CS212736B2 - Method of preparing 3h-pyrido-/3,2-e/-1,4-diazepines - Google Patents

Description

VON BEBENBURG WALTER dr., BUCHSCHLAG, OFFERMANNS HERIBERT dr., GROSSAUHEIM (NSR) (54) Production method of 3H-pyrido- [3,2-e] -1,4-diaazepines

This invention relates to 3H-pyrido · [3 ₅ 2-e] -l, 4-diazepine of general formula I

R 1 represents a halogen atom,

R? and R 3, which may be the same or different, represents a hydrogen atom or a halogen atom,

R 1 represents a hydrogen atom, a hydroxyl group, a hydroxyl group acylated with saturated aliphatic mono- or dicarboxylic acids having a total carbon number of 2 to 4, a methoxy group, an alkyl group having a total number of carbon atoms of 1 to 3 and a benzyl group,

Z represents a nitrogen atom or a group —NO,

R @ 1 represents a hydrogen atom, an alkyl group having a total carbon number of 1 to 4, optionally substituted by a cycloalkyl radical having a total number of carbon atoms of 3, an allyl group, an acetyl group, a piperidinoethyl group, morpholinoethyl group or diethylaminoethyl group;

A represents an oxygen or sulfur atom, a methylamino group, a group = N — NH2, a group = N — NHCO — Alkyl, wherein Alkyl represents an alkyl radical having a total carbon number of 1 to 2, or two hydrogen atoms, the group —N (R5) —C (= A) - may also exist in tautomeric form —N = C (AR5) -, and their acid salts.

The compounds prepared by the process of the invention have significant pharmacodynamic properties. Said compounds have, for example, psychosedative and in particular anxiolytic properties. In addition, these compounds have an anti-inflammatory effect.

The essence of the process for the preparation of the compounds of the invention as defined above is characterized in that:

a) a compound of the formula

wherein R 1 to R 5 - have the above meaning and

W represents either - an oxygen atom or --NH group, or - NOH, optionally condenses with the addition of an acid binding agent with a compound of the general formula

AND

II

Rt — C — CHIR1 — X (III) wherein

-R 1 is as defined above,

A represents an oxygen or sulfur atom, two hydrogen atoms or a group - NR 5, and

R7 represents a hydroxyl group, a halogen atom, an alkoxy group having a total number of carbon atoms of 1 to 6, a mercapto group having a total number of carbon atoms of 1 to 6, an amino group or an alkylamino group having a total number of carbon atoms of 1 to 6; R 2 may also be a nitrile group and X is an amino group or a halogen atom, when it is

W is oxygen and X is halogen, the reaction is carried out in the presence of ammonia or an ammonia derivative, whereupon the products of said process are optionally treated - in an alkaline environment - or

b) converting one or more of R 5, R 4, A and R in a compound of formula (I). For other meanings corresponding to the general formula (I), the obtained products of processes (a) or (b) are optionally acylated in the 1, 2 and / or 3-position with aliphatic acids or derivatives of acids having 2 to 6 carbon atoms.

Process (a) is carried out in customary solvents or suspension media at a temperature in the range of 0 to 200 ° C, preferably at a temperature in the range of 20 to 150 ° C. Particularly suitable are polar solvents such as alcohols, dioxane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide and the like. Where W is oxygen, agents such as pyridine and quinoline are also suitable. Also useful is the optional addition of acidic or basic substances such as piperidine or aliphatic carboxylic acid. In the case where X is halogen, it is preferable to add basic substances which cause acid cleavage. Where R 7 is a hydroxyl group [in this case, - (= A) R 2 may represent a carboxyl group], the addition or addition of customary water-cleaving agents such as dicyclohexylcarbodiimide is preferred or necessary.

When compounds of the formula III are used in which - A represents two hydrogen atoms, R 2 represents chlorine or - bromine and the remaining symbols have the meaning given above (in the case where X represents an amino group, this group is blocked the compound of formula (II) wherein R 5 is hydrogen and W is oxygen and R 2 and R 3 and R 1 are as defined above, in inert solvents such as dioxane , benzene, tetrahydrofuran or dimethylformamide, is acylated at 0- 150 ° C with an aliphatic acid halide, ester, anhydride or ketene or benzoyl chloride. The compound obtained after conversion to the alkali metal salt (sodium hydride or sodium amide) is reacted with the above compound of formula III (for example, in a non-basic solvent such as dioxane, dimethylformamide or dimethylsulfoxide at a temperature between 0 and 200 ° C). Thereafter, the acyl group located on the nitrogen atom in the 3-position of the pyridine ring can be cleaved in an acidic or basic medium, optionally cyclizing to compounds of formula I.

Often, process a) can also be carried out in such a way that the amino group at the 3-position of the formula II and / or the amino group of the formula III (X = NH 2) carries a known protective group.

In many cases, the cleavage of such a protecting group takes place simultaneously with cyclization.

These protecting groups are readily cleavable. It is either ^1-ol easily cleavable acyl groups by solvolysis or hydrogenation leaving groups such as the benzyl radical. Solvolytically cleavable protecting groups are cleaved, for example, by saponification with dilute acids or with bases (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, NH 3) at room temperature or short boiling. Hydrogen-leaving groups, such as a benzyl group or a carbobenzoxyl radical, are preferably cleaved by catalytic hydrogenation in the presence of conventional hydrogenation catalysts, in particular palladium catalysts, in solvents or suspension media at elevated pressure. Suitable solvents or suspending media are, for example: water, lower aliphatic alcohols, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide and the like, as well as mixtures of said agents.

Suitable amine protecting groups are, for example: benzyl, alpha-phenylethyl, substituted benzyl groups on the benzene ring, such as p-bromo- or p-nitrobenzyl, carbobenzoxyl, carbobenzthio, trifluoroacetyl, phthalyl, trityl radical, p-toluenesulfonyl radical and the like, as well as simple acyl groups such as acetyl, formyl, tert-butylcarboxy. In particular, protecting groups and cleavage procedures customary in peptide synthesis are contemplated. In addition, Jesse P. Greenstein and Milton Winitz, "Chemistry of the Amino Acids", N.Y. 1961, John Wiley and Sons, Volume 2, for example, page 883, may also be consulted. A carbalkoxy group (for example, lower) is also contemplated.

Optionally, process a) can also be carried out by isolating the intermediate step of formula (A), prior to cyclization,

This intermediate stage may then be cyclized as such or after purification. Temperatures between -70 ° C and 150 ° C, preferably temperatures between 0 ° C and 150 ° C, are possible. As the solvent or suspension medium, in addition to the above, acetic acid, lower aliphatic alcohols such as methanol and ethanol, acetic anhydride, polyphosphoric acid, aliphatic ethers, chloroform and the like are particularly suitable. Said cyclization may also be carried out using acidic condensing agents such as sulfuric acid, hydrochloric acid, hydrobromic acid, toluenesulfonic acid or phosphoric acid, or else using basic condensing agents such as pyridine or tertiary amines.

When X is a halogen atom, cyclization is carried out in the presence of ammonia (e.g. also liquid ammonia), and tertiary, non-quaternizing amines such as sterically hindered amines such as diisopropylethylamine or 1,8-bis (dimethylamino) - may also be added. naphthalene. Possible halogen atoms are chlorine, bromine or iodine. Other ammonia derivatives, such as, for example, urotropin alkali metal amides, acid amines, in which the acid residue is a conventional and abovementioned protective group which is readily cleavable, may also be used in place of ammonia or in addition to NH3.

If urotropin is used, the process can be carried out, for example, as follows: boiling in chloroform (1/2 hour to 8 hours) and cleaving the separated urotropin compound with aqueous or aqueous-alcoholic inorganic acid (HCl, H2SO1) at temperatures e.g. between 20 and 150 ° C.

If acid amides are used, it is recommended to use condensation agents such as sodium, alkali metal hydrides, alkali metal amides (especially sodium amide), Grignard compounds, alkyllithium (butyl-J), or in some cases, such as tosylamides K2CO3, powdered NaOH or dimethyl, dimethylsulfoxide and dimethylformamide, but also dioxane, tetrahydrofuran, alcohols and ether are particularly suitable as solvents. X is an amino group protected by the corresponding acid moiety, and the cyclization is then carried out simultaneously with the deprotection or after the deprotection of the protecting group. or as a base.

If process (a) uses a starting material of the formula (II) in which R 5 is an acyl group, this may optionally be solvolytically cleaved after completion of the reaction; however, it is also possible, in the case of a purely aliphatic acyl group, to reduce this group to an alkyl group (for example using complex alkali metal hydrides such as LiAlH 4).

However, cyclization according to method a) may not result in a seven-membered ring, but only partially or exclusively in a six-membered ring, so that the product has the following general formula:

In this case, a subsequent alkaline treatment is required. This treatment is generally carried out in polar solvents such as lower alcohols (methanol, ethanol), chloroform, dioxane and the like at temperatures in the range of 0 to 150 ° C. Suitable alkaline mediums are, for example: aqueous or alcoholic, in particular methanolic or ethanolic NaO-I and KOH, optionally in admixture with the abovementioned solvents, NaOH and KOH in solid, powdered form, potash as well as aqueous solutions of tertiary amines, namely Especially those that do not quartize, such as diisoproipylimethylamine. Alkali exchangers are also contemplated. applied as a column or in suspension.

