IE51383B1 - Indanone-oxyalkyl-piperazine derivatives,their preparation,and pharmaceutical formulations containing these compounds - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A compound of the general formula (I) see diagramm : EP0043971,P14,F1 where R**1 is hydrogen or hydroxyl, R**2 is chlorine, fluorine, methoxy or methyl and the oxyalkyl-piperazine side chain is in the 4-, 5- or 7-position of the indan-1-one ring system, and its physiologically tolerated addition salts with acids. For the Contracting State AT 1. A process for the preparation of a compound of the general formula (I) see diagramm : EP0043971,P15,F1 where R**1 is hydrogen or hydroxyl, R**2 is chlorine, fluorine, methoxy or methyl and the oxyalkyl-piperazine side chain is in the 4-, 5- or 7-poistion of the indan-1-one ring system, and its physiologically tolerated addition salts with acids, wherein an indanone derivative of the formula (II) see diagramm : EP0043971,P15,F2 where A is see diagramm : EP0043971,P15,F3 B being a nucleofugic leaving group, is reacted, in a conventional manner, with a piperazine derivative of the general formula (III) see diagramm : EP0043971,P15,F4 where R**2 has the meanings given for formula (I), advantageously in a solvent and in the presence or absence of an acid acceptor, and, if desired, the resulting compound is converted into its addition salt with a physiologically tolerated acid.

Description

The present invention relates to novel indanoneoxyalkyl-piperazine derivatives and their addition salts with acids, the preparation of these compounds, and pharmaceutical formulations which contain these compounds and can be used as sedatives, tranquilizers or neuroleptics, or in the treatment of hypertension, German Laid-Open Application DOS 2,335,432 describes, for example, that 3,4-dihydro-2H-naphthalen-l-one-5-oxypropyl-piperasine derivatives exhibit antihypertensive, anti-edematous, anti-allergic and sedative properties. However, their effect is not always satisfactory.

We have found that compounds of the general formula where is hydrogen or hydroxyl and R is chlorine, fluorine, methyl or methoxy, the oxyalkylpiperazine side chain being in the 4-,5- or 7-position on the indan-lone ring system, and their physiologically tolerated addition salts with acids,exhibit valuable pharmaceutical properties.

Compounds according to the invention include, in addition to those mentioned in the Examples, e.g. the following :5- (3- [4- (4-fluorophenyl ).-piperazin-l-yl].-2-hydroxypropoxy )indan-l-one, 5-(3-^4-(4-chlorophenyl)-piperazin-l-yl] -2-hydroxy-propoxy)-indan-l-one, 5-(3-[A-(3-chlorophenyl) piperazin-l-ylj-2-hydroxy-propoxy)-indan-l-one,5-(3- (j4— (4-fluorophenyl)-piperazin-l-ylJ -propoxy)-indan-l-one, -(3-&-(4-chlorophenyl)-piperazin-l-ylJ -propoxy)-indan1-one, and 7-(3-[4-(3-chloropheriyl)-piperazin-l-yl]-propoxy) indan-l-one.

The compounds according to the invention may be prepared by a process wherein an indanone derivative of the formula (II) 0-CH2-A (II) ,0 OH where A is -CH - CH2, -CH-CH2-B or -CH2-B, B being a nucleofugic leaving group and -OCH2~A being in the 4-, - or 7-position on the indan-l-one ring system, is reacted, e.g. in a conventional manner, with a piperazine derivative of the general formula (III) (III) where has the meanings given for formula (I), advant10 agaously in * «olvent and in the presence or absence of an acid acceptor, and, if desired, the resulting compound is converted to its addition salt with a physiologically tolerated acid.

The leaving group B is preferably a halogen atom, especially chlorine, bromine or iodine. Other examples of nucleofugic leaving groups are aromatic and aliphatic sulfonic acid radicals, such as the p-toluenesulfonic acid radical, p-bromobenzenesulfonic acid radical and methanesulfonic acid radical.

The reaction may be carried out at from 10 to 120°C, i.e. at room temperature or above, advantageously at from 50 to 120°C. It can be carried out under atmospheric pressure or in a closed vessel under super31383 - 4 atmospheric pressure, where appropriate with heating to the stated temperature range.

The starting compounds can be reacted direct, ie. without addition of a diluent or solvent. Advan5 tageously, however, the reactions are carried out in the presence of an inert diluent or solvent, for example a lower alcohol of 1 to 4 carbon atoms, eg. methanol, ethanol or a propanol, preferably isopropanol or ethanol, a'lower saturated dialkyX ether, dlalieyl glyool ether or cyclic ether, eg. diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon, such as benzene or an alkylbenzene, eg.-toluene or xylene, a saturated aliphatic hydrocarbon, eg. hexane, heptane or octane, a lower aliphatic ketone, eg. acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkylformamide, eg. dimethylformamide or diethylformamide, or dimethylsulfoxide, or in the presence of water or of a mixture of the solvents mentioned.

