FI69627B - REFERENCE TO A FRAMEWORK FOR THERAPEUTIC USE OF THERAPEUTIC ANVAENDBARA 1- (3- (3,4,5-TRIMETOXYFENOXY) -2-HYDROXIPROPY) -4-ARYL-PIPERAZINE DERIVATIVES - Google Patents

Description

J Γβ1 ANNOUNCEMENT / λ / λπ

JtgfljB (11) UTLÄGGNIN GSSKRIFT 0KJ Ό Z /

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(51) K ».lk.4 / lnt.a.4 c 07 D 295/08, * 401/04 ^ y Q | __ p | 1 ^ l. A N D (21) Patent application - Patentansöknlng 781009 (22) Filing date - Ansökningsdag 03.0 * 4.78 (EN) (23) Starting date - Giltighetsdag 03.0 * 4.78 (41) Published public - Blivit offentllg 05.10.78

National Board of Patents and Registration ^ Date of publication and publication - 29.11 .85

Patents and registration requirements of the Community and other Community authorities (32) (33) (31) Privilege claimed - Begärd priority 04.0 * 4.77 Eng 1 anti-Eng 1 and (GB) 14100/77 (71) Degussa Aktiengesel1schaft, Weissfrauenstrasse 9 , 6000 Frankfurt 1,

Federal Republic of Germany1ta-Förbundsrepubliken Tyskland (DE) (72) Axel Kleemann, Hanau, Vladimir Jakovlev, Maintal,

Klaus Thiemer, Hanau, Jiirgen Engel, Alzenau,

Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (74) Oy Koister Ab (54) Method for the development of new therapeutically useful 1- [3- (3,4,5-trimethoxy-phenoxy) -2-hydroxypropyl] -4-aryl] piperaz for the preparation of an i-derivative - For the preparation of therapeutically active compounds 1- [3- (3,4,5-trimethoxy-phenoxy) -2-hydroxy-propyl] -4-aryl-piperazine- derivative of

German application 2 23S 597 describes antihypertensive compounds of the general formula: f ~ \ 0-CH2 -CH-CHo-N N- (CH) n- \> I 2 k \ __ / 2 \ - = / 00 wherein A is a hydrogen atom or a hydroxyl group, X is a hydrogen or halogen atom, an alkyl, alkoxy, alkylthio, trifluoromethyl, hydroxy, nitro, amino, acylamino or alkylsulfonylamino group, and n represents 0, 1 or 2 and their salts.

The invention relates to a process for the preparation of new therapeutically useful 1-Z3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl-17-4-arylpiperazine derivatives of the formula I, 26627 0Η3 ° ύζ = \ / \ CH3 ° -V> 0-CH2 -CH-CH2-N N-R2! CH 3 O-R 10 having a hydrogen atom, a C 1 -C 6 alkanoyl, benzoyl, C 1 -C 4 alkoxybenzoyl, nicotinoyl or thienylcarbonyl group, and R 1 is optionally substituted phenyl, naphthyl - or a pyridyl group, R 1 and R 2 are the same or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 C 1 -C 6 alkylthio, C 1 -C 6 alkanoyl, amino, acylamino or acyloxy groups, in each of the latter groups acyl may be acyl as defined in the definition of R 1, and salts thereof.

Alkanoyl residues can be straight or branched. In particular, alkanoyl radicals contain two, three or four C atoms. The thienyl residue may be a thienyl (2) or thienyl (3) carbonyl residue.

The alkyl, alkoxy and alkylthio groups can be straight or branched with respect to the respective alkyl group. Examples of these are: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, methylthio, ethylthio, propylthio, butylthio. Examples of the acylamino group include: acetamino group, benzoylamino group. If R2 is a naphthyl residue, it may be a naphthyl (1) or naphthyl (2) residue, in which case this naphthyl residue may be substituted on each ring by the radicals R8 and Rjj. Preferably, the naphthyl ring is substituted on a 6-ring not attached to the piperazine ring.

If R 1 is a pyridinyl ring, this may be attached to the piperazine ring in the 2-, 3- or 4-position.

