MC1133A1 - DIBENZOTHYPHENE DERIVATIVES - Google Patents

Description

1

The invention relates to compounds of general formula

10

15

20

25

30

in which R represents a hydrogen or halogen atom, or a hydroxy, cyano, lower alkyl, lower hydroxyalkyl, lower alkoxy, acyl, benzyloxy, lower alkyl-thio, tri-fluoromethyl, nitro, amino, lower monoalkyl-amino, lower dialkyl-amino, sulfamoyl, lower dialkyl-sulfamoyl or difluoromethylsulfonyl group; R^ represents a halogen atom or a hydroxy, cyano, lower alkyl, lower hydroxy-alkyl, lower alkoxy, acyl, acylamido, benzyloxy, lower alkyl-thio, trifluoromethyl, nitro, amino, lower mono-alkyl-amino, lower di-alkyl-amino, sulfamoyl, lower di-alkyl-sulfamoyl or difluoromethylsulfonyl group, or adjacent R and R^ groups also represent a lower alkyl-dioxy group; R2 represents a -(CXY)m-A group, in which A = hydroxy, lower alkoxy, lower amino alkoxy, lower mono-alkyl-lower amino alkoxy or lower di-alkyl-lower amino alkoxy, X and Y, independently, represent a hydrogen atom or a lower alkyl group, and m = 1-7, or R2 represents a -(CXY)n~CO-B group, in which B = hydroxy, carboxy,

lower alkoxy, amino, hydroxylamino, lower mono-amino-alkyl, lower di-amino-alkyl, lower amino-alkyl, lower mono-amino-alkyl or lower di-amino-alkyl, X and Y, independently, represent a hydrogen atom or a lower alkyl group, and n = 1-7:

2

when X and Y are different, their enantiomers; when B = hydroxy or carboxy, one of their salts with pharmaceutically acceptable bases; and when R or = amino, lower mono-amino alkyl or lower di-amino alkyl, and/or when B or A = lower amino-alkyl, lower mono-amino alkyl

lower alkoxy or lower di-alkoyl-amino-lower alkoxy, their addition salts with pharmaceutically acceptable acids.

10. "Lower alkyl" represents a linear or branched hydrocarbon group containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, etc. The term "lower alkyl" represents an alkyl ether group in which the alkyl group is described above, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,

pentoxy, etc. The term "lower alkyl-thio" represents an alkyl thioether group whose alkyl group is described above, such as methylthio, ethylthio, 20-propylthio, isopropylthio, butylthio, pentylthio, etc. The term

"Halogen" covers the halogens, namely bromine, chlorine, fluorine, and iodine; bromine and chlorine are preferred. The term "acyl" represents an "alkanoyl" group derived from an aliphatic carboxylic acid containing 1 to 7 carbon atoms, such as formyl, acetyl, propionyl, etc., and an "aroyl" group derived from an aromatic carboxylic acid, such as the benzoyl group, etc. The term "lower alkoylene" represents a linear or branched alkoylene chain containing 1 to 7 carbon atoms, such as methylene, ethylene, propylene, butylene, ethylidene, etc. The term "lower alkoylene-dioxy" preferably represents the methylene-dioxy group, etc.

Examples include methylamino, ethylamino, etc.; lower dialcoyl-amino groups, dimethylamino, diethylamino, etc.; lower amino-alkoxy groups, aminomethoxy, aminoethoxy, etc.; and lower mono-alkyl-amino-alkoxy groups, methylamino-

As it is used in this context, the term

Examples of lower-amino mono-alkyl groups,

methoxy, ethylamino-ethoxy, etc.; as lower di-alkyl groups - lower amino-alkoxy, dimethylamino-methoxy, diethylamino-ethoxy, etc., and as lower di-alkyl groups - amoyl tallow, dimethylsulfamoyl, diethylsulfamoyl, etc.

The preferred new dibenzothiophenes of the present invention are those characterized by the formulas and

10

in which R'^ represents a halogen atom or a lower alkyl or lower alkoxy group, preferably a halogen atom or a lower alkyl group, advantageously a halogen atom, and X and Y have the same meaning as above,

their enantiomers, when X and Y are different, and the salts of compounds of general formula I1 with pharmaceutically acceptable bases. Preferably, in general formula I, m = 2 and n = 1.

20. Preferred compounds with general formula I are as follows:

4

racemic 8-chloro-a-methyl-dibenzothiophene-3-acetic acid; (+)-8-chloro-a-methyl-dibenzothiophene-3-acetic acid;

(-)-8-chloro-a-methyl-dibenzothiophen-3-acetic acid; 2-(8-chloro-3-dibenzothienyl)-racemic propanol;

5 2-(8-chloro-3-dibenzothienyl)-ethanol;

8-chloro-dibenzothiophene-3-acetic acid; 8-chloro-dibenzothiophene-3-acetamide.

Other compounds according to the invention corresponding to general formula I include the following:

10 8-chloro-dibenzothiophene-3-ethyl acetate;

8-methoxy-dibenzothiophene-3-acetate acid;

8-nitro-dibenzothiophene-3-acetic acid;

7-methoxy-dibenzothiophene-3-acetic acid;

7-chloro-dibenzothiophene-3-acetic acid;

15 8-methyl-dibenzothiophene-3-acetic acid;

6-chloro-dibenzothiophene-3-acetic acid;

8,9-dichloro-dibenzothiophene-3-acetic acid;

cc-methyl-dibenzothiophene-3-acetic acid;

7-methyl-dibenzothiophene-3-acetic acid;

20 7,8-dichloro-dibenzothiophene-3-acetic acid;

8-chloro-9-methyl-dibenzothiophene-3-acetic acid;

8-Difluoromethylsulfonyl-dibenzothiophene-3-acetic acid; 2-(8-chloro-3-dibenzothienyl)-racemic propanol methyl ether

25 8-chloro-7-methyl-dibenzothiophene-3-acetic acid;

8-sulfamoyl-dibenzothiophene-3-acetic acid;

8-benzoyl-dibenzothiophene-3-acetic acid;

8-Fluoro-dibenzothiophene-3-acetic acid;

8-trifluoromethyl-dibenzothiophene-3-acetic acid;

30 6,7-dichloro-dibenzothiophene-3-acetic acid;

9-chloro-8-sulfamoyl-dibenzothiophene-3-acetic acid;

8-methylthio-dibenzothiophene-3-acetic acid;

8-ethyl-dibenzothiophene-3-acetic acid;

8-chloro-dibenzothiophene-3-dimethylamino-ethyl acetate;

35 8-methyl-dibenzothiophene-3-ethyl acetate;

8-Dimethylsulfamoyldibenzothiophene-3-acetic acid;

8-iodo-dibenzothiophene-3-acetic acid; 8-chloro-N,N-dimethyl-dibengothiophene-3-acetamide;

5

8-Cyanodibenzothiophene-3-acetic acid;

8-acetyl-dibenzothiophene-3-acetic acid;

8-chloro-dibenzothiophene-3-dimethyl-aminoethyl acetate hydrochloride;

5 8-benzyloxy-dibenzothiophene-3-acetic acid;

7,8-methylenedioxydibenzothiophene-3-acetic acid;

8-hydroxy-dibenzothiophene-3-acetic acid;

7-chloro-dibenzothiophene-3-ethyl acetate; 9-chloro-dibenzothiophene-3-ethyl acetate;

10 8-bromo-dibenzothiophene-3-ethyl acetate;

8-acetamido-dibenzothiophene-3-ethyl acetate; 8-chloro-dibenzothiophene-3-ethyl propionate; 8-chloro-α,α-dimethyl-dibenzothiophene-3-ethyl acetate; 8-chloro-α-methyl-dibenzothiophene-3-dimethylamino- acetate

15 ethyl;

8-chloro-α-methyl-dibenzothiophene-3-acetamide; 8-trifluoromethyl-dibenzothiophene-3-ethyl acetate;

6,7-dichloro-dibenzothiophene-3-ethyl acetate; 8,9-dichloro-dibenzothiophene-3-ethyl acetate;

20 8-methylthio-dibenzothiophene-3-ethyl acetate; 8-fluoro-dibenzothiophene-3-ethyl acetate; 8-N,N-dimethylsulfamoyl-dibenzothiophene-3-ethyl acetate;

7.8-dichloro-dibenzothiophene-3-ethyl acetate; 8-nitro-dibenzothiophene-3-ethyl acetate;

25 7-dimethylaminodibenzothiophene-3-ethyl acetate, etc.

Compounds of general formula I, their pharmaceutically acceptable salts, or their acid addition salts can be prepared by a process characterized in that a) a compound of general formula is aromatized

R

in which R and R2 have the same meaning as above,

or b) for the preparation of compounds of general formula I,

S

ft

6

in which n = 1, X and Y = H, and B = lower alkoxy, a diazoketone of general formula is treated

R

R'

© ©

: H—NEE3N

III

with a lower alkanol,

5 or c) for the preparation of compounds of general formula I, in which B = hydroxy, a compound of general formula I, in which B = lower alkoxy, is hydrolyzed

or d) for the preparation of compounds of general formula I, in which B = amino-alcohol, mono-alcoholamino-alcohol or 10-dialcoholamino-alcohol, a compound of general formula I, in which B = hydroxy, or one of its salts, is reacted

with a suitable acing agent,

or e) for the preparation of compounds of general formula I, in which B = lower alkoxy, an acid of general formula I, in which B = hydroxy, or one of its salts is esterified; or f) for the preparation of compounds of general formula I, in which R or R^ = dialcoylamino, a compound of general formula I, in which R or R^ = amino, is alkylated.

