IL35443A - 4-amino-spiro(cyclohexane-1,9'-thioxanthene)compounds and their preparation - Google Patents

Description

PBEPASAHOH want lasKOi?! »n-9 * .1 -ικορηΐ¾>» ^η»9ο-·η»ρκ- . maiam The present invention is concerned with certain novel spiro compounds, with processes for their preparation, and with compositions containing them.

We have found that -amino-spiro(cyclohexane- ,9'-thioxanthene) compounds of formula I in which: A R is H or an alkyl group with up to 6 carbon atoms, 2 R is H or an alkyl group with up to 3 carbon atoms, or R and R2 , together with the nitrogen' to whic'h they are attached, form a morpholine ring or a pyrrolidine, piperidine or piperazine ring which may, if desired, be substituted by a methyl or ethyl group, and and R4 are H or CI, and their physiologically acceptable acid addition salts and quaternary ammonium salts, have valuable pharmacological properties. These compounds have central nervous system activity (for example, tranquillising or thymoanaleptic effects), circulation-influencing activity, and spasmolytic and/or antihistamine activity. The compounds can accordingly be used as drugs and also as intermediates for the prepar The compounds of formula I and their acid addition and quaternary ammonium salts are novel and constitute one aspect of the present invention.

The present invention also comprises a process for the preparation of these compounds, which comprises ( ) reducing a compound of formula II in which the dashed line in the 2,3-position of the cyclohexane ring means that the compound II may, if desired, have a double bond in this position, X is =N0H, =NR1, (H, NR2Ac1) or (H, NR Ac2) or another group which can be converted by reduction to the group NR 1R2, Ac 1 is an acyl radical with up to 6 parbon atoms, Ac2 is an acyl radical with up to 3 carbon atoms, and R , R2, TOr and R4- have the above-stated meanings, by treatment with a reducing agent , or (2) reducin an enamine of formula III in which the dashed line and R , R , R and R have the above-stated meanings, by treatment witrh a reducing agent, or (3) reacting a compound of formula IV . in which Y is CI, Br, I, OH, or a reactively esterified 4- OH group, and Or and R have the above-stated meanings, Λ -I with a base of the formula, R E BH, V, in which R and 2 R have the above-stated meaning, or with a reactant which yields such a base, or (4-) hydrogenolysing, hydrolysing, alcoholysing or amino-lysing a compound corresponding to formula I and in which the amino group is present in a functionally modified form, in order to liberate the amino group, or (5) reacting an organometallic compound of formula VI in which ΓΊ is Li or Mg Hal, Hal is CI, Br or I, and y - - lamine derivative of the formula R R NA, VII, in which A is an alkoxy group having 1 to carbon atoms or Hal, and R1 , R? and Hal have the above-stated meanings, or (6) reacting a compound of formula VIII in which R , R , ^ and R have the above-stated meanin with a thioether-bridge-forming reactant in order to obtain intramolecular cyclisation.

A primary or secondary amine of formula I (R = H) obtained by any of the foregoing processes may if desired, be treated with an alkylating agent. The compound of formula I obtained may also, if desired, be converted into a physiologically acceptable acid addition or quaternary ammonium salt thereof by treatment, respectively, with an acid or a quaternising agent or, if a salt of a compound of formula I is obtained, the base of formula I may, if desired, be liberated therefrom.

As stated above, the radical R is H or an alkyl group with up to 6 carbon atoms, i.e. hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl-(3)» neopentyl, 3-methyl-butyl-(2) , 2-methyl-butyl-(1), tert.-amyl, n-hexyl, isohexyl and hexyl-(2) of these radicals, hydrogen and alkyl groups with up to 4 carbon atoms, more particularly methyl, ethyl, propyl and isopropyl, are preferred. In addition to hydrogen, p the radical R can be an alkyl group with up to 3 carbon atoms, methyl and ethyl being preferred. When the radicals R 1 and R2, together with the ni■trogen atom to which they are attached, form a ring, it is preferably a morpholine, pyrrolidine, piperazine, piperidine, 2-or 3-methyl pyrrolidine, 2-methylpiperidine , 4-methyl-piperidine , 2-ethylpiperidine , 4-ethylpiperidine or 4-methylpiperazine ring. 4 ~ The substituents ^ and R in the thioxanthene ring may be identical or different„ When the radical X in formula II is (H,NR ?Ac Ί ), 1 then the radical Ac may, in principle, be any acyl group which can be converted by reduction to an alkyl group having up to 6 carbon atoms, and is, preferably, a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl s p isovaleryl or capronyl group. Conversely, Ac in com-pounds II where X = (H, R Ac"), is a formyl, acetyl or propionyl group.

The radical X may also be another radical which can be converted by reduction to the group -NR 1R? , for alkylidene group having up to 6 carbon atoms, preferably methylene, ethylene, propylidene, isopropylidene , butyl- in the compounds of formula IV, Y may be a reac ively esterified hydroxyl group. Preferred reactively esterified hydroxyl groups include alkyl, aralkyl or arylsulphonyloxy groups of the formula -O-SO2-R , where R may, for example, be methyl, ethyl, propyl, isopropyl, n-butyl, benzyl, phenyl, 0-, m- and p-tolyl, naphthyl, and is preferably methyl or p-tolylβ Of the compounds IV where Ύ = Hal, the. compounds in which " 6 Y = CI are preferred. The radical R preferably con-tains up to 10 carbon atoms.

When the radical A of formula VII is an alkoxy group, it is preferably methoxy and ethoxy, but it may also be, for example, propoxy, isopropoxy, n-butoxy and isobutoxy. When A is Hal, it is preferably chlorine.

The amines of formula I are preferably prepared by reduction of compounds of formula II and III.

Of the starting compounds of formula II, the oximes are preferred, e.g. spiro cyclohexane-1 ,9'-thioxanthene7-4-~oxime and spiro/cyclohexene~(2)-1 ,9'-thioxanthene7-4-oxime and the 2'-chloro- or 2', dichloro derivatives of these compounds.

The starting compound of formula II can also be an imine, such as 4-imino-spiro cyclohexane-1 ,9'-thioxanthene7 and 4—imino-spiro cyclohexene-(2)-1 ,9'-thioxanthene7 and the N-alkyl derivatives of these compounds, for example 4-methylimino-, 4~-ethylimino~, 4-propylimino- , 4—isopropylimino-, 4--n-butylimino-, 4— isobutylimino-, 4-sec.-butylimino-, 4-tert .-butylimino-, 4-n-amylimino-, 4-isoamyl mino-, 4~pentyl-(2)-imino, (27-imino-, 4-^2-methylbutyl-(1<7-imino-, 4-tert.-amylimino-, 4-n-hexyl-imino- , 4-isohexyl-imino- , -hexyl- (2)-imino-spiro cyclohexane- ,9,-t o anth.en 7 or -^cyclohexene-(2)-1 ,9'-thioxanthene7, aJ^d acyl derivatives, ecgo 4-formamido- , 4-acetamido-, 4-propionamido-, 4-butyramido- , 4-isobutyramido-, 4-valeramido- , 4-iso-valeramido-, 4-capronamido-, 4-N-methylformamido-, 4-N-methylacetamido-, 4-N-methylpropionamido- , 4-N-ethyl ormamido-, 4—N-ethylacetamido-, 4-N-isopropylformamido- , 4-N-isopropylbutyramido- , 4-N-n-butylacetamido-spiro cyclo-hexane- ,9'-thioxanthene7 or - cyclohexene-(2)- ^'-thio-xanthene^.

The enamines of formula III are preferably compounds with a tertiary amino group in the 4-position, for example 4-dimethylamino-, 4-diethylamino-, 4-methyl-ethylamino-, 4-methylpropylamino-, 4-methylisopropylamino-, 4-methylbutylamino- , 4-ethylbutylamino- , 4-methylisobutyl-amino-, 4-methyl-sec.-butylamino-, 4,-methyl-tert.butylamino-4-methyl-n-amylamino-, 4-methyl-isoamylamino-, 4-methyl-pentyl-(2)-amino-, 4-methyl-pentyl-(5)-amino-, 4-methyl-neopentylamino- , 4-methyl-^3-methyl-butyl-(2_27-amino- , 4-methyl-^-methyl-butyl-( ^7-amino , 4-methyl-tert amylamino- , 4-methyl-n-hexyl-amino-, 4-methylisohexylamino-, 4-methyl-hexyl-(2)~amino-, 4-pyrrolidino- , 4-piperidino- , 4-piperazino-, 4-morpholino- , 4-(4-methyl-piperazino)-, 4-(2-methylpyrrolidino)- , 4-(3-methylpyrrolidino)- , 4-(2-methylpiperidino)-, 4-(2-ethylpiperidino)-, 4-(4-methylpiperidino) and 4-(4-ethylpiperidino)-spiro^cyclo-hexane- ,9' -thioxanthene7 and the corresponding derivatives of these com ounds which are unsaturated in the 2,3-position of the cyclohexane ring and/or mono- or di-substituted by chlorine in the 2'- and/or 7'-position of the thioxanthene system.

