DE2701752A1 - 8-IOD-L-METHYL-6-O-CHLOROPHENYL-4H-S -TRIAZOLO SQUARE CLAMP ON 3.4C SQUARE BRACKET TO THIENO SQUARE BRACKET ON 2.3 SQUARE BRACKET TO L, 4-DIAZEPINE, METHOD FOR ITS MANUFACTURING AND HIS USE IN PHARMACEUTICAL PREPARATIONS - Google Patents

Description

Case 1/575 We / mw

C. H. BOEHRINGER SOHN, D-6507 Ingelheim am Rhein

8-iodo-1-methyl-6-o-chlorophenyl-4H-s-triazolo [3 »4c] thieno [2,3e] 1,4-diazepine, process for its preparation and its use in pharmaceutical preparations

As a new compound, the invention relates to 8-iodo-1-methyl-6-o-chlorophenyl-4H-s-triazolo [3 , Ac] thieno [2,3e] 1,4-diazepine of the formula

Y / S

(D

and its physiologically acceptable acid addition salts.

809829/0372

The new compound and its acid addition salts can be obtained by

a) a compound of the formula

(H)

in the

X denotes a HS, NH ₂ , a lower alkoxy or alkyl mercapto group or a halogen atom, reacts with acetic hydrazide, or

b) 2-hydrazino-7-iodo-5-o-chlorophenyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine is reacted with a suitable functional derivative of acetic acid, or that one

c) 8-iodine-1-methyl-6-o-chlorophenyl-thieno [2,3f] triazolo [3,4a] 4,1-oxazepine of the formula

809829/0372

(III)

into the corresponding thieno [2,3e] triazolo [3 »4c] 5» 6-dihydro-1,4-diazepine converts and dehydrates it. The compound of the formula I obtained according to a), b) or c) can then be converted into a physiologically harmless acid addition salt.

Reaction a) can be carried out at temperatures between 100 and 250 ^° C. both without a solvent and in solvents such as methanol, ethanol, dioxane, chloroform, tetrahydrofuran, benzene, toluene, xylene or mixtures of these solvents without or in the presence of an acidic catalyst (for example hydrochloric acid Acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, {propionic acid, benzenesulfonic acid or toluenesulfonic acid) ; it is generally made without isolation of the; resulting intermediate of the formula

NH-NH-COCH ₃

(IV)

led to the end product, but isolation of the intermediate product is possible without difficulties if milder reaction conditions are observed (for example at room temperature).

The reaction b) proceeds using a suitable functional derivative of acetic acid, for example an orthoester of the formula H ₃ CC (OR ¹ ) * »an imino ether of the formula H ₃ C-CC = NH) -OR ¹ , an ester of the formula H ₃ C-COOR "(for example a methyl, ethyl or nitrophenyl ester), acetic anhydride or an acetic acid halide

809829/0372

R 'is a lower alkyl group and R ^{M is} the residue of an aliphatic, araliphatic or aromatic alcohol. The imino ethers are usually used in the form of their salts with mineral acids, for example as chlorohydrate.

The reaction conditions can be selected depending on the acid derivative used. In general, the reaction can be carried out both with and without solvents (e.g. in methanol, ethanol, chloroform, tetrahydrofuran, benzene, toluene or mixtures of 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, The presence of a base, for example 2-methylimidazole, as a catalyst is also useful. The reaction ^{temperature is between 0} ° C. and 300 ^° C., preferably 20 and 180 ^° C.

Starting from 8-iodine-l-methyl-6-o-chlorophenyl-thieno [2,3f] triazolo [3,4a] 4, l-oxazepine of the formula III, the end product of the formula I is obtained according to the following scheme

809829/0372

(III)

CH ₂ -HaI ₂

(nib) CH ₂ -OH

(IHa)

(inc)

809829/0372

Here, the oxazepine ring of the compound is first used
Formula III split by treatment with strong hydrochloric acid or hydrobromic acid on the oxygen atom. That is enough
It is generally the case to allow the compound to stand for a few minutes to a few hours at room temperature in a strongly hydrochloric or hydrobromic acid solution. This is the case with this
The reaction-forming hydrohalide of the compound of the formula IHa is extracted from the reaction solution in the cold with a water-immiscible solvent, preferably a chlorinated hydrocarbon such as chloroform or: methylene chloride, and - expediently after evaporation of the extraction solution - with a phosphorus or sulfur halide, such as j Thionyl chloride or phosphorus tribromide. The reaction temperature here is between 0 and 40 - preferably about 20 ° C. j

After distilling off the excess halide and
any solvent still present is the ■ residue, consisting of a dihalide of the formula IHb,; with ammonia or ammonia supplying substances, such as urotropin, ', reacted. Suitable solvents for the reaction with ammonia j are lower alcohols, e.g. methanol or ethanol,
Ethyl acetate, dioxane, tetrahydrofuran or inert hydrocarbons such as benzene and its homologues; but also more fluid
Ammonia can be used for the reaction. The reaction temperature is between ⁰ ° C. and the boiling point of the solvent used; However, the reaction is preferred
Autoclave carried out. One obtains the connections of the
Formula IHc in excellent yield.