20 or g) for the preparation of compounds of general formula I, in which R, R^ or A = hydroxy, an ether of general formula I, in which R, R^ or A = lower alkoxy, is split

or h) for the preparation of compounds of general formula I, in which A = alkoxy, amino-alkoxy, mono-alcoylamino-alkoxy 25 or dialcoylamino-alkoxy, an alcohol of general formula I, in which A = hydroxy, is etherified

or i) for the preparation of compounds of general formula I, in which A = hydroxyl, an ester of

7

general formula I, in which B = alkoxy,

or k) for the preparation of compounds of general formula I, in which R^ = amino, an amide of general formula I, in which R = acylamino, is saponified.

5 or 1) for the preparation of compounds of general formula I,

in which R2 = -CHCR-^COR^, R^ being an alkyl group and R^ = H or lower alkoxy, we alkylate a compound of general formula I, in which R2 = -CË^COR^, R^ being as above,

or m) for the preparation of compounds of general formula I, 10 in which R2 = -C(Rg,R^)COR^, R^ being a lower alkyl group, a compound of general formula is alkylated, in which R2 = -CïÙR^COR^, R^ and R4 having the same meaning as above i or n) for the preparation of compounds of general formula I, 15 in which R or R^ = -NH2, a corresponding nitro derivative or one of its 5-oxides is subjected to reduction,

or o) for the preparation of compounds of general formula I,

in which R or R^ = halogen, an amino compound is converted into the corresponding halogenated compound.

20 or p) pharmaceutically acceptable salts are formed of compounds of general formula I, in which B = hydroxy or or q) pharmaceutically acceptable acid addition salts are formed of compounds of general formula I, in which R 25 or R^ = amino, lower mono-amino-alkyl, lower di-amino-alkyl and/or B = lower amino-alkyl, lower mono-alkyl-lower amino-alkyl or lower di-alkyl-lower amino-alkyl,

or r) we solve a racemic mixture of a compound of general formula 30 I, in which X and Y are different, at its optical antipodes.

carboxy,

8

According to step a) of the process, a compound of general formula II is aromatized. This aromatization is carried out using a dehydrogenating agent, for example, p-chloranil, o-chloranil, 2,3-dichloro-5,6-dicyanobenzo-5-quinone (DDQ), sulfur, palladium carbon, lead oxide, etc., in the presence of a solvent such as xylene, benzene, toluene, quinoline, dimethyl sulfoxide (DMSO), dioxane, or dimethylformamide (DMF). The aromatization is carried out at a temperature between ambient temperature and the reflux temperature of the reaction mixture, preferably at the reflux temperature. The compound of general formula I can be separated from the reaction mixture by known processes, such as filtration, crystallization, or distillation.

etc.

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

According to step c) of the process, an ester of general formula I can be converted to the corresponding acid, i.e., to a compound of general formula I in which B represents a hydroxyl group, by saponification according to known processes such as, for example, reaction with an alkali metal hydroxide such as sodium or potassium hydroxide, etc., and subsequent treatment with a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, etc. Furthermore, an ester of general formula I can be converted to the corresponding acid by treatment with a mineral acid, for example, a hydrohalic acid such as hydrochloric acid, etc., in the presence of an organic solvent such as acetic acid, preferably at the reflux temperature of the reaction mixture.

The isolation of the desired compound of general formula I from the reaction mixture can be carried out by means of 35 known techniques such as filtration, crystallization, distillation, etc.

20

25

30

9

Furthermore, according to step d) of the process, an acid of general formula I, that is, a compound of general formula I in which B represents a hydroxyl group, or one of its salts, can be converted into a compound of general formula I in which B represents a lower amino-alkyl, lower mono-alkyl-lower amino-alkyl, or lower di-alkyl-lower amino-alkyl group by known processes. For example, a salt of an acid of general formula I is reacted with a lower amino-alkyl, lower mono-alkyl-lower amino-alkyl, or lower di-alkyl-lower amino-alkyl halide, such as aminoethyl chloride, methylaminoethyl bromide, diethylaminomethyl chloride, etc.

in order to obtain the desired products. The reaction temperature 15 is not critical; advantageously, the reaction is carried out at a temperature between approximately room temperature and the reflux temperature of the reaction mixture. Advantageously, the reaction can be carried out in a polar solvent such as dimethylformamide, dimethyl sulfoxide 20, etc. The molar ratio of the reactants is not critical; preferably, they are used in a 1:1 ratio.

general I, in which B represents a hydroxyl group,

can be converted to the corresponding ester by known processes. For example, (a) an acid of general formula I can be reacted with an alkanol such as methanol, ethanol, propanol, in the presence of an acid catalyst at a temperature between approximately room temperature and the reflux temperature of the reaction mixture, or (b) an alkali metal salt of an acid of general formula I, such as the sodium salt, can be reacted with an alkyl halide using known reaction conditions, for example in a solvent such as benzene, toluene, dimethyl formamide, etc., at a temperature between approximately room temperature and the reflux temperature of the reaction mixture.

According to step f) of the process, a compound of general formula I, in which R or R^ = amino, can be converted into the corresponding compound, in which R or R^ = dialcovlamino,

According to step e) of the process, an acid of formula

10

by known means, for example by using hydrogen at a pressure between about 1 atmosphere and several atmospheres and a catalyst such as Raney nickel, in the presence of an alkyl aldehyde such as formaldehyde, at a temperature between about room temperature and about 100°, in a solvent, such as an alkanool, for example methanol or ethanol, etc. Alkoylation can be carried out, for example, by treating the amine with trimethyl phosphate under known conditions.

10 According to aspect (g) of the process, a compound of general formula I, in which R, R^, or A = alkoxy, can be converted into the corresponding compound in which R, R^, or A = hydroxy, by known processes. For example, a compound of general formula I bearing an alkoxy group can be treated 15 with a mineral acid such as a hydrohalic acid, for example, hydrobromic acid, etc., in a solvent, for example, an alkanool such as ethanol, propanol, etc., at a temperature between approximately room temperature and the reflux temperature of the reaction mixture. The conversion can also 20 be carried out using Lewis acids such as aluminum tribromide, aluminum trichloride, boron tribromide, zinc tetrachloride, etc., in a solvent such as benzene, toluene, dimethylformamide, etc.

According to aspect h) of the process, an alcohol, that is to say 25 a compound of general formula I in which A = hydroxy,

can be converted to the corresponding compound of general formula I, in which A represents a lower alkoxy, lower amino-alkoxy, lower mono-alkyl-lower amino-alkoxy, or lower di-alkyl-lower amino-alkoxy group by known processes. For example, said alcohol is treated with an alkali metal such as sodium. The resulting compound is then treated with a halide of formula RX, in which X represents a halogen atom and R a lower alkyl, lower amino-alkyl, lower mono-alkyl-amino-alkyl, or lower di-alkyl-lower amino-alkyl group, using known reaction conditions.

According to aspect i) of the process, an ester of formula

11

General formula I can be converted into the corresponding alcohol, for example, the one with general formula I, in which A = hydroxyl, by known processes. For example, this ester can be treated with a reagent such as lithium-aluminum hydride, 5, at a temperature between approximately room temperature and the reflux temperature of the reaction mixture. Then, the corresponding alcohol formed can be separated by known processes.

According to aspect k) of the process, a compound of general formula I, in which = acylamido, can be converted 10 into the corresponding compound of general formula I, in which R^ = amino, for example by treatment with an inorganic acid such as a hydrohalic acid, for example hydrochloric acid etc., using known reaction conditions.

According to aspect 1) of the process, a gene-15 line I ester can be alkoylated at the α position. This alkoylation can be carried out by dissolving the ester in liquid ammonia containing sodium amide and adding an alkoyling agent such as methyl iodide or butyl bromide, in order to obtain an α-alkyl product.

20 According to step m) of the process, an α-alcoyl ester of general formula I can be re-alcoylated using the method described above.

According to step n) of the process, a compound of general formula I, in which R or R^ = amino, can be prepared 25 by reduction of a corresponding nitro compound or one of its S-oxides. The reduction can be carried out using hydrogen under pressure, for example 50 psi, and with a noble metal catalyst such as palladium carbon.

According to step o) of the process, a compound of general formula 30I, in which R or R^ = amino, can be converted into the corresponding halogenated compound. For this purpose, the amino compound is first converted into the diazonium salt, for example diazonium sulfate, by treatment with nitrosylsulfuric acid, and then the diazonium salt is reacted 35 with a cuprous halide such as cuprous chloride, in

12

hydrochloric acid.

Starting compounds of general formula II can be prepared by cyclization of a compound of general formula

R

R"

IV

5 in which R, R^ and R2 have the same meaning as above.

Cyclization can be carried out by thermal cyclization or by using a cyclizing agent such as polyphosphoric acid, etc. Preferably, the reaction is carried out at a temperature between approximately -20°C and approximately 120°C. This reaction can be carried out with or without a solvent. Acetic acid, etc., are examples of suitable solvents.

Examples of intermediate compounds with general formula IV include the following:

3-(4-chloro-phenylthio)-4-ketocyclohexane-acetic acid and its ethyl ester;

3-(4-bromo-phenylthio)-4-ketocyclohexane-acetic acid and its methyl ester; etc.

20. Compounds of general formula IV can be prepared by alkylation of a compound of general formula

R

R"

V

!H

S

13

in which R and R-^ have the same meaning as above,

by means of the corresponding haloketocycloalkane of general formula

• in which Hal = halogen and R2 has the same meaning as above.

The reaction is advantageously carried out in a nonpolar solvent, for example a hydrocarbon such as benzene, toluene, etc., or a polar solvent, such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, an alkanool such as ethanol, etc. The reaction temperature is not critical. Preferably, the reaction is carried out at a temperature between approximately room temperature and the reflux temperature of the reaction mixture. The molar ratio of the reactants is not critical; preferably, they are used in a 1:1 ratio.

Starting substances of general formula VI can be prepared by halogenation of a compound of general formula

20

VII

in which R has the same meaning as above.

The compounds of general formula VII are known or can be prepared in a manner analogous to the preparation of known compounds.

