CS208142B2 - Method of making the new substituted benzocycloalkenylcarboxyl acids and event. the esters and amides thereof - Google Patents

Description

The invention relates to a process for the preparation of novel substituted benzocycloalkenyl carboxylic acids and, optionally, their esters and amides of the general formula I,

where one of the two residues

R 1 and R 8 are furoyl or thenoyl or benzoyl optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen, and the other is hydrogen, hydroxy, C 1 -C 4 alkoxy or (C 2 -C 4) alkanoyl,

R 8 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 hydroxyalkyl,

R 4 is carboxy, C 1 -C 7 alkoxycarbonyl, carbamoyl, N-mono- or Ν, Ν-dialkylcarbamoyl, each having 1 to 4 carbon atoms in the alkyl moiety, m is 1 or 2 and n is 0 or 1 , in free form or in the form of their salts.

The acyl radical R @ 1 or R @ ₂ is benzoyl which is optionally substituted several times or in particular once with C1 -C4 alkyl, for example methyl, C1 -C4 alkoxy, for example methoxy and / or halogen, for example chlorine, bromine or fluorine. or an unsubstituted thenoyl residue.

For example, C 1 -C 4 alkyl has a straight or branched chain, as well as being bonded at any position. An example of straight or branched chain C 1 -C 4 alkyl bonded in any position is n-butyl, sec-butyl, isobutyl or tert-butyl, isopropyl, propyl, ethyl or methyl.

C 2 -C 4 alkanoyl is, for example, butyryloxy, propionyloxy and acetoxy.

C 1 -C 4 alkoxy is, for example, n-butoxy-, sec-butoxy-, isobutoxy- or tert-butoxy-, isopropoxy-, propoxy-, ethoxy- or methoxy.

C 1 -C 4 hydroxyalkyl is, for example, C 1 -C 4 monohydroxyalkyl, with the hydroxyl group preferably being in the alpha position. In particular, hydroxymethyl is exemplified.

Alkoxycarbonyl having 1 to 7 carbon atoms in the alkoxy moiety contains, for example, one of the isomeric butoxy, isopropoxy, propoxy, ethoxy or methoxy groups as alkoxy.

N-Monoalkylcarbamoyl having 1 to 4 carbon atoms in the alkyl moiety contains, as amino group, preferably a lower alkoxy or lower mono- or dialkylamino substituted alkylamino group having 1 to 4, in particular 1 or 2, carbon atoms in the alkyl moiety and having 2 to 4, especially 2 carbon atoms in the alkylene moiety. The unsubstituted lower alkylamino group may have a straight or branched chain and contain, for example, 1 to 7, in particular 1 to 4, carbon atoms. Secondary amino groups are dimethylaminoethylamino, diethylaminoethylamino, butylamino, isopropylamino, propylamino, ethylamino or methylamino.

Ν, Ν-Dialkylcarbamoyl, in each case having 1 to 4 carbon atoms in the alkyl moiety, contains on the amino group two identical or different alkyl radicals having 1 to 4 carbon atoms; in particular dimethylamino, diethylamino, ethylmethylamino or dipropylamino.

The novel compounds have valuable pharmacological properties, in particular antipyretic and anti-inflammatory activity. For example, in the yeast-induced fever test at 3 to 30 mg / kg orally in rats, they exhibit an apparent antipyretic effect, as in the kaolin edema test after oral administration at 3 to 100 mg / kg, an apparent anti-inflammatory effect.

The anti-inflammatory effect is particularly significant in the following compounds of the invention:

of methyl 5-benzoyl-6-hydroxyindane-1-carboxylic acid, 5-benzoyl-6-hydroxyindane-1-carboxylic acid, 5-o-chlorobenzoyl) -5-hydroxyindane-1-carboxylic acid, methyl ester of 1- (o (chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid and ethyl 5-benzoyl-6-hydroxyindane-1-carboxylic acid ester, each having an effective dose of 12) 30.40 3 mg / kg po or less. These compounds are also of low toxicity.

The compounds of the invention further have a remarkable serum lipid lowering effect, in particular 5- (p-toluoyl) -6-hydroxyindane-1-carboxylic acid methyl ester and 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, which in rats after oral administration each 10 mg / kg po reduce serum triglycerides by 21 or 27% and serum cholesterol by 24 or 36% ·

The compounds according to the invention can be used as medicaments, in particular as anti-inflammatory drugs, optionally anti-rheumatic agents, anti-pyretics and mild analgesics.

More particularly, the present invention relates to a process for the preparation of compounds of the formula I wherein one of the two radicals R 1 and R 8 represents a benzoyl group optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen and the other hydrogen, hydroxy, (C 2 -C 4) alkanoyloxy or (C 1 -C 4) alkoxy, R 3 is hydrogen, R 4 is carboxy, C 1 -C 7 alkoxycarbonyl, or a carbamoyl group containing a mono- or amine group C1-C4 dialkylamino, n = 0 or 1 and m = 1 or 2.

In particular, the invention relates to a method for producing:

compounds of formula 1 wherein one of R 1 and R 2 is optionally benzoyl-substituted methyl, methoxy and / or chloro and the other is hydrogen or hydroxy, R 3 is hydrogen, R 4 is carboxy, C 1 -C 4 alkoxycarbonyl such as methoxy- or ethoxycarbonyl, or carbamoyl, n is 0 or 1 and m is 1;

compounds of formula I wherein one of R 1 and R 8 is optionally C 1 -C 4 alkyl or C 1 -C 4 alkoxy, such as methoxy or methyl, or halogen, such as chloro, monosubstituted benzoyl, and the other is hydroxy, R 3 is hydrogen, R 4 is carboxy or C 1 -C 4 alkoxycarbonyl, n is 0 and m is 1.

The novel compounds can be prepared according to methods known per se.

The novel compounds are obtained by the process according to the invention by:

where one of the residues

R 1 'and R 2' are furylhydroxymethyl, thienylhydroxymethyl or alpha-hydroxybenzyl, which is optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen, and the other is hydrogen, hydroxy, C 1 -C 4 alkoxy C 4 -C 4 alkanoyloxy or C 2 -C 4 alkanoyloxy;

R 1, R ₄ , n, m are as defined above, oxidizing the above furoyl, thenoyl or benzoyl, which is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen.

