IL29823A - Benzothioxanthene compounds,processes for their preparation,and pharmaceutical compositions containing them - Google Patents

Description

29823/2 JMK o» »3Dn ninpn »n»w3n i Benzothioxanthene compounds^aae. processes for their preparation, and pharmaceutical compositions containing them MERCK & CO., INC. , C: 28250 - la - 29823^ The present invention relates to new therapeutically useful benzothioxanthene derivatives, .their physiologically acceptable salts and a process. for their preparation.

The .benzothioxanthene. derivatives of the present invention correspond to. the formulae . wherein Y is hydrogen or hydroxy, R is lower alkyl of 1 to 6 carbon atoms and B is a fused benzene ring in the (a) or (c) position.

The above-described benzothioxanthene derivatives as shown in. the preceding formulae are prepared in accordance with this invention by reaction of a 5-chloro-2-naphthylthlo-benzolc acid having the formula wherein the naphthyl nucleus may be attached either at the 1 or 2- position. This naphthylthiobenzoic acid, I, is then heated in the presence of a dehydrating agent to produce a halogenated benzothioxanthenone of the formula wherein B is as previously described. The. derived benzo-thioxanthenone is then condensed with a γ-dialkylaminopropyl Grignard reagent followed by hydrolysis of the Grignard adduct to form a hydroxy-(y-dialkylan nopropyl)-halobenzothioxanthene having the ormula wherein B and R have the significance previously described. This intermediate hydroxy benzothloxanthene is new and forms part of the present invention. The compound of formula III is then reduced to the corresponding (γ-dialkylaminopropyl) halobenzothioxanthene by treatment with phosphorus and hydrogen iodide thereby converting the hydroxy substituent into a hydrogen and producing a compound having the formula wherein B and R have the significance ascribed thereto.

Alternatively, the compounds of formula III are contacted with a dehydrating agent to split out water - 2a.- 29823/2 from the hydroxy compounds thereby introducing an exocyclic double bond joining the side chain to the ring system and producing a compound having the formula This compound of formula IVB can likewise be converted into the corresponding dialkylaminopropylbenzothioxanthene, compound IVA shown hereinabove by reduction with phosphorus and hydrogen iodide or by catalytic hydrogenation to reduce the exocyclic double bond.

In a preferred embodiment of our process 5-chloro- 2-iodobenzoic acid is transformed in accordance with the following reaction scheme.

IVB IVA Thus, 5-chloro~2-iodo benzoic acid is condensed with 2 -naphthalene thiol at an elevated temperature of from 100-200°C. in the presence of copper powder and K2 O^, preferably with an added inert liquid diluent, to produce 5-chloro-2- (2-naphthylthio) benzoic acid. The thus-produced acid is con-veniently isolated by dilution of the reaction mixture with water, removal of insoluble material by filtration and precipitation of the thus-produced acid by acidification of the aqueous solution. The above-mentioned substituted benzoic acid is then treated with a dehydrating agent, preferably polyphosphoric acid for a period of several hours at a temperature of from about 100-200°C. to produce 10-chloro-12H-benzo [a] thioxanthenone. The product which is produced in good yield is conveniently isolated by precipitation with water, filtered, washed and dried. The thu^-produced ketone is then reacted in a low boiling inert solvent under anhydrous conditions with an equimolar amount of a γ-dimethylaminopropyl-magnesium halide to form the corresponding γ-dimethylamino-propyl carbinol, i.e. lO-chloro-12- (3-dimethylaminopropyl) -12-hydroxy-12H-benzo [a] thioxanthene. The product produced in this manner is readily recovered from the reaction mixture following hydrolysis by extraction with a hydrocarbon solvent such as benzene and removal of the solvent by distillation. under reduced pressure. The residual material comprising the intermediate carbinol is then reduced with red phosphorus and hydrogen iodide to produce the corresponding 10-chloro-12~ (3~dimethylaminopropyl) ~12H~benzo [a] thioxanthene which is conveniently recovered by neutralization of the reaction solution with alkali followed by extraction of the product from the alkaline reaction solution with benzene and pre-cipitation of the amine as the hydrochloride salt thereof.

