CS208145B2 - Method of making the new substituted benzocycloalkenylcarboxyl acids and event. the esters and amines thereof - Google Patents

Description

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

AND

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

(CH ₂ ) _n -R ₄

2'm (I) 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 C 2 -C 4 alkanoyloxy,

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 alkoxy moiety, a carbamoyl, N-mono- or Ν, Ν-dialkylcarbamoyl group each having 1 to 4 carbon atoms in the alkyl moiety, m is 1 or 2a n is 0 or 1 , in free form or in the form of their salts.

In particular, the acyl radical R @ 1 or R @ 8 is a benzoyl group which is optionally substituted several or especially once with C1 -C4 alkyl, for example methyl, C1 -C4 alkoxy, for example methoxy and / or halogen, for example chlorine, bromine or fluorine or an unsubstituted thenoyl group.

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 equally 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 acetoxy.

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

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

In particular, a hydroxymethyl group is mentioned as an example.

The C 1 -C 7 alkoxycarbonyl moiety contains, for example, one of the isomeric butoxy, isopropoxy, propoxy, ethoxy or methoxy groups as the alkoxy moiety.

The N-monoalkylcarbemoyl group having 1 to 4 carbon atoms in the alkyl moiety preferably contains, as amino group, a lower alkoxy group or a lower mono- or dialkylamino substituted alkylamino group having 1 to 4, in particular 1 or 2 carbon atoms in the alkyl moiety and 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 Ν, Ν-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 activity. For example, in the yeast-induced fever test at 3 to 30 mg / kg in rats, they exhibit an apparent anti-pyretic effect, as well as in the kaolin edema test after oral administration at 3 to 100 mg / kg, a marked anti-inflammatory effect.

The frothing-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 (chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid and 5-benzoyl-6-hydroxyindane-1-carboxylic acid ethyl ester, each having an effective dose of 3 mg / kg po or less. These compounds are also comparatively low toxic.

The compounds of the invention further 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 10 ng / kg po reduce serum triglycerides by 21 or 27% and serum cholesterol levels by 24 to 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 @ 8 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 a mono- or dialkylamino group as the amino group 1-4 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 (1) wherein one of R 1 and R 8 is optionally methyl, methoxy and / or chloro substituted benzdyl and the other is hydrogen or hydroxy, R 1 is hydrogen, R 4 is carboxy, C 1 -C 4 alkoxycarbonyl , such as a methoxy or ethoxycarbonyl group, or a carbamoyl group, n is 0 or 1 and m is 1;

the compounds of formula (I) wherein one of R 1 and R 8 is optionally C 1 -C 4 alkyl or C 1 -C 4 alkoxy such as methoxy or methyl, or halogen such as chloro, a monosubstituted benzoyl group and the other is hydroxy, R 1 is hydrogen, R 1 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 by the process according to the invention by the preparation of a compound of the formula II

(II) or formula (11a), with ^CH 2 ^R 4

(Ha) where

X is - (CH 3) _m or -CH = CH- and R 1, R ₂ , R 3, R ₊ , _m and _n are as defined above, reducing the double bond or double bonds in the alpha, beta or beta position, gamma and / or optionally in the radical X and, if necessary, in the compound of the formula I, a (C1-C4) alkoxy or a (C1-C4) alkanoyloxy group denoting R or Rg is converted simultaneously or additionally to a hydroxyl group and / or if desired the hydroxy group R 1 or R 8 is etherified to a C 1 -C 4 alkoxy group or esterified to a C 2 -C 4 alkanoyloxy group and / or optionally in a compound of formula 1 wherein R 1 is alkoxycarbonyl and 1 to 7 carbon atoms in the the alkoxy moiety converting this group to a carbamoyl group optionally substituted by C 1 -C 4 alkyl, or to another C 1 -C 7 alkoxycarbonyl group, or wherein R 4 is carboxy, this group the compound is converted to a (C 1 -C 7) alkoxycarbonyl or carbamoyl group optionally substituted by C 1 -C 4 alkyl, or wherein R 1 represents a carbamoyl group optionally substituted by C 1 -C 4 alkyl, this group is converted to a carboxy group and / or, if desired, the resulting isomeric mixture is separated into the pure isomers and / or the racemate obtained is resolved into optical antipodes and / or the optionally obtained salt is converted to the free compound or the obtained free compound with salt-forming properties is converted to salt.