This ring expansion produces compounds in which the —N [R5] C [= Aj] grouping in Formula I has the following structures:

—N = C (OH) -, —N = C (NHR5j—), —N = C (OR5) -, —N = C (NHR5-NHR5) -, or —N = C (NR5R5j—).

Often, in addition to the desired diazepine, the ring widening of the compounds of formula (V) can also produce a compound which is formed from the compound of formula (V) without ring expansion by substituting the halogen atom with the appropriate reaction partner. The desired product can then be separated from the product or other by-products in a manner known per se by means of traction crystallization or chromatography. .

According to process b), the ozabenzodiozepines of the formula I can be substituted or reacted in a suitable manner. For example, compounds of formula I in which R 5 represents a hydrogen atom may be alkylated in a manner known per se on nitrogen. Suitable alkylating agents are, for example, esters of the formula R 5 Hal, ArSO 2 OR 5 and SO 2 OR 5, where Hal can be a halogen atom (especially chlorine, bromine or iodine) and Ar can be an aromatic radical, such as phenyl or naphthyl. optionally substituted with one or more lower alkyl radicals, and R 5 may have the meanings given above except for hydrogen. Examples include alkyl esters of pitoluenesulfonic acid and lower dialkyl sulfates. The alkylation reaction is optionally carried out with the addition of customary acid-binding agents, such as, for example, alkali metal carbonates, pyridine and conventional tertiary amines, at temperatures between 0 and 150 ° C in inert solvents such as alcohols, dioxane, dimethylformamide dimethylsulfoxide, aromatic hydrocarbons such as benzene and toluene, or acetone.

The group A in the compound of formula I can be exchanged in various ways. For example, in the case where A is oxygen, this atom can be replaced by a sulfur atom with phosphorus sulfide. This reaction is carried out in inert solvents such as benzene, toluene, dioxane, pyridine, or chlorinated hydrocarbons at a temperature in the range of 0 to 150 ° C. The thus-formed sulfur compound (cyclic thioanide) can in turn react in polar media with alkylamines of the formula NH 2 R 5 (R 5 is as defined above) to give compounds of the formula I in which A is -NH or = NR 5. These reactions are carried out in polar solvents such as methanol, ethanol or in excess at a temperature in the range of 0 to 150 ° C.

For example, compounds of formula I wherein R 1 is other than hydrogen may be prepared as follows from compounds of formula I wherein R 1 is hydrogen and the remaining symbols are as defined above: alkylation, acylation and oxidation. In the alkylation, the reaction is carried out with esters of the formula HalR ', SOzfOR') or ArSOzOR ', where Hal represents a halogen atom, in particular chlorine, bromine or iodine, Ar represents an aromatic radical (especially a phenyl or naphthyl radical optionally substituted by one or more lower radicals). and R 'represents an alkyl group having 1 to 6 carbon atoms. The reaction conditions are the same as those for introducing the residue R 5.

The acylation may be carried out in inert solvents or suspending media, such as dioxane, dimethylformamide, benzene, toluene, at a temperature in the range of 0 to 200 ° C. Suitable acylating agents are: ketenes, as well as acid halides, acid anhydrides or acid esters of carboxylic acids having 2 to 6 carbon atoms, or halides of half esters of carbonic acid having 1 to 6 carbon atoms, optionally with the addition of an acid binding agent such as potassium carbonate or sodium ethylate, or a tertiary amine such as triethylamine.

The esters are especially esters derived from lower aliphatic alcohols. Alkylation and acylation may also be accomplished by first preparing an alkali salt from a compound of formula I in which R 4 is hydrogen by reacting the compound in inert solvents such as dioxane, dimethylformamide , benzene or toluene, with an alkali metal, alkali metal hydrides (especially sodium or sodium compounds) at a temperature of 0 to 150 ° C before the alkylating or acylating agent is added. Carbon dioxide can also be used as the acylating agent in this case to give compounds of formula I wherein R 4 is COOH.

In addition to the aforementioned alkylating and acylating agents, other chemically equivalent chemically equivalent reagents may be used (see, for example: LF and Mary Fieser " Reagents for Organic Synthesis ", John Wlley et al., New York, 1967, Vol. 1, pages 1303-). 4 and Volume 2, page 471). Of course, it is also possible to cleave the acyl groups in the compounds of the formula I in a manner known per se.

By oxidation, for example, compounds can be obtained in which R 4 is a hydroxyl group. Behind it. for this purpose, compounds of formula I in which R4 is a hydrogen atom reacted in inert solvents such as dilute acetic acid, ethyl acetate, acetone, with hydrogen peroxide, acid. peracetic acid or another conventional organic peracid. Temperatures in the range of -10 to 70 ° C are preferably used.

Compounds of formula I in which R 1 is a hydroxyl group can also be obtained by treating compounds of formula I in which R 1 is hydrogen and Z is N - O, either in polar solvents such as ethanol, methanol, methanol-water, a mixture of dioxane-methanol and the like, with alkali (such as sodium hydroxide or potassium hydroxide) or in lower aliphatic acid anhydrides (e.g. acetic anhydride) optionally mixed with other inert solvents; there is a rearrangement in which the oxygen present on the nitrogen forms a hydroxyl group on the adjacent carbon atom. This rearrangement occurs at a temperature in the range of 0 to 150 degrees Celsius, especially at a temperature in the range. Mp 0 to 1010 ° C.

Compounds of formula I wherein Z is N may be converted to the corresponding N-oxides. The reagents and conditions are analogous to those of the hydroxylation of R1. Temperatures that are generally lower; preferably, temperatures in the range of 0 ° to 50 ° C may be used (at the higher temperatures, the above rearrangement occurs).

In compounds of formula I wherein Z is = NO, the oxygen atom may be removed by catalytic hydrogenation or chemical deoxidation. Like. catalysts for catalytic hydrogenation are, for example, suitable metal hydrogenation catalysts, in particular noble metal catalysts (palladium / activated carbon, platinum), or Raney nickel; lower alcohols are mainly used as solvents; temperatures are in the range of 0 to 200 ° C (preferably in the range of 0 to 100 ° C). The hydrogenation can optionally be carried out at elevated pressure up to. 50 atp. For chemical deoxidation, phosphorus trichloride or dimethylsulfoxide is preferably used in inert solvents such as dioxane, benzene or. toluene, at temperatures ranging from 0 to 150 ° C, preferably at temperatures ranging from 0 to 100 ° C.

Compounds of formula (I) in which A is O or S may also be converted by reduction to compounds of formula (I) in which A is two hydrogen atoms. This reduction can, for example, be carried out in solvents or suspension media at temperatures in the range of 0-10 ° C. Suitable solvents or suspending agents are, for example: water, lower aliphatic alcohols, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide. tetramethylurea and the like, as well as mixtures thereof. Preferably, this reduction is carried out as catalytic hydrogenation. Suitable catalysts are finely divided metal catalysts, such as nickel (Raney nickel) or cobalt (Raney cobalt). The catalysts may be used with or without a support. Hydrogenate at normal or elevated pressure.

However, the reduction of the keto or thio group may also be carried out by metal hydrides or complex metal hydrides, such as e.g.

LiH, lithium aluminum hydride, alkylborohydrides, sodium triethoxy aluminum hydride, sodium dihydrobis. (2-methoxyethoxy) aluminate.

The basic compounds of formula (I) may be converted into the compounds of the formula I by known methods. salts. As anions for these salts comes in. consider the known and therapeutically useful acid residues.

If they contain compounds of general use. of Formula I acid groups, then these compounds can be converted. usual way on. alkali salts. metal, for. ammonium salts or substituted ammonium salts. . Suitable substituted ammonium salts are, in particular: tertiary alkylamine salts, lower aminoalcohols as well as. bis- and tris- (hydroxyalkyl) -amines (alkyl radicals having 1 to 6 carbon atoms each); as. For example triethylamine, aminoethanol and. dijhydroxyethyljamin.

Again, the appropriate bases can be prepared from the mentioned salts of the compounds in a conventional manner, for example by treating a solution in an organic reagent. like . in alcohols [methanol] with sodium or sodium hydroxide.

Compounds of general interest. of formula I which contain asymmetric atoms. % of carbon and generally formed as racemates can be separated into optically in a known manner, for example by means of an optically active acid. active isomers. But it is also. an optically active starting material can be used, and the corresponding optically active or diastereomeric form is then obtained as the final product.

The compounds prepared by the process of the invention are suitable for the preparation of pharmaceutical preparations. The pharmaceutical preparations and / or medicaments may contain one or more of the aforementioned compounds or mixtures of these compounds with other pharmaceutically active substances. It can be used to prepare pharmaceutical compositions. conventional pharmaceutical carriers and excipients. The drugs may be administered enterally, parenterally, orally or perlingually. The medicaments may be in the form of tablets, capsules, pills, dragees, suppositories, ointments, jellies, creams, powders, liquid preparations, dusting powders or aerosols. Suitable liquid preparations are, for example: oily or aqueous solutions or suspensions, emulsions and, if appropriate, injectable aqueous or oily solutions or suspensions.

