IE42615B1 - Derivatives of 1-( -bromophenyl)-1-(3-pyridyl)propene and propane - Google Patents

Derivatives of 1-( -bromophenyl)-1-(3-pyridyl)propene and propane

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Publication number
IE42615B1
IE42615B1 IE2530/75A IE253075A IE42615B1 IE 42615 B1 IE42615 B1 IE 42615B1 IE 2530/75 A IE2530/75 A IE 2530/75A IE 253075 A IE253075 A IE 253075A IE 42615 B1 IE42615 B1 IE 42615B1
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compound
isomer
formula
preparation
pyridyl
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IE2530/75A
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IE42615L (en
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Astra Laekemedel Ab
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    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles

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  • Organic Chemistry (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The Z-isomer of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine of the formula (I) or one of its pharmaceutically acceptable acid addition salts exhibits a highly selective inhibitor action on the neuronal uptake of 5-hydroxytryptamine and can be used as an antidepressant or neuroleptic. The said compound is prepared by dehydrating a compound of the formula (II) and recrystallising the resulting stereoisomer mixture repeatedly from a solvent in which the two E- and Z-isomers show a substantially different solubility. The pure Z-isomer is isolated. The dehydration is preferably carried out with sulphuric acid, hydrochloric acid, phosphoric acid, potassium hydrogen sulphate or oxalic acid, especially by heating, or by catalytic dehydration by treatment with kaolin, mineral alumina or aluminium oxide, especially at a temperature of 300 to 500 DEG C. Preferably, the compound of the formula (I) is recrystallised three times as the oxalate from ethanol.

Description

The present invention relates to new rivatives of 1-(p-bromophenyl)-1-(3-pyridyl)ipenes and propanes, to methods for their sparation, and to pharmaceutical preparations staining certain of the new derivatives.
Depressive disorders have previously been sated with various compounds.
The antidepressive agents having the most lespread clinical use are the tricyclic tertiary .nes imipramine having the structural formula: I amitriptyline having the structural formula .CH.
CH. - 3 Secondary amines such as desipramine having the structural formula and nortriptyline having the structural formula are used to a somewhat lesser extent. These substances have, however, undesirable side effects such as orthostatism, anticholinergic effects and above all, an arrhythmogenic i.e. heart arrhythmia developing effect 10 if administered in large doses to old patients. Moreover, all the substances mentioned show that drawback that the antidepressive effect does not start until after some weeks of treatment. It is also known from the literature that certain 1,l-diphenyl-3-aminoprop-l-enes, such as the compound having the formula: 615 have an antidepressive effect, cf J. Med. Chem. 14, 161-4 (1971).
Compounds having the formula wherein X is chlorine or bromine and R is hydrogen or methyl, are said to have an antidepressive effect, cf.
U.S. Patent No. 3,423,510, these compounds however also have a strong antihistaminic effect. From the literature it is also known that a compound having the formula 42815 has an antidepressive activity in animal models, cf. Belgian Patent Specification No. 781,105.
In clinical practice different types of depressive disorders are recognized. Depressed patients respond in different ways to the various antidepressants clinically used. Most of these substances inhibit the neuronal uptake of noradrenaline, and some of them additionally inhibit the uptake of -hydroxytryptamine. It is believed that inhibition of the uptake of 5-hydroxytryptamine is the mechanism behind a mood elevating property seen in some of these anti-depressants. In addition to the absolute values for inhibition of the uptake of either -hydroxytryptamine or noradrenaline the selectivity towards uptake of either of these two amines is of great interest.
The present invention provides a pharmaceutical preparation comprising, as an active compound, a compound of the formula: 615 •CH.
Br (I) >r a pharmaceutically acceptable salt thereof, in issociation with a pharmaceutically acceptable carrier.
