CA1193601A - Indanone-oxyalkyl-piperazine derivatives, their preparation, and pharmaceutical formulations containing these compounds - Google Patents
Indanone-oxyalkyl-piperazine derivatives, their preparation, and pharmaceutical formulations containing these compoundsInfo
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- CA1193601A CA1193601A CA000381476A CA381476A CA1193601A CA 1193601 A CA1193601 A CA 1193601A CA 000381476 A CA000381476 A CA 000381476A CA 381476 A CA381476 A CA 381476A CA 1193601 A CA1193601 A CA 1193601A
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- indan
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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Abstract
ABSTRACT OF THE DISCLOSURE:
The present invention relates to indanone-oxyalkyl-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, transquilizers or neuroleptics or in the treat-ment of hypertension. The derivatives have the general formula (I)
The present invention relates to indanone-oxyalkyl-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, transquilizers or neuroleptics or in the treat-ment of hypertension. The derivatives have the general formula (I)
Description
~ 3~V~ o Z. 0~50/034550 Indanone-oxyalkyl-piperazine derivatives, their prepara-tion, and pharmaceutical formulations containing these compounds The present invention relates to novel indanone-oxyalkyl-piperazine derivatives and their addition salts with acids, the preparation of these compounds 9 and pharmaceutical formulations which contain these compounds and can be used as sedatives, tranquilizers or neuro-leptics ? or in the treatment of hypertension.
German Laid-Open Application DOS 2,335,432 des-crîbes, for example, that 3,4-dihydro-2H-naphthalen~l-one-5-oxypropyl-piperazine derivatives exhibit anti-1o hypertensive, anti-edematous, anti-allergic and sedative properties. However, their effect is not always satisfactory.
We have fo~nd that compounds of the general formula (I) R2 C O-CH2-C~-(CH2)n~N~ N ~ (I) where Rl is hydrogen or hydroxyl and R2 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, trifluoromethyl or nitro and n is ~, 1 or 2 if Rl is hydrogen, and is 1 if R1 is hydroxyl, and their physiologically tolerated addition salts with.
acids exhibit valuable pharmaceu-tical properties.
Examples of R are: as alkyl, me-thyl, ethyl and propyl; as alkoxy, methoxy, ethoxy and propoxy;and as 3 ~ ~
German Laid-Open Application DOS 2,335,432 des-crîbes, for example, that 3,4-dihydro-2H-naphthalen~l-one-5-oxypropyl-piperazine derivatives exhibit anti-1o hypertensive, anti-edematous, anti-allergic and sedative properties. However, their effect is not always satisfactory.
We have fo~nd that compounds of the general formula (I) R2 C O-CH2-C~-(CH2)n~N~ N ~ (I) where Rl is hydrogen or hydroxyl and R2 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, trifluoromethyl or nitro and n is ~, 1 or 2 if Rl is hydrogen, and is 1 if R1 is hydroxyl, and their physiologically tolerated addition salts with.
acids exhibit valuable pharmaceu-tical properties.
Examples of R are: as alkyl, me-thyl, ethyl and propyl; as alkoxy, methoxy, ethoxy and propoxy;and as 3 ~ ~
- 2 - O.Z. 0050/034550 halogen, especially fluorine, chlorine and bromine.
Preferred compounds are those where Rl is hydrogen or hydroxyl, n is 1 and R2 is chlorine, fluor-ine, methoxy or methyl, and the ~.inkage position of the side chain is the 4-, 5- or 7-position of the indan-l-one ring system `
Compounds according to the inven~ion include, in addition to those men-tioned in the Examples, eg. the following: 4-(2-[4-(4-fluorophenyl)-piperazin-1-yl]-ethoxy) indan-1-one, 4-(2-[4-(4-chlorophenyl)-piperazin-l~yl]-ethoxy)-indan-l-one, 4-(2-[4-(3-chlorophenyl)-piperazin-l-yl]-ethoxy)-indan-l-one, 4-(2-~4-(3-tri-fluorophenyl)-piperazin-l-yl]-ethoxy)-indan-l-one, 4-(4-[4-(4-chlorophenyl)-piperazin-1-yl]-butoxy)-indan-1-one, 5-(3-[4-(4-fluorophenyl)-piperazin-1-yl]-2-hydroxy-propox~indan-l-one, 5-(3-[4-(4-chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy~indan-1-one, 5-(3-[4-(3-chloro-phenyl)piperazin-l-yl]-2-hydroxy-propoxy~indan-1-one, 5-(2-[4-(4-fluorophenyl)-piperazin-1-yl]-ethoxy)-indan-l-one, 5-(3-[4-(4-fluorophenyl)-piperazin-1-yl]-propoxy)-indan-l-one, 5-(3-[4-(4-chlorophenyl)-piperazin-1-yl]-propoxy)-indan-l-one~ 5-(4-[4-(4-fluorophenyl)-piperazin-l-yl~-butoxy)-indan-l-one, 7-(2-[4-(4-chlorophenyl)~
piperazin-l-yl]-ethoxy)-indan-l-one, 7-(Z-[4--(3-chloro-phenyl)-piperazin-l-yl]-ethoxy)-indan-l-one, 7-(2-[4-(2-methoxyphenyl)-piperazin-1--yl] ethoxy)-indan-l-one, 7-(3-[4-(~-chlorophenyl)-piperazin-1-yl]-propoxy)-indan-l-one, 7-(4-[4-(4-chlorophenyl)-piperazin-1-yl]-butoxy)-indan-l-one and 7-(4-[4-(3-chlorophenyl)-piperazin-1-yl]-~3~
Preferred compounds are those where Rl is hydrogen or hydroxyl, n is 1 and R2 is chlorine, fluor-ine, methoxy or methyl, and the ~.inkage position of the side chain is the 4-, 5- or 7-position of the indan-l-one ring system `
Compounds according to the inven~ion include, in addition to those men-tioned in the Examples, eg. the following: 4-(2-[4-(4-fluorophenyl)-piperazin-1-yl]-ethoxy) indan-1-one, 4-(2-[4-(4-chlorophenyl)-piperazin-l~yl]-ethoxy)-indan-l-one, 4-(2-[4-(3-chlorophenyl)-piperazin-l-yl]-ethoxy)-indan-l-one, 4-(2-~4-(3-tri-fluorophenyl)-piperazin-l-yl]-ethoxy)-indan-l-one, 4-(4-[4-(4-chlorophenyl)-piperazin-1-yl]-butoxy)-indan-1-one, 5-(3-[4-(4-fluorophenyl)-piperazin-1-yl]-2-hydroxy-propox~indan-l-one, 5-(3-[4-(4-chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy~indan-1-one, 5-(3-[4-(3-chloro-phenyl)piperazin-l-yl]-2-hydroxy-propoxy~indan-1-one, 5-(2-[4-(4-fluorophenyl)-piperazin-1-yl]-ethoxy)-indan-l-one, 5-(3-[4-(4-fluorophenyl)-piperazin-1-yl]-propoxy)-indan-l-one, 5-(3-[4-(4-chlorophenyl)-piperazin-1-yl]-propoxy)-indan-l-one~ 5-(4-[4-(4-fluorophenyl)-piperazin-l-yl~-butoxy)-indan-l-one, 7-(2-[4-(4-chlorophenyl)~
piperazin-l-yl]-ethoxy)-indan-l-one, 7-(Z-[4--(3-chloro-phenyl)-piperazin-l-yl]-ethoxy)-indan-l-one, 7-(2-[4-(2-methoxyphenyl)-piperazin-1--yl] ethoxy)-indan-l-one, 7-(3-[4-(~-chlorophenyl)-piperazin-1-yl]-propoxy)-indan-l-one, 7-(4-[4-(4-chlorophenyl)-piperazin-1-yl]-butoxy)-indan-l-one and 7-(4-[4-(3-chlorophenyl)-piperazin-1-yl]-~3~
3 --butoxy)-indan-l-one.
The compounds according to the invention may be prepared by a process wherein an indanone derivative of the formula ~II) ~ -CH2-A (II) o ~ OE~
where A is -CH - CH2, -CH-CH2 B or -(CH2)n-B and where B is a nucleofugic leaving group and n is an integer from 1 to 3, is reacted with a piperazine derivative of the general formula (III) H ~ N ~ (III) where R has the meanings given for formula (I), ~e.g.
advantageously in a solvent) in the presence or absence of an acid acceptor, and, if desired, the resulting compound is con~erted to an addition salt thereof 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 methane-sulfonic acid radical.
