DE2237502A1 - NEW HETEROCYCLIC COMPOUNDS AND METHODS FOR MAKING THEM - Google Patents

Description

30 June 1972

Wander AG. ■ _ _{cnn r} ~> ro

_ Case 500-5268

Bern - -

. Patent attorneys

Dipl.-Ing. P. VVirth

Dr. V. Sci: r: -. I ·: · J-Kov / arzik

Dip !, l.vj. G. Dcr.pc-fiborg

Dr. P. V / ci.:; V.-l.vD.-. DiGudsl

6 Frankfurt / M., Gr. Esclicnhaimer Str. 39

New heterocyclic compounds and processes for their preparation

The invention relates to new heterocyclic compounds of the formula I,

^(C Vn I 'IL-N N - R

where η is 1, 2, 3 or 4, and R is hydrogen, a benzyl group or an alkoxyalkyl or an alkoxycarbonyl group each having a maximum of 6 carbon atoms represents or represents an alkyl, alkenyl, alkanoyl or a hydroxyalkyl group with in each case at most 4 carbon atoms, the hydroxyalkyl group optionally also additionally can be acylated, as well as processes for the preparation of compounds of the formula I.

The compounds of the formula I can be converted into their salts and vice versa.

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According to the invention, compounds of the formula I and get their salts by either

a) reactive esters of keto alcohols of the formula II,

CH ..- v

\ ^] n CH-OH II

^X CH ₂ ^

where η has the meaning mentioned, with thio ureas of the formula III,

NH ₀ -CN NR III

² g ^ y

in which R has the meaning mentioned, or reacts with their acid addition salts, or

b) reactive esters of alcohols of the formula II with piperazine or piperazine derivatives of the formula Iv,

HN N-R IV

wherein R has the meaning mentioned, can react, with one of the reactants beforehand has been reacted with hydrofluoric acid or a rhodanide,

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into the compounds of the formula I thus obtained, in which R is hydrogen, optionally followed by a Benzyl, alkyl, alkenyl, alkanoyl, hydroxyalkyl group, the latter optionally being acylated, or an alkoxyalkyl or alkoxycarbonyl group, such as ; Number of carbon atoms in each case - is indicated above, introduces, or compounds of the formula I obtained in which R is a hydroxyalkyl group, optionally acylated or from the compounds of the formula I thus obtained, in which R is a benzyl, alkoxycarbonyl, alkenyl, alkanoyl or methyl group, these groups may be split off

and then optionally converting the compounds of the formula I thus obtained into their acid addition salts convicted.

The implementation described in section a) can, as as described below:

Compounds of formula II are mixed with compounds of formula III either in an inert solvent or reacted without a solvent. If a solvent is to be used up, this is recommended an. optionally aqueous alcohol, such as methanol, ethanol or isopropanol, acetone, dioxane, benzene, Toluene, xylene, dimethylformamide or dimethyl sulfoxide.

The reaction is conveniently carried out at temperatures between barely temperature and 140 ° C, preferably between

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see 70 ° and 120 ° C, or - in the absence of one Solvent - carried out at temperatures between 70 ° and 120 ° C.

As reactive esters of alcohols of the formula II Suitable for the above reaction are, for example, hydrogen halide esters, in particular hydrogen bromide or hydrogen chloride acid ester, or toluene sulfonic acid ester. When using them, you get directly to the acid addition salts of the compounds of the formula I. If, however, the free bases of the compounds of the formula If you want to achieve this, it is advisable to add an acid-binding agent to the reaction mixture, e.g. triethylamine, to add.