A compound of formula II or III can be converted to a compound of formula I by, for example, catalytic hydrogenation. Conventional catalysts can be used for this purpose, preferably noble metal, copper-chromium oxide , nickel or cobalt catalysts.

The noble metal catalysts may, for example, be used in the form of supported catalysts (e.g. palladium on carbon), oxide catalysts (e.g. platinum oxide) or finely divided metal catalysts, (e.g. platinum black). Nickel and cobalt catalysts are advantageously used in the form of Raney metals, and nickel may also be used on kieselguhr or pumice stone as support. Hydrogenation is carried out under normal pressure and at room temperature or under elevated pressure (up to about 200 atmospheres) and/or elevated temperature (up to about 200°C). Hydrogenation is advantageously carried out in the presence of a solvent, preferably methanol, ethanol, isopropanol, tert ,-butanol, ethyl acetate, dioxan, tetrahydrofuran, water, acetic acid, an aqueous mineral acid or alkali solution or mixtures of two or more of said solvents, although the constitution of the starting compound must be taken into account. It is possible, in principle, to operate under acid, neutral or basic conditions. Reaction in a neutral or basic medium is preferable for those compounds of formula II which contain a C=N double bond. used as a general reduction method. Hydrogen can be produced, for example, by treating metals with acids or bases. For example, it is possible to use a mixture of zinc with acid or alkali solution, iron with hydro-chloric acid or acetic acid, or tin with hydrochloric acid. The use of sodium or another alkali metal in ethanol, isopropanol or butanol is also suitable. An aluminium-nickel alloy may also be used in an aqueous alkaline solution, if required with the addition of ethanol. Sodium or aluminium amalgam in aqueous-alcoholic or aqueous solution can also be used for the production of nascent hydrogen. The reaction can also be carried out in a heterogeneous phase, an aqueous and a benzene or toluene phase advantageously being used. Suitable reaction temperatures are from room temperature to the boiling point of the solvent used. The reaction is advantageously completed by boiling the reaction mixture.

Starting compounds of formula II can also be converted to amines I by cathodic reduction. For this purpose an aqueous acid reaction solution is used which may also contain another solvent, e.g. glacial acetic acid or ethanol, reduction being carried out on a lead, copper, nickel or carbon electrode.

The reducing agents used may also be complex metal hydrides, preferably lithium aluminium hydride and sodium boron hydride, if required in the presence of a Lewis acid, e.g. aluminium chloride or lithium bromide, and diborane, which can be prepared in situ from boron χ = =NR1) and acylamines ^ΪΙ, X=(H,NR5Ac1 ) or (H,NR Ac7 are particularly suitable as starting materials for this reduction method. Complex metal 'hydrides are particularly suitable for the reduction of 2'-chloro-and 2' , 7'-dichloro- substituted starting compounds » The reaction is advantageously carried out in the presence of an inert solvent, e.g. ether, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether. In the reduction with sodium boron hydride, the reaction may also be carried out in water, aqueous alcohol or aceto-nitrile. The reaction is advantageously carried out at room temperature and with ice cooling and completed by boiling the reaction mixture. The reaction time required is at least half an hour; to complete the reaction, boiling is frequently carried out for a relatively long period, e.g. 12 hours. The decomposition of the resulting metal complexes can be carried out, for example, by means of water and/or dilute aqueous acid, e.g. hydrochloric or sulphuric acid, or with an aqueous ammonium chloride solution.

The amines of formula I can also be obtained 1 1 from the 4~imino- compounds II (X =NR and R = H) by reduction with formic acid or corresponding ammonium formates or formamides. In this reaction, the relatively difficult' accessible imines may be replaced by the ^-keto-spiro^cyclohexane (or cyclohexene)-1 ,9'-thioxanthene_7 compounds, which, under the Leuckart-Vallach reaction conditions indicated in the literature, readily convert in situ to the required -imino com with derivatives thereof). The reaction is continued in the same reaction solution, with isolating the imine.

In principle, any of the reduction methods described in the literature may be used in carrying out the process according to the invention, and the appropriate method will, of course, be chosen in accordance with the starting material used.

Any double bond which may be present in the 2,3-position of the spiro/cyclohexene-1 ,9'-thioxanthene7 starting compound, can be hydrogenated simultaneously with the main reaction e.g. reduction of an oxime or a Schiff's base (II, X= =NOH or ^HR ^.

If the thioxanthene ring of the starting compound II contains chloro-substituents, they can be removed, if required, during reduction with nascent hydrogen or during catalytic hydrogenation. If, on the other hand, the chloro-substituent or substituents is/are to be retained, then it is more advantageous to carry out reduction with complex hydrides, e.g. LiAlH^, or with diborane, since aromatically bonded chloro-groups are, as a rule, not affected by these reagents.

Compounds I can also be obtained by reacting compounds of Formula IV with a base of formula V.

Instead of base V it is also possible to use reactants which yield such a base under the reaction conditions.

The following are suitable starting compounds IV: 4~hydroxy-spiro^cyclohexane-1 ,9' -thioxanthene/, derivatives thereof which are reactively esterified at the 4-hydroxy group, preferably -p-toluenesulphonyloxy- anthene_7, 4-chloro-, 4~bromo and 4—iodo-spiro cyclohexane- ,9'-thioxanthene7 and the derivatives of these compounds whic are unsaturated in the 2,3-position of the cyclo-hexane ring and/or mono- or di-substituted by chlorine in the 2'- and/or in the 7 '-position of the thioxanthene system.

Preferred formula V bases are: ammonia, methyl-, ethyl- propyl- , isopropyl^, butyl-, isobutyl-, sec.-butyl, tert .-butyl-, dimethyl-,'' diethyl-, methylethyl-, methyl-, propyl-, methylisopropyl-, methylbutyl- , methylisobutyl-, methyl-sec.-butyl-, methyl-tert.butylamine, pyrrolidine, piperidine, morpholine, 4—methyl- and 4—ethylpiperazine, 2-methyl- and 3-ethylpyrrolidine , 2- or 4~methyl- and ethylpiperidine also n-amyl-, isoamyl-, pentyl-(2)-, pentyi-0)-, neopentyl-, 3-methylbutyl-(2)-, tert.-amyl-, 2- ethylbutyl-(1 )-, n-hexyl-, isohexyl-, hexyl-(2), methyl-n-amyl- , methylisoamyl- , methyl-pentyl-(2)-, methyl-pentyl-(3)-, meth l-neopentyl-, methyl- 3-∑aethyl-butyl~(2_7-, methyl- 2-methyl-butyl~( J)7-, methyl-ter amyl-, methyl-n-hexyl- , methyl sohexyl- and methyl-hexyl-(2)-amine.

In addition to hexamethylene tetramine, suitable base-yielding reactan s are, for example, the salts of bases V, e.g. the carbonates, bicarbonates or carba-minates.

The reaction of IV with V may be carried out in the presence or absence of a solvent. Suitable solvents include, for example, lower aliphatic alcohols, such as methanol, ethanol or isopropanol, or lower aliphatic ketones such as acetone or but n e acetonitrile , or mixtures of two or more thereof. The nature of the starting compound must, of course, be taken into account in selecting the solvent; for example, for the reaction of a compound IV where Y = OH, the use of alcohols as solvent would be unfavourable because of the possibility of secondary reactions. Depending upon the nature of the starting compound, suitable temperatures are from 0°C to about 200°C, and i -are preferably from room temperature to the boiling temperature of the solvent used.