Suitable compounds are, for example, those compounds of the formula I in which R1 to R5 as well as A and Z have the following meanings:

Ri chlorine,

R 2 is fluorine, chlorine or hydrogen, preferably in the o-position,

R3 is hydrogen, fluorine or chlorine, preferably in the o-position,

R 1 is hydrogen or a hydroxyl group or a hydroxyl group acylated with saturated aliphatic mono- or dicarboxylic acids having a total carbon number of 2 to 4,

R 5 is an alkyl group having 1 to 4 carbon atoms, an allyl group, a hydroxyethyl group, a diethylaminoethyl group, a morpholinoethyl group, a piperidinoethyl group or a cyclopropylmethyl group;

A is oxygen, sulfur, two hydrogen atoms, or a methylamino group, = N-NH2, -N-NHCO-Alkyl, wherein alkyl is an alkyl radical having a total of 1 or 2 carbon atoms, the group -N (R5j-); C (- A) - can also · exist in tautomeric form —N = C (ARs),

Z nitrogen or NO.

The compounds of formula I in which R @ 1 is chlorine, R @ 2 and R @ 3 which are identical or different, are hydrogen, fluorine or chlorine, preferably in the o'-position, have a particularly favorable effect, A is oxygen, Z is nitrogen R 4 is hydrogen or hydroxyl and R 5 is hydrogen or alkyl of 1 to 4 carbon atoms, in particular methyl.

The starting compounds which are used in processes a), b] and c), if they are not known, are prepared as follows:

Method a):

Compound of formula

V / ns.ba

An alkali metal, such as sodium amide, potassium amide, sodium hydride or finely divided sodium, in an inert solvent such as dioxane, dimethylformamide or benzene, is then added dropwise to a calculated amount of 2,6-dichloro-3-nitropyridine dissolved in the same the dropwise addition is carried out under stirring and under a nitrogen atmosphere. In many cases, it seems expedient to change the order of addition, i.e., to add an alkali metal compound to the solution of the phenylacetic acid derivative, optionally the benzyl cyanide derivative and 2,6-dichloro-3-nitropyridine. In general, an exothermic reaction leads to an alkali salt of a compound of formula VIII

(Vlll)

Cy = CN or CO2Ra [Ra - H or a lower alkyl group] which is dark blue to violet colored.

After completion of the reaction, the product is filtered off with suction, washed, dissolved in water and dilute acetic acid is added to this solution until the color disappears. As a rule, the compound of formula VIII crystallizes in sufficient purity.

2 - [(α-cyano) -o-chlorobenzyl]] - 3-nitro-6-chloropyridine is obtained as follows:

To a solution of 120 g of o-chlorobenzyl cyanide in 1.5 L of dioxane was added 42 g of sodium hydride (80% in white oil) at 45 ° C under stirring and under a nitrogen atmosphere, and the reaction mixture was stirred at this temperature for 45 minutes. The solution is then cooled and 140 g of 2,6-dichloro-3-nitropyridine in 500 ml of dioxane are added dropwise at 20 DEG-22 DEG C. over a period of 30 minutes. The saturated sodium salt is filtered off with suction, washed with dioxane, dissolved in water-methanol 1: 1, diluted acetic acid is added until the color changes, and the desired product crystallizes, filtered off with suction and washed thoroughly with methanol. Mp 174-175 ° C, yield 91 g.

The corresponding 2-benzoyl-3-nitro-6-chloropyridine derivatives may be prepared from the compounds of formula VIII (formula IX) by oxidation.

* 5 (Ra represents hydrogen · or a lower alkyl group)

is first reacted with the active compound 212736

This oxidation may, for example, be carried out with selenium dioxide in dioxane or tetrahydrofuran at a temperature in the range of 50 to 150 ° C or may also be carried out by treatment with a 30% hydrogen peroxide solution at a temperature below 100 ° C, preferably at a temperature of 100 ° C. 20 to 50 ° C, in acetone-water, followed by the dropwise addition of a stoichiometric amount of aqueous concentrated potassium hydroxide solution at a rate such that no color change occurs. In the latter process, the chlorine atom in the 6-position is simultaneously hydrolytically cleaved at the same time. Therefore, in addition to the desired compound, a compound of formula IX in which R1 is a hydroxyl group is isolated. This is then chlorinated again in a manner known per se by the PCI3 / PCI5 mixture, at the same time PCI3 again deoxidizing the N-oxides formed as a by-product. In compounds of formula (IX), the nitro group is then reduced catalytically (using Pd, Pt, Raney nickel in alcohols, dioxane or tetrahydrofuran at temperatures between 0 and 60 and pressures between 9.8 and 490.3 MPa chemically (using LiAlH 4). or Al (Hg / H'2'0 in ether, dioxane or tetrahydrofuran at temperatures ranging from 0 to 60 ° C) per amino group, which amino group may then be substituted with the radical R 5.

In order to prepare a compound of formula XIII of formula XIII in which R 1 is a hydroxyl group, by means of brominating agents such as, for example, RОВгз, PBrs or SOBr; optionally in an inert environment at a temperature in the range of 20 ° to 200 ° C. The preparation of compounds of formula XIII in which R 1 is fluorine can also be carried out by slowly adding to a solution of compounds of formula XIII in which R 1 is amino in concentrated aqueous hydrofluoric acid at a temperature between 0 and 50 ° C. or that a slow stream of nitrous gases is introduced into said solution.

The reduction of the nitro group as well as the subsequent introduction of Rs is carried out as described above.

Compounds of formula II wherein W represents -NH, or = N0H, for example, obtained from compounds of the formula II ¹ wherein W is oxygen and the remaining symbols R, R and R have the meaning already mentioned above, so that said the compounds are reacted with ammonia or hydroxylamine. This reaction is preferably carried out in polar solvents (aliphatic alcohols, dioxane, tetrahydrofuran, pyridine, liquid ammonia), preferably at a temperature in the range of 0 to 150 ° C and optionally at a pressure in the range of 9.8-980.6 MPa.

Example 1

5-Phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

in which

R 1 is fluorine or bromine, for example, the compound of formula IX is heated in an autoclave at 100 to 120 ° C for several hours (2 to 4) with a saturated aqueous-alcoholic ammonia solution, then the 6-aminopyridine derivative thus formed diazotized in a manner known per se and further reacted under the conditions of the Sandmeyer reaction or the optionally modified Sandmeyer reaction in the presence of fluoride or bromide ions and / or the corresponding copper salts (CuBr, CuCl) or also fluoroborate ions under heating. Suitable solvents here are water-alcohol mixtures or mixtures of water, dimethylformamide and dimethylsulfoxide. Dry diazonium fluoroborates can also be thermally decomposed to obtain fluorine derivatives.

Compounds of formula (XIII) in which R 1 is bromo can also be obtained by bromination of compounds of general gram of N-benzyloxycarbonylglycine is stirred in 400 ml of dry ether and 21 grams of phosphorus pentachloride are added with stirring. After all that has dissolved, 23 grams of 2-benzoyl-3-amino-6-chloro-pyridine in 90 ml of chloroform are added with stirring, followed by stirring at room temperature for two hours, whereby 2- benzoyl-3- [N- (benzyloxycarbonylaminoacetyl) amino] -6-chloropyridine. This was filtered off with suction and washed with ether (yield 30 g; mp. 130 [deg.] C.). 105 grams of this intermediate is then added portionwise to a solution of 100 grams of hydrogen bromide in 360 ml of acetic acid. Carbon dioxide develops immediately, accompanied by foaming. The reaction mixture was stirred for an additional hour and ether was added to complete the precipitation. The precipitate was filtered off with suction, stirred with methanol, and then concentrated aqueous ammonia solution was added to the solution. Analysis

II shows that the initially formed open glycyl derivative cyclizes when the base is released. After a short standstill, water is added until it becomes cloudy, whereupon the substance crystallizes. This is then recrystallized from isopropanol. Yield 60 grams; mp 198 ° C.

Preparation of starting materials

To a cooled and stirred solution of 190 grams of 2,6-dichloro-3-nitropyridine and 117 grams of benzyl cyanide in two liters of dioxane was slowly added 64 grams of sodium hydride (80% in white oil) under a nitrogen atmosphere. The reaction mixture immediately turns dark deep blue, a fine-grained precipitate slowly begins to precipitate and the temperature rises (while cooling with ice water) to 30 ° C. After three hours about 20 ml of alcohol are added, the reaction mixture is stirred for 20 minutes and then filtered off with suction. Dissolve the dark blue sodium salt in one liter of water and dilute acetic acid is added to this solution until color change. The resulting 2- (alpha-cyanobenzyl) -3-methyl-6-chloropyridine crystallizes pure. Mp 165 ° C; yield 146 grams.

To a mixture of 200 grams of 2- (alpha-cyanobenzyl) -3-nitro-6-chloropyridine, 500 ml of acetone and 160 ml of a 30% hydrogen peroxide solution is added dropwise a concentrated hydroxide solution under stirring at 35 to 40 ° C. potassium (from 75 grams of KOH and 50 ml of water). Dripping happens just so quickly that there is no color transition yet. Immediately after reaching a permanent color transition as an indicator of the completion of the reaction, the reaction mixture is cooled and the precipitated crystalline substance is suctioned off. The amount of which is between 30 and 40 g is 2-benzoyl-3-nitro-6-chloropyridine which is purified by recrystallization from methanol. Mp 106 ° C. The filtrate was acidified with dilute hydrochloric acid to give 2-benzoyl-3-nitro-6-hydroxypyridine in an amount of between 120 ^L and 140 grams. Mp 211 ° C.

