DK145225B - METHOD OF ANALOGUE FOR THE PREPARATION OF 1- (3-TRIMETHOXYPHENOXY-2-HYDROXY-PROPYL) -4-PHENYL-PIPERAZINE DERIVATIVES OR ACID ADDITION SALTS. - Google Patents

Description

(19) DENMARK

| Ρ i «) PUBLICATION MANUAL au 145225 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 1466/78 (51) | rrt.CI.3 C 07 D 295/04 (22) Filing date 3 · Apr. 1978 g 07 D 213/80 (24) Running day Apr 3 1978 C 07 D 333/38 (41) Aim. available 5 Oct 1978 (44) Submitted 1 1 ° ° kt · ^ 982 (86) International Application No. ~ (86) International Filing Day "(85) Continuation Day ~ (62) Stock Application No."

(30) Priority 4 Apr 1977, 14100/77, GB

(71) Applicant DEGUSSA AKTIENGESELLSCHAFT, D-6000 Frankfurt 1, DE.

(72) Inventor Axel IQ.eemann, DE: Vladimir Jakovlev, DE: Klaus

Thiemer, DE: Juergen Engel, DE.

(74) International Patent Bureau.

(54) Analogous process for the preparation of 1 - (] 5-trimethoxy = phenoxy-2-hydroxy-propyl) -4-phe-nyl-piperazine derivatives or acid addition salts thereof.

The present invention relates to an analogous process for the preparation of novel 1- (3-trimethoxyphenoxy-2-hydroxy-propyl) -4-phenyl-piperazine derivatives of the general formula I: Λ CH, OV_ n T CHgO-f vo - CH2 - ch - ch2 - nn 1 M CH.O ^ 'OR1 R4 Ω 3 d- where R4 is a hydrogen atom, a C2-C8 alkanoyl group, a mono-, di- ^ or tri-C -C-alkoxy-benzoyl group, a thienylcarbonyl group or a nicotinoyl group, and R 9 and R 2 are the same or different and are hydrogen, hydroxy, fluoro, chloro, trifluoromethyl, C 1 -C 8 alkyl, C 2 alkoxy, C 1 -C 6 alkylthio, amino, C 2 -C 8 alkanoylamino or C 2 -C 8 alkanoyloxy, or acid addition salts thereof.

U.S. Patent No. 3,951,986 discloses a variety of 2-propanol derivatives comprising those of the formula: T> w * T 2 O <5 ° a wherein R a is hydrogen or lower alkanoyl, is hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl, W = oxygen, d sulfur, sulfinyl or sulfonyl, and R c is hydrogen, halogen, lower alkyl or lower alkoxy, and salts thereof.

For these known 2-propanol derivatives are listed as pharmacological properties anti-psychotic, sedative, analgesic, anti-hypertensive, anti-inflammatory and anti-arrhythmic activities.

German Patent Specification No. 2,235,597 discloses blood pressure lowering compounds of the general formula: 0 - CH0 - CH - CH0 - N ^ H - (CH

οό 1 w V

wherein A is hydrogen or hydroxy, X is hydrogen, halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, hydroxy, nitro, amino, acylamino or alkylsulfonylamino, and n is 0, 1 or 2, and their salts.

The aforementioned novel piperazine derivatives of formula I or their acid addition salts are pharmacodynamically active and have, for example, a pronounced anti-aggressive effect as well as neuroleptic properties, while anti-convulsive and hypnotic effects are only minor or absent. Furthermore, they have fever-lowering and anti-edema effects.

Compared to the known 2-propanol derivatives known from the aforementioned US Patent No. 3,951,986, the compounds of the invention are characterized by a significantly stronger anti-aggressive effect, as will be further shown below.

Compared to the known compounds of the aforementioned German Patent Specification No. 2,235,597, the present compounds of formula I have no or only slight antihypertensive effects.

In the formula I, alkanoyl groups may be straight or branched chain and contain in particular 2, 3 or 4 C atoms. In the case of a thienylcarbonyl group, the thienyl (2) or thienyl (3) carbonyl group may be respectively. In alkoxy-benzoyl groups, alkoxy is preferably methoxy.

In alkyl, alkoxy and alkylthio groups, the alkyl groups in question may be straight or branched. Examples thereof are methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, methylthio, ethylthio, propylthio or butylthio.