14

Halogenation is carried out by known processes, for example using a halogen such as bromide in ether, at a temperature of -10°C. Examples of compounds obtained in this way include the following:

5 3-bromo-4-ketocyclohexane-acetic acid;

3-bromo-4-ketocyclohexane-ethyl acetate; etc.

Starting substances of general formula V are known compounds or can be prepared in a manner analogous to the preparation of known compounds. Examples of such compounds include:

■ 4-chloro-thiophenol;

5-chloro-thiophenol and 4-nitro-thiophenol.

Starting substances of general formula III can be obtained from the corresponding carboxylic acid. This acid is converted into an acid halide, particularly chloride, and then reacted with diazomethane to give diazoketone.

Compounds of general formula I, in which B = 20 hydroxyl or carboxyl groups, form salts with pharmaceutically acceptable bases according to step p) of the process. Examples of such bases include alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides, such as calcium hydroxide, barium hydroxide, etc.; sodium alkoxides, such as sodium ethoxide, potassium ethoxide, etc.; and organic bases, such as piperidine, diethanolamine, N-methylglucamine, etc. Aluminum salts of compounds of general formula I are also included.

Compounds of general formula I, where R or R^ = amino, lower mono-amino-alkyl, lower di-amino-alkyl, and/or where B or A = lower amino-alkyl, lower mono-amino-alkyl or lower di-alkyl

15

lower amino-alkoxy, form according to aspect g) of the process addition salts with pharmaceutically acceptable organic or inorganic acids, such as halogen-hydrates, such as hydrochloride, hydrobromide, iodine, or other salts of mineral acids, such as sulfates, nitrates, phosphates, etc.; alkyl- and mono-aryl-sulfonates, such as ethane-sulfonate, toluene-suifonate, benzene-suifonate, etc.; salts of other organic acids, such as acetate, tartrate, maleate, citrate, benzoate, salicylate, ascorbate, etc.

Compounds of general formula I, including salts of those compounds of general formula I that form salts with pharmaceutically acceptable bases and acids, possess anti-inflammatory, analgesic, and anti-rheumatic activity, and are therefore useful as anti-inflammatory, analgesic, and anti-rheumatic agents. Compounds of general formula I also possess extremely low ulcerogenic activity, making them particularly valuable as anti-inflammatory, analgesic, and anti-rheumatic agents. Their pharmacologically useful activities are demonstrated in warm-blooded animals by means of standard tests.

For example, anti-inflammatory activity is demonstrated in albino "Hart Strain" rats weighing 125-155 g. The test animals are administered 10 ml of vehicle containing the test compound per kg of body weight. The animals are treated daily for 5 consecutive days. Three hours after the first treatment, 0.05 ml of a 0.5% suspension of heat-killed and desiccated Mycobacterium butyricum in steam-sterilized USP olive oil (30 minutes) is injected into the right hind leg of each rat. The leg volume is measured immediately after the injection of the adjuvant and again

^ Hilgar, A.G. and Hummel, D.J.: Endocrine Bioassay Data. No. 1, p. 15, August 19 6 4 (Cancer Chemotherapy National Service Center, N.I.H.) \

16

96 hours later. The difference is recorded as edema volume. The paw volume is measured by immersion in a mercury column up to an ink mark exactly at the level of the lateral malleolus. The percentage of inhibition is calculated by dividing the mean control edema minus the mean treated edema by the mean control edema x 100. The percentage of inhibition is related to the dose on semi-logarithmic probability paper, and the dose producing a 30% reduction in edema is estimated and expressed as ED30.

When 8-chloro-dibenzothiophene-3-acetic acid, which has an LD^q of, for example 775 mg orally in mice, is used as a test substance at a dosage of 0.03 g orally, an anti-inflammatory activity is observed (DE3q = 1/8 mg/kg/day).

The analgesic activity of the compounds of the invention is demonstrated, for example, using a method that is a modification of that described by Eddv (1950), Wolfe and MacDonald (1944), and Eddy and Leimbach (1952). Method 20 determines the reaction time of a mouse released onto a hot plate maintained at 55 ± 0.5°C. Six groups of male mice (5 mice/group) weighing between 20 and 30 g are used. The initial reaction time of these mice is determined once, and then the mean reaction time of each group 25 is calculated. The mice are then administered the vehicle and/or the compound to be tested orally, intraperitoneally, or subcutaneously. The mean reaction time of each group is determined again after 30, 60, and 90 minutes following administration of the compound and compared to the control. The reaction time 30 is recorded as a percentage deviation from the control. The average for all groups is calculated before and after treatment. A combined average reaction time (noted as the percentage deviation from the reaction time threshold relative to the controls) for the three periods is plotted against the dose on graph paper, and a curve is generated. The DEco is derived from this curve.

OF

When 8-chlorodibenzothiophene-3-acetic acid, which has a concentration of, for example, 750 mg orally in the

S

17

In mice, an analgesic activity of ED^q at 120 mg/kg is observed after oral administration.

The compounds of general formula I, their enantiomers 5 and salts as described above have effects qualitatively similar to those of phenylbutazone and indomethacin, known for their use and therapeutic properties.

Thus, the products of the invention demonstrate a network of activity associated with anti-inflammatory agents of known efficacy and safety.

The compounds of general formula I, their enantiomers, and salts as described above can be incorporated into standard pharmaceutical dosage forms. For example, they are useful for oral or parenteral applications in combination with common pharmaceutical excipients, such as common inert organic or inorganic vehicles, like water, gelatin, gums, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. These preparations can be in solid form, for example, tablets.

Coated tablets, suppositories, capsules; or in liquid form, for example as solutions, suspensions, or emulsions. Where appropriate, the preparations may be sterilized and/or may contain excipients, for example, preservatives, stabilizers, wetting agents, or emulsifiers. They may also contain osmotic pressure-regulating salts or buffering compounds, and be combined with other therapeutically useful substances.

Because the compounds of the invention possess, 30 when X and Y in the general formula I are different from each other, an asymmetric carbon atom, they are generally obtained in the form of racemic mixtures. The resolution of such racemates into their optically active isomers can be carried out according to step r) of the process and 35 by known methods. Some racemic mixtures may

can be precipitated as eutectics and can then be resolved. However, chemical resolution is preferred. By this method,

18

Diastereomers are prepared from the racemic mixture using an optically active resolving agent such as an optically active base, for example d-cc-methylbenzylamine, which can react with the 5' carboxyl group. The diastereomers formed are resolved by selective crystallization and converted into the corresponding optical isomers. Thus, the invention covers racemates of compounds of general formula I as well as their optically active isomers.

10 Example 1

Preparation of 8-chloro-cc-methyldibenzothiophene-3-acetic acid.

To a 500 mL three-necked flask containing 100 mL of liquid ammonia and 0.009 mol of sodium amide (prepared from 0.2 g of sodium), a solution of 2.6 g of ethyl 8-chlorodibenzothiophene-3-acetate in 20 mL of ether and 10 mL of tetrahydrofuran is added dropwise. The solution is stirred for 1 hour, and a solution of 1.3 g of methyl iodide in 20 mL of ether is added dropwise. After 1 hour of stirring, 0.5 g of ammonium chloride is added, and the ammonia is allowed to evaporate. The residue is then acidified with dilute hydrochloric acid, and the oil is extracted with ether. The ether is removed, and the residue solidifies slowly. The solid product is crystallized in pentancy and gives 1.5 g of 8-chloro-a-methyldibenzothiophene-3-ethyl acetate; melting point 73-75°.

1.3 g of the product thus obtained are added to 100 ml of absolute ethanol containing 0.6 g of potassium hydroxide. The solution is heated under reflux for 3 hours. Then, the solvent is removed under vacuum and the residue dissolved in

30 ml of water. The solution is acidified with dilute hydrochloric acid and the oil extracted with ether. The ether is removed and the residue, after crystallization in ethyl acetate, gives 0.9 g of 8-chloro-α-methyldibenzothiophene-35 3-acetic acid; w.f. 190-192°.

15

20

25

19

Example 2

Preparation of 8-chloro-a,a-dimethyldibenzothio-phen-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), a solution of 5.1 g of 8-chloro-α-methyldibenzothiophene-3-ethyl acetate in 40 mL of tetrahydrofuran is added dropwise. The solution is stirred for 1 hour, and a solution of 2.3 g 10⁻¹ of methyl iodide in 50 mL of ether is added dropwise. Once this addition is complete, the solution is stirred for 3 hours. Then, 0.5 g of ammonium chloride is added, and the ammonia is allowed to evaporate. The residue is acidified with dilute hydrochloric acid, and the oil is extracted with ether. The ether is eliminated and the residue, crystallized in pentane, gives 1.8 g of 8-chloro-α,α-dimethyldibenzothiophene-3-ethyl acetate; w.p. 57-61°.

1.8 g of the product thus obtained are added to 100 mL of absolute ethanol containing 0.4 g of potassium hydroxide. The solution is heated under reflux for 3 hours. Then, the solvent is removed without vacuum and the residue is dissolved in 75 mL of water. The solution is acidified with dilute hydrochloric acid and the oil extracted with ethyl acetate. The solvent is removed and the residue, after crystallization in aceto-25 nitrile, gives 0.58 g of 8-chloro-α,α-dimethyldibenzo-thiophene-3-acetic acid; mol.f. 198-200°.

Example 3

Preparation of 8-chloro-a-butyldibenzothiophene-3-acetic acid.

30. To a 500 ml three-necked flask containing 200 ml of liquid ammonia and 0.014 moles of sodium amide (prepared from 0.32 g of sodium), a solution of 3.8 g of ethyl 8-chlorodibenzothiophene-3-acetate in 40 ml of

20

Tetrahydrofuran. The solution is stirred for 1 hour, and a solution of 1.8 g of butyl bromide in 50 mL of ether is added dropwise. Once the addition is complete, the solution is stirred for 1 hour. Then, 0.9 g of ammonium chloride is added, and the ammonia is allowed to evaporate. The residue is acidified with dilute hydrochloric acid, and the oil is extracted with ether. The ether is removed by distillation, and the residue yields 3.9 g of crude 8-chloro-c-butyl-dibenzothiophene-3-ethyl acetate.

