EP0000322B1 - Verbindungen mit antidepressiver und beruhigender Wirkung, ihre pharmazeutischen Zusammensetzungen, Verfahren und Zwischenprodukte zu ihrer Herstellung - Google Patents

Verbindungen mit antidepressiver und beruhigender Wirkung, ihre pharmazeutischen Zusammensetzungen, Verfahren und Zwischenprodukte zu ihrer Herstellung Download PDF

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EP0000322B1
EP0000322B1 EP78850006A EP78850006A EP0000322B1 EP 0000322 B1 EP0000322 B1 EP 0000322B1 EP 78850006 A EP78850006 A EP 78850006A EP 78850006 A EP78850006 A EP 78850006A EP 0000322 B1 EP0000322 B1 EP 0000322B1
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group
compound according
formula
compound
bromophenyl
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EP0000322A1 (de
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Bernt Sigfrid Emanuel Carnmalm
Thomas Högberg
Tomas De Paulis
Svante Bertil Ross
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Astra Lakemedel AB
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Astra Lakemedel AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
    • C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/2635—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions involving a phosphorus compound, e.g. Wittig synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/213—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C49/217—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C07C49/223—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the aromatic rings polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/227—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • C07C49/233—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C07C49/235—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings having unsaturation outside the aromatic rings

