Derivatives of 1-[2-(substituted vinyl)]-3,4-dihydro-5h-2,3 - benzodiazepine, the method of production thereof, pharmaceutical composition, method of production of a pharmaceutical composition and method of inhibiting convulsions.


C07D243/02 - having the nitrogen atoms in positions 1 and 2

 

(57) Abstract:

Describes the new derivatives of 1-[2-(substituted vinyl)]-3,4-dihydro-5H-2,3-benzodiazepine General formula I, where R represents hydrogen or C1-4alkanoyl; R1represents phenyl which may contain from 1 to 3 identical or different substituents selected from the group comprising halogen, nitro-, amino-, di(C1-4alkyl)-amino, C1-4alkanolamines, C1-4alkyl, C1-4alkoxygroup, methylenedioxy and hydroxyl, or naphthyl; R2represents hydrogen or C1-4alkyl; R3and R4independently of one another represent C1-4alkyl, or R3and R4together form methylene, and their pharmaceutically acceptable salts obtained by the accession acid. New compounds form strong links with centres, it is specific to homoplasies, therefore, will be a significant activity in vivo against the Central nervous system. Also describes the method of production thereof, pharmaceutical composition and method of its production, and method of inhibiting convulsions. 7 c. and 5 C.p. f-crystals, 6 PL.

The invention relates to new derivatives of 1-[2-(the Yu specified benzodiazepine derivatives for the treatment of diseases and preparation of pharmaceutical compositions suitable for treatment of diseases.

As is well known, the literature describes derivatives of 3,4-dihydro - 5H-2,3-benzodiazepine, containing as substituents, a hydrogen atom, phenyl, naphthyl, substituted phenyl, furyl or thienyl 1 position of the main chain of the molecule (HU 168760, HU 198494, HU 206719; patent Hungary N 8398/90; Chem. Ber. 95, 2012, 1962; Helv. Chem. Acta 59, 2786, 1976; Synthesis, 1973, 159; Synthesis, 1977, 1; Acta Chim. Hung. 83, 115, 1974; Rec. Trav. Chim. 84, 661, 1965; J. Chem. Soc. Chem. Comm. 1972, 823; Il. Farmaco-Ed. Sc. 40, 942, 1985; Chem. Pharm. Bull, 30, 3764, 1982.

Well-known compound 1-(4-AMINOPHENYL)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (which is also the name of the GY-KI-52466) is an antagonist of non-NMDA-glutamic acid, manifesting antispasmodic and anti-ischemic activity, but the duration of its effect is quite short, which is a disadvantage from the point of view of its possible therapeutic applications.

The task of the invention to provide new derivatives of 2,3-benzodiazepine, is comparable with the known benzodiazepines the action on the Central nervous system, but better than duration of exposure.

It was found that the compounds according to the invention are characterized by the following signs.


< / BR>
where R represents hydrogen or C1-4alkanoyl,

R1represents phenyl which may contain from 1 to 3 identical or different substituents selected from the group comprising halogen, nitro-, amino-, C1-4alkylamino-, di(C1-4alkyl)-amino, C1-4alkanolamines, C1-4alkyl, C1-4alkoxygroup, methylenedioxy and hydroxyl, or

naphthyl, which may contain a Deputy selected from the group comprising hydroxyl, C1-4alkyl and C1-4alkoxy,

R2represents hydrogen or C1-4alkyl,

R3and R4independently of one another represent C1-4alkyl, or

R3and R4together form methylene,

their stereoisomers and pharmaceutically acceptable salts of the acid accession.

Preferred compounds of General formula (I) are those compounds in which R represents a C1-4alkanoyl, R1represents phenyl or naphthyl, containing as Deputy C1-4alkanolamines or C1-4alkoxygroup, R2represents hydrogen or ethyl, and R3and R4independently represents a C1-4alkyl is proizvodnye:

1-(4-acetylaminophenol)-3-acetyl-4-methyl-7,8 - dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine,

1-[2-(1-naphthyl)-vinyl] -4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine,

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

their stereoisomers and pharmaceutically acceptable salts of the acid accession.

