Derivatives of 1-[2-(substituted vinyl)]-5h-2,3-benzodiazepine, the retrieval method, the intermediate compound, pharmaceutical composition and a method thereof, a method of treatment of diseases of the central nervous system

 

(57) Abstract:

The invention relates to new derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine, method of production thereof, pharmaceutical composition, method thereof and method of treating diseases of the Central nervous system. Compounds in accordance with the invention have the General formula I, where A and B together form a group of the formula =C=N-or =CH-NH-; R1represents phenyl which may contain from 2 to 3 hydroxyl groups or 1 to 3 identical or different substituents selected from the group comprising halogen, trifluoromethyl, nitro, cyano, amino, di(C1-3alkyl)amino, C1-4alkanolamine-, C1-4alkyl, C1-4alkoxy-, carboxy, (C1-4alkoxy)-carbonyl, methylenedioxy, naphthyl, which may contain a Deputy representing a hydroxyl, furyl, thienyl or indolyl; R2represents hydrogen or C1-4alkyl; R3and R4each represents a C1-4alkoxygroup attached in positions 7 or 8 benzodiazepine ring, or R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group, and their pharmaceutically acceptable salts accession acids. They have means the Invention relates to new derivatives of 1- [2-(substituted vinyl)]-5H-2,3-benzodiazepine the method of production thereof, pharmaceutical composition, use of these benzodiazepine derivatives for the treatment of diseases and preparation of pharmaceutical compositions suitable for the treatment of diseases.

As is well known, the literature describes derivatives of 5H-2,3-benzodiazepine, containing as substituents of the phenyl, naphthyl, substituted phenyl, furyl, thienyl or hydroxystyryl 1 position of the main chain of the molecule (HU patent specifications Nos. 155572, 179018, 195788, 191702, 206719; J. Chem. Soc. Perkin I. 1973, 2543; 1980, 1718; 1984, 849; II. Farmaco-Ed. Sc. 40, 942 (1985); Chem. Ber. 107, 3883 (1974)]. Compounds known groups affect the Central nervous system, while the derivatives of 5H-2,3-benzodiazepine that belongs to a different group, possess a positive myotropic effect and do not show activity against Central nervous system.

Known 2,3-benzodiazepines, active towards the Central nervous system, have a sedative and calming effect, however, in contrast to conventional 1,4-benzodiazepines, do not give the effect of muscle relaxation, in addition, tranquilizing action is accompanied neuroleptic activity. Known connection to nerison belonging to the same group, is known. The task of the invention to provide new derivatives of 2,3-benzodiazepine, is comparable with the known 1,4 - and 2,3-benzodiazepines, which, however, do not have any side kataleptogennoe effect prevents therapeutic application.

In addition, about 20% of the population suffers from a sense of unjustified fear, and therefore the treatment of this disease is particularly important. The vast majority of medicines used in the treatment of fear, is a derivative of 1,4-benzodiazepine. These medications, however, cause undesirable side effects such as sedative, causing muscle relaxation and drowsiness [Patel, J. B. and Malich, J. B.: Neuropharmacological profile of an anxiolytic.in: Anxiolytics: Neurochemical behavioural and clinical perspectives. (Eds.: Malich J. B., Emia, S. J. and Yamuuamura, H. I., Raven Press, New York 1983, p.p.173-191; File, S. L. : The contribution of behavioural studies to the neuropharmacology of anxiety, Neuropharmacology 1987, 26, 877-866].

Another objective of the present invention to provide new derivatives of 2,3-benzodiazepine, which has a significant sedative action, even in small doses, however, in contrast to the known sedatives, practically does not affect the locomotor activity of the animals even in bol is relevant signs.

In accordance with the present invention obtained derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine General formula (I),

< / BR>
where A and B together form a group of the formula =C=N - or =CH-NH-,

R1represents phenyl which may contain from 2 to 3 hydroxyl groups or 1 to 3 identical or different substituents selected from the group comprising halogen, trifluoromethyl, nitro-, cyano-, amino-, C1-3alkylamino-, di(C1-3alkyl)-amino, C1-4alkanolamine-, C1-4alkyl, C1-4alkoxy, carboxy, (C1-4alkoxy)-carbonyl, C1-4alkoxycarbonyl and methylendioxy, naphthyl, which may contain a Deputy selected from the group comprising hydroxyl, C1-4alkoxy and C1-4alloctype, furyl, thienyl or indole,

R2represents hydrogen or C1-4alkyl,

R3and R4each represents a C1-4alkoxygroup attached in positions 7 or 8 benzodiazepine ring, or

R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group, and pharmaceutically acceptable salts of the acid accession.

Preferred compounds of General formula (I) are such compounds, or 2 substituent group, comprising fluorine, cyano, trifluoromethyl, amino, di(C1-3alkyl)-amino group or C1-4alkoxygroup, R2represents hydrogen, and R3and R4together form a 7,8-methylendioxy, as well as pharmaceutically acceptable salts of the acid accession.

In particular, preferred compounds in accordance with the invention are the following derivatives:

1-(4-dimethylaminostyryl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine,

1-(4-aminosterol)-4-methyl-7,8-dimethoxy-5H-2,3 - benzodiazepine,

1-(3,4-dimethoxytrityl)-4-methyl-7,8-dimethoxy-5H-2,3 - benzodiazepine,

1-(4-foresthill)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine, and pharmaceutically acceptable salts obtained by the addition of acids.

Used in the description and the claims, the term "lower" refers to the groups or compounds with the number of carbon atoms from 1 to 4. The term "alkyl" refers to linear or branched groups having the number of carbon atoms, such as methyl, ethyl, n-propyl, etc., the Term "alkenyl" refers to linear or branched groups such as vinyl, 1-methylvinyl, 2-methylvinyl, 1-propenyl, 2-propenyl, etc., the Term "alkanolamine-" refers to linear or SCP, etc). The term "amoxicillina group" refers to carboxylic groups esterified with linear or branched aliphatic alcohols having from 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl group and others, the Term "alloctype" refers to the hydroxyl groups, acylated aliphatic carboxylate having from 1 to 4 carbon atoms, such as acetoxy-, tert-butoxycarbonylamino etc. the Term "halogen atom" includes all four atoms of halogen, i.e. fluorine, chlorine, iodine and bromine.

Pharmaceutically acceptable salts of the acid accession compounds of General formula (I) can be formed with inorganic acids (for example, hydrogen halides), such as chloride or hydrogen bromide, sulfuric, phosphoric or pergolide acids such as perchloric acid), organic carboxylic acids (for example, fumaric, acetic, propionic, glycolic, maleic, hydroxymaleimide, ascorbic, citric, malic, salicylic, lactic, cinnamic, benzoic, phenylacetic, para-aminobenzoic, para-hydroxybenzoic, para-aminosalicylic acid and others ), alkylsulfonate acids (for example, methansulfonate, aftershool, sulfanilic acids).

