CS208143B2 - Method of making the new substituted benzocycloalkenylcarboxyl acids and event. the esters and amides thereof - Google Patents

Description

(54) A process for the preparation of novel substituted benzocycloalkenyl carboxylic acids and, optionally, their esters and amides

The present 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, (CH

2'm (I)

- (CH

2'n wherein one of both 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 alkanoyloxy with 2 to 4 carbon atoms,

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

R1 is carboxy, C1-C7alkoxycarbonyl, carbamoyl, N-mono- or N, M-dialkylcarbaraoyl of 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.

Acyl radical R1 or R 8 is benzoyl which is optionally substituted more than one or more times by C 1 -C 4 alkyl, for example methyl, C 1 -C 4 alkoxy, for example methoxy and / or halogen, for example chlorine, bromine or fluorine or 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 alkanoyloxy is, for example, butyryloxy, propionyloxy and acyloxy.

C 1 -C 4 alkoxy is, for example, η-butoxy-, sec-butoxy-, isobutoxy- or tertiary. butoxy-, isopropoxy-, ethoxy- or methoxy group.

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 butyloxy, isopropyloxy, propyloxy, ethoxy or methoxy groups as alkoxy.

N-Monoalkylcarbamoyl β 1 to 4 carbon atoms in the alkyl moiety contains, as amino group, preferably lower alkoxy or lower mono- or dialkylamino substituted alkylamino groups having 1 to 4, in particular 1 or 2 carbon atoms in the alkyl moiety and 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. The secondary amino groups are dimethylaminoethylamino, diethylaminoethylamino, butylamino, isopropylamino, propylamino, ethylamino or methylamino.

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

New compounds have valuable pharmacological properties, in particular antipyretic and anti-inflammatory effects. For example, in the yeast-induced fever test at 3 to 30 mg / kg in rats, they exhibit an apparent antipyretic effect, as well as in the oral kaolin edema test 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:

5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester, 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester, 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, 1- (o) methyl ester -chlorbenzoyl) -6-hydroxy-indan-1-carboxylic acid ethyl ester 5-benzoyl-6-hydroxy-1-carboxylate, which each have an effective dose ED ₃₀ _ ₄₀ 3 mg / kg or less. These compounds are also of low toxicity.

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

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

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

compounds of formula I wherein one of R 1 and R ₂ is benzoyl optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen, and the other is hydrogen, hydroxy, alkanoyloxy (C 2 -C 4) or (C 1 -C 4) alkoxy, R 8 is hydrogen, R 4 is carboxy, (C 1 -C 7) alkoxycarbonyl, or carbamoyl which contains as the amino group a C 1 -C 4 mono- or dialkylamino group 4 carbon atoms in the alkyl moiety, n is 0 or 1 and m is 1 or 2.

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

compounds of formula I wherein one of R 1 and R ₂ is optionally methyl, methoxy and / or chloro substituted benzoyl and the other is hydrogen or hydroxy, R 8 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;

a compound of formula (I) wherein one of R ₍ and Rg) is optionally C1-C4alkyl or C1-C4alkoxy, such as methoxy or methyl, or halogen, such as chloro, monosubstituted benzoyl, and the other is hydroxy, R 8 is hydrogen, R 4 is carboxy or C 1 -C 4 alkoxycarbonyl, n is 0 and m is 1.

In particular, the invention relates to a process for the preparation of the compounds of formula I mentioned in the examples.

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

The novel compounds are prepared when a compound of formula II,

where

Z represents a group of formula - (0Η _{2) η -Ζ} * in which

Z * represents a functionally modified carboxyl group of the formula -OZ] Z ₂ Zg different from the group R 4 denoting an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety, a carbamoyl group or an N-mono- or Ν, Ν-dialkylcarbamoyl group having 1 to 4 4 carbon atoms in the alkyl moiety,

Z ₍ , Z ₂ and Z -) represents halogen, such as chlorine or bromine, or together a nitrile group, or

Z 1 and Z ₂ together represent an oxo or imino group and Z ₁ represents an esterified hydroxy group, or if

Z, and Zg together represent an imino group,

AND"

Z 1 is an etherified hydroxy group, or is a group of the formula -CH = C = O and

R ", R _2, ®3» ®4 ^{'n <m maai} above meanings, Z is converted by hydrolysis, alcoholysis, and / or on amlnolýzou group of formula - _{(CH2) n} -R4.

