CA1048499A - Halogen pyrazoles derivatives, a method for producing these halogen pyrazole derivatives and medicaments containing them - Google Patents

Abstract

ABSTRACT
The invention relates to pharmaceutically valuable halogen pyrazole derivatives, a method for producing them and medicaments which contain these active substances. The derivatives are of the general formula I
I
in which Ph1 and Ph2 are the same or different phenyl radicals, and halogen denotes a fluorine, chlorine or bromine atom, and their salts.

Description

, ~V4~499 81 Int. August 197~

Byk Gulden Lomberg Chemische Fabrik Geselllschaft mit beschrankter Haftung, Konstanz New halogen pyrazoles derivatives~ a method for produ-cing these halogen pYrazole derivatives and medicaments . _ _ _ . . .
containing them.

The invention relates to pharmaceutically valuable halogen pyrazole derivatives, a method for producing them and medicaments which contain these active substances.

The Belgian patent specification No. 755,924 des-cribes pyrazole-4-acetic acid derivatives of the gene-ral formula R4 R2 ~ H-A -;
~ '`.
N ~ R3 - ' 11 ' ' .
R .
in which R1, R2 and R3 can be the same or diferent and denote respectively a hydrogen atom, a straight chained or branch chained saturated or unsaturated aliphatic or cycloalipIIatic hydrocarbon radical with 1 to 7 carbon atom~ or a possibly substituted aryl or heteroaryl group with up to 12 carbon atoms, with the proviso that when R is hydrogen,R3 i~ neither hydrogen nor a methyl group, , ~'. - ', , and R additionally denotes a benzyl group, which can be substituted with a halogen atom or an alkoxy group w th 1 to 4 carbon atoms, R denotes a hydrogen atom or an alkyl group with 1 to 3 clarbon atoms or a cycloalkyl group with 3 to 6 carbon a'toms, A denotes COOH, CooR5, CoNR6R7, CN or C(=NOH)OH, whereas R denotes an alkyl group with 1 to 4 carbon atoms, a benzyl group, a phenyl group or a 2-carboxy-phenyl group, and R6 and R7 denote respectively a hydrogen atom and/or an alkyl group with 1 to 4 carbon atoms or together with a nitrogen atom form a pyrrolidino, piperidino or morpholino group.
!
The described group of compounds possesses anti-phlogistic, analgesic and antipyretic properties.

A new class of pyrazole acetic acid derivatives has now been discovered which is characterised by a novel quite specific type of substitution which is not mentio-ned in the patent specification or rendered obvious by it, and in which a halogen atom is tied directly with the pyrazole nucleu~. It has further been dis-;
covered that the representatives of this class have particularly a~vantageou~ pharmacological effects. In particular the invention is based upon the knowledge that pyrazole-4-acetic acids with a-halogen subst~tution in the 5-position of the pyrazole nucleus are characterised by distincti~e and specific pharma-cological effec*s. The compounds of the invention in particular exhibit antiinflammatory, but also anti-pyretic and analgesic effects.

- 2 -.

, 1~)48499 One form of subject matter of the present invention is therefore represented by pyrazole-~-acetic acid derivatives of the following general formula I

i~
Ph2~ H2COOH

Halogen Phl in which Ph1 and Ph2 are the same or different phenyl radicals, and halogen denotes a halogen atom selected from the group consisting of fluorine, chlorine or bromine, and their salts with inorganic or organic bases.
.
Preferred pyrazole-4-acetic acid derivatives of the general formula I and their salts with inorganic or organic bases are characterised in that Ph1 denotes an unsubstituted phenyl radical and Ph2 denotes a phenyl radical selected from the group comprising unsub-stituted phen~-l, halogenphenyl, p-lower alkoxy phenyl and p-lower alkyl phenyl and halogen denotes a bromine or chlorine atom. Under the expressions 9'10wer alkoxy"
and ~'lower alkyl" radicals with a carbon atom number of 1 to 4 are understood.

Another group of preferred pyrazole-4-acetic acid derivates of the general formla I and their salts with~
inorganic or organic bases is characterised in that Ph1 denotes an unsubstituted phenyl radical and Ph2 a phenyl radical selected from the group consisting Or unsubstituted phenyl, p-chlorophenyl, p-bromophenyl and _ 3 _ - ' ' ' ' ' .

16)48499 I halogen denotes a fluorin~ or chlorine atom.

¦ Especially valuable pharmacological properties possess ¦ the compounds of the general formula I~ .
Ij ,~
Ph2 ~ CH2COOH

. ~ Cl - ` It ¢~ :

wherein Ph2~ denotes an unsubstituted phenyl radical or a p-chlorophenyl radical, as well as their salts with inorganic or organic basis.
- A. group of compounds, which in a particularly pre-- -ferred extent has the distinctive pharma^ological proper-ties of the pyrazole acetic acid derivatives of the gene- .
ral formula I and their salts is characterised in that Ph denotes an unsubstituted pkenyl radical and Ph2 denotes an unsubstituted phenyl, a p-chlorophenyl, a p-methoxyphe-c nyl or a p-isobutylphenyl radical and halogen denotes a chlorine or bromine atom.

he follo~ing compo~lds, in the form of the free acid or its salts, which are distinguished with respect to their pharmacological properties, are-now mentioned primarily:
...~ 5-chloro-1~3-diphenyl-pyrazole-4-acetic acid . -~ - 5=chloro-3-p-chlorophen~1-1-phenyl-pyr~zole-4-. . . ~ - acetic acid ~~ . . ........... .~-::: -5-chloro-3-m-chlorophen~1-1-phenyl-pyrazole-4- ; :~
; ~ -acetic acid -- . - .- - .`;: . -5-chloro-3-p-~ethoxyphenyl-~-phenyl-pyrazole-4-.`-...acetic acid . -.- ;.-.
. - 4 -- - , `
`` 1~48499 5-chloro-1-phenyi-3-p-tolyl-pyrazo~e-4-acetic acid 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetic acid 5-bromo-1,3-diphenyl-pyrazole-4-acetic acid.