Preferred solvents for the reaction.of an epox20 ide of the formula (II), for example of i-(indan-l-one4-oxy)-2,3-epoxypropane, l-(indan-l-one-5-oxy)-2,3epoxypropane, l-(indan-l-one-6-oxy)-2,3-epoxypropane or l-(indan-l-one-7-oxy)-2,3-epoxypropane, with.a piperazine of the general formula (III) are lower alcohols, especi25 ally n-propanol, the reaction preferably being carried out at from 50 to 120°C and under atmospheric pressure.

For the nucleophilic replacement of a radical B in a compound of the formula (II) possessing a radical -CHg-B, for example of l-(indan-l-one-4-oxy)-351383 - 5 chloropropane or l-(lndan-l-one-7-oxy)-3-chloropropane, by a piperazine derivative of the general formula (III), preferred solvents are a lower aliphatic ketone, e.g. acetone, diethyl ketone, methyl isopropyl ketone or methyl Isobutyl ketone, a cyclic saturated ether, especially tetrahydrofuran or dioxane, or a dialkylformamide, e.g. dimethylformamide, the reaction preferably being carried out at from 50 to 120°C, if appropriate in the presence of a catalytic amount of sodium iodide or potassium iodide.

A mixture of the epoxide with a halohydrin can also be used as the starting compound of the formula (II), since such mixtures are under certain circumstances obtained in the industrial manufacture of the starting compounds of the formula II.

In an .advantageous embodiment of the nucleophilic replacement of the radical B by the piperazine derivative used, the reaction is carried out in the presence of a base as the acid acceptor. Preferred bases are alkali metal hydroxides, carbonates, bicarbon20 ates and alcoholates, or tertiary organic amines, such as pyridine or a trialkylamine, eg. trimethylamine or triethylamine. Amongst the alkali metal compounds, those of sodium and potassium are particularly suitable. The base is used in stoichiometric amount or in slight excess. Under certain circumstances it can be advantageous to use an excess of the piperazine - 6 derivative (HI) employed in the reaction, so that it serves at the same time as an acid acceptor.

The time required for complete conversion depends on the reaction temperature and is in general from 2 to 15 hours. The reaction product can be isolated in a conventional manner, for example by filtering,. or by distilling the diluent or solvent from the reaction mixture. The compound obtained is purified in a conventional manner, for example by recrystallization from a solvent, conversion -to an acid addition compound or column chromatography.

The starting compounds of the formula (II) can be obtained by alkylating the hydroxy-indanone on which they are based, e.g. 4-hydroxy-indan-l-one, 5-hydroxyindan-l-one, and 7-hydroxy-indan-l-one, with an epihalohydrin, an a, ur-dihalo-propan-2-ol or an α,ω-dihalopropane. Suitable epihalohydrins are epichlorohydrin, epibromohydrin and epiiodohydrin, suitable a,u)-dihalo-propan-2_ ols are, in particular, 1,3-dichloro-propan-2-ol and l,3-dibromo-propan-2-ol, and suitable α,ω-dihalopropanes are, in particular, 1,3-chlorobromopropane, 1,3-dichloropane and 1,3-dibromopropane.

The method of preparation of the hydroxy-indan1-ones used is described in the literature (Organic Reactions, volume II, pages 114-117; J.D. Loudon and R.K. Razdan, J.Chem.Soc. 1954. 4,299-4,303).

The alkylation of a hydroxy-indan-l-one, so as 81383 - 7 to prepare a starting confound of the fonnula (II), is advantageously carried out at from 50 to 120¾. under atmospheric pressure or in a closed vessel under superatmospheric pressure. Advantageously, an inert diluent or solvent is used, for example a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol of 1 to 4 carton atoms, such as methanol, ethanol, propanol or butanol, a lower alkyl acetate, suoh as methyl acetate, ethyl acetate' or propyl acetate, a dialkylformamide, such as dimethylformamide or diethylformamide, or dimethylsulfoxide, or using an excess of the alkylating agent as the diluent or solvent.

The reactions are preferably carried out in the presence of a base as the acid acceptor. Suitable bases include alkali metal carbonates, bicarbonates,· hydroxides and alcoholates, especially those of sodium and potassium, basic oxides, eg. aluminum oxide and calcium oxide, and organic tertiary bases,, such as pyridine or lower trialkylamines, eg. trimethylamine or triethylamine. The bases can be employed in catalytic amounts or stoichiometric amount or slight excess, relative to the alkylating agent employed.

Preferably, the hydroxy-indan-l-one is reacted with 25 epichlorohydrin, epihromohydrin, 1,3-dibromopropan-2ol or 1,3-dibromopropane in a lower aliphatic ketone, especially acetone or methyl isobutyl ketone, in the presence of not less than one mole equivalent, based on alkylating S i 3 8 3 - a agent, of a base, especially of potassium carbonate, at from 50 to 80°C.