The etherified hydroxy groups Z 1 are, for example, hydroxy groups etherified with lower alkanols, such as methanol or ethanol, or lower alkanediols, such as ethylene glycol or for ethylene glycol.

Esterified hydroxy groups Zj are, for example, hydroxy groups esterified with strong inorganic or organic acids such as hydrohalic acid, for example hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, phosphoric acid, or strong organic sulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzene , ethanesulfonic or etenesulfonic acids, or also carboxylic acids such as lower alkanecarboxylic acids, for example acetic acid.

Hydrolysis, alkohojysis or aminolysis can be carried out in a conventional manner as described in particular in the literature for analogous reactions, for example by reaction with water, an alcohol or an ammonia or an amine containing at least one hydrogen atom.

Hydrolysis can be converted, for example -CH = C = O to the carboxymethyl skupAu or functionally modified carboxyl group Z 'into a free carboxyl group or cyano group Z', wherein Z * is -CZjZjjZ ^ and Z ,, Z ₂ together represent Rev. a nitrile group, a carbamoyl group R 4, or an imino ether group Z * of the formula -CZjZgZ4, wherein Z ₂ together represent an imino group and Z ₁ represents a C 1 -C 4 alkoxy group to a C 1 -C 4 alkoxycarbonyl group. The hydrolysis may be carried out in a conventional manner, preferably in the presence of a catalyst, for example a strong base such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide or carbonate, or in the presence of a strong acid such as a mineral acid such as hydrochloric acid. sulfuric or phosphoric or carboxylic acids, for example acetic acid, and in the hydrolysis of the cyano group Z * to the free carboxy group, if desired, with the addition of nitrous acid.

The alcoholysis may be converted, for example of an acid anhydride group, wherein Z * is a group -CZiZ Rev. _2, in which Zi _Z2 and Zi represents a nitrile group or Z, and Z ₂ together represent an oxo group, and Zi represents an esterified hydroxy group, to the group R4 denoting alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy part or a ketene group of formula -CH = C = O to alkoxykarbonylmetylovou -CH ₂ -R 4, wherein the alkoxy group contains 1-4 carbon atoms.

The alcoholysis may be carried out in a conventional manner, for example in the presence of a base such as an alcoholate, an alkali metal, for example sodium or potassium alcoholate and / or in the presence of an inorganic base such as sodium or potassium hydroxide or carbonate or calcium carbonate, or an organic nitrogen base such as triethylamine or pyridine or, when starting from nitriles of the hydrohalide of nitrogenous bases, for example ammonium chloride or pyridinium bromide in the presence of an equimolar amount of water. preferably at elevated temperature.

Aminolysis can convert, for example, the acid anhydride moiety Z 'where Z * is -CZfZgZj in which Z and Zg together represent oxo to a carbamoyl group K4, which is optionally alkylated with C 1 -C 4 alkyl or ketene -CH = C = O to a carbamoylmethyl group -CH 2 -R 4, which is optionally alkylated with C 1 -C 4 alkyl.

The aminolysis may be carried out in a manner known per se, preferably in the presence of a basic condensation agent, such as an inorganic base, for example sodium or potassium hydroxide or carbonate or calcium carbonate, or a nitrogenous base such as excess ammonia or amine usable for aminolysis or tertiary organic nitrogenous bases , for example triethylamine or pyridine, operating at elevated temperature if necessary.

In the compounds obtained, substituents may be introduced, altered or cleaved to the extent defined by the final substance.

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

Thus, the carboxyl may be esterified by reaction with a C 1 -C 7 alkanol or a reactive derivative thereof, such as a C 1 -C 7 alkanecarboxylic acid ester of an alkane moiety or a C 1 -C 4 dialkylcarbamate, or a mineral ester or sulfonic acids, for example, hydrochloric, hydrobromic, sulfuric, benzenesulfonic, toluenesulfonic or methanesulfonic acid esters of C 1 -C 7 or C 2 -C 7 alkene, to the C 2 -C 8 alkoxycarbonyl group.

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 a Lewis acid, for example boron trifluoride etherate. %, in an inert solvent, especially in an excess of the alkanol 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 a C1-C7 alkanol 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 or tetrahydrofuran, a hydrocarbon, for example benzene or toluene, or a halogenated hydrocarbon, for example trichloroethane, tetrachloroethane, chloroform, carbon tetrachloride or methylene chloride, or an 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 in 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, in tetrachloroethane, chloroform, methylene chloride or carbon tetrachloride.