10 3.9 g of the product thus obtained are added to a solution of 0.9 g of potassium hydroxide in 100 mL of alcohol. The solution is heated under reflux for 3 hours and the solvent is removed under vacuum. Water is added to the residue, insoluble byproducts are extracted with 15 g of ether, and the ether is removed. The clear aqueous solution is acidified with hydrochloric acid and the desired product is extracted with ethyl acetate. The solvent is removed under vacuum and the residue, after crystallization in acetonitrile, gives 1 g of 8-chloro-α-butyldibenzo-20-thiophene-3-acetic acid; w.f. 156-159°.

Example 4

Preparation of ethyl 3-bromo-4-oxocyclohexaneacetate

74.0 g of ethyl 4-oxocyclohexaneacetate and 1200 mL of anhydrous ether are placed in a 3-liter three-necked flask equipped with a thermometer, a nitrogen introduction tube, a stopcock funnel, a condenser, and a stirrer. The solution is cooled to -10°C using an acetone/dry ice bath, after which 64.0 g of bromine is added dropwise over 30 to 40 minutes. The resulting colorless solution is washed three times with 100 mL of water, twice with 125 mL of cold saturated sodium bicarbonate solution, and 100 mL of water. The combined aqueous solutions are extracted twice with 150 mL of ether. The combined ethereal extracts are dried over anhydrous magnesium sulfate and the ether removed by steam distillation at atmospheric pressure.

21

This yields 105 g of crude 3-bromo-4-oxocyclohexaneacetate ether.

Example 5

Preparation of 3-(4-chlorophenylthio)-4-ketocyclohexane-5 ethyl acetate.

58 g of 4-chlorothiophenol and a solution of 26.5 g of 85% potassium hydroxide in 1500 mL of ethanol are placed in a 3-liter three-necked flask equipped with a condenser, a nitrogen inlet tube, a stopcock funnel, and a stirrer. The solution is heated under reflux, and a solution of 105 g of crude ethyl 3-bromo-4-ketocyclohexaneacetate in 500 mL of ethanol is added to the refluxed solution over one hour. After the addition, the solution is stirred under reflux for one hour, cooled to room temperature, and then filtered to remove the potassium bromide. After removing the ethanol in water (steam bath, rotary evaporator), 300 mL of water are added to the residue. The product is extracted three times with 200 mL of ether, and the ether extract is dried over anhydrous magnesium sulfate. After removing 20 mL of ether in a steam bath at atmospheric pressure, 128 g of residue are distilled under vacuum. A 28.7 g distillation head is collected at 100–190°C (1 mm), while 76.4 g of the main fractions are collected at 190–222°C (1 mm). Gas chromatography analysis of the main fraction reveals the presence of 3-(4-chlorophenylthio)-4-ketocyclohexane ethyl acetate.

Example 6

Preparation of 8-chloro-l,2,3,4-tetrahydrodibenzothio-phen-3-ethyl acetate.

30 76.4 g of the product obtained in the previous example are added to 1000 g of polyphosphoric acid in a 2-liter three-necked flask equipped with a stirrer and a condenser. The mixture is

22

The mixture was heated in a steam bath for 90 minutes, then poured into a mixture of 1 kg of ice and 1 liter of water. The mixture was stirred until the dark oily complex decomposed and a light yellow color appeared. Product 5 was extracted twice with 500 ml of ether. The ether extract was washed twice with 100 ml of water, then with 100 ml of a saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, and distilled under atmospheric pressure in a steam bath to remove the ether.

10 This yields 57.1 g of residue. The gas chromatogram of this crude residue demonstrates the presence of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate and bis-(4-chlorophenyl)-disulfide.

In a 1-liter three-necked flask equipped with a condenser and a nitrogen inlet tube, a solution of 4.8 g of sodium hydroxide in 250 mL of ethanol is added, and the resulting solution is heated under reflux for 1 hour with nitrogen. The ethanol is removed under vacuum (steam bath, rotary evaporator), and 200 mL of water is added. The solution is acidified with dilute hydrochloric acid. Once the precipitation of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene acetic acid is complete, the supernatant is decanted. 100 mL of ether-25 is added to the wet semi-solid acid, and the mixture is stirred. Insoluble 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-acetic acid is separated by filtration, washed with 50 ml of ether, and dried under vacuum overnight at 50°C. This yields 26 g of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-30-acetic acid; mol. gas. 195-202°C. Re-esterification is carried out by adding 25.4 g of the aforementioned acid to 400 ml of ethanol saturated with hydrogen chloride at room temperature.

After heating the solution under reflux for 6 hours, the methanol is removed under vacuum (steam bath, rotary evaporator 35) and 300 ml of benzene is added to the residue. The benzene solution is first extracted twice with 75 ml of water.

then twice with 75 ml of 6% sodium bicarbonate. The benzene solution is dried over anhydrous potassium carbonate and distilled under vacuum to remove the benzene.

In order to eliminate the bis-(4-chlorophenyl)-15 disulfide by-product, 30.9 g of the aforementioned crude mixture are placed

23

The crude ester weighs 26.6 g; w.p. 55-60°. By crystallization in hexane, 22.1 g of pure 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate is obtained; w.p. 64-66°.

Example 7

Preparation of 8-chloro-dibenzothiophene-3-ethyl acetate.

In a 2-liter three-necked flask equipped with a condenser, stirrer, and stopcock funnel, 31.2 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 mL of dioxane are placed. To the refluxed solution, a solution of 21.2 g of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate in 500 mL of dioxane is rapidly added. The solution is refluxed and stirred for 18 hours, then cooled to room temperature and filtered to remove the hydroquinone formed. The solvent is removed under vacuum (steam bath, rotary evaporator), and the residue is dissolved in 300 mL of methylene chloride. The solution is filtered, if necessary, and passed through a column containing approximately 200 g of Woelm alumina. I). The color of the solution is then light yellow. The solvent is removed (steam bath, rotary evaporator) and the weight of the sticky residue is 18.6 g.

The latter is recrystallized in hexane and gives 14 g of 8-chloro-dibenzothiophene-3-ethyl acetate; w.p. 88-90°.

Example 8

Preparation of 8-chloro-dibenzothiophene-3-acetic acid.

14 g of 8-chlorodibenzothiophene-3-ethyl acetate are added to 1.84 g of sodium hydroxide in 150 mL of ethanol in a 500 mL round-bottom flask fitted with a condenser. After heating the solution for 1 hour under reflux, the solvent is removed under vacuum (steam bath, rotary evaporator), the residue is dissolved in 100 mL of water, and acidified.

24

v the aqueous solution with dilute hydrochloric acid. The acid

8-Chloro-dibenzothiophene-3-acetic acid is removed by filtration, washed with water, and dried at 60°C under vacuum overnight. After crystallization in isopropanol, 8 g of 8-chloro-dibenzothiophene-3-acetic acid, melting at 220-221°C, are obtained.

Example 9

Preparation of 3-(2-chlorophenylthio)-4-ketocyclohexane-ethyl acetate.

10.28 g of 2-chlorothiophenol and a solution of 10.8 g of 85% potassium hydroxide in 300 mL of ethanol are placed in a 3-liter three-necked flask equipped with a condenser, a nitrogen inlet tube, a stopcock funnel, and a stirrer. The solution is refluxed, and a solution of 50.6 g of 3-bromo-4-ketocyclohexane-ethyl acetate in 500 mL of ethanol is added over one hour. After the addition, the solution is refluxed for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removal of ethanol in vacuum (20 steam bath, rotary evaporator), 300 ml of water are added to the residue, the product is extracted three times with 200 ml of ether and the ethereal extract is dried on anhydrous magnesium sulfate.

After removal of the ether in a steam bath at atmospheric pressure, the residue is distilled under vacuum. A 25-second distillation head is collected at 100-190°C (1 mm), while the main fraction is collected at 190-222°C (1 mm). This yields 33.9 g of 3-(2-chlorophenylthio)-4-ketocyclohexane-ethyl acetate from the main fraction; boiling point 205-215°C/0.7 mm.

30. Example 10

Preparation of 6-chloro-l,2,3,4-tetrahydrodibenzothio-phen-3-ethyl acetate.

25

33.9 g of the product obtained in the preceding paragraph are added to 600 g of polyphosphoric acid in a 2-liter three-necked flask equipped with a stirrer and a condenser. The mixture is heated in a steam bath for 90 minutes, then poured into a mixture of 1 kg of ice and 1 liter of water. The mixture is stirred until the dark oily complex is decomposed and a light yellow color appears. The product is extracted twice with 500 ml of ether. The ether extract is washed twice with 100 ml of water, then with 100 ml of a saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, and distilled at atmospheric pressure in a steam bath to remove the ether. This yields 8.5 g of 6-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate; boiling point 195-210°/0.7 mm; p.f. 51-53° 15 (pentane).

Example 11

Preparation of 6-chloro-dibenzothiophene-3-ethyl acetate.

6 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 20,500 mL of dioxane are placed in a 2-liter three-necked flask equipped with a condenser, a stirrer, and a stopcock funnel. To the refluxed solution, a solution of 3.3 g of 6-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate in 50.0 mL of dioxane is rapidly added. The solution is refluxed and stirred for 18 hours, cooled to room temperature, and filtered to remove the hydroquinone. The solvent is stirred under vacuum (steam bath, rotary stirrer), and the residue is dissolved in 300 mL of methylene chloride. The solution is filtered, if necessary, and passed through a column containing approximately 200 g of alumina (Woelm, degree I). The solvent is removed (steam bath, rotary evaporator). After recrystallization of the solid in hexane, 1.3 g of 6-chlorodibenzothiophene-3-ethyl acetate is obtained; w.f. 62-64° (hexane).

