CS214776B2 - Method of making the derivatives of the phenylacetic acid - Google Patents

Description

The invention relates to a process for the preparation of novel phenylacetic acid derivatives. Also described herein are pharmaceutical compositions comprising these phenylacetic acid derivatives.

The new phenylacetic acid derivatives correspond to the general formula Ia,

where it means n numbers 1 to 5, \ Group A — B— groups CH— -CHa— _; OF OF \ \ C = CH— or —CH— -WHAT-, OF OF

R1 is a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or an amino group,

R2 and R3 are hydrogen, methyl or ethylene together,

X1 is two hydrogen atoms or oxo; and

Yt a hydroxyamidocarbonyl group, a carbamoyl group, a carboxyl group, its salts with physiologically compatible bases, its esters with physiologically compatible alcohols, or its amides with physiologically compatible amines.

The term halogen atom preferably denotes a fluorine, chlorine or bromine atom.

The present invention also relates to both racemic phenylacetic acid derivatives of general formula (Ia) and optically active antipodes thereof.

Physiologically tolerable salts formed with carboxyl group Y 1 include, for example, alkali metal or alkaline earth metal salts such as sodium or calcium salts, ammonium salts, copper salts, piperazine salts or methylglucamine salts, as well as salts of these compounds with amino acids.

Physiologically compatible alcohols with which the carboxyl group Yt can be esterified are, for example, straight, branched or cyclic, saturated or unsaturated hydrocarbon radicals, which may optionally be interrupted by an oxygen or nitrogen atom, or may be substituted by hydro214778

214776 with 3-xyl, amino or carboxyl groups, such as alkanols (especially having 1 to 6 carbon atoms, alkanols, alkyinols, cycloalkanols, cycloalkylalkanols, phenylalkanols, phenylalkenols, alkanediols, hydroxycarboxylic acids, aminoalkanols or alkylaminoalkanols and dialkylaminoalkanols and dialkylaminoalkanols and dialkylaminoalkanols) atoms in the alkyl radical.

Alcohols which are suitable for esterifying a carboxyl group are, for example, those containing the following radicals:

methylcarboxymethyl, ethyl,

2-hydroxyethyl,

2-Methoxyethyl,

2-aminoethyl,

2-dimethylaminoethyl,

2-carboxyethyl, propyl, allyl, cyclopropylmethyl, isopropyl,

3-hydroxypropyl, propynyl,

3-aminopropyl, butyl, sec-butyl, tert-butyl,

2-butyl, cyclobutyl, pentyl, isopentyl, tert-pentyl,

2-methylbutyl, cyclopentyl, hexyl, cyclohexyl, cyclo-2-enyl, cyclopentylmethyl, heptyl, benzyl,

2-phenylethyl, octyl, bornyl, isobornyl, menthyl, nonyl, decyl,

3-phenylpropyl,

3-phenyl-2-propenyl, undecyl or dodecyl.

Suitable alcohols suitable for esterification are also alcohols which:. lead to labile, i.e., physiologically cleavable, esters such as

5-hydroxyindan, acyloxymethanol, especially acetoxymethanol, pivaloyloxymethanol,

5-indanyloxycarbonylmethanol, glycolic acid, dialkylaminoalkanols, in particular dimethylaminopropanol, and hydroxyphthalide.

Suitable physiologically compatible amines with which the carboxyl group can be amidated are preferably alkylamines, dialkylamines, alkanolamines, dialkanolamines having 1 to 6 carbon atoms in the alkyl or aanol moiety or five- or six-membered nitrogen heterocycles. Suitable amines include, for example: methylamine, ethylamine,. isopropylamine, ethanolamine,.

dimothy lamin, ·, / diethylamine, diethanolamine, pyrrolidine, piperidine, ........

morpholine or N-methylpiperazine.

The process for the preparation of the novel phenylacetic acid derivatives of the formula Ia according to the invention is characterized in that a compound of the formula XIII,

(CH _{z) n}

CHf

IXIV) where

R 6 represents a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms and

R1, R2 and R3 are as defined above, reacted with a Wittig reagent of formula XIV, wherein n is as defined above, or a carbonyl compound of formula XV,

O (XV) wherein n is as defined above, and optionally the compound of formula (Ia) wherein R 1 is halogen, dehalogen 21 * 776 is, optionally, the compound of formula (Ia) wherein R 1 is hydrogen, halogenated or nitrated and the nitro compound obtained is reduced to the amine compound, and optionally the obtained carboxylic acid or its reactive derivatives is converted into its salts, esters, amides or hydroxamic acids.