In the proposed invention is also a method of obtaining derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine General formula (I) in which A, B, R1, R2, R3and R4as described above, including

a) interaction of perchlorate 2-benzopyrene General formula (II)

< / BR>
where R1, R2, R3and R4as described above, with hydrazinehydrate, to obtain the compounds of General formula (I), where A and B together form a group of the formula =C= N-, a R1, R2, R3and R4same as above,

b) compounds of General formula (I), where R1is a nitrophenyl which can contain 2 hydroxyl groups or 1 or 2 identical or different substituent selected from the group comprising halogen, trifluoromethyl, nitro-, cyano-, amino-, methylenedioxy, C1-4alkyl, C1-4alkoxygroup, carboxyl or (C1-4alkoxy)-carbonyl, hydrazinehydrate in the presence of a catalyst and, if necessary, acylation or alkylation thus obtained amino compounds with obtaining 1-[2-(substituted vinyl)] -5H-2,3-benzodiazepine General formula (I), where A and B together form a group of the formula = C= N-, R33and R4together form a 7,8-methylenedioxyphenyl group, R1represents an AMINOPHENYL, (C1-3alkyl)AMINOPHENYL, di(C1-3alkyl)-AMINOPHENYL or (C1-4alkanoyl)-AMINOPHENYL, while these groups may have two hydroxyl groups or one or two identical or different substituent selected from the group comprising halogen, trifluoromethyl, nitro-, cyano-, amino-, methylenedioxy-, C1-4alkyl, C1-4alkoxygroup, carboxyl or (C1-4alkoxy)-carbonyl, a R2- same as above

C) the restoration of compounds of General formula (I), where A and B together form a group of the formula =C=N-, a R1, R2, R3and R4same as above, a complex metal hydride and/or a complex of borane, to obtain the compounds of General formula (I), where A and B together form a group of the formula =CH-NH-, R1represents phenyl containing fluorine atom, trifluoromethyl or cyano, R2represents hydrogen, and R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group

and, if desired, converting the thus obtained base of General formula (I) in its acid salt of the merger.

In accordance with the invention invitaton. The reaction is preferably carried out in a solvent, but it can also take place without solvent in an excess of hydrazine hydrate. As solvents it is possible to use polar or non-polar solvents, preferably water, lower alcohols, dioxane, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, pyridine or mixtures thereof. The reaction is carried out at a temperature of from 0oC to the boiling point of the reaction mixture, preferably from +10oC to +120oC. it is Preferable to carry out the reaction in concentrated (90 to 100%) hydrazinehydrate, with its excess of 1 to 3 moles.

In accordance with the invention, a preferred example of executing variant (a) of the method comprises the interaction of perchlorate 2-benzopyrene General formula (II) with 3 mol equivalents of hydrazine hydrate is added in a lower alcohol, preferably ethanol, at room temperature, separating the resulting crude product from the reaction mixture, leaching Solodovnik by-products from the desired product in hot water, filtering the obtained product and, if necessary, the suspension in a suitable solvent, preferably a lower alcohol, or recrystallization from it.

In accordance with the invention, another preferred example of executing variant (a) of the method involves addition of compounds of General formula (II) to a mixture containing 3 equivalent 90-100% hydrazine hydrate is added and dimethylformamide, at a temperature of from 10 to 15oC and then at room temperature. The end product is separated from the solution by adding to a mixture of water. By-product is then washed away by water and the final product is optionally purified by recrystallization or by boiling in alcohol. In accordance with the invention, an example of executing variant (b) of the method are derived benzodiazepine General formula (I), modalcontainer as the radical R1by reinstatement derived nitrophenyl and, if necessary, acylation or alkylation of the resulting product. For nitrogroup reduction using the method of selective reduction, which does not lead to saturation-C=N-bonds semichasnoho ring or vinyl groups.

Description of the method of recovery of such compounds in the literature is unknown. It was found that the use of hydrazine hydrate is added in the presence of a catalyst can be used for selective reduction of compounds of this type. It is known that hydrazinehydrate in the presence of a catalyst used for the conversion of the amino compounds such nitro compounds, which did not contain other groups, are able to restore [Chem. Rev. 65, 52 (1965); J. Am. Chem. Soc. 75,4334, (1953); Chem. Lett. 1975, 259].

Recovery is preferably carried out in an organic solvent. Preferably you can use the following solvents: lower alcohols, dioxane, tetrahydrofuran, benzene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide and pyridine. It is preferable to conduct the reaction in excess of 90-100% pyridine.

As the catalyst preferably opolski the boiling point of the solvent, preferably from +10oC to +100oC.

In accordance with the invention, a preferred example of execution version (b) of the method comprises the suspension in methanol derived 1-nitrostyryl-5H-2,3-benzodiazepine General formula (I) and its interaction with 2-4, preferably 3 equivalents 98-100% hydrazine hydrate is added in the presence as catalyst of Nickel Raney at room temperature for 1-2 hours the Crude product is separated from the reaction mixture by the known methods. If the received connection trudnorastvorim in methanol, so that there is a partial separation, it is preferable to wash the catalyst with a solvent, the resulting product is easy to be dissolved (e.g., chloroform). The crude product is optionally purified by recrystallization or trituration in powder in the solvent.

In accordance with the invention, another preferred example of executing variant (b) of the method includes providing interaction derived 1-nitrostyryl-5H-2,3-benzodiazepine General formula (I) for 1-2 h with 3 equivalents of 100% hydrazine hydrate is added in alcohol at room temperature, after which the reaction mixture catalysis is the temperature. The mixture is then processed as described above.

Thus obtained derivative linestylelistener General formula (I) optionally acelerou or alkylate.

If it is desirable to carry out the alkylation, it is carried out by known methods, preferably with alkylhalogenide in an indifferent solvent in the presence of an agent that binds acid, at a temperature of from room temperature to the boiling point of the solvent. Preferably you can use the following solvents: aliphatic alcohols, ketones, NITRILES, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulfoxide. As an agent that binds acid, preferably using a carbonate or bicarbonate of an alkali metal or 1-2 equivalent of the lower tertiary amine.

Obtained, as mentioned above, derivatives linestylelistener if necessary acelerou. The acylation is carried out with the help of 1-2 equivalents of the acid halide or acid anhydride. The reaction is preferably carried out in the presence of an agent that binds acid, preferably a lower aliphatic tertiary amine or pyridine. It is preferable to conduct the reaction in a solvent (for example, in lifetimes, in excess of the reagent.

In accordance with the invention, variant (C) of the method includes recovering the complex metal hydride and/or a complex of borane 5-H-2,3-benzodiazepine General formula (I), where A and B together form a group of the formula =C=N-, R1represents a phenyl containing fluorine atom, trifluoromethyl or cyano, R2represents hydrogen, a R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group. You can use the following recovery agents: borohydride sodium, lithium hydride - aluminum, borane and complexes of borane. Recovery is preferably carried out in a solvent. As solvents it is possible to use water, lower alcohols, lower carboxylic acids, solvents, ether type, aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, pyridine or mixtures thereof. The solvent or solvent mixture, which is used in this case depends on the selected remedial agent.

