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EP0000395B1 - 2-piperazinotetraline derivatives, their preparation and their use as medicines - Google Patents

2-piperazinotetraline derivatives, their preparation and their use as medicines Download PDF

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Publication number
EP0000395B1
EP0000395B1 EP78100365A EP78100365A EP0000395B1 EP 0000395 B1 EP0000395 B1 EP 0000395B1 EP 78100365 A EP78100365 A EP 78100365A EP 78100365 A EP78100365 A EP 78100365A EP 0000395 B1 EP0000395 B1 EP 0000395B1
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carbon atoms
alkoxy
hydroxy
compounds
group
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German (de)
French (fr)
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EP0000395A1 (en
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Max-Peter Dr. Seiler
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D295/096—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the invention relates to new 2-piperazinotetralins.
  • 2-Piperazinotetralins are already known from German publication 1,190,466, which are unsubstituted in the benzene ring of the tetralin structure. Furthermore, French patent specification 2,100,935 describes derivatives of 2-piperazino-dihydronaphthalene.
  • the compounds of the formula I can occur in the form of enantiomers or in the form of racemates.
  • the compounds of the formula I obtained according to the invention may be in the form of the free bases or their acid addition salts.
  • the free bases can be converted into their acid addition salts in a manner known per se and vice versa.
  • the compounds of formula I according to the invention can e.g. form acid addition salts with inorganic acids such as hydrochloric acid or with organic acids such as maleic acid.
  • Process a) can be carried out in a manner known per se, e.g. by catalytic hydrogenation.
  • Suitable catalysts include palladium-carbon, platinum or Raney nickel, preferably palladium-carbon.
  • An inert organic solvent e.g. Ethanol or dimethylformamide.
  • the reduction can also be carried out with complex metal hydrides, e.g. Sodium borohydride, in an organic solvent such as trifluoroacetic acid.
  • the process is expediently carried out at temperatures between 10 and 50 ° C., preferably 20 and 30 ° C.
  • Process b) can be carried out in a manner known for the cleavage of ethers.
  • the cleavage is advantageously carried out by the action of cleaving agents, for example hydroiodic acid, hydrobromic acid or hydrochloric acid, preferably in water or acetic acid, advantageously at temperatures from 0 to 100 °, or boron tribromide, preferably in methylene chloride, advantageously from 0 to 50 ° C.
  • the pressure is preferably from 1 to 10 atm. If X, Y or Z are alkoxy groups in positions 2 and 6 of the phenyl ring, these are largely retained when using hydrohalic acids and are not converted to free OH groups.
  • the condensation c) can be carried out according to methods known per se for the production of the piperazine ring.
  • the compounds III and IV are preferably heated in an inert solvent at temperatures between 60 and 120 °.
  • the solvent used is advantageously ethanol, dimethylformamide or higher alcohols.
  • the condensation can in the presence of a base, e.g. tert. Amine or alkali carbonate.
  • the radicals Q and Q ' are preferably chlorine, bromine, iodine, an alkylsulfonyloxy or arylsulfonyloxy group.
  • Process d) can be carried out in a manner known for the acylation of phenols.
  • Acid halides or acid anhydrides, for example, can be used as reactive derivatives of the carboxylic acids.
  • the compounds of the formula can be isolated and purified in a manner known per se.
  • optically active compounds of formula I can e.g. starting from optically active starting materials (prepared by methods customary per se for the cleavage of racemates).
  • the compounds of formula II can be obtained by, for example, compounds of formula V with compounds of formula VI implements.
  • the reaction can be carried out in a manner known per se.
  • the reaction can be carried out in an inert solvent, e.g. Toluene, in the presence of catalytic amounts of p-toluenesulfonic acid with water separation, suitably at the reflux temperature of the solvent used or in the presence of catalytic amounts of a Lewis acid, e.g. Titanium tetrachloride, conveniently between 20 and 100 °.
  • an inert solvent e.g. Toluene
  • p-toluenesulfonic acid with water separation suitably at the reflux temperature of the solvent used or in the presence of catalytic amounts of a Lewis acid, e.g. Titanium tetrachloride, conveniently between 20 and 100 °.
  • a Lewis acid e.g. Titanium tetrachloride
  • reaction of compounds of the formula V with compounds of the formula VI can lead directly to compounds of the formula Ia if the reaction is carried out under reducing conditions.
  • a reducing agent e.g. Hydrogen can be used in the presence of catalysts such as Raney nickel, platinum or palladium-carbon.
  • the process is conveniently carried out in a solvent, e.g. Acetic acid, carried out at room temperature.
  • the compounds of the formulas III, IV, V and VI are either known or can be prepared in a manner known per se.
  • the compounds of formula I are distinguished by interesting pharmacodynamic properties.
  • a unit dose for example a tablet suitable for oral administration, can contain between 4 and 500 mg of the active ingredient together with suitable pharmaceutically indifferent auxiliaries.
  • the invention also relates to medicaments which contain a compound of the formula.
  • These remedies for example a solution or a tablet, can be prepared by known methods using the customary auxiliaries and carriers.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Description

Die Erfindung betrifft neue 2-Piperazinotetraline.The invention relates to new 2-piperazinotetralins.

Aus der deutschen Auslegeschrift 1.190.466 sind schon 2-Piperazinotetraline bekannt, die im Benzolring des Tetralingerüsts unsubstituiert sind. Weiter sind in der französischen Patentschrift 2.100.935 Derivate des 2-Piperazino-dihydronaphthalins beschrieben.2-Piperazinotetralins are already known from German publication 1,190,466, which are unsubstituted in the benzene ring of the tetralin structure. Furthermore, French patent specification 2,100,935 describes derivatives of 2-piperazino-dihydronaphthalene.

