PL89204B1 - 4h-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid amide(s) - CNS inhibitors, anticonvulsants, tranquillizers, etc.[CH567020A5] - Google Patents

Abstract

Title cpds. are of formula (I): where Q = CONR2R3; R' = H or 1-3C alkyl; R2 and R3 = H, 1-6C alkyl, 2-6C hydroxyalkyl, 4-7C dialkylamino-alkyl, or 7-9C aralkyl, or NR2R3 forms a is not >10C cyclic residue opt. contng. O or NR, where R = 1-4C alkyl or hydroxyalkyl; and rings A and B are opt subst. by F, Cl, Br, 1-6C alkyl, 1-6C alkoxy, CF3 or NO2; and include salts and 5-N-oxides of I. I are prepd. (a) by condensing HNR3R2 with a deriv. of I (Q = CO2H) or (reductively) with I (Q = CHO), or (b) by cyclizing a 2-(1H-1,2,4-1-rinzolo-3-carboxylic amide-5-halomethyl) substd. benzophenone, or other suitable deriv. [CH567020A5]

Description

The subject of the invention is a process for the preparation of new diazepine derivatives of the general formula I, in which B5 represents a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, R2 and R3 represent alkyl radicals with 1 to 6 carbon atoms or hydroxyalkyl groups with 2 to 6 atoms carbon or aralkyl groups with 7 to 9 carbon atoms, the lower alkyl radicals R2 and R3 may be linked to each other in the -p or - y position also directly or via an oxygen atom, an imino group, a lower alkylimino or a hydroxyalkylimino group containing at most 4 carbon atoms, forming a divalent group with a total of at most 10 carbon atoms, and rings A and B may be substituted with halogen atoms up to 35, alkyl or alkoxy groups with 1-6 carbon atoms, trifluoromethyl groups or mitric, and 5-oxides of compounds of formula I or addition salts of compounds of formula I with inorganic and organic acids. In compounds of formula I a substituent as an alkyl radical it represents, for example, an ethyl or propyl radical, in particular a methyl radical. R2 and R3 as alkyl radicals having 1-6 carbon atoms mean, for example, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl or hexyl radicals, preferably methyl or ethyl as hydroxyalkyl groups. with 2 to 6 carbon atoms means for example 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 2-hydroxy-1-methylpropyl, 2-hydroxypenty, 2-hydroxyhexyl, and especially 2 -hydroxyethyl, and as aralkyl radicals containing not more than 7-9 atoms (for example, carbon means benzyl, phenylethyl, α-, o-, m or p-methylbenzyl, 3-phenylpropyl or α-methylphenyl radicals. of the alkyl groups, the abovementioned groups are preferably only as R2, i.e. only once, R3 then being a hydrogen atom or a lower alkyl radical. The related alkyl radicals R2 and R3 together with the nitrogen atom that binds them, i.e. the group NR2R3 , they may be groups such as 1-pyrrolidinyl, piperidime, hexahydro-1H-azepin-1-yl, motrpholino, 1-piperazin-1 or hexahydro-1H-1,4-diazepin-1-yl. The last two groups can be shown in the -4 position, i.e. in the imine group, for example (methyl, ethyl, propyl, isopropyl, butyl, isolbutyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or 3-hydroxybutyl, and all the other rings mentioned above may also be substituted on carbon by ethyl, profile or, in particular, methyl radicals. As examples of carbon-substituted alkyl radicals or carbon and nitrogen-substituted NR2R3 groups, groups such as 89 20489 204 2,5-dimethyl-1-pyrrolidinyl, 2-methyl, 3-methyl- and 4-methyl-piperidine, 2,6-dimethyl-piperidine, 2,4,6-trimethyl-piperidine, 2 , 2,6,6- tetramethylpiperidine, 2,5-dimethyl-1-piperazinyl, 2,4,5-trimethyl-1-piperazinyl, 2,4,6- 5 trimethyl-1-piperazine and 3,4, 5-trimethyl-1-perazine. The substituents of the A and B rings as halogen atoms may be fluorine, chlorine or bromine aitoms, and I Alkyl or alkoxy groups with 1 to 6 carbon atoms may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary biutyl, pentyl, isopentyl, 2,2-dimethylpropyl, hexyl, isohexyl, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentylolxyl, isopentyloxy, 2,2-dimertylpropoxy, hexyloxy or isohexyloxy groups. The substituent on ring A is preferably fluorine, bromine, trifluoromethyl, and in particular chlorine or nitro group. Such a substituent is preferably in the -8 position. The ring B is preferably unsubstituted or substituted by fluorine, chlorine, bromine, a trifluoromethyl or nitro group in any position, but in particular with fluorine or chlorine in the ortho position. of the formula I, their 5-oxides and the corresponding inorganic and organic acid addition salts have valuable pharmacological properties. They suppress the central nervous system, especially show anti-spasmodic, anti-aggression and anesthetic action, and inhibit somatic reflexes. An antispasmodic effect can be found, for example, in the pentetrazole cramp test in mice at doses from about 1.0 mg / kg / person. and in the strychnine cramp test in mice at doses ranging from about 1.0 mg / kg per dose. Compared to the outstanding pharmacological activity, the toxicity of the compounds of formula I is low. Observations on various experimental animals have shown a sedative effect with little or no reduction in response to external stimuli. Central nervous system suppressive properties, especially antispasmodic properties, and further action ranges confirmed by selected experiments (e.g. W. Theobald and HA Kunz, Arzneimittelforsch. 13, 122 (1963) and W. Theobald et al., Arzneirnittelforsch. 17, 561 (1967)) are predisposed by compounds of general formula I, their 5-oxides and their pharmaceutically acceptable inorganic and organic acid addition salts as active ingredients for sedatives (Psy Chosedativa), muscle relaxants and antispasmodics which may be used, for example, to treat states of excitement and tension, and to treat epilepsy. The compounds of formula I are of particular importance in which R4 represents a hydrogen atom or a methyl radical, R2 and R3 represent hydrogen atoms and / or lower alkyl groups or together with the nitrogen atom joining them represent a 1-pyrrolidinyl, piperidimine or 4-methyl group. -l-poperazinyl, ring A is unsubstituted or substituted with up to 35 halogen, nitro or trifluoromethyl, and ring B is unsubstituted or substituted with one of the substituents listed for ring A, preferably one of rings A and B it carries one of the substituents listed. Among this group, compounds containing one of the above-mentioned substituents, in particular a trifluoromethyl group, and above all chlorine or a nitro group in ring A in position 3, and compounds with an unsubstituted or ortho-substituted fluorine or chlorine ring B, and in particular compounds which combine the above-mentioned substitution characteristics for rings A and B and at the same time contain a hydrogen atom as RA and ethyl groups or preferably a hydrogen atom and / or methyl radicals as R2 and R3, such as 6-phenyl-8-chloro-4H -s-triazolo / 1,5-a (-) 1,4H-benzodiazepine--2-carbonamide, N, N-dimethyl- and