As further typical represen~atives-within the scope - - I! of the invention the following acids and their salts are j to be considered: - -- .
5-Chloro-3-p-fluorophenyl-1-phenyl-pyrazole-4-acetic acid

3-p-bromophenyl-5-chloro-1-phenyl-pyrazole-4-acetic acid 5-bromo-3-p-fluorophenyl-1-phenyl-pyrazole-4-acetic acid 5-bromo-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazGle-4-acetic acid 5-bromo-3-p-isobutylpheny~ 1-phenyl-pyrazole-4-acet~c ~cid 5-fluoro-1,3-diphenyl-pyrazole-4-acetic acid 3-p-chlorophenyl-5-fluoro-1-phenyl-pyrazole-4-acetic acid 5-fluoro-3-p-methox~henyl-1-phenyl-pyrazole-4-acetic acid -5-chloro-3-p-butoxyphenyl-1-phenyl-pyrazole-4-acetic acid.
.
~- Within the salts in accordance with the invention the - pharmacologically compatible salts are preferred. As cat-ions for salt formation more particularly the cations in the form of alkali metal, alkaline earth metal and earth metal ions are used, or the ammo~ium ion, but also the -corresponding cation acids of single or polybasic organic -- ~itrogen bases, especially organic amines come into question.
.
~, .... . - ~` . ..
`., .
.

For example use is made of the cations of the metals lithium, sodium, potassium, magnesium, calcium and aluminium and the cation acids of ethanolamine, diethanolamine, triethanolamine, ethylene-diamine, dimethylamine, diethylamine, morpholine, piperazine, methyl-cyclohexylamine, glucosamine, N-methylglucamine, N-methylglucosamine, and furthermore of tert.-butylamine, dibutylamine, diisopropylamine, triethylamine, isopropylamine and quinoline.

A further form of subject matter of the invention is consti-tuted by a method for the production of compounds of the general formulae I and I* and their salts with inorganic or organic bases.
This method starts from functional carboxylic acid derivatives of pyrazole-4-acetic acids of the general formula I, which are described by the general formula II

Ph2 B
II, ~N ~ alogen I

Ph1 in which Ph1, Ph2 and halogen have the above-given meanings and B
denotes a functional derivative of an acetic acid group.

A functional derivative of an acetic acid group is a derivative of the acetic acid group (-CH2COOH) which derivative stands in a close chemical relation to the acetic acid group and which can be converted in the free acetic acid group by hydrolysis. Typical representatives of functional derivatives of the acetic acid group are disclosed in the following description.

The method for the production of compound~ of general formulae I and I~ i~ characteri~ed in that compounds of the general formula II are hydroly~ed to form comp~unds of the general formulae I and I~
or their salt~ and, if required,the compounds obtained of the general formulae I and I~ are converted into their salts or if desired a compound obtained in the form of a salt, of the general formulae I and 1~ i~
con~erted into the free acid.

In a preferred embodiment of the hydrolysis func tlonal pyrazole-4-acetic acid derivative~ of the general formula II7 are taken as a basis, that is to say ! ' Ph ~ ~ , T ~halogen II' ' Phl -.
. .- - ~ ~ ; ,...... -in which Ph1, Ph2 and halogen of the above-given meanings, B' denotes the group -CH2CN or the group -CH2-C~ X, ., ~Y
X denotes an oxygen or a sulfur atom or a substituted nitro-gen atom, more particularly an imino, alkylimino or hy-droxyimino group, and Y denotes a hydroxyl group or a monovalent eliminatable electrophilic radical, more particularly a free or sub-.
stituted amino group, preferably a ~onoalkyl or dialkyl or aryl amin~ group, a hydro~yamino or hydrazino 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 radical, a morpholino or a piperidino:group, whereas Y is not a hydroxy:group when X denotes an oxygen atom.

The term alkyl radical of an alkylimino, of a monoal-kylamino, of a dialkylamino, of an alkylthio and an alkoxy group is understood to mean an alkyl radical with up to 6 carbon atoms and the term aryl radical of an arylamino.group is taken to mean an aryl radical with up to 10 carbon atoms.

In a further pre~erred embodiment of the hydrolysis functional pyrazole-4-acetic derivatives of the:general formula II' are taken as a starting material, in which B' denotes the:group -CH2CN or the:group -CH2-C

in which X denotes an ox~gen atom, a sulfur atom or an imino:group and Y denotes an amino, monoalkylamino, dialkyiamino, phenyl-amino, alkoxy, alkylthio, chlorine or bromine radical.

In accordance with a particularly preferred embodiment of the hydrolysis pyrazo~e-4-acetonitriles, pyrazole-4-acetic amides and pyrazole-4-acetic acid alkyl esters of the:general formula II' are taken as a starting material.

.

1~48499 ~ he method ca~ also be carried out in such a manner that a pyrazole derivative i5 used which as an intermea a-te forms a pyraæole derivative of the general for~ulaeII or II', which is react~ later with a water providing medium to produce the desired pyrazole-4-acetic acid derivative of the general formula I. In many cases the hydrolysis is carried ou' in a number of s~ages and if the reaction is carried out suitably intermediate stages can also be iso-lated. ~hus for example the hydrolysis of the nitriles, thioamides, amidines and ~midazolines is via the corres-ponding and corresponding amides or that of the imide acid esters is via carboxylic acid esters. In the case of the reaction of unsubstituted a~ides with nitric acid acyldia-zonium compounds are produced as intermediates which can readily be hydrolysed to form carboxylic acids.