Gegenstand der vorliegenden Erfindung sind neue 2-Piperazinotetraline der Formel I

Figure imgb0001
worin

  • R1 Hydroxy, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-20 C-Atomen oder eine
    Figure imgb0002
    • R4 und R5 unabhängig voneinander Wasserstoff, Fluor, Chlor, Brom, Jod, Alkyl mit 1-4 C-Atomen oder Alkoxy mit 1-4 C-Atomen oder
    • R4 und R5 an benachbarten C-Atomen zusammen eine Methylendioxygruppe,
  • R2 und R3 unabhängig voneinander Wasserstoff,

Hydroxy, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-20 C-Atomen oder eine
Figure imgb0003
oder
  • R1 und R2 an benachbarten C-Atomen zusammen eine Methylendioxygruppe,
    • A a) eine
      Figure imgb0004
      X, Y und Z unabhängig voneinander Wasserstoff, Hydroxy, Alkyl mit 1-4 C-Atomen, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-20 C-Atomen, eine
      Figure imgb0005
      Brom, Jod, CF3, SH, Alkylthio mit 1-4 C-Atomen oder Alkanoylthio mit 1-20 C-Atomen oder X und Y an benachbarten C-Atomen zusammen-eine Methylendioxygruppe, D 0 oder S
    • b) eine
      Figure imgb0006
    • c) einen Fünf- oder Sechsring der Formel
      Figure imgb0007
      worin
      • V entweder zweiwertig ist und für 0, S, NH oder CH2 steht oder dreiwertig ist und für N oder CH steht,
      • W für eine gesättigte oder ungesättigte Alkylenkette mit 2 oder 3 C-Atomen steht
      • under der Ring @ eine, zwei oder drei Doppelbindungen enthalten kann,

      bedeuten, sowie ihre Säureadditionssalze und Verfahren zu ihrer Herstellung.
The present invention relates to new 2-piperazinotetralins of the formula I.
Figure imgb0001
 wherein
  • R 1 is hydroxy, alkoxy with 1-4 C atoms, alkanoyloxy with 1-20 C atoms or one
    Figure imgb0002
    • R 4 and R 5 independently of one another hydrogen, fluorine, chlorine, bromine, iodine, alkyl with 1-4 C atoms or alkoxy with 1-4 C atoms or
    • R 4 and R 5 together form a methylenedioxy group on adjacent C atoms,
  • R 2 and R 3 are independently hydrogen,

Hydroxy, alkoxy with 1-4 C atoms, alkanoyloxy with 1-20 C atoms or one
Figure imgb0003
 or
  • R 1 and R 2 together form a methylenedioxy group on adjacent C atoms,
    • A a) one
      Figure imgb0004
       X, Y and Z independently of one another are hydrogen, hydroxy, alkyl having 1-4 C atoms, alkoxy having 1-4 C atoms, alkanoyloxy having 1-20 C atoms, one
      Figure imgb0005
       Bromine, iodine, CF 3 , SH, alkylthio with 1-4 C atoms or alkanoylthio with 1-20 C atoms or X and Y together on adjacent C atoms - a methylenedioxy group, D 0 or S
    • legs
      Figure imgb0006
    • c) a five or six ring of the formula
      Figure imgb0007
       wherein
      • V is either divalent and represents 0, S, NH or CH 2 or is trivalent and represents N or CH,
      • W stands for a saturated or unsaturated alkylene chain with 2 or 3 carbon atoms
      • the ring @ can contain one, two or three double bonds,

      mean, and their acid addition salts and processes for their preparation.

Die Verbindungen der Formel I können in Form von Enantiomeren oder in Form von Racematen auftreten.The compounds of the formula I can occur in the form of enantiomers or in the form of racemates.

In der obigen Formel können alle Alkyl-, Alkoxy- und Alkanoylgruppen geradkettig oder verzweigt sein.

  • R1, R2 und R3 stehen als Alkoxygruppen bevorzugt für die Methoxygruppe.
  • R1 steht vorzugsweise für die freie OH-Gruppe oder für eine Alkoxygruppe, besonders für die freie OH-Gruppe.
In the above formula, all of the alkyl, alkoxy and alkanoyl groups can be straight or branched.
  • R 1 , R 2 and R 3 as alkoxy groups are preferably the methoxy group.
  • R 1 preferably represents the free OH group or an alkoxy group, especially the free OH group.

Der Rest R1 befindet sich vorzugsweise in Stellung 6 des Tetralinringes.

  • R2 und R3 bedeuten vorzugsweise Wasserstoff oder die freie OH-Gruppe, besonders Wasserstoff.
  • X, Y und Z stehen als Alkylreste bevorzugt für die Methylgruppe, als Alkoxygruppe für die Methoxygruppe.
The rest R 1 is preferably in position 6 of the tetralin ring.
  • R 2 and R 3 are preferably hydrogen or the free OH group, especially hydrogen.
  • X, Y and Z preferably stand for the methyl group as alkyl radicals and for the methoxy group as alkoxy group.

Der Rest X steht vorzugsweise für eine Alkoxy- oder eine Alkylgruppe, die Reste Y und Z für Wasserstoff, Hydroxy- oder Alkoxygruppen.

  • X steht bevorzugt in Stellung 2 des Phenylrestes.
  • A hat vorzugsweise die unter a) angegebenen Bedeutungen.
The radical X preferably represents an alkoxy or an alkyl group, the radicals Y and Z represent hydrogen, hydroxyl or alkoxy groups.
  • X is preferably in position 2 of the phenyl radical.
  • A preferably has the meanings given under a).

Die Substituenten R4 und R5 können in den Resten Rl, R2, R3, X, Y und Z unabhängig voneinander die obenerwähnten Bedeutungen haben.The substituents R 4 and R 5 in the radicals R 1, R 2 , R 3 , X, Y and Z can independently of one another have the meanings mentioned above.

Erfindungsgemäss gelangt man

  • a) zu den Verbindungen der Formel la und ihren Säureadditionssalzen
    Figure imgb0008
    worin
    • R; für eine Alkoxygruppe mit 1-4 C-Atomen und
    • R'2 und R'3 unabhängig voneinander für Wasserstoff oder eine Alkoxygruppe mit 1―4 C-Atomen oder
    • R'1 und R'2 zusammen für eine ―O―CH2―O―Gruppe stehen und
    • A' die gleichen Bedeutungen wie A, mit Ausnahme des durch mindestens eine Alkanoyloxy-, Alkanoylthio- oder
      Figure imgb0009
    • substituierten Phenylrestes, hat, indem man Verbindungen der Formel II
      Figure imgb0010
      reduziert,
  • b) zu den Verbindungen der Formel Ib und ihren Säureadditionssalzen
    Figure imgb0011
    worin
    • R"2 , und R"3 unabhängig voneinander für Wasserstoff oder Hydroxy und
    • A" für eine
      Figure imgb0012
      Gruppe, worin
    • X', Y' und Z' unabhängig voneinander Wasserstoff, Hydroxy, Alkyl mit 1-4 C-Atomen, Fluor,
    • Chlor, Brom, Jod, CF3 oder SH bedeuten,

    oder für eine der oben unter b) und c) angegebenen Bedeutungen für A
    stehen, indem man Verbindungen der Formel la einer Aetherspaltung unterwirft,
  • c) zu den Verbindungen der Formel Ic und ihren Säureadditionssalzen
    Figure imgb0013
    worin
    • R'" 1 für Hydroxy oder Alkoxy mit 1-4 C-Atomen,
    • R"'2 und R"'3 unabhängig voneinander für Wasserstoff, Hydroxy oder Alkoxy mit 1―4 C-Atomen stehen, indem man Verbindungen der Formel III
      Figure imgb0014
      mit Verbindungen der Formel IV
      Figure imgb0015
      worin
    • Q und Q' für den Säurerest eines reaktiven Esters