The oxidation may be carried out in a conventional manner, for example by means of a conventional oxidizing agent, for example an inorganic oxidizing agent, such as a dimethylsulfoxide-chlorine complex in the presence of a tertiary amine such as triethylamine or sodium periodate, preferably in the presence of ruthenium oxide and water. copper or copper sulphate, barium oxide, manganese dioxide or, in particular, chromic acid or chromium trioxide, preferably in a solvent inert to the oxidizing agent used, for example in a lower carboxylic acid such as acetic acid or pyridine or quinoline or similar heterocyclic bases or it may be carried out with organic oxidizing agents, for example with N-chlorosuccinimide in the presence of a dialkylsulfide, such as dimethylsulfide, or halogenates, for example of tert-butyl chlorine or halogenated quinone, e.g. chloro-chlorine, or especially aldehydes, or especially ketones, e.g. cycloalkanones or quinones, such as acetone, cyclohexanone or benzoquinone, in the presence of suitable catalysts such as metal salts, especially aluminum salts and branched lower alkanols or phenols such as aluminum isopropylate, aluminum ether butylate or aluminum phenoleate. The oxidation is also preferably carried out in a solvent, in particular in an excess of the ketone used and / or the metal alcoholate used, derived from the corresponding alcohol. However, when oxidizing, care must be taken not to interfere with other oxidizable groups.

In the compounds obtained, substituents can be introduced, altered or cleaved within the scope defined herein.

Thus, for example, a carboxy group, a C 2 -C 8 alkoxycarbonyl group, a carbamoyl group and an N-mono- and N, N-dialkylcarbamoyl group having 1 to 4 carbon atoms in the alkyl portion may be converted from one another.

Thus, a carboxyl can be esterified by reaction with a C 1 -C 7 alkanol or a reactive derivative thereof, such as an C 1 -C 7 alkanecarboxylic acid ester or a C 1 -C 4 dialkyl carbamate, or a mineral or sulfonic acid ester , for example, with an ester of hydrochloric, hydrobromic, sulfuric, benzenesulfonic, toluenesulfonic or methanesulfonic, with an alkanol of 1 to 7 carbon atoms or an alkene of 2 to 7 carbon atoms, to an alkoxycarbonyl group of 2 to 8 carbon atoms in the alkoxy moiety.

The reaction with a C 1 -C 7 alkanol can be carried out in a customary manner, preferably in the presence of an acid catalyst such as a protic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, boric, benzenesulfonic and / or toluenesulfonic acid, or Lewis acids, for example boron trifluoride etherate, in an inert solvent, especially in an excess of the alkanols used and, if necessary, in the presence of a water-binding agent and / or by distillation, for example by azeotropic removal of the reaction water and / or at elevated temperature.

The reaction with a reactive derivative of C 1 -C 7 alkanols can be carried out in a conventional manner starting from a carboxylic acid or carbonic acid ester, for example in the presence of an acid catalyst such as the above, in an inert solvent such as an ether such as diethyl ether; in tetrahydrofuran, in a hydrocarbon such as benzene or toluene, or in a halogenated hydrocarbon such as trichloroethane, tetrachloroethane, chloroform, carbon tetrachloride or methylene chloride, or in excess of the alkanol derivative or corresponding alkanol used, if desired, for example by azeotropic distillation reaction water. When starting from an ester of a mineral acid or a sulphonic acid, the acid to be esterified is preferably used in the form of salts, for example sodium or potassium salts, and, if necessary, is used in the presence of a basic condensing agent as an inorganic base. , for example sodium, potassium or calcium carbonate, or a tertiary organic nitrogen base, for example triethylamine or pyridine, in an inert solvent such as one of the aforementioned tertiary nitrogen bases or a polar solvent, for example tris (dimethylamide) phosphoric acid and / increased temperature.

The reaction with a C 2 -C 7 alkene can be carried out, for example, in the presence of an acid catalyst such as a Lewis acid such as boron trifluoride, a sulfonic acid such as benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, or especially a basic catalyst such as a strong base such as hydroxide or an alkali metal or alkaline earth metal carbonate such as sodium or potassium hydroxide or carbonate, preferably in an inert solvent such as an ether such as diethyl ether or tetrahydrofuran, a hydrocarbon such as an alkane, benzene or toluene, or a halogenated hydrocarbon , for example in carbon tetrachloride, trichloroethane, chloroform, methylene chloride or carbon tetrachloride.

The carboxyl group can be further converted by reaction with ammonia or N-mono- or N, N-dialkylamine of 1 to 4 carbon atoms, in a conventional manner, for example by dehydrating the intermediate ammonium salt, for example by azeotropic distillation with benzene or toluene or dry heating to carbamoyl a group which is optionally N-mono- or N, N-dialkylated with a C1-C4 alkyl group.

The above-described conversion of the free carboxyl group R1 to its ester or amide can also be carried out by first converting the acid of the formula I into a reactive derivative in the usual manner, for example by using a phosphorus or sulfur halide such as phosphorus trichloride or phosphorus; thionyl chloride, to an acid halide or by reaction with the above alcohols or amines to a reactive ester, i.e. to an ester with electron-attracting structures such as an ester derived from phenol, thiophenol, p-nitrophenol or cyanomethyl alcohol, or to a reactive amide such as from imidazole or 3,5-dimethylpyrazole, and the reactive derivative obtained is then reacted in a customary manner, for example as described below, for the reesterification, reamidation or interconversion of a C 2 -C 8 alkoxycarbonyl group and a carbamoyl group optionally alkylated with a C 1 alkyl group. to 4 carbon atoms, reacted with a C 1 -C 7 alkanol, ammonia or an N-mono- or Ν, do-doalkylamine having 1 to 4 carbon atoms in the alkyl moiety.