The conversion described in section b) can be carried out as described below:

Piperazine or the piperazine derivative of the formula IV or the reactive ester of the alcohol of the formula II are first treated with hydrofluoric acid or a rhodanide, in particular potassium rhodanide or Ammonium rhodanide, in an inert solvent, e.g. in an optionally aqueous ethanol or in dioxane, at a temperature between room temperature and 100 ° C, preferably between 70 ° and 80 ° C implemented. The following main reaction between the formed rhodanic acid salt

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BATH ORIGINAL

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of the pipexcizine or piperazine derivative with the reactive Esters of the alcohol of the formula 11 or between the piperazine or piperazine derivative and the hydrofluoric acid ester of the alcohol of the formula IT is expediently carried out in the section a) specified reaction conditions, the formation of the rhodanic acid required for the reaction Salt of piperazine or the piperazine derivative or the hydrohodanic acid ester of Alcohol of the formula II can also be achieved by having the main reaction in the presence takes place of hydrofluoric acid or a rhodanide.

The subsequent introduction of the above non-hydrogen radicals from R in. Products in which R represents hydrogen, can be done, for example, by combining the unsubstituted compounds with reactive Derivatives, in particular hydrohalic acid esters or sulfuric acid esters, of hydroxy compounds of the formula R - OH converts. ■

The reaction is carried out in the presence or absence of an inert solvent such as alcohol, e.g. ethanol, Benzene, toluene, dioxane, pyridine, at a temperature between room temperature and 120 ° C, preferably between 50 ° and 80 ° C. An acid-binding one is also advantageous in this reaction Agents, for example 1,8-bis (dimethylamino) naphthalene present. One

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Alkyl group R can also by the method of reductive Alkylation can be introduced by removing the unsubstituted Connection with corresponding aldehydes either with simultaneous reduction with the help of. hydrogen in the presence of a catalyst, e.g. platinum oxide at room temperature, or in the presence of a reducing agent such as formic acid. The latter implementation is advantageously carried out in such a way that the unsubstituted compound is dissolved in 90% strength formic acid and with the corresponding aldehyde for 5-20 hours to a temperature between 50 ° and 150 ° C, preferably boiling temperature, warmed up. To introduce a hydroxyalkyl group you can also implement the unsubstituted compound with an alkylene oxide, which is conveniently done in an orga ™ A niche solvent, e.g. an alcohol such as methanol, takes place at a temperature of 0 ° to room temperature.

The compounds of the formula I obtained by one of the above processes, in which R is a hydroxyalkyl group can stand in a manner known per se, for example with the aid of an anhydride such as acetic anhydride in an inert Solvents such as benzene or pyridine can be acylated.

The splitting off of a benzyl group R for the preparation of the compounds in which R is hydrogen takes place e.g. by hydrogenolysis. The hydrogenolysis is advantageously carried out in such a way that the starting compound is in dissolves in an alcohol, e.g. ethanol, or in ethyl acetate and at normal pressure with hydrogen in the presence of a noble metal catalyst, preferably platinum oxide or palladium carbon at a temperature between room temperature and

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Hydrogenated at 50 ° C. If R stands for a benzyl, methyl or alkeny group, this can be split off Groups are carried out in such a way that the starting materials are mixed with cyanogen bromide or with a chloroformic acid ester, E.g. the ethyl or benzyl ester, and the reaction product obtained hydrolytically or hydrogenolytically in the secondary Amiη transferred.

The reaction of the starting material with cyanogen bromide is carried out preferably by heating the reaction ■ subscriber in an inert solvent such as benzene, toluene or dioxane, at temperatures between 80 ° and 120 ° C but advantageously ₁ to boiling temperature. The reaction of the starting materials with the Ch-Io rformic acid ester is carried out either in the absence of an inert solvent or in an inert solvent such as benzene at a temperature between 70 ° and 120 ° C., preferably at the boiling point. This creates compounds that contain a cyano or carbalkoxy group. These groups are then split off hydrolytically or hydrogenolytically.

The hydrogenolysis to the secondary amine takes place under the conditions mentioned earlier. The hydrolysis can e.g. by heating the reaction product with aqueous mineral acid, especially hydrochloric acid, to preferably Boiling temperature can be brought about.

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The subsequent cleavage of an alkanoyl or alkoxycarbony group R also takes place hydrolytically, the above-mentioned conditions can also be used.