- As starting compounds for the method in accordance with the invention for the production of compounds of the general formula I use is made in principle of such compounds as as functional derivatives of the carboxylic acids of the general formula I produce the compounds of the formula I by hydrolysis. As examples for such functional carboxylic acid derivatives it is possible to mention: alkyl esters, phenyl esters, benzyl esters, alkoxyalkyl esters, dialkylaminoal~yl 104`8499 .
esters, amides, N-monoalkylamides, N,~1-dialkylamides, mor-pholides, piperidides, piperazides, ani~ides, N-alkylanilides, N-hydroxyamides, ~-alkoxyamides, hydrazides, azides, mono-thiocarboxylic acids, monothiocar~oxylic acid alkyl esters, thioncarboxylic acid alkyl esters, thioamides, thiomorpho-lides, imideacid ester, amidines, hydrazidines, oxazolines, imidazolines, thiazolines, acid chlorides, acid bromides, acid anhydrides, ketenes and nitr~les.

Starting products which, however, are particularly important are those compounds whose production appears ad-vantageous from commercial and economic points of view and which are best described by the general formula II'. If du-ring the hydrolysis the radicals ~ and Y are eliminated, tbeir chemical structure is, howeYer, of ~ubordinate impor-tance. It is furthermore to be taken into account that a few compounds can be represented by two different formulas -owing to possible tautomers (for example amide and imide acids).
.
As characteristic starting products for the above-men-tioned hydrolysis it is possible to mention fo~ example the nitriles, amides and carboxylic acid lower alkyl esters of the general formula II'.

- As specific compounds the following come into question for example:
.
5-Chloro-1,3-diphenyl-pyrazole-4-acetonitrile 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro-3-m-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro-1-phenyl-3-p-tolyl-pyrazole-4-acetonitrile 5-chloro-3-p isobutyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-fluorophenyl-1-phe~yl-pyrazole-4-acetonitrile . .
. . ~ .

. j ,- ~ - - - .
, ' ' ' ~- ' .

)48~99 5-bromo-1,3-diphenyl-pyrazole-4-acetonitrile -- - - 5-bromo-3-p-fluorophenyl-1-phenyl-pyrazole-4-aceto-nitrile 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-4-aceto-nitrile - 5-bromo-3-p-isobutylphenyl-1-phenyl-pyrazole-4-aceto-nitrile --- 5-bromo-3-p-chlorophenyl-1-phenyl-pyrazole-4-aceto-nitrile 5-fluoro-1,3-diphenyl-pyrazole-4-acetonitrile ,~-p-chlorophen;yl-5-fluoro-1-phenyl-pyrazole-4-acetorlitrile 5-fluoro-3-p-methoxyphen~l-1-phenyl-pyrazole-4-. acetonitrile 5-chloro-3-p-butoxyphen~l-1-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid methyl ester 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid ethyl ester 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid butyl ester 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-2-methoxyethyl ester 5-chloro-3-p-chlorophenyl-1-p~enyl-pyrazole-~-acetmorpholide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetanilide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-thioacetmorpholide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidoxime 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidinhydrochloride -. For the hydrolysis of functional carboxylic acid deriva-- : . tives of the general formula II or II' use is made of a wa-- : ter -.~elivering mediu~ which consists partly or completely of water or agents which split off water in the conditions of hydrolysis. The reaction can be carried out as a homo-.. ' -- . , - 11 - - ~

.

geneous reaction in which case the operation is usùally car-ried out in the presence of a polar organic solvent or a so-lution promotor. Advantageously use can be made as solvents for example of low-molecular weight alcohols, dioxan, acetone, low-molecular weight carboxylic acids, N-methylpyrrolidone, sulfolane or dimethylsulfoxide. Furthermore, however, the hydrolysis can be carried out as a heterogeneous reaction.
Thè pH-value of the water-delivering medium is adjusted in accordance with the chemical nature of the pyrazole-4-acetic acid derivative used, but also in accordance with the nature of the desired compound of the general formula I, and it can therefore be neutral, acidic or basic. It is set with acids, bases or buffers at the desired value.

The hydrolysis temperatures lie between 0C and the boiling point of the water-delivering medium, generally bet-ween 0 and 150C, and more particularly between 20 and 120C. The hydrolysis temperatures depend in individual ca-ses also whether the operation is carried out with or with-out a gauge pressure. The reaction times are in accordance witk the batch, reaction temperatures and other reaction parameters between 10 minutes and 20 hours. After the ter-mination of the hydrolysis the pyrazole-4-acetic acids are isolated in accordance with conventional methods, for example by recrystailisation or acidification of their solutions, possibly with the reduction in volume of their solutions.
For purifying them their alkaline solution can be extracted with an organic solvent which is not mixable with the alka-line solution, as for example ether, benzene, chlorobenzéne, chloroform or methylene chloride.

