NO162907B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BIS (PIPERAZINYL RESP. HOMOPIPERAZINYL) ALKANES. - Google Patents

Abstract

1. Bis-(piperazinyl- or homopiperazinyl) alkanes of the general formula I see diagramm : EP0122488,P21,F1 wherein R1 , R2 , R3 and R4 which may be identical to or different from each other, are each hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyl, alkoxy having 1 to 4 carbon atoms, alkanoyloxy having up to 4 carbon atoms, halogen, trihalomethyl, di-C1-4 alkylamino, C1-4 alkoxycarbonyl, nitro, cyano or acyl having 1 to 3 carbon atoms ; R5 and R6 , which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, C1-4 alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl, R7 and R8 are each hydrogen or methyl ; j and k are integers from 0 to 3, their sum being no more than 4 ; m and n are integers from 0 to 3, their sum being no more than 4 ; A is -CH2 - or -CH2 CH2 - ; or R5 and R7 together or R6 and R8 together are oxo, provided k or m is other than O ; or R5 and R7 together and R6 and R8 together are oxo, provided k or m are other than O ; R9 and R10 , which may be the same or different, represent hydrogen or from one to four methyl substituents on the carbon atoms of the piperazine ring (A = -CH2 -) ; R11 , R12 , R13 and R14 , which may be identical to or different from each other, are each hydrogen or methyl ; or R11 and R12 together and/or R13 and R14 together are oxo ; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxy-substituted with the proviso that when A = -CH2 -, R1 to R14 are hydrogen and j, k, m and n are each zero, then X cannot be 1,2-ethylenediol, and physiologically acceptable acid addition salts thereof.

Description

This invention relates to the production of new bis-(piperazinyl-resp. homopiperazinyl)-alkanes and their physiologically compatible acid addition salts, which can be used in pharmaceutical preparations and are suitable for use as anti-allergic and anti-inflammatory agents.

State of the art

Connections with the formula

where n means one of the numbers 2, 6, 8, 9 or 10, is described by S. Chiavarelli, P. Mazzeo, F. Costa and A.M. Russo in Farmaco, Ed. Pollock. 20, 229 (1965); they have a curare-like effect. J. van Alpen describes in Ree. Trot. Chim. 55, 835 (1936) synthesis of polyamines with the formulas

without reference to any biological effect.

The work of C.B. Pollard, W.M. Lauter and N.O. Nuessle in J.Org. Chem. 24, 764 (1959) deals with the preparation of compounds of the formula

where R means hydrogen, alkyl or halogen. Here, too, there is nothing about the effect. Belgian Patent No. 633,453 describes compounds of the formula

where R is halogen or alkoxy, with antimalarial, anthelmintic and amoebicidal action.

Finally, M.J. describes Dorokhova, V.A. Chernow, S.M. Minakova, O.Y. Tikhonova and A.N. Zamskaya, Khim.- Farm. Zh., 10,

36 (1976), (C. A. 85, 78079) compounds of the formula

where n means one of the numbers 2, 3, 6 or 10. These compounds serve as starting materials for the compounds of the general formula VI.

The invention

The present invention relates to the preparation of new bis-(piperazinyl or homopiperazinyl)alkanes with the general formula

where R^, R2, R^ and R^, which may be the same or different

equal, means hydrogen, an alkyl group of 1 to 4 carbon atoms, a hydroxy group, an alkoxy group of 1 to 4 carbon atoms, an acyloxy group of 1 to 4 carbon atoms, halogen, trihalomethyl, di-C^-C^-alkylamino, C^-C 3-Alkoxycarbonyl, nitro, cyano or acyl having 1 to 3 carbon atoms,

and R 8 , which may be the same or different, means hydrogen, methyl, hydroxy, carboxy, C 1 -C 4 -alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl;

RQ and R^q are hydrogen or methyl;

j and k mean whole numbers from 0 to 3, but together no more than 4;

m and n mean whole numbers from 0 to 3, but together no more than 4;

A means -CH2~ or -CH2-CH2~; or

R^ and Rg together or Rg and R^q together mean oxo, med

the proviso that k or m is different from 0; or

R1^ and R12' which may be the same or different, mean hydrogen or 1 to 4 methyl substituents on the carbon atoms of a piperazine ring (A = -CH1,-);

R13' R14' R15 °9 <R>16' SOm ^an be Uke or different, means hydrogen or methyl; or

R^2 and R14 together and/or R^5 and R1g together mean oxo; and

X means an alkylene chain of 1 to 2 carbon atoms, optionally substituted with hydroxy, with the proviso that when A is

-CH2-, R, R2, R^, Rg and R^-R^g are hydrogen and j, k, m and n are

0, X cannot mean 1,2-ethylenediol, and their physiologically compatible acid addition salts.

A preferred subgroup consists of compounds of the general formula where j, k, m and n are each 0, 1 or 2;

1*2 and is hydrogen, chlorine, methyl or lower alkoxy;

R^ and Rg are both hydrogen, or if k is different from 0,

one of the residues R.^ and Rg is hydrogen and the other is hydroxy, or, if j and k = 0, one of the residues R-, and Rg is hydrogen and the other -CgH^-R-j,

or, if k is different from 0, both residues R 1 and R 2 together are oxo;

R13'<R>14' R15 and <R>16' which may be Uke or different, are hydrogen or methyl, or

R.j ^ and R-j 4 together and/or R^ ^ and R.sub.1 g together are oxo;

Rg and R^q are both hydrogen or, if m is different from 0, one of the residues Rg and"S^ is hydrogen and the other is hydroxy, or one of the residues Rg and R^q is hydrogen and the other -CgH^- Rg or -COO-(alkyl of 1 to 4 carbon atoms), or, if m is different from 0, both residues Rg and R^q together are oxo, and

X is an alkylene chain with 1 to 2 carbon atoms optionally substituted with hydroxy,

and their physiologically compatible acid addition salts. Compounds of the general formula are particularly preferred

where R^ ^ and R^ are hydrogen or together oxo; R 1 is hydrogen or hydroxy; '15 and R^ g is hydrogen or the same oxo; and a and b are each 1,2,3 or 4, and their pharmaceutically acceptable acid addition salts. Particularly preferred single compounds are: 1,3-bis [4-(4-chlorobenzyl)-1-piperazinyl] propane, 1,3-bis [4-(4-chlorobenzyl)-1-piperazinyl]-2-hydroxypropane, 1, 3-bis[4-(4-chlorobenzyl)-1-piperazinyl)-1,3-dioxopropane, 1,3-bis[4-(4-chlorophenethyl)-1-piperazinyl]propane, and 1,3-bis[ 4-(3-[4-chlorophenyl-propyl)-1-piperazinyl]-propane.

