HK1006570B

HK1006570B - 1,7-fused 1h-indole-2-carboxylic n-(1,4-benzodiazepin-3-yl)-amides

Info

Publication number: HK1006570B
Application number: HK98105568.4A
Authority: HK
Inventors: Gregory Peter-Colin; Hamminga Derk; Van Wijngaarden Ineke; Wolf Klaus-Ullrich; Waldeck Harald; Benson Werner; Zeugner Horst
Original assignee: Solvay Pharmaceuticals Gmbh
Priority date: 1989-03-08
Filing date: 1998-06-17
Publication date: 1999-03-05

Description

The present invention relates to novel amides of 3-amino-1,4-benzodiazepine derivatives with 1,7-anelled 1H-indol-2-carbonic acid derivatives and their salts, and pharmaceutical preparations containing these compounds and processes for the manufacture of these compounds.

From EP-A-0 284 256, EP-A-0 167 919, US-A-4 628 084, Chem. Abstracts 105, 107 944z and Chem. Abstracts 109, 204 385h, 2-oxo-5-phenyl-1,4-benzodiazepine derivatives with CCK antagonistic effects are known in the 3-position substituted by acylamine residues.

Cholecystokinin (=CCK) is a peptide found in gastrointestinal tissue and the central nervous system with a wide spectrum of action, which among other things has stimulating effects on colonic motility, gallbladder contraction and exocrine pancreatic secretion and inhibitory effects on gastric emptying and also has an influence on appetite regulation.

The present invention is intended to develop new CCK antagonistic compounds with an improved profile of action.

The purpose of the invention is also to produce new derivatives of 1,7-anelled 1H-indol-2-carbon acids with valuable pharmacological properties.

It has now been found that the 1,7-anelled 1H-indol-2-carbonic acid-N- ((1,4-benzodiazepine-3-yl) amide CCK antagonist properties of the invention are characterized by a novel pharmacological profile of action with a pronounced stomach emptying component with good therapeutic range and low toxicity.

The present invention therefore relates to new 1,7-anelled 1H-Indol-2-Carboxylic Acid N- (1,4-benzodiazepine-3-yl) amide compounds of general formula I. (see formula I) In which R1 means hydrogen, halogen, alkyl with 1 to 4 carbon atoms or cycloalkyl alkyl with 4 to 7 carbon atoms,R2 means hydrogen, halogen, alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 5 carbon atoms or trifluoromethyl andR3 means hydrogen, halogen, alkyl with 1 to 5 carbon atoms or alkoxy with 1 to 5 carbon atoms orR2 and R3 are two adjacent carbon atoms bound together and together represent an alkyl group with 1 to 2 carbon atoms,R4 means cycloalkyl with 5 to 6 carbon atoms, thiophen or a substituted phenyl group, if any, (see formula a) whereinR7 means hydrogen, halogen, alkyl with 1-5 carbon atoms, alkoxy with 1-5 carbon atoms or trifluoromethyl andR8hydrogen, halogen, alkyl with 1-5 carbon atoms or alkoxy with 1-5 carbon atoms,R5 means hydrogen or halogen,R6 means hydrogen, halogen, alkyl with 1-5 carbon atoms, alkoxy with 1-5 carbon atoms or trifluoromethyl andZ means an alkyl chain with 2-4 carbon atoms, which may be monosubstituted or dissolved by an alkyl with 1-4 carbon atoms, or to which a 5-6-membered carbocyclic acid may be phenylacetated, or for a ring -CH2-CH2-CH2, which is bound to the oxygen ring or to the oxygen ring, and its sulphuric acid additives.

In compounds of formula I, R1 is preferred for an alkyl group. It can be straight-chain or branched and contain 1-4 carbon atoms. An example of a cycloalkyl alkyl group is cyclopropylmethyl.

If in the compounds of formula I the substituents R2, R3 and R6 represent or contain an alkyl group, this can be a straight or branched alkyl group with 1 to 5 carbon atoms, preferably 1 to 4, especially methyl or ethyl.

The substituents R2 and R3 are preferably in positions 7 and 8 of the benzodiazepine ring and are preferably hydrogen, alkoxy, especially methoxy, or alkyl, especially methyl, or chlorine.

The substituent R4 is preferably a phenyl group substituted, if any. The substituents R7 and R8 of the 5-phenyl group are preferably hydrogen, alkyl, especially methyl, or halogen, especially fluorine or chlorine, or also an alkoxy with 1-5 carbon atoms, such as isopentyloxy.

If the substituent R4 is a cycloalkyl group, it is preferably cyclohexyl.

The substituent R6 is preferably hydrogen or halogens, particularly fluorine, or alkoxy, particularly methoxy. The substituent R5 is preferably hydrogen. If R5 means halogens, this is preferably chlorine.

Z is a chain with 2-4 chain links, preferably an alkyl chain with 2-4 carbon atoms. Z thus forms a 5- to 7-membered heterocycle with the aminoethyl group to which it is bound. Z is preferably a propylene chain and thus together with the indole scaffold to which it is bound forms a 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline scaffold. If the alkyl chain Z is substituted by an alkyl, this 1-4 carbon atoms may be present and is in particular methyl.

The compounds of formula I contain a chiral carbon atom in the 3-position of the benzodiazepine ring and may be present in the D- and L-form or as a racemate.

According to the invention, the new amides of formula I and their acid addition salts are obtained by adding in a known way amino compounds of general formula II (see formula II) containing by weight: R1, R2, R3 and R4 as specified above, with acids or reactive acid derivatives of general formula III (see formula III) where R5, R6 and Z are the above and Y is a hydroxy or a reactive group, acylated and, where appropriate, converted free compounds of formula I to their acidic addition salts or converted the acidic addition salts to the free compounds of formula I.

The acylation of the amino compounds of formula II can be carried out in isolation to form amide groups by the usual methods of aminoacylation. (see formula IIIa) The reactive groups Y may be, for example, low alkoxy, halogens such as chlorine or bromine, or preferably organic sulphonic acid residues, for example residues of low alkaline sulphonic acids such as methanosulphonic acid or of aromatic sulphonic acids such as benzoic sulphonic acid or of aromatic alkyl or halogen substituted bolsulphonic acids such as tetrofluoric acid or bromobenzene sulphonic acid. Cyclization may occur in an organic solvent under low cyclic conditions, such as at room temperature or between 20 °C or low atmospheric pressure, or as a solvent or a dihydrogen or a hydrogen peroxide.

Acylation may be carried out in the presence of an acid-binding reagent, especially when a mixed anhydride of the acids of formula IIIa with a sulphonic acid is used as the acylation agent. As acid-binding agents, soluble bases are suitable in the reaction mixture, in particular organic bases such as tert, niederalkylamine and pyridines such as triethylamine, tripropylamine, pyridine, 4-dimethylaminopyridine, 4-diethylaminopyridine or 4-pyrrolidinopyridine.

Mixed acid anhydrides of the acids of formula IIIa with organic sulphonic acids can be obtained in situ by conversion of the acids IIIa with an acid halogenide, in particular the acid chloride of organic sulphonic acid, and directly transferred to the amine compound of formula II without isolation.

