NO137094B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-AZA-3H-1,4-BENZODIAZEPINES - Google Patents

Description

The invention relates to analogue methods for the preparation of therapeutically active compounds with the general formula

wherein means a halogen atom,

Rp °S which ^an be the same or different means

hydrogen or halogen atoms or low molecular weight alkyl groups,

R^ means a hydrogen atom, a hydroxy group, a med

.aliphatic mono- or dicarboxylic acids with 2 to 6 C atoms, acylated hydroxy group, a low molecular weight alkoxy group, a low molecular weight alkyl group, a benzyl group and

Z means a nitrogen atom or the group NO and

R^ means a hydrogen atom, a low molecular weight alkyl group optionally substituted by a cycloalkyl residue with 3 to 6 carbon atoms, a low molecular weight alkenyl group, a low molecular weight hydroxyalkyl group, an aliphatic acyl group with 2 to 6 carbon atoms, an optionally substituted at nitrogen with low molecular weight alkyl residues once or twice aminoalkyl group with 2 to 7 carbon atoms, 2 alkyl residues together with the nitrogen atom can also form the piperidine or morpholine ring, and

A means an oxygen or sulfur atom or an imino or alkylimino group with 1 to 6 C atoms, the group =N-NHRg, where Rg means a lower aliphatic acyl group or two hydrogen atoms, the grouping -N(R^)-C-(=A )- can also exist in the tautomeric form -N=C(ARr-)-

and their salts.

The halogen atoms are chlorine, fluorine, bromine, especially chlorine and fluorine. The above-mentioned low molecular weight alkyl, alkenyl, alkoxy, hydroxyalkyl groups are those with 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. The aminoalkyl group may consist of .2 to .7 carbon atoms and may be straight or branched. In particular, it consists of 2 to 5 carbon atoms. The aliphatic acyl groups are those with 2 to 6 carbon atoms, particularly the saturated acyl groups. The dicarboxylic acids are particularly those with 2 to 6, preferably 3 to 5, C atoms. Examples of this are malonic acid, succinic acid, glutaric acid, adipic acid. The alkyl groups as such or as constituents of other groups may optionally be linear or branched. Examples for the latter meanings are: methyl, ethyl, isopropyl, butyl, tert.-butyl, hexyl, isobutyl, cyclopropyl, cyclohexyl, cyclohexyl-propyl, cyclopropyl-methyl, cyclohexyl-pentyl, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy,. tert-butoxy, amyloxy, hexyloxy, oxyethyl, oxopentyl, dimethylamino, diethylamino, di-butylamino, carbmethoxy, carbethoxy, carbpropoxy, carbpentoxy, acetyl, propionyl, butyryl, pentanoyl, isovaleroyl, isobutyryl, cyclobutylmethyl, allyl, butenyl-(2) , piperidinoethyl, morpholino-ethyl.

The compounds according to the invention have valuable pharmacodynamic properties. For example, they have psychosedative and especially anxiolytic properties. In addition, an antiphlogistic effect is also present.

The method according to the invention is characterized by either

a), when A is 0, R^ has the above-mentioned meaning' and R^ hydrogen, low molecular weight alkyl or benzyl group optionally during addition

of acid-binding agent condenses a compound of formula:

in which the symbols R-, to R^ have the above meaning and W either means an oxygen atom or the group =NH resp. =NOH with a compound of the general formula

in which Rjj' is hydrogen, low molecular weight alkyl or a .benzyl group and Ry means a hydroxy group, a halogen atom, a low molecular weight alkoxy group and X means an amino group which is optionally blocked or a halogen atom,

while working in the presence of ammonia or an ammonia derivative, if W = 0 and X = Hal and possibly also treating the process products then in an alkaline medium or

b) a compound of formula I, in which A means an oxygen atom and the other symbols have the indicated meaning, is reduced

to a compound, in which A represents two hydrogen atoms or is reacted with phosphorus pentasulfide to. a compound of formula I, in which A means sulfur or a compound of formula I, in which A means oxygen or sulfur and the other symbols have the indicated meaning, is reacted with ammonia or an alkylamine with 1 to 6 C atoms or a hydrazine with formula HjN-NHRg to a compound of formula I, in which A means an imino- or alkylimino group or the group =N-NHRg or a compound of formula I is alkylated in the 1- and/or 3-position or by means of aliphatic acids with 2 to 6 carbon atoms or their derivatives are acylated in the 1- and/or 3-position or a compound of formula I, in which Z means a nitrogen atom and the other symbols have the indicated meaning, are oxidized with hydrogen peroxide or organic peroxides to a compound of formula I, in which Z means the group NO, or a compound' of formula I, in which A means oxygen or sulphur, R^ means hydrogen and Z means the group NO is transferred by treatment with

lower aliphatic acid anhydrides in connection, in which R^ means a hydroxy- or acyloxy group with 1 to 6 C atoms, the acyl group possibly being present being split off by saponification with dilute acids or basic substances or a compound of formula I, in which Z means the group NO and the other symbols have the indicated meaning, transferred with hydrogen in the presence of metallic hydrogenation catalysts or other common chemical deoxygenating agents for a compound of formula I, in which Z represents a nitrogen atom, the basic amino groups in the reacting starting materials containing protective groups,

and that one optionally transfers the compounds formed in their salts.

Procedure a) takes place in the usual dissolution or suspending agents at temperatures between 0 and 200°C, preferably 20 to 150°C. In particular, polar solvents such as alcohols, dioxane, tetrahydrofuran, dimethylsulphoxide, dimethylformamide and the like come into consideration. If W = 0, it will e.g. also on speech agents such as pyridine and quinoline. Optionally, the addition of acidic or basic substances such as, for example, pyridine or aliphatic carboxylic acids is appropriate. If X represents a halogen atom, it is appropriate to add basic substances, which cause acid decomposition. If Ry is a hydroxy group (in this case the structural element -(=A)Ry can for example be a carboxy group) the addition of special common water splitting agents such as dicyclohexylcarbodiimide is appropriate or necessary.

If compounds of formula III are used, wherein

A means two hydrogen atoms, Ry is chlorine or bromine, the other symbols have already indicated meaning (if X means an amino group, this is preferably blocked with a protecting group), the method can for example be carried out in the following way: A compound with the general formula II, in which R^ is hydrogen and W is oxygen, Rg, R^ and R1 have the indicated meaning, is acylated with an aliphatic acid halide, ester, anhydride or ketene or benzoyl chloride in an inert solvent such as dioxane . benzene, tetrahydrofuran or dimethylformamide between 0 and 150°C. The compound formed is reacted after transfer into the alkali salt (by sodium hydride, sodium amide) with one of the above-mentioned compounds of formula III (e.g. in a non-basic solvent such as dioxane, dimethylformamide or dimethylsulfoxide between 0 and 200°C). Then, the acyl group, which sits on the nitrogen atom in the 3-position of the pyridine ring, can be cleaved off in an acidic or basic medium, as

at the same time, ring closure to compound formula I takes place.

Often, method a) can also be carried out so that the 3-positioned amino group with..forme,l,-I:l. and/or amino groups of formula III (X = NHO bearing an in ^and f or ice.-known protection group. Often such protecting groups are already necessary

for the production of output f orb inde.l's .

In many cases, the splitting of such takes place

protecting group already at the same time as the cyclization.

These protective groups are easily removable. It concerns either easily solvolytic groups of bare acyl groups or hydrating groups, such as, for example, the benzyl residue.

solvolytically: cleavable protective groups are cleaved off, for example, by saponification with dilute acids or with the help of basic

substances, - (pot ash/ -soda aqueous alkali solution';'- alcoholic alkali solution, -NHO at: room temperature or: also:-'brief--boiling-' .'Hydrating removable groups such as: the béhzyl group'- or The carbobenzoxy group is appropriately cleaved by electrolysis: hydrogenation in the presence of common hydrogenation catalysts, especially lladium catalysts, in a solution or suspension medium.

possibly under elevated pressure. As resolution or suspending agents come; -it "for example"'!-- consideration':. Water",'-'lower aliphatic alcohols,- cyclic: ethers-such as d-ioxane or tetrahydrofuran, 'aliphatic e-t ere/ dimethylformamide^etc. 'as well as b landings ' of these agents.' r-■: '' .■••' :'-'"' ■ \ :-'

As a protective group for the amino group, for example: benzyl group, α-phenylethyl group, substituted benzyl groups in the behzen nucleus, for example: p-bromo or p-nitrobenzyl group, carbobenzoxy group, carbobenzthio group , tri f luoracety Igruppen,. -f ta ly Ire ste ny... ■tr.itylre.sten, • p-to luens ul f o-nylresten .and the like as well. simple..acyl groups :s'om; the acetyl group,

formyl group, tert'.;-butylcarboxygr.uppen-j;o.S'V. ;• SpecieIt.-comes to .'talk thereby peptide synthesis. common., protect Is.esgruppe-r ; and the common separation methods are, among other things, reference is also made here to the book by Jesse P. Greenstein. and Milton. Win-i.tZ;.. "Chem-istry .of Amino Acids" ,. NEW. 1961, John -Wiley-: and Sons, Inc. Volume 2, example page. 883 Tf.. The also-carbalkoxy group; .( e.g. low molecular weight) come into question .- .- . ; .. : ,- : -

Procedure a) can sometimes; is also carried out in such a way that before the actual cyclization the intermediate step with formula: .. This can then be purified or cyclized as it appears. In addition, there are temperatures between -70 and 150°C, preferably 0 to 150°C. As a solvent for suspension agents, in addition to the above-mentioned examples, special consideration is given to: Glacial acetic acid, lower aliphatic alcohols such as methanol, et.anol, acetic anhydride, polyphosphoric acid, aliphatic ethers, chloroform, etc. This cyclization can optionally be carried out using acidic condensation agents such as sulfuric acid, hydrochloric acid , hydrobromic acid, toluenesulfonic acid or polyphosphoric acid or also basic condensation agents such as pyridine or tertiary amines.