The new compounds can be produced by different methods:

Procedure A

Reaction of one equivalent of a compound of the general formula where R-, 3, R14» <R>15' R16 and X have the meaning given above, and Y and Z mean reactive groups, which react with an amine to form a carbon-nitrogen bond, e.g. chlorine, bromine, iodine, activated ester, hydroxy, sulfuric acid ester, sulfonic acid ester and the like, with at least two equivalents of a compound of the general formula

where , R2, R7, Rg, R^, j, k and A have the meaning indicated above.

By this method, only symmetrical compounds of formula I are obtained.

Procedure B

Reaction of a compound with the general formula

where R1 , R2, r7, Rgf Rn, <r>13, R14, R15, R16, X, Y, j, k and A have the above meaning, with a compound of the general formula

where R^, Rg, Rg, R-j^q, R^2' m' n °9 A ^are ^a meaning given above.

By this method, both symmetrical and asymmetrical compounds with the general formula I can be obtained.

Procedure C

Compounds of the general formula I which are symmetrical with respect to the central group X can be prepared by reacting a compound of the general formula

where R-, 1 , Ri2' <R>13' <R>14' <R>15' <R>16' X and A have ^a above given_ meaning, with a compound of the general formula

where R^ , R2, Ry, Rg, Y, j and k have the meaning indicated above.

Procedure D

Such compounds with the general formula I where X means a carbinol can also be prepared by reacting a compound with the general formula where R-^, <R>14', R15 and R16 have a meaning indicated above, g means hydrogen or a lower alkyl residue, and Y has the same meaning as in formula II,

with a compound of the general formula V.

The condensation reactions described under methods A to D can be carried out in the presence or absence of a solvent. Aqueous or organic, inert solvents can be used, the choice of solvent being dependent on the nature of the reaction components. Examples of such solvents are: dimethylsulfoxide, dimethylformamide, dioxane, ethoxyethanol and alkanols with up to 5 carbon atoms, with or without the addition of water; aromatic hydrocarbons can also be used. Preferably, the reaction is carried out in the presence of an acid binding agent such as triethylamine, an alkali metal carbonate or an alkali metal hydroxide.

The reaction temperature depends on the starting compounds

and of the solvent used for this reaction,

and lies between room temperature and the reflux temperature of the reaction mixture. The reaction time is temperature dependent and is from a few minutes to several hours.

A final product of the general formula I, where R^ and/or Rg is hydroxy, can be prepared by hydrogenating a compound where R^ and Rg and/or Rg and R^q together mean oxo, with common hydrogenating agents such as sodium borohydride on i and known manner. The corresponding hydroxy compound is thus obtained, whose hydroxy group can then be alkylated or acylated by usual methods.

The compounds of the general formula I are basic and

thus forming addition salts with inorganic or organic acids. Examples of non-toxic, physiologically compatible acid addition salts are those obtained by reaction with a

hydrohalic acid, preferably hydrochloric or hydrobromic acid, with nitric acid, sulfuric acid, o-phosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid, acetic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

The starting compounds for methods A to D are known compounds or can be prepared by known methods per se.

E.g. are compounds of the general formula III described in British Patent No. 480,358 and in J. Am. Chem. Society, 66,

263 (1944).

Syntheses of compounds of the general formula IVT are known from numerous publications, e.g. from Heiv. Chim. Acta 41, 1072 (1958) or Monatshefte 87, 701 (1956).

The compounds of the general formula VI are described in British Patent No. 480,358 and Khim.-Farm. Zh. 10, 36 (1976), cited in CA. 85, 78079.

The following examples shall serve to further illustrate the invention: Example 1

1,3-bis-[4-(4-chlorobenzyl)-1-piperazinyl]-propane tetrahydrochloride

A mixture of 10.5 g of 1-(4-chlorobenzyl)-piperazine, 9.5 g of 1-bromo-3-chloropropane and 100 ml of ethanol is heated for 17 hours under reflux. The solvent is then removed by rotary evaporation, and the remaining oil is mixed with 200 ml of 1 M dibasic potassium phosphate. Solid, tribasic sodium phosphate is added until a pH value above 9 is achieved. This mixture is extracted 5 times with 50 ml of ether, the ether is evaporated, the residue is acidified with 100 ml of 2M phosphoric acid and filtered. The aqueous filtrate is made basic with 2N caustic soda, extracted on

new with 250 ml of ether and dried over magnesium sulphate. After introduction of gaseous hydrogen chloride and recrystallization from ethanol/water, 5.8 g (39% of the theoretical) of the title compound are obtained in the form of white crystals with m.p. 261-274°C (decomp.).

Example 2

1, 3- bis- [. 4-(4-chlorobenzyl)-1-piperazinyl]-2-hydroxypropane

A mixture of 4.4 g of epichlorohydrin, 20.1 g of 1-(4-chlorobenzyl)-piperazine, 6.0 g of triethylamine and 50 g of ethanol is heated for three days under reflux. The solvent is removed from the reaction mixture by rotary evaporation, and the residue is made basic with 2N sodium hydroxide solution and extracted 5 times with 100 ml of ether each time. After drying the ether extract over magnesium sulfate and evaporating the solvent, an oil is obtained which solidifies on standing. After recrystallization from hexane, 18.6 g (82% of the theoretical) of 1,3-bis-[4-(4-chlorobenzyl)-1-piperazinyl]-2-hydroxypropane are obtained in the form of colorless crystals with m.p. 85-86.5°c.

Example 3

1, 4-bis L4-(4-chlorobenzyl)-1-piperazinyl]-butane hemihydrate

A mixture of 2.2 g of 1,4-dibromomutane, 4.2 g of 1 -(4-chlorobenzyl-piperazine, 2.8 g of anhydrous potassium carbonate and 20 ml of ethanol is heated for 18 hours under reflux. The solvent is then evaporated under reduced pressure, and the remaining oil is heated for 16 hours to 160° C. Then the oil is dissolved in 50 ml of hot water and extracted three times with 80 ml of ether each time. The ether extract is evaporated and the remaining oil is chromatographed on a silica gel column (eluent methylene chloride/methanol/ammonium hydroxide 45:5:1).The obtained brown solid mass is dissolved in acetone, and with water the title compound is precipitated in the form of white crystals with m.p. 101-103°C.

Example 4

1, 3- bis-(4- benzyl- 1- piperazinyl)- propane- tetrahydrochloride

A mixture of 7.0 g of 1-benzylpiperazine, 3.2 g of 1-bromo-3-chloropropane, 4.0 g of triethylamine and 100 ml of ethanol is heated for 2 1/2 hours under reflux. The reaction mixture is then poured into 1 liter of ether, and the precipitated triethylamine salt is filtered off. The filtrate is evaporated, and the remaining yellow oil is dissolved in 100 ml of heptane and filtered. The solvent is removed by rotary evaporation, and the residue is dissolved again in 150 ml of ether. By adding an excess of anhydrous hydrochloric acid, 8.8 g (82% of the theoretical) of the title compound are obtained in the form of white crystals with m.p. 250-265°C.

