NO140733B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY EFFECTIVE HALOGENPYRAZOLE DERIVATIVES - Google Patents

Abstract

Analogous process for the preparation of new therapeutically effective halopyrazole derivatives.

Description

The invention relates to an analogue method for the production of new therapeutically effective halopyrazole derivatives.

In Belgian patent document no. 755,924, pyrazole-4-acetic acid derivatives with the general formula are described

in which

R 1 , R 2 and R 3 , which may be the same or different, stand for a hydrogen atom, an unbranched or branched, saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon residue with 1 to 7 carbon atoms or an optionally substituted aryl or hetero-aryl group with up to 12 carbon atoms, whereby it does not occur-2 3

comes that R is a hydrogen atom and R is at the same time a hydrogen atom or a methyl group, and R"^ can also stand for a benzyl group, which can also be substituted with a halogen atom or an alkoxy group with 1 to 4 carbon atoms, R<4> means a hydrogen atom or an alkyl group with 1 to 3 carbon atoms or a cycloalkyl group with 3-6 carbon atoms,

A means COOH, COOR<5>, CONR<6>R<7>, CN or C(=NOH)OH, whereby R<5 >means an alkyl group with 1 to 4 carbon atoms, a benzyl group, a phenyl group or a 2- carboxyphenyl group and R <6> and R <7> each stand for a hydrogen atom and/or an alkyl group with 1 to 4 carbon atoms or together with the nitrogen atom form a pyrrolidine, piperidine or morpholine group.

The described compound group has anti-inflammatory, anal-

getic and antipyretic properties.

A new class of pyrazoleacetic acid derivatives has now been found,

which is characterized by a new, very special type of substitution which is also not mentioned or suggested by the above patent document, where a halogen atom is directly bound to the pyrazole nucleus. It has also been shown that representatives of the aforementioned class have particularly advantageous pharmacological properties. The invention is particularly based on the recognition that pyrazole-4-acetic acids with a halogen substitution in the 5-position of the pyrazole nucleus are distinguished by outstanding and special pharmacological effects. The compounds produced according to the invention have particularly anti-inflammatory, but also antipyretic and analgesic properties.

The invention is based on this realization and relates to an analogous method for the production of pyrazole-4-acetic acid derivatives with the following general formula I

where R means phenyl, halophenyl, p-alkoxyphenyl with 1-4 carbon atoms in the alkoxy part or p-alkylphenyl with 1-4 carbon atoms in the alkyl part, and halogen denotes a chlorine or bromine atom, or salts thereof with inorganic or organic bases.

Among the salts produced according to the invention, the pharmacologically tolerated salts are preferred. As cations for salt formation, above all the cations alkali, alkaline earth and earth metal ions or ammonium are used, but also the corresponding cationic acids of mono- or polyacid organic nitrogen bases, especially of organic amines.

For example, the cations of the metals lithium, sodium, potassium, magnesium, calcium and aluminum and the cationic acids of ethanolamine, diethylanolamine, triethanolamine, ethylenediamine, dimethylamine, diethylamine, morpholine, piperazine, methylcyclohexylamine, glucosamine, N-methylglucamine, N-methylglucosamine are used. , further of tert.-butylamine, dibutylamine, diisopropylamine, triethylamine, isopropylamine, quinoline and ammonia.

The invention relates to a process for the preparation of compounds with the general formula I and their salts with inorganic or organic bases, and is based on functional hydrolysable carboxylic acid derivatives of pyrazole-4-acetic acids with the general formula I, which are described by the general formula II

in which

R and halogen have the meanings given above and B means a functional derivative of an acetic acid group.

A functional derivative of an acetic acid group means a derivative of the acetic acid group (-CH2 COOH), which is closely chemically related to this acetic acid group. Typical representatives of the functional derivatives of the acetic acid group will be discussed in the following.

The method is characterized by hydrolyzing compounds of the general formula II to compounds of the general formula I or their salts and optionally transferring the obtained compounds of the general formula I into their salts or, if desired, transferring a compound obtained in the form of a salt of the general formula I to the free acid.

As a particularly effective compound is produced by this, a particularly preferred variant of the invention involves a compound of the general formula II being used for the hydrolysis, where R denotes a p-R chlorophenyl group, while halogen denotes a chlorine atom.

In a preferred embodiment of the hydrolysis, the starting point is functional pyrazole-4-acetic acid derivatives with the general formula

in which

R and halogen have the meanings given above,

B' means group -CH2CN or the group

X is an oxygen or a sulfur atom or a substituted nitrogen atom, especially an imino, alkylamino or hydroxyimino group and

Y is a hydroxy group or a monovalent eliminable electrophilic residue, especially a free or substituted amino group, preferably a monoalkyl or dialkyl or arylamino group,

a hydroxyamino or hydrazine group, a hydrazobenzene group, a 2-hydroxyethylamino group, a free or substituted mercapto group, preferably an alkylthio group, a substituted hydroxy group, preferably an alkoxy group, an azido, a chlorine or bromine residue, a morpholine group or a piperidine group, whereby

Y is not a hydroxy group, when X constitutes an oxygen atom.

