SU893133A3 - Method of preparing derivatives of 1-/3-(3,4,5-trimethoxyphenoxy)-2-propyl/-4-arylpiperazine - Google Patents

Abstract

The novel compounds correspond to the formula I, in which the substituents have the meaning given in Patent Claim 1. These compounds are prepared by reaction of a compound of the formula II with a compound of the formula III, Y and Z in each case being different and either denoting hydrogen or the group -CH2-CH(OR1)-CH2-V and V being chlorine, bromine or iodine, or, if R1 is hydrogen, can also form the ethylene oxide ring together with this hydroxyl group. If appropriate, one or two nitro groups in a compound of the formula I obtained can be reduced to amino groups and/or the compounds obtained can be acylated with an acid or an acid derivative corresponding to the radical R1. The compounds obtained can be converted into their acid addition salts. The novel compounds are pharmacodynamically active and are suitable as an active component in medicaments. <IMAGE>

Description

(54) METHOD FOR PREPARING 1 - 3- (3,4,5-TRIMET 1) The invention relates to a process for producing new L-O-CHg-CHCHjO- products where R is hydrogen, acetyl, y-coxybenzoyl, thienylcarbonyl, nicotinoyl, C-naphthyl , pyridyl, phenyl, unsubstituted or substituted by one or two substituents, is selected from the group consisting of hydroxy, fluoro, chloro, bromo, nitro, trifluoromethyl, amino, alkyl, alkoxy, Cy, —Cjj, C —C-alkylthio, 20 Sp-C-alkonoylamino, C (2 C-alkanoyl, C "-C-alkanoyloxy, benzoyloxy, thienylcarbonyloxy, cyclehexylcarbonyloxy, or their salts. 25 -ARSHIER XIIHENOXY DERIVATIVES AND) -2- ROPILZ-4AZRAH 2 - (3,4,5-trimetoxyphenoxy) -2-propyl-4-arylpiperazine of the general formula The new compounds are pharmacologically effective and have, for example, an anti-aggressive effect, as well as neuroleptic properties, and anticonvulsant and hypnotic drugs, as well as hypnotic, and hypnotic and hypnotic and hypnotic drugs, and anti-aggressive action, as well as antipsychotic properties, and anti-convulsive and hypnotic and hypnotic and hypnotic and hypnotic and hypnotic, and anti-aggressive, as well as neuroleptic properties, and anticonvulsive and hypnotic, and hypnotic and hypnotic, and hypnotic and hypnotic and hypnotic, and anti-aggressive, as well as neuroleptic properties; manifests itself to a weak degree. In addition, they have antipyretic and anti-edema effects. The interaction of halogen derivatives with ammonia, primary and secondary amines, leading to the formation of alkylation products, is known. The reaction can be carried out in the solvent at a normal or elevated temperature. 111 3 The purpose of the invention is to obtain new piperazine derivatives with valuable pharmacological properties. The goal is achieved by the fact that, according to the method, a compound of the general formula is reacted with a compound of the general formula where Y and Z are different and mean either to the hydrogen, or the group —CH, —CH — CH | -Ha1 or -CH jj-CH-CHj, Hal is chlorine, bromine or iodine R and have these values, followed by either isolating the product, or reducing the nitro group to the amino group and / or acylation by isolating the desired product, in free form or in salt form . The reaction can be carried out in a solvent or without it at a temperature between 20 and, preferably, between 50 and 150 ° C. Aromatic hydrocarbons, such as benzene, toluene, xylene, aliphatic ketones, such as acetone, methyl ethyl ketone, are used as a solvent or dispersant. chlorinated hydrocarbons, such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride, aliphatic ethers, such as butyl ether, cyclic ethers, such as tetrahydrofur dioxane, sulfoxides, such as dimethyl sulfoxide; tertiary amide: acids, such as dimethylformamide, IN-methylpyrrolidone; aliphatic alcohols, such as methanol, ethanol, isopropanol, amyl alcohol, t-b, tanol, cycloaliphatic hydrocarbons, such as cyclohexane, and the like. Mixtures of the listed solvents with water can also be used. Often they operate at the boiling point of the solvent or dispersant used. As a rule, the components of the reaction are taken in equimolar amounts. However, it may be advisable to take in excess (for example, 0.5 mol) a compound of formula III, if Z is a hydrogen atom. The reaction can be carried out in the presence of acid acceptors, such as alkali metal carbonates (potash and soda), alkali metal hydroxides, or tertiary amines, such as triethylamine. Tertiary amines then matter when compounds in which Hal is chlorine, bromine or iodine are used. If, in the compound of formula II, Y is a hydrogen atom, this compound can be used as a metal salt, in particular as an alkali metal salt (e.g. a sodium or potassium salt). This is especially important when in another component of reaction III, the group Z (OH). When carrying out the reaction, the corresponding halohydrin or a mixture of these two compounds (synthesis of the crude product) can be used instead of the compound with the ethylene oxide group. In the resulting products, the amino and / or hydroxy groups as well as the secondary hydroxy group (for introducing the R-acyl group) can be preserved by acylation, i.e. treatment with acids of the formula, where R, has the specified value, in addition to hydrogen, or by processing the corresponding reactive derivatives of the acid. Corresponding derivatives of the acid can be compounds of the formula where W is chlorine, bromine or iodine,, RO-, RS-, (OH) 2 PO-0-, (RIO) Q -PO-, (RO) Q -AS-O- or R-0-CO-group, R - alkyl- or, in the case of R-O- or RS-, also phenyl, p-nitrophenyl, cyanmethyl or carboxymethyl, R - linear or branched alkyl, alkoxy, phenoxy, carbobenzoxy, or groups listed for R. Aliphatic Cp-ketones can also be used as acylating agents. But it is particularly preferable to use such acylnuating agents as derivatives of acids of formula IV in which W represents chlorine or bromine. If R and R are alkyl or

