GB1562943A

GB1562943A - Pyrazole derivatives and their manufacture and use

Info

Publication number: GB1562943A
Application number: GB33042/76A
Authority: GB
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1975-08-08
Filing date: 1976-08-09
Publication date: 1980-03-19
Also published as: NL7608810A; HU175423B; IE43659B1; CS216205B2; AU514889B2; DE2633992A1; NL188696B; CS216207B2; DK147973C; LU75548A1; DK147973B; DE2633992C2; IE43659L; BE844972A; CS216206B2; DK356676A; NL188696C; AU2201477A; DD128130A5

Description

(54) NEW PYRAZOLE DERIVATIVES AND THEIR MANUFACTURE AND USE (71) We, SCHERING AKTZENGESELLSCHAFT, a Body Corporate organised according to the laws of Germany, of Berlin and Bergkamen, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention is concerned with new pyrazole derivatives and with their manufacture and use.

The present invention provides pyrazole derivatives of the general formula I

in which n represents 1, 2, 3 or 4, Rl, R2, R3 and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and R4 being in the ortho meta- or para-position, and X represents a cyano group, an aminocarbonyl group, an alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy group or a carboxyl group, and physiologically tolerable salts of such compounds in which X represents a carboxyl group.

As an alkoxycarbonyl group there may be mentioned, (for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert.-butoxy group, a pentyloxy group or a hexyloxy group).

As physiologically tolerable salts there are to be understood, for example, alkali metal salts or alkaline earth metal salts, for example sodium salts, lithium salts, calcium salts or magnesium salts, copper salts or amine salts, for example N-methylglucamine salts, N,N~dimethylglucamine salts, ethanolamine salts, diethanolamine salts or mrpholine salts.

As an alkyl group represented by each of the symbols R1, R2, R, and Ri there is to be understood preferably a group containing 1 to 4 carbon atoms, for example an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert.-butyl group or especially a methyl group.

As an alkoxy group represented by each of the symbols Rl, R2, R, and R4 there is to be understood preferably a group containing 1 to 4 carbon atoms. Examples of suitable alkoxy groups are ethoxy, propoxy, butoxy or especially methoxy groups.

As a halogen atom represented by each of the symbols R1, R2, R3 and R, there is to be understood especially a fluorine atom or a chlorine atom.

The present invention also provides a process for the inanufacmre of the new pyrazole derivatives and the aforesaid new physiologically tolerable salts, wherein (a) a pyrazole derivative of the general formula II

in which n, R1, R2, R3 and R4 have the meanings given above and Y represents a halogen atom, is reacted with an alkali metal cyanide and, if desired, the resulting compound of the general formula I, in which X represents a cyano group, is hydrolysed to form a compound of the general formula I, in which X represents an aminocarbonyl or a carboxyl group, and/or any nitro group present is reduced to form an amino group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a C16-alkyl ester thereof, or (b) a pyrazole derivative of the general formula III

in which n, R,, R2, R,, R4 and Y have the meanings given above, is reacted, in the presence of a deprotonizing agent with a malonic acid dialkyl ester or a cyanoacetic acid alkyl ester and the resulting reaction product is hydrolysed and decarboxylated to form a compound of the general formula I, in which X represents a carboxyl group or a cyano group (depending on whether a malonic acid dialkyl ester or a cyanoacetic acid alkyl ester, respectively, is used as starting material), and, if desired, any nitro group present is reduced to form an amino group and/or any cyano group is hydrolysed to form an aminocarbonyl group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or a corresponding amide or esterified to form a C, C4-alkzrl ester thereof, or (c) a pyrazole derivative of the general formula II

in which z:, R" R, R R" and Y have the meanings given above, is reacted if appropriate in the presence of an ether, with magnesium or lithium and the resulting organo-metal compound is treated with carbon dioxide to form a compound of the general formula I, in which X represents a carboxyl group, and, if desired, any nitro group present is reduced to form an amino group and/or the resulting carboxylic acid is converted into a physiologically tolerable salt thereof, a corresponding amide or nitrile or a C1--C,-alkyl ester thereof, or (d) a pyrazole derivative of the general formula IV

in which n, R1, R R, and R have the meanings given above, is reacted with diazomethane and the resulting diazoketone is rearranged in the presence of water, ammonia or a C,--C,;-alcohol to form a compound of the general formula I, in which X represents a carboxyl, aminocarbonyl or alkoxycarbonyl group, respectively, and, if desired, any nitro group present is reduced to form an amino group and/or any ester group present is hydrolysed to form a carboxyl group or any aminocarbonyl group present is dehydrated to form a cyano group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof.

Variant (a) of the process according to the present invention may be carried out under the conditions usually employed to replace halogen atoms by a cyano group.

For this variant of the process, there are preferably used as the starting compounds of the general formula II those that carry a chlorine, bromine or iodine atom (repre sented by the symbol Y).

This reaction is preferably carried out in a dipolar, aprotic solvent (for example dimethylformamide, N-methylacetamide, N-methylpyrrolidone, acetonitrile, dimethyl sulphoxide or hexamethylphosphoric acid triamide). Sodium cyanide or potassium cyanide is preferably used as the alkali metal cyanide for this reaction In this reaction, the rate of reaction can be accelerated significantly by carrying out the reaction in the presence of a crown ether.

Variant (b) of the process according to the present invention may be carried out in a manner known per se, by reacting the cyanoacetic acid esters (for example cyanoacetic acid methyl ester or cyanoacetic acid ethyl ester) or the malonic acid dialkyl esters (for example malonic acid dimethyl ester or malonic acid diethyl ester), in an inert solvent, with a deprotonizing agent and then with a pyrazole derivative of the general formula III (preferably a chloride, bromide or iodide).

Suitable inert solvents for this reaction are, for example, hydrocarbons (for example benzene, xylene or toluene) or ethers (for example dioxan, tetrahydrofuran or glycol dimethyl ether). The deprotonizing agents used for this reaction are alkali metal alcoholates (for example sodium methylate or potassium tert.-butylate), alkali metal hydrides (for example sodium hydride or potassium hydride), alkali metal amides (for example sodium amide or potassium amide) or thallium-alkoxy compounds (for example thallium ethylate).

After the reaction has been carried out, the esters formed are hydrolysed in a manner known per se (for example by reaction with bases, for example sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate, in the presence of water) and are decarboxylated by heating. The decarh oxylation can be carried out in the absence of solvents or in the presence of a highboiling solvent (for example xylene, chlorobenzene or decalin).

Variant (c) of the process according to the present invention may be carried out in a manner known per se, for example by reacting the compounds of the general formula II (preferably the chlorides, bromides and iodides) with magnesium or lithium in a suitable solvent (for example diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran or, where appropriate, benzene) and treating the organo-metallic compounds so prepared with solid carbon dioxide.

Variant (d) of the process according to the present invention may be carried out under the conditions that are usually employed in Arndt-Eistert syntheses. Thus, the compounds of the general formula IV (manufactured by reacting the corresponding carboxylic acids with a chlorinating agent, for example thionyl chloride, phosphorus oxychloride or phosphorus pentachloride) can be reacted with a solution of diazo methane in ether, and the resulting diazoketones can be reacted in water, a C1C- alcohol or an ammonia solution, in the presence of colloidal copper, silver, silver oxide or silver nitrate, to give the acids, acid esters or acid amides of the general formula I.