Instead of the compound of the formula IHa, one can use the
Reaction with a phosphorus or sulfur halide too
with the corresponding dihydroxy compound of the formula

809829/0372

CH ₂ -OH < ^IIId >

j perform. They are obtained by heating the strongly acidic ones

; Solution of the compound of formula III and it can be applied to the

j in the same way as described for the compound of the formula IHa

ben, extract from the reaction solution.

The dehydrogenation of the compound of the formula IHc to the end product of the formula I is carried out using suitable dehydrogenating agents such as, for example, halogens of compounds of the higher oxidation states of chromium or Manganese, for example a chromate, a bichromate or a permanganate. As a suitable solvent for the Reaction with a halogen may be mentioned chlorinated hydrocarbons such as chloroform or methylene chloride; expedient in this reaction, a tertiary organic base, for example pyridine, is added to trap the hydrohalic acid formed.

The oxidation with the mentioned compounds of chromium or manganese takes place in solvents such as acetone and tetrahydrofuran or dioxane.

Depending on the type of oxidizing agent, the reaction ^{temperature is generally between 0 °} C. and the boiling point of the solvent used.

809829/0372

The end product of the formula I can, if desired, in a customary manner Way into a physiologically harmless acid addition salt be convicted. Acids suitable for salt formation are, for example, hydrohalic acids, sulfuric acid, Phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, Salicylic acid or methane or toluenesulphonic acid and the like.

Compounds of the formula II are expediently prepared analogously to the compounds described in DT-OS 2,217,157 by iodination of the thieno-diazepin-3-one of the formula

(V)

prepared by mixing them iodinated in the usual manner and the resulting \ iodine compound in a solvent such as pyridine, dimethylformamide or tetrahydrofuran or mixtures thereof are reacted. The temperatures used can be between room temperature and the reflux temperature of the reaction mixture. This gives the corresponding 3-mercapto 'compound which, after it has 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, for example Methyl iodide, can be converted into the corresponding methyl mercapto compound.

809829/0372

The 3-hydrazino-8-iodine-6-o-chlorophenyl-4H-s-triazolo [3, 4c] thieno [2,3e] 1,4-diazepine can be produced by adding a Reacts compound of formula II with hydrazine. This can be done in one of the solvents mentioned above, one of the aforementioned acidic ones, if desired Catalysts can be present. The temperature is expediently between room temperature and the reflux temperature of the reaction mixture.

The starting compound III is described in the DBP (German patent application P 25 31 679); you can, for example obtained by reacting 7-iodo-5- (o-chlorophenyl) -thieno [2,3f] oxazepine-2-thione by means of hydrazine hydrate and an orthoacetic acid ester in a manner known per se.

The compound of the formula I or its acid addition salts have valuable therapeutic properties. she has when using various pharmacological test methods as anxiolytic, tension-relieving and sedative. Proven effective and also shown an intense anticonvulsant effect. It also has the property to significantly increase feed intake in mammals. Their extremely low toxicity is remarkable.

The single dose is 0.05 to 50, preferably 0.1 to 25 mg (orally) and 5 to 150 mg as a daily dose.

The compound obtainable according to the invention can optionally be used alone or in combination with other active ingredients according to the invention also in combination with other pharmacologically active ingredients such as antispasmodics or ß-receptor blockers come into use. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, Emulsions or dispersible powders. Corresponding tablets can, for example, by mixing the active ingredient (s)

809829/0372

with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, Disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Correspondingly, coated tablets can be coated by analogously Tablets produced cores with agents commonly used in dragee coatings, for example Kollidon or Shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or To avoid incompatibilities, the core can also consist of several layers. The coated tablet can also do the same consist of several layers to achieve a depot effect, with the auxiliaries mentioned above for the tablets can be used.

Juices of the active ingredients or combinations of active ingredients according to the invention You can also use a sweetener such as saccharin, cyclamate, glycerin or sugar and a taste-enhancing agent Contain agents, e.g. flavorings such as vanillin or orange extract. You can also use suspension auxiliaries or Thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates, contain.

809829/0372

Injection solutions are used in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates,

j or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid and filled into injection bottles I or ampoules.

The capsules containing one or more active ingredients or combinations of active ingredients can be produced , for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatin capsules.

