Derivatives of 8-oxo-5,8-dihydro-6h-dibenzo[a,g]chinolin-13 - propanoic acid, method for their production and pharmaceutical composition


C07D455/03 - containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine

 

(57) Abstract:

The invention relates to compounds of General formula I

< / BR>
in which X represents a hydrogen atom or halogen, (C1-C3)alkyl group, one or two (C1-C3)alkoxy group, or triptorelin group, Y is a hydrogen atom or halogen, (C1-C3)alkyl or (C1-C3)alkoxygroup, R represents a hydroxy group, a methoxy group, or a group of the General formula NR2R3in which R2and R3each independently represents a hydrogen atom, (C1-C4)alkyl group, 2-methoxyaniline group, 3-methoxyaniline group, 3-aminopropyl group, group 2-(dimethylamino)ethyl group, 3-(dimethylamino)propyl or 2-piperidine-2-retil, or R2and R3form together with the nitrogen atom to which they are connected, morpholine, pyrolidine or pieperazinove ring which may have in position 4 Deputy in the form of a methyl group or groups (1,1-dimethylmethoxy)carbonyl, in the form of free bases or salts formed by the addition of acid. The compounds of formula I have activity binding (benzodiazepine)receptors, ascolani, associated with impaired GABAA- ergicheskoe transfer GABAAreceptors, suryadinata1,2,3and5. A method of obtaining the compounds and pharmaceutical composition thereof. 3 S. p. f-crystals, 1 table.

The object of the present invention are derivatives of 8-oxo-5,8-dihydro-6H-dibenzo[a, g] chinolin-13-propanoic acid, their preparation and use in therapy.

Connection in accordance with the present invention satisfies the General formula (I)

< / BR>
in which X represents a hydrogen atom or halogen or (C1-C3)alkyl group, one or two (C1-C3)alkoxy group or triptorelin group

Y represents a hydrogen atom or halogen, (C-C3)alkyl group or (C1-C3)alkoxy group,

R represents a hydroxy group, methoxy group, or a group of the General formula NR2R3where R2and R3, independently of one another, each represents a hydrogen atom, (C1-C4)alkyl group, 2-methoxyaniline group, 2-aminoethyl group, 3-aminopropyl group, group 2-(dimethylamino)ethyl group, 3-(dimethylamino)propyl or 2-piperidine-1-retil, or LM pieperazinove ring, which may have a substituent in position 4 in the form of a methyl group, or (1,1-dimethylmethoxy)carbonyl group.

These compounds may in some cases exist as bases or salts formed by the addition of acids. In accordance with the invention compounds of General formula (I) can be obtained according to the method shown in scheme 1 (see the end of the description).

The anhydride of General formula (II) in which X is as defined previously, result in interaction with Eminem formula (III) in which Y is as previously defined, in an aromatic solvent, for example toluene, at a temperature of from 70 to 100oC. Get the acid of General formula (IV), which atrificial by the action of thionyl chloride in methanol at a temperature of from 20 to 50oC, then thus obtained ester of General formula (V) is transformed into alcohol of General formula (VI), for example, using mixed hydride such as borohydride sodium, in the ether solvent such as tetrahydrofuran. Then the alcohol is oxidized to the aldehyde of General formula (VII), for example according to the method Swarna obtained aldehyde is treated with methyl ether (dimethoxyphosphinyl)acetic acid (MEDPAC) in ethereal solvent such as tetrahydrofuran, at employ ether of General formula (IX) with quinone, for example 2,3-dichloro-5,6-disentitles-2,5-diene-1,4-dione, for example in an aromatic solvent such as toluene, at a temperature of from 70 to 110oC, and, finally, an ester of General formula (IX) is subjected to hydrogenation in the presence of palladium charcoal, obtaining a complex ester of General formula (Ia), which corresponds to General formula (I), where R represents a methoxy group.

This ester can then be converted, as shown in scheme 2 (see the end of the description): if you want to obtain the compound of General formula (I), where R represents a hydroxy group, an ester of General formula (Ia) is subjected to hydrolysis in an alkaline medium to obtain the acid of General formula (Ib) and, if you want to obtain the compound of General formula (I), where R represents a group of the General formula NR2R3the acid of General formula (Ib) is treated with an amine of General formula HNR2R3passing through the intermediate imidazole obtained in situ by using N,N-carbonyldiimidazole.