The optional subsequent hydrolysis of cyano compounds of the general formula I may also be carried out under conditions that are well known to those skilled in the art.

Thus, for example, the nitriles can be hydrolysed, for example with strong mineral acids (for example hydrogen chloride or sulphuric acid), either partially to the corresponding amides or, under more severe conditions, completely, to the corresponding carboxylic acids.

The optional subsequent conversion of the carboxylic acids to the corresponding amides or nitriles may also be carried out with the aid of well-known methods of working.

Thus, for example, it is possible to convert the acid chlorides, mixed anhydrides or esters, corresponding to the carboxylic acids, into the corresponding amides by treatment with ammonia under the known conditions.

The optional measure of subsequent conversion to nitriles may be carried out, for example, by treating the corresponding aminocarbonyl compounds, under the known conditions, with dehydrating agents, for example dicyclohexylcarbodiimide, carbonyldiimidazole, polyphosphoric acid, thionyl chloride or phosphorus oxychloride.

The optional subsequent esterification of the free acids may also be carried out in accordance with methods of working known per se. Thus, for example, the acids can be reacted with diazomethane or diazoethane, and the corresponding methyl esters or ethyl esters are obtained. A generally applicable method is to react the acids with the alcohols in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide.

Furthermore it is possible, for example, to react the acids with alkyl halides in the presence of copper-(I) oxide or silver oxide.

A further method is to convert the free acids into the corresponding alkyl esters of the acids by means of the corresponding dimethylformamide alkyl-acetals. Furthermore, the acids can be reacted with the alcohols or the lower alkanecarboxylic acid esters of the alcohols in the presence of strongly acidic catalysts, for example hydrogen chloride, sulphuric acid, perchloric acid, trifiuoromethylsulphonic acid or ptoluene- sulphonic acid.

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

The salts of the carboxylic acids are produced, for example, by saponifying the esters by means of basic catalysts, or by neutralizing the acids with bases capable of forming physiologically tolerable salts.

Using the process of the present invention it is possible, for example, to manufacture the following pyrazole derivatives of the general formula I and salts thereof, namely (1,4-diphenyl-3-pyrazolyl)-acetic acid, 3-( 1,4Aiphenyl-3-pyrazolyl)-propionic add, 4-(1,4-diphenyl-3-pyrazolyl)-butyric acid and 5-(1,4-diphenyl-3 -pyrazolyl)-valeric acid and their amides, nitriles, sodium salts, methyl esters, ethyl esters, propyl esters and butyl esters.

The new pyrazole derivatives of the general formula I and the aforesaid physiologically tolerable salts are pharmacologically active substances which are distinguished more especially by the fact that they possess a pronounced anti-inflammatory activity, are well tolerated by the stomach and have only a relatively low toxicity. In addition, these compounds are frequently distinguished by the fact that their action commences rapidly and is of high intensity and of long duration; they also have a favourable resorbability, and a relatively good stability in galenical formulations.

The pyrazole derivatives of the general formula I and the aforesaid salts are metabolized in the body in a different way from known anti-inflammatory compounds.

The new compounds are suitable, in combination with the carrier materials customarily used in, for example, galenical pharmacy, for the treatment of, for example, the following conditions: a) local treatment: contact dermatitis, eczemas of a very wide variety of types, neurodermitis, erythrodermia, first-degree burns, pruritus vulvae et ani, rosacea, erythematodes cutaneus, psoriasis and licen ruber planus et verrucosus; b) oral treatment: acute and chronic polyarthritis, neurodermitis, bronchial asthma and hay fever.

The present invention accordingly further provides a pharmaceutical preparation which comprises a compound of the general formula I or a physiologically tolerable salt of such a compound in which X represents a carboxyl group, in admixture or conjunction with a pharmaceutically suitable carrier.

The pharmaceutical preparations may be prepared in the usual manner by converting the active substances, with suitable additives, excipients and flavour correctants, into the desired forms for administration, for example tablets, drag es, capsules, solutions, powders, salves, aerosols and inhalant preparations.

For oral use, tablets, drawees' and capsules are especially suitable, which contain, for example, 1-250 mg of active substance and 50 mg-2 g of a pharmacologically inactive excipient, fi example lactose, amylose, talc, gelatine or magnesium stearate, as well as the customary additives. Powders, salves, aerosols and similar preparations, which preferably contain 0.01 to 2% by weight of the active substance, are suitable for topical application.

The starting compounds of the general formulae II and III, which have not prP viously been known and are also included within the scope of the present invention, can be prepared from the corresponding carboxylic acid esters by, for example, reducing these with lithium aluminium hydride to form the corresponding carbinols and replacing the hydroxyl group of the latter by a halogen atom, as is described below, by way of example, for the synthesis of 3-bromomethyl-1,4diphenyl-pyrazole: a) 3 g of uiethylamiine and a solution of 6.78 g of (2chloro-2-phenylhydrazono)- acetic acid ethyl ester in 20 ml of dry, ethanol-free chloroform were added successively, at room temperature, to 5.67 g of I -morpholinostyrene in 35 ml of dry ethanol-free chloroform. The reaction mixture was stirred for one hour at 40"C and 16 hours at room temperature and was washed with dilute hydrochloric acid, a dilute sodium carbonate solution and water, dried and concentrated in vacuo.

The residue was digested with hexan and recrystallized from ethanol-hexane, and 7.3 g of 4-morpholino-3-phenyl-2-phenylhydrazono-3-butenoic acid ethyl ester melting at 13()131OC were obtained.

b) 33 g of 4-morpholino-3-phenyl-2-phenylhydrazono-3-butenoic acid ethyl ester were mixed with 330 mi of dioxan and 100 ml of 2N hydrochloric acid and the mixture was heated for 45 minutes under reflux. The reaction mixture was then concentrated in vacuo, the residue was dissolved in chloroform, and the chloroform solution was washed, dried and concentrated in vacua. The residue was recrystallized from ethanol-hexane and 21.15 g of 1,4-diphenyl pyrazolew3-carboxylic acid ethyl ester melting at 103-104 C were obtained.

c) A solution of 17.2 g of 1,4diphenyl-pyrazole-3-carboxylic acid ethyl ester in 80 ml of absolute tetrahydrofuran was added dropwise, at O"C, to 4.63 g of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran, under nitrogen.

The reaction mixture was stirred for a further 30 minutes, 40 ml of a saturated aqueous sodium chloride solution were added, and the batch was acidified with dilute hydrochloric acid and extracted with ether. The organic phase was concentrated, the residue was digested with hexane and 14.65 g of 3-hydioxymethyl-1,4-diphenyl- pyrazole crude product melting at 104-105 C were obtained.

d) 130 ml of 63% strength hydrobromic acid were added to 13.2 g of 3-hydroxy methyl-1,4-diphenyl-pyrazole crude product and the mixture was heated at 90"C for 4 hours.