The C 2 -C 8 alkoxycarbonyl group can be converted in a conventional manner, for example by hydrolysis in the presence of a catalyst such as a strong base such as an alkali metal or alkaline earth hydroxide or carbonate such as sodium or potassium hydroxide or carbonate or a strong acid such as a mineral acid. for example, hydrochloric, sulfuric or phosphoric acids, or carboxylic acids, for example acetic acid, to a carboxy group or, for example, reaction with ammonia or N-mono- or N, N-dialkylamine of 1 to 4 carbon atoms to the corresponding carboxy group in amide form.

Further, the C 2 -C 8 alkoxycarbonyl group may be re-esterified in the usual manner, for example by reaction with a metal salt such as the sodium or potassium salt of another C 1 -C 7 alkanol or with itself in the presence of a catalyst such as a strong base such as hydroxide or an alkali metal or alkaline earth metal carbonate such as sodium or potassium hydroxide or carbonate, or a strong acid such as a mineral acid such as hydrochloric, sulfuric or phosphoric acid, or a carboxylic acid such as acetic acid, benzenesulfonic or toluenesulfonic acid or Lewis acids such as of boron trifluoride etherate to another C 2 -C 8 alkoxycarbonyl group.

A carbamoyl group, which is optionally alkylated with C1-C4 alkyl,

208142 6 can be converted in a conventional manner, for example by hydrolysis in the presence of a catalyst, for example a strong base such as an alkali metal or alkaline earth metal hydroxide or carbonate such as sodium or potassium hydroxide or carbonate, or a strong acid such as a mineral acid such as hydrochloric, sulfuric acid or phosphorus to a carboxyl group.

In the compounds obtained, hydroxy, C2-C4alkanoyloxy or C1-C4alkoxy in the meaning of R may be further converted with one another, or

Thus, for example, a hydroxy group can be esterified by reacting a preferably C 2 -C 4 alkanecarboxylic acid alkane moiety to a C 2 -C 4 alkanoyloxy group, or etherified by a C 1 -C 4 alkoxy group with a C 1 -C 4 alkoxy group. carbon.

A functionally modified C 1-4 alkanecarboxylic acid in the alkane moiety is, for example, the anhydride, chloride or bromide of the alkanecarboxylic acid, or a C 2 -C 4 alkyl ketone, a reactive ester of a C 2 -C 4 alkanoic acid, i.e. an ester of the structure electron-withdrawing, for example phenyl, (p-nitro) phenyl or cyanomethyl ester of a (C 2 -C 4) alkanecarboxylic acid or an N-alkanoylimidazole or -3,5-dimethylpyrazole, in each case of a C 2 -C 4 alkanoyl moiety.

Eterification agents are, for example, reactive esterified C 1 -C 4 alkanols, esterified with a mineral acid such as hydroiodic, hydrochloric, hydrobromic or sulfuric acids, or organic sulfonic acids such as p-toluenesulfonic acid, p-bromobenzenesulfonic acid, benzenesulfonic, methanesulfonic or ethanesulfonic acid. or a fluorosulfonic acid as well as a diazolaalkane having 1 to 4 carbon atoms. Examples of C 1 -C 4 alkylating agents are, for example, alkyl chlorides, alkyl iodides, C 1 -C 4 alkyl bromides, for example methyl iodide, C 1 -C 4 dialkyl sulfonates, for example dimethyl sulfate or diethyl sulfate or methyl fluorosulfonate, alkyl sulfonates such as 1 to 4 alkyl sulfonates. 4 carbon atoms, for example methylsulfonate, p-toluenesulfonate, p-bromobenzenesulfonate, methanesulfonate or ethanesulfonate, as well as diazomethane.

The reaction with the above-mentioned C 2 -C 4 alkanoic acids or C 1 -C 4 alkanols can be carried out in a conventional manner by reaction with C 1 -C 4 diazoalkanes in an inert solvent such as an ether, for example diethyl ether, or by reacting reactively esterified C 1 -C 4 alkanols, for example in the presence of basic condensation agents, such as an inorganic base such as an alkali or alkaline earth metal hydroxide or carbonate, for example sodium, potassium or calcium hydroxide or carbonate, or a tertiary or quaternary nitrogen base , for example pyridine, alpha-picoline, quinoline, triethylamine or tetraethylammonium hydroxide or benzyltriethylammonium hydroxide and / or the solvent customary for this reaction, and also an excess of the C 2 -C 4 alkanoic acid anhydride or chloride or ether may be used, an example of a C 1 -C 4 alkanoic acid halide or sulphate used and / or a tertiary nitrogen base, for example triethylamine or pyridine, used as the basic condensing agent, preferably at elevated temperature. Methylation with methyl iodide in amyl alcohol in the presence of potassium carbonate at boiling point as well as acylation with alkanoic hydride at 50 to 150 ° C or with alkanoyl chloride in pyridine or pyridine and triethylamine at temperatures of -20 ± 100 ° C is particularly recommended.

Conversely, C 1 -C 4 alkoxy or, in particular, C 2 -C 4 alkanoyloxy groups can also be converted, for example, by hydrolysis to hydroxy. This conversion can be carried out in a conventional manner. However, the conversion of a (C 1 -C 4) alkoxy group to a hydroxy group can also be carried out with the above-described reaction of the starting materials of the general formula (II) containing a C 1 -C 4 alkoxy group. or by R2a. Drastic reaction conditions, for example using aluminum chloride as a catalyst, give, in addition to or instead of the final compounds of the formula I in which R1 or R8 is C1 -C4 -alkoxy, the corresponding compounds in which R1, or R ₂ is hydroxyakupina.

Said reactions may optionally be carried out simultaneously or sequentially and in any order.

Said reactions are carried out in the usual manner in the presence or absence of a diluent, a condensation agent and / or a catalyst composition, at a reduced, normal or elevated temperature, optionally in a closed vessel.

