CS254998B2 - Method of new bis-(piperazinyl-or homopiperazinyl)alcanes production - Google Patents

Description

The present invention relates to a process for the preparation of novel bis- (piperazinyl- or homopiperazinyl) alkanes and their physiologically acceptable acid addition salts, which have valuable pharmacological properties and can be used as active pharmaceutical ingredients, in particular as antiallergics and anti-inflammatory agents.

Compounds of the general formula are known in the art

r ~

C ^ N ^ N-C ^ -N ^ N-CH.,

wherein n is one of the numbers 2, 6, 8, 9 or 10 described by S. Chiavarelli, P. Mazzeo, F. Costa, and A. M. Russo in Farmaco, Ed. Sci. 20,

229 (1965). These compounds have an effect similar to that of curare.

J. van Alpen describes in Rec. Trav. Chim. 55, 835 (1936) the synthesis of polyamines of formulas

 -Λh ^ ch ^ cHg-n ^ N-c

without any indication of their biological activity. The works of C. B. Pollard, W. M. Lauter and N

O. Nuessle in J. Org. Chem. 24, 764 (1959) relates to the preparation of compounds of the general formula

N N - CH - CH - CH - - N Ν - Λ němž Ρ Λ němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž němž

R is hydrogen, alkyl or halogen in Belgian Patent 633,453. describes compounds of the general formula

V 7

N7 NN ~ CΗ; CH; CHf N v =. / \ _ / ⁴ _χ /

in which

R is halogen or alkoxy having antimalarial, anthelmintic and amoebic activity.

Finally, they describe M. J. Dorokhova, V. A. Chernow, S. M. Minakova, O. Y. Tikhonova and A. N. Zamskaya, Khim.-Farm. Zh., 10, 36 (1976), (C.A. 85, 78 079)

CH

From ~ \ / - \

N, N-fo ÍCHJrfN ^L \ ~ .yv wherein n denotes one of the numbers 2, 3, 6 or 10. These compounds serve as starting materials for compounds of formula VI.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of novel bls- (piperazinyl- or homopiperazinyl) -alkanes of the formula (R), (R).

Ra f ⁵ Λλ N _N - c - / - _C - f _N (R ₅ ) _x

(AND)

284998 in which

R 1 and R 2, which are the same or different from each other, are hydrogen, methyl, C 1 -C 4 alkoxy, chlorine, bromine, fluorine, trifluoromethyl or acetoxy,

R3 represents a hydrogen atom or a hydroxy group,

R1 is hydrogen or together with R3 is oxo, m being other than zero, n and m being 0, 1 or 2, the sum of which is not more than 3,

A represents a methylene group or an ethylene group,

R 5 represents a hydrogen atom or represents a methyl group on the carbon atoms of the piperazine ring, i.e. when A represents a group -CH 2 - x represents a number from 1 to 4,

R e, R 2, R e and R 9 are the same or different from each other and are hydrogen or methyl, or

R6 and R7 or / and R6 and R9 together represent oxo, and

X represents a C 1 -C 2 alkylene chain optionally substituted by a hydroxy group and their physiologically acceptable acid addition salts.

A preferred subgroup of compounds of formula (I) are those of formula (I *);

R <

Z-Λ ^R f

T ⁸ cI

wherein R 2 stejné, which are the same or different from each other, represents a hydrogen atom, a methyl group, a C 1 -C 4 alkoxy group or a chlorine atom,

R3 represents a hydrogen atom or a hydroxy group,

R1 represents a hydrogen atom or together with R3 represents an oxo group, m having a meaning other than zero, n and m being 0, 1 or 2, the sum of which is not more than 3,

R e, R 7, R e and R e are the same or different from each other and are hydrogen or methyl, and

X represents a C 1 -C 2 alkylene chain optionally substituted by a hydroxy group, as well as their physiologically acceptable acid addition salts.

Particularly preferred are the compounds of formula (I) -Q-I-Q-I

N NC-CH-CN R _11f ^R 10

it) in which:

R 3 and R 1 are hydrogen or together are oxo,

Ris and Ris represent hydrogen or together represent oxo,

R 17 is hydrogen or hydroxy, and a and b are 1, 2, 3 or 4, as well as their pharmaceutically acceptable acid addition salts.

