GB1594914A - Thioxanthene compounds - Google Patents

Description

(54) THIOXANTHENE COMPOUNDS (71) We, YOSHITOMI PHARMACEUTICAL INDUSTRIES LTD, a Japanese Company of No. 35, Hirano-machi 3-chome, Higashi-ku, Osaka-shi, Osaka, Japan do hereby declare the invention for which we pray that a Patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement:- This invention relates to thixanthene compounds and acid addition and quaternary ammonium salts thereof having therapeutically valuable properties, methods for the manufacture of such compounds, pharmaceutical composition containing the said compound and the use thereof.

According to one aspect of the present invention, there is provided a thioxanthene compound of the formula:

or a pharmaceutically acceptable acid addition or ammonium salt thereof, wherein X is hydrogen, C, to C5 (e.g. methyl, ethyl, propyl, isopropyl, butyl or pentyl) halogen (F, Cl, Br or 1), -CF3, -S-R1, -SO2-R1 or -SO-N(R1)2 where R1 is C1 to C5 alkyl; y is hydrogen or fluorine; the dotted line in Ring A is an optical bond, namely Ring A is cyclohexane ring or cyclohexene ring; and Am is a group of the formula:

wherein Z is > N- or > CH-; n is 2 or 3; R is -OH,

where R4 is C1 to C5 alkyl; and R2 and R3 are independently hydrogen, halogen or -CF3.

Preferred classes of thioxanthene compounds of formula (I) are those wherein Am represents a group of the formula:

wherein Z, n and R are as defined above.

The compounds of formula (I) can be produced advantageously by one of the following methods I and II: Method I Reaction of a compound of the formula:

with a compound of the formula: H-Am (III) wherein X, Y, Am and the dotted line in Ring A are as defined above, and represents a reactive atom or group such as halogen (Cl, Br or I) or organic sulfonyloxy (e.g. methylsulfonyloxy orp-tolylsulfonyloxy).

The reaction is usually carried out in an inert solvent such as methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide or N-methylpyrrolidone, in the presence of an acid acceptor such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide lithium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium acetate, potassium acetate, triethylamine or pyridine, if desired in the presence of a catalyst such as potassium iodide, at a temperature of from 10 to 2000 C, for a period of from 30 minutes to several days.

Method II Dehydration reaction of a compound of the formula:

with a compound of formula (III) mentioned above, and reduction of the resulting compound of the formula:

wherein X, Y, Am and the dotted line in Ring A are as defined above.

The dehydration reaction is usually carried out in an inert solvent such as mentioned for Method I, preferably benzene, toluene or xylene, in the presence of an acid catalyst such as hydrogen chloride, sulfuric acid orp-toluenesulfonic acid, at a temperature of from room temperature to a boiling point of the solvent employed, for a period of from several hours to several days.

The enamine intermediate of formula (V) can be isolated and purified by a conventional method such as distillation, recrystallization or chromatography. The isolation is, however, not always necessary.

The reduction includes catalytic and chemical reductions. The catalytic reduction is carried out over a metal (e.g. palladium, platinum, rhodium, nickel, ruthenium or cobalt) on a carrier (e.g. active carbon, alumina, barium sulfate, calcium carbonate or strontium carbonate), in an inert solvent such as mentioned for Method I. The reaction time is dependent on reaction conditions such as pressure and temperature, and many hours are required at room temperature and atmospheric pressure. The chemical reduction is carried out by the use of formic acid (or its derivative) or a complex metal hydride. The reduction by the use of formic acid is usually carried out by adding formic acid to a compound of formula (V), and maintaining the resulting mixture at an elevated temperature. The reduction by the use of a complex metal hydride is carried out in an inert solvent such as mentioned for Method I, at a temperature of from 0 C to the boiling point of the solvent employed, for a period of from several minutes to about 10 hours.

The complex metal hydride includes, for example, lithium aluminum hydride sodiumborohydride, lithium borohydride, boron hydride (e.g. borane or diborane) and NaAl(OCH2CH2OCH3)2H2, and a combination of, for example, lithium aluminium hydride -- aluminium chloride or sodium borohydride -- aluminium chloride may also be use. In the case where a double bond is existent in Ring A, the chemical reduction is preferred.

The thioxanthene compounds of this invention may be present as optical isomers, diastereomers, configrational isomers as well as mixtures of these isomers.

A mixture of the isomers, if desired, may be separated in a conventional manner into the individual isomers.

