DE1937811A1 - New 1,4-substituted phenylpiperazines - Google Patents

Description

The present invention relates to new 1,4-, substituted ones Phenylpiperazines, a process for their production, as well as pharmaceutical preparations, soft these new 1,4-substituted Contain phenylpiperazines. The present invention also relates to anticoagulants and a Methods for combating thrombotic diseases.

The new 1,4-substituted phenylpiperazines according to the invention are compounds of the general formula

(D

wherein the remainder A-B represents the moiety

It

CH CH

CH or

10 stands,

909885/1771

"- 2—

Χ, Y and Z, which can be the same or different, each denote a hydrogen atom, a hydroxyl group, a leather alkoxy group or a phenyl-substituted non-alkoxy group,
η is an integer from 1 to 3 and

R a dimethylaminoethyl, diethylaminoethyl, Dipropylaminoethyl, dimethylaminopropyl, diethylaminopropyl, Dipropylaminopropyl-, Piperidinoäthyl- * Morpholinoäthyl-, Dimorpholinopropyl, pyrrolidinoethyl, piperazinoethyl, jJ'-ketopiperazinoethyl or N * -alkylpiperazinoethyl radical symbolizes, as well as their salts.

The radical in position 1 can thus be an optionally substituted benzyl, phenylethyl or phenylpropyl radical be.

Preferred nuclear substituents in the aralkyl radicals bonded in the 1 position are: one halogen atom in the 2 ¹ , 3 ^f or 4 ¹ % two halogen atoms in the 2 ', 3'positions; 2 ', 4'; 2 ', 5 ¹ J (possibly 2', O ¹ ) and 3 ', 4 ¹ .

Substituted compounds as indicated above can also hydroxyl groups or methoxyl groups in the benzene ring wear.

The phenyl radical in position 2 or 3 of the piperazine ring is always unsubstituted.

It has been found that the 1,4-substituted phenylpiperazine compounds of the above general formula (I) have a marked effect on the blood coagulation system.

In particular, the following new piperazine compounds are provided by the present invention: 1- (4-chlorobenzyl) -2-phenyl-3-keto-4- (diethylaminoethyl) piperazinj

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1- (4-chlorobenzyl) -2-phenyl - ^ - (diethylaminoethyl) -piperazinj 1- (3ί 4-Diehlorbenzyl) ^ - phenyl ^ - (diethylaminoethyl) -piperazinj

1 _ £ "(4-Methoxyphenyl) -äthylJJ-S-phenyl - ^ - (diethylaminoäthy]) - piperazinj

1- ^ 75-Phenylpropyl- (1) JT-2-phenyl-4- (diethylaminoethyl) -piperazinj

1- (4-chlorobenzyl) -2-phenyl-4-pipefidinoethyl-piperazinj 1- (^ -chlorobenzylJ ^ -phenyl - ^ - ^^^ - dimorpholinOpropyl- (2] J- piperazinj

1- (4-chlorobenzyl) -3-phenyl-4- (diethylaminoethyl) piperazine.

The new piperazine compounds of the general formula I.

are obtained according to the invention by ™

a) a 1-R-phenylpiperazine of the general formula

H-N N-R, (ii)

\away/

in which the radicals A-B and R have the meaning given above with an Aralicy! halide of the general formula

C _n H _2n -HaI, (III)

in which X, Y, Ί and η have the meanings given above and Hal stands for halogen, converts, or

b) a l-aralkyl-phenylpiperazine of the general formula

909885/1771

1337811

"■ 7"

wherein the radical ^ A-B '/ X, Y, Z and η are those given above Have meaning with a basic substituted alkyl halide the general formula

HaI-R, (V)

wherein Hai and R have the meaning given above, for Reaction brings, or

c) one in OT position by a reactive radical Q, in particular Halogen, substituted 4-alkyl-1-aralkylphenyl-piperazine the general formula:

where A, B, X, Y, Z and η have the meaning given above and n ^{f is} 1, -2 or 2, with a corresponding amine from the group consisting of dimethylamines, diethylamine, dipropylamine, piperidine, morpholine, pyrrolidine, piperazine, 3 - ketopiperazine or N-alkylpiperazine converts,

if necessary, a product of the general formula I obtained in which the radical \ a — Br represents the group

or

symbolizes, reduced to a compound of the general formula I, in which the radical ^ A-B ^ for the grouping

or ^ CH ₀ - CH ^

and, if desired, the basic compound obtained converted into a salt.

All physiologically harmless acids are suitable as salt-forming acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide satire, benzoic acid, succinic acid, malonic acid, tartaric acid, citric acid, etc.

909885/17 7.1

The following examples further illustrate the invention.

Example Ir l- (4 ^! -Chlorobenzyl) -2-phenyl-> keto-4- (diethylaminoethyl) piperazine j

CHp-CH ₁

A a) 1 - (4'-chlorobenzyl) -2-phenyl-j5-keto-plperazine.