According to the present invention, the novel bis- (piperazinyl- or homopiperazinyl) alkanes of the formula I are prepared by preparing a compound of the formula

i ř .. u ·

AND

J 8 together form an oxo group (by the action of conventional hydrogenating agents such as hydride

P sodnoboritý.

; The compounds of formula (I) are basic NH 3 and thus form addition salts with inorganic acids and / or organic acids.

'Ί As examples of non-toxic, physiologically ^! The acid addition salts which can be used include the salt (s) obtained by reaction with:

in which

R 5, R 6, R 7, R 8, R 9, A, X and x are as defined above, with a compound of formula VII

in which

R1, R2, R3, R1, n and m are as defined above,

Y represents a reactive group such as chlorine, bromine, iodine, an activated ester group or a hydroxy group.

The condensation reaction of the invention may be carried out in the presence or absence of a solvent. Aqueous or organic inert solvents may be used, the choice of solvent depending on the nature of the reactants.

Examples of such solvents include:

dimethylsulfoxide, dimethylformamide, dioxane, ethoxyethanol and alkanols of up to 5 carbon atoms, optionally with the addition of water.

Aromatic solvents may 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 materials and the solvent used for this reaction and is between room temperature and the reflux temperature of the reaction mixture. The reaction time depends on the temperature and ranges from a few minutes to several hours.

Compounds of formula I in which R3 is hydroxy may be obtained by hydrogenating in a known manner a compound in which R3 and R4 are hydrohalic acid, preferably hydrochloric acid or hydrobromic acid, 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 the process according to the invention are known compounds or can be prepared by methods known per se.

Compounds of formula VI are disclosed in British Patent Specification 480,358 and Khim.-Farm. Zh. 10, 36 (1976), reported in C.A. 85, 78 079.

The following compounds of the formula I as well as their acid addition salts can be prepared by the process according to the invention:

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

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

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

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

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

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

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

1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1-methylpropane tetrahydrochloride heml hydrate,

1,3-bis- [4- (4-chlorobenzylhydryl) -1-piperazinyl] propane dihydrochloride dihydrate, 1,3bis- (4-phenacyl-1-piperazinyl) propane tetrahydrochloride monohydrate,

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

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

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

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

1,3-bis- [4- (1-phenylethyl) -1-piperazinyl] for pan-tetrahydrochloride,

1,3-bis-14- (4-chlorobenzyl-2,5-dimethyl-1-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-bis- [4- (2-chlorobenzyl) -1-piperazinyl] propane tetrahydrochloride,

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

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

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

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

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

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

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

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

1,3-bis- (4- (4- (4-chlorophenylbutyl)) -1-piperazinyl) propane,

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

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

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

The following examples serve to illustrate the invention in greater detail without, however, limiting its scope in any way.

He did

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, 3-bis- (1-piperazinyl) propane, 50 g of ethanol and 7.0 g of trlethylamine is heated under reflux for 16 hours. . The reaction mixture is then concentrated in vacuo, 150 ml of water are added to the residue, and the mixture is extracted five times with 100 ml of ether each time. The combined ether extracts were washed three times with 100 ml of 1M sodium carbonate solution each time, dried over magnesium sulfate, filtered and concentrated to give a yellow solid.

6.8 g of a yellow oil. This oil was dissolved in hexane (100 mL) and filtered. The filtrate was extracted three times with 20 ml of 2% aqueous acetic acid each time, the desired product appearing in extracts 2 and 3 (monitored by thin layer chromatography).

These extracts were combined, basified strongly with 2N sodium hydroxide solution and extracted with 100 mL of ether / hexane (1: 1). The extract was dried over anhydrous potassium carbonate and then the solvent was evaporated. The residual oil (2.6 g) was dissolved in 10 ml of methanol. Addition of 30 ml of ether saturated with hydrogen chloride gave a white precipitate. An additional 50 mL of ether was added and the precipitate was filtered off and recrystallized from methanol. The title compound is obtained as colorless crystals, m.p. 265-268 ° C (dec. 250 ° C).