The hydrohalic acid esters used as starting compounds in the process of section a) of alcohols of the formula II are either known or can be produced in a manner known per se can be provided, e.g. by converting ketones. of Formula V,

⁽ % ^{) n} Ah ₂ ν

CH ₂

where η has the meaning mentioned, with halogens. or a halogenating agent such as N-bromosuceinimide or sulfuryl chloride. Hydrohalic acid esters of Alcohols of the formula II need before the subsequent reaction with the thiourea derivative of the formula III not necessarily to be isolated.

Other esters, e.g., toluenesulfenic acid esters, of alcohols of the formula II can be obtained, for example, if the corresponding hydrohalic acid esters are mixed with the salt, especially the sodium salt, of a corresponding other acid.

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The in the process of section a) as starting compounds required thiourea derivatives of the formula III are either also known or can be based on can be prepared in a manner known per se, e.g. by heating piperazine or piperazine derivatives for several hours of the formula IV, wherein R has the abovementioned meaning. tung has concentrated with ammonium rhodanide aqueous solution to temperatures between 80 and 140 ° C.

The piperazine derivatives of the formula IV are either also known or can be known per se Way to be made.

The compounds of the formula I obtained by the process described are known per se Way, for example by extraction, precipitation, salt formation, etc., isolated and then on in a known manner, e.g. by recrystallization.

The basic compounds of the formula I, which if necessary, can be released from acid addition salts obtained in a manner known per se at room temperature solid, optionally crystalline, or oily compounds, which by reaction with suitable inorganic or organic acids in their acid addition salts can be converted.

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For this purpose, the inorganic acids have been hydrogen halide acids, sulfuric acid, nitric acid, phosphoric acid etc. and as organic acids the Toluenesulfonic acid, acetic acid, malonic acid, succinic acid, malic acid, maleic acid, tartaric acid etc. proved suitable.

The compounds of the formula I obtained according to the invention are distinguished by extremely favorable properties pharmacodynamic properties. The compounds of the formula I have in particular one strong effect on the central nervous system.

In animal experiments, the compounds of the formula I show a stimulating effect on the vigilance of the test animals. As part of the increased vigilance, behaviors such as persistent head shaking (in a Dose of 0.5-20 mg / kg p.o. in the mouse - using the following method: groups of 5 mice receive the Test substance applied orally. Every 5 minutes, each individual animal is observed for 2 minutes to see if during this time head shaking occurs. The dose is determined at which the Shake animals with their head), which are known to be psychoactive, highly effective substances. The connections of the Formula I also show serotonin antagonism in vitro and in vivo (demonstrated on the isolated rat uterus according to the method of J.H. Gaddum and K.A. Hameed, Brit. J. Pharmacol. £, 175 and 240 [1954]), as is the case with amphetamine-like Substances is unknown.

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The compounds of formula I are indicated for use as psychostimulants, especially for enhancement of emotional vigilance.

For the above application, the dose to be administered depends on the compound used and the mode of administration as well as the type of treatment. In general, satisfactory results are obtained when compounds of the formula I are administered in one dose from 0.15-20 mg / kg animal body weight. For larger mammals, one should be administered daily Displayed amount of 10-200 mg. This amount to be administered daily can also be used in smaller doses 1-5 times be administered daily or in sustained-release form. A unit dose, for example one for oral administration suitable tablet can be between 2.5 and 200 mg of the active ingredient along with suitable pharmaceutical indifferent auxiliaries such as lactose, corn starch, ' Contain talc, magnesium stearate, etc.

The compounds of formula I can also be in the form of their pharmaceutically acceptable acid addition salts are administered to the same degree Have activity like the free bases »

The administration of compounds of the formula I or their salts can either orally in the form of tablets, Granules, capsules or coated tablets or parenterally in the form of injection solutions.

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An example tablet composition consists of 20 mg 2- (4 "methyl-l-piperazinyl) -5,6-dihydro-4H ~ cyclopentathiazole, 70 mg corn starch, 5 mg talc and 0.1 mg magnesium stearate. The one produced in a manner known per se The tablet has a double notch.

