IE44727B1 - Dibenzothiophene derivatives - Google Patents

Abstract

Dibenzothiophene derivatives which have anti-inflammatory activity and the formula in which R is hydrogen, halogen, hydroxyl, cyano, lower alkyl, hydroxy-lower-alkyl, lower alkoxy, acyl, benzyloxy, lower alkylthio, trifluoromethyl, nitro, amino, mono-lower alkylamino, di-lower alkylamino, sulphamoyl, di-lower alkylsulphamoyl or difluoromethylsulphonyl; R1 is halogen, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acyl, acylamido, benzyloxy, lower alkylthio, trifluoromethyl, hydroxyl, nitro, amino, mono-lower alkylamino, di-lower alkylamino, sulphamoyl, di-lower alkylsulphamoyl or difluoromethylsulphonyl, or R together with an adjacent R1 is alkylenedioxy, R2 is the group where A is hydroxyl, lower alkoxy, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, X and Y are, independently of one another, hydrogen or lower alkyl, m is a number from 1 to 7, R2 is the group , in which B is hydroxyl, carboxyl, lower alkoxy, amino, hydroxyamino, mono-lower alkylamino, di-lower alkylamino, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, Y and X are, independently of one another, hydrogen or lower alkyl, n is a number from 1 to 7, and pharmaceutically utilisable salts thereof are prepared by aromatisation starting from the corresponding 1,2,3,4-tetrahydrodibenzothiophene derivatives.

Description

PATENT APPLICATION BY (71) p. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT, A SWISS COMPANY OF 124-184 GRENZACHERSTRASSE, BASLE, SWITZERLAND.

Price 12ip - 2 ν ' w 44737 The invention relates to compounds of the formula wherein R is hydrogen, halogen, hydroxy, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acyl, benzyloxy, lower alkylthio, trifluoromethyl, nitro, amino, monolower alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl; R^ is halogen, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acyl, acylamino, benzyloxy, lower alkylthio, trifluoromethyl, hydroxy, nitro, amino, mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl, or R taken together with an adjacent R^ is also lower alkylenedioxy; R2 is ,X· ] j-A, wherein A is m hydroxy, lower alkoxy, amino-lower alkoxy - 3 mono-lower alkylamino-lower alkoxy or di-loweralkylamino-lower alkoxy, X and Y, independently, are hydrogen or lower alkyl. and m is 1 to 7, or -C-B wherein B is hydroxy, lower alkoxy, amino, hydroxyamino, mono-lower alkylamino, di-lower alkylamino, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylaminolower alkoxy, Y and X, independently, are hydrogen or lower alkyl; and n is 1 to 7; when X and Y are different, their enantiomers; when B is hydroxy, salts thereof with pharmaceutically acceptable bases; and when R or R^ is amino, mono-lower alkylamino or di-lower alkylamino, and/or when B or A is aminolower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, addition salts thereof with pharmaceutically acceptable acids.

As used herein, the term lower alkyl denotes a straight or branched chain hydrocarbon group containing 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, neopentyl, pentyl and heptyl. The term lower alkoxy denotes an alkyl ether group in which the alkyl group is as described above, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and psntyloxy. term lower alkylthio” denotes an alkyl thioether group in which the alkyl group is as described above, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio and pentylthio. The term halogen· denotes the halogens, that is, bromine, chlorine, fluorine and iodine; bromine and chlorine are preferred. The term acyl denotes an alkanoyl group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyl, acetyl and propionyl, or an aroyl group derived from an aromatic carboxylic acid, such as benzoyl.

The term, lower alkylene denotes a straight or branched chain alkylene of 1-7 carbon atoms, for example, methylene, ethylene, propylene, butylene and methylmethylene. The term lower alkylenedioxy proferably denotes methylenedioxy.

Exemplary of mono-lower alkylamino are methylamino and ethylamino. Exemplary of di-lower alkylamino are dimethylamino and diethylamino. Exemplary of amino-lower alkoxy are aminomethoxy and 2-aminoethoxy. Exemplary of mono-lower alkylamino-lower alkoxy are methylamino-methoxy and 2-(N-ethylamino) ethoxy. Exemplary of di-lower alkylamino-lower alkoxy are di20 methylaminomethoxy and 2-(Ν,Ν-diethylamino)ethoxy. Exemplary • of di-lower alkylsulfamoyl are dimethylsulfamoyl and diethylsulfamoyl.

Preferred dibenzothiophenes of the invention are those characterized by the formulae 4473 and wherein R'is halogen, lower alkyl or lower alkoxy, preferably R'^ is halogen or lower alkyl, and most preferably R'^ is halogen and X and Y are as previously described, their enantiomers when X and Y are different, and salts of the compounds of formula 1' with pharmaceutically acceptable bases. Preferably, in formula I, m is 2 and n is 1.

Preferred compounds of formula I are: racemic 8-chloro-a-methyl-dibenzothiophene-3-acetic acid (+).8-chloro-a-methyl-dibenzothiophene-3-acetic acid; (-) 8-chloro-a-methyl-dibenzothiophene-3-acetiC acid; 44737 - 6 racemic 2-(8-chloro-3-dibenzothienyl)propanol; 2-(8-chloro-3-dibenzothienyl) ethanol; 8-chloro-dibenzothiophene-3-acetic acid; 8-chloro-dibenzothiophene-3-acetamide.

Exemplary of compounds of this invention corresponding to formula I are: 8-chloro-dibenzothiophene-3-acetic acid; 8-chloro-dibenzothiophene-3-acetic acid ethyl ester; 8-methoxy-dibenzothiophene-3-aeetic acid; 8-nitro-d4.benzothiophene-3~acetic acid; 7-methoxy-dibenzothiophene-3-acetic acid; 7- chloro-dibenzothiophene-3-acetic acid; 8- methyl-dibenzothiophene-3-acetic acid; 6- chloro-dibenzothiophene-3-acetic acid; 8,9-dichloro-dibenzothiophene-3-acetic acid; 7- methyl-dibenzothiophene-3-acetic acid; 7,8-dichloro-dibenzothiophene-3-acetic acid; 8- chloro-9-methyl-dibenzothiophene-3-acetic acid; 8-difluoromethylsulfonyl-dibenzothiophene-3-acetic acid; . racemic 2-(8-chloro-3-dibenzothienyl)propanol methyl ether 8-chloro-7-methyl-dibenzothiophene-3-acetic acid; 8-sulfamoyl-dibenzothiophene-3-acetic acid; 8-benzoyl-dibenzothiophene-3-acetic acid; 8-f lUQro-qtibenzothiopheiie-3-acetic acid; 8-triflupromethyl-dibenzothiophene-S-acetic acid; 6,7-dichloro-dihenzothiophene-3-acetic acid; **737 - 7 9-chloro-8-sulfamoyl-dibenzothiophene-3-acetic acid; 8-methylthio-dibenzothiophene-3-acetic acid; 8-ethyl-dibenzothiophene-3-acetic acid; 8-chloro-dibenzothiophene-3-acetic acid 2-dimethylaminoethyl ester; 8-methyl-dibenzothiophene-3-acetic acid ethyl ester; 8-dimethylsulfamoyl-dibenzothiophene-3-acetic acid; 8-iodo-dibenzothiophene-3~acetic acid; 8-chloro-NrN-dimethyl-dibenzothiophene-3-acetamide; 8-cyano-dibenzothiophene-3-acetic acid; 8-acetyl-dibenzothiophene-3-acetic acid; 8-chloro-dibenzothiophene-3-acetic acid 2-dimethylamino) ethyl ester hydrochloride; 8-benzyloxy-dibenzothiophene-3-acetic acid; 7,8-methylenedioxy-dibenzothiophene-3-acetic acid; 8- hydroxy-dibenzothiophene-3-acetic acid; 7- chloro-dibenzothiophene-3-acetic acid ethyl ester; 9- chloro-dibenzothiophene-3-acetic acid ethyl ester; 8- bromo-dibenzothiophene-3-acetic acid ethyl ester; 8-acetamido-dibenzothiophene-3-acetic acid ethyl ester; 8-chloro-dibenzothiophene-3-propionic acid ethyl ester; 8~chloro-a,a-dimethyl-dibenzothiophene-3-acetic acid ethyl ester; 8-chloro-a-methyl-dibenzothiophene-3-acetic acid 2-dimethyl aminoethyl ester; 8-chloro-a-methyl-dibenzothiophene-3-acetamide; 8-trifluoromethyl-dibenzothiophene-3-acetic acid ethyl ester; 6.7- dichloro-dibenzothiophene-3-acetic acid ethyl ester; 8,9-dichloro-dibenzothiophene-3-acetic acid ethyl ester; 8-methylthio-dibenzothiophene-3-acetic acid ethyl ester; 8-fluoro-dibenzothiophene-3-acetic acid ethyl ester; 8-N,N-dimethylsulfamoyl-dibenzothiophene-3-acetic acid ethyl ester; 7.8- dichloro~dibenzothiophene-3-acetic acid ethyl ester; 8-nitro-dibenzothiophene-3-acetic acid ethyl ester; and 7-dimethylaminodibenzothiophene-3-acetic acid ethyl ester.