    stehen, kondensiert,
  • d) zu den Verbindungen der Formel I, worin mindestens einer der Substituenten R1, R2, R3, X, Y oder Z für eine Alkanoyloxy- oder
    Figure imgb0016
    - Gruppe und/oder einer der Substituenten X, Y oder Z für eine Alkanoylthio- oder
    Figure imgb0017
    Gruppe steht, und ihren Säureadditionssalzen, indem man Verbindungen der Formel I, worin mindestens einer der Substituenten R1, R2, R3, X, Y oder Z für eine freie OH-Gruppe und/oder einer der Substituenten X, Y oder Z für eine freie SH-Gruppe steht, mit einem reaktiven Derivat einer Alkancarbonsäure mit 1-20 C-Atomen oder einer aromatischen Carbonsäure der Formel
    Figure imgb0018
    acyliert und die erhaltenen Verbindungen der Formel 1 gegebenenfalls in ihre Säureadditionssalze überführt.
According to the invention one arrives
  • a) to the compounds of formula la and their acid addition salts
    Figure imgb0008
     wherein
    • R; for an alkoxy group with 1-4 C atoms and
    • R ' 2 and R' 3 independently of one another for hydrogen or an alkoxy group with 1―4 C atoms or
    • R ' 1 and R' 2 together represent a ―O ― CH 2 ―O ― group and
    • A 'has the same meanings as A, with the exception of at least one alkanoyloxy, alkanoylthio or
      Figure imgb0009
    • substituted phenyl radical, by using compounds of the formula II
      Figure imgb0010
       reduced,
  • b) to the compounds of formula Ib and their acid addition salts
    Figure imgb0011
     wherein
    • R " 2 , and R" 3 independently of one another for hydrogen or hydroxy and
    • A "for one
      Figure imgb0012
       Group in which
    • X ', Y' and Z 'independently of one another hydrogen, hydroxy, alkyl with 1-4 C atoms, fluorine,
    • Are chlorine, bromine, iodine, CF 3 or SH,

    or for one of the meanings given under b) and c) for A
    stand by subjecting compounds of the formula la to ether cleavage,
  • c) to the compounds of formula Ic and their acid addition salts
    Figure imgb0013
     wherein
    • R '" 1 for hydroxy or alkoxy with 1-4 C atoms,
    • R "' 2 and R"' 3 independently of one another represent hydrogen, hydroxy or alkoxy having 1―4 C atoms by using compounds of the formula III
      Figure imgb0014
       with compounds of formula IV
      Figure imgb0015
      wherein
    • Q and Q 'for the acid residue of a reactive ester

    standing, condensed,
  • d) to the compounds of formula I, wherein at least one of the substituents R 1 , R 2 , R 3 , X, Y or Z is an alkanoyloxy or
    Figure imgb0016
     - Group and / or one of the substituents X, Y or Z for an alkanoylthio or
    Figure imgb0017
     Group, and their acid addition salts, by compounds of formula I, wherein at least one of the substituents R 1 , R 2 , R 3 , X, Y or Z is a free OH group and / or one of the substituents X, Y or Z stands for a free SH group, with a reactive derivative of an alkane carboxylic acid having 1-20 C atoms or an aromatic carboxylic acid of the formula
    Figure imgb0018
     acylated and the compounds of formula 1 obtained optionally converted into their acid addition salts.

Die erfindungsgemäss erhaltenen Verbindungen der Formel I können in Form der freien Basen oder ihrer Säureadditionssalze vorliegen. Die freien Basen können auf an sich bekannte Weise in ihre Säureadditionssalze überführt werden und umgekehrt. So können die erfindungsgemässen Verbindungen der Formel I z.B. mit anorganischen Säuren wie Chlorwasserstoffsäure oder mit organischen Säuren wie Maleinsäure Säureadditionssalze bilden.The compounds of the formula I obtained according to the invention may be in the form of the free bases or their acid addition salts. The free bases can be converted into their acid addition salts in a manner known per se and vice versa. Thus the compounds of formula I according to the invention can e.g. form acid addition salts with inorganic acids such as hydrochloric acid or with organic acids such as maleic acid.

Das Verfahren a) kann in an sich bekannter Weise durchgeführt werden, z.B. durch katalytische Hydrierung. Geeignete Katalysatoren umfassen Palladium-Kohle, Platin oder Raney-Nickel vorzugsweise Palladium-Kohle. Zweckmässigerweise wird ein inertes organisches Lösungsmittel, z.B. Aethanol oder Dimethylformamid, verwendet. Die Reduktion kann auch mit komplexen Metallhydriden, z.B. Natriumborhydrid, in einem organischen Lösungsmittel wie Trifluoressigsäure durchgeführt werden. Das Verfahren wird zweckmässigerweise bei Temperaturen zwischen 10 und 50°C, vorzugsweise 20 und 30°C, durchgeführt.Process a) can be carried out in a manner known per se, e.g. by catalytic hydrogenation. Suitable catalysts include palladium-carbon, platinum or Raney nickel, preferably palladium-carbon. An inert organic solvent, e.g. Ethanol or dimethylformamide. The reduction can also be carried out with complex metal hydrides, e.g. Sodium borohydride, in an organic solvent such as trifluoroacetic acid. The process is expediently carried out at temperatures between 10 and 50 ° C., preferably 20 and 30 ° C.

Das Verfahren b) kann in einer für die Spaltung von Aethern bekannten Weise durchgeführt werden. Die Spaltung erfolgt zweckmässigerweise durch Einwirkung von abspaltenden Agentien, beispielsweise Jodwasserstoffsäure, Bromwasserstoffsäure oder Chlorwasserstoffsäure, vorzuasweise in Wasser oder Essigsäure, zweckmässigerweise bei Temperaturen von 0 bis 100°, oder Bortribromid, vorzugsweise in Methylenchlorid, zweckmässigerweise von 0 bis 50°C. Bei Verwendung von Chlorwasserstoff arbeitet man vorzugsweise bei einem Druck von 1 bis 10 Atm. Falls X, Y oder Z für Alkoxygruppen in den Stellungen 2 und 6 des Phenylringes stehen, bleiben diese bei Verwendung von Halogenwasserstoffsäuren grösstenteils erhalten und werden nicht zu freien OH-Gruppen umgesetzt.Process b) can be carried out in a manner known for the cleavage of ethers. The cleavage is advantageously carried out by the action of cleaving agents, for example hydroiodic acid, hydrobromic acid or hydrochloric acid, preferably in water or acetic acid, advantageously at temperatures from 0 to 100 °, or boron tribromide, preferably in methylene chloride, advantageously from 0 to 50 ° C. When using hydrogen chloride, the pressure is preferably from 1 to 10 atm. If X, Y or Z are alkoxy groups in positions 2 and 6 of the phenyl ring, these are largely retained when using hydrohalic acids and are not converted to free OH groups.