The conversion of the pyrazole-4-acetic acids of the general formulae I or I* into their salts can be carried out by direct alkaline hydrolysis of the pyrazole-4-acetic acid derivatiyes of the general formula II or II'. As an alkaline 10484~9 reaction partner use is made of that inorganic or organic base whose salt it is desired to produce. It is also possible to produce the salts, however, by reacting the pyrazole-4-acetic acids of the general formula I with the stoichiometric equivalent of the corresponding base or converting readily soluble salts by double decomposition into sparingly soluble salts, or converting any desired salts into the pharmacologically compatible salts.
The pyrazole-4-acetic acid derivatives of the general formula II or II' are in principle accessible using halogenation of 2-pyrazoline-5-ones of the general formula III or IV, which can be obtained in accordance with known or inherently known methods, in the 5-position Ph2 ~ Ph2 ~ IV
~,N 0 N ~ O
Phl Phl for example with the help of reactive halides of elements of the V and VI Groups of the Periodic System or of reactive carboxylic acid halides, carboxylic acid imide halides or Vilsmeier reagents and possibly via further known method steps.
In accordance with a preferred embodiment of the method a compound of the general formula III is reacted with at least two mole equivalents of a Vilsmeier reagent, which has been produced from a dialkyl- or alkylarylformamide and an acid halide before the re-action or during the reaction in situ to form corresponding 5-halogen-

4-pyrazolyl-methylene dimethyl ammonium salts, which are then hydrolysed to form 5-halogenpyrazole-4-carboxaldehydes of the general formula V
Ph CH=O
2 ~ V
~ halogen I

Ph1 As dialkylformamides use is made ~or example of dimethyl-formamide, diethylformamide, diisopropylformamide, N-formylpiperidine, N-formylpiperazine, N,N-diformylpipera-zine or N-formylmorpholine. As alkylarylformamides use is made for example of N-methyl-N-phenylformamide or N-ethyl-N-tolylformamide. As acid halides phosphorus oxytrichloride, phosphorus oxytribromide, phosgene and thionyl chloride come preferably into question. In the case of this method, if the reaction is carried out suitably, in addition to the formy-lation in the 4-position there is also halogenation in the

5-position of the pyrazole with an excellent yield. The re-action temperatures generally lie between 10 and 100C and the reaction times between 15 minutes and 30 hours.

A further method coming into question is that of halogen exchan~e, starting fromthe compounds of the general formula V, for example the substitution of chlorine by bromine or fluorine by means of halides or hydrogen halide acids, possibly at a raised temperatuxe and in a pressure vessel.

Besides the 5~chloro-1,3-diphenyl-pyrazole-4-carboxy-aldehyde the compounds of the general formula V are new compounds.

A key intermediate product is the compound 5-chloro-3-p-chlorphenyl-1-phenyl-pyrazole-4-carboxaldehyde, because with this compound 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid and its saits can be prepared and these final products exhibit distinguished pharmacological properties.

104849~
~ he compounds obtained of the general formula V are converted by means of methods kno~m as such (see for ex-ample the Belgian patent specification 755,924) via a series of intermediate sta~es to form the pyrazole-4-ace-tic acid derivatives of the general formula II~ Thereby the carbonyl group is reduced under mild conditions to form a hydroxymethyl group which is converted into a halogen ~ethyl or trialkylammonium methyl group which-is reacted ~ith a cyanide to form nitriles of the general formula TI.
The reduction can be carried out for example with sodium borohydride in an anhydrous or watèr-containing solvents between 0 and 50C. ~he halogen meth~l compounds can be obtained from the hydrox~methyl compounds for exa~le by reaction with sulfur or phosphorus halides or carboxylic acid halides such as phosgene, but also by reaction with hydrogen halide acids and their concentrated aqueous solu-tions, in the case~of which any suitable inert solvents can come into question. The reaction of the 4-halogen-methyl-5-halogen-pyrazoles to for~ nitriles of the general formula II can be carried out in accordance with the me-thods described in the Belgian patent specification 755,~25 for similar com~ounds, preferably in aprotic, dipolar sol-vents, at temperatures between 0 and 80C.

- Pyrazole-4-acetic acid esters of the gener~l formula II can readily be obtained from other reactive pyrazole-4-acetic acid derivatives of the general formula II.in ac-cordance with co~entional methods, for example from acid halides, acid anhydrides and nitriles by alcoholysis, and furthermore from pyrazole-4-acetic acids of the general formula I by reaction with alcohols under conditions lead-ing to the splitting off of water or by reaction of acids and salts with alkylating agents, as for example of benzyl esters by reaction of aIkali metal salts with benzyl hali-des.

. - - - 15 _ . .. -. . - - - . . ~ .

.
.

Unsubstituted amides of the general formula II can be produced by hydrolysis of corresponding nitriles. The aminolysis of reactive carboxylic acid derivatives as for example acid halides or esters with ammonia, with mono or dialkylamines with arylamines, cyclic amines such as pi-peridine, morpholine and piperazine with hydroxylamine, O-alkyl-hydroxylamine and with, possibly substituted hydrazines provides, if required, N-alkyl or aryl substituted amides, piperidides, morpholides, piperazides and further-more hydroxamic acids, O-alkylamides and, if required, N-alkyl or aryl substituted hydrazides of the general formula II.

Thioamides of the general formula II can for example be produced by reaction of nitriles and hydrogen sulfide in the presence of bases or by the sulfurisation of ami-des, for example with phosphorus pentasulfide.

To the nitriles of the general formula II furthermore alcohols can be added on acidic catalysis to form the corresponding imide acid esters while the nitriles react with arylamines with basic catalysts to form corresponding amidines and they react with mercaptans or mercaptoacetic acid to form corresponding thioimide acid esters.

From imide acid esters of the general formula II it is for example possible to produce amidines with amines, oxazolines with amino alcohols and imidazolines with di-amines.

Acid halides of the general formula II can be in a conventional manner produced from the compounds of the formula I by means of halides of the phosphorus or sulfur acids and ketenes can be produced from the acid halides by dehydrohalogenation by means of tertiary organic bases.

It has been found as a matter of experience that in many cases for the intermediate products II or II' and their preliminary stages no special purification operations were necessary and that they can be used without following puri-fication steps in the next method step following.