The compound of general formula I and where applicable their pharmaceutically acceptable salts with acids or bases are prepared by a process which comprises a) aromatizing a compound of the general formula II wherein R, R^ and R2 have the above mentioned meanings, or b) for the preparation of compounds of formula I, wherein n is 1, X and Y are hydrogen and B is lower alkoxy treating a diazoketone of the general formula with a alkanol, or c) for the preparation of compounds of formula I, wherein E is hydroxy, hydrolyzing a compound of formula I, wherein B is lower alkoxy, or d) for the preparation of compounds of formula I, wherein B is amino lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy reacting a compound of formula I, wherein B is hydroxy or a salt thereof with a suitable esterifying agent, or e) for the preparation of compounds of formula I, wherein B is lower alkoxy, esterifying an acid of formula I, wherein B is hydroxy, or a salt thereof, or f) for the preparation of compounds of formula I, wherein R or is di-lower alkylamino, alkylating a compound of formula I, wherein R or is amino, or g) for the preparation of compounds of formula I, wherein R, R^ or A is hydroxy, cleaving an ether of formula X, wherein R, or A is lower alkoxy, or h) for the preparation of compounds of formula I,wherein A is lower-alkoxy, amino-lower alkoxy, mono-lower alkylaminolower alkoxy or di-lower alkylamino-lower alkoxy, etherifying an alcohol of formula I, wherein A is hydroxy, or i) for the preparation of compounds of formula I, - lo 10 wherein A is hydroxy and m is 2 to 7, reducing an ester of formula I, wherein B is alkoxy and n is 1 to 6, or k) for the preparation of compounds of formula X, wherein is amino, saponifying an amide of formula I, wherein Rj is acylamino, or l) for the preparation of a compound of formula X, wherein R2 is -CH-CO-R^, whereby R3 is lower alkyl and R^ is *3 hydroxy or lower alkoxy, alkylating a compound of formula I, wherein R2 is GHj-CO-R^ whereby R^ is as above, or m) for the preparation of a compound of formula I, V5 wherein R2 xs -C-CO-R^, whereby R^ is a lower alkyl group and Rj *3 wherein R2 is -CH-CO-R^ wherein R3 and are as described and R^j are as defined above, alkylating a compound of formula I, s -CH L above, or n) for the preparation of compounds of formula I, wherein R or R^ is amino, reducing a corresponding nitro compound or a 5-0xide thereof, or o) for the preparation of compounds of formula I, wherein R or R^ is halogen converting an amino compound the desired halogenated compound, or p) forming pharmaceutically acceptable salts of compounds or formula Ί wherein B is hydroxy with bases, or g) forming pharmaceutically acceptable acid addition salts of compounds of formula X, wherein R or R^ is amino, mono-lower alkylamino, di-lower alkylamino and/or B is amino25 - 11 lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, or r) resolving a racemic mixture of a compound of formula I, wherein X and Y are different, into the optical antipodes.

The compound of formula I can be separated from the reaction mixture by known procedures, included among which are, for example, filtration, crystallization and distillation.

According to the process a) a compound of formula II is aromatized. The aromatization is effected utilizing a dehydro10 genating agent, for example, p-chloranil, o-chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), sulfur, palladium on carbon or lead oxide, in the presence of a solvent, for example, xylene, benzene, toluene, quinoline, dimethylsulfoxide (DMSO), dioxane, dimethylforamide (DMF). The aromatization is carried out at a temperature in the range of from room temperature to the reflux temperature of the reaction mixture: preferably, it is carried out at the reflux temperature of the reaction mixture.

According to process b) a diazoketone of formula III can be reacted with a lower alkanol. The rearrangement with the alkanol is preferably carried out in the presence of silver ions and at the reflux temperature of the reaction mixture.

According to process c) an ester of formula I can be converted to the corresponding acid, i.e., the compounds of - 12 formula I wherein B is hydroxy, by saponification according to known procedures, for example, by reaction with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide and subsequent treatment with a mineral acid, for example, a hydrohalic acid such as hydrochloric acid. Additionally, an ester of formula I can be converted to the corresponding acid by treatment with a mineral acid, for example, a hydrohalic acid such as hydrochloric acid, in the presence of an organic solvent such as acetic acid, preferably at the reflux temperature of the reaction mixture.

Furthermore, according to process d) an acid of formula I, i.e. compound of formula X wherein B is hydroxy, or a salt thereof can be converted to a compound of formula X wherein B is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy by known procedures.

For example, a salt of an acid of formula I is reacted with an amino-lower alkyl halide, mono-lower alkylamino-lower alkyl halide or di-lower alkylamino-lower alkyl halide, exemplary of which are 2-aminoethyl chloride, 2-(N-methylamino)-ethyl bromide and diethylaminomethyl chloride to yield the desired end product. The temperature at which the reaction is effected 727 is not critical; conveniently, the reaction is carried out at a temperature in the range of from room temperature to the reflux temperature of the reaction mixture.

Conveniently, the reaction can be carried out in a polar solvent, such as dimethylformamide or dimethylsulfoxide.

The molar ratio of reactants is not critical. Preferably, the reactants are utilized in a 1:1 molar ratio.

According to process e) an acid of formula I, wherein B is hydroxy, can be converted to the corresponding ester by known procedures. For instance, (a) an acid of formula I can be reacted with an alkanol such as methanol, ethanol or propanol, in the presence of an acid catalyst at a temperature in the range of from room temperature to the reflux temperature of the reaction mixture, or (b) an alkali metal salt of an acid of formula I, such as the sodium salt, can be reacted with an alkyl halide utilizing known reaction conditions, for example, in an inert solvent such as benzene, toluene, or dimethylformamide, a't a temperature in the range of from ’ room temperature to the reflux temperature of the reaction mixture.

According to process f) a compound of formula I, wherein R or R^ is amino, can be converted to the corresponding compound wherein R or R^ is di-lower alkylamino, utilizing known procedures, for example utilizing hydrogen at a pressure of from 1 atmosphere to several atmospheres and a - 14 44737 catalyst such as Raney nickel, together with an alkyl aldehyde such as formaldehyde, at a temperature in the range of from room temperature to 100°, in a solvent, for example an alkanol such as methanol or ethanol.

The alkylation can also be carried out by treating the amine, for example, with trimethylphosphate under known conditions.

According to process g) a compound of formula I, wherein R, R^ or A is lower alkoxy, can be converted to the .corresponding compound, wherein R, R·^ or A is hydroxy, by known procedures. For example, a compound of formula I bearing a lower alkoxy group can be treated with a mineral acid, for example a hydrohalic acid such as hydrobromic acid, in a solvent, for example alkanols such as ethanol or propanol, at a temperature in the range of from room temperature to the reflux temperature of the reaction mixture. The conversion can also be effected utilizing a Lewis acid, such as aluminum tribromide, aluminum trichloride, boron tribromide or tin tetrachloride, in a solvent such as benzene, toluene or dimethylFormamide.

According to process h) an alcohol i.e'., a compound of formula I, wherein A is hydroxy, can be converted to the corresponding compound of formula I wherein A is lower alkoxy, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy by known procedures. For example, an alcohol of formula I, wherein A is hydroxy, is treated with an alkali metal such as sodium. The resulting 4472? compound is then treated with a halide of the formula RX, wherein X is halogen and R is lower alkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl, utilizing known reaction conditions.

According to process i) an ester of formula I can be converted to the corresponding alcohol, wherein A is hydroxy, by known procedures. For example, an ester of formula I can be treated with a reagent such as lithium aluminum hydride, at a temperature in the range of from room temperature to the reflux temperature of the reaction mixture.

According to process k) a compound of formula I, wherein R^ is acylamiiio, can be converted to the corresponding compound of formula I, wherein R^ is amino, e.g. by treatment with an inorganic acid, for example a hydrohalic acid such as hydrochloric acid, utilizing known reaction conditions.

According to process 1) an ester of formula I can be alkylated in the α-position. This alkylation can be carried out by dissolving the ester in liquid ammonia containing sodium amide and then adding an alkylating agent such as methyl iodide or butyl bromide, to produce the α-alkylated product. - 16 According to process a) an α-alkyiated ester of formula I can be further alkylated using the method as described above.

According to process n) a compound of formula I, wherein E or R^ is amino, can be prepared be reducing a corresponding nitro compound or a S-oxide thereof. The reduction can be performed with hydrogen under pressure, e.g. psi. and using a noble metal catalyst, e.g. palladium on carbon.

According to process o) a compound of formula I, wherein R or is amino can be converted into the corresponding halogen compound'. For this purpose the amino compound is first converted into the diazonium salt, e.g. into the diazonium sulfate by treating with nitrosylsulfuric acid, and then the diazonium salt is reacted with a cuprous halide, e.g. cuprous chloride, in hydrochloric acid.

The starting materials of formula XI can be prepared by cyclizing a compound of the formula wherein R, R^ and R2 are as previously described.

The cyclization can be effected by thermal cyclization or by utilizing a cyclizing agent, such as polyphosphoric acid. Preferably, the reaction is carried out at a temperature in the range of from -20° to 5 120°. The reaction can be conveniently carried out with or without a solvent. Exemplary of convenient solvents is acetic acid.

Exemplary of the intermediates of formula IV are: 3-(4-chloro-phenylthio)-4-oxocyclohexaneacetic acid and ethyl ester thereof; and 3-(4-bromo-phenylthio)-4-oxocyclohexaneacetic acid and methyl ester thereof; The compounds of alkylating a compound of formula IV can be prepared by the formula wherein R and R^ are as previously described, with the corresponding haloketocycloalkane compound of the formula Hal VI - 18 wherein Hal is halogen and R2 is as previously described, to yield a compound of the formula XV.