Example 2

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

A mixture of 4 g of 4-chlorophenylethyl chloride, 5.3 g of 1,3-bis- (1-piperazinyl) propane, 50 g of ethanol and 7.0 g of triethylamine is heated under reflux for 16 hours. The reaction mixture is then evaporated under reduced pressure and 150 ml of water are added to the evaporation residue. The resulting mixture was extracted with ether (5 x 100 mL) and the combined extracts were washed with 1M sodium carbonate solution (3 X 100 mL).

The resulting ethereal solution was extracted three times with 300 ml of 1N hydrochloric acid each. The aqueous extract was basified with 2N sodium hydroxide solution and the product was extracted three times with 200 ml of ether each time. The ethereal extract was dried over magnesium sulfate, filtered, evaporated and evaporated.

5 4 9 98 rec is recrystallized from heptane to give

1,3-bis- [4- (4-chlorophenylethyl) -1-piperazinyl] propane as a white crystalline product (m.p. 87-88 ° C).

In an analogous manner to that described in Examples 1 and 2, the compounds shown in the following Examples are also prepared.

Example 3

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

The product is obtained as white crystals.

Melting point: 261 to 274 ° C (decomposition).

Example 1 a d 4

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

After recrystallization from heptane, the title compound is obtained as colorless crystals.

Melting point: 85-86.5 ° C.

Example 1 a d 5

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

The compound is obtained as white crystals.

Melting point: 101-103 ° C.

Example 6

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

The compound is obtained as white crystals.

Melting point: ^250-265 ° C.

Example 7

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

The compound is obtained as white crystals.

Melting point: 228-237 ° C (decomposition).

Example 1 a d 8

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

The compound is obtained as white phallus rats.

222 DEG-250 DEG C. (decomposition).

Example 9

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

The compound is obtained as white phallus rats.

Melting point: 228-232 ° C.

Example 10

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

The compound is obtained in the form of white crystals.

Melting point: 194-204 ° C ^R

When asked

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

The compound is obtained in the form of white crystals.

Mp: 233-240 ° C.

Example: /

1,3-Bis- (4-phenyl-1-piperazinyl) propane dihydrochloride dihydrate

The compound is obtained in the form of white crystals.

Melting point: 210-225 ° C.

Example 13

1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1,8-dioxopropane dihydrochloride monohydrate

The compound is obtained in the form of slightly yellowish crystals.

Melting point: 199-206 ° C.

Example 1 a d 1 4

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

The compound is obtained in the form of white crystals.

Melting point: 87-88 ° C.

Example 15

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

The compound is obtained as white crystals.

Melting point: 236-246 ^and C (decomposition). Example 16

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

The compound is obtained as white crystals. .

Mp .: 204-214 ° C.

Example 17

1,3-bis-14- (4-ethoxybenzyl) -1-piperazinyl] propane.

The compound is obtained as white crystals.

Melting point: 86-87 ° C.

Example 18

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

The compound is obtained as white needles.

Melting point: 245 to 251 ° C (decomposition).

Example 19

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

The compound is obtained as white crystals.

Melting point: 251-255 ° C.

Example 20

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

The compound is obtained as white crystals.

Melting point: 245-252 ° C (decomposition).

Example 21

1,3-Bis- [4- (3-chlorobenzyl) -1-piperazinyl] proipane dihydrochloride monohydrate

The compound is obtained as white crystals.

Mp 248-257 ° C (dec.).

Example 22

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

The compound is obtained as white crystals.

Mp 245-246 ° C (dec.).

Example 1 a d 2 3

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

The compound is obtained as white crystals.

Mp: 237-243 ^° C.

Example 1 a d 2 4

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

The compound is obtained in the form of white crystals which, after recrystallization from aqueous ethanol, m.p. 218 DEG-224 DEG C. (dec.).

Example 25

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

Recrystallization from ethanol / water gave the title compound as white crystals.

Melting point: 213-217 ° C (decomposition).

Example 26

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

The compound is obtained as white crystals.

Melting point: 102-105 ° C.

Example 27

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

After recrystallization from a mixture of ethanol and

1β in the form of allergic asthma, rhinitis, conjunctivitis, hay fever, urticaria, food allergies, etc.

of water, the title compound is obtained as white crystals.