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 same number of carbon atoms, such as methyl, ethyl, n-propyl, etc., the Term "alkoxygroup" refers to ether groups containing alkali with a linear or branched chain, such as methoxy, ethoxy, isopropoxy etc. the Term "alkanolamine-" refers to linear or branched aliphatic carboxylic acid amide groups (for example, 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, halogenation, such as florescence 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, methanesulfonamido, econsultations) or arylsulfonate acids (for example, para-toluensulfonate, para-bromophenylacetate, aftershool, sulfanilic acids).

In the proposed invention is also a method of obtaining derivatives of 1-[2-(substituted vinyl)] -3,4-dihydro-5H-2,3-benzodiazepine General formula (I), including

a) restoring 5H-2,3-benzodiazepine General formula (II)

< / BR>
where R1, R2, R3and R4as indicated above, the complex metal hydride and/or a complex of borane and, if necessary, subsequent acylation thus obtained compounds of General formula (I), where R is hydrogen, a R1, R2, R3and R4same as above, or

b) compounds of General formula (I), where R1is a nitrophenyl which may contain 1 or 2 identical or different substituent selected from the group including and R4same as above, with hydrazine hydrate in the presence of a catalyst to obtain 1-[2-(substituted vinyl)]-3,4-dihydro-5H-2,3-benzodiazepine General formula (I), where R represents an AMINOPHENYL, (C1-4alkyl)AMINOPHENYL, di(C1-4alkyl)-AMINOPHENYL or (C1-4alkanoyl)-AMINOPHENYL, while these groups may have one or two identical or different substituent selected from the group comprising halogen, nitro-, amino-, methylenedioxy-, C1-4alkyl and C1-4alkoxygroup, a R, R2, R3and R4- same as above, and if necessary, the acylation or alkylation thus obtained amino compounds,

and also, if desired, the dissolution of the thus obtained compounds of General formula (I) or the transformation of the received base of the General formula (I) into a pharmaceutically acceptable acid salt of the merger.

In accordance with the invention by variant (a) of the method includes recovering the complex metal hydride and/or a complex of borane 5-H-2,3-benzodiazepine General formula (I) and, if necessary, the acylation thus obtained compounds of General formula (I) containing as R is hydrogen. For the selective recovery , lithium-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 0 to 100oC using preferably from 1.1 to 25 molar equivalents of restorative agent.

In accordance with the invention, a preferred embodiment of variant (a) 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 (II) in dry dichloromethane at a temperature from 10 to 15oC, adding to the solution thus obtained complex of 1.1 equivalent of the complex of borane-trimethylamine and stirring the resulting reaction mixture at 25oC for from 0.5 to 4 hours the Organic phase is then treated with sodium carbonate, washed with water, dried, evaporated, and crystallized to the desired PR is schego alcohol, or suspended in a suitable solvent.

In accordance with the invention, another preferred embodiment of variant (a) of the method involves the dissolution or suspension of the compounds of General formula (II) in dry tetrahydrofuran, cooled to 0 to 5oC, addition of 1 mole equivalent of lithium hydride-aluminum and stirring the reaction mixture at room temperature for 2 hours the Complex is then subjected to decomposition and the organic phase is evaporated. Of the remainder get the desired 3,4-dihydro-5H-2,3-benzodiazepine, or through column chromatography or by crystallization and optionally convert it to the appropriate acylphosphate.

In accordance with the invention, another embodiment of variant (a) of the method involves the dissolution or suspension in methanol of the original Foundation of the General formula (II), adding an excess of concentrated chloride-hydrogen 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-Dihydrocodeine obtained by crystallization and optionally convert it to the appropriate acylphosphate.

And Urbanovich acids or their anhydrides.