Die Kondensation c) kann nach an sich für die Herstellung des Piperazinringes bekannten Methoden erfolgen. Vorzugsweise werden die Verbindungen III und IV in einem inerten Lösungsmittel bei Temperaturen zwischen 60 und 120° erhitzt. Als Lösungsmittel verwendet man vorteilhafterweise Aethanol, Dimethylformamid oder höhere Alkohole. Die Kondensation kann in Gegenwart eine Base, z.B. tert. Amin oder Alkalicarbonat, durchgeführt werden. Die Reste Q und Q' stehen vorzugsweise für Chlor, Brom, Jod, eine Alkylsulfonyloxy- oder Arylsulfonyloxygruppe.The condensation c) can be carried out according to methods known per se for the production of the piperazine ring. The compounds III and IV are preferably heated in an inert solvent at temperatures between 60 and 120 °. The solvent used is advantageously ethanol, dimethylformamide or higher alcohols. The condensation can in the presence of a base, e.g. tert. Amine or alkali carbonate. The radicals Q and Q 'are preferably chlorine, bromine, iodine, an alkylsulfonyloxy or arylsulfonyloxy group.

Das Verfahren d) kann in einer für die Acylierung von Phenolen bekannten Weise durchgeführt werden. Als reaktive Derivate der Carbonsäuren können beispielsweise Säurehalogenide oder Säureanhydride verwendet werden.Process d) can be carried out in a manner known for the acylation of phenols. Acid halides or acid anhydrides, for example, can be used as reactive derivatives of the carboxylic acids.

Die Verbindungen der Formel können in an sich bekannter Weise isoliert und gereinigt werden.The compounds of the formula can be isolated and purified in a manner known per se.

Die optisch aktiven Verbindungen der Formel I können z.B. ausgehend von optisch aktiven Ausgangsprodukten (hergestellt nach an sich für die Spaltung von Racematen üblichen Methoden) erhalten werden.The optically active compounds of formula I can e.g. starting from optically active starting materials (prepared by methods customary per se for the cleavage of racemates).

Zu den Verbindungen der Formel II kann man gelangen, indem man beispielsweise Verbindungen der Formel V

Figure imgb0019
mit Verbindungen der Formel VI
Figure imgb0020
umsetzt.The compounds of formula II can be obtained by, for example, compounds of formula V
Figure imgb0019
 with compounds of formula VI
Figure imgb0020
 implements.

Die Umsetzung kann in an sich bekannter Weise durchgeführt werden. Beispielsweise kann die Umsetzung in einem inerten Lösungsmittel, z.B. Toluol, in Gegenwart katalytischer Mengen von p-Toluolsulfonsäure unter Wasserabscheidung, zweckmässigerweise bei Rückflusstemperatur des verwendeten Lösungsmittels oder in Gegenwart katalytischer Mengen einer Lewis-Säure, z.B. Titantetrachlorid, zweckmässigerweise zwischen 20 und 100°, erfolgen.The reaction can be carried out in a manner known per se. For example, the reaction can be carried out in an inert solvent, e.g. Toluene, in the presence of catalytic amounts of p-toluenesulfonic acid with water separation, suitably at the reflux temperature of the solvent used or in the presence of catalytic amounts of a Lewis acid, e.g. Titanium tetrachloride, conveniently between 20 and 100 °.

Die so erhalten Verbindungen der Formel II können ohne Isolierung direkt zu Verbindungen der Formel la der Reduktion in situ unterworfen werden.The compounds of the formula II obtained in this way can be subjected directly to compounds of the formula Ia for reduction in situ without isolation.

Die Umsetzung von Verbindungen der Formel V mit Verbindungen der Formel VI kann jedoch direkt zu Verbindungen der Formel la führen, falls man die Umsetzung unter reduzierenden Bedingungen durchführt. Als Reduktionsmittel kann z.B. Wasserstoff in Gegenwart von Katalysatoren wie Raney-Nickel, Platin oder Palladium-Kohle verwendet werden. Das Verfahren wird zweckmässigerweise in einem Lösungsmittel, z.B. Essigsäure, bei Zimmertemperatur durchgeführt.However, the reaction of compounds of the formula V with compounds of the formula VI can lead directly to compounds of the formula Ia if the reaction is carried out under reducing conditions. As a reducing agent e.g. Hydrogen can be used in the presence of catalysts such as Raney nickel, platinum or palladium-carbon. The process is conveniently carried out in a solvent, e.g. Acetic acid, carried out at room temperature.

Die Verbindungen der Formeln III, IV, V und VI sind entweder bekannt oder können in an sich bekannter Weise hergestellt werden.The compounds of the formulas III, IV, V and VI are either known or can be prepared in a manner known per se.

Die Verbindungen der Formel I zeichnen sich durch interessante pharmakodynamische Eigenschaften aus.The compounds of formula I are distinguished by interesting pharmacodynamic properties.

Sie zeigen am narkotisierten Hund eine Blutdrucksenkung und Steigerung der Durchblutung in der Arteria mesenterica, charakteristisch für Dopaminrezeptorenstimulation. Die Verbindungen der Formel 1 können daher zur Behandlung der Hypertonie verwendet werden. Die zu verwendenden Dosen variien naturgemäss je nach Art der Substanz, der Administration und des zu behandelnden Zustandes. Bei grösseren Säugetieren ist eine täglich zu verabreichende Menge zwischen 15 und 1000 mg angezeigt. Diese Dosis kann auch in kleineren Dosen 2-4 mal täglich oder in Retardform verabreicht werden. Eine Einheitsdosis, beispielsweise eine zur oralen Verabreichung geeignete Tablette, kann zwischen 4 und 500 mg des Wirkstoffes zusammen mit geeigneten pharmazeutisch indifferenten Hilfsstoffen enthalten.In anesthetized dogs, they show a decrease in blood pressure and an increase in blood flow in the arteria mesenterica, characteristic of dopamine receptor stimulation. The compounds of formula 1 can therefore be used to treat hypertension. The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. For larger mammals, a daily dose of between 15 and 1000 mg is indicated. This dose can also be administered in smaller doses 2-4 times a day or in sustained release. A unit dose, for example a tablet suitable for oral administration, can contain between 4 and 500 mg of the active ingredient together with suitable pharmaceutically indifferent auxiliaries.

