GB1583372A - 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives - Google Patents

1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives Download PDF

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GB1583372A
GB1583372A GB14100/77A GB1410077A GB1583372A GB 1583372 A GB1583372 A GB 1583372A GB 14100/77 A GB14100/77 A GB 14100/77A GB 1410077 A GB1410077 A GB 1410077A GB 1583372 A GB1583372 A GB 1583372A
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compound
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Evonik Operations GmbH
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Degussa GmbH
Deutsche Gold und Silber Scheideanstalt
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Priority to GB14100/77A priority Critical patent/GB1583372A/en
Priority to FR7809675A priority patent/FR2395264A1/en
Priority to YU767/78A priority patent/YU40513B/en
Priority to HU78DE957A priority patent/HU179952B/en
Priority to PL1978205745A priority patent/PL112249B1/en
Priority to DE19782814168 priority patent/DE2814168A1/en
Priority to CS782141A priority patent/CS249503B2/en
Priority to ES468486A priority patent/ES468486A1/en
Priority to ZA00781889A priority patent/ZA781889B/en
Priority to CH354378A priority patent/CH638795A5/en
Priority to AU34703/78A priority patent/AU516315B2/en
Priority to SU782596099A priority patent/SU893133A3/en
Priority to BE6046420A priority patent/BE865642A/en
Priority to IT48718/78A priority patent/IT1202819B/en
Priority to SE7803742A priority patent/SE435507B/en
Priority to NL7803540A priority patent/NL7803540A/en
Priority to NO781159A priority patent/NO149209C/en
Priority to AT233078A priority patent/AT360997B/en
Priority to DK146678A priority patent/DK145225C/en
Priority to CA300,288A priority patent/CA1124718A/en
Priority to FI781009A priority patent/FI69627C/en
Priority to AR271686A priority patent/AR222149A1/en
Priority to MX786995U priority patent/MX6120E/en
Priority to JP53039626A priority patent/JPS6038383B2/en
Priority to FR8018458A priority patent/FR2488892A2/en
Publication of GB1583372A publication Critical patent/GB1583372A/en
Expired legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • 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
    • C07D295/12—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 or doubly bound nitrogen atoms
    • C07D295/135—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
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Abstract

The novel compounds correspond to the formula I, in which the substituents have the meaning given in Patent Claim 1. These compounds are prepared by reaction of a compound of the formula II with a compound of the formula III, Y and Z in each case being different and either denoting hydrogen or the group -CH2-CH(OR1)-CH2-V and V being chlorine, bromine or iodine, or, if R1 is hydrogen, can also form the ethylene oxide ring together with this hydroxyl group. If appropriate, one or two nitro groups in a compound of the formula I obtained can be reduced to amino groups and/or the compounds obtained can be acylated with an acid or an acid derivative corresponding to the radical R1. The compounds obtained can be converted into their acid addition salts. The novel compounds are pharmacodynamically active and are suitable as an active component in medicaments. <IMAGE>

