IL39036A - Benzofuran and benzothiophene carboxylic acid derivatives,their preparation and compositions containing them - Google Patents

Description

ΤΘ κ»ηι τΛ3ΐ smart m so inn © mn in mnpri 'T^ani ?man ,m» opiKanKj? Benzofuran and benzothiophene carboxylic acid derivatives, their preparation and compositions containing them SPAHAMEDICA Ad. 0:36961 - 2" 39036/2 The present invention relates to novel benzofuran and benzothiophene carboxylic acid derivatives of the general formula wherein R^ and independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano, carbamoyl, carboxy , lower alkoxy carbonyl, nitro, amino, mono-lower alkylamino, di-lower alkylamino, loweralkanoyl or lower alkanoylamido , represents hydrogen, lower alkyl, amino-lower alkyl, mono-lower alk lamino-lower alkyl, or di-lower alk' lamino-lower alkyl, n is 1 or 2 and X represents oxygen or sulfur, provided that at least one of and R2 is other than hydrogen, and salts thereof.

The invention also relates to a process for the preparation of the compounds of the above formula I and of their - 3 39036/2 eaJLts.

The compounds of formula I and the pharmaceutically acceptable salts thereof are useful as anti-inflammatory and anti-rheumatic agents. The pharmaceutically unacceptable salts oan be oonverted into the compounds of formula I or into pharmaceutically acceptable 3alts thereof by known methods.

As used herein, the term "lower alkyl" denotes a straight t or branched chain hydrocarbon group containing 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, .isobutyl, tertiary butyl, neopentyl, pentyl, heptyl, and the like. The term ."lower alkoxy" denotes an alkyl ether group in which the alkyl group is as described above, for example, methoxy, ethoxy, propoxy, isopropoxy, butpxy, pentoxy and the like. The term "halogen" denotes all the halogens; that is, bromine, chlorine, fluorine and iodine; bromine and chlorine are preferred. * The term "lower alkanoyl" denotes an alkanoyl group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, for example, formyl, acetyl, pr0pionyl, and the like. Exemplary of lower alkylami alkanoylamido is acetamido and the like. Exemplary of mono-lower/ are methylamino, ethylamino and the like. Exemplary of di-lower... "' alkylamino are dimethylamino , diethylamino and the like.

Exemplary of amino-lower alkyl are aminomethyl, aminoethyl and the like. Exemplary of mono-lower alkylamino-lower alkyl are methylaminomethyl, ethylaminoethyl and the like. Exemplary of - 4 - 39036/2 di-lower alkylamino-lower alkyl are dime hylaminome hy1, die hylaminoethyl and the like.

A preferred sub-genus of the compo< f formula I is characterized by the formula wherein R^, Rg, R^ and X are as previously described, and addition salts thereof.

Preferred compounds of formula lb comprise compounds of the formula wherein R^, R,,, R^ and X are as previously described, and salts thereof. Preferred compounds of formula Ic are those wherein X is oxygen. - 5 - ···· 39036/2 The preferred compounds of the invention comprise compound of the formula. wherein is as previously described, and R"^ and R'^ are independently hydrogen, chlorine or cyano, provided that at least one of R"^ and R"2 is hydrogen, and salts thereof.

The most preferred compounds of the invention are: 8-chloro-l,2,3, -tetrahydrodibenzofuran-3-carboxylic acid ; 7-chloro-l,2,3, 4-tetrahydrodibenzofuran-3-carboxylic acid ; and 8-cyano-l, 2, 3, 4-tetrahydrodibenzofuran-3-carboxylic acid.

Examples of the compounds of the invention corresponding to formula I wherein n is 2 and X is oxygen are: 8-acetyl-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ' 8-amino-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid; .8-amino-l, 2., 3, -tetrahydrodibenzofuran-3-carboxylic acid ethyl ester; 7-amin -l,2,3,4-totrahydrodibenzofuran-3-carboxylic acid ethyl ester; 7-amino-l,2,3, 4- etrahydrodibenzof ran-3-carboxylic acid; 8-chloro-1,2,3, 4-tetrahydrodibenzofuran-3-carboxylic acid 6-chloro-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid 9-chloro-l,2,3, 4-tetrahydrodibenzofuran-3-carboxylic acid methyl ester; 9-chloro-l, 2, 3, 4-tetrahydrodibenzofuran-3-carboxylic acid 7-chloro-l,2,3, 4-tetrahydrodibenzof ran-3-carboxylic acid 8-nitro-l, 2 , 3 , 4-tetrahydrodibenzofuran-3-carboxylic acid; 8-fluoro-l,2,3, 4-tetrahydrodibenzofuran-3-carboxylic acid 8-methyl-l,2,3, 4-tetrahydrodibenzofuran-3-carboxylic acid 7-acetamido-l,2,3,4-tetreJaydrodibenzofuran-3-carboxylic acid ethyl ester; 7-acetamido-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid; 7-methoxy-l,2,3, 4-tetrahydrodibenzof ran-3-carboxylic acid; 7, 9-dimethoxy-l, 2, 3 , -tetrahydrodibenzof ran-3-carboxylic acid; 7 ,9-dichloro-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid; 8-cyano-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid; 8-cyano-l,2,3,4-tetrahydrodibenzofuran-l-carboxylic acid; 8-carbamo l-l,2,3,4-te rahydrodibenzofuran-3-carboxylic acid ethyl eeter; 8-cyano-l,2,3»4-tetrahydrodibenzofuran-2-car'boxylic acid; and the like.

Examples of compounds of this invention corresponding to formula I wherein n is 1 and X is oxygen are: - 7 - 39036/2 7-chloro-2,3-dihydro-lH-cyclopenta[b]benzofuran-2-carboxylic acid; 7-acety1-2 f 3-dihydro-lH-cyclopentaLb]benzofuran-2-carboxylic acid; -amino-2 , 3-di ydro-lH-cyclopenta[b]b©nzofuran-2-carboxylic acid; 7-amino-2,3-dihydro-lH-cyclopenta[b]benzof ran-2-carboxylic acid ethyl eater; 6-amino-2 , 3-dihydro-lH-cyclopenta[b]benzofuran-2-oarboxylic aoid; -chloro-2,3-dihydro-lH-cyclopenta[b]benzof ran-2-carboxylic acid; 6-chloro-2 , 3-dihydro-lH-cyclopenta[b]benzofuran-2-carboxylic acid; 8-chlorOf-2 , 3-dihydro-lH-cyclopenta[bJbenzofuran-2-carboxylic acid; 7-nitro-2,3-dihydro-lH-cyclopenta[b]benzofuran-2-carboxylic acid; 7-fluoro-2 , 3-dihydro-lH-cyclopenta[b]benzofuran-2-carboxylic acid; 7-methyl-2 , 3-dihydro^lH-cyclopenta[b]benzofuran-2-carboxylic acid 6-acetamido-2 , 3-dihydro-lH-cyclopenta[b]benzofuran-2 carboxylic acid; 6-acetamido-2t3-dihydro-lH^cyclopenta[b]benzofuran-2 carboxylic acid ethyl ester; 6-methoxy-2,3-dihydro-lH-cyclopenta[b]benzofuran-2-carboxylic aoid; - 8 - 39036/2 6,8-dimethoxy-2,3-dihydro-lH-cyclopenta[b]benzpfuran-2- . carboxyllc acid; . 6 ,8-diohloro-2 , 3-aihydro-lH-cyclopenta[b]benzofuran-2- carboxylic acid; - 7-cyano-2 ,3-dihydro-lH-cyclopenta[b]benzofuran-2-carboxylic acid; . 7-carbamoyl-2 , 3-dihydro-lH-cyclopenta[b]benzofuran-2- carboxylic acid, and the like.