An alkyl residue of an alkylamino, a monoalkylamino, a dialkylamino, an alkylthio and an alkoxy group means an alkyl residue with up to 6 carbon atoms, an aryl residue of an arylamino group means an aryl residue with up to 10 carbon atoms.

In another preferred embodiment of hydrolysis one goes

one based on functional pyrazole-4-acetic acid derivatives with

the general formula II', where

B<1> is the group -Cf^CN or the group

whereby

X means an oxygen atom, a sulfur atom or an imino group,

and Y means an amino, monoalkylamino, dialkylamino, phenylamino, alkoxy, alkylthio, chlorine or bromine residue.

In a particularly preferred embodiment of the hydrolysis, the starting point is pyrazole-4-acetic acid nitriles, pyrazole-4-acetic acid amides and pyrazole-4-acetic acid alkyl esters with the general formula II *. The method can also be carried out by using a pyrazole derivative, which intermediately forms a pyrazole derivative of the general formula II or II', which is subsequently reacted with a water-releasing medium to the desired pyrazole-4-acetic acid derivative of the general formula I. In many In some cases, hydrolysis proceeds in several steps and, if the reaction is carried out appropriately, intermediate steps can also be isolated. Thus, e.g. the hydrolysis of the nitriles, thioamides, amidines and imidazolines via corresponding amides or the imidic acid ester via carboxylic acid ester. When reacting unsubstituted amides with nitrous acid, acyldiazonium compounds are formed as an intermediate product, which easily hydrolyse to carboxylic acids. ;As starting compounds for the method according to the invention for producing compounds with the general formula I are in principle compounds in question which, as functional derivatives of carboxylic acids with the general formula I, on hydrolysis give the compounds with the formula I. Examples of such functional carboxylic acid derivatives should be mentioned in alkyl ester, phenyl ester, benzlyl ester, alkoxyalkyl ester/dialkylaminoalkyl ester, amides, N-monoalkylamides, N,N-dialkylamides, morpholides, piperidides, piperazides, anilides, N-alkylanilides, N-hydroxy-amides, N-alkoxyamides, hydrazides, azides, monothiocarboxylic acids, monothiocarboxylic acid alkyl esters, thiocarboxylic acid alkyl esters, thioamides, thiomorpholides, imidic acid esters, amidines, hydrazines, oxazolines, imidazolines, thiazolines, acid chlorides, acid bromides, acid anhydrides, ketenes and nitriles. Especially important as starting products are the compounds whose production seems interesting from a technical and economic point of view and which are best described by the general formula II<1>„ Insofar as the residues X and Y are eliminated during the hydrolysis, their chemical structure is however of subordinate importance. It should also be noted that certain compounds can be formulated in two different ways due to possible tautomers (eg amide - imidic acid). As characteristic starting products for the above-mentioned hydrolysis, e.g. mention is made of the nitriles, amides and carboxylic acid lower alkyl esters with the general formula II'. Specifically, e.g. the following substances come into question: 5-chloro-1, 3-diphenyl-pyr?;ol-4-acetonitrile; 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro- 3-m-chlorophenyl-l-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-methoxyphenyl-l-phenyl-pyrazole-4-acetonitrile 5-chloro-l-phenyl-3-p-tolyl-pyrazole- 4-acetonitrile 5-chloro-3-p-isobutylphenyl-l-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-fluorophenyl-l-phenyl-pyrazole-4-acetonitrile 5-bromo-1,3-diphenyl -pyrazole-4-acetonitrile ;5-bromo-3-p-fluorophenyl-l-phenyl-pyrazole-4-acetonitrile 5-bromo-3-p-methoxyphenyl-l-phenyl-pyrazole-4-acetonitrile 5-bromo-3 -p-isobutylphenyl-l-phenyl-pyrazole-4-acetonitrile 5-bromo-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetonitrile 5-fluoro-1,3-diphenyl-pyrazole-4-acetonitrile ;3 -p-chlorophenyl-5-fluoro-l-phenyl-pyrazole-4-acetonitrile 5-fluoro-3-p-methoxyphenyl-l-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-butoxyphenyl-l-phenyl -pyrazole-4-acetonitrile 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid methyl ester 5-chloro-3- p-Chlorophenyl-1-phenyl-pyrazole-4-acetic acid acid ethyl ester 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid butyl ester 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid 2-methoxy-ethyl ester ;5-chloro- 3-p-chlorophenyl-l-phenyl-pyrazole-4-acetmorpholide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetanilide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole- 4-thioacetmorpholide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamidoxime 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamidine hydrochloride ; For the hydrolysis of functional carboxylic acid derivatives with the general formula II or II<1> a water-releasing medium is used which consists wholly or partly of water or of media that split water under the hydrolysis conditions. The reaction can be carried out as a homogeneous reaction. In this case, one usually works in the presence of a polar organic solvent or solubilizer. Preferably used as solvents, e.g. low molecular weight alcohols, dioxane, acetone, low molecular weight carboxylic acids, N-methylpyrrolidone, sulfolane or dimethyl sulfoxide. However, the hydrolysis can also be carried out as a heterogeneous reaction. The water-releasing medium's pH value depends on the chemical nature of the pyrazole-4-acetic acid derivative used, but also on the nature of the desired compound with the general formula I, and can thus be neutral, acidic or basic. It is adjusted with acids, bases or buffer to the desired value. The hydrolysis temperature is between 0°C and the boiling point of the water-releasing medium, usually between 0° and 150°C, especially between 20° and 120°C. The hydrolysis temperatures also depend on whether work is carried out under pressure or without pressure. Depending on the mixture, the reaction temperatures and other reaction parameters, the reaction times are between 10 minutes and 20 hours. After complete hydrolysis, the pyra3ol-4-acetic acids are isolated by usual methods, e.g. by recrystallization or acidification of their solutions, possibly by boiling their solutions. ;For purification, their alkaline solution can be extracted with an organic solvent, which is not miscible with the alkaline solution, e.g. ether, benzene, chlorobenzene, chloroform or methylene chloride. The conversion of the pyrazole-4-acetic acids of the general formula I or I<+> to their salts can take place by direct alkaline hydrolysis of the pyrazole-4-acetic acid derivatives of the general formula II or II'. The inorganic base or organic base, if salt is desired, is used as an alkaline reaction partner. However, the salts can also be obtained by reacting the pyrazole-4-acetic acids with the general formula I with the stoichiometric equivalent of the corresponding base, or by converting easily soluble salts into difficult-to-dissolve salts by double conversion, or by transferring optional salts to pharmacologically tolerated salts. The pyrazol-4-acetic acid derivatives of the general formula II or II<1> are in principle accessible via a halogenation of 2-pyrazolin-5-ones of the general formula III or IV, where R and B have the aforementioned meanings, which 2-pyrazolin-5-ones of the general formula III or IV can be obtained by known or per se known methods, in the 5-position, e.g. by means of reactive halides of elements in V. and VI. group of the periodic table or of reactive carbonic acid halides, carbonic acid imide halides or Vilsmeier reagents and optionally via further method steps known in and of themselves. In a process variant, a compound with the general formula III is reacted with at least two