N, N-diethyl-6-phenyl-8-chloro-4H-triazolo {l, 5-a) (l, 4) benzodiazepim-2-carbonamide and the corresponding compounds having 6- (o-fluorophenyl) and 6- (o-chlorophenyl) groups instead of the 6-phenyl group, such like 6- (o- -fluorophenyl) -8-chloro-4H- ^ s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide, N, N-dimethyl-6- (o -fluorophenyl) -8-chloro-4H-; s-triazolo (1,5-a (-) 1 , 4) benzodiazepine-2-carbonacmide, N-methyl, N-ethyl and N, N-diethyl-6- (o-fluorophenyl) -8-chiloro-4H-s-triazolo (1,5- a) (1,4) bezodiazepLno-2-carbonamide, 6- - (o-chlorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4-benzodiazepine-2-carbonaimide, N-methyl-, N, N-dimethyl- and N, N-diethyl-6- (o-chlorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine -2-carbonamide and N, N-dimethyl-6-phenyl-8-nitro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide and N, N-dimethyl- 6-phenyl-8- (trifluoromethyl) -4H-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide. Preparation of compounds of general formula 1, their 5-oxides and salts According to the invention, the carboxylic acid of the general formula II, in which R4 has the meaning given above, and rings A and B may be substituted as described for formula 1, or a reactive derivative function of such an acid or a 5-oxide of such a compound is reacted with a compound of general formula (III) in which R 2 and R3 are as defined above, or with a reactive functional derivative of this compound, and the resulting reaction product is then optionally oxidized to the 5-oxide or optionally converted to a T addition salt with an inorganic or organic acid. These reactions are carried out, for example, such that a carboxylic acid of general formula II is reacted with a compound of general formula III in the presence of a barbodiirnide such as dicyclohexylcarbodiimide in an inert solvent, for example tetrahydrofuran. Lower alkyl esters, such as the methyl ester or the ethyl ester of acids of general formula II, can be reacted with compounds of general formula III to the corresponding amides of general formula I by cold or by heating and, if appropriate, overnight. Closed. It is also possible to convert the amides of general formula I into other amides of general formula I by heating with compounds of general formula 3. As further reactive functional derivatives of the carboxylic acids of general formula II, halides, in particular chlorides, and anhydrides, especially anhydrides mixed with half esters of carbonic acid. These functional derivatives are reacted with a compound of general formula III preferably in the presence of an acid-binding agent, for example a strong tertiary organic base such as triethylamine, N-ethyl diisopropylamine, pyridine or s-collidine, which is used in excess it can also serve as a reaction medium, either in the presence of an excess of a compound of formula III in the absence or presence of an inert organic solvent such as dioxane, tetrahydrofuran, benzene or dimethylformamide. Further derivatives of the carboxylic acids of general formula II are, for example, p-initrophenyl esters and cyanomethyl esters which are reacted with compounds of general formula III in an inert organic solvent, optionally with heating. Under analogous conditions, the 1-imidazolides of carboxylic acids of general formula II are reacted with compounds of general formula III. Reactive functional derivatives of compounds of general formula III, which can be reacted directly with acids of general formula 2, are isocyanates and isothiocyanates of compounds of general formula III with hydrogen as R3. These compounds are heated with acids of general formula 2 until an equimolar amount of carbon dioxide or carbon oxysulfate is evolved. The reaction with isocyanates and isothiocyanates can be carried out in the absence or in the presence of an inert organic solvent with a sufficiently high boiling point or boiling range. Further (reactive functional derivatives of compounds of general formula III with hydrogen as R3 are, moreover, for example N-triethylsilyl derivatives obtained by reacting these amines with trimethylsilyl chloride in an inert (anhydrous organic solvent which is reacted with reactive functional derivatives of acids of the general formula II in an inert organic solvent, trimizing the N-trimethylsilyl amide derivatives of the general formula I, from which the desired amides are produced by decomposition with water or with lower alkanols. As functional derivatives of compounds of the general formula 3, in which both R2 and R3 are not hydrogen, for example their N-chlorocarfoonyl derivatives are used and reacted with salts, for example alkali metal salts of carboxylic acids of general formula II in the presence or absence of an inert of an organic solvent, heating the reaction mixture until an equimolar amount of the oxide is released carbon from a carboxylic acid anhydride, carbamic acid, formed at the beginning. Also, the compounds of general formula III with the substituents R2 and R3 which do not represent a hydrogen atom are derived amides of sulfuric acid alkyl monoesters and phosphorous acid o-phenylene diester amides, which are! by reaction with carboxylic acids of general formula II in an organic solvent such as pyridine, dioxane or dimethylformamide, or benzene, the desired amides of general formula (I) are obtained. , the functional derivatives will be discussed below. Most of the compounds of general formula III and their functional derivatives are known, and others can be prepared analogously to the known compounds. Hydrogen peroxide is preferably used as oxidizing agents for the oxidation of compounds of general formula I to their 5-oxides. or peracids at a temperature of about 0-70 ° C. The peracids used are, for example, peracetic acid or perbenzoic acids, such as perbenzoic acid; The oxidizing agents are preferably used in a solvent, for example peracetic acid in acetic acid and perbenzoic acid in halogenated hydrocarbons such as methylene chloride or chloroform. The acid addition salt preparation method is discussed above. is lower. The compounds of the general formula (II) used in the process according to the invention as starting materials are prepared, for example, as follows: The starting materials are compounds of the general formula (IV) in which the rings A and B can be substituted as indicated for formula 1. The compounds are described in the literature, for example 2-amino-5-chlorobenzophenone (FD Chattaway, J. Chem. Soc. 85, 344 (1904)). 