DE2421637A1 - NEW 6-AZA-1,4-BENZODIAZEPINE - Google Patents

Description

GERMAN GOLD AND SILVER SCIIEIDEANSTALT VORKALS ROESSLER 6 Frankfurt / Main, Weissfrauenstrasse 9

New 6-aza-1, ^ - benzodiazepine

The invention relates to new 6-aza-1H-1, ^ - benzodiazepines and 6-Aza-1,2-dihydro-3H-1, ^ - benzodiazepine of the general formula

in which the symbols

R _{1 is} a halogen atom,

R and R "which are the same or different, hydrogen, halogen atoms, the trifluoride group, the nitro group, the nitrile groups, alkyl groups with 1 to 6 carbon atoms or alkoxy groups with 1 to 6 carbon atoms,

Rr is a hydrogen atom, a Plydroxygi'uppe, an alkyl • group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms, an öax-bamoyloxy group (H NCO-O-) or a carbamoyloxy group represented by saturable or unsaturated alkyl radicals with 1 to 6 carbon atoms or a cycloalkyl group with 3 to 6 carbon atoms is substituted,

409848/1077

a nitrogen atom or the group ^ NO

R_ is a carbamoyl group, thiocarbamoyl group or a carbamoyl or thiocarbamoyl group,. which is substituted by saturated or unsaturated alkyl radicals with 1 to 6 carbon atoms or a cycloalkyl group with 3 to 6 carbon atoms and

A is an oxygen or sulfur atom or the group

^ N-R mean, where R is an ¥ hydrogen atom or a Is an alkyl group with 1 to 6 carbon atoms and the grouping -C (SA) -CHRj, - also in the isomeric or tautomeric form -C (AR.) = CH- are present can

and their salts.

The halogen atoms is chlorine, fluorine, bromine, preferably chlorine "in the abovementioned alkyl and Alkoxj groups If it is those having 1 to 6 carbon atoms, particularly 1 to h carbon atoms. The carbamoyl or thiocarbamoyl groups and the carbamoyloxy group can be substituted one or two times on the nitrogen by lower alkyl radicals which preferably contain 1 to k carbon atoms and, for example, can also contain a double bond. Examples of the meanings mentioned are: methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, mothoxy, ethoxy, xsopropoxy, butoxy, isobutoxy, tex * t-butoxy, amyloxy, hexyloxy. Examples of the cycloalkyl group are cyclopropyl and cyclohexyl groups.

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The compounds according to the invention have valuable pharmacodynamic properties Properties. For example, they have psychosedative and iris particular anxiolytic properties, In addition, there is also an anti-inflammatory effect.

The production can take place in a manner known per se by that he

a) a compound of the formula I in which R_ is a hydrogen atom means and the other symbols have the meaning given with a compound of the formula

N-X II

converts, in which X is the group -COCl, -COBr, the group -COOR ¹ , where R ^{1 is} a lower aliphatic alkyl radical (1 to 6 carbon atoms), a phenyl or benzyl radical, the group -CONHY, where Y is NO, Is NO ^ or an acyl radical, the group CON "or the group CO or CS, where in the latter case one of the substituents R or R _{1 is}

a D

falls and there is a double bond between the N atom and X. and R and R, hydrogen or alkyl groups with 1 to 6 carbon atoms or one of the radicals R or R, too

away

Cycloalkyl group. with 3 to 6 carbon atoms or

b) in a compound of the formula I, one or more dex ^% symbols R 1, R 1, A and Z are converted into other meanings corresponding to the formula I.

U 0 i. ' ^: 1 0 7 7

and optionally obtained by process a) or b) Compounds in which Rl is a hydroxyl group, these Hydroxy group allcylated or with a compound of formula II, wherein X, R and R. have the meanings given, acylated.

Process a) takes place, for example, in solvents or suspending agents, in particular dioxane, tetrahydrofuran, toluene, benzene, QC-methylnaphthalene, dimethylformamide, dimethyl sulfoxide, ice cream, water, chloroform and methylene chloride, at temperatures between 0 ° and 200 ° C , especially 20 to I5O ⁰ C. Optionally, the addition of basic substances, for example organic bases such as pyridine, trimethylamine Trialkylamiiic as dimethylaniline, ethylpiperidine or inorganic basic substances such as alkali hydroxides, alkali carbonates, alkali hydrogen carbonates and so on appropriately. It is also possible that when using. Compounds of the formula II which contain halogen atoms, the corresponding hydrogen halide escapes in gaseous form during the reaction or optionally forms a salt with the end compound. If Y is an acyl radical, it is preferably a lower aliphatic acyl group (for example acetyl group) or a substituted lower aliphatic acyl group (for example 3'heiiylacetyl group).

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Compounds of the formula I in which Rk is an alkyl group or alkoxy group can be prepared from compounds of the formula I in which R. is H or 'OH, by alkylation. The alkylation is carried out, for example, by reaction with esters of the formula HaIR ", SO ₂ (OR") or ArSO ₂ OR ", where Hai is a halogen atom, in particular Cl, Br or I, and Ar is an aromatic radical (in particular one, optionally with one or more lower ones Alkyl radicals, substituted phenyl or naphthyl radical) and R ″ is an alkyl group with 1 to 6 carbon atoms. Examples are p-toluenesulfonic acid alkyl esters, lower dialkyl sulfates and the like. The alkylation reaction is carried out, optionally with the addition of customary acid-binding agents such as alkali metal carbonates, pyridine or other customary tertiary amines, at temperatures between 0 and 150 ° C. in inert solvents such as alcohols, dioxane, dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons such as benzene, toluene or acetone as well Mixtures of such solvents made.