The reaction is conveniently carried out in a non-polar solvent, for example a hydrocarbon such as benzene or . 5 toluene, or a polar solvent, such as dimethylsulfoxide, I J t dimethylformamide, hexamethylphosphoric triamide or an alkanol such as ethanol. The reaction temperature is j not critical,Preferably, the reaction is carried out a a temperature in the range of from room temperature to the reflux temperature of the reaction mixture. The molar j ratio of the reactants is not critical. Preferably, they are reacted at a lsl molar ratio.

The starting materials of formula VI can be prepared by halogenating a compound of the formula wherein R- is as previously described; to yield the compound of the formula VI.

The compounds of formula VII are known compounds or can be prepared in an analogous manner to known compounds. i ; 20 The halogenation is effected utilizing known procedures, for example, utilizing a halogen such as bromine in ether, at a temperature of -1O°C. Exemplary of such compounds are: 3-bromo-4-ketocyclohexaneacetic acid; 3-bromo-4-ketocyclohexaneacetic acid ethyl ester.

The starting materials of formula V are known compounds or can be prepared in an analogous manner to known compounds. Exemplary of such compounds are: 4- chlorothiophenol; - chlorothiophenol; and 4-nitrothiophenol.

The starting materials of formula III can be obtained from the corresponding carboxylic acid. The acid is converted to the acid halide, especially chloride, and then reacted with diazomethane to form the diazoketone.

The compounds of formula I, when B is hydroxy, form according to process p) salts with pharmaceutically acceptable bases. Exemplary of such bases are alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide? alkaline earth hydroxides, such as calcium hydroxide and barium hydroxide; sodium alkoxides, such as sodium ethanolate and potassium ethanolate; organic bases such as piperidine, diethanolamine and N-methylglucamine.

Also included are the aluminum salts of the compounds of formula I, as above.

The compounds of formula I when R or Rj is amino, mono-lower alkylamino, di-lower alkylamino, and/or when B or A is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, form according to process aspect g) addition salts with pharmaceutically acceptable - 20 organic or inorganic acids such as hydrohalides, e.g. hydrochloride, hydrobromide, hydriodide, other mineral acid ‘ salts such as Sulfate, nitrate and phosphate, alkyland mono-arylsulfonates such as ethanesulfonate, toluenesul5 fonate.and benzenesulfonate, other-organic acid salts such as acetate, tartrate, maleate, citrate, benzoate, ι salicylate and ascorbate. j f ; The compounds of formula I, including the salts of J those compounds of formula X which form salts with pharmaceu! 10 tically acceptable bases and acids, possess anti-inflammatory, I ; analgesic and anti-rheumatic activity.

( The confounds of formula X also exhibit a significantly -j low incidence of ulcerogenic activity, which renders them highly desirable as anti-inflammatory, analgesic and antij • 15 rheumatic agents. Their pharmacologically useful activities are demonstrated in warm-blooded animals using standard procedures. i ' ' For example, the anti-inflammatory activity is demonstrated in Albino rats of Hart Strain, weighing 125-155 , i gms. The test animals are given 10 mis. of vehicle , which contains the test compound per kg. of body weight. The animals i ^Hilgar, A.G. and Hummel, D.J.: Endocrine Biossay Data. No. 1, p. 15, August 1964 (Cancer Chemotherapy National Service Center, N.I.H.) - 21 are treated daily for 5 consecutive days. Three hours after the first treatment, 0.05 ml. of an 0.5% suspension of heat killed desiccated Mycobacterium butyricum in U.S.P. olive oil, which has been steam sterilized for 30 minutes, is injected into the right hind foot of each rat. The paw volume is measured immediately after the injection of the adjuvant and again 96 hours later. The difference is recorded as volumq of edema. The paw volume is measured by immersion of the paw into a column of mercury to an ink mark exactly at the level of the lateral malleolus. Percent inhibition is calculated by dividing the average control edema minus the average treatment edema by the average control edema times 100. The percent inhibition is plotted against dose on semi-logarithmic probability paper and the dose required to produce a 30% reduction in edema is estimated therefrom and is expressed as ED30· When 8-chloro-dibenzothiophene-3-acetic acid, which has demonstrated an LD^0 of, for example, 775 mg. p.o. in mice, is utilized as the test substance at a dosage of 0.03 gm. p.o., an anti-inflammatory activity is observed (Εϋ^θ = 1.8 mg/kg/day).

The analgesic activity of the compounds of the invention is demonstrated, for example, employing the method which is a modification of that described by Eddy (1950), Wolfe and MacDonald (1944) and Eddy and Leimbach (1952). The method determines the reaction time of mice dropped onto a hot plate - 22 maintained at 55 + 0.5°C. Six groups of male mice (5 mice/group) weighing between 20-30 grams are utilized. The initial reaction time of these mice is determined once, and the reaction time of each group is then averaged. The mice are then administered the vehicle and/or the compound to be tested by the oral, intraperitoneal or subcutaneous route. The average reaction time of each group is determined again at 30, 60 and 90 minutes after compound administration and is compared to controls. Reaction time is recorded as percent changes from control. All groups are averaged before and after treatment. A combined reaction time average (recorded as percent change of reaction time threshhold from controls) for all three periods is plotted against dose on graph paper, and a curve is drawn.

The ED,j0 is read from this curve.

When 8-chloro-dibenzothiophene-3-acetic acid, which has demonstrated an LD^q of, for examle, 775 mg. p.o. in mice, is utilized as the test substance, analgesic activity is observed at an EDgQ of 120 mg/kg after oral administration.

The compounds ,of formula I, their enantiomers and salts thereof as herein described, have effects qualitatively similar to those of phenylbutazone and indomethacin, known for their therapeutic uses and properties. Thus, the end products of this invention demonstrate a pattern of activity associated with anti-inflammatory agents of known efficacy and safety. 44727 > - 23 The compounds of formula X, their enantiomers and salts thereof as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral or parenteral application with the usual pharmaceutical adjuvant material, for example, organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums and polyalkylene-glycols. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, troches, suppositories, capsules, or in liquid form, for example,' as solutions, suspensions, or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.

Since the compounds of the invention when X and Y in formula I are different possess an asymmetric carbon atom, they are ordinarily obtained as recemic mixtures. The resolution of such racemates into the optically active isomers can be carried out according to process r) by known procedures. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, however, preferred. By this method, diastereomers are formed from the racemic mixture with an optically active resolving agent, for example, an optically active base, such ^4727 - 24 as d-a-methylbenzylamine, which can be reacted with the carboxyl group. The formed diastereomers are separated by selective crystallization and converted to the corresponding optical isomer. Thus, the invention covers the reacemates of the compounds of formula I as well as their optically active isomers.

The following Examples further illustrate the invention. All temperatures are in degrees Centigrade, unless otherwise stated. «472? Example 1 Preparation of 8-chloro- a -methyldibcnzothiophene-3-acetic acid To a 500 ml. three-neoked flask containing 100 ml. of liquid ammonia and 0.009 mol of sodium amide (prepared from 0.2 g. sodium) was added dropwise a 5 solution of 2.6 g. of 8-chlorodibenzothiophene-3_-acetic acid ethyl ester in 20 ml. of ether and 10 ml. of tetrahydrofuran. The solution was stirred for 1 hour and then a solution of 1.3 g. of methyl iodide in 20 ml. of ether was added dropwise. After the solution was stirred for 1 hour, 0.5 g. of ammonium chloride was added and the ammonia allowed to evaporate. Then the residue was acidified with dilute hydrochloric acid and the oii extracted with ether. The ether was removed and the residue slowly solidified. The solid was crystallized from pentane and yielded 1.5 g. of 8-chloro- a -methyldibenzothiophene-3-acetic acid ethyl ester, m.p. 73-75°. 1.3 G. of 8-chloro-a -methyldibenzothiophene-3-acetic acid ethyl ester was added to 100 ml. of absolute ethanol containing 0.6 g. of potassium hydroxide.

The solution was refluxed for 3 hours. Then the solvent was removed in vacuo and the residue dissolved in 30 ml. of water. The solution was acidified with dilute hydrochloric acid and the oil extracted with ether. The ether was removed and the residue, crystallized from ethyl acetate, yielded 0.9 g. of 8-chloro-a 20 methyldibenzothiophene-3-acetic acid, m.p. 190-192°.

Example 2 Preparation of 8-chloro- a, a -dimethyldit)cnzotliiophene-3-acetic acid To a 500 ml. three-necked flask containing 400 ml. of liquid ammonia and 0.017 mol of sodium amide (prepared from 0.39 g. of sodium) was added dropwise a solution of 5.1 g. of 8-chloro- a -methyldibenzothiophene-3-acetic acid ethyl ester in 40 ml. of tetrahydrofuran. The solution was stirred for 1 hour and then a solution of 2.3 g. of methyl iodide in 50 ml. of ether was added dropwise. After the addition, the solution was stirred for 3 hours. Then 1.1 g. of ammonium chloride was added and the ammonia allowed to evaporate. The residue was acidified with dilute hydrochloric acid and the oil extracted with ether. The ether was removed and the residue, crystallized from pentane, yielded 1.8 g. of 8-chloro- o , a-dim6thyldibenzothiophene-3-acctic acid ethyl ester, m.p. 57-61°. 1.8 G. of 8-chlqro- a, a -dimethyldibenzothiophene-3-aeetic acid ethyl ester was add^d to a solution of 0.4 g. of potassium hydroxide in 100 ml. of ethanol After the solution had refluxed for 3 hours, the solvent was removed in vacuo.

