CS208144B2 - Method of making the new substituted benzocycloalkebylcarboxyl acids and event. the esters or amides thereof - Google Patents

Description

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 X,

where one of the two residues

R 1 and R ₂ 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 carbon or C 2 -C 4 alkonoyloxy,

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

R 4 represents a carboxy group, an alkoxycarbonyl group having 1 to 7 carbon atoms in the alkyl portion, a carbamoyl, N-mono- or Ν, Ν-dialkylcarbamoyl group each having 1 to 4 carbon atoms in the alkyl portion.

and r 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 in particular benzoyl, which is optionally substituted several times or especially once with 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 an unsubstituted thenoyl residue.

For example, a C 1 -C 4 alkyl group has a straight or branched chain, as well as being bonded at any position. An example of a straight or branched chain alkyl group having 1 to 4 carbon atoms bonded in the same position at 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 acetoxy.

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

A C 1 -C 4 hydroxyalkyl is, for example, a C 1 -C 4 monohydroxyalkyl group, the hydroxyl group preferably being in the alpha position. Hydroxymethyl is particularly mentioned as an example.

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

The N-lionoalkylcarbamoyl group having 1 to 4 carbon atoms in the alkyl moiety contains, as amino group, preferably a lower alkoxy group or a lower mono- or dialkylamino group substituted with 1 to 4, in particular 1 or 2, carbon atoms in the alkyl moiety having 2 to 4, especially 2 atoms carbon 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.

The N, N-dialkylcarbamoyl group each 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 effects. For example, in the yeast-induced fever test at a dose of 3 to 30 mg / kg in rats, they exhibit an apparent antipyretic effect, as well as in the kaolin edema test after oral administration at a dose of 3 to 100 mg / kg, a marked anti-inflammatory effect.

The anti-inflammatory effect is particularly important for 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 (chlorobenzoyl) -6-hydroxyindan-1-carboxylic acid and 5-benzoyl-6-hydroxyindan-1-carboxylic acid ethyl ester, each having an effective dose of ED30-40 of 3 mg / kg P · 0 or less. These compounds are also comparatively low toxic.

The compounds of the invention further have a remarkable serum lipid lowering effect, especially 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 process for the preparation of compounds of the formula I in which one of the two radicals R @ 1 and R @ ₂ represents a benzoyl group optionally substituted by C1 -C4 alkyl, C1 -C4 alkoxy and / or halogen, and the other is hydrogen, hydroxy, C 2 -C 4 alkanoyloxy or C 1 -C 4 alkoxy, R 1 is hydrogen, R 4 is carboxy, C 1 -C 7 alkoxycarbonyl, or carbamoyl containing an amino group mono- or dialkylamino having 1 to 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 process for the preparation of compounds of formula I, wherein one of the radicals R 1 and R ₂ is optionally methyl, methoxy and / or chloro substituted benzoyl and the other is hydrogen or hydroxy, R 1 is hydrogen, R 4 is carboxy, alkoxycarbonyl; 1 to 4 carbon atoms, such as a methoxy or ethoxycarbonyl or carbamoyl group, n is 0 or 1 and m is 1;

compounds of formula I wherein one of R 1 and R ₂ is optionally C 1 -C 4 alkyl or C 1 -C 4 alkoxy such as methoxy or methyl, or halogen such as chloro, a monosubstituted benzoyl group, 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;

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 can be prepared by the formation of a compound of formula II,

where

R 1, R ₂ , R 3, m and n are as defined above

Z represents a formyl group optionally present in hydrated form, a hydroxymethyl group which is optionally esterified, for example with hydrochloric or hydrobromic acid, a carboxycarbonyl group which is optionally a functionally modified or styryl group,

The Z group is oxidized by reaction with a conventional oxidizing agent to form a carboxyl group.

The oxidation of the Z group to the free carboxyl group can be carried out in a conventional manner, for example by means of a conventional oxidizing agent, such as an inorganic oxidizing agent such as silver carbonate, preferably on a surfactant such as diatomaceous earth or sodium periodate, preferably ruthenium oxide and water, by means of copper salts, for example copper acetate or copper sulfate, bismuth oxide, manganese dioxide or, in particular, potassium permanganate, chromic acid or chromium oxide, preferably in a solvent inert to the oxidizing agent used, for example in a lower aliphatic carboxylic acid an acid such as acetic acid, or in pyridine, quinoline or a similar heterocyclic base, or by means of an organic oxidizing agent such as N-chlorosuccinimide, in the presence of dialkyl sulfides, such as dimethyl sulfide, or with a hypohalite, e.g. Carboxycarbonyl groups which are optionally functionally modified are preferably oxidized with hydrogen peroxide in an alkaline region, for example according to German Patent Specification 2,404,159, wherein the starting functionally modified group is first hydrolyzed to the free carboxycarbonyl group.