26

Example 12

Preparation of 6-chloro-dibenzothiophen-3-ace-

tick.

1.3 g of 6-chlorodibenzothiophene-3-ethyl acetate are added to 0.24 g of potassium hydroxide in 30 mL of ethanol in a 100 mL round-bottom flask fitted with a condenser. After heating the solution for 1 hour under reflux, the solvent is removed under vacuum (steam bath, rotary evaporator), the residue is dissolved in 100 mL of water, and the aqueous solution is acidified with dilute hydrochloric acid.

6-Chloro-dibenzothiophene-3-acetic acid is removed by filtration, washed with water, and dried at 60°C under vacuum overnight. After crystallization in acetonitrile, 0.8 g of 6-chloro-dibenzothiophene-3-acetic acid is obtained, melting at 226-228°C.

Example 13

Preparation of 3-(4-isobutylphenylthio)-4-ketocyclohexane-ethyl acetate.

31.4 g of 4-isobutylthiophenol and a solution of 10.6 g of 85% potassium hydroxide in 300 mL of ethanol are placed in a 3-liter three-necked flask equipped with a condenser, a nitrogen inlet tube, a stopcock funnel, and a stirrer. The solution is refluxed, and a solution of 49.5 g of 3-bromo-4-ketocyclohexane-ethyl acetate in 25,500 mL of ethanol is added over a period of one hour. After the addition is complete, the solution is refluxed for one hour, cooled to room temperature, and filtered to remove the potassium bromide. After removing the ethanol in a vacuum (steam bath, rotary evaporator), 30,300 ml of water are added to the residue. The product is extracted three times with 200 ml of water, and the ether extract is dried over anhydrous magnesium sulfate. After removing the ether in a steam bath at atmospheric pressure, the residue is distilled in a vacuum, yielding 42.5 g of 3-(4-isobutyl-

27

phenylthio)-4-ketocyclohexane-ethyl acetate; boiling point 205-220°/2.0 mm.

Preparation of 8-isobutyl-1,2,3,4-tetrahydrodibenzo-thiophene-3-ethyl acetate.

added to 700 g of polyphosphoric acid in a 2-liter three-necked flask equipped with a stirrer and a condenser. The mixture is heated for 90 minutes in a steam bath, then poured into a mixture of 1 kg of ice and 1 liter of water. The mixture is then stirred until the dark oily complex decomposes and a light yellow color appears. The product is extracted twice with 500 mL of ether. The ether extract is 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 in a steam bath to remove the ether. This yields 24.4 g of 8-isobutyl-1,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate; boiling point 195-205°C/0.7 mm.

Preparation of 8-isobutyl-benzothiophene-3-ethyl acetate.

16.6 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 200 mL of xylene are placed in a 2-liter three-necked flask equipped with a condenser, a stirrer, and a stopcock funnel. To this solution, heated under reflux, a solution of 10.7 g of the product from Example 14 in 200 mL of xylene is rapidly added. The solution is heated under reflux and stirred for 18 hours, cooled to room temperature, and filtered to remove the hydroquinone. The solvent is removed under vacuum (steam bath, rotary evaporator), and the residue is dissolved in 300 mL of methylene chloride. The solution is

Example 14

42.5 g of the product obtained in the previous example are

Example 15

28

Filtered, if necessary, and passed through a column containing approximately 200 g of alumina (Woelm, degree I). The solvent is removed (steam bath, rotary evaporator). The product is recrystallized in hexane to give 4.7 g of 8-isobutyldibenzo-thiophene-3-ethyl acetate; boiling point 200-215°C / 0.7 mm.

Example 16

Preparation of 8-isobutyl-dibenzothiophene-3-acetic acid.

4.7 g of ethyl 8-isobutyl-dibenzothiophene-3-acetate are added to 0.81 g of potassium hydroxide in 125 mL of ethanol in a 500 mL round-bottom flask fitted with a condenser. After heating the solution for 1 hour under reflux, the solvent is removed under vacuum (steam bath, rotary evaporator), the residue is dissolved in 100 mL of water, and the aqueous solution is acidified with dilute hydrochloric acid. The product is removed by filtration, washed with water, and dried at 60°C under vacuum overnight. After crystallization in isopropanol, 1.5 g of ethyl 8-isobutyl-dibenzothiophene-3-acetic acid (heptane) with a melting point of 133–135°C is obtained.

Example 17

Preparation of 9-chlorodibenzothiophene-3-acetic acid.

(A) 3-(3-chlorophenylthio)-4-ketocyclohexane-ethyl acetate.

23.8 g of 3-chlorothiophenol and a solution of 10.8 g of 85% potassium hydroxide in 300 mL of ethanol are placed in a 3-liter three-necked flask equipped with a condenser, a nitrogen inlet tube, a stopcock funnel, and a stirrer. The solution is refluxed, and a solution of 43 g of 3-bromo-4-ketocyclohexane-ethyl acetate in 250 mL of ethanol is added over one hour. Then, the solution

29

The mixture is stirred under reflux for 1 hour, cooled to room temperature, and filtered to remove potassium bromide. After removing the ethanol in a steam bath under vacuum, 150 mL of water is added to the residue. The product is extracted three times with 100 mL of ether, and the ether extract is dried over anhydrous magnesium sulfate. After removing the ether in a steam bath at atmospheric pressure, the residue is distilled under vacuum. This yields 12.2 g of 3-(3-chlorophenylthio)-4-ketocyclohexane ethyl acetate; boiling point 195-225°C/2 mm.

(B) 9-chloro-l,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate.

8.0 g of the product obtained in the preceding paragraph are added to 200 g of polyphosphoric acid in a 15-liter three-necked flask equipped with a stirrer and a condenser. The mixture is heated for 90 minutes in a steam bath, then poured into a mixture of 200 g of ice and 200 mL of water while stirring, which is continued until the dark oily complex has decomposed and a light yellow color appears. The product is extracted twice with 200 mL of ether. The ether extract is washed twice with 50 mL of water, then with 50 mL of saturated sodium bicarbonate solution. The solution is dried over anhydrous potassium carbonate and filtered.

The ether is removed by steam bath in a rotary evaporator 25 under atmospheric pressure, and the residue is distilled under reduced pressure. At 205-220°/2 mm, 3.3 g of 9-chloro-1,2,3,4-tetrahydrodibenzothiophene-3-ethyl acetate are obtained.

(C) 9-chlorodibenzothiophene-3-ethyl acetate.

30 11 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 mL of dioxane are placed in a 1-liter three-necked flask equipped with a condenser, a stirrer, and a stopcock funnel. A solution of 6 g of the ester obtained in the preceding paragraph 35 in 100 mL of dioxane is rapidly added to the refluxed solution. The solution is refluxed and stirred for 24 hours, cooled to room temperature, and filtered to remove the hydroquinone. The solvent is removed.

30

The solution was passed through a steam bath under vacuum, and the residue dissolved in 200 ml of methylene chloride. The solution was then passed through a column containing approximately 150 g of alumina (Woelm, degree I). The solvent was removed by steam bath, and the residue was crystallized in alcohol. This yielded 1.1 g of 9-chlorodibenzothiophene-3-ethyl acetate; wt. 82-84°.

(D) 9-Chlorodibenzothiophene-3-acetic acid.

1.1 g of ethyl 9-chlorodibenzothiophene-3-acetate is added to 0.28 g of potassium hydroxide in 50 mL of ethanol in a 100 mL round-bottom flask fitted with a condenser. After heating the solution for 4 hours under reflux, the solvent is removed under vacuum (steam bath, rotary evaporator), the residue is dissolved in 50 mL of water, and the aqueous solution is acidified with dilute hydrochloric acid. The product is isolated by filtration, washed with 20 mL of water, and dried at 60°C in an oven for 12 hours. After crystallization in methanol, 0.8 g of ethyl 9-chlorodibenzothiophene-3-acetic acid is obtained; mol.p. 203–206°.

Example 18

20 Preparation of 8-methyldibenzothiophene-3-

acetic.

(A) 3-(4-methylphenylthio)-4-ethyl ketocyclohexane-carboxylate.

73.5 g of p-toluenethiol and a solution of 33 g of 85% potassium hydroxide in 500 mL of ethanol are placed in a 2-liter three-necked flask equipped with a condenser, a nitrogen inlet tube, a stopcock funnel, and a stirrer. The solution is refluxed, and a solution of 146.4 g of ethyl 3-bromo-4-ketocyclohexane-carboxylate in 500 mL of ethanol is added over one hour. The solution is then refluxed for another hour. After removing the ethanol under vacuum in a steam bath, 300 mL of water is added to the residue, and the product is extracted three times.

31

200 ml of ether and the dried ether extract on anhydrous magnesium sulfate, then the solvent is removed in a steam bath. The residue is crystallized in heptane; this yields 66 g of ethyl 3-(4-methylphenylthio)-4-ketocyclohexane-carboxylate; 5% ethyl; 87-89°.

ethyl carboxylate.

13 g of the product obtained in the preceding paragraph are added to 130 g of polyphosphoric acid in a 10 x 500 mL three-necked flask equipped with a stirrer and a condenser. The mixture is heated for 90 minutes in a steam bath, then poured into a mixture of 200 g of ice and 200 mL of water while stirring, which is continued until the dark oily complex is decomposed and a light yellow color appears. Product 15 is extracted with ether and the solution washed with water until a neutral reaction occurs. After drying over anhydrous potassium carbonate, the ether is removed by steam distillation and the residue is crystallized in methanol. This yields 6 g of ethyl 8-methyl-1,2,3,4-tetrahydrodibenzothiophene-20 3-carboxylate; w.f. 68-89°.