R 1 is, for example, hydrogen or an alkanoyl residue having two, three or four C atoms.

3,69627

If there is a phenyl or pyridyl residue, the substituents R 3 and / or R 2 are preferably in the position adjacent to the point of attachment of the piperazine ring.

Preferably R 1 is hydrogen and R 7. is a C 1 -C 4 alkoxyphenyl residue (for example methoxyphenyl, ethoxyphenyl), a hydroxyphenyl residue, an aminophenyl residue, a C 2 -C 4 alkanoylaminophenyl residue (for example acetylaminophenyl, propionylaminophenyl) or a C 1 -C 4 alkanoyloxyphenyl) acetylphenyl residue, for example these substituents are in the o- or p-position, in particular in the o-position.

The new compounds are pharmacodynamically active and have, for example, a clear anti-aggressive effect as well as stress-triggering properties, with little or no anticonvulsant and hypnotic effects. Furthermore, they have an antipyretic and anti-edematous effect.

In contrast, the Eβ- (5,6,7,8-tetrahydro-naphthyl- (1) -oxypropyl-7-piperazine derivatives described in German Offenlegungsschrift No. 2,235,597 have antihypertensive and thus antihypertensive properties.

In contrast, the compounds of the invention have no or only minor antihypertensive effects.

The compounds according to the invention are prepared in such a way that the compound of the formula oH „0 — i —v // \ ch3o — r V-oy ii ch3o. / - is reacted with a compound of formula / ^

Z-N NR „III

N_ / 2 wherein Y and Z are in each case different and denote either hydrogen or the group -CH2-CH (OR1-CH2-V and V is chlorine, bromine or iodine or, 69627 if hydrogen is, together with this hydroxy group can also forms an ethylene oxide ring, and optionally reducing one or two nitro groups to amino groups and / or acylating the obtained compounds with an acid or acid derivative corresponding to the residue R 1.

The process for the preparation of the compounds of the invention can be carried out with or without the use of solvents at temperatures between 2D and 200 ° C, preferably between 50 and 150 ° C. Examples of suitable solvents or dispersants are: aromatic hydrocarbons, such as, for example, benzene, toluene, xylene; aliphatic ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; aliphatic ethers such as butyl ether; cyclic ethers such as tetrahydrofuran, dioxane; sulfoxides such as dimethyl sulfoxide, tertiary acid amides such as dimethylformamide, N-methylpyrrolidone; aliphatic alcohols such as methanol, ethanol, isopropanol, amyl alcohol, tert-butanol; cycloaliphatic hydrocarbons such as cyclohexane, etc. Aqueous mixtures of said solvents can also be used. It is often possible to work at the reflux temperature of the solvent or dispersant used. In general, the reaction components are reacted in molar amounts. However, it may be appropriate to use a compound of formula III, if Z is a hydrogen atom, in excess (for example 0.5 mol). Optionally, the reaction may also be carried out in the presence of acid scavengers such as alkali metal carbonates (K 2 CO 2, 200200), alkali hydroxides or tert-amines (e.g. triethylamine). The latter is especially true when compounds in which V is a halogen atom are used.

If a compound of the formula II in which Y is hydrogen is used as starting material, then this compound can also be used in the form of a metal salt, in particular an alkali salt (for example a sodium or potassium salt). This is especially true when in the second reaction component III the group Z is -CH 2 -ClKOR 4 -Cl 2 V, where V is a halogen atom.

In carrying out the reaction, the corresponding halogen hydrine or a mixture of both compounds (crude synthesis product) can also be used as the ethylene oxide starting compound instead of the ethylene oxide compound.

69627

In the products obtained, the amino and / or hydroxy groups present and the secondary middle hydroxy group can be obtained by acylation (with the introduction of an R 1 -acyl residue), i.e. by treatment with acids of the formula R 1 OH (where R 4 is except hydrogen, as defined above) or by treatment with the corresponding reactive acid derivatives.