Description

SPECIFICATION NO 1583372 The following amendments were allowed under Section 29 on 20 July 1981: Page 7 Formula for
THE PATENT OFFICE 28 August 1981 Bas 84650/9 (71 We, EDUTSCHE GOLD-UND SILDLR-SCHLID@@@@@@@ ROESSLER a body corporate organised under the laws of Germany of 9 Weissfrauenstrasse, 6 Frankfurt Main 1, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us. and the method by which it is to be performed, to be particularly described in and by the following statement :- This invention relates to new l- [3- (3. 4. 5-trimethoxy-phenoxy)-2-hydroxypropy)]-4-aryt piperazine derivatives and to a process for their production.
German Offenlegungsschrift No. 2, 235. 597 describes blood-pressure-reducing compounds corresponding to the general formula
in which A is a hydrogen atom or a hdroxvl group. X is a hydrogen or a halogen atom. an alkyl. alkoxy. ilkylthio. trifluorométhyl. hydroxv. nitro amino. acylamino or alkyl- su) phony) amino group, and n is the number 0. l or 2, and their salts.
The present invention relates to new compounds corresponding to the general formula
(54)"NEW 1- [3- (3, 4. 5-TRIMETHOXYPHENOXY)-2-HYDROXYPROPYLJ-4-ARYL PIPERAZINE DERIVATIVES" (71 We, DEUTSCHE GOLD-UND SILBER-SCHEIDEANSTALT VORMALS ROESSLER a body corporate organised under the laws of Germany of 9 Weissfrauenstrasse. 6 Frankfurt Main 1. Germany, do hereby declare the invention, for which we pray that a patent may be granted to us. and the method by which it is to be performed, to be particularly described in and by the following statement :- This invention relates to new 1- [3- (3, 4. 5-trimethoxy-phenoxy)-2-hydroxypropyll-4--aryl piperazine derivatives and to a process for their production.
German Offenlegungsschrift No. 2, 235, 597 describes blood-pressure-reducing compounds corresponding to the general formula
in which A is a hvdrooen atom or a hydroxy) group. X is a hydrogen or a halogcn atom, an alkyl, alkoxy, alklthio, trifluoromethyl, hydroxy, nitro, amino, acylumino or alkylsulphonylamino group, and n is the number 0. @ or 2. and their saluts.
The present invention relates to new compounds corresponding to the genera) formula
in which R'is a hydrogen atom, a C2 to C^-alkanoyl radical, a CR to C6-alkenoyl radical, a C3 to C^-cycloalkyl carbonyl radical, a benzoyl radical, a C, to C4-alkoxy benzoyl radical, a nicotinoyl radical, a thienyl carbonyl radical, a furyl carbonyl radical, a phenyl acetyl radical or a C, to C4-alkoxy phenyl acetyl radical and R2 represents a phenyl, naphthyl or pyridyl radical optionally substituted by the radicals R3 and R4, the radicals R3 and R4 which may be the same or different, each representing hydrogen, hydroxyl, fluorine, chlorine, bromine, a nitro group, a trifluoromethyl group, a C, to C"-alkyl radicals, a C, to C"-alkoxy radical, a C, to C6-alkylthio radical, a C, to C6-alkyl sulphonyl radical, a C, to C^-alkanoyl radical, an amino group, an acylamino group or an acyloxy group ; in each of the last two groups, acyl may be an acyl radical of the type defined in respect of R', and to the salts of these compounds.
The alkanoyi and alkenoyl radicals may be linear or branched. The alkanoyl radicals consist in particular of 2,3 or 4 carbon atoms, whilst the alkenoyl group consists in particular of 3, 4 or 5 carbon atoms. The thienyl and furyl carbonyl radicals may be respectively the corresponding thienyl- (2)- or thienyl- (3)-carbonyl radical and the furyl-(2) or furyl- (3)-carbonyl radical. In the case of the Cl to C4-alkoxy phenyl acetyl radical or the C, to C4-alkoxy benzoyl radical, the phenyl radical may be substituted once, twice or three times by the lower alkoxy groups. The preferred alkoxy group is the methoxy group.
The alkyl, alkoxy, alkyl-thio and alkyl sulphonyl radicals may each be linear or branched in regard to the respective alkyl groups. Examples of these radicals are methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.-butoxy, methyl- thio, ethylthio, propylthio, butylthio, methyl sulphonyl, ethyl sulphonyl, propyl sulphonyl.
Examples of the acylamino group are the acetamino group and benzoylamino group.
Where R2 is a naphthyl radical, it may be the naphthyl- (1)- or naphthyl- (2)-radical, this naphthyl radical optionally being substituted in both rings by the radicals R 3 and R4 However, the naphthyl ring is preferably substituted in the 6-ring which is not attached to the piperazine ring. Where R2 is a pyridyl ring, this ring may be attached to the piperazine ring in the 2-, 3-or 4-position.
R1 is preferably hydrogen or an alkanoyl group having 2, 3 or 4 carbon atoms.
When R2 is a phenyl or pyridyl group the substituents R3 and/or R4 are preferably adjacent to the carbon atom coupting R-with the piperazine ring.
Preferably R'is hydrogen and R-is a C1-C4-alkoxyphenyl group (for example, methoxyphenyl, ethoxyphenyl, propoxyphenyh isopropoxyphenyl, butoxyphenyl), a hyd- roxyphenyl group, an amino-phenyl group, a C2-C4-alkanoylaminophenyl group (for example, acetylaminophenyl, propionylaminophenyl, butyrylamino-phenyl) or a C,-C,- alkanoxyloxyphenyl group (for example, acetoxyphenyl, propionyloxyphenyl, butyryloxy- phenvl) where these substituents are in the o-or p-position, particularly the o-position.
The new compounds are pharmacodynamically active and show, for example, a pronounced anti-aggressive action together with neuroleptic properties, anti-convulsive and hypnotic effects being in evidence to a very limited extent only, if at all. In addition, the new compounds show fever-reducing and oedema-inhibiting effects. Accordingly, an object of the invention is to provide compounds with favorable pharmacodynamic properties which may be used as medicaments.
By contrast, the [3-(5,6,7,8-tetrahydronaphthyl-(1)-oxypropyl]-piperazine derivatives described in German Offenfegungsschrift No. 2. 235,597 show blood-pressure-reducing and hence anti-hypertensive properties. Unlike these derivatives, the compounds according to the invention show very little, if any, blood-pressure-reducing activity.
The compounds according to the invention may be produced by reacting a compound corresponding to the formula
with a compound corresponding to the formula
in which Y and Z are different from one another and one represents hydrogen, whilst the other represents the group-CH2-CH (OR')-CH2-V where V represents chlorine, bromine or iodine or, where R'is a hydrogen atom, may also form an ethylene oxide ring together with this hydroxy group, and optionally acylating the compounds obtained with an acid or acid derivative corresponding to the radical R.
The process for producing the compounds according to the invention may be carried out in the presence or absence of a solvent at a temperature in the range from 20 to 200 C and preferably at a temperature in the range from 50 to 150 C. Suitable solvents or dispersants are, for example, aromatic hydrocarbons such as, for example, benzene, toluene, xylene ; aliphatic ketones such as, for example, acetone, methylethyl ketone; halogenated hydrocarbons such as, for example, chloroform, carbon tetrachloride, chlorobenzene, methylene chloride ; aliphatic ethers such as, for example, butyl ether; cyclic ethers such as, for example, tetrahydrofuran, dioxane; sulphoxides such as, for example, dimethyl sulphoxide ; tertiary acid amides such as, for example, dimethyl formamide, N-methyl pyrrolidone ; aliphatic alcools, such as methanol, ethanol, isopropanol, amyt alcool, tert.-butanol ; cyclo-aliphatic hydrocarbons, such as cyclohexane and the like. Mixtures of the above-mentioned solvents may also be used. In many cases, the reaction is carried out at the reflux temperature of the solvent or. dispersant used. In general, the reaction components are reacted in molar quantities. In some cases, however, it can be of advantage to use the compound of formula III in excess (for example 0.5 mol) where Z is a hydrogen atom. The reaction may also be carried out in the presence of an acid-binding agent, such as an alkali metal carbonate (potash, soda), an alkali metal hydroxide or a tertiary amine (for example triethylamine). This applies in particular when compounds in which V is a halogen atom are used.
Where a compound of formula 11 in which Y is a hydrogen atom is used as the starting substance, this compound may also be used in the form of a metal salt. more especially an alkali metal salt (for example the sodium or potassium satt). This applies in particular when, in the other reaction component 111, the symbol V in the group Z, which is -CH2-CH (OR')-CH, V, is a halogen atom., For carrying out the reaction, the ethylene oxide used as the ethylene oxide starting compound may even be replace by the corresponding hatohydrin or by a mixture of these two compounds (crude synthesis product).
In the products obtained, the amino and/or hydroxy groups present and also the secondary hydroxy group in the central position (introduction of the R'-acy] radical) can be obtained by acylation, i. e. by treatment with acids of the formula R'OH, in which R'has any of the meanings defined except hydrogen, or by treatment with the corresponding reactive acid derivatives.