200 mL of dioxane are placed in a 500 mL three-necked flask equipped with a condenser, a stirrer, and a 25 mL stopcock funnel. A solution of 5.5 g of the ester obtained in the previous paragraph in 50 mL of dioxane is rapidly added to the solution under reflux. The solution is heated under reflux and stirred for 24 hours, cooled to room temperature, and filtered to remove the hydroquinone. The solvent is removed under vacuum in a steam bath, and the residue is dissolved in 100 mL of methylene chloride. The solution is passed through a column containing approximately 75 g of alumina (Woelm, degree I). The solvent is removed in a steam bath, and the residue is crystallized in methanol. This yields 4.2 g of ethyl 8-methyl-35-dibenzothiophene-3-carboxylate; mol.f. 83-87°.

(B) 8*-methyl-1,2,3,4-tetrahydrodibenzothiophene-3-

(C) ethyl 8-methyldibenzothiophene-3-carboxylate.

10 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

32

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

To a solution of 0.73 g of potassium hydroxide in 50 mL of ethanol, 3.5 g of ethyl 8-methyldibenzothiophene-3-carboxylate are added. The solution is heated under reflux for 3 hours. The solvent is removed under vacuum in a steam bath, and the crude potassium salt is dissolved in 50 mL of water. The solution is acidified with dilute hydrochloric acid, and the isolated product is filtered and dried. This yields 2 g of 8-methyldibenzothiophene-3-carboxylic acid; 10 wt. 290-291°.

(E) 3-chlorocarbonyl-8-methyldibenzothiophene.

A solution of 3 g of oxalyl chloride in 50 mL of benzene is added dropwise, with stirring, to a suspension of 3.5 g of crude potassium salt of 8,15-methyldibenzothiophene-3-carboxylic acid in 100 mL of benzene. The mixture is filtered, and the solvent is removed under vacuum in a steam bath. After crystallization in hexane, 2.5 g of 3-chlorocarbonyl-8-methyldibenzothiophene, melting at 127–128°C, is obtained.

20 (F) 3-diazomethylcarbonyl-8-methyldibenzothiophene.

A solution of 2.5 g of the product obtained in the preceding paragraph in 75 mL of ether is added dropwise to a solution of 0.81 g of diazomethane in 100 mL of ether in an ice bath. The solution is stirred until the ether is removed in a steam bath. This yields 2.5 g of crude 3-diazomethylcarbonyl-8-methyldibenzothiophene, which is used directly in the next step.

(G) 8-methyldibenzothiophene-3-ethyl acetate.

To a refluxed solution of 2.5 g of product 30 obtained in the preceding paragraph in 50 ml of alcohol, a solution of 1.0 g of silver benzoate in 10 ml of triethylamine is added dropwise, while stirring. The solution is heated under reflux until nitrogen evolution ceases.

33

The solution is filtered and the solvent removed under vacuum in a steam bath. The residue is crystallized in petroleum ether (30-60°) and gives 1.3 g of 8-methyldibenzothiophene-3-ethyl acetate melting at 45-48°.

5 (H) 8-Methyldibenzothiophene-3-acetic acid.

To a solution of 0.27 g of potassium hydroxide in 50 mL of alcohol, 1.3 g of the product obtained in the preceding paragraph is added, and the solution is heated under reflux for 3 hours. The solvent is removed under vacuum, and the residue is dissolved in 10 50 mL of water. The solution is acidified with dilute hydrochloric acid, and the filtered product is dried. Recrystallization in acetonitrile yields 0.5 g of 8-methyl-dibenzothiophene-3-acetic acid, mol.f. 185-187°.

Example 19

15 Preparation of dibenzothiophene-3-acetic acid.

(A) ethyl 3-bromo-4-ketocyclohexane-carboxylate.

24 g of bromine are added dropwise over 45 minutes to a solution of 25.5 g of ethyl 4-ketocyclohexanecarboxylate and 450 mL of anhydrous ether, cooled to -10°C, in a 1-liter three-necked flask equipped with a stirrer, a condenser, and a stopcock funnel. The resulting colorless solution is washed three times with 100 mL of water, then twice with 50 mL of a 5% sodium bicarbonate solution, and finally twice with 100 mL of water. The ether solution is dried over anhydrous magnesium sulfate, and the solvent is removed by steam irrigation. This yields 37 g of crude ethyl 3-bromo-4-ketocyclohexanecarboxylate.

(B) ethyl 3-phenylthio-4-ketocyclohexane-carboxylate-

16.5 g of benzenethiol and a solution of 10 g of potassium hydro-30 oxide in 400 ml of alcohol are placed in a 2-liter three-necked flask equipped with a condenser and an introduction tube.

S

34

nitrogen, a stopcock funnel, and a stirrer are used. The solution is refluxed, and a solution of 37 g of ethyl 3-bromo-4-ketocyclohexanecarboxylate in 200 mL of alcohol is added over one hour. The solution is then stirred at reflux for one hour. After removing the alcohol under vacuum in a steam bath, 200 mL of water is added to the residue, the product is extracted with ether, and the ether-treated extract is dried over anhydrous potassium carbonate. The ether is removed in a steam bath, and the residue is distilled under vacuum. This yields 10 and 20 g of ethyl 3-phenylthio-4-ketocyclohexanecarboxylate; boiling point 198–210°C/2 mm.

(C) 1,2,3,4-ethyl tetrahydrodibenzothiophene-3-carboxylate.

A mixture of 10 g of the product obtained in the preceding paragraph and 130 g of polyphosphoric acid is stirred in a steam bath for 90 minutes, then poured over a mixture of 400 g of ice and 400 ml of water. The oil is extracted with 2 x 100 ml of ether, and the ether extract is washed twice, first with 50 ml of water and then with 50 ml of a 5% sodium bicarbonate solution. The ether solution is dried over anhydrous potassium carbonate, and the solvent is then removed in a steam bath. The crude product is distilled under reduced pressure, yielding 5 g of ethyl 1,2,3,4-tetrahydrodibenzothiophene-3-carboxylate; boiling point 190–195°C/2 mm.

25 (D) Ethyl dibenzothiophene-3-carboxylate.

To a solution of 2.5 g of the product obtained in the preceding paragraph in 100 mL of dioxane, 4.7 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added. The solution is stirred and heated under reflux for 31 hours. The solution is then cooled for 30 minutes and the hydroquinone is removed by filtration. The dioxane is removed in a steam bath under reduced pressure. The residue is dissolved in 100 mL of methylene chloride and the solution passed through a column containing approximately 75 g of alumina (Woelm, degree I). The solvent is removed in a steam bath for 35 minutes and the residue is crystallized in hexane. This yields 1.7 g of ethyl dibenzothiophene-3-carboxylate; w.f. 74-78°.

15

20

35

(E) Potassium salt of dibenzothiophene-3-carboxylic acid.

To 200 ml of alcohol containing 2.7 g of potassium hydroxide, 13.2 g of the ester obtained in the preceding paragraph is added, then the solution is heated under reflux, stirred for 4 hours, and filtered. The potassium salt of insoluble dibenzothiophene-3-carboxylic acid is filtered and weighs 8.9 g after drying at 80°C in an oven. Dibenzothiophene-3-carboxylic acid, which can be obtained from the potassium salt, is a known compound [H. Gilman, A.L. Jacoby and H.A. Pacevitz, J. Org. Chem. 120 (1938)].

(F): 3-chlorocarbonyl-dibenzothiophene.

To a suspension of 8.9 g of the potassium salt obtained in the previous paragraph in 200 mL of benzene, a solution of 6.4 g of oxalyl chloride in 50 mL of benzene is added dropwise, while stirring, over a period of 30 minutes. The mixture is stirred and heated for 2 hours under reflux. The mixture is filtered, and the solvent is removed under vacuum in a steam bath. The residual 3-chlorocarbonyl-dibenzothiophene (7.9 g) is used directly in the next step.

(G) 3-diazomethylcarbonyl-dibenzothiophene.

A solution of 7.9 g of the product obtained in the previous paragraph in 700 ml of ether is added, while stirring,

A solution of 2.7 g of diazomethane in 180 ml of ether is placed in an ice bath. The solution is stirred for 7 hours and the solvent removed in a steam bath. This yields 7.5 g of crude 3-diazomethylcarbonyl-dibenzothiophene, which is used directly in the next step.

(H) Dibenzothiophene-3-ethyl acetate.

To a refluxed solution of 7.5 g of the product obtained in the preceding paragraph in 100 ml of alcohol, a solution of 1 g of silver benzoate in 10 ml of triethylamine is added dropwise, while stirring. The solution is then refluxed for 1 hour, filtered, and the solvent removed.

S

36

in a vacuum. After crystallization of the residue in petroleum ether (30-60°), 2.7 g of dibenzothiophene-3-ethyl acetate is obtained; w.f. 60-62°.

(I) Dibenzothiophene-3-acetic acid.

5. A solution of 0.56 g of potassium hydroxide in

To 75 ml of ethanol, 2.7 g of the ester obtained in the previous paragraph is added. The solution is heated under reflux for 3 hours, and the solvent is removed under vacuum. The residue is dissolved in 50 ml of water, and the solution is acidified with dilute hydrochloric acid. The solid is separated by filtration and dried under vacuum at 50°C. Recrystallization in acetonitrile yields 1 g of dibenzothiophene-3-acetic acid; mol. gas. 174-176°C.

Example 20

15 Preparation of 7-chlorodibenzothiophene-3-

acetic.

(A) 5-dibenzothiophene-3-ethyl carboxylate oxide.

8.3 g of chlorine is passed through a solution of 23.8 g of ethyl dibenzothiophene-3-carboxylate in 600 mL of carbon tetrachloride cooled to 5°C. The solution is poured onto ice and the mixture is thoroughly shaken. The resulting solid is separated by filtration, dried under vacuum at 50°C, and crystallized in acetonitrile. This yields 11.6 g of ethyl dibenzothiophene-3-carboxylate 5-oxide; mol. at 210-213°C.