As an example of C 2 -C 6 alkanoylamino groups can be mentioned the acetamino group.

is, for example, hydrogen or an alkanoyl group having 2, 3 or 4 C atoms.

Preferably, Rg and / or R4 are in the position adjacent to the junction between the phenyl group and the piperazine group. ^

Preferably R 1 is hydrogen and the group is preferably a C 1 -C 4 alkoxy-phenyl group, e.g. methoxyphenyl or ethoxyphenyl, a hydroxyphenyl group, an aminophenyl group, a Cj-C ^ alkanoylamino-phenyl group, e.g. an acetylaminophenyl or propionylaminophenyl group, or a C 2 -C 4 alkanoyloxy-phenyl group, e.g. an acetoxyphenyl or propionyloxyphenyl group wherein the substituents are in the o or p position, especially in the o position.

The analogous preparation method of the invention for the preparation of the compounds of formula I or acid addition salts thereof is characterized in that a compound of formula II:

CH-jO-c '\ -0Y II

ch3oW

is reacted with a compound of the formula III:

Z - N N - <! Zv III

v_y w ^ r.

R 4 is R 2 and R 4 are the same or different and have the same meaning as R 3 and R 2 or means nitro, and Y is hydrogen or a metal atom and Z is a group -Cl 2 -CH (OR 1 - ^) -Cl 2 -V, or Y is the latter group> and Z is hydrogen, where R 1 is the same meaning as R 2, and V is chlorine, bromine or iodine, or OR 2 and V together mean epoxy, whereupon if R R and / or R 'represent nitro, the nitro compound produced is reduced to form the corresponding amino compound, and, if desired, a compound of general formula I is subjected to one or more of the following side reactions: ) acylation of a secondary hydroxy group with an acid corresponding to the R 1 group or a derivative thereof, (ii) acylation of a phenolic hydroxy group with a C 2 -C 8 alkanoyl group by acylation with the corresponding acid or acid derivative, (iii) acylation of an amino group with a C 2 -C 8 alkanoyl group by acylation with the corresponding acid or acid derivative, (iv) cleavage of one or more acyl groups present in a manner known per se to form corresponding hydroxy and / or amino compounds of general formula I, (v) transfer of a free base into a corresponding acid addition salt and (vi) release of the free base of general formula I from a corresponding acid addition salt.

The process for preparing the subject compounds can be carried out with or without solvent at temperatures. between 20 and 200 ° C, preferably 50 to 150 ° C. For example, as a solvent or dispersant, aromatic hydrocarbons such as benzene, toluene or xylene, aliphatic ketones such as acetone or methyl ethyl ketone, halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene or methylene chloride, aliphatic ethers such as butyl ether, cyclic ether may be used. , such as tetrahydrofuran or dioxane, sulfoxides such as dimethyl sulfoxide, tertiary acid amides such as dimethylformamide or N-methylpyrrolidone, aliphatic alcohols such as methanol, ethanol, isopropanol, amyl alcohol or tert-butanol, or cycloaliphatic hydrocarbons such as cyclohexane. Aqueous mixtures of said solvents may also be used. Often worked at reflux temperature for the solvent or dispersant used.

In general, the reaction components are reacted in molar amounts.

However, if Z is a hydrogen atom, it may be appropriate to use the compound of formula III in excess (e.g., 0.5 mole). Optionally, the reaction may also be carried out in the presence of acid-binding agents such as alkali metal carbonates (potassium carbonate or sodium carbonate), alkali metal hydroxides or tert-amines (e.g. triethylamine). The latter is especially true when using compounds where V is a halogen atom.

In the compound of formula II, as mentioned, Y may be a metal atom, especially an alkali metal such as sodium or potassium. This is especially true when in the second reaction component III the symbol V, in the group Z = -CH 2 -CHCOR 4 - CH 2 -V, is a halogen atom.

For said acylation of a secondary hydroxy group with an acid corresponding to the group or a derivative thereof, the acids used have the formula R 1 OH, where R 2 except hydrogen has the same meaning as R 2.