The compounds of formula (I) can be converted into acid addition salts with various inorganic and organic acids (e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, fumaric, succinic, citric or tartaric acid), and also into quaternary ammonium salts with dimethyl sulfate, diethyl sulfate, methyl iodide, ethyl bromide, etc.

The compounds of formula (I) and salts thereof exhibit potent and long-lasting central nervous system depressant effects (especially sedative actions) such as antiapomorphine effect, norepinephrine turnover acceleration, potentiation of chlorprothixene or hexobarbital narcosis, anti-methamphetamine effect, effect on spontaneous locomotor activity, effect on conditioned avoidance response, taming effect, slow waves inducing action on spontaneous electroencephalogram and loss of righting reflex. Thus, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a salt thereof as defined hereinabove, in combination with a pharmaceutically acceptable inert carrier, such compound being present in therapeutically effective amount.

Pharmacological Properties 1. Test Compounds: A: 4 - [4 - (2 - hydroxyethyl) - 1 - piprazinyl] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' - thioxanthene] dimaleate (a mixture of the con figurational isomers in Example 1) B: 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' - thioxanthene] dimaleate (the configurational isomer B in Example 1) C: 4 - [4 - (2 - hydroxyethyl)piperidino] - 2' - trifluoromethyl - spiro[cyclo hexane - 1,9' - thioxanthene] 1/2 - fumarate D: 4 - [4 - (2 - (2 - oxo - 3 - oxazolidinyl)ethyl) - 1 - piperazinyl] - 2' - trifluoro methyl - spiro[cyclohexane -1,9' - thioxanthene] dimaleate E: 6' - fluoro - 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] - 2' - trifluoro methyl - spiro[cyclohexane - 1,9' - thioxanthene] dimaleate F: 6' - fluoro - 4 - [4 - (2 - hydroxyethyl)piperidino] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' - thioxanthene] 1/2 - fumarate Haloperidol (comparison): 1 - [3 - (p - fluorobenzoyl)propyl] - 4 - (p chlorophenyl) - 4 - piperidinol Pimozide (comparison): I - Il - (4,4 - bis(p - fluorophenyl)butyl) - 4 - piperidyl] - 2 - benzimidazolinone Flupenthixol (comparison): 9 - [3 - (4 - (2 - hydroxyethyl) - 1 - piperazinyl)propylidene] - 2 - trifluoromethyl - thioxanthene 2. Animals: The animals used were dd-strain mice weighing 20-25 g and Wistar strain rats weighing 150-200 g.

3. Methods and Results: (a) Anti-apomorphine Effect The test was performed essentially by the method described by Paui A.J.

Janssen et al. in "Arzneimittel-Forschung," vol. 17, 841 (1967). Groups of 7-14 female rats each were used. The test compound was administered orally 1 to 24 hours prior to the treatment with apomorphine hydrochloride (1.25 mg/kg, i.v.).

Five and 20 minutes after the apomorphine treatment, the effects of the test compound on the gnawing behavior were examined respectively for 5 minutes. The ED50, a 50% effective dose was determined on the basis of the maximal inhibitory rate. The results are summarized in Table I wherein the ED50 value is expressed in terms of the base.

TABLE I

Test Compound ED 5 0 mg/kg, p.o.

A 0.075 B 0.043 C 0.089 D 0.070 E 0.067 F 0.045 Haloperidol 0.45 Pimozide 0.25 F lopenthixol 0.186 Anti-apomorphine effect was examined in respect of its durability at a dose of ED50 value obtained by the above method. The results are summarized in Table II.

TABLE II

Inhibition - hr 1 3 6 18 24 48 72 96 120 144 168 Test Compound N p.o.

A O 0 7.1 14.3 42.9 64.3 14.3 0 B (0.043) 0 14.3 35.7 14.3 0 C -(0.089) 0 28.6 42.9 35.7 7.1 0 D rJ o o o 9 9 m O CCI 53.6 57.1 .50.0 39.3 35.7 2-1.4 7.1 c o Oo en as H ~ ~ H (0.045) es r- F b > b" tn v, Haloperidol COAS) oo 50.0 -N m -N vD t m t . m oo 57.1 35.7 7.1 H t t m (0.186). 14;3 35.7 57.1 35.7 7.1 / o < o ( ) o a o O O o O E = o 1/ c= =: Pz L V E < Oe (b) Norepinephrine Turnover Acceleration The turnover of norepinephrine was estimated in the mouse by measuring the content of 3 - methoxy - 4 - hydroxyphenylglycol (MHPG) according to the method described by J.L. Meek et al. in "Journal of Pharmacology and Experimental Therapeutics", vol. 184, 570 (1973).