The reactions may be carriedout at from 10 to 120C, ie. at room temperature or above, advantageously at from 50 to 120C. They can be carried out under atmospheric pressure or in a closed vessel under super-~193~
_ ~ _ o.z 0050~034550 ~mosphericPressure~ where appropriate with heating to the stated ternperature ran~e~
The starting compounds can be reacted direct, ie, without addition of a diluent or solvent. Advan-tageously, however, the reactions are carried out in the presence of an inert diluent or solvent, ~or example a lower a]cohol of 1 to 4 carbon atoms, eg. me-thanol, ethanol or a propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkyl glycol 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 octanel a lower aliphatic ketone, eg. acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkyl-formamide, eg. dimethylformamide or diethylformamide, or dimethylsulfoxide, or in the presence of water or of a mixture of the solvents mentionedu Preferred solvents for the reaction of an epox-ide of the formula (II), for example of l-(indan-l-one-
The compounds according to the invention may be prepared by a process wherein an indanone derivative of the formula ~II) ~ -CH2-A (II) o ~ OE~
where A is -CH - CH2, -CH-CH2 B or -(CH2)n-B and where B is a nucleofugic leaving group and n is an integer from 1 to 3, is reacted with a piperazine derivative of the general formula (III) H ~ N ~ (III) where R has the meanings given for formula (I), ~e.g.
advantageously in a solvent) in the presence or absence of an acid acceptor, and, if desired, the resulting compound is con~erted to an addition salt thereof 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 methane-sulfonic acid radical.
The reactions may be carriedout at from 10 to 120C, ie. at room temperature or above, advantageously at from 50 to 120C. They can be carried out under atmospheric pressure or in a closed vessel under super-~193~
_ ~ _ o.z 0050~034550 ~mosphericPressure~ where appropriate with heating to the stated ternperature ran~e~
The starting compounds can be reacted direct, ie, without addition of a diluent or solvent. Advan-tageously, however, the reactions are carried out in the presence of an inert diluent or solvent, ~or example a lower a]cohol of 1 to 4 carbon atoms, eg. me-thanol, ethanol or a propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkyl glycol 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 octanel a lower aliphatic ketone, eg. acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkyl-formamide, eg. dimethylformamide or diethylformamide, or dimethylsulfoxide, or in the presence of water or of a mixture of the solvents mentionedu Preferred solvents for the reaction of an epox-ide of the formula (II), for example of l-(indan-l-one-
4-oxy)-2,3 epoxypropane, l-(indan 1-one-5-oxy)-2 9 3-epoxypropane, 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, especi-ally n-propanol, the reaction preferably being carried out at from 50 to 120C and under atmospheric pressure For the nucleophilic replacement of a radical B
in a compound of the forrnula (II) possessing a radical -(CH2)n-B, for example o~ l-(indan-l-one-4-oxy)-~-~ 5 O.Z. 0050/034550 chloropropane, l-(indan-l-one-4-oxy)-4-chlorobu-tane, 1-(indan-l~one-7-oxy)-3-chloropropane, 1-(indan-1-one-7 oxy)-4-chlorobutane or 1-(indan-1-one-7-oxy)-2-chloro-ethane, by a piperazine derivative of the general form-ula (III), preferred solvents are a lower aliphatic ketone, eg. acetone, diethyl ketone, methyl isopropyl ketone or methyl isobutyl ketone~ a cyclic saturated ether, especially tetrahydrofuran or dioxane, or a dialkylformamide, eg. dimethylformamide, the reaction preferably being carried out a-t from 50 to 120C~ if appropriate in the presence of a catalytic amount of sodium iodide or potassiwm 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 nucleo-philic replacement of the radical B by the piperazine derivative used, the reaction is carried out in the pre~
sence of a base as the acid acceptor, Preferred bases are alkali metal hydroxides, carbonates, bicarbon-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 ~L93~
- 6 - .Z. 0050/034550 derivative (III) employed in the reaction, so tha-t 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 ~rom 2 to 15 hours. The reac-tion product can be isolated in a conventional manner, for example by filter-ing~ or by distilling the diluent or solvent from -the reaction mixture. The compound obtained is purified in a conventional manner, for example by recrystalliza-tion from a solvent, conversion to an acid addition com-pound or column chromatography.
The starting compounds of the formula (II) can be obtained by alkylating the hydroxy-indanone on which they are based~ eg. 4-hydroxy-indan~l-one, 5-hydroxy-indan-l-one, 6 hydroxy-indan-l-one and 7-hydroxy-indan-l-one, with an epihalohydrin, an ~,~-dihalo-propan-2-ol or an ,~-dihalopropane. Suitable epihalohydrins are epichlorohydrin, epibromohydrin and epiiodohydrin, suitable a~-dihalo-propan-2-ols are9 in particular, 1,3-dichloro-propan-2-ol and 1,~-dibromo-propan-2-ol, and suitable a,~-dihalopropanes are, in particular, 1,3-chlQrobromopropane, 1~3-dichloropropane, 1,3-dibromopropane, 1,2-chlorobromoethane or 1,4-chloro-bromobutane.
The method of preparation of the hydroxy-indan-l-ones used is described in the literature (Organic Reactions, volume II 9 pages 114-117; J.D Loudon and R K, Razdan, J.Chem,Soc 19~4, 4,299-4,303).
The alkylation of a hydroxy-indan-l one 9 SO as - 7 - O.Z. 0050/034550 to prepare a starting compound of the formula (II), is advantageously carried ou-t at from 50 -to 120~, under atmospheric pressure or in a closed vessel under super-atmospheric pressure. Advantageou~ly, an inert diluent or solvent is used, for example a lower ali-phatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol of 1 to 4 carbon - atoms9 such as methanol, ethanol, propanol or butanol, a lower alkyl acetate, such as methyl acetate, ethyl acetate or propyl acetate, a dialkylformamide, such as dimethylformamide or diethylformamide, or dimethylsul-foxide, or using an excess o~ 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 o~ 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 al~ylating agent employed.
Preferably, the hydroxy-indan-l-one is reacted with epichlorohydrin, epibromohydrin, 1,3-dibromopropan-2-ol, l,~-dibromopropane, 1,4-bromochlorobutane or 1,2-bromochloroethane in a lower aliphatic ketone, especi-ally acetone or methyl isobu-tyl ketone, in the presence of not less than one mole equivalent, based on alkylating ` ~9t~36~
- ~ 8 - o Z. 0050/034550 agent, of a base, especially of potassium carbonate, at from 50 to 80C.
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 converted9 by means of the - corresponding hydrohalic acid, to the l-(indan l-one-oxy)-3-halo-propan-2-ol, using, as the diluent or sol-vent, one of the conventional solvents or, preferably, an aliphatic or cyclic ether, eg. diethyl ether, tetra-hydrofuran or dioxane, or a lower alcohol, eg. me-thanol, ethanol or propanol. On the other hand 7 1- (indan-l-one-oxy)-3-halo-propan-2-ols, especially l-(indan-l-one-4-oxy)-3-chloropropan-2-ol and l-(indan-l~one-4-oxy)-3-bromo-propan-2-ol, can be converted to l-(indan-l-one~
4-oxy)-2,3-epoxypropane by means of a base, such as an alkali metal hydroxide, carbonate, bicarbonate, alcohol-ate 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 60-120C
The reaction can be carried out under atmos-pheric pressure or in a closed vessel under super-atmospheric pressure, where appropriate with heating The star-ting materials for the reaction can be isolated beforehand or be produced in situ and further converted direct, without isolation and purification. ~.
;1~9~
- 9 - o.Z. 0050/034550 The compounds according to the invention, of the formula I, where Rl is hydroxyl, have a chirality center and are obtained as racemates which can be separated into the optically active antipodes by con-ventional methods, for example by forming diastereomeric salts with optically active auxiliary acids, such as diben~oyltartaric acid, camphor-lO-sulfonic acid, ditoluyltartaric acid or 3-bromocamphor-8-sulfonic acid.