In the case of compounds of General formula (I), where X and Y are different from the alkoxy group, you can use another method, shown in scheme 3 (see end of description).

Dibenzo[a, g] hemolysin General formula (X) is subjected to processing oxy the (XI), then the aldehyde is treated with methyl ether (dimethoxyphosphinyl)acetic acid in ethereal solvent such as tetrahydrofuran at a temperature of from 20 to 65oC, obtaining a complex ester of General formula (IX), which is finally treated as described on this matter in the scheme 1.

Source anhydride of General formula (II) available for sale, when X represents hydrogen, and, in other cases, it can be obtained by a method such as the method described in Arch. Pharm. (1991) 324 509-518.

Substituted imine General formula (III) can be obtained by methods similar to those described in Synthesis (1974) 4 288-289 and Heterocycles (1982) 19(4) 653-656. Hemolysin General formula (X) can be obtained by methods similar to those described in Synthesis (1980) 10 845-847 and in Tetrahedron Lett. (1992) 33(38) 5653-5654.

The following examples illustrate the obtaining of some compounds according to the invention. Elemental microanalysis, IR and NMR spectra confirm the structures of the obtained compounds. The numbers in brackets in the titles of the examples correspond to the numbers in the first column of the table below. In the names of compounds dash "-" is part of the word, and the dash "_" only serves to transfer at the end of the line; it should be omitted in the absence of the new ester of 8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin-13-propanoic acid.

1.1. 8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin - 13-carboxaldehyde.

Cooled to 0oC, in an atmosphere of argon, 150 ml of dry N,N-dimethylformamide, is added dropwise 5 ml (53.6 mmol) of phosphorus oxychloride, the mixture is stirred for 30 min at room temperature, add 5 g (20,2 mmol) 5,6-dihydro-8H-dibenzo[a,g]chinolin-8-she, the mixture is gradually heated to 110oC and kept at this temperature for 6 hours

Cool it to room temperature, the solvent is evaporated under reduced pressure, add to the residue ice and 30% sodium hydroxide solution, extracted with a mixture of dichloromethane, the organic phase is dried over sodium sulfate, filtered it, and the solvent is evaporated under reduced pressure. The residue is purified chromatographically on a column of silica gel, elwira with a mixture of cyclohexane/dichloromethane, changing the composition of from 100/0 to 0/100, then a mixture of dichloromethane/ethyl acetate composition from 100/0 to 80/20. After recrystallization from cyclohexane allocate 3.6 g (13,08 mmol) of the aldehyde in the form of a white solid.

Melting point: 209-210oC.

1.2. Methyl ester (E)-3-(8-oxa-5,8-dihydro-6H-dibenzo[a, g]chinolin-13-yl)prop-2-ene acid.

In an argon atmosphere is dry tetrahydrofuran, cool the mixture in an ice bath, is added dropwise to 2 g (11 mmol) of methyl ether (dimethoxyphosphinyl)acetic acid, the mixture is stirred for 15 min at 0oC add 2,78 g (10.1 mmol) of 8-oxo-5,8-dihydro-6H-dibenzo[a, g] chinolin-13-carboxaldehyde, the mixture is gradually heated under reflux to boiling and boiled for 6 hours

Cool the mixture to room temperature, add a few ml of methanol, evaporated the solvent under reduced pressure, add to the residue ice, 200 ml of dichloromethane and 1 M hydrochloric acid, the organic phase is separated, dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The residue is purified chromatographically on a column of silica gel, elwira a mixture of dichloromethane/ethyl acetate, changing the composition of from 100/0 to 80/20, and the recrystallized product from cyclohexane. Allocate 2,78 g (8.4 mmol), unsaturated complex ester in the form of white crystals.

Melting point: 201-202,5oC.

