DD219642A5 - PROCESS FOR THE PREPARATION OF BIS- (PIPERAZINYL- AND 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

Process for the preparation of new bis (piperazinyl or homopiperazinyl) alkanes -

Field of application of the invention

The present invention relates to the preparation of novel Bis (piperazinyl or homopiperazinyl) alkanes and their physiologically acceptable acid addition salts, which can be used in the form of pharmaceutical compositions as antiallergic and anti-inflammatory agents.

Known technical solutions Compounds of the formula

/ ~ \ / -Γ

N- (CH ₉ VN ²

wherein η is one of the numbers 2, 6j 8, 9 or 10 are described by U Ghiavarelli, P. Mazzeo, F. Costa and A. M. Russo in Farmaco, Ed. 20, 229 (1965); they have a curare-like effect.

J »van Alpen describes in Rec. Trav. Chira. ^, 835 (1936) the synthesis of polyamines of the formulas

GH ₂ -N

-CH ₂ -CH ₂ -OH ₂ -N

T / = N-CH,

without any indication of biological effectiveness «

The work of C "B · Pollard, W.M. Lauter and N · 0. Nuessle in J. Org. Chem. 2, 764 (1959) is concerned with the preparation of compounds of the formula

N N-GH ₀ -CH ₀ -CH ₉ -NN

where R is hydrogen, alkyl or halogen · Again, no information is given on its effectiveness «

Belgian Patent No. 633453 discloses compounds of the formula

N-CH ₀ -CH ₀ -CH ₀ -N

where R is halogen or alkoxy, claimed with antimalarial, anthelmintic and amoebic effect «

Finally, M. J, Dorokhova, V. A «Chemov, S · M. Minakova, 0. Y. Tikhonova and Α · Έ» Zamskaya »KMm. Farm. Zh ,, JO, 36 (1976), (C A. £ 8, 78079) Compounds of the formula

J O / ~~ "" V O Γ Il -ΝNH H \. -C- - C ^ ^CH 2 η "\ /

wherein η is one of the numbers 2, 3, 6 or 10. These compounds serve as starting materials for the compounds of general formula VI ^1.

Object of the invention

It is an object of the invention to enrich the state of the art with new effective drugs.

Essence of the invention

The invention has for its object to develop processes for the preparation of new bis (piperazinyl or homopiperazinyl) alkanes.

According to the invention, new bis (piperazinyl or homopiperazinyl) alkanes of the general formula are prepared

  '..' - 3a -. -, ':'

wherein R ^, Rg ₉ R ^, R ^, R ^ and Rg, which may be the same or different, hydrogen /, an alkyl group having 1 to 4 carbon atoms, the hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group with 1 to 4 carbon atoms, halogen, trihalomethyl, di- (alkyl of 1 to 4 carbon atoms) amino, (alkoxy of 1 to 4 carbon atoms) carbonyl, nitro, cyano more often acyl of 1 to 3 carbon atoms;

R j and R g , which may be the same or different, are hydrogen, methyl, hydroxy, carboxy, (alkoxy of 1 to 4 carbon atoms) carbonyl, hydroxymethyl, phenyl or p-chlorophenyl;

Rq and R ₁ Q are hydrogen or methyl} j and k are indices from 0 to 3 »but not more than 4 in total;

m and η indices from 0 to 3 »but not more than 4 in total; >

₂ - or or

and Rg together or R _Q and R ₁ together represent oxo with the proviso that k or m are different from 0; or

and R q together and R ₈ and R ₁₀ together are oxo provided that k and m are other than 0;

^ 12 'may be different, one at the carbon atoms of the piperazine ring to four methyl substituents (A = -CHp-) ^ ^e spitting, or; -

^R 13 *% 4 »Rj _- K. uaä R ₁ C ', which may be identical or different, denote hydrogen or methyl; or,

R ₁ , and R ₁ ^ together and / or R ₁ ^ and R ₁ ^ together oxo; and

X is an alkylene chain having 1 to 2 carbon atoms, which is optionally substituted by hydroxy, and their physiologically acceptable acid addition salts.

A preferred subgroup are compounds of the general formula

wherein j, k, m and η are each 0, 1 or 2; "

R ₉ and Rc are hydrogen, chlorine, methyl or lower alkoxy;

· " " · ^F ": '"·'.'.-.

R ₇ and Rq are both hydrogen, or, in, case k £ 0, one of the radicals R ₇ and R _{Q is} hydrogen and the other hydroxy, or, in the case of j and k = 0, one of the radicals R "and R _{0 is} hydrogen and the other-CgH ^ -Rp, or in the case of k Φ 0, both radicals R ₇ and Rq together oxo;

^R 13 * ^R 14 ' ^R 15 ^^ ^R 16 " ^which may be ^light or different, V / assers to ff or methyl, or

R ,, and R, ^ together and / or R ₁ ^ and FLg together oxo; Rg and R _{10 are} both hydrogen or, in the case of m Φ 0 one of the radicals Rg and R ₁ Q hydrogen and the other hydroxy, or one of the radicals R _Q and R _{10 is} hydrogen and the other -C ₆ or -COO- (alkyl with 1 to 4 carbon atoms), or, in the case of m Φ 0, both radicals Rg and R ₁₀ together oxo and

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

and their physiologically acceptable acid addition salts

Particular preference is given to compounds of the general formula

wherein R- and R ₁ ^ are hydrogen or together oxo; ^R 17 ^ ^assers ^ ^{o ££} or hydroxy;

Rt c and R ₁ r are hydrogen or together oxo; and 15o,

a and b are in each case 1, 2, 3 or A.

and their pharmaceutically acceptable acid addition salts.

The new compounds can be obtained by various methods:

Method A

Implementation of an equivalent of a compound of the general formula

^R 13 ^R 15

I Γ '

\ * * Λ \ m> "" "ii

^R 14 ^R 16

wherein R ₁ ^, R ₁ ^, R ₁ ^ »R ^ g una. X is as defined above and Y and Z are reactive groups which react with an amine to form a carbon-nitrogen bond such as chlorine, bromine, iodine, activated ester, hydroxy, sulfuric acid ester, sulfonic acid ester and the like having at least two equivalents of a compound the general formula

I (CH ₂ ).-C- (CH ₂ ) _k -N

^R 3 ^R 7 R

< ^R ll

wherein R ₁ , R ₂ , R- *, Ry, Rq, R ^ ₁ , d, k and A have the abovementioned meaning.

By these methods exclusively symmetrical compounds of formula I are obtained.

Method B

Reaction of a compound of the general formula

(CH ₂ ), - C- (CH ₂ ) _k -N

R ₁₅ (IV)

NCXCY ^R 16

in which R 1, R 2, R 2, R 2, R 2, R 2, and R 2 have the meanings given above, with a compound of the general formula \

R "

- NH

^R 12

, wherein R ^, Rc, Rg, Rq, R] _o ' ^R 12' ¹ ^ ' ^{n υη <ί A have the ot)} given meaning.

By this method, both symmetric and asymmetric compounds of general formula I can be obtained.