Die Erfindung betrifft auch Heilmittel, die eine Verbindung der Formel enthalten. Diese Heilmittel, beispielsweise eine Lösung oder eine Tablette, können nach bekannten Methoden, unter Verwendung der üblichen Hilfs- und Trägerstoffe, hergestellt werden.The invention also relates to medicaments which contain a compound of the formula. These remedies, for example a solution or a tablet, can be prepared by known methods using the customary auxiliaries and carriers.

In einer Gruppe der erfindungsgemässen Verbindungen bedeuten

  • R1 Hydroxy, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-4 C-Atomen oder Benzoyloxy,
  • R2 und R3 unabhängig voneinander Wasserstoff, Hydroxy, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-4 C-Atomen oder Benzoyloxy oder
  • R1 und R2 an benachbarten C-Atomen zusammen eine Methylendioxygruppe,
  • A eine
    Figure imgb0021
    • X, Y und Z unabhängig voneinander Wasserstoff, Hydroxy, Alkyl mit 1―4 C-Atomen, Alkoxy mit 1-4. C-Atomen, Alkanoyloxy mit 1-4 C-Atomen, Benzoyloxy, Fluor, Chlor oder CF3 oder X und Y an benachbarten C-Atomen zusammen eine Methylendioxygruppe.

    In einer zweiten Gruppe bedeuten
  • R1 Hydroxy, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-20 C-Atomen oder eine
    Figure imgb0022
  • R4 und Rs unabhängig voneinander Wasserstoff, Fluor, Chlor, Brom, Jod, Alkyl mit 1-4 C-Atomen oder Alkoxy mit 1-4 C-Atomen oder
  • R4 und R5 an benachbarten C-Atomen zusammen eine Methylendioxygruppe,
  • R2 und R3 unabhängig voneinander Wasserstoff, Hydroxy, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-20 C-Atomen oder eine
    Figure imgb0023
    oder
  • R1 und R2 an benachbarten C-Atomen zusammen eine Methylendioxygruppe,
  • A eine
    Figure imgb0024
    • X, Y und Z unabhängig voneinander Wasserstoff, Hydroxy, Alkyl mit 1-4 C-Atomen, Alkoxy mit 1-4 C-Atomen, Alkanoyloxy mit 1-20 C-Atomen, eine
      Figure imgb0025
      CF3, SH oder Alkylthio mit 1-4 C-Atomen oder
    • X und Y an benachbarten C-Atomen zusammen eine Methylendioxygruppe.
Mean in a group of the compounds according to the invention
  • R 1 is hydroxy, alkoxy with 1-4 C atoms, alkanoyloxy with 1-4 C atoms or benzoyloxy,
  • R 2 and R 3 independently of one another hydrogen, hydroxy, alkoxy with 1-4 C atoms, alkanoyloxy with 1-4 C atoms or benzoyloxy or
  • R 1 and R 2 together form a methylenedioxy group on adjacent C atoms,
  • A a
    Figure imgb0021
    • X, Y and Z independently of one another hydrogen, hydroxy, alkyl with 1 mit4 C atoms, alkoxy with 1-4. C atoms, alkanoyloxy with 1-4 C atoms, benzoyloxy, fluorine, chlorine or CF 3 or X and Y on adjacent C atoms together form a methylenedioxy group.

    Mean in a second group
  • R 1 is hydroxy, alkoxy with 1-4 C atoms, alkanoyloxy with 1-20 C atoms or one
    Figure imgb0022
  • R 4 and R s independently of one another hydrogen, fluorine, chlorine, bromine, iodine, alkyl with 1-4 C atoms or alkoxy with 1-4 C atoms or
  • R 4 and R 5 together form a methylenedioxy group on adjacent C atoms,
  • R 2 and R 3 independently of one another hydrogen, hydroxy, alkoxy with 1-4 C atoms, alkanoyloxy with 1-20 C atoms or one
    Figure imgb0023
     or
  • R 1 and R 2 together form a methylenedioxy group on adjacent C atoms,
  • A a
    Figure imgb0024
    • X, Y and Z independently of one another are hydrogen, hydroxy, alkyl having 1-4 C atoms, alkoxy having 1-4 C atoms, alkanoyloxy having 1-20 C atoms, one
      Figure imgb0025
       CF 3 , SH or alkylthio with 1-4 carbon atoms or
    • X and Y together form a methylenedioxy group on adjacent C atoms.

In den nachfolgenden Beispielen erfolgen alle Temperaturangaben in Celsiusgraden.In the following examples, all temperatures are given in degrees Celsius.

BEISPIEL 1EXAMPLE 1 1,2,3,4-Tetrahydro-6-methoxy-2-[4-(2-methylphenyl)-1-piperazinyl]-naphthalin1,2,3,4-tetrahydro-6-methoxy-2- [4- (2-methylphenyl) -1-piperazinyl] naphthalene

6 g Methoxy-2-tetralon werden zusammen mit 6 g N-(o-Tolyl)-piperazin unter Erwärmen in 100 ml Toluol gelöst, 300 mg p-Toluolsulfonsäure zugefügt und die Lösung während 24 Stunden am Rückfluss erhitzt, wobei das Wasser mit einer Dean-Stark-Falle abgetrennt wird. Das Reaktionsgemisch wird sodann zur Trockne eingedampft, das erhaltene 3,4-Dihydro-6-methoxy-2-[4-(2-methylphenyl)-1-piperazinylJ-naphthalin mit 200 ml Dimethylformamid und 300 mg 10%-igem Palladium-Kohle-Katalysator versetzt und bei Normaldruck hydriert. Nach beendeter Wasserstoffaufnahme wird der Katalysator abfiltriert, das Lösungsmittel abgedampft und der Rückstand an Kieselgel mit Methylenchlorid/Methanol (99 : 1) chromatographiert. Man erhält die Titelverbindung als Festkörper, dessen Hydrochlorid bei 286-288° schmilzt.6 g of methoxy-2-tetralone are dissolved together with 6 g of N- (o-tolyl) piperazine with heating in 100 ml of toluene, 300 mg of p-toluenesulfonic acid are added and the solution is heated under reflux for 24 hours, the water being heated with a Dean Stark trap is disconnected. The reaction mixture is then evaporated to dryness, the 3,4-dihydro-6-methoxy-2- [4- (2-methylphenyl) -1-piperazinylJ-naphthalene obtained with 200 ml of dimethylformamide and 300 mg of 10% palladium-carbon -Catalyst added and hydrogenated at normal pressure. When the uptake of hydrogen has ended, the catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel with methylene chloride / methanol (99: 1). The title compound is obtained as a solid, the hydrochloride of which melts at 286-288 °.