Due to the lack of free rotation in the double rand, the compound of Formula I may exist in different itereoisomeric forms, that is, as cis or trans isomers >r, according to the IUPAC nomenclature (J. Org. Chem. 15, 2849-2867, September 1970), as an E-form or a i-form. The compound may be used therapeutically ,s a mixture of geometrical isomers or in pure E or 2 orm substantially free from other isomers. The pure eometrical isomers may be prepared from an isomer lixture, by using a pure isomer starting material or irectly by a stereoselective synthesis. The 2somer substantially free from other isomers, and harmaceutically acceptable salts thereof, form a urther aspect of the present invention.
In clinical practice, the compounds of ormula I will normally be administered orally, ectally or by injection, in the form of pharmaceutical reparations comprising the active ingredient either - 7 as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. as the hydrobromide, hydrochloride, phosphate sulphate, sulphamate, lactate, acetate, citrate, tartrate, malate and maleate. In this Specification, references to the compounds of Formula I are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples, would be inconsistent with the broad concept.
The carrier may be a solid, semi-solid or liquid diluent, or a capsule. Usually the active substance will constitute from 0.1 to 95% by weight of the preparation, more specifically from 0.5 to 20% by weight for preparations intended for injection and from 2 to 50% by weight for preparation suitable for oral administration.
To produce pharmaceutical preparations containing a compound of Formula I in the form of dosage units for oral application, 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, or gelatine, and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol waxes, and then compressed to - 8 >rm tablets. If coated tablets are required, the jres, prepared as described above, may be coated Lth a concentrated sugar solution which may contain, .g. gum arabic, gelatine, talcum or titanium dioxide. Lternatively, the tablet can be coated with a lacquer issolved in a readily volatile organic solvent or Lxture of organic solvents. Dyestuffs may be added 5 these coatings in order to readily distinguish ’tween tablets containing different active substances -. different amounts of the active compound.
For the preparation of soft gelatine capsules jearl-shaped closed capsules) consisting of gelatine id, for example, glycerol, or similar closed capsules, le active substance may be admixed with a vegetable Ll. Hard gelatine capsules may contain granulates ; the active substance in combination with solid, ilverulent carriers such as lactose, saccharose, irbitol, mannitol, starches (e.g. potato starch, corn Larch or amylopectin), cellulose derivatives or slatine.
Dosage units for rectal application can be repared in the form of suppositories comprising the :tive substance in admixture with a neutral fatty ise, or gelatine rectal capsules comprising the active lbstance in admixture with vegetable oil or paraffin Ll. 4261S _ 9 _ Liquid preparations for oral application may be in the form of syrups or suspensions for example, solutions containing from 0.2% to 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol. Optionally, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose as a thickening agent.
Solutions for parenteral application 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 0.5% to 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 formula I for therapeutic treatment are 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 10-50 mg, preferably 10 to 25 mg of active substance per dosage unit.
Various methods are available for preparation of the Z-isomer of the invention, for example: 2615 -10A. Dehydration of a compound of the formula nd isolating the Z-isomer.
The dehydration of the starting material may, or example, be done by treatment with sulphuric acid nd heating the reacting mixture. The dehydration of. he starting material may also be done by means of other ypes of acid-catalysis, such as hydrochloric acid, hosphoric acid, potassium hydrogen sulphate, or oxalic cid. Other methods for the dehydration of compound I to form a compound of formula I are dehydration using hosphorous oxy-chloride (POGl^) in pyridine, or “hydration with thionyl chloride in pyridine, atalytic dehydration may also be used. The shydration is, in this case, carried out at a amperature of 300 to 500°C using a catalyst such as aolin, alumina or aluminium oxide. 48615 - 11 B. Demethylation of a compound of the formula either using a Z-isomer of compound III or isolating the Z-isomer after demethylation.
C. Alkylation of monomethylamine with a compound of the formula chch2-y wherein Y is a reactive group forming a stable compound HY, either using the Z-isomer of compound IV or isolating the Z-isomer after reaction with monomethylamine.
