DE2410030B2 - 8-BROM-6-PHENYL-4H-S-TRIAZOLO SQUARE CLAMP ON 3.4-C SQUARE CLAMP FOR THIENO SQUARE BRACKET ON 2.3-SQUARE BRACKET FOR 1,4-DIAZEPINE THE PROCESS FOR THEIR MANUFACTURING AND THESE PHARMACEUTICAL ASSOCIATION - Google Patents

Description

_ CONH-NH ₂

(VII)

in which R ^{1 is} hydrogen, a straight or branched C 1 -C 4 alkyl radical or a hydroxyalkyl radical having 1 to 4 carbon atoms, R ^{2 is} a fluorine, chlorine or bromine atom and their physiologically acceptable acid addition salts.

2. Process for the preparation of 8-bromo-6-phenyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepines according to claim 1, characterized in that a compound is established in a manner known per se of the general formula II

in which R ^{1 has} the meanings given,

implements.

3. 8-Bromo-6- (o -chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine as well as its acid addition salts.

4. 8-Bromo-6- (o-bromophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine as well as its acid addition salts.

5. Pharmaceutical compositions containing as active ingredient compounds of the general Formula I in combination with customary auxiliaries and / or carriers.

NH - NH ₂ The invention relates to 8-bromo-6-phenyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepines of the general formula

(ID 30th

R ²

in which R ¹ and R ^{2 have} the abovementioned meanings, with an acid of the general formula III

R ¹ - COOH

(III)

In which R ^{1 has} the meanings given above, Or a functional derivative of this acid with the formulas

R ¹ - C (OR ') ₃ (purple) R ¹ —C (= NH) -OR ' (IHb) R ¹ -C (= NH) -NH ₂ (IHc) R ¹ - CONH ₂ (HId) R ¹ - CS - NH ₈ (HIe) Ri _ COOR " (Ulf) R ¹ - (CO) ₈ O (HIg) R ¹ - COCl (HIh) R ¹ - CN (HIi)

in which R ^{1 is} hydrogen or a straight or branched Cj-Ci-alkyl radical or a hydroxyalkyl radical with 1 to 4 carbon atoms and R ^{2 is} a fluorine, chlorine or bromine atom and its acid addition salts, process for their preparation, their use as active ingredients in medicines.

The principle of the preparation of the compounds of general formula I consists in correspondingly substituted 4-phenyl-thieno-diazepines to add the triazole ring. This can be done as follows:

a) Implementation of a compound of the general formula

in which R ^{1 has} the meanings given, IL 'is a low molecular weight alkyl group and R "is the radical of an aliphatic, araliphatic or aromatic alcohol, or that a compound of the general formula 55

NH-NH ₂

(H)

with an acid of the general formula Ri _ COOH

(III)

(VI) or a functional derivative of this acid.

The functional derivative of the acid of the general formula III is, for example, an orthoester of the general formula formula

R ^ -C (OR ') *

an imino ether of the general formula
R ¹ —C (= NH) -OR ',
an amidine of the general formula

Ri-C (= NH) -NH ₂ ,
an amide of the general formula
R ¹ - CONH ₂ ,
a thioamide of the general formula
R ¹ - COOR "

(for example a methyl, ethyl or nitrophenyl ester), an acid anhydride of the general formula

(Ri-CO) ₂ O,
an acid chloride of the general formula

Ri _ COCl

or a nitrile of the general formula
R ¹ - CN.

Method II

In this case the acid derivative of the general formula HI is an imino ether of the general formula R ¹ - C (= NH) - OR '

(R ¹ and R 'have the meanings given above). The reaction is expediently carried out in one of the abovementioned solvents at a temperature between room temperature and the reflux temperature of the reaction mixture.

Method III

In this case the acid derivative of the general formula III is an amidine of the general formula

R ¹ - C (= NH) - NH ₂ .

