CS214774B2 - 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 In,

CH (Ia) wherein n represents 1 to 5, a moiety

A — B— groups

CH-CH ₂ -,

C — CH— or

CH-CO-, iRj is hydrogen, halogen, trifluoromethyl, nitro or amino-group,

R ₂ and R ₃ are hydrogen, methyl, or together ethylene,

X _t two hydrogen atoms or oxo, and

Y is a hydroxyoxycarbanyl 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 formula (Ia) and optically active antipodes thereof.

As physiologically tolerated salts formed by the carboxylic acid group Y1 for example, alkali or alkaline earth metal salts such as sodium or calcium salts, ammonium salts, copper salts, piperazine salts or methyl glucamine salts, as well as amino acid salts of these compounds.

Physiologically tolerable alcohols with which the carboxyl group Y may be esterified are, for example, straight, branched or cyclic, saturated or unsaturated hydrocarbon radicals which may optionally be interrupted by an oxygen atom or a nitrogen atom, or may be substituted by a hydroxyl group, an amino-carboxylic acid group. alcohols (especially having 1 to 6 carbon atoms), alkanols, alkyinols, cycloalkaniols, cycloalkylalkanols, phenylalkenols, phenylalkenols, alkanediols, hydroxycarboxylic acids, aminoalkanols or ialkylamino alkyl alkanoyl alkanedioalkylaminoalkyl dialkylamino amino groups .

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

methylcarboxymethyl, ethyl, 2-hydroxyphenyl, 2-meithioxyethyl, 2-aminoelethyl, 2-dimethylaminoethyl, ₂₇ carboxyethyl, propyl, α-1-yl, cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propynyl, 3-aminopropyl- 1-butyl, sec-butyl, tert-butyl, 2-butyl, cyclobutyl, peintyl, isopentyl, t-pentyl, 2-methylbutyl, cyclopentyl, hexyl, cyclolihexyl, cyclo-2-einyl, cyclopentylmethyl, heptyl, benzyl, 2-phenylethyl, octyl, bornyl, isobornyl, -menthyl, nonyl, -decyl, 3-phenynylpropyl, 3-phenynyl-2-propenyl, undecyl or dodecyl. Suitable alcohols suitable for esterification are also those which lead to labile, i.e., physiologically cleavable, esters such as 5-hydroxyindan, acyloxymethanols, in particular acetoxymethianol, pivaloyloxymethainol, 5-indanyloxycarboinylmethylamino diallyl, glycolic acid, glycolic acid, glycolic acid, glycolic acid, especially dimethylaminopropanol as well as hydroxyphthalide.

Suitable physiologically compatible amines with which the carboxylic acid group can be amidated are, in particular, alkylamines, dialkylaminines, alkanilimines, dialkyl canolines having from 1 to 6 carbon atoms in the alkyl or alkianol radical, or pyrrolidine or six-membered nitrogen heterocycles. Suitable amines include, for example:

methylamine, ethylamine, isopropylamine, ethanolamine, dimethylamine, -diethylamine, diethunolamine, pyrrolidine, piperidine, morpholine or N-methylpiperazine.

The process for the preparation of the novel femytactic acid derivatives of the formula Ia according to the invention consists in hydrolyzing a compound of the formula III,

where \

η, ^ A — B—, X _1; R _{(R 2} and R ₃ have the abovementioned meaning and

Y ₃ denotes a (C 1 -C 6) alkoxycarbinyl, dithianyilidene or 4,4-dimethyl-2-oxazolazolyl group, and optionally the compound of formula (Ia) wherein R 1 is a halogen atom is dehalogenated or optionally the compound of formula (Ia) wherein R @ 1 is hydrogen, halogenates or isomerized and the resulting nitro compound is reduced to the amine compound and optionally the carboxylic acid or reactive derivatives thereof are converted into their salts, esters, almides or hydrioixamic acids.

The process according to the invention is carried out in a known manner by hydrolyzing compounds of the formula III with dilute mineral acids (e.g. hydrochloric, sulfuric, phosphoric acids). This hydrolysis can be carried out in the absence of additional solvents. in the presence of polar solvents such as lower alcohols (methanol, ethanol, isopropyl alcohol and the like), carboxylic acids (acetic acid, propionic acid and the like), polar ethers (glycolmiomomethyl ether, dioxah, tetrahydrofuran and the like) or in the presence of dipolar aprotic solvents ( dimethylsulfoxide or in the presence of non-polar solvents such as chlorinated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride and the like).

In addition, esters of formula (III) may be hydrolyzed using basic catalysts (such as potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium ethoxide, sodium carbonate, sodium hydroxide, sodium methoxide, and the like), which hydrolysis may be carried out in the presence of the same. solvents such as those used in acid hydrolysis.

