CA1124718A - 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 derivativesInfo
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- CA1124718A CA1124718A CA300,288A CA300288A CA1124718A CA 1124718 A CA1124718 A CA 1124718A CA 300288 A CA300288 A CA 300288A CA 1124718 A CA1124718 A CA 1124718A
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- piperazine
- trimethoxyphenoxy
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- 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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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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- 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
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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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- 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
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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
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
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- Public Health (AREA)
- Anesthesiology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides 1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxypropyl]-4-aryl piperazine derivatives. The derivatives have the formula
The present invention provides 1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxypropyl]-4-aryl piperazine derivatives. The derivatives have the formula
Description
- 1i.247~
The present invention relates to 1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxypropyl]-4-aryl piperazine derivatives and to a process for their production.
German Offenlegungsschrift l~o. 2,235,597 describes blood-pressure-reducing compounds corresponding to the general formula u C1 -CH-CN - N ~ ~ +
in which A is a hydrogen atom or a hydroxyl group, X is a hydrogen or a halogen atom, an alkyl, alkoxy, alkylthio, tri-fluoromethyl, hydroxy, nitro, amino, acylamino or alkyl-sulphonylamino group, and n is the number 0, 1 or 2, and their salts.
The present invention provides compounds corresponding to the general formula .
: 20 CH30 ~ ~ ~ \ R2 CH3) ~ ' O-CH2-CH-cH2 N~ , : in which Rl is a hydrogen atom, a C2 to C6-alkanoyl radical, 3,4,5-trimethoxy benzoyl radical, a nicotinoyl radical or a thienyl carbonyl radicaI and R2 represents a phenyl, napthyl : or pyridyl radical which may be substituted by the radicals R3 and R4, the radicals R3 and R4 which may be the same or differ-ent, each representing hydrogen, hydroxyl, fluorine, chlorine, bromine, a nitro group, a trifluoromethyl group, a Cl to C6-alkyl radical, a Cl to C6-alkoxy radical, a Cl to C6-alkyl thio radical, a C2 to C6-alkanoyl radical, an amino group, a C2-C6 4~Y18 alkanoyl-amino group, a C2-C6-alkanoyl-oxy group, a benzoyl-oxy group, a cyclohexylcarbonyl-oxy group or a thienyl-carbonyl-oxy group.
The compounds are pharmaceodynamically active and show for example, a pronounced anti-aggresive 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 compounds show fever-reducing and oedema-inhibiting effects.
The alkanoyl and alkenoyl radicals may be linear or branched. The alkanoyl radicals consist in particular of 2, 3 or 4 carbon atoms. The thienyl carbonyl radicals may be the corresponding thienyl-(2)- or thienyl-(3)-carbonyl radical.
The alkyl, alkoxy and alkyl-thio 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, methylthio, ethylthio, propylthio, butylthio, methyl sulphonyl, ethyl sulphonyl, propyl sulphonyl. Examples of the acylamino Zo group are the acetamino group and benzoylamino group. Where R2 is a naphthyl radical, it may be the ~ ~ 2 -r~
. . ~ ' l~Z471~
naphthyl-tl)- or naphthyl-(2)-radical, this naphthyl radical optionally being substituted in both rings by the radicals R3 and R4. ~owever, the naphthyl ring is preferably substituted in the 6-ring which is not attached to the piperazine riny.
Where R2 is a pyridyl ring, this ring may be attached to the piperazine ring in the 2-, 3- or 4-position.
Rl is preferably hydrogen or an alkanoyl group having
The present invention relates to 1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxypropyl]-4-aryl piperazine derivatives and to a process for their production.
German Offenlegungsschrift l~o. 2,235,597 describes blood-pressure-reducing compounds corresponding to the general formula u C1 -CH-CN - N ~ ~ +
in which A is a hydrogen atom or a hydroxyl group, X is a hydrogen or a halogen atom, an alkyl, alkoxy, alkylthio, tri-fluoromethyl, hydroxy, nitro, amino, acylamino or alkyl-sulphonylamino group, and n is the number 0, 1 or 2, and their salts.
The present invention provides compounds corresponding to the general formula .
: 20 CH30 ~ ~ ~ \ R2 CH3) ~ ' O-CH2-CH-cH2 N~ , : in which Rl is a hydrogen atom, a C2 to C6-alkanoyl radical, 3,4,5-trimethoxy benzoyl radical, a nicotinoyl radical or a thienyl carbonyl radicaI and R2 represents a phenyl, napthyl : or pyridyl radical which may be substituted by the radicals R3 and R4, the radicals R3 and R4 which may be the same or differ-ent, each representing hydrogen, hydroxyl, fluorine, chlorine, bromine, a nitro group, a trifluoromethyl group, a Cl to C6-alkyl radical, a Cl to C6-alkoxy radical, a Cl to C6-alkyl thio radical, a C2 to C6-alkanoyl radical, an amino group, a C2-C6 4~Y18 alkanoyl-amino group, a C2-C6-alkanoyl-oxy group, a benzoyl-oxy group, a cyclohexylcarbonyl-oxy group or a thienyl-carbonyl-oxy group.
The compounds are pharmaceodynamically active and show for example, a pronounced anti-aggresive 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 compounds show fever-reducing and oedema-inhibiting effects.
The alkanoyl and alkenoyl radicals may be linear or branched. The alkanoyl radicals consist in particular of 2, 3 or 4 carbon atoms. The thienyl carbonyl radicals may be the corresponding thienyl-(2)- or thienyl-(3)-carbonyl radical.
The alkyl, alkoxy and alkyl-thio 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, methylthio, ethylthio, propylthio, butylthio, methyl sulphonyl, ethyl sulphonyl, propyl sulphonyl. Examples of the acylamino Zo group are the acetamino group and benzoylamino group. Where R2 is a naphthyl radical, it may be the ~ ~ 2 -r~
. . ~ ' l~Z471~
naphthyl-tl)- or naphthyl-(2)-radical, this naphthyl radical optionally being substituted in both rings by the radicals R3 and R4. ~owever, the naphthyl ring is preferably substituted in the 6-ring which is not attached to the piperazine riny.
Where R2 is a pyridyl ring, this ring may be attached to the piperazine ring in the 2-, 3- or 4-position.
Rl is preferably hydrogen or an alkanoyl group having
2, 3 or 4 carbon atoms.
In case R2 is a phenyl or pyridyl group the substi-tuents Rl and/or R4 are preferably adjacent to the carbon atom coupling R2 with the piperazine ring.
Preferably Rl is hydrogen and R is a Cl-C4-alkoxy-phenyl group (for example, methoxyphenyl, ethoxyphenyl, propoxy-phenyl, isopropoxyphenyl, butoxyphenyl), a hydroxyphenyl group, t an aminophenyl group, a C2-C4-alkanoylaminophenyl group (for ~ :
example, acetylaminophenyl, propionylaminophenyl, butyrylamino-phenyl) or a C2-C4-alkanoxyloxyphenyl group (for example, ace-toxyphenyl, propionyloxyphenyl, butyryloxyphenyl) wherein these t S
substituents are in the o- or p-position, particularly the o-pOSition.
Accordingly, the object of the invention is to provide compounds with favourable pharmacodynamic properties which may be used as medicaments. ~ `
By contrast, the [3-(5,6,7,8-tetrahydronap~thyl-(1)-oxypropyl]~piperazine derivatives described in German Offenle-gungsschrift 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 pro-duced by reacting a compound corresponding to the formula
In case R2 is a phenyl or pyridyl group the substi-tuents Rl and/or R4 are preferably adjacent to the carbon atom coupling R2 with the piperazine ring.
Preferably Rl is hydrogen and R is a Cl-C4-alkoxy-phenyl group (for example, methoxyphenyl, ethoxyphenyl, propoxy-phenyl, isopropoxyphenyl, butoxyphenyl), a hydroxyphenyl group, t an aminophenyl group, a C2-C4-alkanoylaminophenyl group (for ~ :
example, acetylaminophenyl, propionylaminophenyl, butyrylamino-phenyl) or a C2-C4-alkanoxyloxyphenyl group (for example, ace-toxyphenyl, propionyloxyphenyl, butyryloxyphenyl) wherein these t S
substituents are in the o- or p-position, particularly the o-pOSition.
Accordingly, the object of the invention is to provide compounds with favourable pharmacodynamic properties which may be used as medicaments. ~ `
By contrast, the [3-(5,6,7,8-tetrahydronap~thyl-(1)-oxypropyl]~piperazine derivatives described in German Offenle-gungsschrift 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 pro-duced by reacting a compound corresponding to the formula
- 3 -.. . .. . .
~124718 C 1~ 3~--OY I I
with a compound corresponding to the formula ~ 2 Z-N NR III
/
in which Y and Z are different from one another and one repre-sents hydrogen, whilst the other represents the group -CH2-C~(OR )-CH2-V where V represents chlorine, bromine or iodine or, where Rl is a hydrogen atom, may also form an ethylene oxide ring together with this hydroxy group, and when required, reducing one or two nitro groups to amino groups and/or acylating the compounds obtained with an acid or acid derivative corres- `
ponding to the radical Rl.
The process for producing the compounds according to F
the lnvention may be carried out in the presence or absence of a solvent at a temperature in the range from 20 to 200C and ~20 preferably at a temperature in the range from 50 to 150C.
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, chloro-form, carbon tetrachloridine, chlorobenzene, methylene chloride;
aliphatic ethers such as, for example, butyl ether; cyclic r ethers such as, for example, tetrahydrofuran, dioxane; sulphox-ides such as, for example, dimethyl sulphoxide; tertiary acid amides such as, for example, dimethyl formamide, N-methyl pyrro-lidone; aliphatic alcohols, such as methanol, ethanol, isopro-panol, amyl alcohol, tert.-butanol; cycloaliphatic hydrocarbons, such as cyclohexane and the like. Mixtures of the above-mentioned
~124718 C 1~ 3~--OY I I
with a compound corresponding to the formula ~ 2 Z-N NR III
/
in which Y and Z are different from one another and one repre-sents hydrogen, whilst the other represents the group -CH2-C~(OR )-CH2-V where V represents chlorine, bromine or iodine or, where Rl is a hydrogen atom, may also form an ethylene oxide ring together with this hydroxy group, and when required, reducing one or two nitro groups to amino groups and/or acylating the compounds obtained with an acid or acid derivative corres- `
ponding to the radical Rl.
The process for producing the compounds according to F
the lnvention may be carried out in the presence or absence of a solvent at a temperature in the range from 20 to 200C and ~20 preferably at a temperature in the range from 50 to 150C.
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, chloro-form, carbon tetrachloridine, chlorobenzene, methylene chloride;
aliphatic ethers such as, for example, butyl ether; cyclic r ethers such as, for example, tetrahydrofuran, dioxane; sulphox-ides such as, for example, dimethyl sulphoxide; tertiary acid amides such as, for example, dimethyl formamide, N-methyl pyrro-lidone; aliphatic alcohols, such as methanol, ethanol, isopro-panol, amyl alcohol, tert.-butanol; cycloaliphatic hydrocarbons, such as cyclohexane and the like. Mixtures of the above-mentioned
- 4 -~1~47~8 solvents may also be used. In many cases, the reaction is carried out at the reflux temperature of the solvent or disper- ~
sant used. In general, the reaction components are reacted in 5:
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 tfor example triethylamine). This applies in particular when compounds in which V is a halogen atom are used~
Where a compound of formula II 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 salt). This applies in particular when in the other reaction component III, the symbol V in the group Z, which is -CH2-CH(ORl)-C~2V, is a F
halogen atom.
For carrying out the reaction, the ethylene oxide used as the ethylene oxide starting compound may even be replaced by the corresponding halohydrin 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 cen-tral position( introduction of the Rl-acyl radical) can be ob-tained by acylation, i.e. by treatment with acids of the formula r RlOH, in which Rl has any of the meanings defined except hydro-gen or by treatment with the corresponding reactive acid deri-vatives.
Corresponding acid derivatives are, in particular, F
compounds corresponding to the formula .. .. . . . . .
R W IV
in which W represents chlorine,.bromine or iodine, the group -N-N, a group of the formuLa -OR', -SR' or a group of the formula -OS03H, -O-PO(OH)2, -OP(OR')2, -O-As(OR')2 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-nitro-phenyl radical, a cyanomethyl radical or a carboxymethyl radical;
R" may be a linear or branched alkyl radical, an alkoxy radical, a phenoxy radical, a carbobenzoxy radical or even the radical Rl.