2-amino-2 ', 5-diacetophenone (LH Sterinbach et al., J. Org. Chem. 26, 4488 (1961)), and 2-amino-5-chloro-2 / -fluorobenzophenin and others and (LH Sternlbach et al. J. Org. Chem. 27, 3781-3788 (1962) The compounds of general formula IV are diazotized and the diazonium salts obtained are then combined with diethyl (2-chloroalkanoamido) -malonic acid esters in which the chloralalkinamide group contains at most 5 carbon atoms, such as (2-chloroacetamido) -malonic acid diethyl ester (Ajay Kumar Bose, J. Indian Chem. Soc. 31, 108-110 (1954)) to give the corresponding acid diethyl esters ( 2-Chloroalcoamido (-) 2 -benzoylphenylazo) malonic The coupling products are then converted by the successive treatment of sodium hydroxide and hydrochloric acid into compounds of the general formula where B is as defined above, and The rings A and B may be substituted as indicated in formula 1. These compounds are preferably subjected to pretreatment with potassium iodide after In the reaction with an aqueous ammonia solution or with hexamethylene tetramine, the chlorine or iodine atom being replaced by the amino group, at the same time, there is a ring closure reaction with the separation of water to carboxylic acids of the general formula 2. It is also possible to react the compounds of general formula 5 first, after pretreatment with potassium iodide, with sodium azide to give compounds of the general formula 6, in which Bi is as defined above and rings A and B can be substituted as indicated in the discussion of formula 1. Compounds of general formula 6 are then cyclized with triphenylphosphine with the evolution of nitrogen to give compounds of general formula 2. Carboxylic acids of general formula 2 containing a halogen atom as the ring substituent B or their lower alkyl esters are preferably obtained by treatment with sodium hydroxide on the abovementioned diethyl esters of (2-chloroalkanoamido (-)) 2-ibenzoyl-phenylazo) -malonic, in which the benzoyl or phenyl group may contain the substituents specified for the B or A rings, under mild conditions, i.e. using the highest twice the molar amount of sodium hydroxide in a highly dilute aqueous orbital solution. 10 ° C. to room temperature, and the reaction mixture becomes neutral before further processing. Thus, instead of the carboxylic acids of the general formula 5, their ethyl esters of the general formula 5a are obtained, in which B is as defined above, and the rings A and B may be substituted as indicated in the discussion of formula 1. of the general formula 5a, as well as the corresponding carboxylic acids of the general formula V, can be converted by ring closure reactions, for example by reaction with ammonia or preferably with hexamethylene tetramine, into the ethyl esters of the carboxylic acids of general formula II and these are either hydrolyzed to free carboxylic acids, or they are used directly as starting materials in the process for the preparation of the compounds of formula 1. In addition, the above-mentioned diethyl esters of (2-chloroalkanoimido-2-benz (Oil-phenylazo) -malonic acid, in which the benzoyl or phe-malonic acid group are The nylon can contain the substituents given for the A or B rings, it can also be reacted with ammonia in an aqueous-organic solution, for example in a mixture concentrated aqueous ammonia solution and dimethylformamide. Under mild conditions and with a lower concentration of ammonia, the ethyl ester of the corresponding compound of the general formula V can be obtained, but the reaction conditions can also be so selected that in situ also the aliphatic bound chlorine atom reacts with ammonia and a second ring closure occurs to the ethyl ester of the corresponding carboxylic acid of the general formula 2. When the reaction time is lengthened and / or the higher ammonia concentration is used and, if appropriate, the temperature is increased, ammonolysis of the carboxylic acid ester of the general formula II obtained by (ring closure, to the N-unsubstituted amides of the general formula I according to the present invention. In the above-mentioned reactions, other lower dialkyl esters can also be used in place of the diethyl esters of (2-chloroalkanoamido (-) 2-benzoyl-phenylazo) -malonic acids. Example: dimethyl ester, especially in the latter Variant with in situ ammonolysis . It is also possible, especially in the variant of formation of the triazole ring and in situ closure of the ring in order to produce the diazepine ring with the aid of ammonia solution, instead of 2-chloroalkanamide compounds, 2-bromalkanoamide compounds may be used. From the carboxylic acids of the general formula: 2, optionally, reactive functional derivatives are prepared in a known manner. For example, by treating an excess of thionyl chloride at its boiling point, and by removing the excess thionyl chloride under reduced pressure, carboxylic acid chlorides of the general formula II are obtained, most often in a mixture with their hydrochlorides. These mixtures are preferably reacted directly with an excess of compounds of general formula III which is increased in proportion to the hydrochloride present. The lower alkyl esters of the carboxylic acids of general formula II are obtained, for example, by boiling the carboxylic acids in hydrogen chloride saturated lower alkanols desirable as ether constituents. Further, for example, mixed anhydrides with alkoxy formic acids are obtained by reacting carboxylic acids with of general formula II with cold lower alkyl esters of chloroformic acid in the presence of an acid-binding agent such as triethylamine in an inert solvent such as tetrahydrofuran. In order to obtain the 1-imidazolides, the carboxylic acids of the general formula II are treated, for example, at room temperature or slightly elevated temperature on 1,1-carbonyldiimidazole until the evolution of carbon dioxide is complete. The p-nitrophenic ester is obtained, for example, by reacting carboxylic acids of general formula II with p-nitrophenol in the presence of N, N, dicyclohexyl carbodiimide in an inert solvent such as tetrahydrofuran, in the cold. According to the invention, it is possible to convert in a known manner into addition salts with inorganic or organic acids. Acids used are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, methanesulfonic acid, ethanesulfonic acid or citric acid, preferably in the presence of a solvent such as acetone, methanol, ethanol, ether or mixtures thereof. The compounds of formula I, their 5-oxides and their corresponding pharmaceutically acceptable acid addition salts are preferably administered orally or rectally. The daily dose for warm bloods is 0.01-2 mg / kg. Preferred unit forms, such as dragees, tablets or suppositories, preferably contain 0.5 to 25 mg of active ingredient, that is, of the compound of formula I, its oxide or their pharmaceutically acceptable acid addition salts. These formulations are prepared by leaving the active ingredient with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch or amylopectin, followed by pancake powder or powdered citrus pulp. cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to give tablets or dragee kernels. The latter are coated, for