Examples of compounds of this invention corresponding to formula I wherein n is 2 and X is sulfur are: ¾ 8-chloro-l, 2 , 3 , -tetrahydrodibenzothipphene-3-carboxylic acid ethyl ester; 8-chloro-l, 2, 3, 4-tetrahydrodibenzothiophene-3-carboxylic acid; 8-acetyl-l, 2 , 3 , 4-tetrahydrodibenzothiophene-3-carboxylic acid; 8-amino-l ,2,3, 4-tetrahydrodibenzothiophene-3-carboxylic acid; δτ-amino-l, 2 , 3 , 4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester; 7-amino-l, 2 , 3 , -te rahydrodibenzothiophehe-3-carboxylie acid; 7-amino-l ,2,3, 4-tetrahydrodibenzothiophene-3-carboxylic acid methyl ester; 8-chloro-l, 2 , 3 » 4-tetrahydrodibenzothiophene-3-carboxylic ■ ■ acid; . ' '. ; ■ . ·■ . 6-chloro-l,2,3, 4r-tetrahydrodibenzothiophene-3-carboxylic acid; 9-chloro-l,2,3,4-te rahydrodibenzot iophene-3-carboxylic acid; 9-chloro-l, 2 , 3 , 4-tetrahydrodibenzothiophene-3-carboxylic acid propyl ester; 7-chloro-l,2,3, -tetrahydrodibenzothiophene-3-carboxylic acid; 8-nitro-l,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid; 8-fluoro-1,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid; 8-methyl-l,2,3, 4-tetrahydrodibenzothiophene-3-carboxylic acid; 7-acetamido-l,2,3, 4-tetrahydrodibenzothiophene-3-carboxylic acid; 7-acetamido-l,2,3, 4-tetrahydrodibenzothiophene-3-carboxylic acid methyl ester; 7-methoxy-l,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid; 7 , 9-dimethoxy-l,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid; 7, 9-dichloro-l, 2 , 3 , 4-tetrahydrodibenzothiophene-3-carboxylic acid; 8-cyano-l,2,3» 4-tetrahydrodibenzothiophene-3-carboxylic acid; 8-carbamoyl^l,2,3, 4-tetrahydrodibenzothiophene-3-carboxylic and, and the like. - 10 - 39036/2 Examples of compounds of this invention corresponding mula I wherein n is 1 and X is sulfur are : 7-chloro-2 , 3-dihydro-lH-cyclopenta[b] [l]benzothiop ene-2- carboxylic acid; 7-acetyl~2,3-dihydro-lH-cyclopenta[b][l]benzothiophene-2- carboxylic acid; 7ramino-2 , 3-dihydro-lH-cyclopenta[b] [l]benzothiophene-2- . carboxylic acid; ■ 7-amino-2,3-dihydro-lH-cyclopenta[b] [l]benzothiophene-2- carboxylic acid ethyi ester; 6-amino-2,3-dihydrp-lH-cyclopenta[b] [l]benzothiophene-2- carboxylic acid; . 5-chloro-2,3-dihydro-lH-cyclopenta[b][l]benzothiophene-2- • carboxylic acid; 6-chloro-2,3-dihydro-lH-cyclopenta[b] [l]benzothiophene-2- carboxylic acid; 8-chloro-2f 3-dihydro-lH-cyclopenta[b][l]benzothiophene-2- carbdxylic acid; 7-nitro-2 , 3-dihydro-lH-cyclopenta[b] [l]benzothiophene-2- carboxylic acid; 7-fluoro-2,3-dihydro-lH-cyclopenta[b] [ljbenzothiophene- 2-carboxylic acid; 7-methyl-2,3-dihydro-lH-cyclopenta[b][l]benzothiophene-2- carboxylic acid; 6-acetamido-2,3-dihydro-lH-cyclopenta[b]Ll]benzothiophene 2-icarboxylic acid; 6-acetamido-2 , 3-dihydro-lH-cyclopenta[ ] [1]benzo hiophene- 2-carboxylic acid ethyl ester; 6-methoxy-2,3-dihydro-lH-cyclopenta[b] [l]benzothiophene-2- carboxylic acid; 6 , 8-dimethoxy-2 , 3-dihydro-lH-cyclopenta[b] [ljbenzothio- phene-2-carboxylic acid; 6,8-dichloro-2, 3-dihydro-lH-cyclopenta[b] [l]benzothio- phene-2-carboxylic acid; 7-cyano-2, 3-dihydro-lH-cyclopenta[b] [l]benzothiophene-2- carboxylic acid; 7-carbamoyl-2,3-dihydro-lH-cyclopenta[b] [l]benzothiophene- 2-carboxylic acid, and the like.

The process for preparing the compounds of the above formula I is characterized in that a compound of the general formula wherein R^, R2, X and n have the foregoing meaning, at least one carbon atom of the phenyl ring in ortho position to the carbon atom linked with the atom X being unsubstituted, and Ri^ represents lower alkyl, is cyclised, or, where there is desired a compound of the formula I wherein X re resents ox en and salts thereof a com ound of - 12 - 39036/2 wherein and n have the foregoing meaning and R'^ and R'2 independently represent hydrogen or an electron withdrawing group selected from nitro, ; lower alkoxy / - lower .·. carbonyl, cyano or/alkanoyl groups, a% least one. of R^ and R'2 being other than hydrogen, is reacted with an acidic catalyst and, where an optically active, isomer of a compound of the general formula I above is desired, an obtained racemate of the general formula I is resolved into its optically active isomers and the desired isomer isolated, and where a salt of a compound of the general formula I above is desired, an obtained acidic or basic compound of the general formula I is reacted respectively with a base or an acid, and where a carboxylic acid compound of formula I is desired, an obtained carboxylic acid ester of formula I is saponified, and if desired, a salt of a compound of. formula I wherein R^ is hydrogen, is converted to a compound of formula I wherein ^ is amlno-lower alkyl, mono-lower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl, and if desired, a nitro group present in a compound of formula I is converted to an amino group, and, if desired an amino group is converted to a diazonium salt and the obtained diazonium group is replaced by halogen, cyano, hydroxy , lower alkoxy or hydrogen.

The first embodiment of the above process can be exemplified by the following reaction scheme I.

Scheme I Ie wherein HAL is halogen and R^, Rg, X and n are as ' In Reaction Scheme I, a compound of formula III is alkylated with the corresponding haloketocycloalkane carboxylic acid ester of formula IV to yield a compound of formula II. The reaction is conveniently carried out in a non-polar solvent, for example, a hydrocarbon, such as benzene, toluene and the like, or a polar solvent, such as dimethylsulfoxide , dimethylform-amide, hexamethylphosphoric triamide and the like. The reaction temperature is not critical. Preferably, the reaction is carried out at a temperature in the range of from about room temperature to about the reflux temperature of the reaction mixture. The molar ratio of the reactants is not critical. Preferably, they are reacted at a 1:1 molar ratio.

A compound of formula II is converted to a compound of formula Ie by thermal cyclization or by utilizing a cyclizing agent, such as polyphosphoric acid, sulfuric acid, acetic acid, hydrochloric acid and the like. Preferably, the reaction is carried out at a temperature in the range of from about -20°Cto about 120° C. The reaction can be conveniently carried out with or without a solvent. Examples of convenient solvents are acetic acid and the like.

The esters of formula Ie can be converted to the corresponding acid, i.e., the compounds of formula I wherein is hydrogen, by saponification according to known procedures, for example, by reaction with an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like, and subsequent treatment with a mineral acid, for example, a hydro- The separation of the desired compound of formula Ie and its corresponding acid from the reaction mixture can be effected utilizing known techniques such as, for example, filtration, crystallization, distillation and the like.

The second embodiment of the above prooess can be exemplified by reaction soheme II. - 17 - " · 39036/2 Scheme II wherein HAL is halogen, for. example, ohlorine, fluorine, bromine and iodine; preferred is fluorine; R'^ and independently are hydrogen or an eleotron withdrawing group such as nitro,. lower alkoxy carbonyl, cyano or iowerallcanoy1 , provided > that at least one of . .

R'^ and R'^ is other than hydrogen; and and n are as described herein.

In reaction scheme II, the reaction of a halobenzene of formula Ilia with an oxime of formula IVa to yield an O-phenyl oxime of formula Ila is conveniently carried out in a polar solvent, such as dimethylsulfoxide, dimethylformamide or hexa-methylphosphoric triamide. The reaction temperature is not critical. Preferably, the reaction is carried out at a temperature in the range of from about room temperature to about the reflux temperature of the reaction mixture. The molar ratio of the reactants is not critical. Preferably, they are reacted in a 1:1 molar ratio.

The oxime of formula Ila is converted to the compound of formula la utilizing, for example, an acidic catalyst such as as an organic, inorganic or Lewis acid, exemplary of which are hydrochloric acid, sulfuric acid, phosphoric acid, zinc chloride, copper chloride, boron trifluoride and the like, and various combinations thereof. Conveniently, the reaction can be carried out in a polar solvent such as an alkanol, for example, methanol, ethanol, propanol, and the like, water or a hydrocarbon such as benzene, toluene and the like. The reaction temperature is not critical. Preferably, the reaction is carried out at a temperature in the range of from about room temperature to about the reflux temperature of the reaction mixture. The separation of the desired compound of formula la from the reaction mixture can be effected utilizing known techniques such as, for A nitro group present in the compound of formula I can be converted to an amino group utilizing known procedures, for example, by catalytic reduction. An amino group can be converted to a diazonium salt utilizing known procedures, for example, by reaction with sodium nitrite and a mineral acid such as a hydro-halic acid. A diazonium group can then be replaced by a halogen, cyano, -hydroxy, lower alkoxy or hydrogen utilizing known procedures, for example, by- mixing a diazonium salt solution with, for example, a cuprous halide, cuprous cyanide, water, an alkanol or a reducing agent, such as hypophosphorous acid, respectively, at room temperature or occasionally at elevated temperatures.

Furthermore, a salt of an acid of formula I, i.e., a salt of compounds of formula I wherein is hydrogen, can be converted to a compound of formula I wherein is amino-lower alkyl, mono-lower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl 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 aminoethyl chloride, methylaminoeth l bromide, diethylaminomethyl chloride and the like, to yield the desired end product. The temperature at which the reaction is effected is not critical; conveniently, the reaction is carried out at a temperature in the range of from about room temperature and about the reflux temperature of the reaction mixture. Conveniently, the reaction can be carried out in a polar solvent, such as dimethylformamide , dimethyl-sulfoxide or the like. The molar ratio of reactants is not ratio.