If the acid itself or an ester is used as an acylation agent, the implementation of the amino-binding of formula II with the acid of formula IIIa or its ester can also be carried out in the presence of a coupling agent which is known from peptide chemistry to be suitable for amide formation. An example of coupling agents which promote amide formation with the free acids by reacting with the acid in situ to form a reactive acid derivative is, in particular, alkylcarbodiimides, e.g. cycloalkylcarbodiimides such as diclohexylcarbodiimides, or 1-methylbenzoyl-3[3-dimethylaminopropamide]-carbodiimides, carbonylbenzoylbenzoyl and n-acetyln-methacrylate, in the presence of a solvent containing n-methylbenzoyl, in the presence of a solution of 91°C + 12°C + 30°C. The implementation can be carried out in the presence of two solvents, namely, an aromatic solvent such as n-methylbenzoylbenzoyl, and a solvent of 91°C + 12°C + 30°C + 30°C. The implementation can be carried out in the presence of a solvent of a solvent, in the presence of a solvent, where appropriate, of a solvent, such as n-methylbenzoylbenzoylbenzoyl.

For example, the salts of the compounds of formula I with inorganic acids, e.g. halogenated hydrocarbons, particularly hydrochloric acid, sulphuric acid or phosphoric acid, or with organic acids, e.g. low aliphatic mono- or dicarboxylic acids such as lactic acid, maleic acid, sulphuric acid, sulphuric acid or sulphuric acid, e.g. halogenated hydrocarbons or sulphuric acid, or with organic acids, e.g. low aliphatic mono- or dicarboxylic acids such as lactic acid, maleic acid, sulphuric acid, sulphuric acid or sulphuric acid, as appropriate, substituted by methanol or alkyl sulphuric acid.

If racemates of compounds of formula II are used in the synthesis, the compounds of formula I are obtained in the form of racemates. Optically active forms of compounds of formula II can be used to obtain optically active compounds of formula I. The optically active compounds of formula I can be obtained from the racemic mixtures in a known way, e.g. by chromatographic separation of chiral separating materials or by transformation with suitable optically active acids, e.g. tartaric acid or 10-camphersulfonic acid, and subsequent separation into their optically active antibodies by fronized crystallization of the salts obtained.

The amine compounds of formula II are known or can be produced by known processes or by analogy to known processes. (see formula IV) The reduction of the oxime of formula IV to the amines of formula II can be carried out by conventional methods, such as catalytic hydrogenation, preferably in the presence of a Raney-nickel catalyst or with zinc/iron vinegar as the reducing agent.

The optically active compounds can be obtained from the racemic mixtures in a known way, e.g. by chromatographic separation from chiral separation materials or by translocation with suitable optically active acids, e.g. whey or 10-camphersulfonic acid, and subsequent separation into their optically active antibodies by fractional re-allocation of the obtained salts. Racetides of the amenylate group II can also be obtained by crystallisation with an initially known optically active amenylate group, e.g. phenylalanine, which is known to be similar to the amenylate group II. For example, amenylate can be exposed to the protective compounds known to be amenylate or amethylamine, which are known to be free from the amenylate group II, and can be removed by free crystallisation with the amenylate group.

The oxymers of formula IV can be naturally converted by nitrosation of formula V compounds. (see formula V) Preferably, the unsubstituted compounds of formula V in the 3 position are first treated in an inert organic solvent under reaction conditions, such as an aromatic hydrocarbon such as benzene or toluene or a cyclic ether such as tetrahydrofuran with a strong base, such as an alkali metal alcohol such as potassium tert butylate, and then converted to a nitrosiser such as a niederalkyl nitrite such as tert butyl nitrite or tert.

Compounds of the general formula Va (see formula Va) where R1′ has the value specified for R1 excluding hydrogen and R2, R3 and R4 have the above values, can be obtained in a known way by adding 2-chloromethyl-1,4-benzodiazepine compounds of formula VI (see formula VI) For example, oxidation can be achieved by treating the compounds of formula VI with a suitable oxidizing agent in the presence of a solvent which is inert under the reaction conditions. Oxidizing agents may be used, for example, potassium permanganate, chromium trioxide or dichromate salts. For example, halogenated hydrocarbons such as dichloromethane, water or acetic acid or mixtures thereof may be used as solvents to combat these oxidizing agents.

The starting compounds of formula VI are known or can be produced by known methods or by analogy to known methods.

The compounds can be known, for example, by the methods described in German disclosure notes Nos 22 21 558 or 25 20 937, from 2-hydroxy-1,3-diaminopropane compounds of general formula VIII. (see formula VIII) The compounds of formula VIII are cycled by treatment with phosphorus trichloride. It is appropriate to treat the compounds of formula VIII or their acid addition salt with phosphorus trichloride at a temperature of 100 to 150 °C, preferably at boiling point of the reaction mixture, by mixing a 2-chloromethyl-1,4-benzodiazepine compound of formula VI with the isomeric 3-chlor-1,5-benzodiazepine compound of formula VII. (see formula VII) The benzodiazocin compound of formula VII in the mixture can be recombined in a known way, for example by heating the mixture in an inert organic solvent under the reaction conditions, such as a higher boiling hydrohalogen such as tetrachlorethane, into which the isomeric compound of formula VI is converted.

For the manufacture of 2-hydroxy-1,3-diaminopropane compounds of formula VIII, anilines of formula IX may be used. (see formula IX) where R2 and R3 are of the above importance. In these anilines, the amino group is first monosubstituted by an R1′ group in a known way and then, in the same way as in DE-OS 28 10 349, 1,2-epoxypropylphthalamide or first epichlorohydrin and then phthalamide is used. The phthalamide group is then cleaved in a known way and the resulting compounds of formula X are obtained (see formula X) where R1′, R2 and R3 are the values given above, are replaced by acid halides of formula XI (see formula XI) where R4 is the above value, acylated.

Compounds of formula V may also be prepared from ketones of general formula XII (see formula XII) where R1, R2, R3 and R4 have the above meanings, are obtained in a known way by mixing them with a halogenated acetic acid halogenide to compounds of formula XIII (see formula XIII) (see formula XIII) where R1, R2, R3 and R4 have the above meanings and Hal means chlorine or bromine, and then condenses these with ammonia to form compounds of formula V.

The ketones of formula XII are known or can be produced by known processes or by analogy to known processes, for example by conversion of p-substituted anilines of formula IX with acid halides of formula XI, for example in a Friedel-Craft reaction followed by hydrolysis, or from anthranilic acids by condensation with acetic anhydride, the condensation product in a Grignard reaction with compounds of general formula XIV (see formula XIV) where R4 is of the above value, converted to the N-acetyl derivatives of the compounds of formula XII and hydrolysed.

Compounds of formula V, where R1 stands for hydrogen, can be alkylated in a known way to other compounds of formula V, for example by conversion with compounds of general formula XV (see formula XV) where R1′ has the above meaning and Hal stands for chlorine, bromine or iodine.

The ester of formula IIIb (see formula IIIb) where R6 and Z are the abovementioned values and R9 is the low alkyl, can be obtained in a self-evident way from compounds of formula XVI (see formula XVI) where R6 and Z are the main constituents, obtained by converting the compounds of formula XVI into the corresponding N-nitroso compounds by treatment with sodium nitrite and converting these into the hydrazine compounds of general formula XVII (see formula XVII) where R6 and Z are the predominant ones, and the hydrazine compounds of formula XVII are further reduced to sulphuric acid niederalkylesters of general formula XVIII (see formula XVIII) where R9 is of the above value, is known to be converted in a natural way under fishery indole synthesis conditions,containing by weight: (see formula XIX) For the reduction of nitrous compounds, for example, lithium aluminium hydride in tetrahydrofuran or metallic zinc powder in the presence of acid can be used as a reducing agent. It is also possible to catalytically hydride the nitrous compounds to the hydrazines of formula XVII. It is advantageous to produce the ester of formula IIIb from the compounds of formula XVI in an epintop process without isolating the individual intermediate steps.The reaction mixture is further acidified by the addition of hydrochloric acid and then the reaction mixture is further acidified with the ester of bromoxylic acid of formula XVIII. The intermediate is the hydrazone compound of formula XIX, which under the reaction conditions further condenses to the ester of formula IIIb.