This hydroxy compound can also be converted to the desired 2-benzoyl-3-nitro-6-chloropyridine by chlorination. To this end, 190 grams of 2-benzoyl-3-nitro-6-hydroxypyridine are mixed with a mixture of 200 ml of phosphorus trichloride, 500 ml of phosphorus oxychloride and 190 g of phosphorus pentachloride for 4 hours at 72 ° C. The phosphorus halides are then evaporated in a rotary evaporator under vacuum, then the residue is extracted with 1 liter of chloroform and washed with ice. water, twice with dilute sodium hydroxide solution and twice with water. The chloroform solution is dried, evaporated to dryness in vacuo and the residue is recrystallized from methanol. Yield 145 g; b. 106 degrees Celsius.

110 grams of pure 2-benzoyl-3-nitro-6-chloropyridine are catalytically hydrogenated in 500 ml of dioxane at a pressure of 588.3 MPa and 20 DEG C. using 30 grams of Raney nickel. The filtered solution is concentrated to about one third of its volume in vacuo and cooled to 5 ° C, after which the crystallized 2-benzoyl-3-amino-6-chloropyridine is filtered off with suction after 1 hour and recrystallized from ethanol. Yield: 78 grams; mp 159 ° C.

Example 2

5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one (formula: see Example 1) ml of bromoacetyl chloride is stirred for two hours at room temperature with 33 g of 2 -benzoyl-3-amino-6-chloropyridine in 200 mL of dioxane with the addition of 11.5 grams of pyridine. The product is filtered off with suction and washed with ether. 25 g of this intermediate (2-benzoyl-3-bromoacetylamino-6-chloropyridine, m.p. 130 [deg.] C., yield 38 g) were left overnight in 900 ml of 12% methanolic ammonia solution. The solution is then evaporated to dryness in vacuo and the residue is dissolved in 200 ml of chloroform. This solution was washed with water. The dry solution is acidified with 6 N isopropanolic hydrochloric acid, and petrol is added to the solution until it becomes cloudy. The crystallized HCl-salt was filtered off with suction after two hours, dissolved in methanol, and the base was prepared by the addition of ammonia and crystallized after the addition of water. Yield 10 grams; mp 198-200 ° C.

Example 3

5-Phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide

2-Oximinobenzoyl-3-amino-6-chloropyridine (crude product), obtained from 46 g of 2-benzoyl-3-amino-6-chloropyridine and 70 g of hydroxylamine hydrochloride, is dissolved in 400 ml of acetic acid and 32 ml of chloroacetyl chloride are added. The reaction mixture is allowed to stand for two days, hydrogen chloride is introduced until saturation and the mixture is allowed to stand for a further three days. The solution is then evaporated in vacuo, the residue is extracted with methylene chloride and the solution is washed thoroughly with water and then with iced soda. The solution is then dried over sodium sulphate and, after concentration to 150 ml of petroleum ether (40-70 ° C), is added to the solution until it becomes cloudy. Mon. The precipitated crystals of 5-aza-6-chloro-2-chloromethyl-4-phenyl-quinazoline-3-oxide are filtered off with suction (2 g, 23 grams; m.p. 146 DEG C.) for two hours. 6.5 grams of these crystals are added to a mixture of 8 grams of sodium hydroxide, 20 ml of water and 100 ml of ethanol at room temperature. After stirring for 1 hour, the solution is diluted with water and acidified slightly with hydrochloric acid. The crystallized compound is filtered off with suction and recrystallized from ethanol. Yield 4.5 grams; mp 215 ° C.

Preparation of the starting product

A mixture of 46 grams of 2-benzoyl-3-amino-6-chloropyridine, 100 ml of pyridine and 400 ml of ethanol is heated to reflux with stirring. The mixture is then freed of solvents under vacuum, whereby the reaction product precipitates as a syrup. This product is further processed directly.

Example 4

3-Methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

A mixture of 26 grams of 2-benzoyl-3-amino-6-chloropyridine, 28 grams of benzyloxycarbonyl-d, 1-alanine, 28 grams of phosphorus pentachloride and 500 ml of ether is stirred at room temperature for one hour. This mixture is then evaporated to dryness and the syrup-like residue (50 grams) is treated with a solution of 70 grams of HBr in 200 ml acetic acid as described in Example 1. Embodiment 1 The product precipitated from the ammoniacal solution is partially cyclized and complete The cyclization was carried out by stirring for three hours with 200 ml of boiling toluene, with the addition of 3 ml of pyridine, and the water was split off. The title compound crystallized from a toluene solution and then crystallized from a benzene-petrol mixture. Yield of gram; mp 182 ° C.

Example 5

3-Isopropyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

A mixture of 26 grams of 2-benzoyl-3-amino-6-chloropyridine, 30 grams of benzyloxycarbonyl-d, 1-valine, 25 grams of phosphorus pentachloride and 400 ml of ether is stirred at room temperature for one hour. The mixture is evaporated to dryness and the syrup residue (40 grams) is treated with a solution of 50 grams of HBr in 160 milliliters of acetic acid as described in Example 1.

The ammoniacal solution precipitates a syrupy base which still consists in part of the non-cyclized precursor, as shown by thin layer chromatography analysis. The cyclization of said base with water cleavage is completed by stirring for three hours with 200 ml of boiling toluene with the addition of 3 ml of pyridine. The title compound crystallized from a toluene solution and then crystallized from a benzene / petrol mixture. Yield 14 g; · Tt. 225 DEG-226 DEG.

Example.

5- (o-Chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

To a mixture of 34 grams of 2-o-chlorobenzoyl-3-amino-6-chloropyridine, 27 grams of benzyloxycarbonylglycine and 300 ml of dioxane was stirred with stirring and 27 grams of phosphorus pentachloride were added portionwise.

The temperature will rise from 27 to 37 ° C. After stirring for one hour, 800 ml of petroleum ether are slowly added. After inoculation, 50 g of the 3-N-benzyloxycarbonyl intermediate crystallizes. 20 grams of this intermediate ee are then treated with 70 · ml of a saturated solution of HBr in acetic acid (glacial) as shown in Example 1. The product precipitated from the ammoniacal solution contains an even larger amount of the open precursor which is therefore cyclized to the final product. Steps to cleave the water by stirring for three hours with 200 ml of boiling toluene with the addition of 3 ml of pyridine. The pure compound crystallizes in pure form from a toluene solution. Yield 10 grams; mp 201 ° C.

Example · 7

5- (o-chlorophenyl) -6 ', 4', 2 ', 3'-1,2-dihydro-3H-1,4-benzodiazepidin-2-one; 4-oxide

About 70 grams of 2- (o-chlorobenzoyloximino) -3-amino-6-chloropyridine (crude product) is dissolved in 400 ml of 99% glacial acetic acid and 45 ml of chloroacetyl chloride is added. Hydrogen chloride gas is then introduced into the reaction mixture, and 2- (o-chlorobenzoyloximino) -3-chloroacetylamino-6-chloropyridine is slowly crystallized from the solution (yield 53 grams; mp 138 ° C). 36 grams of this compound are dissolved in 150 ml of 70% ethanol, with stirring, and 40 grams of 50% KOH are added to this solution while stirring and cooling the ice bath. The reaction mixture was allowed to react for 30 minutes at 20 ° C. The clear solution is acidified with acetic acid and 100 ml of water are added. The white crystalline precipitate was filtered off with suction, washed with isopropanol and recrystallized from dioxane / petrol. Yield: 14 g; mp 241 ° C.

The oximine compound is obtained as follows:

A mixture of 70 g of 2- (O-chlorobenzoyl) -3-amino-6-chloropyridine (prepared as in Example 1), 30 g of hydroxylamine hydrochloride and 200 ml of pyridine is stirred at room temperature for 20 hours. An additional 30 grams of hydroxylamine hydrochloride was added to the mixture and stirring was continued for another 20 hours. The pyridine is then evaporated in a rotary evaporator and the residue is extracted with 200 ml of chloroform, washing the solution several times with water. The chloroform solution was briefly dried and washed with water. The chloroform solution is then briefly dried and the desired material partially crystallized from the dry solution. The solution was concentrated by evaporation and the residue immediately worked up.

Example 8

A mixture of 10 grams of 2- (2,5-dlchlorobenzoyl) -3-amino-6-chloropyridine (similar to that described in Example 1), 70 ml of dry dioxane, 10 grams of benzyloxycarbonylglycine and 10 grams of phosphorus pentachloride is stirred at room temperature. temperature for two hours. Thereafter, the solvent was stripped off in vacuo and the residue was further worked up (14 grams) as described in Example 6. Yield: 8 grams; mp 240 ° C.

EXAMPLE 9 1-Methyl-5- (o-fluorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

A mixture of 25 grams of 2-o-fluorobenzoyl-3-N-methylamino-6-chloropyridine (preparation similar to that described in Example 1), 30 grams of benzyloxycarbonylglycine, 100 ml of dioxane and 30 grams of phosphorus pentachloride is stirred at room temperature for two hours. The solvent was then removed in vacuo and the residue (61 grams) was added portionwise to 500 mL of a 40% HBr solution in glacial acetic acid and the mixture was stirred for one hour. The reaction mixture is then added. ether (1.5 L) was added, the amorphous precipitate was filtered off and refluxed in 500 ml of toluene and 100 ml of pyridine for 4 hours with vigorous stirring. The insoluble matter is then filtered off. The solution was evaporated to dryness in a rotary evaporator. The residue was recrystallized from ethanol. Yield: 22 g; mp 139 ° C.