In particular, as acid derivatives are compounds of formula IV:

R '^ W- IV

considering that R R is as defined above and W is chlorine, bromine or iodine, a group -N Ξ N, a group of the formula -OR ', -SR' or a group of the formula -OSOgH, -O- POiOH ^ / -0P (OR ') 2, -O-As (OR') 2, or -COO-R ". Here R 'is an alkyl group or, if W is -OR' or -SR ', also a phenyl group, p-nitrophenyl group, cyanomethyl group or carboxymethyl group, and R "is a straight or branched alkyl group, an alkoxy group, a phenoxy group. group, a carbobenzoxy group or also a group R 1. Scan acylating agent can also be used for aliphatic ketene having 2-6 C atoms.

Particularly used as acylating agent are such acid derivatives of formula IV, wherein W is chlorine or bromine. If R 'or R "is an alkyl group or alkoxy group, these are preferably low molecular weight and have 1-6 C atoms.

The same types of acid derivatives are used in said acylation of a phenolic hydroxy group and / or an amino group having a C 2 -C 8 alkanoyl group.

For example, the acylations may be carried out in inert solvents or suspending agents such as water, lower aliphatic alcohols, lower aliphatic ketones, dioxane, dimethylformamide, benzene or toluene, at temperatures between 0 and 200 ° C. Optionally, it is worked under the addition of an acid-binding agent such as alkali metal hydroxides, alkali metal carbonates (potassium carbonate), alkali metal bicarbonates, alkali metal acetates, alkaline earth metal carbonates, tertiary amines (e.g. trialkylamines or pyridine) or alkali metal

It is also possible to proceed in the first way in the compound to be reacted transfer the groups to be acylated (hydroxy group, amino group) in the corresponding alkali metal compound, the compound in an inert solvent such as dioxane, dimethylformamide, benzene or toluene, is reacted with an alkali metal, alkali metal hydride or alkali metal amide (especially sodium or sodium compounds) at temperatures between 0 and 15d ° C, after which the acylating agent is added.

in

If a free acid is used for the acylation, activation thereof is required in the presence of condensing agents such as dicyclohexylcarbodiimide, sulfuric acid bis-alkylamides (e.g. SOENiQH. ^^) or Ν, Ν'-carbonyldiimidazole (Organic Reactions, Vol. 12, 1962, pages 205 and 239).

Instead of the aforementioned acylating agents, other chemically equivalent agents may also be used in the chemistry (see, e.g., also L.F. and Mary Fieser "Reagents for Organic Synthesis",

John Wiley and Sons, Inc. New York, 1967, Vol. 1, pages 1303-1304, and Vol. 2, page 471).

As mentioned, in the compounds obtained, acyl groups present in a manner known per se can also be cleaved, e.g. with aqueous alkali or alcoholic alkali metal hydroxide solution (e.g. methanolic KOH) or optionally also by mineral acids such as hydrochloric acid or sulfuric acid in alcoholic or aqueous-alcoholic solution at temperatures between 20 and 100 ° C.

In particular, the reduction of one or two nitro groups by Rg and / or catalytic hydrogenation is considered. As catalysts, for example, Raney nickel, precious metals such as palladium and platinum as well as compounds thereof, with and without carriers such as barium sulfate or calcium sulfate may be used. It is convenient to perform the hydrogenation of the nitro group at temperatures between 20 and 80 ° C and at a pressure of approx. 5-50 ato. in a solvent, e.g. alcohols, dioxane or tetrahydrofuran. For the subsequent isolation of the reduced compounds, it may in many cases be advantageous if desiccants such as anhydrous sodium or magnesium sulfate are added initially to the mixture to be hydrogenated.

However, the reduction can also be carried out with hydrogen in statu nascendi, for example zinc / hydrochloric acid, tin / hydrochloric acid or iron / hydrochloric acid, or with salts of hydrogen sulfide in alcohol / water at ca. 70 to approx. 120 ° C or with activated aluminum in aqueous ether at 20-40 ° C or with tin (II) chloride / hydrochloric acid.

The compounds of this invention are generally obtained as racemates. The optically active antibodies are obtained either by using optically active starting materials or by racemate cleavage over the salts with optically active acids such as L - (+) - tartaric acid, D - (-) - tartaric acid, (+) - Ο, Ο'-dibenzoyl- D-tartaric acid, (-) - Ο, Ο'-dibenzoyl-L-tartaric acid, (-) - 0,0'-di-p-toluoyl-L-tartaric acid, (+) - 0.01-di-p-tartaric acid toluoyl-D-tartaric acid or (+) - camphor-10-sulfonic acid.