Suitable suppositories can be produced, for example, by mixing them with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

809829/0372

JH

example 1

8-iodine-l-methyl-6-o-chlorophenyl-4H-s-triazolor3.4c] thienor2.3e] 1,4-diazepine

8.8 g = 20 mmol of 8-iodo-6- (o-chlorophenyl) -l-methyl-thieno [2,3f] Triazolo [3,4a] 4,1-oxazepine are stirred in 200 ml of concentrated hydrobromic acid for 30 minutes at room temperature solved. The solution is poured into 400 ml of ice water, neutralized with ammonia, extracted with methylene chloride and washed with water.

9.7 g = 92 % of theory [1-iodo-2- (5-methyl-3-; hydroxymethyl-triazolyl-4) -thenyl] o-chlorophenylbromomethane are obtained! from F. 205 to 208 ⁰ C. j

8 g = 15 mmol [1-iodo-2- (5-methyl-3-hydroxymethyl-triazolyl-4) -thenyl] o-chlorophenylbromomethane are dissolved in 200 ml of methylene chloride and refluxed with 10 ml of SOCl _{2 for} 30 minutes . Then the reaction mixture with ice water and; washed with dilute ammonia. After drying and evaporation, the residue is triturated with isopropyl ether and the crude product is filtered off with suction. This is dissolved in 200 ml of methanol and! mixed with gaseous ammonia until a pressure of! 5 atm remains constant. The mixture is then heated to 40 ^° C. for 30 minutes, then the solution is suctioned off over kieselguhr and evaporated. The product is purified by column chromatography. 5.9 g = 88 % of theory of 8-iodo-5,6-dihydro-6-o-chlorophenyl-1-methyl-thieno [2,3e] triazolo [3,4c] 1,4-diazepine are obtained.

2 g of the dihydro compound are dissolved in 200 ml of acetone and stirred with 1 g of powdered KMnO ^ for 20 hours at room temperature. The manganese dioxide is filtered off with suction, the solution is evaporated and the residue is crystallized with ether. Yield: 1.7 g »85 % of theory from a melting point of 255 to 257 ° C. ;

809829/0372

The 8-iodo-6- (o-chlorophenyl) -l-methyl-thieno [2,3f] triazolo [3,4a] 4,1-oxazepine used as the starting compound can be made as follows:

a) 7-iodo-5- (o-chlorophenyl) thieno [2,3f] oxazepln-2-one

13 »5 g - 48 mmol of 5- (o-chlorophenyl) -thieno [2,3floxazepln-2-one are dissolved in 500 ml of chloroform and, while stirring at room temperature, 13 g of iodine and 8.8 g of HgO (red) are added ( 10 to 15 minutes). After stirring for 80 minutes, the reaction mixture is filtered off with suction through kieselguhr and washed out with sodium bicarbonate solution and then with sodium thiosulphate solution. The dried chloroform phase is evaporated and the residue caused to crystallize. The crystals freed from the solvent are washed with a little methylene chloride. 15 g »77 % of theory of the title compound with a melting point of 230 ° to 232 ° C. are obtained.

b) 7-iodo-5- (o-chlorophenyl) -thieno [2.3f] oxazepine-2-thione

■ 15 g 37 mmol of oxazepine-2-one are suspended in 80 ml of diglyme and, after adding 6.6 g of 5 Pp ^{S un <i} ^ ^ß NaHCO heated for about 5 minutes at 55 ° C. The reaction mixture is then poured into 200 ml of water, the precipitate is filtered off with suction, washed neutral with water and dried at 50 ° C. in vacuo.

Yield: 14 g «90 % of theory of the title compound with a melting point of 145 ° C. (decomposition).

c) 8-iodo-6- (o-chlorophenyl) -l-methyl-thieno [2.3f] triazolor3,4a] 4.1-oxazepine

2.1 g β 5 mmol of the thione are in 40 ml of tetrahydrofuran dissolved and mixed with 0.5 ml of hydrazine hydrate. After a few minutes, the reaction has ended and it is evaporated Solvent in vacuo. The residue is in

809829/0372

Methylene chloride added, washed with water, the dried solution evaporated again and the reaction mixture with 20 ml of ethanol and 20 ml of triethyl orthoacetate Boiled under reflux for 30 minutes. One sucks off, evaporates the solution and brings with ether to Crystallization.

Yield: 1.6 g = 75 % of theory of the title compound with a melting point of 196.degree. To 198.degree.

Example 2 ^;

8-iodo-l-methyl-6-o-chlorophenyl-4H-s-triazolo [314c] thlenoC 2.3e] 1,4-dlazepine :

5.5 g of 7-iodo-5- (o-chlorophenyl) -3H [2,3e] thieno-1,4-diazepine-2-thione are stirred with 120 ml of tetrahydrofuran and 2.3 g of hydrazine hydrate for 1 hour at room temperature. After that, the precipitated crystals sucked off in vacuo and recrystallized from ether.