For example, in a compound of formula 11b,

(lib) where

R 1, R 3, R 4, n and m have the meanings indicated, reducing the double bond at the alpha, beta position to (CHg) _n -R 4 ·

The reduction can be carried out in a conventional manner, for example by catalytic hydrogenation, where it is reacted in the presence of a hydrogenation catalyst, for example a palladium, platinum or nickel catalyst such as palladium on carbon or calcium carbonate or platinum oxide or Raney nickel. absorbing an approximately etechiometrically required amount, preferably at elevated hydrogen pressure and normal or particularly elevated temperature, preferably in an organic solvent inert under hydrogenation conditions such as ethanol, methanol, acetic acid or dioxane. Particularly suitable are pressures up to 15.0 MPa and temperatures between room temperature and about 150 ° C.

Especially in the presence of halogen atoms, hydrogenation in the presence of platinum oxide, for example in ethanol, methanol or preferably in acetic acid and at normal or at most elevated temperatures and pressures, is also advantageous.

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

Thus, the carboxy group may be esterified by reaction with a C 1 -C 7 alcohol or a reactive derivative thereof, such as a C 1 -C 7 alkanecarboxylic acid ester in an alkane moiety or a mineral or sulphonic acid ester such as hydrochloric, hydrobromic, sulfuric, benzenesulfonic, toluenesulfonic or methanesulfonic with a C 1 -C 7 alkanol or a C 2 -C 7 alkene, to an C 1 -C 7 alkoxycarbonyl group in the alkoxy moiety.

The reaction with an alkanol and 1 to 7 carbon atoms 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 acids or Lewis acids, e.g. of boron trifluoride etherate, in an inert solvent, especially in excess of the alkanols used, and if necessary in the presence of a water binding agent and / or by distillation, for example by azeotropic removal of the reaction water and / or at elevated temperature.

The reaction and the reactive derivative of C1 -C7 alkanols 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, for example diethyl ether or tetrahydrofuran. , in a hydrocarbon such as benzene or toluene, or in a halogenated hydrocarbon such as trichloroethane, tetrachloroethane, chloroform, carbon tetrachloride or methylene chloride, or in excess of the alkanol derivative or corresponding alkanols used, if desired, for example by azeotropic distillation of the reaction water. When starting from an ester of a mineral acid or a sulfonic 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 condensation 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 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 alkane, benzene or toluene, or a halogenated hydrocarbon such as tetrachloroethane , trichloro ether, 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 dehydration of an intermediate ammonium salt, for example by azeotropic distillation with benzene or toluene or by dry heating to a carbamoyl group. which is optionally N-mono- or Ν, Ν-dialkylated with C 1 -C 4 alkyl.

The above-described conversion of the free carboxy-group Rakup 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 bromide, 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, thiophenol, p-nitrophenol or cyanomethyl alcohol, or to 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 as described below, for the reestirification, reamidation or interconversion of a C 2 -C 8 alkoxycarbonyl group and a carbamoyl group optionally substituted by a C 1 -C 4 alkyl group. at The reaction may be carried out with an alkanol having 1 to 7 carbon atoms, ammonia or an N-mono- or Ν, dial-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 the carboxyl group or, for example, by reaction with ammonia or N-mono- or Ν, až-dialkylamine to the corresponding carboxy group in amide form.

Further, the C 2 -C 8 alkoxycarbonyl can 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, benzenesulfonic or toluenesulfonic acid or Lewis acids such as boron trifluoride etherate, to another C 2 -C 8 alkoxycarbonyl group.

The carbamoyl group optionally substituted by C 1 -C 4 alkyl can be converted in a conventional manner, for example by hydrolysis in the presence of a catalyst, for example a strong base such as an alkali metal or alkaline earth metal hydroxide or carbonate such as sodium or potassium hydroxide or carbonate or strong acids, such as mineral acids, for example hydrochloric, sulfuric or phosphoric acids, to the carboxy group.