Aliphatic C2 to C6-ketenes may also be used as acylating agents.
Acid derivatives of formula IV in which W is chlorine or bromine represent particularly appropriate acylating agents. Where R' and R" represent alkyl radicals or alkoxy radicals, these radicals are preferably of low molecular weight and consist of 1 to 6 carbon atoms.
.~ The acylation step may be carried out, for example, E
in an inert solvent or suspending agent such as water, a lower aliphatic alcohol, a lower aliphatic ketone, dioxane, dimethyl : ' formamide, benzene or toluene, at a temperature of from 0 to :~ 20 200C. The acylation step is optionally carried out in the . . .
presence of an acid-binding agent, such as an alkali metal hydroxide, an alkali metal carbonate (potassium carbonate), an .~ alkali metal hydrogen carbonate, an alkali metal acetate, an alkaline earth metal carbonate, a tertiary amine ~or example : trialkylamine, pyridine) or an alkali metal alcoholate (sodium . ~
ethylate).
. It is also possible initially to convert the groups to be acylated (hydroxy group, amino group) in the compound to be reacted into the corresponding alkali metal compound by reacting them with an alkali metal, an alkali metal hydride or F
an alkali metal amide (especially sodium or a sodium compound) at a temperature of from 0 to 150C in an inert solvent, such ~Z47~8 as dioxane, dimethyl formamide, benzene or toluene, and subse-quently addi~g the acylating ayent.
In cases where the free acid with the formula RlOH is used, it has to be activated by the presence of a condensation agent, such as dicyclohexyl carbodiimide, a sulphurous acid-bis-alkyl amide-(for example SO[N(CH3)2]2), N,N'-carbonyl diimidazole and so on (Organic ~eactions, Vol. 12, 1962, pages 205 and 239).
Instead of using the acylating agents mentioned above, F
it is also possible to use other chemically equivalent agents 10commonly encountered in chemistry (cf. 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 exampIe 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 20C to 100C.
For the reduction of one or even two nitro groups '.
there is particularly employed catalytic hydrogen. 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, as for example barium sulphate, calcium sul- .
phate, etc. It is recommended to carry out the hydrogenation of the nitro groups at temperatures between 20 and 80C and a pressure of approximately 5-50 atmospheres absolute in a solvent, for example, an alcohol, e.g., methyl alcohol, ethyl alcohol or isopropyl alcohol, dioxane, tetrahydrofuran, etc. In many cases, it is advantageous for the subsequent isolation of the reduced compounds to add at the beginning to the hyydrogenating mixture a drying agent such as anhydrous sodium sulphate or magnesium ~i2~8 sulphate.
~lowever, the reaction can also be carried out with nascent hydrogen, for example zinc/hydrochloric acid, tin/hydro-chloric acid, iron/hydrochloric acid or with salts of hydrogen sulphide and alcohol/water at about 70 to 120C or with acti-vated aluminum 9n hydrated ether at 20 to 40C or with tin II
chloride/hydrochloric acid.
The compounds according to the invention are generally obtained in the form of racemates. The optically active anti-ln podes are obtained either by using optically active starting materials or by racemate splitting 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-_-toluoyl-L-tartaric acid, (+)-O,O'-di-p-toluoyl-D-tartaric acid, (+)-camphor-10-sulphonic acid and others.
The compounds corresponding to general formula I may be converted into their pharmaceutically acceptable salts by known methods. Suitable anions for these salts are the known and therapeutically useable acid radicals. Examples of acids .
such as these are H2SO4, phosphoric acid, hydrohalic acids, ethylene diamine tetraacetic acid, sulphamic acid, benzene sulphonic acid, ~-toluene sulphonic acid, camphor sulphonic ~;
acid, methane sulphonic acid, guaiazulene sulphonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, ascorbic acid, glycolic acid, salicyclic acid, acetic F
acid, propionic acid, gluconic acid, benzoic acid, citric acid, acetaminoacetic acid, oxyethane 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.
1~24~8 The compounds according to the invention are suitable for the production of pharmaceutical compositions and prepara-tions. The pharmaceutical compositions or medicaments contain, as active principle, one or more of the compounds according to the invention, optionally in admixture with other pharmacologi-cally or pharmaceutically active substances. The medicaments may be prepared in known manner with the usual pharmaceutical excipients, assistants, carriers and dilients.
As carriers and assistants, for example, are those recommended in the following literature as adjuvants for pharmacy, cosmetic and related fields such as in Ullmann's ~ -Encyklop-adie der technischer Chemie, Vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences 52 (1963), pages 918 et seq.; N. v. Czetsch-Lindenwald, Hilftstoffe fùr Pharmazie und angrenzende Gebiete; Pharm. Ind. 2 (1961), pages 72 et ~.; L
Dr. H.P. Fiedler, Lexicon der Hilftstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor Kg. Aulendorf i. Wurtt (1971).
Examples of such materials include gelatin, natural sugars such as sucrose or lactose, lecithin, pectin, starch (for example cornstarch), alginic acid, tylose, talc, lycopodium silica (or example colloidal silica~, glucose, cellulose, cel-lulose ~erivatives for example cellulose ethers in which the cel-lulose hydroxyl group are partially etherified with lower all-phatic alcohols and/or lower saturated oxyalcohols (for example, methyl hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose), stearates, e.g~, methylstearate and glyceryl stear-ate, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially saturated acids (for example, calcium stearate, calcium laurate, magnesium oleate, calcium palmitate, calcium behenate and magnesium stearate), emulsifiers, oils and fats, especially of plant origin (for example, peanut oil, corn oil, wheat germ oil, sunflower seed oil, cod-liver oil), mono-, g _ ~i247~L8 di- and trlglycerides of saturated fatty acids lC12H2402 to C18H36O2 and their mixtures), e.g., glyceryl monostearate, a glyceryl distearate, glyceryl tristearate, glyceryl trilaurate), pharmaceutically compatible mono- or polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaery-thritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, poly-ethylene glycol 400 and other polyethylene glycols, as well as derivatives of such alcohols 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 alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, manni-tol, ethyl alcohol, butyl alcohol, octadecyl alcohol, etc., e.g., glyceryl stearate, glyceryl palmitate, glycol distearate, L;
glycol dilaurate, glycol diacetate, monoacetin, triacetin, ~ -glyceryl oleate, ethylene glycol stearate; such esters of poly- F
valent alcohols can in a given case also be etherified, benzyl benzoate, dioxolane, glycerine formal, tetrahydrofurfuryl alco- t hol, polyglycol ethers with 1 to 12 carbon atom alcohols, dimethyl acetamide, lactamide, lactates, e.g., ethyl lactate, ethyl carbonate, silicones (esp-cially middle vi5c09ity dimethyl polysiloxane), magnesium aarbonate and the like. !' For the production of solutions there can be used 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 sulfoxide, fatty alcohols, 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., monoacetic, diacetin, glyceryl monostearate, glyceryl ;
112471~3 ., glyceryl distearate, glyceryl monopalmitate, paraffins and the like.
In the production of the preparations there can be used known and customary solution aids or emulsifiers. As solution aids and emulsifiers there can be used, for example, polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbi- L
tan trioleate, lecithin, gum acadia, gum tragacanth, polyoxy-ethylated sorbitan monoleate, polyoxyethylated fats, polyoxy-ethylated oleotriglycerides, linolized oleotriglycerides, poly-ethylene oxide-condensation products of fatty alcohols, alkyl-phenols or fatty acids. As used herein polyoxyethylated means that the materials in question contain polyoxyethylene chains whose degree of polymerization generally is between 2 and 40, particularly between 10 and 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 moles of ethylene oxide ~A
per mole of glyceride).
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil (see also Dr. H.P. Friedler, ~ , pages 191-195).
Furthermore, there can be added preservatives, stab-ilizers, buffers, for example, calcium hydrogen phosphate, colloidal aluminum hydroxide, taste correctives, antioxidants r and complex formers (for example, ethylene diamine tetraacetic acid) and the like. In a given case for stabilization of the active molecule the pH is adjusted to about 3 to 7 with physio-logically compatible acids or buffers. Generally, there is pre-ferred as neutral as possible to wek acid (to pH 5) pH value.
As antioxidants there can be used for example sodium metal .
... . .. .
112~718 bisul~ite, ascorbic acid, gallic acid, alkyl gallates, e.g., methyl gallate and ethyl gallate, butyl hydroxyanisole, nordihy-droguararetic acid, tocopherols as well as tocopherol and syner-gists (materials which bind heavy metals by complex formation, for example, lecithin, ascorbic acid, phosphoric acid). The addition of synergists increases considerably the antioxidant activity of tocopherol. AS preservatives there can be used for example sorbic acid, p-hydroxybenzoic acid esters (for example, lower alkyl esters such as the methyl ester and the ethyl ester) benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenul, cresol, benzethonium chloride and formalin 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 materials and assistants or carriers are well mixed by stirring or homo-genization (for example, by means of a colloid mill or ball mill), wherein the operation is generally carried out at tempera- r -tures between 20 and 80C, preferably 20 to 50C.
~`20 The application of active material or drug can take place on the skin or mucous membrane or internally, for example, orally, parenterally, pulmonarily, rectally, nasally, vaginally, perlingually, intravenously, intraarterially, intracardially, l~
intramuscularly, intraperitoneally, intracutaneously or subcu- t taneously.
The addition of other medicines is also possible or r favorahle.
The compounds of the invention in the combat test, mouse ( R.E. Tedeschi and coworkers, J. Pharmacol, Exp. Therap., ~0 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-1~%~718 aggressive or amphetamine-antagonistic ~neuroleptic property) activity.
For example in the above-mentioned test methods at a dosage of 2.0 m~/kg body weight mouse there occurred the anxio- `
lytic-anti-aggressive and amphetamine-antagonistic-activity.
This tranquilizing-neuroleptic activity is comparable with the activity of the known medicines Diazepam and Chloropromazin. E
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 1.0 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 dis-turbances, disturbances of sleep, psychoses, depression condi-tions.
The pharmaceutical preparations generally contain between 0.1 to 50 mg of the active component or components of the invention.
The compounds can be delivered in the form of tablets, t capsules, pills, dragees, plugs, salves, gels, suppositories, ointments, 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 suspension and r emulsions. The preferred forms of use are tablets which contain between 0.5 and 30 mg or solutions which contain between 0.1 and
sant used. In general, the reaction components are reacted in 5:
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 tfor example triethylamine). This applies in particular when compounds in which V is a halogen atom are used~
Where a compound of formula II 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 salt). This applies in particular when in the other reaction component III, the symbol V in the group Z, which is -CH2-CH(ORl)-C~2V, is a F
halogen atom.
For carrying out the reaction, the ethylene oxide used as the ethylene oxide starting compound may even be replaced by the corresponding halohydrin 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 cen-tral position( introduction of the Rl-acyl radical) can be ob-tained by acylation, i.e. by treatment with acids of the formula r RlOH, in which Rl has any of the meanings defined except hydro-gen or by treatment with the corresponding reactive acid deri-vatives.
Corresponding acid derivatives are, in particular, F
compounds corresponding to the formula .. .. . . . . .
R W IV
in which W represents chlorine,.bromine or iodine, the group -N-N, a group of the formuLa -OR', -SR' or a group of the formula -OS03H, -O-PO(OH)2, -OP(OR')2, -O-As(OR')2 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-nitro-phenyl radical, a cyanomethyl radical or a carboxymethyl radical;
R" may be a linear or branched alkyl radical, an alkoxy radical, a phenoxy radical, a carbobenzoxy radical or even the radical Rl.
Aliphatic C2 to C6-ketenes may also be used as acylating agents.
Acid derivatives of formula IV in which W is chlorine or bromine represent particularly appropriate acylating agents. Where R' and R" represent alkyl radicals or alkoxy radicals, these radicals are preferably of low molecular weight and consist of 1 to 6 carbon atoms.