The resulting compounds according to the in~en-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 Ar~neimittelforschung (Birkhauser-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 9 exhibit valuable pharmacological properties.
They can be used as sedatives, tranquilizers or neuro-leptics or as agents for the treatment of hypertension Those of the compounds ~rhich have a preferred seda-tive/-tranquilizing and an-ti-monaminergic action may 11936()1 - 10 - O.Z. 005~/034550 be used as sedatives/hypnotics and as tranquilizers or neuroleptics, whereas the other compounds according to ~he invention which have a preferred relatively selective anti-hypertensive activity can be used for treating hyper-tension and reducing the load of the heart in cases of ~ardiac 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 hyper-motility induced by a new environment is determined photoelectrically, for a period of 30 minutes, starting ~0 minutes after a~inistration 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 intra~enously) 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 e~ al , Psychopharmacologia 11 (1967), 300).
The test compounds are administered intra-~ O.Z. 0050/034550 peritoneally 30 minutes before methamphetamine~ The substance is considered to have an effect if no sniffing mo~ements are observed for a period of 5 minutes after the injection of methamphetamine.
The mean inhibition dose (ED 50~ 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 ac-tion was demonstrated on narcotized rats (Sprague Dawley, weight 230-280 g) under urethane narcosis (1.78 g/kg administered intra-peritoneally). The blood pressure was ~easured in the carotid artery. The compound was administered into the jugular vein (aqueous solution, l ml/kg).
The ED 20% was determined, from linear regression bet ween log dose (mg/kg~ and relative reduction in blood pressu~e (~%), as the dose which produces a 2~/o lowering o~ blood pressure.
Table 1 shows that the compounds of Examples 14, 19, 1, 4 and 30 have a sedative action. The effective doses are somewhat greater than in the case of Chlor-Fromazin~ so that the strength of effect of the compounds according to the invention is from 22% (Example 14) to 690/o (Example l) of the reference subs-tance On the other hand, the hypotensive side-effec-t 9 which is undesirable in sedative~neuroleptics, is markedly less pronounced than with Chlorpromazin. The hypo-tensively active doses are from 6 times (Example 30) to 300 times (Example l9) greater than for the reference 3 ~
~ O.Z, 0050/034550 substance, Accordingly, the compounds of Table l have a more advantageous ratio of` the desired central-depressant effect (inhibition of motility) and the undesired hypo-tensive effect.
On the other hand, some of the compounds claimed have a strong hypotensive action (Table Z). Judged from the hypotensive doses (ED 20%), the activity is from 16% (Example lO) to 8~/o (Example 13) that of Chlorproma~n, whilst in Example 20 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 f.rom 5 times (Example 13) to 20 times (Example,1 and 20) greater doses. The quotient of the effective dose for inhiDition of motility (ED 5~/0) and for reduction of blood pressure (ED 205b) is from 183 (~xample 17) to 4,077 (Example 20) and accord-ingly very much greater than that of the comparative compound Chlorpromazin (Q = 81), The present results show that within the com-pounds according to the invention, there are 2 categories with a different action profile. One category of com-pounds, having a preferred central-nervous action and a lesser hypotensive actionare suitable for use as neuro-leptics and, in low doses,.as sedatives/hypnotics or tranquilizers. The second category, having a pro-nounced hypotensive action, is suitable for the treat-ment of hypertonia, because of having a markedly lesser 6~ ~
- 13 - O.Z. 0050/034550 central~depressant action than Chlorpromazin.
Sedative and hypotensive action Compound Inhibition of motilitya Reduction ofbblood pressure r ~
Example mg/kg R.A.C mg/kg R.A.
No.
14 g, 44 Oo ~2 1 . 00 0. 026 19 5 . 76 0. 37 7, 91 0. 003 3, 05 Oo 69 1. 07 0 . 024 4 3. 56 0. 5g 0, 189 0. 14
in a compound of the forrnula (II) possessing a radical -(CH2)n-B, for example o~ l-(indan-l-one-4-oxy)-~-~ 5 O.Z. 0050/034550 chloropropane, l-(indan-l-one-4-oxy)-4-chlorobu-tane, 1-(indan-l~one-7-oxy)-3-chloropropane, 1-(indan-1-one-7 oxy)-4-chlorobutane or 1-(indan-1-one-7-oxy)-2-chloro-ethane, by a piperazine derivative of the general form-ula (III), preferred solvents are a lower aliphatic ketone, eg. acetone, diethyl ketone, methyl isopropyl ketone or methyl isobutyl ketone~ a cyclic saturated ether, especially tetrahydrofuran or dioxane, or a dialkylformamide, eg. dimethylformamide, the reaction preferably being carried out a-t from 50 to 120C~ if appropriate in the presence of a catalytic amount of sodium iodide or potassiwm 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 nucleo-philic replacement of the radical B by the piperazine derivative used, the reaction is carried out in the pre~
sence of a base as the acid acceptor, Preferred bases are alkali metal hydroxides, carbonates, bicarbon-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 ~L93~
- 6 - .Z. 0050/034550 derivative (III) employed in the reaction, so tha-t 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 ~rom 2 to 15 hours. The reac-tion product can be isolated in a conventional manner, for example by filter-ing~ or by distilling the diluent or solvent from -the reaction mixture. The compound obtained is purified in a conventional manner, for example by recrystalliza-tion from a solvent, conversion to an acid addition com-pound or column chromatography.
The starting compounds of the formula (II) can be obtained by alkylating the hydroxy-indanone on which they are based~ eg. 4-hydroxy-indan~l-one, 5-hydroxy-indan-l-one, 6 hydroxy-indan-l-one and 7-hydroxy-indan-l-one, with an epihalohydrin, an ~,~-dihalo-propan-2-ol or an ,~-dihalopropane. Suitable epihalohydrins are epichlorohydrin, epibromohydrin and epiiodohydrin, suitable a~-dihalo-propan-2-ols are9 in particular, 1,3-dichloro-propan-2-ol and 1,~-dibromo-propan-2-ol, and suitable a,~-dihalopropanes are, in particular, 1,3-chlQrobromopropane, 1~3-dichloropropane, 1,3-dibromopropane, 1,2-chlorobromoethane or 1,4-chloro-bromobutane.
The method of preparation of the hydroxy-indan-l-ones used is described in the literature (Organic Reactions, volume II 9 pages 114-117; J.D Loudon and R K, Razdan, J.Chem,Soc 19~4, 4,299-4,303).
The alkylation of a hydroxy-indan-l one 9 SO as - 7 - O.Z. 0050/034550 to prepare a starting compound of the formula (II), is advantageously carried ou-t at from 50 -to 120~, under atmospheric pressure or in a closed vessel under super-atmospheric pressure. Advantageou~ly, an inert diluent or solvent is used, for example a lower ali-phatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol of 1 to 4 carbon - atoms9 such as methanol, ethanol, propanol or butanol, a lower alkyl acetate, such as methyl acetate, ethyl acetate or propyl acetate, a dialkylformamide, such as dimethylformamide or diethylformamide, or dimethylsul-foxide, or using an excess o~ 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 o~ 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 al~ylating agent employed.
Preferably, the hydroxy-indan-l-one is reacted with epichlorohydrin, epibromohydrin, 1,3-dibromopropan-2-ol, l,~-dibromopropane, 1,4-bromochlorobutane or 1,2-bromochloroethane in a lower aliphatic ketone, especi-ally acetone or methyl isobu-tyl ketone, in the presence of not less than one mole equivalent, based on alkylating ` ~9t~36~
- ~ 8 - o Z. 0050/034550 agent, of a base, especially of potassium carbonate, at from 50 to 80C.
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 converted9 by means of the - corresponding hydrohalic acid, to the l-(indan l-one-oxy)-3-halo-propan-2-ol, using, as the diluent or sol-vent, one of the conventional solvents or, preferably, an aliphatic or cyclic ether, eg. diethyl ether, tetra-hydrofuran or dioxane, or a lower alcohol, eg. me-thanol, ethanol or propanol. On the other hand 7 1- (indan-l-one-oxy)-3-halo-propan-2-ols, especially l-(indan-l-one-4-oxy)-3-chloropropan-2-ol and l-(indan-l~one-4-oxy)-3-bromo-propan-2-ol, can be converted to l-(indan-l-one~
4-oxy)-2,3-epoxypropane by means of a base, such as an alkali metal hydroxide, carbonate, bicarbonate, alcohol-ate 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 60-120C
The reaction can be carried out under atmos-pheric pressure or in a closed vessel under super-atmospheric pressure, where appropriate with heating The star-ting materials for the reaction can be isolated beforehand or be produced in situ and further converted direct, without isolation and purification. ~.