(B) 5-oxide of 7-nitrodibenzothiophene-3-ethyl carboxylate.

25 g of the product obtained in the preceding paragraph are added in portions to 250 ml of 90% nitric acid maintained at 22-25°C. The solution is stirred for 15 minutes, then poured onto ice. The solid substance formed is separated by

1. '>

■

I

37

filtration, washed with water until neutral reaction and dried in the oven at 50°. After recrystallization in 1,2-dichloroethane, 24.7 g of ethyl 7-nitro-dibenzothiophene-3-carboxylate 5-oxide is obtained; w.p. 245-250°.

5 (C) Ethyl 7-aminodibenzothiophene-3-carboxylate hydrochloride.

A mixture of 21.9 g of the product obtained in the preceding paragraph, 250 mL of acetic acid, and 1.7 g of 10% palladium-based charcoal is shaken at an initial hydrogen pressure of 50 psi and heated to 60°C. After 1 hour, hydrogen absorption ceases. The mixture is taken from the hydrogenation apparatus, cooled to room temperature, and filtered. After solvent removal under vacuum in a steam bath, the residue is dissolved in 35 mL of ethyl acetate, and the precipitated product is formed as hydrochloride by the introduction of hydrogen chloride. This yields 17.1 g of ethyl 7-aminodibenzo-thiophene-3-carboxylate hydrochloride; molten at 260-265°C. After crystallization in methanol, the product melts at 270-275°C.

(D) 7-chlorodibenzothiophene-3-ethyl carboxylate.

20. A solution of 28.7 g of the hydrochloride obtained in the preceding paragraph in 300 mL of acetic acid is added, at 15°C, to nitrosylsulfuric acid prepared from 19.4 g of sodium nitrite and 100 mL of concentrated sulfuric acid. The mixture is stirred for 15 minutes, then 25. 1 liter of ether is added to precipitate the diazonium sulfate. The mixture of diazonium sulfate and sodium sulfate is separated by filtration, washed with ether, and air-dried. The mixture is then added in portions, at 5°C, to a cuprous chloride solution prepared with 9.4 g of cuprous chloride, 375 mL of water, and 280 mL of concentrated hydrochloric acid. After the addition, the mixture is heated in a steam bath until nitrogen evolution ceases. The solid substance is separated by filtration, washed with water and dried in an oven. After crystallization in hexane, 18 g 35 of ethyl 7-chlorodibenzothiophene-3-carboxylate is obtained; w.f.

120-122°.

S

38

(E). Potassium salt of 7-chlorodibenzothiophene-3-carboxylic acid.

A solution of 4.1 g of potassium hydroxide (85%)

18.1 g of the ester obtained in the previous paragraph, in 100 ml of alcohol, is added to 450 ml of hot ethanol. The combined solutions are stirred and heated under reflux for 8 hours. After cooling to room temperature, the mixture is filtered, yielding 16.5 g of potassium salt.

10 (F) 3-chlorocarbonyl-7-chlorodibenzothiophene,

A solution of 10.5 g of oxalyl chloride in 100 ml of benzene is added to a stirred suspension of 16.53 g of the potassium salt obtained in the preceding paragraph in 100 ml of benzene. The mixture is stirred and heated under reflux for 15 to 2 hours, then filtered. By steam distillation to dryness in a vacuum bath, 9 g of crude 3-chlorocarbonyl-7-chlorodibenzothiophene is obtained as residue.

(G) 7-chlorodibenzothiophene-3-ethyl acetate.

A solution of 9g of the product obtained in paragraph 20 above in 100 ml of dioxane is added dropwise to a solution of 5.3 g of diazomethane in 250 ml of ether,

The solution is cooled in an ice bath. It is stirred until the following day, and the solvent is removed by vacuum distillation. The residue is dissolved in 600 ml of alcohol. Then, over one hour, a solution of 1 g of silver benzoate in 100 ml of triethylamine is added dropwise to the refluxed solution. The solution is heated under reflux for another hour and then filtered. The solvent is removed by vacuum steam distillation, and the residue is crystallized in hexane. This yields 4.8 g of 7-chlorodibenzothiophene-3-ethyl acetate; 68-70°.

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

A solution of 1 g of potassium hydroxide in 75 ml

39

To the alcohol, 4.8 g of the product obtained in the previous paragraph are added. After heating under reflux for 3 hours, the solvent is removed under vacuum in a steam bath, and 50 mL of water is added to dissolve the residue. The aqueous solution is acidified with hydrochloric acid, and the product is removed by filtration. The solid product is crystallized in acetonitrile, yielding 1.7 g of 7-chloro-dibenzothiophene-3-acetic acid (p.f. 198-200°).

Example 21

10. Preparation of 7-dimethylaminodibenzothiophene-3-

ethyl acetate.

(A) Ethyl 7-aminodibenzothiophene-3-carboxy-late hydrochloride.

A mixture of 24 g of ethyl 7-nitrodibenzothiophene-15 3-carboxylate 5-oxide, 200 mL of acetic acid, and 2.4 g of 10% palladium charcoal is hydrogenated at 50°C, with an initial pressure of 50 psi. After 3 hours, the hydrogenation is complete, the mixture is filtered, and the acetic acid is removed.

in a vacuum (steam bath, rotary evaporator). Residue 20 is dissolved in 250 ml of ethyl acetate, after which hydrogen chloride is passed through the solution. This yields 20 g of ethyl 7-aminodibenzothiophene-3-carboxylate hydrochloride; w.f. 270-275°.

(B) ethyl 7-dimethylaminodibenzothiophene-3-carboxylate 25.

A mixture of 7.3 g of the hydrochloride obtained in the previous paragraph and 5.0 g of trimethyl phosphate is heated at 160°C for 45 minutes. After cooling to room temperature, 75 mL of ethyl acetate is added, and the solution is extracted with 25 mL of water. The ethyl acetate is then removed under vacuum (steam bath, rotary evaporator), and the crystallized residue is separated from ethanol. This yields 2.8 g of 7-dimethylaminodibenzothiophene-3-carboxylate.

40

ethyl; p.f. 160-162°.

(C) Potassium salt of 7-dimethylamino-dibenzothiophene-3-carboxylic acid.

To a solution of 0.5 g of potassium hydroxide in 5100 mL of ethanol, 2.8 g of the product obtained in the preceding paragraph is added. The solution is stirred and heated under reflux for 3 hours, during which time the potassium salt precipitates. This precipitates out by filtration, is washed with ether, and air-dried. This yields 1.9 g of the potassium salt of 7-dimethylaminodibenzothiophene-3-carboxylic acid.

(D) 7-Dimethylaminodibenzothiophene-3-carbonyl chloride.

To a suspension of 1.9 g of the salt obtained in paragraph 15 above in 100 ml of refluxing benzene, a solution of 1.2 g of oxalyl chloride in 25 ml of benzene is added for 20 minutes. The solution is then stirred and heated under reflux for 3 hours. The hot solution is filtered and the filtrate distilled to dryness under vacuum (steam bath, rotary evaporator). This yields 1.8 g of crude 7-dimethylaminodibenzothiophene-3-carbonyl chloride.

(E) 7-dimethylaminodibenzothiophene-3-ethyl acetate.

0.7 g of diazomethane and 50 mL of ether are placed in a 250 mL three-necked flask equipped with a stirrer, a stopcock funnel, and a condenser. The flask is cooled in an ice bath, after which a solution of 1.8 g of 7-dimethylaminodibenzothiophene-3-carbonyl chloride in 50 mL of anhydrous ether and 50 mL of tetrahydrofuran is added dropwise over 15 minutes. The ice bath is removed, and the solution is stirred for 2.5 hours. After removal of the solvent by steam distillation under vacuum, the residue is crystallized in toluene. This yields 0.3 g of 3-diazomethylcarbonyl-7-dimethylaminodibenzothiophene; mol.f. 173-175°. A 0.3 g refluxed solution of this compound in

'41

To 50 ml of alcohol, a solution of 1 g of silver benzoate and 10 ml of triethylamine is added dropwise over one hour, while stirring. The solution is filtered and the solvent removed by steam irrigation under vacuum. Residue 5 is crystallized in methanol to yield 50 mg of 7-dimethylaminodibenzothiophene-3-ethyl acetate; w.f. 115-120°.

Example 22

Preparation of 8-chlorodibenzothiophene-3-acetamide.

A solution of 2.76 g of 8-chlorodibenzothiophene-10 3-acetic acid in 10 mL of thionyl chloride is stirred for 1 hour and then distilled under reduced pressure at room temperature. The remaining crude 8-chlorodibenzothiophene-3-acetyl chloride, melting at 92–99°C, is then dissolved in 100 mL of benzene, after which the solution is saturated 15% with ammonia. The amide is separated by filtration, washed with water, and crystallized in acetic acid. This yields 2 g of 8-chlorodibenzothiophene-3-acetamide, melting at 237–238°C.

Example 23

20 Preparation of 8-chlorodibenzothiophene-3-ethanol.

3.05 g of 8-chlorodibenzothiophene-3-ethyl acetate are added to 0.45 g of lithium aluminum hydride in 100 mL of ether. The solution is heated under reflux for 1 hour and then treated with 2 mL of water. The solution is filtered and the ether removed by steam irrigation. The residue is crystallized in acetonitrile to give 1.1 g of 8-chlorodibenzothiophene-3-ethanol; mol.w. 98-100°.

N

42

Example 24

Preparation of 8-chlorodibenzothiophene-3-acetate 2-dimethylaminoethyl hydrochloride.