example, with concentrated sugar solutions, possibly additionally containing, for example, gum arabic, talc and / or titanium dioxide, or with varnish dissolved in a volatile organic solvent or solvent mixture. Dyes can be added to these coatings, for example for the determination of various doses of active ingredient. * Other examples of unit dose forms are hard gelatine capsules and soft sealed capsules made of gelatin and a softener such as glycerin. The former contain the active ingredients, preferably in the form of granules, in admixture with lubricants such as talc or magnesium stearate, and optionally with stabilizers such as sodium metabisulphite or ascorbic acid. Example I. 5.08 g (0.015 g) moles) of 6-phenyl-8-chloro-4H-s-triazole (1,5-a) (1,4) benzodiazepine-2-carboxylic acid is boiled under reflux: from 50 ml of thionyl chloride within 1 hour. The lapped yellow solution is evaporated at 40 ° under reduced pressure and the residue, in order to completely remove the thionyl chloride, is redissolved in 100 ml of absolute toluene and evaporated. To the obtained crude mixture of 6-phenyl-8-chloro-4H-s-triazolo (1,5) (1,4) benzodiazepine-2-carbonyl chloride and its hydrochloride was added a solution of 22 g (0.3 mole) of diethylamine in 100 ml of absolute dioxane and refluxed for 1 hour. The mixture is then evaporated at 40 ° C under reduced pressure and the residue is dissolved in a mixture of 250 ml of chloroform and 100 ml of water. The organic phase is washed twice with 100 ml of water, dried over sodium sulfate and evaporated at 40 ° under reduced pressure. The residue is crystallized from the benzene-hexane mixture and after drying under reduced pressure gives N, N-diethyl-6-phenyl-8-chloro-4H-s-triazolo (1,5-a) (14) benzodiazepine-2 -carbonamide, mp 175-177 °. In an analogous manner, by using the following amines instead of diethylamine, the end products mentioned below are obtained: by using 13.5 g (0.3 mole) of diethylamine, N, N-di-ethylamine is obtained. 50 55 60 methyl-6-phenyl-8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepm-2-carbonamide, mp 135-137 ° (from methylene chloride-hexane Using 9.3 g (0.3 mol) of methylamine gives N-methyl-6-phenyl-8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide . Using 13.5 g {0.3 mol) of ethylamine gives N-ethyl-6-phenyl-8-chloro-4H-s-triazolo (1,5-a) (1,4) benisodiazepine-2-carbonamide. Using 18 g (0.3 mol) of isopropylamine, N-isopropyl-6-phenyl-8-chloro-4H-s-triazolo (1,5-a) (1,4) tanzodiazepine-2Hcarbonamide is obtained. 3 g (0.3 mol) pyrrolidine gives 1- (6-phenyl-8-chloro-4H-s-triazole (1,5-a) (1,4) benzodiazepin-2-yl) -carbonyl) -pyrrolidine .. • ¦ By using 25.5 g (0.3 mol) of poperidine, 1- (6-pheinyl-8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepines-2- yl) -carbanyl) -piperidine. Using 26 g (0.3 mol) of morpholine, 4- <6-phenyl-8-chloro-4H-s-triazolo diazepin-2-yl) -carbonyl) -morpholine is obtained. g (0.15 moles) of 1-methylpiperazine and using 250 ml of methylene chloride and 100 ml of 0.1N sodium hydroxide solution instead of a chloroform-water mixture to dissolve the residue after evaporating the reaction mixture, 1- (6-phenyl) is obtained -8-chloro-4H-s-triaziolo (1,5-a) (1,4) benzodiazepin-2-yl) -carbonyl) -4-methylpiperazine. Also by analogously using the amounts given below, always corresponding to 0.015 moles of substituted 6-phenyl-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acids and 22 g (0.3 moles) of diethylamine or 13.5 g (0 , 3 moles) of dimethylamine The corresponding amides are used, starting from 5.60 g of 6- (o-chlorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid, Sie N, N-diethyl-6- (o-chlorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide, m.p. 156-158 ° (from isopropanol and N, ^ N-dimethyl-6- (o-chlorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4-benzodiazepine-2Hcarbonamide, m.p. 142-145 ° Starting from 5.35 g of 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid, N is obtained, N-diethyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide, mp 200- 202 ° - (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide, mp 180-182 ° (from isopropanol). with 6.10 g of 6- (α, x, α-trifluoro-o-tolyl) -8-chioro-4H-s-triazolo (1,5-a) (1,4) banzodiazepino-2- carboxylate gives N, N-diethyl - and N, N-dimethyl-6- (a, a, a-trifluoro-o-tolyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2- -carbonamide Starting from 4.83 g of 6-phenyl-8-fluoro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2H-carboxylic acid, N, N-diethyl- and N, N-dimethyl-6-phenyl-8-fluoro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide 11 89 204 12 Starting from 5.75 g 6-phenyl-8-bromo-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid gives N, N-diethyl- and N, N-dimethyl- tyl-6-phenyl-8-bromo-4H-s-triazolo (1,5-a) (1,4- benzodiazepine-2-carbonamide. ((6-Phenyl-8-chloro-4H-s-triazole benzodiazepine-2-carboxylic acid is prepared as follows: a) a solution of 58.0 g (0.25 mol) of 2-amino-5- chlorobenzophenone (FD Chaittaway, J. Chem. Soc. 85, 344 (1904)) in 310 ml of a mixture of glacial acetic acid and concentrated hydrochloric acid (4: 1) is diazotized at room temperature with stirring with 50 ml (0 25 moles) of aqueous sodium nitrite solution, 150 g of ice are added to the resulting diazonium salt solution and a solution of 52.4 g (0.208 moles) of (2-chloroacetamido) malonic acid diethyl ester (Ajay Kumar Boise, J. Indian) is quickly added dropwise. Chem. Soc. 31, 108-110 (1954)) in 600 ml of acetone Then a solution of 276.0 g (2 moles) of potassium carbonate in 500 ml of water is added dropwise at 5-10 ° over the course of 20 minutes. It remains for 1 hour, then the benzene and saturated sodium chloride solution are added.The benzene solution is separated, washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated. 121 g of crude (2-chloroacetamino) - (2-benzoyl-4-chlorophenylazo) -malonic acid diethyl ester. b) The crude diethyl ester obtained according to a) is dissolved in 1.5 liters of dioxane. 36 g (0.9 mol) of sodium hydroxide dissolved in 2 liters of water are introduced into the dioxane solution, stirred for 30 minutes and then evaporated. Dioxane under reduced pressure. The residue is diluted with 500 ml of water, g of activated carbon are added, the mixture is mixed well and filtered through purified diatomaceous earth. 