175 S 2-phenyl ~ 3-keto-plperazine / are refluxed for 7 hours with 177 g of p-chlorobenzyl chloride, 420 nil triethylamine and 2 liters of acetone. The solution freed from the triethylammonium chloride formed by filtration is refluxed for a further 7 hours and filtered hot. The crystals, which are uracrystallized from alcohol / water, separate from the slightly constricted piltrate. White crystals are obtained in a yield of 195 g ^β 65 % of theory (= 65 % dcTh,) j melting point (P.) = 175 ° C.

Ab) 1- (4'-chlorobenzyl) -2-phenyl ~> keto-4 ~ (diethylaminoethyl ) -piperäzin.

6o g l -> (4'-chlorobenzyl) -2-phenyl-5-keto-piperazine, 40 g Diethylaminoethyl chloride, 40 g finely powdered, dried, anhydrous potassium carbonate are "refluxed for 10 hours" in 400 ml of toluene. The reaction mixture is taken up in water and the toluene layer is separated off. The base is shaken out of the toluene solution removed with hydrochloric acid 1: 4, set free by neutralization with ammonia and taken up in benzene.

+) £> see WR Roderick, HJ ₀ Platte, CB. Pollard, J. of Med. Chem. 9, 181 (1961) _7

909885/1771

After the benzene has been distilled off, excess diethylaminoethyl chloride is removed in vacuo. Who froze ' The residue is dissolved in 1.5 liters of petroleum ether and the unreacted The starting ketopiperazine was separated by filtration.

After the petroleum ether has been distilled off, the compound given in the heading is obtained as a viscous yellow oil with a boiling point of 212 ° C. (0.03 torr). After another distillation, the base is chromatographically uniform. Yield: 72 g (90 % of theory). This alkylation can also be achieved, for example, with sodium lumamide in toluene.

Ba) 1- (diethylaminoethyl) -2-keto-3-phenyl-piperazine. 400 g of ethyl 06-chlorophenylacetate are refluxed with 320 g of N ₁ - (diethylaminoethyl) ethylenediamine in 3 liters of absolute alcohol for 12 hours. A sodium alcoholate solution (prepared by dissolving 46 g of sodium in 1 liter of absolute alcohol) is added to the still warm solution. The precipitated common salt is filtered off with suction, the alcohol is distilled off. The residue is taken up in benzene, the base is removed by shaking with acetic acid and released again with sodium hydroxide solution.

The base, which is further taken up in benzene, is distilled in vacuo after the solvent has been removed. After two times Distillation through a Raschigring column gives 307 g of a viscous, yellow oil with a boiling point of 186 to 190 ° C at a pressure of 0.1 to 0.3 Torr. That on 1- (diethylaminoethyl) -2-keto-3-phenyl-piperazine obtained in this way also contains, as has been shown by chromatography, 1- (diethylaminoethyl) -2-phenyl-3-keto-piperazine.

B b) 1- (4 ^t -chlorobenzyl) -2-phenyl-3-keto-4- (diethylaminoethyl) piperazine.

80g 1- (diethylaminoethyl) -2-keto-3-phenyl-piperazine (mixed with the isomer) are mixed with 54 g of p-chlorobenzyl chloride, 101 g of triethylamine and 300 ml of toluene for 5 hours 909885/1 77 1

refluxed. The separated triethylammonium chloride is shaken out of the still warm solution with water. The separated toluene layer is from Freed solvent, the residue taken up in benzene and filtered from insolubles.

In this way, a large part of the non-alkylated 1- (diethylaminoethyl) -2-phenyl-3-keto-piperazine is removed.

The basic components are removed from the benzene solution by shaking with 30 # acetic acid. The acetic acid extract is neutralized and the released base is again taken up in benzene and distilled. Ä

The range from Ij8 to 215 ° C at a pressure of 0.03 Torr passing product is taken up in petroleum ether, Purified again through an acetic acid-ammonia passage and fractionally distilled. It will be 45 g of a very viscous, yellow oil with a boiling point of 0.03 mm = 212 214 ° C.

The compound is isomer-free and identical to the substance obtained according to Example 1 (determined by chromatography and by infrared analysis).

Under the chosen conditions, alkylation does not occur ( with the 4-chlorobenzyl chloride in 1- (diethylaminoethyl) -2-phenyl-3-ketp-piperazine. The alkylation is also possible in an analogous manner with triethylamine in acetone, but it is very slow It is also possible to use acetone-dimethylaniline and acetone-pyridine. Dimethylformamide can also be used, but gives a certain Laetam alkylation even at room temperature. At higher temperatures, N-pormylation also occurs.

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Be is ρ I e 1 2: 1- (4'-chlorobenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine:

a.) ^{1- (4 f} -chlorobenzyl) -2-phenyl-piperazine.

44 g of l- (4 ^t -chlorobenzyl) -2-phenyl-3-keto-piperazine (shown according to Example 1 A a) are dissolved in 550 ml of dioxane and added dropwise with vigorous stirring to a suspension of 15 g of LiAUfy in 800 ml of ether . When the addition is complete, the mixture is refluxed for 12 hours. By successively treating the solution with 15 ml 15 # sodium hydroxide solution, 15 ml water, 45 ml 15 # sodium hydroxide solution and 30 ml water, the lithium complex is broken down and excess LiAlH ^ is destroyed. The solution freed from inorganic components by filtration is evaporated and the residue is recrystallized from isopropanol

sated. There are 37 g of pure white crystals from P. - 103 104 ° C received.

a ₂ ) 1- (4 ^l -chlorobenzyl) -2-phenyl-piperazine.