A mixture of 2.76 g of 8-chlorodibenzothiophene-5,3-acetic acid, 3.04 g of potassium carbonate, 1.73 g of dimethylaminoethyl chloride hydrochloride, and 250 mL of dimethylformamide is stirred and heated at 120°C for 4 hours. The solvent is removed under vacuum in a steam bath, and then 75 mL of water is added to the residue. The oil is extracted with ethyl acetate, and the crude product is precipitated as hydrochloride by the addition of hydrogen chloride.

f

We crystallize from acetone and obtain 1.5 g of 8-chlorodibenzothiophene-3-acetate 2-dimethylaminoethyl hydrochloride; w.p. 179-181°.

15 Example 25

Tablet preparation.

Per tablet

8-Chlorodibenzothiophene-3-acetic acid 25 mg, dicalcium phosphate dihydrate, unground 175 mg

20 mg corn starch, 24 mg magnesium stearate, 1 mg

Total weight 225 mg

Procedure:

25 parts of the active ingredient and 24 parts of corn starch are mixed in a suitable mixer. This premix is then mixed with 175 parts of dicalcium phosphate and 1/2 part of magnesium stearate, and then passed through a comminutor. The resulting pieces are then passed through the comminutor and mixed with the remaining 30 parts of magnesium stearate. The mixture is then blended and compressed into 225 mg tablets.

43

Example 26

Capsule preparation.

Per capsule: 8-chlorodibenzothiophene-3-acetic acid 50 mg

5 lactose 125 mg corn starch 30 mg talc 5 mg

Total weight 210 mg

Procedure.

10.50 parts of 8-chlorodibenzothiophene-3-acetic acid are mixed with 125 parts of lactose and 30 parts of corn starch in a suitable mixer. The mixture is then passed through a comminuter, and the mixture returned to the mixer is mixed with 5 parts of talc. The mixture is then 15.5 parts into hard gelatin capsules.

Example 27

Tablet preparation.

Per tablet

8-Chlorodibenzothiophene-3-acetic acid 100 mg

20 lactose 202 mg corn starch 80 mg

Amijel BOll* (prehydrolyzed corn starch) 20 mg, calcium stearate 8 mg

Total weight 410 mg

25. Procedure:

100 parts of active substance, 202 parts of lactose, 80 parts of corn starch, and 20 parts of Amijel BOll are mixed in a suitable mixer. The mixture is then granulated with water until a paste and mass are formed.

44

The moist material is passed through a commutator. The mass is then dried at 43°C. The dry granules are then sieved and fed into a mixer. Next, calcium stearate is added and mixed again. The mixture is then pressed into 5 tablets of 410 mg each.

Example 28

Preparation of suppositories.

Per 1.3 g suppository

10, 8-chlorodibenzothiophene-3-acetic acid 0.025 mg, hydrogenated coconut oil 1.230 mg, vegetable wax 0.045 mg

Procedure:

123 parts hydrogenated coconut oil and 4.5 parts vegetable wax are melted, thoroughly mixed, and cooled to 45°C. 2.5 parts of finely powdered active ingredient are added, and the mixture is stirred until a homogeneous dispersion is obtained. The mixture is then poured into suppository molds to produce 20 suppositories weighing 1.3 g each. These suppositories are cooled, removed from the molds, and individually wrapped.

K

45

Claims (1)

DEMANDS 1. Process for the preparation of compounds of general formula "r? I in which R represents a hydrogen atom or a halogen atom, or a hydroxy, cyano, lower alkyl, lower hydroxyalkyl, lower alkoxy, acyl, benzyloxy, lower alkyl-thio, trifluoromethyl, nitro, amino, lower monoalkyl-amino, lower dialkyl-amino, sulfamoyl, lower dialkyl-sulfamoyl, or difluoromethyl- sulfonyl; R^ represents a halogen atom or a hydroxy, cyano, lower alkyl, lower hydroxy-alkyl, lower alkoxy, acyl, acylamido, benzyloxy, lower alkyl-thio, trifluoromethyl, 15-nitro, amino, lower mono-alkyl-amino, di- lower alkyl-amino, sulfamoyl, di-alkyl-lower tallow amoyl or difluoromethylsulfonyl, or adjacent R and R^ groups also represent a lower alkylene-dioxy group; R2 represents a 20-(CXY)m-A group, in which A = hydroxy, alkoxy- lower, lower amino-alkoxy, lower mono-alkyl-lower amino-alkoxy, or lower di-alkyl-lower amino-alkoxy, X and Y, independently, represent a hydrogen atom or a lower 25 alkyl group, and m = 1-7, or R2 represents a group -(CXY)n~CO-B, in which B = hydroxy, carboxy, inferior alkoxy, amino, hydroxylamino, inferior mono-amino-alkyl, inferior di-amino-alkyl, inferior amino-alkyl, inferior mono-amino-alkyl, inferior di-amino-alkyl rieur, X and Y, independently, represent a hydrogen atom or a lower alkyl group, and n = 1-7; S 46 h and their enantiomers, as well as their salts with pharmaceutically acceptable bases or pharmaceutically acceptable acid addition salts of compounds in which R or = amino, lower mono-alkyl-amino or lower di-alkyl-amino, and/or B or A = lower amino-alkyl, lower mono-alkyl-lower amino-alkyl or lower di-alkyl-lower amino-alkyl, characterized in that a) a compound of general formula is aromatized R II 10 in which R, R^ and R2 have the same meaning as above, or b) for the preparation of compounds of general formula I, in which n=l, X and Y = H, and B = lower alkoxy, a diazoketone of general formula is treated 15 n r^T>i R- © ©■ ; H—NEE3N III with a lower alkanol, or c) for the preparation of compounds of general formula I, in which B = hydroxy, a compound of general formula I, in which B = lower alkoxy, is hydrolyzed 47 or d) for the preparation of compounds of general formula I, in which B = amino-alcohol, mono-alcoholamino-alcohol or dialcoholamino-alcohol, a compound of general formula I, in which B = hydroxy, or one of its salts, is reacted 5 with a suitable amination agent, or e) for the preparation of compounds of general formula I, in which B = lower alkoxy, an acid of general formula I, in which B = hydroxy, or one of its salts is esterified; 10 or f) for the preparation of compounds of general formula I, in which R or = dialcoylamino, we alkylate a compound of general formula I, in which R or R^ = amino; 4 or g) for the preparation of compounds of general formula I, in which R, R^ or A = hydroxy, we split an ether of general formula I, in which R, R^ or A = lower alkoxy; or h) for the preparation of compounds of general formula I, in which A = alkoxy, amino-alkoxy, monoalcoylamino-alkoxy or dialcoylamino-alkoxy, an alcohol of general formula I is etherified, in which A = hydroxy; 20 or i) for the preparation of compounds of general formula I, in which A = hydroxy, an ester of general formula I, in which B = alkoxy, is subjected to reduction; or k) for the preparation of compounds of general formula I, in which R^ = amino, an amide of general formula is saponified. 25 line I, in which R = acylamino, or 1) for the preparation of compounds of general formula I, in which R2 = -CHCR^COR^, R^ being an alkyl group and R^ of hydrogen or alkoxy, we alkylate a compound of general formula I, in which R = CI^COR^, R^ being as above; 30 or m) for the preparation of compounds of general formula I, in which R2 = -C (R^ ,R,-) COR^ , R<- being a lower alkyl group, we alkylate a compound of general formula, in which t) 48 * 5 10 R2 = -CH(R^)COR^, R^ and R^ having the same meaning as above; or n) for the preparation of compounds of general formula I, in which R or R-^ — -NE^, a corresponding nitro derivative or one of its 5-oxides is subjected to reduction, or o) for the preparation of compounds of general formula I, in which R or R^ = halogen, an amine compound is converted into the corresponding halogenated compound, or p) pharmaceutically acceptable salts are formed from compounds of general formula I, in which B = hydroxy or carboxy, or q) pharmaceutically acceptable acid addition salts are formed from compounds of general formula I, in which R or R^ = amino, lower mono-amino-alkyl, lower di-amino-alkyl and/or B = lower amino-alkyl, lower mono-alkyl-lower amino-alkyl or lower di-alkyl-lower amino-alkyl, or r) we solve a racemic mixture of a compound of general formula I, in which X and Y are different, at its optical antipodes. 2. A process according to claim 1, characterized in that a compound of general formula is prepared C COOH Y r 25 in which R'^ = halogen, lower alkyl or lower alkoxy, and X and Y having the same definition as in claim 1. 49 3. A process according to claim 1, characterized in that a compound of general formula is prepared in which X and Y have the same meaning 5 as in claim 2. 4. A process according to any one of claims 2 or 3, characterized in that a compound of formulas I' or I'' is prepared, in which = halogen. 5. A process according to any one of claims 3 and 4, 10 characterized in that 8-chloro-cc-methyl- acid is prepared dibenzothiophene-3-acetic acid. 6. A process according to any one of claims 3 and 4, characterized in that it prepares ( + )-8-chloro-cc-methyl-dibenzothiophene-3-acetic acid- 15 y\ Method according to any one of claims 3 and 4, characterized in that (-)-8-chloro-a-methyl-dibenzothiophene-3-acetic acid is prepared. 8. A process according to any one of claims 3 and 4, characterized in that 8-chloro-dibenzothiophene-20 3-acetic acid is prepared. ■9. A process according to any one of claims 3 and 4, characterized in that 2-(8-chloro-3-dibenzothienyl)-propanol is prepared. 10. A process according to any one of claims 3 and 4, 25 characterized in that 2-(8-chloro-3-dibenzothienyl)-ethanol is prepared. S 50 11. Process according to claim 1, characterized in that 8-chloro-dibenzothiophene-3-acetamide is prepared. 12. A process for manufacturing preparations having anti-inflammatory, analgesic, and anti-rheumatic action, characterized in that a compound according to the general formula I of claim 1 is a mixture, as an active substance, with solid or liquid carriers, non-toxic, inert and therapeutically compatible, commonly used in such preparations and/or excipients. *** original m 5â> not®* np. . fcûnténant ^ ™ Princess* - Ap P»r ptocutrflo" à* <2 ôe Sœ^