molar equivalents of a Vilsmeier reagent, which for the reaction or during the reaction is prepared in situ from a dialkyl or alkylarylformamide, to the corresponding 5-halo-4-pyrazolyl-methylene -dimethylammonium salts, which are subsequently hydrolysed to 5-halopyrazole-4-carboxyaldehydes with the general formula V ;;where R and halogen have the meanings indicated above. As dialkylformamides are used e.g. dimethylformamide, diethylformamide, diisopropylformamide, N-formylpiperidine, N-formylpiperazine, N,N-diformylpiperazine or N-formylmorpholine. As alkylaryl-formamides, e.g. N-methyl-N-phenylformamide or N-ethyl-N-tolylformamide. Examples of acid halides include phosphoroxytrichloride, phosphoroxytribromide, phosgene and thionyl chloride. In this method, if the reaction is carried out appropriately, in addition to the formylation in the 4-position, halogenation in the 5-position of the pyrazole will also occur with excellent yield. The reaction temperatures are usually between 10° and 100°C and the reaction duration is usually between 15 minutes and 30 hours. Another method that comes into question is halogen replacement based on compounds with the general formula V, e.g. substitution of chlorine with bromine or fluorine using halides or halogen hydroxides, possibly at elevated temperatures and in a pressure vessel. Apart from 5-chloro-1,3-diphenyl-pyrazole-4-carboxaldehyde, the compounds of the general formula V are new compounds. A key intermediate is formed by the compound 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-carboxyaldehyde, the compound 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid and its salts can be prepared via this and the latter end products have particularly advantageous pharmacological properties. ;The obtained compounds with the general formula V are converted accordingly in and of themselves, e.g. from Belgian patent document 755 924 known methods, via a series of intermediate steps to the pyraz.ol-4-acetic acid derivatives of the general formula II. The carbonyl group is first reduced under mild conditions to the hydroxymethyl group, this is transferred to a halogenmethyl or trialkylammoniummethyl group and reacted with a cyanide to form nitriles of the general formula II. The reduction can e.g. carried out with sodium borohydride in anhydrous or aqueous solvents between 0° and 50°C. The halomethyl compounds are obtained from the hydroxymethyl compounds, e.g. by reaction with sulfur or phosphorus halides or carbonic acid halides, such as phosgene, but also by reaction with halogen hydroxides and their concentrated, aqueous solutions, whereby optional inert solvents are used. The reaction of the 4-halo-methyl-5-halo-pyrazoles to nitriles of the general formula II can be carried out according to the methods described in Belgian patent document 755 925 for similar compounds, preferably in aprotic, dipolar solvents, at temperatures between 0 ° and 80°C. Pyrazyl-4-acetic acid esters of the general formula II are easily accessible from other reactive pyrazole-4-acetic acid derivatives of the general formula II according to known methods, e.g. from acid halides, acid anhydrides and nitriles by alcoholysis, further from pyrazole-4-acetic acids of the general formula I by reaction with alcohols under water-splitting conditions or by reaction of acids and salts with alkylating agents, e.g. benzyl ester by reaction of alkali salts with benzyl halides. Unsubstituted amides of the general formula II can be prepared by hydrolysis of corresponding nitriles. The aminolysis of reactive carboxylic acid derivatives such as acid halides or esters with ammonia, with mono- and dialkylamines, with arylamines, cyclic amines, such as piperidine, morpholine and piperazine, with hydroxylamines, O-alkylhydroxylamines and with optionally substituted hydrazines gives, possibly N- alkyl- or aryl-substituted, amides, piperidides, morpholides, piperazides, further hydroxamic acids, O-alkyl amides and optionally N-alkyl- or aryl-substituted hydrazides of the general formula II. Thioamides with the general formula II can e.g. are produced by reacting nitriles and hydrogen sulphide in the presence of bases or by sulfur treatment of amides, e.g. with phosphorus pentasulphide. The nitriles of the general formula II further add alcohols under acid catalysis to corresponding imidic acid esters, aryl amines under basic catalysis to corresponding amidines and mer-captans or marked aptoacetic acid to corresponding thioimidic acid esters. Of imidic acid esters with the general formula II, one can e.g. Amidines can be prepared with amines, oxazolines can be prepared with amino alcohols and imidazolines can be prepared with diamines. Acid halides of the general formula II can be prepared in a known manner from compounds of the formula I using halides of the phosphoric or sulfuric acids and ketenes can be prepared from the acid halides by dehydrohalogenation using tertiary bases. Experience has shown that in many cases it is not necessary to carry out special purification for intermediate steps II or II, so that these could be used for the next step of the process without subsequent purification. The surprising discovery has been made that the compounds of the general formula I and their salts - at relatively low toxicity - have pronounced anti-inflammatory and likewise analgesic and temperature-lowering properties. ;The anti-inflammatory effect could be demonstrated both after a single use and after several times of use in acute and chronic inflammation models. Compared to the commercially available drug phenyl-butazone (I), the compounds according to the invention proved to be clearly superior to the compounds according to the state of the art, as demonstrated in Table 1 by the examples 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4- acetic acid (II) and 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid (III). Also in further pharmacological investigations, the compounds according to the invention showed a special effect and superiority over the standard preparation I, as shown in Table 2 with the following compound examples: 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (II ), 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid (III) and 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid; (IV) . ;;The anti-inflammatory effect of the standard compound or the compounds according to the invention were examined for the substances' prohibitive influence on the carrageenin blood on the rat hind paw /Winter et. eel. Proe.Soc.exp.Biol.Med. 111 (1962) 544/, whereby it is indicated in table 2 which doses after three and five hours of single administration cause an average bdem inhibition of 25%, ;on the inhibition of ultraviolet erythema on guinea pig dorsal skin /winder et al. Arch. int. Pharmacodyn. 116 (1958). et al. J. Pahrmacol. exp. Therapy. 141 (1963) 369, examines the association's influence after administration once per day i 7 ;consecutive days on the granulation tissue formation after subcutaneous implantation of cotton balls in rat; Table 1 lists the doses that inhibit new formation of granulation tissue by 20% (ED2Q). ;Lethal doses were brought to light in the usual way. LD^q or ;LDj- denotes the doses after which 50% (mice) or 5% (rat) of the animals died within ten days after a single or 7-day administration. Comparison tests were carried out with the pyrazole-4-acetic acids described in Belgian patent no. 755,924 and the compounds produced according to the invention, and the results of these are shown in Tables III and IV below. The Roman numerals in the tables denote the following compounds produced according to the invention: 1<1>: 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid II<*>: 5-chloro-3-p-chlorophenyl-1- phenyl-pyrazole-4-acetic acid