It has been found, surprisingly, that the compounds of the general formuia I and their salts while having a comparatively low toxicity have pronounced antiphlogistic and also analgesic and antipyretic lowering properties.

In particular the antiinflammatory action could be shown to exist after single and multiple administration in acute and chronic inflammation experiments as well.
The compounds of this invention exhibited a high superiority over the compounds known in the art as shown in table 1 in comparision with the commercially available medicament phenyl butazone (I) for example by 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazol-4-acetic acid (II) and 5-chloro-1,3-diphenyl-pyrazol-4-acetic acid (III).

.
~4849~

. ` ~

~ ~;aX o C~ o 5 . 6~
. _ ~ .
5~ .
~O C~ U~
,r~~1 ~ N
.~ ~ ~ ~ .
~ ~ __ _ ~ .
_ ~ ~ ~ ~
.. ~ o ~ . .
11~ h ~ 1 ~ O
~ ~ ~
~ O~ 5~
~1 h O O ~ X ~ ~
rl N ~ ~ ~ E3 t~ ..
r~ . _ _ . :
~.
0~ ~ ~ O ~ O
U~ ~ ~ ~
. ~ ;t' ~ol ~ h 11~ .. _ S~ g~ o.
~ ~0~ ~
~ ~ ~ ~ U~ U~
~, è ., o o l H H . . .
'C O H H H
C.~ .
_ _ _ _ 18 --.

10484~9 However, the compounds in accordance with the in-vention also sho~ed a specific action and a degree of superiority, for example also with regard to their therapeutic breadth, as compared with the above-mentioned standard preparation (I) in another form of pharmacological tests, as~hown in table 2 for example by the following compounds:
5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (I~, 5-chloro-1,3-diphenyl-pyrazole-4~acetic acid (III)and 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid (IV), .

Table 2 Antiphlogistic activity9 acute toxicity (LD50) and therapeutic index Q of halogeno-pyrazole derivati~es.
.. ~
Compound Retardation of the I LD50 Q
¦Carrageeni] Edema ¦ i 5 ~mg/kg~ P-1 relati~e [mgJkg]
effect p.o.
I 10 ¦ 1.01 635 1 63.5 _ .
II 1.5 ¦ 6.7530 353 III ¦ 1.0 ¦ 10.0 ~ 1200 ~ 1200 . .~ _ .
Ir 112 1 o.8Illoo , 91.7 - . , '.
.
.

-- 1~ --. . ' - .

lQ48499 -¦ The antiinflammatory action of the standard prepa-¦ ration and the compo~nds of this invention, respectively, - I was determined - ~ on the retarding inflammation at the carrageenin , edema of the rear paw of the rat [Winter et al.
i Proc. Soc. exp. Biol. Med. 111 (1962~ 544], wherein in table 2 those doses are shown which cause a mean retardation of 25 ;0 3 and 5 hours after single administration of the substance to be tested;
on the retardation at the ultraviolet erythema of the skin on the back of the guinea pig [Winder et al. Arch. int. Pharmacodyn. 116 (1958) 261], wherein in table 1 those doses are shown which cause a retardation of 25 h 5 hours after ~ irrida*ion;
- on a chronic inflammation model (cotton granuloma) wherein the influence of the compounds on the granulation tissue formation after subcutanous implantation of cotton plugs in rats was studied after daily administration on 7 following days in taking pattern from the method described by Winter et al. [J. Pharmacol. exp. Therap. 141 (1963) 369], in table 1 those doses are shown which inhibit the reformation of the granulation tissue by 20 % (ED20)o The lethal doses were determined in usual manner. LD50 (mice) and LD5 (rats), respectively, denote the dose at which 50 % and 5 ~ of the animals, respectively, died within 10 days after single and 7 days administration, respectively, of the substance.

. ' . ' ;

`

i In the case of the application of a therapeutically effective and pharmacologically compatible guantity the compounds in accordance with the invention are therefore suitable for the treatment of a large number of disease conditions of mammals, in the case of which one or more symptomes of inflammation, pains and fever occur. Examples of such disease conditions are the most various different inflammatory and degenerative diseases of the rheumatic form circle and other inflammatory disease processes, for example acute and chronic polyarthritis, osteoarthritis, psoriatic arthritis, ankylosespondylitis, polyarthroses, spondyloses, rheumatism of the joints, rheumatic fever;
rheumatism of soft parts as for example tendinitis, per-- iarthritis and periostitis; acute muscuiar rheumatism, for - . example ischias; painful postoperative swellings and in-flammation; pains and swellings after bruising of the - ~oints, sprains and fractures; pains and inflammation connected with dental surgery; pain conditions of the most I various different origins, for example neuritides, head-- aches and spasms; and also human and animal disease con-ditions which give rise to the above symptoms and make ( ~ecessary the use of an inflammation preventing analgesic - . ~and/or antipyretic medicament. .. . - .

- 21 _ .

A further form of subject matter of the invention is therefore a method for the treatment of mammals, which are suffering from one or ~ore of the above symptomes of in-flammation pain or fever. The method is characteri~d in tbat the diseased mammal has administered to a therapeu-tically effective and pharmacolo~ically compatible quan-tity o one or more compounds of the general formula I
and/or their salts.

The invention furthermore therefore comprises also medicinal substances which are characterised by a content of one or more of the new active substances. P~ssibly the new medicaments contain pharmaceutical vehicle materials, in addition to the new active substances, for the latter.
The active substance content of these medicaments amounts to between 1 and 95 % by weight and preferably betl"een 10 and 85 % by weight, expressed in terms of the finished medicament.