The reaction is then expediently in the presence of a basic catalyst such as 2-methylimidazole, at elevated temperature, e.g. B. between 150 and 250 ° C carried out. If the temperature is lower is e.g. B. the reaction is carried out at room temperature, an intermediate is initially formed as with the following formula

R ¹

NH-N = C

Has this in the general formulas. Paragraph R ^{1 has} the meaning given for formula I, while R 'means a low molecular weight alkyl group and R "means the residue of an aliphatic, araliphatic or aromatic alcohol. The imino ethers and amidines are usually in the form of their salts with mineral acids, e.g. as the hydrochloride, The reaction conditions can be selected depending on the acid derivative used

NHj (IV)

in which R ¹ and R ^{a have} the meanings given above. This intermediate product IV can be isolated and subjected to a subsequent ring solvent (for example methanol, ethanol, chlorine final reaction by heating to 150 to 250 ° C., tetrahydrofuran, benzene, toluene) or subject. However, the isolation is in no way

y)

mixing these solvents without or in the presence of an acidic catalyst (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid) can be carried out. Also the presence of a base, e.g. B. 2-methylimidazole catalyst is useful. The reaction temperature is between 0 and 30O ⁰ C, preferably between 20 and 180 ° C.

Special variants of method a) are the following:

necessary.

Method IV

In this case the acid derivative of the general formula III is an amide or thioamide of the general formula formula

R ¹ - CONHg or

Ri-CSNH,

Method I.

In this case the acid derivative of the formula III is an orthoester

R ¹ - C (0R ') ₃

(R ¹ and R 'have the meanings given above). The reaction usually takes place in the presence of an excess of orthoester, which then also serves as a solvent. At temperatures between 90 and 100 ° C. or in one of the abovementioned solvents, optionally in the presence of one of the abovementioned catalysts, at temperatures between room temperature and the reflux temperature of the reaction mixture. (R ¹ has the meanings given above). The reaction can be carried out with or without solvent and with or without a catalyst at temperatures between 0 and 300 ⁰ C.

Method v

Here the acid derivative of the general formula III is an ester of the formula

R ¹ - COOR ",

an anhydride of the general formula

(R ¹ CO) ₁ O,
an acid chloride of the general formula

R ¹ —COCl

or a nitrile of the general formula
R ¹ -CN

(R ¹ and R ″ have the meanings given above). An intermediate of the general formula V is initially formed

NH-NH-C-R ¹
O

(V)

R-

in which R ¹ and R ^{2 have} the meaning given, which can be isolated beforehand when carrying out the reaction under moderate conditions (for example at room temperature). The product V can then subsequently be subjected to a ring closure reaction by heating it to temperatures between 100 and 250 ^° C. without a solvent or in the presence of an acidic catalyst, as mentioned above. However, the previous isolation as is not necessary.

The product of the general formula V can also be obtained by reacting a compound of the general Formula VI

(VI)

35

R ¹ - CONH - NH.

(VII)

can be prepared by reacting compounds of the general formula VI with hydrazine. this can be carried out in one of the above-mentioned solvents, if desired one of the aforementioned acidic catalysts can be present. The temperature is expediently between Room temperature and the reflux temperature of the reaction mixture.

The compounds of the general formula VI (which are either directly linked to compounds of the general Formula VII can be converted to end products of general formula I or by means of Hydrazine can be converted to compounds of the general formula II) is expediently prepared starting from the literature (see DT-OS 2217 157) compounds of the general formula VIII

(VIII)

in which R ^{1 has} the meaning given above and X is an HS group, an H ₂ N group or a low molecular weight alkoxy or alkyl mercapto group, with a compound of the general formula

45

in which R ^{1 has} the meanings given, where the reaction can also be continued right up to the end product of the general formula I. If desired, the reaction can be carried out in a solvent of the type mentioned above and in the presence of an acidic catalyst, as mentioned above.

The end products of the general formula I can, if desired, be converted into their physiological form in the customary manner harmless acid addition salts are transferred. Acids suitable for salt formation are, for example Hydrogen halides, sulfuric acid, phosphoric acid, cyclohexylsulfamic acid or methane or toluenesulfonic acid.