The residue was dissolved in 75 ml. of water and the solution acidified with dilute hydrochloric acid. The crude acid was extracted with ethyl acetate. The solvent was removed in vacuo and the residue, crystallized from acetonitrile, yielded θ·58 g. of 8-chloro- a ,a-dimethyldibenzothiophene-3-acetic acid, m.p. 198-200°. - 27 Example 3 Preparation of 8-chloro- a -butyldibenzothiophene-3-acetic acid To a 500 ml. three-necked flask containing 200 ml. of liquid ammonia and 0.014 mol of sodium amide (prepared from 0.32 g. of sodium) was added dropwise 5 a solution of 3.8 g. of 8-chlorodibenzothiophene-3-acetic acid ethyl ester in 40 ml. of tetrahydrofuran. The solution was stirred for 1 hour and a solution of 1.8 g. of butyl bromide in 50 ml. of ether was added dropwise. The solution was stirred for 1 hour, 0.9 g. of ammonium chloride added and the ammonia allowed to evaporate. The residue was acidified with dilute hydrochloric acid and the oil extracted with ether. The ether was removed by distillation and the residue remaining (3.9 g.) was crude 8-chioro- a -butyldibenzothiophene-3-acetic acid ethyl ester.

To a solution of 0.9 g. of potassium hydroxide in 100 ml. of alcohol was added 3.9 g. of crude 8-chloro- a-butyldibenzothiophene-3-acetic acid ethyl ester.

The solution was refluxed for 3 hours and then the solvent was removed in vacuo.

Water was added to the residue and the insoluble by-products extracted with ether and the ether discarded. The clear aqueous solution was acidified with dilute hydrochloric acid and the desired product extracted with ethyl acetate. The solvent was removed in vacuo and the residue, after crystallization from acetonitrile, yielded 1 g. of 8-chloro- a-butyldibenzothiophene-3-acetic acid, m.p. 156-159°.

Example 4 Preparation of 3-bromo-4-oxocyclohcxanene<.'lic acid ethyl ester 74.0 G. of 4-oxocyclohexaneacetic acid ethyl ester and 1200 ml. of anhydrous ether were placed in a 3 1. three-necked flask, provided with a thermometer, nitrogen inlet, dropping funnel, condenser and stirrer. The solution was cooled to -10° by means of a dry ice-acetone bath, and 64.0 g. of bromine was added dropwise over a period of 30-40 minutes. The resulting colorless solution was washed three times with 100 ml. of water, then two times with 125 ml. of cold saturated sodiuin bicarbonate solution followed by 100 ml. of water. The combined aqueous solutions were extracted twice with 150 ml. of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, and the ether was removed by distillation from a steam bath at atmospheric pressure to give a residue of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester, weighing 105 g.

- Example 5 Preparation of 3~ (4-chlorophenyIthio)-4-oxocyclohexaneacetic acid ethyl ester G. of 4-chlorothiophenol and a solution of 26.5 g. of 85% potassium hydroxide in 1500 ml. of ethanol were each placed in a 3 1. three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 105 g. of crude 3-bromo-4-oxocyclo2o hexaneacetic acid ethyl es‘er in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature. and filtered to remove the potassium bromide· After removal of the ethanol in vacuo (steam bath, rotary 44737 evaporator), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue, weighing 128 g., was distilled in vacuo. A forerun weigh5 ing 28.7 g. was collected at 100-190° (1 mm.), while 76.4 g. of a main fraction collected at 190-222° (1 mm.). A gas chromatographic determination of the main fraction showed that 3-(4-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester was present.

Example 6 1q Preparation of 8-chloro-l,2,3,4-tetrahydroaibenzothlophene-3-acetic acid ethyl ester 76.4 G. of the above-distilled 3-(4-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester (bp 190-222/1 mm.) was added to 1000 g. of polyphosphoric acid, contained in a 2 1. three-necked flask, provided with a stirrer and con15 denser. The mixture was heated on a steam bath for 90 minutes and then poured into a mixture of 1 kilogram of ice and 1 liter of water. The mixture was stirred until the dark oily complex was decomposed and a light yellow color appeared. The product was extracted twice with 500 ml. of ether. The ether extract was washed twice with 100 ml. of water, then with 100 ml. of saturated sodium bicarbonate 2q solution, dried over anhydrous potassium carbonate, and distilled at atmospheric pressure from a steam bath to remove the ether to give 57.1 g. of residue. A gas chromatogram of this crude residue showed the presence of 8-chloro-l,2,3,4tetrahydrodibenzothiophene-3-acetie acid ethyl ester and of bis-(4-chlorophenyl)disulfide.

In order to remove the by-product bis(4-ehlorophenyl)disulfide, 30.9 g. of the above crude mixture was added to a 1 liter three-necked flask provided with a condenser and an inlet for nitrogen. A solution of 4.8 g. of sodium hydroxide in 250 ml. of ethanol was added, and the resulting solution was refluxed for 1 hour under nitrogen. The ethanol was removed in vacuo (steam bath, rotary evaporator) and 200 ml. of water added. The solution Was acidified with dilute hydrochloric acid. After the precipitated 8-chloro-l,2,3,4-tetrahydrodibenzothiophene acetic acid had settled, the supernatant liquid was decanted. 100 Ml. of ether was added to the wet semi-solid acid, and the mixture swirled. The insoluble 8-chloro10 1,2,3,4-tetrahydrodibenzothiopheneacetic acid was filtered off, Washed with ml. of ether, and dried in a vacuum oven overnight at 50°. The yield of 8-chIoro-l,2,3,4-tetrahydrodibenzothiophene acetic acid was 26 g.), mp 195-202°. Re-esterification was carried out by adding 25.4 g. of the above acid to 400 ml. of ethanol saturated at room temperature with hydrogen chloride.

After the solution Was refluxed for 6 hours, the ethanol was removed in vacuo (steam bath, rotary evaporator), and 300 ml. of benzene was added to the residue.

The benzene solution was first extracted twice with 75 ml. of water and then twice with 75 ml. of 6% sodium bicarbonate. The benzene solution. Was dried over anhydrous potassium carbonate and distilled in vacuo to remove the benzene.

The weight of the crude ester was 26.6 g., m.p. 55-60°. Crystallization from hexane gave 22.1 g. of pure 8-chloro-l,2,3,4-tetrahydrodibenzothiophene-3acetic acid ethyl ester, m.p. 64-66°.

Example 7 Preparation of 8-chloro-dibenzothiophene-3-acetic acid ethyl ester Into a 2 liter three-necked flask provided with a condenser, stirrer and dropping funnel was added 31.2 g. of 2,3-dichlorc-5,6-dicyano-l,4-benzoquinone 5 and 500 ml. of dioxane. To the solution, heated to reflux, was added at a rapid rate a solution of 21.2 g. of 8-chIoro-l,2,3,4-tetrahydrodibenzothiophene~3-aeetic acid ethyl ester in 500 ml. of dioxane. The solution was refluxed and stirred for 18 hours, cooled to room temperature, and filtered to remove the formed hydroquinone. The solvent was removed in vacuo (steam bath, rotary evaporator), and the residue was dissolved in 300 ml. of methylene chloride. The solution was filtered, if necessary, and passed through a column containing about 200 g. of alumina (Woelm, grade 1). The color of the solution was now a light yellow. The solvent was removed (steam bath, rotary evaporator), and the weight of sticky solid was 18.6 g. The latter was recrystallized from hexane and yielded 14 g. of 8-chloro-dibenzothiophene-3-aeetic acid ethyl ester, mp 88-90°.

Example 8 Preparation of 8-chloro-diben20thiophene-3-acetic acid To a 500 ml. flask, fitted with a condenser and containing a solution of 1.84 g of sodium hydroxide in 150 ml. of ethanol was added 14 g. of 8-chloro-dibenzothio20 phene-3-acetic acid ethyl ester. After the solution was refluxed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and the aqueous solution acidified with dilute hydrochloric acid. The 8-chloro-dibenzothiophene-3-acetic acid was removed by 44737 filtration, washed with water and dried at 60° in a vacuum oven overnight. The yield of 8-chloro-dibenzolhiophene-3-acetic acid, after crystallization from xpropanol, was 8 g., mp 220-221°.

Example 9 Preparation of 3-(2-ehlorophenyIthio)-4-ketocyciohexane acetic acid ethyl ester G. of 2-chlorothiophenol and a solution of 10.8 g. of 85% potassium hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 50.6 g. of 3-bromo-4-ketoeyclo10 hexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotovapor), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A forerun was collected at 100-190° (1 mm), while a main fraction was collected at 190-222° (1 mm) . The yield of 3-(2-chlorophenylthic)-4-ketoeyclohexaneacetic acid ethyl ester from the main fraction was 33.9 g., 2o b.p. 205-215/0.7 mm.