;1~9~
- 9 - o.Z. 0050/034550 The compounds according to the invention, of the formula I, where Rl is hydroxyl, have a chirality center and are obtained as racemates which can be separated into the optically active antipodes by con-ventional methods, for example by forming diastereomeric salts with optically active auxiliary acids, such as diben~oyltartaric acid, camphor-lO-sulfonic acid, ditoluyltartaric acid or 3-bromocamphor-8-sulfonic acid.
The resulting compounds according to the in~en-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 Ar~neimittelforschung (Birkhauser-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 9 exhibit valuable pharmacological properties.
They can be used as sedatives, tranquilizers or neuro-leptics or as agents for the treatment of hypertension Those of the compounds ~rhich have a preferred seda-tive/-tranquilizing and an-ti-monaminergic action may 11936()1 - 10 - O.Z. 005~/034550 be used as sedatives/hypnotics and as tranquilizers or neuroleptics, whereas the other compounds according to ~he invention which have a preferred relatively selective anti-hypertensive activity can be used for treating hyper-tension and reducing the load of the heart in cases of ~ardiac 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 hyper-motility induced by a new environment is determined photoelectrically, for a period of 30 minutes, starting ~0 minutes after a~inistration 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 intra~enously) 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 e~ al , Psychopharmacologia 11 (1967), 300).
The test compounds are administered intra-~ O.Z. 0050/034550 peritoneally 30 minutes before methamphetamine~ The substance is considered to have an effect if no sniffing mo~ements are observed for a period of 5 minutes after the injection of methamphetamine.
The mean inhibition dose (ED 50~ 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 ac-tion was demonstrated on narcotized rats (Sprague Dawley, weight 230-280 g) under urethane narcosis (1.78 g/kg administered intra-peritoneally). The blood pressure was ~easured in the carotid artery. The compound was administered into the jugular vein (aqueous solution, l ml/kg).
The ED 20% was determined, from linear regression bet ween log dose (mg/kg~ and relative reduction in blood pressu~e (~%), as the dose which produces a 2~/o lowering o~ blood pressure.
Table 1 shows that the compounds of Examples 14, 19, 1, 4 and 30 have a sedative action. The effective doses are somewhat greater than in the case of Chlor-Fromazin~ so that the strength of effect of the compounds according to the invention is from 22% (Example 14) to 690/o (Example l) of the reference subs-tance On the other hand, the hypotensive side-effec-t 9 which is undesirable in sedative~neuroleptics, is markedly less pronounced than with Chlorpromazin. The hypo-tensively active doses are from 6 times (Example 30) to 300 times (Example l9) greater than for the reference 3 ~
~ O.Z, 0050/034550 substance, Accordingly, the compounds of Table l have a more advantageous ratio of` the desired central-depressant effect (inhibition of motility) and the undesired hypo-tensive effect.
On the other hand, some of the compounds claimed have a strong hypotensive action (Table Z). Judged from the hypotensive doses (ED 20%), the activity is from 16% (Example lO) to 8~/o (Example 13) that of Chlorproma~n, whilst in Example 20 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 f.rom 5 times (Example 13) to 20 times (Example,1 and 20) greater doses. The quotient of the effective dose for inhiDition of motility (ED 5~/0) and for reduction of blood pressure (ED 205b) is from 183 (~xample 17) to 4,077 (Example 20) and accord-ingly very much greater than that of the comparative compound Chlorpromazin (Q = 81), The present results show that within the com-pounds according to the invention, there are 2 categories with a different action profile. One category of com-pounds, having a preferred central-nervous action and a lesser hypotensive actionare suitable for use as neuro-leptics and, in low doses,.as sedatives/hypnotics or tranquilizers. The second category, having a pro-nounced hypotensive action, is suitable for the treat-ment of hypertonia, because of having a markedly lesser 6~ ~
- 13 - O.Z. 0050/034550 central~depressant action than Chlorpromazin.
Sedative and hypotensive action Compound Inhibition of motilitya Reduction ofbblood pressure r ~
Example mg/kg R.A.C mg/kg R.A.
No.
14 g, 44 Oo ~2 1 . 00 0. 026 19 5 . 76 0. 37 7, 91 0. 003 3, 05 Oo 69 1. 07 0 . 024 4 3. 56 0. 5g 0, 189 0. 14
5.03 0.42 0.161 0,16 promazin 2,11 1.00 O. 0260 1. 00 a Mouse, oral administration, b Rat, urethane narcosis, intravenous administration~
c Relative activity; Chlorpromazin = 1.00.
~ 3 6~
14 o.Z~ oo~o/o3455o Hypotensive and sedative action Compo~ld Reduction of blood Inhibition of motilityb pressurea ED 2~/~ ED 50% QC
Example mg/kg R,A,d mg/kg R,A, No, 13 . 0,0293 0,89 11,03 0,19 376 7 0,0722 0,36 1~,18 0,16 183 23 0,0570 0,46 18,98 0,11 333 0,0104 2,50 42,4 0,05 4,077 0,158 0, 16 ~6,~ 0, 05 294 Chlor-promazin 00 0260 1. 00 2.11 1. 00 81 a Rat, urethane narcosis, intravenous administration~
b Mouse, oral administration, c ED 50% for inhibition of_motilitv ED 20% for réduction of blood pressure d Relative activity; Chlorpromazin = 1,00,' - Accordingly, the present invention also relates to therapeutic agents or formulations which in addition to the conventional carriers and diluents contain a com-pound of the formula (I), or a physiologically tolera-ted addition salt thereof with an acid, as the active compound, and to the use of the novel compounds for therapeutic purposes, The therapeu-tic agents or forrnula-tions are pre-pared in a conven-tional manner by compounding an appropriate dose with the conventional solid or liquid 3 6~ ~
- 15 ~ o.Z. 0050/~34550 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 190 mg for intravenous administra-tion, The preferred formulations are those suitable for oral administra-tion. Examples of these are tablets, film tablets, dragees, capsules, pills, powders, solutions or suspensions or forms which exert a depot effect.' For practical use, the compounds to be employed according to the invention are formulated with the liquid or solid carriers conventionally used in pharmaceutical product-on. For example, appropriate tablets can be obtained by mixing the active compound with conventional auxiliaries, for example inert dilu-ents, such as dextrose, sugar, sorbitol, polyvinyl-pyrrolidone, mannitol, calcium carbonate, calcium phos-phate or lactose, disin-tegrating agents, such as corn starch,alginic acid or polyvinylpyrrolidone, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxypolymethylene, carboxymethyl-cellulose, cellulose acetate phthalate or polyvinyl acetate, The tablets can also consist of several .. . . .
layers (cf, L,G, Goodman and A, Gilman9 The Pharma~
ceutical Basis of Therapeutics).