The starting materials of the general formulas III and VII are already known. However, they are new Compounds of the general formulas II, IV. V and VI. During the manufacture of the intermediates of the general formulas IV and V has already been described above, the production of the intermediates of the general formulas II and VI are explained in more detail below:

The Hvdrazine derivatives of the general formula II

in which R * has the meaning given above, by brominating them in the customary manner and the compounds of general formula IX obtained

(IX)

in which R * has the meaning given above (and some of which - see DT-OS 22 21 623 - are also already known), in a solvent such as Reacts pyridine, dimethylformamide or tetrahydrofuran or their mixtures. The applied Temperatures can be between room temperature and the reflux temperature of the reaction mixture. This gives you the connections of the general formula VI, in which X is an HS group. They are in tautomeric equilibrium with the corresponding thiono compounds according to the following equation:

(Via)

SH

Br

N '

(VIb)

in which R ^{2 has} the meaning given above. These compounds can, after they have reacted in a solvent with the aid of a metalating agent such as sodium methylate or sodium amide, to give the corresponding salts, without prior separation in the customary manner with alkylating agents, e.g. B. methyl or alkyl iodide, are converted to compounds of the general formula VI in which X is a low molecular weight thioalkyl group.

Compounds of the general formulas VIII and IX can also be prepared by the methods of DT-OS 21 07 356 and DT-OS 21 44 105 win by using compounds of the general formula X

expediently first by way of a Finkelstein reaction (i.e. by reaction with NaI in acetone) the aliphatically bound chlorine atom in the compound of the general formula XIII against iodine. The halogen compound obtained is then reacted with ammonia in dioxane or tetrahydrofuran. An amino compound of the general formula XIV is formed as an intermediate

OR '

S / NH-C-CH ₂ -NH ₂

(XIV)

in which R 'and R * have the abovementioned meanings, but which are directly incorporated into a compound of the general Formula VIc

»5

in which R ^{2 has} the meaning given above and R is hydrogen or bromine, subjected to an intramolecular condensation. A particularly advantageous variant of this reaction consists in carrying out the cyclization by boiling in toluene on a water separator using silica gel as the dehydrating agent. This results in much higher yields and purer products. Compounds of the general formula VI in which X is a lower alkoxy group can be obtained by using known aminoketones of the general formula XI

(VIc)

NH ₂

(Xl)

40

45

in which R ^{2 has} the meaning given above, with a haloacetic acid orthoester of the general formula XII (RO) ₃ C-CH ₈ Hal (XIT)

in which R 'has the abovementioned meaning and Hal is chlorine, bromine or iodine, changes to a compound of the general formula ΧΤΠ in which R' and R ^{2 have} the abovementioned meaning.

The preparation of compounds of the general formula VI in which X is the amino group, can be carried out in such a way that the obtained by halogenation of compounds of the general formula VIII Can react substances of the general formula IX with ammonia. The reaction becomes convenient in a solvent such as tetrahydrofuran in the presence of a Lewis acid, e.g. B. TiCl performed.

These compounds are also subject to a tautomerism according to the following equation:

NH,

OR '

CH ₂ HaI

PCIH)

60

(VId)

NH

(VIe)

where R ^{a has} the meaning given above

The compounds of the general formula or

in the R ', R * and Hai the above meanings, the acid addition salts of which have valuable therapeutic properties, converts If shark means chlorine, one exchanges table properties. When you arrived

609519/498

use of various pharmacological test methods Proven to be anxiolytic, tension-relieving and muscle-relaxing and, moreover, an intensive one shown anticonvulsant effects. They also have the property of feeding in mammals to amplify considerably. Its antagonistic effect on adrenaline is also remarkable and their extremely low toxicity. They are known thieno-1,4-diazepines without additional ones Triazole ring, as they are known for example from DT-OS 21 55 403 and 22 21 623, in particular due to their very pronounced anticonvulsant effects

10

superior, while the 8-alkyl-6-aryl-thieno [2,3-e] 4H-s-triazolo [3,4-c] 1,4-diazepines known from DT-OS 29 845 in the action picture are similar to them, but with regard to the anticonvulsant effect, as can be demonstrated in various tests and in various animal species, are superior to them by a power of ten. S-bromo-o-chlorophenyl-l-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine (R ^li = Cl, R ¹ = CH ₃ ) and its acid addition salts have been shown to have a pronounced sleep-inducing effect.

Pharmacological test results

Compound pentetrazole Pentetrazole Electro conflict Fight mouse LD _H Therap. index antagonism antagonism shock situation test LD ₆₀ : ED ₄₀ mouse rat Rat (2) rat mouse PTZ ED ₁₀ mg / kg ED ₆₀ mg / kg DT ₁₀ mg / kg ED ₅₀ mg / kg mg / kg Mouse p. O. P. o. (1) p. o. (1) P- o. (3) P. o. (4) P. o. (5)

0.07
0.15
0.12

0.7
1.0
1.2

0.7

7.4
2.4
7.5

2.5

28
22nd
11

0.2

1.9

1.5

> 35OO
> 33OO
> 35OO

3070

2300

990

> 50,000
> 22,000
> 29 166

4,386

2,300

825

A = 8-bromo-6- (o -chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine.