Illustrative examples of Y are halogens such as Cl, Br and I or sulphonates such as methanesulphonate, toluenesulphonate and benzene15 sulphonate. 2615 - 12 D. Introduction of a methyl group into a mpound of the formula chch2nh2 ther using the Z-isomer of compound V or isolating e Z-isomer after methylation, E. Hydrolysis of an acyl or sulphonyl npound of the formula /M (VI B) c II CHCH2NCH3~Z erein Z is an acyl or sulphonyl group, e.g. acetyl, ezoyl, methanesulphonyl, benzoylmethanesulphonyl or toluenesulphonyl, either using the Z-isomer of compound VI B or isolating the Z-isomer after hydrolysis.
For the preparation of the compounds of formula I and IA it has been found that certain hitherto unknown compounds can be used.
When using process A, the compound is used as starting material.
This starting material can be prepared according to the reaction scheme - 14 Xn the reaction scheme Y has tho previously iven definition and is a lower alkyl group with -5 carbon atoms, preferably an ethyl group. The eduction in the last step is preferably carried out ith a hydride reagent.
When using process C, compounds of the □rmula chch2_y herein Y is a reactive group forming a stable compound y on reaction with methylamine are used as starting aterial.
This starting material can be prepared . ccording to the reaction scheme CHCH2Y II 43615 - 15 In the reaction scheme above Y and have the previously given definition. The reduction in the first step is preferably carried out using LiAlH^. The last step is preferably accomplished using PBr3, which means that the leaving group Y is BrThe same starting material in which the leaving group is a halogen may also be obtained by the following reaction scheme: wherein Y1 is a halogen such as Cl, Br and I. The allylic halogenation is carried out with a suitable halogenating agent such as a halo succinimide.
When using process D a compound of the formula C CHCH2NH2 61S - 16 used as starting material. This compound may be epared according to methods similar to methods A, B, and E described in paragraph d).
Still further methods exist for the eparation of the starting materials, so for instance cording to the reaction scheme: The compounds of formula VII, VIII and IX form irther aspects of the present invention which will be irther illustrated in the following examples. _ 17 _ EXAMPLE A Step 1 A mixture of 4-bromophenyl-3-pyridylketone [CA 66, 37125^1 (1967)j 50 g, 0.19 moles] and activated zinc (20 g) in benzene (100 ml) was heated to reflux. Ethyl bromoacetate (56 g, 0.35 moles) dissolved in benzene (50 ml) was added carefully during 30 minutes.
Another portion of zinc (50 g) was added and the mixture was refluxed for 14 hours. After cooling and filtration, benzene (300 ml) was added to the filtrate, which was washed three times with 10% aqueous acetic acid solution.
Ethyl ether (200 ml) was added and the solution acidified with 10% hydrochloric acid. The precipitate was filtered off, washed with ether and dried. Yield: 75%. M.p. 168-175°C.
Step 2 - 18 The base (9.5 g, 0.027 moles) from ethyl -(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate ydrochloride (step 1) was prepared and dissolved in thyl ether (50 ml). This solution was added dropwise 4 ;o an ice-cold mixture of lithium aluminium hydride 1.0 g, 0.027 moles) and ethyl ether (150 ml). The reaction mixture was refluxed for 5 hours, cooled and t saturated sodium sulphate solution was added until a zhite precipitate was formed. This was filtered off md the filtrate evaporated. crystallized from chloroform. (3-pyridyl)-1,3-propanediol was obtained. 39%. M.p. 130-132°C.
