LU81494A1 - NEW SUBSTITUTED 4H-S-TRIAZOLO (3,4C) THIENO (2,3E) -1,4-DIAZE-PINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

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The invention relates to compounds of the general formula!

R /, N

-üc, 1 "(Qf2 in the

Hydrogen, fluorine, chlorine or bromine, 'R, chlorine or bromine or an alkyl radical with 1-3 carbon 3' atoms and R ^ and R ^, which can be the same or different leg, 5, hydrogen, an alkyl radical with 1-4 Carbon atoms or a hydroxyalkyl radical with 2-3 carbon atoms i. mean or both radicals together form a 4- or 5-membered alkylene chain, λ ',' - ν w - 7 - Γ ". - * which can optionally be substituted once or twice by methyl and where the 6 ~ ring optionally as further hetero atom can contain an oxygen atom.

The invention further relates to processes for the preparation of the new compounds of general formula I and their use as active ingredients in medicaments.

The new compounds of general formula I can be obtained a) by reacting a compound of general formula JÏ

Hai_ / r JN

BVJ

R, _ / N / \ (II)

HlY / gr2 in which and Rj have the meaning given above, with an arain of the general formula / ¾ h <(ui) ,,,,,, in which R ^ and R ^ have the meaning given above, or; * - 8th - " .

i b) by dehydrogenation of a compound of the general; formula

R, IT

*> - V \

r5 YJ

κ3 / δγ <IV>

* s -N

1 H

[ÔT2 (in the

Rg, R ^ and have the meaning given above, in a manner known per se.

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The reaction of compounds of general formula II with 1 an amine of formula III is carried out either without solvent or in solvents such as benzene, Toluene, dioxane, tetrahydrofuran, chlorinated hydrocarbons * such as carbon tetrachloride or methylene chloride, preferably | '. at the boiling point of the solution used! by means of. When reacting with lower amines (dimethylamine,

Diethylamine etc.) the reaction is preferably carried out in the Autoclaves.

The reaction time depends on the starting material used and can range from a few minutes to several '1! Hours lie, la i 1) ’j

M

Γ i '. -9-

Dehydrogenation of compounds of general formula IV is carried out using suitable dehydrating agents, e.g. Halogens or compounds of the Liier oxidation stages of chromium or manganese, for example a chromate, a bichromate or a permanganate.

Chlorinated hydrocarbons such as chlorine or methylene chloride may be mentioned as suitable solvents for the reaction with a halogen. The oxidation with the mentioned chromium or manganese compounds takes place in solvents such as acetone, tetrahydrofuran or dioxane, if desired with the addition of a phase transfer catalyst.

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

The 1-amino compounds (R ^ and «Wassersteif) are obtained by reacting a 2-hydrazino-thieno £ 2,3e_l, 4-diazepine with cyanogen bromide according to the following scheme; H2Nv HJi N,

NH * N

^> BrC = N ^ j>

^ - \ C = N

ÇT2 I0Γ2

Compare: K.T. Potts and C. Hirsch, J. Irg. Chem. 33, 143 (1968).

Alcohols, benzene, toluene and halogenated hydrocarbons are suitable as solvents.

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If desired, these compounds can be alkylated in a customary manner. Alkyl halo-enides, dialkyl sulfates or esters of toluenesulfonic acid are preferably used as alkylating agents; mao. uses solvents such as tetrahydrofuran dimethylformamide or lower alcohols, but the alkylation can also be carried out without the addition of a solvent.

In the event of the introduction of a hydroxyalkyl radical, reaction with an alkylene oxide is recommended.