If X is a halogen atom, the cyclization is carried out

1 presence of ammonia (for example also liquid ammonia), since tertiary, non-quaternizing amines may also be present, for example sterically hindered amines, such as diisopropylethylamine or 1,8-bis-(dimethylamino)-naphthalene. The halogen atoms in question here are chlorine, bromine or iodine. Instead of ammonia or in addition to NH^, for example, other derivatives of ammonia can also be used which replace a halogen atom with the group NH2, for example urotropin, alkali amides or acid amides, where the acid residue forms a common and, as indicated above, protective group, which is easily cleavable.

If urotropin is used, the procedure can, for example, be carried out as follows: Boiling in chloroform (g to 8 hours)

and cleavage of the secreted urotropin compound in aqueous or aqueous-alcoholic inorganic acid (HC1, HgSOO at temperatures between, for example, 20 and 150°C.

If acid amides are used, it pays to use condensing agents such as sodium, alkali hydrides, alkali amides (especially those of sodium), Grignard compounds, lithium alkyls (-butyl) or in special cases, as with tosylamides, also weaker bases such as K2C0-j, powdered NaOH or potassium hydroxide. Dimethylsulfoxide and dimethylformamide are suitable here above all as solvents, but also dioxane, tetrahydrofuran, alcohols and ethers. When using acid amides, compounds of formula IV are usually obtained from intermediate IV in the first place, in which X is an amino group with the corresponding acid residue protected. The cyclization then takes place simultaneously with or after the removal of the protecting group. By acid removal of the protective group, it is usually possible to isolate compounds of formula IV, in which X is the amino group, as a salt or also as a base.

If, in method a) a starting material of formula II is used, in which R^ is an acyl group (see above), then it can possibly be cleaved off solvolytically after completion of the reaction according to the conditions stated above, however, it is also possible, if it concerns of a pure aliphatic acyl group to reduce this to an alkyl group (e.g. by means of complex alkali hydrides such as LiAlH^)-.

It may happen that the cyclization according to method a) does not produce the 7-ring, but partially or exclusively the 6-ring compound with formula:

In this case, a subsequent treatment in an alkaline medium is also necessary. This is usually carried out in polar agents such as lower alcohols (methanol, ethanol, tertiary butyl alcohol), chloroform, dioxane etc. at temperatures between 0

to 150°C. As an alkaline medium, for example: Aqueous or alcoholic, especially methanolic or ethanolic NaOH, KOH, possibly in a mixture with the above-mentioned solvents,

same reagents in solid, powdered form, likewise pot ash and aqueous solutions of tart. amines, above all those that do not quaternize such as diisopropylamine. Alkaline ion exchangers in column form or in suspension are also mentioned.

By this ring expansion. connections occur where the grouping

During ring expansion of a compound of formula V, next to the desired diazepine, compounds formed by a compound of formula V without ring expansion by substitution of the halogen atom with the possible reaction participant can often also occur. The desired compound can then be separated from these and. possibly also other by-products by fractional crystallization or chromatography in a manner known per se.

According to method b), azabenzodiazepines of formula I can be suitably substituted or further converted. For example, compounds of formula I, in which IV is a hydrogen atom on

in a manner known per se is alkylated at the nitrogen atom. As an alkylating agent, for example, esters of the formula R, -Hal, ArS02OR^ and SC^COR^^ are taken into consideration, as . Hal is a halogen atom (especially chlorine, bromine or iodine) and Ar is an aromatic residue, e.g. a phenyl or naphthyl residue optionally substituted with one or more 'lower' alkyl residues and R^ can, with the exception of hydrogen, have the above-mentioned meanings. Examples are p-toluenesulfonic acid alkyl esters, lower dialkyl sulfates and the like. The alkylation reaction is optionally carried out with the addition of common acid binding agents such as alkali carbonates, pyridine or other common tertiary amines, at temperatures between 0 and 150°C in inert solvents such as alcohols, dioxane, dimethylformamide, dimethylsulfoxide, aromatic hydrocarbons such as benzene, toluene or acetone.

The group A in a compound of formula I can be exchanged in different ways. Thus, if A = oxygen, this atom can be replaced by a sulfur atom by means of phosphorus pentasulphide. This reaction takes place in inert solvents such as benzene, toluene, dioxane, pyridine or chlorohydrocarbons at temperatures between 0 and 150°C. The sulfur compound thus formed (cyclic thioamide) can again react in a polar medium with alkylamines of the formula NH2Rp-(the meaning of R^ as stated above), resulting in compounds of the formula I, in which A means the groups =NH or =NR,_. These reactions are carried out in polar solvents such as methanol, ethanol or excess amine, at temperatures between 0 and 150°C.

Compounds of formula I, in which R^ has a meaning other than hydrogen, can for example also be prepared in the following way for compounds of formula I in which Rj. is hydrogen and the other symbols have the stated meaning: In the case of alkylation, acylation and oxidation. During the alkylation, reactions take place with esters of the formula HalR", SO2(OR") or ArSO2OR", where Hal is a halogen atom, especially chlorine, bromine or iodine, Ar is an aromatic residue (especially a phenyl substituted with one or more lower alkyl residues - or naphthyl residue) and R" is an alkyl group with 1 to 6 C atoms. The procedure conditions are the same as for the corresponding introduction of the residue R z->.

The acylation can take place in inert solutions or suspending agents such as dioxane, dimethylformamide, benzene, toluene at temperatures between 0 and 200°C. Suitable acylating agents are: Ketenes such as acid halides, acid anhydrides or acid esters of aliphatic carboxylic acids with 2 to 6 C atoms or of carboxylic acid half-ester halides with 1 to 6 C atoms, optionally with the addition of an acid binding agent such as potassium carbonate or sodium ethylate or a tertiary amine, e.g. triethylamine. In the case of esters, there is a particular distribution of those with lower aliphatic alcohols. In the alkylation and acylation, one can proceed in such a way that one first prepares an alkali compound from compounds of formula I to be reacted, in which R^ = H, by reacting it in an inert solvent such as dioxane, dimethylformamide, benzene or toluene with ethyl alkali metal , alkali hydrides or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 150°C and then the alkylating or acylating substance is added. In this case, carbon dioxide can also serve as an acylating agent, as compounds of formula I with R 1 = COOH are obtained.

Instead of the stated alkylating and acylating agent, other chemically equivalent agents common in chemistry can also be used (see, for example, also L.F. and Mary Fleser "Reagents for Organic Synthesis", John Wiley and Sons, Inc. New York, 1967, volume 1 , pages 1303-4 and volume 2, page 471). Of course, acyl groups present in compounds of formula I can also be cleaved off again in a known manner.

In case of oxidation, it can e.g. compounds are obtained, in which R; is a hydroxy group. • Compounds of formula I, in which Rjj means a hydrogen atom in inert solvents, such as dilute acetic acid, acetic acid ethyl ester, acetone with hydrogen peroxide, peracetic acid or another common organic peracid, are reacted to this. The temperature is preferably between -10 and +70°C.

Compounds of formula I, in which the hydroxy group is, can also be obtained by treating compounds I, in which R^ is H and Z = N—K>, either in polar solvents such as methanol, methanol-water mixtures, dioxanemethanol mixtures, ethanol etc. with alkali (such as sodium hydroxide, potassium hydroxide) or in low molecular weight aliphatic acid anhydrides (e.g. acetic anhydride) possibly in a mixture with other inert solvents, whereby a rearrangement occurs according to which the N-positioned oxygen atom forms a hydroxyl group with a neighboring C atom. This rearrangement is completed at temperatures between 0 and 150°C, especially 0 to 100°C.

Compounds of formula I, in which Z represents a nitrogen atom, can be transferred in the corresponding N-oxides. The reagents and conditions are thereby analogous to those for hydroxylation of R . The temperatures are usually somewhat lower, preferably at 0 and 50°C (by the way, when the temperature rises, the above-mentioned rearrangement starts).