Method C

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

I ¹⁵

> \ F

HN N - ^ - C X C -N NH

^R 14 ^R 16

^R 12

in which R-tt "^ i?"% 3 '% 4 "% 5'% 6 * ^. ^ Pd. A has the meaning given above, with a compound of the general formula,>

^R 2 \ A- \ T ^{9 lvII)}

^R 7 '

vrarin R ₁ , R ₂ , R ₁ , R y, R q, Y, j and k are as defined above.

Method D

Such compounds of the general formula I in which X represents a carbinol can also be prepared by reacting a compound of the general formula

^R 13 / ° \ / ^R 15 "(VIII)

^R 14 ^R 18 ^R 16

wherein R _n , R ^, R ^ c and R ^ g have the meaning given above,.

R-, o is hydrogen or a lower alkyl radical and

Y has the same meaning as in formula II, with a compound of general formula V.

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

The reaction temperature is dependent on the starting compounds and the solvent used for this reaction and is between room temperature and the reflux temperature of the reaction mixture. The reaction time is temperature dependent, ranging from a few minutes to several hours.

A final product of general formula I in which R ₇ and / or Rg are hydroxy can be obtained by hydrogenating a compound in which Ry and Rq and / or

Ro and R ₁ η together are oxo with usual hydrogenation

such as sodium borohydride in a conventional manner.

This gives the corresponding hydroxy compound, the hydroxy group of which can then be alkylated or acylated by conventional methods.

The compounds of general formula I are basic and therefore form addition salts with inorganic or organic acids. Examples of non "toxic physiologically acceptable acid addition salts are those which are obtained by reaction with a hydrohalic Säures preferably hydrochloric acid or hydrobromic acid, nitric acid, sulfuric acid, o-phosphoric ₉ citric acid, maleic acid, fumaric acid, propionic acid ,. Butyric acid "acetic acid, succinic acid, methanesulfonic acid _s benzenesulfonic acid p-toluenesulfonic acid and the like receives _Θ \

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

For example, compounds of the general formula III are described in British Pat. No. 48G ₉₃₅₈ and Am in Jc * _Chem? Soc., 66, 263 (1944). :

The synthesis of compounds of general formula IV is known from numerous publications, for example, HeIv. Chim. Acta 41, 1072 (1958) or Monatshefte 87, 701 (1956). ;

Compounds of general formula VI are described in British Patent No. ^1. 480.358 and KMm »» Farm Zh ₀ 10, (1976), referenced in CA. 8g, 78079-

The compounds of the general formula ₍ I and their acid addition salts listed below can be prepared by the processes described above. "

1,3-Bis- [4- (hydroxybenzyl) -1-piperazinyl] -propane-tetra-hydrochloride

1,3-bis [4- (A ^ chlorben2yl) -l-piperazinyl] -propane-tetrahydro chlord,

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

1,4-Bis- [4- (4-chlorobenzy1) -1-piperazinyl] -butane hemihydrate, 1,3-bis (Vbenzyl-1-piperazinyl) propane tetrahydrochloride, 1,3-bis [4- (4-fluorobenzyl) -1-piperazinyl] .- propane-tetrahydrochloride, '

1,3-bis [4- (4-chlorobenzyl) -i-piperazinyl] -1-oxoproparitrihydrochloride,

1,3-Bis- [4- (v-chlorobenzyl) -1-piperazinyl-1-methylpropane tetrahydrochloride hemihydrate,

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

1- [4- (4-chlorobenzyl) -1-piperazinyl] -3- [4 - * (2-ethoxycarbonyl)

2-phenylethyl) -1-piperazinyl] -propane-tetrahydro, chloride monohydrate,

1- C ^ - (^ "chlorbenzy 1- 1-piperazinyl] - 3- (4-phen-1-acyl ν 'piperazinyl) propane tetrahydrochloride monohydrate.

1,3-bis (4-phenacyl-1-piperazinyl) -propan-tetrahydrochloridmonohydrat,

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

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

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

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

l, 3 ^ bis [4- (4-chlorophenethyl) -1-piperazinyl] -propane, 1,3-bis [4- (1-phenylethyl) -1-piperazinyl] -prapan-tetrahydrochloride,

1,3-bis [4- (4-chlorobenzyl-2,5-dimethy1-piperazinyl] -propane-tetrahydrochloride dihydrate,

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

1,3-Bi s- [4- (2-chlorobenzyl) -1-piperazinyl] -propane tetrahydro-ciiloride,

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

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

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

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

1,3-Bis- [4- (4-bromo-anicyl) -1-piperazinyl] -propane, 1,3-bis [4- (4-chloro-3-trifluoromethylbenzyl) -1-piperazinyl] -propane-tetrahydrochloride

r, 3-bis- [4 ^ 4- (4-chlorobenzyl) -2,3,5,6-tetramethyl} -lipiperazinyl] -propane,

1,3-Bis- [4- (4- (4-chlorophenyl) butyl] -1-piperazinyl] -propane, 1- [V (4-chlorobenzyl) -1-piperazinyl] -3- [4- (2-carboxy -2- · phenylethyl) -l-piperazinyl] -propane-tetrahydrochloride,

1,3-bis [A- (4-chlorobenzyl) -1-homopiperazinyl] -propantetrahydrochlorid,

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

1,3-bis [A- ( k- chlorobenzyl) -1-homopiperazinyl] -1,3-dioxopropane.

The following examples serve to illustrate the invention without, however, limiting it:

example 1

1.3-bis-4- (4-chlorobenzyl) -1-piperazinyl-1-propane-tetrahydrochloride ,

A mixture of 10.5 g of 1- (1-chlorobenzyl) piperazine, 9.5 g of 1-bromo-3-chloropropane and 100 ml of ethanol are refluxed for 17 hours. The solvent is then removed by rotary evaporation and the remaining oil is mixed with 200 ml of dibasic potassium phosphate. Solid tribasic sodium phosphate is added until a pH of above 9 is reached. This mixture is extracted 5 times with 50 ml of ether, the ether evaporated, the residue acidified with 100 ml of 2M phosphoric acid and filtered. The aqueous filtrate is basified with 2N sodium hydroxide solution, extracted again with 250 ml of ether and dried over magnesium sulfate. After passing in gaseous hydrogen chloride and recrystallizing from ethanol / water, 5.8 g (39% in theory) of the title compound in the form of white crystals of mp. 26l-274 ° c (Zers.)

Example 2

1.3-bis [4- (4-chlorbenzvl) -l-hydroxypropane-piperazinyl1-2

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 are refluxed for three days. The solvent is removed by rotary evaporation from the reaction mixture and the residue is basified with 2N sodium hydroxide solution and extracted 5 times with 100 ml of ether. After drying the ether extracts over magnesium sulfate and evaporation of the solvent to obtain an oil which solidifies on standing. Recrystallization from heptane gives 18.6 g (82 % of theory) of 1,3-bis [4- (4-chlorobenzyl) -1-piperazinyl] -2-hydroxypropane in the form of colorless crystals of melting point 85-86.5 ° C ·

Example 3

1,4-bis- 4- (4-chlorobenzyl) -l-piperazinyl 1-butan-hemihvdrat

A mixture of 2.2 g of 1,4-dibromobutane, 4.2 g of 1- (4-chlorobenzylpiperazine, 2.8 g of anhydrous potassium carbonate and 20 ml of ethanol are heated at reflux for 18 hours, the solvent is then concentrated under reduced pressure withdrawn and heated the residual oil 16 hours 160 ⁰ C. Then the oil is gelösi in 50 ml of hot water;.. and extracted 3 times with 80 ml of ether the ether extract is concentrated and chromatographed, residual oil on a silica gel column (eluent . methylene chloride methanol / ammonium hydroxide 45: 5: the brown-colored solid obtained 1) is dissolved in acetone and diluted with water, the title compound as white crystals, melting lOl · - precipitated 103 ⁰ G..