Corresponding acid derivatives are, in particular, compounds corresponding to the formula R'W IV in which W represents chlorine, bromine or iodine, the group-N-a group of the formula -OR',-SR'or a group of the formula-OSO3H, -O-PO(OH)2, -OP(OR')2, -O-As (OR') or -OCO-R"In these groups, R'represents an alkyl radical or even, in the case of-OR'and -SR', for example a phenyl radical, a p-nitrophenyl radical, a cynomethyt radicat or a carboxymethyl radical ; R"may be a linear or branched alkyl raciical, an atkoxy radical, a phenoxy radical. a carbobenzoxy radical or even the radical R'. Aliphatic C, to C,,-ketenes may also be used as acylation agents. Acid derivatives of formula IV in which W is chiorine or bromine represent particutarty appropriate acytating agents. Where R' and R"represent alkyl radicals or alkoxv radicals. these radicals are preferably of low molecular weight and consist of I to 6 carbon atoms.
The acylation step may be carried out. for example, in an inert solvent or suspending agent such as water, a lower aliphatic alcohol, a lower aliphatic ketone, dioxane, dimethyl formmnide. benzene or toluene. at n temperature of from 0 to 2 00 C. The acvlation step is optionally carried out in the presence of an acid-binding agent, such ns an alkali metal hydroxide, an alkali metut carbonate (potassium carbonate) an llkali metal hydrogen carbonate, an alkali metal acetate, an alkaline earth metat carbonate, a tertiary aminc (for example trialkvlamine. pyridine) or an alkali mctal alcoholate (sodium ethytatc).
It is also possible initiallv to convert the groups to be acytated (hydroxy group, amino group) in the compound to be reacted into the corresponding alkali mctal compound by reacting them with an alkah metal, an alkali metal hydride or an alkali meta anode (especially sodium or a sodium compound) at a temperature of from 0 to 150 C in an inert solvent. such as dioxane dimethyl formamide. benzene or toluene, and subsequently adding the acytaring agent.
In cases where the free acid with the formula R'OH is used. it has to be activatecl by the presence of a condensation agent, such as dicyclohexyl carbodiimide, a sulphurous acid-bis-alkyl amide (for example SO [N (CH3) 212), N, N'-carbonyl diimidazole and so on (Organic Reactions, Vol. 12,1962, pages 205 and 239).
Instead of using the acylating agents mentioned above, it is possible to use other chemically equivalent agents commonly encountered in chemistry (cj for example L. F. and Mary Fieser"Reagents for Organic Synthesis", John Wiley and Sons, Inc. New York, 1967, Vol. 1, pages 1303-4 and Vol. 2, page 471). Any acyl groups present in the compounds obtained may of course also be split off again in known manner, for example with aqueous alkali or alcoholic alkali metal hydroxide (for example methanolic KOH) or possibly even with mineral acids, such as hydrochloric acid or sulphuric acid, in alcoholic or aqueous-alcoholic solution at a temperature in the range from 20 C to 100 C.
For the reduction of one or even two nitro groups hydrogen in the presence of a catalyst is preferably employed. As catalysts there can be used, for example, Raney-nickel, noble metals such as palladium and platinum as well as their compounds, with or without carriers, such as for example barium sulphate, calcium sulphate, etc. It is recommended to carry out hydrogenation of the nitro groups at a temperature of from 20 to 80 C and at a pressure of approximately 5-50 atmospheres absolute in a solvent, for example, an alcool, e. g. meth\) alcool, ethyl alcohol or isopropyl alcool, dioxane, tetrahydrofuran, etc. In many cases, it is advantageous for the subsequent isolation of the reduced compounds to add a drying agent at the start to the hydrogenation mixture. Examples of drying agents are anhydrous sodium sulphate and magnesium sulphate.
However, the reaction can also be carried out with nascent hydrogen, for example, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid or with salts of hydrogen sulphide and alcohol/water at a temperature of 70 to 120 C or with activated aluminium in hydrated ether at 20 to 40 C or with tin II chloride/hydrochloric acid.
The compounds according to the invention are generally obtained in the form of racemates. The optically active antipodes are obtained either by usina optically active starting materials or by solution via the salts of optically active acids such as, for example, L- (+)-tartaric acid, D- (-)-tartaric acid. (+)-O O'-dibenzoyl-D-Tartaric acid. (-)-O. O'- dibenzoyl-L-tartaric acid. (-)-O. O'-di-p-toluoyl-L-tartaric acid. (+)-O, O'-di-p-toluovl-D- tartaric acid. (+)-camphor-10-sulphonic acid and others.
The compounds corresponding to general formula I may be converted into their salts by known methods. Suitable anions for these salts are the known and therapeuticaily useable acid radicals. Examples of acids such as these are H2SO4, phosphoric acid. hydrohalic acids, ethylene diamine tetraacetic acid, sulphamic acid, benzene sulphonic acid, p-toluene sulphonic acid, camphor sulphonic acid, methane sulphonic acid. guaiazulene sulphonic acid. maleic acid. fumaric acid, succinic acid, tartaric acid, lactic acid. ascorbic acid. gtycotic acid. salicyclic acid. acetic acid, propionic acid, gtuconic acid. benzoic acid, citric acid, acetaminoacetic acid. oxvethane sulphonic acid.
The free bases may in turn be produced from the salts of the compounds in known manner, for example by treating a solution in an organic solvent, such as an alcohol (methanol), with soda or sodium hydroxide.
The compounds according to the invention are suitable for the preparation of pharmaceutical compositions and preparations. The pharmaceutical compositions or medicaments contain, as active principle, one or more ot the compounds according to the invention, optionally in admixture with other pharmacologically or pharmaceuticallj active substances. The medicaments may be prepared in known manner with the usua) pharmaceutical excipients. assistants, carriers and diluent.
As carriers and assistants, for example. are those recommended in the fo) ! o\ving literature references as adjuvants for pharmacv, cosmetic and related fields : L't) mann's Encylkopadie der technischen Chemic, Vol. 4 (1953). pages 1 to 39; Journal of Pharmaceutical Sciences 52 (1963). pages 918 et seq; N. v. Czetsch-Lindenwald, Hilftstoffe fur Pharmazie und ungrenzende Gebietc : Pharm. Ind. 2 (19 ), paees 72 et seq ; Dr. H. P.
Fiedler, Lexicon der Hitftstoffe fur Pharmazie. Kosmetik und aml-ellzende Gebiete, Cantor KG. Aulendorf i. Wurtt (1') 71).
Examples of such materials inctudc getatin. natura) sugars such as sucrose or lactose lecithin, pectin, starch (for example cornstarch). alginic acid, tylose, talc, lycopodium, silice (for example colloidal silica), glucose, cellulose. cellulose derivatives for exemple cellulose ethers in which the cellulose hydroxyl groups are partially etherified with lower aliphatic alcools and/or lower saturated hydroxy alcohols (for example, methyl hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose), stearates. e.g., methylstearate and glyceryl stearate, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms. cspeciallv saturated acids (for example. calcium stearate. calcium laur , magnesium oleatc. calcium palmitate, calcium hchenate and magnesium, tearate). emulsifiers, oils fats. especiollv of plant origin (for example. peanut oil. corn oil. wheat germ oil, sunflower seed oil, cod-liver oil), mono-, di-and triglycerides of saturated fatty acids. (C12H24O2 to C18H36O2 and mixtures thereof), (e. g., glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl trilaurate), pharmaceutically compatible mono-or polyhydric alcools and polyglycols such as glycerine, mannitol, sorbitol, pentaerythritol, ethyl alcool, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400 and other polyethylene glycols, as well as derivatives of such alcools and polyglycols, esters of saturated and unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms), with monohydric aliphatic alcohols (1 to 20 carbon atom alkanols) or polyhydric alcools such as glycols, glycerine, diethylene glycol pentaerythritol, sorbitol, mannitol, ethyl alcohol, butyl alcohol, octadecyl alcohol. etc. e. g., glyceryl stearate, glyceryl palmitate, glycol distearate, glycol ditaurate, glycol diacetate, monoacetin, triacetin, glyceryl oleate, ethylene glycol stearate; which esters of polyvalent alcohols may in a given case even be etherified, benzyl benzoate, dioxolanes, glycerine formals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C2-alcohols, dimethy) acetamide, lactamides, lactates, e. g. ethyl lactate, ethyl carbonate, silicones (especially middle viscosity dimethyl polysiloxanes), magnesium carbonate and the like.
Solutions can be prepared, for example, with water or physiologically compatible organic solvents, as for example, ethanol, 1, 2-propylene glycol, polyglycols, e. g. diethylene glycol, triethylene glycol and dipropylene glycol and their derivatives, dimethyl sulphoxide, fatty alcools, e. g. stearyl alcohol, cetyl alcohol, lauryl alcohol and oleyl alcohol, triglycerides, e. g., glyceryl oleate, glyceryl stearate, glyceryl palmitate, and glyceryl acetate, partial esters of glycerine, e. g. monoacetin, diacetin, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate, paraffins and the like.