Mice were killed by decapitation one hour after the treatment with probenecid (200 mg/kg, i.p.). The test compound was administered orally 5 hours before probenecid. The whole brain was immediately removed and washed thoroughly with saline to remove the blood. The brains of three mice were pooled and frozen on dry ice and stored at -800C for subsequent biochemical determination. MHPG was assayed by the gas chromatographic technique according to the method described by C. Braestrup.in "Analytical Biochemistry," vol. 55, 420 (1973), and the ED30, an effective dose required to cause the increase of norepinephrine turnover by 30%, was determined. The results are summarized in Table III wherein the ED30 value is expressed in terms of the base.

TABLE III

Test Compound End30 mg/kg, -P.o.

A 0.29 B 0.20 Haloperidol 2.5 Pimozide 25 Flupenthixol 5.14 (c) Potentiation of Chlorprothixene Narcosis Groups of 7 male mice each were used. The animals were placed in a box kept at 26"C. The test compound was administered orally I to 6 hours prior to the treatment with subnarcotic dose of chlorprothixene hydrochloride (25 mg/kg, p.o.).

The righting reflex was tested one hour after chlorprothixene. The PD50 was calculated by the probit method as the dose with caused loss of. righting reflex for more than 3 seconds in half the mice. The results are summarized in Table IV wherein the PD50 value is expressed in terms of the base.

TABLE IV

Test Compound PD,,mg/kg, p.o.

A 0.34 B 0A8 E 0.06 Haloperidol 13,89 Flupenthixol 3.13 In view of various tests, including those mentioned above, the compounds of the invention represented by formula (I), in base or salt form, are useful as antipsychotic drugs, antianxiety drugs, sedatives, sleep-inducers, potentiating anesthetics, and so on, in the form of a pharmaceutical preparation with a suitable and conventional pharmaceutically acceptable carrier, without adversely affecting the patients.

The pharmaceutical preparations can take any conventional form such as tablets, capsules, granules or powders. The compounds of the invention are very stable in aqueous solutions, and therefore they can also be used in the form of injectable solutions.

The following is an example of formulations when a compound of the invention is administered for pharmaceutical purposes: (a) Tablets are prepared from the following compositions: 0.5 mg 1.0 mug 5.Omg Tablets Tablets Tablets Compound (I) or its salt 0.5 mg 1.0 mg 5.0 mg Lactose 48.1 47.6 43.6 Microcrystalline Cellulose 25.0 25.0 25.0 Corn Starch 20.0 20.0 20.0 Methyl Cellulose 0.4 0.4 0.4 Talc 6.0 6.0 6.0 Total 100 mg 100 mg 100 mg (b) Injectable solutions (1 mg/2 ml or 5 mg/2 ml) are prepared from the following compositions: Compound (I) or its salt 0.05% 0.25% Glucose 5% 5% Water for Injection a sufficient amount to make 2 ml The dose of compound (I) or a salt thereof for human adults usually ranges from 1 to 10 mg per day for oral administration, in single or multiple dose, but it may vary depending upon the age, body weight, and/or severity of the conditions to be treated as well as the response to the medication.

The present invention will be better understood from the following examples, but they are not to be construed as limiting the present invention.

Example 1.

A mixture of 6.5 g of 2' - trifluoromethyl - spiro[cyclohexane - 1,9' thioxanthene] - 4 - one, 5.0 g of N - (2 - hydroxyethyl)piperazine, a catalytic amount of p-toluenesulfonic acid and 40 ml of toluene is heated with stirring for 12 hours, while the water formed is removed. The toluene is then removed under reduced pressure. The residue (crude 4- [4- (2 - hydroxyethyl) - 1 - piperazinyl] - 2' - trifluoromethyl - spiro[3 - cyclohexene - 1,9' - thioxanthene]) is dissolved in 70 ml of methanol whereupon 7.2 g of sodium borohydride is added slowly and the mixture is refluxed for 30 minutes. The methanol is removed, and a saturated ammonium chloride solution is added to the residue and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent is removed. Thus is obtained 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' - thioxanthene]. This product is a mixture of the configurational isomers. The corresponding dimaleate is obtained by adding a solution of maleic acid in methanol to a solution of the base in acetone, and melts at 191"C with decomposition. Isomer A is obtained as white crystals after repeated recrystallization of the above free base mixture from acetone and melts at 174--175"C. The dimaleate of Isomer A occurs as white crystals with a melting point of 199"C (decomposition). Isomer B is recovered as white crystals from the acetone solution obtained frdm the separation of Isomer A and melts at 161--162"C after repeated recrystallization from ligroin. The dimaleate of Isomer B occurs as white crystals with a melting point of 194 C (decomposition).