Example 4 1, 3 "bis (4-benzyl-1-piperrainyl) -propane-tetrahyarochloria

A mixture of 7.0 g of 1-Bsnzylpiperzinzin, 3.2 g of lH3rom-3-chloropropane, 4.0 g of triethylamine and 100 ml of ethanol are heated under reflux for 2 1/2 hours. 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 dissolved in 100 ml of heptane and filtered. The solvent is removed by rotary evaporation and the residue is redissolved in 150 ml of ether. By adding an excess of anhydrous hydrochloric acid, 8.8 g (82 % of theory) of the title compound are obtained in the form of white crystals, mp. 250-265 ⁰ C.

Example 5

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

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 isocyanate in 150 g of ethanol. By a cold water bath, the reaction temperature is maintained at 20 ⁰ C. The reaction mixture is stirred for another 1 1/2 hours and then poured into 2 liters of ether. From the precipitated piperazine hydrochloride is filtered off and the filtrate is evaporated to an oily residue which is chromatographed on silica gel, graphite (eluent: methylene chloride / methanol / ammonium hydroxide 45: 5: 1). After working up of the appropriate fractions 21.7 g (56% of theory) is obtained ^v l- (4-fluorobenzyl) piperazine in the form of a colorless liquid · '... ^·.:. '. <- '. · · ·. , .

b) A mixture of 5.8 g of 1- (4-fluorobenzylpiperazine, 3.2 g of i-bromo-3-chloropropane, 4.0 g of triethylamine and 50 ml of ethanol is refluxed for 3 hours and then in 1 liter Ether poured, precipitate is filtered off and the

Filtrate was concentrated to an oil. This oil is dissolved in 100 ml of ether and precipitated with an excess of anhydrous hydrochloric acid, the tetrahydrochloride, after recrystallization from ethanol / V / asser in a yield of 3.3 g (29 % of theory) in the form of white crystals, mp 228 -237 ⁰ C (Zers.) Is obtained.

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 refluxed for 18 hours and the reaction mixture is filtered and the filtrate is filtered with a Excess of hydrochloric acid saturated ether until acid reaction against litmus. The resulting precipitate is filtered and recrystallized from ethanol / water. This gives 1.2 g (45 % of theory) of the title compound in the form of white crystals, mp. 222-250 ⁰ G (Zers.).

Example 7

1,3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl-1-methylpropane tetrahydro chloride hemihydrate

A mixture of 7.3 g of 1- (4-chlorobenzyl) piperazine, 2.8 g of 1,3-dibromobutane, 11.0 g of triethylamine and 50 ml of ethanol is refluxed for 48 hours. The solvent is removed by rotary evaporation, the residue is mixed with 100 ml of toluene and heated at reflux for 24 hours. The mixture is poured into 1 liter of ether and filtered. The filtrate is concentrated to an oil and this on silica gel chromatographed (eluent: methylene chloride / methanol / Aramoniumhydroxid 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 refilled by adding acetone; obtained 1.2 g (11% of theory) of the title compound as white crystals of mp. 228-232 ⁰ C.

Example 8

1.5-BiS-4- (4-chlorobenzhydryl) -1-piperazinyl 1-propanedihydrochloride 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 refluxed for 15 hours. The reaction mixture is made alkaline with 5N sodium hydroxide solution and extracted 5 times with 50 ml of methylene chloride. The extract is dried over magnesium sulfate and added with hydrogen chloride saturated ether until acidic reaction against litmus. The precipitate of the crude product (2.5 = 27 % of theory) is filtered off and purified by dissolving in methylene chloride and subsequent precipitation by ether addition. 165-196 ⁰ C. (decomp.) Are obtained white crystals of the title compound of mp..

Example 9

1- f4> ( ^ ChlorbenzvD-1-piperazinyli - ^ - [4- (2-ethoxycarbonyl-2-phenylethyl) -1-piperazinyl! -Propane-tetrahydrochloride monohydrate .

a) A mixture of 1.8 g Atropasäureethylester and 0.9 g of piperazine are stirred in a round bottom flask. After the exothermic reaction has subsided, the mixture is heated to 80 ° C and stirred for a further 20 minutes. Then the reaction mixture is allowed to stand overnight at room temperature. The resulting solid is chromatographed on silica gel, starting with ether and then

'18

Methylene chloride / methanol / ammonium hydroxide in the ratio 45: 5: 1 used as the eluent. The 1- (2-ethoxycarbony 1-2-phenylethyl) piperazine (0.75 g = 29 % of theory) comes from the column with the second barrel and is used for the subsequent reaction without further purification.

b) A mixture of 3.0 g i- ^c hlor-3- [4- (4-chlorobenzyl) -lpiperazinyl] propane, 3.5 g of triethylamine, 3.7 g of l- (2-ethoxycarbonyl-2-phenylethyl ) piperazine and 50 ml of ethanol are refluxed for 2 hours and then poured into 1 liter of ether. The mixture is filtered and the filtrate is evaporated. The remaining oil is purified by chromatography on silica gel (mobile phase: methylene chloride / methanol / ammonium hydroxide 45: 5: 1). This gives 3.0 g of an oil which is dissolved in 150 ml of ether and adding an excess of anhydrous hydrochloric acid to obtain 3.4 g of a solid. This is again chromatographed on silica gel _; the first eluent being ether, the second a mixture of methylene chloride / methanol / ammonium hydroxide in the ratio 45: 5: 1. The product obtained is, as described above, converted into the hydrochloride, dissolved in water and by addition of acetone, the title compound in a yield of 1.1 g (15 % of theory) with a Fp-. from 198-201 ⁰ C precipitated 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 are refluxed for 5 hours heated. The solvent is in the

Rotary evaporator removed, the residue was added 150 ml of water, and the mixture .'3 times extracted with 150 ml of ether. The ethereal solution is evaporated and the remaining oil on silica gel with the eluent methylene chloride / Methanql / ammonium hydroxide (45: 5: 1) Chromatograph! This gives 7.0 g (50 % of theory) of crude 1- [4- (4-chlorobenzyl) -1-piperazinyl] -3- (4-phenacyl-1-piperazinyl) propane in the form of an oil. This oil is dissolved in 200 ml of ether, precipitated with an excess of anhydrous hydrochloric acid, the hydrochloride, the precipitate dissolved in water and precipitated by the addition of acetone, the title compound, mp. 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] -5- (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 then the unreacted sodium borohydride is destroyed by the addition of 25 ml of acetone. The solvents are removed under vacuum and added to the residue, 30 ml of water. The mixture is extracted 3 times with 250 ml of ether, the solvent is evaporated and the remaining oil on silica gel with the eluent methylene chloride / methanol / ammonium hydroxide (45: 5: 1) chromatographed. The fractions containing the final product are combined, the solvent evaporated, the residual oil dissolved in 100 ml of ether and the hydrochloride precipitated by addition of excess anhydrous hydrochloric acid. After dissolving in water and Aisfallen with acetone (16% of theory) in the form of white crystals, melting to obtain the final product in a yield of 0.65 g. 240-248 ⁰ C. (dec.)