.~ The acylation step may be carried out, for example, E
in an inert solvent or suspending agent such as water, a lower aliphatic alcohol, a lower aliphatic ketone, dioxane, dimethyl : ' formamide, benzene or toluene, at a temperature of from 0 to :~ 20 200C. The acylation step is optionally carried out in the . . .
presence of an acid-binding agent, such as an alkali metal hydroxide, an alkali metal carbonate (potassium carbonate), an .~ alkali metal hydrogen carbonate, an alkali metal acetate, an alkaline earth metal carbonate, a tertiary amine ~or example : trialkylamine, pyridine) or an alkali metal alcoholate (sodium . ~
ethylate).
. It is also possible initially to convert the groups to be acylated (hydroxy group, amino group) in the compound to be reacted into the corresponding alkali metal compound by reacting them with an alkali metal, an alkali metal hydride or F
an alkali metal amide (especially sodium or a sodium compound) at a temperature of from 0 to 150C in an inert solvent, such ~Z47~8 as dioxane, dimethyl formamide, benzene or toluene, and subse-quently addi~g the acylating ayent.
In cases where the free acid with the formula RlOH is used, it has to be activated by the presence of a condensation agent, such as dicyclohexyl carbodiimide, a sulphurous acid-bis-alkyl amide-(for example SO[N(CH3)2]2), N,N'-carbonyl diimidazole and so on (Organic ~eactions, Vol. 12, 1962, pages 205 and 239).
Instead of using the acylating agents mentioned above, F
it is also possible to use other chemically equivalent agents 10commonly encountered in chemistry (cf. 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 exampIe 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 20C to 100C.
For the reduction of one or even two nitro groups '.
there is particularly employed catalytic hydrogen. 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, as for example barium sulphate, calcium sul- .
phate, etc. It is recommended to carry out the hydrogenation of the nitro groups at temperatures between 20 and 80C and a pressure of approximately 5-50 atmospheres absolute in a solvent, for example, an alcohol, e.g., methyl alcohol, ethyl alcohol or isopropyl alcohol, dioxane, tetrahydrofuran, etc. In many cases, it is advantageous for the subsequent isolation of the reduced compounds to add at the beginning to the hyydrogenating mixture a drying agent such as anhydrous sodium sulphate or magnesium ~i2~8 sulphate.
~lowever, the reaction can also be carried out with nascent hydrogen, for example zinc/hydrochloric acid, tin/hydro-chloric acid, iron/hydrochloric acid or with salts of hydrogen sulphide and alcohol/water at about 70 to 120C or with acti-vated aluminum 9n hydrated ether at 20 to 40C or with tin II
chloride/hydrochloric acid.
The compounds according to the invention are generally obtained in the form of racemates. The optically active anti-ln podes are obtained either by using optically active starting materials or by racemate splitting 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-_-toluoyl-L-tartaric acid, (+)-O,O'-di-p-toluoyl-D-tartaric acid, (+)-camphor-10-sulphonic acid and others.
The compounds corresponding to general formula I may be converted into their pharmaceutically acceptable salts by known methods. Suitable anions for these salts are the known and therapeutically useable acid radicals. Examples of acids .
such as these are H2SO4, phosphoric acid, hydrohalic acids, ethylene diamine tetraacetic acid, sulphamic acid, benzene sulphonic acid, ~-toluene sulphonic acid, camphor sulphonic ~;
acid, methane sulphonic acid, guaiazulene sulphonic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, ascorbic acid, glycolic acid, salicyclic acid, acetic F
acid, propionic acid, gluconic acid, benzoic acid, citric acid, acetaminoacetic acid, oxyethane 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.
1~24~8 The compounds according to the invention are suitable for the production of pharmaceutical compositions and prepara-tions. The pharmaceutical compositions or medicaments contain, as active principle, one or more of the compounds according to the invention, optionally in admixture with other pharmacologi-cally or pharmaceutically active substances. The medicaments may be prepared in known manner with the usual pharmaceutical excipients, assistants, carriers and dilients.
As carriers and assistants, for example, are those recommended in the following literature as adjuvants for pharmacy, cosmetic and related fields such as in Ullmann's ~ -Encyklop-adie der technischer Chemie, Vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences 52 (1963), pages 918 et seq.; N. v. Czetsch-Lindenwald, Hilftstoffe fùr Pharmazie und angrenzende Gebiete; Pharm. Ind. 2 (1961), pages 72 et ~.; L
Dr. H.P. Fiedler, Lexicon der Hilftstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Cantor Kg. Aulendorf i. Wurtt (1971).
Examples of such materials include gelatin, natural sugars such as sucrose or lactose, lecithin, pectin, starch (for example cornstarch), alginic acid, tylose, talc, lycopodium silica (or example colloidal silica~, glucose, cellulose, cel-lulose ~erivatives for example cellulose ethers in which the cel-lulose hydroxyl group are partially etherified with lower all-phatic alcohols and/or lower saturated oxyalcohols (for example, methyl hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose), stearates, e.g~, methylstearate and glyceryl stear-ate, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially saturated acids (for example, calcium stearate, calcium laurate, magnesium oleate, calcium palmitate, calcium behenate and magnesium stearate), emulsifiers, oils and fats, especially of plant origin (for example, peanut oil, corn oil, wheat germ oil, sunflower seed oil, cod-liver oil), mono-, g _ ~i247~L8 di- and trlglycerides of saturated fatty acids lC12H2402 to C18H36O2 and their mixtures), e.g., glyceryl monostearate, a glyceryl distearate, glyceryl tristearate, glyceryl trilaurate), pharmaceutically compatible mono- or polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaery-thritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, poly-ethylene glycol 400 and other polyethylene glycols, as well as derivatives of such alcohols 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 alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, manni-tol, ethyl alcohol, butyl alcohol, octadecyl alcohol, etc., e.g., glyceryl stearate, glyceryl palmitate, glycol distearate, L;
glycol dilaurate, glycol diacetate, monoacetin, triacetin, ~ -glyceryl oleate, ethylene glycol stearate; such esters of poly- F
valent alcohols can in a given case also be etherified, benzyl benzoate, dioxolane, glycerine formal, tetrahydrofurfuryl alco- t hol, polyglycol ethers with 1 to 12 carbon atom alcohols, dimethyl acetamide, lactamide, lactates, e.g., ethyl lactate, ethyl carbonate, silicones (esp-cially middle vi5c09ity dimethyl polysiloxane), magnesium aarbonate and the like. !' For the production of solutions there can be used 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 sulfoxide, fatty alcohols, 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., monoacetic, diacetin, glyceryl monostearate, glyceryl ;
112471~3 ., glyceryl distearate, glyceryl monopalmitate, paraffins and the like.
In the production of the preparations there can be used known and customary solution aids or emulsifiers. As solution aids and emulsifiers there can be used, for example, polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbi- L
tan trioleate, lecithin, gum acadia, gum tragacanth, polyoxy-ethylated sorbitan monoleate, polyoxyethylated fats, polyoxy-ethylated oleotriglycerides, linolized oleotriglycerides, poly-ethylene oxide-condensation products of fatty alcohols, alkyl-phenols or fatty acids. As used herein polyoxyethylated means that the materials in question contain polyoxyethylene chains whose degree of polymerization generally is between 2 and 40, particularly between 10 and 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 moles of ethylene oxide ~A
per mole of glyceride).
Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil (see also Dr. H.P. Friedler, ~ , pages 191-195).
Furthermore, there can be added preservatives, stab-ilizers, buffers, for example, calcium hydrogen phosphate, colloidal aluminum hydroxide, taste correctives, antioxidants r and complex formers (for example, ethylene diamine tetraacetic acid) and the like. In a given case for stabilization of the active molecule the pH is adjusted to about 3 to 7 with physio-logically compatible acids or buffers. Generally, there is pre-ferred as neutral as possible to wek acid (to pH 5) pH value.
As antioxidants there can be used for example sodium metal .
... . .. .
112~718 bisul~ite, ascorbic acid, gallic acid, alkyl gallates, e.g., methyl gallate and ethyl gallate, butyl hydroxyanisole, nordihy-droguararetic acid, tocopherols as well as tocopherol and syner-gists (materials which bind heavy metals by complex formation, for example, lecithin, ascorbic acid, phosphoric acid). The addition of synergists increases considerably the antioxidant activity of tocopherol. AS preservatives there can be used for example sorbic acid, p-hydroxybenzoic acid esters (for example, lower alkyl esters such as the methyl ester and the ethyl ester) benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenul, cresol, benzethonium chloride and formalin 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 materials and assistants or carriers are well mixed by stirring or homo-genization (for example, by means of a colloid mill or ball mill), wherein the operation is generally carried out at tempera- r -tures between 20 and 80C, preferably 20 to 50C.
~`20 The application of active material or drug can take place on the skin or mucous membrane or internally, for example, orally, parenterally, pulmonarily, rectally, nasally, vaginally, perlingually, intravenously, intraarterially, intracardially, l~
intramuscularly, intraperitoneally, intracutaneously or subcu- t taneously.
The addition of other medicines is also possible or r favorahle.
The compounds of the invention in the combat test, mouse ( R.E. Tedeschi and coworkers, J. Pharmacol, Exp. Therap., ~0 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-1~%~718 aggressive or amphetamine-antagonistic ~neuroleptic property) activity.
For example in the above-mentioned test methods at a dosage of 2.0 m~/kg body weight mouse there occurred the anxio- `
lytic-anti-aggressive and amphetamine-antagonistic-activity.
This tranquilizing-neuroleptic activity is comparable with the activity of the known medicines Diazepam and Chloropromazin. E
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 1.0 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 dis-turbances, disturbances of sleep, psychoses, depression condi-tions.
The pharmaceutical preparations generally contain between 0.1 to 50 mg of the active component or components of the invention.
The compounds can be delivered in the form of tablets, t capsules, pills, dragees, plugs, salves, gels, suppositories, ointments, 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 suspension and r emulsions. The preferred forms of use are tablets which contain between 0.5 and 30 mg or solutions which contain between 0.1 and
5% of active material.
In individual doses, the amount of active component ;;
of the invention can be used for example in an amount of: F
a. in oral dispensation between 0.1 and 50 mg;
llZA7~8 b. in parenteral dispensation (for example intraven-ously, intramuscularly) between 0.01 and 10 mg; h c. in dispensation rectally or vaginally between 3 0.2 and 200 mg.
For example, there is recommended the use of 1 to 3 tablets containing 0.5 to 20 mg of active ingredient 3 times daily or for example, intravenously the injection 1 to 6 times daily of a 1 to 10 ml ampoule containing 0.01 to 5.0 mg of active substance. In oral preparations the minimum daily dos-age for example is 10 mg; the maximum daily dosage in oral ad-ministration should not be over 10 grams. e The dosages in each case are based on the free base.
In veterinary medicine the compounds of the invention can be used in treating dogs and cats. The individual dosages in general orally are between approximately 0.1 and 20 mg/kg k body weight; the parenteral dosage approximately between 0.01 - and 5.0 mg/kg body weight.
For the treatment of horses and cattle, the individual oral dosages are general between about 0.1 and 20 mg/ky; the individual parenteral dosages between about 0.01 and 20 mg/kg body weight.
The acute ~oxicity of the compounds of the invention in the mouse (expressed by the ~D50 mg~kg 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 mg/kg, in some cases even above 5000 mg/kg. F
Starting compounds of formula III, in which Z repre-sents the group -CH2-CH(OH)-CH2-V, may be obtained for exarnple in the usual way by reacting epichlorohydrin or epibromohydrin jj with the corresponding piperazine, which contains the radical F
R2 in the 4-position, at 10C in an alcohol, preerably methanol, with approximately 5% of water added. The reaction time amounts ~2~7~8 for example to 30 minutes. The reaction mixture is then heated to 30 to 40C and stirred for 5 hours.
The ratio of piperazine to the hydrin amounts for example to from 1:1 to 1:5 and preferably to from 1:1 to 1:2.
The water content may be -rom 1 to 10% and is preferably from 2 to 6%.
In the compounds thus obtained, the radical Rl may be introduced by acylation with a compound RlW under the conditions specified above. Rl may also be introduced in the same way into starting compounds of formula II in which Y represents the group -CH2-CH(OH)-CH2-V.
The other starting compounds are known.
The invention is illustrated by the following Examples.
(+)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine. ¦
a) 12 g (0.05 mole) of 3,4,5-trimethoxyphenoxy glycidyl F
; 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 solvent is then distilled off, the residue is treated with excess lsopropanolic HCl and the dihydrochloride of the 1-13-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine is precipitated by the addition of ~
diethyl ether, giving 18.4 g (73~ of the theoretical) of a t colourless crystalline substance. M.p. of the dihydrochloride:
196-197C.