1.3. Methyl ester of 8-oxo-5,8-dihydro-6H-dibenzo[a, g]chinolin-13-propanoic acid.

To a solution of 2.8 g (8.4 mmol) of methyl ester of (E)-3-(8-oxo-5,8-dihydro-6H-dibenzo[a, g] chinolin-13-yl)prop-2-ene acid in 150 ml okpara at a pressure of about 0.32 MPa at room temperature for 30 min, then at 40-45oC for 2 h 30 min

The catalyst is separated by filtration, concentrate the filtrate under reduced pressure, to the residue add 250 ml of dichloromethane, ice water and a saturated solution of sodium bicarbonate, the organic phase is separated, washed with water and dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The residue is purified chromatographically on a column of silica gel, using as eluent a mixture of dichloromethane/ethyl acetate from 100/0 to 70/30, then a mixture of dichloromethane/methanol from 95/5 to 90/10, and obtain 2.8 g (8.4 mmol) of oily product. After recrystallization from cyclohexane allocate 2.5 g (7.5 mmol) of ester as white crystals.

Melting point: 157-158,5oC.

Example 2 (Compound No. 2)

8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin-13-propanoic acid.

In a flask with a capacity of 100 ml injected at 2.45 g (7,35 mmol) of methyl ester of 8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin-13-propanoic acid, dissolved in 40 ml of ethanol, add 2 ml of 30% aqueous sodium hydroxide solution and the mixture is refluxed for 3 hours

The solvent is evaporated under reduced pressure, the residue processing is shat. Obtain 2.2 g (6,89 mmol) of the acid.

Melting point: 269-271oC (decomposition).

Example 3 (Compound No. 12)

N,N-dimethyl-8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin-13-propanamide.

In the flask with a capacity of 250 ml in an argon atmosphere to prepare a suspension of 1.2 g (3,76 mmol) of 8-oxo-5,8-dihydro-6H-dibenzo[a, g]chinolin-13-propanoic acid in 100 ml of dichloromethane, added 1.2 g (7.4 mmol) of N,N'-carbonyldiimidazole and stirred at room temperature for 2 h

The reaction mixture was saturated with gaseous dimethylamine for 1 min and left under stirring for 12 h the Solvent is evaporated under reduced pressure, to the residue is added 200 ml of dichloromethane, washed with a solution of 1 N. hydrochloric acid, then water, then 1 N. a solution of sodium hydroxide, then with water again, dried over sodium sulfate, filtered, evaporated the solvent under reduced pressure and purify the residue is chromatographically on a column of silica gel, using as eluent a mixture of dichloromethane/methanol from 100/0 to 90/10. After recrystallization from a mixture of acetonitrile/dichloromethane get 0,93 g (2.68 mmol) of white solid.

Melting point: 192.5 kg-of 193.5oC.

Example 4 (Compound N 38)
3,13 a-tetrahydro-6H-dibenzo[a,g]chinolin-13-carboxylic acid.

In a flask with a capacity of 500 ml is injected to 8.1 g (42,15 mmol) 7-methoxyisoflavone anhydride in solution in 350 ml of toluene, added 5.8 g (a 44.2 mmol) of 3,4-dihydroisoquinoline, and the mixture is refluxed for 3 hours allowed to cool to room temperature and left overnight.

Collect the resulting crystals are washed them diethyl ether and dried in vacuum. Get was 12.75 g (39,43 mmol) of the acid as a mixture of TRANS/CIS about 90/10.

Melting point: 227-232oC.

4.2. Methyl ester of TRANS-10-methoxy-8-oxo-5,8,13,13 a-tetrahydro-6H - dibenzo[a,g]chinolin-13-carboxylic acid.

In a three-neck flask with a capacity of 500 ml of preparing a suspension of 14 g (43,3 mmol) of 10-methoxy-8-oxo-5,8,13,13 a-tetrahydro-6H-dibenzo[a, g] chinolin-13-carboxylic acid in 100 ml of methanol, is added dropwise 3.2 ml (44,11 mmol) of thionyl chloride and boil the mixture under reflux for 4 h

Leave it at room temperature overnight. The resulting crystals are collected, washed with diethyl ether and dried in vacuum. Get 11.5g (34,08 mmol) of pure TRANS-ether.

Melting point: 154,5-157,5oC.