142 * 4 g of l- (4 ^l -chlorobenzyl) -2-phenyl-3-keto-piperazln (shown according to Example 1 A a) are suspended in 400 ml of benzene with vigorous stirring. 800 ml of a 1.5 molar solution of dibutylaluminum hydride are slowly added, the reaction mixture coming to the boil on the reflux condenser, 1/2 hour after the addition has ended, the mixture is cooled to 5 ° C., and the excess dibutylaluminum hydride by carefully adding water decomposed and the aluminum hydroxide dissolved in 40 # sodium hydroxide solution. The separated organic phase becomes 909885/1771

ORIGINAL INSPECTED

washed, freed from the solvent by evaporation and the residue is recrystallized from 1.5 1 isopropanol.

There are pure white crystals with a temperature of 103 - 104 ° C obtain. The yield corresponds to the theoretically expected amount. The substance is according to the results, obtained in chromatography and by infrared spectroscopy, identical to the compound obtainable according to a,).

b) ^{1- (4 l} -chlorobenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine. , ™

30 g of the _{base prepared according to a 1} ) or a “) are dissolved in 100 ml of toluene and refluxed for 8 hours with 20 g of diethylaminoethyl chloride and 20 g of finely powdered anhydrous potassium carbonate. The base is purified by treating with water, separating the toluene layer, »shaking out with hydrochloric acid, releasing the base with ammonia and taking it up in benzene. After the solvent has been distilled off and distilled twice, 34 g of a yellow oil with a boiling point of 0.09 mm = 188-190 ° C. are obtained. Yield: 81 # of theory

Dihydrochloride s P. = 255 - 270 ° C (dec. °) P. des Sueeinat; = 95 - 101 ° C. '

Example 3: 1- (3 ', 4'-Dichlσrbenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine:

ytl ¹ UXl ₂

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1937-11

- 10 a) 1- (3% V-Diehlorbenzyl) -2-phenyl-3-ketQ-piperazine.

140 g of 2-phenyl-3-keto-piperazine are mixed with 163 g of 3,4-dichlorobenzyl chloride boiled under reflux for 6 hours in 1600 ml of acetone tinter addition of 330 ml of triethylamine. The hot solution filtered from the triethylammonium chloride is gradually concentrated and the crystal fractions obtained are recirculated twice from 4 1 96 #Igem alcohol installed.

. 162 g of the above compound of P * = 195 - 208 ° C (decomposition) are obtained (= 52 % of theory)

t>) i- (3 ^f , ^ '- Dichlorbenzyiy ^ -phenyl-piperazine.

132 g of the keto-piperazine prepared according to a) are dissolved in 200 ml of dioxane and a suspension of 21 g of LiAlHh in 900 ml of abs. Ether added dropwise. When the addition is complete, the mixture is refluxed for 12 hours. The reaction mixture is successively mixed with 20 ml of 15% sodium hydroxide solution, 20 ml of water, 60 ml of 15% sodium hydroxide solution and k0 ml of v / ater and thus decomposed. The filtrate is freed from solvent, the residue is distilled and there is a viscous obtained 170-178 ⁰ C at a pressure of 0.02 Torr boiling oil, crystallized This is recrystallized twice from heptane on trituration with Heptanj. P. = 85-87 ° C. Yield: 110 g (= 87 % of theory).

c) 1- (3% ^J i- ⁱ -di-dichlorobenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine.

40 g of the piperazine derivative obtained according to b) are mixed with 18.5 g of diethylaminoethyl chloride in 250 ml of acetone with the addition boiled under reflux for 12 hours from 52 ml of triethylamine. The triethylammonium chloride formed is filtered off, the solution concentrated, the residue with absolute

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alcoholic hydrochloric acid added. The precipitated hydrochloride is dissolved in water after washing with alcohol. "" The base is set free by adding ammonia and taken up in benzene. After drying over anhydrous potassium carbonate and removing the solvent, 34 g of a light yellow oil with a boiling point of 0.05 mm = 192 ° C. are obtained (= 65 K> d.Th.). Dihydrochloride: m.p. = 220-222 ° C; orthophosphate m.p. = 220-226 ° C; Sulphate: F. = 210-214 ° G,

Example 4s 1 - ^ (4 ^l -Methoxyphenyl) -BthylJ7-2-phenyl-4- (diethylaminoethy1) -piperazine:

a) 1- £ "(4'-methoxyphenyl) ethylJ7-2-phenyl-3-keto-piperazine.