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 F
mole) of epichlorohydrin, followed by the dropwise addition over :
~1247~L8 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 NaCl preci-pitated is filtered off. The filtrate is fractionated first under normal pressure and then in vacuo. The 3,4,5-trimethoxy-phenoxy glycidyl ether is obtained as a colourless oil at b.p.
1.0 = 175-180C. 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 l-(2-methoxyphenyl)-piperazine with epichlorohydrin) are boiled under reflux for 8 hours in 50 ml of dioxane. After cooling, the ~aCl precipitated is fil-tered off and the filtrate is concentrated. The residue is treated with isopropanolic hydrochloric acid and ether and the crystalline solid is recrystallised from methanol, giving 8.2 g (32% of the theoretical) of the above-mentioned compound in the form of its dihydrochloride melting at 194-196C.
Another way of carrying out the process is as follows: k A mixture of 0.05 mole of 3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl bromide, 0.05 mole of 1-(2-methoxyphenyl)-piper-azine and 0.06 mole of triethlamine is boiled under reflux for 5 hours in 100 ml of toluene. Thç triethyl ammonium bromide preci-pitated is then filtered off and the filtrate is concentrated. ~
The residue is taken up in a little isopropanol and the dihydro- L
chloride of the above-mentioned compound is precipitated with Y
isopropanolic hydrochloric acid and ether. Recrystallisation from methanol gives 10.1 g of end product (40% of the theoretical) ~11247~8 melting at 195-1~7C.
The compounds listed in Table 1 corresponding to the t formula CH30~ F
CH30. _ ~ _ O - CH2 - CH(OH) - CH2 ~ N N - R
CH30.. . ~
are obtained in the same way as described in the first paragraph of ~xample 1 from 0.05 mole of 3,4,5-trimethoxyphenoxy glycidyl ether and 0.05 mole of a compound corresponding to formula III:
' .
'~ :
-~:~ 20 ~
.~ ~
!
: , .; ~.
, ~ .
l~Z47~8 ~ t ~ ~ ~ co o~ N ~r ~r ~ ~ CO O .--1 ~0 ~1 CJ~ ~1 1` ~1 11~
.,1 ~ ~0 .
_ I .
~ 1t t~ _ lC
O co ~ In (~ .-1 ~ o o~ ~ oo o oo u~
co O a~ 1--o o ~ o ~ ~o ~ cs~ oo ~ ~ O r~
~1 ~ ~ ~1 ~ (~ ~ ~ U~ ~ ~ ~ ~ '`J ~ ~D /~ ~ '`J Q ^
3 ~
~ ~ o ~ l ~ o o ~ o ~ ~,,,, __ _ .0 ~ C~
h S ~--I ~ ~
O ~ ~:
'g~ C ~1 ~ O) (v OJ 0) ~c s a~ s l OJ Q) ~1 ;~ a) 8 0 1~1 rc c s s s ~ ~ P~S a~ O
.~: ooox~ 00~ 5 ~ O O O O .C C O ~C; .C ,r~ U S 1c ~ ~ ~ ~ ~ ~ lJ r ~ v ~ r~
.~ c ~ r ~ ~ a~ S-~
aJ ~ E ~ ~ ~ f~ ~ ~ ~ s~ S C
~ ~ C ~ I I
____ ,................. ~
H ~
:: H ~ C C
1--1 ~ rl N N
I -~ O ~ ~1 N 11~ nl E~ ~
~1 ~ N N rl~
o a~
C C C C~ rl ~1 C ~ ~ W ~ h ~ I I rl ~ rl N N rl I r~ C lu 11) ~rl ~ ~ N
~1 N N N N Id (lJ N ~ N rl ~ N ~1 ~1 W ~ rl O ~ Id h h (~N " rl nl ~ ~ ~ ~ h N
h h ~1 1.1 Q\ ~ h ~ Q. h C~ 1 ~1 W O W ~ Q~ O h I I o ~1 W N N Q- h ~ ~ ~ ~4 n.-,~ ,1 P, ~u ~ a~ ~--~ Q. S .C (~1 N ~1 W rl ~1 Q,~l ~1 -rl ~ Q~ h 0 1:1 s:: Q. ~ ~ ~ I I Q. ~ ~-~ h I ~rl o a~ I I I I ^_ I o I ~ ~
0~ ~ ^ ~ ^ ^ 'I 'I ~~ ~ ^ I Q) W-- ~ ~ rl ~ ~ I
~ ,~ 1 ~ ~ s ~
O N ~ ~ ~ C ~ 1 r-l U 0 ~ C C ~ ~ ~ C U C C ~ ~1 C ~ e ~
h a) Ql W ~J .C C W ~ W W :~ ~ W O O :~1 S C
W S 1~ S Q. ~S o ~ ~c: C .C ~ h I :~ ~ Q~
~ ~ e ~ o o~, ~s .,1 ~1 0 0 0 0 ~ X ~ ~ ~1_ x ~
h O O O O S S Xo ,~ e ~ ~,--~ ~ o o 0 ,, ~,,~,,~~ ~ .~-~1~ 1 ~a~
~ ~ rC~u~ e e ~ e ~ h~-~ s C
~IIIIIII III~I II~II
Q~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 ~ 1 N
-,~ o~ o~
a) ~ z .
E~
~ - --.. . . . . ..
.
11247~8 EX~MPLE 22 (+)-1-[3-~3,4,5-trimethoxyphenoxy)-2-(nicotinoyloxy)-propyl]-4- 3 (2-methoxyphenyl)-piperazine 13.0 ~ (0.03) mole) of (+)-1-[3-(3,4,5-trimethoxyphen-oxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine and 3.34 g of triethylamine (0.003 mole) are dissolved in 80 ml of anhy-drous benzene, followed by the addition over a period of 30 minutes of a solution of 4.67 g (0.003 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 80C. After cooling, the mixture is repeatedly extracted by shaking with water, washed with aqueous NaHC03 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 obtaine~ in the form of its trii~ydrochloride (colourless crystals). r,l.p. 187 - 192C
(decor,lposition). t EX~PLE 23 (+)-1-[2-(3,4,5-trimethoxyphenoxy]-2-[(3,4,5-trimethoxy)-benzoyl-oxy]-propyl]-4-(2-methoxyphenyl-piperazine t (+)-1-l3-(3,4,S-Trimethoxyphenyl)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine is reacted with 3,4,5-trimethoxy-benzoyl chloride in the presence of triethylamine as in Example 20. The reaction product is obtained in the form of the dihydro-chloride meltin~ at 193 - 195C (decomposition). Yield: 38%.
xample of resolution i (+)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl~-4-(2-methoxy-phenyl)-piperazine (base = compound la) and (-)-1-[3-(3,4,5-tri-methoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine (base - compound lb).
; .~ . .
~L124718 4.32 g (0.005 mole) of the racemic compound produced in accordance with Example 1 are dissolved in 80 ml of warm butylacetate, followed by the addition in portions with thorough stirring at 80C of 4.04 g (0.005 mole) of (-)-di-p-toluoyl-L-tartaric acid hydrate, the levo-rotatory diastereomeric salt pair actually being precipitated. After heating for 10 minutes to 110C, the mixture is left to cool to 80C and the deposit is filtered off. The salt pair is recrystallised from acetone-dimethyl formamide-petrol ([a]20 - 48.6; 1% in dimethyl forma-mide), and is subsequently split by treatment with concentrated ammonia. The base is e~tracted with ether and the extract is concentrated. The solid residue is recrystallised from isopro-panol: la-base colourless crystals, m.p. 103 - 104C; [a]D +
7.2 (concentration 2% in CH30H). Dissolution of the base in methanol, followed by the addition of isopropanolic hydrochloric acid and ether gives the dihydrochloride of compound la in the form of colourless crystals melting at 189 - 193C; [~]D ~ 11.4 (concentration = 2% in CH301~). t' The filtrate obtained after precipitation of the salt ~0 pair, which contains the dextrorotatory diastereomeric salt pair, is concentrated in a rotary evaporator, the viscous residue is suspended in water, concentrated ammonia is added and the base t~
extracted with ether. The etherial solution is dried and con-centrated and the solid residue is recrystalllsed from isopro- . i - panol: lb-base, colourless crystals, m.p. 100 - 101C; la]20 - ~
5.8 (concentration = 2% in CH30~). r Dissolution of the base in methanol and treatment with isopropanolic hydrochloric acid and ether gives the dihydro-chloride of compound lb in the form of colourless crystals melting at 182 - 187C; ~a]D + 11.0 (concentration = 2% in CH30H).
, ..... . . . ..
~.
~11247~L8 Examples of Pharmaceutical Preparations Injection Solution For a mixture of 100 liters there are needed:
Compound according to Example 1 (dihydrochloride) 0.25 kg Sodium chloride ' 0.775 kg Water for purpose of injection 98.975 kg e 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 colorless glass. The ampoules after being closed by melting are sterilized for 20 minutes at 120C in superheated steam.
Suppositories Production:
5 g of the compound of Example 7 (dihydrochloride) is t worked into 1995 g of molten suppository composition (for example, ,`
hard fat DAB 7, a mixture of mono-, di- and triglycerides of L
saturated fatty acids C12H24O2 to C18H36O2) and in known manner poured out in forms for 2.0 g suppositor1es.
1 suppository contains 5 mg of active material Capsules To prepare 100,000 capsules there are required the following raw materials:
Compound according to Example 7 (dihydrochloride') 0.125 kg '.0 i~
Lactose 7.200 kg Microcrystalline cellulose 4.800 kg Magnesium stearate 0.375 kg 12.500 kg gLiL2A~7~L8 r To produce gelatin capsules (size 4) which are necessary for production of the capsule composition the previously set forth raw materials are passed through a sieve having a mesh width of 1.5 mm and then mixed for 1 hour at 10 revolutions per minute in a Turbula mixer. This composition is called the capsule filling composition.
This capsule filling composition is filled into gelatin capsules of size 2. Amount of filling per capsule : 125 mg.
` SUPPLEMENTARY DISCLOSURE
Example 30 Preparation of the compound of ~xample 1 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)piperazine 3-[~-(2-methoxy-phenyl)-piperazino]-1,2-epoxy-propane obtained from 1.92 g of 1-(2-methoxy-phenyl)piperazine and 1.36 g of epibromohydrin in 10 ml of methanol by allowing the mixture to stand for 72 hours at room temperature is mixed with 3 g of 3,4,5-trimethoxy-phenol potassium salt without isolation. After boiling the reaction mixture for 6 hours with reflux it is mixed with 400 ml of ether, filtered and acidified with isopropanolic hydrochloric acid. The precipitated dihydrochloride is purified by column chromatography.
(eluant: CHC13 (90 parts)/CH3OH (5 parts)/acetic acid (5 parts)) and by subsequent crystallization from isopropanolic hydrochloric acid; m.p. of the dihydrochloride 196 to 197 C, yield: 0.5 g.
Example 31 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-acetamido-phenyl)piperazine 4 g of (+)-1-[3-(3,4,5-trimethoxy-phenoxy-2-hydroxy-propyl]-4 (2-amino-phenyl)piperazine(monohydrochloride) are dis-solved in 200 ml of dioxane and mixed with 10 ml of triethylamine, whereupon 0.9 ml of acetyl chloride is added dropwise at 7~8 -5C while stirring. A~ter two hours of post-reaction at room temperature the solution is filtered and the solvent is removed under reduced pressure. By dry-column chromatography on silica gel.
(eluant: ether:acetic acid = 1:1) the desired compound is isolated and recrystallized from acetone-ether. Yield: 50%, m.p. = 128 to 130C. (+)-l-r3,4,5--trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-acetamldo-phenyl) piperazine is obtained as a less polar by-product, which can become the main product by increasing the amount of acetyl chloride. m.p. = 54C
Example 32 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-acetoxy-phenyl)piperazine
In individual doses, the amount of active component ;;
of the invention can be used for example in an amount of: F
a. in oral dispensation between 0.1 and 50 mg;
llZA7~8 b. in parenteral dispensation (for example intraven-ously, intramuscularly) between 0.01 and 10 mg; h c. in dispensation rectally or vaginally between 3 0.2 and 200 mg.