The reaction may also be carried out in an excess of base V as the solvent. To accelerate the reaction, it may be carried out under pressure and/or elevated temperature. This method is particularly advisable if an alcohol TV , Y = OR/ is used as the starting compound; in such cases, it is advantageous to add a catalyst, such as Raney nickel, platinum or palladium, and to heat the reaction mixture in a pressure vessel, preferably to 130-220°C. The methods described in the literature are generally applicable for this reaction.

Compounds of formula I can also be prepared by liberating an amino group which is present in a functionally modified form in a compound which is other-wise in accordan'ce with formula I, by hydrogenolysis, hydrolysis, alcoholysis or aminolysis.

The term "functionally modified amino groups" includes, for example, acylated amino groups or amino groups present in the form of N-arylsulphonyl-, N-benzal-, The following starting compounds may, for example, "be used: -formamido-, -acetamido-, 4-propionamido-, 4-benzamido- , 4-trichloroacetamido-, 4^phthalimido-, 4-benzenesulphonaiaido-, 4—methanesulphonamido-, 4-p-toluenesulphonamido-, 4-benzylideneamino-, 4-benzyl-amino-, 4-carbobenzoxyamino- and 4-nitrosamino-spiro-^cyclohexane-1 ,9'-thioxanthene7, and the corresponding derivatives of these compounds which are unsaturated in the 2,3-position of the cyclohexane ring and/or which are mono- or di-substituted by chlorine in the 2'- and/or 7' -position of the thioxanthene system. The amino group may also be present in the form of an isocyanate group, in which case the spiro^yclohexane-1 ,9'-thioxanthene_7 -yl-4-isoc a ates may also be formed as an intermediate in a Hofmann, Curtius, Lossen or Schmidt degradation of spiro cyclohexane- ,9'-thioxanthene7-4-ca boxylic acid amides.

Hydrogenolysis is carried out with catalytically activated hydrogen under the above-indicated conditions.

Hydrolysis can be carried out in an acid or alkaline medium, advantageously in an aqueous-alcoholic medium and at a temperatures of from 0° to 100°C. Suitable acids include hydrochloric acid and sulphuric acid, and suitable bases include sodium and potassium hydroxide or carbonate. ¾n acylated amino group of an amine of formula I can also be liberated by alcoholysis, suitably by treating a starting compound of this type with a lower aliphatic alcohol in the presence of hydrogen chloride or in the presence of an alkali metal or alkaline the boiling temperature. Liberation of the amino group may also be carried out by aminolysis, the starting compound being treated in an autoclave with ammonia or an amine, e.g. methyl or ethyl amine. The amine or ammonia used is simultaneously used as a solvent and is employed in considerable excess. A suitable reaction temperature is up to about 250°C. Other methods described in the literature may also be used to liberate acyl amines. For example, the amino group can be liberated from -phthalimido-spiro cyclohexane (or cyclohexene)- ,9'-thioxanthene7 derivatives by reacting the latter with hydrazine or phenyl hydrazine (hydrazin-olysis). The reaction conditions are relatively mild: thus it is frequently sufficient to boil the alcoholic reaction solution containing hydrazine hydrate for a few hours. If required, the reaction can also be carried out at room temperature by leaving the mixture to stand for a relatively long period. When hydrazine is used, the reaction is carried out in the presence of a mineral acid, preferably hydrochloric acid. When phenyl hydrazines are used, on the other hand, the required amine is obtained directly.

The compound I can also be prepared by reacting an orga ometallic compound of formula VI with a hydrox 1amine derivative of formula VII. Preferred organometallic compounds are spiro^cyclohexane- ,9'-thioxanthene7-4--lithium, spiro^cyclohexane-1 ,9'-thioxan-thene7-4--magnesium chloride, -bromide or -iodide and derivatives of these compounds which are mono- or di- the thioxanthene system. These organometallic compounds can be obtained in the conventional way from the corresponding spiro cyclohexane-1 ,9'-thioxanthene7-4--halides. Preferred hydroxylamine derivatives are O-methyl- and 0-ethylhydroxylamine and chloroamine. The reaction can be carried out under the conditions described in the literature. Low temperatures, suitably between -20°C and room temperature^ are preferred, with reaction times between a few minutes and 2 hours.

Suitable thioether-bridge-forming reactants include, for example, sulphur chlorides, such as sulphur dichloride, disulphur dichloride or thionyl chloride, and also elementary sulphur and agents which liberate sulphur under the reaction conditions, e.g„ sulphides, polysulphides or thiosulpha es. It is advantageous to use catalysts of the Friedel-Crafts type, e.g. aluminium chloride, boron fluoride, lithium bromide, iron (III) chloride or zinc chloride, or the etherates or alcoholates of these compounds; the reaction may, if required, be carried out with other catalysts, e.g. copper, or without a catalyst. If sulphur or a sulphur-liberating agent is used as the reactant, the reaction is preferably carried out in the absence of a solvent, advantageously in the melt, at a temperature of from about 50°C to 250°C. When a sulphur chloride is used, it is preferable to carry out the reaction in the presence of an inert solvent, e.g. carbon disulphide, at a temperature from -20°C to 100°C; suitable reaction times are from 30 minutes to 2 hours.

Following the synthesis of a primary or secondary amine of formula I, the resulting product can be treated with an alkylating agent to obtain a secondary or tertiary amine of formula I.

Preferred alkylating agents are alkyl esters of inorganic acids, for example hydrohalic acids, sulphuric acid and phosphoric acid, or organic sulphonic acids, for example p-toluenesulphonic acid. Alternatively, it is advantageous to carr out the reaction in two stages, an aldehyde or ketone being used in the first stage to form an aldehyde ammonia or Schiff's base by condensation, this intermediate then being alkylated with an alkylating agent, and the product then hydrolysedc For example, the amino group of a compound I (R = R = H) can be condensed with an aromatic aldehyde, preferably benzaldehyde, and the condensation product can then be treated with an alkyl halide, e.g. methyl chloride, methyl bromide, methyl iodide, ethyl bromide, isopropyl bromide or dimethyl sulphate. Under these conditions, the quaternary salt of the Schiff's base is first formed and is then converted to the secondary amine with liberation of the aldehyde, e.g. by treatment with aqueous ethanol or with an acid, such as hydrochloric acid© An amine I (R = H) can also be reacted with an aldehyde in the presence of formic acid. The amine I (R = H) can also be alkylated with an alcohol in the presence of a catalyst such as Raney nickel. Generally speaking, it is possible to use any of the methods described in the literature for the alkylation of primary or secondary amines.

The com ounds of formula I can be converted into their physiologically acceptable acid addition salts by treatment with acids. For this purpose, inorganic or organic acids may be used, for example, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-or poly- basic carboxylic or sulphonic acids. The following may be cited by way of example: mineral acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric 'acid, nitric acid, phosphoric acids, such as orthophosphoric acid, sulphamic acid; organic acids, such as formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, diethyl acetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, citric acid, gluconic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, phenylpropionic acid, ascorbic acid, isonicotinic acid, nicotinic acid, methanesulphonic acid, ethanedisulphonic acid, β-hydroxyethanesulphonic acid, p-toluenesulphonic acid, and naphthalene-mono- or -disulphonic acids.

Amines of formula I can also be converted to their physiologically acceptable quaternary ammonium salts by treatment with quaternising agents, such as methyl iodide, dimethyl sulphate or ethyl halidese If required, the free bases of formula I can be liberated from their salts by treatment with strong bases, such as sodium or potassium hydroxide, or sodium or potassium carbonate.

Preferred novel compounds according to the invention are those of formula IX in which I is H or CI, 7 R . is H or an alkyl group with 1 to 3 carbon atoms, R8 is H or CH5, or R7 and R8 together form - Ci^CH^CCH^CI^CI^-, and their physiologically acceptable acid addition and quaternary ammonium salts. Within this group of compounds, those of formula X and their physiologically acceptable acid addition and quaternary ammonium salts, are particularly valuable.