Further, the starting compounds of the formula (II) containing an epoxy group or having a halohydrin structure can be converted into one another by a simple acid-base reaction. Thus, a l-(indan-l-one-oxy)2,3-epoxypropane can be converted, by means of the corresponding hydrohalie acid, to the 1-(indan-1-oneoxy)-3-halo-propan-2-ol, using, as the diluent or sol10 vent, one of the conventional solvents or, preferably, an aliphatic or cyclic ether, eg. diethyl ether, tetrahydrofuran or dioxane, or a lower alcohol, eg. methanol, ethanol or propanol. On the other hand, l-(indan-lone-oxy)-3-halo-propan-2-ols, especially l-(indan-l-one15 4-oxy)-3-chloropropan-2-ol and l-(indan-l-one-4-oxy)-3bromo-propan-2-ol, can be converted to l-(indan-l-one4-oxy)-2,3-epoxypropane by means of a base, such as an alkali metal hydroxide, carbonate, bicarbonate, alcoholate or hydride, or a tertiary organic amine, such as pyridine, piperidine or a tertiary aliphatic amine, eg. trimethylamine or triethylamine. These reactions can be carried out at room temperature and/or can be acceler ated or completed by heating, for example at 60-120°C.

The reaction can be carried out under atmos25 pheric pressure or in a closed vessel under superatmospheric pressure, where appropriate with heating.

The starting materials for the reaction can be isolated beforehand or be produced in situ and further converted direct, without isolation and purification. - 9 The compounds according to the invention, of the formula I, where R1 is hydroxyl, have a chirality center and are obtained as racemates which can be separated into the optically active antipodes by con5 ventional methods, for example by forming diastereomeric salts with optically active auxiliary, acids, such as dibenzoyltartaric acid, camphor-10-sulfonic acid, ditoluyltartaric acid or 3-bromocamphor-8-sulfonic acid.

The resulting compounds according to the inven10 tion can, if desired, be converted to addition salts with physiologically tolerated acids by known methods. Conventional physiologically tolerated organic or inorganic acids which can be used are, for example, amongst inorganic acids, hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid and, amongst organic acids, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid; other suitable acids are to be found in Fortschritte der Arzneimittelforschung (BirkhSuser-Verlag, Basel and Stuttgart) 10 (1966) 224-225 and J.Pharmac.Sci., 66 (1977), 1-5.

The compounds according to the invention, and their physiologically tolerated addition salts with acids, exhibit valuable pharmacological properties.

They can be used as sedatives, tranquilizers or neuroleptics or as agents for the treatment of hypertension.

Those of the compounds which have a preferred sedative/tranquilizing and anti-monaminergic action may S1383 -10be used as sedatives/hypnotics and as tranquilizers or neuroleptics, whereas the other compounds according to the invention which have a preferred relatively selective anti hypertensive activity can be used for treating hyper5 tension and reducing the load of the heart in cases of cardiac insufficiency.

The following methods were used to demonstrate the pharmacological effects: 1. Sedative action 4-8 groups, each of 3 female NMRI mice, are given the compound orally. The orientation hypermotility induced by a new environment is determined photoelectrically, for a period of 30 minutes, starting 30 minutes after administration of the compound.

The ED 50% is the dose which produces a 50% reduction in orientation hypermotility compared to placebo-treated control animals. 2. Anti-methamphetamine action Methamphetamine-HCl (2.5 mg/kg administered intravenously) regularly causes the following symptoms in rats: motor restlessness, searching and sniffing movements, fur standing on end, and tremor (Janssen et al., Arzneim. Forsch./Drug Res. 13 (1963), 205; Randrup et al., Psychopharmacologia 11 (1967), 300), The test compounds are administered intra51383 - 11 peritoneally 30 minutes before methamphetamine. The substance is considered to have an effect if no sniffing movements are observed for a period of 5 minutes after· the injection of methamphetamine.

The mean inhibition dose (ED 5090 is determined, by means of probit analysis, as the dose which prevents the ·occurrence of the symptom in half the animals. 3. Hypotensive action The hypotensive action was demonstrated on 10 narcotised rats (Sprague Dawley, weight 230-280 g) under urethane narcosis (1.78 g/kg administered intraperitoneally). The blood pressure was measured in the carotid artery. . The compound was administered into the jugular vein (aqueous solution, 1 ml/kg).

The ED- 20% was determined, from linear regression between log dose (mg/kg) and relative reduction in blood pressure (Δ%), as the dose which produces a 20% lowering of blood pressure.