14o g of 2-phenyl-3-keto-piperazine, 148.5 g of 4-methoxyphenylethyl chloride, 330 ml of triethylamine in 1.6 l of acetone are used Boiled under reflux for 12 hours. The acetone is distilled off; 300 ml of dimethylformamide are added to the residue added and the mixture is heated on a water bath for 36 hours. Most of the dimethyl formamide is in the Distilled off in vacuo, the residue with about 500 ml of acetone and 150 ml of triethylamine are added. The boiling hot Gendsdi is freed from triethylammonium chloride by filtration and cooled. After the solvent has been distilled off again, the remaining crystals are washed with petroleum ether, triturated with water and the solution filtered again. When the solution is alkalized, it separates the compound becomes oily at the beginning and then crystallizes

quickly through. After three recrystallizations, 609885/1771

pure white crystals from P. = 142 - 147 ° C (decomp.) obtained. Yield: 110 g (= 44.7 # of theory). If you work with a dirnethylformamide-triethylamine mixture from the start, so the yields are due to the occurrence of formylation reactions worse.

b) 1- ^ "(4'-methoxyphenyl) ethy] J7-2-phenyl-piperazine.

29 g of the ketopiperazine prepared according to a) are dissolved in 200 ml of absolute dioxane and stirred vigorously to a suspension of 8 g of LiAlHh in 700 ml of abs. Ether added dropwise. The mixture is then taken for 12 hours Refluxed. After decomposition with 10 ml 15 # sodium bicarbonate lye, 10 ml water, 30 ml 15 # sodium hydroxide solution and 20 ml Water in the order given is used by the concentrated solution freed from inorganic salts by filtration. Alcoholic hydrochloric acid is added to the residue and sucked off the precipitated HydrooHbrld. The base is set free from the hydrochloride by adding sodium hydroxide solution.

There will be 2? . g viscous one, after some standing durchkristallisierenden oil, bp 0.01 mm "l80 - I85 ⁰ (β 8j5% of theory).

c) l-

aminoethyl) piperazine.

j 18 g of the base obtained according to b) are mixed with 30 g of triethyl ; 25 amine and 12 g of diethylaminoethyl chloride in 120 ml of acetone were refluxed for 15 hours. The filtered after cooling Solution is reduced by concentration of the solvent free, the residue taken up in dilute hydrochloric acid, the base was set free with ammonia and taken up in benzene and freed from the solvent again.

909885/1771 ORIGINAL INSPECTED

The residue is with a mixture of acetone and alcoholic Hydrochloric acid added, the separated hydrochloric! is sucked off. The ones from Hydroehlorld again in Freed base is distilled in vacuo.

17 g of a viscous oil with a boiling point of 0.02 mm = 215 ° C. are obtained (=? 0 # d.Th.) received. P. of the hydrochloride »190 - 201 ° C

Example 5! l- ^ ~ 3 ^t -Phenylpropyl- (l) J ^r ~ 2-phenyl-4- (diethylaminoethyl) -piperazine

CH ₂ -CH,

a) l-

14o g 2-phenyl-3-keto-piperazine and 135 g 3-phenylpropyl chloride (l) are heated in 350 ml of dimethylformamide with the addition of 330 ml of triethylamine for 48 hours on a water bath. Most of the dimethylformamide and triethylamine is distilled off in vacuo, the residue in 2 l of acetone added, mixed with ISO ml of triethylamine and 10 minutes refluxed. The solution, cooled to 30 ° C., is freed from triethylammonium chloride by filtration. From the ternisehung cooled down in an ice and salt quay Solution crystallizes from the ketopiperazine, which by recrystallization from isopropanol and 50 tigern Alcohol is cleaned.

110 g of white crystals of P. = 114 - 116 ° C are obtained (= 4? % Of theory) · ■.

b) 1 ~ ^ ° 3 '»phenylpropyl- (
43 g of the ketopiperazines obtained according to a) are in

'* ■■■■' ■ "'909885/1771

Dissolve 200 ml of dioxane and reduce it as usual with IO g of LlAlH ^ in 800 ml of ether. After the base has been decomposed and worked up by cleaning with the Hydrochloric! 30 g of a viscous oil with a boiling point of 0.01 non = 155 - 16Q ^o c are obtained (= 73 % of theory).

c5 l- £ j3 ^t -I ^> henylpropyl- (l) _iiii 7-2-phenyl-4 ~ (diethylaminoethyl) -piperaain.

23 g of the base prepared according to b) are refluxed for 10 hours with 13.5 g of diethylaminoethyl chloride, 35 ml of triethylamine and 150 ml of acetone. After the base has been worked up in the usual way and purified using the hydrochloride, 22 g of a colorless oil with a boiling point of 0.01 mm »187 189 ° C. ( -70.5 % of theory) are obtained. P. des Hydrochloride - 180-192 ° C-

Example 6; l- (4'-chlorobenzyl) -2-phenyl-4- (piperidinoethyl) -piperazine

31 g of the 1- (4'-ChIOrberi & yl) «2-phenyl-piperazine prepared according to Example 2 a ₂ ), 25 g of piperidinoethyl chloride * 20 g of sriäthylamine and 250 ml of acetone are boiled for 18 hours under a flux, the filtered solution is concentrated by concentration Freed solvent, the residue taken up in benzene and the benzene solution washed with water. After drying and distilling off the solvent, the base is obtained as a viscous, yellow oil at 210 ° C. under a pressure of 0.06 torr. The oil crystallizes when rubbed with isopropanol. After two recrystallization processes, 41 g of yellowish crystals with a temperature of 85-87 ° C (95 % of the temperature) are obtained. Instead of acetone you can also, for example

9098 85/177 1

Use benzene, toluene or xylene and instead of triethylamine, for example, pyridine, dimethylaniline, potassium carbonate, sodium amide or sodium hydride. Suecinate: F. = 156 - "158 ⁰ Q Pumarat: F. = 190 ° Q (sublimation), 250 - 251 ° C (decomp.)