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 N, N-dialkylcarbamoyl group having 1 to 4 carbon atoms in the alkyl portion may be converted from one another.

Thus, the 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 carbonate, or a mineral or sulfonic acid ester , for example, an ester of hydrochloric, hydrobromic, hydrobromic, benzenesulfonic, toluenesulfonic or methanesulfonic, with an alkanol of 1 to 7 carbon atoms or an alkane of 2 to 7 carbon atoms, to an alkoxycarbonyl group of 2 to 8 carbon atoms in the alkoxy part.

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 or Lewis acids, for example boron trifluoride etherate. in an inert solvent, in particular in an excess of the alcohol used and, if necessary, in the presence of a water-binding and / or distillation agent; for example by azeotropic removal of the reaction water and / or at elevated temperature.

The reaction with a reactive derivative of a C1-C7 alcohol can be carried out in a conventional manner starting from a carboxylic or carbonic acid ester, for example in the presence of an acid catalyst such as the above, in an inert solvent such as ether such as diethyl ether or tetrahydrofuran. , a hydrocarbon such as benzene or toluene, or a halogenated hydrocarbon such as trichloroethane, tetrachloroethane, chloroform, carbon tetrachloride or methylene chloride, or an excess of the alkanol derivative or the 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, in the presence of a basic condensing agent such as inorganic a base such as sodium, potassium or calcium carbonate, or a tertiary organic nitrogen base such as triethylamine or pyridine in an inert solvent such as one of the above-mentioned tertiary nitrogen bases or in a polar solvent such as tris (dimethylamide) phosphoric acid and / or at elevated temperature.

The reaction with 8 alkene and 2 to 7 carbon atoms can be carried out, for example, in the presence of an acid catalyst, for example a Lewis acid such as boron trifluoride, a sulfonic acid such as benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid. 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 alkane, benzene or toluene, or a halogenated hydrocarbon such as tetrachloroethane , trichloroethane, chloroform, methylene chloride or carbon tetrachloride.

The carboxy group can be further converted by reaction with ammonia or N-mono- or Ν, Ν-dialkylamine, in a conventional manner, for example by dehydrating an 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 R ₄ to its ester or amide can also be carried out by first converting the acid of the formula I into a reactive derivative in a conventional manner, for example using a phosphorus or sulfur halide such as phosphorus trichloride or phosphorus; thionyl chloride, to an acid halide or by reaction with the abovementioned 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 e.g. from imidazole or 3,5-dimethylpyrazole, and the reactive derivative obtained is then reacted in a customary manner, for example by the method described below, for reesterification, reamidation or interconversion of a C 1 -C 7 alkoxycarbonyl group and a carbamoyl group optionally alkylated with a C 1 alkyl group. to 4 carbon atoms, reacted with an alkanol and 1 to 7 carbon atoms, ammonia or an N-mono- or Ν, Ν-dialkylamine 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, by reaction with ammonia or N-mono- or N, N-dialkylamino having 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 a conventional 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 acid or toluenesulfonic acid, or Lewis acids, for example boron trifluoride ether, to another alkoxycarbonyl group having 2 to 8 carbon atoms in the alkoxy moiety.

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 carboxyl group.

In the obtained compounds, the hydroxy, alkanoyloxy208144 group having 2 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, in the meaning of R, may be further converted with one another or