Definitions

  • the present invention is related to new compounds of the diarylalkylamine type having thereapeutic activity, to methods for preparing such compounds, to pharmaceutical preparations comprising such compounds and to methods of treatment employing such compounds.
  • the object of the invention is to obtain compounds having a therapeutical activity in the central nervous system, especially an anti-depressive or a tranquilizing activity.
  • British Patent 1,429,068 discloses compounds corresponding to the general formula: having anti-depressive activity.
  • Belgian Patent 835,802 discloses compounds of the general formula: having anti-depressive activity.
  • South African Patent 62/4154 discloses i.a. a compound having the formula claimed to have a therapeutic utility especially as an antitussive.
  • Chemical Abstract vol. 82 (1975) 170339c discloses the compound of the formula as a chemical intermediate.
  • Ar represents the group wherein Y is bound in the 2-, 3-, or 4-position and represents a lower alkyl group, a lower alkoxy group, a halogen, a trifluoromethyl group, or an amino or a mono- or di-lower alkyl amino group, or Ar represents a pyridyl group bound in the 2-, 3- or 4-position,
  • X represents hydrogen, a lower alkyl group, a lower alkoxy group, a halogen, a trifluoromethyl group, an amino group or a mono- or di-lower alkyl amino group
  • R is a lower alkyl group and R 1 is hydrogen or a lower alkyl group.
  • lower alkyl and alkoxy groups are meant groups comprising up to 3 carbon atoms.
  • Halogen may be any of the elements F, Cl, Br or I.
  • Therapeutically acceptable salts of the compounds of the invention as well as differently hydrated or anhydrous forms of such compounds or salts are within the scope of the invention.
  • the compounds of formula la above wherein Ar is identical to the group contain one asymmetric carbon atom.
  • the remaining compounds of formula la contain two asymmetric carbon atoms and can therefore exist in two diastereomeric forms which can be separated by methods known in the art.
  • the compounds of formula la above may be resolved into their optical enantiomers by using optically active acids such as i.a. tartaric acid, mandelic acid, dibenzoyl tartaric acid as known in the art.
  • the compounds of the invention may be used as mixtures of diastereomeric forms or as racemic mixtures of the pure diastereomers or as the pure enantiomers mentioned above.
  • the therapeutic properties may reside to a greater or lesser extent in one of the enantiomers or mixtures mentioned above.
  • the compound of formula Ib in which the group Ar is not identical with the group may exist in different stereoisomeric forms, that is in cis-trans isomers or, according to the IUPAC nomenclature (J. Org. Chem. 35, 2849-2867, Sept. 1970), in an E-form and a Z-form.
  • the compound may be used therapeutically as a mixture of geometrical isomers or in pure E or Z form.
  • the pure geometrical isomers may be prepared from an isomer mixture, from an isomer-pure starting material or directly by a stereoselective synthesis.
  • All the compounds of formula Ib further contain one asymmetric carbon atom.
  • the compounds of formula Ib may be resolved into their optical enantiomers by using optically active acids such as i.a. tartaric acid, mandelic acid, dibenzoyl tartaric acid as known in the art.
  • optically active acids such as i.a. tartaric acid, mandelic acid, dibenzoyl tartaric acid as known in the art.
  • the compounds of formula Ib may be used as mixtures especially racemic mixtures, or as the pure enantiomers of the geometrical isomers mentioned above.
  • the therapeutic properties may reside to a greater or lesser extent in one of the enantiomers or mixtures mentioned above.
  • the invention relates in one aspect to pharmaceutical compositions comprising as active ingredient a therapeutically effective amount of a compound of the formula I.
  • the invention relates also to compounds of the formula I for use in the treatment of depressions and for use in the treatment of anxiety.
  • the invention also relates to such compounds per se of the formula I wherein X is hydrogen.
  • the compounds of the invention show an activity in the central nervous system which makes them useful as neuropharmacological agents for treatment of various diseases in animals including man.
  • the compounds are expected to be especially useful as anti-depressive, anxiolytic or tranquilizing agents in man.
  • R 1 represents hydrogen and R represents a methyl group.
  • the compounds of the formula I may be prepared by
  • the intermediates of formula II may be prepared by reacting the ketone of the formula IV above a hydroxylamine derivative of formula NH 2 0R I , wherein R 1 has the meaning defined above.
  • the intermediate of formula III may be prepared by hydride reduction of the compound of formula IV which, in turn, may be obtained by
  • the compounds of formula la are preferably prepared by method a).
  • the reaction according to method a) is preferably performed in diethyl ether with a slight excess of lithium aluminium hydride under inert atmosphere.