4.3. TRANS-13-(hydroxymethyl)-10-methoxy-5,6,13,13 a-tetrahydro-8H-dibenzo[a,g]finalizes-10-methoxy-8-oxo-5,8,13,13 a-tetrahydro-6H-dibenzo[a, g] chinolin-13-carboxylic acid and 75 ml of tetrahydrofuran, add sequentially 4.68 g (146 mmol) of methanol and 5,52 g (146 mmol) of sodium borohydride and stirred the mixture at room temperature for 4 h

Hydrolyzing the mixture, adding 100 ml of water, extracted three times with dichloromethane (150 ml), dried the organic phase over sodium sulfate, evaporated the solvent under reduced pressure and purify the residue is chromatographically on a column of silica gel, using as eluent a mixture of dichloromethane/ethyl acetate from 100/0 to 50/50. After evaporation of the solvent extract crystals of ethyl ether and finally get to 8.3 g (26,83 mmol) of TRANS-alcohol.

Melting point: 180-181,5oC.

4.4. 10-methoxy-8-oxo-5,8,13,13 a-tetrahydro-6H-dibenzo[a,g]chinolin-13-carboxaldehyde.

In a three-neck flask of 500 ml in an atmosphere of argon is injected at 20.2 g (159 mmol) of oxalicacid and 100 ml of dichloromethane, cooled to all -70oC, is added dropwise 16,36 g (209 mmol) of dimethyl sulfoxide, dissolved in 50 ml of dichloromethane, and all was stirred at -70oC for 15 minutes

Added during 30 min of 8.2 g (26,68 mmol), TRANS-13-(hydroxymethyl)-10-methoxy-5,6,13,13-tetrahydro-8H - dibenzo[a, g] chinolin-8-he (209 mmol) of triethylamine, dissolved in 50 ml of dichloromethane, and leave the mixture to warm to room temperature.

Pour 500 ml of a saturated aqueous solution of sodium chloride and extracted three times with dichloromethane (200 ml). The organic phase is dried over sodium sulfate, filtered and evaporated the solvent under reduced pressure. The residue is purified chromatographically on a column of silica gel, using as eluent a mixture of dichloromethane/cyclohexane 2/1, then 1/0, then a mixture of dichloromethane/ethyl acetate from 90/10 to 50/50.

After crystallization from a mixture of ethyl acetate and petroleum ether get 8,02 g (26,09 mmol) of the aldehyde in a mixture of TRANS/CIS 80/20.

Melting point: 146-149oC.

4.5. Methyl ester (E)-3-(10-methoxy-8-oxo-5,8,13,13 a - tetrahydro-6H-dibenzo[a,g]chinolin-13-yl)prop-2-ene acid.

In a three-neck flask with a capacity of 500 ml washed with pentane 1,3 g (32.5 mmol) of sodium hydride as a 60% suspension in oil, prepare the suspension in 200 ml of tetrahydrofuran, cool the suspension to 0oC, is added dropwise to 5.2 g (28,55 mmol) methyl ether (dimethoxyphosphinyl)acetic acid and continue to mix at approximately 10oC for 20 minutes Add 8 g (26 mmol) of 10-methoxy-8-oxoa 4 h 30 min

Allow the mixture to cool to room temperature, add a few drops of methanol, evaporated the solvent under reduced pressure, add to the residue in 250 ml of water and extracted three times with dichloromethane (150 ml). Dried the organic phase over sodium sulfate, filtered, the solvent is evaporated under reduced pressure and the residue is purified chromatographically on a column of silica gel, elwira a mixture of ethyl acetate/cyclohexane 1/2 to 3/1, and get 6,55 g (18,02 mmol) of ester in the form of oil, which is used as is in the next step.

4.6. Methyl ester (E)-3-(10-methoxy-8-oxo-5,8-dihydro-6H-dibenzo[a,g] chinolin-13-yl)prop-2-ene acid.

In the flask 500 ml dissolve 5.5 g (15,13 mmol) methyl ester (E)-3-(10-methoxy-8-oxo-5,8,13,13 a-tetrahydro-6H - dibenzo[a, g]chinolin-13-yl)prop-2-ene acid in 150 ml of toluene, add 5,15 g (22.7 mmol) 2,3-dichloro-5,6-disentitles-2,5 - diene-1,4-dione and boil the mixture under reflux for 2 h 30 min

Allow to cool to room temperature, the solvent is evaporated under reduced pressure and the residue is purified chromatographically on a column of silica gel, elwira a mixture of dichloromethane/ethyl acetate composition from 100/0 to 80/20. Remove the oil obtained from portocristo.