Depending on these production conditions and the starting materials, optionally, the final substances which can form salts are obtained in free form or in the form of their salts, which can be converted into one another in the usual manner or converted into other salts. In this way, acidic end-substances, such as carboxylic or hydroxamic acids, are obtained in free form or in the form of their base salts. The free acid compounds obtained can be converted in the customary manner, for example by reaction with the corresponding basic agents, by treatment with salts, for example salts with organic amines or metal salts. Suitable metal salts are, in particular, alkali metal salts and corrosive earth metal salts, such as sodium, potassium, magnesium or calcium salts. The free acids can be liberated from the salts in a conventional manner, for example by reaction with acidic agents. Likewise, the basic compounds are obtained in free form or in the form of their acid salts. The acid salts obtained can be converted into the free compounds in a manner known per se, for example with alkali or with an ion exchanger. From these, salts can be obtained by reaction with organic or inorganic acids, especially those suitable for the formation of therapeutically useful salts.

Of such acids as examples may be mentioned: hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic _l aromatic or heterocyclic carboxylic or sulfonic acids, as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric , lemon, ascorbic, maleic, hydroxymalein or pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic, embonous, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, methanesulfenesulfonic, sulfenesulfonic, sulfenesulfonic, sulfenesulfonic, sulfenesulfon, , tryptophan, lysine or arginine.

These and other salts can also be used to purify the novel compounds, for example, if the free compounds are converted to their salts, these salts are isolated and converted again to the free compounds. As a result of the close relationships between the novel compounds in the free form and in the form of their salts, it is to be understood in the foregoing and the following that the free compounds according to the meaning and purpose may also be understood as corresponding salts.

The invention also relates to embodiments of the process starting from a compound obtained as an intermediate at any stage of the process and carrying out the missing steps or using the starting material in the form of a salt and / or racemate or antipodes, or formed particularly under reaction conditions .

For example, in the above-described oxidation of compounds of formula II may also be based on the appropriate starting material wherein R _a is aryl or heteroaryl-moiety of the formula R-CH₂-derived from the acyl radical of formula R-CO- different from the radicals R * and Rg *. An intermadiary corresponding hydroxymethyl radical of the formula -CH (OH) -R is formed, which is further oxidized by the process according to the invention.

Depending on the choice of starting materials and process, the novel compounds may be in the form of one or more possible stereoisomers, for example with respect to the R position and Rg (positional isomerism), or as mixtures thereof and depending on the number of asymmetric carbon atoms isomers, for example optical antipodes, or as isomeric mixtures, such as racemates, diastereomeric or racemic mixtures.

The stereoisomeric mixtures obtained, such as diastereomeric mixtures or mixtures with 8-position isomerism and / or racemic mixtures, can be separated into known isomers, such as positional isomers, or diastereomers or racemates, for example by ehromatography and / or fractional crystallization, in a known manner.

The racemates obtained can be resolved by known methods into optical antipodes, for example, by recrystallization from an optically active solvent, by microorganisms or by reaction of the quartz with an optically active acid or base which forms racemic salts, and separation of the salts thus obtained, e.g. to diastereomers from which the antipodes can be released by treatment with a suitable agent. Particularly suitable optically active acids are, for example, the D- and L-forms of tartaric, di-o-toluyltartaric, malic, mandelic, camphorsulfonic or quinic acids. Preferably, the more effective of both antipodes is isolated.

Preferred optically active bases are, for example, brucine, strychnine, morphine, methylamine or alpha-phenylethylamine or their quaternary ammonium bases. Preferably, more effective or less toxic is isolated from both antipodes.

Suitably, starting materials are used for carrying out the reactions according to the invention, which lead to groups of fines initially mentioned in particular and in particular to specially described or emphasized fines.

The starting materials are known or, if new, can be prepared by methods known per se. For example, the starting materials of the formula II can be obtained if the oxo group in the compound of the formula III is reduced,

O where one of the remnants

R 1, R 3 is hydrogen and the second group R q and R q, R j, R 6, n, m are as defined above. The reduction of the oxo group can be carried out according to Wolf-Kishner by conversion to hydrazone or eemicarbazone. The reaction with an alkali metal alcoholate, for example sodium ethylate, is preferably carried out under pressure and / or at elevated temperature or according to Huang-Minlon by heating with hydrazine and alkali metal hydroxide in a high boiling solvent such as diethylene glycol or diethylene glycol monomethyl ester or hydrogen. a birth or hydrogen catalyzed by the presence of a hydrogenation catalyst such as palladium on carbon and, if desired at elevated pressure and / or elevated temperature. Instead of hydrogen r ',' or Rg, a formyl group is introduced, for example according to Vilsmeyer, and the aldehyde thus obtained is reacted with a metal compound, for example lithium, derived from a compound of formula R-H.

Compounds of formula III wherein n is 0, m is 1 and R 1 is hydrogen or alkyl,

II II O can be prepared by condensing S-R 1 -A-R 8 -benzaldehyde, or the corresponding alkylphenyl ketone with a lower alkyl malonic ester, to the benzylidene malonic ester obtained by Michael addition of hydrocyanic acid, the obtained alpha-cyano-alpha- R3-3-R, -4-Rg-benzylmalonic acid is saponified and decarboxylated to beta-carboxy-beta-R3-beta- (3-R'-4-Rg-benzyl) propionic acid, and the compound is ring-closed with acid sulfuric acid or polyphosphoric acid after conversion to aluminum chloride chloride.

*

A compound of formula III wherein n is 0, m is 2 and R 6 is hydrogen or alkyl can be obtained by the alpha-R 6 -alpha- (3-R, -e-R 8 -) alkyl ester or nitrile. the phenyl) acetic acid is reacted with a nitrile or an alkyl ester of acrylic acid, and the resulting nitrile or alkyl ester of gamma-carboxy-gamma- (3-R'-1-Rg-phenylbutyric acid) is saponified to the corresponding gamma-carboxy-gamma- (3- R 1 (4-R 2 -phenyl) butyric, which is cyclized as described above.