In an alternative method of obtaining dimothylaminopropyl-benzothioxantheno compounds, the intermediate carbinol referred to hereinabove is heated in the presence of a dehydrating agent, such as acetyl chloride to produce as an intermediate product lO-chloro-12- (3~dimethylaminop opylidene) -12H-benzo [a] -thioxanthene. The product is usually obtained as a mixture of geometric isomers. These isomers which constitute the cis and trans isomers are readily separated by fractional crystalli-zation of the bases or the appropriate acid addition salts.

The geometric isomers when isolated in their pure form may differ in biological activity. These compounds or the mixtures of geometric isomers in addition to being active as local anesthetics may be also employed as intermediates in the same manner as the precursor carbinols, i.e., by reduction to the desired final products using red phosphorus and hydrogen iodide. Thus,, the 12-dimethylaminopropylidene-benzothioxanthene compounds can be converted in the same manner as the 12~dimethylaminopropyl-12-hydroxybenzothio-xanthene by reduction with red phosphorus and hydrogen iodide to produce the desired 10-chloro -12- (3 -dimethy1ami o -propyl) -12H-benzo [a] thioxanthene.

Thus by selection of the proper starting material our the final compounds produced in accordance with n» invention are 10-chloro~12- (3-dimethylaminopropyl) -12H--benzo [a] thio-xanthene; 9-chloro-7-< 3-dimethylaminopropyl) -7H-benzo [c] -thioxanthene; 10-chloro-12- (3-dimethylaminopropylidene) -12H-benzo [a] thioxanthene; 9-chloro-7- (3-dimethylamino-propylidene) -7H-benzo [c] thioxanthene; 10-chloro-12- (3-diethylaminopropyl) ^121-I-benzo [a] thioxanthene; 9-chloro -7-(3-diethylaminopropyl) -7H-benzo [c] thioxanthene; 10-chloro-12- (3-diethylaminopropylidene) -12H--benzo [a] thioxanthene; -cliloro-12- ( 3-- lipropylumino ro yj.) -1211-bejizo'la] Lliioxaji Uiono; 9~chloro-7- (3-dipropylaminopropyl) -711-benzo tc] thioxanthene; 10-chloro-12- (3-dipropylaminopropylidene) ~12H~benzo [a] -thioxanthene .

The compounds of the present invention are useful because of their local anesthetic activity. Thus, when tested for local anesthetic activity, solutions of the acid addition our salts of the compounds of »y invention are effective at concentrations as low as 0.1 to 2.5%. Due to the low toxicit our of these acid addition salts of the compounds of -ray- invention , the therapeutic index of local anesthesia is favorable. The our compounds of my invention can thus be used in solution as the acid addition salt to effect useful block anesthesia in warm-blooded animals by the injection of, for example, a 0.5% solution of the hydrobromide of 9-chloro-7~ (3~dimethylamino-propyl) -7H-benzo [c] thioxanthene. A solution for injection is conveniently prepared by dissolving a suitable amount of acid our addition salt of one of the compounds of -my invention , e . g . , the hydrochloride of lO-chloro-12- (3-diethylaminopropylidene) -12H-benzo [a] thioxanthene in sterile distilled water. The solution is rendered isotonic by the addition of sodium chloride, mannitol or sodium citrate as required and preferably is stabilized with suitable antioxidants and preservatives. It is then filled into ampules, each ampule containing 5 cc. and the ampules are sterilized in an autoclave at 123 °C.

Injectable solutions can also be prepared by adding the selected base to an aqueous solution of the stoichiometric amount of an acid such as hydrochloric acid, hydrobromic acid or an organic acid such as acetic acid, ascorbic acid, glutamic acid, lactic acid, maleic acid and the like.

EXAMPLE 1 -Chloro-2-iodobenzoic acid A mixture of 171.6 g. of 5-chloro anthranilic acid in a solution of 375 ml. concentrated hydrochloric acid in 2 liters of water is prepared. The resulting slurry is heated to the boiling point with stirring in order to dissolve the solid material. The entire reaction mixture is then cooled to 0°C. and stirred while adding to it a solution of 69 g. sodium nitrite dissolved in 250 ml. of water.

