CS216207B2 - Method of making the derivatives of the 1,4-diphenylpyrazole - Google Patents

Abstract

New pyrazole derivs. are of formula (I) (where n = 1-4; R1-4 are H, halogen, alkyl, alkoxy, CF3, NO2 or NH2; and X is CN, aminocarbonyl, lower alkoxy, carbonyl or carboxyl). (I) and their salts have low toxicity and do not cause stomach disorders. Typical cpds. include (I; n = 1, X is CN; R1-4 are H). They may be prepd. from (I; X is halogen) by reaction with an alkali metal cyanide, opt. followed by hydrolysis or redn. In an example, 2.81g (I; X is Br; n = 1; R1-4 are H) was treated with 1.17g KCN and 300 mg 18-dibenzo-6-crown (catalyst) in acetonitrile at 40 degrees C to give (I: X is CN; n = 1; R1-4 are H).

Description

The invention relates to a process for the preparation of derivatives

1,4-diphenylpyrazole of general formula I

wherein R 1, R 2, R 3 and R 1 are - is ortho, meta, or p-position and denote hydrogen, fluorine, chlorine and bromine, methyl, methoxy, methyl, methoxy, or methyl; the l-group, the intros-upin, or the amine group,

X represents a cyano group, an aminocarbonyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy radical, a carboxyl group.

n denotes 1, 2, 3 or 4, or their physiologically acceptable salts. ·

As the alkoxycarbonyl group derived from a low alkoxy group containing from 1 to 6 and 2 carbon atoms, for example, methoxy, - ethoxy, - propyloxy, isopropyloxy, butyloxy, tert-butyloxy, - pentyloxy or hexyloxy.

Physiologically acceptable salts are, for example, alkali metal and alkaline earth metal salts, such as - - sodium salts, - lithium, calcium or magnesium, copper - - or · - - amine salts, such as: for example, N-methylglucamine, N, N-dimethylbenzamide salts, even salt, ethanolamine, diethyl salt, or morpholine salt.

The process for the preparation of the new pyrazole derivatives of the general formula (I) consists in the formation of a pyrazole derivative of the general formula (II).

in which

R 1, R 2, R 3, R 1, and n are as previously defined and reacted with diazomethane formed by the diazoke. is switched over in the presence of water, ammonia or low alcohol; and. optionally the nitro groups present are reduced, the ester groups. the saponification or amide groups are dehydrated.

The process according to the invention is carried out under the conditions usually used in Arndt-Eistert syntheses. Thus, compounds of general formula II ¹ (prepared by reacting the corresponding carboxylic acid with a chlorinating agent reservoir means as · thiouylchloridem, phosphorous oxychloride, phosphorous pentachloride .or] · reacted with an ether solution of diazomethane by the built · diazoiketony caused to react in · · water · .nízkém an alcohol or a solution of ammonia in the presence of colloidal copper, silver, silver oxide or silver nitrate, to give acids, acid amides or acid esters of the general formula I.

Possible subsequent hydrolysis of the cyano compounds of the formula I is likewise carried out. carried out under conditions:. known to those skilled in the art. Thus, for example, nitriles can be partially hydrolyzed in the corresponding amines with strong mineral acids (such as hydrochloric acid or sulfuric acid) or completely hydrolyzed to the corresponding carboxylic acids under stringent conditions.

The possible subsequent conversion of the carboxylic acids into the corresponding amides or nitriles is also carried out by known working methods.

For example, acid chlorides, mixed anhydrides or esters corresponding to carboxylic acids can be converted under the known conditions by treatment with ammonia in the corresponding amides. ; . . ../·. ''. :

The possible subsequent conversion into nitriles is carried out, for example, in such a way that they are converted to the corresponding aminocarbonyl compounds. the known conditions act by means of water-absorbing agents such as dicyclohexylcarbodiimide; carbonyldiimidazole, polyphosphoric acid, thiúnyl chloride, or phosphorous oxychloride. ·· · 'r' · ·. '

Optional sterification of the free acids is also carried out by known methods. For example, the acids can be reacted with diaisomethane or diazoethane. to give the corresponding methyl esters or ethyl esters. A generally applicable method is the reaction of acids with alcohols in the presence of carbonyldiimidazole or dicyclohexanecarbodiimide.

Furthermore, it is possible, for example, to react the acids with an alkyl halide in the presence of copper oxide or silver oxide.