Compounds of formula III wherein n is 1, can also be obtained if starting from the corresponding 5-R 2 ^- 6 ~ R) -1-indanone, or 5-R2-7-R 'alpha-tetralone according Reformackého is reacted with the corresponding alpha-metal-, e.g. alpha-zinc-acetic acid alkyl ester, to indene- or 3,4-dihydronaphthaleneacetic acid ester, which is hydrogenated and, if necessary, saponified and / or otherwise functionally modified.

In the foregoing explanation of the process for the preparation of the starting materials, R, Rq, r ',', R2 ', R', R ', n', m, unless otherwise indicated, have the previously mentioned particularly preferred meanings.

The pharmacologically useful compounds of the invention may be used for the manufacture of pharmaceutical compositions, for example for the treatment of fever, rheumatic diseases, non-infectious inflammatory states and / or moderate pain states containing an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid. , pharmaceutically acceptable carriers suitable for enteral, for example, oral, parenteral or topical administration. Preferably, tablets or gelatin capsules are used which have the active ingredient together with diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine and lubricants such as diatomaceous earth, talc, stearic acid or its salts such as magnesium or calcium stearate and / or polyethylene glycol; tablets also contain a binder such as magnesium silicate, starches such as corn, wheat, rice or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, a tablet disrupter such as starches, agar, alginic acid or salts thereof, such as sodium alginate, enzymes, binders and / or effervescent mixtures or absorbents, colorants, flavors and sweeteners.

Injectable preparations are preferably isotonic aqueous solutions or suspensions, suppositories or ointments being primarily fatty emulsions or suspensions. The pharmacological preparations may be sterilized and / or contain adjuvants such as preservatives and stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. These pharmaceutical preparations, which, if desired, may contain other pharmaceutically valuable substances, may be prepared in a manner known per se, for example by means of conventional mixing, granulating or auctioning processes, and contain from about 0.1 to 75%, in particular from about 1 to 50% of active ingredient. The recommended daily dose for approximately 75 kg of a warm-blooded individual is 25 to 250 mg.

The invention is described in more detail in the following examples. Temperatures are given in degrees Celsius.

He did

The biphasic mixture of 5- (phenylhydroxyraethyl) indane-1-carboxylic acid methyl ester, dissolved in 50 ml of ether and 2.1 g of sodium dichromate, dissolved in 2.8 g of sulfuric acid and 17 ml of water, is stirred at room temperature for 2 hours. rooms. It is then partitioned between twice 50 ml of ether and three times with 50 ml of water. The organic phases are dried over sodium sulphate and evaporated in vacuo. The residue gives methyl 5-benzoylindane-1208142 ´ · '10

carboxylic acids, such as a colorless oil. IR ^(CH2CH2): 1660 cm ^- '(s), 1770 cm ^-' (s), which is chromatographically uniform.

The 5- (phenylhydroxymethyl) indane-1-carboxylic acid methyl ester used can be prepared as follows:

To a solution of 36 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester in 260 ml of absolute pyridine was added under anhydrous atmosphere 32.4 g of methanesulfonic acid chloride under stirring at room temperature. After stirring for four hours, the mixture was poured into ice water and acidified to pH 1 with concentrated hydrochloric acid and extracted with methylene chloride. The organic phase is washed neutral, dried over sodium sulfate and evaporated in vacuo. After treatment with activated carbon, 5-benzoyl-6-methylsulphonyloxyindane-1-carboxylic acid methyl ester, m.p. 85 DEG-86 DEG, crystallizes from ether and petroleum ether. A solution of 20 g of this ester in 300 ml of absolute methanol and 5.4 g of triethylamine is hydrogenated with 8 g of 5% palladium on carbon at 40 ° under normal pressure until up to 2.4 L of hydrogen is taken up. Then the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue was partitioned between methylene chloride (2 x 200 ml) and 1N hydrochloric acid (2 x 200 ml). The organic phase was washed until neutral, dried with sodium sulfate and brine. Evaporate to dryness under vacuum. Chromatography of the residue on 400 g of silica gel with toluene / ethyl acetate 5:11 gives 5- (phenylhydroxymethyl) indane-1-carboxylic acid methyl ester as a colorless oil.

IR-spectrum (CH2CH2)! V ^_me3t: 3600 cm ^- '(p.) j 1730 cm ^-' (s).

Example 2

To a suspension of 8.05 g of N-chlorosuccinimide in 200 ml of absolute toluene is added under stirring under nitrogen atmosphere at 0 ° 6 ml of dimethylsulfide and then at -25 ° a solution of 12 g of crude 5-phenylhydroxymethyl-6-methoxyindane-1-carboxylic acid methyl ester. in 50 ml of absolute toluene. After addition was complete, it was allowed to stir for 90 minutes at -25 °. The reaction solution was then treated with 8.3 ml of triethylamine, allowed to stir for 5 minutes and partitioned between 2 x 100 ml 2 N hydrochloric acid and 2 x 100 ml ether. The organic phase is washed until neutral, dried over sodium sulphate and evaporated in vacuo. Chromatography of the residue on silica gel with methylene chloride as eluent affords 5-benzyl-6-methoxyindane-1-carboxylic acid methyl ester.

The starting material can be obtained as follows:

To a solution of 103 g of 6-methoxyindane-1-carboxylic acid methyl ester in 500 ml of absolute methylene chloride, 90 ml of titanium tetrachloride was added dropwise under stirring at 0 ° under inert atmosphere, followed by a solution of 60 g of dichloromethyl methyl ester in 100 ml of absolute methylene chloride. It is then left at 0 ° for 40 minutes and stirred at room temperature for a further 60 minutes. It is then poured onto 1 kg of ice and extracted five times with 500 ml of water each time. The organic phase is dried over sodium sulphate and evaporated in vacuo. Distillation of the residue afforded 5- or 7-formyl-6-methoxyindane-1-carboxylic acid methyl ester in the fraction boiling at 180 DEG. The mixture can be separated by fractional crystallization from ether, methylene chloride and pentane or by chromatography on silica gel with methylene chloride as eluent. 5-Formyl-6-methoxyindane-1-carboxylic acid methyl ester melts at 82-84 °.