Following the addition of the sodium nitrite, the reaction mixture is stirred at 0-5°C. for about 30 minutes and filtered to remove a black insoluble solid which consists of impurities contained in the starting material. To the solution is then added a solution of 250 grams of potassium iodide dissolved in 500 ml. of water.. The resulting reaction mixture is then stirred for approximately 45 minutes, during which period a black solid separates from solution and iodine is liberated. During the stirring period the black solid dissolves and a tan precipitate separates from solution and the entire reaction mixture is allowed to stand 18 hours at room temperature. The reaction mixture containing the product is then heated to the boiling point and maintained at the boiling temperature for about one hour with stirring. The solution is then cooled to about 25°C. and treated with a saturated aqueous solution of sodium bisulfite until the reaction mixture is free of iodine. The solid product is then collected by filtration, washed with water, and crystallized from benzene. The crystallized product after drying has a melting point of 161-164°C. Repeated re-crystallization from benzene results in a purified product having mvp. of 166.5-167.5°C.

Analysis Calc'd. for c'7H402ClI:. C, 29.76; H , 1.43; , N.E. 282.48. Found: C, 29.94; H , 1.76; N.E. 279.7.

EXAMPLE 2 -Chlor6-2- (2-naphthylthio) enzoic acid A mixture is prepared of 28.25 grams (0.1 mole) of 5-chloro-2-iodobenzoic acid, 16.02 grams (0.1 mole) of β-naphthalenethiol, 1.0 grams of copper powder and 100 ml. of ethyl cellosolve. The entire reaction mixture is then heated to 100°C. and 13.82 grams (0.1 mole) of anhydrous potassium carbonate is added in small portions over a period of about 5 minutes during which time the temperature is maintained at 100°C. The resulting clear, red-brown solution is heated to reflux temperature and maintained at this temperature for a period of about two hours. Following the reflux period, there is added to the reaction mixture about 200 ml. of warm water, whereupon the separated precipitate redissolves and the solution is then filtered through diatomaceous earth. The filtrate, containing the product is allowed to stand at room temperature for about 18 hours, heated to about 90-95°C. and acidified with 20 ml. of concentrated HC1 to precipitate the desired acid as a crude product, m.p. 190-192°C. The crude product is recrystallized from aqueous alcohol, washed, and dried, m.p. 193-1?4°C. Further recrystallization from 100 ml. of glacial acetic acid yields a product having m.p. of 193.5-194.5°C.

Analysis Calc'd. for C17K1;LC102S: C, 64.86; H, 3.52; CI, 11.27. Found: C, 64.71; H, 3.57; Cl, 11.09.

EXAMPLE 2A -Chloro-2- (1-naphthylthio) benzoic acid A mixture of 40.4 grams (0.143 mole) of 5-chloro-2-iodobenzoic acid, 23.0 grams (0.143 mole) of a-naphthylthiol, 1.43 grams of copper powder, and 150 ml. of ethyl cellosolve is heated to approximately 100°C. and 19.8 grams (0.143 mole) of anhydrous potassium carbonate added in small portions over a period of 5 minutes. The resulting solution is red-brown in color and is heated to reflux temperature for 4 hours . The entire reaction mixture is diluted with 150 ml. of water and filtered through diatomaceous earth. The filtrate con-taining the product is heated to about 80°C. and acidified by the addition of 28 ml. of concentrated hydrochloric acid, whereupon the product precipitates from solution. After standing for a period of about 18 hours, the crude product is recovered by filtration, washed and dried, m.p. 193-196°C. Recrystallization from glacial acetic acid gives a product having m.p. 210.5-212.5°C. Further recrystallization from benzene-hexane mixtures yields fine white needles having m.p. 216.5-218°C.

Analysis Calc'd. for C-^H^CIO^: C, 64.86; H, 3.52; Cl, 11.27. Founds C, 65.05; H, 3.57; CI, 11.19.