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

A functionally modified C 1 -C 4 alkanecarboxylic acid in the alkane moiety is, for example, a C 2 -C 4 carboxylic acid anhydride, a C 1 -C 4 alkanecarboxylic acid chloride or bromide or a C 2 -C 4 alkyl ketene, a 2-reactive alkanoic acid ester. up to 4 carbon atoms, i.e. an ester with an electron-withdrawing structure, for example a phenyl ester, (p-nitro) phenyl ester or a (C 2 -C 4) alkanecarboxylic acid cyanomethyl ester or an N-alkanoylimidazole or 3,5-dimethylpyrazole, in each case 2 to 4 carbon atoms in the 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 acid, methanesulfonic acid or ethanesulfonic acid. fluorosulfonic acid as well as a diazoalkane having 1 to 4 carbon atoms. Examples of C 1 -C 4 alkylating agents are alkyl chlorides, alkyl iodides, C 1 -C 4 alkyl bromides, for example methyl iodide, C 1 -C 4 dialkyl sulfates, for example dimethyl sulfate or diethyl sulfate or methyl fluorosulfate, alkyl sulfonates such as C 1 -C 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 reacting C 1 -C 4 -diazzoalkanes in an inert solvent such as 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 anhydride or chloride used or for etherification, e.g. For example, a C 1 -C 4 alkanoic acid halide or sulphate used and / or a tertiary nitrogen base such as triethylamine or pyridine, preferably at elevated temperature, used as the basic condensing agent. 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, such C 1 -C 4 alkoxy or, in particular, C 2 -C 4 alkenoyloxy groups can 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 to a hydroxy group can also be carried out by the above reaction of the starting materials of formula II containing a C 1 -C 4 alkoxy group as defined by Rf or Rg. Drastic reaction conditions, for example using aluminum chloride as a catalyst , in addition to or instead of the final compounds of the formula I in which R @ 1 or R @ 8 is C1 -C4 alkoxy, the corresponding compounds in which R @ 8 or R @ 8 is hydroxy are also obtained.

Said reactions may optionally be carried out simultaneously or sequentially in any order. Said reaction is carried out in a conventional 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 the process 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 into salts, for example, salts with organic amines or metal salts, in a customary manner, for example by reaction with the corresponding basic agents. Suitable metal salts are, in particular, alkali metal salts of caustic earths, 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 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 exchange resin. From these, salts can be obtained by reaction with organic or inorganic acids, especially 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, tartaric, citric, scorbic, maleic, hydroxymalein or pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p -aminosallcylic, embonous, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, methanesulfenesulfonic, ethylenesulfulfonic, sulfenesulfonic, sulfenesulfonic, sulfenesulfonic, sulfenesulfonic, sulfenesulfon, tryptophan, lysine or arginine.

These and other salts may 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 consequence of the close relationships between the novel compounds in 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 in which the starting material is used in the form of a salt and / or a racemate or antipodes, or is formed in particular under reaction conditions.

The oxidation of the compounds of the formula II in which Z is a formyl group optionally in a hydrated form can furthermore be based on the corresponding styryl compound or hydroxymethyl compound or its ester, for example formed by reaction with hydrochloric or hydrobromic acid or alkanecarboxylic acid with 1 to 7 carbon atoms in the alkane moiety. The corresponding aldehyde is obtained as an intermediate and is further oxidized by the process according to the invention.

However, the oxidation of the compounds of formula (II) may also be based on the corresponding starting material, where (CH 2) _n -Z is optionally functionally altered, for example an esterified 2,3-epoxyproionic acid residue. In carrying out the oxidation, this residue is disproportionated, optionally after hydrolysis, to the free acid residue to the residues of the formulas -CH 2 -COCOOH and -CH 2 CHO, which are allowed to react to the carboxymethyl residue according to the process of the invention.

The oxidation can be carried out in a conventional manner, for example as described above for compounds of formula II, for example with silver oxide and alkali, alkaline hydrogen peroxide, aqueous potassium permanganate solution or a chromate solution which is acidified, for example sulfuric acid, at at room temperature or preferably with heating.

Depending on the choice of starting materials and process, the novel compounds can be in the form of one or more possible stereoisomers, for example with respect to the position R 1 and R ₂ (positional isometry) or as mixtures thereof, depending on the number of asymmetric carbon atoms isomers, for example optical antipodes, or as isomer mixtures, such as racemates, diastereomeric mixtures or racemic mixtures.

The stereoisomeric mixtures obtained, such as diastereomeric mixtures or mixtures with positional isometry 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 the 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 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-formulations 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, bruoin, 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, the starting materials of the formula II in which Z represents a formyl group which is optionally produced in hydrated form are, for example, starting from the corresponding 5-R2-6-R1-indanones or 6-R2-7-R, -alpha- tetralones, which are reacted again with methoxymethylenetrifenylphosphorane, if necessary, and hydrolyzed.

In the above description of the process for the preparation of the starting materials, R 1, R ₂ , R 3, Z, n and r have the already mentioned, but particularly preferred, meanings, unless otherwise indicated.