The carboxy 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 which is optionally N-mono- or N, N-dialkylated with C1-C4 alkyl.

The above-described conversion of the free carboxyl group 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 with a phosphorus or sulfur halide such as phosphorus trichloride or phosphorus pentachloride, phosphorus pentachloride or thionyl chloride. to an acid halide or by reaction with the abovementioned alcohols or amines to a reactive ester, i.e. an ester with electron-attracting structures such as an ester derived from phenol, thlophenol, p-nitrophenol or cyanomethyl alcohol, or a reactive amide such as an imidazole-derived amide or 3,5-dimethylpyrazole, and the reactive derivative obtained is then reacted in a customary manner, for example by the method described below for re-esterification, reamidation, optionally interconversion of a C 1 -C 7 alkoxycarbonyl group and a carbamoyl group optionally alkylated with a C 1 -C 7 alkyl group. 4 carbon atoms, reacted with an alkanoel having 1 to 7 carbon atoms, ammonia or N-mono- or Ν, dial-dialkylamino having 1 to 4 carbon atoms in the alkyl moiety.

The C 1 -C 7 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 the carboxy group or, for example, by 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 1 -C 7 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, for example boron trifluoride etherate, to another alkoxycarbonyl group having 1 to 7 carbon atoms in the alkoxy.

The carbamoyl group, which is optionally alkylated with C 1 -C 4 alkyl, may 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 strong acids, such as mineral acids, for example hydrochloric, sulfuric or phosphoric acids, to the carboxylic acid.

In the compounds obtained, the hydroxy, C 2 -C 4 alkanoyloxy or C 1 -C 4 alkoxy groups, in the meaning of R, may be further converted with one another or

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

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 ketene, a reactive ester of a C 2 -C 4 alkanoic acid, i.e. an ester having the structure electron-attracting, for example, phenyleater, (p-nitro) phenyl or cyanomethyl ester of C 2 -C 4 alkanecarboxylic acid in the alkane moiety or N-alkanoylimidazole or -3,5-dimethylpyrazole in each case of C 2 -C 4 alkanoyl moieties.

The etherification agents are, for example, reactive esterified C 1 -C 4 alkanols esterified with a mineral acid, for example hydroiodic, hydrochloric, hydrobromic or sulfuric acids, or organic sulfonic acids, for example p-toluenesulfonic, p-bromobenzenesulfonic, benzenesulfonic, methanesulfonic or ethanesulfonic acid fluorosulfone 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 dialkylsulfonates, for example dimethyl sulfate or diethylsulfonate or methyl fluorosulfonate, alkylsulfonates such as 1 to 4 alkylsulfonates. 4 carbon atoms, for example methylsulfonate, p-toluenesulfonate, p-bromobenzenesulfonate, methanesulfonate or ethanesulfonate, as well as diazomethane.

The reaction with the aforementioned 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 a basic condensation agent, such as an inorganic base such as an alkali metal or alkaline earth metal hydroxide or carbonate such as 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 anhydride or chloride used or for etherification e.g. example used halide or sulfate of an alkanoic acid having 1 to 4 carbon atoms and / or a basic condensing agent employed a tertiary nitrogen base, for example triethylamine or pyridine, 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 (IX) which contains a C 1 -C 4 alkoxy group represented by R 1 'or R 8'. By drastic reaction conditions, for example using aluminum chloride as a catalyst, they obtain, in addition to or instead of the fines of the general formula I in which R or Rg is C1 -C4 -alkoxy, the corresponding compounds in which R or Rg is hydroxy .

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 r188143 β

a detergent, a condensation agent and / or a catalyst composition, at a reduced, normal or elevated temperature, optionally in a closed vessel.

Depending on these processing 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 each other 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 into salts, for example, salts with organic amines or metal salts, in a customary manner, for example by reaction and the corresponding basic means. 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 the usual manner, for example by reaction with acidic agents. Likewise, the basic compounds are obtained in free form by reaction of their salts with acids. 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, particularly those suitable for the formation of therapeutically useful salts.

Examples of such acids are: hydrohalic, sulfuric, phosphoric, nitric, perchloric, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic acids , tartaric, lemon, ascorbic, maleic, hydroxymalein or pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic, embonous, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, sulfenesulfonic, ethylenesulfulfonic, sulfenesulfonic, , methionine, 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 free form and in the form of their salt, it is to be understood in the foregoing and the following that the free compounds according to the meaning and purpose also include the corresponding salts.