The starting compounds of formulae II to VIII are in some cases known and in other cases they can be the presence of benzyl trimethyl ammonium hydroxide gives bis-(2-cyanoethyl)-thioxanthene sulphoxide (m.p„ 198°C), which is reduced by triphenylphosphine to 9,9-bis-(2-cyanoethyl)thioxanthene. Hydrolysis gives 9,9- hioxanthene dipropionic acid (m.p. 202-203°C), the dimethyl ester of which (m.pe 97-98°C) is cyclised in the presence of sodium methylate to form spiro cyclo-hexane- ,9'-thioxanthene7-4rOne~3-carboxylic acid-methyl ester (m.p. 1 2~193°G)^ Saponification and decarboxylation give spiro^cyclohexane-1 ,9'-thioxanthene7-/t—one (m.p. 148°C). Similarly, 2-chloro- or 2,7-dichlorothioxanthene yields the other ketones of formula II (0 instead of X) by way of the corresponding sulphoxides. The ketones can be reduced (preferably by catalytic hydro enation) to form the corresponding cyclohexanols (IV, Y = OH), can be converted to the oximes (II, X = NOH) with hydroxy-lamine, or to the Schiff's base (II, X = NR 1 ) with amines, or to the enamines (III). The alcohols (IV, Y = OH) when reacted with p-toluenesulphonic acid chloride or methanesulphonic acid chloride, give the corresponding sulphonic acid esters; reaction with hydrochloric or hydrobromic acid, phosphorus tribromide, thionyl chloride or other inorganic acid halides, gives the corresponding —halogen compounds. The corresponding organometallic compounds (VI) can be obtained from the 4—halogen compounds with magnesium or lithium, or the -phthalimido-spiro^cyclohexane-1 ,9'-thioxanthene 7 can be obtained with potassium phthalimide.

Spiro^cyclohexene-1 ,9'-thioxanthene7-4--one and the corresponding 2-chloro or 2,7-dichloro-derivatives can be obtained from 9-formyl-thioxanthenes by condensation with methyl vinyl ketone.

It is also possible to produce the starting materials in situ as transient intermediates. For example, the heating of -keto-spiro cyclohexane- ,9'-thioxanthene7 together with a primary amine in an autoclave, preferably at 150-250°C, gives the Schiff's base (II, X = NR )» which- can then be hydrogenated to form the amine I in the "same vessel after the addition of a catalyst, without isolation of the Schiff's base intermediate.

The new compounds are used in human and veterinary medicine in admixture with solid, liquid and/or semi-solid excipients. The excipients are organic or inorganic substances suitable for parenteral or enteral administration and which do not react with the new compounds, for example, water, vegetable oils, polyethylene glycols, gelatin, lactose, starch, magnesium. stearate, talcum, petroleum ^elly, and cholesterol. Solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants are suitable for parenteral administration. Tablets, dragees, syrups and juices are suitable for enteral administration. The compositions indicated can be sterilised or have adjuvants added thereto, for example, preservatives, stabilisers or wetting agents, salts for influencing osmotic pressure, buffer substances, colouring matter, flavours and/or aromatic substances.

When such compositions are formulated as dosage the new compound per dosage unit.

In order that the invention may be more fully understood, the following examples, in .which all temperatures are in °C, are given by way of illustration only:-Example 1 a) 58 g of crude spiro^cyclohexane- ,9* -thioxanthene7-^-one--oxime '(obtained from the ketone and hydroxy!amine) were dissolved in 1 .3 litres of boiling butanol. 69 g of sodium metal were added thereto in portions and the mixture was boiled until the sodium had dissolved. The butanol was then distilled off, the residue was taken up in water and extracted with ether. The ether phase was dried over sodium sulphate and 4—amino-spiro cyclohexane~ , ' -thioxanthene7-hydrochloride was precipitated with ethereal hydrochloric acid, m.p„ 310° (from ethanol/ether) . ΐ) 13.7 g of -amino-spiro cyclohexane-1 ,9' -thioxanthene7 and 2.6 g of formic acid were dissolved in 250 ml of toluene and boiled for 2 hours with reflux cooling. Boiling was continued for another 2 hours, using a water separator. Another 2.6 g of formic acid were then added and boiling was continued for 2 hours with reflux cooling and for another 12 hours using a water separator.. 4~Formyl-amino-spiro cyclohexane-1 ,9'-thioxanthene7 (m.p. 208°) was obtained by concentrating the reaction mixture. The formyl compound was dissolved in 100 ml of absolute tetrahydrofuran and added dropwise to 3 ·2 g of lithium aluminium hydride in "boiled for -about 6 hours, cooled, and dilute hydrochloric acid was added dropwise with agitation. The bulk of the tetrahydrofuran was then distilled ^off and the residue was washed with ether. Tartaric acid was then added to the aqueous acid, phase, the mixture was stirred into an excess of aqueous caustic soda solution and extracted with chloroform. After drying the extract, the chloroform was distilled off and -methyl-amino- spiro^yclohexane- ,9'-^hioxanthene7 was obtained,.

Hydrochloride, m.pe 279°· c) 12.3 g of -methylamino-spiro cyclohexane- ,9l-thioxanthene_7 were converted to -methylformylamino-spiro^cyclohexane-1 ,9'-thioxanthene7 (m.p. 172°) by boiling with formic acid in toluene as in Example 1 b) and was then reduced with .2 g of lithium aluminium hydride to form -dimeth l-amino-spiro cyclohexane- ,9'-thioxan-thene7. Hydrochloride, m.p. 270°. d) 3.8 g of -amino-spiro^cyclohexane-1 ,9' -thioxanthene7 hydrochloride were heated with 4-0 ml of formic acid, 0.92 g of sodium formate and ml of 35% formaldehyde solution at 60° for 3 hours and then at 100° for another 2 hours. The formic acid was then distilled off, the residue was taken up in dilute caustic soda solution, extracted with ether, and the dried ether extract gave 4-dimethylamino-spiro^cyclohexane- ,9'-thioxanthene7. Hydrochloride, m.p. 270°. e) A solution of 5 g of -amino-spiro cyclo-hexane-1 ,9'-thioxanthene7 in 50 ml of benzene was boiled together with 3 g of benzaldehyde for about 2 hours using Schiff's base was shaleen with 10 g of methyl iodide in a bomb tube for 12 hours at 150° and the benzene and excess methyl iodide were then distilled off. The residue was boiled for 10 minutes in 9¾¾ ethanol, the alcohol was distilled off, the residue was taken up in dilute hydrochloric acid, and the liberated benzaldehyde was extracted with ether. The aqueous acid solution was rendered alkaline witbrcaustic soda solution, and extracted with chloroform. Drying and evaporation of the chloroform solution gave 4-methylamino-spiro cyclo-hexane-1 ,9'-thioxanthene7. Hydrochloride, m.p» 279°· f) 4.22 g of 4-amino-spiro^/cyclohexane- ,9'-thioxanthene7 and 0.96 g of bis-(2-chloroethyl)-methylamine-hydrochloride were boiled for 12 hours in a mixture of 80 ml of acetonitrile and 110 ml of ethanol. The solvent mixture was then distilled off, the residue was taken up in dilute caustic soda solution and chloroform, and the chlorof.orm extract was chromatographed on silica gel, 4-(4-Methylpiperazino)-spiro cyclohexane-1 ,9'-thioxanthene_7 was obtained using benzene/diethylamine (9:1) as the eluant Dihydro-chloride, m.p. 287°; dihydrobromide , m.p, 300°.

Reaction of 4-amino-spiro cyclohexane-1 ,9 ' -thioxanthene_7 in the same way with the following: bis-(2~chloroethyl)-ether 1.4-dichlorobutane .5-dichlo opentane bis-(2-chloroethyl)-amine-hydrochloride ,4-dichloro-pentane ,4-dichloro~2-methyl-butane 1 ,5-dichloro-hexane or bis-(2-chloroethyl)-ethylamine-hydrochloride respectively gave the following compounds: 4-morpholino-spiro^cyclohexane--1 ,9'-thioxanthene7- hydrochloride 4—pyrrolidino-spiro^cyclohexane-1 ,9'-thioxanthene_7- hydrochloride -piperazino-spirOjcyclohexane-l , ' -thioxanthene7- dihydrobromide -(2~methyl-pyrrolidino)-spiro/cyclohexane- ,9'-thioxan- thene7~hydrochloride 4-(3-methyl-pyrrolidino)-spiroJcyclohexane--1-i9,-thioxan- thene_7-hydrochloride 4-(2-methyl-piperidino)-spiro^cyclohexane--1 ,9'-thioxan- thene7-hydrobromide -( -ethylpiperazino)-spiro cyclohexane-*1 ,9'-thioxanthene7 -dihydrochloride. g) 3 g of 4-dimethylamino-spiro^/cyclohexane-- ,9'-thioxanthene7 were dissolved in 30 ml of acetonitrile and shaken with 3 g of methylhromide for 12 hours at 80° in a bomb. The mixture was then diluted with ether and suction filtered. N,N,N-trimethyl-N-spiro cyclohexane~ 1 ^'-thioxanthen^-yl-C^ -ammonium bromide was obtained, m.p. 245-246°.