III': 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid IV: 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetic acid V: 5-bromo-1 ,3-diphenyl-pyrazole-4-acetic acid.

The compounds indicated by the letters A - D and L - Q are the most active comparative compounds described in the Belgian patent, namely for the antiphlogistic effect compounds A-D:

A 1,3,5-triphenyl-pyrazole-4-acetic acid

B 1-phenyl-3,5-di-(2-furyl)-pyrazole-4-acetic acid

C 3,5-diphenyl-1-(3-pyridyl)-pyrazole-4-acetic acid

D 1-phenyl-3-(p-chlorophenyl)-pyrazole-4-acetic acid

and for the analgesic effect:

L 3,5-diphenyl-1-(p-chlorophenyl)-pyrazole-4-acetic acid M 1-phenyl-3,5-bis-^ p-chlorophenyl)-pyrazole-4-acetic acid

N 1-phenyl-3,5-bis-(m-methoxyphenyl)-pyrazole-4-acetic acid

0 3,5-diphenyl-1-(ot,a,a-trifluoro-m-tolyl)-pyrazole-4-acetic acid ethyl ester

Q 3,5-Dimethyl-1-phenyl-pyrazole-4-acetonitrile.

As can be seen from Tables III and IV, the compounds prepared according to the invention are superior with regard to both the antiphlogistic effect and the analgesic effect.

The compounds produced according to the invention exhibit e.g. on cotton granules (so-called cotton-pellet test) a strong anti-phlogistic (antiproliferative) effect and are distinguished here - as can be seen from table 3 - by their greater therapeutic breadth.

The lethal doses required for the calculation of the therapeutic range are determined in the usual way.