Conventional solution promoters and emulsifiers can also be used in the preparation of the compositions. Examples of solution promoters and emulsifiers include polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, lecithin, gum acadia, gum tragacanth, polyoxyethylated sorbitan monoleate, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolised oleotriglycerides. polyethylene oxide condensation products of fatty alcools, alkylphenols or fatty acids. As used herein polyoxyethylated means that the materials in question contain polyoxyethylene chains whose degree of polymerisation generally is from 2 to 40, particularly from 10 to 20.
Such polyoxyethylated materials for example can be obtained by reaction of hydroxyl group containing compounds (for example, mono-or diglycerides) or unsaturated compounds such as, for example, those containing the oleic acid radical with ethylene oxide (for example, 40 mols of ethylene oxide per mole of glyceride).
Examples of oleotriglycerides include olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil, (see also Dr. H. P. Fiedler, supra, pages 191-195).
In addition, it is possible to add preservatives, stabilisers, buffers, for example, calcium hydrogen phosphate, colloidal aluminium hydroxide, flavour correctants, antioxidants and complex formers (for example, ethylene diamine tetraacetic acid) and the like. In a given case for stabilisation of the active molecule the pH is adjusted to about 3 to 7 with physiologically compatible acids or buffers. Generally. a neutral to weak acid (up to pH 5) pH value is preferred. Examples of suitable antioxidants include sodium meta-bisulphite, ascorbic acid. gallic acid, alkyf gallates, e. g. methyl gallate and ethyl galate, butyl hydroxyanisole. nordihvdroouararetic acid. tocopherols as well as tocopherol and synergisis (materials which bind heavv meta) s by complex formation, for example, ecithin. ascorbic acid. phosphoric acid). The additon of synergists increases considerabiy the antioxidant activity of tocopherol. Examples of preservatives include sorbic acid. p-hydroxybenzoic acid esters (for example. lover alkvl esters such as the methyl ester and the ethy ! ester) benzoic acid, sodium henzoate, trichloroisobutyl alcohol, phenol. cresol, benzethonium chloride and forma) in derivatives).
The pharmacological and galenical treatment of the compounds of the invention takes place according to the usual standard methods. For example, the active material or materiafs and assistants or carriers are well mixed bv stirring or homogenisation (for example. bv means of a colloid mill or hall mill). The operation is Eenerativ carried out at a temperature of from 20 C to 80 C, preferably 20 to 50 C.
The application of the active material or the medicament can take place on the skin or mucous membrane or internallv. for example, orally, parenterallv. pulmonarif. rectallv, nasally, vaginallv, perlingually. intravenously, intraarterially, intracardially, intramuscular ly, intraperitoneally, intracutaneouslv or subcutaoeouslv.
The addition of other medicines is also possible or favoura le.
The compounds of the invention in the combat test. mouse (R. E. Tedeschi and coworkers, J. Pharmacol. Exp. Therap. Vol. 125. page 28 (1959) or in the amphetamine group toxicity test. mouse, H. Fujimori and coworkers, J. Pharmacol. Exp. Therap., Vol.
148. page 151 (1965) showed a good anxiolytic-anti-aggressive or amphetamine-antagonistic (neuroleptic property) activity.
For example in the above-mentioned test methods at a dosage of 2.0 mg/kg body weight mouse anxiolytic-anti-aggressive and amphetamine-antagonistic activity occurred. This tranquilising-neuroleptic activity is comparable with the activity of the known medicines Diazepam and Chlorpromazine.
The lowest clearly effective dosage in the above-mentioned animal experiments is, for example, 0. 1 mg/kg orally; 0.01 mg/kg intravenously.
As the general dosage range for the above-mentioned activities (animal experiments as above), there can be used, for example, 0.1 to 20 mg/kg orally, particularly 1. () to 10 mg/kg, 0. 01 to 5.0 mg/kg intravenously, particularly 0.1 to 1. 0 mg/kg.
The compounds of the invention are indicated for use in excitement, internal tension, anxiety, psychoneurotic disturbances, disturbances of sleep, psychoses, depression conditions.
The pharmaceutical preparations generally contain from 0.1 to 50 mg of the active component or components of the invention.
The compounds can be made up in the form of tables, capsules, pills, dragees, suppositories, ointments, gels, jellies, creams, powders, dusts, aerosols or in liquid form.
As liquid forms there can be used for example oily or alcoholic or aqueous solutions as well as suspensions and mulsions. The preferred formulations are tablets which contain from 0.5 to 30 mg or solutions which contain from 0.1 to 5 % of active material.
In individual doses, the active component of the invention can be used for example in an amount of: a. in oral formulations from 0. 1 to 50 mg; b. in parenteral formulations (for example, intravenously, intramuscularly) from 0. 01 to 10 mg; c. in rectally or vaginally administered formulations from 0.2 to 200 mg.
For example, the use of 1 to 3 tablets containing 0.5 to 20 mg of active ingredient 3 times daily is recommended or for example, the injection intravenousiv 1 to 6 times daily of a 1 to 10 mi ampoule containing 0. 01 to 5.0 mg of active substance. In oral preparations the minimum daily dosage for example is 10 mg ; the maximum daily dosage in oral administration should not exceed 10 grams.
The dosages in each case are based on the free base.
In veterinary medicine the compounds of the invention can be used for treating dogs and cats. In general the oral individual doses are from 0. 1 to 20 mg/kg body weight ; the parenteral dose is generally from 0.01 to 5. 0 mg/kg body weight.
For the treatment of horses and cattle. the individual oral dose is generally from 0. 1 to 20 mglke : the individual parenteral dose amounts to from about 0. 01 to 2 () mg/kg body weight.
The acute toxicity of the compounds of the invention in the mouse (expressed bv the LD "mgSkg method of Miller and Tainter, Proc. Soc. Exper. Biol. and Med. 57 (1944). pages 261 et seq). in oral application is between 100 mg/kg and 5000 () () ) mulkg. in some cases even above 5000 mg/kg.
Starting compounds of formula 111. in which Z represents the group-CH,-CH (OH)-CH2 V, may be obtained for example in the usuel way by reacting epichlorohvdrin or epibromohydrin with the corresponding piperazine. which contains the radical R-in the 4-position, at 10 C in an alcool. preferably methanol, with approximately 5 % of water added. The reaction time amounts for example to 3 () minutes. The reaction mixture is then heated to 30 to 40 C and stirred for 5 hours.
The ratio of piperazine to the hydrin, @mounts for example to from) :) to 1 : 5 and preferably to from 1:1 to 1:2, The water content may be from 1 to l ) and is preferably from 2 to 6 %.
In the compounds thus obtained. the radical R1 may be introduced by acylation with a compound R'W under the conditions specified above. R'may n) so be introduced in the same wav into starting compounds of formula 11 in which Y represents the group -CH,-CH (OH)-CH2-V.
The other starting compounds are known.
The invention is illustrated by the following Examples.
Example 1 (~)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine. a) 12 ~ (0. 05 mole) of 3,4,5-trimethoxyphenoxy glycidyl ether and 9.6 g (0.05 mole) of 1-(2-methoxyphenyl)-piperazine are boiled under reflux for 5 hours in 100 ml of isopropanol. Most of the solvant is then distilled off, the residue is treated with excess isopropanolic HCI and the dihydrochloride of the 1-[3-(3,4,5-trimethoxyphenoxy)-2hydroxypropyl]-4-(2-methoxyphenyl)-piperazine is precipitated by the addition of diethyt ether. giving 18.4 g (73 % of the theoretical) of a colourless crvstalline substance. M. p. of the dihydrochloride : 196-197 C.
The 3,4,5-trimethoxyphenoxy glycidyl ether is produced for example as follows : In a suitable reaction vessel fitted with an attachment for the azeotropic separation of water, 18.4 g (0. 1 mole) of 3,4,5-trimethoxyphenol are brought to the boil with 37 g (0. 4 mole) of epichlorohydrin, followed by the dropwise addition over a period of 30 minutes of 10 g (0.1 mole) of 40 % sodium hydroxide, the water being simultaneously removed azeotropically from the circuit. After the sodium hydroxide has been added, the mixture is left to react for 1 hour at boiling temperature, subsequently diluted with approximately 100 ml of toluene and the NaCI precipitated is filtered off. The filtrate is fractionated first under normal pressure and then in vacuo. The 3,4,5-trimethoxyphenoxy glycidvl ether is obtained as a colourless oil at b. p. l"= 175-180 C. Yield : 19.2 g, corresponding to 80 % of the theoretical, based on trimethoxyphenol.
The process for producing the end product may also be carried out as follows : 0. 05 mole of sodium- (3, 4,5-trimethoxy)-phenolate and 0.05 mole of 1- (3-chloro-2- hydroxypropyl)-4- (2-methoxyphenyl)-piperazine (produced by reacting 1- (2- methoxyphenyl)-piperazine with epichlorohydrin) are boiled under reflux for 8 hours in 50 ml of dioxane. After cooling, the NaCI precipitated is filtered off and the filtrate is concentrated. The residue is treated with isopropanolic hydrochloric acid and ether and the crystalline solid is recrystallized from methanol, giving 8.2 g (32 % of the theoretical) of the above-mentioned compound in the form of its dihydrochloride melting at 194-196 C.