For the alkylation by means of alkyl halides (for example iodides) in the presence of NaH, for example a mixture of toluene and a little dimethylformamide ($ 0.1 to $ 5, "for example $ 0.5) proved to be beneficial. In the alkylation, one can also proceed in such a way that only one of the compound I of the formula to be reacted, in which R ^ = H or OH, produces an alkali compound by placing it in an inert solvent such as dioxane, dimethylformamide, Benzene or toluene with an alkali metal, alkali hydrides or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 150 C and then add the alkylating agent.

According to process b), azabenzodiazepines of the formula I further implemented in a suitable manner. The group A in a compound of Fox-mel I can be in several ways be replaced. So, if A = oxygen, this can

409 8 48/1077

Atom replaced by a sulfur atom using phosphorus pentasulphide. This reaction takes place in inert solvents such as benzene, toluene, dioxane, pyridine or hydrochloric chlorides at temperatures between 0 and 150 C. 6 carbon atoms react, forming compounds of the formula I in which A is an imino or alkyliraino group. These reactions are for example in polar solvents such as methanol, ethanol or excess.
executed.

Schüssige amine, at temperatures between 0 and 150 ° C

By oxidation, for example, compounds can be obtained in which R. is a hydroxyl group. To do this will be Compounds of the formula I in which Rr is an hydrogen atom means in inert solvents such as dilute acetic acid, ethyl acetate, acetone with hydrogen peroxide, Peracetic acid or another common organic peracid implemented. The temperatures are preferably here between -10 and + 100 ° .C,

Preliminary bonds of the formula I in which R. is a carbamoyloxy group (in particular a substituted) 1st can also be obtained by adding compounds I in which R = II and Z = ^ NO in inert solvents such as dioxane, tetrahydrofuran, dimethylformamide, Reacts dimethyl sulfoxide with a compound of formula II. A rearrangement occurs after which the The oxygen atom in the N position is now on the neighboring C atom

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2A21637

»
Forms hydroxyl group. This rearrangement takes place at temperatures between 0 and 150 ° C., in particular 0 to 100 ° C. An excess of component II can also act as a solvent. . ■

Compounds of the formula I in which Z is a nitrogen atom can be converted into the corresponding N-oxides. The reagents and conditions are analogous to those for the hydroxylation of Rj ,. The temperatures are generally somewhat lower, preferably at 0 and 50 C.

In compounds of the formula I in which Z is the group = N0, the oxygen atom can be removed by catalytic hydrogenation or chemical de-oxygenation. As catalysts for the catalytic hydrogenation, for example, the usual metallic hydrogenation catalysts are suitable, especially precious metal catalysts (palladium / carbon, platinum) or Raney nickel; Solvents are mainly lower alcohols, the temperatures are between 0 and 200 ° C (preferably between 0 and 100 ° C). If necessary, it can be under pressure up to 50 atmospheres can be worked. For chemical de-oxygenation phosphorus dichloride or dimethyl sulfoxide are preferably used in inert solvents such as dioxane, benzene or toluene at temperatures between 0 and 150 ° C., preferably .0 to 100 ° C.

In compounds of the formula I in which II _{r is} a thiocarbamoyl group, the sulfur can be replaced by oxygen. This conversion of the sleep atom can be done, for example

^ - · / 1 07 7

Treating the thiourea at a temperature between 0 and about 250 ° C, preferably 0 to 100 C or also 0 to 50 ° C with 1 to 5 moles of potassium ferricyanide, iron (Hl) chloride, Potassium permanganate, potassium chlorite, potassium chlorate, Potassium hypochlorite, heavy metal oxides such as lead oxide, mercury oxide or peroxides such as hydrogen peroxide, sodium peroxide, peracetic acid and similarly acting, expediently in the presence of a solvent. The solvent can be water, methanol, ethanol, propanol, Use tetrahydrofuran, dioxane, dimethylformamide, acetone or mixtures of these agents (especially with water).

Furthermore, compounds of the formula I in which R is the OH group can be reacted with compounds of the formula II under the conditions of process a) or compounds in which Rj is H or the OH group can be reacted as indicated above by alkylation be converted into compounds in which R · is an alkyl radical or alkoxy radical. The alkylation is carried out, for example, by reaction with esters of the formula HaIR ", SO ₂ (OR") or ArSO ₂ OR ", where Hai is an ilalogen atom, in particular Cl, Br or I, Ar is an aromatic radical (in particular one optionally with one or more lower ones Alkyl rust substituted phenyl or naphthyl radical} and R "is an alkyl group with 1 to 6 carbon atoms. Examples are p-toluenesulfonic acid alkyl esters, lower dialkyl sulfates and the like. Pyridine or other customary tertiary amines, at temperatures between 0 and 150 ° C in inert solvents such as alcohols, dioxane, dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons

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such as benzene, toluene or acetone and mixtures of such solvents.

For alkylation using alkyl halides (for example Iodides) in the presence of NaH, for example a mixture of toluene and a little dimethylformamide (θ, 1 to 5 $ » for example $ 0.5) has proven to be cheap. In the alkylation, one can also proceed in such a way that only one of the compound I of the formula to be reacted, in which R ^ = H or OH, produces an alkali compound by placing it in an inert solvent such as dioxane, dimethylformamide, Benzene or toluene with an alkali metal, alkali hydrides or alkali amides (especially sodium or sodium compounds) at temperatures between 0 and 15O C converts and then add the alkylating agent.

Basic compounds of the general formula I can according to known methods can be converted into the salts. as Anions for these salts are the known and therapeutically useful acid residues.

The free bases can be prepared again in the usual way from the salts of the compounds, for example by treating a solution in an organic agent such as Alcohols (methanol) with soda or caustic soda.

Those compounds of formula I that are asymmetrical Containing carbon atoms - and usually as racemates can arise in a manner known per se, for example with the aid of an optically active acid, into the optically active one Isomers are split. “But it is also possible from to use an optically active starting substance from the start, a corresponding optically active or diastereomeric form is then obtained as the end product.