The esters of formula IIIb can be hydrolysed to the corresponding acids in a known way and/or converted into a reactive acid derivative of these acids.

The conversion to an acid halogenide involves the simultaneous introduction of a halogen substituent R5 into the compounds.

The 1,7-anellate 1H-indol-2-carbonic acid-N-(1,4-benzodiazepine-3-yl) amide derivatives and their pharmacologically acceptable acid addition salts of the invention have valuable pharmacological properties, in particular CCK antagonistic effects and are characterised by a novel favourable profile of action. Thus, the CCK antagonistic compounds of formula I of the invention have a pronounced gastric emptying component and inhibitory effects on the CCK-induced exocrine pancreatic secretion. They have a low dose range to stimulate gastric emptying, inhibiting the gallbladder contraction and exerting a high therapeutic effect due to their high potency and tooth extraction.

CCK comprises peptides of various chain lengths and acts as a hormone as well as a neuropeptide. Among the CCK peptides, the octapeptide CCK-8 is the smallest unit with the full CCK spectrum of action.

Description of the test methods Determination of the binding capacity of test substances to peripheral CCK receptors.

The affinity of the compounds of formula I to peripheral CCK receptors is measured in vitro on rat pancreatic homogenate to determine the inhibition of the binding of the physiologically relevant octapeptide CCK-8 to peripheral CCK receptors by the test substances.

The receptor binding studies are performed following a modification of the method of van Dijk et al (J. Neuroscience 4 (1984), 1021-1033) using a protease inhibitor called soybean tripsinin inhibitor (= SBTI).

Whole pancreas glands of male Wistar rats killed by decapitation with a body weight of 150-300 g are removed from the fat and homogenised in 50 times the volume of an ice-cold test buffer solution (10 mmol 2-[4-(2-hydroxyethyl) -piperazine-1-yl]ethane sulphonic acid (= HEPES), 130 mmol sodium chloride, 5 mmol magnesium chloride, 0.02 % bacitracin, 0.01 % SBTI, pH 7.4) with a homogeniser of the Kinematica Polytron type for 15 seconds. The homogenised sod is then centrifuged for 10 minutes at 48.000 sod. This washing procedure is repeated. After the last centrifugation, the test tube is used in the form of a 500-volume solution of the obtained sodium chloride and suspended immediately for the test.

For the binding test, 500 μl of tissue homogenate is incubated with 50 μl of test buffer solution or 50 μl of solution of the test compound and 50 μl of 3[H]-CCK-8 solution (final concentration 0,3 nM). The non-specific binding is assumed to be 0,1 μmol of CCK-8. The incubation period is 90 min at 25 °C. All compounds are measured in several concentrations three times each.

The test substance solutions are aqueous solutions obtained by appropriate dilution of 60 x 10−4 molar aqueous stock solutions, whereas the water-soluble test substances are first dissolved in 96% ethanol and this solution is diluted with water to a concentration of not more than 1.6% ethanol by volume.

The separation of bound and free 3[H]-CCK-8 is carried out by filtration via a fiberglass filter. After washing twice with 3 ml of HEPES solution each, the filters are placed overnight in the scintillation solution (F. Packard SAVE scintillation solution) in the dark and calculated in a liquid scintillation meter of the F. Packard (type tri-carb 1500 C). The concentration that produces a 50% inhibition of the specific binding of the tritiated CCK-8 to the receptors is determined as IC50 of the test substance. This is calculated according to the Cheng-Pruso equation of the corresponding p-ki-ki.

The following table A shows pKi values for the affinity of the test substances to peripheral CCK receptors obtained by the above test method.

Determination of the minimum toxic dose.

Male mice weighing 20-25 g are given maximum doses of 300 mg/kg of test substance per dose. The animals are carefully monitored for 3 hours for signs of toxicity. In addition, all symptoms and deaths are recorded for 24 hours after application. Concomitant symptoms are also observed and recorded. If death or severe toxic symptoms are observed, additional mice are given progressively lower doses. The lowest dose that causes death or severe toxic symptoms is the minimum toxic dose as shown in Table A below.

Tabelle A

Bsp. Nr.	in vitro Bindung an peripheren CCK-Rezeptoren (Pankreas) pKi-Werte	Minimale toxische Dosis mg/kg Maus p.o.
1	8,87	> 300
2a	9,59
2b	7,71
4	8,60	> 300
5	8,84	> 300
6	8,49
8	8,04
9	9,10	> 300
10	8,75	300
11	8,62	300
13	9,00	> 300
15	8,91
17	8,00
18	8,93	> 300
20	9,07	> 300
22	9,04	> 300
23	8,00	> 300
25	7,62	> 300
26	8,21
30	8,63	300
33	8,43	> 300
37	9,19
38	9,01

The effect of the test substances on CCK-induced gastric emptying disorders was investigated.

The test chemical is used to determine the concentration of the test chemical in the food and the concentration of the test chemical in the food.

After 24 hours of withdrawal of feed (drinking water ad libitum), the animals are given a dose of the test substance per os suspended in a volume of 10 ml/kg of a 1% TyloseR solution (= methyl cellulose) or in a volume of 10 ml/kg of a solvent solution containing 5% glycerol, 87 % polyethylene glycol 400 and 8% water. A control group is given only the TyloseR solution or the solution containing the polytyl carbon glycol. 60 minutes later, the animals are injected with 80 μK/kg CC-8K. The dose is then subcutaneously administered to the animals.

While all mice were found to have carbon monoxide in the duodenum under control conditions without CCK administration, the control groups with CCK administration prevented the transport of the cooking oil into the duodenum and traces of carbon monoxide were found in no more than 5% of the animals.

Table B below shows the results obtained from the above test description for doses of test substances which showed inhibition of the CCK effect in at least 40% of the animals. Other

Tabelle B

Bsp. Nr.	CCK-antagonistiche Wirkung auf CCK-induzierte Magenentleerungsstörung
	Dosis µMol/kg Maus p.o.	% Tiere mit Aufhebung des CCK-Effektes
1	0,215	50
2a	0,1	100
2b	10	70
4	1,0	45
5	10	75
6	0,681	40
9	0,215	50
10	0,1	40
13	10	83
	1,0*	100
15	1,0	57
	0,10*	90
17	1,0*	50
20	1,0	50
27	1,0	40
33	1,0	50

Tabelle B

* = in Lösungsvermittler enthaltender Lösung verabreicht.

4. Testing of the inhibitory effect of the substances on CCK-induced gallbladder emptying.

CCK causes a contraction of the gallbladder muscles and thus a depletion of the gallbladder, resulting in a decrease in gallbladder weight compared to control animals not treated with CCK.

After 24 hours of withdrawal of feed (drinking water ad libitum), the animals are given a dose of the test substance per os suspended in a volume of 10 ml/kg of a 1% TyloseR solution (= methyl cellulose) or in a volume of 10 ml/kg of a solvent solution containing 5% glycerol, 87 % polyethylene glycol 400 and 8% water. Two control groups receive only the TyloseR solution or the solution containing the solvent containing the injectable polyethylene glycol. One of the control groups and all animals treated with the test substance are given 0,1 μg/kg of CC-8 min. later.

Five minutes after the CCK-8 application, the mice are killed, the gallbladders are prepared and weighed.

The percentage of inhibition of the CCK-8 effect on gallbladder weights by the test substances is shown in Table C below.