Example 2 78 g of crude spiro cyclohexane- ,9'-thioxan-thene7_4-one-oxime were boiled in a mixture of 300 ml N methanolic KOH. 50 g of methanol-wet Raney nickel were added and hydrogenation was carried out at 6 atmospheres and 55° · Hydrogenation stopped after about 5 hours. The reaction mixture was suction filtered from the catalyst, the solvents were distilled off, the residue was taken up in water and extracted with chloroform, the chloroform was evaporated from the extract, the residue was dissolved in a little ethanol, and -a no-spiro cyclohexane- ,9' -thioxanthene_7-hydrochloride , m.p. 310° , was precipitated with ethereal hydrochloric acid.

Example 11.4- g of crude spiro^yclohexene-(2)-1 ,9' -thioxanthene7-4-one~oxime (obtainable from 9-formyl-thioxanthene (m.p. 101°) by condensation with methyl vinyl ketone and reaction of the resulting spiro cyclo-hexene-(2)-1 ,9'-thioxanthene7-4-one with hydroxylamine hydrochloride) were hydrogenated in the presence of Raney nickel as in Example 1 a). After absorption of the amount of hydrogen equivalent to 3 moles and conventional working up, -amino-spiro cyclohexane-1 ,9'-thiox-anthene7-hydrochloride was obtained, m.p. 310°.

Example 4 a) 20 g of spiro^cyclohexane-1 ,9'-thioxanthene7- -one were melted in a bomb tube with 30 g of isopropyl-amine and heated at 200° for 18 hours. The excess isopropylamine was then distilled off, the crude residue of -j^-isopropylimino-spiro cyclohexane- , f-thioxanthene7 was dissolved in 250 ml of absolute tetrahydrofuran and inium hydride in 150 ml of absolute tetrahydrofuran.

The mixture was then boiled for 5 hours, and then worked up conventionally to give -isopropylamino-spiro-^cyclohexane- ,9' -thioxanthene_7; hydrobromide, m.p, 302°; hydrogen malonate, m.p. 179°· Reduction of the following compounds in the same way: -methylimino-spiro cyclohexane-1 ,9'-thioxanthene/, 4-ethylimino-spiro^/cyclohexane-l ,9,-thioxanthene7, 4-n-propylimino-spiro cyclohexane--1 ,91 -thioxanthene7» -n-butylimino-spiro cyclohexane-1 ,9' -thioxanthene7, 4-isobutylimino-spiro cyclohexane-1 ,9' -thioxanthene7» 4-sec.-butylimino-spiro cyclohexane-'1 ,9' - hioxanthene7, ~tert .-butylimino-spiro^cyclohexane-l ,91 -thioxanthene7, -n-amylimino-spiro^cyclohexane- ,9'-;hioxanthene7i -isoamylimino-spiro^cyclohexane- ,9' -thioxanthene7, -pentyl-(2)-imino-spiro/cyclohexane- ,9,-thioxanthene7, 4-pentyl-(3)-imino-spiro^cyclohexane-1 ,9'-thioxanthene7, 4-neopentylimino-spiro cyclohexane- ,9 ' -thioxanthene7, 4-^-methylbutyl-(27-imino-spiroicyclohexane~ ,9'- thioxanthene7, 4-i2-methylbutyl-( 7-imino-spiro cyclohexane-1 ,9' -thio- xanthene7, 4-tert . amylimino-spiro cyclohexane-1 ,9' -thioxanthene7, 4-n-hexylimino-spiro cyclohexane-1 ,9'--thioxanthene7, 4-isohexylimino-spiro cyclohexane- ,9' -thioxanthene7, 4-hexyl-(2)-imino-spiro cyclohexane-1 ,9'-thioxanthene7 gives the following compounds: 4-methylamino~spiro cyclohexane~1 ^'-thioxanthenej7, -ethyla no-spiro^cyclohexane- ,9' -tliiOxanthene7, hydrobromide, m.p. 261°; -propylamino-spiro cycloh.exane-1 , ' -thioxanthene7, hydrobromide, m.p. 277° > -n-butylamino~spiro cyclohexane-1 ,9'-thioxanthene i -isobutylamino-spiro cyclohexane- ,9' -thioxanthene7, -sec .-butylamino-spiro^cyclohexane- ,9 ' -thioxanthene7s -isoamylamino-spiro cyclohexane-1 ^'- hioxanthen^, -pentyl-( 2)-amino-spiro cyclohexane- , 9 '-thioxanthene7, -pentyl-(3)-amino-spiro Example 5 g of spiro cyclohexene-1 ,9'-thioxanthene7-4~one were heated in a bomb together with 30 S of iso-propylamine for 12 hours at 200° . The excess isopropyl-amine was then evaporated, the residue was taken up in methanol and hydrogenated in the presence of Raney nickel and methanolic K0H at 6 atmospheres and 60°.

After absorption of 2 moles of hydrogen, the reaction mixture was filtered off from the catalyst, the methanol was' removed, and the residue was taken up in water and chloroform. Isopropylamino-spiro^yclohexane-1 ,9' -thioxanthene7 was obtained from the chloroform phase; hydrobromide , m.pe 302° .

Example 6 a) 2' r-Cailoro-spiro cyclohexane-l ,9'-thioxan-thene7--one ^m.pe 75° ; obtainable by oxidation of 2-chloro-thioxanthene to form 2-chloro-thioxanthene-sulphoxide (m.p. 121-122°) and conversion of the latter successively to 9 ,9-t>is-( 2-cyanoethyl )-2-chloro- thioxanthene, 2-chloro-9 ,9-thioxanthene-dipropionic acid (m.p. 240°), 2-chloro-9,9-thioxanthenedipropionic acid dimethyl ester (m.p. 97°) and 2'-chloro-spiro^cyclo-hexane- ,9' -thioxanthen 7-4-one-3-carboxylic acid methyl ester (m.p. 142-143° 7 were reacted as in Example 4 a) with 10 times the stoichiometric quantity of methylamine to form 2' -chloro-4—methylimino-spiro^yclohexane- ,9' -thioxanthene7, which was hydrogenated in the crude state to yield 21 -chloro-4-methylamino-spiro cyclohexane-1 ,9 thioxanthen 7 hydrochloride, m.p. 302; hydrogen malonate, m.p. 7 - 75°.

Similarly, the following are obtained with ammonia or with the corresponding primary amines: 21-chloro-4-amino-spiro/cyclohexane-1 ,9' -thioxanthene7 2·-chloro-4-ethylamino-spiro cyclohexane- ,91 -thioxanthene7 2'-chloro- -propylamino-spiro cyiLohexane- ,9'-thioxanthene7 2'-chloro-4-isopropylamino-spiro^cyclohexane- ,9'- thioxanthene7 and from 2' ,7'-dichloro-spiro cyclohexane-1 ,9'-thioxan- thene7~4-one 2' ,7'-dichloro-4-amino-spiro c clohexane- ,9' -thioxanthene7 2' ^'-dichloro-^-methylamino-spiro cyclohexane- ,9'- thioxanthene7 2' ,7'-dichloro- -ethylamino-spiro cyclohexane- ,9'- thioxanthene7 2' ,7'-dichloro- -propylamino-spiro^cyclohexane-1 ,9'- thioxanthene7 2' ,7'-dichloro- -isopropylamino-spiro^cyclohexane- ,9'- thioxanthene7· b B the method described in Exam le 1 c 21 -chloro- ~dimethyl-amino-spiro cylcohexane- ,9' -thiox-anthene7 was prepared from 21 -chloro- -methylamino-spiro-^yclohexane-1 ,9'-thioxanthene7; hydrochloride, m.p. 301-302°.