The pharmacologically usable compounds of the invention may be used for the manufacture of pharmaceutical preparations, 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 which are suitable for enteral, for example, oral, parenteral or topical administration. Preferably, tablets or gelatine capsules are used which have the active ingredient together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and glidants such as diatomaceous earth, talc, stearic acid or the like. salts thereof 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 its salts, 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. if desired, to contain other pharmaceutically valuable substances, they can 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.

Example 1

To a solution of 2.8 g of crude 5-methoxy-6-benzoylindane-1-carboxyl aldehyde in 50 ml of absolute methanol was slowly added dropwise 2.9 g of Caroic acid (prepared according to the procedure described in J. Org) under stirring in an anhydrous atmosphere at 10-15 °. Chem., 33, 2525 (1968). After the addition was complete, stirring was continued for 4 hours at 15 °. 100 ml of water are then added and extracted three times with 50 ml of ether each time. The organic phases are washed successively with 100 ml of a 0.1 N sodium sulfite solution and water, dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on 100 g of silica gel with methylene chloride as eluent followed by fractional crystallization from ether and petroleum ether gave 5-methoxy-6-benzoylindane-1-carboxylic acid methyl ester, m.p. 94-96 ° (colorless crystals).

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

To a suspension of 93 g of aluminum chloride in 100 ml of methylene chloride, 20.8 g of 5-methoxyindane and then 59 g of benzoyl chloride were added dropwise with stirring under an anhydrous atmosphere at 0 to 5 °, and after stirring was allowed to stir for 1 hour at 0 to 5 °. The reaction mixture is then poured onto 1 kg of ice and extracted twice with 500 ml of methylene chloride each time. The organic extracts were combined, washed successively with 2 N hydrochloric acid (2 x 500 mL) and water (2 x 500 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is crystallized by trituration with ether and petroleum ether and treatment with activated carbon 5-methoxy-6-benzoylindane, m.p. 89 DEG-91 DEG.

To a solution of 2 g of the above compound in 5 ml of acetic acid and 2 ml of acetic anhydride, a solution of 1 g of chromium trioxide in 1 ml of water and 4 ml of acetic acid is added dropwise with stirring at 10 °. After the addition was complete, the mixture was further stirred for 2 hours at 10 ° and then for 3 hours at room temperature. The reaction mixture was then poured into 50 ml of ice water. The 5-methoxy-6-benzoyl-1-indanone precipitated is filtered off and recrystallized from methylene chloride, ether and petroleum ether. Its melting point is 141-143 °.

To a mixture of 4 g of triphenyl-2-oxapropylphosphonium bromide and 2.7 g of the above compound in 30 ml of absolute dimethylsulfoxide was added 480 mg of sodium hydride (50%, in mineral oil) in portions under inert atmosphere at room temperature. After the addition was complete, it was further stirred for 2 hours at room temperature and 14 hours at 80 °. The mixture was then cooled to room temperature and partitioned between 50 mL of methylene chloride and 100 mL of water three times. The organic phases are washed neutral, dried over sodium sulphate and evaporated first under vacuum and finally under high vacuum. Chromatography of the residue on 100 g of silica gel with chloroform / ether (20: 1) as eluent gave crude 5-methoxy-6-benzoylindan-1-ylidine methyl ester, which was further worked up by treating to a solution containing 2.1 g. In this 40 ml of tetrahydrofuran, 4 ml of 40% aqueous perchloric acid was added and the mixture was heated to reflux for 90 minutes with stirring. The mixture is then cooled to room temperature, 150 ml of water are added and extracted three times with 50 ml of methylene chloride each time. The organic phases are washed successively with 50 ml each of saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the residue on 1.00 g of silica gel with ether / chloroform 1:20 as eluent gave crude 5-methoxy-6-benzoylindane-1-carboxaldehyde which was further processed directly without further purification.