IO

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The compounds according to the invention are suitable for the production of pharmaceutical compositions. The pharmaceutical compositions or medicaments can contain one or more of the compounds according to the invention or else mixtures thereof with other pharmaceutically active substances. The usual pharmaceutical carriers and auxiliaries can be used to produce the pharmaceutical preparations. The drugs can be used enterally, parenterally, orally or perlingually. For example, administration in the form of tablets, capsules, pills, dragees, suppositories, ointments _f jellies, creams, powders, liquids, dusts or aerosols powder can take place. Examples of liquids that can be used are: oily or aqueous solutions or suspensions, emulsions, injectable aqueous and oily solutions or suspensions.

For example, such compounds come from the general. Formula I into consideration, in which the symbols R ₁ to R ^ and A and Z have the following meanings:

R ₁ : chlorine.

R ₂ : fluorine, chlorine, CF_ or alkyl groups with 1 to 3 carbon atoms, in particular the methyl group, in each case preferably in the o- or p-position, hydrogen; in particular H, fluorine or chlorine, where • o-position is preferred.

R ~: hydrogen, also fluorine or chlorine, the o-position is preferred.

11

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2A21637

R ^: hydrogen or an alkyl group with 1 to 6 carbon atoms, in particular with 1 to 3 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutylj tertiary butyl or a hydroxy group or the alkylcarbamoyloxy group with 1 to k C- Atoms, but especially hydrogen. ·

R_: The ethylaminocarbonyl group, the dimethylamino, Diethylamirio or Dipropylaminocarbonylgruppe or the Allylaminocarboxylgruppe.

A: Oxygen in particular, and also sulfur or imino or alkylimino with 1 to 6 carbon atoms, for example methylimino, 'atbylimino, fropylimino, Butylimino, hexyliinino.

Z: nitrogen.

Compounds of the formula I in which R is chlorine, R ₀ and R, are identical or different and are hydrogen, fluorine and chlorine, preferably in the o-position, A is an oxygen atom and Z is a nitrogen atom, R is hydrogen, have a particularly favorable effect or a HydroX3 ^r gx group and H _{1 represents an} ethylaminocarbonyl or an allylaminocarbonyl group.

The starting materials required for process a) can be found in accordance with the German Offenlegungsschrift 2 259 specified method can be obtained.

12th

AO9848 / 1077

The compounds of the invention are pharmaceutical for the manufacture Compositions and preparations suitable. The pharmaceutical compositions or drugs contain as active ingredient one or more of the invention Compounds, optionally mixed with other pharmacologically or pharmaceutically active substances. The production the medicament can be made using the known and customary pharmaceutical auxiliaries as well as other customary Carriers and diluents take place.

Such carriers and auxiliaries are such. B. those substances in question, which are recommended or indicated in the following literature as auxiliaries for pharmacy, cosmetics and related areas: Ullmanns Encyklopädi.e der technischen Chemie, Volume k (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 and ff., HvCzetsch-Lindenwald, auxiliaries for pharmacy and related areas; Pharm. Ind., Heft 2, I96I, page 72 and following, · Dr. II. P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas Cantor KG. Aulendorf i. Württ. 1971.

Examples are gelatine, natural sugars such as cane sugar or milk sugar, lecithin, pectin, starch (for example Mäisstäx-ke), Tylose, talc, Lycopodium, silicic acid (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers, in which the cellulose Hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols, for example methyl-oxypropylce.1-lulose), stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially the saturated ones (for example stearates ), Emulsifiers, oils and fats, especially vegetable (for example peanut oil, castor oil, olive oil, sesame oil, whole tree seed oil, corn oil, mono-, di- and triglycerides of saturated fatty acids ^c -j2 ^H 2ii ° 2 ^{to C} 18 ^H 36 ° 2 ^and mixtures ^thereof), pharmaceutically acceptable mono- or polyhydric alcohols

13th

^ -J / 1077

and polyglycols such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols such as glycols, glycerol , Diethylene glycol, pentaerythritol, sorbitol, mannitol and so on, which can optionally also be etherified, benzyl benzoate, "dioxolanes, glycerol forraals, glycolfurols, dimethylacetamide, lactainides, lactates, ethyl carbonates, silicones (especially medium viscosity dimothy! Polysiloxanes) and the like.

For the preparation of solutions, for example, water or Physiologically compatible organic solvents in question, such as, for example, ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethyl sulfoxide, fatty alcohols, triglycerides, Partial esters of glycerol, paraffins and the like.

Known and customary solubilizers can be used in the production of the preparations. As solubilizers, for example, in Frag « ¹ 1 there are polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolized oleotriglycerides. Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, building wool seed oil, corn oil (see also Dr, HPFiedler "Lexicon of auxiliaries for pharmacy, cosmetics and adjacent areas 1971, pages 191 to 195). Polyoxyethylated here means that the substances in question contain polyoxyethylene chains , the degree of polymerization of which is generally between 2 and 1/10 and in particular between 10 and 20. Such polyoxyethylated substances can be obtained, for example, by reacting the corresponding glycerides with ethylene oxide (for example, kO moles of ethylene oxide per mole of glyceride).

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In addition, the addition of preservatives, Stabilizers, buffer substances, flavor corrections, antioxidants and complexing agents (e.g. ethylenediaminetetraacetic acid) and the like possible. If necessary, "with" is used to stabilize the active ingredient molecule Adjust physiologically compatible acids or buffers to a pH range of approx. 3 to 7. In general a neutral to slightly acidic (up to pH 5) pH preferred.