Tabelle C

Bsp. Nr.	CCK-antagonistische Wirkung auf Gallenblase
	Dosis µMol/kg Maus p.o.	%Hemmung der CCK-induzierten Gallenblasenentleerung
1	10	66
	1	< 25
2a	0,46	16
2b	46	8,3
6	10	73
9	100	99
	4,6	< 25
15	100	100
	10	< 25
	0,1*	< 25
20	10	25
33	10	19

A comparison of the data in Tables B and C shows that CCK antagonistic effects of the substances on the gallbladder are observed only at doses many times higher than the dosage ranges effective against CCK-induced gastric emptying disorders.

The doses to be used may vary from person to person and naturally vary according to the type of condition to be treated, the substance used and the form of application. For example, parenteral formulations generally contain less active substance than oral preparations. However, generally, drug forms containing 5 to 50 mg of active substance per single dose are suitable for use in larger mammals, particularly humans.

As medicinal products, the compounds of Formula I and their physiologically compatible acid addition salts may be contained in galenic preparations such as tablets, capsules, suppositories or solutions with common pharmaceutical excipients. The compounds of Formula I are characterised by a good solubility in solutions containing common pharmaceutical excipients and a high absorbability. The galenic preparations may be prepared by known methods using common solid carriers such as milk sugar, starches or talcum or liquid diluents such as water, fatty parables or liquid fineness and the use of common pharmaceutical excipients such as tablets or preservatives.

The following examples are intended to explain the invention in more detail.

Example 1: The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

A) 43 g N1-Methyl-N1- ((3-methoxyphenyl) 2-hydroxy-1,3-diaminopropane and 31 ml triethylamine were dissolved in 280 ml dichloromethane. Under ice cooling, a solution of 24.4 ml benzoyl chloride in 20 ml dichloromethane was slowly dripped into the solution. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction solution for processing was then washed with water and sodium chloride solution and the solvent was evaporated. The remaining residue was 70.0 g raw N1-Methyl-N1-methoxyphenyl-3-hydroxyphenyl-2-benzoyl-2-hydroxy-1,3-diaminopropane. The recrystallization point of the product/isopropanol was obtained by melting 64 g of phospholipol after bathing at 130 °C (87 °C) in 64 ml of bath saline before the product was cooled to 64 °C (1/2 hours).The organic phase was separated, washed several times with water, then treated with dilute sodium hydroxide solution, washed again with water, dried over sodium sulphate and evaporated. The residue was 56.7 g of an oily raw product, which is a mixture of approximately 60% 2-chloromethylmethyl-8-methoxy-5-phenyl-2,3-dihydro-1H-1,4-benzenopeptide and approximately 40% 3-chloromethyl-9-methoxy-6-phenyl-1,2,3,4-tetrahydro-1,5-benzocin tetrahydra. To isomerize the benzodiazepine antibody, the raw product was dissolved in 22-2 ml of anodial chloride for 30 minutes. The product was further treated in 56-57 ml of anodial chloride-1-5-methylmethyl-1-methyl-1-benzenopeptide without further heating and treated with the next step of the reaction.322 ml of 32% aqueous hydrochloric acid, 2481 ml of water and 255 ml of dichloromethane were added to the solution. A solution of 32.4 g potassium permanganate was then dripped into 660 ml of water, the internal temperature being kept below 15 °C by ice cooling. The reaction mixture was then stirred at room temperature for another half hour.55 g of the raw product was obtained by column chromatography on silica gel under slightly increased pressure (flash chromatography) using cyclohexane/acetic acid ethyl ester 4 6 as an elution agent, isolating the pure 1-methyl-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine. 15,5 g of the pure oily product was obtained.D) 15,5 g of the above product were suspended in 293 ml of toluene. The suspension was cooled to -20 °C and then 16,4 g of potassium-butyric acid were added to the solution and the mixture was cooled for another 15 minutes. 9,4 ml of the solution were then placed under a critical refrigeration temperature of 30 °C for a long time, so that the reaction was still allowed to continue.The reaction solution was then mixed thoroughly and the organic phase was separated and the aqueous phase was extracted again with acetic acid ester. The combined organic phases were washed with water and evaporated. 21 g of raw product was obtained. This was crystallized from toluene/ethanol. The crystalline was separated and the mother lining was again purified and re-inserted by flash chromatography over 100 g using cyclohexane/acetic acid ester 4 6 as an elution agent. The ethanol was evaporated and combined with the crystalline solution.A total of 9.5 g of 3-hydroxyyimino-1-methyl-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine was obtained with a melting point of 206-207 °C.E) 9.5 g of the product obtained above were added to a mixture of 700 ml of acetic acid and 80 ml of trifluoroacetic acid. The reaction mixture was heated to 40 °C (internal temperature) and a total of 6.9 g of zinc dust were added by portion under stirring, stirring the mixture for another 2 hours at 40 °C and then adding 1 glue dust and stirring it for another 1 1/2 hours at 40 °C. For processing, the mixture was diluted with zinc oil, cooled and evaporated. The remaining residue was dissolved in sodium methanol, sodium carbonate and water.TheoretR was used to extract the substances, dry the solution and evaporate it. 8.1 g of raw 3-amino-1-methyl-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine was obtained, which was further processed without purification in the next reaction step H.F) 150 g of 1,2,3,4-tetrahydroquinoline were dissolved in 1.25 l of ice vinegar. The solution was infused in an ice bath at about 15 °C with a solution of 80 g of sodium nitrite in 300 ml of water and the reaction mixture was further agitated for 45 minutes. The resulting N-nitro-1,2,3,3-T4-hydroquinoline was added to the reaction solution for 1.5 hours in 300 portions of zinc, with the reaction baths kept at a temperature of 15-20 °C by refrigeration of the reaction vessel by ice.The reaction table was mixed twice with a total of 5 l dihydromethane extract containing dichloromethane extract, which was mixed with a total of 1 l of water, over 4 l of chlorodihydromethane, and obtained by using 280 l dihydromethane extract, which was obtained by using 280 l dihydromethane extract and 2-methyl dihydromethane extract, which was purified as a dihydromethane extract using 280 l dihydromethane extract.151.8 g of purified product with a melting point of 70-72 °C were obtained.G) 39 g of 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carboxylic acid ethyl ester were dissolved in 40 ml of ethanol and this solution was given at room temperature to a solution of 11.3 g of potassium hydroxide in a mixture of 20 ml of water and 145 ml of ethanol. The reaction mixture was stirred at room temperature for 90 min and then cooled to 10 °C. The precipitated solid was sucked and washed with 30 ml of ethanol each time. The parent solution was washed in half, and the precipitated solid was also separated and washed with ethanol. The entire solid was then dissolved in 150 ml of water and the acid was removed by acidifying the solution with concentrated hydrochloric acid to pH 1 to 2.The resulting acid was separated, washed three times with 40 ml of water and dried at 60 °C. 32,4 g of 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonic acid were obtained with a melting point of 212-213 °C (Z).H) 5,4 g of 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonic acid and 3,67 ml of triethylamine were dissolved in 119 ml of dichloromethane. The solution was further cooled to -20 °C and 2,08 ml of methanosulfonic acid chloride were slowly added by stirring and the reaction mixture stirred for 15 minutes at -20 °C. The mixture of anhydroquinoline-1-hydroxylamine-1,3,3-dihydroquinoline-1-methylamine was obtained in a solution of between 3,20 and 8,0 g of methanosulfonic acid and methanosulfonic acid chloride at a temperature of 8-3,02-5,15 °C.The reaction mixture was further stirred at -15 °C for 30 minutes and allowed to warm up slowly (within one hour) to room temperature. For processing, the reaction mixture was diluted with water, the dichloromethane phase was removed, washed with sodium bicarbonate solution and then washed with water, dried over sodium sulphate, filtered and evaporated. The residue was 14,3 g of the raw title compound. The raw product was polychromatographed to 700 g of silica gel under slightly increased pressure (flash chromatography) using cyclohexane/acetic acid thickener 1 1 as an elution agent. 6,1 g were obtained. This product was crystallised at 80 °C for 2 days using 25 ml of chloromethylene with an addition of dichloromethane.3,3 g of racemic 3-[(4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl) amino]-8-methoxy-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine was obtained with a melting point of 175 °C to 178 °C.Example 2: Other The manufacture of optical isomers of 3-[(4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl) amino]-8-methoxy-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine. Other 2a: (-) isomers,

\frac{20}{D}

The maximum concentration of the active substance in the product is -88,2° (c = 0,5 in dichloromethane).