Example 10 Preparation of 6-chIoro-l,2,3,4-tetpahydrodibenzothiophene-3-aeetic acid ethyl ester 33.9 G. of the above distilled 3-(2-chlorophenylthio)-4-ketocyclohexane5 acetic acid ethyl ester was added to 600 g. of polyphosphoric acid, contained in a 2 liter, three-necked flask, provided with a stirrer and condenser. The mixture was heated on a steam bath for 90 minutes and then poured into a mixture of 1 kilogram of ice and 1 liter of water. The mixture was stirred until the dark oily complex was decomposed and a light yellow color appeared. The product was extracted twice with 500 ml. of ether. The ether extract was washed twice with 100 ml. of water, then with 100 ml. of saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, and distilled at atmospheric pressure from a steam bath to remove the ether. The yield of 6-chloro-l ,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester was 8.5 g., b.p. 195-210/0.7 mm, mp 51-53° (pentane).

Example 11 Preparation of 6-ehlcro-dibenzothiophene-3-acetic acid ethyl ester Into a 2 liter thrfee-necked flask provided with a condenser, stirrer and dropping funnel was added 6 g. of 2,3-dichlor£-5,6-dicyano-l,4-benzoquinone 20 and 500 ml. of dioxane. To the solution, heated to reflux, was added at a rapid rate a solution of 3.3 g. of 6-chloro-l,2,3,4-tetrahydrodibenzothiophene-3acetic acid ethyl ester in 50.0 ml. of dioxane. The solution was refluxed and stirred for 18 hours, cooled to room temperature, and filtered to remove the hydroquinone. The solvent was removed in vacuo (steam bath, rotary evaporator) and the residue was dissolved in 300 ml. of methylene chloride. The solution was filtered, if necessary, and passed through a column containing about 200 g. of alumina (Woelm, grade I). The solvent was removed (steam hath, rotary evaporator). The resulting solid was recrystallized from hexane and yielded 1.3 g. oi 6-chloro-dibenzothiophene-3-acetic acid ethyl ester, mp 62-64° (hexane).

Example 12 Preparation of 6-chloro-dibenzothiophene-3-acetic acid To a 100 ml. flask, fitted with a condenser and containing a solution of 0.24 g. of potassium hydroxide in 30 ml. of ethanol was added 1.3 g. of 6-chloro10 dibenzothiophene-3-acetic acid ethyl ester. After the solution Was refluxed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and ihe aqueous solution acidified with dilute hydrochloric acid. The 6-chlorodibenzothiophcne-3-acetic acid was removed by filtration, washed with water and dried at 60° in a vacuum oven overnight. The yield of 6-chlorodibenzotbiophene-3-acetic acid, after crystallization from acetonitrile was 0.8 g., mp 220-228°.

Example 13 Preparation of 3-(4-i-butylphenylthio)-4-ketocyclohexaneacetic acid ethyl ester 31.4 G. of 4-i-butylthiophenol and a solution of 10.6 g. of 85% potassium 2o hydroxide in 300 ml. of ethanol were each placed in a 3 liter three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer. The solution was brought to reflux and a solution of 49.5 g. of 3-bromo-4-ketocycIohexaneacetic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour to the refluxing solution. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of the ethanol in vacuo (steam bath, rotary evaporator), 300 ml. of water was added to the residue, the product was extracted three times with 200 ml. of ether and the ether extract dried over anhydrous magnesium sulfate. After removal of ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. A yield of 42.5 g. of 3-(4-i-butylphenylthio)-4-ketooyclohoxane acetic acid ethyl ester was obtained, b.p. 205220/2.0 mm. lo Example 14 Preparation of 8-i-butyl-l,2,3,4-tetrahydrodibenzothiophene-3-acetie acid ethyl ester 42.5 G. of the above distilled 3-(4-i-butylphenylthio)-4-ketocyclohexane acetic acid ethyl ester was added to 700 g. of polyphosphoric acid, contained in a 2 liter three-necked flask, provided with a stirrer and condenser. The mixture was heated on a steam bath for 90 minutes and then poured into a mixture of 1 kilogram of ice and 1 liter of water. The mixture was stirred until the dark oily complex was decomposed and a light yellow color appeared. The product was extracted twice with 500 ml. of ether. The ether extract was washed twice with 100 ml. of water, then with 100 ml. of saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, and distilled at atmospheric pressure from a steam bath to remove the ether. The yield of S-i-butyl-1,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester was 24.4 g., b.p. 195-205/0.7 mm. 44737 Example 15 Preparation of 8-i-butyldibenzothiophene-3-acctic acid ethyl ester Into a 2 liter three-necked flask provided with a condenser, stirrer and dropping funnel was added 16.6 g. of 2,3-dichloro-5,6-dieyano-l,4-benzoquinone and 200 ml. of xylene. To the solution, heated to reflux, was added at a rapid rate a solution of 10.7 g. of 8-i-butyl-l,2,3,4-tetrahydrodibenzothiophene-3acetic acid ethyl ester in 200 ml. of xylene. The solution was refluxed and stirred for 18 hours, cooled to room temperature, and filtered to remove the hydroquinone. The solvent was removed in vaeuo (steam bath, rotary evaporator) and the residue was dissolved in 300 ml. of methylene chloride. The solution was filtered, if necessary, and passed through a column containing about 200 g. of alumina (Woelm, grade I). The solvent was removed (steam bath, rotary evaporator). The product was recrystallized from hexane and yielded 4.7 g. of 8-i-butyldibenzothiophene-3-acetie acid ethyl ester, b.p. 200-215/0.7 mm.

Example 16 Preparation of 8-i-butyl-dibenzothiophene-3-acetic acid To a 500 ml. flask,’ fitted with a condenser and containing a solution of 0.81g. of potassium hydroxide in 125 ml. of ethanol was added 4.7 g. of 8-ibutyldibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for 1 hour , the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and the aqueous solution acidified with dilute hydrochloric acid. The product was removed by filtration, washed with water and dried at 60° in a vacuum oven overnight. The yield of 8-i-butyl-dibenzo«4737 thiophene-3-acetic acid after crystallization from i-propanol was 1.5 g., mp 133135° (heptane).

Example 17 Preparation of 9-ehlorodibenzothiophene-3-acetic acid 5 (A) 3-(3-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester.

In a 3-1. three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer were placed 23.8 g. of 3-chlorothiophenol and a solution of 10.8 g. of 85% potassium hydroxide in 300 ml. of ethanol. The solution was brought to reflux, and a solution of 43 g. of 3-bromo-4-oxocyclohexaneaeetic acid ethyl ester in 250 ml. of ethanol was added over a period of one hour. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature and filtered to remove the potassium bromide. After removal of the ethanol in vacuo on the steam bath, 150 ml. of water was added to the residue, the product extracted three times with 100 ml. of ether, and the ether extract was dried over anhydrous magnesium sulfate. After removal of the ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. The yield of 3-(3-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester was 12.2 g.; b.p. 195-225°/ mm.

(B) 9-chloro-l ,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester.

Tb 200 g. of polyphosphoric acid contained in a 1-1. three-necked flask, provided with a stirrer and condenser was added 8.0 g. of 3-(3-chlorophenylthio)4-oxocyclohexaneacetic acid ethyl ester. The mixture was heated on a steam bath 44737 .18 for 90 minutes and then poured into a mixture of 200 g. of ice and 200 ml. of water with stirring, which was continued until the dark oily complex was decomposed and a light yellow color appeared. The product was extracted twice with 200 ml. of ether . The ether extract was washed twice with 50 ml. of water and then with 50 ml, of saturated sodium bicarbonate solution. The solution was dried over anhydrous potassium carbonate and then filtered. The ether was removed on a steam bath in a rotary evaporator at atmospheric pressure, and the residue was distilled at reduced pressure. At 205-220°/2 mm. a yield of 3.3 g. of 9-chlorol,2,3,4-tetrahydrodibenzothiophene-3-acetic acid ethyl ester was obtained.

(C) S-ehloredibehzothiophene-3-acatic acid ethyl ester.

To a 1-1. three-necked flask provided with a condenser, stirrer and dropping funnel was added 11 g. of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) and 500 ml. of dioxane. To the solution heated to reflux, was added at a rapid rate a solution of 6 g. of 9-chloro-l,2,3,4-tetrahydrodibenzothiophene-3-acetie acid ethyl ester in 100 ml. of dioxane. The solution was refluxed and stirred for 24 hours, cooled to room temperature and then filtered to remove the hydroquinone.

The solvent was removed in vacuo on the steam bath, and the residue was dissolved in 200 ml. of methylene chloride. This solution was passed through a column containing about 150 g. of alumina GVoelm, grade 1). The solvent was removed on the steam bath and the residue was crystallized from alcohol. The yield of 9chlorodibenzothiophene-3-acetie acid ethyl ester was 1.1 g., m.p, 82-84°. - 39 (D) O-chlorodibenzotiiiopliene-3-acetic acid.

To a 100 ml. flask, fitted with a condenser and containing a solution of 0.28 g. of potassium hydroxide in 50 ml. of ethanol was added 1.1 g. of 9-chlorodibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for four hours, the solvent was removed in vacuo on the steam bath, the residue was dissolved in 50 ml. of water, and the aqueous solution was acidified with dilute hydrochloric acid. The product was filtered, washed with 20 ml. of water, and dried at 60° in a vacuum oven for 12 hours. The yield of 9-chlorodibenzothiophene 3-acetie acid, after crystallization from methanol, was 0.8 g. (m.p. 203-206°). , Example 18 Preparation of 8-methyidibenzothiophene-3-acetic acid (A) 3-(4-methyIphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester.