The following are obtained similarly from the secondary amines indicated under (a): 2' -chloro- -methylethylamino-spiro^cyclohexane-1 ,9'- thipxanthene_7, 2' -chloro- -N-methyl-N propylamino-spiro cyclohexane- 1,9'-thioxanthene7i 2' -chloro-4—N-methyl-N-isopropylamino-spiro cyclohexane- 1,9'-thioxanthene7» 2' ,7'-dichloro-4~dimethylamino-spiro cyclohexane-1 ,9'- thioxanthene7* 2' ^'-dichloro-^-methylethylamino-spiro cyclohexane- ,9'- thioxanthene7, 2' ,7'-dichloro-A—N-methyl-N-propylamino-spiro cyclohexane- 1,9'-thioxanthene7 and 21 ,7' -dichloro-4~N-methyl-N-isopropylamino-spiro cyclo- hexane- ,9' -thioxanthene_7.

Example 7 4·.7 g of -acetamido-spiro^cyclohexane- ,9'-thioxanthene_7 (m.p, 213°; obtainable by acetylation of -amino-spiro^cyclohexane~1 ,9'-thioxanthen 7) were boiled overnight with 1.2 g of lithium aluminium hydride and g of anhydrous aluminium chloride in 200 ml of absolute ether. The mixture was then decomposed by the addition of dilute hydrochloric acid, the ethereal phase was separated, tartaric acid was added to the aqueous phase, and the latter was then poured into an excess of caustic soda solution and extracted with chloroform.

Evaporation of the chloroform gave 4—ethylamino-spiro-^cyclohexane-1 ,9'-thioxanthene7; hydrobromide , m.pe 261° (from ethanol/ether) .

Similarly, the following compounds: -propionylamido-spiro cyclohexane-1 ,9' -thioxanthene7 199°), -methylacetamido-spiro cyclohexane-1 ,9'-thioxanthene7 and 4—methylpropionylamido-spiro^cyclohexane- ,9'- hioxanthene_7j gave: -propylamino-spiro cyclohexane-1 ,91 -thioxanthene7; hydrobromide, m.p. 277°; hydrogen malonate, m.p. 168°, -A—(N-ethyl-N-methylamino)-spiro^cyclohexane- ,91-thioxan- thene7; hydrobromide, m.p. 228° and / _(N-methyl-N-propylamino)-spiro/cyclohexane-1 ,9' -thioxan- thene7; hydrochloride, m.p. 217°· Example 8 18 g of crude -^i-propylideneamino7-spiro(cyclo-hexane- ,9'-thioxanthene7 (obtainable from the amine and propionic aldehyde in tetrahydrofuran at 180-200°) were hydrogenated in the presence of 5 g of Raney nickel and ml of methanol at 6 atmospheres and 75°. After absorption of the amount of hydrogen equivalent to 1 mole, the reaction mixture was suction filtered from the catalyst and evaporated to give 4—n-propylamino-spiro cyclohexane-1 ,9 '-thioxanthene_7; hydrobromide , m.p. 277°.

A solution of 6 g of -ethylideneamino-spiro- cyclohexane-1 ,9' -thioxanthene7 (obtainable from the corresponding 4—amino compound by reaction with acetal-dehyde) was hydrogenated in the presence of 0.5 g of platinum oxide and 50 ml of methanol at room temperature and normal pressure. After absorption of the amount of hydrogen equivalent to 1 mole, the reaction mixture was filtered from'the catalyst, acidified with dilute hydrochloric acid, and the methanol was eliminated in vacuo. The remaining aqueous solution was rendered alkaline with caustic soda solution, and extracted with ether. Drying and concentration of the ether extract gave -ethylamino-spiro cyclohexane- ,9'-thioxanthene7; hydrobromide , m.p. 261°.

Example 10 About 13 g of crude 4—methylpropylamino-spiro cyclohexene-(3)- ,9' -thioxanthene7 (obtainable from spiro cyclohexane-1 and methylpropylamine at 180°) were dissolved in 200 ml of methanol and hydrogenated at 6 atmospheres and 60° in the presence of 4- g of Raney nickel. After filtering off the catalyst with suction, the methanol was distilled off to leave a small residue and the hydrochloride of 4—methylpropylamino-spiro^cyclohexane-1 ,9'-thioxan-thene7, m.p. 217?, was precipitated with ethereal hydrochloric acid. Free base, b.p. 183-186°/0.05 mm.

The following are obtained similarly by hydrogenation of the corresponding enamines: 4-dimethylajnino-spiro/cyclohexane- ,9'-thioxanthene7 4-diethylamino~spiro cyclohexane-1 ,9' -thioxanthene7» 4-methyleth.ylamino-spiro cyclohexane- ,9' -thioxanthenej7 (hydrobromide , m.p. 228°), 4-methylisopropylamino-spiro^yclohexane--1 ,9' -thioxanthene_7 (hydrobromide, m.p. 231°), -methylb tylamino~spiro cyclohexane-1 ,9'-th.ioxantb.ene7, 4-methylisobutylamino-spiro^yclohexane-1 ,9' -thioxanthene_7* 4-methyl-sec .-butylamino-splro cyclohexane-1 ,9'-thioxanthene7» -methyl-tert .butylaminb-spiro cyclohexane-1 , ' -thioxanthene_7, 4-methyl-n-amylamino-spiro cyclohexane-1 ,9'- hioxanthene7, 4-methylisoamylamino-spiro^cyclohexane- ,9' -thioxanthene7, 4-methyl-pentyl-(2)-amino-spiro^cyclohexane-1 ,9'-thioxanthenej7 4-methyl-pentyl-(3)-amino-spiro cyclohexane- ,9'-thioxanthene7 4-methylneopentylamino-spiro cyclohexane-1 ,9 -thioxanthene7» 4-methyl-^3--methyl-butyl~(2 7-8mino--spiroicyclohexane~ 1,9' -thioxanthene7, 4-methyl-^2-methyl-butyl-( 7-amino-spiro cyclohexane~ 1,9' -thioxanthene7, 4-methyl-tert ,-amylamino-spiro /cyclohexane- ,91 -thioxanthene_7» 4-methyl~n-hexylamino-spiroicyclohexane-1 ,9'~thioxanthene7» 4-methylisohexylamino-spiro^yclohexane- ,9'-thioxanthene_7 and 4-methyl-hexyl-(2)-amino-spiro cyclohexane-1 ,9'-thioxanthene7. Example 11 11.2 g of spiro cyclohexeaie-(2)-1 ,9'--thioxanthene7 -4-one, 7.9 g of N-methylpiperazine and 50 ml of tetra-hydrofuran were shaken in a bomb tube for 12 hours at 160°. After cooling, the mixture was evaporated, the resulting 4-(4-methylpiperazino)-spiro^cyclohexadiene- - »- - methanol and, after the addition of A- g of Raney nickel, lias hydrogenated at 6 atmospheres and 60°. After filtering off the catalyst with suction, the filtrate was acidified with hydrochloric acid, and the methanol was distilled off to give 4-(4-methylpiperazino-spiro^cyclo-hexane-1 ,9'-thioxanthene7; dihydrobromide , m.p. 300°.

Similarly, reaction of the corresponding spiro cyclohexene-(2)-thioxanthene7- -ones with the corresponding cyclic amines followed by hydrogenation yields the following: -pyrrolidino-spiro cyclohexane- ,9'-thioxanthene/i -piperidino-spiro cyclohexane- ,9'-thioxainthene7i 4-morpholino-spiro cyclohexane- , '-thioxanthene7» -(2-methylpyrrolidino)-spiro cyclohexane- ,9' -thioxanthene7, -(3-methylpyrrolidino)-spiroic3clohexane- ,9 '-thioxanthene_7, 4-(2-methylpiperidino)~spiro cyclohexane- ,9 ' -thioxanthene7, 4-(4-methylpiperidino)-spiro cyclohexane--'1 ,9 ' -thioxanthene7, 4-(2-ethylpiperidino)-spiro cyclohexane-1 , 9' -thioxanthene7, 4-(4-ethylpiperidino)-spiro^/cyclohexane- , 9'-thioxanthene7, 2' -chloro- -pyrrolidino-spiro^yclohexane-1 ,9' -thioxanthene7» 2' -chloro-4-piperidino-spiro/cyclohexane-1 ,9'~thioxanthene7, 21 -chloro-(4-methylpiperazin^-spiro^/cyclohexane-1 ,9 ' - thioxanthene7, 2' ,7'-dichloro-4-pyrrolidino-spiro cyclohexane-1 ,9'- thioxanthene7, 2' ,7' -dichloro-4~piperidino-spiro^cyclohexane- ,9'- thioxanthene7 and 2' ,7t-dichloro-4-(4-methylpiperazino)-spiro/cyclohexane- ,9'-thioxanthene7.