A) 30.5 g racemic 3-amino-1-methyl-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (analogue sample 1 E) were dissolved in 190 ml of dimethylformamide. 28.8 g N-amino-acetyl were added to the solution in succession under moisture-free conditions.Butoxycarbonyl-D-phenylalanine (= BOC-D-phenylalanine), 15 g 1-hydroxybenzotriazole, 20.7 g dimethyl-3-[1-dimethylamino-) -carbodihydrochloride and 15 ml tripropyl phase.The reaction mixture was agitated for 30 min at room temperature.The dimethyl amide was reduced to water at reduced pressure, dissolved in nitric acid and dissolved in water.The solution was dissolved in 10% nitric acid, dissolved in 10% hydrochloric acid and separated by water, the hydrochloric acid and the hydrochloric acid.After distillation of the solvent, 66 g of raw product were obtained, which was again purified by flash chromatography over 700 g of silica gel using cyclohexane/acetic acid ethyl ester 1 : 1 as the elution agent. After evaporation of the solvent, 60 g of 1,1-dimethyl-N-{(R) -2-[(2,3-dihydro-1-methyl-2-oxo-5-phenyl-8-methoxy-1H-1,4-benzodiazepine-3-amino-) 2-oxo-1-benzyl}-carb were obtained as a 1 : 1 dimer.B) 60 g of the resulting three diastereoid acetic acid crystalline were liquefied into acetic acid. To remove the ammonia, 480 ml of the ammonia group was dissolved in a solution of chlorine dioxide. The ammonia group was converted into a 3-dimer solution of chlorine dioxide, which was released from the ammonia-hydrochloride group.3-dihydro-1-methyl-2-oxo-5-phenyl-8-methoxy-1H-1,4-benzodizepine-3-yl) -propionic acid amides. To release the base, the hydrochloride was dissolved in 10% sodium salts and the base was extracted from the aqueous phase with acetic acid ethyl ester. After washing, drying and evaporation of the organic phase, 18.4 g of diastereomeric pure 3-phenyle-2-amino-N- ((2,3-dihydro-1-methyl-2-oxo-5-phenyl-8-methoxy-1H-1,4-benzodiazepine-3-yl) -propionic acid amide was obtained.20 DAfter moisture removal, 5,4 ml of phenylisothiocyanate were added to the solution and the reaction mixture was stirred at room temperature for 10 min. The dichloromethane was then distilled under reduced pressure and the remaining residue was cleaned by flash chromatography over 500 g of silica gel using cyclohexane/acetic acid ethyl ester 1 : 1 as an elution agent. After evaporation of the solvent, a foam solution was obtained which crystallized ethyl ether. 20,1 g of N1-nitroxy-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-methyl-1-methyl-1-methyl-methyl-1-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth [α] 20 D- 11.2° (c = 0.5 in methanol).D) 20 g of the thiocarbonyl product obtained above were added to 30.7 ml of trifluoric acid and the reaction mixture was heated at 50 °C for 20 min. Then the trifluoric acid was distilled at reduced pressure, the remaining residue was evaporated with dichloromethane, dissolved again in dichloromethane and flash chromatographed to 500 g of silica gel, first with a mixture of trifluoric acid/esulfonyl ester 1 1 and then a mixture of dichloromethane/esulfonyl methanol/esulfonyl rock/water: 90: 1: 1,3 h. The remaining hydrofluoroethylene was reduced to the solution of dihydroxy-3-dihydroxy-3-dihydroxy-3-amino-3-dihydroxy-5-amino-dihydroxy-5-methyl ester, and then with the solution of dihydroxy-8-methyl ester, 2-methanol and 2-methanol.20 DAnalogue to the method described in example 1H, 7.0 g of the above obtained (-) 3-amino-1-methyl-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine was incorporated into a reaction solution containing dichloromethane, consisting of a mixed anhydride of 4.9 g 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonic acid and 1.85 ml methanosulfonic acid chloride. The reaction mixture was treated as described in example 1H. After chromatographic cleaning, 9.0 g-methyl-1H-1,4-benzodiazepine was obtained. This product was further purified with a flash-cleaned crystal of approximately 2,5-dihydroxy-2-methyl-1-methyl-1-methyl-1-phenyl-1-methyl-1-phenyl-1-methyl-1-methyl-1-phenyl-1-methyl-1-methyl-1-phenyl-1-methyl-1-methyl-2-phenyl-1-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-phenyl-2-methyl-2-methyl-2-methyl-2-phenyl-2-phenyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-meth20 DThe resulting concentration of -88,2° (c = 0,5 in dichloromethane) is obtained.

The 'C' value is the value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C' value of the 'C'.

A) The parent algae resulting from the production of the diastereomeric pure hydrochloride in 2a B) were evaporated to obtain the other diastereomeric hydrochloride. The resulting hydrochloride was decrystallized four times from a mixture of acetonitrile and isopropylacetate. [α]20 DThe reaction mixture was treated as described in example 2a C. 18.6 g N1-phenyle-N2{2-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-8-methoxy-1H-1,4-benzodiazepine-3-amino]-2-oxo-1-benzyl-ethyl}-thial was obtained. Optical turnover [α]20 DThe resulting hydrotrifluoroacetate of (+) -3-amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-8-methoxy-1H-1,4-benzodiazepine was released from the amine analogue example 2a D. 7,7 g (+) -3-amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-8-methoxy-1H-1,4-benzodiazepine was obtained. Optical turnover [α]20D = +143.8° (c = 0.5 in dichloromethane).D) Similar to the method described in example 1H, 5.0 g of the above obtained (+)-3-amino-1-methyl-8-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine was treated with a mixed anhydride of 3.49 g 3-[(4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonic acid and 1.32 ml methan-2-sulfonic acid in a dichloromethane-containing reaction solution. The reaction mixture as described in example 1H was treated with 10 g of the raw product. After flash chromatographic cleaning, three enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-linked enzyme-methyline-methyl-2-methyl-2-methyl-1-3-methyl-3-methyl-3-methyl-3-methyl-3-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-H4-5-methyl-methyl-methyl-methyl-methyl-methyl-1,3-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl [α]20 DThe maximum value of the product obtained from the product shall be 0,15 °C.