Example 10

5- (o-Fluorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

5- (2,5-dichlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

Whose

⁴ N-C '

A mixture of 35 grams of 2-o-fluorobenzoyl-3-amino-6-chloropyridine (preparation similar to that described in Example 1), 33 grams of benzyloxycarbonylglycine, 500 ml of ether and 33 grams of phosphorus pentachloride is stirred for two hours at room temperature. . The solvents are then removed in vacuo and the residue is treated analogously to Example 6. The product obtained is recrystallized from n-propanol. Yield: 28 grams, m.p. 195-196 ° C.

Example 11 The mixture was cooled and 3 ml of water was added. The desired compound crystallized upon rubbing the bar against the wall of the flask. Yield 0.4 g; 170 ° C - 171 ° C

Others can be obtained from the mother liquor. 0.4 g of material was recrystallized from ethanol-water.

Example 13

3-Benzyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzdiazepin-2-one

3-Hydroxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

A mixture of 35 grams of d, 1-carbobenzoxyphenylalanine, 400 ml of ether and 26 grams of phosphorus pentachloride is stirred for 20 minutes. To this solution is then added. 26 grams of 2-benzoyl-3'-amino-6-chloropyridine and the reaction mixture is stirred at room temperature for one hour. The precipitated product, i.e. 2-benzoyl-3- [N- (benzyloxycarbonylamino-beta-phenylpropropenyl) amino] -6-chloropyridine (m.p.

182 [deg.] C.) is aspirated and after drying [45 grams] is worked up analogously to Example 62801 ml of a 40% solution of HBr in glacial acid. acetic acid by stirring from the above. solution, followed by reaction. process again. analogous.

Yield: 28.4 g; mp 234 ° C.

Example 1 a d 1 2

3- (3-carbox-propionyloxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinePon

gram of 3-hydroxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one sodium salt (prepared from an ethanolic solution of the 3-hydroxy compound) with an equivalent amount of sodium ethoxide solution and exclusion of sodium salt with ether), 0.7 grams of succinic anhydride and 2 ml of dimethylsulfoxide are heated in a water bath for 20 minutes, then re300 grams of 30% KOH solution is added under stirring and 15 ° C to a solution of 110 grams of 1-acetyl-3-acetoxy-5- (o-chlorophenyl) -6-aza-7-chloro-3H-1,4-benzodiazepin-2-one in 400 ml of ethanol. The reaction mixture was stirred at room temperature for 30 minutes. The pH of the clear solution was then adjusted with acetic acid to Sak. The solution was then treated with 250 ml of water. The amorphous precipitate formed is filtered off after addition of activated carbon. The filtrate is diluted with 1 1/2 liter of water and shaken into chloroform. The organic phase is dried and concentrated. The residue was recrystallized twice from ethanol.

Yield: 23 g; . mp 200-202 ° C.

Example 1 a d. '1 4.

5-Phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

Vzo.rec: see Example 1. (reduction of N-oxide) Cenyll6 grams of _{5-aza-7-chloro-7} 2-dihydro-3H-l, 4-benzodiazepin-2-one 4-oxide were hydrogenated in 150 ml of methanol at normal pressure and room temperature using 5 grams of Raney nickel. The theoretical volume of hydrogen is consumed after. 90 minutes. The filtered solution is evaporated to dryness in vacuo and the residue is recrystallized from ethanol. Yield: 2 g; Mp 198 ° C.

Example 15 1-Acyl-3-aceto-5-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-o-n

COCLL I -o Ctá _N X _{c = N} ^ ^C ' ^0C0CH b &

A mixture of 23 grams of 5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide and 120 ml of acetic anhydride is heated to reflux. condenser for 30 minutes. The reaction mixture was then poured into 700 ml of ice water. The precipitate was recrystallized from methanol.

Yield: 15 grams; mp 203-207 ° C.

Example 16

3-Hydroxy-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

Heating 24 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide with 160 ml of acetic anhydride (30 minutes on a water bath) affords after pouring the reaction mixture into 500 ml of water, a mixture of 1-acetyl-3-acetoxy-5-phenyl-6-aza-7-clilor-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 3-acetoxy -5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one. This mixture was de-acetylated with 3 parts of a 30% KOH solution and 4 parts of ethanol at 15 ° C. After acidification and dilution with water, the reaction mixture is shaken into chloroform and the chloroform residue is recrystallized twice from ethanol.

Yield: 11 grams; 11. 177 ° C.

Example 17 1-Methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

To 20 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one in 120 ml of anhydrous dimethylformamide was added portionwise under stirring and under a nitrogen atmosphere. grams of sodium hydride (80% in white oil). The temperature is maintained at 25 ° C.

After one hour, 15 grams of methyl iodide was added to the reaction mixture, and the mixture was stirred at 30 ° C for one hour and at 40 ° C for one hour. After standing overnight, the solvent is evaporated under vacuum, the residue is extracted with methylene chloride, the extract is washed several times with water and once with dilute hydrochloric acid, dried over sodium sulfate and concentrated. The residue was recrystallized from benzene / petrol.

Yield 11 grams; 11. 154 ° C.

Example 18 1-Allyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

The title compound was prepared analogously to Example 17 using 20 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 11 grams of allyl bromide.

Yield: 7 grams; mp 94 ° C.

Example 19 1-Cyclopropylinethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

The title compound was prepared in analogy to Example 17 using 23 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-1H-1H-benzodiazepin-4-one and 12 grams of cy212736 clopropylmethyl chloride. The reaction product is purified by chromatography on an alumina column (length 60 cm, diameter 5 cm, system: chloroform), the syrupy pure compound is dissolved in 1 ml of ether and isopropanolic HCl (6N) is added and the hydrochloride crystallizes.

Yield 5 grams; mp 180-188 ° C.

Example 20

The 1- (beta-diethylaminoethyl) -5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one was washed twice with water and dried. When 6 N-isopropanolic hydrochloric acid is added, the hydrochloride crystallizes. This was recrystallized once from methanol / ether and once from ethanol.

Yield 4 grams; mp 204-206 ° C (decomposition).

Example 22

5-Phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine

To a solution of 20 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one in 50 ml of dimethylformamide was added under stirring and under a nitrogen atmosphere at room temperature. , 5 grams of sodium hydride (80 percent in white oil). The temperature is raised to 50 ° C over 30 minutes, and a solution of 9 grams of freshly prepared diethylaminoethyl chloride in 20 ml of dimethylformamide is added dropwise to the reaction mixture, followed by the addition of 0.5 grams of potassium iodide. The reaction mixture is stirred for one hour at 70 degrees Celsius, then concentrated to a volume of 20 ml under vacuum and 50 ml of ethanol and 60 ml of water are added to the concentrated mixture. The product crystallizes upon rubbing the bar against the wall of the flask. This product is then recrystallized from benzene / petrol.

Yield 15 grams; mp 154 ° C.

Example 2 1

1-Methyl-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

CH ¹

Or ^ct g of 5- (o-chlorophenyl) -6-aza-7-chloro-l, 2-dihydro-3H-l, 4-benzodiazepin-2-one was methylated analogously to Example Embodiment 17. The reaction solution was evaporated under benzene is added to the residue, a benzene layer of 41.5 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H- is added dropwise with stirring over 45 minutes to a mixture of 11.5 g of lithium aluminum hydride in 200 ml of anhydrous tetrahydrofuran. 1,3-benzodiazepin-2-one dissolved in 600 ml tetrahydrofuran. The temperature rises from the initial 30 ° C to 40 ° C. The reaction mixture is then heated to 60 ° C and held at this temperature for about 6 minutes; it is further cooled rapidly to 0-10 ° C and a mixture of 28 grams of water, 15 grams of methanol and 100 ml of tetrahydrofuran is added dropwise. All operations are carried out under a nitrogen atmosphere. The reaction mixture was filtered, the filtrate was dried over magnesium sulphate and evaporated in vacuo. The residue was extracted with benzene. After standing overnight at 5 ° C, the desired product crystallized from the benzene solution. 161. A solution of 10 grams of maleic acid in 50 ml of acetone is added to the mother liquor and the maleate crystallizes. The maleate is recrystallized from ethanol. Mp 186-187 ° C (dec.); yield of maleate 15 g.

Example 23 1-Methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-2-thione

21273 '6

A mixture of 26 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one, 32 grams of phosphorus sulfide and 150 ml of toluene is heated to boiling under stirring for a period of time. two hours. The mixture is then filtered, the solution is evaporated in vacuo, the residue is mixed with the filter residue, and the whole is treated with more concentrated aqueous ammonia and ice. After stirring for 30 minutes, the product is filtered off with suction. This product is dissolved in chloroform, the solution is chromatographed over a column of alumina (length 60 cm, diameter 5 cm, system: chloroform). Purified by evaporation of chloroform, the product obtained is recrystallized from benzene.

Yield 10 g; 1.1. 158 ° C.

Example 24 1-Methyl-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-2-thione

A mixture of 40 grams of 1-methyl-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 29 grams of phosphorus sulfide is treated in 200 ml. toluene analogously to Example 23.

Yield 12 grams; 188-189 ° C.

Example 25

5-Phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-2-thione

A mixture of 54 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one, 44 grams of phosphorus sulfide and 600 ml of toluene is heated to reflux under a nitrogen atmosphere. · Cooler for 2.5 hours. The granular precipitate is filtered off with suction, stirred several times with chloroform, further treated with aqueous ammonia and extracted with chloroform. After drying, thion extracts crystallize in pure form.

