KR800000048B1 - Process for preparing substituted 6-aryl-4h-s-triazolo-(3,4c)-thieno-(2,3e)-1,4-diazepines - Google Patents

Abstract

Title compds. (I; R1=H, Cl, Br, or C1-4 alkyl group, R2 = H, F, Br, nitro or trifluoromethyl group, R3 = Cl, Br, C1-3 alkoxy, alkylmercapto group≉, useful as tranquilizer, were prepd. by the chlorination or bromination of comp. II, and by the substitution of Cl or Br to alkoxy or alkylmercapto group resp.

Description

Method for preparing substituted 6-aryl-4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4-diazepine

The present invention provides substituted 6-aryl-4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4-diazepine of formula (I) and its physiologically toxic acid moiety. It relates to a method for producing a salt.

In the above structural formula

R ₁ is hydrogen, chlorine or bromine or an alkyl group having 1-4 carbon atoms,

R ₂ is hydrogen, fluorine, chlorine or bromine or is a nitro or trifluoromethyl group,

R ₃ is a chlorine or bromine atom, an alkoxy or alkyl mercapto group having 1-3 carbon atoms.

The compound of formula (I) and physiologically toxic acid addition salts of the present invention can be prepared by chlorinating or brominating the following compound of formula (VI) and, if necessary, by replacing chlorine and bromine with an alkoxy or alkylmercapto group, respectively. Seeds are prepared by converting the compound to its physiologically toxic acid addition salt.

In the above structural formula

R ₁ and R ₂ are as described above.

In obtaining the final product of formula (I), the compound of formula (VI) is brominated or chlorinated. Halogenation can be effectively carried out in a solvent such as carbon tetrachloride, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide or a suitable hydrocarbon, optionally by adding a tertiary organic base such as pyridine or by using succinimide or the like. have. The temperature of this reaction is used between room temperature and the reflux temperature of the reaction mixture, depending on the starting materials and methods used.

If desired, the 8-halogen compound thus obtained can be converted into the corresponding alkoxy or alkylmercapto compound.

When an alkoxy group is introduced, the halogen compound is dissolved in alkali alcoholate and the solution is refluxed.

In the production of alkyl mercapto compounds, halogenated compounds are dissolved in an aprotic solvent or alcohol such as dioxane, tetrahydrobutane, dimethylformamide or hexamethylphosphoramide (HMPT) and then reacted with alkali mercaptide. Alkali mercaptide is prepared by introducing mercaptan into a solution of a halogen compound containing an alkali alcoholate. The final product of formula (I) can be converted to its physiologically toxic acid addition salt, if necessary. Acids suitable for salt formation include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid or methane or toluenesulfonic acid.

Synthesis of the compound of formula (VI) is described in German Patent No. 24,100,309, ie prepared by reacting the following compound of formula (II) with alkyl orthoformate.

In the above structural formula

X is SH-, NH _2- , lower alkoxy, or lower alkyl mercapto group

R ₁ and R ₂ are as described above.

Structural formula (I) compounds and their acid addition salts have excellent therapeutic properties. Several pharmacological tests have shown that the compound has anxiety-inhibiting, relaxing and muscle-relaxing effects, in particular, an allergic effect. It is also noteworthy that it has properties that increase food absorption in warm-blooded animals and is extremely toxic. . They are superior to thieno-1,4-diazepine in the potent dystrophic activity demonstrated by the so-called pentetrazol test, for example without the additional triazole ring as known from DT-OS 2,155,403 and 2,221,623. On the other hand, the range of action is known 8-alkyl-6-aryl-thieno- [2,3e] -4H-S-triazolo- [3,4c] -1, as described in DT-OS 2,229,845. Similar to 4-diazepine but at least 10 times better in strength of action.