2M hydrochloric acid is added to the filtrate with vigorous stirring until an acid reaction with Congo is obtained, the precipitated carboxylic acid is filtered off, washed with water and recrystallized from hot methanol. The obtained acid 1- (2-benzoyl-4-chlorophenyl) -5- (chloromethyl ) -1H-1,2,4-triazole-3-carboxylic sinters at 137-138 ° and melts decomposed at 16.9-171 °. The crystals contain an equimolar amount of methanol. By analogy to items a) and b), the following compounds are obtained. Using 66.5 g (0.25 mol) of 2-amino-2 ', 5-dichloroibenzophenone acid is obtained 1- (2-) acid o-chlorobenzoyl (-4-chlorophenyl) 5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid, mp 170-175 ° (decomposition). The substances are precipitated from the aqueous ammonia solution with 2N hydrochloric acid. Using 62.5 g (0.25 moles) of 2-amino-5-chlorro-2'-fluorobenzophenone, the acid 1- (2-) o-fluoro is obtained. robenaoyl) -4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxyyl as a solidified foam. Using 75.0 g {0.25 mol) 2-amino-5-chloro -2'- (trifluoromethyl) -benzophenone is obtained (acid 1- (2-) a, a, a-trifluoro-o-'tolyl (-4-chlorophenyl) -5- (chloromethyl) -1H- 1 ^^ - triazole-S-carboxylic acid. Using 53.8 g (0.25 mol) of 2-amino-5-fluoro-benzophenone, 1- (2-benzoyl-4-fluoro-phenyl (-5-) chloromethyl-1H- acid is obtained. 1,2,4-triazole-3-, carboxylic acid. Using 69.0 g (0.25 mol) of 2-amino-5-bromobenzophenone, the acid is obtained: 1 (2-benzoyl-4-bromophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic. C) 53.2 g (0.20 mol) of potassium iodide are dissolved in 85 ml of water. The resulting solution is diluted with 850 ml of dioxane and at a temperature of 25 °, 71.5 g (0.175 mol) are added while stirring one of 1- (2-benzo-yl-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid according to item b), containing an equimolar amount of methanol. The solution is heated for 1 hour at 45 ° -50 °, 0.5 liters of aqueous ammonia solution are added, the mixture is heated for 2 hours at 45 ° -50 ° and evaporated under reduced pressure. The residue is dissolved in 2 liters of water and the solution is mixed with 2N hydrochloric acid for an acid reaction against Congo. The free carboxylic acid is recovered, sucked off, washed with water until it is neutral, then with methanol and dried under reduced pressure at 120-130 °. We obtain 6-phenyl-8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid, decomposed at 170 ° C. The following procedure is obtained in an analogous manner. compounds: From 72.0 g (0.175 mol) of M2-) o-chlorobenzoyl (-4-chlorophenyl) -5- (chloa: omethyl) -1H-1,2,4-triazol-3-carboxylic acid is obtained 6- (o-chlorophenyl) -8-chloro-4H-s-triazole- (1,5-a) (1,4) benzodiazepine-2-carboxylic acid, m.p. 190-195 ° (with decomposition from methanol) From 69.0 g (0.175 moles) of 1- (2-) o-fluoro-benzoyl (-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazol-3-acid -carboxylic acid, 6- (o-fluoro-phenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid, m.p. 179-182 ° (decomposition) from methanol From 77.6 g (0.175 mol) of 1- (2-) a, a, a-trifluoro-o-tolyl (-4-chlorophenyl) -5- (chloromethyl) -1H- acid 1,2,4-triazole-3-carboxylic acid is obtained (Ma, a, a-trifluoro-o-tolyl-8-chloro-4H-s-triazole) 1,5-a) (1,4) benzodiaz epic-2-carboxylic acid From 63.0 g (0.175 mol) 1- (2-benzoyl-4-fluoroienyl) -5- (chloromethyl) -1H-11,2,4-triazole-3-car- 6-phenyl-8-fluoro-4H-s-triazolo (1,5a-a) (1,4) benzodiazepine-2-carboxylic acid is obtained. From 73.7 g (0.175 mol) of l ( 2-benzoyl-4-bromophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid gives 6-phenyl-8-bromo-4H-s-triazole 1 , 5-a) (1,4) 'benzodiazepine-2-carboxylic acid. C (Example II. 3.63 g (0.0102 mol) of 6-o-fluorophenyl <-8-ichliro-4H-s-triazole acid) o) 1.5-a) (1.4) benzodiazepine- The 2-carboxylate is boiled under reflux for 2 hours with 60 ml of itionyl chloride. The clear yellow solution is evaporated at 40 ° under reduced pressure and the residue, in order to completely remove the thionyl chloride, is redissolved in 50 ml of absolute toluene and evaporated again, the crude 6- chloride being obtained as a residue. (o-yluoro-phenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonyl, which is optionally recrystallized from dioxane. The product has a melting point of 198-198 ° (decomposition). For further processing, the crude product is dissolved in 55 ml of dioxane and mixed with a solution of 5.10 g (0.050 mmol) of 1-methylpiperazine in 5 ml of dioxane. The mixture is stirred for 3 hours at room temperature, then poured into ice-water containing 20 ml of 1N sodium carbonate solution, and extracted three times with methylene chloride. The organic phase is washed twice with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. Obtained as a crude residue l - {[6- (o-fluorophenyio) -8-chloro-4H-s-triazole) 1,5-a) (1,4) benzodiazepine-2-yl] carbonyl} -4-methyl -piperazine is dissolved in a little ethanol and the alkanol solution of hydrogen chloride is introduced until the pH of the sample is 3. It is cooled with a mixture of ice and sodium chloride, treated with ether and the hydrochloride crystallizes by rubbing. The crystals are drained and dried under reduced pressure. We obtain 1 - {[6- (fluorophenyl) -8-chloro-4H-s-thiriazolo (1,5-a) (1,4) benzodiazepine-2-yl] -carbonyl) -4-methyl-piperazine hydrochloride melts at 190 ° -195 °. The starting material, carboxyylic acid, which is toned as a starting substance, is obtained according to example I a), b) and c) as follows: 40 a) 78.6 g (0.315 mol) solution of 2-amimo-5 -chloro-2'-yluorobenzophenone (LH Sternbach et al., J.Org. Chern. 26, 3781-3788 (1926)) in 394 ml of a mixture of glacial acetic acid and concentrated hydrochloric acid (4: 1) Diazotization at room temperature with 63 ml (0.315 mol) of aqueous sodium nitrite solution while stirring. 240 g of ice are added to the resulting diazonium solution and a solution of 79.0 g (0.315 mol) of (2-chloroacetarciido) malonic acid diethyl ester (Ajay Kuraasr Bose, J. Indian Chem. Soc. 31, 108-110) is quickly added dropwise. (1954) in 900 ml of acetone, then a solution of 433.0 g (3.14 moles) of potassium carbonate in 770 ml of water is added dropwise at 10-15 ° over the course of 60 minutes, and the mixture is stirred for an additional hour. ether and saturated sodium chloride solution are added. The ether solution is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The solid residue is dissolved in a little methylene chloride, and hot hexane is added to the solution. to commence metallization and left to crystallize, cooling and seeding to obtain the diethyl ester of the? 2-chloroacetamido) -2- (o-fluoro-benzoyl) -4-chloro-14 phenylazo-malonic acid melts at 98-100 °. b) To a solution of 51.2 g (0.10 mol) of (2-chloroacetamido) - (2-) o-fluoro-benzoyl (-4-chlorophenylaiso) -malonic acid diethyl ester in 600 ml of dioxane is added dropwise Within 2 hours, a solution of 8.0 g (0.20 moles) of sodium hydroxide in 400 ml of water. The temperature of the reaction mixture, initially 20 °, rises to 30 ° at the most, and the pH finally reaches 8.5 °. 