It appears from table 4 that the compounds produced according to the invention are also superior in comparison with the strongly analgesic active compounds, which are described in the aforementioned patent document.

In this experiment, the analgesic effect was measured by the influence of the compounds on the bending of an inflamed ankle joint (AgNO^-inflammation) in rats provoking pain reaction according to the methodology according to Hoffmeister et al., Arzneimittelfor-schung 2_4, 600 (1974) .

The superiority of the compounds produced according to the invention is evident both from their absolute and from their relative potency (compared to the most effective pyrazole derivative from the Belgian patent, namely compound N).

When applied in the therapeutically effective and pharmacologically tolerable amount, the compounds produced according to the invention are therefore suitable for the treatment of a wide range of disease states in mammals, in which disease states one or more symptoms of inflammation, pain and fever occur.

With the compounds produced according to the invention, pharmaceuticals can be prepared which are characterized by a content of one or more of these new compounds. In addition to the previously unknown active substances, the medicinal products in question may contain pharmaceutical carriers for these active substances.

The pharmaceutical preparations contain, when they are present in a unit dose, 1 - 1000 mg, particularly advantageously approx. 5 - 500 mg and most preferably 10 - 250 mg, active substance. The therapeutic administration of the pharmaceutical preparations can take place 1-4 times a day, e.g. after meals and/or in the evening.

The following examples illustrate the invention in more detail.

Example 1

5- chloro- l. 3- diphenyl- pyrazol- 4- acetic acid

19.1 g of 5-chloro-1,3-diphenyl-pyrazole-4-acetonitrile is heated at 93

g 63% sulfuric acid at 115°C for one hour. The mixture is cooled, the acid is precipitated by dilution with 500 ml of water, washed with water and recrystallised from ethanol and water. A crystalline aqueous product is obtained, which is dehydrated by dissolving in benzol and evaporating the solution. A 91% yield is obtained in the form of 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid; Temp. 151-152°C.

Example 2

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid 30 g of 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetonitrile and a mixture of 46 ml of concentrated sulfuric acid and 55 ml of water is heated with stirring to 100° for 2.5 hours. In connection, dilute with 700 ml of water, the precipitate is suctioned off and washed with water. The filter cake is dissolved in diluted caustic soda, it is clarified with activated charcoal and the acid is precipitated with diluted hydrochloric acid. A 95% yield is obtained in the form of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid; Temp. 179.5 - 181°C (from methanol).

From the corresponding pyrazole-4-acetonitrile

5-chloro-3-p-methoxyphenyl-l-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-isobutylphenyl-l-phenyl-pyrazole-4-acetonitrile 5-bromo-1,3-diphenyl-pyrazole- 4-acetonitrile

is achieved in a similar way

5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid (Mp. 166.5 - 167.5°C)

5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetic acid (Mp. 110 - 115°C)

5-bromo-1,3-diphenyl-pyrazole-4-acetic acid (Mp. 187.5 - 188.5°C)

Example 3

5- chloro- 3- p- chlorophenyl- l- phenyl- pyrazole- 4- acetic acid

3.8 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid ethyl

ter, 13 ml of ethanol and 1.0 g of sodium hydroxide in 13 ml of water

heat to boiling for 1 hour. It is adjusted to pH 10, the alcohol is distilled off in a vacuum, the aqueous solution is shaken with ether and clarified with activated charcoal. It is acidified with diluted salt-

acid and a yield of 83% is obtained in the form of 5-chloro-3-p-chlorophenyl-pyrazol-4-acetic acid; Temp. 17 9.5-181°C.

Analogously, one obtains from

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid methyl ester 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid n-butyl ester 5-chloro-3-p- chlorophenyl-l-phenyl-pyrazole-4-acetic acid-n-hexyl ester 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid benzyl ester 5-chloro-3-p-chlorophenyl-l- phenyl-pyrazole-4-acetic acid phenyl ester 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-3-ethoxyethyl-

ester

5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid 3-dimethyl-aminoethyl ester

5-chloro-3-p-chlorophenyl-1-phenyl-pyr a,zol-4-thioacetic acid ethyl ester by alkaline hydrolysis 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (Mp. 179, 5-181°C).

Analogously, one obtains from

5-Chloro-1,3-diphenyl-pyraroyl-4-acetic acid ethyl ester

5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid methyl ester 5-bromo-1,3-diphenyl-pyrazole-4-acetic acid methyl ester

by alkaline hydrolysis

5-chloro-1,3-diphenyl-pyrazole-4-acetic acid (M.P. 151-152°C) 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid (M.P. 166.5- 167.5 C) 5-bromo-1,3-diphenyl-pyrazole-4-acetic acid (Mp. 187.5-188.5°C).

Example 4

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid 1.0 g 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetonitrile, 10 ml ethanol and 1.4 g of sodium hydroxide is heated to boiling for 4 hours until ammonia evolution is complete. The alcohol is distilled off in a vacuum, extracted with ether, clarified with activated charcoal and the aqueous phase acidified with hydrochloric acid to pH 3. A 95% yield is obtained in the form of 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4 -acetic acid; (Mp. 179.5-181°c.