For example, the following end products can be obtained by the above processes: 8-bromo-6-vO-chlorophenyl) -l-amino-4H-s-triazolo [3,4c] thieho | [2,3e] 1,4-diazepine, i 8-bromo-6- (o-chlorophenyl) -1-methylamino-4H-s-triazolo [3 »4c] thieno [2,3e] 1,4-diazepine; \ 8-bromo-6- (o-chlorophenyl) -l-ethylamino-4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepine, i! * 8-Bromo-6- (o-chlorophenyl) -l-dimethylamino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, Γ 8-bromo-6- (o-chlorophenyl ) -l-diethylamino-4H-s-triazolo [3,4c] I thieno [2,3e] l, 4-diazepine, "8-bromo-6- (o-chlorophenyl) -l- (N-methyl-N -ethylamino) -4H-s- | l triazolo [3,4c] thieno [2,3e] l, 4-diazepine, I: 8-bromo-6- (o-chlorophenyl) -ln-propylamino-4H-s- triazolo [3,4c] p thieno [2,3e] l, 4-diazepine, i ί

• J

j 8-Bromo-6- (o-chlorophenyl) -l-di-isopropylamino-4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepine, $ ii ir- - 11 - »8 -Brom-6- (o-chlorophenyl) -l-di-n-butylamino-4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepine, 8-bromo-6- (o- chlorophenyl) -1-N-methyl-N- (β-hydroxyethyl) amino-4H-s-triazolo [3 »4c] thieno [2,3e] l, 4-diazepine, 8-bromo-6- (o- chlorphenyl) -l-di- (ß-hydroxyethyl) amino-4H-s-triazolo [3,4c] thieno [2,3e 31,4-diazepine, 8-ethyl-Ç- (o-chlorophenyl) -1- dimethylamino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-chloro-6- (o-chlorophenyl) -l-dimethylamino-4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepine, 8-bromo-6-phenyl-l-dimethylamino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-bromo 6- (o-bromophenyl) -1-dime thylamino-4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepine, 8-bromo-6- (o-chlorophenyl) -l-piperidino -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (2 ', 4 ^ 111½thylpiperidino) -4H-s- triazolo [3,4c] thieno [2,3e] l, 4-diazepine, 8-bromo-6- (o-chlorophenyl) -l-morpholino-4H-s-triaz olo [3,4c] thieno [2,3e] l, 4-diazepine, 8-bromo-6- (o-chlorophenyl) -l - (^ - methylmorpholino) -4H-s-triazolo [3,4c] thieno [ 2,3e] l, 4-diazepine, - 12 - 8-bromo-6- (o-chlorophenyl) -1- (4-methylpiperidino) -4H-s-triazolo [3,4c] thieno [2,3e] l , 4-diazepine, 8-bromo-6- (o-chlorophenyl) -l-pyrrolidino-4-Hs-triazolo [3,4c] thieno [2,3e] l, 4-diazepine.

The starting compounds of the general formula II are known from the literature. Starting compounds of the general formula IV are obtained by reacting compounds of the formula

Ha] _f N

B YJ

/ (v> 4 _0 (öT2 in which R2 and R ^ have the meaning given above and Hai represents a halogen atom, with an amine of the general formula III under the conditions given in a) and then replacing the ring oxygen atom with a nitrogen atom, as he e.g. has been described in German patent application P 25 31 678.

v 1 - 13 - i

The end products of the general formula I have valuable therapeutic properties. For example, damping, anxiolytic and tension-relieving properties were found when various pharmacological test methods were carried out. Tests on dressage also showed that the new compounds have a pronounced neuroleptic effect. This effect was determined on the basis of the signaled active criminal avoidance behavior (discriminated active avoidance) after a modified test by Dobrin, P.B., Rhyne, Arch. Int. Pharmacodyn. 178: 351-356 (1969).

Î It was shown in particular that the new substances only suppress timely avoidance treatments, but leave the reaction to the immediate shock completely intact. Such a selective effect is seen with the commercially available neuroleptics, e.g. Chlorpromazine, considered a strong indicator of neuroleptic properties. (Cook, L., Sepinwall, J., Proceedings of the sixth | international congress of pharmacology.Vol. 3 - Central! Nervous System and behavioral pharmacology.Oxford: i Pergamon 1976 b).

It is also noteworthy that this selection is particularly pronounced in the present case and clearly exceeds that of the commercial products.

t; The new connections are therefore particularly suitable for | Elimination of pschomotor excitement and anxiety states, such as those that occur in schizophrenia, but this calming and relaxing effect does not cause any disturbance in the level of alertness (vigilance).