In connection with formula I, in which Z is the group =N0, the oxygen atom can be removed by catalytic hydrogenation or by chemical deoxygeration. Suitable catalysts for the catalytic hydrogenation are, for example, the usual metallic hydrogenation catalysts, especially noble metal catalysts (palladium/carbon, platinum)

or Raney nickel, solvent is above all lower alcohols, temperatures are between 0 and 200°C (preferably - between 0 and 100°C. Optionally, work can be done under pressure up to 50 ato. For chemical deoxygenation, phosphorus trichloride is preferably used or dimethylsulfoxide in inert solvents, such as dioxane, benzene or toluene at temperatures between 0 and 150°C, preferably 0 to 100°C.

Compounds of formula I, in which A means an oxygen atom or a sulfur atom, can also be transferred by reduction into such compounds of formula I, in which A means two H atoms. This reduction can, for example, be carried out in a solvent or suspension agent at temperatures between 0 and 100°C. As resolution or suspending agent, for example: Water, lower aliphatic alcohols, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide, tetramethylurea, etc. as well as mixtures of these agents with each other. Preferably, this reduction is carried out by catalytic hydrogenation. Catalysts here include ordinary finely divided metal catalysts, such as nickel (Raney-nickel) or cobalt (Raney-cobalt). The catalysts can be used with or without a carrier. It can be worked at normal pressure or elevated pressure.

This reduction of keto- or however, the thio group can also take place with the help of metal hydrides or complex metal hydrides such as LiH, LiAlHjj, alkali borohydride, sodium triethoxyaluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate.

Basic compounds with the general formula I can be converted into salts by known methods. Anions for these salts include the known and therapeutically applicable acid residues.

If the compounds of formula I contain acidic groups, they can be transferred in the usual way in their alkali, ammonium or substituted ammonium salts. As substituted ammonium salts, the following come into particular consideration: Salts of tertiary alkylamines, lower amino alcohols as well as bis- and tris-(hydroxyalkyl)-amines (alkyl residues each with 1 to 6 C atoms) such as triethylamine, amino-ethanol and di(hydroxyethyl) amine.

Of the salts of the compounds it can be done in the usual way

again, the free bases are produced, for example by treating a solution in an organic agent, such as alcohols (methanol) with soda or caustic soda.

The compounds of formula I, which contain asymmetric carbon atoms and usually appear as racemates, can be split into the optically active isomers in a manner known per se, for example with the aid of an optically active acid. However, it is also possible from the beginning to use an optically active starting material, as the end product is then obtained a corresponding optically active resp. diastereomeric form.

The compounds according to the invention are suitable for the preparation of pharmaceutical compositions. The pharmaceutical compositions or medicines, may contain one or more of the compound according to the invention or also mixtures thereof with other pharmaceutical active substances. For the preparation of the pharmaceutical preparations, the usual pharmaceutical carriers and excipients can be used. The drugs can be used enterally, parenterally, orally or perlingually. For example, administration can take place in the form of tablets, capsules, pills, dragées, suppositories, ointments, gels, creams, powders, liquids, atomizing powders or aerosols. As'liquida it comes e.g. in question: Oily or aqueous solution or suspensions, emulsions, injectable aqueous and oily solutions or suspensions.

Such compounds have a particularly beneficial effect. formula I, wherein means chlorine, Rg and R-^ are the same or different and means hydrogen, fluorine or chlorine, preferably in the o-position, A means an oxygen and Z a nitrogen atom, R^ means hydrogen or a hydroxy group and R^ means hydrogen or a lower alkyl group of 1 to h carbon atoms, especially the methyl group. The output connectors used in methods a) and b) can, as far as it is not known, be obtained, for example, in the following way:

Procedure a) :

A compound with formula

(Ra = H or lower alkyl group),

is first reacted with an active alkali compound, such as sodium amide, potassium amide, sodium hydride, finely divided sodium in an inert solvent such as dioxane, dimethylformamide, benzene and then the calculated amount of 2,6-dichloro-3~nitropyridine, dissolved "" in the same solvent under stirring and nitrogen atmosphere.

In many cases, it proves appropriate to change the order of addition, for example to a solution of phenylacetic acid or the benzyl cyanide derivative and 2,6-dichloro-3-nitropyridine and add alkali compound h. The usually exothermic reaction leads to the alkali salt of the compound of formula VIII

Cy = CN or CO 2 Ra (Ra = H or lower alkyl groups)

which is strong blue to violet colored.

After the end of the reaction, this is sucked off, washed, dissolved in water and mixed with diluted glacial acetic acid until the original color disappears. The compound of formula VIII usually crystallizes out in sufficient purity.

2-_/-α-cyano)-o-chlorobenzyl7-3-nitro-6-chloropyridine is prepared, for example, in the following way:

For a solution of 120 g of o-chlorobenzyl cyanide in 1.5 1 of dioxane, at 45°C under stirring and nitrogen atmosphere, 42 g of sodium hydride (80% in white oil) is added. Then stir again at this temperature for 45 minutes. The solution is then cooled and at 20 to 22°C, 140 g of 2,6-dichloro-3-nitropyridine in 500 ml of dioxane are added dropwise over the course of 30 minutes. -You let it react for 3 hours at this temperature. The dark-colored sodium salt is sucked off, washed with dioxane, dissolved in water/methanol 1:1 and diluted acetic acid is added to cover the color. The desired compound crystallizes, is suctioned off and washed thoroughly with methanol. Melting point 174 - 175°C, yield 91 g. From compounds of formula VIII, the corresponding 2-benzoyl-3~nitro-6-chloropyridine derivatives (formula IX)

produced by oxidation. This can, for example, take place with selenium dioxide in dioxane or tetrahydrofuran at 50 to 150°C or it can also be carried out so that it is treated with 30% hydrogen peroxide at a temperature below 100°C, preferably 20 to 50°C in acetone-water , as the stoichiometric amount of an aqueous concentrated KOH solution is dripped in precisely so quickly that no heat exchange has yet taken place. In the latter mode of operation, the 6-positioned chlorine atom is split off to a large extent hydrolytically. One therefore isolates, in addition to the desired compound, also compounds of formula IX, in which =

OH. The latter is then chlorinated again in a known manner with a mixture of PCl-j/PCl^, with PCl^ again deoxygenating the N-oxide formed as a by-product. In the compound of formula IX, the nitro group is then reduced catalytically (with Pd, Pt, Raney nickel, in alcohols, dioxane, tetrahydrofuran between 0 to 60°C and 1 to 50 atmospheres) or chemically (with LiAlH^ or Al/Hg/H 2 O, in ether, dioxane, tetrahydrofuran between 0 to 60 C to the amino group. This amino group can now be substituted according to the specified procedure with the residue R,-.

For the preparation of compounds of formula XIII

where R^ = F or Br,

for example, a compound of formula IX is heated with a saturated aqueous alcoholic ammonia solution in an autoclave at 100 to 120°C for a few hours (2 to 4) and the 6-aminopyridine derivative thus formed is then diazotized in a known manner and reacted according to the conditions according to the Sandmeyer reaction or modified Sandmeyer reaction in the presence of fluoride or bromide ions and/or corresponding copper (I) salts (CuBr, CuCl) or also fluoroborate ions during heating. As a solvent, it is suitable here for water-alcohol mixtures, or mixtures of water, dimethylformamide and dimethylsulfoxide. For the production of the fluorine derivatives, the dry diazonium fluoroborates can also be thermally decomposed.

Compounds of formula XIII, in which R-^ means a bromine atom can also be brominated from compounds of formula XIII, in which R.^

= OH with a brominating agent such as POBr-,, PBr,- or SOBr~, optionally'

in a dilute medium between 20 and 200 C. The preparation of compounds of formula XIII, in which R-^ = F, can also take place in a modified manner by dissolving a compound of formula XIII, in which R-^ denotes an amino group , in concentrated aqueous hydrofluoric acid, at temperatures between 0 and 50°C, eventually sets NaN02, or

introduces a slow stream of nitrous gases.

The reduction of the nitro group and the subsequent introduction of R 1 takes place in the manner already indicated.

Compounds with the general formula II, in which W is the group =NH or =N0H, can be obtained, for example, from compounds with formula II, in which W is oxygen and the other symbols R-^, R2, R-j and R^ have the already stated meaning by reacting with ammonia or hydroxylamine. This reaction preferably takes place in polar solvents (aliphatic alcohols, dioxane, tetrahydrofuran, pyridine, liquid ammonia), preferably between 0 and 150°C, and optionally under pressure between 1 and 100 ato.

Example 1.

5~phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)

21 g of N-benzyloxycarbonylglyein are suspended in 400 ml of dry ester and, while stirring, 21 g of phosphorus pentachloride are added. After everything has dissolved, 23 g of 2-benzoyl-3-amino-6-chloro-pyridine in 90 ml of chloroform are added while stirring and stirred for 2 hours at room temperature, 2-benzoyl-3-/_ N -(benzyloxycarbonylamino-acetyl)-amino/-6-chloro-pyridine. It is filtered off with suction, washed with ether (yield 30 g, melting point 130°C). 105 g of this intermediate step are now added in portions to a solution of 100 g of hydrogen bromide in 360 ml of glacial acetic acid. It occurs immediately during foaming CC^ development. It is then stirred for an hour and ether is added to complete the precipitation. The precipitate is suctioned off, suspended in methanol and concentrated aqueous ammonia solution is added, after which the substance dissolves. The thin-layer chromatographic examination shows that the initially formed open glycidyl derivative is cyclized upon release of the base. After a short period of time, it is mixed with water until cloudy, after which the substance crystallizes out. It is recrystallized from isopropanol. Yield 60 g, melting point 198°C.