Accordingly, dragees may be prepared by coating cores, prepared analogously to the tablets, with agents - 16 - O,Z, 0050/034550 conventionally used in dragee coatings, for example polyvinylpyrrolidone, shellac 9 gum arabic, talc, titaniu~ dioxide or sugar, The dragee shell can also consist of several layers 7 in which the auxiliaries, mentioned above in connection with tablets 3 may be used, The Examples which follow illustrate the pre-sent invention, I, Preparation of startin~ compounds of the formula ~I) EXAMPLE X
1-(Indan-l-one-4-oxy)-2,3-epoxypropane 50 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 ~re 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 concen-trated under reduced pressure, The resulting residue is purified by fractional distil-la-tion, 54 g (= 77,8% yield) of 1-(indan-1-one-4-oxy)-2,3-epoxypropane, of boiling point 168-170C/O.l-0,2 mm Hg, are obtained; the material crystallizes on cooling, C12H1203 (204,23) calculated: 70,6 C 5,9 H 23,5 0 folmd: 70,6 C 6~1 H 23,6 0 ~ 3 ~ ~
- 17 - O.Z. 0050/034550 EXAMPLE II
1-(Indan-l-one-5 oxy~-2,3-epoxypropane 16 g of 5 hydroxy-indan~l-one (0,11 mole) are dissolved in 150 ml of anhydrous acetone, and 30 g of K2C03, 30 g of epibromohydrin (0,22 mole) and lO0 mg of NaI are added successively~ The batch is refluxed for 24 hours, with stirring. It is then filtered, and the solvent is distilled off ~der reduced pressure, 20 g of l-(indan-l~one-5-oxy)-2,3--epoxypropane remain as a crude product, which is reacted further, without addi-tional purification, EXAMPLE III
l-(Indan-l-one-7-oxy)-2,3-epoxypropane 30 g o~ 7-hydroxy-indan-l-one (0~2 mole) are dissolved in 250 ml of tetrahydrofuran, 28 g of K2C03 and 100 mg of NaI are added and 55 g o~ 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 epi-bromohydrin are distilled off and the residue is parti-tioned between water and toluene, The toluene phase is washed wi-th slightly alkaline water, dried and ulti-mately concentrated, The residue obtained crystal-lizes completely after standing for some time, 26,5 g (= 6~/o yield) of l-(indan-l-one-7-oxy)-2,3-epoxypropane, of melting point 58-60C~ are thus obtained, C12Hl23 (204,23) calculated: 70, 6 C 5 0 9 H 23,5 0 O.Z. 0050/034550 ~ound: 71.3 C 5.7 H
EX~MPLE IV
1-(Indan l-one-4-oxy)-3-chloro-propane 30 g of 1-bromo~3-chloro-propane (OA 19 mole) are added to 20 g of 4-hydroxy-indan-1-one (0.135 mole) in 200 mlof anhydrousDMF and the mixture is thoroughlystir~
red with 20 g of anhydrous K2C03for 12 hours at 60C and is then stirred for a further 8 hours at room tempera-ture, The solvent is then distilled off under reduced pressure and the residue i~ partitioned between ether and slightly alkaline water~ The aqueous phase is repea-tedly extracted with ether, the ether phases are combined, washed with H20 and dried, and the ether is distilled off under reduced pressure. 24,3 g of crude product are obtained as a bro~ oil. The greater part of -the 1,3-bis-(indan-1-one-4-oxy)-propane . formed at the same time is precipita-ted by treatment with petroleum ether/acetone, and the oily residue remaining after filtering off the precipitate and removing the petroleum ether/acetone mixture is dis-tilled in a bulb tube, 12,7 g of l-(indan-l-one-4-oxy)-3-chloropropane pass over at 220C/0.2 mm Hg.
C12H13C102 (224,6) calculated: 64,2 C 5.8 H 15.8 Cl found: 64.4 C 5.9 H 15,3 Cl EXAMPLE V
l-(Indan-l-one-4-oxy)-4-chlorobutane Using a method sirnilar to Example IV, 15 g of = lg - O.Z. 0050/034550 4~hydroxy indan-l-one (0,1 mole), 20 g of 1-bromo-4-chlorobutane (0,12 mole) and 18 g of K2C03 in 200 ml of dimethylformamide give 12,2 g of 1-(indan-1-one-4-oxy)-4-chlorobutane as a pale yellow oil, which crystallizes completely after some time, C13H15C102 (238,6) calculated: 65,4 C 6,3 H 14,85 Cl found: 65,1 C 6,0 H 14,5 Cl E~CAMPLE V~
l-(Inda~ one-7-oxy)-2-chloroethane 105 g of 7-hydroxy-indan-l~one (0,034 mole) are dissolved in 100 ml of anhydrous acetone and 15 g of l-bromo-2-chloroethane (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 thu~ o'otained is parti-tioned 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, 6,7 g of 1-(indan-1-one-7-oxy)-2-chloroethane are isolated as grayish-white crystals of melting point 87C, CllHllC102 (210,6) calculated: 62.7 C 5,2 H 16,8 Cl found: 62,9 C 5,7 H 16,4 Cl 3~
_ ~o - .Z. 0050/034550 EXAMPLE VII
l-(Indan~l-one~7~oxy)-3-chloropropane Using a method similar to Example YI, 5 g of 7-hydroxyindan-l-one, 8 g of 1-bromo-3-chloropropane and 7 g of K2C03 give 6.5 g of l (indan-l-one-7.-oxy)-3-chloropropane as a pale yellow oil, which crystallizes completely after a short time; the crystals melt at 53.5C, Cl2H13Cl02 (224.6) calculated: ~,2 C 5.8 H 15,8 Cl found: 64.6 C 6.2 H 15.5 Cl EXAMPLE VIII
l-(Indan-l-one-7-oxy)-4-chlorobutane Using a method similar to Example VI, 5 g of 7-hydroxy-indan-1-one 9 7 g of l~bromo-4-chlorobutane and 6 g of K~C03 give 5.2 g of l-(indan-l-one-7-oxy)-4-chlorobutane as a pale yellow oil, which crystallizes after some time, Cl3H15Cl02 (238.6) calculated: 65.4 C 6.~ H 14~85 C1 found: 65.1 C 6~3 H lh.6 Cl II. Prepa ation of compounds accordin~ to the invention - 20 4-(3-~4-(4-Fluorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one monohydrochloride 7 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 336~
- 21 - ,Z. 0050/034550 distilled o~f 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 scratch-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)-indan l-one monohydrochloride, of melting point 206-208C, are isolated, C22H~6N2ClF03 (420,5) calculated: 62O7 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 5-(3 ~4-(2-Chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one monohydrochloride
c Relative activity; Chlorpromazin = 1.00.
~ 3 6~
14 o.Z~ oo~o/o3455o Hypotensive and sedative action Compo~ld Reduction of blood Inhibition of motilityb pressurea ED 2~/~ ED 50% QC
Example mg/kg R,A,d mg/kg R,A, No, 13 . 0,0293 0,89 11,03 0,19 376 7 0,0722 0,36 1~,18 0,16 183 23 0,0570 0,46 18,98 0,11 333 0,0104 2,50 42,4 0,05 4,077 0,158 0, 16 ~6,~ 0, 05 294 Chlor-promazin 00 0260 1. 00 2.11 1. 00 81 a Rat, urethane narcosis, intravenous administration~
b Mouse, oral administration, c ED 50% for inhibition of_motilitv ED 20% for réduction of blood pressure d Relative activity; Chlorpromazin = 1,00,' - Accordingly, the present invention also relates to therapeutic agents or formulations which in addition to the conventional carriers and diluents contain a com-pound of the formula (I), or a physiologically tolera-ted addition salt thereof with an acid, as the active compound, and to the use of the novel compounds for therapeutic purposes, The therapeu-tic agents or forrnula-tions are pre-pared in a conven-tional manner by compounding an appropriate dose with the conventional solid or liquid 3 6~ ~
- 15 ~ o.Z. 0050/~34550 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 190 mg for intravenous administra-tion, The preferred formulations are those suitable for oral administra-tion. Examples of these are tablets, film tablets, dragees, capsules, pills, powders, solutions or suspensions or forms which exert a depot effect.' For practical use, the compounds to be employed according to the invention are formulated with the liquid or solid carriers conventionally used in pharmaceutical product-on. For example, appropriate tablets can be obtained by mixing the active compound with conventional auxiliaries, for example inert dilu-ents, such as dextrose, sugar, sorbitol, polyvinyl-pyrrolidone, mannitol, calcium carbonate, calcium phos-phate or lactose, disin-tegrating agents, such as corn starch,alginic acid or polyvinylpyrrolidone, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxypolymethylene, carboxymethyl-cellulose, cellulose acetate phthalate or polyvinyl acetate, The tablets can also consist of several .. . . .
layers (cf, L,G, Goodman and A, Gilman9 The Pharma~
ceutical Basis of Therapeutics).