4

Example 5

1,3-bis-[4-(4-fluorobenzyl-1-piperazinyl]-propanetetrahydrochloride).

a) A solution of 29 g of p-fluorobenzyl chloride in 50 g of ethanol is added dropwise to a stirred solution of 34.4 g of piperazine

in 150 g of ethanol. With the help of a cold water bath, the reaction

the temperature of 20°C. The reaction mixture is stirred for a further 1 1/2 hours and then poured into 2 liters of ether. The precipitated piperazine hydrochloride is filtered off, and the filtrate is evaporated to an oily residue which is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1).

After working up the desired fractions, 21.7 g (56% of the theoretical) of 1-(4-fluorobenzyl)-piperazine are obtained in the form of a colorless liquid. b) A mixture of 5.8 g of 1-(4-fluorobenzyl-piperazine, 3.2 g of 1-bromo-3-chloropropane, 4.0 g of triethylamine and 50 ml of ethanol is heated for 3 hours under reflux and then poured into 1 liter of ether. The precipitate is filtered off, and the filtrate is evaporated to an oil. This oil is dissolved in 100 ml of ether, and with an excess of anhydrous hydrochloric acid the tetrahydrochloride is precipitated, which after recrystallization from ethanol/water is obtained in a yield of 3.3 g (29% of the theoretical) in the form of white crystals with mp 228-237°C (decomp.).

Example 6

1,3-bis-[4-(4-chlorobenzyl)-1-piperazinyl]-1-oxo-propane trihydrochloride

A mixture of 2.0 g of 1-(4-chlorobenzyl)-piperazine, 1.0 g of triethylamine, 20 g of xylene and 0.8 g of 3-bromopropionyl chloride is heated for 18 hours under reflux, and the reaction mixture is filtered, and the filtrate is added to an excess of ether saturated with hydrochloric acid until an acid reaction to litmus is obtained. The resulting precipitate is filtered and recrystallized from ethanol/water. 1.2 g (45% of the theoretical) of the title compound are obtained in the form of white crystals with a m.p. 222-250°C (decomp. ) .

Example 7

1,3-bis-£4-(4-chlorobenzyl)-1-piperazinyl]-1-methylpropane tetrahydrochloride hemihydrate

A mixture of 7.3 g of 1-(4-chlorobenzyl)-piperazine, 2.8 g of 1,3-dibromomutane, 11.0 g of triethylamine and 50 ml of ethanol is heated for 48 hours under reflux. The solvent is removed by rotary evaporation, the residue is mixed with 100 ml of toluene and heated for 24 hours under reflux. The mixture is then poured into 1 liter of ether and filtered. The filtrate is evaporated to an oil and this is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). The oil obtained is dissolved in 100 ml of ether and precipitated with an excess of anhydrous hydrochloric acid. The precipitate is dissolved in water and precipitated again by the addition of acetone; you get 1.2 g (11% of the theoretical) of the title compound in the form of white crystals with m.p. 228-232°C.

Example 8

1,3-bis-[4-(4-chlorobenzhydryl)-1-piperazinyl]-propane dihydrochloride dihydrate

A mixture of 7.4 g of N-(p-chlorobenzhydryl)-piperazine, 2.0 g of 1-bromo-3-chloropropane, 1.6 g of triethylamine and 25 g of ethanol is heated for 15 hours under reflux. The reaction mixture is made alkaline with 5N caustic soda and extracted five times with 50 ml of methylene chloride each time. The extracts are dried over magnesium sulphate, and ether saturated with hydrogen chloride is added until an acid reaction to litmus is obtained. The sedimentation of the crude product

(2.5 g = 27% of the theoretical) is filtered off and purified by dissolution in methylene chloride and subsequent precipitation by addition of ether. White crystals of the title compound with m.p. 163-196°C (decomp.).

Example 9

1 - [_ A-( 4-chlorobenzyl)-1-piperazinyl]-3-[_4-( 2-ethoxycarbonyl-2-phenylethyl)-1-piperazinyl]-propane tetrahydrochloride monohydrate

a) A mixture of 1.8 g of atropic acid ethyl ester and 0.9 g of piperazine is stirred in a round flask. After the exothermic reaction is

ceased, the mixture is heated to 80°C and stirred for a further 20 minutes. The reaction mixture is then allowed to stand overnight at room temperature. The obtained solid mass is chromatographed on silica gel, first using ether and then methylene chloride/methanol/ammonium hydroxide in the ratio 45:5:1 as eluent. 1-{2-ethoxycarbonyl-2-phenylethyl)-piperazine (0.75

g = 29% of the theoretical) comes from the column with the second eluent and is used without further purification for the subsequent reaction.

b) A mixture of 3.0 g of 1-chloro-3-[4-(4-chlorobenzyl)-1-piperazinyl]-propane, 3.5 g of triethylamine, 3.7 g of 1-(2-ethoxycarbonyl- 2-phenylethyl)piperazine and 50 ml of ethanol are heated for 2 hours under reflux and then poured into 1 liter of ether. The mixture is filtered, and the filtrate is evaporated. The remaining one

oil is purified by chromatography on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). You get 3.0 g of an oil that dissolves in 150 ml of ether; and by adding an excess of anhydrous hydrochloric acid, 3.4 g of a solid mass are obtained. This is again chromatographed on silica gel, with ether being used as the first eluent, as well as a mixture of methylene chloride/methanol/ammonium hydroxide in the ratio 45:5:1. The product obtained is transferred to the hydrochloride as described above, dissolved in water, and by adding acetone the title compound is precipitated in a yield of 1.1 g (15% of the theoretical) with a m.p. at 198-201°C as white crystals.

Example 10

1 - [_4-(4-chlorobenzyl)-1-piperazinyl]-3-(4-phenacyl-1-piperazinyl)propane-tetrahydrochloride- monohydrate

A mixture of 4.1 g of 1-phenacylpiperazine, 5.7 g of 1-chloro-3-]_4-(4-chlorobenzyl)-1-piperazinyl]propane, 2.6 g of triethylamine and 35 ml of ethanol is heated for 5 hours under reflux cooling. The solvent is removed in a rotary evaporator, the residue is added to 150 ml of water, and the mixture is extracted three times with 150 ml of ether. The ethereal solution is evaporated, and the remaining oil is chromatographed on silica gel with the eluent methylene chloride/methanol/ammonium hydroxide (45:5:1); 7.0 g (50% of the theoretical) of crude 1-4-(4-chlorobenzyl)-1-piperazinyl-3-(4-phenacyl-1-piperazinyl)propane are obtained in the form of an oil. This oil is dissolved in 200 ml of ether, with an excess of anhydrous hydrochloric acid the hydrochloride is precipitated, the precipitate is dissolved in water, and by adding acetone the title compound is precipitated with a m.p. 211-218°C.