In accordance with the invention in the example execution version (b) of the method are derivatives of 1-[2-(substituted vinyl)]-3,4-dihydro-5H-2,3-benzodiazepine General formula (I), including benzodiazepine General formula (I), where R represents an AMINOPHENYL, mono - or di-(C1-4alkyl)- AMINOPHENYL, which may contain 1 or 2 identical or different substituent selected from the group comprising halogen, nitro, methylenedioxy-, hydroxy-, C1-4alkyl and C1-4alkoxygroup, by restoring the appropriate derived nitrophenyl General formula (I) with hydrazine hydrate in the presence of a catalyst and, if necessary, acylation or alkylation of the obtained amino compounds. For nitrogroup reduction using the method of selective reduction, which does not lead to saturation of the vinyl group. 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 only nitrocompounds such that n is>Recovery is preferably carried out in the presence of an organic solvent. Preferably you can use the following solvents or mixtures thereof: lower alcohols, dioxane, tetrahydrofuran, benzene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide and pyridine. It is preferable to conduct the reaction in excess of 90-100% hydrazine hydrate. As catalyst, preferably palladium on bone coal, platinum or Nickel of Renee. The reaction is carried out at a temperature of from 0oC to the boiling point of the solvent, preferably from +10 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 (II) and the implementation of 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 several times dissolve is purified by recrystallization or trituration in powder in the solvent. As a solvent, you can use alcohol, water or mixtures thereof.

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 gelegenheid acid 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, aliphatic ketone, nitrile, tetrahydrofuran, dioxane, pyridine), however, the reaction can be carried out as without rest the STV, are new and can be obtained by the method described in the literature [HU 195788]. Melting temperature it is shown below.

The new compounds of General formula (I) in accordance with the invention have valuable pharmaceutical properties, in particular the activity in relation to the Central nervous system. These compounds form strong links with centres, it is specific to homoplasies (2,3-benzodiazepine) [FEBS Letters 308(2), 215-217, 1992], in the result, we can assume that, given the similar absorption and metabolism of 2,3-benzodiazepines, they will be significant activity in vivo against the Central nervous system.

Values of Kidefined using 5 nm3H-gersoppa [1-(3-chlorophenyl)-4-methyl-7,8-dimethoxy-5H-2,3 - benzodiazepine] is presented in table 1. The value of Kiwas calculated by the following formula:

< / BR>
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.

New connections in accordance with the invention significantly reduce spontaneous locomotor activity E. value of short-term toxic effects (deceased/process. is indicated in brackets) new compounds are given in table II.

The experiments were conducted according to the method of Irvine [Psychopharmacology, 13, 222, 1968.]

In contrast to known substances whose molecules have a similar chemical structure, the compounds according to the invention are characterized by a significant potentiation of stereotypie caused by amphetamine, showing, thus, likely activity as an antidepressant. Potentiation of stereotypie induced by the introduction of amphetamine was assessed on a scale Constall'a and Naylor'and [Eur. J. Pharmacol. 18, 95, 1972.]. The results are presented in table III.

Compounds of General formula (I) also exhibit moderate anticonvulsive activity. Anticonvulsive activity was measured in mice by the method of Goodman a [J. Pharm. Exp. Ther., 106, 319, 1952]. Convulsions caused by the introduction of 50 mg/kg i.v. pentetrazole, inhibited by 30-40% and 50-55% after the first. p. application of 30 mg/kg of the compounds obtained in examples 10, 11, 13, 19, 28, 35, 40 and examples 34 and 38, respectively.

The effect of compounds on glutamatergic transmission was investigated in hippocampal slice method Tarnawa [Acta Physiol. Hung., 79, 163, 1992]. Were obtained from hippocampal slices of the rat brain with a thickness of 400 μm, which was located in the cell membrane-type Ialy fields of pyramidal cells in area CA1 of the hippocampus. As a neurotransmitter involved glutamate, acting primarily through AMPA receptors. Known antagonist of AMPA, the connection is called GYKI-52466, inhibits the concentration dependence of the potentials of field CA1. The results obtained are presented in table IV.

Compounds in examples 39 and 41 have at least the same activity as molecules of GYKI-52466. However, in the case of the use of the latter compound inhibition observed after washing, which lasted 30 min was significantly lower than the inhibition measured after the incubation period, which lasted 60 min, while in the case of compounds of examples 41 and 49 30-minute flushing has not led to a decrease in effect. These results show that the duration of exposure of the last connections exceeds the duration of the effects of GYKI-52466. The following three subjects of the sample showed that the inhibition observed after washing, was even higher inhibition measured after the incubation period.

The inhibition potentials of the fields of the hippocampus confirms the possibility of therapeutic application of the new compounds as anti-ischemic and neuroprotective sredstv the impact of new connections exceeds the duration of exposure to known compounds of similar effect.

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 ingredient with a suitable inert solid or liquid filler and transfer the mixture in herbal form.