In a 2 1. three-necked flask provided with a condenser, nitrogen inlet, dropping funnel and stirrer were placed 73.5 g. of p-toluenethiol and a solution of 33 g. of 85% potassium hydroxide in 500 ml. of ethanol. The solution was brought to reflux, and a solution of 146.4 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour. After the addition, the solution was stirred at reflux for one hour . After removal of the ethanol in vacuo on tha steam bath, 300 ml. of water was added, and the product was extracted three times with 200 mi. of ether. The ether solution was dried over anhydrous magnesium sulfate, and then the solvent was removed on the steam bath. The residue was crystallized from heptane; yield 66 g. of 3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester, m.p. 87-89°.

(B) 8-methyl-l,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester. , To 130 g. of polyphosphoric acid contained in a 500 ml. three-necked flask provided with a stirrer and condenser, was added 13 g. of 3-(4-methylphenylthio)5 4-ketocyclohexanecarboXylic acid ethyl ester. The mixture was heated on a steam bath for 90 minutes and then poured onto a mixture of 200 g. of ice and 200 ml. of water. The mixture was stirred until the dark oily complex was decomposed, and a light yellow color appeared. The product was extracted with ether, and the solution then washed with water until it was neutral. After drying over IO anhydrous potassium carbonate, the ether was distilled off on the steam bath, and the residue was crystallized from methanol. The yield of 8-methyl-l ,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester, m.p. 68-69°, was 6 g.

(C) 8-methyldibenzothiophene-3-carboxylie acid ethyl ester.

To a 500 ml. three-necked flask provided with a condenser, stirrer and dropping funnel was added 10 g. of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) and 200 ml. of dioxane. To the solution, heated to reflux, was added at a rapid rate a solution of 5.5 g. of 8-methyl-l ,2,3,4-tetrahydrodibenzothiophene3-carboxylic acid ethyl ester in 50 ml. of dioxane. The solution was refluxed and stirred for 20 hours, cooled to room temperature and filtered to remove the hydroquinone. The solvent was removed in vacuo on the steam bath, and the residue was dissolved in 100 ml. of methylene chloride. The solution was passed through a column containing about 75 g. of alumina (Woelm, grade I) . The Solvent was removed, and the residue was crystallized from methanol. The yield of 8i - 41 44727 methyldibenzothiophene-3-carboxylic acid ethyl ester was 4.2 g., m.p. 83-87°.

(D) 8-methyIdibenzothiophene-3-carboxylic acid.

To a solution of 0.73 g. of potassium hydroxide in 50 ml. of ethanol was added 3.5 g. oi 8-methyldibenzothiophene-3~carboxylic acid ethyl ester. The solution was refluxed for 3 hours. The solvent was removed in vacuo on the steam bath, and the crude potassium salt was dissolved in 50 ml. of water. The solution was acidified with dilute hydrochloric acid and the product was filtered off and dried. The yield of 8-methyldibenzothiophene-3-carboxylic acid was 2 g., m.p. 290-291°.

(E) 3-chlorocarbonyl-8-methyldibenzothiophene.

A solution of 3 g. of oxalyl chloride in 50 ml. of benzene was added dropwise with stirring to a suspension of 3.5 g. of the crude potassium salt of 8-methyldibenzothiophene-3-carboxylic acid in 100 ml. of benzene. The mixture was filtered and the solvent removed in vacuo on the steam bath. The residue, after crystallization from hexane, yielded 2.5 g. of 3-chlorocarbonyl-8-methyldibenzothiophene, m.p. 127-128°.

(F) 3-diazomethylcarbonyl-8-methyldibenzothiophene.

A solution of 2.5 g. of 3-chlorocarbonyl-8-methyldibenzothiophene in 75 ml. of ether was added dropwise to a solution of 0.81 g. of diazomethane in 20 100 ml. of ether in an ice bath. The solution was stirred overnight, and the ether was removed on the steam bath. The crude product (2.5 g.), 3-diazomethylcarbonyl-8-methyldibenzothiophene, was used directly in the next step.

(G) 8-mctlfyldibenzothiophene-3-acetic acid ethyl ester.

To a refluxing solution of 2.5 g. of crude 3-diozomcthylcarbonyl-8-methyldibenzothiophene in 50 ml. of ethanol was added dropwise, with stirring, a solution of 1.0 g. of silver benzoate in 10 ml. of triethylamine. The solution was refluxed until evolution of nitrogen had ceased. The solution was filtered, and the solvent was removed in vacuo on the steam bath. The residue was crystallized from petroleum ether (30-60°) to yield 1.3 g. of 8-methyIdibenzothiophene-3acetic acid ethyl ester, m.p. 45-48°.

(H) 8-methyldibcnzothiophene-3-acetic acid.

To a solution of 0.27 g. of potassium hydroxide in 50 ml. of alcohol, was added 1.3 g. of 8-methyIdibenzothiophene-3-acetic acid ethyl ester, and the solution was refluxed for 3 hours. The solvent was removed in vacuo, and the residue was dissolved in 50 ml. of water. The solution was acidified with dilute hydrochloric acid and the product was filtered off and dried. Recrystallization 15 from acetonitrile yielded 0.5 g. of 8-methyldibenzothiophene-3-acetic acid, m.p. 185-187°. .^3 ‘/Dif Example 19 Preparation of 7-chlorodibenzothiophene-3-acetic acid (A) Dibcnzothiophene-3-carboxylic acid ethyl ester 5-oxide. 8,3 G. of chlorine was bubbled into a solution of 23.8 g. of dibenzothio5 phene-3-carboxylic acid ethyl ester in 600 ml. of carbon tetrachloride cooled to °. The solution was poured onto ice, and the mixture was well shaken. The solid was filtered off, dried in vacuum at 50° and then crystallized from acetonitrile to yield 11.6 g. of dibenzothiophene-3-carboxylic acid ethyl ester 5-oxide, m.p. 210-213°.

(B) 7-nitrodibenzothiophene-3-carboxylic acid ethyl ester 5-oxide.

To 250 ml. of 90% nitric acid kept at 22-25°, 25 g. of dibenzothiophene-3carboxylic acid ethyl ester 5-oxide was added, in portions. The solution was stirred for 15 minutes and then poured onto ice. The solid was filtered off, washed with water until neutral and dried in a vacuum oven at 50°. The solid was crystallized from 1,2-dichloroethane to yield 24.7 g. of 7-nitrodibenzothiophene-3earboxylic acid ethyl ester 5-oxide, m.p. 245-250°.

(C) 7-aminodibenzothiophene-3-carboxyIic acid ethyl ester hydrochloride. A mixture of 21,9 g. of 7-nitrodibenzothiophene-3-carboxylic acid ethyl ester 5-oxide, 250 ml. of acetic acid, and 1.7 g. of 10% palladium on carbon was shaken at an initial pressure of 50 pounds of hydrogen and heated to 60°. After one hour the uptake of hydrogen had ceased. The mixture was removed from the hydrogenation apparatus, cooled to room temperature and filtered. After removal of the solvent in vacuo on the steam bath, the residue was dissolved in 300 ml. of ethyl acetate, and the product was precipitated as the hydrochloride by bubbling in hydrogen chloride. The yield of 7-aminodibenzothiophene-3-carboXylic acid XO ethyl ester hydrochloride was 17.1 g. (m.p. 260-265°). A small portion, after crystallization from methanol, melted at 270-275°.

(D) 7-chIorodibenzothiophene-3-curboxylic acid ethyl ester.

A solution of 28.7 g. of 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride in 300 ml. of acetic acid was added at 15° to nitrosylsulfuric acid prepared from 19.4 g. of sodium nitrite and 100 ml. of concentrated sulfuric acid. The mixture was stirred for 15 minutes and then 11. of ether was added to precipitate the diazonium sulfate. The mixture of the diazonium sulfate and sodium sulfate was filtered oif, washed with ether, and air-dried. The mixture was then added, in portions at 5° to a cuprous chloride solution prepared from 9.4 g. of 2o cuprous chloride, 375 ml. of water and 280 ml. of cone, hydrochloric acid.

After the addition, the contents were heated on a steam bath until nitrogen evolution ceased. The solid was filtered off, washed with water and then dried in a vacuum oven. The solid, after crystallization from hexane, yielded 18 g. of 7-chlorodibenzothiophene-3-carboxylic acid ethyl ester, m.p. 120-122°. - 45 44737 (E) 7-chlorodibenzothiophene-3-carboxylic acid potassium salt.

A solution of 4.1 g. of potassium hydroxide (85%) in 100 ml. of alcohol was added to a solution of 18.1 g. of 7-chlorodibenzothiophene-3-carboxylic acid ethyl ester in 450 ml. of warm ethanol. The combined solutions were stirred and refluxed for 8 hours. After cooling to room temperature, the mixture was filtered to give 16.5 g. of the potassium salt.

(F) 3-chlorocarbonyl-7-chlorodibenzothiophene, A solution of 10.5 g. of oxalyl chloride in 100 ml. of benzene was added, with stirring, to a suspension of 16.53 g. of 7-chlorodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of benzene. The mixture was stirred and refluxed for two hours and then filtered. On distillation to dryness on the steam hath in vacuo 9 g. of crude 3-chlorocarbonyl-7-chlorodibenzothiophene was obtained as a residue.