In the examples below are the temperatures Specified in degrees Celsius, the room or room temperature is between 20 and 30 ° C, unless otherwise it is said. The vacuum usually used is, unless otherwise stated, between 8 and 20 mm Hg.

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Example 1; 2- (4-Methyl-1-piperazinyl) -5,6,7,8- tetrahydro- 4 H-cycloheptathiazole

5.7 g of 2-bromocycloheptanone and 4.8 g of 4-methyl-l-piperazinyl-thiocarboxamide are heated in 20 ml of ethanol for 4 hours on the steam bath (approx. 100 °). After evaporation in The residue is dissolved in water in vacuo, 4 N aqueous sodium hydroxide solution is added and the basic 2- (4-methyl-1-piperazinyl) -5, 6,7, 8-tetrahydro-4H-cycloheptathiazole taken up in aether. After concentrating the ethereal solution, the crystallizes Base with a melting point of 73-74 ° (recrystallized from ether / petroleum ether). Treatment with ethanol Hydrochloric acid gives the dihydrochloride with a melting point of 245-247 °.

At game 2; 2- (4-methyl-1- piperazinyl) -5,6-dihydro -

4H-cyclopentathiazole

Using the same procedure as in Example 1, but starting from equivalent proportions of 2-bromocyclopentanone instead 2- (4-methyl-1-piperazinyl) -5,6-dihydro-4H-cyclopentathiazole is obtained from 2-bromocycloheptanone as a base with a melting point of 65 ° (recrystallized from ether / petroleum ether). The dihydrochloride melts at 240 ° (recrystallized from ethanol).

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Example 3: 2- (4- (2-hydroxyethyl) -l ~ piperazinyl) ~ 5,6, 7,8-tetrahydro -4K ~ cycloheptathiazole

With the same procedure as in example 1, but starting of equivalent proportions of 4- (2-hydroxyethyl) -1-piperaziny] -thiocarboxamide instead of 4-methyl-lpiperazinyl-thiocarboxamide 2- (4- (2-hydroxyethyl) -l-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole is obtained as a base with a melting point of 103-103.5 ° (recrystallized from ether / petroleum ether3 :). The dihydrochloride melts at 215 ° (unsharp) (recrystallized from Ethanol / ethyl acetate).

Example 4; 2- (4-Benz y - l piper azinyl) -5,6,7,8-tetrahydro-4H-cyclohep t athiazol

Using the same procedure as in Example 1, but starting from equivalent proportions of 4-benzyl-1-piperazinylthiocarboxamide instead of 4-methyl-1-piperazinyl-thiocarboxamide, 2- (4-benzyl-1-piperazinyl) -5,6,7, 8-tetrahydro-4H-cycloheptathiazole as a base with a melting point of 98-99 ° (recrystallized from ether / petroleum ether). The dihydrochloride melts indistinctly from 215 ° (recrystallized from ethanol / ethyl acetate).

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Example 5: 2- (4-Methy l ~ l-pipejrazin y 1) -4 _f 5.6 _{i f} : 7 ~ - tetra hydro-cy clohex atbi az ol

5.3 g of 2-bromocyclohexanone are mixed with 8 g 4 _f "4-methyl-lpiperazinyl-thiocarboxamide and the mixture heated for 3 hours in an oil bath temperature:.. 130 ° is then dissolved the reaction cake in water, with aqueous 4N sodium hydroxide After adding ethanolic hydrochloric acid, the dihydrochloride of 2- (4-methyl-1-piperazinyl) - 4 _# 5, 6, V-tetrahydrc-cyclohexathiazole from the decomposition point crystallizes. t 215-220 ° from (recrystallized from ethanol).

Example 6; 2- (4-methyl- 1 -pi perazinyl) -4.5 _f 6,7,8 , 9 - hexahydro-cyclooc thiazole

With the same procedure as in Example 5, but starting of equivalent proportions of 2-bromocycloctanone instead of 2-Bromocyclohexanone is obtained 2- (4-methyl-1-piperazinyl) -4,5,6,7,8,9-hexahydro-cyclooctathiazole as a dihydrochloride with a melting point of 206-208 ° (recrystallized from ethanol).