The invention also relates to embodiments of the process according to which the starting material is used in the form of a salt and / or a racemate or antipodes, or is formed separately under reaction conditions.

Thus, for example, in solvolysis of compounds of formula II wherein Z is -CH = C = O, the corresponding diazoketones may be used, wherein Z is -CO-CH-S and this is reacted with water, an alkanol of 1 to 4 carbon atoms, ammonia or lower N-mono- or Ν, Ν-dialkylamine or, if necessary, in the presence of a catalyst, for example silver or its compounds, for example silver oxide and / or at elevated temperature. In this case, the corresponding ketene is formed, wherein Z is -CH = C = O, which is then solvolyzed by the process according to the invention to a -CHgR4 group, carboxy, C1-C4alkoxy, carbamoyl or carbamoylmethyl group, which is optionally substituted with C 1 -C 4 alkyl.

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 position R 1 and R 8 (positional isomerism) or as mixtures thereof, depending on the number of asymmetric carbon atoms. for example, optical antipodes or as isomeric mixtures, such as racemates, diastereomeric mixtures or racemic mixtures.

The stereoisomeric mixtures obtained, such as diastereomeric mixtures or mixtures with positional isomerism and / or racemic mixtures, can be separated in known manner into pure isomers, such as positional isomers, or diastereomers or racemates, for example by chromatography and / or fractional crystallization, based on physicochemical differences of the components. 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 reacting the final compound with an optically active acid or base which forms racemic salts and separating the salts thus obtained, e.g. diastereomers in 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 is isolated from both antipodes.

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 to carry 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.

Thus, a nitrile, as well as an iminoether or iminoester of formula II, wherein Z is - (CH 2 J 2 -C 2 Z 2 Zj), in which Z 1 + Z 2 + Z 1 is nitrile or Z 2 represents an esterified or etherified hydroxyl group and Zj + Zg is imino, e.g. produced by ring closure of beta-cyano-beta-U-Rf-ε-Rg-phenyl-β-Rj-propionic acid or gamma-cyano-gamma- (3-Ri-γ-Rg-phenyl-D-gamma-Rj-butyric acid) or a functional carboxy derivative thereof, which may be prepared, for example, by reacting an alpha-Rj-3-R] -4-Rg-benzylidenemalonic acid ester with an alkali metal cyanide, decarboxylation and hydrolysis, or by the reaction of alpha-Rj-3-R, -4-Rg phenylacetonitrile with an acrylic ester and hydrolysis, as well as, if necessary, functional modification of the acid obtained, and reaction of the obtained nitriles with an acid to the iminoester and, if necessary, an alcohol to the iminoether.

In the foregoing explanation of the process for the preparation of the starting materials, R 1, R 8, R 8, Z, n, m, unless otherwise indicated, have the aforementioned particularly preferred meanings.

The pharmacologically useful compounds according to the invention can be used for the production of pharmaceutical preparations, for example for the treatment of fever, rheumatic diseases, non-infectious inflammatory states and / or moderate pain states which contain an effective amount of active substance 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; the 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, acid 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 dragee processes, and contain from about 0.1 to 79%, in particular from about 1 to% of active ingredient. The recommended daily dose for approximately 75 kg of a warm-blooded individual is up to 250 mg.

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

Example 1

To 5 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid nitrile in 50 µl of ethylene glycol was added 5 g of finely powdered sodium hydroxide and heated to 160 ° under an inert atmosphere for 18 hours with stirring. It is then allowed to cool to room temperature, poured onto 100 g of ice and water and extracted twice with 100 ml of ether each time. The aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid and extracted twice with 100 ml of chloroform each. The organic phases are washed neutral, dried over sodium sulphate and evaporated to dryness in vacuo. Fractionation crystallization from ethanol gave 5-benzoyl-6-hydroxyindane-1-carboxylic acid, m.p. 185-187 °.

For example, the starting material can be obtained as follows:

A solution of 30.9 g of 6-methoxyindan-1-carboxylic acid methyl ester in 60 g of methanol and 31 g of ammonia is heated in an autoclave at 90 DEG C. for 30 hours at a maximum pressure of 20 bar. The suspension thus obtained was evaporated to a third volume in vacuo, ether was added and filtered. The filtered 6-methoxyindane-1-carboxamide has a melting point of 168-169 °.