The compounds of general formula X can be transferred into acid addition salts by methods known per se. As anions for these salts, the known and therapeutically useful acid residues are considered. Examples of such acids are H , propionic acid, gluconic acid, benzoic acid, citric acid, acetaminoacetic acid and oxyethane sulfonic acid.

From the salts of the compounds, the free bases, e.g. by treating a solution in an organic agent such as alcohols (methanol) with sodium carbonate or sodium hydroxide.

The present compounds are to be used in the preparation of pharmaceutical compositions. The pharmaceutical compositions or medicaments may contain one or more of the compounds of the present invention or also mixtures thereof with other pharmaceutical active substances. The usual pharmaceutical carriers and excipients can be used to prepare the pharmaceutical compositions. The drugs may be used enterally, parenterally, orally, or perlingually. For example, use may be in the form of tablets, capsules, pills, dragée, sticks, ointments, gels, creams, powders, liquids, nebulizers or aerosols. For example, liquids may be oil or water solutions or suspensions, emulsions, injectable water and oil solutions or suspensions.

Starting compounds of formula III, where Z is a group -CH 2 -CH (OH) -CH 2 -V, can be obtained, for example, in the usual way by reaction of epichloro or epibromohydrin with the appropriate piperazine. R'3 zinc containing the -χ Cz group at the 4-position, in alcohol, preferably methanol, with the addition of ca. 5% water at 10 ° C. For example, the reaction time is 1/2 hour. Then it is heated to 30-40 ° C and stirred for 5 hours.

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

In the compounds thus obtained, by the acylation with a compound R "jW, under the conditions already mentioned, the group R" can be introduced. Similarly, it is also possible to introduce R R into the starting compounds of formula II wherein Y is the group -dd-CHCHOHOH-C ^ CI -V.

The other starting compounds are known.

The process according to the invention is further described by the following examples.

Example 1 (±) -1 [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxy-phenyl) -piperazine.

12 g (0.05 mole) of 3,4,5-trimethoxyphenoxy-glycidyl ether were refluxed for 5 hours with 9.6 g (0.05 mole) of 1- (2-methoxy-phenyl) -piperazine in 100 ml of isopropanol. . Then, most of the solvent was distilled off and the residue was treated with excess isopropanol HCl and the dihydrochloride of 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxyphenyl) - piperazine was precipitated by the addition of diethyl ether. 18.4 g (73% of theory) were obtained as a colorless crystalline substance, m.p. of dihydrochloride 196-197 ° C.

For example, 3,4,5-trimethoxyphenoxy-glycidyl ether could be prepared as follows: In a reaction vessel equipped with azeotropic water separation means, 18.4 g (0.1 mole) of 3,4,5-trimethoxyphenol was heated to boil along with 37 g (0.4 mole) of epichlorohydrin, and for 30 minutes, 10 g (0.1 mole) of 40% sodium hydroxide solution was added dropwise while azeotropically draining the water. After the addition of sodium hydroxide solution was added, post-reaction was allowed to stand for one hour at boiling temperature and then diluted with ca. 100 ml of toluene, after which the separated NaCl was filtered off. The filtrate was fractionated first under normal pressure and then in vacuo. The 3,4,5-trimethoxyphenoxy-glycidyl ether was watered

kp. = 175-180 ° C as a colorless oil. Yield 19.2 g, corresponding to 1 / U

80% yield, calculated on trimethoxyphenol.

The process for preparing the title compound could also be carried out as follows: 0.05 mole of sodium (3,4,5-trimethoxy) phenolate, together with 0.05 mole of 1- (3-chloro-2-hydroxy-propyl) - 4- (2-methoxyphenyl) -piperazine (prepared by reaction of 1- (2-methoxyphenyl) -piperazine with epichlorohydrin) heated to reflux for 8 hours in 50 ml of dioxane. After cooling, the precipitated NaCl was filtered off and the filtrate was evaporated. The residue was treated with isopropanolic hydrochloric acid and ether and the crystalline solid was recrystallized from methanol. 8.2 g (32% of theory) (-) - 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxyphenyl) -piperazine as dihydrochloride were obtained. with m.p. 194-196 ° C.