  • the new compounds of formula la may be used therapeutically as the racemic mixtures of (+)-and (-)-forms, which in the usual case are obtained at the synthesis. Isomer mixtures obtained may be resolved by methods known per se into corresponding optically active modifications. If desired, the optically active modifications may be prepared by way of direct synthesis, e.g. via an optically active compound as described above.
  • the compounds of the formula I in the invention may be prepared by:
  • the dehydration of the starting material may be done by means of treatment with hydrochloric acid HCI and heating of the reaction mixture.
  • the dehydration of the starting material may also be done by means of other types of acid-catalysis, such as by means of sulfuric acid H 2 SO 4 , phosphoric acid H 3 P0 4 , potassium hydrogen sulphate KHS0 4 , or oxalic acid (COOH) 2 .
  • Other methods for the dehydration of the starting material to the formation of a compound of the formula I are dehydration using phosphoroxichloride POCI 3 in pyridine, and dehydration with thionylchloride, SOCI 2 , in pyridine.
  • a catalytic dehydration of the starting material may be used. The dehydration is in this case carried out at a temperature of about 300 to 500°C using a catalyst such as kaolin, alumina or aluminium oxide.
  • This reaction is also useful for preparation of the compounds of formula la by employing as a starting material a saturated compound corresponding to the compound of formula VIII.
  • the intermediate formula VIII may be isolated (cf. Example 15) and subsequently dehydrated or alternatively the crude product in the preparation of formula VII may be dehydrated directly (cf. Example 17).
  • Z 1 Br
  • Z 1 OH
  • the latter compound may be transformed to a reactive derivative III by treatment with an agent such as SOCl; 2 , SOBr 2 or PBr 3 or with ClSO 2 R 1 .
  • the compounds of the formula I will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulphate, sulphamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable non-toxic, acid addition salt e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulphate, sulphamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable carrier.
  • the carrier may be a solid, semisolid or liquid diluent or capsule.
  • These pharmaceutical preparations constitute a further aspect of this invention.
  • the active substance will constitute from 0.1 to 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 2 and 50% by weight for preparations suitable for oral administration.
  • the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinyl-pyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets.
  • a solid pulverulent carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinyl-pyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets.
  • the tablet can be coated with a lacquer in a readily volatile organic solvent or mixture of organic solvents.
  • Dyestuff may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
  • soft gelatine capsules pearl shaped closed capsules consisting of gelatine and for example, glycerol or similar closed capsules
  • the active substance may be admixed with a vegetable oil.
  • Hard gelatine capsules may contain granulates of the active substance in combination with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
  • Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccarine and carboxymethylcellulose as a thickening agent.
  • Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 10% by weight.
  • These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
  • Suitable daily doses of the compounds of the formula I in therapeutic treatment is 25 to 250 mg for peroral administration, preferably 50 to 150 mg, and 5 to 50 mg for parenteral administration preferably 10 to 30 mg.
  • a preparation in dosage unit form for oral administration may contain 10 to 50 mg, preferably 10 to 25 mg of active substance per dosage unit.
  • the solvents of the first mother liquors of the diamine oxalate prepared according to example 2 were evaporated and the residue was extracted with ether from an alkaline solution. There was obtained 1.2 g of free amine.
  • the fumarate was prepared in ethyl acetate from half an equivalent of fumaric acid and recrystallized twice from acetonitrile-isopropylalcohol affording 0.28 g of the pure beta isomer as the diamine fumarate, mp 184-186°C.
  • the oxalate had mp 106-111°C from acetone.
  • the maleate was prepared by addition of a hot ethanolic solution of 4.9 g of maleic acid into a warm solution of the amine in 100 ml of ethyl acetate. Recrystallization from EtOH-EtOAc gave 8.4 g of the maleate, mp 158-161 °C.
  • 3,3-di-(4-fluorophenyl)-1-methylallylamine (0.9 g, 0.003 mol) was dissolved in 100 ml of ethanol and transferred to a Parr hydrogenation flask. 1.0 ml of concentrated hydrochloric acid was added followed by 0.2 g of 5% palladium on charcoal. The hydrogenation was effected at a pressure of 3.9 atm for 5.5 hours. The reaction mixture was filtered to remove the catalyst and the solvent of the filtrate was evaporated. Crystallization from EtOAc-i-Pr 2 0 gave 0.75 g of the desired product, mp 225-229°C.