A solution of the above amide (5 g) in phosphorus oxychloride (50 ml) was stirred at 60 DEG C. for 1 hour with the exclusion of moisture. It is then evaporated to dryness and the residue is partitioned between methylene chloride and water. The organic phases are washed neutral, dried over sodium sulfate and evaporated in vacuo. After treatment of the remaining activated carbon residue, the colorless oil obtained is used directly for the next reaction. Its IR spectrum (in CH ₂ Cl ₂ : λ _max = 2250 cm -1 ⁾ (middle).

Starting from 5 g of 6-methoxyindan-1-carboxylic acid nitrile and 9.65 g of benzoyl chloride, it is obtained by reaction with 40 g of aluminum chloride in 200 ml of methylene chloride, hydrolysis with ice water and the usual treatment of 5-benzoyl-6- hydroxyindane-1-carboxylic acid, m.p. 86 DEG-87 DEG (from ether and petroleum ether).

Example 2

G 1 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid nitrile and add a solution of 10 ml of partially concentrated methanolic sulfuric acid and reflux for 5 hours with stirring under inert atmosphere. The mixture is then allowed to cool to room temperature, 30 ml of water are added and extracted twice with 20 ml of ether each time. The organic phases are washed neutral, dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on 30 g of silica gel with methylene chloride as eluent followed by crystallization from ether and petroleum ether gave 5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester, m.p. 89-91 °.

Example 3

To 5 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid nitrile was added 50 g of polyphosphoric acid and heated to 80-90 ° under nitrogen for 1 hour. The mixture was then cooled to 30 ° and 200 ml of water were added with stirring and vigorous trituration. The resulting precipitate was filtered off and chromatographed on 200 g of silica gel with acetone as eluent.

Fractionated crystallization is then carried out from a mixture of dimethylformamide and water to give 5-benzoyl-6-hydroxyindane-1-carboxylic acid amide, m.p. 205-207 °.

Example

A solution of 10 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ether in 100 ml of acetic anhydride is refluxed for 4 hours under anhydrous conditions. It is then evaporated to dryness in vacuo. The residue is added to 200 ml of toluene and evaporated in vacuo. Distillation of the residue under high vacuum gave a boiling fraction of 5-benzoyl-6-acetoxyindane-1-carboxylic acid methyl ester as a colorless oil at a boiling point of 195 to 200 ° / 8.0 Pa.

Example 5

To a solution of 3.0 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ether 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 (LC-MS, the CHjClg! Y ^QH: 3600 cm ^-1, Y is _{C = O:} 1725 cm ¹⁾ .

Example 6 o

A solution of 2.8 g of 1-hydroxymethyl-5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ether in 12 ml of 2 K sodium hydroxide solution 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 residue is partitioned between twice 50 ml of water and 50 ml of ether. The aqueous phase was combined, acidified with concentrated hydrochloric acid to pH 1 and extracted twice with 50 ml of ether each time. The organic extracts were washed until neutral, dried over sodium sulfate and evaporated to dryness in vacuo. Chromatography of the residue on 100 g of silica gel with ether as the eluent affords pure 1-hydroxymethyl-5-benzoyl-6-hydroxyindane-1-carboxylic acid as yellow crystals of m.p. 104-110 °.

Example 7

At a temperature of 15-20 ° C with the exclusion of moisture, 27 g of crude 5-benzyl-6-acetoxyindan-1-carboxylic acid chloride in 200 ml of anhydrous benzene are introduced into saturated ammonia until saturated. The reaction solution is then evaporated to dryness in vacuo and the residue is 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. Fractionated crystallization of the residue from hot dimethylformamide and water gave 5-benaoyl-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-acetoxyindene-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-acetoxylndane-1-carboxylic acid chloride is worked up directly in the residue.

Example 8

To a suspension of 440 mg of sodium hydride (58% in mineral oil) in 6 ml of absolute tetrahydrofuran is added under stirring under nitrogen atmosphere a solution of 2.36 g of methyl 5-benzoyl-6-hydroxyindane-1-carboxylic acid in 6 ml of absolute tetrahydrofuran over 30 minutes. , 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 benzene-ethyl acetate 10: 1 as eluant to give a colorless oil, methyl ester of 1-methyl-5-benzoyl-6-methoxy-indan-1-carboxylic acid (MS: l ¹ = 324): and the the compound can be further characterized after hydrolysis as an acid having a melting point of 135-37 °.