alkoxy groups, they are predominantly low molecular weight hydrocarbons containing 1-6 C atoms.

Acylation can be carried out in an inert solvent or suspending agent, such as water, lower aliphatic alcohols, lower aliphatic ketones, dioxane, dimethylformamide, benzene, toluene, at a temperature between 0 and 200 ° C. Acid acceptors, for example hydroxides, carbonates (potassium carbonate), hydrogen carbonates, alkali metal acetates, alkaline earth metal carbonates, tertiary amines (for example trialkylamines, pyridine) or alkali metal alcohols (sodium ethoxide) are added as necessary.

The groups to be acylated (hydroxy and amino groups) can first be converted to the corresponding alkali metal salts, and the reaction between the corresponding compound in an inert solvent, such as dioxane, dimethylformamide, benzene or toluene with an alkali metal, alkali metal hydride or amide ( in particular, with sodium or sodium compound) at a temperature between 0 and, then an acylating agent is added.

If the free acid of the formula is used for acylation, it must be activated by a condensing agent, for example dicyclohexycarbodiimide, sulfuric acid bisalkylamides (for example SOfN (CH) Qp N, N -carbonyldiimidazole).

The acyl groups present in the obtained compounds can be cleaved back by known methods, for example, aqueous or alcoholic alkali solutions (using a methanol solution of conen), or mineral acids, for example hydrochloric or sulfuric acid, as alcoholic or aqueous-alcoholic solutions at a temperature between 20 and 100 ° C.

In particular, catalytic hydrogenation is used to reduce one or two nitro groups. Rane nickel, noble metals such as palladium and platinum, as well as their compounds, with and without a carrier, such as barium sulfate, calcium sulfate, etc., are used as catalysts. Hydrogenation of nitro groups is recommended to be carried out at a temperature between 20 and 80 ° C and pressure 931334

Research institutes at 5-50 atm in a solvent, for example in alcohols, dioxane, tetrahydrofuran, etc. In order to isolate the reduced compounds, in some cases, it is advisable to first add a desiccant, such as anhydrous sodium sulfate or magnesium sulfate, to the mixture to be hydrogenated.

