Bellerophone--carboline

 

(57) Abstract:

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts. The compounds I are suitable for improving kognitivnyh functions. 2 S. and 2 C.p. f-crystals.

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The invention relates to bellrowan-carbolines, their preparation and application in lestai receptors, although structurally they are different from benzodiazepines, and on the basis of affinity to benzodiazepine receptors are used as psychopharmaceuticals funds. -carboline can act on known properties of benzodiazepine receptors antagonistically, agonistically or internaagencies.

Currently, it is found that proposed according to the invention compounds have very good affinity for benzodiazepine receptors and act specifically internaagencies on the known properties of the benzodiazepines. The compounds possess anxiolytic, antiamnesic and neuroprotective activities and improve learning ability and attentiveness. Based on your profile of actions proposed according to the invention compounds suitable for the production of medicines for the treatment of geriatric diseases, and to reduce cognitive deficits and to improve the condition regarding insomnia, without aggravating side effects.

The invention relates to compounds of formula (I):

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their isomers, tautomers and salts, and in the formula (I) R3means hydrogen, (C1-C6)-alkyl, -CO-R1, -CN, phenyl, what maxilom, halogen or-CF3,

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R4means hydrogen, (C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C2)-alkyl;

A means 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by nitrogen, oxygen and/or sulfur and which may be substituted with R5and R6and R5and R6are the same or different and mean hydrogen, (C1-C6)-alkyl, (C1-C6-alkoxyl, hydroxyl, which can be functionally modified, NR7R8, COR, (C1-C6)-alkyl, which, if necessary, replaced by a functionally modified hydroxyl, (C1-C4-alkoxyl or halogen; (C6-C12)-aryl or 5-6-membered heteroaryl residue, which contains one to three atoms of nitrogen, oxygen and/or sulfur, and aryl and heteroaryl residue may be substituted (C1-C4)-alkyl, (C1-C4-alkoxyl, halogen or CF3; or

R5and R6together imply (CH2)ngroup; and

R1and R denote hydroxyl, (C1-C6-alkoxy or NR10R11;

R2means hydrogen, (C1-C4)-alkyl or (C1-C4
R7and R8each mean hydrogen, (C1-C6)-alkyl, acyl or phenyl which may be substituted (C1-C4)-alkyl, (C1-C4-alkoxyl, halogen or trifluoromethyl;

R10and R11each mean hydrogen, (C1-C6)-alkyl, (C3-C7-cycloalkyl or (C6-C12)-aryl or 5-6-membered heteroaryl residue, which contains one to three atoms of nitrogen, oxygen and/or sulfur, and where aryl and heteroaryl residue may be substituted (C1-C4)-alkyl, (C1-C4-alkoxyl, halogen or CF3.

Alkyl, depending on the circumstances, include both linear and branched residues, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl and hexyl.

As the aryl residue R5, R6, R10or R11it should for example be mentioned phenyl, biphenyl and or naphthyl, which may 1-3-fold substituted.

If R5, R6, R10or R11mean heteroaryl residue, the mean six-membered heteroaromatic compounds containing up to three nitrogen atoms, five-membered heteroatom piratin, pyridazine, furan, thiophene, pyrrole, imidazole, thiazole, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, which can be 1-3 times substituted.

Under the halogen, depending on the circumstances, you need to understand fluorine, chlorine, bromine and iodine.

Cycloalkyl, depending on the circumstances, means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

The alkyl residue R5, R6there may be 1-3 times replaced or can also be perhalogenated.

Hydroxyl groups can be functionally modified, for example by esterification with the formation of simple or complex ester. As a simple ester and acyl residues are using well-known specialist residues. Preferred are easily useplease simple ester residues, such as, for example, tetrahydropyranyl, tetrahydrofuranyl, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyl, tribenzylamine balance. As the acyl residues are used, for example, (C1-C6-alkanoyl as acetyl, propionyl, butyryl and benzoyl.

If present as hydroxyl groups, that can mean cyclic acetals or ketals as 1,3-dioxane or 1,3-dioxolane residue, to acetone, simple enol ether, 1,1-dihalogenoalkane or acetonylacetone.

Acyl group, R7or R8includes aromatic and aliphatic acyl group as benzoyl and from once to three times substituted benzoyl, and linear or branched alkanoyl with the number of carbon atoms up to 6.

If A denotes the heteroaromatic five-membered cycle, it may include the following groups:

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As a six-membered heteroaromatic cycle should be specified, for example, the following groups:

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The substituents R5and R6depending on the circumstances, can be in any position of rest or its tautomeric or isomeric forms. As the preferred form of the remainder R3you need to consider COR1and residues R1and R is hydroxyl and (C1-C6-alkoxyl. If present the main functional group, the form of physiologically acceptable salts of inorganic and organic acids. Suitable inorganic acids such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, or organic acids, such as, for example, aliphatic or aromatic is one succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, Glyoxylic acid, or sulfonic acids, for example, (C1-C4-alkanesulfonyl, such as methanesulfonate, or possibly substituted with halogen or (C1-C4)-alkyl of benzosulfimide as p-toluensulfonate.

If there is an acid function, in the form of salts suitable physiologically acceptable salts of organic bases, such as, for example, soluble salts of alkaline and alkaline earth metals as well as salts, N-methylglucamine, dimethylglycine, ethylglycine, lysine, 1,6-hexadiene, ethanolamine, glucosamine, sarcosine, serinol, Tris-hydroxyethylaminomethyl, aminopropanol, the base of sowaka, 1-amino-2,3,4-butanetriol.

The compounds of formula (I) and their salts, based on their affinity for the benzodiazepine receptors are used as medicines. They have different inherent in the activity (i.e. agonistic, antagonistic and/or internaitional activity) in relation to different isoforms benzodiazepine receptor gamma-aminobutyric acid.