EXAMPLE 3 -Chloro-12H--benzo [a] thioxanthen--l2- one To 100 grams of polyphosphoric acid, heated to approximately 130°C, is added 6.30 grams (0.02 mole) of -chloro-2- (2-naphthylthio) benzoic acid with stirring and maintained at 150-152°C. for a period of about 3 hours to form the desired product. The entire reaction mixture is then poured into 1 liter of water and the resulting product precipitates. The entire reaction mixture is then heated and agitated at about 75°C. for a period of about one-half hour. The precipitated product is recovered by filtration and suspended in 25 ml. of 5% sodium hydroxide solution and refiltered to remove impurities, and the filter cake washed with water until completely free of alkalinity. The product obtained in this manner x3 recrystallized from tetrahydrofuran and after drying, had a m.p. of 231-233°C./ dec. Repeated recrystallization from tetrahydrofuran and water yields product having m.p. 237.5-238.5°C. in substantially pure form. An analytical sample melts at 238-239°C, dec.

Analysis Calc'd. for C17H9C10S: C, 68.80; H, 3.06; Cl, 11.95. Found: C, 68.80; H, 2.94; Cl, 11.82.

EXAMPLE 3A 9-Chloro-7H-benzo [c] thioxanthen-7-one To 440 grams of polyphosphoric acid heated to 152°C. is added 27.74 grams (0.088 mole) of 5-chlorb-2-(1-naphthylthio) -benzoic acid with stirring, and the resulting mixture stirred at 152-155°C. for a period of about 3 hours. The resulting reaction mixture containing the product is then poured into 3 liters of water which results in the precipitation of a yellow solid comprising the crude product. The solid product is allowed to stand for several hours and then recovered by filtration, re-suspended in 150 ml. of 5% NaOH, refiltered, washed with water, and dried, m.p. 219-222°C. Recrystallization of the product from tetrahydrofuran-water mixtures gives substantially pure material having m.p. 239-240°C.

Analysis Calc'd. for C17HgC10S: C, 68.80; H, 3.06; Cl, 11.95. Pound: C, 68.87; H, 3.06; Cl, 11.80.

EXAMPLE 4 lO-Chloro-12- (3-diethylaminopropyl) -12H-benzo [a] thioxanthen-12-QI ~ : In a reaction vessel protected from the atmosphere, is placed 2.92 grams of magnesium turnings, a small crystal of iodine, 5 ml. of dry, peroxide-free tetrahydrofuran, and 1 ml. of a tetrahydrofuran solution of γ-dimethylaminopropyl- ■ ■ ' "■ ■ ■ ■· . ' . . . . · ■■. . 1 magnesium chloride as initiator and the entire mixture iieated. 2 to reflux temperature on a steam bath. Addition of a solution 3 of 18.0 grams of γ-diethylaminopropyl chloride in 35 ml. of 4 dry tetrahydrofuran is then begun, whereupon, the heat of reaction causes reflux of the reaction mixture to begin and 6 the rate of addition of the γ-diethylaminopropyl chloride 7 solution is adjusted so that the reaction mixture is maintained 8 at the reflux temperature. The entire addition is accomplished 9 in a period of about 15 minutes. To the reaction mixture is then added another 20 ml. of tetrahydrofuran, and stirring 11 and heating of the solution continued for about 2 hours at 12 which time the Grignard reagent is substantially completely 13 formed. 14 The reaction mixture containing the Grignard reagent is then cooled to about 0°C. and 17.8 grams of 16 lO-chloro-12H-benzo [a] thioxanthen-12-one is added with 17 stirring over a period of about 15 minutes, and stirring. 18 of the resulting solution of product continued at about 19 25°C. for 1 hour. The entire reaction mixture is then heated under reduced pressure at about 50°C. to remove the 21 major portion of tetrahydrofuran, leaving the Grignard re- 22 action product as an impure residue. This residue is f 23 dissolved in 125 ml. of benzene and the resulting solution 24 containing the product, cooled and stirred while adding thereto 40 ml. of water in order to hydrolyze the Grignard 26 reaction complex and liberate the desired 12-hydroxy 27 compound. The benzene solution of product is separated by 28 decantation, and the remaining residue containing traces of 29 product extracted several times with boiling benzene. The benzene extracts are combined, washed with water, and 31 distilled at reduced pressure to remove the bulk of the Following the beginning of the reaction the rate of addition of the tetrahydrofuran solution is adjusted so that the reflux rate is maintained. The addition requires a period of about 15 minutes. Stirring and refluxing of the solution is then continued for a period of about 1 1/2 hours. The resulting solution of Grignard reagent is then cooled to 0°C. and 13.9 grams of 9-chloro-7H-benzo [c] thioxanthen-7-one added in equal portions over a period of about 10 minutes. The dark brown solution containing the Grignard addition complex is stirred at room temperature for a period of about 1 1/4 hours and the entire reaction mixture distilled under reduced pressure at about 50°C. to remove a major portion of the tetrahydrofuran solvent. The residue is then dissolved in 100 ml. of benzene and the benzene solution cooled and stirred while adding thereto 30 ml. of water to hydrolyze the Grignard addition complex and liberate the desired carbinol. The benzene layer containing the product is removed by decantation and the residual material extracted several times with boiling benzene. The benzene extracts of product are combined and washed with water, concentrated to approximately 75 ml. and diluted with hexane, whereupon the product crystallizes, m.p. 165.5-166.5°C. Recrystallization of the product from a benzene-hexane (1:2) mixture produces substantially pure 9-chloro-7- (3-dimethylaminopropyl) -7H-benzo [c] thioxanthen-7-ol melting at 170-171°C.