In the compounds obtained, a hydroxy group, a (C 2 -C 4) alkanoyloxy group or a (C 1 -C 4) alkoxy group in the meaning of R 1 or b ₂ may be further converted with one another.

Thus, for example, a hydroxy group may be etherified by reaction with a preferably C 2 -C 4 alkanecarboxylic acid in the alkane moiety to an alkaloxy and 2 to 4 carbon atoms, or etherified by reaction with a C 1 -C 4 alkylating agent to a C 1 -C 4 alkoxy group. carbon.

A functionally modified C 1 -C 4 alkanecarboxylic acid in the alkane moiety is, for example, a C 2 -C 4 carboxylic anhydride, a C 1 -C 4 alkanecarboxylic acid chloride or bromide, or a C 2 -C 4 alkyl ketene, a reactive alkanoic acid ester having 2 to 4 carbon atoms, i.e. an ester with an electron-withdrawing structure, for example phenyl, (p-nitro) phenyl or cyanomethyl ester alkanecarboxylic acids having 2 to 4 carbon atoms in the alkane moiety or N-alkanoylimidazole or -3,5-dimethylpyrazole with 2 to 4 carbon atoms 4 carbon atoms in the alkanoyl moiety.

The etherification 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 with organic sulfonic acids such as p-toluenesulfonic acid, p-bromobenzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or ethanesulfonic acid ethers. as well as a C 1 -C 4 diazoalkane. Examples of C1-C4 alkylating agents are, for example, alkyl chlorides, alkyl iodides, C1-C4 alkyl bromides, for example methyl iodide, C1-C4 dialkyl sulphates, for example dimethyl sulphate or diethyl sulphate or methyl fluorosulphonate, alkyl sulphonates such as alkyl sulphonates C 1-4 alkyl, for example methylsulfonate, p-toluenesulfonate, p-bromobenzenesulfonate, methanesulfonate or ethanol sulfonate, as well as diazomethane.

Reactions with the above-mentioned C 2 -C 4 alkanoic acids or C 1 -C 4 alkanols 3e can be carried out in a conventional manner, reaction with C 1 -C 4 diazoalkanes in an inert solvent such as an ether, for example diethyl ether or a reaction reactive esterified C1 -C4 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 or potassium or calcium carbonate 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. The alkyl halide or C 1 -C 4 alkyl sulphate used and / or the tertiary nitrogenous base used, for example triethylamine or pyridine, preferably at elevated temperature, is used as the basic condensation agent. In particular, methylation with methyl iodide in amyl alcohol in the presence of potassium carbonate at boiling point is recommended, as is aoylation with alkanoic hydride at 50 to 150 ° C or with alkanoyl chloride in pyridine or pyridine and triethylamine at temperatures between -20 and ± 100 ° C.

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 to a hydroxy group can also be carried out with the above-described reaction of the starting materials of the general formula (II) containing a C 1 -C 4 alkoxy group, R 1 'or R 8'. By drastic reaction conditions, for example using aluminum chloride as a catalyst, in addition to or instead of the final compounds of formula 1 wherein R 1 or R 8 is C 1 -C 4 alkoxy, the corresponding compounds in which R 1 or R ₂ is hydroxy are also obtained.

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

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

Depending on the process conditions and the starting materials, optionally end-products are obtained which can form salts 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 and corrosive earth metal salts, such as sodium, potassium, magnesium or calcium salts. The free acids can be liberated from the salt 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 an ion exchanger. From these, salts can be obtained by reaction with organic or inorganic acids, especially those suitable for the formation of therapeutically useful salts.

208.45

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, ascorbic, malignant, hydroxyaalein or pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminoaallcylic, embonous, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, sulfenesulfonic, ethylenesulfonic, 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 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 new compounds may, depending on the choice of starting substances and working procedures, in the form of one or several possible atereoisomerů example with reference to the position R, and R ₂ (position isomerism) or as mixtures thereof, depending on the number of asymmetric carbon atoms, as pure optical Isomers, for example optical antipodes, or as isomeric mixtures, such as racemates, diastereomeric or racemic mixtures.

