DE2732921A1 - 1-Piperazino-triazolo-thieno-diazepine derivs. - useful as anxiolytics, tranquillisers, sedatives and neuroleptics - Google Patents

Abstract

Diazepines of formula (I) and their acid addition salts are new. In (I) R1 is H, opt. branched alkyl (opt. substd. by halo, OH or dialkylamino), phenyl (opt. substd. by CH3, CH3O,NO2 or halo), pyridyl, pyrimidinyl or R4CO, R2 is H, F, Cl or Br, R3 is Cl, Br or alkyl, R4 is H, 1-17C alkyl, 1-2C alkoxy, phenyl (opt. substd. by CH3, CH3O, halo or NO2) or pyridyl. (I) are prepd. e.g. by reacting the 1-halo cpd. with an R1-substd. piperazine. (I) are administered pref. at 5-150 mg/day. In tests oral doses or around 1.3g/kg caused no deaths in mice. In an example 8-bromo-6-(o-chlorophenyl)-1- N-(2-hydroxyethyl)piperazinyl -4H-s- -triazolol 3,4-c thieno 2,3-e -1,4-diazepine was prepd. from the 1,8-dibromo cpd. and N-(2-hydroxyethyl)piperazine.

Description

New substituted l-acyl-piperidino- or -piperazino-4H-s-

triazolo [3,4cithieno [2,3e] 1,4-diazepines, process for their preparation and pharmaceutical compositions The invention relates to new substituted l-acyl-piperidino- or -piperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4 diazepines of the general formula in which R1 is hydrogen, alkyl with 1 - 17 carbon atoms, alkoxy with 1 - 2 carbon atoms, phenyl, tolyl, methoxyphenyl, halophenyl, nitrophenyl or pyridyl, R2 is fluorine, chlorine or bromine, R3 is bromine, chlorine or alkyl with 1 - 3 carbon atoms and YN or the group CH mean processes for their production and their use as active ingredients in pharmaceuticals.

In the general formula I, the term "alkyl" means a straight chain or branched alkyl radical with 1 - 17 carbon atoms; 1 to 6 carbon atoms are preferred.

"Halogen" refers to the halogen atoms fluorine, chlorine, bromine and iodine; the substituent on the phenyl ring can be in the o-, m- or p-position. The pyridyl residue can be in a-, B- or br-position to the nitrogen atom with the piperidine resp.

Be connected to piperazine ring.

The new compounds can be obtained a) by acylating a compound of the general formula in which the radicals R2, R3 and Y have the meaning given above, or b) by cyclization of compounds of the general formula in which the radicals R1, R2 and R3 have the meaning given above and Y stands for CH, or c) by dehydrogenation of compounds of the general formula in which R1, R2, R3 and Y have the meaning given above, or d) by reacting compounds of the general formula in which R2 and R3 have the meaning given above, with piperazines of the general formula in which R1 has the meaning given above.

The acylation of compounds of the formula II with a piperidine or piperazine carboxylic acid halide or anhydride can using an excess on acylating agents or in a suitable inert solvent such as dioxane, Tetrahydrofuran, benzene, toluene or xylene take place. In some cases it has the addition of an inorganic or organic base, for example pyridine, Triethylamine, potash, or potassium bicarbonate are useful for scavenging the acid proven. Reaction temperature and reaction time can, depending on the one used Starting material, vary within wide limits. So the reaction temperature can be between Room temperature and the boiling point of the solvent or acylating agent used lie; the reaction time can be a few minutes to several hours.

The ring closure of compounds of the general formula III succeeds preferably by boiling with a higher boiling solvent such as dioxane, tetrahydrofuran, Benzene, toluene or xylene under reflux. Most connections use this a spontaneous ring closure; if the ring closure is not or not in this way can be fully achieved, the addition of silica gel and heating on is sufficient Water separator. The reaction time in this process is also of a few Minutes to several hours, depending on the raw material used.

The dehydrogenation of compounds of the general formula IV takes place using suitable dehydrating agents such as halogens or else of compounds of the higher oxidation states of chromium or manganese, for example a chromate, a bichromate or a permanganate.