B = 8-bromo-6- (o-fluorophenyl) -l-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine,

C = 8-Bromo-6- (o-bromophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine.

D = 8-ethyl-6- (o -chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine.

E = e-chloro-o-io-chlorophenyO-l-methyl ^ H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine.

F = 7-chloro-l-methyl-5-phenyl-3H-1,4-benzodiazepine-2 (l H) -on.

Albino mice (NMRI) with a body weight of 20 to 25 g or albino rats were used for the tests (FW49) from 140 to 200 g body weight are used.

The test substances were suspended in olive oil and, in all cases, put into the tube using a stomach tube Stomach brought

1. Pentetrazole antagonism:

Dose at which the lethal effect of 125 mg / kg pentylenetetrazole, the 1 hour after Administration of the test substance administered intraperitoneally is abolished in 50% of the animals (M. I. G 1 u c k m a η η, Curr. Ther. Res., 7, 721 [1965]).

2. Electric shock:

Dose at which the maximum stretching spasm caused by an electric shock (eye electrodes) of 90 volts / 30 mAmp./50 Hertz (sine) / 1 second, ver

(J. E. P. T ο m a η n, E. A. S wi nyard and L. S. Goodmann, J. Neurophysiol. 9, 231 [1946]).

3. Conflict situation (inhibition of passive avoidance):

Dose at which the animals in a conflict situation press a button ten times Press to get a food pill, although a signal that is on at the same time indicates that a punishment in the form of an electric shock is carried out together with the food pill (J. Geller, Arch. Int. Pharmacodyn., 149, 243 [1964]).

4. Combat mouse test (isolation induced fight):

Dose at which the aggressiveness of adults, isolated in the dark for 3 to 4 weeks bucks kept against young bucks are inhibited in 50% of the animals (Wirth, Gösswald, Hörlein, Risse and Kreiskott, Arch. «Int. Pharmacodyn. 115, 1 to 31 [1958]).

5. LD ₅₀ :

Dose that is survived by 50% of the animals (L i t c h f i e 1 d and W i 1 c ο χ ο η, J. Pharmacol. Expü. Therap. 96, 99 [1949]).

The stated values were determined graphically in all tests

The single dose of the substances according to the invention is 0.1 to 50, preferably 0.5 to 25 mg (orally) and 5 to 150 mg as a daily dose.

The compounds obtainable according to the invention

11 12

can be used alone or in combination with others

Active ingredients according to the invention for the use of ge [2,3-e] thieno-1,4-diazepine-2-thione according to formula VIa.

long. Examples of suitable application forms are b) 6.0 g of the above compound are in 100 cm ⁸

wise tablets, capsules, suppositories, solutions, juices, tetrahydrofuran suspended and at room temperature

Emulsions or dispersible powders. Corresponding 5 temperature with 1.2 g of hydrazine hydrate stirred for 20 minutes.

Tablets can, for example, by mixing the After concentrating to about 10 cm ³ , give 20 cm ^a

or the active ingredients with known auxiliaries, with ether and sucks off the crystals.

for example inert diluents, such as calcium Yield: 5.2 g of 7-bromo-5- (o-chlorophenyl) -2-hydra-

carbonate, calcium phosphate or milk sugar, explosive-3H [2,3-e] thieno-1,4-diazepine with a temperature of ~ 300 ° C

agents, such as corn starch or alginic acid, binders, io (decomp.) according to formula II.

like starch or gelatine, lubricants like Ma- c) 5.2 g of the above compound are in 50 cm ³

Magnesium stearate or talc, and / or agents for the Er-Ortho-Acetic acid triethyl ester suspended and on

heated livering of the release, such as carboxypolymethylene, 80 ⁰ C. This takes about 30 minutes

Carboxymethyl cellulose, cellulose acetate phthalate, or temperature initially resulted in a clear solution,

Polyvinyl acetate can be obtained. The tablets can later separate from colorless crystals. Man

also consist of several layers. lets cool, sucks off the crystals and washes with