Melting point: 149-152oC.

4.7. Methyl ester of 10-methoxy-8-oxo-5,8-dihydro-6H - dibenzo[a,g]chinolin-13-propanoic acid.

To a solution of 3.5 g (9,68 mmol) methyl ester (E)-3-(10-methoxy-8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin-13-yl)prop-2-ene acid in 100 ml acetic acid is added 0.5 g of 5% palladium carbon and the suspension hydrogenizing in a Parr apparatus at a pressure of about 0.32 MPa at a temperature of from 50 to 60oC for 3 h

Allow to cool to room temperature, separating the catalyst by filtration, the filtrate is concentrated under reduced pressure, add to the residue in 250 ml of dichloromethane, washed with a solution saturated aqueous solution of hydrocarbonate sodium, dried over sodium sulfate, filtered and evaporated the solvent under reduced pressure. The residue is purified chromatographically on a column of silica gel, elwira a mixture of dichloromethane/ethyl acetate composition from 100/0 to 50/50, and obtain 3.4 g (9,36 mmol) of ester in the form of oil, which is used as is in the next step.

4.8. 10-methoxy-8-oxo-5,8-dihydro-6H-dibenzo[a, g]chinolin-13 - propanoic acid.

In a flask with a capacity of 100 ml injected 3.4 g (9,36 mmol) of the methyl ester of 10-methoxy-8-oxo-5,8-dihydro-6H-droxia sodium and the mixture is refluxed for 3 hours

Evaporated the solvent under reduced pressure, to the residue water is added and 30% hydrochloric acid, collecting fallen in the sediment solid phase, washed with water and dried. The result is 3.0 g (8.58 mmol) of the acid. Melting point: 260-264oC.

Example 5 (Compound No. 40)

10-methoxy-N-methyl-8-oxo-5,8-dihydro-6H-dient[a, g]chinolin-13 - propanamide.

In the flask with a capacity of 250 ml in the atmosphere of argon prepare a suspension of 1 g (2,86 mmol) of 10-methoxy-8-oxo-5,8-dihydro-6H - dibenzo[a,g]chinolin-13-propanoic acid in 100 ml of dichloromethane, added with 0.93 g (5,72 mmol) of N, N'-carbonyldiimidazole and stirred the mixture at room temperature for 2 h

The mixture is then saturated with gaseous methylamine for 1 min and continue stirring for 22 h

Evaporated the solvent under reduced pressure, to the residue is added 200 ml of dichloromethane, the solution is washed with water, then with 1 N. hydrochloric acid, then 1 N. a sodium hydroxide solution, again with water, dried over sodium sulfate, filtered, the solvent is evaporated under reduced pressure and purify the residue is chromatographically on a column of silica gel, using as eluent a mixture of dichloromethane/methanol composition from 100/0 to veshestva.

Melting point: 182-183oC.

The table at the end of the description illustrates the chemical structures and physical properties of some compounds in accordance with the invention.

Compounds in accordance with the present invention were subjected to pharmacological tests which have demonstrated their usefulness as therapeutically active substances.

The study of membrane binding in relation to population (benzodiazepine) receptors associated with GABAAreceptors containing the subunit5.

These receptors can be selectively marked membranes of rat hippocampus, incubated in the presence of [3H]flumazenil and 5 μm zolpidem (to block other receptor subtypes).

Compounds in accordance with the present invention have been the subject of studies in vitro in relation to their affinity to receptors labeled with [3H]flumazenil.

Used male OFA rats (Iffa Credo) weighing 200 to 250 g After the decapitation took the hippocampus, and crushed it with the help of Ultra-TurraxTMor transmitter stationTMfor 20 s at 6/10 maximum speed of 80 volumes of 50 mm bufernogo and 5 mm potassium chloride.

The binding of [3H] - flumazenil (1 nm; specific activity: 80-87 CI/mmol; Du Pont de Nemours/New England Nuclear) was determined by incubating 200 μl of the suspension of membranes in a final volume of 1 ml of buffer solution containing 5 μm zolpidem and tested the connection. After incubation for 45 min at 0oC membranes are filtered in filters Whatman GF/BTMthat washed twice with 5 ml ice-cold buffer solution. Liquid scintigraphy determines the amount of radioactivity retained by the filter.