Another way of carrying out the process is as follows : A mixture of 0. 05 mole of 3- (3, 4, 5-trimethoxyphenoxy)-2-hydroxypropyl bromide, 0. 05 mole of 1- (2-methoxyphenyl)-piperazine and 0. 06 mole of triethylamine is boiled under reflux for 5 hours in 100 mi of toluene. The triethyl ammonium bromide precipitated is then filtered off and the filtrate is concentrated. The residue is taken up in a little ispropanol and the dihydrochloride of the above-mentioned compound is precipitated with isopropanolic hydrochloric acid and ether. Recrystallisation from methanol gives 10. 1 g of end product (40 % of the theoretical) melting at 195-147 C.
The compounds listred in Table I corresponding to the formula
are obtained in the same way as described in the first paragraph of Example 1 from (). 05 mole of 3,4,5-trimethoxy-phenoxy glycidyl ether and 0. 05 mole of a compound corresponding to formula III : TABLE 1 Example Starting component of formula III R2 in the above formula Melting point Yield in % No. C of the theoretical 2 1-phenyl piperazine phenyl 187 - 188**) 65 3 1-(4-fluorophenyl)-piperazine 4-fluorophenyl 202 - 203**) 74 4 1-(2-chlorophenyl)-piperazine 2-chlorophenyl 193 - 195*) 72 5 1-(3-chlorophenyl)-piperazine 3-chlorophenyl 172 - 173*) 68 6 1-(4-chlorophenyl)-piperazine 4-chlorophenyl 199 - 201**) 79 7 1-(3-methoxyphenyl)-piperazine 3-methoxyphenyl 202 - 204**) 82 8 1-(4-methoxyphenyl)-piperazine 4-methoxyphenyl 208 - 210**) 74 9 1-(2-ethoxyphenyl)-piperazine 2-ethoxyphenyl 198 - 200**) 64 (decomposition) 10 1-(2-methylmercaptophenyl)-piperazine 2-methylmercaptophenyl 183 - 185*) 69 11 1-(2-methylphenyl)-piperazine 2-methylphenyl 198 - 199*) 54 12 1-(3-methylphenyl)-piperazine 3-methylphenyl 189 - 192**) 68 13 1-(3,4-dimethylphenyl)-piperazine 3,4-dimethylphenyl 186 - 188**) 80 14 1-(2,6-dimethylphenyl)-piperazine 2,6-dimethylphenyl 228 - 230*) 71 15 1-(4-acetylphenyl)-piperazine 4-acetylphenyl 137 - 138 58 (base) 16 1-(2-trifluoromethylphenyl)-piperazine 2-trifluoromethylphenyl 205 - 206*) 52 17 1-(3-trifluoromethylphenyl)-piperazine 3-trifluoromethylphenyl 169 - 172**) 69 18 1-naphth-(1)-yl-piperazine naphth-(1)-yl 242 - 245*) 61 19 1-pyrid-(2)-yl-piperazine pyrid-(2)-yl 222 - 224**) 47 20 1-(2-hydroxyphenyl)-piperazine 2-hydroxyphenyl 131 (base) 61 21 1-(2-nitrophenyl)-piperazine 2-nitrophenyl 198*) 55 *) monohydrochloride *) dihydrochloride Example 22 (~)-1-[3-(3,4,5-trimethoxyphenoxy)-2-(nicotinoyloxy)-propyl]-4-(2-methoxyphenyl)piperazine 13.0 g (0. 03 mole) of ()-l- [3- (3, 4, 5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2methoxyphenyl)-piperazine and 3.34 g of triethylamine (0.003 mole) are dissolved in 80 ml of anhydrous benzene, followed by the addition over a period of 30 minutes of a solution of 4.67 g (0.033 mole) of nicotinic acid chloride in 50 ml of anhydrous benzene. After stirring for another 2 hours at room temperature, the mixture is finally heated for 1 hour to 70 to 80 C. After cooling, the mixture is repeatedly extracted by shaking with water, washed with aqueous NaHCO3 and water and the benzene phase is dried with magnesium sulphate and concentrated. The solid residue is taken up in dioxane. After the addition of excess isopropanolic hydrochloric acid and ether, 13.0 g (67 % of the theoretical) of the above-mentioned compound are obtained in the form of its trihydrochloride (colourless crystals). M. p. 187-192 C (decomposition).
Exatnple 23 (~)-1-{3-[3, 4,5-trimethoxyphenoxy]-2- [ (3,4,5-trimethoxy)-benzoyloxy]-propyl}-4-(2 methoxyphenyl)-piperazine ()-i-r3l-e (3, 4,5-trimethoxyphenyl)-2-hydroxypropyl]-4- (2-methoxyphenyl)-piperazine is reacted with 3,4,5-trimethoxy-benzoyl chloride in the presence of triethylamine as in Example 22. The reaction product is obtained in the form of the dihydrochloride melting at 193-195 C (decomposition).
Yield : 38%.
Example 24 ()-1- [3- (3, 4, 5-trimethoxyphenoxy)-2-hydroxy-propylJ-4- (2-acetamido-phenyl)- piperazine 4 g ()-1- [3- (3. 4, 5-trimethoxyphenoxy-2-hydroxy-phenyl]-4- (2-amino-phenvl)- piperazine (mono-hydrochloride) are dissolved in 200 ml of dioxane and treated with 10 mi of triethylamine. 0.9 ml of acetyl chloride are then dropped in with stirring at-5'C. After two hours of further reaction at room temperature, the solution is filtered at room temperature and the solvent removed under reduced pressure. The desired compound is isolated by dry column chromatography on silica gel (elution material ether-acetic acid (1 : 1 by volume). Recrystallisation takes place from acetone-ether.
Yield : 50 %. M. p. 128-130 C.
()-I- (3- (3, 4. 5-trimethoxyphenoxy)-2-acetoxy-propyl]-4- (2-acetamido-phenyl)- piperazine (M. p. 54C) is obtained as less polar byproduct. It can be made into the main product by increasing the amount of acetyl chloride.
Example ? 23 ()-1- [3- (3. 4.5-trimethoxyphenoxy)-2-hydroxy-propyl]-4- (2-aminophenyl)-piperazine 6 g (0124 mole) (~)-1-[3-(3, 4. 5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-nitro phenvl)-piperazine are dissolved in 300 m) of methanot and hydrogenated in the presence of 0.5 g Pd-carbon (K) *%) at room temperature. After filtering off the catalyst and removal of the solvent iz vacuo it is recrystallised from ethanol. Yield: 94 %. M. p. of the monohydrochloride : 18 3 C.
Exemple of resolution (~)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine (base = compound la) and (-)-1-[3-(3, 4. 5-trimethoxyphenoxy)-2-livdroxypropyl]-4- (2- methoxy-phenyl)-piperazine (base = compound lb).
4. 32 g (0. 005 mote) of the racemic compound produced in accordance w ith Example I are dissolved in 80 ml of warm butvlacetate. followed bv the addition in portions with thorough stirring at 80 C of 4.04 g (0.005 mole) of (-)-di-p-toluoyl-L-tartaric acid hydrate, the levo-rotatorv diastereomeric salt pair actuallv heing precipitated. After heating for li0 minutes to I 10 C. the mixture is left to cool to 80 C and the deposit is filtered off. The salt pair is recrystallised from acetone-dimethvl formamicle-petrol ([&alpha;]D20-48.6 ; 1 % in dimethyl formamide), and is subsequcntjy spiit by treatment with concentrated ammonia. The base is extracted with ether and the extract is concentrated. The solid residue is recrvstallised from isopropanol : a-base colourless crvstals. m.p. 103 - 104 C; [&alpha;]D20 + 7.2 (concentration 2 % in CH3OH). Dissolution of the base in methanol, followed by the addition of isopropanotic hydrochloric acid and ether gives the dihydrochloride of compound la in the form of colourless crystals melting at 189 - 193 C; [3035]D20 - 11.4 (concentration = 2 % in CH3OH).
The filtriltw obtained after precipitation of the salt pair, which contains the dextrorotatory diastercomeric salt pair. is concentrated in a rotary evaporator. the viscous residue is suspende in water, concentrated ammonia is added and the base extracted with ether. The ethereal solution is dried and concentrated and the solid residue is recrystallised from isopropanol : lb-base, colourless crystals, m. p. 100 - 101 C; [&alpha;]D20 - 5.8 (concentration = 2 % in CH1OH).
Dissolution of the base in methanol and treatment with isopropanolic hydrochloric acid and ether gives the dihydrochloride of compound lb in the form of colourless crystals melting at 182 - 187 C ; [&alpha;]D20 + 11.0 (concentration = 2 % in CHr, OH).
EXAMPLES OF PHARMACEUTICAL PREPARATIONS Example 26 Injection Solution For a mixture of 100 litres there are needed: Compound according to Example 1 0.25 kg (dihydrochloride) Sodium chloride 0. 775 kg Water for purpose of injection 98.975 kg 100. 00 kg Production: The active material together with sodium chloride is dissolved with stirring in the water for purpose of injection. The solution is filtered and is filled into 2 ml ampoules of clear glass. The ampoules after being closed by melting are sterilised for 20 minutes at 120 C in superheated steam.
Example 27 Suppositories Production : 5 g of the compound of Example 7 (dihydrochloride) is worked into 1995 g of molten suppository composition (for example. hard fat DAB 7, a mixture of mono-, di-and triglycerides of saturated fatty acids C12H24O2 to C"H. O2) and in known manner poured out in moulds for 2. 0 g suppositories.
I suppository contains 5 mg of active material.
Exatnple 28 Capsules To prepare 100.000 capsules the following raw materials are required: Compound according to Example 7 (dihydrochloride) 0.125 kg Lactose 7.200 kg Microcrvstalline cellulose 4.800 kg Magnesium stearate (1. 375 kg 12.500 kg To produce eelatin capsules (size 4) uhich are necessarv for production of the capsule composition the previously set forth raw materiats are passed through a sieve having a mesh width of 1. 5 mm and then mixez for 1 hour at 10 revolutions per minute in a Turbula mixer.
This composition is enlled the capsule filling composition.
This capsule filling composition is filled into gelatin capsutes of size 2. Amount of filling per capsule : t25 mg.