Analysis Calc'd. for C22H22C1N0S: C, 68.83; H, 5.78; , 3.65. .Found: C, 69.14; H, 5.89; N, 3.63.

EXAMPLE 5 lO-Chloro-12- (3-diethylaminopropylidene) -12H-benzo [a] -thioxanthene A solution of 13.5 grams (0.0328 mole) of 10-chloro-12- (3-diethylaminopropyl) -12H-benzo [a] thioxanthen-12-ol in 75 ml. of chloroform is cooled in ice and saturated by passing in dry HC1 gas. The resulting dark red solution is mixed with 7.85 grams acetyl chloride and the temperature allowed to rise spontaneously to about 25°C, during which time HCl gas is vigorously evolved. The reaction mixture containing the product is then' heated to reflux temperature for approximately 1 hour. The entire reaction mixture is then distilled at reduced pressure to remove solvent and excess acetyl chloride. The residue containing the impure product is dissolved in 25 ml. ethyl acetate and the resulting solution evaporated to dryness to yield the product as a residual dark yellow syrup. The residual material is then triturated, with 50 ml. of acetone in order to crystallize the product. The crude crystalline solid hydrochloride melts at 98-116°C. Repeated crystallization of the product from ethanol-ether mixtures yields an analytically pure mixture of stereoisomeric hydro- chlorides melting, at 74-105°C.

Analysis Calc'd. for C23H24C1 S«HC1: . C, 66.03 H, 6.02;; N, 3.35. Found: C, 65.82; H, 5.97; N, 3.22.

EXAMPLE 5A 9-Chloro-7- (3-dimethylaminopropylidene) -7H-benzo [c] - thioxanthene " ~ A solution of 4.4 grams (0.0115 mole) of 9-chloro- 7- (3-dimethylaminopropyl) -7H-benzo [c] thioxanthen-7-ol dissolved in 20 ml. of chloroform is treated with 2.7 grams (0.0345 mole) of acetyl chloride. The temperature of the solution spontaneously rises and the color changes to dark red. The resulting solution is heated to reflux temperature for a period of about 1 hour which results in a rapid fading of the color. The product is obtained as the crude hydro- chloride salt by removal of the solvent under reduced pressure. The resulting residual yellow glass-like solid is crystallized from a mixture of 25 ml. of ethanol and 35 ml. of ether, m.p. 75-105°C. Recrystallization from a mixture of alcohol, acetone and ether and then from acetone- ether yields a mixture of the stereoisomeric hydrochlorides product, m.p. 159-187°C.