Another method is to convert the free acids into dimethylformamide alkyl acetal to the corresponding alkyl salts of the acids. In addition, the acids can be reacted with alcohol or esters of low alkanecarboxylic acids and alcohols in the presence of strongly acidic catalysts such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoromethylsulfonic acid or p-toluenesulfonic acid.

However, it is also possible to convert carboxylic acids into acid chlorides or mixed acid anhydrides and to react with alcohols in the presence of basic catalysts such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.

Salts of carboxylic acids are formed, for example, when saponifying esters with basic catalysts or neutralizing acids with physiologically acceptable bases.

For example, the following pyrazole derivatives of the general formula 1 = (1,4-diphenyl-3-pyrazolyl) -acetic acid, 3- (1,4-diphenyl-3-pyrazolyl) -propionic acid can be produced by the process of the invention. , 4- (1,4-diphenyl-3-pyrazolyl) -butyric acid,.

5- (1,4-diphenyl-3-pyrazolyl) valeric acid a. their amides, nitrile, sodium salts, methyl esters, ethyl esters, propyl esters and butyl esters.

The novel 1,4-diphenylpyrazole derivatives of formula (I) are pharmacologically active substances which are characterized in particular by having significant anti-inflammatory activity, good tolerance to the stomach and only relatively low toxicity. In addition, these compounds. they are characterized by · fast-starting: effect · high intensity of effect. They have a favorable resorbability and relatively good stability in galenic formulations. ,

The pyrazole derivatives of formula (I) are metabolized in the body in a manner other than that of. known anti-inflammatory agents.

The novel compounds in combination with carriers customary in galenic pharmacy are suitable for treatment, for example

(a) locally:

contact dermatitis, eczema of various species, neurodermitis, · errythrodermia, burns · 1st degree, · Pruritus vulvae et ani, Rosa-. cea, Erithemiatodes curaneus, Psoriasis, Lichen ruber planus, and verrucosus;

(b) orally:

acute and chronic polyarthritis, neurodermitis, bronchial asthma senné. · Fever and others. . ·. ·. · ... ;

WITH

The preparation of the medicaments is carried out in the usual manner by converting the active ingredient with suitable additives, carriers and flavoring agents into the desired dosage forms, such as tablets, dragees, capsules, solutions, ointments, inhalants, etc.

Especially suitable for oral use are tablets, dragees and encapsules containing, for example, 1 to 250 mg of active ingredient and 5.0 mg to 2 g of a pharmacologically inactive carrier such as lactose, amylose, talc, gelatin, magnesium stearate and the like, as well as conventional additives. Powders, ointments, aerosols and the like, which preferably contain from 0.01 to 2% of active ingredient, are suitable for topical use.

The efficacy of the compounds according to the invention results from the following experimental results and from the attached table.

1. Oairragenine Paw Edema Test (cf. Proc. Soc. Exptl. Biol. Med. 111, 19-2, 544)

In rat rats, acute exudative inflammation was induced by injection of Carragenin. This inflammation is suppressible by anti-inflammatory agents. Edema is measured volumetrically.

Male Wistar rats (SPFs) in the weight range of 12.0 to 140 g are used. 16 hours prior to oral administration of the animals, the animals are removed from the feed, receiving water ad libitum.

Carragenine is the edema-inducing agent. 10 mg / ml is taken to carrageen 0.9 ⁱ⁰ / o saline solution, 0.1 mL was injected into the rat paw introduced.

A single dose of the test substance is administered to the test animal an hour before edema induction in 0.5 ml of binder for 100 g body weight. As a binder serves physiological saline solution; for water-insoluble substances, prepare a microsuspension in physiological saline with Myrj 53 (85 mg / 100 ml).

Experimental Handle:

5 animals are taken per dose group. After plethysmiographic. volumetric measurements of the right hind paw, the substances are administered orally; after one hour, inflammation is induced by intraplantar injection of 0.1 ml of the edema-inducing substance. After a further 3 hours, the volume of the levers is again measured and the inflammation suppression is calculated.

Evaluation:

o / - - mn Y.10D ° / o suppression = 100— —---

Y = mean difference in volume of the levers in the treatment group

Z - mean difference in volume of levers in the control group

2. Adjuvant arthritis test (cf. Brit. J. Pharmacol., 21, 1963, 127) Upon injection of Fraund's Adjuvant (M. butyricum), rats develop polyarthritis within about two weeks, which may be suppressed by anti-inflammatory agents .