Example 12

1,3-Bi s- ^ -phenacyl-1-piperazinylpropane-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 are refluxed for 3 hours. The solvent is evaporated, 250 ml of water are added to the residue and the mixture is extracted 3 times with 150 ml of ether. After evaporating the ether, the residual oil is chromatographed on silica gel with eluent methylene chloride / methanol / ammonium hydroxide (45: 5: 1). The fractions of high purity are combined, the solvent evaporated, the residual oil in 150 ml of ether and precipitated with an excess of anhydrous hydrochloric acid. After dissolving in water and precipitation by addition of acetone 1.3 g (14% of theory) of the title compound of mp. 194-204 ⁰ C in the form of white crystals. \

Example 13

1,3-Bis Γ4- (2-phenyl-2-hydroxypropyl) -1-piperazinylpropane-tetrahydrochloride

A solution of 2.5 gl, 3- ^B is (4-phenacyl-l-piperazinyl) propane in 50 ml of ethanol is mixed with 2.5 g of sodium borohydride and stirred for 4 hours. The excess sodium borohydride is destroyed by adding 25 ml of acetone and the solvents are removed by rotary evaporation. 50 ml of water are added to the residue and the mixture is extracted 3 times with 150 ml of ether each time. After evaporating the ether, the remaining product is chromatographed on silica gel with the mobile phase methylene chloride / methanol / ammonium hydroxide (45: 5: 1). The resulting oil is dissolved in 100 ml of ether and the title compound is added by addition of excess aqueous hydrochloric acid in a

Yield 0.75 g (22% of theory) of mp. 233-240 ⁰ C precipitated as white crystals "

Example 14

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

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 refluxed for 3 hours. Thereafter, 50 ml of water are added, the mixture is concentrated by rotary evaporation to about 40 ml and this mixture is extracted 3 times with 150 ml of ether. The combined extracts are evaporated, the remaining brown oil dissolved in 150 ml of ether and precipitated by addition of an excess of anhydrous hydrochloric acid, the hydrochloride. It is dissolved in ater. V / and by addition of acetone 3.1 g (37% of theory) of the title compound of mp. 210-225 ⁰ C obtained as white crystals.

Example 15 ,

Ij 3-Bis- [4- (V-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 are stirred for 60 hours. The reaction mixture is made alkaline with 2N sodium hydroxide solution, the organic; Separate layer and the aqueous phase extracted 3 times with 50 ml of ether, then 3 times with 50 ml of methylene chloride. The organic phases are combined and mixed with 100 ml of 2N hydrochloric acid. The aqueous phase is separated off and basified with 2N sodium hydroxide solution. The remaining oil is collected and purified on silica gel with the eluent methylene chloride / methanol / ammonium hydroxide (200: 5: 1.).

extracted. The appropriate fractions are combined, the solvent evaporated, the residual oil dissolved in 100 ml of ether and precipitated with an excess of anhydrous hydrochloric acid. The precipitate is recrystallized from ethanol; This gives 1.3 g (22 % of theory) of the title compound of mp. 199-206 ⁰ C in the form of slightly yellowish crystals.

Example 16

1,5-Bi s- [4- (1-chlorophenethyl) -1-piperazinyl-i-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 is refluxed for 3 hours. The reaction mixture is diluted with 50 ml of water and concentrated by rotary evaporation to about 50 ml. The remaining mixture is extracted 3 times with 150 ml of ether and the extract was concentrated. The remaining colorless solid is recrystallized from heptane; This gives 3.3 g (45 ⁰ A of theory) of the title compound of mp. 87-88 ⁰ C in the form of white crystals ..

Example 17

1,3-Bis- [4- (1-phenylethyl) -l-piperazinyl-i-propane-tetrahydro-chloro-id '

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 refluxed for 5 hours. The solvent is then removed under vacuum, 50 ml of water are added and the mixture is extracted 3 times with 150 ml of ether. The ethereal solvent is evaporated off and the remaining oil is chromatographed on silica gel (run medium: methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The resulting yellow oil is dissolved in 150 ml of ether and washed with excess anhydrous hydrogen chloride

6.1 g (51 % of theory) of Titelverbindurig precipitated ;, after recrystallization from ethanol / water to give white crystals, mp. 236-246 ⁰ C (Zers.)

Example 18

1 '3-bis [4- (4-chlorobenzyl) -2.5-dimethyl-1-piperazinyl] -propane-tetrahydrochlorid' 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-D imethylpiperazine in 75 ml of ethanol, the mixture over ^! Stirred overnight and then filtered. The solvent is removed by vacuum distillation, the residue is extracted 3 times with 350 ml of ether, the solvent is evaporated off and the residual oil is chromatographed on silica gel (mobile phase methylene chloride / methanol / ammonium hydroxide 45: 5, 1). Are thus obtained 9.1 g (38% of theory) of l- (4-chlorobenzyl) ^-2,5-dimetn y ¹ P ⁱ P as ^erazin. colorless liquid; it is used without further purification for the following reaction.

b) A mixture of 6.0 g of 1- (4-chlorobenzyl) -2,5-dimethylpiperazine, 2.0 g of 1-bromo-3-chloropropane, 3.2 g of triethylamine and 50 ml of ethanol are refluxed for 6 hours , The solvent is removed in vacuo, the residue 50 ml V / asser added and the mixture extracted 3 times with 150 ml of ether. The solvent is evaporated off and the remaining oil is chromatographed on silica gel (mobile phase methylene chloride / methanol ammonium hydroxide 45: 5: 1). The product obtained is dissolved in 150 ml of ether and precipitated with an excess of anhydrous hydrochloric acid. The precipitate is dissolved in water and by addition of acetone 0.7 g of the title compound as white crystals of mp. 204-214 ⁰ C obtained. , -

Example 19

1.3-bis-4- (4-methoxybenzyl) -1-piperazinyl-propane

A mixture of 4.1 g of 1- (p-methoxybenzyl) -piperazine, 1% of 6 g of 1-bromo-3-chloropropane, 25 ml of ethanol and 2.5 ml of triethylamine are refluxed for 5 hours. 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 theory) of the title compound in the form of white crystals, mp. 86-87 ⁰ C.

Example 20

1,3-bis- [4- ^^ - dichlorobenzyl-1-piperazinyl] propyl

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 are heated to reflux. After one hour, a further 0.06 g of 1-bromo-3-chloropropane are added, after a further hour another 0.06 g. The mixture is refluxed overnight and then the solvent is removed in vacuo; a gummi.artige solid mass is obtained, which is mixed with 150 ml of ether and filtered. The filtrate is dried over magnesium sulfate and then with saturated hydrochloric ether until the mixture reacts to litmus sour .. The resulting precipitate is dissolved in a little water and concentrated hydrochloric acid dropwise added to form a precipitate. The addition of hydrochloric acid is continued until no precipitate forms. After filtering and drying. In vacuo, 4.5 g '(44 % of theory) of the title compound in the form of white needles, mp. 245-251 ⁰ C (Zers.).