The starting materials of formula Ilia are known compounds or can be prepared in an analogous manner to known compounds. Examples of such compounds are : 4-fluoronitrobenzene ; 4-fluorocyanobenzene ; 4-fluoroacetophenone; and the like.

The starting materials of formula IVa are known compounds or can be prepared in an analogous manner to known compounds. Examples of such compounds are: 3-oxyiminocyclohexanecarboxylic acid methyl ester; 4-oxyiminocyclohexanecarboxylic acid ethyl ester; 2-oxyiminocyclohexanecarboxylic acid methyl ester; 3-oxyiminocyclopentanecarboxylic acid propyl ester; 2-oxyiminocyclopentanecarboxylic acid methyl ester; 4-oxyiminocyclopentanecarboxylic acid methyl ester; and the like .

The intermediates of formula Ila are novel compounds.

Examples of such compounds are: 3- (4-nitrophenoxyimino)cyclohexanecarboxylic acid and methyl ester thereof; 3-(2-nitrophenoxyimino)cyclohexanecarboxylic acid and 3-( 4-cyanophenoxyimino )cyclohexanecarboxylic acid ; 3- ( 2-trifluoromethylphenoxyimono ) cyclohexanecarboxylic acid 2-(4-nitrophenoxyimino)cyclopentanecarboxylic acid and methyl ester thereof; 2- (4-cyanophenoxyimino )cyclopentanecarboxylic acid and methyl ester thereof; and the like.

The starting materials of formula III are known compounds or can be prepared in an analogous manner to known compounds.

Examples of such compounds are: 4-chlorophenol; -chlorophenol; .. 4-nitrophenol; p-cresol; 4-chlorothiophenol The starting materials of formula IV can be prepared as exemplified in reaction scheme III: Scheme III prepared in an analogous manner to known compounds.

The halogenation is effected utilizing known procedures, for example, utilizing a halogen such as bromine in ether, at a temperature of -10°C. Exemplary of compounds of formula IV are: 3-bromo-4- oxocyclohexanecarboxylic acid; 3-bromo-4- oxocyclohexanecarboxylic acid ethyl ester; 2-bromo-3- oxocyclohexanecarboxylic acid; 4-bromo-5- oxocyclohexanecarboxylic acid; 3-bromo-4- oxocyclopentanecarboxylic acid; 3-bromo-4- oxocyclopentanecarboxylic acid ethyl ester; 2-brorao-3- oxocyclopentanecarboxylic acid; 4-bromo-5- oxocyclopentanecarboxylic acid, and the like.

The intermediates of formula II as well as the corresponding carboxyiic acid compounds of formula II, wherein the lower alkyl group R'^ is replaced by hydrogen, are novel compounds. Examples of such compounds are : 3- ( 4-chlorophenoxy)-4-oxocyclohexanecarboxylic acid and ethyl ester thereof; 3- (4-chlorophenylthio)-4-oxocyclohexanecarboxylic acid and ethyl ester thereof; 3- ( 4-chlorophenoxy )-4-oxocyclopentanecarboxylic acid and methyl ester thereof; 3- ( 4-chlorophenylthio )-4-oxocyclopentanecarboxylic acid and methyl ester thereof; The compounds of formula I, when and/or is amino, mono-lower alkylamino or di-lower alkylamino, and/or when is amino-lower alkyl, mono-lower alkylamino-lower alicyl or di-lower alkylamino-lower alkyl, form addition salts with pharma-ceutically acceptable organic or inorganic acids such as hydro-halides, e.g., hydrochloride, hydrobromide , hydroiodide, other mineral acid salts such as sulfate, nitrate, phosphate and the like, alkyl and mono-arylsulfonates such as ethanesulfonate , toluenesulfonate , benzenesulfonate , or the like, other organic acid salts, such as acetate, tartrate, maleate, citrate, benzoate, salicylate , ascorbate and the like .

The compounds of formula I, when R^ and/or is carboxy and/or R^ is hydrogen, form salts with pharmaceutically acceptable bases. Examples of such bases are alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, and the like; alkaline earth hydroxides, such as calcium hydroxide, barium hydroxide and the like; sodium alkoxides, such as sodium eth late, potassium ethylate and the like; organic bases such as piperidine, di-ethanolamine , N-methylglucamine and the like. Also included are the aluminum salts of the compounds of formula I, when R-^ and/or ^ is carboxy and/or R^ is hydrogen.

The compounds of formula I, including the salts of those compounds of formula I which form salts with pharmaceutically acceptable bases and acids, possess anti-inflammatory activity and anti-rheumatic activity, and are therefore useful as antiinflammatory agents and anti-rheumatic agents. Their pharmaco animals using standard procedures.

For example, the anti-rinflammatory activity is demonstrated in Albino rats of Hart Strain, weighing 125-155 g. The test animals are given 10 ml of vehicle (Hilgar, A.G. and Hummel, D.J.: Endocrine Bioassay Data, No. 1, p. 15, August 1964 [Cancer Chemotherapy National Service Center, N.I.H.]), which contains 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 an 0.5 percent suspension of heat killed dessiccated Mycobacterium butyricum in 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 volume 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 percent reduction in edema is estimated therefrom and is expressed as When 7-chloro-l,2 , 3 , 4-tetrahydrodibenzofuran-3-carboxylic acid is utilized as the test substance at a dosage of 11.5 mg P.O., an anti-inflammatory activity is observed = 11.5). as herein described, have effects qualitatively similar to those of phenylbutazone, known for its therapeutic' uses and properties. Thus, the compounds of this invention demonstrate a pattern of activity associated with anti-inflammatory agents of known efficacy and safety.

The compounds of formula I, their enantiomers and salts as herein described can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral, enteral 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, polyalkylene-gl cols and the like.

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 possess asymmetric carbon atoms, they are ordinarily obtained as racemic mixtures.

The resolution of such racemates into the optically active isomers can be carried out by known procedures. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, however, preferred. By this an optically active resolving agent, for example, an optically active base, such as d-a-(l-naphthyl)ethylamine, 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 racemates 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 mentioned .

Example 1 A solution of 23.4 g of 3- (4-nitrophenoxyimino )cyclo-hexanecarboxylic acid in 250 ml of acetic acid containing 29 g of hydrogen chloride is stirred at 90° for 17 hours. Thereafter, the reaction mixture is cooled to 30° and filtered. The solid residue is washed successively with acetic acid, hexane and water, and dried to give 8.5 g of 8-nitro-l,2,3,4-tetrahydro-dibenzofuran-3-carboxylic acid as tan crystals, m.p. 229-231.5°. This material can be used for a further step without purification. After recrystallization from acetone-ether, the 8-nitro-l, 2 , 3 , 4-tetrahydrodibenzofuran-3-carboxylic acid has a melting point of 226-230°.

The 3- (4-nitrophenoxyimino )cyclohexane carboxylic acid used as starting material in the above process can be obtained A mixture of 12.1 g of potassium t-butoxide and 8.5 g of 3-oxyiminocyclohexanecarboxylic acid in 90 ml of dimethyl-sulfoxide is treated with 5.73 ml of 4-fluoronitrobenzene, stirred vigorously at room temperature for two hours, diluted with 450 ml of saturated sodium chloride solution and acidified with acetic acid. The precipitate is removed by filtration, washed successively with water and pentane, and dried to give 14.25 g of 3-(4-nitrophenoxyimino )-cyclohexanecarboxylic acid as light yellow crystals, m.p. 146-151° dec. This material can be used for a further step without purification. After recrystal-lization from methylene chloride-ether 3-(4-nitrophenoxyimino )-cyclohexanecarboxylic acid has a melting point of 158.5-159° dec.

Example 2 A solution of 4.83 g of 8-nitro-l,2,3,4-tetrahydro-dibenzofuran-3-carboxylic acid in 150 ml of acetic acid is reduced with 1 g of 10 percent palladium-on-charcoal catalyst.

The catalyst is removed by filtration. The filtrate is evaporated, and the residue is crystallized from acetonitrile-ether to give 3.4 g of 8-amino-l,2,3,4-tetrahydrodibenzofuran- 3-carboxylic acid as brown crystals, m.p. 235-235.5° dec. This material may be used in succeeding steps without further purification. After crystallization from acetonitrile-ether as light brown crystals, the 8-amino-l,2,3,4-tetrahydrodibenzo-furan-3-carboxylic acid has a melting point of 231-231.5° dec.

Example 3 A solution of 1 g of 8-amino-l, 2,3, 4~tetrahydrodibenzo-furan-3-carboxylic acid in 100 ml of ethanol saturated with hydrogen chloride is heated at reflux temperature for two hours and then evaporated to dryness. The residue is crystallized from ethanol-ether to give 986 mg (89 percent) of 8-amino-l, 2 , 3 , 4 -tetrahydrodibenzofuran-3-carboxylic acid ethyl ester hydrochloride as white crystals, m.p. 250-251° dec. After crystallization from ethanol-ether as white crystals, the 8-amino-l, 2,3, 4-tetra-hydrodibenzofuran-3-carboxylic acid ethyl ester hydrochloride has a melting point of 251-252° dec.