Another possibility for implementing the procedure is the following:

A mixture of 0.05 mole of 3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl bromide, 0.05 mole. 1- (2-Methoxyphenyl) -piperazine and 0.06 mol of triethylamine in 100 ml of toluene were heated at reflux for 5 hours. Then, the precipitated triethylammonium bromide was filtered off and the filtrate was evaporated. The residue was taken up in slightly isopropanol, and with isopropanolic hydrochloric acid and ether the dihydrochloride of (-) - 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxyphenyl) - piperazine precipitated. After recrystallization of methanol, 10.1 g of the pure compound (40% of theory), m.p. 195-197 ° C.

In a manner analogous to that described in the first section of Example 1, from the 0.05 moles of 3,4,5-trimethoxyphenoxy-glycidyl ether and 0.05 moles of a compound of formula III, the compounds listed in Table I were obtained. : 1A5225 ίο

Table I

CH, 0 CH3 ° -P 'V-O - CH2 - CH (OH) - CH2 - N N - CH30 --- ^ \ - /

Ex. Starting Component with Mp ° C Yield,% of No. Formula III 7- - Theoretical 2 1-phenyl-piperazine phenyl 187 -. 1- (4-fluoro-phenyl) -4-fluoro-phenyl 202 -. 74 piperazine 203 '4 1- (2-chloro-phenyl) - 2-chloro-phenyl 193χγ 72 piperazine 195x' 5 1- (3-chloro-phenyl) -3-chloro-phenyl 172 γ 68 piperazine 173x '6 (4-chloro-phenyl) -4-chloro-phenyl 199 79

piperazine 20lXXJ

7 1- (3-methoxy-phenyl) -3-methoxy-202χ-. 82 piperazine phenyl 204 x 8 1- (4-methoxy-phenyl) -4-methoxy-208 -. 74 piperazine phenyl 210xx 9 1- (2-ethoxy-phenyl) -2-ethoxy-phenyl 198 64 piperazine 200; (dec.) 10 1- (2-methylmercapto-2-methylmercap- 183 r 69

phenyl) -piperazine to-phenyl 185XJ

11 1- (2-methyl-phenyl) - 2-methyl-phenyl 198 r 54 piperazine 199 12 1- (3-methyl-phenyl) -3-methyl-phenyl 189 -. 68 piperazine 192xx; 13 1- (3,4-dimethyl-3,4-dimethyl-186χ-) phenyl) -piperazine phenyl 188 14 1- (2,6-dimethyl-2,6-dimethyl-228χ-, 71-phenyl) -piperazine phenyl 230 '1§ 1- (2-trifluoromethyl-2-trifluoro-205 γ 52 phenyl) -piperazine methyl-phenyl 206X' 16 1- (3-trifluoromethyl-3-trifluoro-169 γ 69 phenyl) -piperazine methyl-phenyl 172x '17 1- (2-hydroxyphenyl) -2-hydroxy-piperazine phenyl (base) acid monohydrochloride dihydrochloride

Example 18 (-) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2- (nicotinoyloxy) propyl] -4- (2-methoxyphenyl) -piperazine.

13.0 g (0.03 mol) (-) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxyphenyl) -piperazine was added together with 3, 34 g of triethylamine (0.033 mol) dissolved in 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 was added. The mixture was stirred for an additional 2 hours at room temperature and then the mixture was heated for an additional 1 hour at 70-80 ° C. After cooling, the mixture was shaken several times with water, washed with aqueous NaHCO 3 and water, then the benzene phase was dried with magnesium sulfate and evaporated. The solid evaporation residue was taken up in dioxane. After addition of excess isopropanolic hydrochloric acid and ether, 13.0 g (67% of theory) of the title compound was obtained as trihydrochloride (colorless crystals), m.p. 187-192 ° C (dec.).

Example 19 (β) -I- (3- [3,4,5-Trimethoxyphenoxy] -2 - [(3,4,5-trimethoxy) -benzoyl-oxy] -propyl] -4- (2-methoxyphenyl) piperazine.

+ (-) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxyphenyl) -piperazine was reacted analogously to Example 18 with 3,4,5-trimethoxybenzoyl chloride in the presence of triethylamine. The reaction product was obtained as dihydrochloride, m.p. 193-195 ° C (dec.), Yield 38%.

Example 20 (-) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-acetamido-phenyl) -piperazine.