To apply the proposed soglasno with the active substance contains suitable for enteral or parenteral administration of the pharmaceutical, organic or inorganic, inert carriers, such as water, gelatin, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. of the Dosage form can be in a solid state, for example, in the form of tablets, pills, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary they contain, moreover, auxiliary substances, such as preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or buffers.

For parenteral application, particularly suitable solutions for injection or suspensions, especially aqueous solutions of the active compounds in polyhydroxyserratane castor oil.

As systems media can be used as surface-active auxiliary substances, such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof, as well as liposomes or their components.

For oral administration, particularly suitable tablets, coated tablets or capsules with talc and/or hydrocarbon carrier or binder, as, for example, lactose, maize is, to which, if necessary, add sweetener. Proposed according to the invention compounds are used in a single dose with a content of 0.05-100.0 mg of the active substance in a physiologically acceptable medium.

The dose of active substances can be changed depending on the method of administration, age and weight of the patient, type and severity of curable diseases and similar factors. The daily dose is 0.1-300,0 mg, preferably 0.1 to 30 mg, and the dose can be administered in the form once received a single dose or divided into 2 or more daily doses.

Proposed according to the invention the connection get itself known methods. For example, the compounds of formula (I) can be obtained by the fact that

a) compound of formula (II):

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enter into interaction with 2-azadienes formula (III):

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where R3, R4and A have the above meaning and X and Y represent the deleted group, in the presence of acids; or

b) the compound of formula (IV):

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where R3, R4and A have the abovementioned meaning, are flavoured; or

C) the compound of formula (V):

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where R3and R4have the above significance, is injected into the interaction between the H2-R5obtaining precondensation imidazole, or received via nitrite diazonium salts enter into interaction with derivatives of acetoacetic acid with the formation of derived utilitiesin that cyclist to pyrrole, or enter into interaction with thiocyanate or isothiocyanate derivatives with getting precondensation thiazole; or

g) the compound of formula (VI):

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where R3and R4have the above significance, enter into interaction with the primary amine; H2N-CH2R5obtaining precondensation oxazole or enter into interaction with vicinal primary diamine:

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obtaining precondensation of pyrazine; or

e) nitricoxide formula (VII):

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cyclist using acetylene derivative - R2obtaining derived isoxazol;

e) -halogenation formula (VIII):

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where R4and A have the above-mentioned value, a Z means a halogen, enter into interaction with thioamides; H2N-CS-R9obtaining compounds, where R3means thiazolyl; or

W) nitrile of formula (IX):

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where R4and A have the above value, the loop is malaut or preterition ester group, atrificial carboxyl group, alkylate or acelerou the amino group, release functionally modified hydroxyl group, share isomers or get a physiologically acceptable salt.

The interaction of compounds of the formula (II) with 2-azadiene formula (III) according to the invention, to obtain the compounds of formula (I) are carried out by the method according to EP-A-110813 in the presence of acids at temperatures from 0 to 150oC. Remove groups X and Y may be the same or different; particularly suitable (C1-C3-dialkylamide as dimethyl-, diethyl - and Diisopropylamine, and cyclic amines, as pyrrolidine.

Interaction, for example, carried out so that the derivative of indole and azadian first stirred at room temperature in an organic acid, such as, for example, formic acid, acetic acid, propionic acid or triperoxonane acid, and then the reaction mixture is heated up to the boiling point.

Acid can serve as a component of the reaction and also as a solvent. However, it is also possible to add a solvent, such as, for example, alcohols, ethers, ketones, esters like ethyl acetate is islote can be changed within wide limits, however, it is used in excess. Preferably choose a 3-10-fold excess of acid per azadian.

The molar ratio of indole to azadiene for successful course of interaction is not critical. In General, use approximately equal molar quantities of the components of the reaction, preferably quantitative ratio of 1 mol of aniline and 1-3 mol azadiene. Carried out according to the invention, the interaction can in principle also be carried out in the abovementioned solvents in the presence of catalytic amounts of inorganic acids such as sulfuric, hydrochloric, perchloric acid, or organic acids such as p-toluensulfonate and triperoxonane acid.

For flavoring compounds of the formula (IV) is suitable known for-carbolines, which means, as, for example, the dehydrogenation using tert-butylhypochlorite (EP-A-190987) or by using Trichloroisocyanuric acid (international application WO 94/12498).

Condensirovanniye unsaturated cycle And options method C) and d) are carried out depending on the location of the amino group or hydroxyl group in position 5, 6 or 6, 7-carboline, preferably in position 5,6. Perhaps the resulting mixture of isomers sec is dinova ring, it can be carried out according to the synthesis of Skroupa [G. Alunni-Bistocchi and others, J. Chem.Soc.Perkin Trans. 1, 2935 (1992)] , so that, for example ,-unsaturated aldehyde, which can be obtained intermediate, attached to the amine and then cyclist by the action of acids and flavored with an oxidant, such as, for example, arsenic pentoxide, ferric oxide or picric acid. The reaction is carried out at temperatures from room temperature up to 150oC in inert solvents, such as toluene, xylene. To obtain imidazole, for example, the derived amino--carboline condensed with a primary amine; R5-CH2-NH2in the presence of an oxidant, as MnO2at room temperature or at elevated temperature and in inert solvents, such as dichloromethane, dichloroethane, or a simple ester of ethylene glycol.

Terracarbon can be obtained, for example, derived from ethylenediamino--carboline the fact that this compound in an inert solvent, such as hydrocarbons, for example toluene, xylene, benzene, is heated in the presence of organic or inorganic acids or esters of polyphosphoric acid.