The reduction can also be carried out with hydrogen at the time of its preparation, for example, in systems of zinc / hydrochloric acid, tin / hydrochloric acid, or with hydrogen sulfide salts in an aqueous-alcoholic mixture at 70-120 seconds, or

$ 1 with activated alginium in aqueous ester with ZO-AO C, or in the system tin chloride (I) / hydrochloric acid. The compounds are obtained as racemates. Optically active antipodes

20 are obtained either by using optically active starting materials, or by splitting the racemates through salts of optically active acids, for example, L - (+) - tartaric acid, 0 - (-) - tartaric acid, (+) - 0.0 -dibenzoyl-O-tartaric acid, (-) - 0,0-dibenzoyl-1-tartaric acid, (-) - 0.0 -di-p-toluene-L-vinyl acid, (+) -O, O - di-p-toluoyl-O-tartaric acid, (+) - camphor-10-sulfonic acid and others.

The compounds of general formula I can be converted into salts by known methods. As anions of these salts J, the well-known acidic groups used in pharmacology are used. Such acids may be: HnSO, phosphoric acid, hydrohalic acids, ethylenediaminetetrauxus

Q. Sulphate, Benz.

. Salt compounds can be back

50 to transfer to free bases by conventional methods, for example, by treating a solution in an organic solvent, such as alcohols (methanol), soda, or sodium hydroxide solution.

55

Compounds I are suitable for the preparation of pharmaceutical formulations. Pharmaceutical formulations or medicines may contain one or more compounds, as well as their mixtures with other pharmaceutically effective substances. Conventional pharmaceutical materials and auxiliary materials can be used to prepare pharmaceutical formulations. Drugs can be administered enterally, parenterally, through the mouth, under the tongue. Drug release can be in the form of tablets, capsules, pills, dragees, swabs, ointments, jelly creams, powders, gums, fine powders or aerosols. In the form of liquids, oily or aqueous solutions or suspensions are used, such as aqueous, oily solutions or suspensions of dp injections. Starting compounds of the formula III, where Z is the group -CH (2 -CH {OH) -CHP , can be obtained in the usual way, for example by the interaction of zichloro- or epibromohydrin with the corresponding piperazine, which contains R (in position 4, in an alcohol solution, preferably in methanol, with addition of about 5% water at 10 ° С. conditions is 1/2 hr. Then the mixture is heated to 30-40 ° C and stirring for 5 hours. The ratio of piperazine to hydrin is from 1: 1 to 1: 5, preferably from 1: 1 to 1: 2. The water content may be from I to 10%, preferably from 2 to 6%. The compounds can be introduced by the group R by acylation with a compound under the previously mentioned conditions. The same methods can be used to introduce the group R into the starting compound of formula II, where Y is the (OH) -CH, -Hal group. The remaining starting compounds are known. Example 1. (+) (3,4,5-Trimethoxyphenoxy) -2-hydroxypropyl -4 - (2-methoxyphenyl) -piperazine. 12 g (0.05 mol) of 3,4,5-trimethoxyphenoxyglycidyl ether are boiled with 9.6 g (0.05 mol) of 1- (2-methoxyphenyl) piperazine in 100 ml of isopropanol under reflux