The reaction mixture was then concentrated in vacuo and the excess hydrogen bromide was removed by repeatedly taking up the residue in toluene and concentrating in v'w.

The residue was recrystallized from isopropanol and 10.8 g of 3-bromomethyl 1,4diphenl-pyrazole melting at 99 C were obtained.

The following Examples illustrate the invention: Example 1 a) 2.81 g of 3-bromomethyl-1,4diphenylpyrazole in 30 mi of absolute aceto nitrile were stirred with 1.17 g of potassium cyanide and 300 mg of dibenzo 18-crownZ for 10 hours at 40 C.

The reaction mixture was then concentrated in vacuol, mixed with water and extracted with methylene chloride, and the organic phase was washed, dried and concentrated in vak:'so.

2.6 g of (1,4-diphenyl-3-pyrazolyl)-acetonitrile were thus obtained as a crude prods b) 2.6 g of (1,4diphenyl-3-pyrazolyl)-acetonitrile crude product were stirred with 20 ml of concentrated hydrochloric acid for one hour at a reaction temperature of 50"C. The reaction mixture was then diluted with water and extracted with methyl isobutyl ketone, the organic phase was washed and concentrated in value, and 2.3 g of (1,4-diphenyl-3-pyrazolyl)-acetamide were obtained as a crude product c) 2.3 g of (1,4-diphenyl-3-pyrazolyl)-acetamide crude product and 40 ml of a 10% strength aqueous sodium hydroxide solution were heated under reflux for 30 minutes, under argon. The reaction mixture was then cooled in an ice bath, acidified with 2N hydrochloric acid and extracted with methylene chloride, and the methylene chloride phase was washed, dried and con centrated tn vxuo.

The resulting crude product was recrystallized from toluene and 1.25 g of (1,4diphenyl-3-pyrazolyl)-acetic acid melting at 131--133"C were obtained.

Example 2 a) A mixture of 2.6 g of (1P-diphenyl-3-pyrazolyl)-acetonitrile crude product prepared as described in Example 1 (a)] and 15 ml of 80% strength sulphuric acid was heated to 1200C and stirred for 2 hours at this tempera ture. The reaction mixture was then poured into ice water and extracted with methylene chloride, and the methylene chloride phase was washed, dried and concentrated in vaciw.

The residue was dissolved in a 5% strength aqueous sodium carbonate solution and the product was precipitated with 10% strength hydrochloric acid, filtered off, washed and dried in vxuo at 60"C. It was then recrystallized from toluene and 1.6 g of (1,4-diphenyl-3-pyrazolyl)-acetic acid melting at 131--133"C were obtained.

b) 200 mg of (1,4-diphenyl-3-pyrazolyl)-acetic acid were dissolved in l0 ml of absolute ethanol, 7.6 ml of a 0.1N aqueous sodium hydroxide solution were added to the ethanol solution, and the mixture was concentrated in wouo.

The residue was again taken up in 10 ml of absolute ethanol and again concentrated m wcs.

The resulting crude product was dissolved in a small amount of absolute ethanol, absolute diethyl ether was added to the solution and sodium (1,4-diphenyl-3-pyrazolyl)" acetate was obtained as an amorphous powder.

Example 3 a) 3.84 g of malonic acid diethyl ester and 4.7 g of 3-bromomethyl-1,4-diphenyl pyrazole were added successively to a solution of 5.6 g of thallium ethylate in 120 ml of absolute benzene, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was then diluted with diethyl ether and 100 ml of ice water were added. The organic phase was separated off, washed, dried and concentrated in vacua. 5.3 g of 2-(1,4-diphenyl-3-pyrazolyl methyl)-malonic acid diethyl ester were thus obtained as a crude product b) To 6.9 g of the resulting 2-(1,4-diphenyl-3-pyrazolyl-methyl)-malonic acid diethyl ester crude product were added 2.7 g of sodium hydroxide--dissolved in 30 ml of water-and 30 ml of dioxan, and the mixture was heated for 3 hours under reflux.

The reaction mixture was then substantially evaporated in uacuo, the residue was diluted with 100 ml of water, the mixture was extracted with diethyl ether, the aqueous phase was acidified to a pH-value of 1 with concentrated hydrochloric acid and the oily crude product which had separated out was isolated.

The resulting crude product was dissolved in diethyl ether and the solution was washed with water, dried and concentrated in vacuo.

4.25 g of 2-(1,4 diphenyl-3-pyrazolyl-methyl)-malonic acid melting at 172"C were thus obtained.

c) 4.1 g of 2-(1,4diphenyl-3-pyrazolyl-methyl)-malonic acid were slowly heated to 200"C. The reaction temperature was maintained at 200"C for a further 20 minutes, it was then allowed to cool, the resulting product was crystallized from toluene and 2.9 g of 3-(l,Wiphenyl-3-pyrazolyl)-propionic acid melting at 128--129"C were obtained.

d) 200 mg of 3-(1,4-diphenyl-3-pyrazolyl)-propionic acid were converted into amorphous sodium 3-(1,4-diphenyl-3-pyrazolyl)-propionate under the con ditions described in Example 2 (b).

Example 4 a) 10 ml of thionyl chloride, which had been distilled over linseed oil, were added to 2.7 g of 3 < 1,Sdiphenyl-3-pyrazolyl)-propionic acid and the mixture was heated for two hours under reflux. The reaction mixture was then con centrated in,o, 25 ml of absolute benzene were added to the residue, the mixture was again concentrated in vacao and 2.6 g of 3-(1,4-diphenyl-3 pyrazolylXpropionyl chloride were obtained as a crude product.

b) 5 ml of absolute benzene and 5 ml of absolute ethanol were added to 50 mg of 3-(1,4-diphenyl-3-pyrazolyl)-propionyl chloride crude product. 0.2 ml of pyridine was added dropwise to the mixture which was then allowed to stand for 16 hours at room temperature, and diluted with 20 ml of benzene; the reaction mixture was then washed with water, dilute hydrochloric acid and water, dried and concentrated in vacuo. The residue was recrystallized from acetone-hexane and 38 mg of 3-(1P-diphenyl-3-pyrazolyl)-propionic acid ethyl ester melting at 95.5-98.5 C were obtained.

Example 5 a) A solution of diazomethane in ether, prepared from 3.5 g of nitrosomethyl urea, 50 ml of anhydrous ether and 11 ml of a 50 to strength aqueous potassium hydroxide solution, was added to 1.9 g of 3-(1,4-diphenyl-3- pyr olyl)-propionyl chloride crude product in 20 ml of absolute ether and the mixture was allowed to stand for 4 hours at room temperature.

The reaction mixture was then concentrated in vaciw, 40 ml of ethanol were added, the mixture was heated to 60"C, 02 g of freshly prepared silver oxide was added and the batch was heated until the evolution of nitrogen had ceased.

The reaction mixture was then clarified with active charcoal, filtered and concentrated in vacuo, and 1.7 g of 1,4 < liphenyl-3-pyrazolyl)-butyric acid ethyl ester were obtained as a crude product.

b) 1.7 g of 4 < 1,4-diphenyl-3-pyrazolyl)-butyric acid ethyl ester were dissolved in 20 ml of ethanol, 5 ml of a 10% strength sodium hydroxide solution were added and the mixture was heated for two hours under reflux. The ethanol was then removed in wcuo, the residue was diluted with 10 ml of water and acidified with hydrochloric acid to a pH-value of 1, and the product which had separated out was filtered off.