Source atransitive connection can be obtained through reaction of Sandmeyer, kotoe with salts of alkali metals complex ester of acetoacetic acid in proton solvents, as water or alcohols, at temperatures from 0oC to room temperature.

Diazocarbonyl can be obtained, for example, by reacting compounds of the formula (V) with thiocyanates or isothioscyanates. Interaction best conducted in an inert solvent in the presence of an organic or inorganic acid, and, if used organic acid, it may serve as a solvent. For cyclization in General add an oxidizing agent, such as bromine. Based on hydroxy-carbolines, which, by analogy to the above synthesis of Skroupa, by reacting with the primary amine in the presence of an oxidant, as MnO2at room temperature or at elevated temperature and in an inert solvent receive oxazolidine. If the interaction instead of the primary amine used vicinal primary diaminododecane, then get the appropriate pyrazinone derivative, mixture of isomers which can be divided in the usual way using chromatography or by fractional crystallization.

The interaction of nitrilosides formula (VII) derivative of acetylene can be done, for example, as described K. G. B. Torsell methods (K. G. B. Torsell, suffix is then no selection enter into interaction with the derivatives of acetylene.

The molar ratio of nitriloside and acetylene can vary within wide limits. In General, use approximately equal molar quantities of the components of the reaction, however, often may also be favorable to use more derivative of acetylene. The interaction takes place at temperatures from -78oC to 150oC, preferably from -20oC to 50oC, in an aprotic solvent.

As a suitable solvent, for example, aliphatic and cyclic ethers like diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons, as dichloroethane, dichloromethane, chloroform, hydrocarbons as hexane, pentane and dimethyl formamide, dimethyl sulfoxide.

If the source compounds are gaseous, such as acetylene, the reaction it is preferable to use the appropriate liquid compounds that contain then easily removed from the group. As an easily removable group are suitable, for example, trialkylsilyl group. Cleavage is carried out before the processing of the reaction mixture by known methods, as, for example, by adding bases at room temperature. Suitable bases are, for example, hydroaid cesium or Tetra-n-butylammonium.

If necessary, the reaction can be used secured in position 9 derivatives-carboline. The protective group otscheplaut usual in the processing of the reaction mixture or later by treatment with bases or acids depending on the kind of the protective group.

Nitricoxide receive, for example, by transformation-carbolin-3-carbaldehyde into the corresponding oximes, which, for example, using N-halogenating, tert-butoxylate or halogencontaining sodium tert-butoxylate or sodium hypochlorite in an aprotic solvents can be converted to halides hydroxamic acids. Using reason as a sodium alcoholate or potassium trialkylamine, the base of Chenega, DBU or diazabicyclo, from halides hydroxamic acid otscheplaut galgenwaard and get nitricoxide that no allocation is subjected to cycloaddition reaction (R. Annunziata, etc., J. Chem.Soc., 529 (1987)).

-Carbolin-3-carbaldehyde can be obtained, for example, described in EP-305322 method of alilovic esters-carbolin-3-carboxylic acid. Interaction with halogenatom method e) implement the methods described in "the Chemistry of heterocyclic compounds", volume 34, Casa reaction mixture tioned enter into interaction-halogenatom, in particular, chlorine - or bromoketones. As inert solvents suitable alcohols, cyclic and acyclic ethers, esters, hydrocarbons and halogenated hydrocarbons.

3-Tetrazolyl--carboline can be obtained, for example, described in EP-A-54507 method using ammonia or by the methods described E. W. Thomas, Synthesis, 767 (1993) and P. Ornstein and others, J. Med.Chem., 36, 2046 (1993).

Hydrolysis of the ester group as acid and alkali, can be performed in the usual manner, for example using aqueous solutions of alkali or alkaline earth metal, optionally with the addition of organic solvents, such as alcohols, at temperatures from room temperature up to 150oC or described in EP-A-161574 way.

If desired transesterification, you can use described in EP-A-237467 method, according to which praeteritio carried out using alkali metal alcoholate or the corresponding alcohols, optionally with the addition of tetraisopropyl titanium as a catalyst, at elevated temperature. The introduction of tert-butilkoi ester groups are, for example, by reacting carboxylic acid with tert-butoxy-bis-dimethylaminoethanol.

appropriate alcohol in the acid or in the presence of an activated derivative of the acid. As an activated derivative of the acid used, for example, acid chloride, imidazole or acid anhydride.

If it is desirable alkylation of an amino group, you can alkilirovanii conventional methods, for example, using alkylhalogenide. The acylation of the amino group carried out by known methods, for example, in an aqueous medium in the presence of a base using the corresponding anhydrides or acid halides.

Release functionally modified hydroxyl groups by prominent professional ways. For example, simple protective ester group otscheplaut in an aqueous solution of an organic acid, such as formic, acetic, propionic, triperoxonane, citric acid, etc. or an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid, or by the use of Lewis acids as athirat of boron TRIFLUORIDE.

Silyl protective group can be removed, for example, using fluorides, as tetrabutylammonium or cesium fluoride.

Saponification acyl groups hold a well-known specialist of ways, as, for example, using basic catalysts, such as, for example, carbonates or hydroxides of alkali or alkaline can be isolated from the reaction mixture and purify. Salt accession acid in the usual manner can be converted to free base and desirable if they can be converted in a known manner in the physiologically acceptable salts, for example, by mixing a solution of the compound with concentrated solution of the desired acid.

If the compounds of formula (I) contain a center of chirality, the optically active compounds can be obtained from optically active starting compounds or known by way of the racemate. The enantiomers can be divided in the usual manner, for example by chromatography on optically active media, by entering into interaction with optically active acids and subsequent fractional crystallization.