Melting point: 207-218 ° C.

Example 28

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

The compound is obtained from an ether solution by precipitation of an excess of ethereal hydrogen chloride and recrystallization from ethanol as white crystals.

Example 29

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

The compound is obtained in crystalline form.

Release of the mediator from fat cells and basophil cells occurs in many allergic and inflammatory diseases. The efficacy of agents that inhibit the non-cytotoxic exocytosis of such mediators can be tested in in vitro models, which are represented by inhibiting the release of mediator from isolated cell systems that are induced by reaction with an antigen antibody.

The following table summarizes the data obtained from various assays that show the biological activity of some of the compounds of the invention.

The following cellular systems are listed in the table:

Example 30 RPMC:

peritoneal fat cell preparations

1,3-bis- [4- (4-chlorobenzyl) -1-homopiperazin-2-yl] -1,3-dioxopropane dihydrochloride

GPBL:

The compound is obtained in crystalline form. guinea pig leukocytes enriched basophilic cells Compounds of formula (I) and their non- toxic, physiologically usable addition salts URL: with acids, they have valuable pharmacological human leukocytes enriched with basophil cells Properties. These compounds have in particular kami due to its strong effect on inhibition release of mediator in numerous cellular As clinically used comparators anti-inflammatory and antiallergic systems (standard) served: warm-blooded properties, such as rats; and are therefore suitable for combating allergic theophylline a diseases such as: disodium cromoglycate (DSCG) Table Example compound Inhibic effect on mediator release number IC50 (/ tm) * RPMC GPBL HBI, 3 3 40 2 4 80 20 May 3 13 10 50 3 14 NT 10 0.7 22nd 0.5 9 0.7 theophylline > 1000 200 400 DSCG - -> 1000

Note:

* concentration of compound that is required to mediate from corresponding cells by 50%

NT = Not tested

In pharmaceutical use, the compounds produced by the process of the invention may be administered to warm-blooded animals topically, orally, parenterally, rectally, or by inhalation. The compounds are used to inhibit the release of pharmacological agents as active ingredients in conventional dosage forms, for example in the form of preparations which essentially consist of an inert pharmaceutical carrier and an effective dose of the active ingredient.

Compounds of formula I that are orally administered may be in the form of syrups, tablets, capsules, pills, and the like. Preference is given to formulations which contain a single dose of the active ingredient or preparations which enable the patient to use a single dose. Tablets, powders or lozenges can be prepared using any excipient suitable for the preparation of solid pharmaceutical preparations.

Examples of such excipients are:

various types of starches, lactose, glucose, sucrose, cellulose, calcium phosphate and limestone.

These preparations may also be in the form of capsules [for example of gelatin] containing the active ingredient or in the form of a syrup, solution or suspension. Suitable liquid pharmaceutical carriers are:

ethyl alcohol, glycerin, sodium chloride solution, water, propylene glycol or sorbitol solution, to which flavorings or colorants may be added.

The compounds according to the invention can also be used in the form of suppositories for rectal administration or in the form of an aqueous or non-aqueous solution for injection, in the form of a suspension or emulsion in a pharmaceutically acceptable liquid, such as sterile, pyrogen-free defect or oil suitable for parenteral use; a mixture of liquids which contains bacteriostatic agents, antioxidants, preservatives, buffers or solutions which are added to the solution to be used in an isotonic state.

Thickeners, suspending aids or other pharmaceutically acceptable additives may also be added. Administration is carried out in unit dose form, such as ampoules or disposable injectables, or in multi-dose containers such as bottles from which appropriate quantities can be taken, or in solid or concentrate form which may be used. for the preparation of a solution for injection.

The compounds according to the invention can also be used in the form of aerosols or inhalable solutions, which can be sprayed in a nebulizer or in the form of a microcrystalline inhalation powder, either alone or in combination with an inert carrier, for example lactose. Particles of the active compounds with a diameter of less than 20 μΐη, preferably with a diameter of less than 10 ₍ µm) are suitable for this purpose.

isoprenaline, isoetarin, metaproterenol, salbutamol, phenylephrine, phenoteril and ephedrine, xanthine derivatives such as theophylline and aminophylline net corticosteroids such as prednisolone and adrenergetics such as ACTH.