Example 2.

A mixture of 0.9 g of 4 - chloro - 2' - fluoro - spiro[2 - cyclohexene - 1,9' thioxanthene], 0.37 g of N - (2 - hydroxyethyl)piperazine, 0.39 g of potassium carbonate, 0.47 g of potassium iodide and 15 ml of dimethylformamide is heated at 65-700C with stirring for 3 hours. Water is added to the reaction mixture, and the separated oil is extracted with benzene. The extract is dried over anhydrous magnesium sulfate, and the solvent is removed. The free base thus obtained is converted into the maleate by the conventional method to give 2' - fluoro - 4 [4 - (2 - hydroxyethyl) - I - piperazinyl] - spiro[2 - cyclohexene - 1,9' thioxanthene] dimaleate, melting at 1570C with decomposition.

Example 3.

A mixture of 5.6 g of 2' - fluoro - 4 - (p - tolylsulfonyloxy) - spiro [cvclohexane - 1,9' - thioxanthene], 1.6 g of N - (2 - hydroxyethyl)piperazine, 1.7 g of potassium carbonate, 2.0 g of potassium iodine and 25 ml of toluene is refluxed with stirring for 92 hours. After cooling water is added to the reaction mixture. The toluene layer is separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure.

The residue is purified by column chromatography on silica gel using chloroform - methanol (9:1) as an eluent. Thus is obtained 2' - fluoro - 4 - [4 - (2 hydroxyethyl) - 1 - piperazinyl] - spiro[cyclohexane - 1,9'-thioxanthene]. The corresponding dimaleate occurs as white crystals with a melting point of 153"C (decomposition).

Example 4.

A mixture of 7.9 g of 2' - chloro - 4- methylsulfonyloxy spiro[cyclohexane - 1,9'-thioxanthene], 5.0 g of 5 - chloro - 1 - (4 - piperidyl) 2 - benzimidazoline, 2.7 g of potassium carbonate, 3.2 g of potassium iodide and 50 ml of dimethylformamide is stirred at 650C for 90 hours. The reaction mixture is cooled to room temperature and poured into ice water. The precipitate is dissolved in chloroform. The solution is washed with water and dried over anhydrous magnesium sulfate, and the solvent is removed. The residue is purified by column chromatography on silica gel using chloroform - methanol (9:1) as an eluent. Thus is obtained 2' - chloro - 4 - [4 - (5 - chloro - 2 - oxo - 1 - benzimidazolinyl)piperidino] - spiro[cyclohexane - 1,9' - thioxanthene]. The corresponding hydrochloride (3/4H2O) occurs as white crystals and melts at 293"C with decomposition.

Example 5.

A mixture of 4.0 g of 2' - chloro - 4- - methylsulfonyloxy spiro[cyclohexane - 1,9' - thioxanthene], 2.5 g of 4 - chloro - 3 - trifluoromethylphenyl) - 4 - piperidinol, 1.2 g of potassium carbonate, 1.5 g of potassium iodide and 20 ml of toluene is refluxed with stirring tor 92 hours. The toluene layer is then washed with water and dried over anhydrous magnesium sulfate, and the toluene is removed. The residue is purified by column chromatography on silica gel using chloroform - methanol (9:1) as an eluent. Thus is obtained 2' - chloro - 4 - [4 (4 - chloro - 3 - trifluoromethylphenyl) - 4 - hydroxypiperidino] spiro[cyclohexane - 1,9'-thioxanthene]. The corresponding hydrochloride occurs as white crystals and melts at 2790C with decomposition.

Examples 6 to 29.

Using the procedures set forth in the above examples, but substituting equivalent amount of the appropriate starting materials, the following compounds are also produced: (6) 4 - [4 - (2 - hydroxyethyl)piperidino] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' - thioxathen] 1/2-fumarate, m.p. 240"C (decomposition) (7) 4 - [4 - (3 - hydroxypropyl) - I - piperazinyl] - 2' - - trifluoromethyl spiro[cyclohexane - 1,9' - thioxanthene] dimaleate hemihydrate, m.p. 1830C (decomposition) (8) 4 - [4 - (2 - (2 - oxo - 3 - oxadizolidinyl)ethyl) - 1 - piperazinyl] - 2' trifluoromethyl - spiro[cyclohexane - 1,9' - thioxanthene] dimaleate, m.p.