To obtain physiologically acceptable salts accession acid compound of the formula (I), for example, dissolved in a little alcohol and mixed with a concentrated solution of the desired acid.

If the starting compounds is not described, they are known for or receive them by analogy with known compounds or the above-described methods.

For example, the production of esters 3-carboxylic acid of formula (VI) is described in EP-A-130140, and getting connected is to study the ability of test compounds to displace radioactively labeled benzodiazepines from the benzodiazepine of receptor. To study anxiolytic activity of a compound experience in the test with 4 - plates by the method of Boise and others (Boissier and others, Eur. J. Pharmacol., 4, 145-150 (1968)).

Antiamnesic activity determined by the method of B. J. Cole and others, Psychopharmacology, 111, 465-471, (1993) (DMTP-test), and test for care can be performed according to the method of J. L. Muir and others, Exp. Brain. Res., 89, 611-622 (1982) (9-Hole Box).

So, for example, isopropyl-11-methoxymethyl-3-methylpyrazine [2,3-g] --carboline-10-carboxylate in "tests on the behavior about the ability of learning and memory (e.g., Cole and others, Psychopharmacology, 116, 135-142 (1994)) to rats in doses of 10 mg/kg administered intraperitoneally causes an improvement in the cognitive measure.

The following examples illustrate how the proposed according to the invention method.

EXAMPLE 1

Isopropyl-11-ethyl-3-methyl-pyrazino[2,3-g] --carboline-10-carboxylate and isopropyl-11-ethyl-2-methyl-pyrazino[2,3-g]--carboline-10-carboxylate

By passing nitrogen and at room temperature, 20 g of isopropyl - 4-ethyl--hydroxy--carboline-3-carboxylate are dissolved in 800 ml of dimethyl ether of ethylene glycol (DME) and 7.2 ml of 1,2-diaminopropane. To the resulting solution for 30 min and stirring portions add 175 g of manganese oxide (IV), so that the temperature of the of propane. The reaction mixture was stirred in nitrogen atmosphere during the night.

The reaction mixture is filtered through diatomaceous earth and the filter residue optionally washed five times dimethyl ether of ethylene glycol, using each time 100 ml of ether. The combined filtrates are concentrated almost to dryness and allocate the precipitated crystals. The resulting crude crystallized recrystallized three times from methanol. Get 9.5 g isopropyl-11-ethyl-3-methyl-pyrazino[2,3-g] --carboline-10-carboxylate with a melting point 236,5-237,5oC.

United uterine fluid is concentrated to dryness and then boiled with isopropylacetate. The insoluble residue is filtered off and recrystallized four times from methanol.

Obtain 265 mg of isopropyl-11-ethyl-2-methyl-pyrazino[2,3-g]--carboline-10-carboxylate with so pl. 215-216oC.

Similarly get:

Isopropyl-11-methoxymethyl-3-ethyl-pyrazino[2,3-g] --carboline-10-carboxylate, T. pl. 202-203oC;

Isopropyl-11-methyl-3-ethyl-pyrazino[2,3-g] --carboline-10-carboxylate, T. pl. 204-206oC;

Isopropyl-3,11-diethyl-pyrazino [2, 3-g]--carboline-10-carboxylate, T. pl. 188-190oC;

Isopropyl-11-methoxymethyl-pyrazino[2,3-g] --carboline-10-carboxylicacid, so pl. 224-225oC (decomposition);

Isopropyl-11-methoxymethyl-3-phenyl-pyrazino[2,3-g] -carbolin-10-carboxylate, T. pl. 262-263oC;

Isopropyl-11-ethyl-3-phenyl-pyrazino [2,3-g]--carboline-10-carboxylate, T. pl. 235-236oC;

Isopropyl-11-methoxymethyl-3-methyl-pyrazino [2,3-g] --carboline-10-carboxylate, T. pl. 195-197oC;

Isopropyl-3,11-dimethyl-pyrazino [2,3-g]--carboline-10-carboxylate, T. pl. 155-160oC;

Isopropyl-11-methoxymethyl-2,3-dimethyl-pyrazino [2,3-g] --carboline-10-carboxylate, T. pl. 244-245oC;

Isopropyl-11-ethyl-2,3-dimethyl-pyrazino [2,3-g] --carboline-10-carboxylate, T. pl. 233-236oC;

Isopropyl-11-methyl-2,3-dimethyl-pyrazino [2,3-g] --carboline-10-carboxylate, T. pl. 305oC (decomposition);

Isopropyl-11-methoxymethyl-3-propyl-pyrazino[2,3-g] --carboline-10-carboxylate, T. pl. 172-173oC;

Isopropyl-11-ethyl-3-propyl-pyrazino[2,3-g]--carboline-10-carboxylate, T. pl. 184-186oC;

Isopropyl-11-ethyl-3-methoxymethyl-pyrazino[2,3-g] --carboline-10-carboxylate, T. pl. 198-199oC;

Isopropyl-3,11-bis-methoxymethyl-pyrazino [2,3-g] --carboline-10-carboxylate, T. pl. 193-194oC.

EXAMPLE 2

Ethyl ester 7H-benzo[e]pyrido[3,4]-indole-10-carboxylic acid

Similar to the method described in example 1 of EP-110813, 3H-be who are the target connection with so pl. 278-280oC.

EXAMPLE 3

Isopropyl ether 7H-benzo[e] pyrido[3,4-b]indole-11-methoxymethyl-10-carboxylic acid

a) Analogously to the method described in example 19 EP-A-54507 of 3H-benzo[e] indole get ethyl ester 7H-benzo[e]pyrido [3,4-b]-indole-11-methoxymethyl-10-carboxylic acid with so pl. 195-197oC.

b) By interesterification with isopropylate titanium (IV) complex of ethyl ether to obtain the target compound with so pl. 163-164oC.