A solution of 15.7 g of bromobenzene in 100 ml of absolute tetrahydrofuran was slowly added dropwise under stirring to 2.4 g of magnesium sawdust overlaid with absolute tetrahydrofuran. After addition was complete, the mixture was allowed to stir at 40 ° for 1 hour. After cooling to room temperature, the reaction solution was transferred to a dropper and slowly added dropwise with stirring under inert atmosphere at -10 ° to 23 g of 5-formyl-6-methoxyindane-1-carbonyl acid methyl ester in 150 ml of absolute tetrahydrofuran. After the addition was complete, it was left at 0 ° for 1 hour and further stirred at room temperature overnight. The reaction solution was then poured into 200 ml of saturated aqueous ammonium chloride solution and extracted twice with 500 ml of methylene chloride each time. The organic phases are washed neutral, dried over sodium sulfate, treated twice with activated carbon and evaporated in vacuo. The crude 5-phenylhydroxymethyl-6-methoxyindane-1-carboxylic acid methyl ester obtained in the residue (diastereomeric mixture) is directly processed further without further purification.

Example 3

To a solution of 13 g of 6-benzoylindane-1-carboxylic acid methyl ester in 500 ml of methanol is added 75 ml of 2 N sodium hydroxide and the mixture is refluxed for 3 hours. It is then evaporated to dryness in vacuo and the residue is partitioned between 100 ml of 2 N hydrochloric acid and three times with 100 ml of methylene chloride. The organic phase is washed neutral, dried over sodium sulfate, treated with charcoal, evaporated in vacuo and distilled under vacuum. 6-Benzoylindane-1-carboxylic acid having a boiling point of 200 ° / 5.3 Pa was obtained as a yellowish oil.

In an analogous manner, starting from 4.7 g of 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester and 20 ml of 1 N sodium hydroxide in 50 ml of methanol, 5-benzoyl-6-methoxyindane-1-carboxylic acid is obtained. mp 126-128 ° (from ether and petroleum ether).

Example 4

In a similar manner as described in Examples 1 to 3, the following additional compounds can be prepared:

5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester, m.p. 89-91 °, 5-benzoyl-6-hydroxyindane-1-carboxylic acid, melting point 185-187 °, 5-benzoyl-6 n-butyl ester -hydroxyindane-1-carboxylic acid, melting point 43-44 °, 5-benzoyl-6-hydroxyindane-1-carboxylic acid ethyl ester, melting point 83-84 °, 5- (p-toluyl) -6-hydroxyindan-1-methyl ester 74-76 °, 5- (p-toluyl) -6-hydroxylndane-1-carboxylic acid, melting point 186-188 °, 5- (p-chlorobenzoyl) -6-hydroxyindan-1- methyl ester 96-98 °; 5- (p-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 187-189 °, 5-benzoyl-6-acetoxyindane-1-carboxylic acid methyl ester, methyl ester 5-thenoyl-6-hydroxyindane-1-carboxylic acid, melting point 111-113 °, 5-thenoyl-6-hydroxyindane-1-carboxylic acid, melting point 183-184 °, 5- (o-chlorobenzoyl) -6-methyl ester -hydroxyindane-1-carboxylic acid, m.p. 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, m.p. 188-190 °, 1-hydroxymethyl-5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester,

IR i) _0H = 3 ^{em "1>} CO ⁼ '^ 25 cm ^-1 in metylenehloridu acid 1-hydroxymethyl-5-benzoyl-6-hydroxy-1-carboxylic acid, melting point 104-110 DEG acid amide, 5 -benzoyl-6-acetoxyindan-1-carboxylic acid, melting point 205-207 °, 5-benzoylindan-1-acetic acid methyl ester, 6-benzoylindan-1-acetic acid methyl ester, 5-benzoylindan-1-acetic acid, 6- benzoylindan-1-acetic acid, methyl 5-benzoyl-6-hydroxyindan-1-acetic acid, boiling point 180-185 ° / 5.3 Pa, 5-benzoyl-6-hydroxyindan-1-acetic acid, melting point 148-150 °, 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydronaphthylacetic acid ethyl ester, boiling point 190 ° / 5.3 Pa, 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydronaphthylacetic acid melting point 118-120 °?

1-methyl-5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester, mass spectrum M * = 324, 1-methyl-5-benzoyl-6-methoxyindane-1-carboxylic acid, m.p. 135-137 °, methyl ester 6-benzoyl-5-hydroxyindan-1-carboxylic acid, melting point 90-92 °, 6-benzoyl-5-hydroxyindan-1-carboxylic acid, melting point 135-137 °, 5-fluoro-6-hydroxyindane- methyl ester 1-carboxylic acid, melting point 100-102 °, 5- (2,6-dichlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, melting point 130-133 °, 5- (2,6-dichlorobenzoyl) -6 -hydroxyindane-1-carboxylic acid, m.p. 233 DEG-235 DEG.

5- (m-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, m.p. 75-77 °, 5- (m-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 159-161 °, methyl ester 5- (o-fluorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 97-98 °, 5- (o-methylbenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, melting point 60-61 °, acid 5- (o-methylbenzoyl) -6-hydroxy-indan-1-carboxylic acid, mp 169-170 °, methyl 5-benzoylindan-1-carboxylic acid ¹H spectrum: 1660 and 1730 cm ^- '(in CH ₂ C1 ₂ ), 5-benzoylindane-1-carboxylic acid, melting point 125-127 °,

5-Benzoyl-6-hydroxyindan-1-carboxylic acid N-methylamide, m.p. 183-185 °,

5-Benzoyl-6-hydroxyindane-1-carboxylic acid N-ethylamide, melting point 187-189 °, 6-benzoyl-5-methoxyindane-1-carboxylic acid methyl ester, melting point 94-96 ° and

5-Benzoyl-6-methoxyindane-1-carboxylic acid N- (p-chlorophenyl) amide, m.p. 229-231 °.