Example 21

1 "5-BJs [Ar- (2-chlorobenzyl-1-piperazinyl-i-propane _x tetrahvdrochlorid

A mixture of 8.4. g l- (2-C-chlorobenzyl) -piperazine, 3.2 g of 1-bromo-3-chloropropane, 4.0 g of triethylamine and 30 g of ethanol are heated at reflux overnight. Thereafter, the solvent is removed in vacuo, the residue mixed with 150 ml of ether and filtered. The filtrate is dried over magnesium sulfate and then added slowly with hydrogen chloride saturated ether until the acidic reaction to litmus. The resulting precipitate is filtered, dried and weighed. This gives 6.1 g (50 % of theory) of the title compound, which after recrystallization from ethanol / water in the form of white crystals, mp. 251-255 ⁰ C is present. '

Example 22

1,3-bis [4- (4-methvlbenzvl) -l-piperazinyl1-propantetrahvdrochlorid

A mixture of 5.7 g of 1- (4-methylbenzyl) -piperazine, 2.4 g of 1-bromo-3-chloropentane, 25 ml of ethanol and 3.0 g of triethylamine are refluxed for 5 hours. The solvent is removed in vacuo and the residue is mixed with 40 ml of water. The aqueous mixture is extracted 3 times with 150 ml of ether; Evaporation of the ether gives a slightly yellowish oil which solidifies on standing. This product is dissolved in 50 ml of ether and added with hydrochloric acid saturated ether until acidic reaction on litmus. The precipitate obtained is dissolved in 20 ml of water and by adding acetone the title compound in a yield (dec.) Of- 5.8 g (68% of theory) in the form of white crystals vomFp.245-252 ⁰ C precipitated.

Example 25 '

1,3-bis [4- (5-chlorobenzyl) -l-pipera2invl] -propandihvdro cullo d i * 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 are refluxed for 4 hours. Then 70 ml of water are added, the mixture is concentrated under vacuum to about 70 ml and the resulting aqueous mixture extracted 3 times with 150 ml of ether. After concentrating the extract in vacuo, a reddish yellowish oil is obtained which is chromatographed on silica gel (run medium methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The resulting oil is dissolved in 50 ml of ethanol and washed with Hydrogen chloride saturated ¹ * ether added until acid reaction to litmus. The precipitate is filtered off, dried and recrystallized from water. This gives 5.6 g (68 % of theory) of the title compound in the form of white crystals of mp. 248-257 ⁰ C (Zers.).

Example 24

1,3-bis [4- (3-C4-chlorophenyl-1-propyl) -1-piperazinyl] -propane-tetrahydrochloride monohydrate '; _v

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 refluxed for 2 hours. The solvent is removed in vacuo and the residue is chromatographed on silica gel (mobile phase methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The appropriate fractions are combined and concentrated 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 4 times with 200 ml

Ether extracted. The extract is dried over magnesium sulfate and concentrated to an oil which solidifies on standing. The resulting l- [3- (4-chlorophenyl) propyl] piperazine, mp. 54-62 ⁰ C is used without further purification for the next step.

b) A mixture of 7.2 g of 1- [3- (4-chlorophenyl) propyl] piperazine, 2.4 g of 1-bromo-3-chloropropane, 3.5 g of triethylamine and 30 ml of ethanol is refluxed for 6 hours , The solvent is then removed in vacuo, the residue is mixed with 40 ml of water and extracted 3 times with 150 ml of ether. The extract is 'concentrated to a yellow oil' which is chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). This gives 4.6 g (59 % of theory) of l, 3-bis- [4- (3-T, 4-chlorophenylj-propyl) -1-piperazinyl] -propane as a colorless oil. 3.0 g of this oil are dissolved in 100 ml

, Ether dissolved and added to the acidic reaction to litmus with hydrogen chloride saturated ether. The resulting precipitate is dissolved in 25 ml of water and acetone is added until precipitation is complete. This gives 2.7 g (41 % of theory) of the title compound of mp. 245-246 ⁰ C (dec.) 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 5-chloro-4-trifluoromethylbenzyl chloride, 5.3 g of l, 3-bis (1-piperazinyl) propane, 50 g of ethanol and 7 x 0 g of triethylamine are heated under reflux for 16 hours. Thereafter, the reaction mixture is concentrated in vacuo, the residue is mixed with 150 ml of water and the mixture is extracted 5 times with 100 ml of ether. The combined ethereal extracts are washed 3 times with 100 ml of IM

Sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to give 6.8 g of a yellow oil. This oil is dissolved in 100 ml of hexane and filtered. The filtrate is extracted 3 times with 20 ml of 2% aqueous acetic acid, whereby the desired product appears in the 2nd and 3x extract (test by thin-layer chromatography). These extracts are combined, made strongly alkaline with 2N sodium hydroxide solution 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; after adding 30 ml of with. Hydrogen chloride of saturated ether gives a white precipitate. Another 50 ml of ether are added and the precipitate is filtered off and recrystallized from methanol. The title compound is obtained in the form of colorless crystals of mp ₀ 265-268 ⁰ C (dec.> 25O ⁰ C).

Example 26

1,3-Bis- [4- (4-hydroxybenzyl) -1-piperazinyl ] -propane A mixture of 4,5-gl, 3-bis [4- (4-methoxybenzyl) -lpiperazinyl] propane (see Example 19) and 250 ml of 49% acid hydrobromic acid are heated under reflux for 2 hours, then cooled and diluted with 125 ml of water. The aqueous solution is filtered and brought to pH 8 with 2N sodium hydroxide solution. This mixture is extracted 3 times with 150 ml of ethanol each time, the alcohol is removed by rotary evaporation and the residue is chromatographed on silica gel (mobile phase: methylene chloride with 1 % ammonium hydroxide and 10 % methanol). 1.3 g (31 % of theory) of Title compound of mp. 197-201 ⁰ C in the form of white crystals.

Example 27 ,

1,3-bis [4- (4-bromobenzyl) ^A l-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-chloro-propyl and 1.6 g of triethylamine are refluxed for 18 hours. The solvent is removed by rotary evaporation, the residue mixed with 50 ml of water and brought to pH 10 with 2N sodium hydroxide solution. This mixture is extracted 2 times with ether (75 + 25 ml), the combined extracts 2 times. washed with 25 ml of water, dried over magnesium sulfate and filtered. This solution is mixed with hydrogen chloride-saturated ether until acidic reaction and the precipitate precipitated, filtered off and mixed with 100 ml of ethanol. The mixture is brought to reflux temperature and treated dropwise with water until it has gone into solution. Upon cooling, the final product crystallizes, which is filtered off. This gives 4.2 g (81 % of theory) of the title compound of mp. 237-243 ⁰ C in the form of white crystals. '

Example 28

l, 3-bis [4- (4 ~ chlorbenzvl) -l-homopiperazinvl] -proOantetrahydrochlorid

A mixture of 4.5 g of l- (4-chlorobenzyl) homopiperazine, 1.6 g of lB.rom-3-chloropropane and 20 g of ethanol are refluxed for 18 hours. The solvent is removed under vacuum and the remaining mixture is extracted 3 times with 75 ml of ether. Evaporation of the ether leaves an oil which is digested on silica gel (eluent methylene chloride containing 0.5 % concentrated ammonium hydroxide and 2.5 % methanol). The fractions containing the final product are combined, the solvent evaporated, the residual oil

dissolved in ether and the solution filtered. The remaining Etherlösimg is mixed with hydrogen chloride saturated ether until an acidic reaction to litmus. The precipitate which forms is dried; 1.4 g is obtained (22% of theory) of the title compound as white crystals after recrystallisation from aqueous ethanol, mp. 218-224 ⁰ C by having (dec.).