The following can be produced in an analogous manner:

5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester, m.p. 89-91 °, 5-benzoyl-6-hydroxyindane-1-carboxylic acid n-butyl ester, m.p. 43-44 °, 5-benzoyl- 83-84 [deg.], Methyl 5- (p-toluyl) -6-hydroxyindan-1-carboxylic acid methyl ester, m.p. 74-76 [deg.], 5- (p-chlorobenzoyl) methyl ester, 6-hydroxyindan-1-carboxylic acid, melting point 96-98 °, 5-benzoyl-6-acetoxyindene-1-carboxylic acid methyl ester, 5-thenoyl-6-hydroxyindane-1-carboxylic acid methyl ester, melting point 111-113 °, 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, m.p. 78-80 °, 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester, m.p. 107-109 °, 1- methyl ester hydroxymethyl-5-benzoyl-6-hydroxyindane-1-carboxylic acid,

IR spectrum: OH ⁼ 3,600 cm @ -1, Co ⁼ 725 cm @ -1, in methylene chloride, 6-benzoylindane-1-carboxylic acid methyl ester, boiling point 165-170 DEG / 6.7 Pa, 5-benzoylindane acid methyl ester 1-acetic acid, 6-benzoylindan-1-acetic acid methyl ester, 5-benzoyl-6-hydroxyindan-1-acetic acid methyl ether, boiling point 180-185 ° / 5.3 Pa, 6-hydroxy-7- ethyl ethyl ester benzoyl-1,2,3,4-tetrahydronaphthyloot, boiling point 190 ° / 5.3 Pa a

1-methyl-5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester, mass spectrum

M @ ⁺ = 324.

Example 2

A solution of 8.2 g of 5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester in 150 ml of methanol is mixed with 20 ml of 2 N sodium hydroxide solution and refluxed for 3 hours.

It is then evaporated to dryness in vacuo and the residue is partitioned between 100 ml of 2N hydrochloric acid and three times with 100 ml of methylene chloride. The organic phase is washed neutral, dried over sodium sulfate, treated with charcoal and evaporated in vacuo. 5-Benzoyl-6-hydroxyindan-1-carboxylic acid crystallized from the residue with ethanol and petroleum ether as yellow plates, m.p. 185-187 °.

Similarly, the following may be produced:

5- (p-toluyl) -6-hydroxyindane-1-carboxylic acid, melting point 186-188 °, 5- (p-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 187-189 °, acid 5 -thenoyl-6-hydroxyindane-1-carboxylic acid, melting point 183-184 °, 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 188-190 °, 5-benzoyl-6-methoxyindane -1-carboxylic acid, melting point 125-128 °, 6-benzoylindan-1-carboxylic acid, boiling point 200 ° / 5.3 Pa, 5-benzoylindan-1-acetic acid and 6-benzoylindan-1-acetic acid, m.p. 133-135 °, 5-benzoyl-6-hydroxyindan-1-acetic acid, melting point 148-150 °, 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydronaphthyloic acid, melting point 118-150 120 °,

208.44

Example 3

A solution of 10 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester in 100 ml of acetic anhydride is heated under reflux 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. The boiling fraction of 5-benzoyl-6-acetoxyindane-1-carboxylic acid methyl ester as a colorless oil is obtained by boiling off the residue under high vacuum Be at a boiling point of 195 to 200 ° / 8.0 Pa.

Example 4

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 benzyltrimethylaminium hydroxide (40% in methanol) and stirred to remove moisture. hours at 80 °. It is then allowed 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 (IR spectrum in C ^ C ^ ^ IVOH · 600 cm ^"1, Y q = q '. 1725 cm ^-1 ).

Example 5

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 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 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 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 eluent gives pure 1-hydroxymethyl-5-benzoyl-6-hydroxyindane-1-carboxylic acid as yellow crystals, m.p.

Example 6

At a temperature of 15-20 ° C, with the exclusion of moisture, 27 g of crude 5-benzoyl-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. Fractionation by crystallization of the residue from hot dimethylformamide and water gave 5-benzoyl-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-benzoal-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 was repeated two more times, the crude 5-benzoyl-6-acetoxyindane-1-carboxylic acid obtained being 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 7

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 for 30 minutes a solution of 2.36 g of methyl 5-benzoyl-6-hydroxyindanecarboxylic acid in 6 ml of absolute tetrahydrofuran. gas evolution. After completion of the addition, 440 mg of sodium hydride (58% in mineral oil) and 1 ml of methyl iodide are added once more and the mixture is allowed to stir for 30 minutes at 40 DEG C. The reaction mixture is then carefully poured onto 50 led ice and extracted twice with 50 ml of chloroform. . The organic phases are combined, washed successively with cold saturated sodium bicarbonate solution and water, dried, 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 ⁺ = 324).