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 use the e filler for solutions 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, the pharmaceutical compositions can contain auxiliary components commonly used in the pharmaceutical 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 such as 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 soedinyayuschih compositions, 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 acid salt of the merger.

In more detail, the invention described in the following examples of its implementation, which, however, do not limit the scope of the invention.

The new compounds obtained in accordance with the invention, were studied by elemental analysis, IR spectroscopy, H-NMR (nuclear magnetic resonance and mass spectroscopy. The protons are saturated links are found exclusively in TRANS-positions.

Example 1

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

To a solution 2,04 g (5.6 mmol) of 1-(3,4-dimethoxytrityl)-4-methyl-7,8 - methylenedioxy-2,3-benzopyrene in 40 ml of anhydrous dichloromethane was added 1.0 ml (8,4 mole) of epirate of nortryptaline when cooled under running water and then 0.45 g (6,16 mol) of trimethylamine complex of borane. The reaction mixture was stirred at a temperature of 25oC for half an hour and then added 30 ml of 10% aqueous RF. The organic phase is separated, washed four times with portions of distilled water 30 ml, dried and subjected to evaporation. The crystalline precipitate is suspended in 10 ml of ethanol, filtered, washed three times with portions of 1 ml of ethanol and dried at 80-100oC. Was obtained of 1.76 g of the desired product. Tpl.: 166-168oC.

For purification the crude product was boiled in 10 ml of ethanol, cooled, filtered, washed with three portions of 1 ml of ethanol and dried. The result was 1.69 g (82,4%) of the final product. TPL: 168-170oC.

Other compounds of General formula (I), where R represents hydrogen, obtained by the method described in example 1 are presented in table V.

Example 16

1-(2,3-dimethoxytrityl)-4-methyl-7,8 - methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine hydrochloride

1.5 g (4,12 mmol) 1-(2,3-dimethoxytrityl)-4-methyl-7,8 - methylenedioxy-5H-2,3-benzodiazepine was recovered as described in example 1, then the residue after evaporation was dissolved in ethyl acetate and to the solution was added 10 ml of 10% ethyl acetate saturated with gaseous hydrogen chloride. The separated product was filtered, washed three times with portions of 5 ml of ethyl acetate and dried at 80-100oC. Was Estoril)-4-methyl-7,8-methylenedioxy-3,4-dihydro - 5H-2,3-benzodiazepine

To a suspension of 1.1 g (3.0 mmol) of 1-(2,4-dimethoxytrityl)-4-methyl - 7,8-methylenedioxy-5H-2,3-benzodiazepine in 15 ml of anhydrous tetrahydrofuran cooled to a temperature of from 0 to 5oC and added 0,114 g (3,0 mole) of lithium hydride-aluminum. The reaction mixture was stirred at a temperature of 25oC for 2 h, again cooled to a temperature of from 0 to 5oC and subjected to decomposition by the addition of 0.36 ml of 10% aqueous solution of tartrate potassium-sodium. Then the mixture was stirred for 1 h at 25oC, the precipitate was filtered, the filtrate dried and boiled away under reduced pressure. The crude product was subjected to recrystallization from 10 ml of ethanol, filtered, washed three times with portions of 1 ml of ethanol and dried at 80-100oC. Was obtained 0.84 g (76%) of the desired product. Tpl.: 176-178oC.

Example 18

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

As starting substances used 1-(2,4-dimethoxytrityl)-4 - methyl-7,8-dimethoxy-5H-2,3-benzodiazepine, which was subjected to the operations described in example 17, with the difference that the crude product obtained after evaporation was purified on a chromatographic column, the adsorbent used Kieselgel 60 with a particle size is ristalliceski form. Yield 53%. Tpl.: 118-120oC.

Example 19

1-(2,4-dimethoxytrityl)-3-acetyl-4-methyl-7,8 - methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

The crude product obtained after evaporation of the compound in example 17, was dissolved in 7 ml of chloroform, was added 0.7 ml of acetic anhydride and the resulting mixture is boiled for 2 hours Then the mixture was cooled to room temperature, was added 10 ml of water and added sodium bicarbonate to achieve pH 7 - 8. The organic phase was separated, the aqueous phase was extracted three times with chloroform, portions (5 ml), the extracts combined and washed twice with distilled water 10 ml, dried and boiled away under reduced pressure. The residue after evaporation was subjected to recrystallization from ethanol. There was obtained 0.8 g (65%) of the final product. Tpl.: 185-187oC.