Specific binding of [3H] flumazenil defined as the amount of radioactivity retained on the filters, and which can be ingibirovany co-incubation with 1 μm of flunitrazepam. For each concentration of tested compound determine the percentage of inhibition of binding of [3H]flumazenil, then the concentration CI50the concentration that inhibits 50% of specific binding.

Compounds in accordance with the present invention, the most active in this trial have CI50order from 1 to 100 nm.

The study of membrane binding of2(benzodiazepine type II)receptors associated with GABAAreceptors in the pain is on the brain were determined using variations of the method, described S. Z. Langer and S. Arbilla in the Fund. Clin. Pharmacol. (1988) 2 159-170, with the use of [3H]flumazenil instead of [3H]diazepam as a radioactive ligand.

The spinal-cord tissue homogenized for 60 s and 30 volumes of ice-cold buffer solution (50 ml Tris/HCl, pH/of 7.4, NaCl 120 mm, KCl 5 mm), then, after dilution 1/3 the suspension is incubated with [3H] - flumazenil (specific activity: 78 CI/mmol; New England Nuclear) at a concentration of 1 nm and compounds in accordance with the present invention in different concentrations in a final volume of 525 ml. After 30 min incubation at 0oC samples filtered in a vacuum filter Whatman GF/BTMand immediately washed with ice-cold buffer solution. Specific binding of [3H]flumazenil determined in the presence of 1 μm unlabeled diazepam. Data analyzed by conventional methods and calculate CI50the concentration that inhibits 50% of the binding of [3H]flumazenil.

Values of CI50compounds according to the present invention in this test are between 1 and 500 nm.

The study of membrane binding1(benzodiazepine type I) receptors associated with GABAAreceptors containing the subunit1.

3H]flumazenil instead of [3H]diazepam as a radioactive ligand.

Fabric cerebellum was homogenized for 60 s in 120 volumes of ice-cold buffer solution (50 ml Tris/HCl, pH 7,4, NaCl 120 mm, KCl 5 mm), then, after dilution 1/3, incubated in suspension with [3H] - flumazenil (specific activity: CI/mmol, New England Nuclear) at a concentration of 1 nm and compounds in accordance with the invention in different concentrations in a final volume of 525 ml. After incubation for 30 min at 0oC samples filtered in a vacuum filter Whatman GF/BTMand immediately washed with ice-cold buffer solution. Specific binding of [3H]flumazenil was determined in the presence of 1 ám its diazepam. Data were analyzed by conventional methods and expected CI50the concentration that inhibits 50% of the binding of [3H]flumazenil.

Values of CI50compounds according to the invention in this test are between 1 and 500 nm.

The results of the tests carried out with the compounds according to the invention show that, in vitro, some of them selectively displace [3H] flumazenil from its sites of membrane binding is asimi subunit 5compared with subtype receptors1associated with GABA receptorsAcontaining subunit1and compared to the sum 2(benzodiazepine type II) receptors associated with GABA receptorsAcontaining the most subunit2and3.

Other compounds have a strong affinity for the sub5,1,2and3and are not selective. In other words, these compounds have an affinity

- strong to sites of membrane binding of [3H]flumazenil in relation to population (benzodiazepine) receptors associated with GABAAreceptors containing the subunit5,

- strong, medium or weak subtypes1(benzodiazepine type I) receptors associated with GABAAreceptors containing the subunit 1,

- strong, medium or weak to conjunction2(benzodiazepine type II) receptors associated with GABAAreceptors, most containing subunit2and3.

Selectivity represented by the ratio CI501-cerebellum/CI50the hippocampus lies between 1 and 25, and selectivity, before the x2">

Compounds in accordance with the invention can be used in the treatment of diseases associated with impaired GABAA-ergicheskoe transfer GABAAreceptors associated with subunit5. The preferred distribution of receptors associated with subunit5GABAAreceptor complex, in the olfactory bulb, in the limbic structures such as the hippocampus and hypothalamus, and spinal cord suggests that the compounds in accordance with the invention can be used in the treatment of disorders of smell, cognitive function, hormonal disorders associated with dysfunction of the hypothalamus, some emotional disorders and disorders of pain perception. They can also be used in the treatment of spastic reactions and muscle contractures.