The restoration carried out at a temperature from 0oC to 100oC using preferably from 1.1 to 25 molar equivalents of restorative agent.

In accordance with the invention, another example implementation is ormula (I), the addition of excess concentrated hydrochloric or acetic acid, and the introduction of sodium borohydride to the thus obtained chloride or acetate. After treatment of the reaction mixture to the desired 3,4-dihydro-connection is obtained by crystallization.

In accordance with the invention, a preferred embodiment of variant (b) of the method comprises adding from 1.5 to 2.0 equivalents of epirate of borontrifluoride to the solution or suspension derived 5H-2,3-benzodiazepine General formula (I) in dry dichloromethane and added to a solution of thus obtained complex of 1.1 equivalent of the complex of borane-trimethylamine. The organic phase is then treated with sodium carbonate, washed with water, dried, evaporated, the desired product crystallized, filtered and, if necessary, recrystallized of a suitable solvent, e.g. a lower alcohol, or suspended in a suitable solvent.

In accordance with the invention, another preferred embodiment of variant (b) of the method involves the dissolution or suspension of the compounds of General formula (II) in dry tetrahydrofuran, cooled tooC to 5oC, adding 1 mol-equivalent of hidri the Oia and the organic phase is evaporated. The residue obtained after evaporation, is subjected to chromatography or crystallization to obtain the desired 2,3-benzodiazepine.

These starting substances of the General formula (II), where R1represents a phenyl containing fluorine atom, trifluoromethyl or cyano, R2represents hydrogen, a R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group, still have not been described in the literature. Both new and known compounds can be obtained by the method similar to the method of synthesis [Khim. Geterotsikl. Soed. 1970, 1308 [C. A. 74, 7629 w (1971)]; Khim. Geterotsikl. Soed. 1973, 568, 1458 [C. A. 79, 18629 (1973), 80, 70649 u (1974)].

New connections in accordance with the invention have significant activity against Central nervous system, in particular, anxiolytic, antipsychotic and taking aggressive action. At the same time, they are devoid of side effects, causing catalepsy. Most of these compounds forms a connection with the centres, it is specific to homoplasies (2,3-benzodiazepine) [FEBS Letters 308 (2), 215-217 (1992)], with high affinity, resulting in it can be assumed that, given the similar absorption and metabolism of 2,3-benzodiazepines, and strange, compounds of General formula (I), where R1represents a phenyl containing fluorine atom, trifluoromethyl or cyano, R2represents hydrogen, and R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group, have significant anxiolytic effect and at the same time, they are virtually devoid of sedative effects. This feature is a huge benefit in the treatment of pathological conditions of fear. These molecules do not form relationships with centers of communication homoplasies.

The activity of the new compounds was confirmed in the following experiments.

As comparative compounds used chlorodiazepoxide (7-chloro-2-methylamino-5-phenyl-3H - 1,1-benzodiazepine-4-oxide), diazepam (7-chloro-2,3-dihydro-1-methyl - 5-phenyl-1H-1,4-benzodiazepine-2-one) chlorpromazine [KhPZ, 2-chloro-10- (3-dimethylaminopropyl)-fentazin] . Were used for comparison also girisham [1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3 - benzodiazepine] and nerison [1-(4-AMINOPHENYL)-4-methyl-7,8 - dimethoxy-5H-2,3-benzodiazepine] , since these compounds also form bonds with binding sites homophilia and have activity against Central nervous system.

Affinity new Soeder) -4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine] drug stripped membranes of rat brain. The value of Kiwas calculated by the following formula:

Ki=IC50:(1+[L]/KD)

where KDthe dissociation constant of labeled complex ligand-receptor

[L] is the concentration of labeled ligand and IC50the half maximal inhibitory concentration of the test sample. The results are presented in table 1.

The effect of compounds on the behavioral effects were measured by the method of Irvine [Psycho-pharmacology, 13, 222 (1968)]. The results obtained and the amount of short-term toxic effects (deceased/process. is indicated in brackets) are given in table II.

As can be seen from the data presented in table II, the compounds obtained in accordance with the invention, significantly reduce spontaneous locomotor activity (SDA) mice after intraperitoneal or oral administration.

Potential antipsychotic activity of new compounds was tested by the method of Puech et al. [Psychopharmacology, 75. 84, 1981] by measuring the inhibitory effects on the reaction of "getting" caused by apomorphine. Because inhibition of spontaneous motor activity is an important characteristic of antipsychotic drugs for several compounds have been measured values of the ED="ptx2">

The test results show that its antipsychotic action of the most active derivatives have almost the same efficiency as chlorpromazine (CPZ).

Kataleptogennoe effect of the compounds was measured in mice [Schlichtengroll: Arzneim. Forsch., 8, 489, 1958] and rats [Morpurgo: Arch. Int. Pharmacodyn. 137. 87, 1962]. The results obtained are presented in table IV.

On the basis of obtained results it can be argued that the compounds in accordance with the invention do not have kataleptogennoe action, which could limit their therapeutic use. The specified property is a significant advantage compared with chlorpromazine and presobama having side kataleptogennoe effect.

Furthermore, the new compounds according to the invention also have significant sedative and calming effect. Tranquilizing effect was studied on rats according to the method of "licking-conflict", developed by Vogel et al. [Psychopharmacology, 21, 1, 1971], as well as accelerated test plus-maze described Pellow [ellow, J. et al: Neurosci. Meth. 14, 149, 1985] . The calming effect was tested in mice by the method of "fighting behavior described Tedeschi [Tedeshi: J. Pharm. Exp. Ther., 125, 28, 1959] . Obtained knowledge the experiments show, what tranquilizing action of some prototypes exceeds the appropriate value for gersoppa and hlordiazepoksida, while the calming effect of the new compounds is comparable with the effect of the comparative samples.

As already mentioned, some of the compounds of General formula (1) are greater anxiolytic activity, in contrast to the known 1,4 - and 2,3-benzodiazepines, i.e., they are virtually devoid of any sedative effect. This property is an advantage from the point of view of therapeutic applications. In addition, these compounds have weak anticonvulsive action.

Anxiolytic activity of the compounds of the above group explored on "accelerated test + labyrinth. As experimental animals used male rats belonging to the genus Sprague Dawley and weighing from 220 g to 260, the Test was performed using the wooden cross (in the form +) maze that is installed at a height of 50 cm and having two open and two closed end (length 50 cm and 15 cm wide). After treatment for 60 min, animals were placed in the maze and watched for 5 minutes the Action of the drug was expressed in Protea expected minimum effective dose causing a significant increase in time spent in the open ends [Pelow. S., Chopin, P., File, S. E., Briley, M.: J. Neurosci. Methods 14, 149- 167 (1985)].