In examples 20-23 were the compounds obtained according to the method described in example 19.

Example 20

1 styryl-3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine

Output: 50,0%. Tpl.: 118-120oC.

Example 21

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

Output 56,0%. Tpl.: 85-87oC.

Example 22

1-(2,4-dimethoate. SP.).

Example 23

1-(2,3-dimethoxytrityl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro - 5H-2,3-benzodiazepine

Output: 60,0%. Tpl.: 125-128oC (FL. SP.).

Example 24

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

To a suspension of 3.6 g (10.3 mmol) of 1-(4-nitrostyryl)-4-methyl - 7,8-methylenedioxy-5H-2,3-benzodiazepine in 130 ml of methanol was added to 17.7 ml (0,218 moles) of concentrated hydrochloric acid with stirring. To the resulting solution in a few minutes added to 9.8 g (0,259 mol) of hydrobomide sodium portions over 30 min, and the mixture continued to stir for another 30 minutes Then to the resulting orange suspension was added 150 ml of distilled water dropwise, filtered, the crude product was washed four times with distilled water 20 ml and dried at a temperature of from 80 to 100oC. Was obtained 3,37 g of the desired product. For purification the crude product is boiled in 17 ml of ethanol, cooled, filtered, washed and dried. The result is 2.67 g (73,8%) of the final product. Tpl.: 175-177oC (decomp.).

Compounds in examples 25-29 can be obtained by the method described in example 24.

Example 25

1-(4-nitrostyryl) -4-methyl-7,8 the example 26

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

Output: 64,5%. Tpl.: 168-169oC (decomp.) (FL.SP.).

Example 27

1 styryl-4-methyl-5-ethyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3 - benzodiazepine

Perform the operations specified in example 24, except that after addition of sodium borohydride and the completion of the reaction the mixture is evaporated and the crude product is precipitated with water, subjected to recrystallization from ethanol. Output: 40,0%. Tpl.: 153-154oC.

Example 28

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

Perform operations, as described in example 24, and then the reaction mixture is treated as described in example 27. Output: 54,0%. Tpl.: 132-133oC (FL. SP.).

Example 29

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

Perform operations, as described in example 24, and then the reaction mixture is treated as described in example 27. Output: 40,0%. Tpl.: 114-117oC (FL. SP.).

Example 30

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

2.6 g (7,07 mol) of the compound obtained in example 25 were mixed in 13 ml of acetic anhydride for filytrovali, washed three times with distilled water portions of 15 ml and dried at a temperature of from 80 to 100oC. Was obtained in 2.68 g of crude product, which was subjected to recrystallization from 13 ml of hot ethanol. Received 2,62 g (90,6%) of the final product in pure form. Tpl.: 182-184oC.

In examples 31-32 were the compounds obtained according to the method described in example 30.

Example 31

1-(4-nitrostyryl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro - 5H-2,3-benzodiazepine

Output: 91,0%. Tpl.: 188-190oC (FL. SP.).

Example 32

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

Output: 88,0%. Tpl.: 184-185oC.

Example 33

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

of 6.95 g (18.9 mmol) of 1-(4-nitrostyryl)-4-methyl-7,8-dimethoxy-3,4 - dihydro-5H-2,3-benzodiazepine is obtained in accordance with example 25, suspended in 170 ml of methanol, was added 0.7 g of dry (which corresponds to 1.4 g wet) catalyst of Nickel Raney and 3.3 ml (66 moles) of 100% hydrazine hydrate, and then stirred the reaction mixture for 1 h was obtained solution, the temperature was first raised to 40-45oC. the Catalyst hoteltravel in 80 ml of water, washed three times with water portions of 15 ml and dried. Received 5,46 g of the desired product. For purification the crude product was subjected to recrystallization from 25 ml of 50% ethanol. The result is 4.21 g (66,0%) of the final product. Tpl.: 152-154oC.

Compounds in examples 34-38 can be obtained by the method described in example 33.