Example 4 A suspension of 2 g of 8-amino-l, 2,3, 4-tetrahydrodibenzo-furan-3-carboxylic acid in 12 ml of water and 20 ml of concen-trated hydrochloric acid, stirred at 0°, is treated dropwise with a cold solution of 716 mg of sodium nitrite in 20 ml of water. The diazotization solution is stirred at 0° for 30 minutes and then is added gradually to a cold solution of 1.3 g of cuprous chloride in 18 ml of concentrated hydrochloric acid.

The mixture is stirred for 2.5 hours at room temperature, diluted with water, and filtered to give 1.78 g of 8-chloro-l, 2 , , 4-tetrahydrodibenzofuran-3-carboxylic acid as tan crystals, m.p. 194-198.5°. A pure sample of 8-chloro-l, 2,3, 4-tetrahydrodibenzo-furan-3-carboxylic acid as white crystals, m.p. 198-201°, is obtained in about 50 percent yield by sublimation at 190°/0.05 mm.

Example 5 A suspension of sodium 4-chlorophenoxide , prepared from 11.6 g of 4-chlorophenol and 4.86 g of sodium methoxide, and 22.5 g of 3-bromo-4— oxocyclohexanecarboxylic acid ethyl ester in 300 ml of benzene is stirred for 64 hours at room temperature. The mixture is then washed successively with IN sodium hydroxide and water. The organic layer is dried over sodium sulfate and evaporated to give 18.30 g of 3-(4-chlorophenoxy)-4-oxocyclo-hexanecarboxylic acid ethyl ester as a yellow oil. A mixture of 18.25 g of this material and 180 g of polyphosphoric acid is stirred for.10 minutes at room temperature and then quenched with ice and water. The resulting solution is extracted with ether. The organic layer is washed successively with IN sodium hydroxide and water, dried and evaporated to give 15.6 g of viscous oil, which, after distillation, give 10.2 g of 8-chloro-l, 2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester as a light yellow oil, b.p. 175-185°/1 mm. A solution of 10.2 g of 8-chloro-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester, 150 ml of IN sodium hydroxide and 300 ml of ethanol is heated at reflux temperature for 1.5 hours and then concentrated at reduced pressure. After extraction with methylene chloride, the aqueous layer is treated with charcoal and filtered. The filtrate is cooled in ice water and acidified with 25 ml of concentrated hydrochloric acid. The precipitate is filtered, washed with water and dried to give 7 g of crystals, m.p. 199.5-201°, which are identical with the 8-chloro- 1,2,3,4-tetra- hydrodibenzoruran-3-carboxylic acid obtained by the method The 3-bromo-4—oxocyclohexanecarboxylic acid ethyl ester used as starting material in the above process can be obtained as follows: A solution of 40 g of 4— oxocyclohexanecarboxylic acid ethyl ester in 650 ml of ether is stirred at -10° during the dropwise addition of 12.05 ml of bromine. The resultant colorless solution is washed successively with water, saturated sodium bicarbonate solution and again with water. The organic layer is dried over sodium sulfate and evaporated to give 59 g of 3-bromo-4— oxocyclohexanecarboxylic acid ethyl ester as a colorless oil. This material may be used for a succeeding step without further purification, and may be kept for 2 to 3 days under nitrogen, without significant decomposition.

Example 6 A suspension of sodium 4-fluorophenoxide , prepared from 11.2 g of 4-fluorophenol, 5.4 g sodium methoxide and 26.8 g of 3-bromo-4— oxocyclohexanecarboxylic acid ethyl ester in 200 ml of benzene is stirred for 16 hours at room temperature . The reaction mixture is washed with water, IN sodium hydroxide, and saturated sodium chloride solution, and is dried over sodium sulfate. Evaporation of the solvent gives 22.1 g of 3-(4-fluoro-phenoxy )-4-oxocyclohexanecarboxylic acid ethyl ester.

A mixture of 17.1 g of this material and 150 g of poly-phosphoric acid is stirred for 10 minutes at room temperature, ether. The organic portion is washed with sodium bicarbonate and saturated sodium chloride solutions, dried and evaporated to dryness to give 15.8 g of an oil which is distilled to give 7.75 g of 8-fluoro-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester as a colorless oil. This material is heated at reflux temperature for 1 hour in a mixture of 75 ml of ethanol and 50 ml of IN sodium hydroxide. The ethanol is evaporated under reduced pressure. After the addition of 50 ml of water, the reaction mixture is treated with charcoal and neutralized with 25 ml of 2N hydrochloric acid. The solids which formed are removed by filtration and crystallized from acetone-water to give 3.65 g of 8-fluoro-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid as white crystals, m.p. 208-210^.

Example 7 A suspension of sodium p-cresolate, prepared from 3.24 g of p-cresol and 1.62 g of sodium methoxide, and 7.45 g of 3-bromo-4— oxocyclohexanecarboxylic acid ethyl ester in 100 ml of dry benzene is stirred for 64 hours at room temperature. The mixture is then washed successively with water, IN sodium hydroxide and water. The aqueous layers are extracted two times with benzene. The organic layers are dried over sodium sulfate and evaporated to give 6.11 g of 3-(4-methylphenoxy )-4-oxocyclohexanecarboxylic acid ethyl ester as a yellow oil.

A solution of 1.9 g of the above material in 5 ml of ether was combined with 19 g of polyphosphoric acid and stirred is quenched by addition of ice water, and the resulting mixture is stirred until a solution is obtained. This solution is extracted three times with ether. The organic layers are washed with water, saturated sodium bicarbonate solution and water, and dried over sodium sulfate. Evaporation of the solvent gives 1.62 g of a yellow oil which is distilled under vacuum to give 1.2 g of 8-methyl-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester. A solution of this material (1.2 g) in 9 ml of IN sodium hydroxide and 9 ml of ethanol is heated at reflux temperature for 1 hour under a nitrogen atmosphere. The ethanol is removed under vacuum. The residue is dissolved in water, treated with charcoal and filtered. The filtrate is cooled in an ice water bath and acidified with 2N hydrochloric acid. The precipitate which formed is filtered and crystallized from ether- entane to give 250 mg of 8-inethyl-l,2,3,4-tetrahydrodi-benzofuran-3-carboxylic acid, m.p. 199-201°.

Example 8 To a solution of 6.43 g of freshly distilled 2-chloro-phenol in 100 ml of methanol is added 2.7 g of sodium methoxide, and the resulting solution is evaporated to dryness under re -duced pressure to give 7.5 g of sodium 2-chlorophenoxide . A suspension of the above sodium salt and of 12.5 g of 3-bromo- 4-ox ocyclohexanecarboxylic acid ethyl ester in 150 ml of benzene is stirred overnight at room temperature. The reaction mixture is washed with two 50 ml portions of water, two 50 ml portions of IN sodium hydroxide and three 50 ml portions of evaporated to dryness to give 11.85 g of 3-(l-chlorophenoxy )- 4-oxocyclohexanecarboxylic acid ethyl ester as a dark yellow oil.

A mixture of 1 g of 3-(l-chlorophenoxy )-4-oxocyclohexane- carboxylic acid ethyl ester and 10 g of polyphosphoric acid is stirred for 1 hour at 75°. After the addition of 25 ml of ice water, the reaction mixture is extracted three times with 100 ml portions of ether. The organic layers are washed with water, IN sodium bicarbonate and with brine. The ether extracts are dried over sodium sulfate, evaporated to dryness, and the residue (955 mg) is distilled at 200°/0.2 mm to give 475 mg of 6-chloro- l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester as a yellow oil. A solution of this material in 10 ml of ethanol and 5 ml of 2N sodium hydroxide is heated at reflux temperature -for 1 hour. After removal of the ethanol, the resulting cloudy solution is treated with charcoal, filtered and treated with 5 ml of 2N HCl. The solids which form are removed by filtration and crystallized from acetonitrile to give 250 mg of 6-chloro- l,2,3,4-tetrahydrodibenzofuran-3-carboxyl±c acid as white crystals, m.p. 188-192°0. Recrystallization from acetone-water gives 230 mg of 6-chloro-l,2,3,4-^tetrahydrodibenzofuran-3- carboxylic acid, m.p. 190-193°C Example 9 Sodium 3-chlorophenoxide, prepared from 11.6 g of 3- chlorophenol and 4.86 g of sodium methoxide, in 300 ml of dry of 3-bromo-4—oxocyclohexanecarboxylic acid ethyl ester. The suspension is washed twice with 100 ml portions of water, once with 100 ml of IN sodium hydroxide and three times with 100 ml portions of water. The aqueous layers, are extracted twice with 150 ml portions of benzene. The combined organic layers are dried with sodium sulfate and evaporated to give 20.4 g of 3-(3-chlorophenox )-4-oxocyclohexanecarboxylic acid ethyl ester. A mixture of 5.63 g of this material and 85 g of polyphosphoric acid is stirred at 75° for 1 hour, decomposed with ice and water, and extracted three times with 250 ml portions of ether. The organic layers are washed twice with 200 ml portions of water, once with 150 ml of saturated sodium bicarbonate solution, and three times with 200 ml portions of water, and are then dried with sodium sulfate and evaporated to give 4.5 g of brown oil. Distillation at 190°/0.2 mm gives 3.5 g of a mixture of the isomeric esters 7-chloro-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester and 9-chloro-l, 2 , 3 , 4-tetrahydrodi-benzofuran->3-carboxylic acid ethyl ester. A solution of 3.48 g of this material in 70 ml of IN sodium hydroxide and 140 ml of ethanol is stirred at reflux temperature for 1 hour and then evaporated. The residue is dissolved in water, stirred with charcoal and filtered. The filtrate is acidified with concentrated hydrochloric acid, and the resulting precipitate is collected to give 2.72 g of an isomeric mixture of 7-chloro-l,2,3»4-tetra-hydrodibenzofuran-3-carboxylic acid and 9-chloro-l, 2, 3, 4-tetra-hydrodibenzofuran-3-carboxylic acid as a gray solid, m.p. 148-163°. Recrystallization from ether-pentane gives 1.51 g of the isomeric mixture 7-chloro-l,2,3,4-tetrahydrodibenzofuran-3- carboxylic acid as yellowish crystals, m.p. 152-180°. After crystallization from, methylene chloride-ether-pentane as white crystals, the mixture of 7-chloro-l,2,3,4-tetrahydrodibenzofuran- 3-carboxylic acid and 9-chloro-l, 2,3,4-tetrahydrodibenzofuran-3-carboxylic acid has a melting point of 167-185°.