For example, there is recommended the use of 1 to 3 tablets containing 0.5 to 20 mg of active ingredient 3 times daily or for example, intravenously the injection 1 to 6 times daily of a 1 to 10 ml ampoule containing 0.01 to 5.0 mg of active substance. In oral preparations the minimum daily dos-age for example is 10 mg; the maximum daily dosage in oral ad-ministration should not be over 10 grams. e The dosages in each case are based on the free base.
In veterinary medicine the compounds of the invention can be used in treating dogs and cats. The individual dosages in general orally are between approximately 0.1 and 20 mg/kg k body weight; the parenteral dosage approximately between 0.01 - and 5.0 mg/kg body weight.
For the treatment of horses and cattle, the individual oral dosages are general between about 0.1 and 20 mg/ky; the individual parenteral dosages between about 0.01 and 20 mg/kg body weight.
The acute ~oxicity of the compounds of the invention in the mouse (expressed by the ~D50 mg~kg 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 mg/kg, in some cases even above 5000 mg/kg. F
Starting compounds of formula III, in which Z repre-sents the group -CH2-CH(OH)-CH2-V, may be obtained for exarnple in the usual way by reacting epichlorohydrin or epibromohydrin jj with the corresponding piperazine, which contains the radical F
R2 in the 4-position, at 10C in an alcohol, preerably methanol, with approximately 5% of water added. The reaction time amounts ~2~7~8 for example to 30 minutes. The reaction mixture is then heated to 30 to 40C and stirred for 5 hours.
The ratio of piperazine to the hydrin amounts for example to from 1:1 to 1:5 and preferably to from 1:1 to 1:2.
The water content may be -rom 1 to 10% and is preferably from 2 to 6%.
In the compounds thus obtained, the radical Rl may be introduced by acylation with a compound RlW under the conditions specified above. Rl may also be introduced in the same way into starting compounds of formula II in which Y represents the group -CH2-CH(OH)-CH2-V.
The other starting compounds are known.
The invention is illustrated by the following Examples.
(+)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine. ¦
a) 12 g (0.05 mole) of 3,4,5-trimethoxyphenoxy glycidyl F
; 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 solvent is then distilled off, the residue is treated with excess lsopropanolic HCl and the dihydrochloride of the 1-13-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine is precipitated by the addition of ~
diethyl ether, giving 18.4 g (73~ of the theoretical) of a t colourless crystalline substance. M.p. of the dihydrochloride:
196-197C.
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 F
mole) of epichlorohydrin, followed by the dropwise addition over :
~1247~L8 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 NaCl preci-pitated is filtered off. The filtrate is fractionated first under normal pressure and then in vacuo. The 3,4,5-trimethoxy-phenoxy glycidyl ether is obtained as a colourless oil at b.p.
1.0 = 175-180C. 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 l-(2-methoxyphenyl)-piperazine with epichlorohydrin) are boiled under reflux for 8 hours in 50 ml of dioxane. After cooling, the ~aCl precipitated is fil-tered off and the filtrate is concentrated. The residue is treated with isopropanolic hydrochloric acid and ether and the crystalline solid is recrystallised from methanol, giving 8.2 g (32% of the theoretical) of the above-mentioned compound in the form of its dihydrochloride melting at 194-196C.
Another way of carrying out the process is as follows: k A mixture of 0.05 mole of 3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl bromide, 0.05 mole of 1-(2-methoxyphenyl)-piper-azine and 0.06 mole of triethlamine is boiled under reflux for 5 hours in 100 ml of toluene. Thç triethyl ammonium bromide preci-pitated is then filtered off and the filtrate is concentrated. ~
The residue is taken up in a little isopropanol and the dihydro- L
chloride of the above-mentioned compound is precipitated with Y
isopropanolic hydrochloric acid and ether. Recrystallisation from methanol gives 10.1 g of end product (40% of the theoretical) ~11247~8 melting at 195-1~7C.
The compounds listed in Table 1 corresponding to the t formula CH30~ F
CH30. _ ~ _ O - CH2 - CH(OH) - CH2 ~ N N - R
CH30.. . ~
are obtained in the same way as described in the first paragraph of ~xample 1 from 0.05 mole of 3,4,5-trimethoxyphenoxy glycidyl ether and 0.05 mole of a compound corresponding to formula III:
' .
'~ :
-~:~ 20 ~
.~ ~
!
: , .; ~.
, ~ .
l~Z47~8 ~ t ~ ~ ~ co o~ N ~r ~r ~ ~ CO O .--1 ~0 ~1 CJ~ ~1 1` ~1 11~
.,1 ~ ~0 .
_ I .
~ 1t t~ _ lC
O co ~ In (~ .-1 ~ o o~ ~ oo o oo u~
co O a~ 1--o o ~ o ~ ~o ~ cs~ oo ~ ~ O r~
~1 ~ ~ ~1 ~ (~ ~ ~ U~ ~ ~ ~ ~ '`J ~ ~D /~ ~ '`J Q ^
3 ~
~ ~ o ~ l ~ o o ~ o ~ ~,,,, __ _ .0 ~ C~
h S ~--I ~ ~
O ~ ~:
'g~ C ~1 ~ O) (v OJ 0) ~c s a~ s l OJ Q) ~1 ;~ a) 8 0 1~1 rc c s s s ~ ~ P~S a~ O
.~: ooox~ 00~ 5 ~ O O O O .C C O ~C; .C ,r~ U S 1c ~ ~ ~ ~ ~ ~ lJ r ~ v ~ r~
.~ c ~ r ~ ~ a~ S-~
aJ ~ E ~ ~ ~ f~ ~ ~ ~ s~ S C
~ ~ C ~ I I
____ ,................. ~
H ~
:: H ~ C C
1--1 ~ rl N N
I -~ O ~ ~1 N 11~ nl E~ ~
~1 ~ N N rl~
o a~
C C C C~ rl ~1 C ~ ~ W ~ h ~ I I rl ~ rl N N rl I r~ C lu 11) ~rl ~ ~ N
~1 N N N N Id (lJ N ~ N rl ~ N ~1 ~1 W ~ rl O ~ Id h h (~N " rl nl ~ ~ ~ ~ h N
h h ~1 1.1 Q\ ~ h ~ Q. h C~ 1 ~1 W O W ~ Q~ O h I I o ~1 W N N Q- h ~ ~ ~ ~4 n.-,~ ,1 P, ~u ~ a~ ~--~ Q. S .C (~1 N ~1 W rl ~1 Q,~l ~1 -rl ~ Q~ h 0 1:1 s:: Q. ~ ~ ~ I I Q. ~ ~-~ h I ~rl o a~ I I I I ^_ I o I ~ ~
0~ ~ ^ ~ ^ ^ 'I 'I ~~ ~ ^ I Q) W-- ~ ~ rl ~ ~ I
~ ,~ 1 ~ ~ s ~
O N ~ ~ ~ C ~ 1 r-l U 0 ~ C C ~ ~ ~ C U C C ~ ~1 C ~ e ~
h a) Ql W ~J .C C W ~ W W :~ ~ W O O :~1 S C
W S 1~ S Q. ~S o ~ ~c: C .C ~ h I :~ ~ Q~
~ ~ e ~ o o~, ~s .,1 ~1 0 0 0 0 ~ X ~ ~ ~1_ x ~
h O O O O S S Xo ,~ e ~ ~,--~ ~ o o 0 ,, ~,,~,,~~ ~ .~-~1~ 1 ~a~
~ ~ rC~u~ e e ~ e ~ h~-~ s C
~IIIIIII III~I II~II
Q~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 ~ 1 N
-,~ o~ o~
a) ~ z .
E~
~ - --.. . . . . ..
.
11247~8 EX~MPLE 22 (+)-1-[3-~3,4,5-trimethoxyphenoxy)-2-(nicotinoyloxy)-propyl]-4- 3 (2-methoxyphenyl)-piperazine 13.0 ~ (0.03) mole) of (+)-1-[3-(3,4,5-trimethoxyphen-oxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine and 3.34 g of triethylamine (0.003 mole) are dissolved in 80 ml of anhy-drous benzene, followed by the addition over a period of 30 minutes of a solution of 4.67 g (0.003 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 80C. After cooling, the mixture is repeatedly extracted by shaking with water, washed with aqueous NaHC03 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 obtaine~ in the form of its trii~ydrochloride (colourless crystals). r,l.p. 187 - 192C
(decor,lposition). t EX~PLE 23 (+)-1-[2-(3,4,5-trimethoxyphenoxy]-2-[(3,4,5-trimethoxy)-benzoyl-oxy]-propyl]-4-(2-methoxyphenyl-piperazine t (+)-1-l3-(3,4,S-Trimethoxyphenyl)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine is reacted with 3,4,5-trimethoxy-benzoyl chloride in the presence of triethylamine as in Example 20. The reaction product is obtained in the form of the dihydro-chloride meltin~ at 193 - 195C (decomposition). Yield: 38%.
xample of resolution i (+)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl~-4-(2-methoxy-phenyl)-piperazine (base = compound la) and (-)-1-[3-(3,4,5-tri-methoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine (base - compound lb).
; .~ . .
~L124718 4.32 g (0.005 mole) of the racemic compound produced in accordance with Example 1 are dissolved in 80 ml of warm butylacetate, followed by the addition in portions with thorough stirring at 80C of 4.04 g (0.005 mole) of (-)-di-p-toluoyl-L-tartaric acid hydrate, the levo-rotatory diastereomeric salt pair actually being precipitated. After heating for 10 minutes to 110C, the mixture is left to cool to 80C and the deposit is filtered off. The salt pair is recrystallised from acetone-dimethyl formamide-petrol ([a]20 - 48.6; 1% in dimethyl forma-mide), and is subsequently split by treatment with concentrated ammonia. The base is e~tracted with ether and the extract is concentrated. The solid residue is recrystallised from isopro-panol: la-base colourless crystals, m.p. 103 - 104C; [a]D +
7.2 (concentration 2% in CH30H). Dissolution of the base in methanol, followed by the addition of isopropanolic hydrochloric acid and ether gives the dihydrochloride of compound la in the form of colourless crystals melting at 189 - 193C; [~]D ~ 11.4 (concentration = 2% in CH301~). t' The filtrate obtained after precipitation of the salt ~0 pair, which contains the dextrorotatory diastereomeric salt pair, is concentrated in a rotary evaporator, the viscous residue is suspended in water, concentrated ammonia is added and the base t~
extracted with ether. The etherial solution is dried and con-centrated and the solid residue is recrystalllsed from isopro- . i - panol: lb-base, colourless crystals, m.p. 100 - 101C; la]20 - ~
5.8 (concentration = 2% in CH30~). r Dissolution of the base in methanol and treatment with isopropanolic hydrochloric acid and ether gives the dihydro-chloride of compound lb in the form of colourless crystals melting at 182 - 187C; ~a]D + 11.0 (concentration = 2% in CH30H).
, ..... . . . ..
~.
~11247~L8 Examples of Pharmaceutical Preparations Injection Solution For a mixture of 100 liters there are needed:
Compound according to Example 1 (dihydrochloride) 0.25 kg Sodium chloride ' 0.775 kg Water for purpose of injection 98.975 kg e 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 colorless glass. The ampoules after being closed by melting are sterilized for 20 minutes at 120C in superheated steam.
Suppositories Production:
5 g of the compound of Example 7 (dihydrochloride) is t worked into 1995 g of molten suppository composition (for example, ,`
hard fat DAB 7, a mixture of mono-, di- and triglycerides of L
saturated fatty acids C12H24O2 to C18H36O2) and in known manner poured out in forms for 2.0 g suppositor1es.
1 suppository contains 5 mg of active material Capsules To prepare 100,000 capsules there are required the following raw materials:
Compound according to Example 7 (dihydrochloride') 0.125 kg '.0 i~
Lactose 7.200 kg Microcrystalline cellulose 4.800 kg Magnesium stearate 0.375 kg 12.500 kg gLiL2A~7~L8 r To produce gelatin capsules (size 4) which are necessary for production of the capsule composition the previously set forth raw materials are passed through a sieve having a mesh width of 1.5 mm and then mixed for 1 hour at 10 revolutions per minute in a Turbula mixer. This composition is called the capsule filling composition.
This capsule filling composition is filled into gelatin capsules of size 2. Amount of filling per capsule : 125 mg.