The stereoisomeric mixtures obtained, such as diastereomeric mixtures or mixtures with 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 from which the antipodes can be released by treatment with a suitable agent. Particularly suitable optically active acids are, for example, the D- and L-forms of tartaric, dl-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.

The starting materials of formulas II, 11a and IIb, where n is 1, can be prepared, for example, by reacting a compound of formula V, ^R 1 -γ (V)

X 'X where

R, R ₂ and X are as defined above, with an alpha zinekoctové acid by elimination of water, for example by treatment with an acid, such as treatment with p-toluenesulfonic acid in benzene, resulting from the primary hydroxy compounds of formula VI,

OH

where

Rf and Rg are as defined above and

R ₄ 'represents an alkoxycarbonyl group having 1 to 7 carbon atoms in the alkoxy group and, if necessary, hydrolysis and / or amidation of the ester obtained. Compounds of formula V may be obtained by reaction of a compound of formula VII,

Ro (VII) where

R _o represents hydrogen, hydroxy, alkoxy having 1 to 4 carbon atoms or alkanoyloxy having 2 to 4 carbon atoms, with a compound of formula

R-COC1, where

R represents a thenoyl group, or a benzoyl group optionally substituted with C1-C4 alkyl, C1-C4 alkoxy and / or halogen.

The starting materials of the formulas II and IIb, where X is a methylene group, m is 1 and n is 0, can be prepared, for example, when a compound of the formula VIII,

Ro (VIII) where

Q and _R4 have the above meanings, is reacted in the presence of aluminum chloride with a compound of formula

R-COC1 where

R is as defined above.

The 1-oxo group is reduced in a conventional manner, for example with sodium borohydride, and water is cleaved from the hydroxy compound obtained in a conventional manner by allyl rearrangement.

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 impressive amount.

208.45 of 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 they use tablets or gelatin capsules having 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 polyvinyolpyrrolidone and, if desired, a tablet disrupter such as starches, agar, alginic acid or salts thereof, such as sodium alginate, enzymes, binders and / or effervescent mixtures or absorbents, colorants, flavors and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions, suppositories or ointments being primarily fatty emulsions or suspensions.

The pharmacological preparations may be sterilized and / or contain adjuvants such as preservatives and stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. These pharmaceutical preparations, which, if desired, can contain other pharmaceutically valuable substances, 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 75%. 50% of active substance. The recommended daily dose for approximately 75 kg of a warm-blooded individual is 25 to 250 mg.

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

He did

To a solution of 3 g of 5-benzoyl-6-methoxy-1-indane-1-carboxylic acid methyl ester in 30 ml of methyl acetate was added 0.5 g of palladium (0.5% on carbon) and hydrogenated until 1 equivalent of hydrogen was taken up. Then the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. Chromatography of the residue on 140 g of silica gel with methylene chloride as eluent and fractional crystallization from ether and petroleum ether gave 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester, m.p. 108-110 °.

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

To a solution of 6.48 g of 3-oxo-5-benzoyl-6-methoxyindan-1-carboxylic acid methyl ester (obtainable, for example, by reaction of 3-oxo-6-methoxyindan-1-carboxylic acid methyl ester with benzoyl chloride in the presence of aluminum chloride); (125 to 126 °, from ether and petroleum ether) in 100 ml of methanol are added in portions of 250 mg of sodium borohydride with stirring at 5 °. It was then allowed to warm to room temperature and further stirred for 3 hours. It is then poured onto 100 g of ice, 5 ml of 2 N hydrochloric acid are added and extracted twice with 100 ml of methylene chloride each time. The organic phase was washed neutral, dried over sodium sulfate and evaporated in vacuo. The crude diastereomeric mixture of 3-hydroxy-5-benzoyl-6-methoxyindan-1-carboxylic acid methyl ester, obtained in the residue as a greenish oil, was dissolved in 60 ml of acetic acid, 60 ml of 2 N hydrochloric acid was added and heated to reflux. 5 minutes. It is then allowed to cool to room temperature, 200 ml of ice-water are added and extracted twice with 100 ml of methylene chloride each time. The organic phase is washed neutral, dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on 150 g of silica gel with methylene chloride as eluent followed by crystallization from methylene chloride / ether / petroleum ether gave 5-benzoyl-6-methoxy-1-indene-1-carboxylic acid methyl ester, m.p. 173-175 ° (yellowish crystals). ).

