CS214775B2 - 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,

n number 1 to 5, grouping

(Ia.)

A — B— groups

CH-CH ₂ -,

C = CH— or CH — CO—, //

R ₍₁₎ is hydrogen, halogen, trifluoromethyl, nitro, or amino,

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

X1 is hydrogen or oxo; and

Y is a hydroxyoxycarbonyl group, a carbamoyl group, a carboxyl group, its salts with physiologically tolerable bases, its esters with physiologically tolerable alkenyls, or its amides with physiologically compatible amines.

The term halogen atom means preferably 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.

Suitable physiologically tolerable salts formed kairboxylcvou group Y _t can be mentioned, for example, salts with alkali metals or alkaline earth metals, · the sodium or calcium salt, ammonium salts, mědmaté, piperazine salt or methylglucamine salt, and salts thereof with amino acids .

Physiologically compatible alcohols, which may be the carboxyl group Y 1 are esterified, 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, amino or carboxyl group, such as altoanols (especially with 1 to 6) carbon atoms], alkenols, alkynyl, cycloalkanols, cycloalkylalkanols, phenylalkanotyl phenylalkemoles, alkanediols, hydroxycarbaxylic acids, aminoaltoanols or alkylaminoaltoanoils and dlalkylaminoalkanols 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-kerboxyethyl, propyl, allyl, cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propynyl, 3-aminopropyl, butyl, sec-butyl, target butyl, 2-butyl, cyclobutyl, pentyl, isopentyl, t-pentyl, 2-methylbutyl, cyclopentyl, hexyil, cyclohexyl, cyclo-2-enyl, cyclopentylmethyl, heptyl, benzyl, 2-phenylethyl, octyl, boinnyl, isobornyl, msylthyl , 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-hydroxyindene, acyloxymethanols, in particular acetoxymethianol, pivaloyloxymethanethane, 5-inclanyloxycarbcinylmethanol, glycolic acid, dlalkylaminoalcoholopropanol as well as hydroxyphthalide.

Suitable physiologically compatible amines with which the carboxyl group can be amidated are preferably alkylamines, dialkylamines, alkanolamines, diaicanolamines having 1 to 6 carbon atoms in the alkyl or alkanol residue, or five- or six-membered nitrogenous hsterocycles. Suitable amines include, for example:

methylamine, ethylamine, isopropylamine, ethanolamine, dimethylamine, diethylamine, diethamolamine, pyrrolidine, plperidine, morpholphin or N-methylplperazine.

The process for the preparation of the novel phenyioetic acid derivatives of formula (Ia) according to the invention is characterized in that the oxo group of the compound of the

\ n, A - B -, X ₁ , R _b, R ₂ and R ₃ are as defined above, wherein at least one of the groups \

A — B— or

C = X ₃ represents a carbonyl group, is reduced with hydrazine at a temperature of 100-250 ° C and optionally a compound of formula Ia, wherein R _L represents halogen, dehalogeinuje or a compound of formula Ia wherein R | it is hydrogen, halogenated or nitrated and the resulting nitro compound is reduced to an amino compound, and optionally the converted carboxylic acid or reactive derivatives thereof are converted into their salts, esters, amides, or hydroxamic acids.

The process according to the invention is carried out under conditions known to those skilled in the art under the designations Wolff-Kishner reduction and Huang-Minloni reduction.

Thus, for example, the compounds of formula VIII can be heated in a high-boiling solvent (such as ethylene glycol, triethylene glycol, and the like) in the presence of alkali metal hydroxides (sodium hydroxide or potassium hydroxide) with hydrazine to a temperature of 100-250 ° C. of formula Ia.

The starting compounds for the process according to the invention can be prepared, for example, under the conditions described below and in the following examples.

For example, the starting materials are prepared under conventional Friedel-Crafts reaction conditions. (Houben-Weyl Band VII / 2a, 1973, 38).

