CS214777B2 - 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 n is 1 to 5, group A — B—, group CH — CH2—,

C = CH— or CH — CO—,

R1 is hydrogen, halogen, trifluoromethyl, nitro or amino,

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.

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.

Physiologically tolerable salts formed by 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 methylglutamine salts, as well as salts of these compounds with amino acids.

Physiologically tolerable alcohols with which the carboxyl group Y 1 may 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 a hydroxyl, amino or are, for example, alkanols (especially having 1 to 6 carbon atoms), alkenols, alkyinols, cycloalkanols, cycloalkylalkanols, phenylalkanols, phenylalkenols, alkanediols, hydroxycarboxylic acids, aminoalkanols or alkylaminoalkanols and dialkylaminoalkanols having 1 to 4 carbon 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, behzyl,

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

3-phenylpropyl,

3-phenyl-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-hydroxyindane, acyloxymethanol, in particular acetoxymethanol, pivaloyloxymethanol, 5-indanyloxycarbonylmethanol, glycolic acid, dialkylaminoalkanols, in particular dimethylaminoalkanols, in particular dimethylaminalkanols, as well as hydroxyphthalide.

Suitable physiologically compatible amines with which the carboxyl group can be amidated are preferably alkylamines, dialkylamines, alkanolamines, dialkanolamines having 1 to β carbon atoms in the alkyl or alkanol moiety or five- or six-membered nitrogen heterocycles. As

Suitable amines include, for example: methylamine, ethylamine, isopropylamine, ethanolamine, dimethylamine, 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 consists in condensing in a known manner the compound of the formula XVIII,

where

R 6 represents a hydrogen atom or an allyl group having 1 to 6 carbon atoms and

R 1, R 2 and R 3 are as defined above, with the β-ketoester of formula (XIX), (CH 2 _h)

AND

COOR _V

I *

wherein n is as defined above and

R 7 is C 1 -C 6 alkyl, the ester group is saponified and the β-keto acid formed is decarboxylated and optionally the compound of formula Ia wherein R 1 is halogen is dehalogenated, optionally the compound of formula Ia wherein R 1 is atom hydrogen, halogenated or nitrated and the resulting nitro compound is reduced to an amino compound and optionally the obtained carboxylic acid or its reactive derivatives is converted into its salts, esters, amides, or hydroxamic acids.

The process according to the invention is carried out under known conditions by, for example, reacting the ketoester of formula XIX and the compound of formula XVIII in an inert solvent such as methanol, ethanol, dioxane, glycol monomethyl ether or dimethylformamide with bases, in particular sodium alkoxide or alkoxide. potassium, and then the resulting compound is saponified and decarboxylated with acids (such as sulfuric acid, p-toluenesulfonic acid, and the like).

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

Optionally, the subsequent resolution of the acid racenates is carried out by known methods such that they are reacted with optically active bases and the diastereomeric mixtures obtained are separated by fractional crystallization. ’

Suitable optically active bases are, for example, optically active amino acids, d- or l-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 in an inert solvent (e.g. dichloroethane, methylene chloride, chloroform, nitrobenzene, and the like) in the presence of a Friedel-Crafts reaction catalyst (e.g. 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, 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 or ethyl esters. A generally applicable method is also the reaction of acids with alcohols in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide.

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

A further 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 p-toluenesulfonic acid, with alcohols or with esters of lower alkanecarboxylic acid 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 such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.

Salts of carboxylic acids are formed, for example, by saponification of esters with the aid of basic catalysts or. in the neutralization of acids with alkali metal carbonates or hydroxides such as sodium carbonate, bicarbonate. sodium hydroxide, sodium hydroxide, potassium carbonate, potassium bicarbonate or potassium hydroxide.

⁷ Furthermore, it is also possible to react este + ry 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 amides 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 dicyclohexylcarhodiimide to give the corresponding aminocarbonyl compounds. 't *

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-cyclopentylcarbonylindan-1-carboxylic acid, 6-chloro-5-cyclohexylidenemethylindane-1-carboxylic acid, 6-chloro-5-cyclopropylidenemethylindane 1-carboxylic acid, 6-chloro-5-cyclopropylcarbonylindane-1-carboxylic acid, 6-chloro-5-cyclopropylmethylindane-1-carboxylic acid, 5-cyclopentylmethyl-6-nitroindane-1-carboxylic acid, 6-amino-5 -cyclopentylmethyl-indane-1-carboxylic acid, 5-cyclopentylmethyl-6-fluoroindane-1-carboxylic acid, 6-chloro-5-cycloheptylmethylindan-1-carboxylic acid, 2- (3-chloro-4-cycloheptylmethylphenyl) propionic acid, 2- (3-chloro-4-cycloheptylidenemethylphenyl) propionic acid, 6-chloro-5-cyclobeptylidenemethylindane-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-cyclobutylidenemeth ylindam-1-carboxylic acid, 2- (3-chloro-4-cyclopropylmethyl-214777 phenyl) propionic acid, 2- (3-chloro-4-cyclopropylidenemethylphenyl) propionic 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 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 only relatively low toxicity. In addition, these compounds are often characterized by a rapid onset of action, a high intensity of action and a 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:

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

10 rats are used for each test group. Mycobacterium butyricum Suspension 0.5 milligram of Mycobacterium butyricum in 0.1 ml of liquid paraffin (DAB 7) is injected subplantally 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 / oj 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 adjuvants are 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 achieved is determined.