Example 8

In analogy to Example 2, starting from 0.4 g of 1-methyl-5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester and 5 ml of 2 H sodium hydroxide in 5 ml of methanol, I- methyl 5-benzoyl-6-methoxyindane-1-carboxylic acid, m.p. 135-137 ° (from ether and petroleum ether).

Example 9

To a solution of 0.326 g of sodium in 10 ml of absolute ethanol is added a solution of 4 g of 5-benzoyl-6-hydroxyindane-1-carboxylic acid in 60 ml of warm ethanol. The precipitated 5-benzoyl-6-hydroxyindane-1-carboxylic acid sodium salt can be further purified by recrystallization from isopropyl alcohol, a small amount of water and acetone. The yellow crystals obtained have a melting point above 275 and are hygroscopic.

Example 10

In addition, the following compounds can be prepared in an analogous manner to those described in Examples 1 to 9:

6-benzoyl-5-hydroxyindan-1-carboxylic acid methyl ester, melting point 90-92 °, 6-benzoyl-5-hydroxyindan-1-carboxylic acid, melting point 135-137 °, 5-furoyl-6-hydroxy methyl ester 100 DEG-102 DEG C., 5- (2,6-dichlorobenzoyl) -6-hydroxyindan-1-carboxylic acid methyl ester, melting point 130 DEG-133 DEG, 5- (2,6-dichlorobenzoyl), m.p. 233 DEG-235 DEG, 5- (m-chlorobenzoyl) -6-hydroxyindan-1-carboxylic acid methyl ester, m.p. 75 DEG-77 DEG, 5- (m-chlorobenzoyl) m.p. 6-hydroxyindan-1-carboxylic acid, melting point, 59-161 °, 5- (o-fluorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, 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, 69-170 °, 5-benzoylindane-1- methyl ester carboxylic acid, IR spectrum: 1660 and 1730 ca ^-1 (in CH 2 Cl 2) 5-ben acid zoylindane-1-carboxylic acid, melting point, 25-127 °,

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

1,

208.44

5-Benzoyl-6-hydroxyindan-1-carboxylic acid N-ethylamide, melting point, 87-169 °, 6-benzoyl-5-methoxyindane-1-carboxylic acid methyl ester, melting point 94-96 °, N- (p- 5-benzoyl-6-methoxyindan-1-carboxylic acid chlorophenyl) amide, m.p. 229-231 °.

Claims (8)