Example 5

To a solution of 3.0 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester in 20 ml of absolute dimethylsulfoxide was added 0.45 g of paraformaldehyde and 0.4 ml of benzyltrimethylammonium hydroxide (40% in methanol) and stirred to remove moisture. hours at 80 °. After allowing to cool to room temperature, the reaction mixture is treated with 100 g of ice, adjusted to pH 7 with acetic acid and extracted three times with 50 ml of ether each time. The organic phases are combined, washed neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Give methyl 1-hydroxymethyl-5-benzoyl-6-hydroxy-1-carboxylate as a yellow oil (IFI-spectrum in CH ₂ C1 _2: qjj: 3600 cm '"- ý _{c = 0:} 1 725 cm ^-1 ).

Example 6

A solution of 2.8 g of 1-hydroxymethyl-5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester in 12 ml of 2 N sodium hydroxide and 50 ml of methanol is heated under reflux for 5 hours. It is then evaporated in vacuo to a volume of about 10 ml and the evaporated residue is partitioned between twice

ml of water and 50 ml of ether. The aqueous phases were combined, acidified with concentrated hydrochloric acid to pH 1 and extracted twice with 50 ml of ether each time. The organic extracts were washed neutral, dried over sodium sulfate and evaporated to dryness in vacuo. Chromatography of the residue on 100 g of silica gel with ether as eluent affords pure 1-hydroxymethyl-5-benzoyl-6-hydroxyindane-1-carboxylic acid as yellow crystals of m.p. 104-110 °.

Example 7

At 15 DEG -20 DEG C. with exclusion of moisture, 27 g of crude 5-benzoyl-6-acetoxyindan-1-carboxylic acid chloride in 200 ml of anhydrous benzene are introduced into a solution of dried ammonia until saturated. The reaction solution is then evaporated to dryness in vacuo. and the residue was partitioned between 200 ml of water and three times with 200 ml of methylene chloride. The organic phases are washed neutral, dried over sodium sulphate and evaporated in vacuo. Fractional crystallization of the residue from hot dimethylformamide and water gives 5-henzoyl-6-hydroxyindane-1-carboxylic acid amide, m.p. 205-207 °.

The starting material can be produced as follows:

A solution of 20 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid in 200 ml of acetic anhydride was refluxed for 4 hours. It is then evaporated to dryness in vacuo, the residue is added to 50 ml of toluene and evaporated to dryness. This is repeated two more times. The crude 5-benzoyl-6-acetoxyindane-1-carboxylic acid obtained is further processed directly.

To a solution of the above crude product in 200 mL of anhydrous benzene was added 20 mL of oxalyl chloride at 0 ° and allowed to stand overnight at room temperature to exclude water. It is then evaporated to dryness in vacuo. To completely remove excess oxalyl chloride, add 50 ml of absolute benzene and evaporate to dryness in vacuo. This evaporation is repeated twice. The remaining crude 5-benzoyl-6-acetoxyindane-1-carboxylic acid chloride is further processed directly in the residue.

Example 8

A solution of 1.4 g of 5-benzoyl-6-hydroxyindan-1-acetic acid in 300 ml of absolute methanol is mixed with 0.5 ml of concentrated sulfuric acid and refluxed for 8 hours under the exclusion of water. It is then concentrated in vacuo to a volume of 5 ml and the reaction mixture is partitioned between 20 ml of water and twice 20 ml of ether. The organic phases were combined, washed to neutral, dried over sodium sulfate and evaporated in vacuo. Distillation of the residue in a high vacuum yielded 5-benzoyl-6-hydroxyindan-1-acetic acid methyl ester as a yellow oil in the fraction boiling at 180 ° / 5.3 Pa., Boiling at 180-185 ° / 5.3 Pa.

Example 9

To a suspension of 440 mg of sodium hydride (58% in mineral oil) in 6 ml of absolute tetrahydrofuran was added under stirring under nitrogen atmosphere for 30 minutes a solution of 2.36 g of methyl 5-benzoyl-6-hydroxyindane-1-carboxylic acid in 6 ml of absolute tetrahydrofuran. , with strong gas evolution. After the addition was complete, 440 mg of sodium hydride (58% in mineral oil) and 1 ml of methyl iodide were added once more and allowed to stir for 30 minutes at 40 °. The reaction mixture was then carefully poured onto 50 g of ice and extracted twice with 50 ml of chloroform each. The organic phases were combined, washed successively with cold saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on 30 g of silica gel with 10: 1 benzene and ethyl acetate as eluent gave 1-methyl-5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester as a colorless oil (mass spectrum: M @ ¹ = 324) ).

Claims (8)