Example 1 and d 2

To a solution of 4.7 g of 5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester in 50 ml of methanol was added 20 ml of 2 N sodium hydroxide and the mixture was heated to reflux 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 100 ml of methylene chloride. The organic phase is washed neutral, dried over sodium sulfate, treated with charcoal and evaporated in vacuo. 5-Benzoyl-5-methoxyindane-1-carboxylic acid crystallized from ethanol and petroleum ether, m.p. 126 DEG-28 DEG.

Example 3

In addition, the following compounds can be prepared in an analogous manner to those described in Examples 1 and 2:

5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester, melting point 89-91 °, 5-benzoyl-6-hydroxyindane-1-carboxylic acid, melting point 185-187 °, 5- (p-toluyl) methyl ester 6-hydroxyindan-1-carboxylic acid, m.p. 74-76 °, 5- (p-toluyl) -6-hydroxyindan-1-carboxylic acid, mp 186-188 °, 5- (p-chlorobenzoyl) methyl ester - 6-hydroxyindan-1-carboxylic acid, melting point 96-98 °, 5- (p-chlorobenzoyl) -6-hydroxyindan-1-carboxylic acid, melting point 187-189 °, 5-benzoyl-6-acetoxyindan-1-methyl ester -carboxylic acid, 5-thenoyl-6-hydroxyindane-1-carboxylic acid methyl ester, melting point 1.1-113 °, 5-thenoyl-6-hydroxyindane-1-carboxylic acid, melting point, 83-184 °, methyl ester 5 - (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 78-80 °, 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 188-190 °, methyl 6- ester benzoylindane-1-carboxylic acid, boiling point 165-170 ° / 6.7 Pa, acid 6 -benzoylindane-1-carboxylic acid, boiling point 200 ° / 5.3 Pa, 5-benzoylindan-1-acetic acid methyl ester, 6-benzoylindan-1-acetic acid methyl ester, 5-benzoylindan-1-acetic acid, 6-benzoylindane 1-acetic acid, 5-benzoyl-6-hydroxyindan-1-acetic acid, melting point, 48-150 °, ethyl 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydronaphthylacetic acid, boiling point 190 ° 5.3 Pa, 6-hydroxy-7-benzoyl-1,2,3,4-tetrahydronaphthylacetic acid, melting point, 18-120 °, 6-benzoyl-5-hydroxyindane-1-carboxylic acid methyl ester, melting point 90 to 92 °, 6-benzoyl-5-hydroxyindane-1-carboxylic acid, melting point 135-137 °, 5-furoyl-6-hydroxyindane-1-carboxylic acid methyl ester, melting point, 00 to 102 °, 5- methyl ester (2,6-dichlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 130-133 °, 5- (2,6-dichlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 233-235 °, methyl ester 5- (m-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, m.p. 75-77 °; 5- (m-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid, m.p. 159-161 °, 5- (o-fluorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester, melting point 97-98 °, methyl ester 5- (o-methylbenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 60-61 °, 5- (o-methylbenzoyl) -6-hydroxyindane-1-carboxylic acid, melting point 169-170 °,

208145 12 5-benzoylindane-1-carboxylic acid methyl ester, ifl spectrum 1 660 and 1 730 cc (in CH 2 Cl 2), 5-benzoylindane-1-carboxylic acid, melting point 125-127 °,

5-Benzoyl-6-hydroxyindan-1-carboxylic acid N-methylamide, mp 183-185 °,

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

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

Example 4

A solution of 12 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid in 100 ml of n-butanol and 8 drops of concentrated sulfuric acid was refluxed for 6 hours in an anhydrous atmosphere. It is then evaporated to about 20 ml in vacuo and the residue is partitioned between three times 100 ml of methylene chloride and three times 100 ml of water. The organic phase is dried over sodium sulphate and evaporated in vacuo. 5-Benzoyl-6-hydroxyindane-1-carboxylic acid cold n-butyl ester crystallized from the residue in ethanol and petroleum ether as yellow plates, m.p. 43-44 °.