Such compounds and acid addition salts thereof include those in which R ₁ is a bromine atom, R ₂ is a chlorine or bromine atom, R ³ is a bromine atom or a methoxy group, especially 1,8-dibromo-6-0-chlorophenyl-4H-S- Triazolo- [3,4c] -thieno- [2,3e] -1,4-diazepine (R ₁ = Br, R ₂ = Cl, R ₃ Br), and 8-bromo-6-0- Chlorophenyl-1-methoxy-4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4-diazepine (R ₁ -Br, R ₂ = C 1, R ₃ = OCH ₃ ) and its acid addition salts proved particularly good.

The single dose of the substance according to the invention is 0.05 to 50 mg, preferably 0.1 to 25 mg (oral administration), and the daily dose is 5 to 150 mg.

The compounds obtainable according to the invention can be used either singly or in admixture with other active ingredients according to the invention and also optionally in admixture with pharmacologically active ingredients such as antispasmodic or β-receptor blockers. Suitable dosage forms include, for example, tablets, capsules, suppositories, solutions, juices, emulsions or powders. For example, the active ingredient may be a known excipient, i.e., an inert diluent (e.g. calcium carbonate, calcium phosphate or lactose), a disintegrant (e.g. corn starch, or alginic acid), a binder (starch or gelatin), a lubricant (i.e. magnesium steare). Or talc) and / or release retardants such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate-phthalate or polyvinylacetate, and the like. The tablet may consist of several layers.

Nuclei prepared in a similar manner to tablets may be coated with a preparation used in conventional coatings such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar to make a coated tablet. The nucleus can be composed of several layers to delay release or to avoid incompatibility. The coating can also consist of several layers for delayed release and therefore excipients can be used for tablets.

Juices of the active ingredient and the active ingredient combination may also contain sweetening agents such as saccharin, cyclate, glycerin or sugar as well as flavoring agents such as vanillin or orange juice. In addition they may also contain suspending aids, or weighting agents such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or protective agents such as P-hydroxybenzoates.

Injection solutions are prepared in conventional manner, ie, by filling the vials or ampoules with the addition of preservatives such as P-hydroxybenzoate or stabilizers such as alkali salts of ethylenediaminetetraacetic acid.

Capsules containing one or several active ingredients and active ingredient combinations are prepared by mixing the active ingredients with an inert carrier such as lactose or sorbitol to fill the gelatin capsules. Suitable suppositories may be prepared by mixing with a carrier such as, for example, fat or polyethylene glycol and derivatives thereof.

Example 1

1,8-Dibromo-6 (0-chlorophenyl) -4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4-diazepine

a) 20 ml of 10 g of 8-bromo-6- (0-colophenyl) -4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4-diazepine Dissolved in a mixture of pyridine and 100 ml of methylene chloride and heated for 7 hours. Within 5 minutes, a solution of 6.3 g bromine in 25 ml of methylene chloride was added and the mixture was refluxed for another 3 hours. After cooling the reaction mixture and diluting with methylene chloride, the solution is shaken twice with 1N hydrochloric acid and once with water. After drying the methylene chloride solution is evaporated and the residue is recrystallized from ethanol to give 7.0 g = 60% of the title compound having a melting point of 210-211 ° C.

b) Starting compound is obtained as follows.

27 g of 7-bromo-5- (0-chlorophenyl) -2-hydrazino-3H- [2,3e] -thieno-1,4-diazepine at a melting point of 300 ° C. for 30 minutes was 23 It is refluxed in a mixture of ml orthoformate and 300 ml ethanol. The solvent is evaporated and the residue is treated with ether to give 26 g of product at melting point 214-216 ° C.

Example 2

8-Bromo-6- (0-chlorophenyl) -1-methoxy-4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4-diazepine

12 g of 1,8-dibromo-6- (0-chlorophenyl) -4H-S-triazolo- [3,4c] -thieno- [2,3e] -1.4-diazepine, 70 ml It is refluxed for 2 hours in a solution of 0.6 g sodium in methanol. The reaction mixture is evaporated, diluted with water and shaken repeatedly with methylene chloride. The methylene chloride phase is dried and evaporated and then recrystallized in ethanol to give 7 g (76% of theory) of the title compound having a melting point of 198-200 ° C.