Claims (22)

  1. WHAT WE CLAIM í 1. Compounds corresponding to the general formula
    in which R'is a hydrogen atom, a C2 to C6-alkanoyl radical, a C3 to C6-alkenoyl radical, a C3 to C6-cycloalkyl carbonyl radical, a benzoyl radical, a C, to C4-alkoxy benzoyl radical, a nicotinoyl radical, a thienyl carbonyl radical, a furyl carbonyl radical, a phenylacetyl radical or a C, to C,-alkoxyphenyl acetyl radical and R2 represents a phenyl, naphthyl or pyridyl radical optionally substituted by the radicals R and R, the radicals R and R, which may be the same or different, each representing hydrogen, hydroxyl, fluorine, chlorine, bromine, a nitro group, a trifluoromethyI group, a C, to C6-alkyl radical, a C, to C6-alkoxy radical, a C, to C6-alkyl thio radical, a Cl to C6-alkyl sulphonyl radical, a C, to C6-alkanoyl radical, an amino group, an acylamino group or an acyloxy group in which acyl may represent an acyl radical of the type defined in the respect of R', and their salts.
  2. 2. Compounds corresponding to the general formula
    in which R1 is a hydrogen atom. a C2 to C6-alkanoyl radical, a C3 to C6-alkenoyl radical, a C3 to C6-cycloalkyl carbonyl radical, a benzoyl radical, a nicotinoyl radical, a thienyl carbonyl radical, a fur) carbonyl radical, a phenylacetyl radical or a C, to C,-alkoxyphenyl acetyl radical and R-represents a phenyl. naphthyl or pvridyl radical optionally substituted by the radicals R3 and R4, the radicals R3 and R4, which may be the same or different, each representing hydrogen, hydroxy, fluorine, chlorine, bromine, a nitro group, a trif luoromethyl group, a C, to C6-alkyl radical, a C1 to C6-alkoxy radical a C, to C,-alkyl thio radical, a C, to C,-alkvl sulphonyl radical, a C, to C6-alkanoyl radical, an amino group, or an acytoxy group in which acyl may represent an acyl radical of the type defined in respect of R. and their salts.
  3. 3. The compounds as claimed in Claim 2 specifically exemplified herein in Examples I to 19, 22 and 23.
  4. 4. The compounds as claimed in Claim I specifically exemplified herein in Examples 20 21, 24 and 25.
  5. 5. A process for the production of compounds corresponding to the general formula
    in which R1 is a hydrogen atom. a C@ to C6-alkanoyl radical, a C3 to C6-alkenoyl-radical, a C3 to C6-cycloalkyl carbonyl radical, a benzoyl radical, a C1 to C4-alkoxy benzoyl radical, a nicotinoyl radical a thienyl cabonyl radical, a furyl carbonyl radical. a phenylacetyl radical or a C1 to C4-alkoxyphenyl acetyl radical and R2 represents a phenyl, naphthyl or pyridyl radical optionally substituted hy the radicals R'anci R'. the radicals R3 and R4, which may be the same or different. each representing hydrogen, hydroxyl, fluorine, chlorine, bromine, a nitro group, a trifluoromethyl group, a C1 to C6-alkyl radical, a C1 to C6-alkoxy radical, a C, to C6-alkyl thio radical, a C1 to C6-alkyl sulphonyl radical. a C2 to C,,-alkanovl radical, an amino group, an acylamino group or an acyloxy group in which acyl may represent an acyl radical of the type defined in respect of R, and their salts, which comprises reacting a compound corresponding to the formula
    with a compound corresponding to the formula
    in which Y and Z are different from one another and one represents a hydrogen atom whilst the other represents the group-CH,-CH (OR')-CH,-V where V represents chlorine, bromine or iodine or, where R'is hydrogen, may also form an ethylene oxide ring with this hydroxy group.
  6. 6. A process as claimed in Claim 5, in which the compound obtained is acylated with an acid or acid derivative corresponding to the radical R'.
  7. 7. A process as claimed in Claim 5 or 6, wherein the compound obtained is converted into an acid addition salt.
  8. 8. A process for the production of compounds corresponding to the general formula
    in which Ru ils a hydrogen atom, a C, to C6-alkanoyl radical, a C3 to C6-alkenoyl radical, a C3 to C6-cycloalkyl carbonyl radicaf, a benzoyl radical, a nicotinoyl radical. a thienyl carbonyl radical, a furyl carbonyl radical, a phenylacetyl radical or a C, to C4-alkoxyphenyl acetyl radical and R2 represents a phenyl, naphthyl or pyridyl radical optionally substituted by the radicals R3 and R4, the radicals R and R 1, which may be the same or different, each representing hydrogen, hydroxyl. fluorine, chlorine, bromine, a nitro group, a trif luoromethvl eroup. a C, to C,,-alkvl radical, a C, to C,,-alkoxy radical. a C, to C,-alkyl thio radical, a C1 to C6-alkyl sulphonyl radical, a C2 to C6-alkanoyl raclicul, an amino group, an acytamino group or an acyloxv group in which acyl may represent an iicvl radical of the type defined in respect of R'. and their salts. which comprises reacting a compound corresponding to the formula
    with n compound corresponding to the formula
    in which Y and Z are different from one another and one represents a hvdrogen atom whiist the other represents the group -CH2-CH(OR1)-CH2-V where V represents chourine. bromine or iodine or, where R'is a hydrogen, may also form an ethylene oxide ring with this hydroxy group.
  9. 9. A process as claimed in Claim 8, in which the compound obtained is acylated with an acid or acid derivative corresponding to the radical R'.
  10. 10. A process as claimed in Claim 8 or 9, wherein the compound obtained is converted into an acid addition salt.
  11. I 1. A process as claimed in Claim 8, substantially as described with particular reference to any of Examples I to 19, 22 and 23.
  12. 12. A process as claimed in Claim 5, substantially as described with particular reference to any of Examples 20, 21,24 and 25.
  13. 13. A compound as defined in Claim 1, when prepared by a process as claimed in any of Claims 5 to 7 or 12.
  14. 14. A compound as defined in Claim 2, when prepared by a process as claimed in any of Claims 8 to 11.
  15. 15. A medicament containing at least one compound as defined in any of Claims 1, 4 or 13.
  16. 16. A medicament containing at least one compound as defined in any of Claims 2, 3 or 14.
  17. 17. A medicament containing at least one compound as defined in any of Claims 1, 4 or 13, including the pharmaceutically compatible acid addition salts. together with at least one inert excipient.
  18. 18. A medicament containing at least one compound as defined in any of Claims 2,3 or 14, including the pharmaceutically compatible acid addition salts, together with at least one inert excipient.
  19. 19. A medicament substantially as described with particular reference to any of Examples 26 to 28.
  20. 20. A process for producing a medicament, which comprises processing at least one compound as defined in any of Claims 1. 4 or 13 with at least one pharmaceutical excipient or diluent to form a pharmaceutical preparation.
  21. 21. A process for producing a medicament, which comprises processing at least one compound as defined in any of Claims 2, 3 or 14 with at least one pharmaceutical excipient or diluent to form a pharmaceutical preparation.
  22. 22. A process for producing a medicament substantially as described with particular reference to any of Examples 26 to 28.
GB14100/77A 1977-04-04 1977-04-04 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives Expired GB1583372A (en)