(G) 7-chlorodibenzothiophene-3-acetic acid ethyl ester.

A solution of 9 g. of 3-chlorocarbonyl-7-chlorodibenzothiophene in 100 ml. of dioxane was added dropwise to a solution of 5.3 g. of diazomethane in 250 ml. of ether with cooling in an ice bath. The solution was stirred overnight, and the solvent was then removed by distillation in vacuo. The residue was dissolved in 600 ml. of ethanol, and to the refluxing solution was added drojwise over one hour 2q a solution of 1 g. of silver benzoate in 100 ml. of triethylamine. The solution was refluxed for one hour after the addition and then filtered. The solvent was removed by distillation in vaeuo from a steam bath and the residue was crystallized from hexane, yield, 4.8 g. of 7-chlorodibenzothiophene-3-acetic acid ethyl ester, m.p. 68-70°.

(H) 7-chlorodibenzothiophene-3-acetic acid.

To a solution of 1 g. of potassium hydroxide in 75 ml. of ethanol was added 5 4.8 g. of 7-chlorodibenzothiophene-3-acetic acid ethyl ester. After refluxing for hours, the solvent was removed in vacuo on the steam bath, and 50 ml. of water was added to dissolve the residue. The aqueous solution was acidified with hydrochloric acid, and the product filtered off. The solid was crystallized from acetonitrile to yield 1.7 g. of 7-chlorodibenzothiophene-3-acetic acid, m.p. 198-200°.

Example 20 Preparation of 7-dimcthylaminodibenzothiophcnc-3-acetic acid ethyl ester (A) 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride A mixture of 24 g. of 7-nitrodibenzothiophene-3-carboxylic acid ethyl ester 5-oxide, 200 ml. of aCetic acid and 2.4g. of 10% palladium carbon was hydrogenated at 50° at an initial pressure of 50 lbs. After completion of the hydrogenation in 3 hours, the mixture was filtered, and the acetic acid was removed in vacuo (steam bath, rotary evaporator). The residue was dissolved in 250 ml. of ethyl acetate, and hydrogen chloride was bubbled into the solution.

The precipitated hydrochloride of 7-aminodibenzothiophene-3-carboxylic acid ethyl ester weighed 20 g.; mp 270-275°. (Β) 7-dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester A mixture of 7.3 g. of 7-aminodibenzothiophene-3-carboxylic acid ethyl ester hydrochloride and 5.0 g. of triraethyl phosphate were heated at 160° for 45 minutes. After cooling to room temperature, 75 ml. of ethyl acetate was added, and the solution was extracted with 25 ml. of water. The ethyl acetate was removed in vacuo (steam bath, rotary evaporator), and the residue was crystallized from ethanol. The yield οί 7-dimethylaminodibenzothiophene-3carboxylic acid ethyl ester was 2.8 g.; mp 160-162°.

(C) 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt To a solution of 0.5 g. of potassium hydroxide in 100 ml. of ethanol was added 2.8 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid ethyl ester. The solution was stirred and refluxed for 3 hours during which time the potassium salt precipitated. The salt was filtered off, washed with ether and air dried.

The yield of 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt was 1.9 g.

(D) 7-dimethylaminodibenzothiophene-3-carbonyl chloride To a suspension of 1.9 g. of 7-dimethylaminodibenzothiophene-3-carboxylic acid potassium salt in 100 ml. of refluxing benzene was added over a period of 20 minutes a solution of 1.2 g. of oxalyl chloride in 25 ml. of benzene. The solution 2o was then stirred and refluxed for 3 hours. The hot solution was filtered, and the filtrate was distilled to dryness in vacuo (steam bath, rotary evaporator).

The residue of crude 7-dimethylaminodibenzothiophene-3-earbonyl chloride weighed 1.8 g. - 48 (E) 7-dimethyIaminodibenzothiophene-3- acetic acid ethyl cater To a 250 ml. 3-necked flask provided with a stirrer, dropping funnel and condenser was added a solution, of 0.7 g. of diazomethane in 50 ml. of ether.

The flask was cooled in an ice bath, and a solution of 1. S g. of 7-dimethylamino5 dibenzothiophene-3-carbonyl chloride in 50 ml. of anhydrous ether and 50 ml. of tetrahydrofuran was added dropwise over a period of 15 minutes. The ice bath was removed and the solution stirred for 2.5 hours. After removal of the solvent by distillution in vacuo on the steam bath, the residue was crystallized from toluene. The yield of 3-diazomethylcarbonyl-7-dimethylaminodibenzo10 thiophene was 0.3 g; mp 173-175°. To a refluxing solution of the diazo compound (0.3 g.) in 50 ml. of ethanol was added dropwise, over 1 hour with stirring a solution of 1 g. of silver benzoate in 10 ml. of triethylamine. The solution was filtered and the solvents removed from a steam bath in vacuo. The residue was crystallized from methanol and yielded 50 mg. of 7-dimethylaminodibenzo15 thiophene-3-acetic acid ethyl ester; mp 115-120°.

Example 21 Preparation of 8-chlorodibenzothiophene-3-acetamide A solution of 2.76 g. of 8-chlorodibenzotliiophene-3-acetic acid in 10 ml. of thionyl chloride was stirred for 1 hour and then distilled at reduced pressure at room temperature. The residue of crude 8-chlorodibenzothiophene-3-acetyl chloride, m.p. 92-99°, was then dissolved in 100 ml. of benzene, and the solution was saturated witli ammonia. The amide was filtered off, washed with water and crystallized from acetic acid. The product, 8-chIorodibenzothiophene-3-acetamide weighed 2 g. and melted at 237-238°.

Example 22 Preparation of 2-(8-chloro-3-dlbenzothienyl) ethanol 3.05 G. of 8-chlorodibenzothiophene-3-acetic acid ethyl ester was added to 0.45 g. of lithium aluminum hydride in 100 ml. of ether. The solution was refluxed for one hour and then treated with 2 ml. of water. The solution was filtered and the ether removed from a steam bath. The residue was crystallized from acetonitrile and-yielded 1.1 g. of 2-(8-chloro-3-dibenzothienyl)ethanol, m.p. 98-100°.

Example 23.

Preparation of 8-chlorodibenzothiophene-3-acetic acid, 2-dimethylaminoethyl ester hydrochloride A mixture of 2.76 g. of 8-chIorodibenzothiophene-3-acetic acid, 3.04 g.

X5 of potassium carbonate, 1.73 g. of dimethylaminoethyl chloride hydrochloride, and 250 ml. of diriiethyiformamide was stirred and heated at 120° for 4 hours. The solvent was removed in vaeuo on the steam bath, and 75 ml. of water added to the residue. The oil was extracted with ethyl acetate and the crude product precipitated as the Hydrochloride by the addition of hydrogen chloride. On crystallization frtSm acetone, 1.5 g. of 8-chlorodibenzothiophene-3-acetic acid 2-dimethylaminoethyl ester hydrochloride, m.p. 179-181°, was obtained. _ 50 Example 24 Tablet Formulation Per Tablet 8-chloro-dibenzotbiophene5 3-acetic acid 25 mg.

Dicaleium Phosphate Dihydrate, unmilled 175 mg.

Corn Starch 24 mg.

Magnesium Stearate . 1 mg.

Total Weight 225 mg.

Procedure: 1. 25 Parts of 8-chloro-dibenzothiophene-3-acetic acid and 24 parts of corn starch are mixed together and passed through a No. 00 screen in Model J Fitzmill with hammers forward. 2. This premix is then mixed with 175 parts of dicalcium phosphate and one15 half of a part of the magnesium stearate, and passed through a No. IA screen in Model J Fitzmill with knives forward, and slugged. 3. The slugs are passed through a No. 2A plate in a Model D Fitzmill at slow speed with knives forward, and the other one-half of a part magnesium stearate is added. 4. The mixture is mixed and compressed into tablets weighing 225 mg.

Example 25 Capsule Formulation Per Capsule 8-chloro-dibenzothiophene-3- acetic acid 50 mg. Lactose, U.S.P. 125 mg. Corn Starch, U.S.P. 30 mg. Talc, U.S.P.5 mg· Total Weight 210 mg.

Procedure: 1. 50 Parts of 8-chloro-dibenzothiophene-3-acetic acid is mixed with 125 parts of lactose and 30 parts of corn starch in a suitable mixer. 2. The mixture is further blended by passing through a Fitzpatrick Comminuting Machine with a No. 1A screen with knives forward. 3. The blended powder is returned to the mixer, 5 parts talc are added and blended thoroughly. 4. The mixture is filled into No. 4 hard shell gelatin capsules on a Parke Davis eapsulating'machine. $4727 Example 26 1 Tablet Formulation Per Tablet 8-chloro-dibenzothiophene-3- acetic acid 100 mg. Lactose, U.S.P. 202 mg. Corn Starch, U.S.P. 80 mg. Amijel BO111 20 mg. Calcium Stearate 8 mg. 10 Total Weight 410 mg.

Procedure: 1. 100 Parts of 8-chloro-dibenzothiophene-3-acetic acid, 202 parts of lactose, 80 parts of corn starch and 20 parts Amijel BO11 are blended in a suitable mixer. 2. The mixture is granulated to a heavy paste with water and the moist mass is passed through a No. 12 screen. It is then dried overnight at 110 °F. 3. The dried granules are passed through a No. 16 screen and transferred to a suitable mixer. The calcium stearate is added and mixed until uniform. 4. The mixture is compressed at a tablet weight of 410 mg. using tablet 20 punches having a diameter of approximately 3/8. (Tablets may be either flat or biconvex and may be scored if desired.) - 53 JA prehydrolyzed food grade corn starch. Any similar prehydrolyzed corn starch may be used.