4 g of (δ) -1- [3- (3,4,5-Trimethoxyphenoxy-2-hydroxy-propyl] -4- (2-amino-phenyl) -piperazine (monohydrochloride) was dissolved in 200 ml of dioxane and there 0.9 ml of acetyl chloride were added dropwise with stirring at -5 ° C. After two hours of post-reaction at room temperature, the solution was filtered and the solvent removed under reduced pressure by dry column chromatography on silica gel (eluent ether -acetic acid ethyl ester = 1: 1), the desired compound was isolated Recrystallization took place from acetone ether Yield: 50%, mp 128-130 ° C.

145225 12

As a less polar by-product which, by increasing the amount of acetyl chloride, can become the main product, (-) - 1- [3- (3,4,5-tri-methoxyphenoxy) -2-acetoxy-propyl] -4- ( 2-acetamido-phenyl) -piperazine, m.p. 54 ° C.

Example 21 (-) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-acetoxy-propyl] -4- (2-acetoxy-phenyl) -piperazine.

6 g (0.0143 mol) (-) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-hydroxy-phenyl) -piperazine and 2.9 g (0.0286 mol) of triethylamine was dissolved in 80 ml of absolute methylene chloride, and at 0 ° C a solution of 2.24 g (0.0286 mol) of acetyl chloride in 20 ml of absolute methylene chloride was added dropwise. The reaction mixture was stirred for 2 hours at room temperature and the precipitated triethylamine hydrochloride was filtered off. Then, the solvent was distilled off in vacuo and the residue was recrystallized from ether / petroleum ether. Yield: 57%, m.p. 70 ° C.

Example 22 (-) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-amino-phenyl) -piperazine.

6 g (0.0124 mol) (ί) -1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-nitro-phenyl) -piperazine, prepared analogously to the In the manner described in Example 1, first paragraph, was dissolved in 300 ml of methanol and hydrogenated in the presence of 0.5 g of Pd-C (10%) at room temperature. After filtering off the catalyst and removing the solvent in vacuo, ethanol was recrystallized. Yield: 94%, m.p. of monohydrochloride: 181-183 ° C.

U5225 13

Example 23 (β) -1- [3- (3,4,5-Trimethoxy-phenoxy) -2-hydroxy-propyl] -4- (2-acetoxy-phenyl) -piperazine.

CH3 CH30 O-CH2 CH (OH) - CH2 - t / N - CH3 ° OCO - CH3 0.03 moles of 1- (2-Acetoxy-phenyl) -piperazine (crude product) and 7.2 g (0.03 mol) 3,4,5-trimethoxy-phenoxy-glycidyl ether was heated under reflux in 150 ml of isopropanol until the reaction according to thin layer chromatography control was completed. After distilling off the solvent, the hydrochloride was obtained by treatment with isopropanol hydrochloric acid and this was purified by recrystallization from isopropanol, m.p. 189-191 ° C, yield 18%.

The 1- [2-acetyloxy-phenyl] -piperazine used as starting material was prepared as follows: 192.8 g (1 mole) of 2-Methoxyphenylpiperazine, 130 ml (1.1 mole) of benzyl chloride and 150 g (1.10 mole) potassium carbonate was heated under reflux in 800 ml of xylene until the reaction by thin layer chromatography control was complete. Filtrate, remove the solvent in vacuo and transfer into hydrochloride with isopropanolic hydrochloric acid as usual (yield 70%).

Of the hydrochloride thus obtained, 60 g (0.2 mole) in 800 ml of 63% aqueous hydrobromic acid were heated at reflux until the ether cleavage was complete (thin layer chromatography control). Then, the solvent was removed in vacuo and the obtained crystalline evaporation residue was washed with ether (yield 70%). From the dihydrobromide, the free base was released in the usual manner with dilute aqueous ammonia.

Of the free base thus obtained, 10 g (0.029 mol) and 15 ml of triethylamine in 50 ml of dioxane were cooled to 5 ° C and 0.032 mol of acetyl chloride was added dropwise at a temperature not exceeding 10 ° C. After stirring for 1 hour at 10 ° C, the precipitated triethylamine hydrochloride was aspirated and the solvent was distilled off in vacuo.

In the obtained oily free base, without further purification, the benzyl group was dehydrogenated as follows: 0.04 mole of free base was dissolved in 150 ml of methanol and hydrogenated in the presence of 2 g of Pd / C 10% at 50 ° C. and 5 bar. After hydrogen uptake was completed, the catalyst was filtered off and the solvent was removed in vacuo. The 1- (2-acetoxy-phenyl) -piperazine thus obtained could be further reacted directly without further purification.