The resuking crude product was washed with water, dried in 7xcuo at 60"C and recrystallized from toluene, and 1.05 g of 4-(1,4-diphenyl-3-pyrazolylfbutyric acid melting at 107--109 C were obtained.

Example 6 a) A solution of 15.2 g of sodium nitrite in 40 ml of water was added dropwise to a solution, at 0 C, of 21.4 g of pwtoluidine and 400 ml of 7.5% strength hydrochloric acid. The ptoluenediazonium chloride suspension so obtained was added dropwise to a mixture, at 5 C.C, of 36.2 g of 2-chloroacetoacetic acid ethyl ester, 400 ml of 50% strength ethanol and 164 g of sodium acetate. The mixture was then stirred for 3 hours at 20"C and was extracted with ethyl acetate, the organic phase was concentrated, the residue was treated with petroleum ether, and 41 g of 2-chloro-2-(4-methylphenylhydrazono) acetic acid ethyl ester melting at 100-101 C were obtained.

b) A solution of 24.7 g of 2-chloro-2-(4-methylphenylhydrazono)-acetic acid ethyl ester in 100 ml of chloroform was added dropwise to a solution of 18.9 g of -morpholinostyrene in 100 ml of chloroform and 13.8 g of tri ethylamine. The reaction mixture was allowed to stand for one hour at 50"C and 16 hours at 20"C and was washed with 2N hydrochloric acid and then with a saturated sodium bicarbonate solution. The chloroform solution was then concentrated in vacso, the residue was treated with petroleum ether, and 27.6 g of 24methylphenylhydrazono)-3-morpholino-methylene-3 phenylpropionic add ethyl ester melting at 131-132 C were obtained.

c) 260 ml of dioxan and 80 ml of 2N hydrochloric acid were added to 27.6 g of 2 - (4 - methylphenylhydrazono) - 3 - morpholino - methylene - 3 - phenyl- propionic acid ethyl ester and the mixture was hea hydrofuran. The mixture was stirred for a further hour, and 25 ml of a saturated sodium chloride solution were added, followed by 63 ml of 20% strength hydrochloric acid. The reaction mixture was then extracted with ether, the ether phase was concentrated in va, the residue was treated with petroleum ether, and 12 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylmethanol melting at 125"C were obtains e) 2.65 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylmethanol in 60 ml of 63% strength hydrobromic acid were heated at 90"C for 5 hours. The reaction mixture was then diluted with water, the product which had separated out was filtered off with suction and recrystallized from isopropanol, and 2.9 g of 3-bromomethyl-4-phenyl-1-(4-tolyl)-pyrazole melting at 98 C were obtained.

f) 4.7 g of potassium cyanide, 70 ml of acetonitrile and 500 mg of dibenzo-18- crown-6 were added to 5.9 g of 3-bromomethyl-4-phenyl-1-(4-tolyl)-pyrazole and the mixture was stirred for 10 hours at 40"C. The reaction mixture was then concentrated in vacwa, the residue was mixed with water and the mix ture was extracted with methylene chloride. The methylene chloride phase was washed and concentrated, the residue was recrystallized from methanol, and 4.7 g of 4phenyl-1-(4-tolyl)-3-pyrazolylacetoritrile melting at 91--92"C were obtained.

g) 4.7 g of 4phenyi-1-(4tolyi)-3-pyrazolylacetonitrile in 27 ml of 80% strength sulphuric acid were heated for 2 hours at 12000. The reaction mixture was allowed to cool and was diluted with water and extracted with methylene chloride. The organic phase was washed and concentrated, the residue was recrystallized from toluene, and 3.2 g of 4-phenyl-1-(4-tolyl)3-pyrazolylacetic0.

acid melting at 12F125 C were obtained.

Example 7 a) 2.5 g of 4-phenyl-1*-tolyl)-3-pyrazolylacetonitrile were stirred for one hour with 20 ml of concentrated hydrochloric acid at a reaction temperature of 500cm The reaction mixture was then diluted with water and extracted with methyl isobutyl ketone, the organic phase was washed and concentrated in ewnco, and 1.9 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetamide were obtained as a crude product.

b) 1.9 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetamide crude product in 40 ml of a 10% strength aqueous sodium hydroxide solution were heated under reflux for 30 minutes, under argon. The reaction mixture was then cooled in an ice bath, acidified with 2N hydrochloric acid and extracted with methylene chloride, and the methylene chloride phase was washed, dried and concen trated in vacua. The resulting crude product was recrystallized from toluene and 0.95 g of 4-phenyl-1-4-tolyl)-3-pyrazolylacetic acid melting at 124.5- 126"C were obtained.

Example 8 a) 10 ml of thionyl chloride, which had been distilled over linseed oil, were added to 2.5 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetic acid, and the mixture was heated for 2 hours under reflux. The reaction mixture was then concen trated in vo, 25 ml of absolute benzene were added to the residue, the mixture was again concentrated in veaea, and 2.2 g of 4-phenyl-1 < 4-tolyl)- 3-pyrazolylacetyl chloride were obtained as a crude product.

b) 5 ml of absolute benzene and 5 ml of absolute ethanol were added to 2.2 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetyl chloride crude product. 0.2 ml of pyridine was added dropwise to the mixture which was allowed to stand for 16 hours at room temperature, and diluted with 20 ml of benzene, and the reaction mixture was then washed with water, dilute hydrochloric acid and water, dried and concentrated in vacteo. The residue was recrystallized from acetone/hexane and 1.7 g of 4-phenyl-1-(4-tolyl)-3-pyrazolylacetic acid ethyl ester melting at 7679 C were obtained.

Example 9 a) Toluidine was reacted to form 2-chloro-2-(2-methylphenylhydrazono)-acetic acid ethyl ester, melting at 72"C, under the conditions described in Example 6 (a).

b) The resulting product was reacted, as described in Example 6 (b), to form 2 - (2 - methylphenylhydrazono) - 3 - morpholinomethylene - 3 - phenyl propionic acid ethyl ester melting at 109"C.

c) The resulting compound was converted into 4-phenyl-1-(2-tolyl)-3-pyrazolyl carboxylic acid ethyl ester, melting at 80"C, under the conditions described in Example 6 (c).

d) The resulting product was reduced, as described in Example 6 (d), to form 4-phenyl-1-(2-tolyl)-3-pyrazolylmethanol melting at 121 C.

e) The bromination of this compound, as described in Example 6 (e), yielded 3-bromomethyl-4-phenyl-1-(2-tolyl)-pyrazole melting at 67"C.

f) The bromide was converted into phenyl-1-(2-tolyl)-3-pyrazelylacetomtrile, melting at 23"C, under the conditions described in Example 6 (f).

g) The resulting nitrile was hydrolysed as described in Example 6 (g) and 4-phenyl-1-(2-tolyl)-3-pyrazolylacetic acid, melting at 177"C, was obtained.