Example 5

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid 2.0 g 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamide and 10 g 63% sulfuric acid heated for 1.5 hours to 100° and processed in the same way as stated in example 2. 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; Temp. 179.5-181°C.

Analogously obtained from

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid-n-butylamide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid diethylamide 5-chloro-3-p- chlorophenyl-l-phenyl-pyrazole-4-acetmorpholide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetpiperidide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetpyrrolidide 5 -chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetanilide 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid-N-methylanilide 5-chloro-3-p-chlorophenyl -l-phenyl-pyrazole-4-acethydroxamic acid 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamidoxime 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acethydrazide 5- chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamidine hydrochloride by sulfuric acid hydrolysis

5-chloro-3-p-chlorophenyl-1-phenyl-pyrazol-4-acetic acid (Mp. 179 , 5-181°C).

Example 6

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid 0.3 g 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-thioacetmorpholide and 6 ml of 20% hydrochloric acid is heated to boiling to hydrogen sulphide - development is finished. 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; Temp. 179.5-181°C.

Analogously, one obtains from

5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidic acid ethyl ester hydrochloride

2-/(5-chloro-3-p-chlorophenyl-1-4-pyrazolyl)-methyl/-oxazoline 2-/(5-chloro-3-p-chlorophenyl-1-phenyl-4-pyrazolyl)-methyl/ -thiazoline l-methyl-2-(5-chloro-3-p-chlorophenyl-l-phenyl-4-pyrazolyl)-methyl/- imidazoline

by hydrolysis with hydrochloric acid

5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (Mp. 179.5-181°C).

Example 7

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid Dissolve 3.5 g of 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamide in 15 ml of 90% sulfuric acid and, while stirring at 20-30°, a solution of 0.7 g of sodium nitrite in a little water is dripped under the surface. It is heated carefully until gas evolution is complete and poured over ice/water. 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazol-4-acetic acid is obtained; Temp. 179.5-181C.

Example 8

Sodium salt of 5- chloro- 3- p- chlorophenyl- 1- phenyl- pyrazole- 4- acetic acid

3.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid are dissolved in 10 ml of 1/10 caustic soda, the solution is evaporated in vacuo to dryness and the residue is pulverized with ether. The sodium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; Temp. 275 - 279°C.

Example 9

Calcium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pvrazole-4-acetic acid A solution of 3.5 g of 5-chloro-3-p-chlorophenyl1-1 is dripped

-phenyl-pyrazole-4-acetic acid in an equivalent amount of dilute caustic soda in heat to a solution of 1.6 g of calcium chloride-

hexahydrate in 12 ml of water. The precipitate is washed with dilute calcium chloride solution and ice-cold water. A quantitative yield of the calcium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazol-4-acetic acid is obtained; Temp. 302-307°C (dec.).

Example 10

Morpholine salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid

0.25 g of morpholine is added dropwise to a solution of 1.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid in 45 ml of ether. An 87% yield is obtained in the form of the morpholine salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid; Temp. 14 4-14 5.5°C.

Preparation of starting materials:

Example A

5-chloro-1,3-diphenyl-pvra, zol-4-carboxyaldehyde To 92.7 g of dimethylformamide, 97.3 g of phosphorus oxytrichloride are added dropwise at 5-10°. It is stirred until complex formation is complete for 30 minutes at room temperature. In addition, 30 g of 1,3-diphenyl-2-pyrazolin-5-one are added and heated with stirring for 1 hour to 55° and 20 hours to 70°. One prefers approx. 600 g of ice, neutralize with concentrated caustic soda to pH 3-4, suck off and wash with water. A 93% yield is obtained in the form of 5-chloro-1,3-diphenyl-pyrazol-4-carboxyaldehyde; Sm<p>. 109-110°C (from petroleum ether).

Example B

5- chloro- 3- p- chlorophenyl- l- phenyl- pyrazole- 4- carboxyaldehyde

a) To 270 g of dimethylformamide, 284 g of phosphorus oxytrichloride are added dropwise at 5-10° over the course of 90 minutes, stirring for 30 minutes

at 15° and then introduce 100 g of 3-p-chlorophenyl-1-phenyl-2-pyrazolin-5-one. Heat for 1.5 hours to 50° and 21 hours to 70°, pour on 2 kg of ice, adjust with 20% caustic soda to pH 3-4 and filter off the precipitate. A 99% yield is obtained in the form of 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-carboxyaldehyde? Temp. 169.5-171°C (from acetone).

In a similar way, a) is obtained from the corresponding 2-pyrazolin-5-ones

5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-carboxaldehyde

(Mp. 103 - 110°C)

5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-carboxaldehyde

(Mp. 56.5-5.7°C)

b) 3-p-chlorophenyl-1-phenyl-2-pyrazolin-5-one required as starting product is obtained as follows: 50.8 g of p-chlorobenzoylacetic acid ethyl ester (preparable, for example, from p-chloroacetophenone, carbonic acid diethyl ester and sodium hydride in 72% yield), 29 g phenylhydrazine, 5 ml glacial acetic acid and 150 ml

ethanol is heated to boiling for 1 hour under a nitrogen atmosphere

few. After cooling in an ice bath, 84% yield is obtained in the form of 3-p-chloro-phenyl-1-phenyl-2-pyrazolin-5-one; Temp. 160.5-161.5°C.