Suitable acid derivatives are, in particular, compounds of the formula:

R1W IV

wherein W is chlorine, bromine or iodine, a group -NN, a group of the formula -OR ', -SR' or a group of the formula -OSO ^ H, -O-PO (OH) ^, -OPiOR '^, -O-AsiOR'4 or -OCO-R ". In this case, R 'is an alkyl residue or, in the case of -OR' or -SR ', for example also a phenyl residue, a p-nitrophenyl residue, a cyanomethyl residue or a carboxymethyl residue; R "may be a protecting or branched alkyl residue, an alkoxy residue, a phenoxy residue, a carbobenzoxy residue or also a residue. Aliphatic C 1 -C 6 ketenes can also be used as acylating agents. In particular, acid derivatives of the formula IV in which W is chlorine or bromine are used as acylating agents. If R 'or R "denote alkyl radicals or alkoxy radicals, then these are preferably lower molecular and comprise 1 to 6 carbon atoms.

The acylation can take place, for example, in inert solvents or suspending agents, such as water, lower aliphatic alcohols, lower aliphatic ketones, dioxane, dimethylformamide, benzene, toluene at temperatures between 0-200 ° C. Optionally work by adding an acid scavenger such as alkali metal hydroxides, alkali metal carbonates (potassium carbonate), alkali metal bicarbonates, alkali acetate, alkaline earth metal carbonates, tertiary amines (e.g. trialkylamines, pyridine) or early alcoholates (sodium ethylate).

It is also possible to first convert the acylable groups (hydroxy group, amino group) in the compound to be reacted to the corresponding alkali compound by reacting them in a solvent such as dioxane, dimethylformamide, benzene or toluene with alkali metal, alkali metal hydrides or alkali amides (especially sodium) between 0-150 ° C and then your acylated reagent is added.

If a free acid of the formula R 1 OH is used, then its activation is necessary with condensing agents such as dicyclohexylcarbodiimide, sulfuric acid bis-alkylamides (for example SO 2 NiCH 3)? By N, N1-carbonyldiimidazole, etc. (Organic Reactions, Volume 12, 1962, pages 205 and 239).

Instead of the acylating agents shown, other chemically equivalent chemically equivalent substances may be used (see also, for example, LF and Mary Fieser, "Reagents for Organic Synthesis", John Wiley & Sons, Inc. New York, 1967, Volume 1, pages 1303-4 and Vol. 2, page 471). Of course, the acyl groups present in the obtained compounds can also be cleaved in a known manner, for example with an aqueous alkali or an alcoholic alkali solution (for example methanolic KOH) or possibly also with mineral acids such as hydrochloric acid or sulfuric acid in an alcoholic or aqueous-alcoholic solution at temperatures between .

Catalytic hydrogenation is particularly suitable for the reduction of one or also two nitro groups. Catalysts come into question; Raney nickel, precious metals such as palladium and platinum and their compounds, both with and without a support such as barium sulphate, potassium sulphate, etc. It is recommended to carry out the hydrogenation of the nitro group at temperatures between 20-80 ° C and about 600-5200 kPa in a solvent, for example in alcohols, dioxane, tetrahydrofuran, etc. For the subsequent isolation of the reduced compounds, it may in many cases be advantageous to add a drying agent, such as anhydrous sodium or magnesium sulphate, to the mixture to be initially hydrogenated.

However, the reduction can also be carried out with the resulting hydrogen, for example with zinc / hydrochloric acid, tin / hydrochloric acid, iron / hydrochloric acid or hydrogen sulfide salts in an alcohol / water mixture of about 70. At 120 ° C or with activated aluminum in aqueous ether at 20-40 ° C or with stannous chloride / hydrochloric acid.

The compounds of the invention are generally obtained as racemates. Optically active antipodes are obtained either by using optically active starting materials or by racemic resolution of optically active acids such as: L- (+) - tartaric acid, D - (-) - tartaric acid 7,69627, (+) -0.01-dibenzoyl- D-tartaric acid, (-) - 0,0 T-dibenzoyl-L-tartaric acid, (-) - 0,01-di-p-toluoyl-L-tartaric acid, (+) - 0,0f-di-p-toluyl ] via salts of iD-tartaric acid, (+) - camphor-10-sulfonic acid and other acids, etc.