For topical application to the skin, nose or eye, the compounds produced by the process of the invention may also be in the form of an ointment, cream, lotion, gel, aerosol or solution. In addition, topical nasal and eye solutions may contain, in addition to the compounds of the invention, suitable buffers, bacteriostats, antioxidants and viscosity-reducing agents in aqueous media.

Examples of viscosity enhancers include:

polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbitanesters or glycerin.

Examples of suitable bacteriostats include:

benzalkonium chlorides, thimerosal, chlorobutanol or phenylethyl alcohol.

Formulations topically applied to the eyes may 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, a suitable dose comprises from 0.005 to 500 mg of active ingredient. The effective dose of a compound produced by the process of the invention will depend upon the particular compound employed, the condition of the patient and the frequency and type of administration. Generally it is between 0.0001 mg / kg to 10 mg / kg body weight ·

Usually, written or printed data for the appropriate medical application, in this case as an antiallergic, for prophylaxis and treatment, for example asthma, hay fever, rhinitis or allergic eczema, is added to the pharmaceutical preparations.

For the manufacture of pharmaceutical preparations, the compounds of formula I are mixed in conventional manner with suitable pharmaceutical carriers and flavorings as well as colorants, and are compressed, for example, into tablets, filled into capsules or suspended or dissolved in water with the addition of appropriate adjuvants; in an oil such as corn oil.

The compounds produced by the process of the invention may be administered orally or parenterally in liquid or solid form. Water for injectable solutions is preferably used which contains such stabilizers, co-solvents and / or buffers as are commonly used for injectable solutions.

Additives of this type include, for example:

tartrate buffer, citrate buffer and acetate buffer, ethanol, propylene glycol, polyethylene glycol, complexing agents such as ethylenediaminetetraacetic acid, antioxidants such as: sodium bisulfite, sodium metabisulfite or ascorbic acid, high molecular weight polymers and liquid polymers such as liquid polymers and liquid polymers Sorbitol anhydride polyethylene derivatives.

Optionally, preservatives, such as:

benzoic acid, methylparaben or propylparaben, benzalkonium chloride or quaternary ammonium compounds.

Solid carriers which are suitably used are, for example:

starches, lactose, mannitol, methylcellulose, microcrystalline cellulose, talc, silicic acid, secondary calcium phosphate, and high molecular weight polymers such as polyethylene glycol.

Formulations for oral administration may optionally contain fragrances and / or sweeteners.

For topical use, the compounds produced by the process of the invention may also be used in the form of solutions, powders or ointments. In such cases, the compounds are mixed with, for example, physiologically compatible diluents or conventional ointment bases.

The following examples describe some formulations for pharmaceutical use which contain as an active ingredient a compound produced according to the invention. Parts are parts by weight unless otherwise stated. Example 31

Tablets

The tablet contains the following ingredients:

parts

1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] propane tetrahydrochloride 0.010 stearic acid 0.010 glucose 1,890 1,910 Production: The ingredients are blended in the usual manner and compressed to give tablets weighing 0.91 g. In the summer it contains 10 mg of the active substance. Example 32 Ointment The ointment contains the following ingredients: parts 1,3-bis- (4- (4-chlorobenzyl) -1-piperazinyl) -2-hydroxy- propane fuming hydrochloric acid 2,000 díková 0.011 sodium bisulphite a mixture of cetyl alcohol and 0.050 steryl alcohol (1: 1) 20,000 white vaseline 5,000 synthetic bergamot oil 0,075 distilled water to 100,000 Production: The individual components are mixed in the usual manner to an ointment. 100 g ointment contains 2.0 g Active substance.

Example 33

Aerosol for inhalation:

The aerosol consists of the following components:

parts

1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1,3-dioxopropane dihydrochloride monohydrate 1.00 soya lecithin 0.20 propellant (freon 11, 12 and 14) to 100, 00

Production:

The components are mixed in a conventional manner and filled into an aerosol container equipped with a metering valve, with the metering valve delivering 0.5-2.0 mg of active ingredient per actuation of the valve.