Example 3: The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

A) 10 g 2-Oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine were dissolved in 100 ml of tetrahydrofuran under nitrogen atmosphere. To the solution were added 1.4 g sodium hydride in the form of an 80% oily suspension per serving under nitrogen atmosphere and the reaction mixture was heated at the return flow for 30 minutes. 9.2 g (= 5.5 ml) of iodine pentane were slowly added, the mixture was heated at the return flow for another 1.5 hours and then added again 0.3 g sodium hydride in the form of an oily suspension, and after another 10 minutes 5.5 ml of iodine pentane were added and the mixture was heated at the return flow for another hour.13,5 g of raw product were obtained, which was purified by flash chromatography over approximately 300 g of silica gel using cyclohexane/acetic acid ethyl ester 1 1 as elution agent. The purified product was crystallized and dried from cyclohexane. 6,2 g of pure 2-Oxo-1-n-pentyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine with a melting point of 93-95 °C were obtained. (b) 6,5 g of the above product were suspended in 122 ml of tertol. The suspension was cooled to -20 °C and then 5,88 g of potassium nitrite was added to the solution as described in the example R.D. and butyl in 1 ml.The reaction mixture was further processed as in example 1D, to obtain 4.7 g 3-hydroxyimino-2-oxo-1-n-pentyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine with a melting point of 188-191 °C.C) 4.6 g of the above product were dissolved in a mixture of 328 ml of acetic acid and 37.6 ml of trifluoroacetic acid and further treated with a total of 3.1 g of zinc dust as described in example 1E. The reaction mixture was further processed as in example 1E. 4.2 g of raw 3-amino-2-oxo-1-n-pentyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine were obtained without purification.D) The mixture was treated in a solution containing methanol and 4,6 ml of dihydroxybenzoyl-1,4-methanol in a solution containing methanol and 2,6 ml of dihydroxybenzoyl-1,4-methanol in a solution containing methanol and 1,6-dihydroxybenzoyl-1,4-methanol in a solution containing methanol.The reaction mixture was treated as described in example 1H) and 3,9 g 3-[(4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl) amino]-2-oxo-1-n-pentyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine was obtained as white foam resin. The IR spectrum is 1682 cm−1, 1662 cm−1, 1524 cm−1, 1499 cm−1.

Example 4: The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

A) 75.6 g N1-Methyl-N1-phenyl-2-hydroxy-1,3-diaminopropane and 65 ml triethylamine were dissolved in 600 ml dichloromethane. A solution of 61 ml cyclohexylcarboxylic acid chloride in 50 ml dichloromethane was slowly added to the solution under ice cooling. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction solution was then washed for processing with water and sodium chloride solution and the solvent was evaporated raw. 131 g N1-Methyl-N1-phenyl-N2-cyclohexylcarbonyl-2-hydroxy-1,3-diopropane remained as a residue. The raw product was crystallised, washed with ethyl chloride and obtained in a bathtub at a temperature of 87 °C. The product was obtained by reacting with 87 g/m3 of ethyl chloride at a temperature of 87 °C.The organic phase was separated, washed several times with water, then treated with dilute sodium hydroxide solution, washed again with water, dried over sodium sulphate and steamed. The residue was 76.1 g of an oily raw product, which was a mixture of approximately 40% 2-Chlormethyl-1-methyl-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepine and approximately 60% 3-Chlormethyl-1-dihydro-1H-1,2,3,4-tetrahydro-1,5-tetrahydro-1,5-benzodiazepine. To hydrolyse the Benzodiazepine, the raw compound was dissolved in 300 ml of anthracene for 30 minutes before being further treated in the next step of treatment, dissolved in anthracene 2-Chlormethyl-1-methyl-1,3-5-methyl-5-methyl-1,3-5-methyl-1,3-methyl-1,3-methyl-1-3-methyl-1-3-methyl-1-3-methyl-1-3-methyl-1.The solution was then added 116 ml of 32% aqueous hydrochloric acid, 882 ml of water and 91 ml of dichloromethane. A solution of 11.65 g of potassium permanganate was then dripped into 238 ml of water, with ice cooling to keep the internal temperature below 15 °C. The reaction mixture was stirred at room temperature for 1.5 hours. Then 2 g of potassium permanganate were dissolved in 50 ml of water, dripped again and stirred for another hour at room temperature. Solid sodium bicarbonate was added portion by portion to the reaction mixture until neutralized.55 g of raw product was obtained by column chromatography of 1 kg of silica gel under slightly increased pressure (flash chromatography) using cyclohexane/acetic acid ethyl ester 1 : 1 as an elution agent, the pure 1-methyl-2-oxo-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepine was isolated from ether, crystallized and dried. 2,3 g of pure product with a melting point of 98-100 °C were obtained.D) 8,9 g of the above product were suspended in 201 ml of toluene. The suspension was cooled to -20 °C and then 9,63 g of calico-nitritem B-nitrate were added to the vegetable and further refrigerated for 15 minutes, then added to 5,5 ml.The reaction solution was then stirred for 30 minutes in a mixture of 347 ml of ice-cold water, 16.7 ml of ice vinegar and 347 ml of acetic acid ester. It was thoroughly mixed and then the organic phase was separated and the aqueous phase was extracted again with acetic acid ester. The combined organic phases were washed with water and evaporated. The residue was absorbed in toluene and decarboxylated from toluene/ethyl alcohol. 12,4 g of raw product was obtained. This was purified by flash chromatography over 500 g, using a cycloacetic acid ester:After crystallization of the product obtained from ethanol, 4.4 g 3-hydroxyimino-1-methyl-2-oxo-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepine were obtained with a melting point of 205-210 °C.E) 4.4 g of the product obtained above were added to a mixture of 375 ml of iron vinegar and 42.3 ml of trifluoroacetic acid. The reaction mixture was heated to 40 °C (internal temperature) and a total of 2.36 g of zinc dust were added per serving under stirring, the mixture was stirred for another 2 hours at 40 °C and then added another 1.1 g of zinc dust and stirred for another 1 hour at 40 °C. The mixture was cooled with tin, evaporated and then allowed to ferment.The remaining residue was incorporated into dichloromethane, washed with aqueous sodium carbonate solution and water, dried and evaporated, and 4,0 g of raw 3-amino-1-methyl-2-oxo-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepine were obtained, which was further processed without purification in the next reaction step.F) 2,92 g of 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carboxylic acid (obtained as 1F to 1G) and 1,99 ml of tri-sulphur were dissolved in 64 ml of dichloromethyl-2-oxo-5-cyclohexyl. The solution was cooled to -20 °C and slowly agitated to 1,13 g of methionine chloride, which was dissolved in the reaction state for 15 minutes, and 4,0 ml of methionine-methyl-2-oxy-2-oxy-2-oxy-2-oxy-methyl-2-oxy-methyl-2-oxy-methyl-2-oxy-methyl was added to the solution at 4 °C.3-dihydro-1H-1,4-benzodiazepine and 1.99 ml triethylamine were dripped into 54 ml of dichloromethane at -15 to -20 °C, the reaction mixture was stirred for another 30 minutes at -15 °C and allowed to warm up slowly (within one hour) to room temperature. For preparation, the reaction mixture was diluted with water, the dichloromethane phase was separated, washed with sodium carbonate solution and then washed with water, dried over sodium sulphate, filtered and evaporated. The raw title compound was obtained as a residue of 7.6 g. The raw product was slightly increased to 400 g by column chromatography using a silica gel (flash chromatography) using Cyclooxylenedioxylenedioxylate: 1 The product was purified and purified from ethanol.1,5 g 3-[(4H-Pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl) amino]-1-methyl-2-oxo-5-cyclohexyl-1H-2,3-dihydro-1,4-benzodiazepine was obtained with a melting point of 147 to 152 °C.