Suitable solvents for the reaction with a halogen are Called chlorinated hydrocarbons such as chloroform or methylene chloride. The oxidation with the mentioned compounds of chromium or manganese takes place in solvents such as acetone, tetrahydrofuran or dioxane.

Depending on the type of oxidizing agent, the reaction temperature is im generally between OOC and the boiling point of the solvent used.

The implementation of compounds of the general formula V with a Piperazine of the formula VI takes place either without a solvent or in a higher-boiling one Solvents such as benzene, toluene, dioxane, tetrahydrofuran, chlorinated hydrocarbons such as carbon tetrachloride or methylene chloride, preferably at the boiling point of the solvent used in each case. The reaction time depends on the one used Starting material and can take a few minutes to several hours.

According to the method given above, for example, the the following end products are obtained: 8-Bromo-6- (o-chlorophenyl) -l-N-formylpiperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 1- (N-acetylpiperazino) -8-bromo-6- (o -chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e ] 1,4-diazepine, l- (N-Acetylpiperazino) -8-ethyl-6- (o-chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine, l- (N-acetylpiperazino) -8-chloro-6- (o-chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine, 1- (N-acetylpiperazino) -8-bromo-6- (o-fluorophenyl) -4H-striazolo ( 3,4cithieno [2,3e] 1,4-diazepine, l- (N-acetylpiperazino) -8-bromo-6- (o-bromophenyl) -4H-striazolo [3,4c] thienot2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-stearylpiperazino) -4H-striazolo3,4c] thienoC2,3e11,4-diazepine, 8-bromo-1- (N-caproylpiperazino) -6- (o-chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-benzoylpiperazino) -4H-striazoloC3,4c) thienoC2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- [N- (p-fluorobenzoyl) -piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-Bromo-6- (o-chlorophenyl) -1- [N- (o-methylbenzoyl) -piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- [N- (p-chlorobenzoyl) piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-Bromo-6- (o-chlorophenyl) -1-tN- (p-nitrobenzoyl) -piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-nicotinoyl-piperazino) -4H-striazolot3,4c] thienot2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-picolinoyl-piperazino) -4H-striazoloC3,4c] thieno [2,3e1,4-diazepine, l- (N-ethoxycarbonyl-piperazino) -8-bromo-6- (o-Chlorophenyl) 4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-bromo-6- (o -bromophenyl) -1- (N-formylpiperidino) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine, l- (N-Acetylpiperidino) -8-bromo-6- (o-chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-Bromo-6- (o-chlorophenyl) -l- (N-benzoylpiperidino) -4H-s triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- [N- (p-fluorobenzoyl) -piperidino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 8-Bromo-1- (N-isobutyrylpiperidino) -6- (o -chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine.

The starting compounds of the general formula II can be obtained, for example are carried out according to the information in the DBP (German patent application P, Case 1/586) Implementation of appropriately substituted l-halo-4H-s-triazolo [3, 4c] thieno [2,3e] 1,4-diazepines with a piperazine or by dehydration of a l-piperazinyl-4H-s-triazolo [3,4c] thieno t2.3e] 5,6-dihydro-1,4-diazepines.

Starting materials of the general formula III can be prepared by reacting thieno-benzodiazepine-2-thiones of the general formula in which R2 and R3 have the meaning given above, with an N-acylpiperidinecarboxylic acid hydrazide of the general formula in which R1 has the meaning given above.

Compounds of the general formula IV are obtained by reacting compounds of the general formula in which R2 and R3 have the abovementioned meaning, with a piperazine derivative of the general formula in which R1 has the meaning given above and the subsequent replacement of the ring oxygen atom by a nitrogen atom, as has been described, for example, in German application P 25 31 678.

The end products of general formula I have valuable therapeutic properties Properties on. When using various pharmacological test methods do they initially show a significant neuroleptic effect; with their fading away After about 24 to 48 hours, an anxiolytic, tension-relieving effect develops and sedative effect.

The new connections are therefore particularly suitable for rectification psychomotor agitation and anxiety, such as those in schizophrenia occur, also for the treatment of convulsive states and sleep disorders of various Genesis.

Such end products have proven to be particularly effective in general Formula I proved, in which R1 is hydrogen or methyl, R2 is chlorine, R3 is bromine and Y Ch or N mean.