Example 10 A solution of 5.65 g of the mixture of isomers 7-chloro-1, ,3,4-tetrahydrodibenzofuran-3-carboxylic acid and 9-chloro-l,2,3,4-te†rahydrodibenzofuran-3-carboxylic acid, m.p. 131-155°, in 10.0 ml of methanol saturated with hydrogen chloride is stirred at reflux temperature for 1 hour, Evaporation of the solvent and crystallization of the residue from ether-pentane gives 884 mg of 9-chloro-l, 2,3»4-tetrahydrodibenzofuran-3-carboxyiic acid methyl ester as yellowish crystals, m.p. 99-102°. A sample for analysis was sublimed at 90-100°/0.12 mm as white crystals, m.p. 101-102.5°.

Example 11 A solution of 840 mg of 9-chloro-l, 2,3, 4-tetrahydrodi-benzofuran-3-carboxylic acid methyl ester in 15 ml of IN sodium hydroxide and 30 ml of ethanol is stirred at reflux temperature for 1 hour and then evaporated. The residue is dissolved in water and extracted three times with 75 ml portions of methylene chloride. The aqueous layer is stirred with charcoal and filtered, and the filtrate is acidified with concentrated hydrochloric acid. hydrofuran-ether-pentane to give 452 mg of 9-chloro-l, 2 , 3 , 4-tetrahydrodibenzofuran-3-carboxylic acid as white crystals, m.p. 189-190°.

Example 12 A suspension of 15.1 g of 3-acetamidophenol and 13.8 g of potassium carbonate in 60 ml of dimethylformamide is heated with stirring at 100° for 10 minutes. A solution of 24.9 g of 3-bromo-4— oxocyclohexanecarboxylic acid ethyl ester in 25 ml of dimethylformamide is added dropwise to the above suspension. After 15 minutes, the reaction mixture is concentrated, diluted with water and extracted three times with ether. The ether extracts are washed with IN sodium hydroxide and water, and dried over sodium sulfate. Evaporation of the solvent gives 18.0 g of 3-(3-acetamidophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester. A mixture of 16 g of this material and 160 g of polyphosphoric acid is stirred for 30 minutes at room temperature. An excess of ice water is added. The precipitate which forms is filtered, dried, dissolved in methylene chloride and filtered through a column of alumina. The methylene chloride eluates are evaporated to give 11.1 g of an oil which is crystallized from methylene chloride-ether-pentane to give 4.5 g of 7-acetamido-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester, m.p. 115-116°.

Example 13 benzofuran-3-carboxylic acid ethyl ester in ethanolic hydrogen chloride is heated at reflux temperature for 2 hours. The solvent is removed under vacuum. Crystallization of the residue from ethanol-ether gives 2.2 g of 7-amino-l,2,3,4-tetrahydrodibenzo-furan-3-carboxylic acid ethyl ester hydrochloride, m.p. 226-228°.

Example 14 A solution of 145 mg of sodium nitrite in 2 ml of water is added dropwise, under nitrogen, to a cooled solution of 590 mg of 7-amino-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester hydrochloride in 5 ml of acetic acid:water (1:1). The resulting solution is added dropwise, under nitrogen, to a suspension of 238 mg of cuprous chloride in 2 ml of concentrated hydrochloric acid at 5°· The reaction mixture is stirred at room temperature for 30 minutes, then extracted three times with ether. The ether layers are washed with IN hydrochloric acid, IN sodium hydroxide and water, and dried' over sodium sulfate. Evaporation of the solvent gives 510 mg of an oil, which is distilled to give 444 mg of 7-chloro-l,2,3,4-tetrahydrodibenzo-furan-3-carboxylic acid ethyl ester as a yellow oil. A solution of 420 mg of this material, 5 ml of IN sodium hydroxide and ml of ethanol is heated at reflux temperature for 1 hour.

The solvent is removed under vacuum. The remaining residue is dissolved in water. The aqueous solution is extracted two times with ether, cooled and acidified with 2N hydrochloric acid. The precipitate which forms is filtered and crystallized from material is recrystallized from acetone-ether to give 110 mg of 7-chloro-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid, m.p. 194-196°.

Example 15 A mixture of 251 mg of 7-chloro-l,2,3,4-tetrahydrodibenzo-furan-3-carboxylic acid, 304 mg of anhydrous potassium carbonate and 25 ml of dimethylformamide is stirred at room temperature for 0.75 hour. A solution of 173 mg of 2-dimethylaminoethyl chloride hydrochloride in 5 ml of dimethylformamide is then added and the mixture is stirred for 16 hours, heated at reflux temperature for one hour and evaporated. The residue is dissolved in 100 ml of methylene chloride and washed with three 50 ml portions of water. The aqueous layers are extracted with two 100 ml portions of methylene chloride. The organic layers are combined, dried with anhydrous sodium sulfate and evaporated. A solution of the residual oil in methanol is acidified with methanolic hydrogen chloride and evaporated. Crystallization of the residue from methylene chloride-ether containing a little methanol yields 174 mg of 7-chloro-l,2,3,4-tetrahydrodibenzo-furan-3-carboxylic acid 2-dimethylaminoethyl ester hydrochloride, m.p. 178.5-181°.

Example 16 A solution of 1.2 g of 7-acetamido-l,2,3,4-tetrahydro-dibenzofuran-3-carboxylic acid ethyl ester, 10 ml of IN sodium for 1 hour. The solvent is removed under vacuum. The residue is dissolved in water and acidified with 2N hydrochloric acid. The precipitate is filtered and crystallized from acetone-water to give 75 mg of 7-acetamido-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid, m.p. 229-230°.

Example 17 A solution of 100 mg of 7-amino-l,2,3,4-tetrahydrodibenzo-furan-3-carboxylic acid ethyl ester hydrochloride, 3 ml of N sodium hydroxide and 10 ml of ethanol is heated at reflux temperature for 1 hour. The solvent is removed under vacuum.

The residue is dissolved in water, cooled and acidified with IN hydrochloric acid. The solid is filtered and crystallized from methanol-ether to give 45 mg of 7-amino-l, 2,3,4-tetrahydro-dibenzofuran-3-carboxylic acid hydrochloride, m.p. 290-300°.

Example 18 A suspension of 6.2 g of freshly distilled 3-methoxy-phenol and 6.9 g of potassium carbonate in 20 ml of dimethyl-formamide is heated at 100° for 15 minutes. To the stirred suspension is added dropwise 12.5 g of 3-bromo-4-oxocyclo-hexanecarboxylic acid ethyl ester in 5 ml of dimethylformamide , and the resulting mixture is stirred at 100° for 30 minutes.

After cooling, 150 ml of water are added and the reaction mixture is extracted with three 150 ml portions of ether. The ether layers are washed with IN sodium hydroxide and water, of the solvent gives 8.5 g of 3-(3-methoxyphenoxy )-4-oxocyclo-hexane-carboxylic acid ethyl ester as a yellow oil. A mixture of this material and 85 g of polyphosphoric acid is stirred for 15 minutes at room temperature, and added to 150 ml of ice water. Thereafter, the mixture is extracted with three 150 ml portions of ether. The ether extracts are washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Evaporation of the solvent gives 7 g of 7-methoxy-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester as a dark oil, which is dissolved in 100 ml of ethanol and 50 ml of 2N sodium hydroxide. The resulting solution is heated at reflux temperature for 1 hour. The ethanol is removed under reduced pressure. After the addition of 150 ml of water, the reaction mixture is extracted with ether. The aqueous layer is treated with charcoal, cooled in an ice water bath and neutralized with 50 ml of 2N hydrochloric acid. The solids which form are removed by filtration and are crystallized from acetone-water to give 3.8 g of crystals, m.p. 175-180°. Re-crystallization from acetonitrile-water gives 7-methoxy-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid as white crystals, m.p. 181-183°.