EXAMPLE 4

Isopropyl ether 7H-benzo[e]pyrido [3,4-b]indole-11-methyl-10-carboxylic acid

a) Analogously to the method described in example 60 EP-A-54507 of 3H-benzo[e] indole get ethyl ester 7H-benzo[e]pyrido [3,4-b]-indole-H-methyl-10-carboxylic acid with so pl. 244-246oC.

b) By interesterification with isopropylate titanium (IV) complex of ethyl ether to obtain the target compound with so pl. 171-173oC.

EXAMPLE 5

Isopropyl ether 7H-benzo[e]pyrido[3,4-b]indole-11-ethyl-10-carboxylic acid

a) Analogously to the method described in example 60 EP-A-54507 of 3H-benzo[e] indole get ethyl ester 7H-benzo[e]pyrido [3,4-b]indole-11-ethyl-10-carboxylic acid with so pl. 201-205oC.

b) By interesterification with ptx2">

EXAMPLE 6

Isopropyl ester of 10-methyl-2-propyl - oxazolo[4,5-g]--carboline-9-carboxylic acid

A solution of 570 mg of isopropyl ester of 6-hydroxy-4-methyl--carbolin-3-carboxylic acid in 15 ml of dimethyl ether of ethylene glycol mixed with 1 ml of n-butylamine and 5.2 g of manganese dioxide and stirred over night at room temperature. The reaction mixture was filtered through celite. Obtained after concentration of the organic phase the residue chromatographic on silica gel using ethyl acetate. The desired fractions are concentrated and stirred with diethyl ether. Receive 325 mg of isopropyl ether 10-methyl-2-propyl-oxazolo-[4,5-g]--carboline-9-carboxylic acid with so pl. p.223-224oC.

Similarly get:

Isopropyl ester of 10-ethyl-2-isopropyl-oxazolo [4,5-g] --carboline-9-carboxylic acid, so pl. 205-207oC;

Isopropyl ester of 10-ethyl-2-propyl-oxazolo[4,5-g] --carboline-9-carboxylic acid, so pl. 163-165oC;

Isopropyl ester of 10-methyl-2-isopropyl-oxazolo[4,5-g] --carboline-9-carboxylic acid, so pl. 248-249oC;

Isopropyl ether 10-methoxymethyl-2-ethyl-oxazolo [4,5-g]--carboline-9-carboxylic acid, so pl. 188-189oC;

Isopropyl ether 10-methoxymethyl-2-methyl-is l-oxazolo [4,5-g]--carboline-9-carboxylic acid, so pl. 188-190oC;

Isopropyl ether 10-methoxymethyl-2-isopropyl-oxazolo[4,5-g] --carboline-9-carboxylic acid, so pl. 174-176oC;

Isopropyl ether 10-methoxymethyl-2-phenyl-oxazolo [4,5-g]--carboline-9-carboxylic acid,

so pl. 274-276oC;

Isopropyl ether 10-methoxymethyl-2-propyl-oxazolo[4,5-g]--carboline-9-carboxylic acid, so pl. 188-189oC;

Isopropyl ether 10-methoxymethyl-2-(2,2-dimethyl - 1,3-dioxolane-4-yl)-oxazolo [4,5-g]--carboline-9-carboxylic acid, so pl. 202-203oC.

Isopropyl ester of 2-(2,2-dimethyl-1,3-dioxolane-4-yl)-10-methyl-oxazolo[4,5-g]--carboline-9-carboxylic acid, so pl. 278-280oC;

Isopropyl ester of 2-(2,2-dimethyl-1,3-dioxolane-4-yl)-10-ethyl-oxazolo [4,5-g]--carboline-9-carboxylic acid, so pl. 228-230oC.

EXAMPLE 7

Isopropyl ester of 2-(1,2-dihydroxyethyl)-10-methoxymethyl-oxazolo[4,5-g]--carboline-9-carboxylic acid

A solution of 200 mg of isopropyl ether 2-(2,2-dimethyl-1,3-dioxolane-4-yl)-10-methoxymethyl-oxazolo[4,5-g] --carbolin-3-carboxylic acid in 20 ml of methylene chloride at room temperature dropwise mixed with 1 ml triperoxonane acid and stirred for 4 hours in an atmosphere of protective gas at room temperature. The reaction is oduct filtered under vacuum and washed with methylene chloride. After drying in vacuum at 50oC obtain 112 mg of isopropyl ether 2-(1,2-dihydroxyethyl)-10-methoxymethyl - oxazolo[4,5-g]--carboline-9-carboxylic acid with so pl. 168oC (decomposition).

Similarly get:

Isopropyl ester of 2-(1,2-dihydroxyethyl)-10-methyl-oxazolo [4,5-g] --carboline-9-carboxylic acid, so pl. 195-196oC (decomposition);

Isopropyl ester of 2-(1,2-dihydroxyethyl)-10-ethyl-oxazolo [4,5-g] --carboline-9-carboxylic acid, so pl. 184-186oC (decomposition).

EXAMPLE 8

10-Methoxymethyl-2-isopropyl-oxazolo[4,5-g] -9-(5-methoxymethyl-3-isoxazolyl)--carbolin

To a solution of hydrochloride 10 methoxymethyl-2-isopropyl-oxazolo [4,5-g]-6-tosyl--carbolin-3-carbaldehyde in 6 ml of absolute tetrahydrofuran at room temperature and in a protective gas atmosphere was added dropwise 1.4 ml of sodium hypochlorite solution. Stirred for 1 hour at room temperature until the disappearance of the reaction (monitoring by thin layer chromatography), then added dropwise 210 mg methylpropanamide simple ether and stirred overnight. After removal of the solvent the residue is distributed between ethyl acetate and water and the organic phase is dried, filtered and concentri refrigerator. After concentrating the organic phase to receive the remainder, which chromatographic using silica gel using a mixture of toluene with ethyl acetate in the ratio of 1: 1. The desired fractions are concentrated and the residue crystallized from ethyl acetate. Get 81 mg 10-methoxymethyl-2-isopropyl-oxazolo [4,5-g]-9-(5-methoxymethyl-3-isoxazolyl)--carboline with so pl. 121-122oC.