Accordingly, dragees may be prepared by coating cores, prepared analogously to the tablets, with agents - 16 - O,Z, 0050/034550 conventionally used in dragee coatings, for example polyvinylpyrrolidone, shellac 9 gum arabic, talc, titaniu~ dioxide or sugar, The dragee shell can also consist of several layers 7 in which the auxiliaries, mentioned above in connection with tablets 3 may be used, The Examples which follow illustrate the pre-sent invention, I, Preparation of startin~ compounds of the formula ~I) EXAMPLE X
1-(Indan-l-one-4-oxy)-2,3-epoxypropane 50 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 ~re 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 concen-trated under reduced pressure, The resulting residue is purified by fractional distil-la-tion, 54 g (= 77,8% yield) of 1-(indan-1-one-4-oxy)-2,3-epoxypropane, of boiling point 168-170C/O.l-0,2 mm Hg, are obtained; the material crystallizes on cooling, C12H1203 (204,23) calculated: 70,6 C 5,9 H 23,5 0 folmd: 70,6 C 6~1 H 23,6 0 ~ 3 ~ ~
- 17 - O.Z. 0050/034550 EXAMPLE II
1-(Indan-l-one-5 oxy~-2,3-epoxypropane 16 g of 5 hydroxy-indan~l-one (0,11 mole) are dissolved in 150 ml of anhydrous acetone, and 30 g of K2C03, 30 g of epibromohydrin (0,22 mole) and lO0 mg of NaI are added successively~ The batch is refluxed for 24 hours, with stirring. It is then filtered, and the solvent is distilled off ~der reduced pressure, 20 g of l-(indan-l~one-5-oxy)-2,3--epoxypropane remain as a crude product, which is reacted further, without addi-tional purification, EXAMPLE III
l-(Indan-l-one-7-oxy)-2,3-epoxypropane 30 g o~ 7-hydroxy-indan-l-one (0~2 mole) are dissolved in 250 ml of tetrahydrofuran, 28 g of K2C03 and 100 mg of NaI are added and 55 g o~ 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 epi-bromohydrin are distilled off and the residue is parti-tioned between water and toluene, The toluene phase is washed wi-th slightly alkaline water, dried and ulti-mately concentrated, The residue obtained crystal-lizes completely after standing for some time, 26,5 g (= 6~/o yield) of l-(indan-l-one-7-oxy)-2,3-epoxypropane, of melting point 58-60C~ are thus obtained, C12Hl23 (204,23) calculated: 70, 6 C 5 0 9 H 23,5 0 O.Z. 0050/034550 ~ound: 71.3 C 5.7 H
EX~MPLE IV
1-(Indan l-one-4-oxy)-3-chloro-propane 30 g of 1-bromo~3-chloro-propane (OA 19 mole) are added to 20 g of 4-hydroxy-indan-1-one (0.135 mole) in 200 mlof anhydrousDMF and the mixture is thoroughlystir~
red with 20 g of anhydrous K2C03for 12 hours at 60C and is then stirred for a further 8 hours at room tempera-ture, The solvent is then distilled off under reduced pressure and the residue i~ partitioned between ether and slightly alkaline water~ The aqueous phase is repea-tedly extracted with ether, the ether phases are combined, washed with H20 and dried, and the ether is distilled off under reduced pressure. 24,3 g of crude product are obtained as a bro~ oil. The greater part of -the 1,3-bis-(indan-1-one-4-oxy)-propane . formed at the same time is precipita-ted by treatment with petroleum ether/acetone, and the oily residue remaining after filtering off the precipitate and removing the petroleum ether/acetone mixture is dis-tilled in a bulb tube, 12,7 g of l-(indan-l-one-4-oxy)-3-chloropropane pass over at 220C/0.2 mm Hg.
C12H13C102 (224,6) calculated: 64,2 C 5.8 H 15.8 Cl found: 64.4 C 5.9 H 15,3 Cl EXAMPLE V
l-(Indan-l-one-4-oxy)-4-chlorobutane Using a method sirnilar to Example IV, 15 g of = lg - O.Z. 0050/034550 4~hydroxy indan-l-one (0,1 mole), 20 g of 1-bromo-4-chlorobutane (0,12 mole) and 18 g of K2C03 in 200 ml of dimethylformamide give 12,2 g of 1-(indan-1-one-4-oxy)-4-chlorobutane as a pale yellow oil, which crystallizes completely after some time, C13H15C102 (238,6) calculated: 65,4 C 6,3 H 14,85 Cl found: 65,1 C 6,0 H 14,5 Cl E~CAMPLE V~
l-(Inda~ one-7-oxy)-2-chloroethane 105 g of 7-hydroxy-indan-l~one (0,034 mole) are dissolved in 100 ml of anhydrous acetone and 15 g of l-bromo-2-chloroethane (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 thu~ o'otained is parti-tioned 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, 6,7 g of 1-(indan-1-one-7-oxy)-2-chloroethane are isolated as grayish-white crystals of melting point 87C, CllHllC102 (210,6) calculated: 62.7 C 5,2 H 16,8 Cl found: 62,9 C 5,7 H 16,4 Cl 3~
_ ~o - .Z. 0050/034550 EXAMPLE VII
l-(Indan~l-one~7~oxy)-3-chloropropane Using a method similar to Example YI, 5 g of 7-hydroxyindan-l-one, 8 g of 1-bromo-3-chloropropane and 7 g of K2C03 give 6.5 g of l (indan-l-one-7.-oxy)-3-chloropropane as a pale yellow oil, which crystallizes completely after a short time; the crystals melt at 53.5C, Cl2H13Cl02 (224.6) calculated: ~,2 C 5.8 H 15,8 Cl found: 64.6 C 6.2 H 15.5 Cl EXAMPLE VIII
l-(Indan-l-one-7-oxy)-4-chlorobutane Using a method similar to Example VI, 5 g of 7-hydroxy-indan-1-one 9 7 g of l~bromo-4-chlorobutane and 6 g of K~C03 give 5.2 g of l-(indan-l-one-7-oxy)-4-chlorobutane as a pale yellow oil, which crystallizes after some time, Cl3H15Cl02 (238.6) calculated: 65.4 C 6.~ H 14~85 C1 found: 65.1 C 6~3 H lh.6 Cl II. Prepa ation of compounds accordin~ to the invention - 20 4-(3-~4-(4-Fluorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one monohydrochloride 7 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 336~
- 21 - ,Z. 0050/034550 distilled o~f 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 scratch-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)-indan l-one monohydrochloride, of melting point 206-208C, are isolated, C22H~6N2ClF03 (420,5) calculated: 62O7 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 5-(3 ~4-(2-Chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one monohydrochloride
6 g of 1-(indan-1-one~5-oxy)-2,3-epoxypropane and 6.7 g o~ 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 me-thanol, The hydrochloride is precipi-tated by dropwise addition of a solution of hydrogen chloride in ether, and is subsequently filtered off and recrystallized from methanol/ether, 207 g of 5-(3-[4-(2-chlorophenyl)-piperazin-1-yl]-2-hydroxy-propoxy)-indan-l one monohydrochloride, of melting point 249-252C, are thus obtained, C22H26N2C1202 (437.1) calculated: 60,4 C 5,9 H 6,4 N 16,2 Cl ~L~L9~
_ o,Z. 0050/03455 found: 60.5 C 6,1 H 6,5 N 16,1 C1
_ o,Z. 0050/03455 found: 60.5 C 6,1 H 6,5 N 16,1 C1
7-(3-C4~(4-Chlorophenyl)-piperazirl-l-yl]-2-hydroxy-propoxy)-indan-l-one monohydrochloride 7 g of 1-(indan-1-one-7-oxy)-2,3-epox~propane and 6,7 g of 4-chlorophenylpiperazine in 100 ml of n-propanol are left to stand for 3 days at room tempera-ture, The solvent is then distilled off, the resi-due is dissolved in a small amount of methanol, and the hydroch~oride is precipitated by dropwise addition of a solution of hydrogen chloride in ether and then filtered off and recrystallized from ethanol, 5.2 g of 7-(3-~4-(4-chlorophenyl)-piperazin-1-yl]-2-hydroxy-propoxy)-indan-l-one monohydrochloride, o~ melting point 126-128C, are thus obtained, C22H26NzCl203 (437) calculated: 60.4 C 5,9 EI 6,4 N 16,2 Cl found: 60,1 C 6,2 H 6,4 N 15,9 Cl EXAMPL~ 4 4-(3-[4-(4-Fluorophenyl)-piperazin-l-yl]-propoxy)-indan-l-one bis~=hydrochloride 5 g of 1-(indan-1-one-4-oxy)-3-chloropropane and 4 g of 4-fluorophenyl-piperazine in 120 ml of anhydrous DMF are stirred thoroughly with 5 g of K2C03 for 8 hours at 120C, The mixture is then filtered, the solution evaporated, the residue parti.tioned bet-ween sligh-tly alkaline water and ether, the aqueous phase repeatedly re-extracted with ether, the ether phases combined, washed with water and dried, and the 3~ ~
_ ~3 _ o.z. 0050/034550 solvent distilled off, 6,5 g O:e a brown oil remain;
this is taken up in a small amount of me-thanol/ether and converted to the hydrochloride by dropwise addition of a solution of hydrogen chloride in ether. The crys-tals are filtered off and recrystallized from acetone!
methanol/ether. 3.5 g of 4-~3-[4~(4-fluorophenyl)-piperazin-l~yl~-propoxy)-indan-l-one bis-hydrochloride, OI melting poin-t 223C, are thus ob-tained.