BEISPIEL 2EXAMPLE 2 1,2,3,4-Tetrahydro-6-methoxy-2-[4-(2-methyl-phenyl)-1-piperazinyl]-naphthalin1,2,3,4-tetrahydro-6-methoxy-2- [4- (2-methylphenyl) -1-piperazinyl] naphthalene

3,6 g 6-Methoxy-2-tetralon werden zusammen mit 3,9 g N-(o-Tolyl)-piperazin in 50 ml Essigsäure gelöst, mit 1 g 10%-igem Palladium-Kohle-Katalysator versetzt und hydriert. Nach beendeter Wasserstoffaufnahme wird der Katalysator abfiltriert, das Lösungsmittel abgedampft und der Rückstand analog Beispiel 1 an Kieselgel chromatographiert. Man erhält die Titelverbindung als Festkörper, dessen Hydrochlorid bei 286-288° schmilzt.3.6 g of 6-methoxy-2-tetralone are dissolved together with 3.9 g of N- (o-tolyl) piperazine in 50 ml of acetic acid, mixed with 1 g of 10% palladium-carbon catalyst and hydrogenated. When the uptake of hydrogen has ended, the catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel as in Example 1. The title compound is obtained as a solid, the hydrochloride of which melts at 286-288 °.

BEISPIEL 3EXAMPLE 3 1,2,3,4-Tetrahydro-6-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]-naphthalin1,2,3,4-tetrahydro-6-hydroxy-2- [4- (2-methylphenyl) -1-piperazinyl] naphthalene

10 g. 1,2,3,4-Tetrahydro-6-methoxy-2-[4-(2-methylphenyl)-1-piperazinyl]-naphthalin werden in 200 ml 4796-iger wässriger Bromwasserstoffsäure suspendiert und unter Stickstoff während 3 Stunden am Rückfluss erhitzt. Die Bromwasserstoffsäure wird anschliessend abgedampft, das als Hydrobromid anfallende kristalline Produkt durch Extraktion mit 1 n wässriger Natriumbicarbonatlösung/Methylenchlorid in die freie Base überführt und diese aus Acetonitril umkristallisiert. Die als Festkörper erhaltene Titelverbindung schmilzt bei 177-179°, deren Hydrochlorid bei 304-306°C.10 g. 1,2,3,4-tetrahydro-6-methoxy-2- [4- (2-methylphenyl) -1-piperazinyl] -naphthalene are described in 200 ml of 4796 aqueous hydrobromic acid suspended and heated under reflux under nitrogen for 3 hours. The hydrobromic acid is then evaporated off, and the crystalline product obtained as the hydrobromide is converted into the free base by extraction with 1N aqueous sodium bicarbonate solution / methylene chloride and this is recrystallized from acetonitrile. The title compound obtained as a solid melts at 177-179 °, its hydrochloride at 304-306 ° C.

BEISPIEL 4EXAMPLE 4 1,2,3,4-Tetrahydro-6-hydroxy-2-[4-(2-methoxy-phenyl)-1-piperazinyl]-naphthalin1,2,3,4-tetrahydro-6-hydroxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] naphthalene

2,48 g N,N-Di(2-chloräthyl)-2-methoxyanilin werden zusammen mit 1,63 g 2-Amino-1,2,3,4-tetrahydro-6-hydroxynaphthalin in 100 ml Aethanol gelöst und anschliessend während 20 Stunden am Rückfluss gekocht. Das Lösungsmittel wird abgedampft und der Rückstand aus Methanol/Aether umkristallisiert. Man erhält die Titelverbindung in Form ihres Hydrochlorids, das bei 282-286° schmilzt.2.48 g of N, N-di (2-chloroethyl) -2-methoxyaniline are dissolved together with 1.63 g of 2-amino-1,2,3,4-tetrahydro-6-hydroxynaphthalene in 100 ml of ethanol and then during Cooked at reflux for 20 hours. The solvent is evaporated off and the residue is recrystallized from methanol / ether. The title compound is obtained in the form of its hydrochloride, which melts at 282-286 °.

BEISPIEL 5EXAMPLE 5 1,2,3,4-Tetrahydro-6-acetoxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-naphthalin1,2,3,4-tetrahydro-6-acetoxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] naphthalene

170 mg 1,2,3,4-Tetrahydro-6-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-naphthalin werden in 2 ml Pyridin vorgelegt, 70µl Essigsäureanhydrid unter Rühren zugetropft und die Lösung während 3 Stunden bei Zimmertemperatur stehen gelassen. Die Reaktionslösung wird anschliessend zur Trockene eingeengt, der Rückstand in Essigester aufgenommen, mit 1 n Natriumcarbonatlösung gewaschen, getrocknet und zur Trockene eingedampft. Die so erhaltene rohe Titelverbindung wird anschliessend ins Hydrochlorid überführt, welches, nach Umkristallisation aus Methanol/Aether, bei 249―253° schmilzt.170 mg of 1,2,3,4-tetrahydro-6-hydroxy-2- [4- (2-methoxyphenyl) -1-piperazinyl] naphthalene are placed in 2 ml of pyridine, 70 μl of acetic anhydride are added dropwise with stirring and the solution is added for 3 Let stand at room temperature for hours. The reaction solution is then evaporated to dryness, the residue is taken up in ethyl acetate, washed with 1N sodium carbonate solution, dried and evaporated to dryness. The crude title compound thus obtained is then converted into the hydrochloride which, after recrystallization from methanol / ether, melts at 249-253 °.

BEISPIEL 6EXAMPLE 6 (+- bzw. (-)-1,2,3,4-Tetrahydro-6-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]-naphthalin(+ - or (-) - 1,2,3,4-tetrahydro-6-hydroxy-2- [4- (2-methylphenyl) -1-piperazinyl] naphthalene a) (+)- bzw. (-)-2-Amino-1,2,3,4-tetrahydro-6-methoxy-naphthalina) (+) - or (-) - 2-amino-1,2,3,4-tetrahydro-6-methoxy-naphthalene

Zu einer Lösung von 55 g 2-Amino-1,2,3,4-tetrahydro-6-methoxy-naphthalin in 650 ml Methanol werden unter Rühren 47 g D-(-)-Mandelsäure, gelöst in 650 ml Methanol, zugetropft. Die entstandene Reaktionslösung wird während 3 Stunden bei Zimmertemperatur stehen gelassen, das ausgefallene Kristallisat abfiltriert, mit Aether gewaschen und getrocknet. Das so erhaltene (-)-Mandelsäure-Salz wird nun aus heissem Methanol umkristallisiert und der Vorgang wiederholt, bis eine Probe des jeweils durch Extraktion mit 1 n Natriumcarbonatlösung/Methylenchlorid aus dem Mandelsäuresalz freigesetzten Amins einen konstanten Drehwert aufweist. Der so erhaltene freigesetzte (+)-Antipode der Titelverbindung wird ins Hydrochlorid überführt, das aus Methanol umkristallisiert, bei 262-264° schmilzt.