The process of the invention is carried out under the conditions conventionally used in the Wittig reaction ("Organic" Organisch chemisches Grundpraktikum-VEB Deutscher Verlag der Wiessenschaften, Berlin, 1976, 492). Thus, for example, it can be prepared from a cycloalkyltriphenylphosphonium halide in an inert solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran or dimethylsulfoxide using a base such as sodium hydride or butyllithium corresponding to triphenylphosphincycloalkylene and the solution thus obtained is allowed to react at -20 ° to 120 ° C 5 _: aldehyde of formula XIII.

The reaction of the aldehyde with the carbonyl compound of formula XV takes place under conditions commonly used for aldol condensation ("Organikum", 1976, 563), for example in an aqueous-alcoholic solution in the presence of bases such as potassium hydroxide or acids such as sulfuric acid, hydrochloric or acetic.

If desired, the subsequent dehalogenation also proceeds in a conventional manner, for example by halogenation of the halogen. This can be done by hydrogenating the compounds, for example, in ethanol or acetic acid, in the presence of platinum or palladium catalysts.

Optionally, the subsequent resolution of the acid racemates takes place by known methods by reacting with optically active bases and separating the diastereomeric mixtures obtained by fractional crystallization.

Suitable optically active bases are, for example, optically active amino acids, d- or 1-1-phenylethylamine, d- or 1-1-naphthylethylamine, brucine, strychnine or quinine. ‘

Optionally, the subsequent halogenation of compounds of formula (Ia) wherein R 1 is hydrogen is carried out in a conventional manner by treating the compound with an inert solvent (e.g. dichloroethane, methylene chloride, chloroform, nitrobenzene, and the like) in the presence of a Friedel-Crafta reaction catalyst. for example ferric chloride, ferric bromide, aluminum chloride and the like) with halogen (e.g. chlorine or bromine).

Optionally, the subsequent nitration of the compounds of formula (Ia) wherein R 1 is hydrogen is carried out in a known manner by treating the compounds with nitric acid in admixture with sulfuric acid.

Optionally, the subsequent reduction of the nitro group present is carried out under conditions known to those skilled in the art (Houben-Weyl, Vol. XI / 1, 1957,? Θθ),

If desired, the subsequent esterification of the free acids also takes place according to known methods. Thus, for example, acids can be reacted with, for example, diazomethane or diazoethane to give the corresponding methyl or ethyl esters. A generally applicable method is also the reaction of acids with alcohols in the presence of carbonyldlimidazole or dicyclohexylcarbodiimide.

It is furthermore possible, for example, to react the acids in the presence of copper oxide or silver oxide with alkyl halides.

Another method is to convert the free acids with the corresponding dimethylformamidalkylacetals into the corresponding alkyl esters of the acids. Furthermore, the acids can be reacted in the presence of strongly acidic catalysts such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoromethylsulfonic acid or ρ-toluenesulfonic acid, with alcohols or with lower alkanecarboxylic acid esters of alcohols.

However, carboxylic acids can also be converted to acid chlorides or mixed acid anhydrides and reacted with alcohols in the presence of basic catalysts, for example pyridine, collidine, lutidine or 4-dimethylaminopyridine.

Carboxylic acid salts are formed, for example, by saponifying esters with basic catalysts or by neutralizing acids with alkali metal carbonates or hydroxides, such as sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate or potassium hydroxide.

Furthermore, it is also possible to react the esters of formula Ia in the presence of acidic or basic catalysts with the finally desired alcohol. The acid or base catalysts used are preferably hydrogen chloride, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, alkali metal alkoxides, alkaline earth metal alkoxides or aluminum alkoxide.

Optionally, the subsequent preparation of amines or hydroxamic acids from the free carboxylic acids or their reactive derivatives is also carried out according to known methods. Thus, for example, carboxylic acids can be reacted under known conditions with amines or hydroxylamine in the presence of dicyclohexylcarbodiimide to give the corresponding aminocarbonyl compounds.

It is furthermore possible, for example, to convert carboxylic acids corresponding acid chlorides, mixed anhydrides or esters under known conditions by treatment with ammonia, amines or hydroxylamine into the corresponding amides or hydroxamic acids.