9.0. The mixture is stirred for a further 45 minutes at room temperature, neutralized with glacial acetic acid and evaporated under reduced pressure. The remainder is treated with ice and 5% sodium carbonate acid solution, the mixture is shaken twice with ether and the aqueous phase is retained. The boundary phases are combined, washed with ice-cold 5% acid sodium carbonate solution and water, dried over sodium sulfate and evaporated under reduced pressure. The residue recrystallizes from isopropainol. After drying, the obtained 1- (2) o-fluoro-benzoyl (-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid ethyl ester melts at 97 —98 °. c) A solution of 8.44 g (0.02 mol) of 1- (2-) o-fluorobenzoyl-3-acid ethyl ester (-4-chlorophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3 6 g (0.04 moles) of hexamethylene tetramine in 140 ml of absolute ethanol is boiled under reflux for 6 hours, then the solution is evaporated at 40 ° under reduced pressure, the remainder is used in 400 ml ice water and extracted twice with methylene chloride. The organic phase is washed twice with ice-cold 1N hydrochloric acid and three times with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from isopropanol and dried. The obtained 6- (o-yluoro-phenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-acid ethyl ester is obtained. -carboxylic acid melts at 177-179 °. d) 4.81 g (0.0125 mol) 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) -benzodiazepidno-2-acid ethyl ester of carboxylic acid in 250 ml of methanol and 25.5 ml (0.0255 moles) of sodium hydroxide solution is refluxed for 30 minutes. The reaction solution is then evaporated, the residue is dissolved in 50 ml of water and mixed with 2N hydrochloric acid for an acid reaction with Congo. The precipitated carboxylic acid is suction filtered and washed with water until neutral. Then it is washed three more times with 50 ml of methanol each time and dried under reduced pressure at 100 °. The obtained 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) beinzodiazeipine-2-carboxylic acid decomposes at a temperature of 179-182 °. Example III. Analogously to Example I with 5.58 g (0.015 mol) of 6-phenyl-8- (trifluoromethyl) -4H-s-triazolo (1,5-a) (1,4) benzodiazepine-acid. 2-carboxylic acid and 50 ml of thionyl chloride, the crude acid chloride is obtained, which is reacted with 100 ml of a 20% solution of dimethylamine in absolute dioxane. After working up according to Example I, N, N-dimethyl-6-phenyl-8- (trifluoromethyl) -4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide at a temperature of mp 195-197 ° (from ether). By analogy using 22 g (03 moles) of diethylamine in 100 ml of absolute dioxane, N, N-diethyl-6-phenyl-8- (trifluoromethyl) -4H-s-triazole ( 1,5-a) (1,4) benzodiazepine-2-carbonamide. The carboxylic acid used as a starting compound is prepared analogously to example II a) - d): a) from 83.5 g (0.315 mol) 2- Amino-5- (trifluoromethyl) benzophenone gives the diethyl ester of (2-chloroacetamido (-) 2-benzoyl-a, a, a-trifluoro-p-tolylazo) -malonic acid as a red oil. it can be processed further without cleaning. b) From 53.0 g (0.10 mol) of the ester prepared according to a), the ethyl ester of 1-, (2-benzoyl-trifluoro-p-tolyl (-5-) chloromethyl (-1H-1) is obtained. , 2,4-triazole-3-carboxylic acid, melting point 110-111 ° (from petroleum ether) .c) From 8.76 g (0.02 moles (of the ester obtained according to b), the ethyl ester of the acid is obtained. - -phenyl-C- (1,4) beriECK-Hazepine-2-carboxylic acid, mp 162-164 ° (from absolute ethanol) .d) Hydrolysis of 5.0 g (0.0125 moles) of the ester obtained according to c) 6-phenyl-8- (trifluoromethyl) -4H-s-triazolo (1,5-a) - - (1,4) benzodiazepine-2-carboxylic acid is obtained which decomposes at 195 °. Example IV. Analogously to example I with 2.4 g (0.0069 mol) of 6-phenyl-9H-nitro-4H-s-triazolo (1,5-a) (1,4) ibenzodiazepine-2-carboxylic acid and 50 ml of thionyl chloride, the crude acid chloride is reacted with 50 ml of a 20% solution of dimethyl amine in absolute dioxane, anologically N, N-dimethyl-6-phenyl-8-nitrite being obtained from Example I. tro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbamide, m.p. 209-211 ° (from ethyl acetate). Using 50 ml of a 20% bi- of ethylamine in dioxane is obtained from N, N-diethyl-6-phenyl-8-nitro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide. 2.5 g (0.0068 moles) of 6- (o-fluorophenyl) -8-nitro-4H-s-triazol (1,5-a) (1,4) benzodiazepio-2H carboxylic acid, 50 ml of thionyl chloride and 50 ml of a 2Q% solution of dimethylamine in absolute dioxane or 50 ml of a 20% solution of diethylamine in absolute dioxane gives N, N-dimethyl-6- (o-fluorophenyl) -8-n tro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-3-carboxamide, m.p. 178 * -180 ° C (from ethyl acetate) or N, N-diethyl-6- ( o-fluoro-phenyl) -8-nitro-4H-s-triazolo (1,5-a) (1 (4) benzodiazepine-3-carbonamide. The carboxylic acids used as starting compounds are prepared as follows: a) a solution of 20 g (0.0826 mol) of 2-amino-5-nitrobenzophenone (Ullmann, Ber. 31, 1965) in 400 ml of glacial acetic acid and 20 ml of concentrated hydrochloric acid diazotium at 20-25 ° with 16.5 ml (0.0826 mol) of aqueous sodium nitrite solution with stirring. The resulting diazonium solution is mixed with 400 g of ice and a solution of 17.4 g (0.69 mol) of (2-chloroacetamido) -malonic acid diethyl ester (Ajay Kumar Bose, J. Indian Chem. Soc. 31, 108-) is quickly added dropwise. 110 (1954)) in 400 ml of acetone. A solution of 114 g (0.826 mol) of potassium carbonate in 250 ml of water is then added dropwise at 5-10 ° in a period of 20 minutes, the mixture is stirred for another hour, and then benzene and saturated sodium chloride solution are added. The benzene solution is separated, washed several times with a mixture of saturated sodium chloride solution and 5% sodium carbonate acid solution until acid disappearance, dried over sodium sulphate and evaporated to leave the crude ester and diethyl acid (2- chloroacetamido (-) 2-benzoyl-4-nitrophenylazo) rnalone. In a similar manner, using 21.5 g (0.0826 mol) of 2-amino-5-nitro-2'-fluorobenzophenin (Dutch Patent No. 64.05644 CA 62.16137f, and French Patent No. 1,403,125), the crude acid diethyl ester (2-chloroacetamido (-) 2 - (o-fluorobenzoyl) -4- (nitrophenylazo) - - is obtained to a solution of 42 g (0.082 moles) of (2-chloroacetamido (-) 2-benzoyl-4-nitrophenylazo) malonic acid diethyl ester in 1 liter of dioxane is added dropwise over 2 hours 310 ml (0.155 moles) ) 0.5 N sodium hydroxide solution, cooling is applied so that the temperature is 17-20 ° and the pH is finally between 8.0 and 8. 5. The mixture is stirred for 40-30 minutes at 17-20 ° C, then it is neutralized with glacial acetic acid and evaporated under reduced pressure to a volume of about 300 ml. The concentrate is mixed with ice and 5% solution of acidic sodium carbonate and twice with extract. - 45 transients with ethyl acetate. The organic phases are combined, washed with ice-cold 5% acid sodium carbonate solution and water, dried over sodium sulphate and evaporated under reduced pressure. The residue is treated with 250 ml of ether, which causes crystallization. After recrystallization of the product from benzene-ether, 1- (2-benzoyl-4-nitrophenyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid ethyl ester is obtained at a temperature of mp 151-152 °. 