~ he medicaments are preferably administered orally, rectally, as solutions of salts parenterally, for example subcutaneously, intramuscularly or intravenously by in-Jection or topically (percutaneously). Preferabl~ the pharmaceutical preparation of the active substance is in the form of unitary doses, which are matched to suit the desired administration. A unitary dose can be for example a tablet, a capsule, a suppositor~ or a neasured volume quantity of a powder, a granulate, a solution, an emul-sion, a suspension or a gel or of an ointment. The term "unitary dose" within the meaning of the present irven-tion is to be understood to mean a physicall~ determined unit, which comprises the individual quantity of the ac-tive component mixed with a pbarmaceutical diluent lor it or together with a pharmaceutical vehicle material.- In tbis respect the quantity of the active substance is so - _ 22 _ selected that o~e ox more units are conventionally required for a single therapeutic administration.

The unitary dose can, however, also be capable of be-ing split up, for example in the form of tablets provided with notches, if for the individual therapeutic administra-tion only a ~raction, as for example a half or a quarter, of the unit which can be subdivided is required.

The pharmaceutical preparations in accordance with the present invention comprise, if they are produced as unita-ry doses, 1 to 1000 mg, and with more particularly advan-tageous effects approcimately 5 to 500 mg and more particu-larly approximately 10 to 250 mg of active substance. The therapeutic administration of the pharmaceutical prepara-tions can be carried out 1 to 4 times daily, for example respectively after the mealtimes and/or in the evening. The dose which is administered is determined in accordance with the frequency of the administration, the duration of treat-ment, the nature and severity of the illness, and in accor-dance with the weight, age and the:general condition of health of the patient. The daily dose generally lies bet-ween 0.05 and 70 mg/kg body weight for mammals.

The pharmaceutical preparations consist generally of the active substances in accordanve with the invention and non-toxid pharmaceutically acceptable medicament vehicles, which are used as an addition to the mixture in thé form of solid, semi-solid or liquid materials or as encasing means, for example in the form of a capsule, of a tablet coating, of a bag or another container, which come into question for the therapeutically active component. A vehicle material can serve for example as a promotor for the take up of the medicament by the body, as an adjuvant for formulation, as a sweetening agent, as a flavoring materials; as a dye or as a preserving agent.

For oxal administxati~ it is possible to use fo~ eXamp~e tablets, dragées, hard and so~t capsules, for ex~mple of:ge-latine, dispersible powders, granulates~ aqueous and oily suspensions, emulsions, solutions or sirups.

Tablets can comprise inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lac-tose;:granulation and distributing agen~s, as for example maize starch or alginates; binding agents, as for example starch,:gelatine or acacia:gum; and lubricants, as for ex-ample aluminium or magnesium stearate, talc or silicone oil.
They can be additionally provided with a coating, which can be so made that it brings about a delay in breaking up and resorption of the medicament in the:gastrointestinal tract and thus an improved compatibility or a longer period of action for example. Gelatine capsules can be used to hold the medicament mixed with a solid agent, such as calcium carbonate or kaolin or an oily diluting agent, as for ex-ample olive,.ground nut or liquid paraffin.

Aqueous suspensions can comprise suspending agents, as for example sodium.carboxymethylcelluIose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, gum traganth or acacia:gum.; dispersing and wetting agents, as for example polyoxiethylene stearate, heptadecaethylene, oxicetanol, polyoxie'thylenesorbitol monooleate, polyoxiethylene-sorbitane monooleate or lecithin; preserving agents, as for example methyl or propylhydroxybenzoate; flavoring agents;
sweeting agents, as for example saccharose, lactose, dex-trose, invert sugar sirup.

Oily suspensions can comprise for example.ground nut, olive, sesame, coconut or paraffin oil and thickening agents, as for example beeswax, paraffin wax or cetylalcohol; and furthermore sweetening agents, flavoring agents and anti-oxidants.

1048499 ~ -Powders and granulates which can be dispersed in water can comprise the medicaments in admixtu~e with dispersing, wetting and suspending agents, for example the above-men-tioned ones and with sweetening agents, flavoring agents and dyes.
.
.
Emulsions can comprise for example olive, ground nut - or paraffin oil in addition to emulsifying agents as for ~xample acacia gum, gum traOanth, phosphatides, sorbitane ~onooleate, polyoxiethylenesorbitane monooleate, sweeten-- . ing and flavoring agents. ~ -, I . . . - -For rectal application of the medicinal substances -- it is possible to use suppositories, which can be produ-ced with the help of binding agents fusing at rectal tem- -peratures, for example cacao butter or polyethyleneglycols.

For parenterai application of the medlcaments it is possible to use sterile injection aqueous suspensions, isotonic salt solutions or other solutions, which can com-- prise dispersing and/or wetting agents and/or pharmacolo-- gically compatible diluting agents, as for example propy-lene or butyleneglycol.
- . .
I~ addition to the novel pyrazole-4-acetic acids-the ~- pharmaceuticai preparations can comprise for example one - or more pharmacologically active components from other groups of medi aments as for example corticosteroids ac-ting to suppress inflammation (as for example predni80ne, - prednisolone, dexamethasone and their derivatives);
analgesics,`as for example pyrazolone derivatives (for ` example aminophenazone), propoxyphene, phenacetine, sali- --cyl acid derivatives etc.;
- muscle relaxants, as for example pyridazine derivatives, - -carbamates (for example phenprobamate) etc.;

- _ 25 _ .
- .: , . . .
- . . . . . .

. . ~ ' - .
.

" . 1048499 substances with an antiulcerogenic action;
an~iacid materials (as for example magne'sium trisilicate and aluminium hydroxide);
s~abstances encouraging local blood circulation as for ex-ample nicotinic acid derivatives and dimethylsulfoxide;
local anastesics (as for example lidocain) and vitamines (as for example vitamine-B1-chloride-hydrochloride, ~it~mine-B6-hydrochloride, vitamine-B12-cyanocomplex and thiamin disulfide).-.