Yield 30 grams; mp 202 ° C.

Example 26

2-achthydrazino-5-phen61-6-aza-7-chloro-3H ', 4-benzodiazepine

Η H

NN-COCH ^or -Q-C - N ^'Hl

A mixture of 6 grams of 2-ethylhedrarine, 10 grams of 5-phenel-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-2-thione and 50 ml of dioxane is heated to 50-60 ° C. for 20 minutes. The desired product crystallizes. After cooling the reaction mixture, the product is filtered off with suction and recrystallized from ethanol. Yield 10 grams; mp · 176 ° C.

Example 2 7

2-mytdlamm5-5-phenyl-ardZ7-7-chior-3H-1,4-benrodiazepine

g 5-phenyl-6-aza-7-chloro-2'dihyd _^ ro-3H-4-benrodi2zepin-2-thione was heated on a water bath for 10 · minutes in 200 ml of 10% · metyl2minového · Solution. The desired product crystallizes out. The product is filtered off with suction and recrystallized using activated carbon from benzene.

Yield 5 grams; mp 214 ° C.

Example 28 1-Methyl-3-mefoxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-1,4-benrodiazepin-2-one

grams (0.0-65 µol) of 3-hydroxy-5- (o-chlorophenyl) -6 aza-7-chloro-1,2-dihydro-3H-benzodiazepin-2-one is dissolved in 300 ml of dioxane and the solution thus obtained 3 ml of dimethylformamide are added. 4.1 g of 80% sodium hydroxide in white oil are added and the mixture is stirred at room temperature for 30 minutes. Thereafter, the reaction mixture is heated to 65 ° C, 28.4 g (0.2 mol) of methyl iodide are added dropwise over 15 minutes, and the resulting mixture is stirred at that temperature for one hour. 5% Acetic acid is then added to the reaction mixture to precipitate the reaction product which is filtered off with suction and recrystallized from ethanol. Yield 10.2 g; mp 247-248 ° C.

Example 29

1-N-morpholinoethyl-5-phenyl-e-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

To a solution of 27 grams (0.1 mol) of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one in 250 ml of dimethylformamide was added at room temperature and under nitrogen. 3.5 grams of sodium hydride (80% solution in white oil) was added with stirring. The reaction mixture was stirred for 30 minutes, then 20 grams of N-2-chloroethyl morpholine was added and the mixture was heated at 80-90 ° C for 2 hours. The dimethylformamide was stripped off in vacuo and the residue was stirred in water. The water is then separated from the syrup by decantation and the product is dissolved in warm ethanol. Activated charcoal is added, the suspension is filtered and the filtrate is cooled to crystallize the reaction product.

Yield: 14 g; mp 162-164 ° C.

Example 30

grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one is heated with stirring at 50 ° C with 50 ml of acetic anhydride for two hours. . A white substance slowly precipitates from the blue solution. This material is filtered off with suction and recrystallized twice from dimethylsulfoxide. Yield: 5 g, mp 256-260 ° C.

Example 1 a d 3 1

Ι-β-hydroxyethyl-5- (2-fluorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

CL

To a solution of 27 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one in 250 ml of dimethylformamide, 3 grams of sodium hydride are added with stirring at 25 ° C. (80% solution in white oil) in portions. The reaction mixture was then stirred for a further 30 minutes. 9 ml of bromoethanol are then added dropwise to the resulting reaction mixture, followed by stirring at 80-90 [deg.] C. for 7 hours. The solvent is then evaporated under vacuum. 300 ml of ether and 200 ml of 5% sodium hydroxide solution were added to the obtained residue, and the resulting mixture was shaken. The ether layer was washed several times with dilute sodium hydroxide solution and then with water. The ether solution was dried and then evaporated to dryness. The crystalline residue was recrystallized twice from ethanol. Mp 154-156 ° C.

Example 32 1-Acetyl 1-methyl-5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-o-oxide 5-Phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

grams of 5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide are dissolved in a mixture of 450 ml of dioxane and 45 ml of dimethylformamide, 3.3 g of sodium hydride (80% solution in white oil) are then added to the solution thus obtained with stirring at 20 ° C. The temperature rose to 34 ° C. 28.4 g of methyl iodide are then added dropwise with stirring, and the reaction mixture is then stirred at 40 [deg.] C. for 30 minutes. The mixture was then filtered off with suction, acidified with acetic acid and evaporated in vacuo. The residue is crystallized from 300 ml of ethanol with 50 ml of gasoline. The pure product is then filtered off with suction and washed with ethanol. Mp 213 degrees celsius.

Example 33 1-Methyl-3-acetoxy-5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

grams of 1-methyl-5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide are heated to boiling for 15 minutes with stirring in a mixture of 33 ml of acetic anhydride and 29 ml of acetic acid. Upon cooling and seeding, the desired product crystallizes. This product was washed with acetic acid and then with water. Mp 178-179 ° C.

Example 34

3-Acetoxy-5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

Cl

724 grams of 5- (2-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1 are added to a mixture of 1150 ml of acetic anhydride and 1020 ml of acetic acid with stirring at 100 ° C. 4-Benzodiazepin-2-one-4-oxide. The resulting solution was then heated to 120 degrees Celsius. An exothermic reaction takes place and the reaction mixture is heated to the boiling point. The reaction is complete after 15 minutes and then allowed to cool without cooling. The product crystallizes. This product was then washed with water and methanol. Mp 243 ° C (dec.).

Example 35

5- (2-Fluorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide

2- (of luorbenzoyl) -3-amino-6-chloro-pyridine oxime (crude product) prepared by boiling for four hours 100 grams of 2- (of luorbenzoyl) -3-amino-6-chloropyridine (see Example 10) and 170 > grams of hydroxylamine hydrochloride in 450 ml of pyridine with stirring under reflux and usual isolation (evaporation of the reaction mixture under vacuum, leaching 500 ml of chloroform, shaking three times into water and distilling off chloroform) as an oil, is dissolved in 400 ml of warm acetic acid. 90 grams of chloroacetyl chloride are added to the solution thus obtained with stirring. An exothermic reaction takes place and is completed within one hour. The reaction mixture was then removed overnight and concentrated on a rotary evaporator under vacuum to dryness. The solid residue (166 g) is suspended in 600 ml of ethanol and 300 g of ice and 92.5 g of potassium hydroxide in 100 ml of water are added to the suspension under stirring. The temperature is then kept below 5 ° C by further addition of ice. After 30 minutes, the solution was filtered, and 110 ml of acetic acid was added to the filtrate with stirring, followed by water until turbidity started to form. 95 g of crude product are obtained. Recrystallization from 10 grams of methanol / acetone gave 4 grams of pure product. Mp 239 ° C.

Example 36

3-hydroxy-5- (2-fluorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one cv

gram of 5- (2-fluorophenyl) -6-aza-7-1,2-dihydro-3H-1,4-benzodiazepin-4-one-4-oxide (crude product) was heated to 130 ° C with stirring. in 130 ml of acetic anhydride. An exothermic reaction occurs, which is complete after 10 minutes. Then the reaction mixture was cooled and poured onto ice. The precipitated product is filtered off with suction and washed with water. This product consists of a mixture of the mono- and diacetyl derivative of the desired compound. 30 g of this product are suspended in 100 ml of n-propanol. A solution of 3 grams of sodium in 40 ml of n-propanol is added to the suspension thus obtained under cold conditions (0-5 ° C) and with stirring; 700 ml of water are added to this mixture after 15 minutes and the mixture is acidified with acetic acid. Upon cooling, the desired product precipitates. After standing overnight, the product is filtered off with suction and then crystallized from n-propanol.

Mp 177-179 ° C.

Example 37

1- (β-piperidinoethyl) -5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

To a solution of 27 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one in 250 ml of dimethylformamide is added 3.6 grams at room temperature. sodium hydride (80% solution in white oil) and then at 40 ° C 32 grams of piperidinoethyl chloride (freshly prepared from 36.6 grams of N-chloroethylpiperidine hydrochloride) in a small amount of dimethylformamide, whereupon the mixture is heated for 15 hours. minutes to 85-90 ° C. The mixture is then neutralized and evaporated in vacuo. The oily residue crystallizes slowly when triturated with ethanol. This product is then crystallized once more from ethanol with the addition of activated carbon.

Mp 136-137 ° C.

-1,2-dihydro-3H-1,4-benzodiazepin-2-one

To 27.2 grams (0.1 mole) of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one in 200 ml of anhydrous of dioxane and 5 ml of dimethylformamide were added 4.5 grams of sodium hydride (57% in aqueous oil) at 20 ° C under stirring and under a nitrogen atmosphere. The temperature of the reaction mixture is raised to < 30 ° C, whereby the reaction mixture becomes a clear solution. · · The solution was then heated to 80 · 85 to · ^Q C, then was added dropwise over two hours, 25 g of n-propyl bromide; The reaction mixture is then stirred at 85 ° C for 10 hours. The reaction mixture was poured into 700 ml of water and the product crystallized out. The product is filtered off with suction and recrystallized twice from methanol.

Yield: 17 grams; · 139 to 142 · cc

Example 39 1-n-butyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

This compound was prepared from 27.2 grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 20 grams. N-bromobutane · analogously to the embodiment 38.