. The process of this invention is conveniently carried out at a reaction temperature in the range of -20 to 10-0 ° C.

The preparation of the starting compounds of formula III, wherein Y ₃ is alkanoyloxy, is carried out by condensing a compound of formula XI,

R} D r $ -c < ³ _ \ _l_y ^ cooR _&> ^Rl (Xl) where

R 1, R ₂ and R ₃ are as defined above for ^1a

R ₆ represents an alkyl radical having 1 to 6 carbon atoms, in the presence of a Friedel-Cra-fts catalyst with a cycloalkanoyl chloride of the formula XII,

Ch

CHCOCl (XII) wherein, n is as defined above.

The starting compounds of formula III, where Y ₃ is a dithianylindene group, can be prepared, for example, from ketones of formula XX by reacting these ketones under known conditions (J. Med. Chem. 15, 1972, 1279) with dithlain.

n, X 1, R ₁ , R ₂ and R ₃ have the above meanings and groupings;

A -Bi- _x = CH-CH ₂ -, \

• C = CH- or s s / c-c ~

Used as starting materials compounds of general formula III, wherein Y ₃ represents a 4,4-dimethyl-2-oxazolidenovou group can for example be prepared under conditions which are described in the following examples.

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

Optionally, the subsequent separation of the acid iracemates takes place by known methods by reacting with optically active bases and separating the diastereomeric mixtures by fractionated crystallization.

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

Optionally, the subsequent halogenation of the compounds of formula (Ia) wherein R 1 is hydrogen is carried out in a conventional manner by treating the compound in an inert solvent (e.g. dichloroethane, methylene chloride, chloroform, nitrobenzene, and the like) in the presence of a Friedel-Criaft 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 compound 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, 360).

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 esters ethyl esters. A generally applicable method is also the reaction of acids with alcohols in the presence of carbonyldiimidazoil or dicyclahexylcarbodiimide.

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

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

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

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

Furthermore, it is also possible to react the esters of formula (Ia) in the presence of the acidity of the 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 with amines or hydroxylamine under known conditions 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:

2- (3-chloro-4-cyclohexylmethylphenyl) propionic acid, 6-chloro-5-cyclopentylcarbeinylindian-1-carboxylic acid, 6-chloro-5-cyclohexylidenemethylindan-1-carboxylic acid, 6-chloro-5 6-chloro-5-cyclopropylcarbonylindan-1-carboxylic acid, 6-chloro-5-cyclopropylmethylenedane-1-carboxylic acid, 5-cyclopentylmethyl-6-nitroin-dam-1-carboxylic acid , 6-amino-5-cyclopentylmethylindane-1-carboxylic acid, 5-cyclopeintylimethyl-6-fluoroindane-1-carboxylic acid, B-chloro-S-cycloheptylmethylindane-1-carbioxylic acid, 2- (3-chloro-4- cycloheptylmethylphenyl J propionic acid, 2- [3-chloro-4-cycloheptylidenemethylphenyl) propionic acid, 6-chloro-5-cycloheptylidene-ethylindan-1-carboxylic acid, 2- (3-chloro-4-cyclopentylidenemethylphenyl) propionic acid, 2 - (3-chloro-4-cyclobutylmethylphenyl) propionic acid, 6-chloro-5-cyclobutylmethylindane-1-carboxylic acid, 6- ' Chloro-5-cyclobutylidenemethylindan-1-carboxylic acid, 2- (3-chloro-4-cyclopropylmethylphenyl) propionic acid, 2- (3-chloro-4-cyclopropylidenemethylphenyl) propionic acid, 6-chloro-5-cyclopentylmethylenedane-1 -carbohydroxamic acid, 2- (3-chloro-4-cyclopentylmethylphenyl) propihydroxamic acid, and

6-chloro-5-cyclopentylmethylindane-1-carboxylic acid 2-dimethylaminoethyl ester.

The novel phenylacetic acid derivatives of formula (Ia) are, as previously mentioned, 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 relatively low toxicity problems. 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 very good resorbability.

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

Male and male Lewiis rats (LEW) weighing between 110 and 190 g are used. Drinking water and compressed ailtromine feed are administered ad libitum.

10 rats are used for each test group.

Mycohacterium butyricum is used as an irritant. A suspension of 0.5 mg Mycobaicterium butyricum in 0.1 ml liquid paraffin (DAB 7) is injected subplantarly into the right hind paw.

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% J in isotonic sodium chloride solution).

To try:

The rats are divided as evenly as possible according to their body weight into different ski 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 (= ED ₄₀ ) is reached is determined.

A common complication with non-sterile 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 at which a 40% recovery is observed in the Adjuvans-Arthritis test.