The compounds of general formula I can be converted into their salts by known methods. Suitable anions for these salts are known and therapeutically useful acid residues. Examples of such acids are: H 2 SO 4, phosphoric acid, hydrohalic acids, ethylenediaminetetraacetic acid, sulfamic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, methanesulfonic acid, guaulosulfonic acid, Glycolic acid, salicylic acid, acetic acid, pripionic acid, gluconic acid, benzoic acid, citric acid, acetaminoacetic acid, oxyethanesulfonic acid.

Salts of the compounds can again be prepared in the usual manner, for example by treating a solution in an organic substance such as an alcohol, (methanol) with soda or sodium hydroxide.

The compounds of the invention are suitable for the preparation of pharmaceutical combinations. The pharmaceutical combinations or medicaments may contain one or more compounds according to the invention or also mixtures thereof with other pharmaceutically active substances. Ordinary pharmaceutical carriers and excipients can be used for the preparation of pharmaceutical preparations. The drugs can be administered intravenously, parenterally, orally, or through the surface of the tongue. Administration may take the form of, for example, tablets, capsules, pills, granules, suppositories, ointments, jellies, creams, powders, liquids, dust powders or aerosols. Suitable liquids are, for example: oily or aqueous solutions or suspensions, emulsions, injectable aqueous and oily solutions or suspensions.

The starting compounds of the formula II in which Z represents a group -CH 2 ** CH (OH) -CH 2 * V can be obtained, for example, in the customary manner by reacting epichloro- or epibromohydrin with the corresponding piperazine containing a residue in the M-position in an alcohol, preferably methanol with the addition of n. 5% water at 10 ° C. The reaction time is, for example, half an hour. It is then warmed to 30-40 ° C and stirred for 5 hours.

The ratio of piperazine to hydrine is, for example, 1: 1 to 1: 5, preferably 1: 1 to 1: 2. The water content may be between 1 and 10%, preferably between 2 and 6%.

In the compounds thus obtained, the residue R can be introduced by acylation with a compound R 1 W under the above conditions. Similarly, the introduction of R. into the starting compounds of formula II wherein Y is a group -CH 2 -CH (OH) -CH 2 -V is possible.

Other starting compounds are known.

Therapeutic comparative trials

The antiagressive effect of the compounds according to the invention was studied in the so-called "combat test" (Kampf-Test) in mice using the method described by R.E. Tedeschi et al., J. Pharmacol. Exp. Therap. 125 (1959) 28. In this test, male mice were placed in pairs in a lattice-based cage (size approximately 13 cm x 13 cm), and the animals were stimulated through the base for 3 minutes with an electric current, at which point they began to behave aggressively towards each other. Such typical combat behavior can be prevented with anti-aggressive agents. The ED 1 value of the test compounds was then determined from a large number of mouse pairs by probit analysis. The ED 2 value in this context refers to the dose at which 50% of the mouse pairs studied do not show typical fighting behavior due to the antiagressive compound administered to the animals.

The compounds of Example 1 of U.S. Patent 3,951,986 (column 9, b.p. 199-200 ° C) and the compound mentioned in column 11, lines 13-15 (b.p. 104-104.5 ° C) were used as reference compounds in this experiment.

The results shown in the following table show that the compounds of the present invention have a significantly more potent antiagressive effect than the structurally related reference compounds. The first compound known from U.S. Pat. No. 3,951,986 has such an ED 2 value (115 mg / kg orally) that there are already adverse effects on the central nervous system. The compounds of the present invention, on the other hand, have an ED 2 value well below the dose level at which adverse side effects occur.

9,69627

Table

Results of therapeutic comparative trials

Compound of the invention, ED 2 -g Example No. "battle test" 1 1,4 4 16 7 5,5 9 19 10 14 12 12 13 13 16 21 17 9 2 0 1,3 22 14 23 16 2 4 3, 3 26 1.4 2 7 3, 2 30 3, 8 31 9.7 32 6.4 The compound of Example 1 of U.S. Patent 3,951,986 (column 9), ip. 115 19 9-20 ° C.