Example 19 A suspension of 3.08 g of 3, 5-dimethoxyphenol, 2.76 g of potassium carbonate and 4.98 g of 3-bromo-4- oxocyclohexane-carboxylic acid ethyl ester in 30 ml of dimethylformamide is stirred at 100° for 2 hours. Thereafter 150 ml of ice water with 100 ml portions of ether. The ether layers are washed with IN sodium hydroxide and with water, dried over sodium sulfate and evaporated to dryness. The residue (3.3 g) 3-(3, 5-dimethoxy-phenox )-4-oxocyclohexanecarboxylic acid ethyl ester is stirred at room temperature for 15 minutes with 33 g of polyphosphoric acid. After the addition of 150 ml of water, the reaction mixture is extracted three times with 100 ml portions of ether. The ether layers are washed with sodium bicarbonate and saturated sodium chloride solutions, dried over sodium sulfate, and eva-porated to dryness to give 2.7 g of 7,9-dimethoxy-l,2,3,4-te-trahydrodibenzofuran-3-carboxylic acid ethyl ester. This material is dissolved in 50 ml of ethanol and 25 ml of 2N sodium hydroxide, and the resulting solution is heated at reflux temperature for 1 hour. The reaction mixture is cooled, and the ethanol is removed under reduced pressure. The residue which forms is diluted with water, treated with charcoal, cooled in an ice bath and neutralized with 25 ml of 2N hydrochloric acid. The solids which form are removed by filtration and crystallized from acetone-water to give 1 g of 7,9-dimethoxy-l,2,3,4-tetrahydro-dibenzofuran-3-carboxylic acid, m.p. 194-196°.

Example 20 A solution of 3.12 g of 3-bromo-4-oxocyclohexane-carboxylic acid ethyl ester in 5 ml of dimethylformamide is added dropwise to a suspension of 2.04 g of 3, 5-dichlorophenol and 0.865 g of potassium carbonate in 25 ml of dimethylformamide. The resulting mixture is heated for 2 hours at 100°. Thereafter, tracted three times with ether. The organic layers are washed with water, saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to give 3.7 g of 3-(3,5-dichlorophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester. This material is combined with .38 g of polyphosphoric acid and heated for 1 hour at 70°. The reaction is quenched by addition of ice water, and the resulting solution is extracted three times with ether. The organic layers are washed with water, saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to give 2.7 g of 7,9-dichloro-l,2, 3,4-tetrahydrodibenziofuran-3-carboxylic acid ethyl ester. A solution of 2.7 g of 7,9-dichloro-i,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester, 25 ml of IN sodium hydroxide and 25 ml of e.thanol is heated at reflux temperature for 1 hour. The ethanol is removed under vacuum. The residue is dissolved in water, extracted two times with ether, cooled in an ice water bath' and acidified with 2N hydrochloric acid. The precipitate which forms is filtered and dried under vacuum to give 2.0 g of a solid, m.p. 190-200°. Crystallization from acetone-ether gives 1.06 g of 7,9-dichloro-l,2,3,4-tetrahydro-dibenzofuran-3-carboxylic acid, nup. 223-225°.

Example 21 A solution of 258 mg of 3-(4-cyanophenoxyimino)cyclo-hexane-carboxylic acid in 25 ml of acetic acid saturated with hydrogen chloride is heated on a steambath overnight, and then evaporated to dryness. The residue is digested on the steam- cooled to 25°, and the solid which forms is removed by filtration to give 99 mg of 8-cyano-l,2,3,4-tetrahydrodibenzo-furan-3-carboxylic acid as white crystals, m.p. 255-255°.

After crystallization from tetrahydrofuran^ether-pentane as white crystals, 8-cyano-l,2,3,4-tetrahydr0dibenzofuran-3-carboxylic acid has a melting point of 249-250°.

The 3-(4-cyanophenoxyimino)cyclohexanecarboxylic acid used as starting material in the above process can be obtained as follows : To a solution of 2.26 of potassium t-butoxide in 18 ml of dimethylsulfoxide, stirred vigorously at room temperature, is added 1.57 g of 3i-oxyiminocyclohexanecarboxylic acid. After 15 minutes, the mixture is treated with 1.21 g of 4-fluoro-benzonitrile* stirred for 2 hours, diluted with 150 ml of saturated sodium chloride solution . and acidified with acetic acid. The solid which forms is removed by filtration, dried and crystallized from tetrahydrofuran-ether-pentane to give 1.6 g of 3-(4-cyanophenoxyimino )cyclphexanecarboxylic acid as white crystals, m.p. 153-Ί540.

Example 22 Fractional crystallization of 15 g of the mother liquors obtained from the preparation of 8-cyano-l,2,3,4-te-trahydrodibenzofuran-3-!-carboxylic aeid gives 4.5 g of a tan solid, m.p. 185-190°. Two g of this material are filtered successively with benzene, methylene chloride, ether and ethyl acetate. The methylene chloride and the ether eluates are combined and crystallized twice from methylene chloride-ether-pentane to give 340 mg of 8-cyano-l,2,3,4-tetrahydrodibenzo-furan-l-carboxylic acid, m.p. 195-196°.

Example 23 A suspension of 1 g of 8-cyano-l , 2 , 3 , 4-tetrahydrodi-benzofuran-3-carboxylic acid in 100 ml of ethanol is stirred in an ice water bath and is saturated with hydrogen chloride. The mixture is refrigerated overnight and then heated to reflux temperature for 4 hours with the introduction of hydrogen chloride. The solution is evaporated to dryness and the residue is partitioned between methylene chloride and dilute sodium hydroxide. The organic layer is washed with water, dried and evaporated to give 1.1 g of solid, which is crystallized from methylene chloride-ether to give 283 mg of 8-carbamoyl-l , 2 , 3 , 4-tetrahydrodibenzofuran-3-carboxylic acid ethyl ester as white crystals, m.p. 206.5-207.5°. Crystallized twice from methylene chloride-ether as white crystals, 8-carbamoyl-l,2,3,4-tetra-hydrodibenzofuran-3-carboxylic acid ethyl ester has a melting point of 207.5-208°.

Example 24 A mixture of 250 mg of 8-cyano-l, 2,3, 4-tetrahydrodi-benzofuran-3-carboxylic acid and 3 ml of a 30 percent solution The solution thus obtained is diluted with water, cooled in an ice water bath and acidified with 2N hydrochloric acid. The precipitate which forms is filtered and dried under vacuum.

The solid obtained is crystallized from methanol to give 75 mg of l,2,3,4-tetrahydrodibenzofuran-3,8-dicarboxylic acid, m.p. 322-323°. An additional 130 mg of product, m.p. 321-322°, is obtained from the mother liquors.

Example 25 A solution of 226 mg of 1,2,3,4-tetrahydrodibenzofuran-3,8-dicarboxylic acid in 50 ml of ethanol saturated with hydrogen chloride is heated at reflux temperature for one hour while continuing introduction of hydrogen chloride.' Gas introduction is terminated and the solution is boiled for an additional two hours and then evaporated. The oily residue is dissolved in 75 ml of methylene chloride and the solution is washed with one 25 ml portion of IN sodium hydroxide and two 25 ml portions of water. The aqueous layers are extracted with two 50 ml portions of methylene chloride. The organic layers are combined, dried with anhydrous sodium sulfate and evaporated to dryness to give 247 mg of oil which crystallizes, m.p. 58-61°. Recrystallization from ether-pentane affords 179 mg of 1,2,3,4-tetrahydrodibenzo-furan-3,8-dicarboxylic acid diethyl ester, m.p. 63-63.5°.

Example 26 To a solution of 1.47 g of potassium t-butoxide in 11 ml added 993 mg of 4-oxyiminocyclohexanecarboxylic acid. After minutes, the reaction mixture is treated with 754 mg of 4-fluorobenzonitrile, stirred for 2 hours, diluted with 100 ml of saturated sodium chloride solution and acidified with acetic acid. Precipitate is removed by filtration, washed with water and with pentane and dried to give 670 mg of 4-(4-cyanophenoxy-imino) cyclohexanecarboxylic acid as a tan powder, m.p. 160-161° dec. This material can be used in the succeeding step without further purification.

A solution of 570 mg of 4- (4-cyanophenoxyimino) cyclohexanecarboxylic acid in 10 ml of acetic acid saturated with hydrogen chloride is heated on a steambath for 15 hours. The reaction mixture is cooled to about 25°, and the solid which forms is removed by filtration. Crystallization from tetra-hydrofuran-ether gives 230 mg of 8-cyano-l, 2, 3, 4-tetrahydro-dibenzofuran-2-carboxylic acid as white crystals, m.p. 251-251.5°. After recrystallization from etrahydrofuran-ether as white crystals , 8-cyano-l,2,3, 4-tetrahydrodibenzofuran-2-carboxylic acid has a melting point of 249.5-250.5°.