Example 24 (i) -1- [3- (3,4,5-Trimethoxy-phenoxy) -2-acetoxy-propyl] -4- (2-methoxy-phenyl) -piperazin.

10 g (0.023 mol) of (±) -1- [3- (3,4,5-Trimethoxy-phenoxy) -2-hydroxy-propyl] -4- (2-methoxy-phenyl) -piperazine was suspended in 100 ml. xyl-one. To this was added 10 ml of triethylamine and then slowly added 9 ml of acetyl chloride at room temperature. The solution was left to stand for 2 hours at room temperature. The triethylammonium hydrochloride was then filtered off and the solvent was distilled off in vacuo. The crude product obtained was purified by dry column chromatography on silica gel (eluent chloroform / methanol 98: 2). The hydrochloride was washed in the usual manner by treatment with isopropanol hydrochloric acid and was recrystallized from isopropanol, m.p. of hydrochloride 178-179 ° C, yield 80%.

Examples 25-25 (+) - 1- [3- (3,4,5-Trimethoxy-phenoxy) -2- (thienyl- (2) -carbonyloxy) -propyl] -4- (2-methoxy-phenyl) - piperazine (D 15 077).

° CH3 / "Λ Jr \ CH30—0" CH2 "CH" CH2 "y ch3o

0 - CO

15 g (0.0319 mol) (i) -1- [3- (3,4,5-Trimethoxy-phenoxy) -2-hydroxy-propyl] -4- (2-methoxyphenyl) -piperazine dihydrochloride and 3.3 g of triethylamine were suspended in 100 ml of xylene. With stirring, 4.7 g (0.0319 mol) of thiophene-2-carboxylic acid chloride was added dropwise at room temperature. It was further stirred for one hour at room temperature. Then, the precipitated triethylammonium hydrochloride from filter 145225 was extracted and the solution was evaporated under reduced pressure. The evaporation residue was taken up in ether and isopropanol HCl was added. The obtained dihydrochloride was recrystallized from isopropanol.

Mp. of dihydrochloride 198-199 ° C (the substance contained 1 mole of isopropanol as a crystal solvent). Yield 42%.

Analogously, the corresponding thienyl (3) compound (D 15 076) was prepared, m.p. of dihydrochloride 193-194 ° C, yield 48%.

Example of racemate cleavage.

(+) - 1- [3- (3,4,5-Trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxy-phenyl) -piperazine (base = compound Ia) and (-) - 1- [3- (3,4,5-trimethoxyphenoxy) -2-hydroxy-propyl] -4- (2-methoxy-phenyl) -piperazine (base = compound 1b).

4.32 g (0.005 mole) of the racemic compound of Example 1 was dissolved hot in 80 ml of butyl acetate and at 80 ° C was added portionwise with good stirring 4.04 g (0.005 mole) (-) - di-p-toluoyl-L-tartaric acid hydrate, whereby the left-turn diastereomeric salt pair precipitated immediately. Then it was heated. a further 10 minutes at 110 ° C, then allowed to cool to 80 ° C and the precipitate filtered off. The salt pair was recrystallized from acetone-dimethylformamide gasoline ([α] ° -48.6 °, 1% in dimethylformamide) and then digested with concentrated ammonia. The base was extracted with ether and the extract was evaporated. The solid evaporation residue was recrystallized from isopropanol: la-Baase in the form of colorless crystals, m.p. 103-104 ° C, [α] 20 ° + 7.2 ° (concentration 2% in CH 2 OH). By dissolving the base in methanol and adding isopropanolic hydrochloric acid and ether, the dihydrochloride of compound 1a was obtained in the form of colorless crystals, m.p. 189-193 ° C, [α] p ° - 11.4 ° (concentration = 2% in CH 2 OH).

The filtrate from the salt pair precipitate containing the right-turn diastereomeric salt pair was evaporated on rotary evaporator and the viscous evaporation residue was slurried in water, then concentrated ammonia was added and the base was then extracted with ether. The ether solution was dried and evaporated and the solid evaporation residue was recrystallized from isopropanol: lb-Base in the form of colorless crystals, m.p. 100-101 ° C, [α] 20 ° ~ 5.8 ° (concentration = 2% in CH 2 OH).