The data obtained are presented in table VI.

The table shows that some compounds in accordance with the invention have a tranquilizing effect, superior to the action of diazepam. The activity of the most effective substances was significantly higher than the comparative activity of the drug.

The effect of compounds on the spontaneous locomotor activity was determined by the method of Borsy et al. For groups of three mice were injected orally with varying doses of the test compounds. Then the animals were placed in a 10-channel device Dews'a, which determined the number of interrupts the infrared beam within 30 minutes On the basis of these data by the method of linear regression was calculated in 50% inhibitory dose (IC50)[Borsy.J., Csanyi, E., Lazar, I.: Arch. Int. Pharmacodyn. 124, 1 (1960)].

The obtained data are presented in table VII.

From the table it is seen that the introduction of the oral dose of the studied compounds in accordance with the invention in quantities of 100 mg/kg practically no effect on spontaneous locomotor activity Missa IC50was 23 mg/kg

Inhibitory effect against seizures induced by introduction of pentetrazole, was determined by the modified method Benziger and NAPA. As experimental animals used male and female rats belonging to the genus NMRI and weighing from 20 g to 25 g of Tonic external convulsions hind limbs, caused by intraperitoneal introduction of 125 mg/kg pentetrazole, recorded on groups of animals consisting of 6-12 individuals. The compounds and carriers injected within 1 h before application of pentetrazole [Benziger, R., NAPA, D.: Arch. Pharmacodyn. 167, 245 (1967)].

The obtained data are presented in table VIII.

The test results show that the compounds according to the invention have a mild anticonvulsive action.

The present invention also includes pharmaceutical compositions comprising as an active ingredient a compound of General formula (I) or its pharmaceutically acceptable salt in a mixture with suitable inert solid or liquid pharmaceutical excipient.

The pharmaceutical composition in accordance with the present invention can be obtained by known methods by mixing the active is="ptx2">

The pharmaceutical composition in accordance with the present invention can be applied orally (e.g. in the form of tablets, granules, granules, coated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions), parenteral (e.g., in the form of solution for injection) or rectally (e.g. in the form of a suppository).

As filler for the preparation of tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn and potato starch, talc, magnesium carbonate, magnesium stearate, calcium carbonate, stearic acid or its salts, etc. as a filler of soft gelatin capsules can be used, for example, vegetable oils, fats, waxes, or polyols suitable consistency. As filler for mortars and syrups can be used, for example, water, polyhydric alcohols (ethylene glycol), sucrose or glucose. Injectable solutions may contain, for example, water, alcohols, polyols, glycerol and vegetable oils. Suppositories can be prepared using, for example, oils, waxes, fats or polyhydric alcohols suitable consistency.

In addition to this the th industry, for example, wetting agents, sweetening and flavouring agents, salts, causing the change of osmotic pressure, buffers, etc., the Pharmaceutical compositions can also contain other active ingredients.

Daily dose of the compounds of General formula (I) can vary within a wide range depending on several factors, for example, the activity of the active component, condition and age of the patient, severity of disease, etc., Preferably oral dose of from 0.1 to 500 mg/day. It should be emphasized that the above dose is for reference only and to apply the composition only in the doses prescribed by a doctor-therapist.

The present invention also includes the use of compounds of General formula (I) or its pharmaceutically acceptable salts acid accession to receive pharmaceutical compounds, affecting, in particular, on the Central nervous system.

The present invention also includes a method of treatment of disorders of the Central nervous system, including the appointment to the patient an effective amount of compounds of General formula (I) or its pharmaceutically acceptable salts obtained by the accession acid.

Boley invention.

Example 1

1-(4-bromostyrene)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine

To a suspension of 4.6 g (9.47 mmol) of powdered perchlorate 1-(4-bromostyrene)-3-methyl-6,7-dimethoxy-2-benzopyrene (Tpl.(decomp.): 274-275oC) in 46 ml of 99.5% ethanol was added to 1.4 ml (28,4 mole) of 100% hydrazine hydrate and the mixture was stirred until complete dissolution. Then it was kept at a temperature of 25oC for half an hour and evaporated under vacuum. The residue in 100 ml of water was filtered, washed three times with portions of water and 15 ml, the crude product is suspended in hot form in 400 ml of water for 30 min, filtered, washed three times with portions of water, 15 ml) and dried at 80-100oC. there Was obtained 2.8 g of crude product. For purification the crude product is boiled in 15 ml of ethanol, cooled, filtered, washed with three portions of 1 ml of ethanol and dried. The result of 2.26 g (60%) of the final product. Tpl.: 156-158oC.

Example 2

1-(4-nitrostyryl)-4-methyl-5-ethyl-7,8-dimethoxy-5H - 2,3-benzodiazepine

To a suspension of 1,58 r (3.3 mmole) of powdered perchlorate 1-(4-nitrostyryl)-3-methyl-4-ethyl-6,7-dimethoxy-2-benzopyrene (Tpl.(decomp. ): 277-278oC) in 16 ml of 99.5% ethanol was added 0.5 ml (10,0 moles) of 100% hydrazine hydrate is separated in crystalline form from a solution. The mixture was stirred for another hour, the product was filtered, washed three times with portions of ethanol and 1 ml three times with portions of water (5 ml) and dried at 80-100oC. there Was obtained 1.1 g of the final product. Tpl.: 218 - 220oC (decomp.). For purification the crude product was boiled in 5 ml of ethanol, cooled, filtered, washed with three portions of 1 ml of ethanol and dried. The result of 1.03 g (80%) of the final product. Tpl.: 220-221oC.

Example 3

1-(3,4-dimethoxytrityl)-4-methyl-7,8-dimethoxy-5H - 2,3-benzodiazepine

How A

4.0 g (8,56 mmole) of perchlorate 1-(3,4-dimethoxytrityl)- 3-methyl-6,7-dimethoxy-2-benzopyrene suspended in 80 ml of ethanol, to the suspension was added 1.3 ml (25,7 mole) of 100% hydrazine hydrate and the reaction mixture is boiled under reflux for 5 minutes the Solution is evaporated under vacuum. Then he repeated the operation of Example 1. The result was obtained 1.5 g (46.6%) of the final product. Tpl.: 156-158oC.

Method B

To a mixture of 0.32 ml (6.42 per mmole) of 100% hydrazine hydrate and 5 ml of dimethylformamide was added 1.0 g (2,14 moles) of perchlorate 2-benzopyrene, prepared as described above, when cooled under running water. The resulting solution was stirred for 0.5 h, stormon. The chloroform phase was dried and evaporated under vacuum. Received 0,86 g crude product. For purification the crude product was subjected to recrystallization from 4 ml of ethanol, suspended in 20 ml of hot water, filtered, washed with hot water and dried. The result of 0.59 g (71,9%) of the final product is obtained in pure form. Tpl.: 156-158oC.