Necessary as the original product hydrochloride carbaldehyde receive according to EP-305322 method.

Similarly get:

10-methoxymethyl-2-isopropyl-oxazolo[4,5-g] -9-(5-methyl-3-isoxazolyl)--carbolin, so pl. 252-255oC.

EXAMPLE 9

Isopropyl ether 2-amino-10-ethyl-thiazolo[4,5-g]--carboline-9-carboxylic acid

297 mg of Isopropyl ester of 6-amino-4-ethyl-carbolin-3-carboxylic acid are dissolved in 5 ml of acetic acid, mixed with 152 mg of ammonium thiocyanate and stirred for 1 hour at room temperature. Then the reaction solution is cooled to 10oC dropwise and mixed with 0.05 ml of acetic acid solution of bromine (0.5 ml Br29.5 ml of acetic acid). Additionally stirred for 1 hour at 10oC and then left to warm to room temperature. what I have. The organic phase is separated, dried and evaporated to dryness. The residue is triturated with ether. Obtain 214 mg of the target compound with so pl. 160oC (decomposition).

EXAMPLE 10

Isopropyl ether 2-amino-10-methoxymethyl-thiazolo[4,5-g]--carboline-9-carboxylic acid

Of isopropyl ester of 6-amino-4-methoxymethyl--carbolin-3-carboxylic acid described in example 9 method are the target connection so pl. 188-192oC (decomposition).

EXAMPLE 11

Isopropyl ester of 2-acetamido-10-ethyl-thiazolo[4,5-g]--carboline-9-carboxylic acid

100 mg of Isopropyl ether 2-amino-10-ethyl-thiazolo[4,5-g]--carboline-9-carboxylic acid are suspended in 10 ml of acetic anhydride and heated for 15 minutes at 80oC. Precipitated after cooling, the precipitate is filtered off and recrystallized from ethyl acetate. Obtain 51 mg of isopropyl ether 2-acetamido-10-utilizalo[4,5-g] --carboline-9-carboxylic acid with so pl. 208-210oC.

EXAMPLE 12

Isopropyl ether 2-ethylamino-10-ethyl-thiazolo[4,5-g]--carboline-9-carboxylic acid

a) 297 mg of Isopropyl ester of 6-amino-4-ethyl-carbolin-3-carboxylic acid and 88 mg methylisothiocyanate in 20 ml of isopropanol is refluxed for two chasm. Obtain 257 mg isopropyl ester 4-ethyl-6-(3-ethyl - touraid)--carbolin-3-carboxylic acid with so pl. 234-236oC.

b) At room temperature or 0.035 ml of bromine was added dropwise to a suspension of 180 mg of isopropyl ester 4-ethyl-6-(3-ethyl-touraid)--carbolin-3-carboxylic acid in 20 ml of chloroform and then for three hours refluxed. The reaction solution is concentrated and the residue is treated with ethyl acetate and 20% potassium carbonate solution. The organic phase is separated, dried and concentrated. The residue is recrystallized from ethyl acetate. Obtain 141 mg of the target compound with so pl. 275-276oC.

EXAMPLE 13

Similar to that described in example 11 method get:

Isopropyl ether 2-methylamino-10-ethyl-thiazolo[4,5-g]--carboline-9-carboxylic acid, so pl. 200oC (decomposition);

Isopropyl ether 2-methylamino-10-methyl-thiazolo[4,5-g]--carboline-9-carboxylic acid;

Isopropyl ether 2-methylamino-10-methoxymethyl-thiazolo [4,5-g] --carboline-9-carboxylic acid.

EXAMPLE 14

Diethyl ether pyrrolo[4,5-g]--carbolin-2,5-dicarboxylic acid

a) 710 mg of Ethyl ester of 6-amino-carbolin-3-carboxylic acid in 18 ml of water at temperatureoC is mixed with 1.2 modi and mix the following 15 minutes at a temperature of 4oC. This solution was added dropwise at a temperature of 4oC to 410 mg of ethyl-2-methylacetoacetate and 1 ml of 50% solution of KOH in 3 ml of ethanol and 6 ml of water and stirred for a further 3 hours. The reaction mixture is mixed with 50 ml of water and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated. Receive 250 mg of ethyl ester of 6-(1-ethoxy-carbonyl-utilitiesin)--carbolin-3-carboxylic acid, which is used further without further purification.

b) 750 mg of Ethyl ester of 6-(1-ethoxycarbonylmethylene)--carbolin-3-carboxylic acid together with 1,83 g of ethyl ester of polyphosphoric acid in 35 ml of absolute xylene is refluxed in an atmosphere of protective gas for two hours. After cooling, the xylene is removed by decantation and the residue is treated with ethyl acetate, filtered through celite and concentrated. The obtained residue chromatographic using silica gel and ethanol. Receive 45 mg of target compound with so pl. 198-201oC.