сНз-0

sna-o- / 3-o-cng-cmoH) -cH2-: N ir-ii

listed in the table using 0.05 mol of 3,4,5-trimethoxyphenoxyl-glycidyl ether and 0.05 mol of the compound of formula III. 38 for 5 hours. Then most of the solvent is distilled off, the residue is treated with excess HC1 in isopropanol and l-f3- (3, 4, 5-trimethoxyphenoxy) -2-hydroxypropyl -4- (2-methoxyphenyl) -piperazine precipitates . Obtain 18.4 g (73% of theory) of a colorless crystalline substance with so pl. 196-197 ° C. 3,4,5-Trimethoxyphenoxyglycidyl ether was prepared as follows. A, In a suitable reaction vessel with a device for removal of azeotropic water, 18.4 g (0.1 mol) of 3,4,5-trimethoxyphenol with 37 g (0.4 mol) of epichlorohydrin is heated to boiling and 10 are added dropwise within 30 min. g (o, i mol) of a 40% sodium hydroxide solution, and water is simultaneously released from the azeotrope. Upon completion of the addition of the alkali solution, the reaction mixture is boiled for an additional 1 hour, then diluted with about 100 ml of toluene and filtered off from precipitated NaCl. The filtrate is distilled off first at normal pressure and then under reduced pressure. Get 3,4,5-trimethoxyphenoxyglycidyl ether in the form of a colorless oil with BP. 175180 ° С / 1, 0 mm. The output is 19.2 g, which corresponds to 80% relative to trimethoxyphenol. B, A mixture of 0.05 mol of 3- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl bromide, 0.05 mol of 1- (2-methoxyphenyl) piperazine and 0.06 mol of triethylamine in 100 ml of toluene is boiled for 5 hours. Then the precipitated triethylammonium bromide is filtered off and the filtrate is evaporated. The residue is dissolved in a small amount of isopropanol, treated with a solution of HCl in isopropynol and precipitated with ether (±) -1 -EZ- (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl -4- (2-methoxyphenyl) -piperazine dihydrochloride . After crystallization from methanol, 10.1 g of pure compound are obtained (40% of theory), m.p. - 195-197s. Analogously to Example 1A, compounds of the formula

Example 22. (±) (3,4,5-Trimethoxyphenoxy) -2- (nicotinoyloxy-propyl; j-4- (2-methoxyphenyl) -piperazine.

13.0 g (0.03 mol) (±) (3,4,5-trimethoxyphenoxy) -2-okCHpropyl 1-4- (2-methoxyphenyl) piperazine together with 3.34 g of triethylamine (0.033 mol) is dissolved in 80 ml of anhydrous benzene and mixed for 30 minutes with a solution of 4.67 g (0.033 mol) of nicotinic acid chloride in 50 ml of anhydrous benzene. The mixture is stirred at room temperature for 2 hours and at 70-80 ° C for 1 hour. After cooling, the mixture is repeatedly shaken with water, washed with water with NaHCOj, and the benzene phase is dried over magnesium sulfate and evaporated. The solid residue is dissolved in dioxane. After treatment with a solution of HCl in isopropanol and ether, 13 g of product are obtained in the form of trihydrochloride (colorless crystals), mp. - 187-192 ° C (decomposed).

Etc. and measure 23. (±) -1- {3- 3,4,5-Trimethoxyphenoxy -2- G (3,4,5-trimethoxy) benzoyl-propyl-4- (2-methoxyphenyl) piperazine.

(+) (3,4,5-Trimethoxyphenoxy) -2-hydroxypropyl 3-4- (2-methoxyphenyl) -piperazine was prepared as in Example 22 with 3,4,5-trimethoxybenzyl chloride in the presence of triethylamine. The reaction product is isolated as a dihydrochloride with m.p. 193-195 0 (decomposed). Exit 38%.

Example 24. (±), 4,5-Trimethoxyphenoxy) -2-hydroxypropyl2-4- (2-acetamidophenyl) piperazine.

4 g of (+) (3,4,5-Trimethoxyphenoxy-2-hydroxypropyl 3-4 (2-aminofensh1) -piperazine (monohydrochloride) is dissolved in 200 ml of dioxane and mixed with 10 ml of triethylamine. After that, 9 ml of acetyl chloride with stirring at -5 ° C. After 2 hours of reaction at room temperature, the solution is filtered and the solvent is distilled off under reduced pressure. The product is isolated by dry silica gel chromatography (eluant ether: ethyl acetate 1: 1) and recrystallized from ether / acetone. Yield 50%, mp 128-130 ° C.

As a side, less polar product, (±) (3,4,5-trimethoxyphenoxy) -29313310 is obtained.