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 are heated at reflux overnight. The solvent is evaporated and the residue is chromatographed twice on silica gel (mobile phase methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The first fraction contains mainly excess piperazine containing the second

15.2 g of 1- [4- (4-chlorophenyl) -butyl] -piperazine as a colorless oil which solidifies on standing. (Mp 139-145 ⁰ C). The crude product is used without further purification for the next step.

b) A mixture of 1,5-gl- [4- (4-chlorophenyl) -butyl] -piperazine, 0.5 g of 1-bromo-3-chloropropane, 0.7 g of triethylamine and 10 g of ethanol is heated at reflux overnight , After adding 3.5 ml of 2N sodium hydroxide solution, 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 concentrated to an oil and this is dissolved in ether. After addition of hydrogen chloride-saturated ether, a precipitation of 0.7 g (31 # of theory) of

Title compound as a light brown solid mass, which can be converted by recrystallization from ethanol / water into white crystals, mp. 213-217 ° C (dec.).

Example 30

1 »3-Bis- [4> - (4 * - acetoxybenzyl) -l-piperazinyl! -Propane

A mixture of 2.0 gl, 3-bis [A- (A-hydroxybenzyl) -lpiperazinylpropane (see Example 26), 1.0 g of pyridine and 50 g of acetic anhydride are over. Stirred at room temperature overnight. The mixture is concentrated under vacuum to an amber oil, which is mixed with 100 ml of phosphate buffer (pH 8) and extracted 3 times with 100 ml of ether each time. The extract is dried over magnesium sulfate and concentrated to a white solid. After recrystallization from heptane gives 1.9 g (78 % of theory) of the title compound in the form of white crystals, mp. 102-105 ⁰ C. '

Example 31

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

A mixture of 1.0 g, 3-bis [4-hydroxybenzyl] -1-piperazinyl] propane (see Example 26), 10 ml of 2N sodium hydroxide solution, 0.2 g of tetrabutylammonium hydroxide (40 % in water) and 5.0 g of 1 -3rombutan are heated for 3 hours on the steam bath. The mixture is then extracted 3 times with 75 ml of ether, dried over magnesium sulfate and concentrated to a colorless oil which solidifies on standing. This product is dissolved in 100 ml of ether and saturated with hydrogen chloride saturated ether Ms ₁ to stop the precipitate. After filtration, 1 »^ g (91 % of theory) of the title compound, which after recrystallization from ethanol / water in the form of white crystals, mp. 207-218 ⁰ C is present. .

Example, 32

1 _{t of} 3-bis- [4- (4-chlorobenzyl-2,3,5,6-tetramethyl-1- piperazinyl) JbbBr-PPan-tetrahydrochloride

A mixture of 3 g of 1- (4-chlorobenzyl) -2,3,5,6-tetramethylpiperazine, 1 g of 1-bromo-3-chloropropane and 1 g of triethylamine * is refluxed for 24 hours in 20 ml of ethanol. Thereafter, the solvent is removed in vacuo, the remaining oil dissolved in water and extracted with ether. The ether extract is washed with water and dried over magnesium sulfate. The Titeiverbindung 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] - 5- [4- (2-carboxy- 2-phenylethyl ) -l-piperazine-propane-tetrahydro-chloro- xd. A suspension of 340 mg of 1- [4- (4-Chlorobenzyl) -1-piperazinyl J-3- [4- (2-ethoxycarbonyl-2-phenylethyl) -1-piperazinyl propane-tetrahydrochloride in 10 ml of ethanol are combined with 1% aqueous 5M sodium hydroxide solution and heated under reflux for one hour , 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 of the aqueous phase is adjusted to 5.5 with 1N hydrochloric acid. Then 10 ml of saturated saline solution are added and the mixture is extracted twice with 10 ml of butanol each time. The butanol extract is filtered and treated with an excess of ethereal salt acid. The white precipitate is collected and recrystallized from aqueous ethanol. You get

140 ml (40 % of theory) of the title compound in the form of white crystals, mp. 230-245 ⁰ C (Zers.). , _t

Example 34 ^v

1.3- Bi s »[4- (3- £ 4-chlorophenyr * * -propylVl-homopipera zinvl 1-propane-tetrahydrochloride

A mixture of 3.3 g of 1-C3- (4-chlorophenyl) propyl} -homopiperazine, 1.2 g of 1-bromo-3-chloropropane, 1.8 g of triethylamine are refluxed in 10 ml of ethanol for 18 hours. 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 (mobile phase methylene chloride / methanol / ammonium hydroxide 35: 5Jl). The resulting oil is dissolved in ether and the title compound is precipitated with an excess of ethereal hydrochloric acid. After recrystallization from ethanol gives the l, 3-bis [4- (3- {i ^ chlorophenyl ^ - propyl) - 1-homopiperazinyl] propane tetrahydrochloride in crystalline form.

Example 35

1,3-Bis Γ4- (4-chlorobenzyl) -1-homopiperazinyl 1-1,3-dioxopropane dihydrochloride

To a solution of 2.2 g of l- (4-chlorobenzyl) homopiperazine and 1 g of triethylamine in 10 ml of methylene chloride are added at room temperature at once 0.7 g of malonic acid dichloride and the reaction mixture is refluxed for one hour. The solvent is stripped 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 (mobile phase methylene chloride / methanol / hydroxylamine 200: 5: 1).

Fractions are collected, the solvent evaporated, the residue dissolved in ether and treated with excess ethereal hydrochloric acid; the title compound is obtained in crystalline form. , .

The compounds of general formula I and their non-toxic, physiologically acceptable acid addition salts have valuable pharmacodynamic properties. In particular, because of their strong inhibition of mediator release in numerous cell systems, they exhibit anti-inflammatory and antiallergic properties in warm-blooded animals, such as rats, and are therefore suitable for combating allergic diseases such as allergic asthma, rhinitis, conjunctivitis, hay fever, urticaria, food allergies and the like. Mediator release from mast cells and basophils occurs in many allergic and inflammatory diseases. The activity of substances which inhibit the non-cytotoxic exocytosis of such mediators can be tested in in vitro models of inhibition of mediator release from isolated cell systems elicited by an Ahtigen antibody response. ,

The following table summarizes the data showing the biological activity of some of the compounds of the invention by various tests. The following cell systems are listed in the table:

RPMC: Peritoneal Mast Cell Preparations of

Rats ''

GPBL ^{:! B} asophilen enriched leukocytes

of guinea pigs

ι. ,

HBL: Basophil-enriched human leukocytes.