_ 26 -1~48499 The following examples explain the invention in more detail without restricting it. The temperatures mentioned are given in C. The abbreviation F denotes the melting point, the abbreviation Kp1o the boiling point at 10 Torr.

Example 1 5-Chloro-1,3-diphenyl-p~razole-4-acetic acid 19.1 g of 5-chloro-1,3-diphenyl-pyrazole-4-acetonitrile are heated in 96 g of 63 percent suIfuric acid for 1 hour at 115C. The solution is cooled and the acid is precipita-ted by diluting with 500 ml of water and it is washed with water and crystallised from ethanol and water. A product containing water of crystallisation is obtained which af-ter dissolving in benzene and reduction in volume of the solution is dehydrated. With the yield of 91 % 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid is obtained; F 151-152.

Example 2 5-Chloro-3-p-chlorophenYl-1-phenyl-pyrazole-4-acetic acid 30 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile and a mixture of 46 ml of concentrated sul-furic acid and 55 ml water are heated for 2.5 hours while stirring at 100C. Then the solution is diluted with 700 ml of water, the precipitate is drawn off and washed with wa-ter. The filter cake is dissolved in diluted sodium hydro-xide and purified with active charcoal and the acid is precipitated with diluted hydrochloric acid. 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained with a yield of 95 %; F 179.5 - 181 (from methanol).

From the corresponding pyrazole-4-acetonitriles 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro-1-phenyl-3-p-tolyl-pyrazole-4-acetonitrile 5-chloro-3-m-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-aceto~
nitrile 5-bromo-1,3-diphenyl-pyrazole-4-acetonitrile 5-bromo-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile 3-p-bromophenyl-5-chlo ~1-phenyl-pyrazole-4-acetonitrile the following compounds 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid (F 166.5-167.5) 5-chloro-1-phenyl-3-p-tolyl-pyrazole-4-acetic acid 5-chloro-3-m-chlorophenyl-1-phenyl-pyrazole-4-acetic acid 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetic acid (F 110-110.3) 5-bromo-1,3-diphenyl-pyrazole-4-acetic acid (F 187.5-188.5) 5-bromo-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid 3-p-bromophenyl-5-chloro-1-phenyl-pyrazole-4-acetic acid are obtained in a similar manner.

Example 3 5-Chloro-3-P-chlorophenyl-1-PhenYl-pyrazole-4-acetic acid 3.8 g of ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-py-razole-4-acetatet 13 ml of ethanol and 1.0 g of sodium hy-1~)48499 droxide are heated in 13 ml of water or 1 hour for boiling. The pH is reduced to 10 and the alcohol is distilled off in vacuo. The aqueous solution is shaken up with ether and purified with active charcoal. Acidification is carried out with dilute hydrochloric acid and with a yield of 83% 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained; F 179.5-181.
In a similar manner it is possible to produce from methyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate n-butyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate n-hexyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate benzyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate phenyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate o? e~J7 o"~, e,~/
5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate ~-dimethylaminoethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-thioacetate using alkaline hydrolysis 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (F 179.5-181).
In a similar manner it is possible to produce from ethyl 5-chloro-1,3-diphenyl-pyrazole-4-acetate methyl 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetate methyl 5-bromo-1,3-diphenyl-pyrazole-4-acetate by alkaline hydrolysis 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid (F 151-152) 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid (F 166.5-167.5) 5-bromo-1,3-diphenyl-pyrazole-4-acetic acid (F 187.5-188.5).

~. ., : 104~' ~xample 4 5-Chloro-3-~-chlorophenyl-1-phenyl-R~zole-4-acetic acid 1.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile, 10 ml of ethanol and 1.4 g of so~m hydro-xide are heated at boiling point for 4 hours until the evo-lution of ammonia is terminated. ~he alcohol is distilled in ~acuo, treated with ether, puri~ied with active char-coal and the aqueous phase is acidified with hydrochloric acid to pH 3. With a yield of 5 % 5-chloro--3-p-chloro-phenyl-1-phenyl-pyrazole-4-acetic acid is obtained;
F 179.5-181~ -.
_ , Example 5 5-Chloro-3-p_ hlorophenyl-1-pher~ razole-4-acetic_acid 2.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide and 10 g of 63 % sulfuric acid are heated for 1.5 hours at 100C and prepared in accordance with example 2. 5-Chloro-3-p-chlorophenyl-1-phenyl- yrazole-4-acetic a-cid is obtained; F 179.5-181.
In a similar manner it is possible to produce from 5-chloro-3-p-chlorophenyl-1-phenyl-pyraS~ole-4-acetic acid-n-butylamide 5-chloro-3-p-chlorphenyl-1-phenyl-p~razole-4-acetiG acid-diethylamide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetmorpholide 5-chloro-3-p-chlorophenyl=1-phenyl-pyrazole-4-acetpiperidide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4- -acetpyrrolidide -5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4- - - -acetanilide . .
. . - - . ~ .-: , - 3 . . . -- : . ..
.
'', - - -.

-10~
5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid-N-methylanilide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acethydroxamic acid 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamidoxime 5-chloro-3-p-chlorophenyl-`1-phenyl-pyrazole-4-aceth~drazide 5-chloro-3-p-chloro~henyl-1-phenyl-pyrazole-4-acetamidine-hydrochloride by hydrolysis with sulfuric acid 5-chloro-3-p-chlorophenyl-1-phen~l-p~razole-4- ..
acetic acid (F 179.5-181).