End products of the general formula I in which R2 is chlorine, R ^ bromine and R ^ and R ^ are lower alkyl groups or a β-hydroxyethyl radical have proven particularly effective.

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

The compounds obtainable according to the invention can be used alone or in combination with other active compounds according to the invention, optionally also in combination with other pharmacologically active compounds such as antispasmodics or β-receptor blockers. Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) 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 produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, it being possible to use the auxiliaries mentioned above for the tablets.

t! Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. You can also use j suspending agents 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.

Injection solutions are made in the usual way, e.g. with the addition of preservatives, such as p-hydroxybenzoates! or stabilizers, such as alkali metal salts of ethylenediamine-i-tetraacetic acid, and prepared in injection bottles or | Bottled 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 milk sugar or sorbitol, and encapsulating them in gelatin capsules.

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

w - 16 - *

Example 1 l-Dlmpthy] fiTnino-8-bromo-6- (o-chlorophenvl) -4H-s-trlazolor 3.4c] thienof 2.5ell.4-diazepine 0.01 mol «4.5 gl, 8-dibromo-6 - (o-Chlorophenyl) -4H-s-triazolo [3t4c] thieno [2,5e] l, 4-diazepine are heated with 50 ml dimethylamine in 150 ml dioxane for 1 hour at 100 ° C in an autoclave.

The solvent is distilled off, the residue is partitioned between water and methylene chloride, the methylene chloride phase is separated off, washed with water and dried over magnesium sulfate. The residue is placed on an SiO 2 column and the substance is eluted with methylene chloride / methanol 98: 2. After distilling off the solvent, 2.2 g = 52% of theory is obtained from ethyl acetate. the title compound of mp 166-168 ° C.

Example 2 l-dimethvlamino-8-bromo-6- {o-chlorophenvl) -4H- s-triazolof 5.4c 1 thlenor2.5e] l.4-dlazepln 9 - 4.2 g «0.01 mol l-dimethylamino- 8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 5,6-dihydro-1,4-diazepine are dissolved in 50 ml methylene chloride and after adding 0 , 2 g of triethyl-N-benzylammonium chloride at 0 - 5 ° C with a solution of 2 g of potassium permanganate in 20 ml of acetone. After 15 minutes, Na bisulfite solution is added and the reaction mixture is acidified with dilute sulfuric acid. The title compound is obtained from the organic phase.

The yield is 3 »1 g = 73% of theory mp 165-167 ° C.

The 5,6-dihydro compound was obtained as follows: if "j - 17 - a) 53 mmol = 20 g 7-bromo-5- (o-chlorophenyl) thieno [2,3e] 4,1-oxazepine-2- thione (prepared analogously to the information in Belgian Patent No. 844 170) are stirred in 600 ml of methylene chloride with 12 g of formyl hydrazide and 80 ml of pyridine at room temperature for 45 minutes. Then drop 10 g of P0C1 ^ in 50 ml of methylene chloride at a maximum of 35 ° C and stir for 5 hours under reflux. After cooling, the organic phase is shaken out with 200 ml of 2N hydrochloric acid and washed with water. After drying, the organic phase is evaporated and the residue is taken up in hot ethyl acetate. When cooling, 15 g = * 73% of theory 8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3 »4c] thieno [2,3e] 4,1-oxazepine, mp 176-178 ° C.

Ί (] b) 28 g of this compound are dissolved in 280 ml methylene chloride | and 8.9 ml of pyridine with 5.4 ml of bromine. You cook | 3 hours under reflux, shakes after cooling with | Water out, the organic phase dries with magnesium sulfate, evaporates and gives the residue over Si0 £.

19.2 g * 57% of theory is obtained from methanol 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 4,1-oxazepine, mp 138 ° C.

ί c) 9.2 g = 0.02 mol of the dibromo compound with 300 ml

Dioxane and 100 ml of dimethylamine heated at 100 ° C in an autoclave for 1 hour. After distilling off the solvent | the residue is taken up in methylene chloride, washed with water, the organic phase is dried over magnesium sulfate and the residue obtained is l-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 4,1-oxazepine as an oil (7.0 g »82% of theory).