Example 5: The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

0,99 g 8-fluor-4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonic acid, 1,4 g 2-chloro-1-methylpyridinium iodide, 1,1 ml triethylamine and 1,2 g 3-amino-2-oxo-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine were dissolved in 120 ml dichloromethane and the reaction mixture was boiled for 1 hour at the return flow. The reaction mixture was cooled, 5% sodium bicarbonate solution was added to the solution, the organic phase was separated and the water phase extracted with dichloromethane. 181 combined dichloromethane extracts were added to nitriol nitrite and the solution was reduced by means of a solvent called dihydroxy-dihydroxy-dihydroxy-dihydroxy-methyl-1-methyl-1-methyl-1-methyl-1-dihydroxy-dihydroxy-dihydroxy-diphenyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1-methyl-1,3-methyl-1-methyl-1,3-methyl-1-methyl-1-methyl-1,3-methyl-1-methyl-1,3-methyl-1-methyl-1,3-methyl-1, and the solution was reduced by using a solution of hydrogel-dihydroxy-dihydroxy-dihydroxy-dihydroxy-dihydroxy-diethyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-methyl-1-meth

Example 6: The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

A) 98.6 g 2-aminobenzophenone were dissolved in a mixture of 650 ml dichloromethane and 50 ml water. At -10 °C, a solution of 116.1 g bromacetyl bromide was added to this mixture in 150 ml dichloromethane. The reaction mixture was then stirred at room temperature for another 2 hours. For processing, the reaction mixture was mixed with water, the organic phase was separated, washed again with water, dried and evaporated under reduced pressure. The remaining residue was crystallized from crude/petroleum ether. 142 g 2-[2-acetyl]amino-bromobenzophenone with a melting point of 96-98 °C were obtained. 71 g of the previously dissolved 2-acetyl-amino-bromophenone were obtained in a 500 ml yellow bromophenol.For this solution, a solution of 75 g of ammonia was dripped into 1.2 l of methanol at 10 °C. The reaction mixture was then stirred at room temperature for 1.5 hours and then heated at the return stream for 2 hours. For processing, the methanol was distilled at reduced pressure, the residue dissolved in dichloromethane, the solution was washed with 10% aqueous baking soda and dried and pressurised at reduced pressure. The remaining residual raw product was crystallized from methanol. 20 g of 2-OO-5-phenyl-1H-2,3-dihydro-1,4-benzoxodiazepine with a melting point of 178-180 °C were obtained. 60 g of the product obtained were dissolved in 1,2 l of uranium.After moisture removal, 34.2 g of potassium tert-butylate was added to the solution. Then a solution of 20.6 ml methyl iodide was dripped into 75 ml tetrahydrofuran and the reaction mixture stirred for one hour at room temperature. To prepare the reaction mixture, the mixture was mixed with an ice-cold sodium chloride solution, diluted with dichloromethane, the aqueous phase was separated, the organic phase was washed with neutral water, dried with sodium sulphate, filtered and evaporated. The residual product was decrystallized from ethanol. 56 g of 1-Myl-2-oxo-5-phenyl-1,3H-24-dibenzodiazepine, with a melting point of 154-155 °C, were obtained.The reaction mixture was treated as described in example 1 D and the resulting raw material was crystallized from ethanol. 47,2 g of 3-hydroxyimino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine with a melting point of 239-242 °C were obtained.E) 6,8 g of the above product were obtained in 500 ml of methanol gel. 12 g of Raney nickel were added to the solution and then hydrolysed for 12 hours at a hydrogen pressure of 6 bar at room temperature.The resulting crystalline precipitate was vacuumed, washed with acetonitrile and then hexane and then dried under reduced pressure. 5.9 g of benzene sulfonate of the 3-amino compound was obtained with a melting point of 224-227 °C. For the release of the amine, 5 g of the above obtained benzene sulfonate were dissolved in dichloromethane and the solution was dissolved in water-soluble sodium carbonate.3,1 g 3-amino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine was obtained.F) 0,38 g 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonic acid, 0,50 g 3-amino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine and 0,46 g triaminoacetate were dissolved in 50 ml dichloromethane. 0,58 g 2-chloromethylpyridinium iodide was added to the solution and the reaction mixture was boiled for one hour at the return flow. The reaction table was then processed as described in example 5. It was obtained as 0,69 g 3-hydroquinoline-1,3-dihydroxy-1-pyrrolo-1,3-dihydroxy-2-pyrrolo-1,3-dihydroxy-2-pyrronyl-2-o-2-methyl-1-o-2-methyl-1-o-carbamethane. The following information shall be provided for the purpose of the test: The following shall be indicated in the column for the product:The Commission shall, by means of implementing acts, lay down the rules for the application of this Regulation.

Example 7: The manufacture of optical isomers of 3-[(4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl) amino]-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine. The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

A) From racemic 3-amino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (production see example 6 E) an analogue was obtained Example 2a A-D (-)-(3S) 3-amino-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine with an optical rotational value [α] 20 D(b) In the same way as in example 1H, 1,7 g of the above obtained (-) - (((3S) -3-amino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine was incorporated into a reaction solution containing dichloromethane containing 1,36 g of mixed anhydride of 1,36 g of 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonate and 0,52 ml of methanosulfonic acid chloride. The reaction mixture was treated as described in example 1H. 2,6 g of 2,6-amino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-fenyl-1-oxyquinoline was obtained by crystallographic flash point. This product was obtained by the removal of enzyme glycol-carbonyl-methyl-1-cyl-methyl-1-cyl-dihydroxy-methyl-1-cyl-dihydroxy-methyl-1-cyl-dihydroxy-methyl-1-cyl-dihydroxy-methyl-1,3-phenyl-1,3-dihydroxy-carbonyl-dihydroxy.20 DThe resulting product is a solution of - 61,6° (c = 0,5 in methanol).

The active substance is a substance that is capable of being used as a solvent for the production of a substance.

A) Analogue Example 2b A-C was (+) - (((3R) 3-amino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H1,4-benzodiazepine with an optical rotation value [α]20 D(b) In the same way as in example 1 H, 0,65 g of the above obtained (+) - ((3R) -3-amino-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine was converted into a reaction solution containing dichloromethane from 0,52 g of mixed anhydride of 0,52 g of 4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonate and 0,2 ml of methane sulphonic acid chloride. The reaction mixture was treated as in example 1 H. After flash chromatography and crystallization from ethanol, 596 enantiomethylenes (+ 3R-3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-benzodiazepine were obtained at 147 °C.20 DThe maximum value of the product obtained from the product shall be:

Example 8: The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons.