  • the mixture was stirred and then made alkaline and filtered. After separation of the ether phase the aqueous phase was extracted with ether. The combined ethereal layers were extracted twice with 2 M hydrogen chloride. The aqueous phase was made alkaline and extracted with ether and dried over sodium sulphate. After evaporation of the solvent 10.1 g of yellow oil was obtained, which was dissolved in 75 ml of acetic acid and 15 ml of conc. aqueous hydrogen chloride.
  • the amine was converted to the fumarate, which was recrystallized twice from ethanol/ethyl acetate/hexane to give 6.2 g (17% yield) of the fumaric acid salt in the form C 18 H 21 NO 2 ⁇ 3/4C 4 H 4 O 4 . M.p. 167­167.5°C.
  • the product was extracted with 3 x 50 ml of 0.5 M HCI, the combined aqueous layer was made alkaline with 10 M NaOH and extracted with 2 x 50 ml of ether. Drying and evaporation of the solvent gave 0.23 g of the title compound as an oil.
  • the maleate had m.p. 174-176°C from ethanol.
  • the UV spectrum in ethanol had ⁇ max 237 nm.
  • NMR of a sample in CDCI 3 showed a double quartet at 5.0 ppm from TMS and a doublet at 6.6 ppm.
  • TLC on silica in diisopropylether showed a spot with Rf 0.28, identical with the Rf-value of the material prepared according to Example 22.
  • 500 g of active substance were mixed with 500 g of corn oil, whereupon the mixture was filled in soft gelatin capsules, each capsule containing 100 mg of the mxiture (i.e. 50 mg of active substance).
  • depressions are considered to be connected with changes in the biochemical processes of the brain which processes control the mood.
  • the nature of these biochemical processes are largely unknown but in depressive states there is evidence for a decreased activity of monoaminergic brain neurons.
  • the monoamines, noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT), are of great interest in this respect.
  • NA, DA and 5-HT is localised in three different types on neurons and may function as transmittors in the central nervous system.
  • the monoamines are stored in special structures, granules, situated in enlargements of the nerve endings, varicosities.
  • the varicosity is separated from the effector neuron by a space, the synaptic cleft or Simonm.
  • the transmittor is released from the granule into the synaptic cleft and reaches the receptor of the effector neuron and generates a nerve impulse.
  • the amines After impulse generation the amines are inactivated by mainly two mechanisms: a re-uptake mechanism at the cell membrane and enzymatic conversion by catechol-0-methyltransferase to form methylated metabolites. There is also an inactivating enzyme within the varicosities, monoamine oxidase (MAO), that is stored in the mitochondria and inactivates the amines intracellularly.
  • MAO monoamine oxidase
  • An antidepressant effect should thus be obtained with compounds which are able to inhibit the re-uptake of one or both NA and 5-HT.
  • test method described in Europ. J. Pharmacol. 17, 107, 1972. This method involves the measurement of the decrease in the uptake of 14C-5-hydroxytryptamine ( 14 C-5-HT) and 3 H-noradrenaline ( 3 H-NA) in brain slices from mice after in vivo and in vitro administration of the test substance.
  • 14 C-5-HT 14C-5-hydroxytryptamine
  • 3 H-NA 3 H-noradrenaline
  • test substances were administered intraperitoneally half an hour before the animals were killed.
  • the midbrain was taken out, sliced and incubated in a mixture consisting of 0.2 nmole of 14 C-5-HT, 0.2 nmole of 3 H-NA and 11 ⁇ mole of glucose in 2 ml of Krebs Henseleit-buffer, pH 7.4 per 100 mg of brain slices.
  • the incubation time was 5 minutes with 5 minutes of preincubation before the labelled amines were added.
  • the slices were dissolved in Soluene (Trade Mark) and the amounts of radioactive amines taken up were determined by liquid scintillation.
  • the doses producing 50 percent decrease of the active uptake (ED 50 ) of 14 C-5-HT and 3 H-NA were determined graphically from dose response curves. Active uptake is defined as that part of the radioactive uptake which is inhibited by a high concentration of cocaine.
  • the pharmacological tests show that the compounds are able to inhibit the uptake of noradrenaline and 5-hydroxytryptamine.
  • a pronounced non-selective activity is shown for the compounds having codes CPK 170, CPK 171, CPK 180 and CPK 184.
  • a pronounced selective activity on uptake of noradrenaline is seen in compounds CPK 185, CPK 215 and CPK 217 while a pronounced selective activity on uptake of 5-hydroxytryptamine is seen in compounds FLA 611, FLA 615, CPK 198 and CPK 204.
  • a strong non-selective activity is considered to be especially advantageous, as compounds having such activity may be employed in the treatment of depressions in which the neurotransmittor deficiency is unknown as well as in those cases wherein it is established that the deficiency pertains to both noradrenaline and 5-hydroxytryptamine.