For example, the following compounds of formula Ia can be prepared by the process of the invention:

2S-chloro-.alpha.-cyclohexylmethylphenyl] propionic acid, 6-chloro-5-cyclopentylcarbonylindane-1-carboxylic acid, 6-chloro-5-cyclohexylidene-ethylindane-1-carboxylic acid, e-chloro-5-cyclopropylidenemethylindane-1-carboxylic acid, 6-chloro-5-cyclopropylcarbonylindan-1-carboxylic acid, 6-chloro-5-cyclopropylmethylindan-1-carboxylic acid, 5-cyclopentylmethyl-6-nitroindane-1-carboxylic acid, 6-amino-5-cyclopentylmethyltodane-1- carboxylic acid, 5-cyclopentyl-ethyl-6-fluoroindane-1-carboxylic acid, 6-chloro-5-cycloheptylmethylindane-1-carboxylic acid, 2- (3-chloro-4-cycloheptylmethylphenyl) propionic acid, 2- (3- (3-) chloro-4-cycloheptylidenemethylphenyl] propionic acid, 6-chloro-5-cycloheptylldenemethylindane-1-carboxylic acid, 2- (3-chloro-4-cyclopentylidenemethylphenyl) propionic acid, 2- (3-chloro-4-cyclobutylmethylphenyl) propionic acid, 6i 6-chloro-5-cyclobutylidene-5-cyclobutylmethylindane-1-carboxylic acid 2- (3-chloro-4-cyclopropylmethylphenyl) propionic acid, 2- (3-chloro-4-cyclopropylidenemethylphenyl) iiproponic acid, 6-chloro-5-cyclopentylmethylindane-1-carbohydroxamic acid, 2- 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid (3-chloro-4-cyclopentylmethylphenyl) propiohydroxamic acid and 2-dimethylaminoethyl ester.

The novel phenylacetic acid derivatives of the formula Ia are, as mentioned above, pharmacologically active substances or intermediates for their preparation. In particular, the pharmacological activity of these compounds is manifested in that they exhibit considerable anti-inflammatory activity, are well acceptable to the stomach and exhibit only relatively low toxicity. In addition, these compounds are often characterized by rapid onset of action, high intensity of action and long duration of action. Furthermore, these compounds have a very good resorbability.

The anti-inflammatory activity of the substances according to the invention can be determined by the known AdjUvans-Arthritis test, which is carried out as follows:

Lewis (LEW) female and male rats weighing 110-190 g are used. Drinking water and pressed altromine feed are administered ad libitum.

10 rats are used for each test group. Myeobacterium butyricum is used as an irritant. A suspension of 0.5 milligram of Myeobacterium butyricum in 0.1 ml of liquid paraffin (DAB ⁷ ) is injected into the right hind paw by a plant.

The test substance is administered orally from day 11 of the experiment daily for 4 days. The substance is administered as a clear aqueous solution or as a crystal suspension with the addition of Myrj 53 (85 mg%) in isotonic sodium chloride solution.

To try:

The rats are divided as evenly as possible according to their body weight into different groups. After plethysmographic measurement of the right hind paw volume, 0.1 ml of adjuvant is injected into the paw by subplantar injection. The right hind paw is measured from day 14 of the experiment until the end of the experiment. The experiment time is 3 weeks.

The dose level of the test substance at which 40% healing (ED40) is reached is determined.

A common complication in non-steroidal anti-inflammatory therapy is the occurrence of gastric ulcers. These side effects can be demonstrated by animal experiments, using as a dose the amount of test substance observed in the Adjuvans-Arthritis 40 o / o recovery test.

The ulcer test is performed as follows:

• Male Wlster rats (SPF) are used. Animals have a weight range of 130 and 10; G; 18 hours prior to the start of the experiment, the rats are not fed, but are given water ad libitum.

5 animals are used per dose. The substance is applied once orally, dissolved in sodium chloride solution, or as a crystal suspension with the addition of 85 mg / ml Myrj 53.

hours after administration of the substance, 1 ml of a 3% pure diphenyl blue dye solution is injected intravenously and the animals are sacrificed. The stomachs are removed and the number of epithelial lesions and the number of tumors that excel with the dye are examined microscopically.