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Upon dissolving the base in methanol and treating with isopropanol hydrochloric acid and ether, the dihydrochloride of compound 1b was obtained in the form of colorless crystals, m.p. 182-187 ° C, [α] + + 11.0 ° (concentration = 2% in CH 3 OH).

Pharmacological data.

To assess the pharmacological action of the compounds of this invention, the anti-aggressive activity of the compounds was determined by the match test method (mouse) of R.E. Tedeschi et al., J.Pharmacol.Exp. Therap. 125, 28 (1959).

In this method, adult male mice, always in pairs, were placed in a cage with a grid floor of ca. 13 x 13 cm and through the bottom stimulated with an electric current for 3 minutes, after which the two mice took on a specific characteristic fighting position (the two mice get up and look at each other, and sometimes they also attack).

This type of fighting behavior in mice can be eliminated with anti-aggressive drugs.

Based on a larger number of mouse pairs, probit analysis is determined ED5q. ED ^ q is the dose at which the typical fighting position is absent in 50% of the studied mouse pairs.

Table II below lists ED ^ q (per os) for a number of the compounds of the present invention. Comparative compounds have been used two compounds known from the aforementioned U.S. Patent No. 3,951,986, namely the 1- [2-hydroxy-3- (p-methoxyphenoxy) propyl] mentioned in column 11, lines 13-15 4- (p-chlorophenyl) -4-hydroxypiperidine, which, like the compounds of the present invention, contains a methoxy-substituted phenyl ring (the three methoxy substituents of the first phenyl group of the compounds of this invention are an essential element of the structure of the compounds), and partly that of Example 1 Compound prepared in the US patent, 1- [2-hydroxy-3- (p-fluorophenoxy) propyl] -4- (o-methoxyphenylpiperazine dihydrochloride, which, like the compounds in question, is a piperazine compound.

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Table II

Compound according to ED50

Example No. Ntg / kg (per ounce) 1 1.4 4 16 7 5.5 9 19 10 14 12 12 13 13 15 21 16 9 17 1.3 18 14 19 '16 20 3.3 22 1.4 23 3.2 24 3.8 25 9.7 26 6.4

Comparison:

Compound of U.S. Patent No. 3,951,986, column 11, lines 13-15, m.p. 104-104.5 ° C 30

Compound of the same US patent, Example 1, 115

It is evident from the data set out in Table II that the compounds in question in said match test have a significantly stronger anti-aggressive effect than said known compounds. In addition, it should be noted that the value for the latter compound of ED ED q of 115 mg / kg per oz is so high that there are side effects on the central nervous system, namely light to strong sedation, abdominal distention in the mice as a symptom of severe obscurity. The anti-aggressive effect of the compounds of the present invention, on the other hand, is at a dose level much lower than that in which the above side effects occur.

Claims (1)

Analogous Process for the Preparation of 1- (3-Trimethoxypheno-xy-2-hydroxy-propyl) -4-phenyl-piperazine Derivatives of the General Formula I: CH3 ° \ _ ^ R; 3 ch3o-ff y ~ ° ~ CH2 ~ R 4 is R a hydrogen atom, a C 2 -C 6 alkanoyl group, a mono-, or tri-C 1 -C 6 -alkoxy-benzoyl group, a thienylcarbonyl group or a C nicotinoyl group, and R 3 and R 2 are the same or different and are hydrogen, hydroxy, fluoro, chloro, trifluoromethyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio, amino, C 2 -C 8 -alkanoylamino or C 2 -C 6 -alkyl-noyloxy, or acid addition salts thereof, characterized in that a compound of formula Il: CH3O3 ch3o - (f \ -oy ii οη3ο- · is reacted with a compound of formula III: r ~ \ jr, 3 'Z - NN') III where R'3 and R'4 are the same or different and have the same meaning as R3 and R4 or denote nitro and Y is hydrogen or a metal atom and Z is a group -CH 2 -CH (OR ') - CH 2 -V, or Y is the latter group and Z is hydrogen where R'has and V is chlorine, bromine or iodine, or OR1 and V together mean epoxy, where, if R'3 and / or R'4 denote nitro, the nitro compound produced is reduced to form the a corresponding amino compound, wherein, if desired, a compound of general formula I is subjected to one or more of the following side reactions: (i) acylation of a secondary hydroxy group with an acid corresponding to the group R 1 or a derivative thereof;