Priority Applications (25)

Application Number Priority Date Filing Date Title
GB14100/77A GB1583372A (en) 1977-04-04 1977-04-04 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives
FR7809675A FR2395264A1 (en) 1977-04-04 1978-03-31 NEW DERIVATIVES 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINIQUES, PROCESS FOR THEIR PREPARATION AND APPLICATION AS A MEDICINAL PRODUCT
YU767/78A YU40513B (en) 1977-04-04 1978-03-31 Process for manufacture of 1-(3-(3,4,5-trimethoxypheoxy)-2-hydroxypropyl)-4-akryl-piperazines
HU78DE957A HU179952B (en) 1977-04-04 1978-04-01 Process for preparing new 1-/3-/3,4,5-trimethoxy-phenoxy/-2-hydroxy-propyl/-4-aryl-piperazine derivatives
PL1978205745A PL112249B1 (en) 1977-04-04 1978-04-01 Process for preparing novel derivatives of 1-/3-/3,4,5-trimethoxyphenoxy/-2-hydroxypropyl/-4-arylpiperazine
DE19782814168 DE2814168A1 (en) 1977-04-04 1978-04-01 NEW 1- CORNER CLAMP ON 3- (3,4,5- TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL CORNER CLAMP ON -4-ARYL-PIPERAZINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
CS782141A CS249503B2 (en) 1977-04-04 1978-04-03 Method of new 1-(3-/3,4,5-trimethoxyphenoxy/-2-hydroxypropyl-4-aryl-piperazine derivatives production
ES468486A ES468486A1 (en) 1977-04-04 1978-04-03 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives
ZA00781889A ZA781889B (en) 1977-04-04 1978-04-03 New 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives
CH354378A CH638795A5 (en) 1977-04-04 1978-04-03 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-arylpiperazine derivatives and process for their preparation
AU34703/78A AU516315B2 (en) 1977-04-04 1978-04-03 1 (3 (3, 4, 5-trimethoxyphenoxy) 2-hydroxypropyl) 4-aryl piperazine derivatives
SU782596099A SU893133A3 (en) 1977-04-04 1978-04-03 Method of preparing derivatives of 1-/3-(3,4,5-trimethoxyphenoxy)-2-propyl/-4-arylpiperazine
BE6046420A BE865642A (en) 1977-04-04 1978-04-03 NEW DERIVATIVES OF 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXY-PROPYL) -4-ARYL-PIPERAZINES AND PROCESS FOR THEIR PREPARATION AS WELL AS THEIR USE AS A MEDICINAL PRODUCT
IT48718/78A IT1202819B (en) 1977-04-04 1978-04-03 REPLACED PIPERAZINE DERIVATIVES EQUIPPED WITH PHARMACOLOGICAL ACTIVITY, AND PROCEDURE FOR THEIR PRODUCTION
SE7803742A SE435507B (en) 1977-04-04 1978-04-03 PROCEDURE FOR THE PREPARATION OF TRIMETOXIFENOXY-PROPYL-PIPEREZINE DERIVATIVES
NL7803540A NL7803540A (en) 1977-04-04 1978-04-03 NEW 1- 3- (3.4.5-TRIMETHOXY PHENOXY) -2-HYDRO- XYPROPYL -4-ARYL-PIPERAZINE DERIVATIVES AND METHOD FOR THEIR PREPARATION.
NO781159A NO149209C (en) 1977-04-04 1978-04-03 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1- (3- (3,4,5-TRIMETOXYPHENOXY) -2-HYDROXYPROPYL) - 4-ARYL-PIPERAZINE DERIVATIVES
AT233078A AT360997B (en) 1977-04-04 1978-04-03 METHOD FOR PRODUCING NEW 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES AND THE SALTS THEREOF
DK146678A DK145225C (en) 1977-04-04 1978-04-03 ANALOGY PROCEDURE FOR PREPARING 1- (3-TRIMETHOXYPHENOXY-2-HYDROXY-PROPYL) -4-PHENYL-PIPERAZINE DERIVATIVES OR ACID ADDITION SALTS.
CA300,288A CA1124718A (en) 1977-04-04 1978-04-03 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4- aryl piperazine derivatives
FI781009A FI69627C (en) 1977-04-04 1978-04-03 REFERENCE TO A FRAMEWORK FOR THERAPEUTIC USE OF THERAPEUTIC ANVAENDBARA 1- (3- (3,4,5-TRIMETOXYFENOXY) -2-HYDROXIPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES
AR271686A AR222149A1 (en) 1977-04-04 1978-04-04 PROCEDURE FOR PREPARING NEW DERIVATIVES OF 1- (3- (3,4,5-TRIMETOXIFENOXI) -2-HIDROXIPROPIL) -4-ARIL PIPERAZINE
MX786995U MX6120E (en) 1977-04-04 1978-04-04 IMPROVED PROCEDURE FOR PREPARING DERIVATIVES OF 1- (3- (3,4,5-TRIMETOXIFENOXI) -2-HYDROXIPROPIL) -4-ARYL-PIPERAZINE
JP53039626A JPS6038383B2 (en) 1977-04-04 1978-04-04 Novel 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy-propyl]-4-aryl-piperazine derivatives and their production method
FR8018458A FR2488892A2 (en) 1977-04-04 1980-08-25 NOVEL 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB14100/77A GB1583372A (en) 1977-04-04 1977-04-04 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives

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GB1583372A true GB1583372A (en) 1981-01-28

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GB14100/77A Expired GB1583372A (en) 1977-04-04 1977-04-04 1-(3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl)-4-aryl piperazine derivatives

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JP (1) JPS6038383B2 (en)
AR (1) AR222149A1 (en)
AT (1) AT360997B (en)
AU (1) AU516315B2 (en)
BE (1) BE865642A (en)
CA (1) CA1124718A (en)
CH (1) CH638795A5 (en)
CS (1) CS249503B2 (en)
DE (1) DE2814168A1 (en)
DK (1) DK145225C (en)
ES (1) ES468486A1 (en)
FI (1) FI69627C (en)
FR (1) FR2395264A1 (en)
GB (1) GB1583372A (en)
HU (1) HU179952B (en)
MX (1) MX6120E (en)
NL (1) NL7803540A (en)
NO (1) NO149209C (en)
PL (1) PL112249B1 (en)
SE (1) SE435507B (en)
SU (1) SU893133A3 (en)
YU (1) YU40513B (en)
ZA (1) ZA781889B (en)

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US4335126A (en) * 1977-03-10 1982-06-15 Degussa Aktiengesellschaft 1-[3-(3,4,5-Trimethoxyphenoxy)-2-hydroxy-propyl]-4-aryl-piperazine-derivatives having pharmaceutical activity
FR2488892A2 (en) * 1977-04-04 1982-02-26 Degussa NOVEL 1- (3- (3,4,5-TRIMETHOXYPHENOXY) -2-HYDROXYPROPYL) -4-ARYL-PIPERAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT
DE2824764A1 (en) * 1978-06-06 1979-12-20 Hoechst Ag NEW PYRIDYL PIPERAZINE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION
DE3023369A1 (en) * 1980-06-23 1982-01-14 Boehringer Mannheim Gmbh, 6800 Mannheim ARYLOXYPROPANOLAMINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
FR2568878B1 (en) * 1984-08-07 1986-11-21 Cortial NOVEL (PHENYLPIPERAZINYLETHYLAMINE ETHOXY) -4 PHENOL DERIVATIVES, THEIR PREPARATION METHOD AND THEIR THERAPEUTIC APPLICATION

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CA967965A (en) * 1968-12-24 1975-05-20 Hoffmann-La Roche Limited Aromatic ethers and process for the manufacture thereof
FR2068051A5 (en) * 1969-11-26 1971-08-20 Robert Jean
CA1012540A (en) * 1972-06-17 1977-06-21 Sumitomo Chemical Company 2-propanol derivatives and preparation thereof
DE2235597A1 (en) * 1972-07-20 1974-01-31 Boehringer Mannheim Gmbh SINGLE SQUARE CLIP ON 3- (5,6,7,8TETRAHYDRONAPHTH-1-YL-OXY) -PROPYL SQUARE CLIP FOR -PIPERAZINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION

Also Published As

Publication number Publication date
PL205745A1 (en) 1979-05-07
ATA233078A (en) 1980-07-15
JPS6038383B2 (en) 1985-08-31
ES468486A1 (en) 1979-01-16
FI781009A (en) 1978-10-05
AT360997B (en) 1981-02-10
JPS53130682A (en) 1978-11-14
CH638795A5 (en) 1983-10-14
ZA781889B (en) 1979-03-28
AU3470378A (en) 1979-10-11
DE2814168C2 (en) 1989-02-16
HU179952B (en) 1983-01-28
YU76778A (en) 1982-10-31
AR222149A1 (en) 1981-04-30
FR2395264B1 (en) 1980-03-07
SE435507B (en) 1984-10-01
PL112249B1 (en) 1980-10-31
NO149209B (en) 1983-11-28
DK145225B (en) 1982-10-11
SU893133A3 (en) 1981-12-23
NO781159L (en) 1978-10-05
DK145225C (en) 1983-04-11
FI69627B (en) 1985-11-29
AU516315B2 (en) 1981-05-28
YU40513B (en) 1986-02-28
DK146678A (en) 1978-10-05
FI69627C (en) 1986-03-10
CS249503B2 (en) 1987-03-12
CA1124718A (en) 1982-06-01
BE865642A (en) 1978-10-03
NO149209C (en) 1984-03-07
NL7803540A (en) 1978-10-06
MX6120E (en) 1984-11-19
DE2814168A1 (en) 1978-10-05
FR2395264A1 (en) 1979-01-19
SE7803742L (en) 1978-10-05

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Legal Events

Date Code Title Description
429A Application made for amendment of specification (sect. 29/1949)
429H Application (made) for amendment of specification now open to opposition (sect. 29/1949)
PS Patent sealed [section 19, patents act 1949]
SP Amendment (slips) printed
704A Declaration that licence is not available as of right for an excepted use (par. 4a/1977)
PCNP Patent ceased through non-payment of renewal fee