The compound of U.S. Patent 3,951,986 (column 11, lines 13-15), ip. 30

104 to 104.5 ° C

69627 10

Example 1 (N - 1 - [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -N4- (2-methoxyphenyl) piperazine.

12 g (0.005 mol) of 3,4,5-trimethoxyphenoxy glycidyl ether are refluxed for five hours with 9.6 g (0.05 mol) of 1- (2-methoxyphenyl) piperazine in 100 ml of isopropanol. Most of the solvent is then distilled off and the residue is treated with excess HCl containing isopropanol and precipitated by adding 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine dihydrochloride diethyl-ether. 18.4 g (73% of theory) of colorless crystals are obtained, m.p. 196-197 ° C.

For example, 3,4,5-trimethoxyphenoxy glycidyl ether is prepared as follows:

In a suitable reaction vessel equipped with azeotropic water separation, 18.4 g (0.1 mol) of 3,4,5-trimethoxyphenol with 37 g (0.4 mol) of epichlorohydrin are heated to boiling and added dropwise over 30 minutes. 10 g (0.1 mol) of 40% NaOH, at the same time azeotropically removing water. After the addition of NaOH is complete, the mixture is allowed to react for a further hour at reflux temperature, diluted with about 100 ml of toluene and filtered off from the precipitated NaCl. The filtrate is partitioned first under normal pressure and then under vacuum. 3,4,5-trimethoxyphenoxy glycidyl ether is obtained at b.p. = 175-180 ° C as a colorless oil;

Yield: 19.2 g, corresponding to a yield of 80% based on trimethoxyphenol.

Methods / method for preparing the product can be carried out as follows: 0.05 moles of sodium (3,4,5-trimethoxy) phenolate are boiled with 0.05 moles of 1- (3-chloro-2-hydroxypropyl) -4- (2 -methoxy-phenyl) -piperazine (prepared by the reaction of 1- (2-methoxyphenyl) -piperazine with epichlorohydrin) in 50 ml of dioxane at reflux for eight hours. After cooling, the precipitated NaCl is filtered off and the filtrate is evaporated. The residue is treated with isopropanol-containing hydrochloric acid and ether and the crystalline solid is recrystallized from methanol. 8.2 g (32% of theory) of (-) - 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine are obtained in the form of the dihydrochloride, m.p. . is 194-196 ° C.

Another possibility to implement the method is as follows:

A mixture of 0.05 moles of 3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropylboramide, 0.05 moles of 1- (2-methoxyphenyl) piperazine and 0.06 moles of triethylamine in 100 ml of toluene is boiled five times. hours at reflux. The precipitated triethylammonium bromide is then filtered off and the filtrate is evaporated. The residue is taken up in a small amount of isopropanol and (*) -1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine dihydrochloride is precipitated with isopropanol-containing hydrochloric acid and ether. After recrystallization from methanol, 10.1 g of pure compound (40% of theory) are obtained, m.p. 195-197 ° C.

In the same manner as described in the first paragraph of Example 1, 0.05 moles of 3,4,5-trimethoxyphenoxy glycidyl ether and 0.05 moles of the compound of formula III are obtained from the compounds shown in Table 1, which have the formula: \ CH3 ° - \ Vo-CH2-CH (OH) -CH2— n n-r2 ch3o \ - / 12 69627 3 ρ 3 3 m νϊ. p +3 Lftp-CMCOONCMp-p- 0 \ J (D O <- ® CM On> - t— - U ~ \

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13 69627

Example 22 (1) -1- [3- (3,4,5-Trimethoxyphenoxy) -2- (nicotinoyloxy) -propyl] -4- (2-methoxyphenyl) -piperazine 13.0 g (0 .3 moles of (i) -1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine are dissolved together with 3.34 g of triethylamine (0.033 moles). To 80 ml of anhydrous benzene and over 30 minutes a solution of 4.67 g (0.033 mol) of nicotinic acid chloride in 50 ml of anhydrous benzene is added, stirred for a further two hours at room temperature and finally heated for a further hour at 70-80 ° C: After cooling, the mixture is shaken several times with water, aqueous NaHCO3 and after washing with water and the benzene phase is dried over magnesium sulphate and evaporated. The solid residue is taken up in dioxane. % of theory) of the above compound as trihydrochloride (colorless crystals), mp 187-192 ° C (decomposes).