EXAMPLE B The residue was 1-(4-bromophenyl)-1Yield: Step 1 3-(4Abromophenyl)-3-hvdroxv“N-methvl-3(3-pyridyl)-propidnamide 19.4 g (0.05 mole) of ethyl 3-(4-hromophenyl)3-hydroXy-3-(3-pyridyl)-propanoate, 200 ml of 40% solution of methylamine in water and 30 ml of absolute _ 19 _ ethanol was stirred for 24 hours at room temperature. The precipitate was filtered off and recrystallized from isopropyl alcohol, which gave 13.2 g (79%) of the amide. M.p. 188-191°C. The formula c15H15BrN2O2 was verified through elemental analysis. (The elemental analyses throughout this application were carried out for all elements of the compounds prepared, and are within ί 0.4 per cent of the theoretical values if not otherwise stated.) S^P 2 3-(4-bromophenyl)-3-hydroxv-N-methyl-3(pyridyl)-propylamine To 1.0'g (3.1 mmole) of 3-(4-bromophenyl)15 3-hydroxy-N-methyl-3-(3-pyridyl)-propionamide and 0.8 g (0.02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at 0° and under N2, was added dropwise over 20 minutes 4-6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred over night at room temperature, and then cautiously hydrolyzed with water. Alkalization with 2M NaOH and extraction with ether gave after evaporation - 20 _ g of a semicrystalline residue. Recrystallization n ether-petroleumether gave 0.2 g (23%) of the amine. . 81-88°C.
MPLE C E_I 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)ipionamide 0.8,.g (2.5 m mole) of ethyl 3-(4-bromophenyl)iydroxy-3-(3-pyridyl)-propanoate, 50 ml of aqueous nonia and 10 ml of absolute ethanol was stirred at om temperature for 24 hours. The white precipitate tained was collected by filtration. Recrystallization om isopropyl alcohol gave 0.45 g (56%), M.p. 213-214°C. ie formula was verified through elemental lalysis, C calculated 52-4< found 51.9. ;ep 2 - 21 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)propylamine To 1.0 g (3.1 m mole) of 3-(4-bromophenyl)3-hydroxy-3-(3-pyridyl)-propionamide and 0.8 g (0.02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at 0°C and under N2> was added dropwise over 20 minutes 4·6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred for 48 hours at room temperature, and then cautiously hydrolyzed with water. Alkalization with 2M NaOH and extraction with ether gave after evaporation a semi-crystalline residue. Recrystallization from ether-petroleumether gave 0.6 g (63%) of the amine, M.p. 95-115°C NMR15 spectrum (CDC13): 2H(2.4, 1-CH2) : 2H(3.0, 2-CH2)m: 3H(3.6, -OH, -NH2)b: 6H(7.1-8.0 ArH)m: 2H(8.6)m.
Step 3 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine 20 The raw product of 3-(4-bromophenyl)-3hydroxy-3-(3-pyridyl)-propylamine (from 0-4 g of 3(4-bromophenyl)-3-hydroxy-3-pyridyl)-propionamide) was -22idded with stirring to 50 ml of acetic anhydride and ).25 ml of concentrated sulphuric acid and the mixture vas heated at 130° for 45 minutes. The mixture was then cooled, poured on to crushed ice, alkalized with 30% NaOH and extracted with ether. Evaporation gave ).36 g of an oil. After hydrolysis with 15 ml of concentrated hydrochloric acid for four hours 0.25 g of an oil was obtained, thin layer chromatography showed two spots with Rf=0.1 and 0.8. Column chromatography □n Silica Gel with methanol as eluant gave 0-06 g of the faster moving fraction and 0.19 g of the slower one, which was the amine. The oxalate of this compound was prepared. It was recrystallized from ethanol, M.p. 153.5-155.5°C.
The NMR spectrum shows the vinyl proton as a double triplet at 6.1-6.5 ppm indicating an isomer ratio 1:1.
The formula: C^^H^^BrN^ . 1 H^O was verified through elemental analysis.