Figure imgb0026
(c = 1 in Methanol)47 g of D - (-) - mandelic acid, dissolved in 650 ml of methanol, are added dropwise to a solution of 55 g of 2-amino-1,2,3,4-tetrahydro-6-methoxy-naphthalene in 650 ml of methanol with stirring. The resulting reaction solution is left to stand at room temperature for 3 hours, the precipitated crystals are filtered off, washed with ether and dried. The (-) - mandelic acid salt thus obtained is then recrystallized from hot methanol and the process repeated until a sample of the amine released from the mandelic acid salt by extraction with 1N sodium carbonate solution / methylene chloride has a constant rotation value. The released (+) - antipode of the title compound thus obtained is converted into the hydrochloride, which recrystallizes from methanol and melts at 262-264 °.
Figure imgb0026
 (c = 1 in methanol)

Aus der 1. Mutterlauge des oben beschriebenen (-)-Mandelsäuresalzes wird das Amin durch Extraktion mit 1 n Natriumcarbonatlösung/Methylenchlorid freigesetzt und unter Verwendung von (+)-Mandelsäure, analog dem für (-)-Mandelsäure beschriebenen Verfahren, der (-)-Antipode der Titelverbindung hergestellt, dessen Hydrochlorid, nach Umkristallisation aus Methanol, bei 263-265° schmilzt.
[α]20 D = -78,6° (c = 1 in Methanol)The amine is released from the 1st mother liquor of the (-) - mandelic acid salt described above by extraction with 1N sodium carbonate solution / methylene chloride and using (+) - mandelic acid, analogously to the process described for (-) - mandelic acid, the (-) -Antipode of the title compound prepared, the hydrochloride, after recrystallization from methanol, melts at 263-265 °.
[α] 20 D = -78.6 ° (c = 1 in methanol)

b) (+)- bzw. (-)-2-Amino-1,2,3,4-tetrahydro-6-hydroxynaphthalinb) (+) - or (-) - 2-amino-1,2,3,4-tetrahydro-6-hydroxynaphthalene

Das oben beschriebene (+)-2-Amino-1,2,3,4-tetrahydro-6-methoxynaphthalin wird durch Aetherspaltung analog Verfahren b) in die entsprechende Hydroxyverbindung überführt, in das Hydrochlorid umgewandelt und letzteres aus Methanol umkristallisiert. Man erhält so den (+)-Antipoden der Titelverbindung.The (+) - 2-amino-1,2,3,4-tetrahydro-6-methoxynaphthalene described above is converted into the corresponding hydroxy compound by ether cleavage analogously to process b), converted into the hydrochloride and the latter recrystallized from methanol. The (+) - antipode of the title compound is thus obtained.

Smp. 276―278°

Figure imgb0027
(c = 1 in Methanol)M.p. 276-278 °
Figure imgb0027
 (c = 1 in methanol)

In entsprechender Weise, unter Verwendung von (-)-2-Amino-1,2,3,4-tetrahydro-6-methoxy- naphthalin, erhält man den (-)-Antipoden der Titvelverbindung.In a corresponding manner, using (-) - 2-amino-1,2,3,4-tetrahydro-6-methoxynaphthalene, the (-) - antipode of the Titvel compound is obtained.

Smp. 276-278° [α] DZU D = -83,0° (c = 1 in MethanolMp 276-278 ° [α] D ZU D = -83.0 ° (c = 1 in methanol

c) (+)- bzw. (-)-1,2,3,4-Tetrahydro-6-hydroxy-2-(4-(2-methylphenyl)-1-piperazinylJ-naphthalinc) (+) - or (-) - 1,2,3,4-tetrahydro-6-hydroxy-2- (4- (2-methylphenyl) -1-piperazinylJ-naphthalene

Ausgehend von (+)-2-Amino-1,2,3,4-tetrahydro-6-hydroxynaphthalin erhält man durch Kondensation mit N,N-Di(2-chloräthyl)-2-methylanilin, entsprechend Verfahren c), und anschliessender Umkristallisation des Produktes aus Acetonitril den (+)-Antipoden der Titelverbindung.Starting from (+) - 2-amino-1,2,3,4-tetrahydro-6-hydroxynaphthalene, condensation with N, N-di (2-chloroethyl) -2-methylaniline is obtained in accordance with process c) and then Recrystallization of the product from acetonitrile the (+) - antipode of the title compound.

Smp. 147-149° [α]20 D = +49,7° (c = 1 in Methanol).Mp 147-149 ° [α] 20 D = + 49.7 ° (c = 1 in methanol).

Entsprechend gelangt man, ausgehend von (-)-2-Amino-1,2,3,4-tetrahydro-6-hydroxynaphthalin, zum (-)-Antipoden der Titelverbindung.Correspondingly, starting from (-) - 2-amino-1,2,3,4-tetrahydro-6-hydroxynaphthalene, the (-) - antipode of the title compound is obtained.

Smp. 146-148° [α]20 D = -50,3° (c = 1 in Methanol)Mp 146-148 ° [α] 20 D = -50.3 ° (c = 1 in methanol)

Analog zu den Beispielen 1), 3) und 4) wurden aus den entsprechenden Ausgangsprodukten die nachfolgenden Verbindungen der Tabellen I und II hergestellt.

Figure imgb0028
Figure imgb0029
Figure imgb0030
 Analogously to Examples 1), 3) and 4), the following compounds of Tables I and II were prepared from the corresponding starting products.
Figure imgb0028
Figure imgb0029
Figure imgb0030

Claims (13)