In a similar way, the following 2-pyrazolin-5-ones are obtained according to b): 3-p-methoxyphenyl-1-phenyl-2-pyrazolin-5-one (M.P. 137-138°C) 3-p-isobutylphenyl-1 -phenyl-2-pyrazolin-5-one (Sm<p.> 124.5-

125°C)

Example C

5- bromo- 1, 3- diphenyl- pvrazole- 4- carboxyaldehvd

175 g of molten phosphorus oxytribromide is allowed to drip into 306 g of dimethylformamide during 75 minutes while stirring and cooling at 10-16°. 29 g of 1,3-diphenyl-2-pyrazolin-5-one are added to the crystal suspension of the Vilsmeier complex and subsequently heated to 65-70° for 20 hours. Pour on 850 g of ice, set

clay with 2 n caustic soda to pH 4-5, suction off and wash the precipitate

thoroughly with water. An 85% yield is obtained in the form of crude 5-bromo-1,3-diphenyl-pyrazole-4-carboxyaldehyde, which is purified by filtration

ring of a chloroform solution over silica gel; Temp. 128-128.5°C.

In a similar way one obtains of

3- p~chlorophenyl-1-phenyl-2-pyrazolin-5-one

and the Vilsmeier complex of phosphoroxytribromide and dimethylformamide

5-Bromo-3-p-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde

(Mp. 178-179.5°C)

5-Bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-4-carboxaldehyde.

Example D

5- chloro- 4- hydroxymethyl- 1, 3- diphenyl-pyra^ ol

To a solution of 21 g of 5-chloro-1,3-diphenyl-pyrazole-4-carboxyaldehyde in 80 ml of dioxane, a solution of 1.11 g of sodium borohydride in 35 ml of water at 23-27° is added dropwise. The formed suspension is stirred for a further 30 min. and precipitates on addition of 200 ml of water in 99% yield in the form of 5-chloro-4-hydroxymethyl-1,3-diphenyl-pyrazole. Temp. 140.5-141.5°C (from toluene).

Example E

5-chloro-3-p-chlorophenyl-4-hydroxymethyl-l-phenyl-pyrazole In a suspension of 46.5 g of 5-chloro-3-p-chloro-phenyl-l-phenyl-pyrazole-4-carboxyaldehyde in 700 ml of dimethylformamide and 100 ml of water, 2.8 g of sodium borohydride are introduced, whereby the temperature can rise to 35°. After 30 min. clarified with activated charcoal, precipitated with 700 ml of water and washed well. A 95% yield is obtained in the form of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenylpyra;:ol. Temp. 152.5-153.5°C (from acetone).

In a similar way one obtains from the corresponding pyra. 1-4-carboxy-aldehydes by reduction

5-chloro-4-hydroxymethyl-3-p-methoxyphenyl-l-phenyl-pyrazo 1 (Mp. 126-127°C)

5-chloro-4-hydroxymethyl-3-p-isobutylphenyl-1-phenyl-pyrazole (M.P. 140-140.5°C)

5-bromo-4-hydroxymethyl-1,3-diphenyl-pyrazole (Mp. 134-135°C).

Example F

5-chloro-4-chloromethyl-3-p-chlorophenyl-l-phenyl-pyrazole To a suspension of 45 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole in 45 ml of benzene dropwise 17.6 g of thionyl chloride, whereby a strong evolution of gas and dissolution is observed. In connection, heat to completion of the reaction to boiling for 30 minutes. The solvent is distilled off in a vacuum and this operation is repeated while adding benzene. The residue is brought to crystallisation with petroleum ether. 98.5% of 5-chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained.

F. 96.5-97°.

In a similar way, the following 4-chloromethylpyrazoles are obtained from the corresponding 4-hydroxymethylpyrazoles: 5-chloro-4-chloromethyl-1,3-diphenyl-pyrazole (M.P. 67.5-68.5°C) 5-chloro-4 -chloromethyl-3-p-methoxyphenyl-l-phenylpyrazole (M.P. 129-129.5°C)

5-chloro-4-chloromethyl-3-p-isobutylphenyl-1-phenyl-pyrazole (Mp. 87-87.3°C)

5-bromo-4-chloromethyl-1,3-diphenyl-pyrazole (Mp. 83.5-84°C).

Example G

5-chloro-4-chloromethyl-3-p-chlorophenyl-l-phenyl-pyrazole In a mixture of 15 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-l-phenyl-pyrazole and 25 ml of concentrated hydrochloric acid, hydrogen chloride gas and it is heated for 4 hours to boiling. Finally, 25 ml of toluene is added, the layers are separated and the aqueous phase is shaken with toluene. The organic layers are evaporated in vacuo.

Toluene is added again and it evaporates. In quantitative yield, 5-chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyra ol is obtained. Sm<p>. 96.5-97°C (from petroleum ether).