185 C(decomposition) (9) 4 - [4 - (2 - (3 methyl - 2 - oxo - I - imidazolidinyl)ethyl) - 1 - piperazinyl]- 2' - trifluoromethyl - spiro[cyclohexane - 1,9' - thioxanthene] (10) 4. [4 - (2 - hydroxyethyl) - I - piperazinyl] - spiro[cyclohexane - 1,9' - thio xanthene] dimaleate hemihydrate, m.p. 167-169 C (Il) 2' - ethyl - 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] spirocyclohexane - 1,9' - thioxanthene] dihydrochloride 1/4 - hydrate, m.p.

279 C(decomposition) (12) 2' - ethyl - 4 - [4 - (2 - hydroxyethyl)piperidino] - spiro[cyclohexane - 1,9' thioxanthene], m.p. 181--1840C (13) 2' - chloro - 4 - [4 - (2- hydroxyethyl) - I - piperazinyl] - spiro[cyclohexane 1,9' - thioxanthene] dimaleate 1/4 - hydrate, m.p. 1770C (decomposition) (14) 2' - chloro - 4 - [4 - (2 - hydroxyethyl)piperidino] - spiro[cyclohexane 1,9' - thioxanthene] 1/2-fumarate, m.p. 2560C (decomposition) (15) 2' - fluoro - 4 - [4 - (2 - hydroxyethyl)piperidino] - spiro[cyclohexane 1,9' - thioxanthene] 1/2-fumarate, m.p. 250 C(decompositon) (16) 6' - fluoro - 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] - 2' trifluaromethyl - spiro[cyclohexane - 1,9' - thioxanthene] dimaleate, m.p.

187 C(decomposition) (17) 6' - fluoro - 4 - [4 - (2 - hydroxyethyl)piperidino] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' - thioxanthene] 1/2-fumarate, m.p. 244 C (decomposition) (18) 4 - [4 - (2 - hydroxyethyl) - I - piperazinyl] - 2' - methylthio spiro[cyclohexane - 1,9' - thioxanthene] dimaleate, m.p. 182 C (decomposition) (19) 4 - [4 - (2 - hydroxyethyl) - I - piperazinyl] - 2' - methylsulfonyl - spiro [cyclohexane - I ,9' - thioxanthene] dimaleate, m.p. 154-l560C (20) 4 - [4 - (2 - hydroxyethyl)piperidino] - 2' - methylsulfonyl sDiro[cyclohexane - 1,9' - thioxanthene], m.p. 216--2180C (21) 2' - dimethylsulfamoyl - 4 - [4 - (2 - hydroxyethyl) - I - piperazinyl] spiro[cyclohexane - 1,9' - thioxanthene] dimaleate hemihydrate, m.p. 186 C (decomposition) (22) 2' - chloro - 4 - [4 - (2 - hydroxyethyl) - I - piperazinyl] - spiro[2 cyclohexene - 1,9' -thioxanthene] dimaleate, m.p. 163"C (decomposition) (23) 2' - chloro - 4 - [4 - (5 - chloro - 2 - oxo - I - benzimidazolinyl)piperidino] spiro - [2 - cyclohexene - 1,9' - thioxanthene] hydrochloride, m.p. 290 C (decomposition) (24) 4 - [4 - (5 - chloro - 2 - oxo - 1 - benzimidazolinyl)piperidino] - 2' trifluoromethyl - spiro[cyclohexane - 1,9'-thioxanthene] maleate, m.p. 223 C (decomposition) (25) 2' - chloro - 4 - [4 - (4 - chloro - 3 - trifluoromethylphenyl) - 4 hydroxypiperidino] - spiro[2 - cyclohexene - 1,9' - thioxanthene] hydrochloride, m.p. 2610C (decomposition) (26) 2' - chloro - 4 - - [1 - (4 - chlorophenyl) - 4 - oxo - 1,3,8 triazaspiro[4,5]decan - 8 - yell - spiro[2 - cyclohexene - 1,9' - thioxanthene] hydrochloride, m.p. 284 C (decomposition) (27) 2' - chloro - 4 - [1 - (4 - fluorophenyl) - 4 - oxo - 1,3,8 triazaspiro[4,5]decan - 8 - yl] - spiro[cyclohexane - 1,9' - thioxanthene] hydrochloride monohydrate, m.p. 289 C (decomposition) Starting Materials The starting materials, namely compounds of formula (II) and (IV) to be used in the production of the compounds of the present invention can be prepared by conventional methods described in the following reaction scheme