EXAMPLE 15

Isopropyl ester of 2-isopropyl-10-methoxymethyl-1H - imidazo[4,5-g] --carboline-9-carboxylic acid

627 mg of Isopropyl ester of 6-amino-4 - methoxymethyl--carbolin-3-carboxylic acid in 10 ml of dimethyl ether of these is the temperature. The reaction mixture was filtered through celite, the filtrate concentrated and chromatographic using silica gel and a mixture of methylene chloride with ethanol in a ratio of 10:1. Of the desired fractions receive 499 mg of isopropyl ether 2-isopropyl-10-methoxymethyl-1H-imidazo[4,5-g] --carboline-9-carboxylic acid (oil).

Similarly get:

Isopropyl ester of 2-isopropyl-10-methyl-1H-imidazo[4,5-g]--carboline-9-carboxylic acid;

Isopropyl ester of 2-isopropyl-10-ethyl-1H-imidazo[4,5-g]--carboline-9-carboxylic acid;

Isopropyl ester of 2-phenyl-10-methoxymethyl-1H-imidazo[4,5-g] --carboline-9-carboxylic acid;

Isopropyl ester of 2-butyl-10-methoxymethyl-1H-imidazo[4,5-g] --carboline-9-carboxylic acid;

Isopropyl ester of 2-(2,2-dimethyl-1,3-dioxolane-4-yl)-10-ethyl-1H-imidazo [4,5-g]--carboline-9-carboxylic acid;

Isopropyl ester of 2-(2,2-dimethyl-1,3-dioxolane-4-yl)-10 - methoxymethyl-1H-imidazo[4,5-g]--carboline-9-carboxylic acid;

Isopropyl ester 2-ethyl-10-methoxymethyl-1H-imidazo[4,5-g]--carboline-9-carboxylic acid;

Isopropyl ether 10-methoxymethyl-2-trifluoromethyl-1H-imidazo[4,5-g] --carboline-9-carboxylic acid;

Isopropyl ether 10-methoxymethyl-2-(2-thienyl)-1H-imidazo[4,5-g] --Carbo is Oh acid;

Isopropyl ester of 2-(4-chlorophenyl)-10-methoxymethyl-1H-imidazo [4,5-g] --carboline-9-carboxylic acid, so pl. 270oC (decomposition);

Isopropyl ester of 2-(2-chlorophenyl)-10-methoxymethyl-1H-imidazo [4,5-g] --carboline-9-carboxylic acid, so pl. 205-207oC;

Isopropyl ester of 2-(4-were)-10-methoxymethyl-1H-imidazo [4,5-g] --carboline-9-carboxylic acid, so pl. 168oC (decomposition);

Isopropyl ester of 2-(4-methoxyphenyl)-10-methoxymethyl-1H-imidazo [4,5-g] --carboline-9-carboxylic acid, so pl. 258-260oC;

Isopropyl ester of 2-(2-methoxyphenyl)-10-methoxymethyl-1H-imidazo-[4,5-g] --carboline-9-carboxylic acid, so pl. 225-228oC.

EXAMPLE 16

Similar to that described in example 7 method get:

Isopropyl ester of 2-(1,2-dihydroxyethyl)-10-methoxymethyl-1H-imidazo[4,5-g]--carboline-9-carboxylic acid, so pl. 198oC;

Isopropyl ester of 2-(1,2-dihydroxyethyl)-10-ethyl-1H-imidazo [4,5-g] ---carbolin-9-carboxylic acid, so pl. 168oC.

EXAMPLE 17

Isopropyl ester of 10-ethyl-2-methyl-thiazolo[5,4-g]--carboline-9-carboxylic acid

a) 2500 mg of Isopropyl ester of 6-amino-4-ethyl-carbolin-3-carboxylic acid are dissolved in 40 ml of pyridine, mixed with 0,79 ml acetanhydride and heated for two is acetate and washed with water. The organic phase is separated, dried and concentrated to dryness. The balance in the number 3110 mg of isopropyl ester of 6-acetylamino-4-ethyl-carbolin-3-carboxylic acid is used further without further purification.

b) 2741 mg of Isopropyl ester of 6-acetylamino-4-ethyl-carbolin-3-carboxylic acid in 110 ml of dioxane together with 3915 mg of reagent Lawesson heated with stirring to 70oC. After cooling, mixed with 100 ml ethyl acetate and washed with a saturated solution of sodium chloride. The organic phase is dried and concentrated in vacuo. The remainder chromatographic using silica gel and a mixture of toluene with methanol in the ratio 8:2. Of the desired fractions get 1541 mg isopropyl ester 4-ethyl-6-diacetylene--carbolin-3-carboxylic acid with so pl. 158-160oC.

in) 450 mg K3Fe(CN)6dissolved in 1.8 ml of water, mixed with 1.4 ml of 1 n NaOH solution and cooled to 4oC. To this solution was added dropwise a solution of 200 mg of isopropyl ester 4-ethyl-6-diacetylene--carbolin-3-carboxylic acid in 4 ml of pyridine and stirred for two hours at this temperature. The reaction mixture is treated with ethyl acetate, washed with water, dried and concentrated. The remainder chromatographic on silica gel sym ether. Receive 30 mg of target compound with so pl. 239-240oC.

We studied the affinity for benzodiazepine receptors compounds of formula (I), was determined by the ability of test compounds to displace Radiometrie the benzodiazepines benzodiazepine-receptors. The binding of benzodiazepine studied in vitro, as a result, for compounds of the following structural formula defined value IC50nmol:

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< / BR>
Antiamnesic effect tested (DMTP-test) in accordance with the method described by J. Cole et al., Psychopharmacology (1993) 111, 465-471, and action, improving care, tested in accordance with the method described by J. L. Muir et al., Exp. Brain Res (1982) 89, 611-622.

For example isopropyl-11-methoxymethyl-3-methyl-pyrazino-[2,3-g] --carboline-10-carboxylate in behavioral tests of learning and memory" (according to Cole et al., Psychopharmacol. (1993), 116, 135-142), conducted on rats at doses of 10 mg/kg i.p., contributed to the improvement of cognitive actions.