C22H27N2Cl2Fo2 (4 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
E~AMPLE 5 7-(4-[4-(4-Fluorophenyl)-piperazin-l-yl]-butoxy)-indan-l-one bis-hydrochloride 5 g of l-(indan-l-one-7-oxy)-4-chlorobutane and 3 g of 4-fluorophenyl-piperazine in 150 ml of dicxane are heated for 12 hours at 120C in an autoclave, After having distilled o~f the solvent under reduced pressure, the residue is partitioned between ether and 2N sulfuric acid, and the aqueous phase is rendered alkaline with sodium hydroxide solution and repeatedly e~tracted with ether. The combined ether extracts are dried, the solvent is distilled off, the residue is taken up in methanol/ether and the hydrochloride is precipitated with a solution of hydrogen chloride in ether; After recrystallization, 2;1 g of of 8-(4-[4-(4-fluorophenyl)-piperazin~l-yl~-butoxy)-indan-l-one bis-hydrochloride, of melting point 195C 7 are, obtained.
C23H29N2Cl2F2 (456) 3~
~ 2~ 0,Z. 0050/034550 calculated: 60.6 C 6,3 H 6,1 N 15.6 Cl 4.2 F
found: 60,4 C 6,4 H 6,1 N 15,4 Cl 4.0 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-l-one-oxy-chloroalkanes and the corresponding phenylpiperazines.
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11~3~
- 2~ - O.Z. 0050/034550 Formulation examples prepared in a conventional mar~er:
1, Tablets-.
a) An active compound of formula I,40 mg Lactose 200 mg Me-thylcellulose 15 mg Corn starch 50 mg Talc 11 mg Magnesium s-tearate 4 mg 320 mg b) An active compo~nd of formula I80 mg Lactose 178 mg A~icel 80 mg Polywachs 6000 20 mg Magnesium stearate 2 mg 360 mg c) An ac-tive compound of formula I50 mg Polyvinylpyrrolidone (mean molecular weight 25,000)170 mg Polyethylene glycol (mean molecular weight 4,000)14 mg Hydroxypropylmethylcellulose40 mg Talc 4 mg Magnesium stearate 2 mg 280 mg The active compound is moistened with a 10%
streng-th aqueous solution of polyvinylpyrrolidone and forced through a sleve o~ 1,0 mm mesh size, and the granules are dried at 50C. They are then mixed with 3 ~ ~
30 ~ o,Z. 0050/034550 polyethylene glycol (mean molecular weight 4,000), hydroxypropylmethylcellulose~ talc and magnesium stearate 7 and the mixture is pressed to give tablets weighing 280 mg, 2. Example of dra~es An active compound of formula I60 mg Lactose 90 mg Corn starch 60 mg Polyvinylpyrrolidone 6 mg 'Magnesium stearate 1 mg 217 mg The active compound, lactose and corn starch 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 aredried at50C
and forced through a 1.0 mm sieve. The material thus obtained is mixed with magnesium stearate and the mix-ture 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:
An active compound of form~a I 5,0 mg Magnesium stearate 2.0 mg Lactose '19.3 mg 4, In~iectlon solution:
An active compound o~ formula I 10 mg Sodium chloride 9 mg Distilled water, to make up to 1,0 ml
_ ~3 _ o.z. 0050/034550 solvent distilled off, 6,5 g O:e a brown oil remain;
this is taken up in a small amount of me-thanol/ether and converted to the hydrochloride by dropwise addition of a solution of hydrogen chloride in ether. The crys-tals are filtered off and recrystallized from acetone!
methanol/ether. 3.5 g of 4-~3-[4~(4-fluorophenyl)-piperazin-l~yl~-propoxy)-indan-l-one bis-hydrochloride, OI melting poin-t 223C, are thus ob-tained.
C22H27N2Cl2Fo2 (4 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
E~AMPLE 5 7-(4-[4-(4-Fluorophenyl)-piperazin-l-yl]-butoxy)-indan-l-one bis-hydrochloride 5 g of l-(indan-l-one-7-oxy)-4-chlorobutane and 3 g of 4-fluorophenyl-piperazine in 150 ml of dicxane are heated for 12 hours at 120C in an autoclave, After having distilled o~f the solvent under reduced pressure, the residue is partitioned between ether and 2N sulfuric acid, and the aqueous phase is rendered alkaline with sodium hydroxide solution and repeatedly e~tracted with ether. The combined ether extracts are dried, the solvent is distilled off, the residue is taken up in methanol/ether and the hydrochloride is precipitated with a solution of hydrogen chloride in ether; After recrystallization, 2;1 g of of 8-(4-[4-(4-fluorophenyl)-piperazin~l-yl~-butoxy)-indan-l-one bis-hydrochloride, of melting point 195C 7 are, obtained.
C23H29N2Cl2F2 (456) 3~
~ 2~ 0,Z. 0050/034550 calculated: 60.6 C 6,3 H 6,1 N 15.6 Cl 4.2 F
found: 60,4 C 6,4 H 6,1 N 15,4 Cl 4.0 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-l-one-oxy-chloroalkanes and the corresponding phenylpiperazines.
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11~3~
- 2~ - O.Z. 0050/034550 Formulation examples prepared in a conventional mar~er:
1, Tablets-.
a) An active compound of formula I,40 mg Lactose 200 mg Me-thylcellulose 15 mg Corn starch 50 mg Talc 11 mg Magnesium s-tearate 4 mg 320 mg b) An active compo~nd of formula I80 mg Lactose 178 mg A~icel 80 mg Polywachs 6000 20 mg Magnesium stearate 2 mg 360 mg c) An ac-tive compound of formula I50 mg Polyvinylpyrrolidone (mean molecular weight 25,000)170 mg Polyethylene glycol (mean molecular weight 4,000)14 mg Hydroxypropylmethylcellulose40 mg Talc 4 mg Magnesium stearate 2 mg 280 mg The active compound is moistened with a 10%
streng-th aqueous solution of polyvinylpyrrolidone and forced through a sleve o~ 1,0 mm mesh size, and the granules are dried at 50C. They are then mixed with 3 ~ ~
30 ~ o,Z. 0050/034550 polyethylene glycol (mean molecular weight 4,000), hydroxypropylmethylcellulose~ talc and magnesium stearate 7 and the mixture is pressed to give tablets weighing 280 mg, 2. Example of dra~es An active compound of formula I60 mg Lactose 90 mg Corn starch 60 mg Polyvinylpyrrolidone 6 mg 'Magnesium stearate 1 mg 217 mg The active compound, lactose and corn starch 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 aredried at50C
and forced through a 1.0 mm sieve. The material thus obtained is mixed with magnesium stearate and the mix-ture 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:
An active compound of form~a I 5,0 mg Magnesium stearate 2.0 mg Lactose '19.3 mg 4, In~iectlon solution:
An active compound o~ formula I 10 mg Sodium chloride 9 mg Distilled water, to make up to 1,0 ml
Claims (14)
1. A process for the preparation of a compound of the general formula (I) (I) where R1 is hydrogen or hydroxyl. and R2 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, trifluoromethyl or nitro and n is 0, 1 or 2 if R1 is hydrogen, and is 1 if R1 is hydroxyl, and its physiologi-cally tolerated addition salts with acids, characterized in that an indanone derivative of the formula (II) (II) where A is -CH-CH2, -CH-CH2-B or -(CH2)n-B and where B is a nucleofugic leaving group and n is an integer from 1 to 3, is reacted with a piperazine derivative of the general formula (III) (III) where R2 has the meanings given for formula (I) in the presence or absence of an acid acceptor, and, if desired, the resulting compound is converted to an addition salt thereof with a physiologically tolerated acid.