- 18- i- d) 8.5 g = 0.02 mol of the oxazepine obtained according to c) are stirred with 50 ml of concentrated hydrobromic acid at room temperature for 1 hour. It is diluted with 200 ml of water, made alkaline with ammonia and shaken out with 100 ml of methylene chloride. The methylene chloride solution is stirred with 4 ml of thionyl chloride for 1 hour. The excess of thionyl chloride is carefully decomposed with water and dilute ammonia, the organic phase is separated off and, after evaporation and addition of ether, 4.8 g = 92% of theory 3-Dimethylamino-4-13- (o-chlorophenyl-bromomethyl) -5-bromothienyl- (2)] - 5-chloromethyl-l, 2-4-triazole, mp. 203 ° C.

e) 5.3 g = 0.01 mol of the triazole are heated to 60 ° C. in an autoclave with 100 ml of ammonia-saturated methanol for 30 minutes. You evaporate and work up accordingly. The yield is 2.8 g * 66% of theory »1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 5, 6-dihydro-1,4-diazepine, mp 155-157 ° C.

Example 3 * l-amino-8-bromo-6- (o-chlorophenyl) -4H- s-triazolo Γ 3.4c] thieno 2.5e1l.4-diazepine 0.013 mol = 5 g of 2-hydrazino-5- (o-chlorophenyl ) -7-bromothieno [2,3e] l, 4-diazepine are heated to 60 ° C. for 30 minutes with 100 ml of ethanol, 1.4 g of cyanogen bromide and 1.4 g of sodium carbonate. It is evaporated, the residue is taken up in methylene chloride and chromatographed on SiO 2. The yield is 1.5 g * 29 96 of theory mp 251-252 ° C (from ethanol).

r - 19 - m i

Example 4 l-Dimethvlamino-8-brc: a-6- (o-chlorophenvl) -4H-s-triazolo Γ5.4c1thlenof 2.5e1l.4-diazepine 395 mg 1-amino-8-broa-6- (o-chlorophenyl ) -4H-s-triazolo [3 »4c] thieno [2,3e] l, 4-diaze? In are refluxed for 15 hours together with 5 mml of 85% formic acid and 2 times JOJéiger formalin solution. After cooling, the reaction product is shaken out with methylene chloride. The organic phase is evaporated and the residue is chromatographed on a silica gel column. 250 mg of the title compound of mp 164-166 ° C. (* 60% of theory) are obtained from the eluates.

/ i iü t- 1 - 20 -

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W

The following end products were obtained analogously to Examples 1-4:

Example R0 R, mp ° C

No. ^ R5 ά * 5 -HN-CH3 CI Br 166 - 168 6 -HN-C2H5 CI Br 224 - 226 7 -N (C2H5) 2 CI Br 143 - 145 • -o CI Br 224 - 226 9 -N ^ ^ 0 CI Br 205 - 207 / Ch5 10 -N CI Br 175 - 176 ^ ch2-ch2-oh 11 -0-CH3 CI Br 180 12 <1 CI Br 209 - 210 13 -N (CH3) 2 CI C2H5 130 - 132 14 -N (CH3) 2 CI CI 154 - 155 15 -N (CH3) 2 H Br 216 - 217 16 -N (CH3) 2 Br Br 171 17 -NH- (CH2) 2-CH3 CI Br 148 - 150 «- 21 -»

Formulation examples a) coated tablets 1 coated tablet core contains:

Active ingredient according to the invention 1.0 mg

Milk sugar 28.5 mg

Corn starch 19.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mg 50.0 mg

Manufacturing:

The mixture of the active substance with milk sugar and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with a 1 mm mesh size, dried at 40 ° C. and passed through a sieve again. The granules obtained in this way are mixed with magnesium stearate and pressed. i! The cores obtained in this way are coated in a conventional manner with a casing which is applied with the aid of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax.