x x x x 4 e CHIPCH2HgC1--J S 0 CHpcHgC1 S CH2OCH3 Y Y x x S CHOCH3 HC00}1/H2so4 ECHO HN Sr= d y X x CHZ=CHCOCH S CHNZ ' + S < =O a H2 y (IV-a) x S0 W0 y y ('V)

x NaBHq S A OH esterifying agent y x S A T (tri) y esterifying agent: Pals, p-CH3C6H4SO2CI, CH3SO2CI, etc.

Preparative Example A To 300 ml of tetrahydrofuran (THF) are added 52.5 g of magnesium turnings and 4 g of murcuric chloride, and the mixture is stirred under a nitrogen atmosphere for about 30 minutes whereupon a solution of 174 g of chlorodimethyl ether in 300 ml of THF is added dropwise over a period of about 2 hours.

Immediately after the beginning of the reaction the mixture is cooled to -50C to -lO0C, and the same temperature is maintained during the addition. After the addition is complete, the mixture is stirred for one hour, and an additional 1.3 liters of THF is added. To the Grinnard reagent is added by portions 200 ml of 2 trifluoromethyl - thioxanthone over a period of 30 minutes. The temperature of the mixture is maintained at --50 to -100C for 30 minutes and then at room temperature for 30 minutes, and finally raised to 400 C. The reaction mixture is then cooled and treated with a saturated ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The solvent is removed from the extract and the residue is distilled to give 9 - methoxymethylene - 2 - trifluoromethylthioxanthene, boiling at 1670C/0.12 mmHg (during the distillation 9 - methoxy methyl - 2 - trifluoromethyl - thioxanthen - 9 - ol formed by the reaction is dehydrated to 9 - methoxymethylene - 2 - trifluoromethyl - thioxanthene).

140 g of 9 - methoxymethylene - 2 - trifluoromethyl - thioxanthene is added to 890 ml of 99% formic acid whereupon 61.5 ml of 2M sulfuric acid is added at 70"C and the mixture is stirred for 2.5 hours. The reaction mixture is poured into ice water and the aqueous mixture is extracted with ethyl acetate. The extract is washed successively with water, a dilute sodium hydrogen carbonate solution, and water and dried over anhydrous magnesium sulfate. The solvent is removed from the extract to give 2 - trifluoromethyl - thioxanthenecarbaldehyde as a viscous oil.

The 2,4- dinitrophenylhydrazone of this product melts at 1940C with decomposition.

A mixture of 102 g of 2 - trifluoromethyl - thioxanthene - 9 - carbaldehyde, 50 g of pyrrolidine and 500 ml of benzene is refluxed for one hour, while the water formed is removed. The reaction mixture is then washed with cold water and dried, and the benzene is removed to give pyrrolidine enamine of 2 - trifluoromethyl thioxanthene - 9 - carbaldehyde. This product, without purification, is reacted with 35 g of methyl vinyl ketone in 450 ml of benzene under reflux and a nitrogen atmosphere. After 65 hours 75 ml of acetic acid, 37.5 g of sodium acetate and 75 ml of water are added, and the resulting mixture is stirred under reflux for 4 hours. The reaction mixture is washed successively with water and an aqueous sodium hydrogen carbonate solution and dried, and 20 g of p-toluenesulfonic acid is added to the benzene solution. The mixture is stirred under reflux for 5 hours, while the water formed is removed. The reaction mixture is washed with water and dried, and the benzene is removed. The oily residue is crystallized from a mixture of n-hexane and ethanol to give 2' - trifluoromethyl - spiro[cyclohexane - 1,9' thioxanthene] -4 -one, melting at 100-102 C.

To a solution of 10 g of 2'-trifluoromethyl - spirol[2 - cyclohexene - 1,9' thioxanthene] - 4 - one in 200 ml of glacial acetic acid is added 4 g of 10% palladium carbon, and hydrogen is introduced at 600C for 12 hours. The catalyst is then filtered off, and water is added to the filtrate. The aqueous solution is made alkaline with potassium carbonate and extracted with benzene. The extract is washed with water and dried, and the benzene is removed. The oily residue is recrystallized from ethanol, and crude product is recrystallized from ethanol to give 2' - trifluoromethyl - spiro[cyclohexane - 1,9' - thioxanthene] - 4 - one, melting at 115-117 C.