Example 9

In addition, the following compounds can be prepared in an analogous manner to those described in Examples 1 to 8:

5-benzoyl-6-hydroxyindane-1-carboxylic acid n-butyl ester, m.p. 43-44 °, 5-benzoyl-6-hydroxyindane-1-carboxylic acid ethyl ester, melting point 83-84 °, 5- (p-methyl) ester 74-76 °, 5- (p-toluyl) -6-hydroxyindane-1-carboxylic acid, melting point 186-188 °, 5- (p- chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 96-98 °, 5- (p-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 187-189 °, 5-thenoyl-6- methyl ester 111-113 °, 5-thenoyl-6-hydroxyindan-1-carboxylic acid, mp 183-184 °, 5- (o-chlorobenzoyl) -6-hydroxyindan-1-carboxylic acid methyl ester mp 78-80 °, 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 188-190 °, 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester, melting point, 07 to 109 °, 5-benzoyl-6-methoxyindane-1-carboxylic acid, m.p. 125-128 °, 6-benzoylindane-1-carboxylic acid methyl ester, boiling point, 65-170 ° / 6.7 Pa, 6-benzoylindane-1-carboxylic acid, boiling point 200 ° / 5.3 Pa, 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, 48 up to 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- 118-120 °, 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, m.p. 118-120 ° , 6-benzoyl-5-hydroxyindane-1-carboxylic acid methyl ester, melting point 90-92 °, 6-benzoyl-5-hydroxyindane-1-carboxylic acid, melting point 135-137 °, 5-furoyl-6- methyl ester hydroxyindane-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) 233 DEG-235 DEG, 5- (m-chlorobenzoyl) -6-hydroxyindan-1-carboxylic acid methyl ester, m.p. 75 DEG-77 DEG, 5- (m-chlorobenzoyl) - 6-hydroxyindan-1-carboxylic acid, m.p. 159-161 °, methyl 5- (o-fluorobenzoyl) -6-hydroxyindan-1-carboxylic acid, melting point 97-98 °, 5- (o-methylbenzoyl) methyl ester 6-hydroxyindane-1-carboxylic acid, melting point 60-61 °, 5- (o-methylbenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 169-170 °, 5-benzoylindane-1-carboxylic acid methyl ester, XCN -spektrum 1660 and 1730 cm ^- '(v of CH₂Cl₂) 5- benzoylindane-1-carboxylic acid, melting point 125-127 °,

5-Benzoyl-6-hydroxyindane-1-carboxylic acid N-methylamide, melting point, 83-185 °,

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-methoxyindan-1-carboxylic acid N-p-chlorophenyl m.p.

Claims (12)