Dragee final weight: 100 mg 1 b) tablets j -! Active ingredient according to the invention 0.5 mg j milk sugar 50.0 mg

Corn starch 43.5 mg soluble starch 5.0 mg

Magnesium stearate 1.0 mg - s | 100.0 mg l j i i i. _ - 22 - »

Manufacturing:

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

c) Suppositories 1 suppository contains:

Active ingredient according to the invention 5 »0 mg, suppository mass 1,695.0 mg

Manufacturing:

The finely powdered substance is stirred into the molten suppository mass, which has been cooled to 40 ° C., using an immersion homogenizer. The mass is poured into slightly pre-cooled molds at 35 ° C.

d) Ampoules (In.1 ection solutions)

Composition:

Active ingredient according to the invention 0.5 part by weight

Sodium pyrosulfite 1.0 part by weight

Disodium salt of ethylenediamine 0 parts by weight of tetraacetic acid

Sodium chloride 8.5 parts by weight of double distilled water ad 1000.0 parts by weight

Manufacturing:

The active ingredient and the excipients are dissolved in a sufficient amount of water and brought to the desired concentration with the necessary amount of water. The solution is filtered and filled into 1 ml ampoules under aseptic conditions. Finally, the ampoules are sterilized and sealed. Each ampoule contains 0.5 mg of active ingredient.

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Claims (5)

1. New substituted AH-s-triazolotî ^ clthienotZ ^ ell, A-diazepines of the general formula RV Nx: - ^ u vfY y «(στ2 S in the Rg hydrogen, fluorine, chlorine or bromine, Rj chlorine or bromine or an alkyl radical with 1-3 carbon atoms and R ^ and R ^, which may be the same or different, are hydrogen, an alkyl radical with 1 - h carbon atoms or a hydroxyalkyl radical with 2-3 carbon atoms or both radicals together a 4 _ or 5-membered alkylene chain form, which can optionally be mono- or disubstituted by methyl and the 6-ring can optionally contain an oxygen atom as a further heteroatom. \ 1 r \ \ f Γ * * · i ^ jy - 3 - * 2. New substituted 4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepines of the general formula I in which a chlorine atom, R. * a bromine atom and 3 R ^ and R ^ alkyl groups with 1 -3 carbon atoms or one of the radicals mean a β-hydroxyethyl group. a. '3. l-Dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e3l »4-diazepine. 4. l-diethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3, 4c] thieno [2,3e] 1,4-diazepine. 5. 1- [N-methyl-N- (β-hydroxyethyl) amino] -8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine. 6. Process for the preparation of new substituted 4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepines of the general formula:. r4 »> - / \> M p Y) —Ν = · / 0 h L * - k - in which R2 is hydrogen, fluorine, chlorine or bromine, chlorine or bromine or an alkyl radical with 1-3 carbon atoms and and Ry the same or can be different, mean hydrogen, an alkyl radical with 1-4 carbon atoms or a hydroxyalkyl radical with 2-3 carbon atoms or both radicals together form a 5- or 6-membered saturated heterocyclic ring which may be mono- to disubstituted by methyl can and where the '. 6-ring can optionally contain an oxygen atom as a further heteroatom, characterized in that a) compounds of the general formula N \ Hai ^ N c N ((II) H .- / V \ LI / \ __. N QP in the [ Rg and R ^ have the meaning given above and | Hai a halogen atom means with amines of the general formula! R4 | HN ^ "(III)! _« 5 • 't - 5 - in which R ^ and R ^ the above Have meaning, or that b) compounds of the general formula R4v N.; R ^ \ //, 3γγ “Λ> -N 1 H (Qp in which Rg, Rj, R ^ and R ^ have the abovementioned meaning, are dehydrated in a manner known per se. 7. Pharmaceutical preparations containing as active ingredient compounds of the general formula I in combination with customary auxiliaries and / or carrier substances. 8. Method for the treatment of psychomotor excitement and anxiety and diseases of the schizophrenic form by means of preparations according to claim 7. »* '^ * \ * 1 i