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Claims (24)

1. Verbindung der allgemeinen Formel
Figure imgb0057
worin die gepunktete Linie eine eventuelle Doppelbindung bedeutet und Ar die Gruppe
Figure imgb0058
bedeutet, worin Y in der 2-, 3- oder 4-Stellung gebunden ist und eine niedermolekulare Alkylgruppe oder niedermolekulare Alkoxygruppe, ein Haloqenatom, eine Trifluormethylgruppe oder eine Aminogruppe, Mono- oder Diniederalkylaminogruppe bedeutet, oder Ar eine in der 2-, 3- oder 4-Stellung gebundenen Pyridylgruppe bedeutet, X ein Wasserstoffatom bedeutet, R eine niedermolekulare Alkylgruppe bedeutet und R1 Wasserstoff oder eine niedermolekulare Alkylgruppe bedeutet, worin "niedermolekular" bzw. "nieder" eine Gruppe mit bis zu 3 Kohlenstoffatomen bedeutet, oder ein therapeutisch verträgliches Säureadditionssalz derselben in wasserfreier oder hydratisierter Form.
2. Verbindung nach Anspruch 1 der Formel
Figure imgb0059
worin Ar, X, R und R1 die in Anspruch 1 angegebene Bedeutung haben, oder ein therapeutisch verträgliches Salz derselben.
3. Verbindung nach Anspruch 1 der Formel
Figure imgb0060
worin Ar, X, R und R1 die in Anspruch 1 angegebene Bedeutung haben, oder ein therapeutisch verträgliches Salz derselben.
4. Verbindung nach einem der Ansprüche 1, 2 und 3 in der Form
a) eines reinen Diastereoisomeren,
b) eines reinen geometrischen Isomeren oder
c) eines reinen optischen Enantiomeren.
5. Verbindung nach einem der Ansprüche 1, 2 und 3, worin Ar die Gruppe
Figure imgb0061
bedeutet.
6. Verbindung nach Anspruch 5, worin Y, F, Br der CH30- bedeutet.
7. Verbindung nach einem der Ansprüche 1 bis 6, worin R eine Methylgruppe ist.
8. Verbindung nach einem der Ansprüche 1 bis 7, worin R1 Wasserstoff ist.
9. Verbindung nach Anspruch 1, bestehend aus (ß)-3-(4-Fluorphenyl)-1-methyl-3-phenylpropyl- amin.
10. Verbindung nach Anspruch 1, bestehend aus (ß)-3-(4-Bromphenyl)-1-methyl-3-phenyl- propylamin.
11. Verbindung nach Anspruch 1, bestehend aus (a)-3-(4-Methoxyphenyl)-1 -methyl-3-phenyl- propylamin.
12. Verbindung nach Anspruch 1, bestehend aus (β)-3-(3-Bromphenyl)-1-methyl-3-phenyl- propylamin.
13. Verbindung nach Anspruch 1, bestehend aus (a)-3-(2-Bromphenyl)-1-methyl-3-phenyl- propylamin.
14. Verbindung nach Anspruch 1, bestehend aus (E)-3-Amino-1-(3-bromphenyl)-1-phenylbuten.
15. Verbindung nach Anspruch 1, bestehend aus (Z)-3-Amino-1-(3-bromphenyl)-1-phenylbuten.
16. Verbindung nach Anspruch 1, bestehend aus (ß)-3-(4-Methoxyphenyl)-1-methyl-3-phenyl- propylamin.
17. Verbindung nach Anspruch 1, bestehend aus (E)-3-Amino-1-(4-bromphenyl)-1-phenylbuten.
18. Pharmazeutisches Präparat, das als aktiven Bestandteil eine therapeutisch wirksame Menge einer Verbindung der Formel
Figure imgb0062
worin die gepunktete Linie eine eventuelle Doppelbindung bedeutet und Ar die Gruppe
Figure imgb0063
bedeutet, worin Y in der 2-, 3- oder 4-Stellung gebunden ist und eine niedermolekulare Alkylgruppe 5 oder niedermolekulare Alkoxygruppe, eine Halogenatom, eine Trifluormethylgruppe oder eine Aminogruppe, Mono- oder Diniederalkylaminogruppe bedeutet, oder Ar eine in der 2-, 3- oder 4-Stellung gebundenen Pyridylgruppe bedeutet, X Wasserstoffatom, eine niedermolekulare Alkylgruppe oder niedermolekulare Alkoxygruppe, ein Halogenatom, eine Trifluormethylgruppe oder eine Aminogruppe, Mono-oder Diniederalkylaminogruppe bedeutet, R eine niedermolekulare Alkylgruppe bedeutet und R1 Wasserstoff oder eine niedermolekulare Alkylgruppe bedeutet, worin "niedermolekular" bzw. "nieder" eine Gruppe mit bis zu 3 Kohlenstoffatomen bedeutet, oder ein therapeutisch verträgliches Säureadditionssalz derselben in wasserfreier oder hydratisierter Form in Verbindung mit einem pharmazeutisch verträglichen Trägermaterial enthält.
19. Pharmazeutisches Präparat nach Anspruch 18, das als aktiven Bestandteil ein Verbindung nach einem der Ansprüche 1 bis 17 enthält.
20. Verbindung der Formel
Figure imgb0064
worin Ar, X, R und R1 die in Anspruch 18 angegebene Bedeutung haben, für die Verwendung bei der Behandlung von Depressionen.
21. Verbindung nach einem der Ansprüche 1 bis 17 für die Verwendung bei der Behandlung von Depressionen.
22. Verbindung der Formel
Figure imgb0065
worin Ar, X, R und R1 die in Anspruch 18 angegebene Bedeutung haben, für die Verwendung bei der Behandlung von Beklemmungen oder Angstzuständen.
23. Verbindung nach einem def-Ansprüche 1 bis 17 für die Verwendug bei der Behandlung von Beklemmungen oder Angstzuständen.
24. Verbindungen, brauchbar als Zwischenprodukte bei der Herstellung der in Anspruch 1 definierten Verbindung, gekennzeichnet durch die Formel
Figure imgb0066
worin Ar, X und R die in Anspruch 1 angegebene Bedeutung haben und R" und R"' Schutzgruppen für die Aminofunktion sind, und durch die Formel
Figure imgb0067
worin Ar, X und R die in Anspruch 1 angegebene Bedeutung haben und R" und R"' Schutzgruppen für die Aminofunktion sind.
EP78850006A 1977-07-04 1978-07-03 Verbindungen mit antidepressiver und beruhigender Wirkung, ihre pharmazeutischen Zusammensetzungen, Verfahren und Zwischenprodukte zu ihrer Herstellung Expired EP0000322B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB2799277 1977-07-04
GB27992/77A GB1602290A (en) 1977-07-04 1977-07-04 Substituted aralkyl amines and amino-aryl alkenes having therapeutic activity
GB2124978 1978-05-22
GB2124978 1978-05-22