Preparation of the starting materials:

To a cooled and stirred solution of 190 g of 2,6-dichloro-3-nitropyridine and 117 g of benzyl cyanide in 2 liters of dioxane, 64 g of sodium hydride (Q0% in white oil) is gradually added under a nitrogen atmosphere. The reaction mixture immediately turns dark blue, eventually a fine-grained precipitate begins to separate, the temperature increases (by cooling with ice water) to 30°C. After 3 hours, mix with approx. 20 ml of alcohol, stir again for 20 minutes, then aspirate. The dark blue sodium salt is dissolved in a liter of water, mixed with diluted acetic acid to form a color coating. The 2-(α-cyano-benzyl)-3-nitro-6-chloro-pyridine formed crystallizes out cleanly. Melting point 165°C,

■yield 146 g.

A mixture of 200 g of 2-(a.-cyano-benzyl)-3-nitro-6-chloro-pyridine, 500 ml of acetone and 160 ml of 30% hydrogen peroxide solution is mixed with stirring at 35 - 40°C dropwise with a concentrated potassium hydroxide solution (from 75 g KOH and 50 ml water). The dripping takes place exactly so quickly that a color change does not yet take place. Immediately after a permanent color coating, which shows the end of the reaction, cools down, the separated crystalline substances are sucked off. This substance, the amount of which can fluctuate between 30 and 40 g, is 2-benzoyl-"3-nitro-6-chloro-pyridine, which is purified by recrystallization from methanol. Melting point 106°C. The filtrate is acidified with dilute hydrochloric acid, whereupon it precipitates 2-benzoyl-3-nitro-6-hydroxy-pyridine in an amount between 120 and 140 g. Melting point 211°C.

This hydroxy compound is also transferred by -chlorination into the desired 2-benzoyl-3-nitro-6-chloro-pyridine. To this end, 190 g of 2-benzoyl-3-nitro-6-hydroxypyridine is stirred in 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 phorsforhalides are then evaporated in a rotary evaporator in vacuum, the residue is taken up in 1 liter of chloroform, washed with ice water, 2 times with diluted caustic soda and 2 times with water. The chloroform solution is dried, brought to dryness in vacuo and the residue recrystallized from methanol. Yield 145 g. Melting point 106°C.

110 g of pure 2-benzoyl-3~nitro-6-chloro-pyridine are hydrogenated in 500 ml of dioxane at 60 ato and 20°C on 30 g of Raney nickel catalytically. The filtered solution is evaporated in vacuo to approx. one-third, cooled to 5°C, the crystallized 2-benzoyl-3_amino-6-chloro-pyridine is suctioned off after one hour and recrystallized from ethanol. Yield 78 g, melting point 159°C.

Example 2.

5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine(2)

- Formula see example 1 - 15 ml of bromoacetyl chloride is stirred for 2 hours at room temperature with 33 g of 2-benzoyl-3-amino-6-chloro-pyridine in 200 ml of dioxane, while adding 11.5 g of pyridine. It is suctioned off, washed with ether and then 25 g of the intermediate step (2-benzoyl-3-bromoacetylamino-6-chloropyridine, melting point 130°C, yield 38 g) is dissolved in 900 ml of a 12% methanolic ammonia solution and allowed to stand overnight. The solution is evaporated in vacuo to dryness, the residue is dissolved in 200 ml of chloroform and the solution is washed with water. The dry solution is acidified with 6 N isopropanolic hydrochloric acid and mixed with gasoline until cloudy. The crystallized HCl salt is suctioned off after 2 hours, dissolved in methanol and with ammonia the base is prepared, which crystallizes when water is added. Yield 10 g, melting point 198 - 200 C.

Example 3-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide.

The 2-oximinobenzoyl-3-amino-6-chloropyridine (crude product) formed from 46 g of 2-benzoyl-3-amino-6-chloropyridine, 70 g of hydroxylamine hydrochloride (crude product) is dissolved in 400 ml of acetic acid and 32 ml of chloroacetyl chloride is added. It is allowed to stand for 2 days, then hydrogen chloride is introduced to saturation and allowed to stand for a further 3 days. The solution is evaporated in vacuo, the residue is taken up in methylene chloride and the solution is washed thoroughly with water and then with ice-cold soda solution. Then dry with sodium sulfate and evaporate to 150 ml and petroleum ether (40 to 70°C) is added until cloudy. After 2 hours, the separated crystals of .5-aza-6-chloro-2-chloromethyl-4-phenyl-quinazoline-3-oxide are filtered off with suction (yield 23 g, melting point 146°C). 6.5 g of this is now added to a mixture of 8 g of sodium hydroxide, 20 ml of water and 100 ml of ethanol at room temperature. After stirring for an hour, the solution is diluted with water and made slightly acidic with hydrochloric acid. The crystallising compound is suctioned off and recrystallized from ethanol. Yield 4.5 g, melting point 215°C.

Production of output products:

A mixture of 46 g of 2-benzoyl-3-amino-6-chloropyridine, 100 ml of pyridine and 400 ml of ethanol is boiled for 6 hours with stirring and reflux. The mixture is freed of solvent in a vacuum, as the reaction product appears as syrup. This is further processed directly.

Example 4.

3-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

A mixture of 26 g of 2-benzoyl-3-amino-6-chloropyridine3

28 g of benzyloxycarbonyl-d,£-alanine, 28 g of phosphorus pentachloride and 500 ml of ether are stirred for one hour at room temperature. It is then evaporated to dryness and the syrupy residue (50 g) is treated with a solution of 70 g of HBr in 200 ml of glacial acetic acid, as indicated in example 1. The product formed from the ammoniacal solution is partially cyclized and is cyclized to completion by stirring for 3 hours in 200 ml of boiling toluene with the addition of 3 ml of pyridine during water separation. The desired compound crystallizes from the toluene solution and recrystallizes from benzene/gasoline. Yield 26 g, melting point 182°C. Example 5-3-isopropyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiaz.epinone-(2).

A mixture of 26 g of 2-benzoyl-3-amino-6-chloropyridine,

30 g of benzyloxycarbonyl-d,£-valine, 25 g of phosphorus pentachloride and 400 ml of ether are stirred for one hour at room temperature. It is then evaporated to dryness and the syrupy residue (40 g) is treated with a solution of 50 g HBr in 160 ml glacial acetic acid analogously to example 1.

A syrupy base precipitates from the ammoniacal solution, which, according to thin-layer chromatograms, still partly consists of the uncyclized advantage. This base is then cyclized by stirring for 3 hours in 200 ml of boiling toluene with the addition of 3 ml of pyridine during water elimination to completion. The desired compound crystallizes from the toluene solution and is recrystallized from benzene/gasoline. Yield 14 g, melting point 225 to 226°C.

Example 6.

5-(o-chlorophenyl)-6-aza-7-chloro-132-dihydro-3H-1,4-benzodiazepinone-(2).

To a mixture of 34 g of 2-o-chlorobenzoyl-3-amino-6-chloro-pyridine, 27 g of benzyloxycarbonylglycine and 300 ml of dioxane, 27 g of phosphorus pentachloride are added in portions while stirring. The temperature increases from 27° to 37°C. Stirring is continued for 1 hour and then gradually 800 ml of petroleum ether is added to the mixture. After seeding, 50 g of the 3-N-benzyloxycarbonyl intermediate crystallizes out. 20 g of this is now reacted in 70 ml of a saturated solution and HBr in glacial acetic acid as in example 1. The product formed from the ammoniacal solution still contains a larger amount of the open advantage and is therefore completely cyclized by stirring for 3 hours in 200 ml of boiling toluene with the addition of 3 ml of pyridine during water elimination. The pure compound crystallizes in pure form from the toluene solution. Yield 10 g, melting point 201°C.

Example 7.

5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide.

About. 70 g of 2-(o-chlorobenzoyloximino)-3-amino-6-chloro-pyridine (crude product) are dissolved in 400 ml of 99% glacial acetic acid and 45 ml of chloroacetyl chloride are added. HCl gas is then introduced, whereby 2-(o-chlorobenzoyloximino)-3-chloroacetylamino-6-chloropyridine gradually crystallizes out (yield 53 g, melting point 13° to 138°C). 36 g of this compound are now dissolved in 150 ml of 70% ethanol and, while stirring and cooling in an ice bath, 40 g of 50% KOH are added. It is allowed to react for 30 minutes at 20°C. The clear solution is acidified with acetic acid and mixed with 100 ml of H2O. The white crystalline precipitate is suctioned off, washed with isopropanol and recrystallized from dioxane/gasoline. Yield 14 g, melting point 241 to 243°C.