The method C

1.0 g (2,14 mmole) of perchlorate 2-benzopyrene, prepared as above, was heated in a mixture of 20 ml of chloroform and 0.32 ml (6.42 per mole) of 100% hydrazine hydrate for 30 minutes was obtained solution. The solvent is then evaporated and the residue triturated in 40 ml of hot water. The crude product was dried and subjected to recrystallization from 3 ml of ethanol. He was then suspended in 25 ml of hot water, filtered, washed three times with portions of hot water to 1 ml and dried. The result was obtained 0.21 g (25.6 percent) of the final product is obtained in pure form. Tpl.: 156-158oC.

Method D

A mixture containing 2.0 g (4,28 mmole) of perchlorate 2-benzopyrene, prepared as above, 4 g of pyridine and 0.65 ml (12.8 mmole) of 100% hydrazine hydrate was stirred at room temperature for 1 h, the Reaction mixture then was poured into 100 ml of water, and RGALI recrystallization from 10 ml of ethanol. The result was obtained 1.06 g (64,6%) of the final product. Tpl.: 156-158oC.

Method B

A mixture containing 2.0 g (4,28 mmole) of perchlorate 2-benzopyrene, prepared as above, 4 ml of tetrahydrofuran and 0.64 ml (12,84 mmole) of 100% hydrazine hydrate was heated under reflux for 30 minutes, the Suspension was cooled to room temperature, filtered and the filtrate was poured into 100 ml of water, and the separated precipitate was extracted with 15 ml of chloroform, and then repeated the cleaning operation shown in Example 2. The result of 0.37 g (22.6%) of the final product.pl.: 156-158oC.

Method F

A mixture containing 2.0 g (4,28 mmole) of perchlorate 2-benzopyrene, prepared as described above, 20 ml of benzene and 0.64 ml (12,84 mmole) of 100% hydrazine hydrate was heated under reflux for 7 hours Then filtered at 25oC, the filtrate evaporated and the residue was boiled for 30 min in hot water, decantation hot and the crude product was subjected to recrystallization from 5 ml of ethanol. The result of 0.83 g (50,6%) of the final product. Sopl.: 156-158oC.

Method G

A mixture containing 2.0 g (4,28 mmole) of perchlorate 2-benzopyrene, prigotovlennaja, as in Method B. the result was obtained 1.2 g (73.6 per cent) of the final product. Tpl.: 156-158oC.

Example 4

1-(4-dimethylaminostyryl)-4-methyl-7,8-dimethoxy-5H - 2,3-benzodiazepine

To the mixture 80,0 ml of dimethylformamide and 5.7 ml (114,0 mmol) of 100% hydrazine hydrate, which is cooled by flowing water, added 17,07 g (of 37.9 mmol) of perchlorate 1-(4 - dimethylaminostyryl)-3-methyl-6,7-dimethoxy-2-benzopyrene (Tpl.: 245-246oC). The resulting solution was stirred for 40 min, then was released dropwise to 800 ml of water. The separated crude product was filtered, washed three times with portions of 60 ml of water and dried at a temperature of from 80 to 100oC. Was obtained by 12.9 g of crude product. For purification the crude product was subjected to boiling with 100 ml of 50% ethanol for 15 min, the suspension was cooled to room temperature, filtered, washed three times with portions of 15 ml of 50% ethanol and dried. The result of 10.5 g (76,3%) of the final product is obtained in pure form. Tpl.: 170-172oC.

Example 5

1-(2,4-dimethoxytrityl)-4-methyl-7,8-dimethoxy-5H - 2,3-benzodiazepine

To a mixture of 21.5 ml of dimethylformamide and 2.3 ml (46,0 mmol) of 100% hydrazine hydrate, which is cooled by flowing water, added to 7.15 g (15,3 is giving 15 minutes The obtained yellow solution was stirred for 30 min, and then thereto dropwise added 43 ml of water under cooling. Thus obtained crystalline suspension was kept at a temperature ofoC for 12 h, filtered, washed three times with 20 ml of water and dried at a temperature of from 80 to 100oC. Was obtained by 5.18 g of crude product. After recrystallization from 26 ml of ethanol was obtained 5,01 g (86,1%) of the final product. Tpl.: 151-153oC.

Further in accordance with the methods described in Examples 1-5 were obtained compounds of General formula (I) shown in table IX

Example 73

1-(4-aminosterol)-4-methyl-7,8-dimethoxy-5H-2,3 - benzodiazepine

How A

4 g (10.9 mmol) of 1-(4-nitrostyryl)-4-methyl-7,8-dimethoxy - 5H-2,3-benzodiazepine (compound from example 50) suspended in 100 ml of ethanol. To the mixture was added 0.4 g of dry (or at a moisture content of 0.8 g) of the Nickel catalyst of Raney and 1.63 ml (to 32.7 mmol) of 100% hydrazine hydrate and stirred for 1 h was obtained solution, the temperature of which is raised to 40-45oC. the Catalyst was filtered and washed three times with portions of 15 ml of ethanol, the filtrates were combined and subjected to evaporation under vacuum, the crude product is added to the product. For purification the crude product was subjected to recrystallization from 35 ml of 50% ethanol. Received 3,17 g (86.4 per cent) of the final product. Tpl.: 196-198oC.

Hydrochloric salt was obtained in the following way: 0.34 g base suspended in 4 ml of hot water was added 0.10 ml of concentrated HCl and the solution is quickly cooled. The output amounted to 0.30 g (80,0%) Tpl.: 227 - 228oC.

Method B

of 4.25 g (10 mmol) of perchlorate 1-(4-nitrostyryl)-3-methyl-6,7 - dimethoxy-5H-2,3-benzopyrene (Tpl.: 273-274oC, decomp.) suspended in 150 ml of methanol. To the mixture was added 1.5 ml (30 mmol) of 100% hydrazine hydrate and stirred at room temperature for 2 hours Of the thus obtained solution after 5 min began to stand out yellow crystals (compound from example 50). Then added about 0.4 g of dry (or at a moisture content of 0.8 g) of the Nickel catalyst of Raney and 1.00 ml (20 mmol) of 100% hydrazine hydrate and stirred for 1-2 hours (until gas evolution stops). The catalyst was filtered and washed three times with 10 ml of methanol and the filtrates were combined and subjected to evaporation in a water bath at a temperature not exceeding 25oC. the Residue was added to 50 ml of water, was filtered, washed three times portion of the : 148-155oC.

For purification the crude product was subjected to recrystallization from 10 ml of 50% ethanol and then suspended first in 200 ml, and then 150 ml of hot water, again filtered, washed three times with 10 ml of water and dried at a temperature of from 80 to 100oC. Was obtained of 1.37 g (41%) of the final product. Tpl.: 196-198oC (decomp.).