Thus, for example, compounds of formula XI can be reacted,

where

R j, R ₂ and _R} have the abovementioned meaning and

Rf represents a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, with a cycloalkanoyl chloride of the formula XII, <CH3 _n | (xll) in which n is as defined above, in an inert solvent, carbon disulfide, nitride or nitrobenzane with Friedel-Craits reaction catalysts such as aluminum chloride, iron (III) chloride, tin (II) chloride, titanium (IV) chloride, boron trifluoride or chloride zinc.

Preferred compounds for this reaction are those compounds of formula (XI) which contain hydrogen or halogen as the substituent R 1.

The production of the starting materials is also carried out under the conditions conventionally used in the Wittig reaction ("Organikum"; Organisch chemisches Grundpraktikum-VEB Deutscher Verlag der Wissenschaften, Berlin, 1976, 492). Thus, for example prepared from cykloalkyltrifeinylfosfoniumhatogenídu in an inert solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran or dimethyl sulfoxide, with the aid of a base, such as butyllithium or inatriumhydridu corresponding trios phine íncykloalky- ₄ fiefs solution thus obtained was allowed to respond 'vat at a temperature range from -20 ° C to 120 ° C with aldehyde (XIII,

CHO

COOR _f (Xll) where

R _b R ₂ , R ₃ and R 8 are as defined above. Reaction (of aldehyde with carbonyl compound of formula XV,

(XV) where n is as hereinbefore defined, proceeds under conditions common to 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 acid sulfuric, hydrochloric or acetic.

For example, the starting materials are also prepared under conventional conditions starting from compounds of the general formula XVI where:

R ₁ , R ₂ , R ₃ and Y ₃ are as defined above and

Z is a formyl or cyano group, or also under known conditions by condensing a compound of formula XVIII,

where

R ₍ , R ₂ , R ₃ and R _(i) are as defined above, with the β-ketoester of formula (XIX),

(XfX) wherein n is as defined above and | R ₇ denotes a lower alkyl group, the reaction being carried out in an inert solvent such as (for example, methanol, ethanol, dioxane, glycol monomethyl ether or dimethylformamide) with bases, in particular with sodium alkoxide or potassium alkoxide.

The process for the preparation of the starting compound can also be carried out under conditions known to those skilled in the art under the designation TOSMIC reafece (Tetrahedron Letters 1973, 1357).

Thus, for example, ketones of formula XX may be reacted,

wherein n, R 1, R ₂ and R ₃ have the above meanings and groupings \

And _{t -} B - denotes a group

CH.

CH - CH ₂ -, (Group

C = CH- or a group (XV1)> C-C 'with arylsulfonylmethyl isocyanide, in a polar ether (such as glycol dimethyl ether, dtoxane, tetrahydrofuran and the like) or in a dipolar aprotic solvent (such as dimethylformamide, dimethylsulfoxide, N-methylmorpholine, phosphoric acid hexamethylamide and the like) in the presence of alkali metal alkoxides (such as sodium methoxide, potassium ethoxide, potassium tert-butoxide and the like) with nrylsulfonylmethyl isocyanides (especially p-toluenesulfonylmethyl isocyanide) to give the desired compound.

If desired, the subsequent dehalogenation is also carried out in a conventional manner, for example by halogenation of the halogen. 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 resolution of the acid racemates takes place by known methods by reacting with optically active bases and separating the diastereomeric mixtures 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 ₍ 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-Cruft reaction catalyst. for example ferric chloride, ferric bromide ·, aluminum chloride and the like) halogen · (for example 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 palladoethane 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 dicyclohexyltoarbodiimide.

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

A further method consists in converting the free acids with the corresponding diimethylformiamidalkylacetals 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 saponifying the esters with the aid of basic catalysts or by neutralizing the 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 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 dicyclinhexylcarbodiimide to give the corresponding aminocarbonyl compounds.