SUBJECT OF THE INVENTION A process for the preparation of novel substituted benzocycloalkenyl carboxylic acids and, optionally, its esters and amides of the general formula I, (I) (CH ₂ ) _n —R ₄ (CH ₂ ) < 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) alkanoyloxy, R1 is hydrogen, C1-C4alkyl or C1-C4hydroxyalkyl, R4 is carboxy, C1-C7alkoxycarbonyl, carbamoyl, N-mono- or Ν, Ν-dialkylcarbomoyl of 1 to 4 carbon atoms in the alkyl moiety, m is 1 or 2 and n is 0 or 1, or an acid salt of formula (1), characterized in that in a compound of formula (XI) wherein Z represents a group of formula - (CH ₂ ) _n -Z 'in which Z 'represents a functionally modified carboxyl group of the formula -CZ 2 Z ₂ Zj, different from an alkoxycarbonyl of 1 to 7 carbon atoms in the alkoxy moiety or a carbamoyl R 4, which is optionally alkylated with a group of 1 to 4 carbon atoms in which Z 1, Z ₂ and Z ₁ represent halogen or together a nitrile group, or Z, and Z ₂ together are oxo or lmino and Z 1 represents an esterified hydroxy group, or when Z 1 and Z 2 together represent an imino group, Z 1 represents an etherified hydroxy group, or Z is -CH = C = O and R 1, R ₂ , R ₃ , R 4, _n and _m are as defined above, converting Z by hydrolysis, alcoholysis and / or aminolysis to a group of the formula - (CH ₂ ) _n -R 4 and, if desired, R, or R _2, denoting an alkoxy group having 1 to 4 carbon atoms or alkanoyloxy group and 2-4 carbon atoms, is converted to a hydroxy group, a hydroxy group R or R ₂ is etherified to an alkoxy group having 1 to 4 carbon atoms or esterified to an alkanoyloxy group having 2-4 carbon 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, or another an alkoxycarbonyl group, or wherein R 4 represents a carboxyl group, this is converted to an alkoxycarbonyl group having 1 to 7 carbon atoms in the alkoxy moiety or to a carbamoyl optionally substituted (C 1 -C 4) -alkyl, or wherein R 4 represents a carbanoyl group optionally substituted by C 1 -C 4 -alkyl, which group is converted to a carboxyl group and / or the isomeric mixture optionally separated into isomers and / or the racemates obtained resolved into optical antipodes and / or the obtained salts are converted to the free acids or the obtained free acids are converted to the salts. 2. A method according to claim 1, characterized by hydrolyzing the compound of formula II includes groups Z 'cyano group or Z', wherein Z 'is a group of the formula -CZ, Z ₂ Z 3 and Z |, Z ₂ and Z 3 together represent a nitrile group , to a carbamoyl group R 4, or an iminoalkylate group Z 'and 1 to 4 carbon atoms in the alkyl moiety -CZ, Z ₂ Z 3, where Z 1 and Z ₂ together represent an imino group and Z 3 represents an alkoxy group having 1 to 7 carbon atoms C 1 -C 7 alkoxy. 3. The method according to claim 1, characterized in that in a compound of formula II wherein Z 'represents a group of the formula -CZ, Z ^ Z _2, wherein Z, and Z ₂ together represent an oxo group and Z 3 represents esterified hydroxy, Z' alcoholys to the alkoxycarbonyl group R4 having 1 to 7 carbon atoms in the alkoxy moiety. 4. A method according to claim 1, characterized in that in a compound of formula II wherein Z 'represents a group of formula ₂ -CZiZ ZG wherein Z, and Z ₂ together represent an oxo group, and Zs represents esterified hydroxy group, Z' into carbamoyl aminolyzuje R 4 is optionally substituted with C 1 -C 4 alkyl. 5. A process according to any one of Claims 1 to 4, wherein in the compound of formula I wherein R8 is hydrogen, it is replaced by a C1-C4 alkyl or C1-C4 hydroxyalkyl by reaction with an alkyl halide with C 1 -C 4 or C 1 -C 4 alkanal in the presence of a base. 6. A process according to any one of items 1 to 5 for the preparation of compounds of formula I according to item 1, wherein one of the two radicals R @ 1 and R @ ₂ represents an R group representing a benzoyl radical optionally substituted by C1-4 alkyl, alkoxy. C 1 -C 4 and / or halogen, or unsubstituted thenoyl, and the other is a hydroxy group which is optionally esterified with C 2 -C 4 alkanecarboxylic acid in the alkane moiety or etherified with C 1 -C 4 alkanol, R 8 is hydrogen or C 1-4 alkyl, R 4 is a carbamoyl radical optionally esterified with C 1-4 alkanol, or optionally having N-mono- or má, Ν-dialkylated C 1-4 alkylamino as an amino group 0 or 1 and m is 1 or 2, and an acid salt of the formula I, characterized in that a compound of the formula I is used as the starting material. e II, wherein one of R 1 'and R ₂ ' is R and the other is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy, R, R 8, m and n are as defined above, Z and R 4 are as defined in 1 and Z 1 is as defined in any one of 1 to 4. 7. Method according to one of claims 1 to 4 for preparing compounds of formula I according to claim 1, wherein one of the radicals R, and R ₂ represents a group R denoting a benzoyl radical which is optionally substituted by methyl, methoxy, chlorine and / or trifluoromethyl, or the thenoyl radical and the other is acetoxy, methoxy, ethoxy or hydroxy, R 8 is hydrogen, R 4 is carboxy or C 1 -C 4 alkoxycarbonyl, n is 0 and m is 1, and the acid salts of formula I, characterized by starting from a compound of formula (II) wherein one of R 1 and R ₂ is R and the other is hydroxy, C 2 -C 4 alkanoyloxy or C 1 -C 4 alkoxy and R, R 8, m, n are as defined above, Z and R 4 are as defined in item 1, and Z 'is as defined in any one of items 1 to 5, and in the obtained compound wherein one of the radicals R @ 1 and R @ ₂ denotes a C1 -C4 alkoxy group other than a methoxy or ethoxy group or a C2 -C4 alkanoyloxy group other than acetoxy group, this group is converted to a hydroxy group and / or in the obtained compound of formula (I) wherein R 4 is other than carboxy or C 1 -C 4 alkoxycarbonyl, R 1 is converted to this group. 