Example H

5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile Into a mixture of 6.15 g of sodium cyanide in 150 ml of dimethylsulfoxide are introduced with stirring and slight cooling at 25° 35 g of 5-chloro-4-chloromethyl -3-p-chlorophenyl-pyrazole. You stir for a further 2-5 hours at this temperature until the conversion is complete. 200 ml of water and 200 ml of trichlorethylene or benzol are added, the layers are separated, washed with the organic solvent, dried with sodium sulphate and the organic phase is clarified with tonsil. By evaporation in a vacuum, 99% of the theoretical yield of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile is obtained. Temp. 129.5

- 130.5°C (from acetonitrile).

In a similar way, the following pyrazole-4-acetonitrile is obtained from the corresponding 4-chloromethylpyrazoles

5-chloro-1,3-diphenyl-pyrazole-4-acetonitrile (M.P. 78.5-79.5°C) 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile (M.P. 91.5

- 92.5°C)

5-chloro-3-p<->isobutylphenyl-1-phenyl-pyrazole-4-acetonitrile (Mp. 98-98.5°C)

5-bromo-1,3-diphenyl-pyrazole-4-acetonitrile (M.P. 99-100.5°C).

Example I

5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid ethyl ester 10 g 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile, 100

ml of ethanol, 1.5 ml of water and 15 ml of concentrated sulfuric acid are heated for 16 hours to boiling. You pour it on ice, make alkaline with it

sodium bicarbonate solution, shake with ether and evaporate. After recrystallization from ethanol and water, a 69% yield is obtained in the form of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid ethyl ester. Temp. 51.5-52.5°C (of ether/petroleum ether).

In a similar way, 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid methyl ester can be prepared with corresponding alcohols

(Mp. 66-67.5°C)

5-chloro~3-p-chlorophenyl-l-phenyl-pyrazol-4-acetic acid n-butyl ester

(Kp 0.0001 210-215°)

Example J

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid ethyl ester 6.5 g 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetic acid, 70 ml ethanol and 4 g concentrated sulfuric acid is heated for 8 hours to boiling. Evaporate, pour on ice water, extract with ether, wash with sodium carbonate solution, dry the organic solution and evaporate. 85% of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid ethyl ester is obtained. Temp. 51.5-52.5°C.

Example K

5- chloro- 3- p- chlorophenyl- l- phenyl- pyr az. ol-4-acetamide 5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyra?iol-4-acetonitrile and 10 ml of 96% sulfuric acid are stirred for four hours at room temperature. The precipitate is introduced into 50 g of ice, the precipitate is suctioned off and washed with water. A 99% yield of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazol-4-acetamide is obtained. Temp. 192-193°C.

Example L

5- chloro- 3- p- chlorophenyl- l- phenyl- pyrazole- 4- acetanilide

a) 1.1 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid,

15 ml of benzene and 0.5 g of phosphorus oxytrichloride are heated for 2 hours

to boiling, whereby 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetyl chloride is obtained.

b) For the dissolution of the acid chloride in benzene, one drops

4

0.31 ml of aniline and stir for 1 hour at room temperature. It is distilled and crystallized. 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetanilide is obtained. Temp. 201-202°c.

In a similar way, one obtains from 5-chloro-3~p-chlorophenyl-1-phenyl-pyrazole-4-acetyl chloride and ammonia, morpholine, piperidine, ethylamine, 2-amine ethanol and phenylhydrazine: 5-chloro-3-p-chlorophenyl- 1-phenyl-pyrazole-4-acetamide, m.p. 192-195°C 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetmorpholide, M.p. 182-183°C.

Example M

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-thioacetmorpholide 1.5 g 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetmorpholide, 8 ml pyridine and 0.8 g phosphorus pentasulphide is heated for 5 hours under reflux. The solution is then supplied with 30 g of ice and the precipitate is suctioned off. 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-thioacetmorpholide is obtained. Temp. 204-205.5°C (of dimethylformamide/H^O) .

Example N

5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetamidoxime To a hot solution of 1.0 g of 5-chloro-3-p-chlorophenyl-l-phenyl-pyrazole-4-acetonitrile in 75 ml ethanol, a solution of 0.42 g of hydroxylamine hydrochloride is placed in 6.05 ml of 1 N sodium bicarbonate solution and it is heated for 11 hours to boiling under reflux. It is evaporated to dryness and recrystallized from methanol/water. 86% of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidoxime is obtained. Temp. 184-186°C (from toluene).

Claims (2)

1. Analogy method for the preparation of new therapeutically active pyrazole-4-acetic acid derivatives with the general formula where R means phenyl, halophenyl, p-alkoxyphenyl with 1-4 carbon atoms in the alkoxy part or p-alkylphenyl with 1-4 carbon atoms in the alkyl part, and halogen denotes a chlorine or bromine atom, or salts thereof with inorganic or organic bases, characterized in that a compound of the general formula II where R and halogen have the meanings mentioned above, and B denotes a hydrolysable functional derivative of an acetic acid group, is hydrolyzed, and the obtained compounds of the general formula I are optionally transferred to their salts, or, if desired, a compound obtained with it. general formula I in the form of a salt is converted to the free acid. 2. Process according to claim 1, characterized in that a compound with the general formula II stated in claim 1 is used for the hydrolysis where R means a p-chloro-phenyl group and halogen means a chlorine atom.