Example 11

1 - [_4-( 4-chlorobenzyl)-1-piperazinyl]-3-^4-(2-hydroxy-2-phenylethyl)- 1- piperazinyl] propane- tetrahydrochloride

A solution of 3.0 g of 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-(4-phenacyl-1-piperazinyl)propane in 50 ml of ethanol is mixed with 3.0 g of sodium borohydride. The mixture is stirred for 4 hours and unreacted sodium borohydride is then destroyed by the addition of 25 ml of acetone. The solvent is removed under vacuum, and 50 ml of water is added to the residue. The mixture is extracted three times with 250 ml of ether each time, the solvent is evaporated, and the remaining oil is chromatographed on silica gel with the eluent methylene chloride/methanol/ammonium hydroxide (45:5:1). The fractions containing the final product are collected, the solvent is evaporated, the remaining oil is dissolved in 100 ml of ether, and the hydrochloride is precipitated by adding an excess of anhydrous hydrochloric acid. After dissolution in water and removal with acetone, the final product is obtained in a yield of 0.65 g (16% of the theoretical) in the form of white crystals with m.p. 240-248°C (decomp.).

Example 12

1,3-bis-(4-phenacyl-1-piperazinyl)propane tetrahydrochloride monohydrate

A mixture of 6.1 g of 1-phenacylpiperazine, 2.4 g of 1-bromo-3-chloropropane, 3.1 g of triethylamine and 50 ml of ethanol is heated for 3 hours under reflux. The solvent is evaporated,

250 ml of water are added to the residue, and the mixture is extracted three times with 150 ml of ether each time. After evaporation of the ether, the remaining oil is chromatographed on silica gel with the eluent methylene chloride/methanol/ammonium hydroxide (45:5:1). The high-purity fractions are collected, the solvent is evaporated, the remaining oil is dissolved in 150 ml of ether, and precipitation is carried out with an excess of anhydrous hydrochloric acid. After dissolution in water and precipitation by addition of acetone, 1.3 g (14% of the theoretical) of the title compound with m.p. 194-204°C in the form of white crystals.

Example 13

1 , 3-bis-[^4-(2-phenyl-2-hydroxyethyl)-1-piperazinyl] propane tetrahydrochloride

2.5 g of 1,3-bis(4-phenacyl-1-piperazinyl)propane in 50 ml of ethanol are mixed with 2.5 g of sodium borohydride and stirred for 4 hours. Excess sodium borohydride is destroyed by the addition of 25 ml of acetone, and the solvent is removed by rotary evaporation. 50 ml of water is added to the residue, and the mixture is extracted three times with 150 ml of ether each time. After evaporation of the ether, the remaining product is chromatographed on silica gel with the eluent methylene chloride/methanol/ammonium hydroxide (45:5:1). The oil obtained is dissolved in 100 ml of ether, and by adding an excess of anhydrous hydrochloric acid, the title compound is precipitated with a yield of 0.75 g (22% of the theoretical) with m.p. 233-240°C in the form of white crystals.

Example 14

1,3-bis-(4-phenethyl-1-piperazinyl)-propane dihydrochloride dihydrate

A mixture of 5.7 g of 1-phenethylpiperazine, 2.4 g of 1-bromo-3-chloropropane, 4.1 g of triethylamine and 30 ml of ethanol is heated for hours under reflux. Then 50 ml of water is added, the mixture is evaporated to approx. 40 ml by rotary evaporation,

and this mixture is extracted three times with 150 ml of ether each time. The combined extracts are evaporated, the remaining brown oil is dissolved in 150 ml of ether, and the hydrochloride is precipitated by adding an excess of anhydrous hydrochloric acid. It is dissolved in water, and by adding acetone 3.1 g (37% of the theoretical) of the title compound with m.p. 210-225°C as white crystals.

Example 15

1,3-bis-[_4-(4-chlorobenzyl)-1-piperazinyl]-1,3-dioxopropane dihydrochloride monohydrate

A mixture of 4.2 g of 1-(4-chlorobenzyl)piperazine, 1.4 g of malonic acid dichloride, 10 g of methylene chloride and 2.0 g of triethylamine is stirred for 60 hours. The reaction mixture is made alkaline with 2N caustic soda, the organic layer is separated, and the aqueous phase is extracted 3 times with 50 ml of ether each time, then 3 times with 50 ml of methylene chloride each time. The organic phases are collected and mixed with 100 ml of 2 N hydrochloric acid. The aqueous phase is separated and made basic with 2N caustic soda. The remaining oil is collected and extracted on silica gel with the eluent methylene chloride/methanol/ammonium hydroxide (200:5:1). The desired fractions are collected, the solvent is evaporated, the remaining oil is dissolved in 100 ml of ether, and precipitation is carried out with an excess of anhydrous hydrochloric acid. The precipitate is recrystallized from ethanol; you get 1.3 g (22% of the theoretical) of the title compound with m.p. 199-206°c in the form of slightly yellowish crystals.

Example 16

1 , 3- bis- |_ 4-( 4- chlorophenyl)- 1 - piperazinyl] - propane

A mixture of 6.7 g of 1-(4-chlorophenethyl)piperazine, 2.4 g of 1-bromo-3-chloropropane, 3.1 g of triethylamine and 20 ml of ethanol was heated

mes for 3 hours under reflux. The reaction mixture is diluted with 50 ml of water and evaporated to approx. 50 ml by rotary evaporation. The remaining mixture is extracted three times with 150 ml of ether each time, and the extract is evaporated.

The remaining colorless solid mass is recrystallized from heptane; you get 3.3 g (45% of the theoretical) of the title compound with m.p. 87-88°C in the form of white crystals.

Example 17

1,3-bis-1_4-(1-phenylethyl)-1-piperazinyl]-propane tetrahydrochloride

A mixture of 7.6 g of 1-(1-phenylethyl)piperazine, 3.2 g of 1-bromo-3-chloropropane and 50 ml of ethanol is heated for 5 hours under reflux. The solvent is then removed under vacuum, 50 ml of water is added, and the mixture is extracted three times with 150 ml of ether each time. The ethereal solvent is evaporated, and the remaining oil is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). The yellow oil thus obtained is dissolved in 150 ml of ether, and with an excess of anhydrous hydrogen chloride, 6.1 g (51% of the theoretical) of the title compound is precipitated; after recrystallization from ethanol/water, white crystals with m.p. 236-246°C (decomp.).

Example' 18

1,3-bis(4-chlorobenzyl)-2,5-dimethyl-1-piperazinyl]-propane tetrahydrochloride dihydrate

a) A solution of 16 g of p-chlorobenzyl chloride in 75 ml of ethanol is added dropwise to a solution of 25 g of 2,5-dimethylpiperazine in 75 ml of ethanol, the mixture is stirred overnight and filtered. thereafter. The solvent is removed by vacuum distillation, the residue is extracted three times with 350 ml of ether, the solvent is evaporated, and the remaining oil is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). One thus obtains 9.1 g (38% of the theoretical) 1-(4-chlorobenzyl)-2,5-dimethylpiperazine as a colorless liquid; it is used without further purification for the following turnover.

b) A mixture of 6.0 g 1-(4-chlorobenzyl)-2,5-dimethylpiperazine, 2.0 g 1-bromo-3-chloropropane, 3.2 g triethylamine and 50 ml ethanol

heated for 6 hours under reflux. The solvent is removed in vacuo, 50 ml of water is added to the residue, and the mixture is extracted three times with 150 ml of ether. The solvent is evaporated, and the remaining oil is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). The product obtained is dissolved in 150 ml of ether, and precipitation is carried out with an excess of anhydrous hydrochloric acid. The precipitate is dissolved in water, and by adding acetone 0.7 g of the title compound is obtained in the form of white crystals with m.p. 204-214°C.