Example 7; 2- (4- (2- Hydroxyeth yl) -l-piperazinyl), 5.6,

7th , 8-tetrahydro-4H-cycloheptathiazole

5.2 g of 1- (2-hydroxyethyl) piperazine v / earth in 20 ml of ethanol are mixed with 3.0 4 g of ammonium thiocyanate and for so long in a water bath (bath temperature 100 °) to boiling

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heated until no more ammonia escapes (approx. half an hour). After adding 9.55 g of 2-Bromcydlüheptanon _r diluted with 10 ml of ethanol, the mixture is heated for a further 12 hours at the same bath temperature. It is then evaporated in vacuo and the residue is dissolved in a little dilute hydrochloric acid. The mixture obtained is extracted twice with ether. The aqueous phase is made alkaline with concentrated sodium hydroxide solution and extracted exhaustively with ether. When the dried ether solution is concentrated, the base of 2- (4- (2-hydroxyethyl) -l-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole crystallizes with a melting point of 103 °.

Example 8; 2- (4-Methy 1-.1 -pipex'aziny 1) -5, 6,7 , 8-tetrahydro-4H-qycj _L oheptat.hi clZOl

Using the same procedure as in Example 7, but starting from equivalent proportions of 1-methylpiperazine instead 1- (2-hydroxyethyl) piperazine gives 2- (4-Kethyl · ™ 1-piperazinyl) -5, 6,7, 8-tetrahydro-4IJ-cycloheptathiazole of melting point 73 °.

Example 9: 2- (4- (2-Methoxyät hyl) -l- piperazinyl) -5.6,

7, 8-tetrahydro-4H-cycl ohe ptathl, azole

6.4 g of 2-bromocycloheptanone and 3.25 g of potassium thiocyanate are mixed in 30 ml of ethanol and 5 ml of water for 1 1/2 hours heated on the steam bath (100 °). After adding 4.8 et 1- (2-MethoxyiJUr / l) -piperazine in 15 ml of ethanol

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heated to 100 ° for a further 15 hours. After evaporation in vacuo, the residue is taken up in a little water and extracted twice with ether. After the ethereal solution has been dried, hydrogen chloride is introduced gas is the dihydrochloride of 2- (4- (2-methoxyethyl) -1-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole precipitated in crystalline form. Melting point after recrystallization from absolute ethanol 203-205 °.

2- ( 4- Methyl-1-piperazinyl) -5, 6 , 7, 8-tetra hydro-4H-cy el oheptathiazojL.

With the same procedure as in Example 9, but starting from equivalent proportions of 1-methylpiperazine Instead of 1- (2-methoxyethyl) piperazine, 2- (4-methyl-1-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole dihydrochloride is obtained with a melting point of 246 °.

Bei pie l 11: 2- (4- (2-hydroxyethyl) -1-pipera z i nyl) -5,6-7,8-tetrahydro-4H-cycloheptathiazol

Using the same procedure as in Example 9, but starting from equivalent proportions of 1- (2-hydroxyethyl) piperazine Instead of 1- (2-methoxyethyl) piperazine, 2- (4- (2-hydroxyethyl) -1-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole dihydrochloride is obtained from melting point 212-215 ° (blurred).

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Example 12: 2 ^ Ρ ^ 1ββ £ 2 £ inyJJjL5 _z 6 _f J7 ,. 8-tetrahydro-4H- cyc 1 olijKp ta th ia ζ ο 1

30 g of 2- (4-benzyl-1-piperazinyl) _{-5.6 f} 7 _f 8-tetrrihydro-4H-cycloheptathiazole and 13.6 g of cyanogen bromide are heated in 280 ml of absolute benzene in an oil bath (90 °) for 18 hours. The reaction solution is then extracted with 1000 ml of 5N hydrochloric acid and the aqueous solution is heated in an oil bath (120-140 °) for 26 hours after adding 100 ml of concentrated hydrochloric acid. After concentration in vacuo to 1/5 of the original volume, it is mixed with conc. aqueous sodium hydroxide solution made alkaline and extracted with ether. After concentration, the 2- (1-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole with a melting point of 70 ° -73 ° crystallizes out of the ethereal solution.