Analysis Calc'd. for C22H2()C1NS.HC1: C, 65.67; H, 5.26; N, 3.48. Found: C, 65.47; H, 5.43; N, 3.48.

EXAMPLE 6 lO-Chloro-12- (3-diethylaminopropyl) -12H-benzo [a] thioxanthene A mixture of 7.0 grams, of lO-chloro-12- (3-diethyl- aminopropylidene) -12H-benzo [a] thioxanthene, 18 ml. of 55% hydriodic acid, 18 ml. of glacial acetic acid, and 2.1 grams , of red phosphorus is prepared and protected from the atmosphere. The resulting dark red solution is heated to reflux temperature in a stream of nitrogen gas for a period of about 2 hours. The resulting colorless solution containing the product is then filtered to remove the phosphorus, and the filtrate containing the product is diluted to approximately 300 ml. with water and mixed with 100 ml. of ION. aqueous sodium hydroxide solution. The resulting alkaline mixture is then heated to about 80°C. with stirring for about' one-half hour, cooled, and the product extracted with three 100 ml. portions of benzene. The benzene extracts are combined and washed with water and the combined extracts are coh-centrated at reduced pressure to remove the bulk of t e benzene leaving the product as a residual oily solid.

Crystallization of this residue from acetone-petroleum ether yields the. solid hydriodide salt, m.p. 165-168°C.

Evaporation of the acetone-petroleum ether mother liquor leaves the oily base. The hydriodide salt may be converted to the base by refluxing an ethanolic suspension of the salt with aqueous sodium hydroxide evaporating the solvent, and recovering the oily base by extraction of the residue with hexane. The hydrochloride of the product precipitates from an ethanolic solution of lO-chloro-12- (3-diethylamino-propyl) -12H-benzo [a] thioxanthene on trea.tment with an ethanolic solution of hydrogen chloride and dilution with ether, m.p. 190-192°C. Recrystallization from ethanol-ether yields substantially pure product, m.p. 189-191°C.

Analysis Calc'd. for C^H^Cl S-HCl: C, 66.66; H, 6.29; N, 3.24. Found: C, 66.36; H, 6.32; N, 3.22.

EXAMPLE 6A 9-Chloro-7- (3-dimethylaminopropyl) -7H-benzo [c] thioxanthene To 25 ml. of 55% hydriodic acid is added 25 ml. glacial acetic acid, 3.1 grams red phosphorus and 9.6 grams of 9-chloro-7- (3-dimethylaminopropyl) -7H-benzo [c] thioxanthen- - nitrogen gas. The resulting dark red solution is heated to reflux temperature under nitrogen for a period of about 3 hours. The solid phosphorus is removed from the hot solution of product by filtration and the filtrate containing the product is diluted with 200 ml. of water and made alkaline by the addition of 100 ml. of sodium hydroxide solution. To the mixture is added 200 ml. of benzene with stirring and heating fo a period of about 15 minutes, whereupon, the product dissolves in the benzene layer. The mixture is cooled, the, benzene layer separated and the aqueous layer is extracted with two 100 ml. portions of benzene. The benzene extracts of product are combined and washed with water. The benzene is removed by distillation leaving the crude product as a residual yellow oily material. The hydrobromide of the product is precipitated by the addition of a slight excess of dry hydrogen bromide to a solution of the crude base in 100 ml. of ether and a 2 hour digestion period at 25 °C. The hydrobromide salt of the product is collected by filtration and dried, m.p. 186-188°C.

Repeated recrystallization from 1:1 mixtures of ethanol and ether yields substantially pure product having m.p. 194-195°C.

Analysis Calc'd. for C22H22C1 S 'HBr: C, 58.86; H, 5.16; N, 3.05. Found: C, 58.92 H, 5.16; N, 3.08. ,

Claims (9)

1. - 17 - 29823/2 GLAH-'IS 1. Sensothioxanthene compounds of the formula Y Is hydrogen or hydroxy, R is lower alkyl of 1 to 6 carbon atoms and B is a fused benzene ring in the (a) or (c) position.