Example 7: l- (4'-chlorobenzyl) -2-phenyl-4- £ "l", 5 "-dimorpholinopropyl (2") J7-P ⁱ P ^erazin:

^ { V

51 g of the 1 - (^ 'benzyl) -2-phenyl-piperazine obtained according to Example 2 a _g ), 52 g of 1, J-dimorpholinopropyl- ^ chloride- (2) ^ "made from 1,3-Diniorphollnopfopanol- ^ 7 25 g of triethylamine and 250 ml of acetone are refluxed for 48 hours. The base remaining after filtration and driving off the solvent is purified by taking up in hydrochloric acid and releasing it with ammonia, taken up in benzene and dried over anhydrous potassium carbonate of the solvent, a first run of up to 110 ° C. is _{distilled off under a pressure of O 1} I Torr, which consists mainly of unreacted dimorpholinopropyl chloride.

The remaining substance is taken up in PetrolSther and separated from undissolved fractions in the cold by filtration. The solvent is driven off and the remaining product is distilled.

There are Jk g of a solidifying oil, boiling point 0.001 mm = en.

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23O ⁰ C obtained.

Example 8: 1- (4'-chlorobenzyl) -; 5-phenyl-4- (diethylaminoethyl) piperazine:

CH ₂ -CH ₂

a) 1- (Diethylaminoethyl) -2-phenylpiperazine.

1- (diethylaminoethyl) -2-phenyl -> - keto-piperazine was prepared by reacting N ₁ - (diethylaminoethyl) -äthylendlamln with oCr-chlorophenylaoetyl chloride and isolating it from the isomer mixture. .

89 g of the Ketopiperazine become one in 200 ml of Dioxari Slurry of 20 g LiAlH ^ in 800 ml ether added dropwise, After the addition has ended, the mixture is refluxed for 6 hours. After decomposition with 20 ml 15 # sodium hydroxide solution, 20 ml water, 60 ml 15 ml caustic soda and 40 ml water the filtered solution is concentrated and the residue im Vacuum distilled. The oil obtained is distilling at 102 to 115 ° C under a pressure of 0.05 mm Hg taken up in benzene and extracted with 10 # HCl. The base is freed from the hydrochloride with 10% sodium hydroxide solution and distilled repeatedly. Man receives an almost colorless oil of bp Q.01 to "ll4 - 117 ° C"

The yield corresponds to the theoretically expected amount. The product still contains a small amount of 3-phenyl-1- (diethylaminoethyl) piperazine. ;

b) 1- (4'-chlorobenzyl) -3-phenyl-4- (diethylaminoethyl) piperazine.

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ORlQtNALINSPECTED

26 g of the base prepared according to a) are 17 * 7 g 4-chlorobenzyl chloride and 42 ml of triethylamine in 200 ml Acetone boiled under reflux for 10 hours. After filtering and driving off the solvent, the base becomes more normal Purified via the hydrochloride and released from it with ammonia. The one from the solvent The freed residue is dissolved in ethyl acetate and the hydrochloride is made from this solution with absolute alcoholic strength Hydrochloric acid precipitated.

It is recrystallized from ethyl acetate, F. des Hydrochloride = 24l - 255 ° C (decomposition). The base is liberated from the hydrochloride with ammonia and distilled in vacuo. It passes over as an almost colorless oil with a boiling point of 0.01 mm = 180 ° C. .

Yield: 30 g (= 78 % of theory).

The substance can be identified by its infrared spectrum of the isomeric 1- (4'-chlorobenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine can be distinguished by direct comparison.

The 1- (4'-chlorobenzyl) -3-phenyl-4- (dläthylaraino) -piperazine can also be obtained from 1- (diethylaminoethyl) -2-ρ1ιβ ^ 1'-3 ^ β ^ - (4,4 ^! -Ohlorbenzyl ) -piperazine can be obtained by reduction.

Example 9: 1- (Diethylaminoethyl) -2-phenyl-4- (4 ^f -ethoxybenzyl) -piperazineϊ

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a) l-Diethylaminoethyl-S-phenyl - ^ - ketopiperazine.

144 g of 2-phenyl-3-ketopiperazine are refluxed for 24 hours with 121 g of diethylaminoethyl chloride, 150 ml of triethylamine and 1600 ml of acetone. The cooled solution, freed from triethylamine hydrochloride by filtration, is concentrated to dryness. The residue is dissolved in water, 40% sodium hydroxide solution is added and the floating oil is extracted with benzene. The benzene solution is dried over potassium carbonate, the benzene is distilled off and the residue is distilled. A pale yellow, viscous oil with a boiling point of 0.05 mm = 175 ° C. is obtained. The oil is crystallized twice from n-heptane. 145 g of the abovementioned compound from P. = 53-56 ^ are obtained (64 # of theory).

b) l-diethylaminoethyl-2-phenylpiperazine.