Sodium metabisulphite, for example, can be used as antioxidants, Ascorbic acid, gallic acid, gallic acid alkyl ester, butylhydroxyanisole, Nordihydroguajaretic acid, tocopherols and tocopherols + 'Synergists (substances the heavy metals through complex formation bind, for example lecithin, ascorbic acid, phosphoric acid) for use. The addition of the synergists increases the antioxidant effect of tocopherols is considerable. _ Sorbic acid, for example, are used as preservatives, p-Hydroxybenzoic acid ester (for example lower alkyl ester), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, Cresol, benzethonium chloride and formalin derivatives are possible.

The pharmacological and galenical handling of the invention Connections are made according to the usual standard methods. For example, active ingredient (s) and Auxiliary or carrier materials by stirring or homogenizing (for example using colloid mills, Ball mills) well mixed, generally at temperatures between 20 and 80 ° C, preferably 20 to 50 ° C is worked.

The drugs can be used, for example, orally, parenterally, can be used rectally, vaginally, perlingually or locally.

The addition of other active pharmaceutical ingredients is possible.

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The compounds according to the invention show in the fight test Tedeschi (mouse) and in the motility test on the. Mouse in Ring cage according to F. Heim a good anxiolytic and calming Effect. "·

This effect is comparable to the effect of the well-known drug diazepoxide. ._

The lowest effective dose in the animal experiment given above is

for example ' ' .

0.5 mg / kg orally '0.1 mg / kg sublingually 0.05 mg / kg intravenously

A possible general dose range for effect (animal experiment as above) is, for example:

0.5-10 mg / kg orally 0.1-2 mg / kg sublingually 0.05-1 mg / kg intravenously

Indications for the compounds according to the invention in The following can be considered:

Anxiety, tension and calm, vegetative dystonia, Nervousness, irritability, mood lability, stage fright, weather sensitivity, behavioral and adjustment disorders Children, functional cardiovascular, gastrointestinal and respiratory complaints. For menstrual and climacteric Disruptions. Before surgical interventions. In obstetrics

ZZ '.-Γ. / 107-7-

The pharmaceutical preparations generally contain between 1 and 10% of the active component (s) according to the invention.

The administration can take the form of tablets, capsules, pills, coated tablets, suppositories, ointments, jellies, creams, powders, liquids, dust powders or aerosols.As liquids, for example: Oily or aqueous solutions or suspensions ionenj ^^ ulsionen ^ Preferred forms of application are tablets which contain between 1 and 50 mg or solutions which contain between 0.1-5 $ of active substance.

The single dose of the active components according to the invention can be, for example

a) for oral medicine fountains between 1-50

mg

b) with parenteral dosage forms (for example intravenous, ■ intramuscular) between 0.1-5 mg

c) for dosage forms for inhalation (solutions or aerosols) between _0.5 - 10 mg

d) for drug forms for rectal or vaginal application between ι - ₅₀ mg

- (The doses are based on the free base) -

17th

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For example, 1 to 3 tablets can be used 3 times a day a content of 1 to 50 mg of active substance or, for example, with intravenous injection 1 to 3 times a day an ampoule of 1 to .2 ml Contents with 0.1 to 10 mg of substance are recommended. In the case of oral administration, the minimum daily dose is, for example, 3 mg; the maximum daily dose should not are over 200 mg. . '

For the treatment of dogs and cats, the single oral dose is recommended generally between approximately 0.5 and 5 ° mg / kg body weight j the parenteral dose approximately between and 0.1-10 mg / kg body weight »

For the treatment of horses and cattle, the oral single dose is generally between about 5 and 10 ° mg / kg, the parenteral single dose between about 1 and 20 mg / lig of body weight, ·· "" ■ "

The acute toxicity of the compounds according to the invention in the mouse (expressed by the LD 50 mg / kg; Miller and Tainter method: Proc. Soc. Exper * Biol. A. Med. 5J £ (19hh) 26Ί) is between, for example, when administered orally 500 and ίο 000 mg / kg (or above 8000 mg / kg.

The drugs can be used in human medicine, veterinary medicine and in agriculture alone or in a mixture used with other pharmacologically active substances.

984871077

example 1

? -1, 2-dihydro-

3H-1 t 4-benzodiazepin-one- (2)

C3T ^ N

A mixture of 13.5 S (θ »Ο5 mol) 5-phenyl-6-aza-7-chloro-1,2 · dihydro-3H-1» 4-benzodiazepin-one- (2), 200 ml tetrahydrofuran and hO ml of ethyl isocyanate is boiled for 8 hours with stirring and under reflux, then another 10 ml of ethyl isocyanate are added twice at intervals of 4 hours and the mixture is further boiled. The solution is evaporated in vacuo and the syrupy residue is recrystallized from a little n-propanol.
Yield 6.5 g, mp 127 ° C.

Example 2

1-ethylaminocarbonyl-3-hydroxy-5- (o-ch.lorxjhenyl) -6-aza-7-chloro-1,2-dihydro-3H-1 , 4-benzodiazepin-one- (2)

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A mixture of 13 g of 3-hydroxy-57 (o-chlorophenyl) -6-aza-7-chloro-1, 2-dihydro-3H-1, 4-benzodiazepin-one- (2). _f 100 ml of tetrahydrofuran and HO ml of ethyl isocyanate is refluxed under nitrogen for one hour. The mixture is evaporated in vacuo and the solid residue is recrystallized from n-propanol. ·
Yield 11.5 S, F · 259 t> is 2.63 ° G (decomposition).

Example 3

1-Allylaminocarbonyl ^ -phenyl-o-aza-Y-chloro-i, 2-dihydro 311-1, 4-benzodiazepin-one- (2)

■ HN-CH ₂ -CH = CIIj

A mixture of 13 »5 e 5-I * henyl-6-aza ~ 7-chloro-1,2-dihydro-3" H-1, ^ -benzodiazepine-oii- (2), 100 ml tetrahydrofuran and ^ O ml Allyl isocyanate is refluxed for 4 hours under nitrogen with stirring, then another 10 ml of allyl isocyanate are added and boiled for a further 30 minutes. After cooling, the desired compound slowly crystallizes out. It is filtered off with suction and recrystallized from ethanol.
Yield 3.2 g, mp 137-139 ° C.