The starting oximine compound is obtained as follows:

A mixture of 70 g of 2-(o-chlorobenzoyl)-3-amino-6-chloropyridine (prepared analogously to the prescription given in example 1), 30 g of hydroxylamine hydrochloride and 200 ml of pyridine is stirred for 20 hours at room temperature. A further 30 g of hydroxylamine-HCl is added and stirred for a further 20 hours. The pyridine is then evaporated in a rotary evaporator, the residue is taken up in 200 ml of chloroform and the solution is washed several times with water. The chloroform solution is dried briefly and washed with water. The chloroform solution is dried briefly, the desired substance partially crystallizes out of the dry solution. The solution is evaporated and the residue is converted immediately. Example 8. 5-(2,5-Dichlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2). A mixture of 10 g of 2-(2,5-dichlorobenzoyl)-3-amino-6-chloropyridine (prepared analogously to example 1), 70 ml of dry dioxane, 10 g of benzyloxycarbonylglycine and 10 g of phosphorus pentachloride is stirred for 2 hours at room temperature. The solvent is then removed in vacuo and the residue (14 g) is further processed as indicated in example 6. Yield 8 g, melting point 240°C.

Example 9.

1-methyl-5-(o-fluorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

A mixture of 25 g of 2-o-fluorobenzoyl-3-N-methylamino-6-chloro-pyridine (prepared analogously to example 1), 30 g of benzyloxycarbonylglycine, 100 ml of dioxane and 30 g of phosphorus pentachloride is stirred for 2 hours at room temperature. The solvent is then removed in vacuo and. the residue (6l g) is added in portions to 500 ml of 40% HBr-containing glacial acetic acid and stirred for 1 hour. The reaction solution is then mixed with 1.5 l of ether, the amorphous precipitate is filtered off and heated under reflux in 500 ml of toluene and 100 ml of pyridine for 4 hours under a water separator with vigorous stirring. Undissolved is then filtered off. The solution is evaporated to dryness on a rotary evaporator. The residue is recrystallized from ethanol. Yield 22 g, melting point 139°C..,

Example 10.

5-(o-fluorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

A mixture of 35 g of 2-o-fluorobenzoyl-3-amino-6-chloro-pyridine (prepared analogously to example 1), 33 g of benzyloxycarbonylglycine, 500 ml of ether and 33 g of phosphorus pentachloride is stirred for 2 hours at room temperature. The solvent is then removed in vacuo and the residue (55 g) is further processed analogously to example 6. The product formed is recrystallized from n-propanol. Yield 28 g, melting point 195 to 196°C.

Example 11.

3-Benzyl-5~phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzdiazepinone-(2).

A mixture of 35 g of d,i-carbobenzoxy-phenylalanine,

400 ml of ether and 26 g of phosphorus pentachloride are stirred for 20 minutes. 26 g of 2-benzoyl-3-amino-6-chloro-pyridine are then added to the solution and stirred for one hour at room temperature. The thus precipitated product (2-benzoyl-3-N-(benzyloxycarbonylamino-g-phenylpropionyl)-amino-6-chloro-pyridine, melting point 182°C) is filtered off with suction and stirred after drying (45 g) analogously to the method as discussed in example 6 with 280 ml of 40% HBr-containing glacial acetic acid and further processed analogously. Yield 28.4 g, melting point 234°C. Example 12.

3-(3-carboxy-propionyloxy-5-(o-chlorophenyl-)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

1 g sodium salt of 3-hydroxy-5-(o-chlorophenyl-)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) (prepared from an ethanolic solution of 3 -hydroxy compound with the equivalent amount of sodium ethylate solution and precipitation of the sodium salt with ether), 0.7 g of succinic anhydride and 2 ml of dimethylsulfoxide are heated for 10 minutes on a water bath, then cooled and mixed with 3 ml of water. The desired compound crystallized upon trituration. Yield 0.4 g, melting point 170-171°C.

A further 0.4 g of substance could also be obtained from the mother liquor, which was recrystallized from ethanol/water.

Example 13»

3-Hydroxy-5-(o-chlorophenyl)-6-aza-7-chloro-1',2-dihydro-3H-1,4-benzo-diazepinone-(2).

300 g of 30% KOH are added at 15°C with stirring to a solution of 110 g of 1-acetyl-3-acetoxy-5~(o-chlorophenyl)-6-aza-7-chloro-3H-1,4 -benzodiazepine-(2) in 400 ml of ethanol. Stir for 30 minutes at room temperature. The clear solution is adjusted with acetic acid to pH 5 and mixed with 250 ml H 2 O. The amorphous precipitate that separates is filtered off under activated carbon loading. The filtrate is mixed with -1| 1 ll^ Q and equipped with chloroform. The organic phase is dried and evaporated. The residue is recrystallized twice from ethanol. Yield 23 g, melting point 200 to 202°C. Example 14.

5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

- Formula see example 1 -

(Reduction of the N-oxide)

3 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-one-(2)-4-oxide are hydrated in 150 ml of methanol at normal pressure and room temperature on 5 g of Raney nickel . The theoretical hydrogen volume is occupied after 90 minutes. The filtered solution is evaporated to dryness in vacuo, the residue is recrystallized from ethanol. Yield 2 g, melting point - 198°C. Example 15" 1-Acetyl-3-acetoxy-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

A mixture of 23 g of 5-(o-chlorophenyl)-6-aza-?-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide and 120 ml of acetic anhydride is refluxed in 30 minutes. Then pour in 700 ml of ice water. The crystallized substance is recrystallized from methanol. Yield 15 g, melting point 203 to 207°C.

Example 16.

3-Hydroxy-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

By heating 24 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide with 160 ml of acetic anhydride (30 minutes on a water bath) you get after pouring into 500 ml of water a mixture of 1-acetyl-3_acetoxy-5_phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 3-acetoxy-5-phenyl -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2). This mixture is deacetylated with 3 parts 30% KOH and 4 parts ethanol at 15°C. After acidification and dilution with water, shake off with chloroform and the chloroform residue is recrystallized twice from ethanol. Yield 11 g, melting point 177°C.

Example 17.

1-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzo-diazepin-one-(2).

Add 20 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4- • benzodiazepine-one-(2) in 120 ml of dry dimethylformamide under a nitrogen atmosphere and stir in portions 2.5 g sodium hydride (80% in white oil). The temperature is kept at 25°C. After an hour to-

. 15 g of methyl iodide are added drop by drop, then stirred for 1 hour at 30°C

and 1 hour at 40°C. After standing overnight, the solvent is evaporated in vacuo, the residue is taken up in methylene chloride, washed several times with water and once with dilute hydrochloric acid, dried with sodium sulphate and evaporated. The residue is recrystallized from benzene/gasoline. Yield 11 g, melting point 154°C.

Example 18.

1-allyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine.

The compound is prepared analogously to example 17 using 20 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) and 11 g of allyl bromide. Yield 7 g, melting point 9^°C. Example 19.

1-cyclopropylmethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzo-diazepinone-(2)

The compound is prepared analogously to example 17 using 23 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine (2) and 12 g of cyclopropylmethyl chloride. The reaction product is purified by chromatography over an aluminum column (length 60 cm, diameter 5 cm, eluent chloroform), the syrup of the pure compound is then dissolved in approx. 100 ml of ether and isopropanolic HCl (6 N) are added, after which the hydrochloride crystallizes out. Yield 5 g, melting point 180 - 188°C. 1 O / U iJ HL Example 20. 1-(B-diethylaminoethyl)-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2).

To a solution of 20 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) in 50 ml. dimethylformamide, one has, with stirring and under nitrogen at room temperature, 2.5 g of sodium hydride ($80 in white oil). The temperature is raised to 50°C over the course of 30 minutes, then a solution of 9 g of freshly prepared diethylaminoethyl chloride in 20 ml of dimethylformamide is added dropwise and then added. 0.5 g of potassium iodide. It is stirred for 1 hour at 70°C, then concentrated in vacuo to 20 ml and 50 ml of ethanol and 60 ml of water are added. The substance crystallized out by rubbing. It is recrystallized from benzene/gasoline. Yield 15 g, melting point 154°C.

Example 21. 1-Methyl-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2). 10 g of 5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) are methylated analogously to example 17. The reaction solution is evaporated in vacuo, the residue is mixed with water and benzene, the benzene layer is washed twice with water and then dried. On addition of 6 N isopropanolic hydrochloric acid, the hydrochloride crystallizes out. This is recrystallized once from methanol/ether and once from ethanol. Yield 4 g, melting point 204 to 206°C during cleavage.

Example 22.