The following compounds of General formula (I) shown in table X were obtained by the method A of example 73.

Example 83

1-(4-acetylaminophenol)-4-methyl-7,8-methylenedioxy - 5H-2,3-benzodiazepine

4.0 g (12.5 mmol) of 1-(4-aminosterol)-4-methyl-7,8 - methylenedioxy-5H-2,3-benzodiazepine (compound of example 68) suspended in 20 ml of acetic anhydride. The suspension was stirred at room temperature for 1 h During this time the starting material dissolved and the desired product began to separate, leading to thickening of the reaction mixture. The separated product was filtered, washed three times with portions of 25 ml of diethyl ether and dried at a temperature of from 80 to 100oC. there Was obtained 4.0 g of the desired product. For purification the crude product was boiled in 15 ml of 50% ethanol for 15 min, cooled, filtered, washed three times with portions of 5 the>the l
: 218-220oC (decomp.).

In accordance with the method outlined in Example 83, were obtained new compounds in Examples 84 and 85.

Example 84

1-(4-acetylaminophenol)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine Output: 88,9%. Tpl.: 208-210oC (decomp.) (50% et.SP.)

Example 85

1-(3-acetylamino-4-chlorostyryl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine. Output: 87,7%. Tpl.: 202-204oC (decomp.) (50% et.SP.)

Example 86

1-(4-forsteri)-4-methyl-7,8-methylenedioxy-5H-2,3 - benzodiazepine

To a suspension of 15.1 g (37 mmole) of powdered perchlorate 1-(4-forsteri)-3-methyl-6,7-methylenedioxy-2-benzopyrene in 150 ml of methanol was added to 4.1 ml (82 mmole) of hydrazine hydrate and the mixture was stirred until complete dissolution. Then the mixture stood for 1 h at 25oC, boiled away in vacuum, the residue is stirred in a mixture of 50 ml water and 50 ml of ethyl acetate. An ethyl acetate phase was separated, dried over magnesium sulfate and the solvent is boiled away in a vacuum. The residue was dissolved in 50 ml of ethanol and the final product was separated from the ethanol by adding some water. Received of 8.9 g of crude product. For purification the crude product was subjected to recrystallization from ethanol. The result of 8.1 g (68%) chromatographies)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

To a suspension 9,17 g (20 mmol) of powdered perchlorate 1-[(4-trifluoromethyl)-styryl] -3-methyl-6,7-methylenedioxy-2-benzopyrene in 100 ml of methanol was added 2.5 ml (50 mmol) of hydrazine hydrate and have carried out a reaction as described in Example 86. Was obtained 6.7 g of crude product. For purification the crude product was subjected to recrystallization from ethanol. The result of 6.1 g (82%) chromatographic (TLC) of pure final product. Tpl.: 188-191oC.

Example 88

1-(4-lanosterol)-4-methyl-7,8-methylenedioxy-5H-2,3 - benzodiazepine

To a suspension of of 9.30 g (23.1 mmole) of perchlorate 1-(4 - lanosterol)-3-methyl-6,7-methylenedioxy-2-benzopyrene, prepared as described in Example 95, 100 ml of methanol was added 3.5 ml (70 mmol) of hydrazine hydrate is added dropwise with stirring. The reaction mixture was stirred at room temperature for 3 h, filtered, and some amount of water added to the filtrate with stirring. The separated crystals were filtered and subjected to recrystallization from ethanol. The resulting 2,90 g (38%) of the final product. Tpl.: 197,5-202,5oC.

Example 89

1-(3-foresthill)-4-methyl-7,8-methylenedioxy-5H - 2,3-benzodiazepine

8,17 g (0,02 mol) of perchlorate 1-(3-Forester is Nola and to the suspension was added dropwise 2.5 ml of 0.05 mol) of hydrazine hydrate. The reaction mixture was stirred at room temperature for 2 h, filtered, and the filtrate is boiled away. The residue was dissolved in a mixture of 50 ml water and 50 ml of ethyl acetate, the organic phase is separated, dried over magnesium sulfate and again boiled away. The residue was subjected to crystallization from ethanol and recrystallization from acetonitrile. The resulting 4,30 g (67%) chromatographic (TLC) of pure final product. Tpl.: 161-162oC.

Example 90

1-(2-foresthill)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

8,17 g (0,02 mol) of perchlorate 1-(2-foresthill)-3-methyl-6,7-methylenedioxy-2-benzopyrene, prepared as described in Example 97, stirred in 100 ml of acetonitrile and to the mixture was added 2.5 ml (0.05 m) of hydrazine hydrate is added dropwise. The reaction mixture was stirred at room temperature for 2 h, filtered, and the filtrate is boiled away. The residue was dissolved in a mixture of 50 ml water and 50 ml of ethyl acetate, the organic phase is separated, dried over magnesium sulfate and again boiled away. The residue was subjected to crystallization from ethanol and purified by recrystallization from ethanol. The result was obtained with 3.79 g (59%) chromatographic (TLC) of pure final product. Tpl.: 138-141oC.

Example 91

Example 92

1-(4-foresthill)-4-methyl-7,8-methylenedioxy-3,4 - dihydroxy-5H-2,3-benzodiazepine

To a mixture of 2.0 g (6.2 mmole) of 1-(4-foresthill)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine prepared as described in Example 86, and 10 ml of glacial acetic acid in small portions was added a solution of 3.0 g (79 mmol) of sodium borohydride, maintaining the temperature of the mixture below 35oC. the Mixture was stirred for 2 h, after which it was added to the sodium carbonate solution to obtain an alkaline reaction. Having an alkaline reaction solution was extracted three times with ethyl acetate portions to 20 ml of an ethyl acetate phase was dried, boiled away and the remainder, for example, the network of 1.39 g (69%) chromatographic (TLC) of pure final product. Tpl.: 170-174oC.

Obtaining a new source of substances:

Example 93

Chlorate 1-(4-foresthill)-3-methyl-6,7-methylenedioxy-2-benzopyrene

The mixture 15,10 g (0.05 moles) of perchlorate 1,3-dimethyl-6,7 - methylenedioxy-2-benzopyrene, 80 ml of glacial acetic acid and of 6.20 g (0.05 moles) of 4-forventelige was stirred on an oil bath at a temperature of 150oC for 3 hours, the Reaction mixture was cooled, filtered, the precipitate washed twice with acetic acid 10 ml and twice with ethyl acetate 30 ml and dried at room temperature. The result was obtained by 9.60 g (47%) of the final product. The product decomposes at a temperature of about 203 - 204oC. the resulting material can be used for further reactions without purification.