The following compounds are prepared in an analogous manner: (a) spiro[2 - cyclohexene - 1,9' - thioxanthene] - 4 - one, m.p. 173--1750C (b) 2' - ethyl - spiro[2 - cyclohexene - 1,9' - thioxanthene] - 4 - one, m.p.

126--127"C (c) 2' - chloro - spiro[2 - cyclohexene - 1,9' - thioxanthene] - 4 - one, m.p.

122--124"C.

(d) 2' - fluoro - spi-ro[2 - cyclohexene - 1,9' - thoxanthene] - 4 - one, m.p.

135--136"C (e) 6' - fluoro - 2' - trifluoromethyl - spiro[cyclohexane - 1,9' thioxanthene] -4 -one, m.p. 100-102 C (f) 2' - methylthio - spiro[cyclohexane - 1,9' - thioxanthene] - 4 - one, m.p.

100-1020C (g) 2' - methylsulfonyl - spiro[2 - cyclohexene - 1,9' - thioxanthene] - 4 - one, m.p. 158-1600C (h) 2' - dimethylsulfamoyl-spiro[2 - cyclohexene-l,9' - thioxanthene] - 4 - one, m.p. 176-1780C (i) spiro[cyclohexane - I ,9' -thioxanthene] -4 -one, m.p. 156-1570C (j) 2' - ethyl - spiro[cyclohexane - 1,9 - thioxanthene] - 4 - one, m.p. 95--97"C (k) 2' - chloro - spiro[cyclohexane - 1,9' - thioxanthene] - 4 - one, m.p 1ll-1130C (1) 2' - fluoro - spiro[cyclohexane - 1,9' - thioxanthene] - 4 - one, m.p. 116-1 180C (m) 6' - fluoro - 2 - trifluoromethyl - spiro[cyclohexane - 1,9' - thioxanthene] 4 - one, m.p. 145-147 C (n) 2' - methylthio - spiro[cyclohexane - 1,9' - thioxanthene] - 4 - one, 2,4 dinitrophenylhydrazone: m.p. 118--1200C (o) 2' - methylsulfonyl - spiro[cyclohexane - 1,9' - thioxanthene] - 4 - one, m.p.

197--199"C (p) 2' - dimethylsulfamoyl - spiro[cyclohexane - 1,9' - thioxanthene] - 4 - one, m.p. 150-1520C Preparative Example B 2.6 g of sodium borohydride is added to a suspension of 20 g of 2' - fluoro spiro[2 - cyclohexane - 1,9' - thioxanthene] - 4 - one in 250 ml of ethanol, and the mixture is stirred at room temperature for one hour. The ethanol is then removed.

Water is added to the residue and extracted with chloroform. The extract is washed ;with water and dried, and the chloroform is removed to give 2' - fluoro - spiro[2 cyclohexene - 1,9' - thioxanthene] - 4 - ol, as a viscous oil. This product is used without purification to the next reaction. TLC (benzene): Rf = 0.1 6.3 g of phosphorus pentachloride is added to 50 ml of benzene whereupon a solution of 8.9 g of 2' - fluoro - spiro[2 - cyclohexene - 1,9' - thioxanthene] - 4 ol in 50 ml of benzene is added dropwise, and the mixture is stirred at room temperature for one hour. The reaction mixture is then poured into ice water, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water and dried, and the ethyl acetate is removed to give 4 - chloro - 2' - fluoro spiro[2 - cyclohexene - 1,9' - thioxanthene] as a viscous oil. TLC (benzene): R, = 0.8

Claims (22)