Example 19

1, 3- bis- L4-(4- methoxybenzyl)- 1- piperazinyl]- propane

A mixture of 4.1 g of 1-(p-methoxybenzyl)piperazine, 1.6 g of 1-bromo-3-chloropropane, 25 ml of ethanol and 2.5 ml of triethylamine is heated for 5 hours under reflux. The solvent is removed in vacuo, the residue is mixed with 25 ml of water and extracted with ether. After evaporation of the solvent, a yellow oil is obtained which solidifies on standing. After two recrystallizations from heptane, 2.3 g (51% of the theoretical) of the title compound are obtained in the form of white crystals with m.p. 86-87°C.

Example 20

1,3-bis-[4-(3,4-dichlorobenzyl-1-piperazinyl]-propane tetrahydrochloride

A mixture of 5.2 g of 1-(3,4-dichlorobenzyl)-piperazine, 2.2 g of 1-bromo-3-chloropropane, 3.0 g of triethylamine and 20 g of ethanol is heated under reflux. After 1 hour, a further 0.06 g of 1-bromo-3-chloropropane is added, after another hour a further 0.06 g. The mixture is heated overnight under reflux, and then the solvent is driven off in vacuo; a rubbery, solid mass is obtained which is mixed with 150 ml of ether and filtered. The filtrate is dried over magnesium sulphate and then ether saturated with hydrogen chloride is added until the mixture reacts acidly to litmus. The precipitate obtained is dissolved in a little water, and concentrated hydrochloric acid is added drop by drop until a precipitate forms. The addition of the hydrochloric acid continues until no further precipitate is formed. After filtration and drying in vacuum, 4.5 g (44% of the theoretical) of the title compound are obtained in the form of white needles with m.p. 245-251°C (decomp.).

Example 21

1,3-Bis-[4-(2-chlorobenzyl)-1-piperazinyl]-propane tetrahydrochloride

A mixture of 8.4 g of 1-(2-chlorobenzyl)piperazine, 3.2 g of 1-bromo-3-chloropropane, 4.0 g of triethylamine and 30 g of ethanol is heated overnight under reflux. The solvent is then removed in vacuo, the residue is mixed with 150 ml of ether and filtered. The filtrate is dried over magnesium sulphate and then ether saturated with hydrogen chloride is added slowly until an acid reaction to litmus is obtained. The precipitate obtained is filtered, dried and weighed. 6.1 g (50% of the theoretical) of the title compound is obtained, which after recrystallization from ethanol/water is in the form of white crystals with m.p. 251-255°C.

Example 22

1,3-bis-{_4-(4-methylbenzyl)-1-piperazinyl]-propane tetrahydrochloride

A mixture of 5.7 g of 1-(4-methylbenzyl)piperazine, 2.4 g of 1-bromo-3-chloropropane, 25 ml of ethanol and 3.0 g of triethylamine is heated for 5 hours under reflux. The solvent is removed in vacuo, and the residue is mixed with 40 ml of water. The aqueous mixture is extracted three times with 150 ml of ether; and after evaporation of the ether, a light yellowish oil is obtained which solidifies on standing. This product is dissolved in 50 ml of ether and ether saturated with hydrogen chloride is added until an acid reaction to litmus is obtained. The obtained precipitate is dissolved in 20 ml of water, and by adding acetone the title compound is precipitated in a yield of 5.8 g (68% of the theoretical) in the form of white crystals with m.p. 245-252°C (decomp.).

Example 23

1 , 3-bis]_4-(3-chlorobenzyl)-1-piperazinyl]-propane dihydro chloride monohydrate

A mixture of 6.3 g of 1-(3-chlorobenzyl)piperazine, 2.4 g of 1-bromo-3-chloropropane, 50 ml of ethanol and 3.0 g of triethylamine is heated for 4 hours under reflux. Then add 70 ml. water, the mixture is evaporated to approx. 70 ml under vacuum,

and the aqueous mixture thus obtained is extracted three times with 150 ml of ether each time. After evaporation of the extract in vacuum, a reddish-yellow oil is obtained, which is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). The oil thus obtained is dissolved in 50 ml of ethanol and ether saturated with hydrogen chloride is added until an acid reaction to litmus is obtained. The precipitate is filtered off, dried and recrystallized from water. 5.6 g (68% of the theoretical) of the title compound are obtained in the form of white crystals with m.p. 248-257°C (decomp.).

Example 24

1,3-bis-[4-(3-^4-chlorophenyl)-propyl)-1-piperazinyl]-propane- tetrahydrochloride- monohydrate

a) A mixture of 40.6 g of 3-(4-chlorophenyl)propyl chloride, 130.0 g of anhydrous piperazine and 550 ml of ethanol is heated for 2 hours under

reflux cooling. The solvent is removed in vacuo, and

the residue is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). The desired fractions are collected and evaporated to an oil which is mixed with 1400 ml of 1N hydrochloric acid and then filtered. The filtrate is brought to pH 10 with concentrated aqueous sodium hydroxide solution and then extracted four times with 200 ml of ether each time. The extract is dried over magnesium sulphate and evaporated to an oil which solidifies on standing. The thus obtained 1-[_3-(4-chlorophenyl)propyl]piperazine with m.p. 54-62°C is used in the next step without further purification.

b) A mixture of 7.2 g of 1-[3-(4-chlorophenyl)propyl]piperazine,

2.4 g 1-bromo-3-chloropropane, 3.5 g triethylamine and 30 ml ethanol

heated for 6 hours under reflux. The solvent is then removed in vacuo, the residue is mixed with 40 ml of water, and extracted three times with 150 ml of ether each time. The extract is evaporated to a yellow oil which is chromatographed on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). 4.6 g (59% of the theoretical) of 1,3-bis-[/l-(3-^4-chlorophenyl}-propyl)-1-piperazinyl]-propane are thus obtained as a colorless oil. Dissolve 3.0 g of this oil in 100 ml of ether and add ether saturated with hydrogen chloride until an acidic reaction to litmus is obtained. The resulting precipitate is dissolved in 25 ml of water and acetone is added until the precipitation is complete. 2.7 g (41% of theoretical) of the title compound with m.p. 245-246°C (decomp.)

in the form of white crystals.