As and standard clinical substances serve theophylline disodium cromoglycate (DSCG). ^v - IC ₅₀ (UM) *, - HBL Connection j -. _ GPBL 2 of the Seispiels 40 3 20 3 1 Inhibition of mediator release ' ^! 50 0.7 2 10 0.7 15 RPMC 9 400 16 3 200 > 1000 24 80 10 NT 0.5 Theophylline> 1000 DSCG

Concentration of the compound needed to inhibit the release of pharmacological mediators from the corresponding cells by 50 % .

NT = not tested. , '

For pharmaceutical use, the compounds of the invention can be administered to warm-blooded animals topically, 'perorally, parenterally' rectally or by inhalation. The compounds are present as active ingredients in conventional dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient.

Compounds of general formula I which are given orally may be in the form of syrups, tablets, capsules, pills and the like. Preferred are compositions in a unit dosage or in a form in which the patient can take a single dose. Tablets, powders or lozenges may be mixed with any excipient suitable for the formulation of solid pharmaceutical compositions. Examples of such excipients are various types of starch, lactose, glucose, sucrose, cellulose, calcium phosphate and lime. The compositions may also be in the form of capsules (e.g., gelatin) containing the active ingredient or in the form of a syrup, solution or suspension. Suitable liquid pharmaceutical excipients include ethyl alcohol, glycerol, saline, water, propylene glycol or sorbitol solution "which may be flavored or colored.

The compounds of the invention may also be in the form of suppository for rectal use or in the form of an aqueous or non-aqueous injection solution, suspension or emulsion in a pharmaceutically acceptable liquid, such as sterile, pyfogen-free water or an oil suitable for parenteral use or a mixture of liquids,

bacteriostatic agents, antioxidants, preservative system contains ¹ tives buffer substances or solutions ,, which enable the use solution in an isotonic state; further, thickening agents, suspending aids or other pharmaceutically acceptable additives may be added. The application is in the form of single dosages such as ampoules or disposable injection devices or in multiple dose containers, eg a bottle from which the appropriate amount can be withdrawn, or in solid form or in the form of a concentrate which can be used to make an injection solution.

The compounds of the present invention may also be in the form of inhalable aerosols or solutions which may be sprayed in a nebulizer, or in the form of a microcrystalline powder for inhalation, either alone or in combination with an inert carrier, e.g. Lactose, to be applied. Suitable for this purpose are particles of the active compounds with a diameter of less than 20 microns, preferably less than 10 microns. If necessary, smaller amounts of other antiallergic drugs, antiasthmatics and bronchodilators, ZoB. Sympatikomymetika such as isoprenaline, isoetarin, metaproterenol, salbutamol, phenylephrine, fenoterol and ephedrine, also xanthine derivatives such as theophylline and aminophylline or corticosteroids such as prednisolone and adrenergics such as ACTH are added.

For topical application of the skin, nose or eyes, the compounds according to the invention may also be in the form of an ointment, a cream, a lotion, a gel, an aerosol or a solution. Topical solutions for the nose and eyes can, in addition to the compounds according to the invention, also be suitable puff substances, bacteriostats, antioxidants and viscosity reducing agents

Agent, contained in an aqueous vehicle.

Examples of agents which increase the viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbitan esters or glycerol. Suitable bacteriostatic agents include benzalkonium chloride, thimerosal, ^chloro: butanol or phenylethyl alcohol. Topical ophthalmic preparations may also be in the form of ointments in a suitable inert base consisting of mineral oil, petrolatum, polyethylene glycols or lanolin derivatives, together with bacteriostats. ·

In the above formulations contains a suitable dose of 0.005-500 mg active ingredient. The effective dose of the compounds of the invention depends on the particular compound used, the condition of the patient and the frequency and mode of administration, but is generally between 0.0001 mg / kg to 10 mg / kg of body weight.

Usually, written or printed instructions for the medical application in question, in this case as antiallergic for prophylaxis and treatment for e.g. Asthma, hay fever, rhinitis or allergic eczema, attached.

For the preparation of pharmaceutical preparations, the compounds of general formula I are mixed in a customary manner with suitable pharmaceutical excipients and flavorings, Durf.tstoffen and dyes and compressed, for example, into tablets, filled into capsules, or with the addition of appropriate adjuvants, in water or in an oil For example, corn oil, suspended or dissolved.

The compounds of the invention may be administered orally or parenterally in liquid or solid form. For solutions for injection water is preferably used which contains those stabilizing agents, solubilizers and / or buffers which are usually used for injection solutions ^v. Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complexing agents (eg EDTA), antioxidants (eg sodium bisulfite, sodium tetrabislite or ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for controlling viscosity and polyethylene derivatives of sorbitol anhydrides. ⁱ

If desired, preservatives may be added, e.g. Benzoic acid Methyl or propyl paraben Benzalkonium chloride or quaternary ammonium compounds.

Suitable solid carriers for use include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silicic acid, dicalcium phosphate, and high molecular weight polymers (for example, polyethylene glycol).

Oral preparations may, if desired, contain odorants and / or sweeteners. ,

For topical application, the compounds according to the invention can also be used in the form of solutions, powders or ointments; For this they are e.g. mixed with physiologically acceptable diluents or conventional ointment bases. .

The following examples describe some pharmaceutical compositions containing a compound of the invention as an active ingredient. Unless otherwise indicated, these are the parts

; , , · '- 40 · -'. , , , around parts by weight » '

Example 56 · ....,

Tablets ·

The tablet contains the following ingredients:

, 1,3-Bis [4- (4-chlorobenzyl) -1-piperazinyl] propane tetrahydrochloride 0.010 parts stearic acid 0.010 parts

, Glucose 1,890 parts

1,910 parts

Production: .... _t .

The ingredients are mixed in a conventional manner and the mixture is compressed into tablets of 1.91 g; Each tablet contains 10 mg of active ingredient.

Example 57

Ointment · '. .

The ointment is composed as follows:

l, 5-bis [4- (4-chlorobenzyl) -l-

piperazinyl] -2-hydroxypropane 2,000 parts

Fuming hydrochloric acid 0.011 parts

Sodium pyrosulfite 0.050 parts cetyl alcohol / stearyl alcohol (1: 1) 20,000 parts

White vaseline 5,000 parts

Synthetic bergamot oil. 0.075 parts of distilled water ad 100,000 parts

Production:,

The ingredients are meshed in a conventional manner to an ointment; 100 g of the ointment contains 2.0 g of the active ingredient.

Example 58

Inhalation aerosol '

The aerosol is composed of the following components:

1,3-3is [4- (4-chlorobenzyl) -1-

piperazinyl] -1,5-dioxopröpanedihydrochloride monohydrate 1.00 parts. ⁷

Soy lecithin. 0.20 parts

Propellant mixture

(Freon 11, 12 and 14) ad 100.00 parts

production:

The ingredients are conventionally mixed and filled into a metered-dose aerosol container, with the metering valve delivering 0.5-2.0 mg of the active agent per actuation of the valve.