Yield: 16.5 g; mp 108-110 ° C

Example 1 a d 4 0

5-Phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide

Example 38 1-n-Propyl-5-phenyl-6-aza-7-chloro-212,736

grams of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one is dissolved in 250 ml of chloroform and then added dropwise with stirring at 0 DEG. to 5 ° C a solution of 11 grams of m-chloroperbenzoic acid in 150 ml of chloroform. The mixture was stirred for one hour and then left overnight at room temperature. The reaction mixture was then shaken with 5% sodium hydroxide solution. This extract was acidified with acetic acid and the reaction product crystallized. This product was recrystallized from ethanol. Mp 156-158 ° C (as monohydrate after dehydration at 215 ° C). Yield 11 grams. This compound is identical to the compound obtained in Example 3.

Example 41

5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one (N-oxide reduction)

grams of 5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one-4-oxide were hydrogenated in 250 ml dioxane using 5 grams of Raney nickel at 490.3 MPa and 50 ° C. The reaction product is then separated from the filtered hydrogenation solution with water and the product is recrystallized twice from n-propanol.

Yield: 9 grams; mp 200 ° C

Example 42 1-Methyl-5-phenyl-6-aza-7-bromo-1,2-dihydro-3H-1,4-benzodiazepin-2-one

To a solution of 32 grams of 5-phenyl-6-aza-7-bromo-1,2-dihydro-3H-1,4-benzodiazepin-2-one in 300 ml of dimethylformamide was added 3.5 grams of hydride with stirring at room temperature. sodium (80% solution in white oil). After 15 minutes, 16 grams of methyl iodide was added and the reaction mixture was then stirred for one hour at 40 ° C. The resulting solution is then concentrated under vacuum to a final volume of 50 ml, the residue is stirred with water and the crystalline product is recrystallized from ethanol.

Yield: 19 grams; mp 148-150 ° C

Example 43 l-allyl-5- (o-chlorophenyl) -6-aza-7-chloro-l, 2-dihydro-3H-l, 4-benzodiazepin-2-one CH-CH = CH ₂ _

To a solution of 31 grams of 5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dlhydro-3H-1,4-benzodiazepin-2-one. 2.5 g of sodium hydride (80% solution in white oil) were added portionwise at 25 ° C in 120 ml of anhydrous dimethylformamide under stirring and under a nitrogen atmosphere. After one hour, 10 ml of allyl bromide was added to the reaction mixture, followed by <RTIgt;

the mixture was stirred at 30 ° C for one hour and then at 40 ° C for one hour. After standing overnight, the catalyst is stripped off in vacuo, the residue is stirred with water, washed several times with water and then with dilute hydrochloric acid and dried over sodium sulphate, then the solution is evaporated. The reaction product thus obtained is converted to the hydrochloride by dissolving in acetone and adding an isopropanolic hydrochloric acid solution; this hydrochloride melts at 200-202 ° C (dec.). Yield: 20 g.

The following compounds were prepared in an analogous manner:

a) 1,3-dimethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

This compound was obtained from 13 grams of 3-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 8 grams of methyl iodide. The reaction product obtained is recrystallized from benzene / petrol.

Yield: 9 grams; mp 132-134 ° C

b) 1- 1,3-dimethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one.

grams of 1-methyl-3-acetoxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one is added to a solution of 1.5 grams of sodium metal in 150 ml of n-propanol and the reaction mixture thus obtained is stirred at room temperature for 20 minutes. A clear solution is formed from which a portion of the product precipitates as the sodium salt. The solution is acidified with acetic acid and the product is precipitated by adding 200 ml of water. The aspirated product is recrystallized from methanol.

Yield: 11 grams; mp 247-250 ° C.

Example.45

1-Allyl-3-acetoxy-5- (chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

CHfCH-CH1

Cl

CH-O-COClL N ' ³

This compound was obtained from 11 grams of 1-3-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 8 grams of methyl iodide. This product was recrystallized from petrol / benzene.

Yield: 7 grams; mp 143-144 ° C.

c] 1-allyl-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H1,4-benzodiazepin-2-one-4'-oxide

This compound was obtained from 16 grams of 5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one (4) -oxide and 6.7 g. gram of allyl bromide. This reaction product was recrystallized from dimethylformamide / ethanol 30:70.

Yield: 9 grams; mp 220 ° C.

Example 44 1-Methyl-3-hydroxy-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-1,4-benzodiazepin-2-one

grams of 1-allyl-5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-13-benzodiazepin-2-one. - (4) -oxide se. Heat to boiling in a mixture of 29 ml of acetic acid and 33 ml of acetic anhydride with stirring and for 15 minutes. Upon cooling and seeding, the desired product crystallizes. This product was then washed with acetic acid and then with water.

Yield: 20 grams; mp 176-177 ° C.

Example 46

5-Phenyl-6-aza-7-bromo-1,2-dihydro-3H-1,4-benzodiazepin-2-one

To a 200 ml solution of hydrogen bromide in acetic acid (40%) was added 43 grams of 2-benzoyl-3- [N- (benzyloxycarbonylaminoacetyl) amino] -6-bromopyridine with stirring and at room temperature while vigorously evolving carbon dioxide . After one hour, more ether is added, with. a precipitate is formed which is suctioned off. The precipitate is then stirred with 200 ml of methanol and the resulting mixture is heated to boiling in a water bath. Aqueous ammonia is then added until an alkaline reaction is obtained, resulting in a clear solution. After stirring briefly, crystals of the reaction product begin to precipitate from the solution, and one liter of water is added. After one hour, the crystals are filtered off with suction, washed with water and crystallized from methanol.

Yield: 11 grams; mp 202-204 ° C.

If the corresponding 6-fluoro derivative is used in place of 2-benzoyl-3- [N- (benzyloxycarbonylamino-acetyl) amino] -6-bromopyridine, then 5-phenyl-6-aza-7-fluoro-1,2- 218 DEG-220 DEG C. (from ethanol), starting from 180 g of 2-benzoyl-3-nitro-6-chloropyridine. 100 DEG-120 DEG C. for 5 hours in an autoclave solution of 80 g of ammonia in 1 liter of ethanol, then the reaction solution is evaporated to dryness, the residue is boiled with acetone and the product is precipitated from the acetone extract by addition of water. Yield: 161 grams 50 grams of the 2-benzoyl-3-nitro-6-amino-pyridine thus obtained are dissolved in 300 ml of dimethylformamide, and 125 ml of a 47% aqueous hydrobromic acid solution are added thereto at 0 DEG C. with stirring. and then constantly stirring at 0 ° C a solution of 20 grams of sodium nitrite at 50 ° C The reaction mixture is stirred at room temperature for one hour and then at 60 to 70 ° C for one hour. The reaction mixture was then poured into 2.5 liters of water, extracted with chloroform, and the chloroform fraction was washed with sodium hydroxide solution and then with water, dried and evaporated. The residue was recrystallized from alcohol / petrol (m.p. 98-100 ° C). 45 grams of the 2-benzoyl-3-nitro-6-bromopyridine thus obtained are dissolved in 450 ml of dioxane, and the solution is hydrogenated using Raney nickel at a pressure of 60 to 70 ° C. The hydrogenation mixture is filtered, the filtrate is concentrated to a volume of 150 ml and the product is precipitated by the addition of water.

Yield: 35 grams; mp 146-148 ° C.

30 g of N- (benzyloxycarbonyl) -glycine are dissolved in a mixture of 300 ml of chloroform and 400 ml of ester, and then 30 g of phosphorus pentachloride are added with stirring. After stirring for 30 minutes, 35 grams of 2-benzoyl-3-amino-6-bromopyridine, the preparation of which is described above, is added. After one hour, the flake precipitate is filtered off, 1 liter of petrol is added to the filtrate, whereupon 2-benzoyl-3- [N- (benzyloxycarbonylamino-acetyl) amino] -6-bromopyridine precipitates as crystals.

Yield: 43 g; mp 124-126 ° C.

The starting materials for the preparation of the fluorine compound are prepared in an analogous manner.

Example 4 7

3-Methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepin-2-one

CW-CH3

A mixture of 2-benzoyl-3-amino-6-chloropyridine (11.6 g), N-benzyloxycarbonyl-1-alanine (11.15 g), phosphorus pentachloride (12 g) and ether (500 ml) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and a solution of 70 grams of hydrobromic acid in 200 ml of acetic acid as in Example 1 was added to the syrup-like residue (50 grams). The product precipitated from the ammonium solution was partially cyclized, with cyclization being terminated by stirring for three hours. in 200 ml boiling. toluene with the addition of 3 ml of pyridine by cleavage of water. The desired product crystallizes from a toluene solution and is then crystallized. recrystallized from a benzene / petrol mixture.

Yield: 4.5 g; mp 113-116 ° C.

Example 48

2-Propionylhydrazino-5-phenyl-6-aza-7-chloro-m.p.

-3H-1,4-benzodiazepine

H N-COCH

I ^Л »

NH

A mixture of 6.5 g of propionylhydrazine, 10-g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-2-thione and 50 ml of dioxane is heated for 20 min. 50 to 60 degrees Celsius. The desired compound crystallizes out. After cooling, the precipitated product is filtered off with suction and recrystallized from ethanol.

Yield: 7 grams; mp 196-198 ° C.

The compounds prepared by the process according to the invention have a very pronounced anxiolytic effect. Anxiolytic effect means an effect in which the feeling of fear is suppressed. This type of effect cannot naturally be measured directly in animal experiments. On the other hand, the anxiolytic active compounds also have anticonvulsant properties. Therefore, if certain compounds exhibit anticonvulsant properties in animal experiments, the same compounds generally act anxiolytically when used in humans. One method by which it can be demonstrated whether a compound has anticonvulsant properties and thus anxiolytic activity is the cardiazole shock method.

