vessel melt the basis for suppository, thoroughly mixed and cooled to 45°C. After that it was added finely ground active ingredient and mix until full dispersion. The mixture is poured into forms for suppositories appropriate size, leave to cool, then suppositories are removed from the molds and placed in individual packages of wax paper or metal foil.

1. The compound of General formula

in which R1denotes a halogen atom or (ness.)alkyl;

R2denotes a hydrogen atom, (ness.)alkyl, C3-C7cycloalkyl, -(CH2)m-phenyl, in which phenyl ring may be substituted (ness.)alkoxy, or represents -(CH2) m-indolyl;

R3denotes-C(O)O-(ness.)alkyl, -C(O)HE or five-membered heteroaromatic group containing as heteroatoms nitrogen and oxygen, the ring which may be substituted (ness.)the alkyl or C3-C7cycloalkyl;

n denotes 0, 1 or 2;

m denotes 0, 1 or 2;

and its pharmaceutically acceptable acid additive salt.

2. The compound of formula I according to claim 1, in which R3represents a five-membered heteroaromatic group containing as heteroatoms nitrogen and oxygen, the ring which may be substituted With3-C7cycloalkyl;

3. The compound of formula I according to claim 1, in which R3denotes the group-C(O)O-(ness.)alkyl, n denotes 0, and R2matter specified in claim 1.

4. The compound of formula I according to claim 3, which is the ethyl ester N-imidazo[1,5-a]pyrimido[5,4-a][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-propyl-N-imidazo[1,5-a]pyrimido[5,4-d] [1]benzazepine-10-carboxylic acid,

ethyl ester of 6-(1-methylethyl)-N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-cyclopropyl-N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-[(4-methoxyphenyl)methyl]-N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid, or

ethyl is the fir 6-methyl-N-imidazo[1,5-a]pyrimido[5,4-a][1]benzazepine-10-carboxylic acid.

5. The compound of formula I according to claim 1, in which R3denotes the group-C(O)O-(ness.)alkyl, R2matter specified in claim 1, a R1denotes a halogen atom.

6. The compound of formula I according to claim 5, which is a

ethyl ester of 3-fluoro-6-methyl-N-imidazo[1,5-a]pyrimido[5,4-d] [1]benzazepine-10-carboxylic acid,

ethyl ester of 3-fluoro-6-propyl-N-imidazo[1,5-a]pyrimido[5,4-d] [1]benzazepine-10-carboxylic acid,

ethyl ester of 3-fluoro-6-(1-methylethyl)-N-imidazo[1,5-d]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid,

ethyl ester of 6-cyclopropyl-3-fluoro-N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid, or

ethyl ester of 3-bromo-6-methyl-N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid.

7. The compound of formula I according to claim 1, in which R3refers to a group of 1,2,4-oxadiazolyl or isoxazolyl, optionally substituted (ness.)the alkyl or C3-C7cycloalkyl, R2means (ness.)alkyl, n denotes 0 or 1, a R' denotes a halogen atom.

8. The compound of formula I according to claim 7, which is 10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-methyl-N-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepin or 2-bromo-11-methyl-7-(5-methylisoxazol-3-yl)-8H-4b,6,10,12-tetraethylene[e,g]azulene.

9. Drug, having affinity and selectivity for binding site α5 Retz is ptor GABA And comprising one or more compounds of the formula I according to claims 1-8 and pharmaceutically acceptable excipients.

10. The drug according to claim 9 for the treatment of diseases caused by subunit α5 GABA A.



 

Same patents:

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

FIELD: organic chemistry, labeled compounds.

SUBSTANCE: invention relates to a new highly labeled compound that represent an analog of the known physiologically active compound that is the strongest toxin and inhibitor of some viable important processes, for example, sodium ions transporting. [3H]-Saxitoxin dihydrochloride highly labeled with tritium corresponds to the formula: .

EFFECT: valuable properties of compound.