Compounds in accordance with the present invention similarly can be used to treat diseases associated with impaired GABA-ergicheskoe transfer GABAAreceptor-related subunits1,2and3i.e. for the treatment of anxiety, sleep disorders, epilepsy and abnormalities that occur in the treatment of alcoholism. Finally, they may be used which may be represented in all galenic forms in combination with suitable eccipienti, for enteral or parenteral administration, for example in the form of tablets, pills, gels, capsules, solutions or suspensions for drinking or injection of suppostories and so on, dosed so that the daily dose of the active substance ranged from 1 to 1000 mg.

Examples of pharmaceutical compounds

Solution for injection:

Active principle 5 mg;

Glucose is 250 mg;

Water for injection as necessary to obtain 5 ml of solution per 5 ml ampoule.

Gelatin capsule:

Active principle, 100 mg;

Talc - 24 mg;

Silica gel - 1 mg for one 125 mg capsule.

Tablet:

The active principle is 400 mg;

Silica gel 10 mg;

Stearic acid 20 mg;

Corn starch - 45 mg per 475 mg tablet.

Syrup:

Active principle 5 g;

Methyl ester of 4-hydroxybenzoic acid 150 mg;

Saccharose - 50 g;

Distilled water as necessary to obtain 100 ml of solution per one 100 ml bottle.

1. Derivatives of 8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin-13-propanoic acid of General formula I

< / BR>
in which X represents a hydrogen atom or halogen, (C1-Cdstanley a hydrogen atom or halogen, (C1-C3)alkyl group or (C1-C3)alkoxy group;

R represents a hydroxy group, methoxy group, or a group of the General formula NR2R3in which R2and R3each independently represents a hydrogen atom, (C1-C4)alkyl group, 2-meixoeiro group, 2-aminoethyl group, 3-aminopropyl group, group 2-(dimethylamino)ethyl group, 3-(dimethylamino)propyl or 2-piperidine-1-retil, or R2and R3form together with the nitrogen atom to which they are connected, morpholine, pyrolidine or pieperazinove ring which may have in position 4 Deputy in the form of a methyl group or groups (1,1-dimethylmethoxy)carbonyl,

in the form of free bases or salts formed by the addition of acid.

2. The method of obtaining derivatives of 8-oxo-5,8-dihydro-6H-dibenzo[a,g]chinolin-13-propanoic acid under item 1, characterized in that the anhydride of General formula II

< / BR>
in which X is as defined in paragraph 1, the lead in the interaction with Eminem General formula III

< / BR>
in which Y is as defined in paragraph 1, to obtain the acid of General formula IV

< / BR>
which etherification with thionyl chloride in IU the mules VI

< / BR>
and then the alcohol is oxidized to the aldehyde, the General formula VII

< / BR>
then the aldehyde is treated with methyl ether (dimethoxy-phosphinyl)acetic acid, and produce thus obtained ester of General formula VIII

< / BR>
then oxidizes this ester in the ester of General formula IX

< / BR>
and finally, this ester is subjected to catalytic hydrogenation to obtain a complex ester of General formula Ia

< / BR>
which corresponds to the General formula I, in which R represents a methoxy group, then, if you want to obtain the compound of General formula I, in which R represents a hydroxy-group, an ester of General formula Ia is subjected to hydrolysis to obtain the acid of General formula Ib

< / BR>
and, if you want to obtain the compound of General formula I, in which R represents a group of the General formula NR2R3the acid of General formula Ib is treated with the amine of General formula HNR2R3.

3. Pharmaceutical composition for binding (benzodiazepine) receptors associated with GABAAreceptors, characterized in that it contains a connection on p. 1 in combination with excipients.

 

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FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to derivatives of camptothecin of the general formula (I): wherein R1 represents alkyl or their pharmaceutically acceptable salts. Compounds of the formula (I) are intermediate compounds used in synthesis of camptothecin derivatives that possess anticancer activity.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 ex

FIELD: medical engineering.