Table 1 shows that the compounds of Examples 11, , 1, 4 and 22 have a sedative action. The effective doses are somewhat greater than in the case of Chlorpromazin, so that the strength of effect of the compounds according to the invention is from 227. (Example 11) to 697. (Example 1) of the reference substance. On the other hand, the hypotensive side-effect, which is undesirable in sedatives/neuroleptics, is markedly less pronounced than with Chlorpromazin. The hypotensively active doses are from 6 times (Example 22) to 300 times (Example 15) greater than for the reference substance. 513 83 - 12 Accordingly, the compounds of Table 1 have a more advantageous ratio of the desired central-depressant effect (inhibition of motility) and the undesired hypotensive effect.

On the other hand, some of the compounds claimed have a strong hypotensive action (Table 2). Judged from the hypotensive doses (ED 20%), the activity is from 16% (Example 8) to 89% (Example 10) that of Chlorpromazin, whilst in Example 16 it is even 2.5 times greater than that of Chlorpromazin. On the other hand, the sedative action of these compounds is substantially less than that of the reference substance. A 50% inhibition of motility requires from 5 times (Example 10) to 20 times (Examples 1 and 16) greater doses. The quotient of the effective dose for inhibition of motility (ED 50%) and for reduction of blood pressure (ED 20%) is from 183 (Example 13) to 4,077 (Example 16) and accordingly very much greater than that of the comparative compound Chlorpromazin (Q = 81).

The present results show that within the compounds according to the invention, there are 2 categories v/ith a different action profile. One category of compounds, having a preferred central-nervous action and a lesser hypotensive action are suitable for use as neuro25 leptics and, in low doses, as sedatives/hypnotios or tranquilizers. The second category, having a pronounced hypotensive action, is suitable for the treatment of hypertonia, because of having a markedly lesser - 13 central-depressant action than Chlorpromazin. TABLE 1 Sedative and hypotensive action Compound Inhibition of motility8 ED 50% Reduction of blood pressure·3 ED 20% Example No. ng/kg R.A.C mg/kg R.A. 11 9.44 0.22 1.00 0.026 15 5.76 0.37 7.91 0.003 1 3.05 0.69 1.07 0.024 4 3.56 0.59 _ 0.189 0.14 22 5.03 0.42 0.161 0.16 Chlor- promazin. 2.11 1.00 . 0.0260 1.00 a Mouse, oral administration.

Rat, urethane narcosis, intravenous administration. c Relative activity; Chlorpromazin = 1.00. - 14 TABLE 2 Hypotensive and sedative action Compound Reduction of blood Inhibition of motility13 pressure3 ED 20JS ED 50S( Qc Example Wo. mg/kg’ R.A.d mg/kg R.A. 10 0.0293 0.89 11.03 0.19 376 . 13 0.0722 0.36 13.18 0.16 183' · 19 0.0570 0.46 18.98 0.11 333 16 0.0104 2.50 42.4 0.05 4,077 8 0.158 0.16 46. ip 0.05 294 Chlor- promazin 0.0260 1.00 2.11 1.00 81 a Rat, urethane narcosis, intravenous administration. b Mouse, oral administration. 0 ED 50¾ for inhibition of motility_ ED 20% for"reduction of blood pressure 5 d Relative activity; Chlorpromazin = 1.00.

Accordingly, the present invention also provides therapeutic agents or formulations which in addition to a conventional carrier or diluent contain a compound of the formula (I), or a physiologically tolerated addi10 tion salt thereof with an acid, as the active compound, and the use of the novel compounds for therapeutic purposes.

The therapeutic agents or formulations may be prepared in a conventional manner by compounding an appropriate dose with the conventional solid or liquid B1383 - 15 carriers or diluents and the conventional pharmaceutical auxiliaries, in accordance with the desired route of administration. Suitable doses for man are from 10 to 200 mg for oral administration and from 10 to 100 mg for intravenous administration.

The preferred formulations are those suitable for oral administration. Examples of these are tablets, film tablets, dragees, capsules, pills, powders, solutions or suspensions or forms which exert a depot effect, Por practical use, the compounds to be employed according to the invention are formulated with the liquid or solid carriers conventionally used in pharmaceutical production. For example, appropriate tablets can be obtained by mixing the active compound with conventional auxiliaries, for example inert diluents, suoh as dextrose, sugar, sorbitol, polyvinylpyrrolidone, mannitol, calcium carbonate, calcium phosphate or lactose, disintegrating agents, such as corn starch,alginic acid or polyvinylpyrrolidone, binders, suoh as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers (cf. L.G. Goodman and A. Gilman, The Pharma- , ceutioal Basis of Therapeutics).

Accordingly, dragees may be prepared by coating cores, prepared analogously to the tablets, with agents 5138 3 - 16 conventionally used in dragee coatings, for example polyvinylpyrrolidone, shellac, gum arabic, talc, titanium dioxide or sugar. The dragee shell can also consist of several layers, in which the auxiliaries, mentioned above in connection with tablets, may be used.