55 By analogy, starting from 43.5 g (0.082 moles) of diethyl ester of (2-chloroacetamido (-) 2- - (o-fluorobenzoyl) -4-nitrophenylazo) -malonic acid ethyl ester of 1- (2-) acid is obtained o-Fluoro-benzoyl (-4H-nitrophenyl) -5- (chloromethyl) -1H-1,2,4-60-triazole-3-carboxylic, m.p. 160-162 ° C (from benzene). c) A solution of 11.8 g (0.0285 moles) of the ester obtained according to the first paragraph of point t) and 12 g (0.0853 g g moles) of hexamethylene tetraamine in 750 ml absolute ethanol is boiled under the refrigerator. feedback within 6 hours. Then the solution is evaporated at 40 ° under reduced pressure, the residue is mixed with 500 ml of ice water and extracted twice with methylene chloride. The organic phase is washed twice with ice-cold 1 M hydrochloric acid and once with water, dried over sodium sulphate and evaporated under reduced pressure. The residue is recrystallized from ethanol and dried under reduced pressure. The obtained 6-phenyl-3-initro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid ethyl ester melts at 145-147 °. in an analogous manner, 12.3 g (0.0285 moles) of the ester according to the second paragraph of point b) are reacted with 12 g of hexomethylene ether amine to give 6- (o-fluoro-phenyl) -8-nitro-4H-triazolo ethyl ester ( 1,5-a) (1,4) beinzodiazepine-2-carboxylic acid, m.p. 165-167 ° C (from ethanol). d) A solution of 2.85 g (0.0075 mole) of the ester obtained according to the first paragraph of point c) in -25 ml of dioxane is added with a solution of 1 ml (0.01 mole) of a concentrated (40%) sodium hydroxide solution in 50 ml of methanol. The mixture is allowed to stand for 30 minutes at room temperature, then acidified with 10 ml of 1N hydrochloric acid and evaporated under reduced pressure. The residue is washed several times with water and dried at 80-100 ° under reduced pressure. The resulting 6-phenyl-8-initro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2 acid is obtained. -carboxylic acid decomposes at 208 °. Analogously with 3.0 g (0.0075 moles) of the ester mentioned in the second paragraph of point c), 6- (o-fluorophenyl) -8-initro-4H-s- acid is obtained triazolo (1,5-a) - (], 4) benzodiazepine-2-carboxylic acid with a decomposition temperature of 190 ° C. Example 5 3.67 g (0.10 mol) of 6-phenyl-8- acid ethyl ester are dissolved chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-cathboxylic acid in 300 ml of ethanol at 40 ° and 50 ml of concentrated aqueous ammonia solution are then added. The clear solution is allowed to stand at room temperature for 24 hours and then evaporated at 40 ° under reduced pressure. The red residue is made into a thick suspension in 100 ml of water, sucked off and washed with water. The product is recrystallized from methanol and dried at 100-120 ° in vacuo to give 6-phenyl-8-chloro-4H-s-triazolo (1,5-a) (1,4) benzocliazepine-2 - carbonamide, m.p. 252-254 °. The following 2 compounds are prepared in an analogous manner: Using 4.02 g (0.010 mol) of ethyl 6- (o-chlorophenyl) -8-chloro-4H-s-triazolo (1.5 -a) (1,4) -benzodiazepine-2-carboxylic acid 6- - (o-chlorophenyl) -8-chloro-4H-s-triazolo {1,5-a) benzodiazepine-2-carbonamide at mp 283-255 ° (from methanol). Using 3.85 g (0.010 mol) of 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,4) benzodiazepine acid ethyl ester 2-carboxylic acid (example II a) -c)) gives 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbon- mp 250 ° -252 ° (decomposed from ethanol). Using 4.00 g (0.010 moles) of 6-phenyl-8- (trifluoromethyl) -4H-s-triazolo (1,5 a) - (l, 4) benzodiazepine-2- carboxylic acid (Example III a) -c)), 8- (trifluoromethyl) -4H-s-triazolo (1,5-a) (1,4) benzodiazep'ine-2-carbonamide is obtained using 3.77 g (0.010 mole of (6-phenyl-8-nitro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid ethyl ester (Example IV a) -c)) o- sticks to 6-phenyl-8-nitro-4H-s-triazolo (1,5-a) - (1,4) benzodiazepine-2-carbonamide, Used as a starting compound (the first ethyl ester is prepared as follows: a) 6.77 g (0.020 mol) of 6-phenyl-8-chloro-4H-s-triazolo- (1,5-a) (1,4) benzodiazepine-2-carboxylic acid (example la), b) and c)) is suspended in 250 ml of absolute ethanol, while stirring and, while boiling under reflux, saturate the solution with gaseous hydrogen chloride. The resulting clear solution is further refluxed for 10 hours and then evaporated at 40 ° under reduced pressure. The residue is dissolved in 100 ml of ice-cold 5% acid sodium carbonate solution and 100 ml of methylene chloride, the organic phase is separated, washed with water, dried over sodium sulphate and evaporated at 40 ° under reduced pressure. The crude residue in the form of a lubricant is refluxed for 1 hour with 100 ml of ether, whereby crystallization takes place. After cooling to 0 °, the crystals are suction filtered and washed with ether to give 6-phenyl-ethyl ether. 8-chloro-4H-s-triiazolo (1,5-a) (1,4) -40 benzodiazepine-2-carboxylic acid, mp 137-138 °. By analogy starting with 7.46 g (0.020 mol) of acid ¬ su 6- (o-chloro-phenyl) -8-chloro-4H-s-triazolo (1,5-a) 45 (1,4) benzodiazepine-2-carboxylic acid is obtained its ethyl ester, m.p. 211-213 ° (from ethanol). Example VI. 5.0 g (0.013 moles) of 6- (o-fluoro-phenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carboxylic acid ethyl ester (Example II a) -c)) is dissolved with heating in 150 ml of methanol. A solution of 5.0 g (0.16 mole) of methylamine in 25 ml of methanol is introduced into the warm solution at 30 ° -40 °, followed by 55 months at room temperature for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in methylene chloride and the opalescent solution is filtered through a 2 cm layer of inert M aluminum oxide of activity I. It is washed with plenty of methylene chloride and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride-hexane. After drying, the obtained N-methyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) 19 20 2-Zarbonamide melts at 202-203 °. The following compounds are obtained in an analogous manner. From 5.22 g (0.013 mol) of ethyl ester 6- - (o-chlorophenylamide) -8-chloro-4H-s-triazole (1,5-a) (1,4) - benzodiazepine-2-carboxylic acid (example Va) is N-methyl-6- (o-chlorophenyl) -8-chloro-4H-s-triazolO '( 1,5-a) (1,4) benzodiazepine-2-carbonamide, m.p. 211-213 ° from isopropanol) From 5.20 g (0.013 mol) of 6-phenyl-8- acid ethyl ester ( trifluoromethyl) -4H-s-triazolo (1,5-a) - (1,4) benzodiazepine-2-carboxylic acid (example III a) —c)) gives N-methyl76-phenyl-8- (trifluoromethyl) -4H-s-triazolo (1,5-a) (1,4) benzodiazepine--2-carbonamide. Z 