1. New compounds of formula I,
Figure imgb0079
wherein R1 is hydroxy, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 20 carbon atoms or a
Figure imgb0080
wherein
R4 and R5 are, independently, hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or
R4 and R5 together are a methylenedioxy group and are bonded to adjacent carbon atoms,
R2 and R3 are, independently, hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 20 carbon atoms or a
Figure imgb0081
or
R1 and R2 together are a methylenedioxy group and are bonded to adjacent carbon atoms,
A is
a) a
Figure imgb0082
group, wherein
X, Y and Z are, independently, hydrogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 20 carbon atoms, a
Figure imgb0083
chlorine, bromine, iodine, CF3, SH, alkylthio of 1 to 4 carbon atoms or alkanoylthio of 1 to 20 carbon atoms, or
X and Y together are methylenedioxy and are bonded to adjacent carbon atoms,
D is 0 or S
b) a
Figure imgb0084
group,
c) a five or six membered ring of formula
Figure imgb0085
wherein
V is either divalent and signifies 0, S, NH or CH2 or trivalent and signifies N or CH, W is a saturated or unsaturated alkylene chain of 2 or 3 carbon atoms
and ring B can contain 1, 2 or 3 double bonds, and their acid addition salts.
2. Compounds according to claim 1 wherein R, is a hydroxyl group.
3. Compounds according to claim 1 or 2 wherein R1 is located at position 6.
4. Compounds according to claim 1, 2 or 3 wherein R2 and R3 are hydrogen.
5. Compounds according to any one of claims 1 to 4 wherein A signifies a group
Figure imgb0086
6. Compounds according to any one of claims 1 to 5 wherein X is alkyl or alkoxy.
7. Compounds according to any one of claims 1 to 6 wherein X is in position 2 of the phenyl radical.
8. 1,2,3,4-tetrahydro-6-hydroxy-2-[4-(2-methylphenyl)piperazinyl-1]naphthalene and its acid addition salts.
9. 1,2,3,4-tetrahydro-6-hydroxy-2-[4-(2-methoxyphenyl)piperazinyi-1 ]naphthalene and its acid addition salts.
10. Compounds of claim 1 wherein R1 is hydroxy, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms or benzoyloxy, R2 and R3 are, independently, hydrogen, hydroxy, alkoxy of 1 to 4r carbon atoms, alkanoyloxy of 1 to 4 carbon atoms or benzoyloxy, or R, and R2 are together a methylene-dioxy group and are bonded to adjacent carbon atoms, A is a
Figure imgb0087
group wherein X, Y and Z are, independently, hydrogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, benzoyloxy, fluorine, chlorine or CF3, or X and Y are together a methylenedioxy group and are bonded to adjacent carbon atoms.
11. Compounds of claim 1 wherein R1 is hydroxy, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 20 carbon atoms or a
Figure imgb0088
wherein R4 and R5 are, independently, hydrogen, fluorine, chlorine, bromine, iodine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, or R4 and R5 are together a methylendioxy group and are bonded to adjacent carbon atoms, R2 and R3 are, independently, hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 20 carbon atoms or a
Figure imgb0089
or R1 and R2 together are a methylenedioxy group and are bonded to adjacent carbon atoms.
A is
a -
Figure imgb0090
group, wherein
X, Y and Z are, independently, hydrogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 20 carbon atoms, a
Figure imgb0091
chlorine, bromine, iodine, CF3, SH, alkylthio of 1 to 4 carbon atoms or
X and Y together are a methylenedioxy group and are bonded to adjacent carbon atoms.
12. Process for the production of compounds of formula I and their acid addition salts according to claim 1, characterised by
a) producing compounds of formula la,
Figure imgb0092
wherein
R'1 is alkoxy of 1 to 4 carbon atoms,
R2 and R3 are, independently, hydrogen or alkoxy of 1 to 4 carbon atoms, or
R'1 and R'2, together are a -0-CH2-0- group and,
A' has the same significances as A other than a phenyl residue substituted by at least one of the groups alkanoyloxy, alkanoylthio or
Figure imgb0093
 by reducing compounds of formula II,
Figure imgb0094
b) producing compounds of formula Ib,
Figure imgb0095
wherein each of R''2 and R''3 is, independently, hydrogen or hydroxy and
A" is a
Figure imgb0096
group, wherein each of X', Y' and Z' is, independently, hydrogen, hydroxy, alkyl of 1 to 4 carbon atoms, fluorine, chlorine, bromine, iodine, CF3 or SH or a moiety as previously defined for A under b) and c) above, by subjecting compounds of formula la to an ether cleavage reaction,
c) producing compounds of formula Ic,
Figure imgb0097
wherein R1''' is hydroxy or alkoxy of 1 to 4 carbon atoms, and
each of R2''' and R3''' is, independently, hydrogen, hydroxy or alkoxy of 1 to 4 carbon atoms, by condensing compounds of formula III,
Figure imgb0098
with compounds of formula IV,
Figure imgb0099
wherein Q and Q' signify an acid residue of a reactive ester or
d) producing compounds of formula I wherein at least one of the substituents R1, R2, R3, X, Y and Z is an alkanoyloxy or a
Figure imgb0100
and/or one of the substituents X, Y and Z is an alkanoylthio or
Figure imgb0101
by acylating compounds of formula 1, wherein at least one of the substituents R1, R2, R3, X, Y and Z is a free hydroxy group and/or one of the substituents X, Y and Z is a free SH group,
with a reactive derivative of an alkanoic acid of 1 to 20 carbon atoms or an aromatic carboxylic acid of formula
Figure imgb0102
and the resulting compounds of formula I are optionally converted into their acid addition salts.
13. Therapeutic compositions containing at least one compound according to claim 1.
EP78100365A 1977-07-18 1978-07-11 2-piperazinotetraline derivatives, their preparation and their use as medicines Expired EP0000395B1 (en)

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US4590274A (en) * 1985-01-03 1986-05-20 E. I. Du Pont De Nemours And Company Antihypertensive 1-[bis-(substituted phenyl)methyl]-4[2-(1,2,3,4-tetrahydro-substituted naphthalen-1-ylidene)ethyl]piperazines
GB8615560D0 (en) * 1986-06-25 1986-07-30 Maggioni Farma Aminoalcohols
WO1987002035A1 (en) * 1985-10-04 1987-04-09 Maggioni-Winthrop S.P.A. Fused cycloaliphatic aminoalcohols
IL85700A0 (en) * 1987-03-24 1988-08-31 Takeda Chemical Industries Ltd 1,4-disubstituted piperazine compounds,their production and use
US4845221A (en) * 1988-04-15 1989-07-04 American Home Products Corporation Serotonergic substituted piperazinyl tetralins
CA1335591C (en) * 1988-05-23 1995-05-16 James Arthur Nixon Ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes
US4988699A (en) * 1989-03-14 1991-01-29 Warner-Lambert Company Substituted tetrahydrobenzothiazoles as dopaminergic agents
GB8907865D0 (en) * 1989-04-07 1989-05-24 Wyeth John & Brother Ltd Tetrahydroquinoline derivatives
US5194439A (en) * 1990-04-06 1993-03-16 John Wyeth & Brother Limited N-(2,3-dihydro-1,4-benzodioxinyl)-N-substituted aminopyrido-fused cycloalkanes
GB2290790A (en) * 1994-06-30 1996-01-10 Merck & Co Inc Asymmetric synthesis of 6-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes

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US4018773A (en) * 1975-09-15 1977-04-19 E. R. Squibb & Sons, Inc. Phenylpiperazinotetrahydronaphthols and derivatives

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