Example 27 To a solution of 9 g of potassium t-butoxide in 50 ml of dimethylsulfoxide, stirred vigorously at room temperature under a nitrogen atmosphere, are added 6.3 g of 3-oxyiminocyclo-hexanecarboxylic acid. After 30 minutes, the mixture is treated with 4.86 ml of 4-fluoroacetophenone, stirred for 3.5 hours, and acidified with acetic acid. The solid is removed by filtration, washed with water and with pentane, dried and digested with 400 ml of boiling tetrahydrofuran. Insoluble inorganic material which forms is removed by filtration and the filtrate is evaporated to dryness. The residue is crystallized from methanol-ether to give 2.1 g of 3-(4-acetylphenoxyimino) cyclohexanecarboxylic acid as light brown crystals, m.p. 167-168.5° dec. A solution of 1.9 g of this material in 25 ml of acetic acid saturated with hydrogen chloride is heated on a steambath for 15 hours. The reaction mixture is cooled to about 25°, and the solid which forms is removed by filtration.

Crystallization from tetrahydrofuran-ether gives 522 mg of 8-acetyl-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid as grayish crystals, m.p. 234-235°. After recrystallization from tetrahydrofuran-ether as white crystals, 8r-acetyl-l, 2,3,4-tetrahydrodibenzofuran-3-carboxylic acid has a melting point of 234-235°.

Example 28 A mixture of 5.5 g of potassium t-butoxide and 3.5 g of .3-oxyiminocyclopentanecarboxylic acid in 45 ml of dimethyl-sulfoxide is treated with 2.6 ml of 4-fluoronitrobenzene , stirred at room temperature for 1.5 hours, diluted with 475 ml of saturated sodium chloride solution and acidified with acetic acid. The precipitate which forms is removed by filtration, washed successively with water and pentane, dried and crystallized from tetrahydrofuran-ether-pentane to give 811 mg of obtained is treated with 3.5 ml of a saturated solution of hydrogen chloride in acetic acid, and the mixture is stirred for 17 hours at room temperature. The solid is removed by filtration, washed with acetic acid and dried to give 201 mg of white crystals, m.p. 203-205° (dec). The product was shown by MR spectra to contain a 7:3 ratio of 2, 3-dihydro-7-nitro-lH-cyclo-penta[b]benzofuran-l-carboxylic acid and 1, 3-dihydro-7-nitro-2H-cyclopenta[b]benzofuran-2-carboxylic acid. 2 , 3-Dihydro-7-nitro-lH-cyclopenta[b]benzofuran-l-carboxylic acid or 1, 3-dihydro-7-nitro-2H-cyclopenta[b]benzofuran-2-carboxylic acid can be converted to 2,3-dihydro-7-amino-lH-cyclo-penta[b]benzofuran-l-carboxylic acid or l,3-dihydro-7-amino-2H-cyclopenta[b]benzofuran-2-carboxylic acid, respectively, utilizing known procedures, for example, by chemical reduction, for instance, with iron and hydrochloric acid, or by catalytic reduction employing a catalyst, such as Raney nickel and the like. 2 , 3-Dihydro-7-amino-lH-cyclopenta[b]benzofuran-l-carboxylic acid or l,3-dihydro-7-amino-2H-cyclopenta[b]benzofuran-2-carboxylic acid can be converted to a diazonium salt utilizing known procedures, for example, by reaction with sodium nitrite and a mineral acid, such as hydrohalic acid. The diazonium group can then be replaced by halogen, cyano, hydroxy, lower alkoxy or hydrogen, utilizing known procedures, for example, by mixing a diazonium salt solution with, for example, a cuprous halide, cuprous cyanide, water, an alcohol or a reducing agent, such as hypophosphoric acid', respectively, at room temperature - 49 - 39036/2 ponding 2 , 3-dihydro-7-halo-lH-cyclopenta[b] enzofuran-l-carboxyl acid or l,3-dihydro-7-halo-2H-cyclopenta[b]benzofuran-2- carboxylic acid, respectively, or tho oorroopondlng 2^3 dihydro. , or the corresponding 2 , 3-dihydro-7-lower alkoxy- lH-cyoiopenta[b]benzofuran-l-carboxylic acid or l,3-dihydro-7- lower alkoxy-2H-cyclopenta[b]benzofuran-2-carboxylic acid, respectively^ " ' '■" ' - ] Example 29 A mixture of 1.06 g of 3-(4-cyanophenoxyimino)cyclopenta carboxylic acid and 5 ml of a saturated solution of hydrogen chloride in acetic acid is stirred for 21 hours at room tempera ture. The solid is removed by filtration,- washed with hexane- acetic acid (2:1) and then with hexane, and dried to give 1.05 g of a tan powder, m.p. 206-208° (dec). The product is shown by NMR spectra to be a mixture containing an approximately 1:1 ratio of 7-cyano-2,3-dihydro-lH-cyclopenta[b]benzofuran-l- oarboxylic acid and 7-cyano-l,3-dihydro-2H-oyclopenta[b]benzo- furan-2-oarboxylio acid.

The 3-(4-eyanophenoxyimino)cyclopentanecarboxylic acid used as starting material in. the above process can be obtained as follows: A mixture of 5.5 g. of potassium t-butoxide and 3.65 g of 3-oxyiminocyclopentanecarboxylic acid in 40 ml of dimethyl-sulfoxide is treated with 2.96 g of 4-fluorobenzonitrile, stirred at room temperature for 3 hours, diluted with 400 ml of saturated sodium chloride solution and acidified with 25 ml of acetic acid. The precipitate which forms is removed by filtration, washed successively with water and pentane, dried and crystallized from tetrahydrofuran-ether-pentane to give 2.5 g of 3-(4-cyanophenoxyimino)cyclopentanecarboxylic acid, tan crystals, m.p. 160.5-161° (dec).

Example 30 A solution of 59 g of 3-bromo-4—oxocyclohexanecarboxylic acid ethyl ester in 250 ml of ethanol is added at reflux temperature over a one-hour period to a stirred solution of 34 g of 4-chlorobenzenethiol and 15.2 g of potassium hydroxide in 750 ml of ethanol. The reaction mixture is heated for another hour, cooled and filtered. The filtrate is evaporated and the residue partitioned between ether and water. The ether layer is dried, evaporated, and the residue (75 g) is distilled to give 55 g of 3-(4~chlorophenylthio)-4-oxocyclohexanecarboxylic acid ethyl ester as a light yellow oil, b.p. 190°/0.04 mm. The product solidifyes on standing to give pale yellow crystals, m.p. 63-72°. The mixture of 25 g of this material and 375 g of polyphosphoric acid is stirred at 80-85° for 3 hours, decomposed with ice and water and extracted with ether. The ether solution is washed successively with saturated sodium bicarbonate solution and water, dried with sodium sulfate and ually crystallizes, m.p. 60-66°. This material may he used in a succeeding step without further purification. After recrystallizatio from hexane as white crystals, 8-chloro-l, 2,3, 4-tetrahydrodi-benzothiophene-3-carboxylic acid ethyl ester has a melting point of 75-77°. f] [I Example 31 A solution of 22.8 g of 8-chloro-l, 2,3,4-tetrahydrodi-benzothiophene-3-carboxylic acid ethyl ester, 320 ml of IN sodium hydroxide and 640 ml of ethanol are stirred at reflux temperature for 5 hours and then concentrated to a small volume. The residue is mixed with 0.5 liter of water and charcoal, and thereafter filtered. The filtrate is cooled while adding 50 ml of concentrated hydrochloric acid. The resultant precipitate is removed by filtration and dried to give 19.1 g of a solid, m.p. 222-229°. Crystallization from acetone-ether gives 10.75 g of 8-chloro-l,2,3» 4-tetrahydrodibenzothiophene-3-carboxylic acid as yellow crystals, m.p. 228-231°.

The following Examples are illustrative of pharmaceutical compositions containing the tricyclic compounds of the invention: Example 32 Capsule Formulation Per Capsule 8-Cyano-l,2,3»4-tetrahydrodibenzo furan-3-carboxylic acid 50 mg Lactose 125 mg Corn starch 30 mg Talc Total Weight 210 mg Procedure ; 1. 50 Parts of 8-cyano-l, 2,3,4-tetrahydrodibenzofuran-3-carboxylic acid are 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 comminuting machine. 3. The blended powder is returned to the mixer, 5 parts talc are added and blended thoroughly. 4. The mixture is filled into hard shell gelatin capsules on a capsulating machine.

Example 33 Tablet Formulation Per Tablet 8-Cyano-l,2,3, 4-tetrahydrodibenzofuran- 3-carboxylic acid 25 mg Dicalcium phosphate dihydrate, unmilled 175 mg Corn starch 24 mg Magnesium stearate 1 mg Total Weight 225 mg Procedure ; 1. 25 Parts of 8-cyano-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid and 24 parts of corn starch are mixed together and milled. 2. This premix is then mixed with .175 parts of dicalcium phosphate and one-half of a part of the magnesium stearate and milled. The mixture is then slugged. 3. The slugs are passed through a mill at slow speed and the other one-half of a part magnesium stearate is added. 4. The mixture is mixed and compressed.