1. The following compounds are prepared in an analogous manner: (a) 2',4 - dichloro - spiro[2 - cyclohexene - 1,9' - thioxanthene], viscous oil; TLC (benzene): Rf = 0.8 (b) 2' - chloro - 4 - methyldulfonyloxy -spiro[cyclohexane - 1,9' - thioxanthene], viscous oil; TLC (benzene: Rf=0.5 (c) 2' - chloro - 4 - (p - tolylsulfonyloxy) - spiro[cyclohexane - 1,9' thioxanthene], viscous oil; TLC (benzene): Rf = 0.5 WHAT WE CLAIM IS: 1. A thioxanthene compound of the formula:

   or a pharmaceutically acceptable acid addition or ammonium salt thereof, wherein X is hydrogen, C1 to C5 alkyl halogen, -CF3, -S-R, -SO2-R or -SO2-N(R) where R is C1 to C5 alkyl; Y represents hydrogen of fluorine; the dotted line in Ring A is an optional bond; and Am is a group of the formula:

   wherein Z is > N- or > CH-; n is 2 or 3; R is -OH

   where R4 is C1 to C5 alkyl; and R2 and R3 are independently hydrogen, halogen or CH3
2. 2. A compound as claimed in Claim 1, wherein Am is a group of the formula:

   wherein Z, n and Rare as defined in Claim.
3. 3. 4 - [4 - (2 - Hydroxyethyl) - 1 - piperazinyl] - 2 - trifluoromethyl spiro[cyclohexane - 1,9' - thioxanthene]
4. 4. 2' - Fluoro - 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] spiro[cyclohexane - 1,9' - thioxanthene].
5. 5. 4 - [4 - (2 - (Hydroxyethyl)piperidino] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' -thioxanthene].
6. 6. 4 - [4 - (3 - Hydroxypropyl) - I - piperazinyl] - 2' - trifluoromethyl spiro[cyclohexane - 1,9' -thioxanthene].
7. 7. 4 - [4 - (2 - (2 - Oxo - 3 - oxazolisinyl)ethyl) - 1 - piperazinyl] - 2' trifluoromethyl -spiro[cyclohexane - 1,9' - thioxanthene]
8. 8. 2' - Chloro - 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] spiro[cyclohexane - 1,9' - thioxanthene]
9. 9. 2 - Chloro - 4 - [4 - (2 - hydroxyethyl)piperidino] - spiro[cyclohexane 1,9' -thioxanthene]
10. 10. 6' - Fluoro - 4 - [4 - (2 - hydroyethyl) - 1 - piperazinyl] - 2' trifluoromethyl -spiro -[cyclohexane - 1,9' - thioxanthene].
11. 11. 6' -Fluoro -4 -[4 -(2 -hydroxyethyl)piperidino] -2' -trifluoromethyl spiro -[cyclohexane - 1,9' - thioxanthene].
12. 12. 4 - [4 - (2 - Hydroxyethyl) - 1 - piperazinyl] - 2' - methylthio spiro[cyclohexane - 1,9' - thioxanthene].
13. 13. 4 - [4 - (2 - Hydroxyethyl) - 1 - piperazinyl] - 2' - methylsulfonyl spiro[cyclohexane - 1,9' - thioxanthene].
14. 14. 4 - [4 - (2 - Hydroxyethyl)piperidino] - 2' - methylsulfonyl spiro[cyclohexane - 1,9' -thioxanthene].
15. 15. 2' - Dimethylsulfamoyl - 4 - [4 - (2 - hydroxyethyl) - 1 - piperazinyl] spiro[cyclohexane - 1,9' - thioxanthene].
16. 16. 2' - Chloro - 4 - [4 -(5 - chloro - 2 - oxo - 1 benzimidazolinyl)piperidino] - spiro - [cyclohexane - 1,9' - thioxanthene].
17. 17. 4 - [4 - (5 - Chloro - 2 - oxo - 1 - benzimidanzolinyl)piperidino] - 2' trifluoromethyl -spiro[cyclohexane - 1,9' - thioxanthene].
18. 18. 2' - Chloro - 4 - [4 - (4 - chloro - 3 - trifluoromethylphenyl) - 4 hydroxypiperidino] -spiro[cyclohexane - 1,9' - thioxanthene].
19. 19. 2' - Chloro - 4 - [1 - (4 - fluorophenyl - 4 - oxo - 1,3,8 triazaspiro[4,5]decan -8 -yl] -spiro[cyclohexane - 1,9' - thioxanthene].
20. 20. A method for producing a tionxanthene compound of the formula:

    which comprises (a) reacting a compound of the formula:

    with a compound of the formula: H-Am or (b) reducing a compound of the formula:

    wherein X, Y, Am and the dotted line in Ring A are as defined in Claim 1, and T represents a reactive atom or group.
21. 21. A pharmaceutical composition comprising a compound as claimed in any one of claims I to 19 in combination with a pharmaceutically acceptable inert carrier, said compound being present in a therapeutically effective amount.
22. 22. A method as claimed in claim 20, substantially as hereinbefore described in any one of Examples 1 to 27.