Example 10 a) o-Chloroaniline was converted into 2-chloro-2-(2-chlorophenylhydrazono) acetic acid ethyl ester, melting at 92"C, as described in Example 6 (a).

b) The resulting compound was converted into 2-(2-chlorophenylhydrazono)-3 morpholinomethylene3-phenyipropionic acid ethyl ester, melting at 122 C, as described in Example 6 (b).

c) The resulting product was converted into 4-phenyl-1-(2-chlorophenyl)-3- pyrazolylcarboxylic acid ethyl ester, melting at 109"C, under the conditions described in Example 6 (c).

d) The reduction of this compound, as described in Example 6 (d), yielded 4 phenyl-1-(2-chlorophenyl)-3 -pyrazolylmethanol melting at 132"C.

e) The bromination of the alcohol, as described in Example 6 (e), yielded 3 bromomethyl-4-phenyl-1-(2-chlorophenyl)-pyrazole melting at 91"C.

f) The bromide was converted into 4-phenyl-1-(2-chlorophenyl)-3-pyrazolyl- acetonitrile, melting at 62"C, under the conditions described in Example 6 (f).

g) The resulting nitrile was converted into 4-phenyl-1-(2-chlorophenyl)-3- pyrazolylacetic acid melting at 146"C, as described in Example 6 (g).

Example 11 4Phenyl-1-(4-chlorophenyl)-3-pyrazolylacetonitrile, melting at 121"C, was prepared from 4-chloroaniiine under the conditions described in Example 6 (a) to 6 (f), and was hydrolysed, as described in Example 6 (g), to form 4-phenyl-1-(4-chloro- phenyl)-3-pyrazolylacetic acid melting at 137"C.

The intermediate products obtained in the course of the preparation of the nitrile had the following physical data: 2-chloro-2-(4-chlorophenylhydrazono)-acetic acid ethyl ester, melting at 1500C, 2 - (4 - chlorophenylhydrazono) - 3 - morpholinomethylene - 3 - phenylpropionic acid ethyl ester, melting at 164"C, 4phenyl-1-(4chlorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 91"C, 4phenyi-1-(4-chiorophenyl)-3-pyrazolylnaethanol, melting at 117"C, and 3-bromomethyl4pheayl-1-(4-chlorophenyl)-pyrazole, melting at 125"C.

Example 12 4 - Phenyl - 1 - (3,4 - dichlorophenyl) - 3 - pyrazolylacetonitrile, melting at 131 OC, was prepared from 3,4-dichloroaniline, as described in Example 6 (a) to 6 (f), and was hyurolysed to form 4-phenyl-1-(3,Wichlorophenyl)-3-pyrazolylacetic acid, melting at 158"C, under the conditions described in Example 6 (g).

The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data: 2chloro-2-(3,4dichlorophenylhydrazono)-acetic acid ethyl esther, melting at 154"C, 2 - (3,4 - dichlorophenylhydrazono) - 3 - morpholinomethylene - 3 - phenylpropionic acid ethyl ester, melting at 141 0C, 4-phenyl-1-(3,4-dichlorophenyl)-3-pyrazolykarboxylic acid ethyl ester, melting at 1170C, uphenyl-1-(3,4-dichlorophenyl)-3-pyrazolylmethanol, melting at 121"C, and 3-bromornethylOphenyl-1-(3,4-dichlorophenyl)-pyrazole, melting at 108 C.

Example 13 4-Phenyl-1-(4fiuorophenyl)-3-pyrazolylacetonitrile, melting at 79 C, was prepared from pfluoroaniline under the same conditions as those described in Example 6 a)- 6 (f), and was hydrolysed to form 4phenyl-1-(4fiuorophenyl)-3-pyrazolyl-acetic acid, melting at 171"C, as described in Example 6 (g).

The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data: 2-chloro-2-(4-fluorophenvlhydrazono)-acetic acid ethyl ester, melting at 109"C, 2 - (4 - fluorophenylhydrazono) - 3 - morpholinomethylene - 3 - phenylpropionic acid ethyl ester, melting at 161 C, 4-phenyl-1-(4-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 125 C, 4phenyl-1-(4-fluorophenyl)-3-pyrazolylmethanol, melting at 146"C, and 3-bromomethylXphenyl-1-(4-fluorophenyl)-pyrazole, melting at 89"C.

Example 14 4XPhenyl-1-(2-fluorophenyl)-3-pyrazolylacetonitrile, melting at 70"C, was prepared from o-fluoroaniline under the conditions described in Example 6 (a) to 6 (f), and was hydrolysed to form 4-phenyl-1-(2-fluorophenyl)-3-pyrazolylacetic acid, melting at 154"C, as described in Example 6 (g).

The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data: 2-chloro-2-(2-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 70 C, 2 - (2 - fluorophenylhydrazono) - 3 - morpholinomethylene - 3 - phenylpropionic acid ethyl ester, melting at 99 C, 4phenyl- 1 - (2-fluorophenyl)-3 -pyrazolylcarboxylic acid ethyl ester, melting at 62"C, 4-phenyl-1-(2-fluorophenyl)-3-pyrazolylmethanol, melting at 109"C, and 3-bromomethyl-4-phenyl- l-(2-fluorophenyl)-pyrazole, melting at 102"C.

Example 15 4-Phenyl-1-(3-fluorophenyl)-3 -pyrazolylacetonitrile, melting at 74"C, was prepared from n > fluoroaniline under the conditions described in Example 6 (a) to 6 (f) and was hydrolysed to form 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylacetic acid, melting at 159 C, as described in Example 6 (g).

The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data: 2-chloro-2-(3-fluorophenylhydrazono)-acetic acid ethyl ester, melting at 1110C, 2 - (3 - fluorophenylhydrazono) - 3 - morpholinomethylene - 3 - phenylpropionic acid ethyl ester, melting at 110 C, 4-phenyl-1-(3-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester, melting at 81"C, 4-phenyl-1-(3-fluorophenyl)-3-pyrazolyl methanol, melting at 74 C, and 3-bromomethylXphenyl-1-(3-fluorophenyl) pyrazole, melting at 75 C.

Example 16 4 - Phenyl - 1 - (3 - trifluoromethylphenyl) - 3 - pyrazolylacetonitrile, melting at 76 C, was prepared from n'-trrIuoromethylaniline under the conditions described in Example 6 (a) to 6 (f) and was hydrolysed to form 4-phenyl-1-(3-trifluoromethyl- phenyl)-3-pyrazolylacetic acid, melting at 169"C, under the conditions described in Example 6 (g).

The intermediate products which were obtained in the course of the preparation of the nitrile had the following physical data: 2khloro-2 < 3-trifluoromethyl-phenylhydrazono)-acetic acid ethyl ester, melting at 131 C, 2 - (3 - trifluoromethyl - phenylhydrazono) - 3 - morpholinomethylene - 3 - phenyl propionic acid ethyl ester, melting at 125"C, 4-pheayi-1-(3-trifluoromethyl-phenyl)-3-pyrazolyka'rboxylic acid ethyl ester, melting at 66 C, 4-phenyl-1 < 3-trifluoromethyl-phenyl)-3-pyrazolylmethanol, melting at 94"C, and 3-bromomethylXphenyl-1-(3-urifluoromethyl-phenylfpyrazole, melting at 120 C.