The results obtained in these tests with compounds 5 to 8 according to the invention as compared to known compounds 1 to 4 are shown in the following table.

Table

2- (4-Isopropylphenyl) propionic acid 2- (4-Cyclohexylphenyl) propionic acid 5-Cyclohexylindane-1-carboxylic acid 6-Chloro-5-cyclohexylindane-1-carboxylic acid 2- (4-Cyclopentylphenyl) propionic acid 2- (3 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid 6-chloro-5-cyclopentylphenyl] propionic acid 6-chloro-5-cyclophenylAdjuvans-Arthritis test (mg / kg animal)

100 ALIGN!

Number of gastric ulcers at the same dose of 6.8 idenomethylindane-1-carboxylic acid

40 7.6 50 8.3 4.0 7.8 10.0 0.6 3.0 0.6 30 2.2 40 0.7

The novel compounds are useful in combination with carriers conventional in pharmaceutical pharmacy for administration in, for example, acute and chronic arthritis, neurodermitis, bronchial asthma, hay fever and the like.

The preparation of special medicaments is carried out in a conventional manner by treating the active substances with suitable additives, carriers and flavoring agents into the desired dosage forms, such as tablets, dragees, capsules, solutions, inhalants and the like.

Especially suitable for oral administration are tablets, coated tablets and capsules containing, for example, 1 to 250 mg of active ingredient and 50 mg to 2 g of pharmacologically inactive carrier, such as lactose, amylose, talc, gelatin, magnesium stearate and the like, as well as conventional additives.

The following examples serve to illustrate the method according to the invention:

(a) 7.45 g of cyclopentyl bromide and 19.7 g of triphenylphosphine are heated in a pressure vessel under argon atmosphere for 6 hours at a bath temperature of 160 ° C. After cooling, the solid reaction product is boiled several times with benzene and then dried. 15.7 g of cyclopentyltriphenylphosphonium bromide are obtained.

(b) 4.11 g of cyclopentyltriphenylphosphonium bromide are suspended in tetrahydrofuran under argon, and 4.3 ml of a 3 M solution of butyllithium in n-hexane are added at 20 ° C. After stirring at 20 ° C for 2 hours, a solution was added at 5 ° C

2.24 g of N-chloro-5-formylindane-1-carboxylic acid in 15 ml of tetrahydrofuran. After stirring at 20 ° C for 16 hours, the reaction mixture was evaporated, the residue was treated with dilute hydrochloric acid and extracted with ether. The ether phase was washed and evaporated and the residue (2 g) was chromatographed on silica gel (eluent: 325 parts of cyclohexane -f- 160 parts of toluene -j 190 parts of ethyl acetate + 19 parts of acetic acid). 1 g of 6-chloro-5-cyclopentylidenemethylindane-1-carboxylic acid, m.p.

c) 1.58 g of 6-chloro-5-cyclopentylidenemethylindane-1-carboxylic acid is hydrogenated at 20 ° C and atmospheric pressure in 32 ml of ethanol after addition of 158 mg of platinum oxide. The catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from petrol. 0.89 g of acid is obtained

126 DEG C. 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid.

Claims (1)

Subject OF THE INVENTION A process for the preparation of phenylacetic acid derivatives of the general formula (Ia) in which n represents 1 to 5, \ n from A-B-, CH-CHa- X X R1 is a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or an amino group, R2 and R3 are hydrogen, methyl or ethylene together, X1 is two hydrogen atoms or oxo; and Yi a hydroxyamidocarbonyl group, a carbamoyl group, a carboxyl group, its salts with physiologically compatible bases, its esters with physiologically compatible alcohols, or its amides with physiologically compatible amines. characterized by condensing a compound of formula (XIII), C = CH- or CH-CO-, z z AND CH n (Xtv) wherein n is as defined above, or with a carbonyl compound of formula XV, (CH 2) _h CH 2; where R 6 represents a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms and R 1, R 2 and R 3 are as defined above, with a Wittig reagent of formula XIV, wherein n is as defined above, and optionally compounds of formula Ia wherein R 1 is halogen are dehalogenated, compounds of formula Ia wherein R 1 is hydrogen , are halogenated or filtered and the resulting nitro compounds are reduced to amino compounds, and optionally the obtained carboxylic acids or their reactive derivatives are converted into their salts, esters, amides or hydroxamic acids. Severography, n. P., Plant 7, Most