JPS59108787A - Manufacture of diazepine compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel substituted 6-aryl-4H-8-triazolo-[ro,4C]-cheno-[2,3e1-1,4-diazepines of the general formula and their physiologically acceptable The present invention relates to acid addition salts that can be used.

In this formula, R represents a hydrogen, chlorine or bromine atom or an alkyl group having 1 to 4 carbon atoms, R2 represents a hydrogen, chlorine or bromine atom, and R3 represents a chlorine or bromine atom.

Furthermore, the present invention provides a process for producing compounds of general formula I, and their use as active ingredients in medicine. It can be obtained by chlorination or bromination of a compound having Furthermore, optionally, the compounds of formula 1 thus obtained can be converted into physiologically acceptable acid addition salts.

Bromination or chlorination of compounds of formula (2) can be carried out using a tertiary organic base such as pyridine in a solvent such as carbon tetrachloride, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide, or a suitable hydrocarbon. with addition or using halodane succinimide.

The temperature of this reaction is from room temperature to the reflux temperature of the reaction mixture, depending on the starting materials used and the method of application.

In general formula I, the final product optionally has the following properties: unless the substituent is a 5-membered or 6-negative, saturated or unsaturated ring containing one sulfur atom in the 1-position of the molecule; They can be converted into their physiologically acceptable acid addition salts by conventional methods. Suitable acids for salt formation include, for example, hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, manic acid, formic acid, zaritelic acid or methane- or toluenesulfonic acid. .

The starting compounds of general formula (1) can be prepared by methods known from the literature for analogous compounds.

Compounds of general formula I and their acid addition salts exhibit valuable therapeutic properties. Extensive pharmacological tests have demonstrated that these compounds have anxiolytic, tone-relaxing, and muscle-relaxing effects, as well as potent anticonvulsant activity.

It also has the property of significantly increasing food intake in warm-blooded animals. The very low toxicity is also noteworthy. These compounds include, for example, DT-"os2.155.
As known from 403 and 2,221,623,
Compared to cheno-1,4-diazepines without an additional triazole ring, it stands out in particular in its very high anticonvulsant activity shown in the so-called bentetrazole test. Additionally, the known 8-alkyl-6-aryl-cheno-[2゜3e]-4H-s-triazolo-[ro, 4C'
:l-1,4-diazepines (DT-O82,229,
845) in its range of activity, or is more than 10 times superior to the latter in terms of the strength of its activity.

Compounds showing particular value or acid addition salts thereof are R
is a bromine atom, R2 is chlorine or a bromine atom, and RlS is a bromine atom, especially 1,8-
Dibromo-6-0-chlorophenyl-48-s-triazolo-[3,4G]-cheno-[2,3e]-1,4-
Soazepine (R1-Br, R2-C1, R3""
]Br) and their acid addition salts have been found to be of value.

A single dose of the compound of the present invention is 0.05 to 50 T da,
Preferably, the dosage is O-1 to 25 (oral) and the daily dosage is 5 to 150 rny"C".

The compounds obtained according to the invention can be used alone or in combination with other active ingredients of the invention, optionally also in combination with other pharmacologically active ingredients, such as antispasmodics or Peter blockers. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions, dispersible powders. Corresponding tablets are, for example,
The active ingredient is combined with known excipients, such as inert diluents such as calcium carbonate, calcium phosphate, or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, magnesium stearate or talc. and/or release prolonging agents such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets can also consist of several layers.

Coated tablets are similarly prepared by coating cores prepared in the same manner as tablets with adjuvants commonly used in coating tablets such as polyvinylpyrrolidone or shellac, gum arabic, Merck, titanium dioxide or sugar. Be able to do that. In order to obtain a sustained activity or to avoid contraindications, this core can consist of several layers. The tablet coating can also consist of several layers in order to have a sustained action, and in this case the excipients mentioned above for tablets can be used.

Juices using the active ingredients or active ingredient combinations according to the invention can additionally contain sweetening agents, such as saccharin, cyclamate, glycerin or sugar, as well as taste-improving auxiliaries, such as vanillin, orange extract. It can also be infused with fragrances. Furthermore,
Suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents such as condensation products of aliphatic alcohols and ethylene dihydride, or protectants such as p-hydroxybenzoates may also be included. reactor.

The injection solution is prepared by a conventional method, that is, by adding a preservative such as p-hydroxybenzoate or a stabilizer such as an alkali salt of ethylenediaminetetraacetic acid, and filling the injection solution into raspins or ampoules.

Capsules containing one or several active ingredients or combinations of active ingredients can be prepared, for example, by mixing the active ingredients with an inert carrier such as lactose or sorbitol;
This is then manufactured by filling it into gelatin capsules.

Suitable suppositories are prepared, for example, by mixing the active ingredient with a compatible carrier such as a neutral fatty oil or polyethylene glycol or its derivatives.

Example 1 [2,3e]-1,4-diazepine a) 8-promo 6-(o-chlorophenyl)-4
H-8-triazolo-[3,4C]-cheno-[2,3
10g of el-1,4-diazepine to 20rnl of pyridino
and methylene chloride 1001W7;
Heat for an hour. To this was added 25 g of methylene chloride and 6.6 g of bromine over 5 minutes, and the mixture was further heated under reflux for 6 hours. The reaction mixture is subsequently cooled, diluted with methylene chloride, shaken twice with 1N hydrochloric acid and once with water, and the methylene chloride bath is dried, evaporated and recrystallized from neat ethanol. .

7.0 g (60 Ll of theory) to the title compound o mp: 210-211 °C0 b) The starting compound vD was prepared by the following method: near-promo-5-(0-chlorophenyl)-2- hydrazino-3H-
[2,3e]-]cheno14-diazabiy (mp
: ~3000C% decomposition) 27g in a mixture of 231M ortho+=o ester and 300d ethanol 6
Heat at reflux for 0 minutes. The bath medium is evaporated and the residue is triturated with ether. Yield: 26g, nap: 214-216
°C In addition, the following final product was obtained analogously to the above method: Agent: Asamura Akira (DE) [P] 2445430.6 ■ 1974 1
February 21st ■ West Germany (DE) P 2460776.9 @ Inventor
Adolf Bauer Ingelheim Rheinstrasse, Federal Republic of Germany 55 0 Inventor Beter Danneberg Otzkenheim, Federal Republic of Germany Jacobsberg 14 0 Inventor Franz Josef Kundeut Bingen-Waldstrasse 2

Claims (1)

[Claims] In the general formula C, R1 is a hydrogen, chlorine or bromine atom, or 1 to
an alkyl group having 4 carbon atoms, R2 represents a hydrogen, chlorine or bromine atom, and R3 represents a chlorine or bromine atom) and physiologically acceptable acid addition salts thereof A process for producing a compound of the formula (C, in which R and R2 have the meanings given above) is chlorinated or brominated, and, if desired, the compound of the formula I thus obtained is subjected to a physiologically acceptable acid addition. A method characterized by converting it into salt.