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

To a mixture of 11.5. g of LiAlH^ in 200 ml of dry tetrahydrofuran is added dropwise to 4 l g of 5-phenyl-6-aza-7~chloro-1,2-dihydro-3H-1,3-benzodiazepine-2-(2), dissolved in 600 ml of tetrahydrofuran with stirring within 45 minutes. From initially 30°C, the temperature thereby increases to 40°C. Now heat to 60° and keep approx. 6 minutes at this temperature, then cool rapidly to 0 to 10°C and a mixture of 28 g water, 15 g methanol and 100 ml tetrahydrofuran is added dropwise. All these operations are carried out under a nitrogen atmosphere. The reaction mixture is filtered, the filtrate is dried with MgSO 4 and evaporated in vacuo. The residue is taken up in benzene. From the benzene solution, 7 g of the desired compound as a base crystallizes on standing overnight at 5°C. Melting point l6l°C. A solution of 10 g of maleic acid in 50 ml of acetone is added to the mother liquor, after which the maleate crystallizes out. The maleate is recrystallized from ethanol. Melting point 186 to 187°C during cleavage, yield of maleate 15 g. Example 23. 1-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinethione-(2 )

A mixture of 26 g of 5~phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2), 32 g of phosphorus pentasulphide and 150 ml of toluene is heated with stirring for 2 hours to boiling . It is then filtered, the solution is evaporated in a vacuum, the residue is combined with the filter residue and treated with very aqueous concentrated ammonia and ice. After 30 minutes of stirring, aspirate. The product is dissolved in chloroform, chromatographed over an aluminum oxide column (length 60 cm, diameter 5 cm, eluent chloroform) and the purified product obtained by evaporation of the chloroform is recrystallized from benzene. Dividend,

10 g, melting point 158°C.

Example 24.

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

A mixture of 40 g of 1-methyl-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) and 29 g of phosphorus pentasulfide is reacted according to example 23 in 200 ml of toluene and worked up. Yield 12 g, melting point 188 to 189°C.

Example 25.

5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinethione-(2).

A mixture of 54 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2), 44 g of phosphorus pentasulphide and 600 ml of toluene is boiled for 2.5 hours under nitrogen and reflux . The granular precipitate is suctioned off, stirred several times with chloroform, finally treated with aqueous ammonia and extracted again with chloroform. The thione crystallizes from the extract after drying. Yield 30 g, melting point 202°C.

Example 26.

2-acethydrazino-5-phenyl-6-aza-7-chloro-3H-1. 4-benzodiazepine.

A mixture of 6 g of acetylhydrazine, 10 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinethione-(2) and 50 ml of dioxane is heated for 20 minutes at 60 to 60° C. The desired compound thereby crystallizes. It is sucked off after cooling and recrystallized from ethanol. Yield 10 g, melting point 176°C Example 27.

2-methylamino-5-phenyl-6-aza-7-chloro-3H-1,4-benzodiazepine.

10 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzo-diazepinethion-(2) are heated in 200 ml of 10% methylamine solution for 10 minutes on a water bath. The desired product thereby crystallizes. It is sucked off and recrystallized using activated carbon from benzene. Yield 5 g> melting point 2l4°G. Example 28. 1-Methyl-3-methoxy-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro~3H-1,4-benzodiazepinone-(2) 21 g (0.065 mol) 3-Hydroxy-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-benzodiazepine-(2) is dissolved in 300 ml of dioxane and 3 ml of dimethylformamide is added. 4.1 g of 80% sodium hydride in white oil are then added and stirred for 30 minutes at room temperature. It is then heated to 65°C, 28.4 g (0.2 mol) of methyl iodide is added dropwise over the course of 15 minutes and it is further stirred for 1 hour at this temperature. The reaction mixture is mixed with 5% acetic acid until precipitation of the reaction product, this is sucked off and recrystallized from ethanol. Yield 10.2 g, melting point 247 to 249°C. Example 29-1-(6-Morpholinoethyl)-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4- benzodiazepinone-(2) To a solution of 27 g (0.1 mol) of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) in 250 ml of dimethylformamide is added at room temperature below. N2 and, with stirring, 3.5 g of sodium hydride (80% in white oil). It is stirred for 30 min. otter, 20 g of N-2-chloroethylmorpholine are added and it is heated for 2 hours at 80 to 90°C. The dimethylformamide is removed in vacuo and the residue is stirred with water. The water is decanted from the syrupy product which is dissolved in hot ethanol. Activated charcoal is added, filtered and cooled. The reaction product crystallizes out. Yield 14 g, melting point 162 to 164°C. Example 30-1-acetyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) 20 g 5-phenyl-6-aza-7-chloro- 1,2-dihydro-3H-1,4-benzodiazepine-(2) is heated in 50 ml of acetic anhydride for 2 hours with stirring at 120°C. A white substance eventually separates from the blue solution. This is suctioned off and recrystallized twice from dimethylsulfoxide. Yield 5 g - melting point 256 to 260°C.

Example 31.

1-S-Hydroxyethyl-5-(2-fluoro-phenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzo-diazepinone- (2)

3 g of sodium hydride ( 80$ in white oil) in portions. It is then stirred for 30 minutes. Then, 9 ml of bromoethanol are added dropwise and stirred for 7 hours at 80 to 90°C. The solvent is evaporated in vacuo. The residue is mixed with 300 ml of ether and 200 ml of 5% sodium hydroxide solution and shaken. The ether layer is washed several times with dilute caustic soda, then with water. The ether solution is dried and evaporated to dryness. The crystalline residue is recrystallized twice from ethanol. Melting point 154 - 156°C.

Example 32.

1-methyl-5-(2-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzo-diazepinone-(2)-4-oxide

32 g of 5-(2-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide are dissolved in a mixture of 450 ml.dioxane and 45 ml of dimethylformamide, then add 3.3 g of NaH (80% in white oil) while stirring at 20°C. The temperature rises to 34°C. 28.4 g of methyl iodide are then added dropwise while stirring and further stirred for 30 minutes at 40°C. The mixture is suctioned off, acidified with glacial acetic acid, evaporated in vacuo. The residue crystallizes from 300 ml of ethanol by adding 50 ml of petrol. The pure substance is suctioned off and washed with ethanol. Melting point 213°C. Example 33-1-Methyl-3-acetoxy-5-(2-chlorophenyl)-6-aza-7-chloro-1,2-dihydro~3H-1,4-benzo-diazepinone-(2)

21 g of 1-methyl-5-(2-chlorophenyl-)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide is heated in a mixture of 33 ml of acetic anhydride and 29 ml of glacial acetic acid for 15 minutes while stirring until boiling. After cooling and inoculation, the desired substance crystallizes. It is washed with glacial acetic acid, where-

after with water. Melting point 178 to 179°C.

Example 34.

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

In a mixture of 1150 ml of acetic anhydride and

1020 ml of glacial acetic acid are introduced at 100° C. with stirring 724 g of 5~(2-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide. The solution is then heated to 120°C. It pre-

an exothermic reaction takes place, the mixture boils. The reaction goes to completion after 15 minutes, then the mixture is cooled without cooling while stirring. The substance crystallizes. It is washed with water and methanol. Melting point 243°C during decomposition.

Example , 35• 5-(2-fluorophen<y>l)-6-aza-7-chloro-1,2-di<y>dro~3H-1,4-benzodiazepine-(2)-4-oxide

The oxime of 2-(o-fluorobenzoyl)-3-amino-6-chloropyridine) (crude product), which is previously prepared by boiling 100 g of 2-(o-fluorobenzoyl)-3-amino-6-chloropyridine for four hours (see example 10) and 170 g of hydroxylamine hydrochloride in 450 ml of pyridine with stirring and reflux and usual isolation (evaporation of the reaction mixture in a vacuum, absorption in 500 ml of chloroform, shaking three times with water and distilling off the chloroform) as of oil is dissolved in 400 ml of hot glacial acetic acid and 90 g of chloroacetyl chloride are added to this while stirring. An exothermic reaction takes place which is finished after 1 hour. The mixture is then allowed to stand overnight and then evaporated to dryness on a rotary evaporator in vacuum. The solid residue (166 g) is suspended in 600 ml of ethanol, then 300 g of ice and 92.5 g of potassium hydroxide in 100 ml of water are added with stirring. The temperature is then maintained by further addition of

ice below 5°C. After 30 minutes, the solution is filtered, the filtrate is mixed with stirring with 110 ml of glacial acetic acid, and then water is added until it becomes cloudy. In this way, you get 95 g of raw material. By recrystallization of 10 g from methanol/acetone, 4 g of pure substance are obtained. Melting point 239°C.

Example 36.

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

85 g of 5-(2-fluorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide (crude product) are heated in 130 ml of acetic anhydride while stirring at 130°C. An exothermic reaction occurs. This is finished after 10 minutes, then the mixture is cooled and poured onto ice. The precipitated substance is sucked off and washed with water. It consists of a mixture of the mono- and diacetyl derivative of the desired compound. 30 g of this substance (dry) is suspended in 100 ml of n-propanol. A solution of 3 g of sodium in 40 ml of n-propanol is added cold (0-5°C) while stirring; after 15 minutes, mix with 700 ml of water and acidify with glacial acetic acid. The desired substance crystallizes on cooling. After standing overnight, it is filtered off with suction and recrystallized from n-propanol. Melting point 177-179°C. Example 37-1-(g-piperidinoethyl)-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)

To a solution of 27 g of 5~phenyl-6-aza-7-chloro-J,2-dihydro-3H-1,4-benzodiazepine-(2) in 250 ml of dimethylformamide is added at room temperature 3.6 g of sodium hydride (Q0% in white oil), then at 40°C 32 g of piperidinoethyl chloride (freshly prepared from 36.6 g of N-chloroethylpiperidine.HCl) in a little dimethylformamide, heated for 15 minutes at 85 to 90°C. The mixture is neutralized with glacial acetic acid and evaporated in vacuo. The oily residue crystallizes out slowly when extracted with ethanol. The substance is recrystallized once again from ethanol with the addition of activated carbon. Melting point 136 to 137°C.