A) 30 g N1-Methyl-N1- ((4-methylphenyl) 2-hydroxy-1,3-diaminopropane and 24.2 ml triethylamine were dissolved in 225 ml dichloromethane. Under ice cooling, a solution of 16.5 ml thiophen-2-carbonate chloride was slowly dripped into the solution in 50 ml dichloromethane. The reaction mixture was left at room temperature for 12 hours. For processing, the reaction solution was then washed with water and aqueous saline, the organic phase was separated, dried and the solvent was dissolved under reduced pressure. The residue was 52.2 g crude oily N1-Methyl-N1-methylphenyl-N2-methyl-N2-902-diaminophen-2-hydroxylamine (150 ml) which was added to the product before further washing and obtained in the next reaction step.The raw mixture was dissolved in 280 ml of tetrachlorethane and boiled for one hour at the boiling point as described in example 1B. The oil-based product was obtained by evaporating the tetrachlorethane, dissolving the residue in dichlorethane, dissolving it in a 10% solution of sodium chloride and then reducing the residue with a solution of chlorophyll and methanol, dissolving it in a solution of methanol and methanol.32.4 g 2-Chlormethyl-1,7-dimethyl-5- ((2-thienyl) 2,3-dihydro-1H-1,4-benzodiazepine was obtained as an oily substance which was further processed in the next reaction step without further purification.C) 13.6 g of the above obtained substance were oxidised with 8.2 g of potassium permanganate by the method described in example 1C. The reaction mixture was processed as described in example 1C. The resulting product was dissolved in dichloromethane and flash-chromatographed over a silica gel using dichloromethane/methanol 95: 5 as an elution agent. 3.8 g of 1,7-dimethyl-2-o-methyl-52-dihydroxydehyde-3-dihydroxydehyde-1,4 g were obtained under the method described in example 1C. 7,2 g of the resulting product were dissolved in a dissolved N-methyl-1-1-1-1-1-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4- add butylate and stir the mixture for another 15 min. Then add 4.6 ml of isomyl nitrite so slowly under cooling that the temperature of the reaction mixture is kept below 0 °C. stir for another 30 min at 0 °C. Stir the mixture under preparation into a mixture of 300 ml of ice-cold water, 300 ml of acetic acid ether and 15 ml of acetic ice. Separate the organic phase and extract the aqueous phase again with acetic acid ether. Combine the organic phases, wash with water and aqueous cooking salt, dry them and reduce pressure.E) 2.0 g of the above product were dissolved in 150 ml of methanol. 8 g of Raney nickel were added and then hydrated for 7.5 hours at a hydrogen pressure of 4 bar. For processing, the catalyst was filtered and the solvent was distilled at reduced pressure. A residue of 1.4 g of the raw product was left. This was absorbed into dichloromethane and extracted with dilute aqueous hydrochloric acid solution. The hydrochloric acid phase was separated, alkaline extracted by addition of dilute aqueous sodium solution and with dihydromethane.The reaction mixture was treated as described in example 1H) and obtained 2,3 g of raw product which was dissolved in dichloromethane and purified by flash chromatography using silicon gel using dichloromethane/methanol 96-4 as the elution point. After dilution, 0,7 g of the solution was obtained: 0,7 g of dicloromethane, 0,7 g of dicloromethane, 0,4 g of dicloromethane, 0,4 g of dihydroxyethyl-2-methyl-2-methyl-2-methyl-1-methyl-1-methyl-1, 0,4 g of dihydroxyethyl-2-methyl-2-methyl-1,4-methyl-2-methyl-2-methyl-1,4-methyl-2-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-1,4-methyl-2-methyl-1,4-methyl-1,4-methyl-1,4-methyl-2-methyl-1,4-methyl-1,4-methyl-2-methyl-1,4-methyl-1,4-methyl-2-methyl-1,4-methyl-2-methyl-1,4-methyl-2-methyl-1,4-methyl-2-methyl-1,4-methyl-2-methyl-1,4-methyl-2-methyl-1,4-methyl-2-methyl-1,4-methyl-2-methyl-2-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-meth

The formula I compounds in the following table were obtained by acylation of the corresponding 3-aminobenzodiazepine derivatives of formula II, following the methods described in the examples above.

Example I: 3-[(4H-Pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl) amino]-8-methoxy-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine tablets, which are to be classified in the same class as the active substance.

The tablets were manufactured in the following composition per tablet: Other

3-[ (4H-Pyrrolo[3,2,1-ij]-5,6-dihydrochinolin-2-carbonyl)-amino]-8-methoxy-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepin	20 mg
Maisstärke	60 mg
Milchzucker	135 mg
Gelatine (als 10%-ige Lösung)	6 mg

The active substance, maize starch and milk sugar were thickened with the 10% gelatine solution. The paste was crushed and the resulting granules were placed on a suitable sheet and dried at 45 °C. The dried granules were passed through a crushing machine and mixed in a blender with the following additional ingredients: Other

Talkum	5 mg
Magnesiumstearat	5 mg
Maisstärke	9 mg

Other and then sold as 240 mg tablets.

Example II: 3-[(4H-Pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl) amino]-8-methoxy-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine tablets, which are to be classified in the same class as the active substance.

Tablets in the following composition per tablet were produced in analogy to Example I.

3-[(4H-Pyrrolo[3,2,1-ij]-5,6-dihydrochinolin-2-carbonyl)-amino]-8-methoxy-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepin	20 mg
Maisstärke	60 mg
Milchzucker	135 mg
Gelatine (als 10%-ige Lösung)	6 mg
Talkum	5 mg
Magnesiumstearat	5 mg
Maisstärke	9 mg

Claims

Compounds of the general formula I in which
R¹ denotes hydrogen, alkyl with 1-4 carbon atoms or cycloalkylalkyl with 4-7 carbon atoms,

R² denotes hydrogen, halogen, alkyl with 1-5 carbon atoms, alkoxy with 1-5 carbon atoms or trifluoromethyl, and

R³ denotes hydrogen, halogen, alkyl with 1-5 carbon atoms or alkoxy with 1-5 carbon atoms, or

R² and R³ are bonded to two adjacent carbon atoms and together denote an alkylenedioxy group with 1-2 carbon atoms,

R⁴ stands for cycloalkyl with 5 to 6 carbon atoms, thiophene or an optionally substituted phenyl group a in which

R⁷ denotes hydrogen, halogen, alkyl with 1-5 carbon atoms, alkoxy with 1-5 carbon atoms or trifluoromethyl, and

R⁸ denotes hydrogen, halogen, alkyl with 1-5 carbon atoms or alkoxy with 1-5 carbon atoms,

R⁵ denotes hydrogen or halogen,

R⁶ denotes hydrogen, halogen, alkyl with 1-5 carbon atoms, alkoxy with 1-5 carbon atoms or trifluoromethyl, and

Z stands for an alkylene chain with 2-4 carbon atoms, which can optionally be mono- or disubstituted by alkyl with 1-4 carbon atoms, or onto which a 5-6-member carbocyclic ring can optionally be fused, or for an -X-CH₂-CH₂- chain in which X is bonded to the phenyl ring of the indole framework and denotes oxygen or sulphur,
and the acid addition salts thereof.
Compounds according to Claim 1, in which R⁵ denotes hydrogen and Z represents a propylene chain.
Compounds according to Claim 1, in which R⁴ represents an optionally substituted phenyl group a in which R⁷ and R⁸ have the above meanings.
Compounds according to Claim 3, in which Z denotes an alkylene chain with 2-3 carbon atoms, R² denotes hydrogen, alkoxy with 1-5 carbon atoms, in particular methoxy, alkyl with 1-5 carbon atoms, in particular methyl, or halogen, in particular chlorine, and R³ denotes hydrogen, R⁷ denotes hydrogen, alkyl with 1-5 carbon atoms, in particular methyl, or halogen, in particular fluorine, and R⁸ denotes hydrogen or halogen, in particular fluorine, R⁵ denotes hydrogen, and R⁶ denotes hydrogen or halogen.
Compounds according to Claim 4 which represent 3-[(4H-pyrrolo[3,2,1-ij]-5,6-dihydroquinoline-2-carbonyl)-amino]-8-methoxy-1-methyl-2-oxo-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine and the acid addition salts and optical isomers thereof.
Compounds according to Claim 2, in which R² denotes hydrogen, alkoxy with 1-5 carbon atoms, in particular methoxy, alkyl with 1-5 carbon atoms, in particular methyl, or halogen, in particular chlorine, and R³ denotes hydrogen, R⁴ denotes cycloalkyl with 5-6 carbon atoms or thienyl, and R⁶ denotes hydrogen or halogen.
Compounds according to Claim 6, in which R⁴ denotes cyclohexyl.
Medicaments, containing a pharmacologically effective amount of a compound according to Claim 1 and customary pharmaceutical auxiliaries and vehicles.
A process for the preparation of compounds of the general formula I in accordance with Claim 1 in which R¹, R², R³, R⁴, R⁵, R⁶ and Z have the meanings given in Claim 1, and the acid addition salts thereof, characterised in that amino compounds of the general formula II in which R¹, R², R³ and R⁴ have the above meanings, are acylated with acids or reactive acid derivatives of the general formula III in which R⁵, R⁶ and Z have the above meanings and Y denotes hydroxy or a reactive group, and, optionally, free compounds of Formula I are converted into the acid addition salts thereof, or the acid addition salts are converted into the free compounds of Formula I.