1. Bellerophone-carboline formulas (1)

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where R3- -CO-R1or

< / BR>
R1- C1-6-alkoxy;

R4- H, C1-6-alkyl, C1-4-alkoxy-C1-2-alkyl;

A - 5-6-membered unsaturated cycle, in which 1-2 atom at the
R5and R6the same or different, is hydrogen, C1-6-alkyl, NR7R8C1-6-alkyl which can be substituted by hydroxyl or C1-4-alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-4-alkyl, C1-4-alkoxyl, halogen, or R5and R6together -(CH2)ngroup, where n=4;

R2- H, C1-4-alkyl, C1-4-alkoxy-C1-2-alkyl;

R7and R8each - H, C1-6-alkyl, acyl,

as well as their isomers, tautomers and salts.

2. Bellerophone-carboline formula (1) under item 1, where a denotes-N= CR5-CR6=N-.

3. Bellerophone-carboline under item 1, which represents isopropyl-11-ethyl-3-methyl-pyrazino[2,3-q] --carboline-10-carboxylate; isopropyl-11-ethyl-2-methyl-pyrazino[2,3-q] --carboline-10-carboxylate; isopropyl-11-methoxymethyl-2,3,4,5-tetrahydroquinoxaline[2,3-q] --carbolin-12-carboxylate; isopropyl-3,11-bismethoxy-pyrazino[2,3-q] --carboline-10-carboxylate; isopropyl ether 7H-benzo[e] pyrido[3,4-b]-indole-11-methoxymethyl-10-carboxylic acid; isopropyl ester of 10-methyl-2-propyl-oxazolo[4,5-q] --carboline-9-carboxylic acid is imethyl-2-isopropyl-oxazolo[4,5-q] -9-(5-methoxymethyl-3-isoxazolyl)--carbolin; isopropyl ether 2-amino-10-ethyl-thiazolo[4,5-q] --carboline-9-carboxylic acid; isopropyl ester of 2-amino-10-methoxymethyl-thiazolo[4,5-q] --carboline-9-carboxylic acid; diethyl ether pyrrolo[4,5-q] --carbolin-2,5-dicarboxylic acid; isopropyl ester of 2-isopropyl-10-methoxymethyl-1H-imidazo[4,5-q] --carboline-9-carboxylic acid; isopropyl ester of 10-ethyl-2-methyl-thiazolo[5,4-q] --carboline-9-carboxylic acid.

4. Bellerophone-carboline on PP.1-3, suitable for improving cognitive functions.

 

Same patents:

-lactams" target="_blank">

-lactams // 2143435
The invention relates to new derivatives-lactam of General formula I given in the description, in which Z denotes a methylene, oxygen or sulfur and R represents hydrogen, optionally substituted, lower alkoxycarbonyl, carbamoyl, lower (cyclo)allylcarbamate, phenylcarbamoyl or hydroxyphenylarsonic lower alkyl, lower alkenylacyl, formyl, optionally substituted with halogen, CYANOGEN, carbarnoyl-lowest alkylthiol, lower alkanoyl, respectively alkylsulfonyl, optionally substituted by lower (cyclo)alkyl, lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl lower alkyl or carboxy-lower alkyl carbarnoyl or ring structure of a General formula

Q-X-CO- (A1),

Q-X-SO2(A2),

where is a five - or six-digit, optionally containing nitrogen, sulfur and/or oxygen ring;

X denotes one of the groups-CH2, -CH2CH2-, -NH-, NHCH2-, -CH2NH-, -CH(NH2)--CH2CH2NH-, -C(=NOCH3)-, -OCH2-, -SCH2-;

A represents lower alkyl, hydroxy-(lower alkyl, vinyl, cianfrini, lower alkoxy, optionally phenylselenenyl lower alkylsulfonate, the remainder is-S-Het or-S- 2-L, where L is a lower alkanoyloxy, respectively carbamoylated, low-alkoxycarbonyl, carboxy, azido, lower alkanolamine, lower alkylsulfonyl, six-membered ring attached to the nitrogen atom, or a residue - or-S-CH2-Het, where Het has the above significance,

and pharmaceutically acceptable, readily hydrolyzable esters and salts of these compounds

The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity

The invention relates to new derivatives of 1,4-diazepine and their pharmacologically acceptable salts, methods for their production and pharmaceutical applications

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

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

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

I,

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

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

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

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

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

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

The invention relates to tricyclic 5,6-dihydro-N-pyrazolo [3,4-c] -1,2,4-triazolo[4,3-a]pyridinium, which have a selective inhibitory activity against phosphodiesterase (PDE) type IV or tumor-specific factor necrosis (TNF) and therefore effective in the treatment of asthma, arthritis, bronchitis, chronic obstructive Airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, such as AIDS, sepsis, septic shock and other diseases, in particular cachexia, causing the formation of tumor-specific factor necrosis

The invention relates to novel pyrido[3,2-e]pyrazinone f-ly I, where X,Y and Z Is N or CR3and at least one of X,Y and Z must be N, R1- C1-C10-alkyl which can be substituted by aryl, R2- H, C5-C7-cycloalkyl, C1-C10-alkyl which can be substituted by the Deputy selected from the group comprising aryl, aryloxy, hydroxyl, SO3H-group, pyridinyl, chinoline, A - CH2N - R3or Oh, R3is hydrogen, C1-C6-alkyl, or their physiologically tolerable salts, which possess anti-asthma and anti-allergic effect

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

The invention relates to compounds, pharmaceutical compositions and methods of using compounds of formula (II) in the treatment or prevention of certain diseases or conditions
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