20th

1077

example H

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

HN-C ₂ H ₅

A mixture of 20 g of 5- (o-fluorophenyl) -6-aza-7-chloro-1 _t 2-dihydro-3H-1,4-benzodiazepin-one- (2), 50 ml of ethyl isocyanate and 100 ml of tetrahydrofuran are 8 boiled under stirring and reflux for hours, then again added 10 nil ethyl isocyanate · and continued boiling h hours. The compound crystallizes out on cooling. Yield 9.5 g »F. 119 to 121 ° C.

21

£ 09848/1077

Example 5

1 _ (Cycloliexylaminocarbonyl) -5-plienyl-6-aza-7-chloro-1 > 2-dihydro-3H-1,4-benzodiazepinone- (2).

A mixture of 20 g of 5-phenyl- * 6-aza-7-chloro-1, 2-dihydro-3H-1, k benzodiazepinone- (2), kO ml of cyclohexyl isocyanate and 100 ml of tetrahydrofuran is refluxed for 6 hours with stirring , then 60 ml of tetrahydrofuran are distilled off and the mixture is refluxed for a further 5 hours. After cooling, the reaction product crystallizes out. It is uracrystallized from $ 0 inl dimethylformamide and 150 ml methanol. F. 252 ° C.

Example 6

1 - (Allylaminocarhonyl) -5- (o-fluorophenyl) -o-aza-7-chloro-i, 2-dihydro 3H-T, A-benzodiazepinone- (2).

HN-CH ₀ -CH = CH ₀

I ^{2 2}

I.
1 °

N C

A098 487107

A mixture of 20 g of 5- (o-fluorophenyl -) - 6-aza-7-chloro-1,2-dihydro-3H-1, Jj-benzodiazepinon- (2), ^ to ml of allyl isocyanate and 100 ml Tetrahydrofuran is refluxed for 7 hours. The reaction product crystallizes out on cooling. It will be with Washed ethanol. F. 138-1 ^ 0 ° C.

Example 7

1-Ethylaminocarbonyl ^ -hydroxy ^ - (o-chlorophenyl) -6-aza-7-chloro-1 , 2-dihydro-3H-1, '1-benzodiazepinone- (2).

HN-C ₂ H ₅

CO

j Ο

II HC-OH

A mixture of 13 g of 3-hydroxy-5- (o-chlorophenyl) -6-aza-J-chloro -1, 2-dihydro-3H-1 »^ -benzodiazepinone- (2), ^ to 0 ml of ethyl isocyanate and TOO ml of tetrahydrofuran is refluxed for 1 hour under nitrogen and with stirring. The mixture is carefully concentrated in vacuo and the residue is purified from n-propanol. F ". 259-63 ° C.

09848 / 1077- 23

Example 8

1-Ethylinocarbonyl - ^ - io-chlorophenylJ-o-aza-T-ch.lor-i, 2-dihydro-3H-1, ^ - benzodiazepinone- (2) -4-oxide

HN-C _O H _C , 2 5-

20 g of 5- (o-chlorophenyl) -6-aza-7-chloro-1,2-dihydro-3H-1,4-benzodiazcpiiion- (2) -A-oxide uez'den in 50 ml of ethyl isocyanate for 8 hours with stirring heated to reflux. The cooled mixture was initially mixed with 100 ml of gasoline each time, removed from the syrup which had precipitated, and the desired substance slowly crystallized out after the last gasoline addition. 129 ° C.

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Zh

Claims (6)