Example 25

1,3-bis-£4-(4-chloro-3-trifluoromethylbenzyl)-1-piperazinyl]-propane- tetrahydrochloride

A mixture of 11.5 g of 3-chloro-4-trifluoromethylbenzyl chloride, 5.3 g of 1,3-bis(1-piperazinyl)propane, 50 g of ethanol and 7.0 g of triethylamine is heated for 16 hours under reflux. The reaction mixture is then evaporated in vacuo, the residue is mixed with 150 ml of water, and the mixture is extracted five times with 100 ml of ether each time. The combined ether extracts are washed three times with 100 ml of 1 M sodium carbonate solution each time, dried over magnesium sulfate, filtered and evaporated to 6.8 g of a yellow oil. This oil is dissolved in 100 ml of hexane and filtered. The filtrate is extracted three times with 20 ml of a 2% aqueous acetic acid each time, whereby the desired product occurs in the 2nd and 3rd extracts (examination by thin-layer chromatography). These extracts are collected, made strongly alkaline with 2N caustic soda and extracted with 100 ml of ether/hexane (1:1). The extract is dried over anhydrous potassium carbonate, and then the solvent is evaporated. The remaining oil (2.6 g) is dissolved in 10 ml of methanol, and after the addition of 30 ml of ether saturated with hydrogen chloride, a white precipitate is obtained. A further 50 ml of ether is added, and the precipitate is filtered off and recrystallized from methanol.

The title compound is obtained in the form of colorless crystals with m.p. 265-268°C (decomp. > 250°C).

Example 26

1,3-bis-1_4-(4-hydroxybenzyl)-1-piperazinyl-propane

A mixture of 4.5 g of 1,3-bis [4-(4-methoxybenzyl)-1-piperazinyl] propane (see example 19) and 250 ml of 49% hydrobromic acid

heated for 2 hours under reflux, then cooled and diluted with 125 ml of water. The aqueous solution is filtered and brought to pH 8 with 2N caustic soda. This mixture is extracted three times with 150 ml of ethanol each time, the alcohol is removed

by rotary evaporation, and the residue is chromatographed on silica gel (eluent: methylene chloride with 1% ammonium hydroxide and 10% methanol). 1.3 g (31% of the theoretical) of the title compound with m.p. 197-201°C in the form of white crystals.

Example 27

1,3-bis-[4-(4-bromobenzyl)-1-piperazinyl]-propane tetrahydrochloride

A mixture of 3.8 g of 1-(4-bromobenzyl)piperazine, 7 g of ethanol, 1.2 g of 1-bromo-3-chloropropane and 1.6 g of triethylamine is heated for 18 hours under reflux. The solvent is removed by rotary evaporation, the residue is mixed with 50 ml of water and brought to pH 10 with 2N caustic soda. This mixture is extracted twice with ether (75 + 25 ml), the combined extracts are washed twice with 25 ml of water each time, dried over magnesium sulphate and filtered. This solution is added to ether saturated with hydrogen chloride until an acidic reaction is obtained, and the precipitate that has formed is filtered off and mixed with 100 ml of ethanol. The mixture is brought to reflux temperature and water is added dropwise until it has dissolved. On cooling, the end product crystallizes out and is filtered off. You get 4.2 g (81% of the theoretical)

of the title compound with m.p. 237-243°C in the form of white crystals.

Example 28

1,3-bis-[4-(4-chlorobenzyl)-1-homopiperazinyl]-propane tetrahydrochloride

A mixture of 4.5 g of 1-(4-chlorobenzyl)-homopiperazine, 1.6 g of 1-bromo-3-chloropropane and 20 g of ethanol is heated for 18 hours under reflux. The solvent is removed under vacuum,

and the remaining mixture is extracted three times with 75 ml of ether each time. After evaporation of the ether, an oil remains which is chromatographed on silica gel (eluent: methylene chloride containing 0.5% concentrated ammonium hydroxide and 2.5% methanol). The fractions containing the final product are collected, the solvent is evaporated, the remaining oil is dissolved in ether, and the solution is filtered. The remaining ether solution is added to ether saturated with hydrogen chloride until an acid reaction to litmus is obtained. The precipitate formed is dried; and one obtains 1.4 g (22% of the theoretical) of the title compound in the form of white crystals, which after recrystallization from aqueous ethanol show a m.p. at 218-224°C (decomp.).

Example 29

1,3-bis-[.4-(4-[4-chlorophenyl]-butyl)-1-piperazinyl]-propane tetrahydrochloride

a) A mixture of 26.4 g of 4-(4-chlorophenyl)butyl chloride, 86.1 g of anhydrous piperazine and 250 ml of ethanol is heated overnight under reflux. The solvent is evaporated, and the residue is chromatographed twice on silica gel (eluent: methylene chloride/methanol/ammonium hydroxide 45:5:1). The first fraction contains mainly excess piperazine, the second contains 15.2 g of 1-(4-chlorophenyl)-butyl]-piperazine as a colorless oil which solidifies on standing (m.p. 139-145°C). This crude product is used without further purification for the next step.

b) A mixture of 1.5 g of 1 - (_4-(4-chlorophenyl)butyl piperazine,

0.5 g 1-bromo-3-chloropropane, 0.7 g triethylamine and 10 g ethanol

heated overnight under reflux. After adding 3.5 ml of 2N caustic soda, the solvent is removed in vacuo. The residue is extracted with methylene chloride, and the extract is chromatographed on silica gel (eluent methylene chloride/methanol/ammonium hydroxide 90:10:1). The fractions containing the desired product are evaporated to an oil and this is dissolved in ether. After addition of ether saturated with hydrogen chloride, a precipitate of 0.7 g (31% of the theoretical) of the title compound is obtained as a light brown, solid mass which can be converted into white crystals with m.p. 213-217°C (decomp.).

Example 30

1,3-bis-L4-(4-acetoxybenzyl)-1-piperazinyl]-propane

A mixture of 2.0 g of 1,3-bis-[4-(4-hydroxybenzyl)-1-piperazinyl]-propane (see example 26), 1.0 g of pyridine and 50 g of acetic anhydride is stirred overnight at room temperature. The mixture is evaporated under vacuum to an amber oil which is mixed with 100 ml of phosphate buffer (pH 8) and extracted three times with 100 ml of ether each time. The extract is dried over magnesium sulfate and evaporated to a white, solid mass. After recrystallization from heptane, 1.9 g (78% of the theoretical) of the title compound are obtained in the form of white crystals with m.p. 102-105°C.

Example 31

1,3-bis-[4-(4-butoxybenzyl)-1-piperazinyl]-propane tetrahydrochloride

A mixture of 1.0 g of 1,3-bis^4-hydroxybenzyl)-1-piperazinyl]propane (see Example 26), 10 ml of 2N caustic soda, 0.2 g of tetra-butylammonium hydroxide (40% in water) and 5, 0 g of 1-bromobutane is heated for 3 hours on a steam bath. The mixture is then extracted three times with 75 ml of ether each time, dried over magnesium sulphate and evaporated to a colorless oil which solidifies on standing. This product is dissolved in 100 ml of ether and ether saturated with hydrogen chloride is added until precipitation ceases. After filtration, you get 1.4 g (91% of the theoretical) of the title compound, which after recrystallization from ethanol/water is in the form of white crystals with m.p. 207-218°C.