A common complication in non-steroidal anti-inflammatory therapy is the occurrence of gastric ulcers. These side effects can be proven by animal experiments using 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 Wistar rats (SPF) are used. Animals have a weight range of 130 + 10 g; 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 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

Number Compound Adjuvans-Arthritistest (mg / kg animal J Number of gastric ulcers at the same dose 1 2- (4-isopropylphenyl) propionic acid 100 ALIGN! 6.8 2 2- (4-cyclohexylphenyl) propionic acid 40 7.6 3 5-Cyclohexylindane-1-carboxylic acid 50 8.3 4 6-chloro-5-cyclohexylindane-1-carboxylic acid 4.0 7.8 5 2- (4-cyclopentylphenyl) propionic acid 10.0 0.6 6 2- (3-chloro-4-cyclopentylphenyl) propionic acid 3.0 0.6 7 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid 30 2.2 8 6-chloro-5-cyclophenyl- 40 0.7

idenemethylindane-1-carboxylic acid

The novel compounds are useful in combination with carriers conventional in galenical pharmacy for administration in, for example, acute and chronic arthritis, 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, capsules, solutions, inhalants and the like.

Especially suitable for oral administration are tablets, dragees 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 and conventional ingredients.

The following exemplary embodiment serves to illustrate the method of the invention:

a) 10 g of O-chloroindane-1-carboxylic acid are mixed with 12 g of aluminum chloride in 100 ml of absolute dichloromethane and the reaction mixture is cooled to -40 ° C. To this mixture was added dropwise a solution of 8.0 g of 1,1-dichloromethyl methyl ether in 50 ml of dichloromethane over 30 minutes. The reaction mixture is then stirred for a further 30 minutes at -40 ° C, allowed to warm and then poured onto 100 g of ice with stirring. The dichloromethane phase was then separated, evaporated in vacuo and the residue recrystallized from toluene. It is obtained

8.9 g of 6-chloro-5-formylindane-1-carboxylic acid, m.p. 162 ° C.

(b) 5 g of 6-chloro-5-formylindane-1-carboxylic acid are mixed with 20 ml of absolute ethanol and 1.5 ml of concentrated sulfuric acid and the reaction mixture is refluxed for 4 hours. Then, the mixture is poured into. 50 ml of water and extracted with chloroform. The chloroform phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is purified by distillation to give 4.2 g of 6-chloro-5-formylindane-1-carboxylic acid ethyl ester, b.p. 150 DEG C. at 5 mbar.

(c) 304 mg of 6-chloro-5-formylindane-1-carboxylic acid ethyl ester was dissolved in 10 ml of ethyl alcohol and added dropwise to a mixture of 21 mg of sodium borohydride and 10 ml of ethanol with stirring. The reaction mixture was stirred at 80 ° C for 4 hours and treated with 50 mL of 10% sulfuric acid. It is then extracted with chloroform, the chloroform phase is washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. It is obtained

200 mg of 6-chloro-5-hydroxymethylindane-1-carboxylic acid ethyl ester as an oily product.

d) A mixture of 6.5 g of thionyl chloride, 5 ml of benzene and one drop of pyridine was added dropwise to a solution of 1.2 g of ethyl 6-chloro-5-hydroxymethylindane-1-carboxylic acid. The reaction mixture was then heated under reflux for one hour, allowed to cool and poured into ice water. The benzene phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. 300 mg of 6-chloro-5-chloromethylindane-1-carboxylic acid ethyl ester are obtained in the form of an oily product.

e) 2.2 g of 6-chloro-5-chloromethylindan-1-carboxylic acid ethyl ester are dissolved in 20 ml of absolute ethyl alcohol, treated with 1.38 g of cyclopentan-2-on-1-carboxylic acid ethyl ester potassium salt and was heated under reflux for 6 hours. 40 ml of water are then added to the reaction mixture, extracted with ether, the ether phase is washed with water, dried over sodium sulphate and evaporated in vacuo.

The residue was heated under reflux in 20 ml of 10% aqueous sulfuric acid for 8 hours. The reaction mixture is then allowed to cool and dilute sodium hydroxide solution is added until alkaline and finally extracted with ether. The aqueous phase is acidified and extracted once more with ether. The acidic ether extract was washed with water and dried over anhydrous sodium sulfate. 6-Chloro-5- (2-oxocyclopentylmethyl) indan-1-carboxylic acid, m.p. 126 DEG C. (from petroleum ether), is obtained.

The acid thus obtained is mixed with 15 ml of triglycol, 1 g of sodium hydroxide and 10 g of hydrazine hydrate and heated at 200 DEG C. for 2 hours. The reaction mixture was then acidified with hydrochloric acid and extracted with chloroform. The chloroform phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. Acid is obtained

6-chloro-5-cyclopentylmethylindane-1-carboxylic acid as an oily product.

NMR Spectrum in Deuterochloroform: Signals at

1.5 ppm (mc, 9H);

2.6 ppm (Mc, 6H);

3.9 ppm (t, J = 7Hz, 1 H);

7.0 ppm (s, 1 H);

7.3 ppm (s, 1H).

Claims (1)

A process for the preparation of phenylacetoacetic acid derivatives of the general formula (Ia) wherein Λ Λ fl &) n numbers 1 to 5, COOR ^ (XIX) \ \ Group A — B—, CH — CH2—, \ \ C = CH— or CH — CO—, Rt is hydrogen, halogen, trifluoromethyl, nitro or amino, R2 and R3 are hydrogen, methyl or ethylene together, X1 is hydrogen 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 (XVIII) wherein R 6 is hydrogen or C 1 -C 6 alkyl and R 1, R 2 and R 6 are as defined above, with the β-keto ester of formula XIX, wherein n is as defined above, and R 7 is C 1 -C 6 alkyl, the ester group is saponified and the β-keto acid formed is decarboxylated, and optionally compounds of formula Ia wherein R 1 is halogen are dehalogenated, compounds of formula Ia where R 1 is hydrogen, The compounds of formula (I) are halogenated or nitrated 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.