2k Claims 6-Aza-1H-1, ^ - benzodiazepines and 6-Aza-1,2-dihydro-3H-1, k benzodiazepines of the general formula voi'iii the symbols R _{1 is} an Ilalogenatom, R and R "which are the same or different, hydrogen, halogen atoms, the trifluoromethyl group, the nitro groups the Nitrj lgx ^ uppe, alkyl groups with 1 to 6 carbon atoms or alkoxy groups with 1 to 6 carbon atoms, Rk a liasserstoffatom, a LLJ ^r droxygruppe _f • an alkyl group having 1 to 6 carbon atoms, an alkoxy group having. 1 to 6 carbon atoms, an oarbamoyloxy group (iI-NCO-O-) or a carbamoyloxy group which is substituted by saturated or unsaturated alkyl radicals with 1 to 6 carbon atoms or a cyclocilkyl group with 3 to 6 carbon atoms, 409848/1077 a nitrogen atom or the group ^ R_ a carbamoyl group, thiocarbamoyl group or a carbamoyl or thiocarbamoyl group, that by saturated or unsaturated alkyl radicals with 1 to 6 carbon atoms or a cycloalkyl group is substituted by 3 to 6 carbon atoms and A is an oxygen or sulfur atom or the group / N-R, where R is an ¥ hydrogen atom or is an alkyl group with 1 to 6 carbon atoms and where the grouping -C (= A) -CHRr- is also in the isomeric or tautomeric form -C (ARjl) = CH- are present can and their salts. 2. Compounds of formula I in which R _{1 is} chlorine, A is an oxygen atom, Z is a nitrogen atom or the group NO, R ~ is hydrogen, R "is hydrogen, chlorine, fluorine, bromine or the trifluoromethyl group and R. is hydrogen or the hydroxyl group and R_ denotes the carbamoyl group, a carbamoyl group which is substituted by saturated alkyl radicals having 1 to f> carbon atoms, a carbamoyl group having an unsaturated alkyl radical having 3 to 6 carbon atoms or a carbamoyl group having a cycloalkyl group having 3 to 6 carbon atoms. 3. Compounds of the formula I in which R _{1 is} chlorine, A is oxygen, Z is nitrogen or NO, R _{2 is} hydrogen, R, hydrogen and R ^ is hydrogen and R is either a carbamoyl group or a methylcarbamoyl group or an ethylcarbamoyl group or a 26th 409848/1077 ■ Propylcarbamoyl group or an isopropylcarbamoyl group or a butylcarbamoyl group or an isobutylcarbamoyl group or a tert-butylcarbamoyl group or a Pentylcarbamoyl group or a methylbutylcarbamoyl group or a hexylcarbamoyl group or a methylpentylcarbamoyl group or an allylcarbamoyl group or a butenyicarbamoyl group or a pentenylcarbamoyl group or a hexenylcarbamoyl group or a thiocarbamoyl group or a methylthiocarbamoyl group or an ethylthiocarbamoyl group or a propylthiocarbamoyl group or an iso- §
propylthiocarbamoyl group or a butylthiocarbamoyl group or an isobutylthiocarbainoyl group or a tert. Butylthiocarbamoyl group or a peiityltliiocarbamoyl group or a methylbutylthiocarbamoyl group or a hexylthiocarbamoyl group or a methylpentylthiocarbamoyl group or an allylthiocarbainoyl group or a butenylthiocarbamoyl group or a salarylthiocarbamoyl group or a pentenylthiocarbamoyl group. 4. Compounds of the formula I in which R is chlorine, A is oxygen, Z nitrogen or NO, R chlorine, R hydrogen and R. Is hydrogen and R_ is either a carbamoyl group or a methylcarbamoyl group or an ethylcarbamoyl group or a propylcarbamoyl group or an isopropylcarbamoyl group or a butylcarbamoyl group or an isobutylcarbamoyl group or a tert-butylcarbamoyl group or a pentylcarbamoyl group or a methyIbutylcarbainoylgruppe or a hexylcarbamoyl group or a methylpentylcarbamoyl group or an allylcarbamoyl group or a butenylcarbamoyl group or a pentenylcarbamoyl group or a hexenylcarbamoyl group or a thiocarbamoyl group or a methylthiocarbamoyl group or an ethylthiocarbamoyl group or a propylthiocarbamoyl 409848/1 077 27 - group or an isopropylthiocarbamoyl group or a Butylthiocarbamoyl group or an isobutylthiocarbamoyl group or a tert-butylthiocarbamoyl group or a pentylthiocarbamoyl group or a methylbutylthiocarbamoyl group or a hexylthiocarbamoyl group or a Methyl / pentylthiocarbamoyl group or an ally / thiocarbamoyl group or a butenylthiocarbamoyl group or a pentenylthiocarbamoyl group or a hexenylthiocarbamoyl group is and their salts. 5 Compounds of the formula I in which R _{1 is} chlorine, A is oxygen, Z is nitrogen or NO, R _{2 is} fluorine, R is hydrogen and Rj is hydrogen and R_ is either a carbamoyl group or a methylcarbamoyl group or an ethylcarbanioyl group or a propylcarbamoyl group or ^{1 is} an isopropylcarbalnoyl group or a Butylcarbamoylgruppe or an isobutylcarbamoylgruppe or a tert. Butylcarbaraoyl group or a pentylcarbainoyl group or a methylbiitylcarbainoyl group or a hexylcarbaraoyl group or a methylpentylcarbamoyl group or an illylcarbainoyl group or? a butenylcarbamoyl group or a pentenylcarbaiaoyl group or an ilexenylcarbamoyl group or a thio ~ carbamoyl group or a methylthiocarbamoyl group or an ethylthiocarbamoyl group or a propylthiocarbamoyl group or a propylthiocai-banoylthio group or a iso-carbamoutylthio group or a tertio-carbamoutylthio-banoylthio or a biocarbamoutylthio group or a biocarbamoutylthio-iso-carbamoutylthio group or a iso-carbamoutylthio group or a biocarbamoutylthio-group or an isobamoylthio Butylthiocarbamoylgrnppe Odei "a Pentylthiocarbaraoylgruppo or Methj'lbutylthiocarbamoylgruppc or HexylthiocarbamoyJ group or a Me thy Ip en ty 1 thi ο c arb aino3 ^r lci * upp e or e ine Al iyi thi ο c ίΐι> · bainoylgruijpe or Butenyltljiocarbaiuoylgruppe or Pentenylthiocarbaraoyl