Example 34

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

Output: 80,0%. Tpl.: 159-161oC (50% et. SP.).

Example 35

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

Output: 75,5%. Tpl.: 155-158oC (50% VC. SP.).

Example 36

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

Perform the operations specified in example 33, except that due to the poor solubility of the source materials and the final product in the solvent used a mixture of dichloromethane and methanol 2:1. Output: 81,4%. Tpl.: 253-255oC (decomp.) (FL.SP.).

Example 37

1-(4-aminosterol)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro - 5H-2,3-benzodiazepine

Output: 68,9%. Tpl.: 233-234oC (decomp.) (FL. SP.).

Example 38

1-(4-06oC (FL.SP.).

Example 39

1-(4-acetylaminophenol)-3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro - 5H-2,3-benzodiazepine

1.2 g (3.56 mmol) of 1-(4-aminosterol)-4-methyl-7,8-dimethoxy-3,4 - dihydro-5H-2,3-benzodiazepine is obtained in accordance with example 33, suspended in 6 ml of acetic anhydride. The suspension was stirred for 1 h at room temperature. During this time the starting material had dissolved, began the separation of the final product and thickening of the reaction mixture. The separated product was filtered, washed three times with diethyl ether portions 15 ml) and dried at a temperature of from 80 to 100oC. Was obtained 1.07 g (71.3 per cent) of the final product. TPL: 243-246oC (decomp.).

Using as the starting material the compound obtained in example 36, and performing operations of example 39, it is possible to obtain a final product with a yield of 78%.

Connection examples 40-41 can be obtained by the method described in example 39.

Example 40

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

Output: 91,0%. Tpl.: 252-255oC (decomp.).

Example 41

1-(4-acetylaminophenol)-3-acetyl-4-methyl-5-ethyl-7,8-methylenedioxy-3,4 - dihydro-5H-2,3-benzo is Il-7,8-dimethoxy-3,4-dihydro-5H-2,3 - benzodiazepine

To a solution of 5.35 g (14.3 mmol) of 1-[2-(1-naphthyl)-vinyl]-4-methyl-7,8 - dimethoxy-5H-2,3-benzodiazepine in 30 ml of glacial acetic acid was added a solution of 1.76 g (46.3 mmol) of sodium borohydride in 10 ml of water dropwise at 50oC under stirring and then stirred the reaction mixture for another 2 hours the Product is then stirred in 250 ml of water, was added ammonium hydroxide solution to obtain an alkaline reaction, filtered the obtained yellow precipitate, washed with water and subjected to recrystallization from isopropanol. The result of 3.75 g (70.5%) of the final product.

Tpl.: 148-152oC.

Table VI presents new source of matter for producing compounds in accordance with the above examples.

1. Derivatives of 1-[2-(substituted vinyl)]-3,4 dihydro-5H-2,3-benzodiazepine General formula I

< / BR>
where R represents hydrogen or C1-4alkanoyl;

R1represents phenyl which may contain from 1 to 3 identical or different substituents selected from the group comprising halogen, nitro-, amino-, di(C1-4alkyl)-amino, C1-4alkanolamines, C1-4alkyl, C1-4alkoxygroup, methylenedioxy and hydroxyl, or naphthyl;

R2predstavlja>1-4alkyl or

R3and R4together form methylene,

and their pharmaceutically acceptable salts obtained by the accession acid.

2. Derivatives under item 1, characterized in that R represents a C1-4alkanoyl; R1represents a phenyl containing as Deputy C1-4alkanolamines or C1-4alkoxygroup, or naphthyl; R2represents hydrogen or ethyl, and R3and R4independently represents a C1-4alkyl.

3. Compounds of General formula I on p. 1:

1-(4-acetylaminophenol)-3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine,

1-[2-(1-naphthyl)-vinyl] -4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine,

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

and their pharmaceutically acceptable salts obtained by the accession acid.

4. The method of obtaining derivatives of 1-[2-(substituted vinyl)]-3,4-dihydro-5H-2,3-benzodiazepine General formula I

< / BR>
where R, R1, R2, R3and R4same as specified in paragraph 1,

including the restoration of the 5H-2,3-benzodiazepine General formula II

< / BR>
where R, R1, R2, R3and R4are the same as indicated is of the thus obtained compounds of General formula I, where R is hydrogen and R1, R2, R3and R4same as above, and, optionally, dissolving the thus obtained compounds of General formula I or the transformation of the received base of the General formula I in a pharmaceutically acceptable salt, obtained by joining acids.