The Examples which follow illustrate the present invention.

I. Preparation of starting compounds of the formula (II) EXAMPLE I l-(lndari-l-one-4-oxy)-2,3-epoxypropane g of 4-hydroxy-indan-1-one (0.34 mole) are suspended in 500 ml of isopropanol'and 13.5 g (0.34 mole) of NaOH and 150 ml of H20 are then added. Thereafter, 220 ml (2.8 moles) of epichlorohydrin are added in the course of half an hour and the mixture is then stirred thoroughly for 8 hours at room temperature. The solvent and excess epichlorohydrin are then distilled off under reduced pressure, the residue is repeatedly extracted with toluene, and the combined toluene phases are dried and concentrated under reduced pressure.

The resulting residue is purified by fractional distillation. 54 g (= 77.8% yield) of l-(indan-l-one-4oxy)-2,3-epoxypropane, of boiling point l68-170°C/0,l0.2 mm Hg, are obtained; the material crystallizes on cooling.

Ci2Hi2°3 (204.23) calculated: 70.6 C 5.9 H 23.5 0 found: 70.6 C 6.Ϊ H 23.6 0 81383 - 17 EXAMPLE XI l-(lndan-l-one-5-oxy)-2,3-epoxypropane g of 5-hydroxy-indan-l-one (0.11 mole) are dissolved in 150 ml of anhydrous acetone, and 30 g of 5 KgCOj, 30 g of epibromohydrin (0.22 mole) and 100 mg of Nal are added successively. The batch Is refluxed for.24 hours, with stirring. It is then filtered, and the solvent is distilled off under reduced pressure. 20 g of l-(indan-l-one-5-oxy)-2,3-epoxypropane remain as a crude'product, which is reacted further, without additional purification.

EXAMPLE III l-(Indan-l~one-7-oxy)-2,3-epoxypropane g of 7-hydroxy-indan-l-one (0,2 mole) are dissolved in 250 ml of tetrahydrofuran, 28 g of K2CO^ and 100 mg of Nal are added and 55 g of epibromohydrin are then introduced dropwise at room temperature, whilst stirring. . The solution IS then refluxed for 30 hours, with thorough stirring. When it has cooled, the mixture is filtered, the solvent and excess epibromohydrin are distilled off and the residue is partitioned between water and toluene. The toluene phase is washed with slightly alkaline water, dried and ultimately concentrated. The residue obtained crystal25 lizes completely after standing for some time. 26,5 g (= 69% yield) of l-(indan-l-one-7-oxy)-2,3-epoxypropane, of melting point 58-60°C, are thus obtained.

C12H12°3 <204.23) calculated: 70.6 C 5.9 H 23.5 0 - 18 found: 71.3 C 5.7 H EXAMPLE IV 1-(Indan-l-one-4-oxy)-3-chloro-propane g of l-bromo-3-chloro-propane (0.19 mole) are added to 20 g of 4-hydroxy-indan-l-one (0.135 mole) in 200 ml of anhydrous DMF and the mixture is thoroughly stir red-with 20 g of anhydrous KgCO^ for 12 hours at 60°C and is then stirred for a further 8 hours at room temperature. The solvent is then distilled off MaAtr lo reduced’ pressure and the residue is partitioned between ether and slightly alkaline water. The aqueous phase is repeatedly extracted v/ithether, the ether phases are combined, washed with H^O and dried, and the ether is distilled off under reduced pressure. 24.3 g of crude product are obtained as a brown oil. The greater part of the 1,3-bis-(indan-l-one-4-oxy)-propane formed at the same time is precipitated by treatment with petroleum ether/acetone, and the oily residue remaining after filtering off the precipitate and removing the petroleum ether/acetone mixture.is distilled in a bulb tube, 12.7 g of l-(indan-lone-4-oxy)-3-chloropropane pass over at 220°C/0.2 mm Hg.

C^H^ClOg (224.6) calculated: 64.2 C 5.8 H 15.'8 Cl found: 64.4 C 5.*9 H 15.3 Cl - 19 EXAMPLE V 1-(Indan-l-one-7-oxy)-3-chloropropane g of 7-hydroxy-indan-l-one (0.034 mole) are dissolved In 100 ml of anhydrous acetone and 8 g of 1-bromo3- chloropropane (0.1 mole) and 7 g of K2C03 are added.

The mixture is then refluxed for 3 days, with stirring, after which it is filtered, the residue is thoroughly washed with acetone and the filtrate is concentrated.

The residue thus obtained is partitioned between methylene chloride and slightly alkaline water, the aqueous phase Is repeatedly extracted with methylene chloride, the combined methylene chloride phases are dried and the solvent is distilled off under reduced pressure. 6.5 g of l-(indan-l-one-7-oxy)-3-chloropropane are isolated as a pale yellow oil, which crystallizes completely after a short time; the crystals melt at 53.5°C.