Example 34

Solution for injection:

Solution for injection consists of the following components:

parts

1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] propane dihydrochloride 5.0 sodium bisulfite 1.0 sodium ethylenediaminetetraacetic acid 0.5 sodium chloride 8.5 double distilled water up to 1000.0

Production:

Dissolve the constituents in a sufficient quantity of twice distilled water, dilute the solution with a further amount of twice distilled water to achieve the indicated concentration, filter the solution to remove suspended particles and fill the filtrate under aseptic conditions into 1 ml ampoules which are then sterilized and sealed. Each ampoule contains 5 mg of active substance.

Example 35

Solution for topical use (eye or nose drops):

The solution consists of the following components:

parts

1,3-bis- [4- (4-chlorobenzyl) - -1-piperazinyl] -2-hydroxypropane tetrahydrochloride secondary phosphate 0.020 sodium 0,758 primary sodium phosphate 0.184 sodium chloride 0.3 * 65 polyvinyl alcohol 3,500 benzalkonium chloride 0.010 distilled water to 1 000,000 Production:

The components are dissolved in the usual manner. The solution is filtered, and the eye drop solution requires sterile filtration. Each ml of solution contains 0.2 mg of active substance.

The active ingredients of Examples 31-35 may be replaced by any other active ingredient within Formula I or a non-toxic pharmaceutically acceptable acid addition salt thereof. It is also possible to vary the proportion of active ingredient within the above dosages, and the amount and type of inert pharmaceutically acceptable carriers can be varied according to special requirements.

Claims (6)

OBJECT OF THE INVENTION 1. A process for the preparation of novel bis- (piperazinyl- or homopiperazinyl) alkanes of the formula I R, R, i R-. (R «) J'X in which R 1 and R 2, which are the same or different from each other, are hydrogen, methyl (I), C 1 -C 4 alkoxy, chlorine, bromine, fluorine, trifluoromethyl or acethoxy, R3 represents a hydrogen atom or a hydroxy group, R a represents a hydrogen atom or together with R 3 represents an oxo group, m being other than zero, n and m being 0, 1 or 2, the sum of which is not more than 3, A represents a methylene group or an ethylene group, R 5 represents a hydrogen atom or represents a methyl group on the carbon atoms of the piperazine ring, i.e. when A represents a group - CH 2 -, x represents a number from 1 to 4, R e, R '7, R e and R 9 are the same or different from each other and are hydrogen or methyl, or Re and R7 or / and Re and Ro are together oxo, and X represents a C 1 -C 2 alkylene chain optionally substituted by a hydroxy group and their physiologically acceptable acid addition salts, characterized in that a compound of formula VI in which: R 5, R 6, R 7, R 8, R 9, A, X and x have the above meanings, with a compound of formula VII ^{R 1} ,> (CHp-C (Vin in which R1, R2, R3, Ra, m and n are as defined above, A reactive group such as chlorine, bromine, iodine, an activated ester group or a hydroxy group is optionally substituted, whereupon the compound of formula (I) is optionally converted into a physiologically acceptable acid addition salt. 2. A process according to claim 1, wherein the corresponding compounds of the general formulas (VI) and (VII) are used as starting materials to form 1,34bls- [4- (4-chlorobenzyl) -1-piperazinyl] propane and its physiologically acceptable addition salts thereof. acids. 3. The process of claim 1, wherein the corresponding compounds of formulas VI and VII are used as starting materials to give 1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] -2-hydroxypropane and its physiologically acceptable acid addition salts. 4. A process according to claim 1, wherein the corresponding compounds of formulas VI and VII are used as starting materials to give 1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1,3. -dioxopropane and its physiologically acceptable acid addition salts. 5. A process according to claim 1, wherein the corresponding compounds of formulas VI and VII are used as starting materials to produce 1,3-bis- [4- (4-chlorophenethyl) -1-piperazinyl] propane and its physiologically useful compounds. acid addition salts. 6. The process of claim 1, wherein the corresponding compounds of formulas VI and Vil are used as starting materials to give 1,3-bis- [4- (3- (4-chlorophenyl) propyl] -1-piperazinyl] propane. and its physiologically acceptable acid addition salts.