8. Method according to one of claims 1 to 4 for the production of substituted derivatives benzocykloalkenylalkankarboxylových acids of formula I wherein one of the radicals R, and R ₂ represents a group R denoting a benzoyl radical which is optionally substituted once by alkyl having 1 to 4 carbon atoms or alkoxy 1-4 denotes hydroxy or halogen, and the other denotes hydroxy, R3 denotes hydrogen, R4 denotes carboxy or C1-4 alkoxycarbonyl in the alkoxy moiety, n denotes 0 and m denotes 1, or an acid salt of the general formula 1, characterized by: A compound of formula (II) wherein one of the radicals R @ 1 and R @ ₂ is a group of the formula R and the other one is hydroxy, alkoxy of 3 to 4 carbon atoms or C2 -C4 alkanoyloxy and R, R8, m, n are as defined above, Z and R 4 are as defined in item 1, and Z 'is as defined in any one of items 1 to 4, and obtained compound of formula I wherein one of the radicals R, and R ₂ is alkoxy of 1 to 4 carbon atoms, or alkanoyloxy of from 8 2 to 4 carbon atoms, this group is converted to a hydroxy and / or in the resulting compound of formula I wherein R4 represents a group other than a carboxyl or alkoxycarbonyl group being of 1 to 4 carbon atoms, R ₄ is converted to this group. 9. A process according to any one of items 1 to 4 for the preparation of compounds of general formula 1 according to item 1, wherein one of the radicals R 1 and R 8 is benzoyl and the other is hydroxy, R 1 is hydrogen, R 4 is carboxy or alkoxycarbonyl of 1 to 4. the carbon atoms in the alkoxy moiety, n is 0 and m is 1, and the acid salts of formula I, wherein the compounds of formula II are used as starting materials, wherein one of R 1 and R p is benzoyl and the other hydroxy; C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxyacin, R 1, m, n are as defined above, Z and R 4 are as defined in 1 and Z 1 is as defined in any of 1 to 4, and in a compound of formula (I) wherein one of the radicals R 1 and R 8 represents an alkoxy group having 1 to 4 carbon atoms or an alkanoyloxy group having 2 to 4 carbon atoms, this group is converted to hydroxy and / or in the obtained compound of formula I wherein R 4 is other than carboxy or C 1 -C 4 alkoxycarbonyl, R 4 is converted to this group. Process according to one of Claims 1 to 5 for the preparation of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester or 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester and their salts, characterized in that the compounds of formula (II) wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy, R 8 is benzoyl, R 1 is hydrogen, m is 1, n is 0, Z and R4 are as defined in 1 and Z ' is as defined in any one of 1 to 5 and converted to hydroxy in the compound of formula R1, C1-C4 alkoxy or C2-C4 alkanoyloxy. and / or ee R 4, which is different from C 1 -C 4 alkoxycarbonyl or carboxy, is converted to C 1 -C 4 carboxy or alkoxycarbonyl and optionally the methyl ester obtained is converted to the free acid . Process according to one of Claims 1 to 4 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 characterized in that the starting materials used are those compounds of formula (II) wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 3 -C 4 alkanoyloxy, R 8 is o-chlorobenzoyl, R 3 is hydrogen, m 1, n is 0, Z and R 4 are as defined in 1 and Z 1 is as defined in any one of 1 to 4 and in the compound of formula (R) obtained, a (C 1 -C 4) alkoxy or 2-alkanoyloxy group; is converted to a hydroxy group, and R4, which is different from a carboxy or alkoxycarbonyl group and from 1 to 4 carbon atoms in the alkoxy moiety, is converted into a carboxy or alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy moiety, and optionally If it is not obtained the methyl ester is converted to the free acid. Process according to one of Claims 1 to 4, for the preparation of 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester or 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester or salts thereof, characterized in that starting materials used are compounds of formula II wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy, R 8 is benzoyl, R 6 is hydrogen, m is 1, n is 0, Z and R 4 are as defined in 1 and Z 1 is as defined in any one of 1 to 4, and in the compound of formula I, wherein R; is hydroxy, (C 2 -C 4) alkanoyloxy or (C 1 -C 4) alkoxy, the hydroxy group is converted to methoxy or the C 2 -C 4 alkanoyloxy or C 2 -C 4 alkoxy group is first converted to a hydroxy group and then to the methoxy and R ₄ group, which is different from the carboxy or C 1 -C 4 alkoxycarbonyl group, is converted to the carboxy or C 1 -C 4 alkoxycarbonyl group and, optionally, the methyl ester obtained is converted to the free ester acid.