It is furthermore possible, for example, to convert the carboxylic acid 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-cyclopentylcarbonylindian-1-carboxylic acid, 6-chloro-5-cyclohexylidenemethyl] indine-1-carboxylic acid, 6-chloro-5-cyclopropylidenemethylindine 6-chloro-5-cyclopropylcarboinylindane-1-carboxylic acid, 6-chloro-5-cyclopropylmethylindane-1-carboxylic acid, 5-cyclopentylmethyl-6-nitroindane-1-carboxylic acid, 6-amino-5-carboxylic acid -cyclopentylmethyllindane-1-carboxylic acid, 5-cyclopentylmethyl-6-fruorindan-1-carboxylic acid, 6-chloro-5-cyclohexylmethyl-1-carboxylic acid, 2- (3-chloro-4-cycloheptylmethylphenyl) propionic acid, 2 - (3-chloro-4-cyclohexylidenemethylphenyl) propionic acid, 6-chloro-5-cycloheptylidenemethylindane-1-carboxylic acid, 2- (3-chloro-4-cyclopentylidenemethylphenyl) propionic acid, 2- ( 3-chloro-4-cyclobutylmethylphenynyl propionic acid, 6-chloro-5-cyclobutyimethylindane-1-carboxylic acid, 6-chloro-5-cyclo butylidenemethylindane-1-carboxylic acid, 2- (3-chloro-4-cyclopropylmiethylphenyl) propionic acid, 2- (3-chloro-4-cyclopropylpropylmethylphenyl) propionic acid, 6-chloro-5-cyclopentylmethyl · indau-1 -carbohydroxamic acid, 2- (3-chloro-4-cyclopentylniethylphenyl) propiohydroxamic acid, and

6-Chloro-5-cyclopentylmethyl-indane-1-carboxylic acid 2-dimethylamino-ethyl ester.

The novel phenylacetic acid derivatives of formula (Ia) are, as mentioned above, pharmacologically active substances or intermediates for their preparation. The pharmacological activity of these compounds is particularly 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:

Male and male Lewis rats (LEWj 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 butyria is used as an irritant.

0.5 mg Mycobacterium 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 suspension of crystals from 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 on 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 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 at which a 40% recovery is observed in the Adjuvans-Arthritls test.

The ulcer test is performed as follows:

Male Wistar rats (SPF) 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 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.

T. A b u 1 k a

2- (4-Isoipropylphenyl) propionic acid 2- (4-Cyclohexylphenyl) propionic acid 5-Cyclohexylindane-1-carboxylic acid 6-Chloro-5-cyclohexylidane-1-carboxylic acid 2- (4-cyclopeintylphenyl) propionic acid 2- (3-chloro-4-cyclopentylphenyl) propionic acid 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid 6-chloro-5-cyclophenylidenemethylindane-1-carboxylic acid

The novel compounds are useful in combination with carriers conventional in galenic pharmacy for administration in, for example, acute and chronic arthritis, meurodermitis, 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 conventional additives.

The following examples serve to illustrate the process according to the invention.

Example 1 and 10 g of O-chloroindane-1-carboxylic acid are mixed in 100 ml of absolute dichloromethane with 12 g of aluminum chloride and the reaction mixture is cooled to -40 ° C.

To this mixture was added dropwise a solution of 8.0 g of 1 H -dichloromethyl methyl ether in 50 ml of dichloromethane over 30 minutes. The reaction mixture was stirred for 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. 8.9 g of 6-chloro-5-formylindan-1-carboxylic acid of melting point 162 DEG C. are obtained.

(b) 5 g of 6-chloro-5-aminomethylindan-1-carboxylic acid are mixed with 20 ml of absolute ethyl alcohol and 1,5 ml of concentrated sulfuric acid and the reaction mixture is heated

Adjuvians-Arthritis test (mg / kg animal) Number of gastric ulcers at the same dose 100, 6.8 40 7.6 50 8.3 / 4,0 7.8 10.0 0.6 3.0 • 0.6 30 2.2 40 0.7

for 4 hours under reflux. The mixture was then 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-formylindan-1-carboxylate, ethyl ester, b.p. 150 DEG C. at 5 Pa.