This compound is in the example 8, step a) given way.

e) i-Diethylaminoethyl ^ -phenyl ^ - (4'-ethoxybenzyl) piperazine.

40 g of the piperazine derivative obtained according to b) are mixed with 27 g of p-ethoxybenzyl chloride in 400 ml of acetone with the addition boiled under reflux for 12 hours by 50 ml of triethylamine. The formed triethylammonium hydrochloride is filtered off, the acetone is distilled off, the residue is taken up in benzene and the base is removed from the residue with dilute HCl detached. The base is set free with ammonia and extracted with benzene. The benzene solution will dried over potassium carbonate, the solvent evaporated and the residue distilled. 39 g light

50 yellow viscous oil with a boiling point of 0.05 mm = 200 ° C. was obtained (64 % of theory).

According to the method according to the invention, the the following 1,4-substituted-phenylpiperazines are produced: 909885/1771

1.) 1- (Diethylaminoethyl) - ^ - phenyl - ^ - keto - ^ - (4'-chloro- · benzyl) -piperazine; light yellow oil bp 0.03 now = 187-190 ⁰ Oj made from 1- (diethylaminoethyl) -2-phenyl-3-ketopiperrazine. ,

2.) 1- (3 ', 4'-dichlorobenzyl) -2-phenyl-4- (dimethylaminoethyl) -piperazinj light yellow oil; Bp. 0.01 mm = 190 ° Cj produced from 1- (3 ', 4 ^l -dichlorobenzyl) -2-phenyl-piperazine.

5.) 1- (3 ¹ * 4 '-Dichlorbenzyl) -2-phenyl-4 - (/ 3umorpholinoäthyl) -piperazinj light yellow oil; Bp. 0.04 mm = 230 ° C, produced from 1- (3 '* ^ ¹ -dichlorobenzyl) -2-phenyl-piperazine.

¹ ^ -) 1- (3 ¹ , 4'-dichlorobenzyl) -2-phenyl-4- (diethylaminopropyl) -piperazinej light yellow oilj b.p. 0.04 mm = 210 ^Q Cj made from l- (3 ', 4'- Dichlorobenzyl) -2-phenyl-piperazine. ,

5) 1- (4'-Benzyloxybenzyl) -2-phenyl-4- (diethylaminoethyl) -piperazinj light yellow oilj bp 0.01 mm = 235 ° Cj made from 1- (4'-benzyloxybenzyl) -2-phenyl-3-ketopiperazine (white crystals: m.p. = 207-211 ° C) above 1- (4'-Benzyloxybenzyl) -2-phenylpiperazine (white crystals: F. = 140 - 141 ° C).

6.) 1- (3 ', 4', 5 '-Trimethoxybenzyli - ^ - phenyl ^ - (diethylaminoethyl) - piperazinej light yellow oilj Bp. 0.0> mm β 20Q ° Gj made from l- (3 ^, 4 ^1, 5 ^l -Trimethoxybenayl) -2-phenyl-3-ketopiperazine (white crystals: mp = I56 - 157 ° C) for 1- (3 '* ^ ¹ »5 ^I -Trimethoxybenzyl) -2-phenylpiperazine (yellow oil : Bp. 0.08 mm «185-195 ° C).

7.) 1- / ~ 4 ^M -methoxyphenylpropyl (1 ') J7 ~ 2-phenyl-4- (diethyl-aminoethyl) -piperazine:

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'2 ^H 5

light yellow oil; Bp, 0.01 mm = 180-190 ° C made from 1 - £ P \ "-methoxyphenylpropyl (1 'J7 ~ 2-phenyl-j5-ketopiperazine (white crystals: P. = 109-110 ° C) above i - £ "4 ^IT -Methoxyphenylpropyl (1 ') _J7-2-phenylpiperazinj (light yellow oil; b.p. 0.05 mm = 1? 6 ^° C).

The new compounds obtainable according to the invention or their pharmacologically usable acid addition salts are anticoagulants. They have been found to show a prolonged clotting time when administered orally or parenterally and inhibit platelet aggregation (as induced by the supply of adenosine phosphate) when added to platelet rich plasma. These compounds may be used to achieve pharmacological effects over a wide dosage range, for example, in amounts of about 2 to 6o mg per kg of body weight per day by oral administration, and in somewhat lower amounts for parenteral administration tral W. You can use particular application

found in the treatment of thrombotic diseases, especially of the arterial system, e.g. to prevent thrombosis of the coronary or cerebral arteries. These anticoagulants can in the form of dosage units, e.g. together with a significant amount of a pharmaceutical Carrier containing about 50-500 mg of the anticoagulant contains, are administered.

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Example 10: ^{1- (4 t} -chlorobenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine.