Example 5

Analogous to Example 3, starting from 12 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid and sulfuric acid of acidified ethanol, 5-benzoyl-6-hydroxyindan-1-carboxylic acid ethyl ester is obtained in the form of yellow plates. mp 83-84 °.

Example 5a

To a solution of 3.0 g of 5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester vs 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 were combined, washed neutral, dried over sodium sulfate and evaporated to dryness in vacuo. Give methyl 1-hydroxymethyl-5-benzoyl-5-hydroxyinden-1-carboxylic acid as a yellowish oil (XC-spectrum, of ^{CH₂Cl₂! Vqjj:} om 3600 "', V: 1725 cm').

Example

A solution of 2.8 g of 1-hydroxymethyl-5-benzoyl-6-hydroxyindan-1-carboxylic acid methyl ester in 12 ml of 2 N sodium hydroxide and 50 ml of methanol is heated under reflux for 5 hours. It is then concentrated in vacuo to a volume of about 10 ml and the residue is partitioned twice with 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 the eluent gives pure 1-hydroxymethyl-5-benzoyl-6-hydroxyindane-1-carboxylic acid as yellow crystals of m.p.

Example 1 a d 7

At a temperature of 15 to 20 ° under exclusion of moisture, dried ammonia is introduced into a solution of 27 g of crude 5-benzoyl-6-acetoxyindan-1-carboxylic acid chloride in 200 ml of anhydrous benzene 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 sulfate 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-benzoyl-6-hydroxyindan-1-carboxylic acid in 200 ml of acetic anhydride was refluxed for 4 hours. It is then evaporated to dryness in vacuo, the residue is added to 50 ml of toluene and evaporated to dryness. This is repeated two more times. The crude 5-benzoyl-6-acetoxyindane-1-carboxylic acid obtained is further processed directly.

To a solution of the above crude product in 200 ml of anhydrous benzene was added at 0 ° 20 ml of oxalyl chloride and allowed to stand overnight at room temperature, excluding 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

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

Example 9

To a suspension of 440 mg of sodium hydride (58% in mineral oil) in 6 ml of absolute tetrahydrofuran was added a solution of 0.75 ml of methyl iodide under stirring under nitrogen at 45 ° followed by a solution of 2.36 g of methyl 5-benzoyl-6 over 30 minutes. hydroxyindane-1-carboxylic acid in 6 ml of absolute tetrahydrofuran with strong gas evolution. After the addition was complete, 440 mg of sodium hydride (58% in mineral oil) and 1 ml of methyl iodide were added once more and allowed to stir for 30 minutes at 40 °. The reaction mixture was then carefully poured onto 50 g of ice and extracted twice with 50 ml of chloroform each. The organic phases were combined, washed successively with cold saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo. Chromatography of the residue on 30 g of silica gel with 10: 1 benzene and ethyl acetate as eluent gave 1-methyl-5-benzoyl-6-methoxyindane-1-carboxylic acid methyl ester as a colorless oil (mass spectrum: = 324), which can be further characterized by saponification to 1-methyl-5-benzoyl-6-methoxyindane-1-carboxylic acid, m.p. 135-137 °.