The ulcer test is performed as follows:

Male Wistair rats (SPFs) are used. Animals have a weight range of 130 + 10 grams; 16 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% Myrj 53.

hours after application of the substance, 1 ml of a 3% pure diphenyl blue dye solution is injected intravenously and the animals are sacrificed. The stomachs were removed and the microscope of the oven examined for the number of epithelial lesions the results obtained in these tests were combined and the number of tumors that excel with dice 5 to 8 according to the invention in comparative dyes. with known compounds 1 to 4.

The following table shows Table No. · Compound Ajuvans-Arthritis- number, gastric

-test (mg / kg ulcers in the same animal) dose

1 2- (4-isopropylphenyl) -100 propionová 6.8 2 2- (4-cyclohexylphenyl) propionic acid 40 7.8 3 5-Cyclohexylindan-1- -carboxyl 4.0 8.3 4 6-chloro-5-cyclohexylindin-1-carboxylic acid 10.0 7.3 5 2- (4-cyclopentylphenyl) propionic acid 3.0 0.6 6 2- (3-chloro-4-cyclopentylphenyl) propionic acid 50 0.6 7 6-chloro-5-cyclopentylmethyilindam-1-carboxylic acid 30 2.2 8 6-chloro-5-cyclo-phenylidenemethyl- 40 0.7

indian-1-carboxylic acid

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

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

Especially suitable for oral administration are tablets, coated tablets and capsules which contain, 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 exemplary embodiment serves to illustrate the method of the invention:

(a) A solution of 7,1 g of 2,2-dimethyliaziridine a

12.1 g of triethylamine in 100 ml of benzene are cooled to 10 DEG C. and this solution is treated with 1.94 g of 2- (4-cyainophenyl) propionic acid chloride in 100 ml of benzene and the reaction mixture is stirred for 15 hours at room temperature. The residue was dissolved in 350 ml of dichloromethane, treated with 0.1 ml of concentrated sulfuric acid and stirred for 15 hours at room temperature.

The solution was then neutralized by the addition of sodium bicarbonate, filtered and evaporated in vacuo. 1- (4,4-Dimethyl-2-oxazolinyl) -1- (4-chloromethyl) ethane was obtained as an oil as a crude product.

b) A solution of 5.7 g of crude product, 1- (4,4-diimethyl-2-oxazolinyl) -1- (4-cyanophenyl) ethane in 30 ml of ether, was added dropwise to the boiling solution over 20 minutes. 4.75 g of cyclilopentylmagnesium bromide in 30 ml of ether.

The reaction mixture is stirred for a further 6 hours under reflux, then a mixture of ice and hydrochloric acid is added and extracted with chloroform. The chloroform phase was washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude product obtained, 1- (4,4-dimethyl-2-oxazolinyl) -1- (4-cyclopentanoylphenyl) ethane, is added to 200 ml of 5% aqueous hydrochloric acid and refluxed for one hour. The reaction mixture was then allowed to cool and extracted with ether. The ether phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. 2- (4-Cyclopentylcarbinylphenyl) propionic acid is obtained in the form of a colorless oil.

NMR spectrum in deuterochloroform: signals at

1.5 ppm (d, J = 7 Hz, CH _3);

1.8 ppm (mc, 8H);

3.7 ppm (mc, 2H);

7.3 ppm (d, J = 7Hz, 2H);

7.9 ppm (d, J = 7Hz, 2H).

2148 7 4

Claims (1)

A process for the preparation of phenylacetic acid derivatives of the general formula (Ia) in which n represents 1 to 5, a grouping. A-B group CH-CH ₂ -, C — CH- · - or CH — CO—, // R @ 1 is hydrogen, halogen, trifluoromethyl, oitro or amino; R ₂ and R ₃ are hydrogen, methyl, or together ethylene, Xj is two hydrogen or oxococcine atoms; and Yx a hydrioixyiaiminokiairbonyl group, a kairbaimoyl group, a carboxyl group, its salts with physiologically tolerable bases, its esters with physiologically tolerable alcohols, or its amides with physiologically tolerable amines, characterized in that the compound of the formula IIIa is hydrolyzed, wherein: η, ^ A - B- X _L5 Ri, R ₂ and R ₃ have the abovementioned meaning and Y ₃ represents an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, a dithianylidene group or a 4,4-dimethyl-2-oxazolinyl group, and optionally the compounds of formula Ia wherein ^R x represents a halogen atom are dehailogenated The compounds of formula (Ia) wherein R @ 1 represents a hydrogen atom are halogenated or nitrated and the initially obtained compounds are reduced to amino compounds and, optionally, the resulting carboxylic acids or their reactive derivatives are converted into salts, esters, amides or hydroxamic acids.