A solution of 7.2 g of 4—chloro-spiro cyclo-hexane-1 ,9'-thioxanthene7 (obtainable by reduction of spiro cyclobexane- ^'- hioxanthene -^-one with LiAlH^ to form spiro^yclohexane-1 ,9 ' -thioxanthene_7-4-ol and reaction of the latter with SOCL^) and 3.6 g of isopropylamine in 50 m o toluene was boiled until there was no further precipitation of isopropylamine hydrochloride. The mixture was cooled, filtered, the filtrate was extracted with dilute hydrochloric acid, and the bulk of the organic solvent was eliminated in vacuo. The remaining aqueous solution was rendered alkaline with caustic soda solution, and extracted with ether. 4-Isopropylamino-spiro^cyclohexane-l ,9'-thiox-anthene_7 w s obtained from the ethereal extract; hydrogen malonate, m.p. 179° .

Similarly, reaction with the corresponding amines gives the following from the corresponding -chloro-spiro cyclohexane- ,9 ' -thioxanthene7: 4-methyl-amino-spiro cyclohexane- ,9'-thioxanthene7; hydrochloride, m.p. 279° and 2f-chloro-4-methylamino-spiro cyclohexane-1 ,9,~thioxanthene7; hydrochloride, m.p. 302° .

Example 11 g of spiro cyclohexane- , 9'-thioxantheneT- -ol were dissolved in 40 ml of isopropylamine and, after the addition of 2 g of Raney nickel, the solution was shaken in a bomb tube for 15 hours at 160°. After filtering off the catalyst, the excess isopropylamine was distilled off, was added to the residue, the mixture was extracted with ether, and the ethereal extract was spiro cyclohexane- ,9'-thioxanthene_7 was obtained from the ethereal extract; hydrobromide, m.p. 302°.

Similarly, reaction of the corresponding 4-hydroxy-spiro/cyclohexane-1 ,9' -thioxanthenes7 with the corresponding primary or secondary amines yielded the following: 4--methylamino-spiro cyclohexane-1 ,9' -thioxanthene7; ..hydrochloride, m.p. 279°» 4-ethylamino-spiro/cyclohexane-1 , ' -thioxanthene ; hydrobromide, m.p. 261°, 4—n-propylamino-spiro cyclohexane-1 ,9' -thioxanthene_7; hydrobromide, m.p. 277°» 4-n-butylamino-spiro/cyclohexane-1 ,9 ' -thioxanthene7, 4-sec.-butylamino-spiro/cyclohexane-1 ,9'-thioxanthene_7» -dimethylamino-spiro cyclohexane- ,9'-thioxanthene7j hydrochloride, m.p. 270°, 4--diethylamino-spiro/cyclohexane-1 ,9 '-thioxanthene7, -methylethylamino-spiro cyclohexane-1 ,9 ' -thioxanthene7» hydrobromide, m.p. 228°, 4-methylpropylamino-spiro/cyclohexane-1 ,9 ' -thioxanthene7; hydrochloride, m.p. 217°» 4-methylisopropylamino-spiro/cyclohexane- , ' -thioxanthene_7, 4-pyrrolidino-spiro/cyclohexane- ,91 -thioxanthene7, 4~piperidino-spiro/cyclohexane-1 ,9 ' -thioxanthene7, 4—morpholino-spiro/cyclohexane- ,9' -thioxanthene_7 and 4-(4—methylpiperazino)-spiro/cyclohexane-1 ,9 ' -thioxanthene7; dihydrochloride, m.p. 287°· Example 14 a) 10 g of crude 4-benzylamino-spiro/cyclohexane- thioxantherfe7-4-one by reaction with benzylamine to form -benzylimino-spiro cyclohexane-1 ,91 -thioxanthene followed by reduction with LiAlH^) were dissolved in 200 ml of methanol and, after the addition of 6 g of Raney nickel, hydrogenation was effected at 60-70° and IOO-I5O atmospheres. -Amino-spiro^cyclohexane- ,9 ' -thioxanthen 7 was obtained; hydrochloride, m.p. 310° . b) Hydrogenation of -benzylimino-spiro-^cyclohexane-1 ,9'-thioxanthene7 in methanol in the presence of Raney nickel gave -amino-spiro cyslohexane- ,9'-thioxanthene_7; hydrochloride, m.p. 310°.

Example 15 2.5 g of crude 4-benzylamino-spiro^cyclohexane-1 were dissolved in 50 ml of methanol, and, after the addition of 200 mg of 5% palladium charcoal, were hydrogenated until completion at room temperature and normal pressure. The solution was filtered from the catalyst, acidified with dilute hydrochloric acid, and the methanol was removed in vacuo. The remaining aqueous solution was rendered alkaline with caustic soda solution, and extracted with ether. Drying and stripping of the ether from the ethereal extract gave -amino-spiro cyclohexane-1 ,9'-thioxanthene7.

Hydrochloride, m.p. 310° (from ethanol/ether).

Example 16 8.2 g of -phthalimido-spiro^cyclohexane- ,9 ' -thioxanthene7 (obtainable from -chloro-spiro cyclohexane-1 ,9'-thioxanthene7 by reaction with potassium phthalimide and 1 .3 g of 80% hydrazine hydrate in ethanolic suspension centrated hydrochloric acid were then* added and the phthalic acid hydrazide was filtered off hot after 30 minutes. The filtrate was evaporated -and gave 4- amino-spiro^cyclohexane-l ,9'-thioxanthene7> hydrochloride, m.p. 310° .

Example 17 1 g of 4-phthalimido-spiro cyclohexane-1 ,9 ' - thioxanthene7 was boiled with 10 ml of concentrated hydrochloric acid for 6 hours. The bulk of the hydrochloric acid was distilled off, the solution was rendered alkaline with caustic soda solution, and the base was extracted with ether. After drying of the ethereal solution, ethereal hydrochloric acid was added and 4- amino-spiro cyclohexane-1 , 9 ' -thioxanthene7 hydrochloride was filtered off; m.p. 310° (from ethanol/ether) .

Example 18 12 g of 4-chloro-spiro^cyclohexane-1 ,9'-thiox-anthene_7 were dissolved in 60 ml of absolute tetrahydro- furan. A few ml of this solution were allowed to run into a suspension of 1 .1 g of magnesium chips in 10 ml of absolute tetrahydrofuran and, after the addition of iodine, the mixture was heated at 50-60° until the reaction started. The remainder of the solution was slowly added dropwise to the reaction mixture, heating being continued,- and the mixture was agitated, while maintaining the temperature at 50-60° , until a considerable proportion of the magnesium had been consumed. The mixture was cooled to -10° and, at this temperature, a solution of 2 g of O-methyl-hydroxylamine in absolute continued for 2 hours at -10° and for 2 hours at room temperature. The mixture was decomposed by the addition of aqueous hydrochloric acid, the bulk of the tetrahydrofuran was removed, the solution was washed with ether, the acid aqueous phase was rendered alkaline with caustic soda solution and extracted with ether. The alkaline ether extract gave -amino-spiro^cyclohexane- ,9'-thioxanthene7; . hydrochloride, m.p. 310°.

The following were obtained similarly with , 0,N-dimethyl- and Ο,Ν,Ν-trimethylhydroxylamine: 4-methylamino-spiro^cyclohexane-1 ,9' -thioxanthene/; hydrochloride, m.p. 279° and 4-dimethylamino-spiro cyclohexane-1 , 1 -thioxanthene7; hydrochloride, m.p. 270°.

Example 19 A mixture of 13 g of sulphur dichloride and 17.4 g of anhydrous aluminium chloride in 0 ml of carbon disulphide was added to 24.8 g of dimethylamino-4,4-diphenyl-cyclohexane hydrochloride and the mixture was agitated for 13 hours at 30°. The mixture was then poured on to hydrochloric acid-containing ice, the organic layer was separated and tartaric acid was added to the aqueous layer. Caustic soda solution was then added and the aqueous layer was extracted with ether to give 4-dimethylamino-spiro^/cyclohexane-1 ,9'-thioxanthene_7; hydrochloride, m.p. 270°.