Male and female Lewis rats (LEW) weighing 110 to 19 g g are used. The animals receive drinking water and compressed feed Altromin ad libitum.

10 rats were used for each group. Mycofoaoterium buityricum from Difko, Detroit, is used as the edema-inducing agent. A 0.5 mg suspension of M. butyricum in 0.1 ml of thinly liquid paraffin (DAB 7) is injected into the right hind paw.

The test substances were administered orally daily for 4 days from day 11. The substances are applied as a clear aqueous solution or as a crystal suspension with the addition of Myrj 53 (85 mg%) in isitonic sodium chloride solution.

Experimental Handle:

Preferably, the rats are divided into different groups relative to body weight. After plethymogrophic measurement of the volume of the right and left hind paws, a subplantar injection of 0.1 ml of the adjuvant is injected into the right hind paw. The right hind paws are measured from the 14th experimental day until the end of the experiment. Also, measurement of the non-irritated left hind paws is performed from the 14th day of the experiment. The experiment duration is <3> weeks.

Evaluation:

v Ю0% suppression = 100— --у = average volume difference of the treated group z = average volume difference of the control group

3. Gastric wall damage test:

(cf. Arch. Int. Pharmacodys. 192, 1971, 370 ff.)

Gastric ulcers are a common complication in the treatment of non-steroidal inflammatory suppressants. This side effect can be demonstrated by animal experiments.

Male Wistar rats (SPF) are used. The animals are in a weight range of 130 + 10 g. 16 hours prior to the start of the experiment, the animals are removed from the feed; receive water ad libitum.

5 animals are used per dose. The substances are applied once orally dissolved in sodium chloride or as a crystal suspension with the addition of 85; mg% Myrj 53.

hours after administration of the substances, 1 ml of a 3% diphenyl blue dye solution is injected intravenously and the animal is killed. The stomach is resected and examined microscopically for the number and size of the forests in the epithelium and ulcerations exiting the dye enrichment.

Evaluation of experiments:

The table below shows that the substances 1 and 2 according to the invention are more potent than the previously known structurally analogous compounds 3, 4Ή5 because they have a strong anti-inflammatory effect and / or induce smaller gastric ulcers.

Substance Carragenm test Adjuvant arthritis test Damage test for paw edema of the stomach wall

Dose in% suppression- Dose in ° / o suppression-% suppression- Dose in No. Area mg / kg reading mg / kg reading value mg / kg in animal animal right paw left paw mm 'Ф CM CD' r-Γ т-Г cnT

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21G207

Example 1

a) 10 ml of 2.7 g of 3- (1,4-diphenyl-3-pyrazolyl) -propionic acid are added through distilled flaxseed oil of thionyl chloride and the mixture is heated under reflux for 2 hours. The reaction mixture was then concentrated in vacuo, to the residue was added 25 ml of absolute benzene, concentrated again in vacuo to give 2.6 g.

3- (1,4-Diphenyl-3-pyrazolyl) -piropionyil chloride as a crude product.

(b) To 50 mg of crude 3- (1,4-diphenyl-3-pyrazolyl) -propionyl chloride, 5 ml of absolute benzene and 5 ml of absolute ethanol are added, and 0.2 ml of pyridine is added dropwise and the mixture is allowed to stand at room temperature for 16 hours. The reaction mixture was washed with water, dilute hydrochloric acid and water, dried and concentrated in vacuo, and the residue was recrystallized from acetone-hexane to give 38 mg of ethyl 3- (l, 95.5 DEG-98.5 DEG C. 4-diphenyl-3-pyrazolyl) propionic acid.

Example 2

a) To 1.9 g of crude 3- (1,4-diphenyl-3-pyrazolyl) -propionyl chloride in 20 ml of absolute ether is added an ethereal solution of diazomethane (prepared from 3.5 g of nitroso * methylurea, 50 ml of anhydrous ether) and 11 ml of 50% aqueous potassium hydroxide solution] and allowed to stand at room temperature for 4 hours, then the reaction mixture is concentrated in vacuo, 40 ml of ethanol are added, heated to 60 ° C, 0.2 g of freshly prepared silver oxide is added. Thereafter, the reaction mixture is clarified with activated carbon, filtered, concentrated in vacuo to give 1.7 g of 4- (1,4-diphenyl: 1-3-pyrazolyl) -maleic acid ethyl ester. as a crude product.