C12H13C1O2 (224.6) calculated: 64.2 C 5.8 H 15.8 Cl found: 64.6 C 6.2 H 15.5 Cl II. Preparation of compounds according to the Invention EXAMPLE 1 4- (3-[4-(4-Fluorophenyl)-piperazin-l-yl] -2-hydroxypropoxy)-lndan-1-one monohydrochloride g of 1-(indan-l-one-4-oxy)-2,3-epoxypropane and 6.1 g of 4-fluorophenylpiperazine are dissolved in 100 ml of n-propanol and the solution is kept on a water bath for 8 hours. The solvent is then - 20 distilled off under reduced pressure. The residue is taken up in methanol/ether and the hydrochloride is precipitated with a solution of hydrogen chloride in ether. The crystals, which may only form on scratch5 ing or leaving the mixture to stand for a lengthy period, are filtered off and recrystallized from water, with addition of animal charcoal. 5.1 g of 4-(3-[4(4-fluorophenyl)-piperazin-1-yl]-2-hydroxy-propoxy)indon-l-ens menohydreahlorida, of melting point 20610 208°C, are isolated.

C22H26N2C1F03 ^20.5) calculated: 62.7 C 6.1 H 6.6 N 4.5 F 8.4 Cl found: 62.5 C 6.1 H 6.8 N 4.3 F 8.4 Cl EXAMPLE 2 -(3-[4-(2-Chlorophenyl)-piperazin-l-yl]-2-hydroxypropoxy) -indan-l-one monohydrochloride g of l-(indan-l-one-5-oxy)-2,3-epoxypropane and 6.7 g of 2-chlorophenylpiperazine in 100 ml of ethanol are refluxed for 10 hours. The solvent is then distilled off and the residue dissolved in a small amount of methanol. The hydrochloride is precipitated by dropwise addition of a solution of hydrogen chloride in ether, and is subsequently filtered off and recrystallized from methanol/ether. 2.7 g of E 5-(3-E4-(2-chlorophenyl)-piperazin-l-yl]-2-hydroxypropoxy)-indan-l-one monohydrochloride, of melting point 249-252°C, are thus obtained.

C22H26N2C12°2 ^7.1) calculated: 60.4 C 5."9 H 6.4 N 16.2 Cl 81383 - 21 founds 60.5 C 6.1 H 6.6 N 16.1 Cl EXAMPLE 3 7-(3-[4-(4-Chlorophenyl)-piperazin-l-yl]-2-hydroxypropoxy)-indan-1-one monohydrochloride g of l-(indan-l-one-7-oxy)-2,3-epoxypropane 5 and 6.7 g of 4-chlorophenylpiperazine in 100 ml of npropanol are left to stand for 3 days at room temperature. The solvent is then distilled off, the residue is dissolved in a small amount of methanol, and the hydrochloride is precipitated by dropwise addition of a solution of hydrogen chloride in ether and then filtered off and reorystallized from ethanol. 5.2 g of 7-(3—[4—(4-chlorophenyl)-piperazin-l-yl]-2-hydroxypropoxy)-indan-l-one monohydrochloride, of melting point 126-128°C, are thus obtained.

C22H26N2Cl203 (437) calculated: 60.4 C 5.9 H 6.4 N 16,2 Cl found: 60.1 C 6.2 H 6.4 N 15.9 Cl EXAMPLE 4 4-(3-C4-(4-Fluorophenyl)-piperazin-l-yl]-propoxy)20 indan-l-one bis-hydrochloride g of l-(indan-l-one-4-oxy)-3-chloropropane and 4 g of 4-fluorophenyl-piperazine in 120 ml of anhydrous EMF are stirred thoroughly with 5 g of K2C03 for 8 hours at 120°C. The mixture is then filtered, the solution evaporated, the residue partitioned between slightly alkaline water and ether, the aqueous phase repeatedly re-extracted with ether, the ether phases combined, washed with water and dried, and the solvent distilled off. 6.5 g of a brown oil remain; this is taken up in a small amount of methanol/ether and converted to the hydrochloride by dropwise addition of a solution of hydrogen chloride in ether. The crystals are filtered off and recrystallized from acetone/methanol/ ether. 3.5 g of 4-(3-[4-(4-fluorophenyl)-piperazin-lylj-propoxy)-indan-l-one bis-hydrochloride, of melting point 223°C, are thus obtained.