A.) ^{1- (4!} -Chlorobenzyl) -2-phenyl-4- £ n [ ^jS - ⁿ y ^drox y) ~ ^{ä1; n} yi7-piperazine. ' ~

₂
Cl- / V ^ -CH ₂ -I / ^^: N-CH ₂ -CH ₂ -OH

a) 30 g of 1- ( ¹ S -'-chlorobenzyl) -2-phenyl-piperazine, prepared according to Example 2, Section E ₁ ), 20 g of ethylene chloride, 20 g of triethylamine and 250 saline of methyl ethyl ketone are refluxed for 24 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off, the filtrate is concentrated in vacuo, the residue is taken up in benzene * the benzene solution is washed with water and dried over anhydrous potassium carbonate. After evaporation of the benaol, the residue is distilled in vacuo, a yellow zMhes oil _{passing over at a boiling point of 0} Ω Ql mni = 195 ° C. It is crystallized from isopropanol and then from n-heptane at a temperature of 91-94 ° C., yield = 22 g.

b) 28.6 g of 1- (4 ⁸ -chlorobenzyl) -2-phenyl-piperazine, 6.0 g of ethylene oxide and 200 ml of methanol are left to stand sealed for 4 days at room temperature. The methanol is then distilled off and the residue is distilled in vacuo; Kp _{n Λ,} "_ -. 195 ° C. It is sswelmal from n-heptane umkristallisierto thereby obtaining a product with a mp ■ m 91 - 94 g C erhältj yield» 19.

909885/1771

ο) 50 gl - ^ - caalorbenzylJ ^ -phenyl-plperazine are dissolved in 100 ml of dioxane. 31 g of acetylglycolic acid chloride, dissolved in 50 oil of dioxane, are added to this solution. It is refluxed for 2 hours. The dioxane is evaporated off in vacuo and the residue is taken up in benzene! the benzene solution is washed with 10 # NaOH and dried over anhydrous potassium carbonate. After the solvent has been distilled off, the residue is recrystallized three times from isopropanol. M.p. = 136-157 ° C j Yield = 46 g.

44 g of the product obtained as stated above are in 120 ml of abs. Dissolved dioxane and form a suspension of 10 g LiAlH ^ In 700 ml abs. Ether slowly added dropwise refluxed for 2 1/2 hours. The reaction mixture is mixed with 10 ml of 15 # NaOH, 10 ml of water, 30 ml of 15 # NaOH and 20 ml of water · -decomposed, the precipitated inorganic The substance is filtered off and the solvent is distilled off in vacuo. The residue is recrystallized three times from n-heptane. P. = 91-94 ° Cj Yield = 17 g.

B,) ^{1- (4 f} -chlorobenzyl) -2-phenyl-4 - ^ (ß-chloro) -ethyl_7-piperasine hydrochloride.

N-CH ₂ -CH ₂ -Cl

24 gl "(4 ^I -Chlorbenzyl) -2-phenyl-4- / TSS-hydroxy) -äthyl_7-piperazln'werden dissolved in 150 ml of chloroform and added dropwise to a solution of 15 g of thionyl chloride in 150 ml of chloroform. After boiling under reflux for 5 hours, the solvent was driven off in vacuo on a water bath, whereupon abs. alcoholic hydrochloric acid this distilled off. The crystallized residue is from abs. Alcohol encapsulated. M.p. = 178-195 ° G (decomp.) J Yield> 30 g.

9C9885 / 1771

C.) ^{1- (4 l} -chlorobenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine.

20 g of 1- (4'-chlorobenzyl) -2-phyl-4- (S-chloroethyl) piperazine hydrochloride, 14 g of diethylamine and 200 ml of acetone are refluxed for 12 hours. After cooling, the precipitated diethylamine hydrochloride is filtered off with suction and the solvent in the filtrate is driven off in vacuo. The residue is distilled. 15 g of light yellow oil, bp. 06 mm ^{a 1} ^ ^{0 c,} are obtained. This product is identical to the product obtained according to Example 2 b.

Example 11 s l- (4 ^I -chlorobenzyl) »2-phenyl-4- ^"

(4 ^M -methyl) -piperazinoäthyI- (1) _7-piF ^e ^ a ⁱⁱ i «· a

, CHVt -CH ^ ^ fCH ₀ -CH ₀

.H-CH ₂ -CHg-IK ** "" ^ N-CH ₅

"CH ₂ CH ₂ -CH ₂

47 g of l- (4'-chlorobenzyl) »2-ph®nyl-4- (ß-chloroethyl) -piperazine-hydrochlorM, 16.5 g of N-methylpiperazinj, 75 ml of triethylamine and 300 ml of methyl ethyl ketone are taken for 12 hours Refluxed. After cooling, the precipitated triethylamine hydrochloride becomes suctioned off and the solvent was distilled off in vacuo. The residue is taken up in benzene with Washed with water and dried over anhydrous potassium carbonate. The solvent is distilled off and the residue is dissolved in abs. Alcohol ingested. One relocates with abs. alcoholic hydrochloric acid, the hydrochloride salt precipitates. Mach cooling is sucked off, with abs. Alcohol washed and dried. P. = 250-269 ° C (dec.).

To prepare the free base, the hydrochloride is dissolved in mass and the base is set free with ammonia. It is taken up in benzene and dried over anhydrous potassium carbonate. The solvent is evaporated and the residue is distilled. Kp. _{Q 01} , ^, = 220-223 ° 0 $ Yield = 30 g.