(b) 1.7 g of 4- (1, 4-diphinyl-3-pyrazolyl) -butyrate are dissolved in 20 ml of ethanol, 5 ml of 10% sodium hydroxide solution are added and refluxed for 2 hours. ethanol is removed in vacuo, diluted with 10 ml of water, acidified to pH 1 with hydrochloric acid and the precipitated product is filtered off.

The crude product obtained is washed with water, dried in vacuo at 60 DEG C., recrystallized from toluene to give 1.05 g of 4- (1,4-diphenyl-3'-pyrazolyl) -butyric acid, m.p. 107-109 ^g. C.

Example 3

а) To 2.5 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylacetic acid was added 10 ml of thioinyl chloride distilled with the addition of linseed oil, and the mixture was heated under reflux for 2 hours. The reaction mixture is then concentrated in vacuo, 26 ml of absolute benzene are added to the residue, concentrated again in vacuo to give 2.2 g of 4-phenyl-1- (4-tolyl) -3-pyrazolylacetyl chloride as a crude product.

(b) To 2.2 g of crude 4-phenyl-1- (4-tolyl) -3-pyrazolylation of chloride, 5 ml of absolute benzene and 5 ml of absolute ethanol are added. The reaction mixture was washed with water, dilute hydrochloric acid and water, dried and concentrated in vacuo. The residue was recrystallized from acetone-hexane to give 1.7 g of ethyl ester. 4-Phenyl-1- (4-tolyl) -3-pyrazolylacetic acid, m.p. 76-79 ° C.

Example 4

(a) To 2 g of 4- (4-nitrophenyl) -1-phenyl-3-pyrazolecarboxylic acid ethyl ester is added 70 ml of isopropanol and 15 ml of 401% potassium hydroxide solution and heated under reflux for 2 hours. The mixture is concentrated in vacuo, the precipitated crystals are filtered off with suction, and 1.67 g of 4 ', 4-nitrophenyl] -1-phenyl-3-pyrazolecarboxylic acid is obtained at a melting point of 273 ° C.

b] 0.6 ml of dimethylformamide and 10 ml of thionyl chloride are added to the carboixylic acid and refluxed for 14 hours. The reaction mixture was then concentrated in vacuo to give 1.55 g of 4- (4-nitrophenyl) -1-phenyl-3-pyrazolecarboxylic acid chloride, m.p. 226 ° C.

(c) 25 ml of dioxane and 5 ml of ether are added to the acid chloride and cooled to 10 ° C. Then, 3 equivalents of an amyl diazomethane solution was added to the mixture and allowed to stand at 10 ° C for 2 hours. The reaction mixture is concentrated in vacuo, 80 ml of isoamyl alcohol are added to the residue and filtered. A solution of 4.4 g of silver benzoate in 45 ml of triethylamine is added dropwise to the obtained solution and allowed to stand for 72 hours.

It is filtered, the filtrate is washed with aqueous sodium carbonate solution and concentrated in vacuo. The residue was purified by column chromatography on silica gel with cyclohexane ethyl acetate to give 30 mg of 4- (4-nitrophenyl) -1-phenyl-3-pyrazolylacetic acid isoamyl ester, m.p. 81 ° C.

d) The ester thus obtained was saponified to give 145 mg of 4- (4-nitrophenyl) -1-phenyl-3-pyrazolylacetic acid, m.p. 306 DEG C.

n is 1, 2, 3 or 4, or a physiologically acceptable salt thereof, characterized in that the pyrazole derivative of the general formula II

Claims (1)

A process for the preparation of 1,4-diphenylpyrazole derivatives of the general formula I in which: R 1, R 2, R 1 and R 1 are substituents in the ortho, meta or para position and are hydrogen, fluorine, chlorine and bromine, methyl, methoxy, trifluoromethyl, nitro or amino, X represents a cyano group, an aminocarbonyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy radical, a carboxyl group in which R 1, R 2, R 3, R 1 and n are as previously defined, reacted with diazomethane, the diazoketone formed is passed in the presence of water, ammonium or a low alcohol, and optionally the nitro groups present are reduced, the soap ester or amide groups are dehydrated.