group or a hexenylthiocarbamoy group and their salts. '409848/1077 - 20 - 6. Compounds of formula I wherein R. chloro, A is oxygen, Z is nitrogen or NO, R ₂ is a trifluoromethyl group, R "is hydrogen and R. is hydrogen and R _1, either a carbamoyl group or a methylcarbamoyl group or an Äthylcarbai2io} ^r lgruppe or a Px-opylcarbaiiioylgruppe or an isopropylcarbamoylgruppe or a butylcarbamoylgruppe or an IsobutyXcarbamoyXgruppe or a tert. Butylcarbanioylgruppe or Pentylcarbanioylgruppe or Methylbutylcarbamoylgruppe or Hexylcarbamo} ^r lgruppe or Methylpentylcarbamoylgruppe or Allylcarbainoylgruppe or Buteriylcarbainoylgruppe or Pentenylcarbamoylgi-upjje or Hexenylcarbamoylgrupi> e or Thxocax "bamoylgruppe or opyltliiocarbamoylgruppe a Metliylthiocarbamoylgruppe or Äthylthiocarbamoylgruppe or Pz ^ or Isopropylthiocarbamoylgruppe or Butylthiocarbamoylgruppe or Jsobutylthiocarbamoylgruppe or a tert. Butylthioearbamoylgruppe or Pentylthiocarbamoylgruppe or Methylbutylthiocarbamoylgruppe or HexylthiocarbanK ^ lgruppe or Methylpentylthiocarbamoylgruppo or Allylthiocarbamoylgi'uppe or Butenyltliiocarbainoylgruppe or Pentenyithiocarbaiüoylgruppe or Ilexenylthiocai-bamoylgi'uppe is and salts thereof. 7. Compounds of the formula I in which R _{1 is} chlorine, A is oxygen, Z is nitrogen or NO, R is a methyl group, ethyl group or propyl group, II is hydrogen and I is hydrogen and R is either a carbamoyl group or a methyl carbamoyl group or an ethyl carbanioyl group or a propylcarbauioyl group or an Is.opropylc.arba · moylgi group or a butylcarbamoyl group or an isobutyloai'bamo3 "" I group or a tert. ButylcarbamoyXgruppo or a PentyXcax-bamoylgruppe or a Methylbutylcarba- - 29 Λ09848 / 1077 moyl group or a hexylcarbamoyl group or a methyl pentylcarbamoyl or Allylcarbamoylgruppe or butene ylcarbamoylgruppe or Pentenylcarbamo) ^r lgruppe or Ilexenylcarbamoylgruppe or a thiocarbamoyl group or a Methylthiocarbamoylgruppe or Äthyltliiocarbamoylgruppe or Propylthiocarbamoylgruppe or Isopropylthiocarbamoylgruppe or Butylthiocarbamoylgruppe or Isobutylthiocarbamoylgruppe or a tert. Butyl thio carbamo3 ^r lgruppe or a Pentylthiocarbamoylgruppe or Mcthylbutylthiocarbamoylgruppe or Hexylthiocarbarnoylgruppe or Metliylpentylthiocarbamoylgruppe or Allylthiocarbamoylgruppe or Butenylthiocarbamoylgruppe or Pentenylthiocarbamoylgruppe or Hexenylthiocarbamoylgruppe and their salts ·. 8. Compounds of the formula I in which R _{1 is} chlorine, A is oxygen, Z is nitrogen or KO ₁ R _{2 is} hydrogen, R "is hydrogen and R. is a hydroxy group or methoxy group or ethoxy group and R_ is either a carbamoyl group or a metliylcarbamoyl group or an Ätliylcarbanioylgruppe or a propylcarbamoyl group odor an isopropylcarbanioyl group or a butylcarbauioyl group or an isobutylcarbanioyl group or a tert. Butylcarbamoyl group or a pentylcarbamoyl group or a methylbutylcarbamoyl group or an ilexylcarbamoyl group or a methylpeiitylcax-bamoyl group or an allylcarbamoyl group or a. Butenylcarbamoyl group or a Pontoiiylcarbainoylgruppe or a Hexenylcarbarnoylgupiie or a Thiocarbamoylgruppe or a Methylthiocarbamoylsruppe or an Ethylthiocarbamoy! Group or a Propylthiocarbanc} 1- 30th A098A8 / 1077 group or an xsopropylthiocarbamoyl group or a butylthiocarbamoyl group or an isobutylthiocarbamoyl group or a tert. Butylthiocarbamoyl group or a pentylthiocarbamoyl group or a methylbutylthiocarbamoyl group or a hexylthiocarbamoyl group or a methylpentylthiocarbamoyl group or an allylthiocarbamoyl group or a butenylthiocarbamoyl group or a pentenylthiocarbamoyl group or a pentenylthiocarbamoyl group thereof. Compounds of the formula I, above R _{1 is} chlorine, A is oxygen, Z is nitrogen or NO, R _{2 is} chlorine, R is hydrogen and R is a hydroxyl group or methoxy group or ethoxy group and R is either a carbamoyl group or a methylcarbamoyl group or an ethylcarbanioyl group or a pi "opylcarbamoyl group :) e odor a ISOPROX ^ ylcarbamoylgruppe or a butylcarbamoyl group, or an iso ~ ^r butylcarbamo3 lgruppe or tei't But'ylcai-bamoylgrupije or Pentylcarbanioylgruppe or Methylbutylcarbamoylgruppe or Hexylcarbamcylgriippe or Methylpentylcarbamoylgx-uppe or an Al ^ lcarbamoylgruppe or. Butenylcarbamoylgruppe or Peiitenylcarbamoylgruppe or Hexenylcarbamojdgruppe or odor Th.iocarbamoylgruppe a Methylthiocarbainoylgruppe or ethyl thiocarbamoyl odeir a Propylthiocarbariioylgruppe or Isopropylthiocar "batiiO3 ^r lgruppe or Butylthiocarbamoylgruppe or Isobutylthiocarbamoylgruppe or te rt. Butylthiocarbamoyl group or a pentylthiocarbamoyl group or a methylbutylthiocarbamoyl group or a hoxylthiocarbamoyl group or a methylpentyl thiocarbamoyl group or an allyl thiocarbamoyl group or a butamozeyl thiocarbamoyl group or a butamozeyl thiocarbamoylthiocarbamoyl group or a hexa-carbenyl thiocarbamoyl group or a hexa-carbamoyl group thereof. 