Example 38.

1-n-propyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine- (2)

To 27.2 g (0.1 mol) of 5~phenyl-6-aza-7-chloro-1,2-dihydro~3H-1,4-benzo-diazepinone-(2) in 200 ml of dry dioxane and 5 ml dimethylformamide, with stirring and nitrogen at 20°C, 4.5 g of sodium hydride (57% in white oil). The temperature rises to 30°C, a clear solution occurs. It is then heated to 80-85°C and 85 g of n-propyl bromide is added dropwise over the course of 2 hours; then stir for another 1 hour at 85°C. The reaction mixture is poured into 700 ml of water, after which the product crystallizes. It is filtered off with suction and recrystallized from methanol twice.

Yield 17 g, melting point 139-142°C.

Example 39-1-n-butyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)

This compound is prepared from 27.2 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) and 20 g of n-

bromobutane analogous to example 38. Yield 16.5 g, melting point 108 - 110°C.

Example 40.

5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide

(Formula as in example 3)

14 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine are dissolved in 250 ml of chloroform, then a solution of 11 g of m-chlorobenzo-

peracid in.150 ml of chloroform. The mixture is stirred for one hour,

then set aside overnight at room temperature. Equipping with 5% sodium hydroxide solution. This extract is acidified with glacial acetic acid, after which the reaction product crystallizes

looks. It is recrystallized from ethanol. Melting point 156 to 158°C (as monohydrate, after dehydration at 215°C). Yield 11 g. The compound is identical to that prepared according to example 3.

Example 41.

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

(2) (reduction of the N-oxide)

(Formula as in example 6)

20 g of 5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-4-oxide in 250 ml of dioxane are hydrated with 5 g of Raney nickel at 50 ato and 50°C. From the filtered hydration solution, the reaction product is precipitated with water and recrystallized twice from n-propanol. Yield 9 g, melting point 200°C.

Example 42.

1-methyl-5-phenyl-6-aza-7-thyrom-1. 2-dihydro-3H-1,4-benzodiazepine-(2)

To a solution of 32 g of 5-phenyl-6-aza-7-bromo-1,2-dihydro-3H-1,4-benzodiazepine-one-(2) in 300 ml of dimethylformamide

3.5 g of sodium hydride (80% in white oil) are added while stirring at room temperature. After 15 minutes, 16 g of methyl iodide are added and then stirred for one hour at 40°C. The solution is evaporated under vacuum to 50 ml, the residue is stirred with water and the crystalline product is recrystallized from methanol. Yield 19 g, melting point 148 - 150°C.

Example 43.

a) 1-allyl-5-(o-chlorophenyl)-6-aza-7-klpr-1,2-dihydro-3H-1,4-benzodiazepine-(2).

Under a nitrogen atmosphere and with stirring, add to a solution 31 g of 5~(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2) in 120 ml of dry dimethylformamide 2.5 g of sodium hydride (80% in white oil) in portions at 25°C. After 1 hour, 100 ml of allyl bromide is added dropwise. and the mixture is stirred for 1 hour at 30°C and then for 1 hour at 40°C. After standing overnight, the solvent is removed in vacuo, the residue is taken up with methylene chloride, washed again with water, then with dilute hydrochloric acid, dried with sodium sulphate and the solution is evaporated. The reaction product thus formed is transferred from dissolution of acetone and addition of isopropanolic hydrochloric acid to the hydrochloride which melts at 200 to 202°C during cleavage. Yield 20 g.

The following compounds are prepared in an analogous manner: b) 1,3.-dimethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzo- diazepinone-(2)

This compound is obtained from 13 g of 3-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) and 8 g of methyl iodide. The reaction product formed is recrystallized from

benzene/gasoline. Yield 9 g, melting point 132-134°C.

c) -£-1,3-dimethyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzo-diazepinone-(2)

From 11 g of ^-3-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) and 8 g of methyl iodide. The reaction product is recrystallized from benzene/gasoline. Melting point 143-144°C, yield 7 g.

d) 1-ally1-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)-oxide-(4)

From 16 g of 5~(o-chlorophenyl)-6-aza-7~chloro-1,2-dihydro-3H-1,4-benzodiazepinone-(2)-oxide-(4) and 6.7 g of allyl bromide. The reaction product is recrystallized from dimethylformamide/ethanol 30:70. Melting point 220°C, yield 9 g.

Example l 44.

1-methyl-3-hydroxy-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-■3H-1,4-benzodiazepine-(2)

24 g of 1-methyl-3-acetoxy-5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro~3H-1,4-benzodiazepinone-(2) are introduced into a solution of 1.5 g of sodium metal in 150 ml of n-propanol and mixer: stir at room temperature for 20 minutes. A clear solution occurs, of which part of the product precipitates? as sodium salt. It is acidified with glacial acetic acid and the product is precipitated by adding 200 ml of water. The aspirated compound is recrystallized from methanol. Yield 11 g, melting point 247-250°C. Example 45-1-allyl-3-acetoxy-5-(o-chlorophenyl)-6-aza-7~chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2) 24 g of 1-allyl -5-(o-chlorophenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzcdiazepine-(2)-oxide - (4) is heated in a mixture of 29 ml of glacial acetic acid and 33 ml of acetic anhydride for 15 minutes while stirring until boiling. After cooling and grafting. crystallizes the desired substance. It is washed with glacial acetic acid, then with water, yield 20 g, melting point 176 - 177°C. Example 1 46 .. 5-phenyl-6-aza-7-bromo(fluoro)-1,2-dihydro-3H-1,4-benzodiazepine-(2)

In a mixture of 300 ml of chloroform and 400 ml of ether, 30 g of N-(benzyloxycarbonyl)-glycine are dissolved, then 30 g of phosphorus pentachloride are added while stirring. After stirring for 30 minutes, 35 g of 2-benzoyl-3-amino-6-bromopyridine are added (see below for preparation). After 1 hour, a cloudy precipitate is filtered off and the filtrate is mixed with 1 liter of petrol. The crystallized intermediate product (2-benzoyl-3-N(benzyloxycarbonyl 1-amino-acetyl)-amino7-6-bromopyridine; 43 g) is introduced after drying under stirring at room temperature into 200 ml of a solution of brcir.bydrogen in glacial acetic acid (40%), CO^ being vigorously evolved. After 1 hour, precipitate with ether, the precipitate is filtered off with suction.

This precipitate is stirred with 200 ml of methanol and heated in a water bath until boiling. Aqueous ammonia is then added for a basic reaction, after which it a clear resolution occurs. After brief stirring, the reaction product begins to crystallize, then another 1 liter of water is added. After one hour, suction off, wash with water and recrystallize once from methanol. Yield 11 g, melting point 202 - 204°C.

If the corresponding 6-fluoro derivative is used instead of 2-benzoyl-3-amino-6-bromo-pyridine, 5-phenyl-6-aza-7-fluoro-1,2-dihydro-3H-1,4- benzodiazepinone-(2), mp 218 to 220°C (from ethanol).

The starting material is obtained as follows:

180 g of 2-benzoyl-3-nitro-6-chloropyridine are heated in a solution of 80 g of ammonia in 1 liter of ethanol in an autoclave for 5 hours at 100 to 120°C. The reaction solution is evaporated to dryness, the residue is boiled off with acetone and the product is precipitated from the acetone extract with water. Yield 161 g. 50 g of the thus formed 2-benzoyl-3~nitro-6-aminopyridine is dissolved in 300 ml of dimethylformamide while stirring at 0°C, 125 ml of 47% aqueous hydrobromic acid is added, then added dropwise while stirring at 0° C a solution of 20 g of sodium nitrite in 50 ml of water. It is stirred for 1 hour at room temperature and 1 hour at 60 to 70°C. Then pour in 2.5 liter of water and extracted with chloroform, the chloroform solution is washed with caustic soda and water, dried and evaporated. The residue is recrystallized from alcohol-gasoline (melting point 98 to 100°C). 45 g of the 2-benzoyl-3-nitro-6-bromopyridine thus formed are dissolved in 450 ml of dioxane and hydrated on 10 g of Raney nickel at 50 ato and 60 to 70°C. The solution is filtered, evaporated to 150 ml and added with water. Yield 35 g of 2-benzoyl-3-amino-6-bromo-pyridine.