Claims (11)

SUBJECT OF THE INVENTION A process for the preparation of novel substituted benzocycloalkenyl carboxylic acids and optionally their esters or amides of the general formula 1, wherein one of both residues R 1 and R 8 are then thenoyl or benzoyl, optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen, and the other is hydrogen, C 1 -C 4 alkoxy, hydroxy, or (C 2 -C 4) alkanoyloxy group; 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 1, or an acid salt of formula 1, characterized by: A compound of formula II or formula IIa, (IIa) (IIa) wherein X is - (CH 3) _m or -CH = CH- and R 3, R 3, R 3, R 3, n and _m are as defined above, reducing the double bond or double bonds in the alpha, beta or beta position, gamma to R4 and / or in the radical X and, if desired in the compound of formula 1, a C 1 -C 4 alkoxy or a C 2 -C 4 alkanoyloxy group denoting R or R g is converted to a hydroxy group and / or, if desired, a hydroxy group Rj or R g is etherified to a C 1 -C 4 alkoxy or esterified to a C 2 -C 4 alkanoyloxy group, the hydrogen atom at the 1-position of the indane ring system is replaced by a C 1 -C 4 alkyl group or a C 1 -C 4 hydroxyalkyl group In the compound of formula I wherein R 4 is C 1 -C 7 alkoxycarbonyl, this group is converted to a carboxy or carbamoyl group, optionally substituted with C 1 -C 4 alkyl. or to another alkoxycarbonyl group having 1 to 7 carbon atoms in the alkoxy moiety, or wherein R 4 represents a carboxy group, this group is converted to an alkoxycarbonyl group having 1 to 7 carbon atoms in the alkoxy moiety or a carbamoyl group optionally substituted with 1 alkyl or wherein R 4 represents a carbamoyl group optionally substituted with C 1 -C 4 alkyl, which group is converted to a carboxy group, the isomer mixture obtained is separated into pure isomers and / or the racemate obtained is resolved into optical antipodes and / or optionally converting the salt obtained into the free acid or converting the obtained free acid into a salt. 2. The method of item 1 for the preparation of compounds of formula I, wherein R, Rg, R4, n, m are as defined in item 1 and Rj is hydrogen, or a salt of a salt-forming compound, starting from a compound of formula lib, (lib) where R 1, R 8, R 6, m, n are as defined in 1 above, or from a salt thereof. 3. The process according to claim 1, wherein the reduction is carried out by reaction with hydrogen in the presence of a hydrogenation catalyst, for example palladium on carbon. 4. The process according to claim 2, wherein the reduction is carried out by reaction with hydrogen in the presence of a hydrogenation catalyst, for example palladium on carbon. 5. A process according to any one of items 1, 2 and 3 for the preparation of compounds of formula I, wherein one of the two radicals R @ 1 and R @ 8 is optionally C1 -C4 alkyl, C1 -C4 alkoxy and / or halogen substituted. benzoyl or thenoyl and the other is hydrogen or optionally C 2 -C 4 alkanecarboxylic acid esterified or C 1 -C 4 alkanol, R 1 is hydrogen or C 1 -C 4 alkyl, R 4 is carbamoyl optionally esterified with 1 to 7 carbon atoms or a carbamoyl group optionally substituted as amino group with N-mono- or Ν, Ν-dialkylamine of 1 to 4 carbon atoms and n is 0 or 1 and m is 1 or 2, and an acid salt of the formula I, characterized by The method of claim 1, wherein the starting materials used are compounds of the formula II, IIa or IIb, wherein R 1 and R 8 are as defined above, and X is as defined in point 1. 6. The process of any one of items 1, 2 and 3 for the preparation of compounds of formula (I) wherein one of R 1 and R 8 is optionally methylene, methoxy and / or chloro-substituted benzoyl or thenoyl R and the other is acetoxy or hydroxy; R1 represents hydrogen, R1 represents a carboxy group or a (C1-C4) alkoxycarbonyl group or a carbamoyl group; n represents 0 or 1 and m is 1, and an acid salt of formula I, wherein the starting material is a compound of formula II, IIa or IIb, wherein one of the radicals R 1 and R 8 is hydroxy, C 1 -C 4 alkoxy and the other R and R, m and n are as defined above, X is methylene and R 4 is as defined in point 1, and in the compound of formula I obtained, wherein one of R 1 and R 8 is (C 1 -C 4) alkoxy or (C 2 -C 4) alkanoyloxy group other than acetoxy, is converted to an acetoxy or hydroxy group and / or to a compound of formula (I) wherein R 4 is other than a carboxy or C 1-6 alkoxycarbonyl group 4 carbon atoms or carbamoyl group, this group is converted to R4. 