` SUPPLEMENTARY DISCLOSURE
Example 30 Preparation of the compound of ~xample 1 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)piperazine 3-[~-(2-methoxy-phenyl)-piperazino]-1,2-epoxy-propane obtained from 1.92 g of 1-(2-methoxy-phenyl)piperazine and 1.36 g of epibromohydrin in 10 ml of methanol by allowing the mixture to stand for 72 hours at room temperature is mixed with 3 g of 3,4,5-trimethoxy-phenol potassium salt without isolation. After boiling the reaction mixture for 6 hours with reflux it is mixed with 400 ml of ether, filtered and acidified with isopropanolic hydrochloric acid. The precipitated dihydrochloride is purified by column chromatography.
(eluant: CHC13 (90 parts)/CH3OH (5 parts)/acetic acid (5 parts)) and by subsequent crystallization from isopropanolic hydrochloric acid; m.p. of the dihydrochloride 196 to 197 C, yield: 0.5 g.
Example 31 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-acetamido-phenyl)piperazine 4 g of (+)-1-[3-(3,4,5-trimethoxy-phenoxy-2-hydroxy-propyl]-4 (2-amino-phenyl)piperazine(monohydrochloride) are dis-solved in 200 ml of dioxane and mixed with 10 ml of triethylamine, whereupon 0.9 ml of acetyl chloride is added dropwise at 7~8 -5C while stirring. A~ter two hours of post-reaction at room temperature the solution is filtered and the solvent is removed under reduced pressure. By dry-column chromatography on silica gel.
(eluant: ether:acetic acid = 1:1) the desired compound is isolated and recrystallized from acetone-ether. Yield: 50%, m.p. = 128 to 130C. (+)-l-r3,4,5--trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-acetamldo-phenyl) piperazine is obtained as a less polar by-product, which can become the main product by increasing the amount of acetyl chloride. m.p. = 54C
Example 32 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-acetoxy-phenyl)piperazine
6 g (0.0143 mole) of (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-hydroxy-phenyl)piperazine and 2.9 g (0.0286 mole) of triethylamine are dissolved in 80 ml of absolute methylene chloride and mixed dropwise with a solution of 2.24 g (0.0286 mole) of acetyl chloride in 20 ml of absolute methylene chloride at 0C. The reaction mixture is stirred for two hours at room temperature and the precipitated triethylamine hydro-chloride is filtered off. The solvent is then distilled off in vacuo and the residue is recrystallized from ether/petroleum ether.
Yield: 57%, m.p. = 70C.
Example 33 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl~-4-(2-aminophenyl)piperazine 6 g (0.0124 mole) of (+)-1-~3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-nitro-phenyl)piperazine are dissolved in 300 ml of methanol and hydrogenated in the presence of 0.5 g of a 10% Pd-C at room temperature. After filtering off the catalyst and removing the solvent in vacuo the residue is recrystallized ~1247~8 from ethanol in vacuo.
Yield: 94%, m.p. of the monohydrochloride = 181 to 183C.
Example 34 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(hydroxy-`propyl]-4-(2-acetoxy~phenyl)piperazine CH30~0-CH2-CH(OH)-CH2-lr\N ~
0.03 mole of 1-(2-acetoxy-phenyl)piperazine (crude product) and 7.2 g (0.03 mole) of 3,4,5-trimethoxy-phenoxy glycide ether are heated in 150 ml of isopropanol with reflux until the reaction is complete as determined by thin layer chromatography. After distilling off the solvent the hydro-chloride is obtained by treatment with isopropanolic hydro-chloric acid and is purified by recrystallization from isopropanol.
Yield: 18%, m.p. = 189 to 191C.
The 1-[2-acetyl-oxy-phenyl]piperazine used as the starting material is obtained in the following manner:
192.8 g (1 mole) of 2-methoxy-phenyl piperazine, 130 ml (1.1 moles) of benzyl chloride and 150 g (1.10 moles) of potassium carbonate are heated in 800 ml af xylene with re1ux until the reaction is complete according to DC examination ~i.e.
examination, by thin layer chromatography). The solution is filtered and the solvent is removed in vacuo. By treatment with isopropanolic hydrochloric acid in the usual manner the hydrochloride is then obtained (yield: 70%).
60 g (0.2 mole) of the hydrochloride thus obtained are heated in 800 ml of a 63% a~ueous hydrobromic acid with reflux until the ether cleavage is complete ~DC examination).
The solvent is then removed in vacuo and the crystalline resi-due obtained is washed with ether (yield 70%). The free base llZ4718 is liberated from the dihydro bromide with dilute aqueous ammonia in the usual manner.
10 g (0.029 mole) of the free base thus obtained and l~ ml of triethyl amine are cooled in 50 ml of dioxane to 5C
and mixed dropwise with 0.032 mole of acetyl chloride at a temper~ture not higher than 10C. After stirring for one hour at 10C the precipitated triethylamine hydrochloride is filtered witll suction and the solvent is distilled off in vacuo. In the oily free base obtained the benzyl group is hydrogenated off without any further purification in the following manner: 0.4 mole of the free base is dissolved in 150 ml of methanol and hydrogenated in the presence of 2 g of a 10% Pd/C at 50~C and 5 bars. After completed water absorption the catalyst is filtered off and the solvent is removed in vacuo. The 1-(2-acetoxy-phenyl)piperazine thus obtained can be further reacted directly without any further purification.
Examples 35 and 36 In a manner analogously to that of Example 34 the compounds listed in Table 2 are obtained from 0.03 mole of 3,4,5-trimethoxy-phenoxy glycide ether and 0.03 mole of the corres-ponding piperazine compound. The starting piperazine compound is obtained in an analogous manner as the starting compound o the preceding example and instead of using the acetyl chloride in the acylating step the corresponding other acid chloride (benzoyl chloride, cyclohexane carboxylic chloride) is used.
TAsLE 2 Starting Piperazine R2 in Formula 1 Melting Point Yield in % Example Compound Rl = H (hydrochloride) of the ~o.
theoreti-cal yield 1-(2-benzoyloxy 2-benzoyl-oxy-phenyl 194-196C 31% 35 -phenyl)piperazine 1-(2-cyclohexyl- 2-cyclohexyl carbonyl 151-152 C 22% 36 carbonyl-oxy- -oxy-phenyl phenyl)piperazine 11;;~47i~8 Example 37 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-methoxy-phenyl)piperazine 10 g (0.023 mole) of (+)-1[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)piperazine are suspended in 100 ml of xylene and 10 ml of triethylamine are added, whereupon 9 ml of acetyl chloride are slowly added dropwise at room temperature. The solutioniisleft at room temperature for 2 hours. The triethyl ammonium chloride is then filtered off and the solvent is distilled off in vacuo. The crude product obtained is purified by dry column chromatography on silica gel ~eluant chloroform/methanol 98:2). The hydrochloride is obtained in the usual manner by treatment with isopropanolic hydrochloric acid and recrystallized from isopropanol.
Yield: 80%, m.p. of the hydrochloride _ 178 to 179C.
CH30~ OCOCH3 Example 38 :
t+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(thienyl-(2-carbonyl-oxy)propyl]-4-(2-methoxy-phenyl)piperaæine CH30 \ OCH3 CH30 ~ 0-CH2-CH-CH2- 3 N
CH30 CO ~
15 g (0.0319 mole) of (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)-piperazine dihydrochloride and 3.3 g of triethylamine are suspended in 100 ml of xylene, whereupon 4.7 g (0.0319 mole) of thiophene-2-carboxylic chloride are added dropwise at room temperature while stirring. Stirring is then continued for . ~
one hour at room temperature. The precipitated triethyl ammonium hydrochloride is then filtered off and the solution concentrated under reduced pressure. The residue is taken up in ether and mixed with isopropanolic HCl. The dihydrochloride obtained is recrystallized from isopropanol. ~elting point of the dihydrochloride 198 to 199C. (The substance contains 1 mole of isopropanol as the crystal solvent).
Yield: 42%.
Example 39 The corresponding thienyl-(3) compound is produced analogously as in Example 38. Melting point of the dihydro-chloride 193 to 194C.
Yield: 48% --Example 40 (+)-1-~3-(3,4,5-trimethoxy-phenoxy)-2-~thienyl-(2)-carbonyl-oxy)-propyl]-4-[2-thienyl-(2)-carbonyl-oxy)-phenyl]
piperazine : : ~,co oc(~3 oco ~
~o H ~,CO~ c~z-c~-c~2-^~ N~)
Yield: 57%, m.p. = 70C.
Example 33 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl~-4-(2-aminophenyl)piperazine 6 g (0.0124 mole) of (+)-1-~3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-nitro-phenyl)piperazine are dissolved in 300 ml of methanol and hydrogenated in the presence of 0.5 g of a 10% Pd-C at room temperature. After filtering off the catalyst and removing the solvent in vacuo the residue is recrystallized ~1247~8 from ethanol in vacuo.
Yield: 94%, m.p. of the monohydrochloride = 181 to 183C.
Example 34 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(hydroxy-`propyl]-4-(2-acetoxy~phenyl)piperazine CH30~0-CH2-CH(OH)-CH2-lr\N ~
0.03 mole of 1-(2-acetoxy-phenyl)piperazine (crude product) and 7.2 g (0.03 mole) of 3,4,5-trimethoxy-phenoxy glycide ether are heated in 150 ml of isopropanol with reflux until the reaction is complete as determined by thin layer chromatography. After distilling off the solvent the hydro-chloride is obtained by treatment with isopropanolic hydro-chloric acid and is purified by recrystallization from isopropanol.
Yield: 18%, m.p. = 189 to 191C.
The 1-[2-acetyl-oxy-phenyl]piperazine used as the starting material is obtained in the following manner:
192.8 g (1 mole) of 2-methoxy-phenyl piperazine, 130 ml (1.1 moles) of benzyl chloride and 150 g (1.10 moles) of potassium carbonate are heated in 800 ml af xylene with re1ux until the reaction is complete according to DC examination ~i.e.
examination, by thin layer chromatography). The solution is filtered and the solvent is removed in vacuo. By treatment with isopropanolic hydrochloric acid in the usual manner the hydrochloride is then obtained (yield: 70%).
60 g (0.2 mole) of the hydrochloride thus obtained are heated in 800 ml of a 63% a~ueous hydrobromic acid with reflux until the ether cleavage is complete ~DC examination).
The solvent is then removed in vacuo and the crystalline resi-due obtained is washed with ether (yield 70%). The free base llZ4718 is liberated from the dihydro bromide with dilute aqueous ammonia in the usual manner.
10 g (0.029 mole) of the free base thus obtained and l~ ml of triethyl amine are cooled in 50 ml of dioxane to 5C
and mixed dropwise with 0.032 mole of acetyl chloride at a temper~ture not higher than 10C. After stirring for one hour at 10C the precipitated triethylamine hydrochloride is filtered witll suction and the solvent is distilled off in vacuo. In the oily free base obtained the benzyl group is hydrogenated off without any further purification in the following manner: 0.4 mole of the free base is dissolved in 150 ml of methanol and hydrogenated in the presence of 2 g of a 10% Pd/C at 50~C and 5 bars. After completed water absorption the catalyst is filtered off and the solvent is removed in vacuo. The 1-(2-acetoxy-phenyl)piperazine thus obtained can be further reacted directly without any further purification.
Examples 35 and 36 In a manner analogously to that of Example 34 the compounds listed in Table 2 are obtained from 0.03 mole of 3,4,5-trimethoxy-phenoxy glycide ether and 0.03 mole of the corres-ponding piperazine compound. The starting piperazine compound is obtained in an analogous manner as the starting compound o the preceding example and instead of using the acetyl chloride in the acylating step the corresponding other acid chloride (benzoyl chloride, cyclohexane carboxylic chloride) is used.
TAsLE 2 Starting Piperazine R2 in Formula 1 Melting Point Yield in % Example Compound Rl = H (hydrochloride) of the ~o.
theoreti-cal yield 1-(2-benzoyloxy 2-benzoyl-oxy-phenyl 194-196C 31% 35 -phenyl)piperazine 1-(2-cyclohexyl- 2-cyclohexyl carbonyl 151-152 C 22% 36 carbonyl-oxy- -oxy-phenyl phenyl)piperazine 11;;~47i~8 Example 37 (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-methoxy-phenyl)piperazine 10 g (0.023 mole) of (+)-1[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)piperazine are suspended in 100 ml of xylene and 10 ml of triethylamine are added, whereupon 9 ml of acetyl chloride are slowly added dropwise at room temperature. The solutioniisleft at room temperature for 2 hours. The triethyl ammonium chloride is then filtered off and the solvent is distilled off in vacuo. The crude product obtained is purified by dry column chromatography on silica gel ~eluant chloroform/methanol 98:2). The hydrochloride is obtained in the usual manner by treatment with isopropanolic hydrochloric acid and recrystallized from isopropanol.