909885/1771

Example 12: l- (4 ^l -chlorobenzyl) -2-phenyl-4 (5 ^M -keto) -piperazinoäthyl- (1) ^ / -

H ₂ -CH ₂

25 g of 1- (4 ^f -chlorobenzyl) -2-phenyl-4- (ß-chloroethyl) piperazine hydrochloride, 7 * 3 g of monoketopiperazine, 200 ml of methyl ethyl ketone and 200 ml of triethyl araine are refluxed for 24 hours. The precipitated triethylamine hydrochloride is filtered off with suction, the solvent is expelled, the residue is taken up in benzene, washed with water and dried over anhydrous potassium carbonate. After the solvent has been distilled off, the residue is distilled.

Kp · η λ £ «m," 230 - 250 ° C (with little decomposition), u, Up mm

The distillate is taken up in ether, extracted with about 0.5N hydrochloric acid, the hydrochloric acid extract is filtered through charcoal and the base is released with ammonia. The base is taken up in benzene, dried over anhydrous potassium carbonate and, after the solvent has been driven off, the residue is distilled from a bulb tube. ^Kp * 0 005 mm ™ ²² ^ ~ ² ^ ° ^ (bath temperature). Very tough, brownish 01.

909885/1771

Claims (21)

- 25 claims 1. New 1,4-substituted Pheny! Piperazines of the general formula Z. wherein the remainder A-B represents the moiety -C it "2 stands, Χ, Y and Z, which can be the same or different, each represent a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group or a phenyl-substituted lower alkoxy group, η is an integer from 1 to 3 and R is dimethylaminoethyl, diethylaminoethyl, dipropylaminoethyl -, Dimethylaminopropyl, diethylaminopropyl, dipropylaminopropyl, piperidinoethyl, morpholinoethyl, dimorpholinopropyl, pyrrolidinoethyl, piperazinoethyl, 3'-ketopiperazinoethyl or N'-alkylpiperazinoethyl radical symbolizes,
and their salts. 2. 1- (4-chlorobenzyl) -2 ~ phenyl-5-keto-4- (diethylaminoethyl) piperazine and its salts. . 3. 1- (4 '"chlorobenzyl)" 2 = "phenyl-4- (diethylaminoethyl) -pipera zin and its salts. • 909885/1771 4. 1- (J ¹ , * ¹ -Diehlorbenzyl) -a-phenyl ^ - (diethylaminoethyl) pip'erazine and its salts. 5. 1 -C (* '-Methoxyphenyl) -äthyl_7-2-phenyl-4- (diethylaminoethyl) -piperazine and its salts. 6. 1 - ^ "3" -Phenylpropyl ~ (l) _r 7-2-phenyl-4- (diethylaminoethyl) -piperazine and its salts. 7. 1- (4'-Chlorobenzyl) -2-phenyl-4- (piperidinoethyl) piperazine and its salts. 8. l- (4'-chlorobenzyl) -2-phenyl-4- ^ ~ l ^n, 3 ⁿ -dimorpholinopropyl- (2 ") ~ 7-plperazin and its salts. 9. 1- (4 ^l -chlorobenzyl) - '5-phenyl-4- (diethylaiainoäthyl) -piperaziri and its salts. 10. 1 - (Diethylaminoethyl) -2-phenyl-4- (4 ¹ -ethoxybenzyl) piperazine and its salts. 11. 1 - (Diethylaminoethyl) -2-phenyl - ^ - keto ^ - (4'-chlorobenzyl) piperazine and its salts. 12. 1- (3 ', 4' -Dichlorobenzyl) -2-phenyl-4- (dimethylaminoethyl) piperazine and its salts. 1 - (3 ^! * 4 '-Diehlorbenzyl) -2-phenyl-4- (ß-morpholinoethyl) piperazine and its salts. 14. 1- (3 ^!, 4 ¹ -Dichlorobenzyl) -2-phenyl-4- (diethylaminopropyl) piperazine and its salts. 15. 1- (4 ^! -Benzyloxybenzyl) -2-phenyl-4- (diethylaminoethyl) piperazine and its salts. 9 0 9885/17 16. 1- (3 ^! Λ ^% , 5'-trimethoxybenzyl) -2-phenyl-4- (diethylaminoethyl) -piperazln and its salts. 17. l - ^ "- methoxyphenylpropyl- (1 '27-2-phenyl-4- (diethylaminoethyl) piperazine and its salts. 18. 1- (4 ■ -chlorobenzyl) -2-phenyl-4- (pyrrolidinoethyl) -pipe razln and its salts. 19. l- (4'-Chlorobenzyl) -2-phenyl-4 - ^ "(4" -methyl) -piperazinoäthyl- (l) 7 "Piperazln and its salts. 20. 1- (4'-Chlorobenzyl) -2-phenyl-4 - ^ "" (3 "-keto) -piperazinoethyl- (1) _7-PipePazin and its salts. 21. Anticoagulants labeled duroh one
Content of one or more compounds according to the
previous claims. 909885/1771