Example 17 a) Under the conditions described in Example 6 (b) 22.7 g of - dimethylamino- 4ritrostyrene were reacted with 19.2 g of 2-chloro-2-phenylhydrazonoacetic acid ethyl ester and worked up. 3-Dimethylaminomethylene-3-(4-nitrophenyl)- 2-phenylhydrazono-propionic acid ethyl ester melting at 1390C was obtained.

b) The resulting compound was cyclized under the conditions described in Example 6 (c) to form 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester melting at 143 C.

c) 24 g of the compound obtained as described in Example 17 (b) were dissolved in 500 ml of ethanol, 5 g of Raney nickel were added and the compound was hydrogenated at room temperature under normal pressure. The catalyst was then filtered off, the filtrate was concentrated bn vacuo, the residue was recrystallized from methanol and 20 g of 4-(4-aminophenyl)-1-phenyl-3- pyrazolyl-carboxylic acid ethyl ester melting at 142"C were obtained.

d) A solution of 760 mg of sodium nitrate in 1.5 ml of water was added to 3.1 g of 4-(4-aminophenyl)-1-phenyl-3-pyrazolyl-carboxylic acid ethyl ester in 13 ml of 15% strength hydrochloric acid at -50C. 25 ml of 3% strength hydrochloric acid were then also added to the mixture and the whole, at d5 , was added dropwise to a warm solution, at 60"C, of 1.5 gof copper-(II) chloride in 30 ml of 12 % strength hydrochloric acid. The mixture was allowed to stand for a further 10 minutes at 60"C and was then cooled and extracted with ethyl acetate, the extract was concentrated, the residue was taken up in toluene, the solution was filtered through a silica gel column and was concentrated, and 2.47 g of 4(4-chlorophenyl)-1-phenyl-3-pyrazolyl- carboxylic acid ethyl ester melting at 96"C were obtained.

e) 4-(4-Chlorophenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester was con verted into 4(4-chlorophenyl)-1-phenyl-3-pyrazolylacetic acid, melting at 142"C, under the conditions described in Example 6 (d) to 6 (g).

The intermediate products obtained in the course of the synthesis of this compound had the following physical constants: 4(4chlorophenyl)-1 -phenyl-3-pyrazolylmethanol, melting at 145"C, 3-bromomethyl4(4 chlorophenyl)-1-phenylpyrazole, melting at 1100 C, and (4chlorophenyl 1-phenyl-3-pyrazolylacetonitrile, melting at 97"C.

Example 18 a) 28 ml of 1N hydrochloric acid were added to 2.4 g of 4-(4-aminophenyl)-1- phenyl-3-pyrazolylcarboxylic acid ethyl ester, the mixture was cooled to 0 C and the ester was slowly diazotized with a solution of 830 mg of sodium nitrite in 5 ml of water. The mixture was diluted with 10 ml of water and was stirred for 15 minutes at O"C. 953 mg of zinc chloride were then added to the mixture, which was allowed to stand for 30 minutes. The precipitate which had separated out was filtered off with suction, dried and taken up in 50 ml of methanol, and the solution was allowed to stand for 16 hours at room temperature and was then heated for one hour under reflux. The reac tion mixture was concentrated in vacua, the residue was taken up in benzene and the benzene phase was washed and concentrated in wcuo. 2 equivalents of sodium hydroxide solution and 2.02 g of dimethyl sulphate were added to the residue and the mixture was heated for 30 minutes at 80"C. After it had cooled, the mixture was extracted with methylene chloride, the organic phase was concentrated, the residue was recrystallized from isopropanol and 1.92 g of 4(4methoxyphenyl)-lrphenyl-3-pyrazolylcarboxylic acid ethyl ester melt ing at 94"C were obtained.

b) 4-(4-Methoxyphenyl)-l-phenyl-3-pyrazolylcarboxylic acid ethyl ester was converted into 4-(4-methoxyphenyl)-1-phenyl-3-pyrazolylacetic acid, melting at 1700C. under the conditions described in Example 6 (d) to 6 (g).

The intermediate products obtained in the course of the synthesis of this com pound had the following physical constants: 4(4methoxyphenyl)-1-phenyl-3-pyrazolylmethanol, melting at 101"C, 3 - chloromethyl - 4 - (4 - methoxyphenyl) - 1 - phenyl - pyrazole, melting at 125"C (the compound was obtained from the immediately preceding compound by reac tion with 1.1 equivalents of methanesuiphonyl chloride in pyridine at - 15 0C), and 4(methoxyphenyl)-1-phenyl-3-pyrazolylacetonitrile, melting at 83"C.

Example 19 a) 70 ml of isopropanol and 15 ml of a 40% strength potassium hydroxide solution were added to 2 g of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylcarboxylic acid ethyl ester and the mixture was heated for 2 hours under reflux. The reaction mixture was then concentrated in vacuo to a far reaching extent, the crystals which had separated out were filtered off with suction, and 1.67 g of 4-(4nitrophenyl)-1-phenyl-3-pyrazolykarboxylic acid melting at 273 0C were obtained.

b) 0.5 mI of dimethylfonnarnide and 10 ml of thionyl chloride were added to the carboxylic acid and the mixture was heated for 14 hours under reflux.

The reaction mixture was concentrated in vactto and 1.55 g of 4-($nitro- phenyl)-1-phenyl-3-pyrazolyl-:arboxylic acid chloride melting at 226"C were obtained.

c) 25 ml of dioxan and 5 ml of ether were added to the acid chloride and the mixture was cooled to 10"C. 3 equivalents of a solution of diazomethane in ether were then added to the mixture, which was allowed to stand for 2 hours at 10 C. The reaction mixture was concentrated in vacua, 80 ml of isoamyl alcohol were added to the residue, and the mixture was filtered. A solution of 4.4 g of silver benzoate in 45 ml of triethylamine was added dropwise to the solution so obtained, and the mixture was allowed to stand for 72 hours. It was then filtered and the filtrate was washed with an aqueous sodium carbonate solution and concentrated in vacuo. The residue was purified by chromatography over a silica gel column, using cyclohexane/ethyl acetate, and 395 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylacetic acid isoamyl ester melting at 81 C were obtained.

d) The resulting ester was hydrolysed as described in Example 19 (a) and 145 mg of 4(4nitrophenyl)-1-phenyl-3-pyrazolylacetic acid melting at 306 C were obtained.

Example 20 20 ml of glycol monomethyl ether and 1 g of Raney nickel were added to 210 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolyl-acetic acid, and the acid was hydrogenated at room temperature under normal pressure. The reaction mixture was worked up as described in Example 17 (c) and 4-(4-aminophenyl)-1-phenyl-3-pyrazolylacetic acid was obtained Example 21 4 - Phenyl - 1 - (3 - chloro - 4 - fluorophenyl) - 3 - pyrazolylacetic acid was prepared from 3-chloroA-fluoroanlline under the conditions described in Example 6 (a) to 6 (g).