The oxalate was further recrystallized from a mixture of equal volumes of methanol and isopropyl alcohol and once from pure methanol. A substance melting at 160-162°C was obtained. The NMR spectrum showed it to be the z-isomer. _ 23 _ EXAMPLE D Step 1 propionitrile A mixture of 6.5 g (0.16 mole) of acetonitrile and 50 ml of dry tetrahydrofuran (THF) was slowly added under N2-atm to a mixture of 100 ml of 1.5 M n-butyllithium in hexane and 50 ml of dry THF at -50°C. After stirring for 35 minutes a solution of 36.5 g (0.14 mole) of 4-bromophenyl-3-pyridylketone in 250 ml of dry THF was added at -50°C. The temperature was kept at -70°C for 15 minutes, then the reaction mixture became viscous and it was allowed to reach ambient temperature. The product was poured into a stirred mixture of 500 g of ice-water and 500 ml of methylene chloride. The layers were separated and the aqueous layer was extracted with 2x200 ml of CH2C12. The combined organic layers were washed with water and dried. The solvent was evaporated giving 39.7 g of an oil. Xt was dissolved in 550 ml of hot i-PrOH and a solution of 35 ml of 4M HCl-ether (0.14 mole) in 100 ml of i-PrOII was added. After cooling there was collected 34.6 g (74%) of the 12615 - 24 irochloride of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl) opionit-.rile. M.p. 158-161°C. ep 2 3-(4-bromophenyl-3-hydroxy-3-(3-pyridyl)ropyl amine 17.2 g (0.056 mole) of 3-(4-bromophenyl)-3zdroxy-3-(3-pyridyl)-propionitrile was dissolved in 75 ml of THF and diluted with 200 ml of ether. The jlution was cooled to -35°C and 4.0 g (0.112 mole) of (AlH^ was added in portions under N^-atm. The mixture as held at 0°C for 2 hours and then at 15°C for 2 hours. ml. of a solution of saturated Na^SO^ was slowly added, fter 30 minutes the mixture was filtered and the aorganic salts vwere washed with 2x100 ml of ether. The iltrate was collected and the solvent was evaporated iving 14.7 g of an oil. Xt was diluted with 500 ml of ot i-PrOH and 4.3 g (0.048 mole) of oxalic acid in 00 ml of hot i-PrOH was dropwise added. After ooling over night 11.8 g of crystals, m.p. 98-105°C ere collected. An analytical sample of the free amine ad m.p. 118-120°C from i-PrOII. Yield 51%. 42015 - 25 Step 3 3-(4-bromophenyl)-3-(3-pyridyl)-allylamine To 0.80 g (0.002 mole) of the oxalate of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propylamine Was added 6 ml of 70% H2S°4 ^or 35 minutes. Ice-water was added, then 30 ml of 30% NaOH and the mixture was extracted with 3x100 ml of ether. Drying and evaporation of the solvent gave 0.62 g of an oil. This was dissolved in 10 ml of hot ethanol and a hot solution of 0.20 g of oxalic acid in 5 ml of ethanol was added. Upon cooling 0.49 g of crystals were collected. NMR showed the f product to be a mixture of the E and Z isomers of 3-(4-bromophenyl)-3-(3-pyridyl)-allylimine as in Example C step 3.
EXAMPLE 1, (Method C) Br 1) .2οη2°η PBr, 2) nh2ch3 HO \h.
CHCH2NHCH3 X _ 26 1-(4-bromophenyl)-1-(3-pyridyl)-1,3-propanediol (prepared in accordance with Example A, 7.2 g, 0.023 moles) was dissolved in dry acetone (70 ml). Hydrogen bromide was bubbled through the solution and the solvent was removed -in vacuum. Methylene chloride (50 ml) and phosphorus tribromide (6.4 g, 0.047 mole) were added to the residue and the mixture was refluxed for 14 hours, poured into ice and made alkaline with sodium carbonate. Methanol (50ml) was added to the organic phase and the solution was evaporated in vacuum at 30°C to 30 ml. The solution was heated with monomethylamine (14 g, 0.47 mole) in an autoclave at 110°C for 15 hours. After cooling, the solvent Was evaporated and the residue was dissolved in ether (25 ml) and water (25 ml). The pH pf the mixture was adjusted to 9.0 v/ith ammonia and the layers were separated. Another portion of water was added to the etheral layer and pH was adjusted to 2.1 with HCl. The water-phase was treated with carbon black and then made alkaline with ammonia and extracted with ether. The organicphase was dried with sodium sulphate and evaporated in vacuum. The residual base was dissolved in ether (40ml) and cooled on an ice bath. Hydrochloric acid in ether was added dropwise whereby a slightly yellow precipitate was obtained. The precipitate was filtered off, washed with ether and dried in vacuum. The hydrochloride 43615 _ 27 _ of 3-(4-bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine was obtained.