7. A process according to any one of items 2 and 4 for the preparation of compounds of formula I, wherein one of the radicals R @ 1 and R @ 8 is optionally methyl, methoxy and / or chloro substituted benzoyl or thenoyl R and the other is acetoxy-, methoxy-, ethoxy or hydroxy, R1 represents hydrogen, R1 represents a carboxy or C1-C4alkoxycarbonyl group in the alkoxy moiety, n denotes 0 and m denotes 1, or a salt of such compounds having salt-forming properties, characterized in that: starting from compounds of formula 11b wherein one of R 1 and R 8 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy and the other R and R 4 and m are as defined above, R 4 is as defined in (1), and in the obtained compound of formula (1) wherein one of R 1 and R 8 is C 1 -C 4 alkoxy other than a methoxy or ethoxy group or a (C 2 -C 4) alkanoyloxy group other than an acetoxy group, this group is converted to an acetoxy, methoxy, ethoxy or hydroxy group and / or in the compound of formula I obtained, where R R is other than carboxy or C 1 -C 4 alkoxycarbonyl is converted to R 4. 8. A process according to any one of items 1, 2 and 3 for the preparation of substituted benzocycloalkenyl carboxylic acid derivatives of the general formula I, wherein one of the radicals R @ 1 and R @ 8 represents a benzoyl group optionally monosubstituted by C1 -C4 alkyl or halogen; R1 represents hydrogen, R1 represents a carboxy or C1-C4alkoxycarbonyl group in the alkoxy moiety, n represents 0 and m represents 1, and an acid salt of the formula I, characterized in that the compound of the formula II is used as starting material or IIb, wherein one of R 1 and R 8 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy and the other benzoyl group optionally substituted with C 1 -C 4 alkyl or halogen, R 1, man are as defined above, X is methylene, R1 is as defined in 1, and in the obtained compound ob wherein one of the radicals R @ 1 and R @ 8 represents a C1 -C4 alkoxy or C2 -C4 alkanoyloxy group, this group is converted to a hydroxy group and / or to a compound of the formula I in which it has a meaning other than carboxy or C 1 -C 4 alkoxycarbonyl is converted to R 4. 9. A process according to claim 2 for the preparation of 5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester or 5-benzoyl-6-hydroxyindane-1-carboxylic acid methyl ester or a salt thereof, characterized in that the compounds of formula (IIb) wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy, R 8 is benzoyl, m is 1, n is 0 and R 4 is as defined in 1, and in the compound obtained, the C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy group is converted to a hydroxy group and an R 4 group other than a carboxy or methoxycarbonyl group is converted to a carboxy or methoxycarbonyl group, and the methyl ester obtained is converted as necessary to free acid. Process according to one of items 2 and 4 for the preparation of 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester or of 5- (o-chlorobenzoyl) -6-hydroxyindane-1-carboxylic acid methyl ester and salts thereof, characterized in that a compound of formula IIb is used as starting material, wherein R 1 is hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy, R 8 is o-chlorobenzoyl, m is 1, n is 0 and R ^ is as defined in point 1, and in the compound obtained, the C až-C alko alkoxy or the C alk-C alk alkanoyloxy group is converted to a hydroxy group and the R, group, other than a carboxy or methoxycarbonyl group, is converted into a hydroxy group. It is converted to a carboxy or methoxycarbonyl group and, if desired, the methyl ester obtained is converted to the free acid. Process according to one of Claims 2 and 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 its salts, characterized in that the compounds of formula (II) wherein R 1 is methoxy or hydroxy and R 8 is benzoyl, m is 1, n is 0 and R 1 is as defined in (1) and optionally in the compound of formula (I) where R, R _{@ 4} , which is different from carboxy or methoxycarbonyl, is converted to carboxy or methoxycarbonyl, and the methyl ester obtained is converted to the free acid, if necessary.