Related Child Applications (2)

Application Number Title Priority Date Filing Date
EP80105028A Division EP0028682A3 (de) 1977-07-04 1978-07-03 Bei der Herstellung von Verbindungen mit antidepressiver oder tranquillisierender Wirkung nützliche Zwischenprodukte
EP80105028.7 Division-Into 1980-08-24

Publications (2)

Publication Number Publication Date
EP0000322A1 EP0000322A1 (de) 1979-01-10
EP0000322B1 true EP0000322B1 (de) 1982-05-05

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EP80105028A Withdrawn EP0028682A3 (de) 1977-07-04 1978-07-03 Bei der Herstellung von Verbindungen mit antidepressiver oder tranquillisierender Wirkung nützliche Zwischenprodukte
EP78850006A Expired EP0000322B1 (de) 1977-07-04 1978-07-03 Verbindungen mit antidepressiver und beruhigender Wirkung, ihre pharmazeutischen Zusammensetzungen, Verfahren und Zwischenprodukte zu ihrer Herstellung

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EP (2) EP0028682A3 (de)
JP (1) JPS5511563A (de)
IE (1) IE47628B1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE7909514L (sv) * 1979-11-16 1981-05-17 Astra Laekemedel Ab Nya halofenyl-pyridyl-allylaminderivat
DE9409012U1 (de) * 1994-06-03 1995-10-05 Kemper Gmbh Maschf Maschine zum Mähen und Häckseln von Mais u.dgl. stengelartigem Erntegut
JP2944431B2 (ja) * 1994-10-18 1999-09-06 富士車輌株式会社 塵芥収集車
IT1277597B1 (it) * 1995-09-15 1997-11-11 Smithkline Beecham Spa Derivati di diarilalchenilammina
CA2336962A1 (en) * 1998-07-13 2000-01-20 Alan Mueller Methods and compounds for treating depression and other disorders
GB0016271D0 (en) 2000-07-04 2000-08-23 Meritor Automotive Inc Vehicle braking systems

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB624117A (en) * 1946-12-07 1949-05-27 Wellcome Found Improvements in and relating to the preparation of substituted allylamines and propylamines
FR1226401A (fr) * 1948-11-09 1960-07-11 Composés basiques et leur préparation
FR1021301A (fr) * 1949-04-07 1953-02-17 Lundbeck Corp Amines non saturées et leur préparation
NL90373C (de) * 1953-03-19
BE520042A (de) * 1953-05-18
FR1578702A (de) * 1961-10-10 1969-08-22

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IE781333L (en) 1979-01-04
EP0028682A2 (de) 1981-05-20
IE47628B1 (en) 1984-05-16
EP0028682A3 (de) 1981-08-05
EP0000322A1 (de) 1979-01-10
JPS5511563A (en) 1980-01-26

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