Yield: 43%. M.p. 138-144°C.
EXAMPLE 2. (Method A) The raw product of 3-(4-bromophenyl)-3-hydroxy-Nmethyl-3-(3-pyridyl)-propylamine (prepared in accordance with Example B from 5.0 g of 3-(4-bromophenyl)-3hydroxy-N-methyl-3-pyridyl)-propionamide) was added with stirring to 50% sulphuric acid (50 ml) and the mixture was heated at 110° for 10 minutes. The mixture was then cooled, poured on to crushed ice, basified by the addition of 30% NaCH and extracted with ether. Evaporation gave 4-9 <3 of semicrystalline residue. 150 ml acetone was added and the solution was clarified by filtration. 0.9g (0.01 mole) of oxalic acid dissolved in 25 ml of acetone was added dropwise to the filtrate. The White precipitate was collected and recrystallized from 350 ml isopropyl alcohol to yield 1.7 g of white crystals of the oxalate of 3-(4bromophenyl)-N-methyl-3-(3-pyridyl)-allylamine.
M.p. 180-208°C. The NMR spectrum shows the vinyl - 28protonas a double triplet at 6,1-6,4 ppm, indicating a mixture of E and Z isomers.
Isolation of the Z-isomer: After reerystallization three times from ethanol 0.5 g substance was obtained. M.p. 202-205°C. The NMR spectrum shows the vinyl proton as a single triplet with J = 3.4 Hz and in a position which indicates that the compound is the Z-isomer.
The amine oxalate obtained was converted into the corresponding hydrochloride via the free base. Reerystallization from acetonitrile containing a few pet cent of water gave a compound melting at 161-165°C. Elemental analysis showed it to be a dihydrochloride with the composition C^^H^gBrN^ . 2HC1 - ^0.
Isolation of the E-isomer: Mother liquors from the isolation of the Z-isomer, containing both isomers in a ratio of about 60:40 E and Z respectively, was used. The oxalate of this amine mixture was recrystallized three times from acetonitrile containing 15% of water, giving a substance melting at 198-201°C. According to the NMR spectrum this substance was the E isomer.
It is not possible by experimental means to induce depressions in laboratory animals. In order to evaluate a possible anti-depressive effect of new substances biochemical-pharmacological test methods must be resorted to. One such method, which seems to give a good indication of the potential anti-depressive effects of the test substances, is described in Europ.
J. Pharmacol. 17, 107, 1972.
This method involves the measurement of the decrease in the uptake of 1^C-5-hydroxytryptamine (lZ|O-5-HT) and 3H-noradrenaline (3H-NA) in brain slices from mice after in vivo and in vitro administration of the test substance.