SUBJECT OF THE INVENTION A process for the preparation of novel substituted benzocycloalkanyl carboxylic acids and optionally their esters or amides of the general formula I, wherein one of both residues R f and R g are furyl 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, R 4 is carboxy, C 1 -C 7 alkoxycarbonyl, carbamoyl optionally substituted with C 1 -C 4 alkyl, m is 1 or 2 and n is 0 or,. as well as salts of the compounds of the formula I, characterized in that in the substituted benzocycloalkenyl compound of the formula II, Z represents a formyl group present optionally in hydrated form, a hydroxymethyl group, which is optionally esterified or carboxycarbonyl group, which is optionally functionally modified, ¹ R> ^r 2 ^"R 3 ^Man as hereinbefore defined, the Z group is oxidized by reaction with a conventional oxidizing agent to a carboxyl group, and if necessary the compound of formula I, Rf or Rg denoting an alkoxy group having 1 to 4 carbon atoms or an alkanoyloxy group with 2 to R @ 4 denoting hydrogen replaces C1 -C4 alkyl or C1 -C4 hydroxyalkyl and / or, if necessary, the hydroxy group R @ 1 or R @ ₂ is etherified to an alkoxy group having 4 carbon atoms, Or (1 to 4 carbon atoms) or esterified to (2 to 4) alkanoyloxy and / or, if desired, in the compound of formula (I) in which R4 is a carboxyl group, which is converted to an esterified (C1-C7) alkoxycarbonyl group; a carbamoyl group, optionally substituted with 1 to 4 carbon atoms, and / or, if desired, the iso obtained the mercurial mixture is separated into isomers and / or the racemal obtained is resolved into optical antipodes and / or the obtained salt is converted to the free acid or the obtained free acid is converted to a salt. 2. A process according to claim 1, wherein the starting material is a compound of formula (II) wherein Z is a formyl group, optionally in hydrated form, or a hydroxymethyl group, optionally esterified. 3. The method according to one of claims 1 and 2 for preparing compounds of formula I wherein one of the two radicals R and R ₂ represents a group R denoting a benzoyl radical which is optionally substituted by alkyl having 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon and / or halogen, or unsubstituted thenoyl, and the other is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyl, R 1 is hydrogen or C 1 -C 4 alkyl, R 4 is carboxy, alkoxycarbonyl (C 1 -C 7) alkoxy or carbamoyl group, which is optionally N-mono- or Ν, Ν-disubstituted with (C 1 -C 4) alkyl, n = 0 or 1 and m is 1 or 2, and acid salts of formula I, characterized in that as starting material a compound of formula II wherein Z is as defined in paragraph 1 or 2, one of the radicals R, and R ₂ is hydroxy C1-C4alkoxy or C2-C4alkanoyl; and the other is R, wherein R, R ^, m, n are as defined above. 4. A method according to claim 2 for the manufacture of compounds of formula I wherein one of Ri and _R2 represents optionally methylene, methoxy and / or chlorine-substituted benzoyl or thenoyl group and the other represents acetoxy, methoxy, ethoxy .or hydroxy, R ₃ is hydrogen, R 4 is carboxy or C 1 -C 4 alkoxycarbonyl, n is 0 and m is 1, or an acid salt of formula I, wherein the starting material is a compound of formula II, wherein Z is as defined in 2, one of R 1 and R ₂ is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyl, and the other R, wherein R 1, m, n have as defined above, and in the compound of formula I obtained, wherein one of R 1 and R ₂ is C 1 -C 4 alkoxy which is different from methoxy or ethoxy, or alkanoy a (C 4-C) alkoxy group which is different from the acetoxy group is converted into an acetoxy-, methoxy-, ethoxy- or hydroxy group and / or, optionally in the compound of the formula I obtained, the carboxy group R R4 is converted to an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety. 5. Method according to one of claims 1 and 2 for preparing acid derivatives benzocykloalkenylalkankarboxylové of formula I wherein one of Ri and _R2 represents a phenyl group optionally substituted once substituted alkyl having 1 to 4 carbon atoms or halogen, and the other is hydroxy, R3 is hydrogen, R4 is carboxy or C1-C4alkoxycarbonyl, n is 0 and m is 1, and salts of the compounds of formula I having salt-forming properties, characterized in that the compounds of the formula I are used as starting materials of formula IX, wherein Z is as defined in 1 or 2, one of the radicals R 1 and R 8 is hydroxy, alkoxy of 1 to 2 208.44 C 4 -C 4 alkanoyloxy or C 2 -C 4 alkanoyloxy and the other denotes a group of the formula R, wherein R, R 8, m, n are as defined above, and R 8 is C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy, this group is converted to a hydroxy group and / or, optionally in the compound of formula I obtained, the carboxy group R 1 is converted to a C 1 -C 4 alkoxycarbonyl group alkoxy moieties. 6. A process as claimed in claim 2 for the preparation of 5-benzoyl-6-hydroxyindane-1-carboxylic acid and 5-benzoyl-6-hydroxyindane-1-carboxylic acid salts or methyl ester thereof, of formula II, wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy and R ₂ is benzoyl, Z is as defined in point 2, R 8 is hydrogen, m is 1 and _n is 0 and in the compound obtained, the C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy group is converted to the hydroxy group and the carboxy group R 4 is converted to the methoxycarbonyl group, as appropriate. 7. The process of item 2 for the preparation of 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid and 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid salts or methyl ester thereof, The compound of formula (II) wherein R @ 1 is hydroxy, C1 -C4 alkoxy or C2 -C4 alkanoyloxy and R @ ₂ is o-chlorobenzoyl, R @ 8 is hydrogen, m is 1 and _n is the starting material. As defined in point 2, and in the compound obtained, the C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy group is converted to the hydroxy group and the carboxy group R 4 is converted to the methoxycarbonyl group as necessary. 8. A process according to claim 2 for the preparation of 5-benzoyl-6-methoxyindane-1-carboxylic acid or 5-benzoyl-6-methoxyindane-1-carboxylic acid salts or methyl ester thereof, characterized in that of formula II wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy and R 8 is benzoyl, R 8 is hydrogen, m is 1 and n is 0, Z is as defined in 2, and the hydroxy, C 2 -C 4 alkanoyloxy or C 1 -C 4 alkoxy group, which is different from the methoxy group, is converted to the methoxy group and optionally the carboxy group R 4 is converted to a methoxycarbonyl group.