1 ex

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

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

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>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to a method for producing a condensed polycyclic alkaloids of General formula I, including new, including phase cyclization of azometynoylid General formula II, where a is optionally substituted aryl, Z is oxygen, n = 1, Y is optionally substituted aryl, W and X together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group, possibly substituted and possibly condensed with aryl, carbocyclic or heterocyclic group

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

The invention relates to polypeptide to the compound of General formula I, where R1indicates the lowest alkanoyl, substituted unsaturated 6-membered heterophilically group containing at least one nitrogen atom which may have one or more suitable substituents; lower alkanoyl, substituted 1,2,3,4-tetrahydroisoquinoline, which may have one or more suitable substituents; lower alkanoyl, substituted unsaturated condensed heterocyclic group containing at least one oxygen atom, which may have one or more suitable substituents, or pharmaceutically acceptable salts

-,or- cyclodextrin or its alkyl - or hydroxyalkylated and (6r)- or (6s)-5,10-methylenetetrahydrofolic acid or a salt thereof, a method of stabilizing aqueous solutions and the method of obtaining stable solutions" target="_blank">

The invention relates to new compounds include,-,or-cyclodextrin or its alkyl - or hydroxyalkylated and (6R)-, (6S) - or (6R,S)-5,10 - methylenetetrahydrofolic acid or its salts, stable solutions of compounds include cyclodextrin, a method of stabilizing aqueous solutions and the way to obtain stable solutions, which can be used in the pharmaceutical industry

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

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

FIELD: organic chemistry, labeled compounds.

SUBSTANCE: invention relates to a new highly labeled compound that represent an analog of the known physiologically active compound that is the strongest toxin and inhibitor of some viable important processes, for example, sodium ions transporting. [3H]-Saxitoxin dihydrochloride highly labeled with tritium corresponds to the formula: .

EFFECT: valuable properties of compound.

1 ex

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

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine of the formula (I): , wherein R1 means halogen atom or (lower)alkyl; R2 means hydrogen atom, (lower)alkyl, (C3-C7)-cycloalkyl, -(CH2)m-phenyl wherein phenyl ring can be substituted with (lower)alkoxy-group or it means -(CH2)m-indolyl; R3 means -C(O)O-(lower)alkyl, -C(O)OH or five-membered heteroaromatic group comprising nitrogen and oxygen atoms as heteroatoms and wherein rings can be substituted with (lower)alkyl or (C3-C7)-cycloalkyl; n means 0, 1 or 2; m means 0, 1 or 2, and their pharmaceutically acceptable acid-additive salts. Compounds of this class elicit the high degree and selectivity to binding sites of GABA A α5-receptor and can be used in treatment of the conception enhancer or disorders of cognitive ability similar with Alzheimer's disease.

EFFECT: valuable medicinal properties of derivatives.

10 cl, 6 sch, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel imidazo-condensed compounds of the general formula (I): wherein Z represents nitrogen atom (N); Z1 represents N whein a bond between C5 and Z1 represents a simple bond, and Z1 represents carbon atom (C) when a bond between C5 and Z1 represents a double bond; R1 represents hydrogen atom; R2 represents (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, phenyl-(C1-C4)-alkyl substituted with halogen atom, ((C1-C4)-alkyl)-SO2, (C1-C6)-alkyl, (C5-C6)-cycloalkyl possibly substituted with hydroxy-group, phenyl substituted with halogen atom, heterocyclyl possibly substituted and chosen from group consisting of tetrahydropyranyl, (N-methylsulfonyl)piperidinyl or tetrahydro-1,1-dioxide-2H-thiopyranyl; A is absent or represents -O-; a bond between C5 and Z1 is a simple or double bond; a bond between C8 and C9 is a simple or double bond; Y represents phenyl substituted with halogen atom, or their pharmaceutically acceptable salts possessing inhibitory activity with respect to p38 MAP kinase, and pharmaceutical composition containing thereof. Proposed compounds can be used, for example, in treatment/or prophylaxis of such diseases as rheumatic arthritis, fever and reduced bone resorption.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of 5-aminopyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine of the general formula: wherein R means furanyl, possibly substituted pyrrolyl, possibly substituted pyridyl, possibly substituted phenyl or (C4-C6)-cycloalkenyl; X means (C2-C6)-alkylene or -C(O)CH2-; Y means the following groups: -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)- wherein R2 and R3 mean hydrogen atom or (C1-C6)-alkyl, -O-, -S-, -CH2S-, -(CH2)2-NH- or compound of the formula: wherein Q means or R4 means hydrogen atom or (C1-C6)-alkyl, or two R at one carbon atom form group =O; Z means phenyl comprising from 1 to 5 of different substitutes, phenylalkyl or heteroaryl, diphenylmethyl and other values; or Z and Y in common can form substituted piperidinyl or substituted phenyl also possessing activity of antagonist of A2a adenosine receptors. Also, invention relates to a pharmaceutical composition based on these compounds, using novel compounds for preparing medicinal agents in treatment, for example, Parkinson's disease, and two methods for synthesis of intermediate compounds of formulae (II) and (IIIa) .