Yield: 80%, m.p. of the hydrochloride _ 178 to 179C.
CH30~ OCOCH3 Example 38 :
t+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(thienyl-(2-carbonyl-oxy)propyl]-4-(2-methoxy-phenyl)piperaæine CH30 \ OCH3 CH30 ~ 0-CH2-CH-CH2- 3 N
CH30 CO ~
15 g (0.0319 mole) of (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)-piperazine dihydrochloride and 3.3 g of triethylamine are suspended in 100 ml of xylene, whereupon 4.7 g (0.0319 mole) of thiophene-2-carboxylic chloride are added dropwise at room temperature while stirring. Stirring is then continued for . ~
one hour at room temperature. The precipitated triethyl ammonium hydrochloride is then filtered off and the solution concentrated under reduced pressure. The residue is taken up in ether and mixed with isopropanolic HCl. The dihydrochloride obtained is recrystallized from isopropanol. ~elting point of the dihydrochloride 198 to 199C. (The substance contains 1 mole of isopropanol as the crystal solvent).
Yield: 42%.
Example 39 The corresponding thienyl-(3) compound is produced analogously as in Example 38. Melting point of the dihydro-chloride 193 to 194C.
Yield: 48% --Example 40 (+)-1-~3-(3,4,5-trimethoxy-phenoxy)-2-~thienyl-(2)-carbonyl-oxy)-propyl]-4-[2-thienyl-(2)-carbonyl-oxy)-phenyl]
piperazine : : ~,co oc(~3 oco ~
~o H ~,CO~ c~z-c~-c~2-^~ N~)
7 g (0.0167 mole) of (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-hydroxy-phenyl)piperazine are suspended in 100 ml of dioxane and 4 ml of triethylamine, where-upon 5 g (0.034 mole) of thiophene-2-carboxylic chloride are added in portions at room temperature while stirring. On completed addition stirring is continued for further six hours.
The mixture is then allowed to stand at room temperature. The triethyl ammonium hydrochloride formed is filtered off and the solvent is distilled off in vacuo. The remaining oil product is taken up in 100 ml of ether and mixed with isopropanolic llZ4~718 hydrochloric acid to the acid reaction, whereupon the precipi-tated hydrochloride is filtered with suction and recrystallized from isopropanol in order to purify it.
Yield: 61%, m.p. of the hydrochloride = 221 to 222~C.
~ 20 , ~
~ ~ .
., ~ 28 -
The mixture is then allowed to stand at room temperature. The triethyl ammonium hydrochloride formed is filtered off and the solvent is distilled off in vacuo. The remaining oil product is taken up in 100 ml of ether and mixed with isopropanolic llZ4~718 hydrochloric acid to the acid reaction, whereupon the precipi-tated hydrochloride is filtered with suction and recrystallized from isopropanol in order to purify it.
Yield: 61%, m.p. of the hydrochloride = 221 to 222~C.
~ 20 , ~
~ ~ .
., ~ 28 -
Claims (85)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of a compound corespond-ing to the general formula (I) in which R1 is a hydrogen atom, a C2 to C6-alkanoyl radical, a 3,4,5-trimethoxy benzoyl radical or a nicotinoyl radical and R2 represents a phenyl, naphthyl or pyridyl radical which may be sub-stituted 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 C1 to C6-alkyl radical, a C1 to C6-alkoxy radical, a C1 to C6-alkyl thio radical or a C2 to C6-alkanoyl radical, and their pharmaceutically acceptable salts, which comprises reacting a compound corresponding to the formula (II) or a metal salt thereof with a compound corresponding to the formula (III) in which Y and Z are different from one another and one represents a hydrogen atom whilst the other represents the group -CH2-CH(OR1) -CH2-V where V represents chlorine, bromine or iodine, or, where R1 is hydrogen, may also form an ethylene oxide ring with this hydroxy group, when required reducing one or two nitrogen groups to amino groups, when in the product obtained R1 is hydrogen and R1 is required to be acyl acylating said compound with an acid or acid derivative corresponding to the radical R1 and when the salt is required, reacting the free base obtained with a suitable acid.
2. A process as claimed in claim 1 in which the reac-tion is effected in a solvent at temperatures from 20°C to 200°C.
3. A process as claimed in claim 2 in which the reac-tion is effected in the presence of an acid agent.
4. A compound corresponding to the general formula in which R1 is a hydrogen atom, a C2 to C6-alkanoyl radical, a 3,4,5-trimethoxy benzoyl radical or a nicotinoyl radical, and R2 represents a phenyl, naphthyl or pyridyl radical which may be 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 trifluoro-methyl group, a C1 to C6-alkyl radical, a C1 to C6-alkoxy radical, a C1 to C6-alkyl thio radical or a C2 to C6-alkanoyl radical, and their ... . ..
pharmaceutically acceptable salts whenever prepared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
pharmaceutically acceptable salts whenever prepared or produced by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which R2 is 2-methoxyphenyl, phenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chloro-phenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-eth-oxyphenyl, 2-methylmercaptophenyl, 2-methylphenyl, 3-methylphenyl, 3,4-dimethylphenyl, 2,6-dimethylphenyl, 4-acetylphenyl, 2-tri-fluoromethylphenyl, 3-trifluoromethylphenyl, naphth-(l)-yl, pyrid-(2)-yl, 2-hydroxyphenyl or 2-nitrophenyl and R1 is hydrogen, nico-tinoyl or 3,4,5-trimethoxybenzoyl.
6. A compound of Formula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 5 whenever prepared or produced by the process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-methoxyphenyl)-piperazine in isopropanol.
8. A process as claimed in claim 1 which comprises refluxing 3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl bromide with 1-(2-methoxyphenyl)-piperazine in toluene and triethylamine.
9. A process as claimed in claim 1 which comprises refluxing sodium-(3,4,5-trimethoxy)-phenolate with 1-(3-chloro-2-hydroxypropyl)-4-(2-methoxyphenyl)-piperazine in dioxane.
10. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine whenever prepared or produced by the process as claimed in claim 7, 8 or 9 or an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-phenyl piperazine in isopropanol.
12. 1-[-3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-phenyl-piperazine whenever prepared or produced by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(4-fluorophenyl)-piperazine in isopropanol.
14. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]- 4-(4-fluorophenyl)-piperazine whenever prepared or produced by the process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-chlorophenyl)-piperazine in isopropanol.
16. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2-chlorophenyl)-piperazine whenever prepared or produced by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(3-chlorophenyl)-piperazine in isopropanol.
18. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(3-chlorophenyl) -piperazine whenever prepared or produced by the process as ciaimed in claim 17 or an obvious chemical equivalent thereof.
19. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(4-chlorophenyl)-piperazine in isopropanol.
20. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(4-chlorophenyl)-piperazine whenever prepared or produced by the process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(3-methoxyphenyl)-piperazine in isopropanol.
22. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(3-methoxypheny)-piperazine whenever prepared or produced by the process as claimed in claim 21 or an obvious chemical equivalent thereof.
23. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(4-methoxyphenyl)-piperazine in isopropanol.
24. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(4-methoxyphenyl)-piperazine whenever prepared or produced by the process as claimed in claim 23 or an obvious chemical equivalent thereof.
25. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-ethoxyphenyl)-piperazine in isopropanol.
26. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2-ethoxypheny)-piperazine whenever prepared or produced by the process as claimed in claim 25 or an obvious chemical equivalent thereof.
27. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-methylmercaptophenyl)-piperazine in isopropanol.
28. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2-methyl mercaptophenyl)-piperazine whenever prepared or produced by the process as claimed in claim 27 or an obvious chemical equivalent thereof.
29. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-methylphenyl)-piperazine in isopropanol.
30. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2-methylphenyl)-piperazine whenever prepared orproducedby the process as claimed in claim 29 or an obvious chemical eauivalent thereof.
31. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(3-methylphenyl)-piperazine in isopropanol.
32. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(3-methylphenyl)-piperazine whenever prepared or produced by the process as claimed in claim 31 or an obvious chemical equivalent thereof.
33. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(3,4-dimethylphenyl)-piperazine in isopropanol.
34. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(3,4-dimethylphenyl)-piperazine whenever prepared or produced by the process as claimed in claim 33 or an obvious chemical equivalent thereof.
35. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2,6-dimethylphenyl)-piperazine in isopropanol.
36. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2,6-dimethylphenyl) piperazine whenever prepared or produced by the process as claimed in claim 35 or an obvious chemical equivalent thereof.
37. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(4-acetylphenyl)-piperazine in isopropanol.
38. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(4-acetylphenyl) piperazine whenever prepared or producedby the process as claimed in claim 37, or an obvious chemical equivalent thereof.
39. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-trifluoromethylphenyl)-piperazine in isopropanol.
40. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2-trifluoromethylphenyl) piperazine whenever prepared or produced by the process as claimed in claim 39, or an obvious chemical equivalent thereof.
41. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(3-trifluoromethylphenyl)-piperazine in isopropanol.
42. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(3-trifluoromethylphenyl) piperazine whenever prepared or produced by the process as claimed in claim 41 or an obvious chemical equivalent thereof.
43. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-naphth-(1)-yl-piperazine in isopropanol.
44. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(naphth-(1)-yl) piperazine whenever prepared or produced by the process as claimed in claim 43, or an obvious chemical equivalent thereof.
45. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-pyrid-(2)-yl-piperazine in isopropanol.
46. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]- 4-(pyrid-(2)-yl) piperazine whenever prepared or produced by the process as claimed in claim 45 or an obvious chemical equivalent thereof.
47. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-hydroxyphenyl)-piperazine in isopropanol.
48. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2-hydroxyphenyl) piperazine whenever prepared or produced by the pro-cess asclaimed in claim 47 or an obvious chemical equivalent thereof.
49. A process as claimed in claim 1 which comprises refluxing 3,4,5-trimethoxyphenoxy glycidyl ether with 1-(2-nitrophenyl)-piperazine in isopropanol.
50. 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxy propyl]-4-(2-nitrophenyl)piperazine whenever prepared or produced by the process as claimed in claim 49 or an obvious chemical equivalent thereof.
51. A process as claimed in claim 7 in which the 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine so obtained is reacted in the presence of triethyl amine and in a solution of anhydrous benzene with nicotinic acid chloride.
52. (+)-1-[3-(3,4,5-trimethoxyphenoxy)-2-(nicotinoyl-oxy)-propyl]-4-(2-methoxyphenyl)-piperazine whenever prepared or produced by the process as claimed in claim 51, or an obvious chemical equivalent thereof.
53. A process as claimed in claim 7, in which the 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine so obtained is reacted in the presence of triethyl amine and in a solution of anhydrous benzene with 3,4,5-trimethoxy benzoyl chloride.
54. (+-1-{3-[3,4,5-trimethoxyphenoxy]-2-[(3,4,5-tri-methoxy)-benzoyloxy]-propyl}-4-(2-methoxyphenyl)-piperazine when-ever prepared or produced by the process as claimed in claim 53, or an obvious chemical equivalent thereof.