Inhibition of the uptake of ^C-5-HT and ^i-NA in vitro and in vivo The 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 ^C-5-HT, 0.2 nmole of 3H-NA and 11 μπιοίβ 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 per cent decrease of the active uptake (ED5Q) of 14 3 C-5-HT and 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. sets - 30 In the in vitro method slices of mouse dbrain were preincubated for 5 minutes with solution the compound to be tested and then incubated as scribed above. -31 0» rl 0 t> Ο rt ·Η xn o β Q g ,r| H a OJ o H in OJ co in ω (ft oi vo of neuronal uptake of 5-hydroxytryptamine and noradrenaline from mouse brain. l-W kJ V OJ MJ--0 8 o +) in H in tn co I ci Η o rM io OJ OJ OJ co in OJ σι co m H H o Cft Ol H Λ H in in O 0 H m • · o OJ Γ* H CO * · · rt 10 0 +) s a ai +> rt ri rt rt S X S ΤΓ « rt rt s $ Λ a> 'il Φ Λ Λ 0+)0 o rt ρ -a ji $ £ 0 Λ Ν Ν ω NW ti -3 rt | ft 0 Ό ω •υ ia ω +> _ 32 _ As can be seen from tlie Table the compounds of the invention are potent inhibitors of the neuronal uptake of 5-hydroxytryptamine and noradrenaline. The Z-form of the compound of the invention shows a stronger inhibition of the uptake of 5-HT in vivo than do any of the prior art, compounds tested.
The Z-form of the compound of the invention tested as the hydrochloride, is further a more potent inhibitor of the uptake of 5-HT in vitro than any of the prior art compounds. (The difference appearing between the oxalate and the hydrochloride is believed to be due to the fact that the hydrochloride was prepared from the oxalate whereby a more pure Z-isomer was obtained. The E-form of the compound of the invention primarily inhibits the uptake of noradrenaline. The inhibition of neuronal uptake of 5-hydroxytryptamine and noradrenaline disclosed, may give the compounds of the invention value as anti-depressive agents. Likewise the compounds of the invention may be useful as anxiolytic agents.

Claims (16)

1. CLAIMS:1. A pharmaceutical preparation comprising, as an active compound, a compound of the formula: 5 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
2. A preparation according to claim 1, wherein the active compound is in the form of a geometrical isomer. 10
3. A preparation according to claim 2, wherein the active compound is a Z-isomer of formula: or a pharmaceutically acceptable salt thereof. _ 34 _
4. A preparation according to claim 1, substantially as hereinbefore described with reference to any one of the Examples.
5. A compound in the form of a Z-isomer of formula: substantially free from other isomers, and pharmaceutical acceptable salts thereof.
6. A process for the preparation of a Z-isomer as defined in claim 5 which comprises dehydrating a compound of the formula: and isolating the Z-isomer. - 35
7. A process for the preparation of a Z-isomer as defined in claim 5 which comprises demethylating a compound of the formula: either using the Z-isomer of compound III or isolating the Z-isomer after demethylation.
8. A process for the preparation of a Z-isomer as defined in claim 5 which comprises reacting monomethylamine with a compound of the formula: (IV) wherein Y is a reactive group forming a stable compound of formula HY, either using the Z-isomer of compound IV or isolating the Z-isomer after reaction with monomethyl amine. - 36
9. A process for t'he preparation of a Z-isomer as defined in claim 5 which comprises methylating a compound of the formula chch 2 nh 2 either using the Z-isomer of compound V or isolating the Z-isomer after methylation.
10. A process for the preparation of a Z-isomer as defined in claim 5 which comprises hydrolysing an acyl or sulphonyl compound of the formula VI A VI B wherein Z is an acyl or sulphonyl group, either using the Z-isomer of compound VI B or isolating the Z-isomer after hydrolysis.
11. A process according to any one of claims 6-10 wherein the compound is prepared in the form of a free base and is thep converted to a salt by reaction with a pharmaceutically acceptable acid. 426 _ 37 _
12. A process according to any one of _ claims 6-1Q mibstanH.^.ly-asJhc > T-PL'{j>haf(nra-(3a«-CT.iB»w*»~. with reference to any one of the Examples.
13. A compound or salt as defined in claim 5 5 obtained by a process according to any one of claims 6-12.
14. A compound of the formula cr HO XH 2 CH 2 NHCH 3 r VIX or a salt thereof.
15. A compound of the formula VIII or a salt thereof, wherein Y is a reactive group forming a stable compound HY on reaction with methylamine.
16. A compound of the formula IX F. R. KELLY & CO.,
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