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 17 tbl, 29 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) and their pharmaceutically acceptable salts with antagonistic properties towards adenosine A2A receptor, which can be used for treating central nervous system diseases such as Parkinson's disease. In general formula (I) , R is ,, R1, R2, R3, R4 and R5 is independently selected from a group which consists of hydrogen; R6 is hydrogen, (C1-C6)alkyl or -CH2F; R7, R8 and R9 are independently selected from a group which consists of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, haloid and -CF3; Z is R10-phenyl, R10-5-6-member heteroaryl, which contains 1 or 2 hetwroatoms, selected from nitrogen or from nitrogen and oxygen, possibly condensed with a benzene ring, or ; R10 represents 1 to 3 substitutes, independently selected from a group which consists of hydrogen, (C1-C6)-alkyl, hydroxy, (C1-C6)-alkoxy, hydroxy-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, (di-(C1-C6)-alkoxy)-(C1-C6)-alkyl, (hydroxy)-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C6)-cycloalkyloxy, (C3-C6)-cycloalkyl-O-(C3-C6)-alkoxy, (C1-C6)-alkyl-SO2-, (C1-C6)-alkyl-SO-, haloid, -CN, cyano-(C1-C6)-alkyl, -CHF2, -CF3, -C(O)R13, -C(O)O-(C1-C6)-alkyl, -N(R11)(R12), N(R11)(R12)- (C1-C6)-alkyl, - C(O)N(R13)(R16), R11-5-6-member nitrogen-containing heteroaryl, possibly condensed with a benzene ring, R15-5-6-member heterocycoalkyl, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-(C1-C6)-alkyl, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-(C1-C6)-alkoxy, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-oxy, with 1 or 2 heteroatoms in a heterocyclic ring selected from nitrogen and oxygen, CF3-(C1-C4)alkylene-O-(C1-C6)alkyl, CF3-hydroxy(C1-C6)alkyl, cyano-(C1-C6)-alkoxy, (C1-C4)alkylene-C(O)-O-(C1-C6)alkyl, -SO2-N((C1-C4)alkyl)2, ((C3-C4)cycloalkyl)hydroxy(C1-C6)alkyl, (hydroxy(C1-C6)alkyl)-(C1-C4)alkoxy, (dihydroxy)-(C1-C6)-alkyl, (dihydroxy)(C1-C6)alkoxy, -C(=NOR17)- (C1-C6)alkyl and -C(=NOR17)-CF3; or two R10 groups, on neighbouring carbon atoms of the ring, together form -O-CH2-O-, -O-(CH2)2-O-, -CH2-O(CH2)2-O-, -O-(CH2)2-, -(CH2)3-O-, -O-(CH2)3-O, -(CH2)3-, where the ring, formed by two R10 substitutes and ring carbon atoms with which they are bonded, is substituted with R16; or two R10 groups on neighbouring ring carbon atoms, together form -O(CH2)3CH((OR18)-, each R11 is independently selected from a group which consists of hydrogen and (C1-C6)alkyl; each R12 is independently selected from a group which consists of (C1-C6)alkyl, hydroxy(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, ((C1-C6)alkoxy)hydroxy(C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkyl-C(O)-, -SO2(C1-C6)alkyl; R13 is hydrogen, (C1-C6)alkyl or -CF3; R14 is (C1-C6)alkoxy-C(O)-; R15 represents 1 to 3 substitutes, independently selected from a group which consists of (C1-C6)alkoxy, hydroxy-(C1-C6)alkyl; or two R15 substitutes, taken together with the carbon atom with which they are bonded, form a -C(=O)- group; R16 is (C1-C6)alkoxy(C1-C6)alkyl, hydroxy or hydroxy(C1-C6)alkyl; R17 is hydrogen or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: increased effectiveness of composition and method of treatment.

17 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

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