Treatment with ethanolic hydrochloric acid gives the dihydrochloride with a melting point of 185 ° (indistinct) (recrystallized from ethanol / ethyl acetate).

Example 13: 2- (4-allyl-lp ip erazinyl) -5,6, 1, 8-tetrahydro-4H ~ cyclohept athiazol

2.4 g of 2- (1-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole, 1.4 g of allyl bromide and 2.14 g of 1,8-bis (dimethylamino) naphthalene are heated in 30 ml of ethanol for 10 hours in an oil bath (90 °). After evaporation in vacuo, the crystalline residue is 2 times with Aether extracted. After that, the essential solution

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concentrated to give the 2- (4 ~ ~ l ~ Ällyl piperäzinyl) ~ 5.6 _t .7 _r ~ tetrcihydro -8-4H-cycloheptathiazoi from S \ ehmel2pürikt 59-61 ^b crystallized (recrystallized 'from hexane). Treatment with ethanolic hydrochloric acid gives the dihydrochloride with a melting point of 196-200 ^ö (recrystallized from ethanol / ether).

i_L 2- (4- (2-hydroxyethyl) -l-pipe.razinylI-5,6,

2.6 g of ethylene oxide are introduced into a solution of 4.75 g of 2- ( 1- ^ piperazinyl) -5,6,7,8- tetrahydro-4H-cycloheptathiazole in 20 ml of methanol at 0 ° with stirring. The solution is stirred for five hours at 0 ° and then for 10 hours at room temperature. It is then evaporated in vacuo _f the residue is taken up in ether. the ethereal solution is filtered and the dihydrochloride of 2- (4- (2-hydroxyethyl) ~ 1-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole with a melting point of 212-215 ° (recrystallizes with hydrogen chloride gas Ethanol / ethyl acetate) deposited in crystalline form.

Example 15 i 2- (4-acetyl-lr-piperazinyl) -5, 6,7,8-

tetrahydro ^ H'-cycloheptathi azo.-l

2, Q g of 2- (l-piperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole are heated to 90 "in 15 ml of acetic anhydride for 3 hours. After decomposition of the excess

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Acetic anhydride with water v / ird with aqueous 2N Made alkaline sodium hydroxide solution and extracted with chloroform. The basic 2- (4-acetyl ~ lpiperazinyl) -5,6,7,8-tetrahydro-4H-cycloheptathiazole crystallizes out on concentration of the chloroform solution, melting point: 114-115 °.

Be i sp_i_e 1 IG: 2- (4 -Ae the xy carb onyJL -1 - ρ ig e_r _a ζ in Vl) jZ

_5 _L 6, 7, 8 -1 etrahy dr ο -4 H - cy_ c 1 oh e ρ tat hiazoJL

2.4 g of 2- (l-piperaxinyl) -5 _f 6, 7, 8-tetrahydi: o ~ 4lI-cycloheptathiazole and 1.1: g of 1, B-bis (Dimcthylami.no) -naphthalene are in 50 ml Dissolved ether and treated at + 1 to + 3 ° with a solution of 1.1 g of ethyl chloramidate in 10 ml of ether. After standing for one hour at 20 °, it is extracted with water. The ethereal solution is evaporated. Here, the 2- (4-ethoxycarbonyl-l-piperazinyl) -5..6, 7, 8-tetrahydro-4H-cycloheptathiazole with a melting point of 98-100 ° remains in crystalline form. Treatment with ethanolic hydrochloric acid gives this Monohydrochloride with a melting point of 163-165 ° (decomposition) (recrystallized from ethanol / ether).