Example 27 Suppository Formulation g Per 1.3 Gm.

Suppository 8-chloro-dibeuzothiophene-3acetic acid 0.025 mg.

Hydrogenated coconut oil 1.230 mg.

Carnauba Wax 0.045 gm.

Procedure: 1. 123 Parts of hydrogenated coconut oil and 4.5 parts of carnauba wax are melted in a suitable size glass-lined container (stainless steel may also be used), mixed well and cooled to 45°C. 2. 2.5 Parts of 8-chloro-dibenzothiophene-3-acetic acid, which has been reduced to a fine powder with no lumps, is added and stirred until completely and uniformly dispersed. 3. The mixture is poured into suppository molds to yield suppositories having an individual weight of 1.3 gms. 44737 4. The suppositories are cooled and removed from molds, and individually wrapped in wax paper for packaging.

(Foil may also be used.)

Claims (2)

CLAIMS:44737

1. A process for the preparation of compounds of the general formula Wherein R is hydrogen, halogen, hydroxy, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acyl, benzyloxy, lower alkylthio, trifluoromethyl, nitro, amino, monolower alkylamino, di-lower alkylamino, sulfapioyl, di-lower alkylsulfamovl or difluoromethylsulfonyl; R^ is halogen, cyano, lower alkyl, hydroxy-lower alkyl, lower alkoxy, acyl, acyl amino a benzyloxy, lower alkylthio, trifluoromethyl, hydroxy, nitro, amino, mono-lower alkylamino, di-lower alkylamino, sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl, or R taken together with an adjacent R^ is also lower alkvlenedioxy; R 2 is ,X j j-A, wherein A is m hydroxy, lower alkoxy, amino-lower alkoxy 4 47 27 mono-lower alkylamino-lower alkoxy or di-loweralkylamino-lower alkoxy, X and Y, independently, are hydrogen or lower alkyl, and m is 1 to 7, or R^ is -X Ύ0 -C-B wherein B is hydroxy, lower alkoxy, amino, hydroxyamino, mono-lower alkylamino, di-lower alkylamino, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylaminolower alkoxy, Y and X, independently, are hydrogen or lower alkyl; and n is 1 to 7; when X and Y are different, of their enantiomers; when B is hydroxy, of salts thereof with pharmaceutically acceptable bases; and when R or R^ is amino, mono-lower alkyl amino or di-lower alkylamino, and/or when B or A is aminolower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylamino-lower alkoxy, of addition salts thereof with pharmaceutically acceptable acids, which process comprises a) aromatizing a compound of the general formula wherein R, Rj and R 2 have the above mentioned meanings, or b) for the preparation of compounds of formula I, wherein n is 1, X and Y are hydrogen and B is lower alkoxy treating a diazoketone of the general formula R 5 with a C 1-7 alkanol, or . c) for the preparation of compounds of formula I, wherein B is hydroxy, hydrolyzing a compound of formula I, wherein B is lower alkoxy, or d) for the preparation of compounds of formula I, wherein B is 10 amino-lower alkoxy, inono-lower alkylamino-lcwer alkoxy or di-lcwer alkylaminolcwer alkoxy, reacting a compound of formula X, wherein B is hydroxy or a salt thereof with a suitable esterifying agent, or e) for the preparation of compounds of formula I, wherein B is lower alkoxy, esterifying an acid of formula I, 15 wherein B is hydroxy, or a salt thereof, or f) for the preparation of compounds of formula I, wherein R or R^ is di-lower alkylamino, alkylating a ccmpound of formula I, wherein R or is amino, or g) for the preparation of compounds of formula I, 20 wherein R, or A is hydroxy, cleaving an ether of formula I, wherein R, R^ or A is lower alkoxy, or h) for the preparation of compounds of formula I, wherein A is lower alkoxy, amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or - 58 10 di-lower alkylamino lower-alkoxy, etherifying an alcohol of formula I, wherein A is hydroxy, or i) for the preparation of compounds of formula I, wherein A is hydroxy and m is 2 to 7, reducing an ester of formula I,wherein B is alkoxy and n is 1 to 6, or k) for the preparation of compounds of formula I, wherein R^ is amino, saponifying an amide of formula I, wherein Rj is acylamino , or l) for the preparation of a compound of formula I, wherein R 2 is -CH-CO-R^, wherein R3 is lower alkyl and R^ is *3 hydroxy or lower alkoxy, alkylating a compound of formula I, wherein R 2 is -CHj-CO-R^ wherein R 4 is as above, or m) for the preparation of a compound of formula I, r 5 wherein R 2 is -C-CO-R^, wherein is a i ower alkyl group and R *3 and R^ are as defined above, alkylating a compound of formula I wherein R 2 is -CH-CO-R^ wherein R^ and are as described «3 above, or n) for the preparation of compounds of formula I, where’in R or R^ is amino, reducing a corresponding nitro compound or a 5-oxide thereof, or 0) for the preparation of compounds of formula I, wherein R or R^ is halogen converting an amino compound to the desired halogenated compound, or p) forming pharmaceutically acceptable salts of compounds or formula I wherein B is hydroxy with bases, or - 59 q) forming pharmaceutically acceptable acid addition salts of compounds of formula I, wherein R or is amino, mono-lower alkylamino, di-lower alkylamino and/or B is aminolower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower 5 alkylamino-lower alkoxy, or r) resolving a racemic mixture of a compound of formula I, wherein X and Y are different, into the optical antipodes wherein R'^ is halogen, lower alkyl or lower alkoxy and X and Y are as defined in claim, 1, an enantiomer thereof when X and Y are different or a salt with a pharmaceutically acceptable base is prepared. 3. A process as claimed in claim 1, wherein a compound 'of general formula «472? - 60 _ wherein R'·^ is halogen, lower alkyl or lower alkoxy and X and Y are as defined in claim 1 or an enantiomer thereof when X and Y are different 5 is prepared. 4. A process according to claims 2 or 3, wherein a compound of formula 1' or I” , wherein R'^ is halogen, is prepared. 5. A process according to claims 2 and 4, wherein 8-chloro-a-methyl-dibenzothiophene-3-acetic acid is 10 prepared. 6. A process according to claims 2 and 4, wherein (+) 8-chloro-a-methyl-dibenzothiophene-3-acetic-acid is prepared. 7. A process according to claims 2 and 4, wherein 15 (-) 8-chloro-a-methyl-dibenzothiophene-3-acetic acid is prepared. 8. A process according to claims 2 and 4, wherein 8-chloro-dibenzothiophene-3-acetic acid is prepared. 9. A process according to claim 3 and 4, wherein 20 racemic 2-(8-chloro-3-dibenzothienyl)-propanol is prepared. - 61 10. A process according to claim 3 and 4, wherein 2-(8—chloro-3-dibenzothienyl)ethanol is prepared. 11. A process according to claim 1, wherein 8-chlorodibenzothiophene-3-acetamlde is prepared. 5 12. A process for the preparation of compounds of general formula I given in claim 1 as hereinbefore particularly described, especially with reference to the foregoing Examples 1 to 3,7,8,11,12 and 15-23. 13. A process for the manufacture of preparations having 15 antiinflammatory, analgesic and antirheumatic properties, characterized in that a compound of formula I given in claim 1 or, where applicable, a phaanacsatically acceptable base addition or acid addition salt thereof is mixed, as active substance, with nontoxic inert, therapeutically compatible solid or liquid carriers, 20 commonly used in such preparations, and/or excipients. 14 . Pharmaceutical compositions having antiinflaimatory, analgesic and antirheumatic properties, containing a compound of general formula I given in claim 1 or, where applicable, a pharmaceutically acceptable base addition or acid addition salt and a 25 carrier. ¢4787 - 62 15. Compounds of general formula I given and defined in claim 1: when X and Y are different, their enantiomers; when B is hydroxy, salts thereof with pharmac5 eutically acceptable bases; and when R or R^ is amino, mono-lower alkylamino or di-lower alkylamino and/or when B or A is amino-lower alkoxy, mono-lower alkylamino-lower alkoxy or di-lower alkylaminolower alkoxy, addition salts thereof with pharmaclo eutically acceptable acids. 16. Compounds of formula 1 1 given and defined in claim 2, enantiomers thereof when X and Y are different and salts with pharmaceutically acceptable bases. 17. Compounds of general formula I given and defined in 15 claim 3, and enantiomers thereof when X and Y are different. 18. Compounds of general formula I' or -pi, wherein R 1 . ti* ** is halogen. 19. 8-Chloro-a-methyl dibenzothiophene-3-acetic acid. 20. (+) 8-Chloro-a-methyl-dibenzothiophene~3-acetic-acid. 21. (-) 8-Chloro-a-methyl-dibenzothiophene-3-acetic acid. 4 4 7 2 7 - 63 22. 23. 24. 25. 8-Chloro-dibenzothiophene-3-acetic acid. 2-(8-chloro-3-dibenzothienyl)-propanol.

2. -(8-chloro-3-dibenzothienyl)ethanol.