Example 23 (±) -1- {3- [3,4,5-trimethoxyphenoxy] -2 - [(3,4,5-trimethoxy) -benzoyloxy] -7-propyl] -4- (2-methoxyphenyl) - piperazine (1) -1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine is reacted in the same manner as in Example 20 with 3,4,5-trimethoxybenzoyl chloride. with in the presence of triethylamine. The reaction product is obtained as the dihydrochloride, m.p. 193-195 ° C (decomposes). Yield 38%.

Example 24 (1) -1- [N- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-acetamidophenyl) piperazine 4 g (1) -1- 3- (3,4,5-Trimethoxyphenoxy-2-hydroxy-propyl) -4- (2-amino-phenyl) -piperazine (monohydrochloride) is dissolved in 200 ml of dioxane and 10 ml of triethylamine are added, followed by dropwise addition and stirring - 0.9 ml of acetyl chloride at 5 [deg.] C. After a reaction time of 2 hours at room temperature, the solution is filtered and the solvent is removed under reduced pressure.

The compound is isolated using dry column chromatography on silica gel (eluent: ether / acetic acid = 1: 1). The recrystallization is performed from acetone-ether.

Yield: 50%. Sp. 128-130 ° C.

As a less polar by-product which, by increasing the amount of acetyl chloride, can become the main product, (+) - 1- [3- (3,4,5-trimethoxyphenoxy) -2-acetoxypropyl] -4- (2-acetamido-phenyl) - piperazine. Sp. 54 ° C.

Example 25 (+) -1- [3- (3,4,5-Trimethoxyphenoxy) -2-acetoxy-propyl] -4- (2-acetoxy-phenyl) -piperazine 6 g (0.0143 mol) of (t) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-hydroxyphenyl) piperazine and 2.9 g (0.0286 mol) of triethylamine are dissolved in 80 ml of absolute methylene chloride and a solution of 2.24 g (0.0286 mol) of acetyl chloride in 20 ml of absolute methylene chloride is added dropwise at 0 ° C. The reaction mixture is stirred for two hours at room temperature and the precipitated triethylamine hydrochloride is filtered off. The solvent is then evaporated off under vacuum and the residue is recrystallized from ether / petroleum ether.

Yield: 57%. Sp. 70 ° C.

Example 26 (±) -1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-aminophenyl) piperazine 6 g (0.1, G124 moles) (+) - 1- Z3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-nitrophenyl) piperazine is dissolved in 300 ml of methanol and hydrogenated at room temperature with 0.5 g of Pd-C (10- %) in the presence of. After filtration of the catalyst and removal of the solvent in vacuo, it is recrystallized from ethanol.

Yield: 94%. Monohydrochloride m.p. 181-183 ° C.

15 69627

Example of racemate separation (+) -1 - ['3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine (base = compound 1a) and (-) - 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine (base = compound 1b).

4.32 g (0.005 mol) of the racemic compound prepared according to Example 1 are dissolved warm in 80 ml of butyl acetate and 4.04 g (0.005 mol) of (-) - di-p-toluoyl are added portionwise at 80 ° C with good stirring. -L-tartaric acid hydrate, whereby a pair of diastereomeric salts already turning to the left precipitates. It is then heated for a further 10 minutes at 110 ° C, allowed to cool to 80 ° C and the precipitate is filtered off. The salt pair is recrystallized from acetone-dimethylformamide-petrol (ϋ *] -48.6 °; 1% in dimethylformamide) and then separated by treatment with concentrated ammonia. The base is extracted with ether and the extract is evaporated. The solid residue is recrystallized from isopropanol: 1α base, colorless crystals, m.p. 103-104 ° C; + 7.2 ° (concentration in 2% CH 2 OH). Dissolution of the base in methanol and addition of isopropanoic hydrochloric acid and ether gives the dihydrochloride of compound 1a in the form of colorless crystals, m.p. 89 DEG-93 DEG C. [.alpha.] D @ 20 = -7.4 DEG (concentration = 2% in CH2OH).