SUBJECT OF THE INVENTION A process for the preparation of novel substituted benzocycloalkenyl carboxylic acids and optionally their esters or amides of the general formula I, wherein one of the two residues R f and R g are furoyl or thenoyl or benzoyl optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen and the other is hydrogen, hydroxy, C 1 -C 4 alkoxy or alkanoyloxy; 2 to 4 carbon atoms, rj is hydrogen, (C 1 -C 4) alkyl or (C 1 -C 4) hydroxyalkyl, R 4 is carboxy, C 1 -C 7 alkoxycarbonyl, carbamoyl, N-mono- or Ν, dial-dialkylcarbamoyl of C 1 -C 4 alkyl, m is 1 or 2 and n is 0 or 1, or an acid salt of formula (I), characterized in that it is present in a compound of formula (II) wherein one of the radicals is one or more radicals R * and Rg are furylhydroxymethyl, thienylhydroxymethyl or alpha-hydroxybenzyl which is optionally substituted with C1-C4 alkyl, C1-C4 alkoxy and / or halogen and the other is hydrogen, hydroxy, C1-C4 alkoxy or (C 2 -C 4) alkanoyloxy; and R 1, R 2, n and m are as defined above, oxidizing the above furoyl, thenoyl or benzoyl, which is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen, and if desired, in the compound of formula (I), Rf or Rg, C1-C4 alkoxy or C2-C4 alkanoyloxy, is converted to hydroxy, R1 or Rg is etherified to C1-C4 alkoxy or esterified to alkanoyloxy in a compound of formula I wherein R 4 is C 1 -C 7 alkoxycarbonyl is converted to a carboxyl or carbamoyl group optionally substituted with C 1 -C 4 alkyl carbon atoms, or to another alkoxycarbonyl group having 1 to 7 carbon atoms in the alkyl moiety, or in a compound of formula I, wherein R is 4 represents a carboxyl group, this is converted to a C 1 -C 7 alkoxycarbonyl group or to a carbamoyl optionally substituted by a C 1 -C 4 alkyl group, or in a compound of formula I wherein R 4 is a carbamoyl group optionally substituted by alkyl having from 1 to 4 carbon atoms, this group is converted to a carboxyl group and / or optionally the isomer mixture obtained is separated into isomers and / or the racemates obtained are resolved into optical antipodes and / or the resulting salts are converted into free acids or the free acids obtained converted into salts. 2. A process according to claim 1 for the preparation of compounds of formula I wherein R1 is C1-C4alkyl or C1-C4hydroxyalkyl, characterized in that in the compound of formula I wherein R8 is hydrogen, this atom is replaced by reaction with a C1-C4 alkyl halide or a C1-C4 alkanal, in the presence of a base, a C1-C4 alkyl or C1-C4 hydroxyalkyl. 3. The process of any one of items 1 and 2 for the preparation of compounds of formula I wherein one of R1 and R2 is C1-C4 alkyl, C1-C4 alkoxy and / or halogen substituted benzoyl or unsubstituted. thenoyl and the other is hydroxyl, which is optionally esterified with C 2 -C 4 alkanecarboxylic acid or etherified with C 1 -C 4 alkanol, R 3 is hydrogen or C 1 -C 4 alkyl, R 4 is carboxy, C 1 -C 4 alkoxycarbonyl carbon in the alkoxy radical, carbamoyl or N-mono- or Ν, Ν-dialkylcarbamoyl in each case having 1 to 4 carbon atoms in the alkyl moiety, n is 0 or 1 and m is 1 or 2, and an acid salt of the formula I, 2. The method according to claim 1, wherein one of the radicals R @ 1 and R @ 8 is furylhydroxymethyl, thienylhydroxymethyl or .alpha.-hydroxybenzyl, which is optionally substituted by alkyl having 1 and 2; 1-4 carbon atoms, C 1 -C 4 alkoxy and / or halogen, and the other is hydroxyl, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy and R 1, R 2, m, n are as defined above . 4. The process of item 1 for the preparation of compounds of formula I wherein one of the radicals R @ 1 and R @ 8 is optionally methylene, methoxy and / or chloro-substituted benzoyl or theonyl and the other is acetoxy, methoxy, ethoxy or hydroxyl; R4 represents a carboxyl or C1-C4alkoxycarbonyl group in the alkoxy moiety, n denotes 0 and m denotes 1, and an acid salt of the formula I, starting from a compound of the formula II, wherein one of the radicals R { and R 8 is methoxy, methyl and / or halogen substituted alpha-hydroxybenzyl or thienylhydroxymethyl and the other is C 1 -C 4 alkoxy, C 2 -C 4 alkanoyloxy, hydroxyl and R 1, R 4, m, n are as defined above, and in the compound obtained in which the alkoxy group having 1 to 4 carbon atoms is different from the methoxy or ethoxy group or the alkanoyloxy group having 2 to 4 carbon atoms different from acetoxyl, the corresponding group is converted to a hydroxy group. 5. The process of item 1 for producing substituted benzocycloalkenyl carboxylic acid derivatives of formula I wherein one of R1 and R8 is optionally C1-C4 alkyl or C1-C4 alkoxy or halogen-substituted benzoyl and the other is hydroxyl, R 1 is hydrogen, R 4 is carboxy or C 1 -C 4 alkoxycarbonyl, n is 0 and m is 1, and an acid salt of formula (I), starting from a compound of formula (II) wherein one of R @ 1 and R @ 8 are alpha-hydroxymethyl, optionally substituted by C1 -C4 alkyl, C1 -C4 alkoxy or halogen, and the other is hydroxyl, C1 -C4 alkoxy or C2 -C4 alkanoyloxy. , R1, n, m are as defined above and R4 is carboxyl, carbamoyl or N-mono or Ν, Ν-dialkylcarbonyl having from 1 to 4 carbon atoms in each and in the obtained compound of formula I, where one of the radicals R 1 and R 8 represents a C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy group, this group is converted to hydroxyl and / or in the obtained compound of the formula Even where R 4 is a radical other than a carboxyl group esterified with a C 1 -C 4 alkanol, R _{4 is} converted to this radical. 6. A process according to claim 1 for the preparation of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester or 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester or a salt thereof, characterized in that of formula IX wherein R 1 is hydroxyl, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy and R 8 is alpha-hydroxybenzoyl, R 1 is hydrogen, m is 1, n is 0 and R 4 is as defined in 1, and in the compound obtained, the C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy group is converted to hydroxyl and the 1-position different from the carboxy or methyl carboxyl group is converted to the carboxy group, or methylcarbonyl group and optionally converting the obtained methyleater into the free acid. 7. The process of item 1 for the preparation of 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester or 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester and salts thereof, The compound of formula (II) wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy and R g is 2-chloro-alpha-hydroxybenzyl, R 1 is hydrogen, m is 1, n is 0 and R < ₄ > is as defined in 1, and in the obtained compound the C1-C4 alkoxy or C2-C4 alkanoyloxy group is converted to hydroxyl and the 1-position is different from the carboxy group or a methoxycarbonyl group is converted to a carboxy or methoxycarbonyl group, and optionally the methyl ester obtained is converted to the free acid. 8. A process according to claim 1 for the preparation of 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester or 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester or a salt thereof, characterized in that of formula II wherein R 1 is methoxy, R 8 is alpha-hydroxybenzyl, R 1 is hydrogen, m is 1, n is 0 and R 6 is as defined in 1, and in the compound of formula I obtained, the group is in the 1-position, which is different from the carboxy or methoxycarbonyl group, is converted to the carboxy or methoxycarbonyl group, and optionally the resulting methyl ester is converted to the free acid.