2. Compounds of formula IV in Claim 1 in which Y is -OH.

3. 9(10)-Chlorp-substituted (dialk laminoalkyl)-7 or 12H-benzothioxanthen-7- or 12-ols.

4. 10-Chloro-12-(dialkylaminoalkyl)-12H-benzo[a] thioxanthen-12-ol.

5. 9-ChlorOT.7-(dialkylaminoalkyl)-7H-benzo[c]-thioxan' 7 then-0-ol.

6. 10-0hloro-12-(dime h laminopropyl)-12H-benzo-[a]thioxanthen-12-ol.

7. 9-Chloro-7-(dimethylaminopropyl)-7H-benzo[c]thi-oxanthen-7-oi. - 18 - 29823/2

8. Compounds of formula IV in Claim 1 in which I is hydrogen. 9/ 9(10)-0hloro-sub8tituted 7 or 12-(dialkylaminoalkyl)-7 or 12H-benzothioxanthene; 10. lO-Chloro-12-(dialkylaminoalkyl)-12H-benzo[a] thioxanthene· 11. 9-Chloro-7-(dialkylaminoalkyl)-7H-benzo[c]-thioxan-thene. . . 12. 10-Chloro-12~(dimethylaminopropyl)-12H-benzo[a] thioxanthene. I?. 9-Chloro-7-(dime h lamlnopropyl)-7H-benzo[c]thioxanthene.; . Ohloro-substituted 7 or 14.9(10)-Λ2-(dialkylaminoalkylidene)-7 or i2Ji-benzothioxan-thene· . 15. 10-Chloro-12-(dialkylaminoalkylidene)-l2H-benzo[a] thioxanthene. 16. , 9-Chloro-7-(dialkylaminoalk lidene)-7H-benzo[c] thioxanthene. , 17. 10-C oro-12-.(dimethylaminopropylidene)-12H-benzo [a]thioxanthene* 18. „ . 9-Ghloro-7-7(dimethylaminopropylidene)-7H-benzo[c]-thioxanthene. 1

9. _ A process for the preparation of compounds according to any of Claims, 2 to 7, wherein an o-iodobenzolc acid of the formula : . - 19 - 29823/2 is condensed with a naphthylthlol . to form a halonaphthyl thiolbenzoic acid of the formula a the latter is heated in the presence of a polyphosphoric - 20 - 29823/2 21. A process according to Claim 19 wherein 5-chloro-2-iodobenzoic acid is condensed with 2-naphthylthiol and subjected -to ring closure to form 10^chloro-12H-benzo[a]-thioxanthen-12-bhe and the latter is condensed with an N,N-diloweralkylaminppropyl magnesium halide to produce 10-chloro-12-.(dialkylaminoprop 1)-12-hydroxy-12H-benzo[a]thl-oxanthene. 22. A process according to any of Claims 19 to 21 wherein th© iJ, ~dlalkylaminopropy1 magnesium halide. employed is di-methylaminopropyl magnesium chloride. 23· A prooess for the preparation of compounds according to Claims 14 to 18 having the formula IVB in Claim 1 wherein a compound of the formula III "in Claim 19 is reacted with an acidic dehydrating agent. 24. A process according to Claim 23 wherein a compound of formula III prepared by the process of Claim 20 or 21 is reduced with an acidic dehydrating agent to the corresponding 9- or lO-chloro-7 (or 12)-dialkylaminoalkylidene-benzothioxanthene. 25. A process for the preparation of benzothioxanthene compounds according to Claims 8 to 13 wherein a compound of formula III in Claim 19 or the corresponding 7 or 12-dlalkyl-aminoalk lidene compound according to Claim 14 to 18 is reduced with hydrogen iodide and phosphorus. 26. Processes for the "preparation of benzothioxanthene compounds according to Claim 1, substantially as described herein with reference to the Examples. - 21 - 29823/2 27. Pharmaceutical compositions for use in local anaesthesis comprising a sterile injectable solution of a compound of the^ formula IV in Claim 1 in which Y is hydrogen or a compound of formula IVB in Olaim 1 in which formulae R and B have the same meaning as in Claim 1. For DR. PARTNERS PC/rb