The filtrate of the salt droplet containing the dextrorotatory diastereomeric salt pair is evaporated on a rotary evaporator, the viscous residue is slurried in water, concentrated ammonia is added and the base is extracted with ether. The ether solution is dried and evaporated and the solid residue is recrystallized from isopropanol: 1b base, colorless crystals, m.p. 100-101 ° C; /> 7 ^ -5.8 ° (concentration = 2% in CH 2 OH).

Dissolution of the base in methanol and treatment with isopropanol-containing hydrochloric acid and ether gives the dihydrochloride of compound ib in the form of colorless crystals, m.p. 182-187 ° C-, 1 ° 0 → 0 + 11.0 ° (concentration = 2% in CH 3 OH).

16 69627

Example 27 (+) - 1-C3- (3,4,5) -trimethoxyphenoxy) -2-hydroxypropyl-4- (2- (2-acetoxyphenyl) -piperazine ch3o CHqO-PO-CH0-CH (OH) -CH - / \\ ww CH3 ° / \ 0CO-CH3 Q, 03 moles of 1- (2-acetoxyphenyl) piperazine (crude product) and 7.2 g (0.03 moles) of 3,4,5-trimethoxyphenoxyglycidyl ether are added 150 ml: isopropanol, and the mixture is refluxed until the reaction is complete (determined by thin layer chromatography). The solvent is distilled off and the residue is treated with isopropanol / hydrochloric acid to give the hydrochloride, which is purified by recrystallization from isopropanol. Sp. 189-191 ° C. Yield 18%.

The starting 1- [2-acetyloxyphenyl] piperazine is prepared as follows: 192.8 g (1 mol) of 2-methoxyphenylpiperazine, 130 ml (1.1 mol) of benzyl chloride and 150 g (1.10 mol) of potassium carbonate are added in 800 ml: xylene, and the mixture is refluxed until the reaction is complete (determined by thin layer chromatography). The product is filtered off, the solvent is evaporated off under vacuum and the product is converted into the hydrochloride in the usual manner in an isopropanol / hydrochloric acid mixture (yield 70%).

60 g (0.2 mol) of the hydrochloride thus prepared are added to 800 ml of a 63% aqueous solution of hydrobromic acid, and the mixture is refluxed under cooling until all the ether groups have been cleaved (determined by thin-layer chromatography). The solvent is then evaporated off under reduced pressure and the crystalline residue obtained is washed with ether (yield 70%). The free base is liberated from the dihydrobromide with dilute aqueous ammonia in the usual manner.

10 g (0.029 mol) of the free base thus prepared and 15 ml of triethylamine are added to 50 ml of dioxane, the mixture is cooled to 5 ° C and 0.032 mol of acetyl chloride are added dropwise at a temperature of not more than 10 ° C. The mixture is stirred at 10 DEG C. for one hour, after which the precipitated triethylamine hydrochloride is filtered off with suction and the solvent is evaporated off under vacuum. The oily free base thus obtained is treated without further purification by hydrogenation of the benzyl groups as follows: 0.04 mol of the free base are dissolved in 150 ml of methanol and the solution is hydrogenated at 50 [deg.] C. at 5 bar using 2 g of 10% Pd / C as catalyst. After completion of the reaction, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. The 1- (2-acetoxyphenyl) piperazine thus obtained can be used for further reactions without further purification.

In the same manner as in the previous example, the compounds listed in Table 2 are prepared starting from 0.03 mol of 3,4,5-trimethoxyphenoxyglycidyl ether and 0.03 mol of the corresponding piperazine compound. the piperazine compound used as a starting material is prepared in the same manner as the starting material of the previous example, using the corresponding acid chloride (benzoyl chloride, cyclohexanecarboxylic acid chloride) instead of acetyl chloride in the acylation step.