C22H27C12FO2 (441) calculated: 59.8 C 6.1 H 6.3 N 16.1 Cl 4.3 F found: 60.1 C 6.2 H 6.1 N 15.9 Cl 4.2 F The compounds listed in the Table which follows are obtained by a method similar to Example 1 from the corresponding glycidyl ethers and the phenylpiperazines, or;by a method similar to Example 4, from the indan-1one-oxy-chloroalkanes and the corresponding phenylpiperazines . 81383 gc »r4 -r4 u cd •HX 0] 0 0 CU (U Ό φ τ4 bO (A cd X<+4 C 0 Φ r-4 a ε ed · X 0 ω & X r—l SO in co cn o 00 SO Os CM o cn CM 00 cn CM i-4 OS CM r-4 CM r-% CM CM r—l CM CM CM 1-4 1 1 I cr i 1 1 1 | I I ΙΠ cr m r-1 cn so o cr Γ. mt SO CM CO o cn CM 00 CM CM r-l O' CM t-4 CM CM CM r—4 CM CM CM r—l r-4 r-4 i—l I—l i—l i-l R*1 I—1 I—l 1—4 ϋ u o o Q a u u ϋ Q Q X X X X X X X X X X X CM CM CM co co cn cn cn cn cn a a X X X X rM r—1 r-4 X X u o u o O Q o υ ϋ ϋ o o o o o I O I O 1 Mt 1 cn 1 CM 1 cM Mt CM co Mt 1 CM cn Mt X X a a X a a X a X X o o o o o o o o o o o in CM CO Mt ΙΛ rM i-l vl Ή £383 - 24 ι—ι ο ο L_L Cu ε μ Ο 4Η <0 W CM CZ rl & c Ο C ♦rl ·Η U Φ •Η X ω υ ο (X Φ Ό φ 1-1 W φ X 4-1 C Ο Φ r—I · G. ε φ · X o Cd X Pi I—1 O' CO Pl m CM 00 pi rH 00 O O' 00 r-1 l"H rH rH I rH 1 CM rH rH I ] © 1 CM 1 00 1 1/Ί ) © pi rH CO 00 t-H rH rH r-l rH rH rH rH rH rH rH rH rH © © © © © © © © X X X X X X X X CM CM CM CM CO CO X X rH rH © © rH r-H © © U I o O I © 1 Ui © 1 1 CM 1 co 1 1 CM 1 CO 1 CO 1 1 X X X X X X X X o o o o O Ρι pi pi pi ρ* P* CO O' © rH rH t-H CM rH CM CM CM CO CM • 25 Λ ® 1 rt © 1 rl fi rt rt 1 1 rd s rt c: 1 rt ί 2 rt 1 £ © rt fi •t« 1 £ 1 fi fi Φ fi 0) rt fi rt fi A £ •rl C •η fi fi 0 ϋ ο fi O •rt fi rt fi N fi N fi rt O tf O tf •0 •rl 1 Ή 1 •rt | NO NO fi O fi 0 Ν 1 d 1 (0 1 Ν Η Ν rt N rt α 1 fil fi 1 fi 1 d rt fd rt fc rt Λ 1 © ±. a L fi rt fi rt fi rl firt fc i © 1 ·© fi C fc S fi £ 4) 1 4>l a i ai Φ £ ft £ ft C β α φ 0 fi Φ ag as rt fi rt fi ft d rt d rt «3 ΛΈ Ρ»Έ a 2 rt 3 rt 3 an a« rt ό ftO ft Ό *γ! 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O ft ft ft S 0 S 0 ϋ C ft C 1 u 1 1 I 1 II I u I t« 1 «Η 1 Ή jS· Ό CM ft cn ft -=r ft CM Ό ng on ι fi· I »-* ft X X *— X >-* ft «*- ft ***** r*x 1 Δ . 1 o i o io l-v 1 X t >3 1 ft sr I sr fc· & t- fi* u fi- 1 fi- 1 fi· X fi- X .—.cm *3 «—»*3 — CM mCM |_J o «—» o t 1 1 >4 t -ft I ft 1 1 1 1 1 ft 1 ft rn*·? m.fi rn.fi en.fi ΓΊ«—» fn·* cn o cn O '*-** i • I V-* 1 *** rH *** Jj *-* u ί ft 1 CM I CM I CM t ft ι ft 1 ft 1 ft tn e— C** * t*· t- e* *=T 1 e— l ftft ft ft tnm cn o JT«* fi-fi* Φ >» 'φ rH rH rH rH rH rH rH i—( rH rH rH rH rH rH rH rH o o o o o o ο o Ο ϋ o o o o Ο ϋ ri σκ CM CA CM CK m rH OK CM. CO cnco o co # · in^r κο tn κο tn coco in-=c CO t·- mew κο tn rH rH rM rH *—1 rH rH rH CM CM rH rH 2 2 2 2 2 2 XX S 2 2 2 z z z z CKKO ZT e* rH κο in CK rH 43 rH rH rH mrH 9 a mm KO\O KO \0 KO\O • in κο KOKO KOKO KO KO 2S IX as aa a a a a aa a a fi- tn enO c\in rH t- fi-KO C-O CK rH rH rH KOKO in κο in κο KOKO KOKO KO t— in κο KOKO ο o o o ο o o o o o ϋ ϋ Ο ϋ o o c\t— - o OK C*· *H CKe*. CO b- co in < < coco O O O cn CM CM coco men σκσκ tntn KOKO κο in KOKO tntn KO Ό tntn tntn -Xj ••d . ·*α •Ό •xi o fi o fi O fi o fi 5 & 5 s rH d rH 3 rH 3 rH 3 rH 3 rd § © (0 O ¢0 O CO O ¢0 0 (0 0 cd o rH Ufa Ufa Oft U fa O ft O ft 1 ft m rH xO rH r* rH co rH CP rH o CM ss (0 o Oft •*6 SS (0 o Oft rH CM CH CM Calc. : 57,7'C 5,9 Η 6.1 Ν 23,2 01 7-(3-14-(4-Chlorphenyl)-plperazin-l-yl]Found . eg.! q β'.Ο Η 6.0 Ν 22.8 Cl -propoxy)-diulan-l-one 51383.