Example 59 iektionslösunff In _t

The solution consists of the following components:

1 _? 3-bis [4- (4-chlorophenethyl) -l-

piperazinyl] propane

dihydrochloride 5, ρ parts

Sodium pyrosulfite 1.0 parts

EDTA ^ sodium salt. 0.5 parts

Sodium chloride, "; 8.5 parts of double distilled water ad1000.0 parts

Production %

The individual ingredients are dissolved in a sufficient amount of double-distilled water, the solution diluted to the concentration indicated with more double-distilled water, the resulting solution was removed by filtration of suspended particles and the filtrate filled under aseptic conditions in 1 ml ampoules, which are then sterilized and sealed become. Each vial contains 5 ml of the active ingredient.

Example_40. ·.

Tppische. Solution (for eye or nose drops)

The solution is composed of the following components;

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

tetrahydrochloride 0.020 parts

Disodium hydrogen phosphate 0.758 parts

Sodium dihydrogen phosphate 0.184 parts

Sodium chloride 0.365 parts

Polyvinyl alcohol 3,500 parts

Benzalkonium chloride 0.010 parts

Distilled water ad 100,000 parts

Making!

The ingredients are dissolved in the usual way. The solution is filtered, with the eye drop solution requiring sterile filtration. Each ml of solution contains 0.2 mg of active ingredient.

The active substances mentioned in Examples 36 to 40 can be replaced by any other active substance encompassed by the general formula I or one of its non-toxic pharmaceutically acceptable acid addition salts. Also, the amount of active ingredient within the above dosage may be varied, and also the amount and type of inert pharmaceutical excipients may be altered based on specific requirements. ,

Claims (3)

may be hydrogen, an alkyl group having 1 to 4 carbon atoms, the hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, halogen, trihalomethyl, di- (alkyl having 1 to 4 carbon atoms) amino, ( Alkoxy of 1 to 4 carbon atoms) carbonyl, nitro, cyano or acyl of 1 to 3 carbon atoms; and Rg, which may be the same or different, are hydrogen, methyl, hydroxy, carboxy, (alkoxy of 1 to 4 carbon atoms) carbonyl, hydroxymethyl, phenyl or p-chlorophenyl; and Hydrogen or methyl j and k indices from O to 3, but no more than 4 in total m and η indices from O to 3 * but not more than 4 in total 2. The method according to item 1, characterized by reacting compounds of the formula ι ·. R ₁₄ R ₁₆ ^R 8 produces, in which j, k, m and η are 0, 1 or 2; R ₂ and Rc are hydrogen, chlorine, methyl or lower alkoxy; and Rq are both hydrogen or - in the case of k Φ 0 - one of the radicals R and Rq is hydrogen and the other hydroxyl, or - in the case of j and k = 0 - one of the radicals R ₇ and R _{Q is} hydrogen and the other -C- -H.-R _{o Q is} hydrogen and the other -C / - or - in the case lc ^ O - both radicals R ^ and R _q together oxo; - 4Θ - ^R 13 * ^ 14 * ^R 15 ¹ ^ ^R i6 · ^ ^β may be the same or different, hydrogen or methyl, or L. and L, together and / or R ₁₁ - and R. r together oxo; Ro and RQ are both hydrogen or - in the case m £ 0 - one of R ₈ and R _{10 is} hydrogen and the other hydroxy, or one of the radicals R ₈ and R _{10 is} hydrogen and the other -C ₆ H ₄ -R ₅ or -COO-alkyl having 1 to 4 carbon atoms), or - in the case πι Φ 0 - both radicals R _Q and R ₁₀ together oxo and X is an alkylene chain having 1 to 2 carbon atoms, which is optionally substituted by hydroxy, and their physiologically acceptable acid addition salts. ₂ - or -CHg-CHg- or r, and Rq together or R ₀ and R " _A together oxo, with the proviso that k or m are different from 0, or j and Rq together and Rq and R ₁₀ together are oxo, with the proviso that k and m are different from 0, or i R ^ ₁ and Rio · ^ ^e may be the same or different, one at the carbon atoms of the piperazine ring to four methyl substituents (A '-CH ^ -) R ₁ O, Rj / »R-JC and R ₁ ^, which may be the same or different, are hydrogen or methyl or R ₁ O and R ₁ α together and / or R ^ e and Rg together oxo and X denotes an alkylene chain having 1 to 2 carbon atoms, which is optionally substituted by hydroxyl, and, if appropriate, denotes their physiologically acceptable acid addition salts and / or pharmaceutical preparations, a) a compound of the general formula f13 ^ 15 ·
YCXCZ (II) • I -.- ». ,. , : ' ^R 14 ^R 16 wherein R ^ o »Rj /» R ^ c »R ₁ ^ and X have the meaning given in point 1 and Y and Z are reactive groups, with a ^ compound of the general formula C - -N NH (III) R. Ί1 wherein R ₁ , Rg, R ₃ , Ry, Rq, Riι »Ο» k and A have the meaning given in point 1, or that b) a compound of the general formula N-C-X-C-Y (IV) 16 wherein R ₁ , Rg, R ₃ , R ^, R ^, R ₁₁ VR ₁₃ , Rj ^ "R-J5" ^ 16 '"^ * Y, 3, k and A have the meaning given in point 1, with a Compound of the general formula (CH ₂ ) _n ^R 10 C - - N (V) 12 wherein have ^{the abovementioned} meaning R., Rc, Rg, Rg, R-iq ^'R 12 * ^m * ^{n un'} ^ ^A ^ ^e, is reacted, or in that c) for the preparation of such end products of the general formula I which are symmetrical with respect to the central group X _, a compound of the general formula _A - ^ ^R 13 ^R 15 ρ- _χ HN N - C - X - C - Ν NH (VI) I i ^E 14 ^R 16 ^R 12 wherein R ₁ 1, R ₁₂ * ^R -J3 » ^R 1A» ^R 15 » ^R 16» ^{x 1} ^ ^{A have the} meaning given ⁱⁿ point 1, with a compound of the general formula R ₁ ) ^ - C - (CH ₂ ) _k - Y (VII) R ₃ . ; ^R 7 wherein R ₁ , R ₂ , R-, R ", Rq, Y, j and k have the meaning given in point 1, reacting, or that d) for the preparation of such end products of the general formula 1 in which X represents a carbinol group, a compound of the general formula ^R 13 / ° \ c - c - σ (viii) I I I ^R 14 ^R 18 ^R 16 wherein R ₁ ^, R m »R-in and R ^ have the meaning given in point 1, R _{18 is} hydrogen or a lower alkyl radical and Y has the same meaning as in formula II, with a compound of the general formula V, and that optionally converted into a physiologically acceptable acid addition salt according to one of the processes a to d end product of the general formula I in known manner and / or with other pharmafcodynamisch active substances and conventional Hilfs ~ and / or carriers processed into conventional pharmaceutical applications. 3 · Method according to item 1, characterized in that compounds of the general formula 's V ^fi3 * 17^R ₁₅ ^ - (CH ₀ ) -N NC CH - <3 ~ N N- (CH ₀ ) ^R 14 ^R 16 produces, in which R ₁ VltId-R ₁ ^ hydrogen or together oxo; R ₁ Y is hydrogen or hydroxy;
R ₁ C and R _{16 are} hydrogen or together oxo; and a and b are 1, 2, 3 or 4 and their physiologically acceptable acid addition salts · '