Cardiazole shock method:

The cardiazole shock experiments were carried out using the method described by Berger, F. M. et al. in J. Pharmacol. Exper. Therap. 116, 337-34 (1956).

In mice, a subcutaneous injection of 150 mg / kg of cardiazole first results in short-lived and then persistent and severe convulsions, which results in the death of all test animals within 10 to 15 minutes. Early (one hour before the administration of cardiazole) by oral administration of the anticonvulsant agent at different doses, the 100% lethal effect of the administered cardiazole can be suppressed depending on the dosage. From the percentage of animals surviving cardiacol administration in each treatment group, the ED50 dose is determined by plotting dose-effect lines. ED50 refers to the dose at which 50% of the test animals are shown to have an anticonvulsant effect.

By way of comparison, the effects of both the compound of Example 2 (with respect to the chemical structure, the compound of the present invention closest to the compounds of the invention) and Austrian Patent Specification No. 272 351 are shown below. Example 17 was chosen because it is a 6-aza compound, i.e. a compound in which the nitrogen atom of the benzene moiety of the diazepine ring system is also accurately, as in the case of the compounds of the invention, it is located at the 6-position, so that the compound of Example 17 is very similar in chemical structure to the compounds of the invention.

Both compounds show no effect in the cardiazole shock method up to doses of 100 mg / kg in mice (per os). Therefore, the effect of the compounds of the invention is unexpected.

Table I

Example number

1,2

12

17 20 21 24 26

38 and 43b 43c 46a 46b 47

Anticonvulsive effect in the cardiazole shock method - ED 50 (mg / kg - - per os)

6.6

2.7

1.58

1.63

7.4

2.4

6.3

4.2

9.75

0.98

3.3

4.8

3.2

4.1

2,0

1.5

2.7

4.8

2.2

8.4

5.8

5.9

8.9

Claims (4)

OBJECT OF THE INVENTION A process for the preparation of 3H-pyrido [3,2-e] -1,4-diazepines of the general formula I in which: R 1 represents a halogen atom, R 2 and R 5, which are identical or different, represent a hydrogen atom or a halogen atom, R1 represents a hydrogen atom, a hydroxyl group, a hydroxyl group acylated with saturated aliphatic mono- or dicarboxylic acids having a total carbon number of 2 to 4, a methoxy group, an alkyl group having a total carbon number of 1 to 3 and a benzyl group, Z is nitrogen or ^ NO, R 5 represents a hydrogen atom, an alkyl group having a total number of carbon atoms of 1 to 4, optionally substituted by a cycloalkyl radical having a total number of carbon atoms of 3, allyl, hydroxyethyl, acetyl, piperidinoethyl, morpholinoethyl or dlethylaminoethyl; A represents an oxygen or sulfur atom, a methylamino group, a group = N-NH 2, a group = N-NHCO-Alkyl, wherein Alkyl represents an alkyl radical having a total number of carbon atoms of 1 to 2, or two hydrogen atoms; - C (= A) - may also exist in tautomeric form - N = C (ARs) -, and their acid salts, characterized in that the compound of formula II wherein R 1 to R 5 are as defined above and W represents either an oxygen atom or a group = NH, or a group = NOOH, is condensed with a compound of formula III AND II R 7 —C — CHR d --- X in which Rd is as defined above, A represents an oxygen or sulfur atom, or two hydrogen atoms or a group = NR5, R7 represents a hydroxyl group, a halogen atom, an alkoxy group having a total carbon number of 1 to 6, a mercapto group, an alkylmercapto group having a total number of carbon atoms of 1 to 6, an amino group or an alkylamino group having a total number of carbon atoms of 1 to 6; R7 can also be a nitrile group and X is an amino group or a halogen atom, and when W is oxygen and X is halogen, the reaction is carried out in the presence of ammonia or an ammonia derivative, either condensing directly to a compound of formula I or first to an intermediate of formula IV A, W and X are as defined above, either spontaneously cycling to or cyclized to the compound of formula (I) after isolation, and the products of said process optionally being recovered in an alkaline medium or to the resulting compound of formula (I), wherein R 5 is hydrogen and the other symbols are as defined above, is introduced by alkylation or acylation of the radical R 5 or is introduced into the 3-position and / or 1-alkyl group by alkylation at the 3-position and / or 1-position in a compound of formula I wherein R d is hydrogen; having 1 to 6 carbon atoms or acylating to the 3-position an aliphatic acyl group; (2-6C) carboxyl, (1-6C) carbalkoxy or oxidation or, in the case where Z is = NO, also by rearrangement of the hydroxyl group to the 3-position or to compounds of formula (i) in which: A is oxygen and the other symbols are as defined above, treating with phosphorus pentasulfide or ammonia, hydroxylamine of formula H2NOR5, hydrazine of formula H2N — NHR5 or an amine of formula NH2R5, or in the compound of formula I in which A is oxygen or sulfur is reduced by oxo- or or a compound of formula I wherein Z is N and the other symbols are as defined above by oxidation to a compound of formula I wherein Z is = NO, or a compound of formula I wherein Z is = NO, wherein the other symbols are as defined above, converted by chemical deoxidation or catalytic reduction to compounds of formula I in which Z is N or optionally acyl groups are cleaved in the compound of formula I or the resulting compounds of formula I are optionally acylated at the 1, 2 and / or 3 position with aliphatic acids or acid derivatives The compounds of formula (I) are optionally converted into their salts by treatment with acids. 2. The process of item 1 for the preparation of 3H-pyrido [3,2-e] -1,4-diazepines of the formula I, wherein: R 1 represents a halogen atom, R? and R 3, which may be the same or different, represents a hydrogen atom or a halogen atom, R1 represents a hydrogen atom, a hydroxyl group, a hydroxyl group acylated with saturated mono- or dicarboxylic acids having a total carbon number of 2 to 4, a methoxy group, an alkyl group having a total number of carbon atoms of 1 to 3, Z represents a nitrogen atom or a group = NO, R 5 represents a hydrogen atom, an alkyl group having a total carbon number of 1 to 4, which contains a cycloalkyl radical having a total number of carbon atoms of 3, an allyl group, a hydroxyethyl group, a piperidinoethyl group, a morpholinoethyl group or a diethylaminoethyl group; A represents an oxygen or sulfur atom, a methylamino group or two hydrogen atoms, wherein the group --NfR 5 J - C [= A) may also exist in the tautomeric form 4 - N = C (AR 5j), and their acid salts, characterized in that a compound of formula II wherein the symbols R to R are as defined in this section, and W represents • either ^one oxygen atom or the group = NH, = NOH group optionally condensed with a compound of formula III wherein a and R? have the meanings given in this point, R7 is a hydroxyl group, a halogen atom, an alkoxy group having a total carbon number of 1 to 6, a mercapto group, an alkylmercapto group having a total carbon number of 1 to 6, an amino group or an alkylamino group having a total carbon number of 1 to 6; wherein the group —C (= A) R7 may also be a nitrile group and X is an amino group or a halogen atom, operating in the presence of ammonia or an ammonia derivative, when W is oxygen and X = halogen, and in this condensation either the compound of formula (I) is formed directly or the intermediate of formula (IV) in which R1 to R5, A, W and X have the abovementioned either spontaneously cyclizing to or cyclized upon isolation of the compound of formula (I) and optionally treating the products of the process in an alkaline environment or in the resulting compounds of formula (I) wherein R 5 is hydrogen and other symbols, are as defined herein, are alkylated by introducing the radical R 5 or are introduced into the 3-position and / or 1-alkyl group having 1 to 6 carbon atoms by alkylation at the 3-position and / or 1-position in the compounds of formula I in which Rd is hydrogen; atoms or is introduced by acylation at the 3-position with an aliphatic acyl group having 2 to 6 carbon atoms, a carboxyl group having 1 to 6 carbon atoms or is introduced by oxidation or, in the case of Z = NO, also by rearrangement of the hydroxyl group at the 3-position, or compounds of formula I in which A is oxygen and the other symbols are defined at this point either with phosphorus pentasulfide or with ammonia or an amine of formula NH2R5, or in compounds of formula I in which A is oxygen or sulfur, the oxo or thio group is reduced to = CH2 or compounds of formula I in which Z is nitrogen and others the symbols are as defined herein, converted by oxidation to compounds of formula I wherein Z is = NO, and / or compounds of formula I wherein Z is = NO and the other symbols are as defined at this point, are converted by chemical deoxidation or catalytic hydrogenation to compounds of formula I in which Z is a nitrogen atom, whereupon the compounds are both The compounds of formula (I) may be converted into their acid salts. 3. Process according to claim 1, characterized in that the basic amino groups in the starting materials are protected by solvolytically cleavable acyl or sulphonic acid groups or hydrogen-cleavable alpha-phenylethyl groups which can also be substituted on the phenyl radical by halogen or nitro groups, or carbobenzoxy, optionally carbobenzithio. 4. Process according to claim 2, characterized in that the basic amino groups in the starting materials are protected by solvolytically cleavable acyl or sulphonic acid groups or hydrogen-cleavable alpha-phenylethyl groups which may also be substituted on the phenyl radical by halogen or nitro groups. or a carbobenzoxy or carbobenzthio group.