Example 32

1,3-bis-[4-(4-chlorobenzyl-2,3,5,6-tetramethyl-1-piperazinyl]-propane tetrahydrochloride

A mixture of 3 g of 1-(4-chlorobenzyl)-2,3,5,6-tetramethyl-piperazine, 1 g of 1-bromo-3-chloropropane and 1 g of triethylamine is heated for 24 hours in 20 ml of ethanol under reflux. The solvent is then removed in vacuo, the remaining oil is dissolved in water and extracted with ether. The ether extract is washed with water and dried over magnesium sulfate. The title compound is obtained from the ethereal solution by precipitation with an excess of ethereal hydrochloric acid and recrystallization from ethanol, in the form of white crystals.

Example 33

1 -[4-(4-Chlorobenzyl)-1-piperazinyl]-3- ^4-(2-carboxy-2-phenylethyl)- 1-piperazinyl]-propane tetrahydrochloride

A suspension of 340 mg of 1-[4-(4-chlorobenzyl)-1-piperazinyl]-3-[4-(2-ethoxycarbonyl-2-phenylethyl)-1-piperazinyl]-propane tetrahydrochloride in 10 ml of ethanol is added 1 ml of aqueous 5M caustic soda and heated for 1 hour under reflux. The reaction mixture is then evaporated to dryness under reduced pressure. The residue is mixed with 1N hydrochloric acid (3 ml), and this mixture is extracted twice with 10 ml of ether each time. The extract is discarded, and the pH value in the aqueous phase is adjusted to 5.5 med

1N hydrochloric acid. 10 ml of saturated sodium chloride solution are then added, and the mixture is extracted twice with 10 ml of butanol each time. The butanol extract is filtered and an excess of ethereal hydrochloric acid is added. The white precipitate is collected and recrystallized from

aqueous ethanol. You get 140 ml (40% of the theoretical) of the title compound in the form of white crystals with m.p. 230-245°C (decomp.).

Example 34

1 , 3-bis-[_4-(3-^4-Chlorophenyl-propyl)-1-homopiperazinyl]-propane-tetrahydrochloride

A mixture of 3.8 g of 1-[_3-(4-chlorophenyl)propyl)-homopiperazine, 1.2 g of 1-bromo-3-chloropropane, 1.8 g of triethylamine is heated in 10 ml of ethanol for 18 hours during reflux cooling. The reaction mixture is evaporated under reduced pressure, the residue is mixed with water and extracted with ether. The ether is evaporated, and the residue is chromatographed on silica gel (eluent methylene chloride/methanol/ammonium hydroxide 35:5:1). The oil obtained is dissolved in ether, and the title compound is precipitated with an excess of ethereal hydrochloric acid. After recrystallization from ethanol, 1,3-bis[_4-(3-{.4-chlorophenyl]-propyl)-1-homopiperazinyl]propane tetrahydrochloride is obtained in crystalline form.

Example 35

1,3-bis-[4-(4-chlorobenzyl)-1-homopiperazinyl]-1,3-dioxopropane dihydrochloride

To a solution of 2.2 g of 1-(4-chlorobenzyl)homopiperazine and 1 g of triethylamine in 10 ml of methylene chloride, 0.7 g of malonic acid dichloride is added in one go at room temperature, and the reaction mixture is heated for 1 hour under reflux. The solvent is driven off under reduced pressure, the residue is triturated with water, the crude product is extracted with methylene chloride and purified by chromatography on silica gel (eluent methylene chloride/methanol/hydroxylamine 200:5:1). The evaporated fractions are collected, the solvent is evaporated, the residue is dissolved in ether and an excess of ethereal hydrochloric acid is added, and the title compound is obtained in crystalline form.

The compounds of the general formula I and their non-toxic physiologically compatible acid addition salts have valuable pharmacological properties.

Especially due to their strong inhibition of mediator release in a number of cell systems, they have anti-inflammatory and anti-allergic properties in warm-blooded animals such as rats, and are therefore suitable for combating allergic disorders such as allergic asthma, rhinitis, conjunctivitis, hay fever , hives, food allergies and the like.

Mediator release from mast cells and basophils occurs in many allergic disorders and inflammations. The activity of substances that inhibit the non-cytotoxic exocytosis of such mediators can be investigated in in vitro models, which demonstrate the inhibition of mediator release from isolated cell systems, triggered by an antigen-antibody reaction.

The following table compiles the data showing the biological effect of some of the compounds produced according to the invention, in various investigations. The following cell systems are indicated in the table:

RPMC: rat peritoneal mast cell preparations

GPBL: guinea pig leukocytes enriched with basophils

HBL: human leukocytes enriched with basophils.

Theophylline and disodium cromoglycate (DSCG) serve as clinical standard substances.

For pharmaceutical use, the new compounds can be administered to warm-blooded animals topically, perorally, parenterally, rectally or by inhalation. The compounds are then available as active ingredients in common preparation forms, e.g. in compositions which essentially consist of an inert pharmaceutical carrier and an effective dose of the active substance.

Compounds of the general formula I which are administered orally may be in the form of syrups, tablets, capsules, pills and the like. Preferably, the preparations are used in a unit dose or in a form where the patient can take a single dose. Tablets, powders or pastilles can be prepared by mixing with excipients which are suitable for the preparation of solid pharmaceutical preparations. Examples of such excipients are different types of starch, lactose, glucose, sucrose, cellulose, calcium phosphate and lime. The compositions can also be in the form of capsules (e.g. of gelatin), which contain the active ingredient, or in the form of a syrup, a solution or suspension.

Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerol, saline solution, water, propylene glycol or sorbitol solution, which may have added flavoring or tartar

substances.

The new compounds may also be in the form of suppositories for rectal use or in the form of an aqueous or non-aqueous injection solution, a suspension or an emulsion in a pharmaceutically acceptable liquid, e.g. sterile, pyrogen-free water or an oil suitable for parenteral use or a mixture of liquids containing bacteriostatic agents, antioxidants, preservatives, buffer substances or solutions which cause the final solution to be isotonic; furthermore, thickeners, suspending aids or other pharmaceutically acceptable additives can be included. The application takes place in the form of single doses such as ampoules or available injection devices or in multi-dose containers, e.g. a bottle from which an appropriate amount can be withdrawn, or in solid form or in the form of a concentrate that can be used for the preparation of an injection solution.