c) 304 mg of 6-chloro-5-formylindain-1-carboxylic acid ethyl ester was dissolved in 10 ml of ethanol 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. 200 mg of 6-chloro-5-hydroxymethylindan-1-carboxylic acid ethyl ester are obtained in the form of an oily product.

dj 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.

a) 2.2 g of 6-chloro-5-chloro-methylindane-1-carboxylic acid ethyl ester are dissolved in 20 ml of absolute ethyl alcohol, treated with 1.38 g of potassium salt of cyclopentan-2-one-1-carboxylic acid ethyl ester, and was heated under reflux for 6 hours. The reaction mixture is then added to 40 ml of water, 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 was acidified and re-etherified once more with ether. The acidic ether extract was washed with water and dried over anhydrous sodium sulfate. There was obtained 6-chloro-5- (2-oxocyclopentylmethyl) indan-1-toairboxylic acid, m.p. 126 [deg.] C (from petroleum ether).

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. 6-Chloro-5-cyclopentylmethylindane-1-carboxylic acid is obtained in the form of an oily product.

NMR spectrum in deuterocloroform:

Signals at

1.5 ppm (mc, 9H);

2.6 ppim (me, 6H);

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

7.0 ppm (s, 1H);

7.3 ppm (s, 1H).

Example 2

(a) 0.50 g of cyclopentanone and 1.35 g of 6-chloro-5-formylindane-1-carboxylic acid are stirred in a mixture of 6.2 ml of acetic acid and 2 ml of concentrated sulfuric acid for one hour at 20 ° C. The reaction mixture was then poured into ice water and extracted with ether. The ether phase was washed neutral, evaporated and the residue chromatographed on a silica gel column (eluent 325 parts cyclohexane + 160 parts toluene + 190 parts ethyl acetate 19 parts acetic acid). 0.41 g of 6-chloro-5- (2-oxopentylidenemethyl) indan-1-carboxylic acid is obtained, m.p. b) 2.5 g of 6-chloro-5- (2-oxopentylideinomethyl) 170 ° C.

of indan-1-carboxylic acid is mixed with 1.3 g of hydrazine hydrate, 26 g of sodium hydroxide and 40 ml of triglycol, and the reaction mixture is heated at 200-220 ° C for 2 hours. After cooling, it is mixed with water, acidified with dilute hydrochloric acid and extracted with ether. The ether phase was washed with water, evaporated and the residue recrystallized from gasoline. 0.9 g of 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid of melting point 126 DEG C. is obtained.

Example 3

From cyclopentanone and 2- (4-formylphenyl) propionic acid, 2- [4- (2-oxopentylidenemethyl) phenyl] propionic acid, m.p. 158 [deg.] C., was obtained as described in Example 2a. 2- (4-Cyclopentylidenemethyl) phenynylpropionic m.p.

Claims (1)

A process for the preparation of phenylacetic acid derivatives of the general formula Ia, X, two hydrogen atoms or oxococcus and Y _t hydroxyamidokarbonylovou group, a carbamoyl group, a carboxyl group, salts thereof with physiologically tolerated bases, esters thereof with physiologically tolerated alcohols or amides with physiologically tolerated amines, characterized in that the oxo compound of formula VIII, where n is the numbers 1-5 , grouping A - B - groups (CH - CH ₂ -. COOH IVII) where G — CH— or CH — CO—, // R1 is a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or an amino group, R ₂ and R ₃ are hydrogen, methyl, or together an ethylene group, n, A-B, R 1, R ₂ , R ₃ and X ₃ are as defined above, with at least one of A — B— or / \ C ~ X | denotes a carbonyl group, reduced with hydrazine at a temperature in the range of 100 to 250 ° C, and optionally a compound of formula Ia, wherein denotes halogen, dehalogenates, compounds of the formula Ia, in which R 1 denotes hydrogen, halogen; or nitrates, and the resulting nitro compounds are reduced to the amino compounds and the resulting carboxylic acids or their reactive derivatives are converted to their salts, esters, amides or hydroxaimic acids, optionally.