The single dose of the substances according to the invention is from 0.05 to 50, preferably 0.1 to 25 mg and 5 to 150 mg as the daily dose.

The compounds obtainable according to the invention can be used alone or in Combination with other active ingredients according to the invention, optionally also in combination with other pharmacologically active ingredients such as antispasmodics or B-receptor blockers come into use. Suitable application forms are, for example, tablets, Capsules, suppositories, solutions, juices, emulsions or dispersible powders. Appropriate Tablets can be made, for example, by mixing the active ingredient (s) with known ones 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 made by coating analogously to the tablets manufactured Kerner with agents commonly used in dragee coatings, for example Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar will. To achieve a depot effect or to avoid incompatibilities the core can too consist of several layers. Likewise The coated tablet can also consist of several layers to achieve a depot effect exist, the excipients mentioned above for the tablets being used can.

Juices of the active ingredients or combinations of active ingredients according to the invention can also use a sweetener such as saccharin, cyclamate, glycerin or Sugar and a flavor-enhancing agent, e.g. flavorings such as vanillin or orange extract. You can also use suspension aids 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.

The one or more active ingredients or combinations of active ingredients Capsules can be produced, for example, by combining the active ingredients with inert Carriers, such as lactose or sorbitol, mixed and encapsulated in gelatin capsules.

Suitable suppositories can be made, for example, by mixing with Carriers provided for this purpose, such as neutral fats or polyethylene glycol or its derivatives.

Example 1 1- (N-acetylpiperazino) -8-bromo-6- (o -chloroshenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine 4.6 g (0.01 mol) of 8-bromo-6- (o-chlorophenyl) l-piperazino-4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine are stirred in 100 ml of acetic anhydride for 20 minutes. The reaction mixture is poured on ice and makes alkaline with ammonia.

The acetyl compound is taken up in methylene chloride, the methylene chloride phase dried and the residue brought to crystallization by adding ether.

Yield: 3.8 g = 76% of theory of m.p. 247-2490C.

For example 2 l- (N-AcetYl-4-piperidino) -8-bromo-6- (o-chlorophenyl) -4H-striazolor3.4clthienor2.3e] 1,4-diazepine 7.43 g (0.02 mol) of 7-bromo-5- (o-chlorophenyl) -1,4-diazepine-2-thione are mixed with 4 g of N-acetyl-4-piperidinecarboxylic acid hydrazide and 150 ml of dioxane refluxed for 4 hours. The reaction mixture is evaporated and after the addition of ether, 2.7 g of a semi-crystalline product are obtained heated in 60 ml of xylene and 14 g of silica gel for 2 hours on a water separator. The suspension is filtered off with suction and the title compound is eluted with methanol. One obtains according to the corresponding Purification 2.4 g = 25% of theory the title compound of m.p. 221-2230C.

Example 3 8-Bromo-6- (o-chlorophenyl) -1- (N-ethoxy carbonyl piperazino) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 4.6 g (0.01 mole) of 8-bromo-6- (o -chlorophenyl) -l-piperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine are in 100 ml of tetrahydrofuran with 2 ml of ethyl chloroformate for 30 minutes stirred at room temperature. It is evaporated, water and methylene chloride are poured in, make alkaline with ammonia and chromatograph the residue from the dried Methylene chloride phase.

Yield: 4.8 g = 91% of theory, melting point 216-2180C.

Example 4 1- (N-Formylpiperazino) -8-bromo-6- (o-Chlorophyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine 4.6 g (0.01 mole) of 8-bromo-6- (o -chlorophenyl) -l-piperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine are refluxed in 100 ml of formic acid for 3 hours.

It is poured onto ice, made alkaline with 2N sodium hydroxide solution and taken Formyl compound in methylene chloride and works up as in Example 1.

Yield: 3.9 g of 80% of theory, melting point 205-215 ° C.