2-benzoyl-3-amino-6-fluoro-pyridine can, for example, be obtained in an analogous way by diazotizing 2-benzoyl-3_nitro-6-amino-pyridine in anhydrous hydrofluoric acid and subsequent heating at 30 to 40°C (yield 10 g) . The nitro groups are then reduced to amino groups as discussed above.

Example 47-€-3-methyl-5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)

A mixture of 11.6 g of 2-benzoyl-3-amino-6-chloro-pyridine, 11.15 g of N-benzyl-oxycarbonyl-β-alanine, 12 g of phosphorus pentachloride and 500 ml of ether is stirred for one hour at room temperature. It is then evaporated to dryness and the syrupy residue (50 g) is treated with a solution of 70 g of HBr in 200 ml of glacial acetic acid as indicated in example 1. The product formed from the ammoniacal solution is partially cyclized and is completely cyclized by stirring for three hours in 200 ml boiling toluene with the addition of 3 ml of pyridine while splitting off water. The desired compound crystallizes from toluene solution and is recrystallized from benzene/gasoline. Yield 4.5 g, melting point 113-116°C.

Example 48.

2-acethydrazino-5-(o-chloro-phenyl)-6-aza-7-chloro-3H-1,4-benzodiazepine

A mixture of 6 g of acetylhydrazine, 10 g of 5~(o-chloro-phenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinethione-(2) and 50 ml of dioxane is heated 20 minutes at 50 to 60°C. The desired compound thereby crystallizes. It is sucked off after cooling and recrystallized from methanol. Yield 10 g, melting point 196 to 198°C. Example 49• 5-(o-methyl-phenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepine-(2)

Starting from 9.5 g of N-benzyloxycarbonylglycine and 11 g of 2-(o-methyl-benzoyl)-3-amino-6-chloropyridine, proceed analogously to example 1. The HBr salt precipitated with ether of the open glycyl compound is boiled with 10 ml of 25% ammonia, 5 ml of pyridine and 60 ml of toluene under water for 9 hours. Dissolve-a ginger - i nnd amp s r e s id ue t is dissolved<;>in a little acetone, with ethereal hydrochloric acid the HC 1-salt is precipitated'-and this is recrystallized from

'methanol/ether. Yield 5.3 g (51.5%), hydrogen chloride, melting point <:>214 to 220<C>C .

Example ' 50 •

- 2-hydra z i no-5~ (o-chloro-pheny 1)-6-aza-7-k'16r-3H-1, 4-benzodiazepine

Into a mixture of 20 g of hydrazine hydrate in 100 ml of methanol, 11 g of 5~(o-chloro-phenyl)-6-aza-7-chloro-1,2-dihydro-3H-1,4- benzodiazepine thione-'( 2 ) . Reaks j onsb landing is cooled slightly with ice water. The reaction product precipitates after some time. It is sucked off and washed with methanol. It can "'^not ■ be recrystallized .'■ 'Yield 3 g,' melting point 238 to 210°C. Example ■ 51 • - \. • ... ' - - 2-propionylhydrazind-5-f ény l-5- aza-7'-chloro-r3H-l, 4-be h z od ia z ep in

A mixture of 6.5 g of propionylhydrazine, 10 g of 5-phenyl-6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazepinethione-(2) and 50 ml of dioxane is heated for 20 minutes at 50 to 60°C. The desired one

compound thereby crystallizes. It is filtered off after cooling and recrystallized from ethanol. Yield 7 g, melting point

■-■196 .:to -198°C. ; 1 '.'

Example 52.

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

(2)

Dissolve 26.7 g of 2-o-chloro-benzoyl-3-amino-6-chloro-pyridine in 30 g of imidazole or pyridine at 100 to 115°C and now add 26.2 g of glycine methyl ester-HCl in portions while stirring. After the addition (15 minutes), stir again for 75 minutes at 110°C. Then add 100 ml of methanol and pour on 400 ml of water. The substance that separates is recrystallized from toluene. Yield 3 g, melting point 101°C.

Attempt.

The compounds according to the invention have a distinctly very good anxiolytic effect. Anxiolytic means anxiety-relieving or anti-anxiety. Such an effect is of course not directly measurable in animal experiments. On the other hand, anxiolytic-acting substances have anticonvulsant properties. Compounds that show anticonvulsant properties in animal experiments therefore usually have anxiolytic properties when applied to humans. One method to investigate whether a compound has anticonvulsant properties and thus also acts as an anxiolytic is the cardiazole shock method.

To demonstrate the therapeutic value of the compounds produced according to the invention, the following table lists values of the anticonvulsive effect of the compounds (examined on cardiazole shock).

For comparison, the effect of the compound corresponding to example 17 is indicated in US patent 3-314,941.

The compound from this patent shows no effect on the cardiazole shock test up to a dose of 100 mg/kg mouse (per os). The effect of the compounds produced according to the invention is therefore unexpected.

Cardiazole shock method:

Experiments on cardiazole shock were carried out under adaptation of the method by Berger, F.M. et al; J. Pharmacol.

Exper. Therapy. 116, 337-32 (1956).

In mice, the subcutaneous injection of 150 mg/kg of cardiazole first leads to short-term, then to prolonged and severe convulsions with subsequent death of all animals used within 10 to 15 minutes. With previous (1 hour now in advance) oral administration of the anticonvulsant active test substance in different dosages, the 100% lethal effect of cardiazole is reduced dose-dependently. From the percentage of surviving animals in the individual trial groups, the ED 50 is determined by graphical representation of the dose-effect straight line. ED 50

is the dose at which 50% of the examined animals show a pronounced anticonvulsant effect.

Claims (1)

Analogous process for the preparation of therapeutically active compounds of the general formula wherein R-^ means a halogen atom, R2 and Rj which may be the same or different, mean hydrogen or halogen atoms or low molecular weight alkyl groups, Ri| means a hydrogen atom, a hydroxy<y>gru<p>pe,--'e~n~-mec<T>~ aliphatic mono- or dicarboxylic acids with 2 to 6 C atoms acylated hydroxy group, a low molecular weight alkoxy group, a low molecular weight alkyl group , a benzyl group^and Z means a nitrogen atom or the group MO., and Rcj means a hydrogen atom, a low molecular weight alkyl group optionally substituted by a cycloalkyl residue with 3 to 6 carbon atoms, a low molecular weight alkenyl group, a low molecular weight hydroxyalkyl group, an aliphatic acyl group with 2 to 6 carbon atoms, an optionally' at nitrogen with low molecular weight alkyl residues mono- or doubly substituted aminoalkyl group with 2 to 7 carbon atoms, 2 alkyl residues together with the nitrogen atom can also form the piperidine or morpholine ring, and A means an oxygen or sulfur atom or an imino or alkylimino group with 1 to 6 C atoms, the group =N-NHRg», where Rg means a lower aliphatic acyl group or two hydrogen atoms, the grouping -N (R,- )-C- ( = A) - can also exist in the tautomeric form -N = C(ARO- and their salts, characterized in that either a) when A is 0, R^ has the above-mentioned meaning and R^ is hydrogen, low molecular weight alkyl or benzyl group^ optionally with the addition of an acid-binding agent, a compound of formula is condensed: in which the symbols R-^ to R^ have the above meaning and W either means an oxygen atom or the group =NH resp. =N0H with a compound of the general formula in which Rjj' is hydrogen, low molecular weight alkyl or a benzyl group and Ry means a hydroxy group, a halogen atom, a low molecular weight alkoxy group and X means an amino group which is optionally blocked or a halogen atom, while working in the presence of ammonia or an ammonia derivative, if W = 0 and X = Hal and optionally also treating the process products subsequently in an alkaline medium^or b) a compound of formula I, in which A means an oxygen atom and the other symbols have the indicated meaning, are reduced to a compound in which A means two hydrogen atoms or reacted with phosphorus pentasulphide to a compound of formula I, in which A means sulfur or a compound of formula I in which A means oxygen or sulfur and the other symbols have the indicated meaning, is reacted with ammonia or an alkylamine with 1 to 6 C atoms or a hydrazine of formula H^N-NHRg to a compound of formula I, in which A means an imino or alkylimino group or the group =N-NHRg or a compound of formula I is alkylated in the 1- and/or 3-position or by means of aliphatic acids with 2 to 6 carbon atoms or their derivatives are acylated in the 1- and/or 3-position or a compound of formula I, in which Z represents a nitrogen atom and the other symbols have the indicated meaning, are oxidized with hydrogen peroxide or organic peroxides to a compound of formula I, in which Z represents the group NO, or a compound of formula I, in which A means oxygen or sulphur, R^ means hydrogen and Z means the group NO is transferred by treatment with lower aliphatic acid anhydrides in compounds, in which Ri| means a hydroxy- or acyloxy group with 1 to 6 C atoms, the acyl group possibly being present being split off by saponification with dilute acids or basic substances or a compound of formula I, in which Z means the group MO and the other symbols have the indicated meaning, transferred with hydrogen in the presence of metallic hydrogenation catalysts or other common chemical deoxygenating agents to a compound of formula I, in which Z means a nitrogen atom, the basic amino groups in the reacting starting materials containing protective groups, and that one optionally transfers the formed compounds in their salts.