5. The method according to p. 4, characterized in that the reaction is carried out in an organic solvent.

6. The method according to p. 5, characterized in that the solvent used, the solvent or mixture of solvents, which do not interact with the used regenerating agent or interact with him very slowly.

7. The method according to p. 4 or any one of paragraphs.5 and 6, characterized in that the reducing agent used borohydride sodium, lithium hydride-aluminum or complex with borane-trimethylamine.

8. The method according to any of paragraphs.5 to 7, characterized in that the reaction is carried out at a temperature of from 0othe boiling point of the used solvent, preferably in the range from +10o100oC.

9. Pharmaceutical composition with anticonvulsive activity, containing as an active ingredient at least one compound is ramlau salt, received by the accession of the acid in the mixture in a suitable inert solid or liquid carrier.

10. The pharmaceutical composition according to p. 9, characterized in that it contains as an active ingredient

1-(4-acetylaminophenol)-3-acetyl-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine,

1-[2-(1-naphthyl)-vinyl] -4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine,

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

or their pharmaceutically acceptable salts obtained by the accession acid.

11. A method of obtaining a pharmaceutical composition with anticonvulsive activity, characterized in that the compound of General formula I on p. 1 or its pharmaceutically acceptable salts obtained by the accession acid, is mixed with an inert solid or liquid carrier.

12. Method of inhibiting convulsions, characterized in that the patient an effective amount of the compounds of General formula I on p. 1 or its pharmaceutically acceptable salts obtained by the accession acid.

 

Same patents:

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds

The invention relates to new derivatives of N-acyl-2,3-benzodiazepine General formula [I]

< / BR>
in which R is C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkylamino, di(C1-4alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s), or R is a benzoyl, cyclopropanecarbonyl, C1-5-carbarnoyl or phenylcarbamoyl group, or R is absent when the N(3) and C(4) atoms there is a double bond, R1represents a hydrogen atom, or R1no, when between N(3) and C(4) atoms there is a double bond, R2represents C1-3alkyl, or R1and R2together represent a methylene group, and between the N(3) and C(4) atoms, no double bond, R3means a hydrogen atom or a C1-4-aliphatic acyl group, R4represents a hydrogen atom, a C1-6aliphatic acyl group, possibly substituted by methoxy, cyano, carboxyl, amino, C1-4-alkyl-amino-, di (C1-4alkyl) amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen (s), and benzoyl, Palmitoyl, cyclo who can present valence bonds, provided that, when both of the substituent R3and R4represent hydrogen atoms between the N(3) and C(4) atoms, no double bonds, as well as the stereoisomers of these compounds along with acidic salts accession (when possible) and pharmaceutical compositions containing these compounds

The invention relates to a new derived 5H-2,3-benzodiazepine of the formula (I), namely 1-(3-chlorophenyl)-4-oxymethyl-7,8-dimethoxy-5H-2,3-benzodiazepine and its salts accession acid formula

< / BR>
(I)

Known derived 5H-2,3-benzodiazepine, namely 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (Grandaxin) (Patent Hungary N 155572, U.S. patent N 3736 315) affecting the Central nervous system

The invention relates to medicine, in particular to derivatives of diazepine formula, where the values of the radicals A, R1X, Y, and R4specified in the claims, to a pharmaceutical composition having anti-arrhythmic activity, and to a method of treating arrhythmia

The invention relates to medicine, namely, neurology, and can be used to treat epilepsy in children

The invention relates to a new physical form derivatives of dihydro-2,3-benzodiazepine, useful as pharmaceutical agents in the treatment of disorders of the nervous system

The invention relates to a derivative of 4.1-benzoxazepin-2, or their salts, which are useful for inhibiting stvalentines and fungus growth, and to their use

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treating mammals infected with HIV

The invention relates to derivatives of 3-acylamino-5-phenyl-1,4-benzodiazepine-2-it, and to their salts, retrieval method and intermediate products for their production

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

17 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

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