Example 3

8-Bromo-6- (0-chlorophenyl) -1-methylmercapto-4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4 diazepine

0.15 g of sodium is dissolved in 40 ml of anhydrous methanol, and then 340 mg of methyl mercaptan is introduced into the solution. Then use 2.5 g of 1,8-dibromo-6- (0-chlorophenyl) -4H-S-triazolo- [3,4c] -thieno- [2,3e] -1,4-dia Mix with zepin and heat to a temperature of 40-50 ° C. After about 30 minutes, thin layer chromatography shows that the dibromo compound is no longer present. The solution is then evaporated, the residue is placed in methylene chloride, the methylene chloride is shaken several times with water and the organic base is dried, the solvent is evaporated and the residue is chromatographed over SiO ₂ -column to give a melting point of 158-160 ° C. 920 mg = 40%.

Example 4

1-ethoxy-8-bromo-6- (0-chlorophenyl) -4H-S-triazolo- [3,4c] -thieno [2,3e] -1,4-diazepine

3.7 g of 7-bromo-5- (0-chlorophenyl) -3H- [2,3e] -thieno-1,4-diazepine-2thione, 60 ml of n-butanol and 1 g of hydrazine ethylcarbonate Was refluxed for 30 minutes and then cooled to precipitate 2 g of hydrazide (melting point 236 ° C.). The crystals were aspirated, boiled for 3 hours in a water separator with 100 ml of xylene and 20 g of SiO ₂ and then aspirated again and eluted on silica gel with methanol to give 0.7 g of the title compound having a melting point of 144 to 146 ° C. 37%) is obtained.

Combination Example

a) tablets

One skin-refining tablet is comprised as follows.

1.0 mg of active ingredient of formula (I)

Lactose 28.5mg

Corn starch 19.0mg

Gelatin 1.0mg

Magnesium Stearate 0.5mg

50.0 mg

Legislation

The mixture of lactose starch and the active ingredient is granulated with 10% gelatin aqueous solution through a 1 mm mesh screen, dried at 40 ° C. and ground once more through the screen. The granules thus obtained are mixed with magnesiumstearate and compressed. The resulting nucleus is coated in a conventional manner using a suspension of sugar, titanium dioxide, talc, gum arabic and the like. The finished tablet is polished with beeswax.

Final weight of the tablet tablet: 100mg

b) tablets

0.5 mg of active ingredient of formula (I)

Lactose 50.0mg

Corn starch 43.5mg

Soluble starch 5.0mg

Magnesium Stearate 1.5mg

100.0 mg

quite

The active ingredient and magnesium stearate are granulated in an aqueous solution of soluble starch, dried and mixed well with lactose and corn starch. The mixture is compressed into tablets weighing 100 mg. Each tablet contains 0.5 mg of active ingredient.

c) suppositories

One suppository is composed as follows.

5.0 mg of active ingredient of formula (I)

Suppository weight 1,695.0 mg

quite

The finely ground substrate is placed in a molten suppository using an immersion homogenizer and stirred and then cooled to 40 ° C. It is poured into the mold cooled at 35 degreeC previously.

Claims (1)

A process for preparing the compound of formula (I) and acid addition salts thereof, characterized in that the compound of formula (VI) is chlorinated or brominated and, if necessary, is substituted for chlorine or bromine atoms with alkoxy or alkylmercapto groups, respectively.

In the above structural formula R ₁ is hydrogen, chlorine or bromine or an alkyl group having 1-4 carbon atoms R ₂ is hydrogen, fluorine chlorine or bromine atom or nitro or trifluoro methyl group R ₃ is a chlorine or bromine atom, an alkoxy or alkyl mercapto group having 1-3 carbon atoms.