Similarly, N-methyl-N-ethylamino-4,4-diphenyl-cyclohexane hydrochloride • N-methyl-N-n-propylamino-^^-diphenyl-cyclohexane hydrochloride gave: 4-(N-methyl-N-ethylamino)-spiroii/cyclohexane- ,9 ' -thioxanthene7; hydrobromide , m.pe 228°; -(N-methyl~N-n-propylamino)-spiro cyclohexane-1 ,9'-thioxan- thenej7; hydrochloride, m.p. 217°· The following examples illustrate pharmaceutical compositions containing the new compounds: Example A ' Tablets Each tablet contains: -methylamino-spiro^cyclohexane- , 9 ' - hioxanthene7 hydrochloride: 2 mg lactose: 70 mg corn starch: . 26 mg magnesium stearate: 2 mg Example B Coated tablets Each, tablet contains: 4-dimethylamlno-spiro/cyclohexane-1 ,,9 ' -thioxanthene7 hydrochloride: 3 m lactose: 80 mg potato starch: 15 m talcum: 2 mg The coating (150 mg) is a conventional mixture of corn starch, sugar, talcum and tragacanth.

Example C Injection solution A solution bf 2 kg of -methylamino-spiro cyclO' hexane-1 ,9'-thioxanthene/ hydrochloride in 998 kg of distilled water was prepared and packed in ampoules so that each ampoule contained 2 mg of the hydrochloride.

Example D Syrup A mixture of 2' -chloro- -methylamino-spiro cVclohexane-1 ,9'-thioxanthene hydrochloride: 0.2 kg glycerin (2 x distilled): 7«5 kS cane sugar: 56.0 kg methyl-p-hydroxybenzoate: 0.07 kg n-propyl-p-hydroxybenzoate: , 5 0.03 kg i '■ ethanol: 10.0 kg fruit flavouring (as required) was prepared and mixed with distilled water so that the volume of the total mixture was 100 litres. A dosage unit (5 ml) contains 10 mg of active substance.

Instead of the salts of the active- substances indicated in Examples A - D, other physiologically acceptable acid addition salts of these compounds, the corresponding free bases or other compounds of formula I, and their physiologically acceptable acid addition salts and quaternary ammonium salts, may be used.

Claims (30)

WHAT WE CLAIM IS:

1. A 4-amino-spiro^/cyclohexane- ,9'-thioxanthene7 compound of formula I in which R is H or an alkyl group with up to 6 carbon atoms, p R is H or an alkyl group with up to 3 carbon atoms, or R1 and R2, together with the nitrogen atom to which they are attached, forma morpholine ring or a pyrrolidine, piperidine or piperazine ring which ..may, if desired, be substituted by a methyl or ethyl group, and R5 and R are H or CI, or a physiologically acceptable acid addition salt or quaternary ammonium salt thereof.

2. A -amino~spiro cyclohexane-1 ,9'-thioxanthene7 compound of formula IX herein, or a physiologically acceptable acid addition or quaternary ammonium salt thereof.

3. A -amino-spiro cyclohexane-1 ,9'-thioxanthene7 compound of formula X herein, or a physiologically accept- able acid addition or quaternary ammonium salt thereof.

4. 4-Amino-spiro^cyclohexane-1 i l-"thioxanthene7»

5. 4-Methylamino-spiro cyclohexane- ,9'-t ioxanthene7o

6. 4-Ethylamino-spiro^cyclohexane-1 ,9'-thioxanthene_7»

7. 4-n-Propylami*i0-spiro cyclohexane-1 ,9'-thioxanthene7«

8. 4-Isopropylamino~spiro cyclohexane-1 ,9'-thioxan-thene7.

9. · 4-Dimethylamino-spiro^cyclohexane-1 ,91 -t ioxanthene7.

10. -(N-methyl-N-ethyl-amino)-spiro cyciohexane- ,9'-thioxanthene_7· *

11. -(N-riethyl-N-n-propyl-amino)-spiro cyclohexane-

12. 4-(N-Methyl-N-isopropyl-amino)-spiro cyclohexane-1 ,9'-thioxanthene7«

13. 4-(4-Nethylpiperazino)-spiro/cyclohexane- ,9'-thioxanthene7.

14. 4-Hethylamino-2'-chloro-spiro/cyclohexane--1 ,91 — thioxanthene7.

15. 4-Dimethylamino-2' -chloro-spiro cyclohexane-1 ,9 '-thioxanthene7.

16. An acid addition salt of the compound claimed in any of claims 4 to 15 ·

17. . The hydrochloride, hydrobromide or hydrogen malonate of the compound claimed in any of claims to 15

18. N,N,N-Trimethyl-N-spiro cyclohexane-1 ,9'-thiox-anthene7-(4)yl ammonium bromide.

19. A pharmaceutical composition comprising at least one compou d as claimed in any of claims 1 to 18 and an inert, physiologically acceptable, carrier.

20. A pharmaceutical composition according to claim 19 in dosage unit form, each dosage unit containing from 2 to 100 mg of said compound.

21. A process for the preparation of a 4-aminb-spiro cyclohexane-1 ,9'-thioxanthene7 compound of formula 1 specified in claim 1 , which comprises reducing a compound of formula II * in which the dashed line in the cyclohexane ring represents a double bond that may, if desired, be present in this position in the compound of formula II, X is =NOH, =NR1, (H,NR2Ac1) or (H,NR1Ac2) or another group which can be converted by reduction to the group NR 1R2, Ac1 is an acyl radical with up to 6 carbon atoms, Ac is an acyl radical with up to 3 carbon atoms, and R 1 , R2, and R4 have the meanings specified in claim , by treatment with a reducing agent.

22. A process for the preparation of a 4-amino-spiro/cyclohexane-1 ,9'-thioxanthene7 compound of formula I specified in claim 1, which comprises reducing an enamine of formula III in which the dashed line has the meaning specified in claim 21 and R 1 , R2, and R4 have the meanings specified in claim 1, by treatment with a reducing agent.

23. A process for the preparation of a 4-amino-spiro ^cyclohexane-1 ,9'-thioxanthene7 compound of formula I specified in claim 1 , which comprises reacting a compound of formula IV in which Y is CI, Br, I, OH, or a reactively esterified OH group, and R and R4 have the meanings specified in 1 2 claim 1, with a base of the formula, E B HE, in which R1 and R2 have the meanings specified in claim , or with a reactant that yields such a base.

24. A process for the preparation of a 4-amino-spiro cyclohexane- ,9' -thioxanthen 7 compound of formula I specified in claim 1 , which comprises hydro-genolysing, hydrolysing, alcoholysing or aminolysing a compound corresponding to formula I and in which the amino group is present in a functionally modified form, in order to liberate the amino group.

25. · A process for the preparation of a 4-amino-spiro cyclohexane-1 ,9'-thioxanthene7 compound of formula I specified in claim , which comprises reacting an organometallic compound of formula VI M in which M is Li or MgHal,,Hal is CI, Br or I, and Ir■5 and R4 have the meanings specified in claim , with a hydroxylamine derivative of the formula, R 1E2NA, in which A is an alkoxy group having 1 to carbon atoms or Hal, and R1 and R2 have the meanings specified in claim 1.

26. A process for the preparation of a 4-amino-spiro cyclohexane-1 ,9'-thioxanthene7 compound of formula I specified in claim , which comprises reacting a compound of formula VIII in which R , R , R"^ and R have the meanings specified in claim 1 , with a thioether-bridge-forming reactant in order to obtain intramolecular cyclisation.

27. · A' process according to any of claims 21 to 26, in which a primary or secondary amine of formula I (R = H) is obtained and is then treated with an alkylating agent.

28. A process according to any of claims 21 to 27» in which a base of formula I is obtained and is converted into a physiologically acceptable acid addition or quaternary ammonium salt thereof by treatment, respectively, with an acid or a quaternising agent, or in which a salt of a compound of formula I is obtained and is treated to liberate the base therefrom.

29. · A process for the preparation of a -amino-spiro cyclohexane- ,9'-thioxanthene7 compound of formula I specified in claim 1 substantially as herein described in any of Examples 1 to 19·

30. A pharmaceutical composition according to claim 19 substantially as herein described in any of Examples A to D. COHEN ZEDEK & SPISBACH P. O. Box 33116 , Tel-Aviv Attorneys for Applicant