-acetoxypropyl -4- (2-acetamidophenyl) -piperazine. with so pl. 54C, the yield of which may increase with an increase in the amount of acetyl chloride. 5 Example 25. (+) - 1-C3- (3,4D-Trimethoxyphenoxy) -2-acetoxypropyl 1-4- (2-acetoxyphenyl) piperazine,

6 g (0,0143 mol) (+) (3,4,5 | -trimethoxyphenoxy) -2-hydroxypropyl 1-44

 - (2-hydroxyphenyl) -piperazine and 2.9 g. (0.0286 mol) triethylamine is dissolved in 80 ml of absolute methylene chloride and a solution of 2.24 g (0.0286 mol) of acetyl chloride is added dropwise.

 in 20 ml of absolute methylene chloride. The reaction mixture is stirred at room temperature for 2 hours and the precipitated triethylaminohydrochloride is filtered off. Then the solvent was distilled off W in a vacuum, and the residue was recrystallized from ether / petroleum ether. Yield 57%, mp. .

Example 26. (+) (3,4,5 and -Trimethoxyphenoxy) -2-hydroxypropyl 3-4 (2-aminophenyl) -piperazine.

6 g (0.0124 mol) (±) (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl 1-4- (2-nitrophenyl) -piperazine M are dissolved in 300 ml of methanol and hydrogenated at room temperature in acid; 5 g Pd-C (10%). After separation of the catalyst and removal of the solvent by distillation in vacuo | . the product is recrystallized from ethanol. Yield 94%, mp. monohydrochloride 181-183s.

An example of the breakdown of rematov. 40 (+) (3,4,5-Trimethoxyphenoxy) -2-hydroxypropyl 1-4- (2-methoxyphenyl) piperazine (base compound 1a) and (-) (3,4,5-trimethoxyphenoxy) -2-hydroxypropyl - 4- (2-methoxyphenyl) -piperazine (base "

4S connection 1b).

4.32 g (0.005 mol) of the racemic compound obtained in Example 1 is dissolved, when heated, in 80 ml of butyl acetate and at 80 ° C at

SO vigorous stirring added 4.04 g (0.005 mol) of the hydrate of (-) - di-p-toluene-1-tartaric acid, and immediately the left-rotating diastereomeric salt precipitates. Then warm up and hold for 10 minutes, cooled to 80 ° C and the precipitate is filtered off. The salt is recrystallized from acetone-dimethylformamide-ben1- (3, D-Dimethylphenyl) -piperazine.

1 -. (2,6-Dimethylphenyl) -piperazine

1- (4-Acetylphenyl) piperazine

186-188

80

X /

228-230

71 137-138 58

Table continuation

Claims (1)

Claim The method of obtaining derivatives 1 [3- (3,4,5-trimethoxyphenoxy) -2 where I? R ¹ or c i of formula II propyl] -4-arylpiperazine of the general formula I Chjo Y and Z where - hydrogen, acetyl, C ^ -SC.-alkoxybenzoyl, thienylcarbonyl, nicotinoyl, - naphthyl, pyridyl, phenyl unsubstituted or substituted by one or two substituents selected from the group consisting of hydroxy, fluoro, chloro, bromo, nitro, trifluoromethyl, amino, alkyl C ^ -C _fo , alkoxy C ^ -Cfe, C-Cg alkylthio, C ^ -C θ alkanoylamino, C ^ -C-alkanoyl, C ^ -C ^ alkanoyloxy, benzoyloxy, thienidecarbonyloxy, cyclohexylcarbonyloxy, salts containing the general compound being reacted with a compound of the general formula III -K ² X ___ / are different and mean either hydrogen or a group of the formula '-CH ^ -CH-CH ^ -Ha1 or HE -CH.-CH-CH _P , ABOUT R has the indicated Na I - chlorine, bromine or iodine, their meanings, followed by isolation of the product or its reduction with the conversion of the nitro group into an amino group and / or acylation and isolation of the target product in free form or in the form of a salt.