Example 94

Chlorate 1-(4-trifloromethyl)-3-methyl-6,7-methylenedioxy-2-benzopyrene

The mixture 15,10 g (0.05 moles) of perchlorate 1,3-dimethyl-6,7 - methylenedioxy-2-benzopyrene, 80 ml of glacial acetic acid and to 8.70 g (0.05 moles) of 4-triftormetilfullerenov was stirred on an oil bath at a temperature of 150oC for 3 hours, the Reaction mixture was subjected to processing as in Example 1. The result is 13,30 g (58%) of the final product. The product decomposes at temperature is>Example 95

Chlorate 1-(4-lanosterol)-3-methyl-6,7-methylenedioxy-2-benzopyrene

The mixture was 9.33 g (0,031 mole) of perchlorate 1,3-dimethyl-6,7 - methylenedioxy-2-benzopyrene, 50 ml of glacial acetic acid and 4.0 g (to 0.032 mole) of 4-cyanobenzaldehyde was stirred on an oil bath at a temperature of 150oC for 3 hours, the Reaction mixture was subjected to processing as in Example 86. The result of 9.30 g (75%) of the final product. The product decomposes at a temperature of about 241-247oC.

Example 96

Chlorate 1-(3-foresthill)-3-methyl-6,7-methylenedioxy-2-benzopyrene

The mixture 15,10 g (0.05 moles) of perchlorate 1,3-dimethyl-6,7 - methylenedioxy-2-benzopyrene, 80 ml of glacial acetic acid and of 6.20 g (0.05 moles) of 3-forventelige was stirred on an oil bath at a temperature of 150oC for 3 hours, the Reaction mixture was subjected to processing as in Example 86. The result is a 11,20 g (55%) of the final product. The product decomposes at a temperature of about 186 to 190oC.

Example 97

Chlorate 1-(2-foresthill)-3-methyl-6,7-methylenedioxy-2 - benzopyrene

The mixture 15,10 g (0.05 moles) of perchlorate 1,3-dimethyl-6,7 - methylenedioxy-2-benzopyrene, 80 ml of glacial acetic acid and of 6.20 g (0.05 moles) of 2-forventelige was stirred on an oil bath at tengchen 10.0 g (49%) of the final product. The product decomposes at a temperature of about 235-238oC and can be used for further reactions without purification.

Example 98

Chlorate 1-(4-foresthill)-3-methyl-7,8-methylenedioxy-2 - benzopyrene

A mixture of 5.0 g (of 16.6 mmole) of perchlorate 1,3-dimethyl-7,8 - methylenedioxy-2-benzopyrene, 30 ml glacial acetic acid and 2.10 g (of 16.6 mmole) of 4-forventelige was stirred on an oil bath at a temperature of 150oC for 1 h, the Reaction mixture was subjected to processing as in Example 86. The result is 2.70 g (40%) of the final product. The product decomposes at a temperature of about 205-209oC and can be used for further reactions without purification.

LITERATURE

1. HU 155 572.

2. HU 179 018.

3. HU 195 788.

4. HU 191 702.

5. HU 206 719.

6. J. Chem. Soc. Perkin I. 1973, 2543.

7. J. Chem. Soc. Perkin I. 1980, 1718.

8. J. Chem. Soc. Perkin I. 1984, 849.

9. I1. Farmaco-Ed. Sc. 40, 942, 1985.

10. Chem. Ber. 107, 3883, 1974.

11. Patel, J. C. and Malich, J. C.: Neuropharmacological profile of an anxiolytic. in: Anxiolytics: Neurochemical behavioural and clinical perspectives. (Eds.: Malich J. B., Eppe, S. J. and Yamuuamura, H. I., Raven Press, New York 1983, p.p. 173-191.

12. File, S. L.: The contribution of behavioural studies to the neuropharmacology of anxiety, Neuropharmacology 1987, 26, 877-866.

13. Chem. Rev. 651971].

17. Khim. Geterotsikl. Soed. 1973, 568 [C. A. 79, 18629c, 1973].

18. Khim. Geterotsikl. Soed. 1973, 1458 [C. A. 80, 70649u, 1974].

19. FEBS Letters 308(2), 215-217, 1992.

20. Psychopharmacology, 13, 222, 1968.

21. Psychopharmacology, 75, 84, 1981.

22. Borsy, J., et al: Arch. Int. Pharmacodyn. 124, 1, 1960.

23. Schlichtengroll: Arzneim. Forsch., 8, 489, 1958.

24. Morpurgo: Arch. Int. Pharmacodyn. 137, 87, 1962.

25. Psychopharmacology, 21, 1, 1971.

26. Pellow, J. et al: Neurosci. Meth. 14, 149-167, 1985.

27. Tedeshi: J. Pharm. Exp. Ther., 125, 28, 1959.

28. Benziger, R.: Arch. Int. Pharmacodyn. 167, 245, 1967.

1. Derivatives of 1-[2-(substituted vinyl)] -5H-2,3-benzodiazepine General formula I

< / BR>
where A and B together form a group of the formula-C=N - or-CH-NH-;

R1represents phenyl which may contain from 2 to 3 hydroxyl groups or 1 to 3 identical or different substituents selected from the group comprising halogen, trifluoromethyl, nitro-, cyano-, amino-, di(C1-3alkyl)amino, C1-4alkanolamine-, C1-4alkyl, C1-4alkoxy-, carboxy, (C1-4alkoxy)-carbonyl and methylendioxy; naphthyl, which may contain a Deputy representing a hydroxyl; furyl, thienyl or indolyl;

R2represents hydrogen or C1-4alkyl,

R3and R4each is own the/SUP> together form a 7,8 - or 8,9-methylenedioxyphenyl group

and their pharmaceutically acceptable salts accession acids.

2. Derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine General formula I on p. 1, wherein A and B together form a group of the formula-C= N; R1represents phenyl which may contain from 2 to 3 hydroxyl groups or 1 to 3 identical or different substituents selected from the group comprising halogen, trifluoromethyl, nitro-, cyano-, amino-, di(C1-3alkyl)amino, C1-4alkanolamine-, C1-4alkyl, C1-4alkoxy-, carboxy, (C1-4alkoxy)-carbonyl and methylendioxy; naphthyl, which may contain a Deputy representing a hydroxyl; furyl, thienyl or indolyl; R2represents hydrogen or C1-4alkyl, R3and R4each represents a C1-4alkoxygroup attached in positions 7 or 8 benzodiazepine ring, or R3and R4together form a 7,8-methylenedioxyphenyl group, and their pharmaceutically acceptable salts accession acids.

3. Derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine General formula I on p. 1, wherein A and B together form a group of formula C is ecstasy a hydrogen; R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group, and their pharmaceutically acceptable salts accession acids.

4. Derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine General formula I on p. 2, wherein A and B together form a group of the formula-C= N; R1represents phenyl which may contain 1 or 2 substituent selected from the group comprising amino, di(C1-3alkyl)amino or C1-4alkoxygroup; R2represents hydrogen; and R3and R4together form a 7,8-methylenedioxyphenyl group, and their pharmaceutically acceptable salts accession acids.