Correspondingly, coated tablets can be covered with ether.

of cores prepared analogously to the tablets with a yield: 5 g of the title compound of mp 211 bis

^{Mit- 213 0} C. usually used in dragee coatings.

materials, for example Kollidon or shellac, rubber * ° B e i s ρ i e 1 2 arabic, talc, titanium dioxide or sugar

will. To achieve a depot effect or for S-bromo-o-to-chlorophenyO-l-hydroxyäthyWH-s-tri-

To avoid incompatibilities, the azolo [3,4-c] thieno [2 ₎ 3-e] 1,4-diazepine core can also consist of several layers. Likewise

the coated tablet can also be used to achieve a depot a ₅ 4.8 g 7-bromo-5- (o-chlorophenyl) -3H [2,3-e] thieno-

Effect consist of several layers, whereby the 1,4-diazepine-2-thione (see example la) are to-

Auxiliary substances mentioned above for the tablets together with 3.4 g glycolic acid hydrazide in 100 cm ³

can be turned. Boiling n-butanol under an N ₂ atmosphere

The juices of the active ingredients or active ingredients according to the specification are heated. The mixture is left under reflux for a further 5 hours

Combinations of substances can also boil a sweet 30, partially evaporate and bring the title

ßmittel such as saccharin, cyclamate, glycerin or compound by adding isopropyl ether to

Sugar as well as a taste-enhancing agent, crystallization.

z. B. Flavors such as vanillin or orange extract, yield: 4.2 g (76% of theory) from F. 212 to

contain. You can also use suspension aids at 214 ° C.

or thickeners, such as sodium carboxymethylcellu- 35. Wetting agents, for example, condensation products, compounds compiled in the following table products of fatty alcohols with ethylene oxide, or according to general formula I. Contain protective substances such as p-hydroxybenzoates.

Injection solutions are used in the usual way, for. B.

with the addition of preservatives such as p-Hy- 40:

droxybenzoates, or stabilizers, such as alkali salts _{R1 R1 p of the compound}

the ethylenediaminetetraacetic acid produced and in according to formula I.

Injection bottles or ampoules filled.

The containing one or more active ingredients or active ingredient combinations capsules can examples 45 CH ₃ Br are prepared as game 205-206 ⁰ C by ρ is the active ^ 210 ⁰ C substances with inert carriers such as lactose or ³
Sorbitol, mixes and encapsulates in gelatin capsules. CH ₃ H 284 ° C

Suitable suppositories can be used, for example. "

^{Mix with the appropriate} carriers, 50 ^a ^ ^{1 Zi0 DIS Zi} * ^u

such as neutral fats or polyethylene glycol or its _c ^ __ CH (CH ₃ ) ₂ Cl 203 to 205 ⁰ C derivatives.

example 1

SS The starting connections of the general for-

8-Bromo-6- (o-chlorophenyl) -l-methyl-4H-s-tn- _{mel K} were obtained as follows: azolo [3,4-c] thieno [2,3-e] 1,4-diazepine

a) 11.5 g of 7-bromo-5- (o-chlorophenyl) -3H [2,3-e] thieno-

1,4-diazepin-2-one (see DT-OS 22 21623) according to formula a) 0.03 mol of a compound of the general formula TLC with 100 cm ^{3 of} absolute pyridine and 60 mel VIII are similar to the example of 6.5 g of phosphorus pentasulfide described for 4 hours under stirring to DT-OS 22 21 623 ⁸ cm chloro-55 to 6O ⁰ C is heated to 60 is allowed to cool and poured onto a form dissolved or suspended and, after adding 100 cm ³ of ice-cold saturated NaCl -Solution. The low of 6 cm * pyridine over 5 minutes with impact is suction filtered and washed with water, 4.7 g of bromine is allowed at 25 to 30 ⁰ C then poured into 100 cm ³ of methylene chloride, stirred for 65 45 minutes and wherein the compound solution dried, evaporated and the residue of the general formula TLC worked through mostly as yellow with a little methylene chloride. After the preferential precipitate separates out, which is suctioned off and suctioned off, 6 g of brown crystals are obtained after washing with ether