The new compounds can also be used in the form of aerosols or solutions which are suitable for inhalation and which can be sprayed from a nebulizer, or in the form of a microcrystalline powder for inhalation either alone or in combination with an inert carrier, e.g. lactose. Particles of the active compounds with a diameter of less than 20 um, preferably less than 10 um, are suitably used here. If necessary, smaller quantities of other anti-allergic drugs, anti-asthmatics and bronchodilators can also be added, e.g. sympathomimetics such as isoprenaline, isoetarine, metaproterenol, salbutamol, phenylephrine, fenoterol and ephedrine, also xanthine derivatives such as theophyllines and aminophyllines or corticosteroids such as prednisolone and adrenergics such as ACTH.

For topical application to the skin, nose and eyes, they can

new compounds also exist in the form of an ointment, a cream, a liquid, a gel, an aerosol or a solution. Topical solutions for the nose and eyes can also contain, in addition to the new compounds, suitable buffer substances, bacteriostatic agents, antioxidants and viscosity-reducing agents,

in an aqueous carrier.

Examples of agents which increase the viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbitan esters or glycerol. Suitable bacteriostatic agents include benzalkonium chlorides, thimerosal, chlorobutanol or phenylethyl alcohol. Topical eye preparations can also be available in the form of ointments in a suitable, inert base, consisting of mineral oil, petrolatum, polyethylene glycols or lanolin derivatives together with bacteriostatic agents.

In the above-mentioned preparations, a suitable dose contains 0.005 - 500 mg of active ingredient. The effective dose of the new compounds depends on the particular compound used, the condition of the patient and the frequency and nature of use, but is usually between 0.0001 and 10 mg/kg body weight.

Usually, the pharmaceutical preparations are accompanied by a written or printed guide for the relevant medical application, in this case as an anti-allergic preparation for the prevention and treatment of e.g. asthma, hay fever, rhinitis or allergic eczema.

For the production of pharmaceutical preparations, the compounds of the general formula I are mixed in the usual way with suitable pharmaceutical carriers and flavoring substances, odorants and coloring substances and pressed, e.g. into tablets, filled into capsules or suspended or dissolved with the addition of suitable excipients, in water or in an oil, e.g. corn oil.

The new compounds can be used orally or parenterally

in liquid or solid form. For injection solutions, water is preferred, which contains suitable stabilizers,

dissolution promoting agents and/or buffer substances, which are usually used for injection solutions. Additives of this type include e.g. tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complexing agents (e.g. EDTA), antioxidants (e.g. sodium bisulfite, sodium metabisulfite or ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides.

Optionally, preservatives can be added, e.g. benzoic acid, methyl or propyl paraben, benzalkonium chloride or quaternary ammonium compounds.

Suitable solid carriers are e.g. starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silicic acid, dicalcium phosphate and high molecular weight polymers (e.g. polyethylene glycol).

Preparations for oral use may possibly contain odorants and/or sweeteners.

For topical application, the new compounds can also be used in the form of solutions, powders or ointments, and they are then mixed e.g. with physiologically compatible diluents or common ointment bases.

Claims (6)

1. Analogous process for the production of therapeutically active bis-(piperazinyl- or homopiperazinyl)alkanes with the general formula I where Ri, R2 » R4 and R5 which can be the same or different, means hydrogen, an alkyl group of 1 to 4 carbon atoms, a hydroxy group, an alkoxy group of 1 to 4 carbon atoms, an acyloxy group of 1 to 4 carbon atoms, halogen, trihalomethyl, di-C1-C4-alkylamino, C₁-C₄ alkoxycarbonyl, nit.ro, cyano or acyl of 1 to 3 carbon atoms; R 7 and R 8 , which may be the same or different, mean hydrogen, methyl, hydroxy, carboxy, C₁-C₁ alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl; R9 and R2. 0 means hydrogen or methyl; j and k mean whole numbers from 0 to 3, but together no more than 4; m and n mean whole numbers from 0 to 3, but together no more than 4; A means -CH2- or -CH2-CH2-; or R 7 and R 8 together or R 8 and R 8 together means oxo, with the proviso that k or m is different from 0; or Rll °9 R12 » which may be the same or different, means hydrogen or 1 to 4 methyl substituents on the carbon atoms of a piperazine ring (A = -CH2-); hydrogen or 1 to 4 methyl substituents on the carbon atoms of a piperazine ring (A = -CH2-); <R>13• R14 > R15 °9 R16> which may be the same or different, means hydrogen or methyl, or <R>^3 and R14 together and/or R15 and R^g together means oxo; and X means an alkylene chain with 1 to 2 carbon atoms optionally substituted with hydroxy, with the proviso that when A is -CH2-, Ri, R2, R4, R5 and R7-<R>16 is hydrogen and j, k, m and n is 0, X cannot be 1,2-ethylenediol, and their physiologically compatible acid addition salts, characterized in that a) for the production of symmetrical compounds with the general formula I, react a compound with the general formula where <R>13, <R>14, <R>15, Rig and X have the above meaning, and Y and Z mean reactive groups, with a compound of the general formula where R-1, R2, R7, Rg, R^, j, k and A have the meaning given above, or react with a compound of the general formula where Rlt R2, R7, Rg, Rn, <R>13, <R>14, <R>15. R3.6. X, Y, j, k and A have the meaning given above, with a compound of the general formula where R4, R5, <R>g, Rio»<R>12' m' n °9 A nar the meaning indicated above, or c) for the production of such end products of the general formula I which are symmetrical with respect to the central group X, reacts a compound with the general formula where R;li , R12 » R13 » R14 » <R>15» <R>16. X and A are as defined above, with a compound having the general formula wherein R1, R2. R7 » Rg, Y, j and k have the meaning indicated above, or d) for the preparation of such end products of the general formula I where X means a carbinol group, reacts a compound of the general formula where Ri3, <R>14, R15 and R16 have the above meaning, R 18 is hydrogen or a lower alkyl residue, and Y has the same meaning as in formula II, with a compound of the general formula V, and that an end product with the general formula I produced by methods a to d is optionally transferred in a manner known per se to a physiologically acceptable acid addition salt. 2. Process according to claim 1 for the production of 1,3-bis[4-(4-chlorobenzyl)-1-piperazinyl]propane and its physiologically compatible acid addition salts, characterized in that correspondingly substituted starting materials are used. 3. Process according to claim 1 for the production of 1,3-bis[4-(4-chlorobenzyl)-1-piperazinyl]-2-hydroxypropane and its physiologically compatible acid addition salts, characterized in that correspondingly substituted starting materials are used. 4. Process according to claim 1 for the production of 1,3-bis[4-(4-chlorobenzyl)-1-piperazinyl]-1,3-dioxopropane and its physiologically compatible acid addition salts, characterized in that correspondingly substituted starting materials are used. 5. Process according to claim 1 for the production of 1,3-bis[4-(4-chlorophenethyl)-1-piperazinyl]propane and its physiologically compatible acid addition salts, characterized in that correspondingly substituted starting materials are used. 6. Method according to claim 1 for the production of 1,3-bis[4-(3-[4-chlorophenyl]-propyl)-1-piperazinyl]-propane and its physiologically compatible acid addition salts, characterized in that correspondingly substituted starting materials are used.