5. Compounds of General formula I on p. 1: 1-(4-dimethylaminostyryl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine, 1-(4-aminosterol)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine, 1-(3,4-dimethoxytrityl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine and their pharmaceutically acceptable salts accession acids.

6. The compound of General formula I on p. 1: 1-(4-foresthill)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine and its pharmaceutically acceptable salts accession acids.

7. The method of obtaining derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine General formula I

< / BR>
where A and B together obrazuje perchlorate 2-benzopyrene General formula II

< / BR>
where R1, R2, R3and R4- same as above

with hydrazinehydrate and, if necessary, the transformation of the thus obtained base of the General formula I in his salt accession acid.

8. The way to obtain 1-[2-(substituted vinyl)] -5H-2,3-benzodiazepines of General formula I

< / BR>
where A and B together form a group of the formula-C=NH;

R1represents a phenyl containing amino, di(C1-3alkyl)amino, or (C1-4alkanoyl)-amino group, while the phenyl may optionally contain 1 or 2 identical or different substituent selected from the group comprising halogen, trifluoromethyl, nitro-, cyano-, amino-, methylenedioxy-, C1-4alkyl, C1-4alkoxygroup, carboxyl or (C1-4alkoxy)-carbonyl;

R2as stated in paragraph 1;

R3and R4independently of one another represent C1-4alkoxygroup attached in positions 7 and 8 of the benzodiazepine ring, or R3and R4together form a 7,8-methylenedioxyphenyl group

including the restoration of the compounds of General formula I, where R1is a nitrophenyl which may contain 1 or 2 identical or different substituent selected from B> alkoxygroup, carboxyl and (C1-4alkoxy)-carbonyl, hydrazinehydrate in the presence of a catalyst and, if necessary, acylation or alkylation thus obtained amino compounds and, if necessary, the transformation of the thus obtained base of the General formula I in his salt accession acid.

9. The method of obtaining derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine General formula I

< / BR>
where A and B together form a group of the formula-CH-NH-;

R1represents a phenyl containing fluorine atom, trifluoromethyl or cyano;

R2represents hydrogen;

R3and R4together form a 7,8 - or 8,9-methylenedioxyphenyl group

including the restoration of the compounds of General formula I, where A and B together form a group of the formula-C=N; R1, R2, R3and R4- same as above, the complex metal hydride and/or a complex of boron and, if necessary, the transformation of the thus obtained base of the General formula I in his salt accession acid.

10. Pharmaceutical composition, possessing anxiolytic, antipsychotic and anticonvulsive effect, containing an effective amount of the active companywho component composition contains a compound of General formula I, where A, B, R1, R2, R3and R4are the same as indicated in paragraph 1, or its pharmaceutically acceptable salt.

11. The pharmaceutical composition according to p. 10, characterized in that it contains as active ingredient at least one compound of General formula I, where A, B, R1, R2, R3and R4are the same as indicated in paragraph 2, or its pharmaceutically acceptable salt.

12. The pharmaceutical composition according to p. 10, characterized in that it contains as active ingredient at least one compound of General formula I, where A, B, R1, R2, R3and R4are the same as indicated in paragraph 3, or its pharmaceutically acceptable salt.

13. The pharmaceutical composition according to p. 10, characterized in that it contains as an active ingredient 1-(4-dimethylaminostyryl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine, 1-(4-aminosterol)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine, 1-(3,4-dimethoxytrityl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine and their pharmaceutically acceptable salts accession acids.

14. The pharmaceutical composition according to p. 10, characterized in that it contains as an active ingredient 1-(4-foresthill)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine and its farmaceutycznego tranquilizing, antipsychotic and anticonvulsive action, by mixing an effective amount of the active ingredient with a suitable inert solid or liquid pharmaceutical carrier and the subsequent transfer of the mixture in herbal form, characterized in that the active component is used as a compound of General formula (1), where A, B, R1, R2, R3and R4are the same as indicated in paragraph 1, or its pharmaceutically acceptable salt.

16. A method of obtaining a pharmaceutical composition, possessing anxiolytic, antipsychotic and anticonvulsive action under item 15, wherein the active component is used as a compound of General formula I, where A, B, R1, R2, R3and R4are the same as indicated in paragraph 2, or its pharmaceutically acceptable salt.

17. A method of obtaining a pharmaceutical composition, possessing anxiolytic, antipsychotic and anticonvulsive action under item 15, wherein the active component is used as a compound of General formula I, where A, B, R1, R2, R3and R4are the same as indicated in paragraph 3, or its pharmaceutically acceptable salt.

18. A method of treating patol is that as a drug is administered an effective amount of the compounds of General formula I, where A, B, R1, R2, R3and R4are the same as indicated in paragraph 1, or its pharmaceutically acceptable salt.

19. Derivatives of chlorite 2-benzopyrene General formula II, where R1, R2, R3and R4are the same as indicated in paragraph 3.

Priority signs:

09.02.95 - PP.2,4,5,11,13,15 and 16;

24.11.95 - PP.3,6,12,14,17 and 19.

 

Same patents:

The invention relates to the derivatives of pyrazole and herbicides containing them

The invention relates to disubstituted polycyclic compounds, their derivatives, pharmaceutical preparations and methods of use in treating mammals disorders mental and/or neurological dysfunction and/or depressions such as diseases associated with degeneration of the nervous system, and not only their

The invention relates to anti-inflammatory and analgesic agents, in particular to the enol ester and ether prodrugs of 3-acyl-2-oxindole-1-carboxamides constituting a new class of well-known non-steroidal anti-inflammatory agents

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, in particular fungicidal activity, and more particularly to a derivative triazolyl, the way they are received and fungicidal tool

The invention relates to the derivatives of pyrazole and herbicides containing them

The invention relates to a new vysokomernoa tritium compound -(2-propylene-4,6-dimethyl-8-oxymethyl)octyl-(3-hydroxy-4,5,6-trimethyl-6-ene)heptylene General formula I

< / BR>
which finds application in biochemical and biomedical studies, and to a method thereof, which lies in the interaction of the parent substance of General formula I with tritium water, by introducing into the reactor the initial substance, РdO or a mixture РdО with 5% РdО/Al2O3, the evacuation of the reactor filled with gaseous tritium and heated at local cold by freezing its upper part, then the reactor re-vacuum, heated to 65 - 85oC, then give him dioxane or a mixture of dioxane with triethylamine

The invention relates to new biologically active compound from a number of heterocyclic compounds of the formula I, showing the property activator germination of wheat seeds

The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, possibly substituted C1-C8-alkyl; R3- peloid in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt

The invention relates to compounds which inhibit the protease encoded by human immunodeficiency virus, or their pharmaceutically acceptable salts, and such compounds are used for the prevention of infection by HIV, treating infection by HIV and the treatment of acquired as a result immunodeficiency syndrome (AIDS)
Up!