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Example 30 (_ +) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-acetoxypropyl] -4- (2-methoxyphenyl) piperazine 10 g (0.023 mol) (O- 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine is suspended in 100 ml of xylene, 10 ml of triethylamine are added to the suspension, followed by slow addition at room temperature. 9 ml of acetyl chloride are added dropwise, the solution is left for 2 hours at room temperature, the triethylammonium hydrochloride is filtered off and the solvent is evaporated off under reduced pressure. , and the hydrochloride is recrystallized from isopropanol, the solidification point of the hydrochloride being 178-179 ° C, yield 80%.

Example 31 (_ +) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2- (thienyl- (2) -carbonyloxy) -propyl] -4- (2-methoxyphenyl) -piperazine CH- 0? CH3 V \ _ ^ J ~ \ CH3 ° \ / ° - CH2 - CH - CH2 - N u— / y! - 15 g (0.0319 moles) of (+) - 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine dihydrochloride and 3 .3 g of triethylamine are suspended in 100 ml of xylene. 4.7 g (0.0319 mol) of thiophene-2-carboxylic acid chloride are added dropwise to the suspension with stirring at room temperature.

The mixture is then stirred for one hour at room temperature. The precipitated triethylammonium hydrochloride is filtered off and the solution is concentrated under reduced pressure. The residue is dissolved in ether and isopropanol / HCl is added to the solution. The dihydrochloride obtained is recrystallized from isopropanol.

20 69627

Solidification point of the dihydrochloride 198-199 ° C (compound contains one mole of isopropanol. Yield 4 2%.

Example 32

In the same manner as in Example 31, the corresponding thienyl (3) compound is prepared.

Solidification point of the dihydrochloride 193-194 ° C. Yield 48%.

Example 33 (O -1- [3- (3,4,5-Trimethoxyphenoxy) -2- (thienyl- (2) -carbonyloxy) -propyl] -4- [2-thienyl- (2 ) -carbonyloxy) -phenyl-7-piperazine

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Suspend 7 g (0.0167 mol) of (+) - 1- [2- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl] -4- (2-hydroxyphenyl) piperazine in a mixture containing 10.0 ml of dioxane and 4 ml of triethylamine. 5 g (0.034 mol) of thiophene-2-carboxylic acid chloride are added to the suspension in small portions with stirring at room temperature. The reaction mixture is then stirred for a further 6 hours, after which the precipitate formed is allowed to settle. The precipitated triethylammonium hydrochloride is filtered off and the solvent is evaporated off under reduced pressure. The oily residue is dissolved in 100 ml of ether, the isopropanol / hydrochloric acid mixture is added to the solution until it becomes acidic and the precipitated hydrochloride is filtered off with suction. The hydrochloride is purified by recrystallization from isopropanol. Yield 61%. Hydrochloride solidification point 221-222 ° C.

Claims (1)

2i 69627 Claim A process for the preparation of new therapeutically useful 1-Ci- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl-7 + -aryl-piperazine derivatives of the formula I, CH CH-CH2-N N-R2 I CH2O-^ -'O0R1 \ / / wherein R1 is a hydrogen atom, a C1-C6-alkanoyl, benzoyl, C1-C4-alkoxy-benzoyl, nicontinoyl or thienylcarbonyl group, and R 2 is an optionally substituted phenyl, naphthyl or pyridyl group of R 1 and R 1, R 8 and R 4 are the same or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, C 1 -C 6 alkyl C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkanoyl, amino, acylamino or acyloxy groups, in each of the latter groups acyl may be the acyl mentioned in the definition of R 1, and their for the preparation of salts, characterized in that a compound of the formula: CHgO — Γ Λ — ΟΥ II CHgO-A = / is reacted with a compound of the formula: ZN NR, III already wherein Y and Z are different and represent hydrogen or the group -CH2-CH (OR1) -CH2-V and V is chlorine, bromine or iodine, or if R is hydrogen, together with this hydroxy group can also form an ethylene oxide ring and optionally be reduced one or two introgroups to an amino group and / or acylation of the obtained compounds with an acid or an acid derivative corresponding to the residue R 1, and the resulting compounds are converted, if desired, into their acid addition salts.