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
55. A process for the production of a compound corres-ponding to the general formula (I) in which R1 is a hydrogen atom, a C2 to C6-alkanoyl radical, a 3,4,5-trimethoxy benzoyl radical, a nicotinoyl radical or a thienyl carbonyl radical and R2 represents a phenyl, naphthyl or pyridyl radical which may be substituted by the radicals R3 and R4, the radicals R3 and R4 which may be the same or differ-ent, 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 C1 to C6-alkyl thio radical, a C2 to C6-alkanoyl radical, an amino group, a C2-C6-alkanoyl-amino group, a C2-C6-alkanoyl-oxy group, a benzoyl-oxy group, a cyclohexylcarbonyl-oxy group or a thienyl-carbonyl-oxy group and their pharmaceutically acceptable salts, which comprises reacting a compound corresponding to the formula II
or a metal salt thereof with a compound corresponding to the formula III
in which Y and Z are different from one another and one represents a hydrogen atom whilst the other represents the group -CH2-CH(OR1)-CH2-V where V represents chlorine, bromine or iodine, or, where R1 is hydrogen, may also form an ethylene oxide ring with this hydroxy group, when required reducing one or two nitrogen groups to amino groups, when in the product obtained R1 is hydrogen and R1 is required to be acyl acylating said compound with an acid or acid derivative corresponding to the radical R1 and when the salt is required, reacting the free base obtained with a suitable acid.
or a metal salt thereof with a compound corresponding to the formula III
in which Y and Z are different from one another and one represents a hydrogen atom whilst the other represents the group -CH2-CH(OR1)-CH2-V where V represents chlorine, bromine or iodine, or, where R1 is hydrogen, may also form an ethylene oxide ring with this hydroxy group, when required reducing one or two nitrogen groups to amino groups, when in the product obtained R1 is hydrogen and R1 is required to be acyl acylating said compound with an acid or acid derivative corresponding to the radical R1 and when the salt is required, reacting the free base obtained with a suitable acid.
56. A process as claimed in claim 55 in which the re-action is effected in a solvent at temperatures from 20°C to 200°C.
57. A process as claimed in claim 56 in which the re-action is effected in the presence of an acid agent.
58. A compound corresponding to the general formula in which R1 is a hydrogen atom, a C2 to C6-alkanoyl radical , a 3,4,5-trimethoxy benzoyl radical, a nicotinoyl radical or a thienyl carbonyl radical, and R2 represents a phenyl, naphthyl or pyridyl radical which may be substituted by the radicals R3 and R4, the radicals R3 and R4, which may be the same or differ-ent, 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 C1 to C6-alkyl thio radical, a C2 to C6-alkanoyl radical, an amino group, a C2-C6-alkanoyl-amino group, a C2-C6-alkanoyl-oxy group, a benzoyl-oxy group, a cyclohexyl-carbonyl-oxy group or a thienyl-carbonyl-oxy group and their pharmaceutically acceptable salts whenever prepared or produced by the process as claimed in claim 55, 56, or 57 or an obvious chemical equivalent thereof.
59. A process as claimed in claim 55, in which R2 is 2-methoxyphenyl, phenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chloro-phenyl, 4-chlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethy-oxyphenyl, 2-methylmercaptophenyl, 2-methylphenyl, 3-methylphenyl, 3,4-dimethylphenyl, 2,6-dimethvlphenyl, 4-acetylphenyl, 2-tri-fluoromethylphenyl, 3-trifluoromethylphenyl, naphth-(1)-yl, pyrid-(2)-yl, 2-hydroxyphenyl or 2-nitrophenyl and R1 is hydrogen, nico-tinoyl or 3,4,5-trimethoxybenzoyl.
60. A compound of Formula I given in claim 55 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 59 whenever prepared or produced by the process as claimed in claim 59 or an obvious chemical equivalent thereof.
61. A process as claimed in claim 55 in which R3 and R4 each represent amino, C2 to C6 alkanoyl amino, C2 to C6 alkanoyloxy, benzoyloxy, cyclohexyl-carbonyloxy or thienyl-carbonyloxy.
62. A compound of Formula I given in claim 55 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 61 and R3 and R4 are as in claim 61 whenever prepared or produced by the process as claimed in claim 61 or an obvious chemical equivalent thereof.
63. A process as claimed in claim 55, which comprises reacting 3-[4-(2-methoxy-phenyl)-piperazino]-1,2-epoxy-propane with 3,4,5-trimethoxy-phenol potassium salt under reflux.
64. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)piperazine, whenever prepared or produced by the process as claimed in claim 63, or an obvious chemical equivalent thereof.
65. A process as claimed in claim 49, in which the (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-nitro-phenyl)piperazine so obtained is hydrogenated in methanol in the presence of a Pd/c catalyst.
66. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-aminophenyl)-piperazine, whenever prepared or produced by the process as claimed in claim 65, or an obvious chemical equivalent thereof.
67. A process as claimed in claim 65, which comprises reacting the (+)-1 [3-t3,4,5-trimethoxy-phenoxy-2-hydroxy-propyl]-4-(2-amino-phenyl)piperazine (monohydrochloride) obtained with acetyl chloride in the presence of triethyl amine and separating the product obtained by drying column chromotography.
68. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-acetamido-phenyl)piperazine, whenever prepared or produced by the process as claimed in claim 67, or an obvious chemical equivalent thereof.
69. (+)-1-[3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]
-4-(2-acetamido-phenyl) piperazine, whenever prepared or produced by the process as claimed in claim 67, or an obvious chemical equivalent thereof.
-4-(2-acetamido-phenyl) piperazine, whenever prepared or produced by the process as claimed in claim 67, or an obvious chemical equivalent thereof.
70. A process as claimed in claim 47, which comprises reacting the (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]
-4-(2-hydroxy-phenyl) piperazine so obtained in absolute methylene chloride in the presence of triethylamine with acetyl chloride.
-4-(2-hydroxy-phenyl) piperazine so obtained in absolute methylene chloride in the presence of triethylamine with acetyl chloride.
71. (+)-1- [ 3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-acetoxy-phenyl) piperazine, whenever prepared or produced by the process as claimed in claim 70, or an obvious chemical equivalent thereof.
72. A process as claimed in claim 55,which comprises refluxing 1-(2-acetoxy-phenyl)piperazine with 3,4,5-trimethoxy-phenoxy glycide ether in isopropanol.
73. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(hydroxy-propyl]-4-(2-acetoxy-phenyl) piperazine, whenever prepared or produced by the process as claimed in claim 72, or an obvious chemical equivalent thereof.
74. A process as claimed in claim 55, which comprises refluxing 1-(2-benzoyloxy-phenyl) piperazine with 3,4,5-trimethoxy-phenoxy glycide ether in isopropanol.
75. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-[2-benzoyloxy phenyl)-piperazine, whenever prepared or produced by the process as claimed in claim 74, or an obvious chemical equivalent thereof.
76. A process as claimed in claim 55, which comprises refluxing 1-(2-cyclohexyl-carbonyl-oxy-phenyl) piperazine with 3,4,5-trimethoxy-phenoxy glycide ether in isopropanol.
77. A process as claimed in claim 76, which comprises refluxing 1-(2-cyclohexyl carbonyloxy phenyl) piperazine with 3,4,5-trimethoxy-phenoxy glycide ether in isopropanol.
78. A process as claimed in claim 9, in which the (+)-1[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl) piperazine so obtained is reacted with acetyl chloride, in xylene and in the presence of triethyl amine.
79. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-4-(2-methoxy-phenyl) piperazine, whenever prepared or produced by the process as claimed in claim 78, or an obvious chemical equivalent thereof.
80. A process as claimed in claim 9, in which the (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy -phenyl)-piperazine dihydrochloride obtained is reacted with thiophene-2-carboxylic chloride in xylene and in the presence of triethyl amine.
81. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(thienyl-(2)-carbonyl-oxy)propyl]-4-(2-methoxy-phenyl) piperazine, whenever prepared or produced by the process as claimed in claim 80, or an obvious chemical equivalent thereof.
82. A process as claimed in claim 47, in which the (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-hydroxy-phenyl) piperazine so ohtained is reacted with thiophene-2-carboxylic chloride in dioxane in the presence of triethylamine.
83. (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(thienyl-(2)-carbonyl-oxy)-propyl]-4-[2-thienyl-(2)-carbonyl-oxy)-phenyl]
piperazine, whenever prepared or produced by the process as claimed in claim 82, or an obvious chemical equivalent thereof.
piperazine, whenever prepared or produced by the process as claimed in claim 82, or an obvious chemical equivalent thereof.
84. A process as claimed in claim 9, in which the (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)-piperazine dihydrochloride obtained is reacted with thiophene-3-carboxylic chloride in xylene and in the presence of triethyl amine.
85. (+)-l-[3-(3,4,5-trimethoxy-phenoxy)-2-(thienyl-(3)-carbonyl-oxy)propyl]-4-(2-methoxy-phenyl) piperazine, whenever prepared or produced by the process as claimed in claim 84,or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| 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 |
| GB14100/77 | 1977-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1124718A true CA1124718A (en) | 1982-06-01 |
Family
ID=10034980
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA300,288A Expired CA1124718A (en) | 1977-04-04 | 1978-04-03 | 1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4- aryl piperazine derivatives |
Country Status (23)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1977
- 1977-04-04 GB GB14100/77A patent/GB1583372A/en not_active Expired
-
1978
- 1978-03-31 FR FR7809675A patent/FR2395264A1/en active Granted
- 1978-03-31 YU YU767/78A patent/YU40513B/en unknown
- 1978-04-01 DE DE19782814168 patent/DE2814168A1/en active Granted
- 1978-04-01 HU HU78DE957A patent/HU179952B/en not_active IP Right Cessation
- 1978-04-01 PL PL1978205745A patent/PL112249B1/en unknown
- 1978-04-03 CA CA300,288A patent/CA1124718A/en not_active Expired
- 1978-04-03 ZA ZA00781889A patent/ZA781889B/en unknown
- 1978-04-03 AU AU34703/78A patent/AU516315B2/en not_active Expired
- 1978-04-03 CH CH354378A patent/CH638795A5/en not_active IP Right Cessation
- 1978-04-03 FI FI781009A patent/FI69627C/en not_active IP Right Cessation
- 1978-04-03 ES ES468486A patent/ES468486A1/en not_active Expired
- 1978-04-03 NL NL7803540A patent/NL7803540A/en not_active Application Discontinuation
- 1978-04-03 SU SU782596099A patent/SU893133A3/en active
- 1978-04-03 AT AT233078A patent/AT360997B/en not_active IP Right Cessation
- 1978-04-03 SE SE7803742A patent/SE435507B/en not_active IP Right Cessation
- 1978-04-03 DK DK146678A patent/DK145225C/en not_active IP Right Cessation
- 1978-04-03 BE BE6046420A patent/BE865642A/en not_active IP Right Cessation
- 1978-04-03 CS CS782141A patent/CS249503B2/en unknown
- 1978-04-03 NO NO781159A patent/NO149209C/en unknown
- 1978-04-04 AR AR271686A patent/AR222149A1/en active
- 1978-04-04 JP JP53039626A patent/JPS6038383B2/en not_active Expired
- 1978-04-04 MX MX786995U patent/MX6120E/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO149209C (en) | 1984-03-07 |
| HU179952B (en) | 1983-01-28 |
| PL112249B1 (en) | 1980-10-31 |
| ES468486A1 (en) | 1979-01-16 |
| DK146678A (en) | 1978-10-05 |
| SU893133A3 (en) | 1981-12-23 |
| YU40513B (en) | 1986-02-28 |
| ATA233078A (en) | 1980-07-15 |
| FR2395264B1 (en) | 1980-03-07 |
| DK145225B (en) | 1982-10-11 |
| FI781009A (en) | 1978-10-05 |
| FI69627B (en) | 1985-11-29 |
| FI69627C (en) | 1986-03-10 |
| NO149209B (en) | 1983-11-28 |
| PL205745A1 (en) | 1979-05-07 |
| SE7803742L (en) | 1978-10-05 |
| DE2814168A1 (en) | 1978-10-05 |
| ZA781889B (en) | 1979-03-28 |
| NL7803540A (en) | 1978-10-06 |
| AU3470378A (en) | 1979-10-11 |
| YU76778A (en) | 1982-10-31 |
| BE865642A (en) | 1978-10-03 |
| MX6120E (en) | 1984-11-19 |
| JPS53130682A (en) | 1978-11-14 |
| NO781159L (en) | 1978-10-05 |
| DK145225C (en) | 1983-04-11 |
| CS249503B2 (en) | 1987-03-12 |
| AR222149A1 (en) | 1981-04-30 |
| FR2395264A1 (en) | 1979-01-19 |
| AU516315B2 (en) | 1981-05-28 |
| SE435507B (en) | 1984-10-01 |
| AT360997B (en) | 1981-02-10 |
| GB1583372A (en) | 1981-01-28 |
| CH638795A5 (en) | 1983-10-14 |
| JPS6038383B2 (en) | 1985-08-31 |
| DE2814168C2 (en) | 1989-02-16 |
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| MKEX | Expiry |