31 409848/1077 10, compounds of the formula I in which B _{1 is} chlorine, A is oxygen, Z is nitrogen or NO, R 1 is fluorine, R 1 is hydrogen and R. is an Ilydroxy group or a methoxy group or ethoxy group and R is either a carbamoyl group or a methyl alcohol ! group or an Äthylcarbainoylgruppe or "a Propylcarbaiaoylgrupx ^ e orei" an isopropylcarbamoylgruppe or a butylcarbaruoylgruppe or an isobutylcarbamoylgruppe or a tert. Butylcarbamoyl group or a pentylcarbamoyl group or a methylbutylcarbamoyl group or a hexylcarbamoyl group or a methylpentylcarbamoyl group or an allylcarbamoyl group or a butenylcarbamoyl group or a pentenylcarbamoylgroup or a gamoocylcarbiocyl group or a gamoocylcarbiocyl group or a methylamoocarbamoylcarbiotyl group or a hexenylcarbamoyl-oarbamoyl group or a hexenylcarbamoyl-oarbamoyl-group or a methyl-o-benzamoylarbi a propylthiocarbanioyl group or an isopropylthiocarbanioyl group or a butylthiocarbamoyl group or an isobutylthiocarbanioyl group or a tert. Butylthiocarbamoyl group or a pentylthiocarbamoyl group or a methylbutylthiocarbamoyl group, or a llexylthiocarbamoyl group, or a methylpentylthiocarbanioyl group or an allyl thiocarbamoyl group or a butenylthiocarbamoyl group or a butenylthiocarbamoyl group or a butenylthiocarbamoyl group or a butenylthiocarbamozeyl group or a butenylthiocarbamamoyl group or a butenylthiocarbamamoyl group or a hexylthiocarbamoyl group. . Compounds of the formula I in which R. is chlorine, A is oxygen, Z nitrogen or NO, R "a trifluoromethyl group, R" hydrogen and Rl is a hydroxy group or methoxy group or ethoxy group and JR is either a carbamoyl group or .4.09848 / 107 a methylcarbamoyl group or an ethylcarbamoyl group or a propylcarbamoyl group or an isopropylcarbamoyl group or a butylcarbamoyl group or an isobutylcarbamoyl group or a tert. Butylcarbamoyl or Pentylcarbamo) ^r lgruppe or Methylbutylcarbamoylgruppe or hexylcarbamoyl or Methylpentylcarbamoylgruppe or Allylcarbamoylgruppe or Butenylcarbainoylgruppe or Pentenylcarbamo} ^r lgruppe or Hexenylcarbamoylgruppe or Tliiocarbamoylgruppe or Methylthiocarbarnoylgruppe or Ätliyltliiocarbamoylgruppe or Propyltliiocarbamoylgruppe or Isopropyltbiocarbamoylgruppe or Butyltlxiocarbamoylgruppe or an isobutylthiocarbamoyl group or a tert. Butylthiocarbamoyl group or a pentylthiocarbanioyl group or a methylbutyltniooarbamoyl group or * a hexylthiocarbamoyl group or a methylpentylthiocarbamoyl group or an allylthiocarbamoyl group or a "butenylthiocarbamoyl group or a" butenylthiocarbamoyl group or a salbanylthiocarbamoyl group or a salbanylthiocarbamoyl group. 12. Process for the preparation of 6-Aza-1H-1, 4-benzodlazepineii and 6-Aza-1, 2-dihydro-3H.-1, 4-benzodiazepines of the general formula £ 0984ü / 1077 in which the symbols R _{1 is} a halogen atom, R "and R", which are identical or different, hydrogen, halogen atoms, the trifluoronicthyl group, the nitro group, the nitro group, alkyl groups with 1 to 6 carbon atoms or alkoxy groups with 1 to 6 carbon atoms, Rj is a hydrogen atom, a hydroxyl group, an alkyl group with 1 to 6 C atoms, an alkoxy group with 1 to 6 C atoms, an Oarbamoyloxygruppe (11 _? NCO-O ~) or a Carbamoyloxygruppe, which is replaced by saturated or unsaturated alkyl radicals is substituted with 1 to 6 carbon atoms or a cyclotillcyl group with 3 t) is 6 carbon atoms » a nitrogen atom or the R is a-Cax-bamoyl group, Thiocai "banioy3.gi-uppe or a carbamoyl or thiocarbamoyl group, the saturated or unsaturated alkyl radicals with 1 to 6 carbon atoms or a cycloalkyl group is substituted by 3 to 6 carbon atoms and an oxygen, or Schv / ef elatom or the group N-R mean, where R is a hydrogenator or a Is an alkyl group with 1 to ό carbon atoms and v / ob ei the grouping ~ C (= A) -CIIRk- also in the isomeric Bezielxmigsiveise tautomsrcu form -C (ARi) = CH- are present can - 3h Λ098Α8 / 107 7 - 3k - and their salts, characterized in that one a) a compound of the formula I in which R_ is a hydrogen atom means and the other symbols have the meaning given with a compound of the formula N-X II converts, in which X is the group -COCl, -COBr, the group -COOIl ', where R ^{1 is} a lower aliphatic alkyl radical (1 to 6 carbon atoms), a phenyl or benzyl radical, the group -CONIIT, where Y KO, N0 _? or an Acylx ^% cst, the Gx group CON "or the Gx ^ group CO or CS, where in the latter case one of the substituents R odci" R, is omitted and there is a double bond between the N atom and X and R and R, hydrogen or alkyl groups with 1 to 6 carbon atoms mean "or one of the radicals R or R, too away Cycloalkyl group with 3 to 6 carbon atoms can be or b) in a compound of the * formula I, one or more of the * symbols R ^, R, A and Z are converted into other meanings corresponding to the formula I. and optionally obtained by process a) or b) Compounds in which R. is a hydroxoxy group, these Hydroxy group alkylated or with a Vcx'-bilide of the form.! II, wox-in X, Ii, and R, di'e have entered meanings, acylicrt-, £ 1 D 35 409848 / 1Q77 13. The method according to claim 2 and / or 3, characterized in that that the compounds obtained are converted into the salts. ■ 1 h. Medicament containing at least one compound according to one or more of the preceding claims. · Medicines, characterized in that there is at least one compound according to one or more of the as active ingredient Contains the above claims together with customary pharmaceutical carriers and / or diluents. 6. Vorfahreη for the production of a drug, characterized in that that at least one compound according to one or more of the preceding claims with customary pharmaceutical carriers or diluents is processed into pharmaceutical preparations. * Use of compounds according to one or more of the preceding claims for the production of medicaments. PL / Dr.Stm-he
29 · h.7h U 0 9 8 Iv 8/1 Ü 7 7