Example 22 4-Phenyl-(4-tri luoromethyl-phenylf3-pyrazolylacetic acid was prepared from 4trifluoromethylaniline under the conditions described in Example 6 (a) to 6 (g).

Example 23 3-Meth)xy-ixpbo1inostyrene and 2-chloro-2-phenylhydrazonoacetic acid ethvl ester were reacted as described in Example 6 (b) to 6 (g) to yield 4-(3-methoxyphenyl) 1-phenyl-3-pyrazolylacetic acid.

Example 24 a) /-Dimethylamin-nitrostyrene was reacted with 2-chloro-2-(4-fluorophenyl- hydrazono)-acetic acid ethyl ester under the conditions described in Example 17 (a) to 17 (c), and 4-(4aminophenyl)- 1-(fluorophenyl)-3-pyrazolylcar- boxylic acid ethyl ester was obtained.

b) The resulting compound was converted into 4-(Schlorophenyl)-1-(4-fluoro- pheaylY3-pyrazolylacetic acid as described in Example 17 (d) and 17 (e).

Example 25 4 (4-Aminophenyl)-1-(4-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester was converted into 4-(4methoxyphenyl)-1-(4-fluorophenyl)-3-pyrazolylacetic acid under the conditions described in Example 18 (a) and 18 (b).

WHAT WE CLAIM IS: 1. A pyrazole derivative of the general formula I

in which n represents 1, 2, 3 or 4, R1, R2, Ra and R4 each represents a hydrogen atone, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and Rr being in the ortho-, meta- or para-position, and X represents a cyano group, an aminocarbonyl group, an aikoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy group or a carboxyl group.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

mixture was cooled to 10"C. 3 equivalents of a solution of diazomethane in ether were then added to the mixture, which was allowed to stand for 2 hours at 10 C. The reaction mixture was concentrated in vacua, 80 ml of isoamyl alcohol were added to the residue, and the mixture was filtered. A solution of

4.4 g of silver benzoate in 45 ml of triethylamine was added dropwise to the solution so obtained, and the mixture was allowed to stand for 72 hours. It was then filtered and the filtrate was washed with an aqueous sodium carbonate solution and concentrated in vacuo. The residue was purified by chromatography over a silica gel column, using cyclohexane/ethyl acetate, and 395 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolylacetic acid isoamyl ester melting at 81 C were obtained.

d) The resulting ester was hydrolysed as described in Example 19 (a) and 145 mg of 4(4nitrophenyl)-1-phenyl-3-pyrazolylacetic acid melting at 306 C were obtained.

Example 20 20 ml of glycol monomethyl ether and 1 g of Raney nickel were added to 210 mg of 4-(4-nitrophenyl)-1-phenyl-3-pyrazolyl-acetic acid, and the acid was hydrogenated at room temperature under normal pressure. The reaction mixture was worked up as described in Example 17 (c) and 4-(4-aminophenyl)-1-phenyl-3-pyrazolylacetic acid was obtained Example 21 4 - Phenyl - 1 - (3 - chloro - 4 - fluorophenyl) - 3 - pyrazolylacetic acid was prepared from 3-chloroA-fluoroanlline under the conditions described in Example 6 (a) to 6 (g).

Example 22 4-Phenyl-(4-triíluoromethyl-phenylf3-pyrazolylacetic acid was prepared from 4trifluoromethylaniline under the conditions described in Example 6 (a) to 6 (g).

Example 23 3-Meth)xy-ixpbo1inostyrene and 2-chloro-2-phenylhydrazonoacetic acid ethvl ester were reacted as described in Example 6 (b) to 6 (g) to yield 4-(3-methoxyphenyl) 1-phenyl-3-pyrazolylacetic acid.

Example 24 a) /-Dimethylamin-nitrostyrene was reacted with 2-chloro-2-(4-fluorophenyl- hydrazono)-acetic acid ethyl ester under the conditions described in Example 17 (a) to 17 (c), and 4-(4aminophenyl)- 1-(fluorophenyl)-3-pyrazolylcar- boxylic acid ethyl ester was obtained.

b) The resulting compound was converted into 4-(Schlorophenyl)-1-(4-fluoro- pheaylY3-pyrazolylacetic acid as described in Example 17 (d) and 17 (e).

Example 25 4 (4-Aminophenyl)-1-(4-fluorophenyl)-3-pyrazolylcarboxylic acid ethyl ester was converted into 4-(4methoxyphenyl)-1-(4-fluorophenyl)-3-pyrazolylacetic acid under the conditions described in Example 18 (a) and 18 (b).

WHAT WE CLAIM IS:

1. A pyrazole derivative of the general formula I

in which n represents 1, 2, 3 or 4, R1, R2, Ra and R4 each represents a hydrogen atone, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and Rr being in the ortho-, meta- or para-position, and X represents a cyano group, an aminocarbonyl group, an aikoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy group or a carboxyl group.

2. A physiologically tolerable salt of a compound as claimed in claim 1 in which

X represents a carboxyl group.

3. A compound as claimed in claim 1, wherein the halogen atom in a fluorine or chlorine atom.

4. A compound as claimed in claim 1 or 3, wherein the alkyl group contains 1 to 4 carbon atoms.

5. A compound as claimed in claim 4, wherein the alkyl group is a methyl group.

6. A compound as claimed in any one of claims 1, 4 and 5, wherein the alkoxy group represented by each of the symbols R1, R2, R3 and R4 contains 1 to 4 carbon atoms

7. A compound as claimed in claim 6, wherein the alkoxy group is a methoxy group.

8. A physiologically tolerable salt of a compound as claimed in any one of claims 3 to 7, in which X represents a carboxyl group.

9. A salt as claimed in daim 2 or 8, which is an alkali metal salt, an alkaline earth medal salt, a copper salt or an amine salt.

10. (1,4-Diphenyl-3-pyrazolyl)-acetonitrile.

11. (1.4-Diphenyl-3-pyrazolyl)-acetamide.

12. (1P-Diphenyl-3-pqrazolyl)-acetic acid.

1 i. odlurn (1,4-diphenyl-3-pyrazolyl)-acetate.

14. 3-(1,4-Diphenyl-3-pyrazolyl)-propionic acid.

15. Sodium 3-(1,4-diphenyl-3-pyrazolyl)-propionate.

16. 3-(1,4Diphenyl-3-pyrazolyl)-propionic acid ethyl ester.

17. 4-(1,4-Diphenyl-3-pyrazolyl)-butyric acid ethyl ester.

18. 4(1,4Diphenyi-3-pyrazolyl)-butyric acid.

19. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetonitrile.

20. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetic acid.

21. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetamide.

22. 4-Phenyl-1-(4-tolyl)-3-pyrazolylacetic acid ethyl ester.

23. 4Phenyl- 1 < 2-tolyl)-3-pyrazolylacetonitrile.

24. 4-Phenyl-1-(2-tolyl)-3-pyrazolylacetic acid.

25. 4-Phenyl-1-(2 chtorophenyl) 3-pyrazolylacetonitrile.

26. 4-Phenyl-1-(2-chlorophenyl-3-pyrazolylacetic acid.

27. 4-Phenyl-1-(4diorophenyl)-3-pyrazolylacetoniuile.