Example 17: 2- ( 4- (2-Acetoxyethyl ) -1-piperazinyl) -5.67 7 f 8-tetrahydro-4H-cycloheptathiazole

3 g 2- (4- (2-Hydroxyäthy1) -1-piperazinyl) -5,6,7,8-tetrahydro * 4II cycloheptathiazole and 1.2 g acetic anhydride

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v / ground in 5 ml of benzene heated to 50-60 ° for 20 hours. To Evaporation in a vacuum remains the "2- (4 - ^ - Αα ^ ρχγΜ-υιγΙ ^ Ι-ρΙρΘΓΒζΙηγΙ) -5,6,7,8-tetrahydro-4H-cycloheptathiazole a] s crystalline product back. Melting point: 48-50 ° (recrystallized from ethyl acetate).

Example 18: 2- (4-AlIy3-1-piperazinyl) -5,6,7,8-tetrahydro-4H- cyclohopathiazole

Using the same procedure as in Example Ί, but starting from equivalent proportions of l-allyl-piperazine instead of 1- (2-hydroxyethyl) -piperazine, 2- (4-AlIyI-I-piperazinyl) -5,6,7 are obtained , e-tetrahydix ^ H-cycloheptathiazole, its dihydrochloride at 196-200 ° (uinkrystallisiert from Aethanol / Ae the r) s chmi1ζ t.

Example 19: 2- (4-allyl-l-piperazinyl) -5,6, 7,8-tetr ahydro- 4H cycloheptath iazol

Using the same procedure as in Example 1, but starting from equivalent proportions of 4-allyl-1-piperazinyl-thiocarboxamide instead of 4-methyl-1-piperazinyl-thiocarboxamide 2- (4-allyl-1-piperazinyl) -5,6,7,8- is obtained. tetrahydro-4H-cycloheptathiazole, whose dihydrochloride "melts at 196-200 ° (uncrystallized from ethanol / ether),

BATH

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Claims (1)

- 22 - 500-5268 Claim; Process for the preparation of compounds of the formula I, where η for 1, .2. 3 or 4, and R is hydrogen, a Benzyl group or an alkoxyalkyl or an alkoxycarbonyl group each having a maximum of 6 carbon atoms or for an alkyl, alkenyl, alkanoyl or a hydroxyalkyl group each having a maximum of 4 carbon atoms stands, the hydroxyalkyl group optionally additionally can still be acylated, and their salts thereby marked that one either a) reactive esters of keto alcohols of the formula II, C = O CIl-OII II ? 2 where η has the meaning mentioned, with thio ureas of the formula III, ₀ -CN NR III ² ί ^ in which R has the meaning mentioned, or reacts with their acid addition salts, or 309809/1212 BATH ORIGINAL - 23 - ".500-5268 b) reactive esters of alcohols of the formula II with piperazine or piperazine derivatives of the formula IV, IV where Pv has the meaning mentioned, react leaves, with one of the reactants beforehand with hydrofluoric acid or a rhodanide was implemented, • in the compounds of the formula I thus obtained, in which R is hydrogen, optionally followed by a benzyl, alkyl, alkenyl, alkanoyl, hydroxy] q alky! Group, the latter optionally being acylated, or a Alkoxyalkyl or alkoxycarbonyl "group, the number of carbon atoms in each case being indicated above, or compounds of the formula I obtained in which R is a hydroxyalkyl group _f optionally acylated or from the compounds of the formula I thus obtained in which R is a benzyl, alkoxycarbonyl, alkenyl, alkanoyl or methyl group, these groups optionally splitting off and the compounds of the formula I thus obtained are optionally subsequently converted into their acid addition salts. BAD ORIGINAL 309809 / Ί 2 1 2 '' - '■ Germany 2t compounds of the formula I, ^ici y " NO wherein η is 1, 2, 3 or 4, and R is hydrogen, a Benzyl group or an alkoxyalkyl or an alkoxycarbonyl group each having a maximum of 6 carbon atoms or for an alkyl, alkenyl, alkanoyl or is a hydroxyalkyl group, where the hydroxyalkyl group can optionally also be acyl-tertiary, and their salts. 3. Therapeutic composition characterized by the content of compounds of the formula I. WANDER A.Q, 309809/1212