Further compounds of the general formula I are obtained in an analogous manner, as the table below shows: Example R1 f R2 R3 | Y | Fp.OC 5 1 -C6H5 | C1 Br N 294 6 Fe j Cl Br N 311-312 7 2 for C1 Br N 247-248 8 CH3 | C1 C2H5 N 220-224 9 CH3 i C1 C1 N 222 - 225 10 CH3- (CH2) 17-C1 | Br | N | 126 - 128 Formulation Examples a) Dragees 1 Dragee core contains: Active ingredient according to the invention 1.0 mg lactose 28.5 mg corn starch 19.0 mg celatine 1.0 mg magnesium stearate 0.5 mg 50.0 mg Production: The mixture of the active ingredient with lactose and corn starch is made with granulated a 10/3 aqueous gelatin solution through a sieve with a mesh size of 1 mm, dried at 40 ° C. and forced through a sieve again. 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 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 b) tablets active ingredient according to the invention 0.5 mg lactose 50.0 mg corn starch 43.5 mg soluble starch 5.0 mg magnesium stearate 1.0 mg 100.0 mg Production: Active ingredient and magnesium stearate are made granulated with an aqueous solution of the soluble starch, the granules dried and intimately mixed with milk sugar and corn starch. The mixture then becomes 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 Production: The finely powdered substance is mixed with Using an immersion homogenizer in the melted suppository mass cooled to 400C stirred in. The mass is poured into slightly pre-cooled molds at 35 ° C.

Claims (13)

Claims fNew substituted l-acyl-piperidino- or -piperazino-4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepines of the general formula in which R1 is hydrogen, alkyl with 1 - 17 carbon atoms, alkoxy with 1 - 2 carbon atoms, phenyl, tolyl, methoxyphenyl, halophenyl, nitrophenyl or pyridyl, R2 is fluorine, chlorine or bromine, R3 is bromine, chlorine or alkyl with 1 - 3 carbon atoms and YN or the group CH mean. 2. Compounds of the general formula I in which R1 is hydrogen or Methyl, R2 signifies chlorine, R3 signifies bromine and Y signifies CH or N. 3. 1- (N-Acetylpiperazino) -8-bromo-6- (o -chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine. 4. 1- (N-Acetyl-4-piperidino) -8-bromo-6- (o -chlorophenyl) -4H-striazolo [3,4c] thieno [2,3e] 1,4-diazepine. 5. 1- (N-Formylpiperazino) -8-bromo-6- (o -chlorophenyl) -4H-s triazolo [3,4c] thieno [2,3e] 1,4-diazepine. 6. Process for the preparation of new substituted l-acylpiperidino- or -piperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines of the general formula in which R1 is hydrogen, alkyl with 1 - 17 carbon atoms, alkoxy with 1 - 2 carbon atoms, phenyl, tolyl, methoxyphenyl, halophenyl, nitrophenyl or pyridyl, R2 is fluorine, chlorine or bromine, R3 is bromine, chlorine or alkyl with 1 - 3 carbon atoms and YN or the group CH, characterized in that a) compounds of the general formula in which R2, R3 and Y have the meaning given above, acylated in a manner known per se, or that b) compounds of the general formula in which R1, R2 and R3 have the meaning given above and Y is CH, cyclized, or that c) compounds of the general formula in which R1, R2, R3 and Y have the meaning given above, dehydrogenated in a manner known per se, or that d) compounds of the general formula in which R2 and R3 have the meaning given above and Hal denotes a halogen atom, with piperazines of the general formula in which R1 has the meaning given above. 7. Pharmaceutical preparations containing compounds as active ingredients of the general formula I in combination with customary auxiliaries and / or carriers. 8. Pharmaceutical preparations containing substances of general Formula I in combination with other pharmacodynamically active substances as well as common ones Auxiliary and / or carrier materials. 9. Process for the production of pharmaceutical preparations according to Claim 7, characterized in that compounds of the general formula I with customary pharmaceutical auxiliaries and / or carriers to customary pharmaceutical Application forms processed. 10. Process for the production of pharmaceutical preparations according to Claim 8, characterized in that substances of the general formula I in combination with other pharmacodynamically active substances as well as usual Processed auxiliaries and / or carriers into customary pharmaceutical application forms. 11. Method for the treatment of psychomotor agitation and anxiety by means of preparations according to claims 7 and 8. 12. Method of treating convulsive states of various origins by means of preparations according to claims 7 and 8. 13. Method of correcting sleep disorders of various causes by means of preparations according to claims 7 and 8.