28. 4-Phenyl-1-(4-chlorophenyl)-3-pyrazolylacetic acid.

29. 4-Phenyl-1 < 3,4-dichlorophenyl)-3-pyrazolylacetonitrite.

30. 4-Phenyl-1 < 3,4-dichlorophenyl)-3-pyrazolylacetic acid.

31. 4Phenyl-1 -(4-fluorophenyl)-3-pyrazolylacetonitrile.

32. 4Phenyl-1-(4fiuorophenyl)-3-pyrazolylacetic acid.

33. 4-Phenyl-l-(2-fluorophenyl)-3 -pyrazolylacetonitrile.

34. 4-Phenyl-1-(2-fluorophenyl)-3-pyrazolylacetic acid.

35. 4-Phenyl-1 < 3-fluorophenyl)-3-pyrazolylacetonitrile.

36. 4-Phenyl- 1-(3-fluorophenyl)-3-pyrazolylacetic add.

37. Phenyl-1 -(3-trifluoromethylphenyl)-3-pyrazolylacetonitrile.

38. 4-Phenyl-1 < 3-trifluoromethylphenyl)-3-pyrazolylacetic acid.

39. 4-(4-Chlorophenyl)-l-phenyl-3-pyrazolylacetic acid.

40. 4-(4-Chlorophenyl)-l-phenyl-3 -pyrazolylacetonitrile.

41. 4-(4-Methoxyphenyll-phenyl-3-pyrazolylacetic acid.

42. 4-(4-Methoxyphenyl)-1-phenyl-3-pyrazolylacetonitrile.

43. 4-(4-Nitrophenyl)-l-phenyl-3-pyrazolylacetic acid isoamyl ester.

44. 4-(Nitrophenyl)-1 -phenyl-3-pyrazolylacetic acid.

45. 4-(4-Aminophenyl)- 1 -phenyl-3-pyrazolylacetic acid.

46. 4-Phenyl-1-(3-chtoro4-fluorophenyl)-3-pyrazolylacetic acid.

47. 4-Phenyl-1-(4-trifluoromethyl-phenyl)-3-pyrazolylacetic acid.

48. 4-(3-Methoxyphenyl)-l-phenyl-3-pyrazolylacetic acid.

49. 4(4chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolylacetic acid.

50. 4-(4-Methoxyphenyl)-1Kfluorophenyl)-3-pyrazolylacetic acid.

51. A pharnaceutical preparation which comprises a compound as claimed in any one of claims 1 and 3 to 7, in admixture or conjunction with a pharmaceutically suitable carrier.

52. A pharmaceutical preparation which comprises a salt as claimed in any one of claims 2, 8 and 9, in admixture or conjunction with a pharmaceutically suitable carrier.

53. A pharmacentical preparation which comprises the compound claimed in any one of daims 10 to 12, 14 and 16 to 50, in admixture or conjunction with a pharmaceutically suitable carrier.

54. A pharmaceutical preparation which comprises the compound claimed in claim 13 or 15, in admixture or conjunction with a pharmaceutically suitable carrier.

55. A preparation as claimed in any one of claims 51 to 54, which is in the form of a tablet, drawee', capsule, solution, powder, salve, aerosol or inhalant preparation.

56. A preparation as claimed in any one of claims 51 to 54, which is in a form suitable for oral administration.

57. A preparation as claimed in claim 56, which is in the form of a tablet, dragée or capsule containing 1 to 250 mg of active substance.

58. A preparation as claimed in any one of claims 51 to 54, which is in a form suitable for topical administration.

59. A preparation as claimed in claim 58, which is in the form of a powder, salve or aerosol containing 0.01 to 2% by weight of active substance.

60. A process for the manufacture of a pyrazole derivative of the general formula I

in which represents 1, 2, 3 or 4, Rl, R2, Ra and R4 each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols R1, R2, R3 and R being in the ortho-, meta- or para-position, and X represents a cyano group, an aminocarbonyl group, an alkoxycarbonyl group containing 1 to 6 carbon atoms in the alkoxy group or a carboxyl group, or a physiologically tolerable salt of such a compound in which X represents a carboxyl group, wherein: (a) a pyrazole derivative of the general formula II

in which m, R1, Ra, Ra and Rs have the meanings given above and Y represents a halogen atom, is reacted with an alkali metal cyanide and, if desired, the resulting compound of the general formula I, in which X represents a cyano group, is hydrolysed to form a compound of the general formula I, in which X represents an aminocarbonyl or a carboxyl group, and/or any nitro group present is reduced to form an amino group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or esterified to form a C1-C0-alkyl ester thereof, or (b) a pyrazole derivative of the general formula III

in which n, R1 Ra, R3, R4 and Y have the meanings given above, is reacted in the presence of a deprotonizing agent with a malonic acid dialkyl ester or a cyanoacetic acid alkyl ester and the resulting reaction product is hydrolysed and decarboxylated to form a compound of the general formula I, in which X represents a carboxyl group or a cyano group, and, if desired, any nitro group present is reduced to form an amino group and/or any cyano group is hydrolysed to form an aminocarbonyl group and/or any resulting carboxylic acid is converted into a physiologically tolerable salt thereof or a correspond ing amide or esterified to form a C,--Cu-alkyl ester thereof, or (c) a pyrazole derivative of the general formula II

in which tt, Rl, R,, R3, R4 and Y have the meanings given above, is reacted with magnesium or lithium and the resulting organo-metal compound is treated with carbon dioxide to form a compound of the general formula I, in which X represents a carboxyl group, and, if desired, any nitro group present is reduced to form an amino group and/or the resulting carboxylic acid is converted into a physiologically tolerable salt thereof, a corresponding amide or nitrile or a C1C6-alky1 ester thereof, or (d) a pyrazole derivative of the general formula IV

in which n, R1, R2, Ra and Ri have the meanings given above, is reacted with diazomethane and the resulting diazoketone is rearranged in the presence of water, ammonia or a C1-C,-alcohol to form a compound of the general formula I, in which X represents a carboxyl, aminocarbonyl or C2C,- alkoxycarbonyl group, respectively, and, if desired, any nitro group present is reduced to form an amino group and/or any ester group present is hydrolysed to form a carboxyl group or any aminocarbonyl group present is dehydrated to form a cyano group and/or any resulting carboxylic acid is converted into a physiologicaly tolerable salt thereof.

61. A process as claimed in claim 60, conducted substantially as described herein.

62. A process for the manufacture of a compound as claimed in claim 1 or 2, conducted substantially as described in any one of Examples 1 to 5 herein.

63. A process for the manufacture of a compound as claimed in claim 1, conducted substantially as described in any one of Examples 6 to 25 herein.

64. A pyrazole derivative of the general formula IIa

in which n' represents 0, 1, 2, 3 or 4, R1, Ra, Ra and Ri each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a trifluoromethyl group, a nitro group or an amino group, the atom or group represented by each of the symbols Rl, R2, R, and R being in the ortho-, meta- or para-position, and Y represents a halogen atom.

65. 3-Bromomethyl-1,4-diphenyl-pyrazole.

66. Any one of the compounds as claimed in claim 64 and described in Examples 6 and 9 to 18 herein.