SUBSTANCE: pill taken per os comprises pharmaceutically active agent selectable from (S,S)-Reboxetin or its salt and Pramipexol or its salt. The pharmaceutically active agent is taken in the amount of 0.01% by mass to 25% by mass of composition. It is dispersed in matrix composed of hydrophilic polymer and starch having rupture strength of at least approximately 0.15 kN·cm-2, at least approximately 0.175 kN·cm-2 or at least approximately 0.2 kN·cm-2, when having solid substance usable for producing pills where hydrophilic polymer takes approximately 20-70% by mass and starch is available in the amount of approximately 25-75% by mass. Method involves determining starch usability and composition applicability for treating the cases of disorders and states selected from depressive psychosis, neuropathic pains and Parkinson disease. Starch of specified rupture strength allows pill to withstand high speed pelletization operation and to provide prolonged drug release and to take a pill once a day.

EFFECT: controlled and prolonged drug action; enhanced effectiveness of treatment.

21 cl, 9 tbl

FIELD: medicine.

SUBSTANCE: preparation contains chemical compound of formula (I) and new amido-substituted imidazoquinolines of formula (I).

EFFECT: enhanced effectiveness of cytokine biosynthesis.

41 cl, 23 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-phenyl-substituted tetrahydroisoquinolines of the formulae: (IA) , (IB) , (IIA) , (IIB) , (IIIA) and (IIIC) wherein values X and R1-R7 are given in the invention description. Proposed compounds show selective binding of neurotransmitters and therefore they can be used in treatment of different neurological or psychological disorders, for example, ADHD. Also, invention relates to a pharmaceutical composition based on proposed compounds and to a method for treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

36 cl, 1 dwg, 16 tbl, 131 ex

FIELD: medicine, sexology, biochemistry, pharmacy.

SUBSTANCE: invention discloses a rapidly acting pharmaceutical composition showing high bioavailability containing active compound in sexual dysfunction and not presenting chew elastic. Active compound is chosen from derivatives of compounds of the formula (I) or (II) given in the invention description, or compound chosen from inhibitors of phosphodiesterase type 5, such as sildenafil, vardenafil, tadalafil, or compound chosen from dopaminergic agonists, such as apomorphine, or compound chosen from noradrenergic α-antagonists, or compound chosen from activators of cyclic AMP with a addition of cacao powder as not component of chocolate for adequate taste masking, and one or more lipid components.

EFFECT: valuable biological properties of pharmaceutical compositions.

19 cl, 4 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7, cycle A, cycles B, X, Y and Z have values given in the invention claims and in description of the claim, and to their pharmaceutically acceptable salts also. Proposed compound possess an antitumor activity and can be used in treatment of oncological diseases. Also, invention relates to a pharmaceutical composition based on these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

23 cl, 1 tbl, 57 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a method for preparing a liquid antitumor composition containing derivative of camptothecin. Derivative is prepared by binding compound of the formula (I): with polysaccharide having carboxyl groups through amino acid or peptide, and pH value of composition is brought about to 5-8 using a buffer. As a buffer method involves using one or more compounds chosen from group consisting of citric acid, alkaline metal citrate, acetic acid, alkaline metal acetate and alkaline metal dihydrophosphate that provides the excellent stability of composition at storage being not only as a lyophilizate but as a solution also.

EFFECT: improved and valuable pharmaceutical properties of preparation.

17 cl, 6 tbl, 5 ex

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

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides composite therapeutical agent exhibiting antituberculous effect and made in the form of solid dosage form containing as active principle combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides high-activity antituberculous formulation made in the form of solid dosage form containing as active principle combination of lomefloxacin, protionamide, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides antituberculous formulation made in the form of solid dosage form containing as active principle combination of isoniazid, rifampicin, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries: starch, lubricant, and optionally microcrystalline cellulose. Composition is characterized by storage stability and high therapeutical efficiency.

EFFECT: increased assortment of antituberculous drugs.

6 cl, 2 tbl, 3 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides antituberculous formulation made in the form of solid dosage form containing as active principle combination of isoniazid, rifampicin, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries: starch, lubricant, and optionally microcrystalline cellulose. Composition is characterized by storage stability and high therapeutical efficiency.

EFFECT: increased assortment of antituberculous drugs.

6 cl, 2 tbl, 3 ex

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

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

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