Example 34 Tablet Formulation Per Tablet 8-Cyano-l, 2 , 3 , 4-tetrahydrodibenzo- furan-3-carboxylic acid Lactose Corn starch Prehydrolyzed food grade corn starch Calcium stearate Total Weight Procedure ; 1. 100 Parts of 8-cyano-l, 2 , 3 , 4-tetrahydrodibenzofuran-3-carboxylic acid, 202 parts of lactose, 80 parts of corn starch and 20 parts prehydrolyzed food grade corn starch are blended in a suitable mixer. 2. The mixture is granulated to a heavy paste with water and the moist mass is screened. It is then dried overnight at 43°. 3. The dried granules are screened 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.

Example 55 Parenteral Formulation Per ml Each 1 ml ampul contains: 8-Cyano-l,2,5, 4-tetrahydrodibenzofuran-3- carboxylic acid 10.2 mg (2 percent excess) Methyl paraben 1.8 mg Propyl paraben 0.2 mg Sodium hydroxide q.s. ph 9.0 Water for injection q.s. ad 1.0 ml Procedure (for 10,000 ml): 1. In a clean glass or glass-lined vessel, 8,000 ml of water for injection are heated to 90°C. It is then cooled to 50-60°C, and 18 g of methyl paraben and 2 g of propyl paraben are added and dissolved with stirring. The solution is then allowed to cool to room temperature. 2. The 102.0 g of 8-cyano-l,2,5,4-tetrahydrodibenzofuran-5-carboxylic acid are added under an atmosphere of nitrogen and stirred until completely dispersed.

. The sodium hydroxide is added as a 10 percent solution until the pH is adjusted to 9.0 plus or minus 0.1 and the drug is completely dissolved. 4. Sufficient water for injection is then added to make a total volume of 10,000 ml.

. This solution is then filtered, filled into suitable size ampuls, gassed with nitrogen and sealed. It is autoclaved at 0,7 atm for 30 minutes.

Example 36 Suppository Formulation per 1.3 g Suppository 8-Cyano-l,2,3, -tetrahydrodibenzo furan-3-carboxylic acid 0.025 mg Wecobee M* 1.230 mg Carnauba wax 0.045 g *E.F. Drew Company 522 Fifth Avenue New York, New York Procedure ; 1. 123 parts of Wecobee M and 4.5 parts of camauba 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-cyano-l,2,3,4-tetrahydrodibenzofuran-3-carboxylic acid, which have been reduced to a fine powder with no lumps, are 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 g. 4. The suppositories are cooled and removed from molds, and individually wrapped in wax paper for packaging. (Foil may also be used). - 58 - 39036/2

Claims (4)

1. CLAIMS 1. Benzofuran and benzothiophene carboxylic acid derivatives of the general formula wherein R^ and R2 independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano, carbamoyl, carboxy, lower alkoxy carbonyl, nitro, amino, mono-lower alkylamino, di-lower alkylamino, lower alkanoyl, lower alkanoylamido, R^ represents hydrogen, lower alkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alkyl, n is 1 or 2 and X represents oxygen or sulfur, provided that at least one of. R^ and R2 is other than hydrogen, and salts thereof.

2. Compounds as claimed in Claim 1 and having the general formula wherein R'^ and '2 independently represent hydrogen or an electron withdrawing group selected from nitro, lower alkoxy- carbonyl, cyano or loweralkanoyl groups, at least one of R' and - 61 - 39036/2 carboxylic acid. - ' 18„ 7-chloro-l ,2,3, 4~ e rahydrodibenzothiophene-3-carboxylic acid. 19. A process for the preparation of benzofuran and benzothiophene carboxylic acid derivatives of the general formula Lin Claim 1 and of ■ salts thereof, wherein a compound of the general formula wherein R^, R^, X and n have the j same meaning as in, Claim 1, at least one carbon atom of the phenyl ring in ortho position to the carbon atom linked with the atom X being unsubst tu ed, . and R'^ represents lower alkyl, s cyclised, or, where there is desired a compound of the - 62 - 39036/2 formula I wherein X represents oxygen, or a salt thereof, a compound of the general formula wherein R^ and n have the foregoing meaning and and R'2 independently represent hydrogen or an electron withdrawing group selected from nitro, lower alkoxy carbonyl, ■ lovieralkahoy'l cyano or / Jroups, at least one of R'^ and '2 being other than hydrogen, is reacted with an acidic catalyst and, where an optically active isomer of a oompound of the general formula I above is desired, an obtained racemate of the general formula I is resolved into its optically active isomers and the desired isomer isolated, and, where a salt of a compound of the general formula I above is desired, an obtained acidic or basio oompound of the general formula I is reacted respectively with a base or an acid, and, where a carboxylic acid oompound of formula I is desired, an obtained carboxylic acid ester of formula I is saponified, and if desired, a salt of a compound of formula I wherein R^ is hydrogen, is converted to a compound of formula I wherein R^ is amino-lower alkyl, mono-lower alk lamino-lower alkyl or di-lower alk lamino- lower alkyl', and, if desired, a nitro group present in a oompound of formula I is converted to an amino group, and, if desired, an amino group is converted to a diazonium salt and - 63 - 39036/2 the obtained diazonium group is replaced by halogen, cyano, hgpd-eogcjr-, lower alkoxy or hydrogen. 20. A process according to claim 39 for the preparation of tricyclic compounds., of the general formula I in Claim 1, wherein R^, Rg, R^, X and n have the same meanings as in Claim 1 and when and/or R2 is carboxy and/or R^ is hydrogen, salts thereof with a base, and when R1 and/or R2 is amino, mono-lower alkylamino or di-lower alkylamino, and/or when R, is amino-lower alkyl, mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alkyl, addition salts thereof with an acid, characterised in that, where there is desired a compound of the general formula 1 wherein is lower alkyl or a salt thereof, a compound of the formula - 64 - 39036/2 wherein R^, R2, X and n have the foregoing meaning-,:) at least one carbon atom of the phenyl ring in ortho position to the carbon atom linked with the atom X being unsubstituted and R'^ represents . lower alkyl', is cyclised, or, where there is desired a compound of the general formula . wherein R'^ and R'2 independently represent hydrogen or an electron withdrawing group selected from nitro, lower alkoxy carbonyl, loweralkanoyl cyano or / /groups, at least one of ^ and R'2 being other than hydrogen, represents hydrogen, lower alkyl, amino-lower alkyl, mono- lower alk lamino-lower alkyl, or di-lower alkyl- amino-lower alkyl and n is 1.or 2, or a ealt thereof, a compound of the general formula ■' Ila - 65 - 39036/2 wherein R^, R"2, ^ and n have the foregoing, meaning, is reacted with an acidic catalyst and,, where an optically active isomer of a compound of the general formula I above is desired, an obtained racemate of the generaT formula. I is resolved into its optically active isomers and the desired isomer isolated, and, where a salt of a compound of the general formula I above is desired, an obtained acidic or basic compound of the general formula I is reacted respectively with a base or jan-acid and, where a carboxylic acid compound of formula I is desired, an obtained compound of formula I wherein is lower alkyl is saponified, and, if desired, a salt of a compound of formula I wherein is hydrogen, is converted to a compound of formula I wherein R, is araino-lower alkyl, mono-lower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl, and, if desired, a nitro group present in a compound of formula la is converted to an amino group, and, if desired, an amino group "is converted to a diazonium salt and the obtained diazonium group is replaced by halogen, cyano, tayd ojey-, lower alkoxy or hydrogen. 21. A process according to Claim 19 or 20, characterised in that a compound of formula II or Ila in which n is 1, is used as starting material. - 22. A process according to Claim 19 or 20, characterised in that a compound of formula II or Ila wherein n is 2, is used as starting material. in that a 3-(3-chlorophenoxy )-4-oxocyclohexanecarboxylio acid lower alkyl eater is used as starting material. ' 29. A process according to claim 26 ,< characterized in that a 3-(4-cyanophenoxyimino)cyclohexanecarboxylio acid is used aa . starting material . . j 30. A process according to Claim 24, characterized in 1 that a compound of formula II is used as starting material wherein one of the substituents R- and R2 is hydrogen and . the other is chlorine or cyano in position 3 or 4. 31. A process according to claim 30, characterized in that a 3-(3-chlorophenylthio)-4-oxocyolohexanecarbox lic aoid lower alkyl ester is used as starting material. 32.; A prooess according to claim 30, oharaoterized in that a 3-(4-ohlorophenylthio)-4-oxooyclohexaneoarboxylio aoid lower alkyl ester is used as starting material. ■ 3

3. Process for the preparation of benzofuran and benzothiophene carboxylic acid derivatives of the general formula I in C^aim 1, optically active isomers and salts thereof aadhereinbefore particularly described, especially with referenoe to the foregoing Examples. - 68 - 39036/2 3

4. Compounds of formula I In Claim 1, optically active isomers and salts thereof when prepared by a process according to any of Claims 19 to 33. 35· Compositions havin anti-inflammatory and antirheumatic properties, containing a benzofuran or benzothlo-phene carboxylic acid derivative of the general formula I in Claim 1 or a pharmaceutically acceptable salt thereof and a carrier. PC/rb