4.8 g - 96 % of theory of 7-iodo-5- (o-chlorophenyl) -2-hydrazino-3H [2,3e] thieno-1,4-diazepine with a melting point of 145 ° C. (decomposition) are obtained.

4.8 g of the hydrazino compound are stirred under reflux for 2 hours with 50 ml of absolute alcohol and 30 ml of triethyl orthoacetate, the reaction mixture is evaporated in vacuo, the residue is eluted over silica gel with methylene chloride containing 5% methanol and recrystallized from acetonitrile. 4.6 g = 90.2 % of theory of the title compound with a melting point of 254 ° to 256 ° C. are obtained.

809829/0372

The starting compound was obtained as follows:

a) 5 g of 5- (o-chlorophenyl) -3H [2,3e] thieno-1,4-diazepin-2-one are suspended in 200 ml of chloroform and alternately entered a total of 3 »3 g HgO and 4.9 g iodine. After stirring for 15 minutes at room temperature, the precipitated Sucked off crystals and washed them with sodium bicarbonate and sodium thiosulfate until a neutral reaction. After evaporation and recrystallization of the residue from alcohol, the 7-iodo-5 (o-chlorophenyl) -3H [2,3e] thieno-1,4-diazepin-2-one with a melting point of 222 ° to 224 ° C. is obtained in one yield of 6.4 g »87.7 % of theory.

b) 6.4 g of the 7-iodine compound are in 100 ml of pyridine and

6.2 g of P ₂ S _{5 were} stirred at 70 to 80 ^° C. for 4 hours. The reaction mixture is then decomposed in 200 ml of sodium chloride solution and ice. The resulting crystals are washed with ether.

This gives 6.1 g of "92.4% of theory 7-iodo-5- (o-chlorophenyl) -3H [2,3-e] thieno-l, 4-diazepin-2-thione, mp 202 ⁰ C.

809829/0372

a) Dragees 2701752 - 16 - 1 dragee contains: Formulation examples Active ingredient according to the invention 1.0 mg Lactose 28.5 mg Cornstarch 19.0 mg gelatin 1.0 mg Magnesium stearate 0.5 mg

50.0 mg

Manufacture: [

The mixture of the active substance with lactose and corn starch is treated with a lO ^ aqueous gelatin solution granulated through a sieve with 1 mm mesh width, dried at 40 ⁰ C and again forced through a sieve. The granules obtained in this way are mixed with magnesium stearate and pressed. The cores obtained in this way are coated in the usual way with a shell that is made up with the help of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic; is brought. The finished coated tablets are polished with beeswax. :

: Final coated weight: 100 mg

b) tablets

Active ingredient according to the invention 0.5 mg

Milk sugar 50.0 mg

Corn starch 43.5 mg

soluble starch 5.0 mg

Magnesium stearate 1.0 mg

100.0 mg

809829/0372

Manufacturing:

The active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules dried and mixed intimately with lactose and corn starch. The mixture then becomes tablets of 100 mg Compressed weight, each containing 0.5 mg of active ingredient.

c) suppositories

1 suppository contains:

Active ingredient according to d <

Suppository mass 1,695.0 mg

! Active ingredient according to the invention 5.0 mg

Manufacturing:

The finely powdered substance is made using an immersion homogenizer stirred into the melted suppository mass cooled to 40 ° C. The mass is at 35 ° C in slightly pre-cooled molds poured.

809829/0372 ORIGINAL INSPECTED

Claims (3)

Claims Iodine-1-methyl-e-o-chlorophenyl-AH-s-triazolo [3 »4c] thleno V- ^ [2,3e] 1,4-diazepine and its physiologically acceptable Acid addition salts. 2. Process for the preparation of e-iodine-l-methyl-o-o-chlorophenyl-4H-s-triazolo [3 »4c] thieno [2,3e] 1,4-diazepine and its ι physiologically acceptable acid addition salts, thereby ^! marked that one \ yes) a compound of the formula '■ (II) in the X denotes an SH, NHp, a lower alkoxy or alkyl mercapto group or a halogen atom, reacts with acetic acid hydrazide, or that one b) 2-hydrazino-7-iodo-5-o-chlorophenyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine is reacted with a suitable functional derivative of acetic acid, or that one 809829/0372 ORIGINAL INSPECTED Sl c) 8-iodo-1-methyl-6-o-chlorophenyl-thieno [2,3f] triazolo [3 _t 4a] 4,1-oxazepine of the formula (III) into the corresponding thieno [2,3e] triazolo [3,4c] 5,6-dihydro-1,4-diazepine converts, this dehydrated in a known manner and a compound obtained in this way of the formula I optionally converted into a physiologically acceptable acid addition salt. 3. A pharmaceutical preparation containing as active ingredient a compound of the formula I or a Acid addition salt of this compound in combination with customary auxiliaries and / or carriers. 809829/0372