13 14

10 to 12 g of the compound according to the pharmaceutical compositions are obtained

general formula IX. . _n

This can be used for thionation as a crude product ^a > uragees

can be used. 1 dragee contains:

b) 17 g of 2-bromoacetylamino-3- [aryl] thiophene dissolves 5 active ingredient according to Example 1

one in 200 to 250 cm ^{3 of} chloroform and added 1.0 mg gender application

at room temperature with 20 cm ^{3 of} pyridine followed by lactose 28.5 mg

of 5 cm ⁸ bromine. After stirring for 2 hours. Corn starch 19.0 mg

it is shaken out several times with water, gelatin 1.0 mg is dried

the chloroform phase with MgSOi, evaporated and io magnesium stearate 0.5 mg

stir the residue with diisopropyl ether. 50 0 me

Yield 10 to 15 g of 2-bromoacetylamino preparation · ' 3- [aryl] -4-bromothiophene.

10 g of this compound are dissolved in 400 cm ^{3 of} vinegar and the mixture of the active ingredient with lactose ester and within 2 hours at 15 and corn starch is passed with a 10% aqueous room temperature gaseous ammonia gelatin solution through a sieve with 1 mm mesh. The precipitate is filtered, the precipitated Ammon wide granulated, dried at 4O ⁰ C dried and still mali chloride, the filtrate is evaporated driven a by a sieve under vacuum. The granules thus obtained and obtains 7 to 8 g Aminoacylaminoverbindung is mixed with magnesium stearate and compressed, according to ao of the general formula X. The cores thus obtained are in usual manner with 7 g of this compound are plated in 80 cm ³ of toluene, a sheath with Using an aqueous and 35 g of silica gel for 1 hour on a water separator suspension of sugar, titanium dioxide, talc and boiled. It is cooled to 50 to 60 ° C and then gum arabic is applied. The finished Dra-50 cm ^{3 of} methanol too. After vacuuming and gees are polished with beeswax. Dragee end washout is obtained from the filtrate 3 to 4 g weight: 100 mg. the desired connection according to the general, _Λ "
my formula IX. o)!

Active ingredient according to Example 1 available

The production of starting material of the general application 0.5 mg

my formula VIc is explained by the following: 30 lactose 50.0 mg

0.2 mole of 2-amino-5-bromo-3- (o-chlorobenzoyl) thio corn starch 43.5 mg

phen according to the general formula XI are 5.0 mg with soluble starch

78.4 g (0.4 mol) of chloroacetic acid orthoethyl ester (see magnesium stearate 1.0 mg

general formula XII) boiled 100 0 me in 1 liter of benzene for 8 hours with stirring, adding 0.01 ml of trifluoroacetic acid after about 4 hours of preparation. You steam that
Solvent and removes the rest of the ortho-active ingredient and magnesium stearate with an ester in a high vacuum. The raw material is dried in 1.5 liters of acetone with 16 granules and intimately mixed with lactose and up to 20 g of sodium iodide for 6 hours at room temperature. The mixture is then stirred to temperature. It is evaporated and the back tablets of 100 mg weight are compressed, each of which was 0.5 mg in methylene chloride. The solution containing methylene chloride is extracted several times with ice water. _o ... and dried with magnesium sulfate. ^c > Suppository The residue (crude product of the general formula 45 1 suppository contains: mel XIII) is taken up in 150 cm ^{3 of} absolute dioxane active ingredient according to Example 2 and, if the application is made, 5.0 mg is passed within 1 to 2 hours

Room temperature ammonia gas on. Then suppository mass 1695.0 mg

the solvent is removed in vacuo, the

Residue taken up in methylene chloride, with 50 production:

Ice water washed, the solution with magnesium- The finely powdered substance is made with the help of a

sulfate dried and evaporated. The remaining immersion homogenizer in the melted unc

Bende oil is the title compound and can stirred analogous to the cooled to 40 ⁰ C suppository mass. Ie

Thio compound, as described above, is massed at 35 ° C in slightly pre-cooled formula

Hydrazino derivative can be implemented. 55 cast.

Claims (1)

Patent claims: 1. 8-Bromo-6-phenyl-4H-s-triazolo [3,4-c] thieno- [2,3-e] 1,4-diazepines the general formula (D in which R ^{2 has} the meaning given and X is an HS group, an H ₂ N group or a low molecular weight alkoxy or alkylthio group, with a compound of the general formula VII