4.90 g (0.013 mole of 6-phenyl-8-riitro-4H-s-thiriazole) ethyl ester (1,5-a) (1,4) benzodiazepine-2-carboxylic acid (Example IV a) -c)) is obtained N-methyl-6-phenyl-8-initro-4H-s-triazole- (1,5-a) (1,4) benzodiazepine-2-carbonamide. Example VII. For a suspension of 3.85 g (0.01 mol) of ethyl 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbohydrate - xylic acid (Example II a) ^ c)) in 200 ml of methanol is introduced under stirring at room temperature for 2 hours with gaseous pure dimethylamine, especially free of methylamine. The clear reaction mixture is evaporated to dryness under reduced pressure. The residue is recrystallized from isopropanol to give pure N, N-dimethyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine- 2-cairbonamide with a melting point of 180-182 °. The following end products are obtained anologically by using the amines given below instead of dimethylamine under the conditions indicated: Ethylamine, which is gaseous for 4 hours at 50 ° C. N-ethyl-6- -4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-carbonamide, mp 232-234 ° (from isopropanol) is obtained. 19 g. (0.32 moles) of isopropylamine, N-isopropyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1.5-a) is obtained within 4 hours at 60 °. - (1,4) benzodiazepine-2-carbionamide, m.p. 255-258 ° (from isopropanol). 2.1 g (0.034 mol) of 2-aminoethanol are obtained in 3 hours at 65 ° C. N- (2 -hydroxyethyl) -6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4-benzodiazepine-2-carbo Namid with a melting point of 236-240 ° (decomposition, from isopropanol). From 10.0 g (0.15 moles) of morpholine in 16 hours at 65 °, 4 - {[6-] fluorophenyl) -8-chloro-4H-s-triaBolo (1,5-a) (1,4) benzodiazepino-2-yl] carbonyl} morpholine, mp 180-182 ° (from isopropainol) From 2.1 g (0.0298 * hioli) pyrrolidine in 3 hours at 65 °, 1 - {[6- (o-fluoro-phenyl) -8-chloro-4H-s-triazolo (l, 5-a) (1,4) benzodiazepine-2-yl] carbonyl} -pyrrolidine, m.p. 202-204 ° (from isopropanol). From 3.5 g (0.041 moles (piperidine within 12 hours) at 65 °, the amorphous 1- {16- (o-fluorophenyl) -8-chloro-4H-s-triazolo- (1,5-a) (1,4) benzodiazepin-2-yl] carbonyl} is obtained -piperidine, which liquefies at a temperature of 100-105 ° L. Example VIII. A solution of 2.56 g (0.005 mol) of (2-chloroacetamido) -2- (o-fluorobenzoyl) -4-chlorophenylazo (-malonic acid) (example II a)) in 10 ml of dimethylformamide is prepared at room temperature 3.0 ml (0.042 mol) of concentrated ammonia. The mixture is stirred for 16 hours at room temperature and then heated for an additional 6 hours at 70 °. The mixture is then poured into 100 ml of ice-water and extracted three times with ethyl acetate. The organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in a mixture of methylene chloride and methanol (94: 6) and the solution is chromatographed on 100 g of silica gel. A mixture of methylene chloride and methanol (94: 6) is used as eluent. Crude product fractions (Rf value = 0.5 in the methylene chloride-methanol (95: 5) system) 3 * are combined and recrystallized from ethanol-methylene chloride . The 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazepine-2-cathaphonamide obtained after drying melts at 250-252 ° ( decomposition), Example IX. For a solution of 6.8 g (0.018 mol) of N, N-dimethyl-6- (o-fluorophenyl) -8-chloro-4H-s-triazolo (1,5-a) (1,4) benzodiazapine-2 - carbonamide in 270 ml of methylene chloride is added dropwise at 0 ° to a solution of 6.1 g (0.035 mole-75% 40 m-chloro-perbenzoic acid in 140 ml of methylene chloride for 20 minutes.) The clear mixture is stirred for 20 minutes. 3 hours at 0-5 ° C and then 20 hours at room temperature The reaction solution is then evaporated to dryness under reduced pressure, the residue is dissolved in a little methylene chloride and ether is added until a slight cloudiness appears. the crystals are filtered off and recrystallized from the methylene chloride-ether mixture. After drying for 20 hours at 100 ° (0.05 torr) N, N-dimethyl-6- (o-fluorophenyl) -8 5-oxide is obtained -chloro-4H-s-triazolo (1,4) benzodiazepine-2-caribonamide, mp 170-172 ° (decomposition) The compound contains about 1/2 mole of methylene chloride. Another method can be used to obtain the 5-oxides of the other end products of Examples I-VIII. 60 PL

Claims (5)

Claims 1. Process for the preparation of new diazepine derivatives of the general formula I, in which Ri represents a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, R2 and R3 are hydrogen, 5089 204 2122 alkyl radicals of 1-6 carbon atoms or hydroxyalkyl groups with 2 to 6 carbon atoms or aralkyl groups with 7 to 9 carbon atoms, the lower alkyl radicals R2 and R3 may be linked to each other in the position - p or y - also directly or via an atom oxygen, imino, lower alkylimine or hydroxyalkylimino of up to 4 carbon atoms to form a divalent group with a total of up to 10 carbon atoms, and rings A and B may be substituted with halogen atoms up to 35, alkyl or alkoxy groups 1-8 carbon atoms, trifluoromethyl or nitro groups, and 5-oxides and inorganic and organic acid addition salts of compounds of formula I, characterized by the carboxylic acid of general formula II, in which B is as defined above, and the rings A and B may be substituted as described in formula 1, or a reactive functional derivative of such a carboxylic acid or a 5-oxide of such a compound is reacted with a compound of general formula (III), in which R2 and R3 are as defined above, or with a reactive functional derivative of this compound, and the resulting reaction product is optionally oxidized to the 5-oxide or optionally converted to 6o1 addition with with an inorganic or organic acid. 2. Way according to satrz. The process of claim 1, wherein the starting material of general formula 3 is dimethylamine. 3. The method according to p. A carboxylic acid chloride or lower alkyl ester of the general formula II wherein R 1 is hydrogen and wherein ring A is -8 substituted with chlorine and ring B is ortho substituted fluorine, reacts with dimethylamine. 4. The method according to p. A compound according to claim 1, characterized in that the obtained compound of formula I, in which R1, R2 and R3 are as defined in claim 1, 1, and rings A and B are substituted as specified in claim 1 1, is oxidized to its 5-oxide with hydrogen peroxide or peracid. 5. The method according to p. A compound according to claim 1, characterized in that the obtained compound of formula I, in which R1, R2 and R3 are as defined in claim 1, 1, and rings A and B may be substituted as stated therein, oxidized to its 5-oxide with m-chloro-perbenzoic acid. 89 204 / R2 CO-N and ^ aT. Ch-r,; = n Formula / / ^ 2 R3 Formula 3 sr CO-OH o C = N. CH-R, C00H N— (X. CH-R, and COO-CHJ-CH3 ^ -0 6 IVzOf 5a Formula 2 ^^ CO COOH ^ vN_CxrH-R Pattern 4 Pattern S Print WZ Order card D-5035 Price 10 units