2. A compound of the general formula (I) (I) where R1 is hydrogen or hydroxyl and R2 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, trifluoromethyl or nitro and n is 0, 1 or 2 if R1 is hydrogen, and is 1 if R1 is hydroxyl, and its physiologi-cally tolerated addition salts with acids, whenever obtained by a process as defined in claim 1 or an obvious chemical equivalent thereof.
3. A process for the preparation of a compound of formula (I) as defined in claim 1 and its physiologically tolerated addition salts with acids wherein the reaction between the derivative of the formula (II) and the derivative of the formula (III) is carried out in the presence of a suitable solvent.
4. A compound of the general formula (I) (I) where R1 is hydrogen or hydroxyl and R2 is hydrogen, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen, trifluoromethyl or nitro and n is 0, 1 or 2 if R1 is hydrogen, and is 1 if R1 is hydroxyl, and its physiologi-cally tolerated addition salts with acids, whenever obtained by a process as defined in claim 3 or an obvious chemical equivalent thereof.
5. A process as defined in claim 1 for the preparation of a compound of formula (I), wherein R1 is hydrogen or hydroxy, n is 1, R2 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 characterized in that for the compound of formula (II) n is 1 and the linkage position of the side chain is the 4-, 5- or 7-position of the indan-1-one ring system and for the compound of formula (III) R2 is as defined above.
6. A compound having the general formula (I) as defined in claim 1, wherein R1 is hydrogen or hydroxyl, n is 1, R2 is chlorine, fluorine, methoxy or methyl and the oxy-alkyl-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 whenever obtained by a process as defined in claim 5 or an obvious chemical equivalent thereof.
7. A process for the preparation of 4-(3-[4-(4-fluorophenyl)-piperazin-1-yl]-2-hydroxy-propoxy)-indan-1-one, and its physiologically tolerated addition salts with acids, characterized in that an indanone derivative of the formula wherein A is or and B is a nucleofugic leaving group, is reacted with in the presence or absence of an acid acceptor, and, if desired, the obtained 4-(3-[4-(4-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one, is converted to an addition salt thereof with a physiologically tolerated acid.
8. 4-(3-[4-(4-fluorophenyl)-pipera-in-l-yl]-2-hydroxy-propoxy)-indan-l-one, and its physiologically tolerated addition salts with acids, whenever obtained by a process as defined in claim 7 or an obvious chemical equivalent thereof.
9. A process for the preparation of 4-(3-[4-(4-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one and its physiologically tolerated addition salts with acids, characterized in that l-(indan-l-one-4-oxy)-2,3 epoxypropane is reacted with in the presence of a suitable solvant, and if desired, the obtained 4-(3-[4-(4-fluorophenyl)-piperazin-1-yl]-2-hydroxy-propoxy)-indan-l-one is converted to an addition salt thereof with a physiologically tolerated acid.
10. 4-(3-[4-(4-fluorophenyl)-piperazin-1-yl]-2-hydroxy-propoxy)-indan-l-one and its physiologically tolerated addition salts with acids, whenever obtained by a process as defined in claim 9 or an obvious chemical equivalent thereof.
11. A process for the preparation of 5-(3-[4-(2-chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one, and its physiologically tolerated addition salts with acids, characterized in that an indanone derivative of the formula wherein A is or and B is a nucleofugic leaving group, is reacted with in the presence or absence of an acid acceptor, and, if desired, the obtained 5-(3-[4-(2-chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one, is converted to an addition salt thereof with a physiologically tolerated acid.
12. 5-(3-[4-(2-chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one, and its physiologically tolerated addition salts with acids, whenever obtained by a process as defined in claim 11 or an obvious chemical equivalent thereof.
13. A process for the preparation of 5-(3-[4-(2-chlorophenyl)-piperazin-l-yl]2-hydroxy-propoxy)-indan-l-one and its physiologically tolerated addition salts with acids characterized in that l-(indan-l-one-5-oxy)-2,3 epoxypropane is reacted with in the presence of a suitable solvent, and if desired, the obtained 5-(3-[4-(2-chlorophenyl) piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one is converted to an addition salt thereof with a physiologically tolerated acid.
14. 5-(3-[4-(2-chlorophenyl)-piperazin-l-yl]-2-hydroxy-propoxy)-indan-l-one and its physiologically tolerated addition salts with acids, whenever obtained by a process as defined in claim 13 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803026331 DE3026331A1 (en) | 1980-07-11 | 1980-07-11 | INDANONE OXYALKYL PIPERAZINE DERIVATIVES, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATION CONTAINING THEM |
| DEP3026331.1 | 1980-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1193601A true CA1193601A (en) | 1985-09-17 |
Family
ID=6106977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000381476A Expired CA1193601A (en) | 1980-07-11 | 1981-07-09 | Indanone-oxyalkyl-piperazine derivatives, their preparation, and pharmaceutical formulations containing these compounds |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0043971B1 (en) |
| JP (1) | JPS5748978A (en) |
| AT (1) | ATE10842T1 (en) |
| CA (1) | CA1193601A (en) |
| DE (2) | DE3026331A1 (en) |
| DK (1) | DK308881A (en) |
| GR (1) | GR74879B (en) |
| IE (1) | IE51383B1 (en) |
| ZA (1) | ZA814688B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2004323810B2 (en) * | 2004-10-08 | 2011-11-17 | Suven Life Sciences Limited | Novel intermediates useful for the preparation of aripiprazole and methods for the preparation of the novel intermediates and aripiprazole |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7101573A (en) * | 1970-04-13 | 1971-10-15 | ||
| DE2335432A1 (en) * | 1973-07-12 | 1975-01-30 | Boehringer Mannheim Gmbh | 3,4-DIHYDRO-2H-NAPHTHALINONE- (1) 5-OXY-PROPYL-PIPERAZINE DERIVATIVES AND THE METHOD FOR THEIR PRODUCTION |
| US4130646A (en) * | 1975-07-25 | 1978-12-19 | E. R. Squibb & Sons, Inc. | 1,2,3,4-Tetrahydro-2-((4-(phenyl)-1-piperazinyl)methyl)-1-naphthalenols and derivatives and analogs thereof |
| DE2824677A1 (en) * | 1978-06-06 | 1979-12-20 | Hoechst Ag | 3-Phenyl:piperazino-propoxy-indoline and quinoline derivs. - useful as psychotropic and cardiovascular agents |
-
1980
- 1980-07-11 DE DE19803026331 patent/DE3026331A1/en not_active Withdrawn
-
1981
- 1981-06-24 GR GR65333A patent/GR74879B/el unknown
- 1981-06-29 EP EP81105028A patent/EP0043971B1/en not_active Expired
- 1981-06-29 AT AT81105028T patent/ATE10842T1/en not_active IP Right Cessation
- 1981-06-29 DE DE8181105028T patent/DE3167816D1/en not_active Expired
- 1981-07-09 JP JP56106305A patent/JPS5748978A/en active Pending
- 1981-07-09 CA CA000381476A patent/CA1193601A/en not_active Expired
- 1981-07-10 DK DK308881A patent/DK308881A/en not_active Application Discontinuation
- 1981-07-10 IE IE1560/81A patent/IE51383B1/en unknown
- 1981-07-10 ZA ZA814688A patent/ZA814688B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3167816D1 (en) | 1985-01-31 |
| DE3026331A1 (en) | 1982-02-18 |
| ATE10842T1 (en) | 1985-01-15 |
| JPS5748978A (en) | 1982-03-20 |
| IE811560L (en) | 1982-01-11 |
| EP0043971B1 (en) | 1984-12-19 |
| IE51383B1 (en) | 1986-12-10 |
| ZA814688B (en) | 1982-08-25 |
| GR74879B (en) | 1984-07-12 |
| DK308881A (en) | 1982-01-12 |
| EP0043971A1 (en) | 1982-01-20 |
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