Formulation examples prepared in a conventional manner: 1. Tablets: a) An active compound of formula I Lactose Methylcellulose Coro starch Talc Magnesium stearate b) An active compound of formula I Lactose Avicel Polywachs 6000 Magnesium stearate c) An active compound of formula I Polyvinylpyrrolidone (mean molecular weight 25,000) Polyethylene glycol (mean molecular weight 4,000) Hydroxypropylmethylcellulose Talc Magnesium stearate Ao mg 200 mg 15 mg 50 mg 11 mg 4 mg 320 mg 80 mg 178 mg 80 mg 20 mg 2 mg 360 mg 50 mg 170 mg 14 mg 40 mg 4 mg 2 mg 280 mg The active compound is moistened with a 10% strength aqueous solution of polyvinylpyrrolidone and forced through a sieve of 1.0 mm mesh size, and the granules are dried at 50°C.

They are then mixed with 513 83', polyethylene glycol (mean molecular weight 4,000), hydroxypropylmethylcellulose, talc and magnesium stearate, and the mixture is pressed to give tablets weighing 2S0 mg. 2. Example of dragees: An active compound of formula I 60 mg Lactose 90 mg Com starch 60 mg Polyvinylpyrrolidone 6 mg Magnesium stearate 1 mg 217 mg The active compound, lactose and corn staroh are mixed, moistened with an 8% strength aqueous solution of the polyvinylpyrrolidone, and granulated by passing through a 1.5 mm mesh sieve. The granules are dried at 50°C and forced through a 1.0 mm sieve. The material thus obtained is mixed with magnesium stearate and the mixture is pressed to form dragee cores. These are coated in a conventional manner with a shell consisting essentially of sugar and talc. 3. Capsule formulation: 4.

An active compound of formula I Magnesium stearate Lactose Injection solution: An active compound of formula I Sodium chloride Distilled water, to make up to 1.0 ml .0 mg 2.0 mg 19.3 mg mg 9 mg

Claims (4)

CLAIMS 1. 2 where R is hydrogen or hydroxyl and R is chlorine, fluorine, methoxy or methyl, the oxy-alkyl-piperazine side chain being in the 4-, 5- or 7-position of the indan5 l-one ring system, and its physiologically tolerated addition salts with acids.

1. A compound of the general formula (I) 2. R where R has the meaning given in claim 1, in the presence or absence of a solvent and an acid acceptor, and, if desired, the resulting compound is converted to its addition salt with a physiologically tolerated acid. (III) - 30 6. A compound as claimed in claim 1, when prepared by a process as claimed in claim 5. 7. A pharmaceutical formulation which contains a compound as claimed in any of claims 1 to 4 or 6 as 5 the active compound, together with a pharmaceutically acceptable carrier or diluent. 8. A compound as claimed in any of claims 1 to

2. A compound as claimed in claim 1 and individually named hereinbefore or identified in any of the foregoing Examples 1 to 23. 10

3. 4- (3- [4- (4-Hluorophenyl) -piperazin-l-yl] -2-hydroxypropoxy)-indan-l-one. 4. 7-(3-/4-(2-Chlorophenyl) --piperazin-l-yl7-2-hydroxypropoxy)-indan-l-one. 5. A process for the preparation of a compound 15 as claimed in claim 1, wherein an indanone derivative of the formula (II) n un χ υ \ , where A is -CH-Cl·^, -CH-CI^-B or -Cl^-B, B being a nucleofugic leaving group and -O-CHg-A being in the 4,-5 or 7-posttion of the indan-l-one ring system, is reacted 20 with a piperazine derivative of the general formula (III) Hlf~\ W

4. Or 6 for use as a sedative, tranquilizer or neuroleptic or in the treatment of hypertension.