Rxample 6 5-Chloro-3-~-chloro~hen~l-1-phenyl-p~razole-4-ace lC acid 0.3 g of 5-chloro-3-~-chlorophenyl-1-phenyl-pyrazole-4-thioacetmorpholide and 6 ml of 20 % hydrochloric acid are heated at boiling point until the evolution o~ hydrogen sul-.
f.ide is finished. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyra-zole-4-acetic acid is obtai~ed;(F 179.5-181).
In a similar manner.it is possible to~produce from 5-chioro-3-p-chlorophenyl-1-phen~l-pyrazole-4-acetimide-ethyl ester hydrochloride 2-Ct5-chloro-3-p-chlorophenyl-1-phenyl-4-pyrazol~l)-methyl~-oxazoline - ~.
2-[(5-chloro-3-p-chlorophenyl-1-phenyl-4-pyrazolyl)-methyl]-thiazoline . ~-- - -1-methyl-2-C(5-chloro-3-p-chlorophenyl-1-phenyl-4-pyrazolyl)-meth~l]-imidazoline by hydrolysis with hydrochloric acid .-5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (F 179.5-181), .
. .
'' - - " - . ' , - -~ . - 3~ ~ . .
.
, . ~ -. ., . ,: ' ' ' . , , --, . 10~ 9 ' I~:xample 7 ~-Chloro-3-p-chlorophenvl-1-phen~ razoie-4-acetic acid 3.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole~4-~cetamide are dissolved in 15 ml of 90 % sulfuric acid and while stirrin~ at 20 to 30 a solution of 0.7 g so~ium ni-trite in a little water is passed dropwise under the sur-face. Gentle heatin~ is carried out until the evolution of ~as is terminated and the mixture is thenpoured on to an ice and water mixture. 5-Chloro-3-p-chlorophenyl-'i-phenyl-pyrazole-4-acetic acid is produced; ~ 179.5-181.
- ' '.
Exam~le 8 Sodium salt of 5-chloro-3-p-chloro~hen~l-1-phenyl-p~razole-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.n sodium hy-droxide, the solution is evaporated in ~acuo to dryness and the residue is taken up with e~her; ~he sodi~m salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic.acid is obtained; ~ 275-279.
.
' ~ ' ,' .
Example 9 Calcium salt of 5-chloro-3-p-chloro~henyl-1-phenyl-~razole-4-acetic acid .
' .
A solution of 3.5 g of-5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid in the equivalent quantit~
o~ diluted sodium hydroxide is added dropwise.at a raised temperature to a ,solution of 1.6 g of calcium chloride he-xahydrate in 12 ml of water. The precipitate is washed wi`,h diluted calcium chloride solution and ice-cold water. ~he.

. -.
- ' 104~499 calcium salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained with a quantitative yield; F 302-307 (decomposition).

Example 10 Morpholine salt of 5-chloro-3-p-chloroPhenyl-1-phenyl-pyrazole-4-acetic acid To a solution of 1.0 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid in 45 ml of ether 0.25 g of morpholine is added, dropwise. The morpholine salt of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid is obtained with a 87 ~ yield; F 144-145.5.

Example 11 5-Chloro-1,3-diphenyl-pYrazole-4-carboxaldehyde At 5 to 10 97.3 g of phosphorus oxitrichloride are added dropwise to 92.7 g of dimethylformamide and the mix-ture is stirred for completion of the complex formation for 30 minutes at room temperature~ Following this 30 g of 1,3-diphenyl-2-pyrazoline-5-one are added and while stirring heating is carried out for 1 hour at 55C and for 20 hours at 70. The product is poured on to approximately 600 g of ice neutralised with concentrated sodium hydro-xide solution to pH 3-4, vacuum filtered and washed with water. 5-Chloro-1,3-diphenyl-pyrazole-4-carboxaldehyde is obtained with a yield of 93 %; F 109-110 (from petro-leum ether).

1~)48~99 Example 12 5-Chloro-3-p-chlorophenyl-1-phenyl-pyraiole-4-carboxaldehyde (a) At 5 to 10 284 g of phosphorus oxytrichloride are added dropwise during a period of 90 minutes to 270 g of di-methylformamide. Stirring is carried out for 30 minutes at 15 and then lO0 g of 3-p-chlorophenyl-1-phenyl-2-pyrazoline-5-one are added. Heating is carried out for 1.5 hours at 50 and for 21 hours at 70. The product is poured on to 2 kg of ice, the pH is adjusted to 3-4 with 20% of sodium hydroxide and the precipitate is filtered off. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde is obtained with a yield of 99%; F 169.5-171 (from acetone).
In accordance with procedure (a) from the corresponding 2-pyrazoline-5-ones the following:
5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-carboxaldehyde (F 108-110) 5-chloro-3-m-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde 5-chloro-1-phenyl-3-p-tolyl-pyrazole-4-carboxaldehyde 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-carboxaldehyde (F 56.5-57) b cqr o~ ~6 5-chloro-3-p-fluorophenyl-l-phenyl-pyrazole-4-ea~ qrk~bth-~3-p-bromophenyl-5-chloro-1-phenyl-pyrazole-4-carboxaldehyde are prepared.

(b) The 3-p-chloro-phenyl-1-phenyl-2-pyrazoline-5- one required as a starting product is produced in the following manner:
50.8 g of ethyl p-chlorobenzoylacetate (produced for example from p-chloroacetophenone, diethyl carbonate and sodium hydride with a yield of 72%), 29 g of phenylhydrazine, 5 ml of glacial acetic acid and 150 ml of ethanol are heated in a nitrogen atmosphere for 1 hour at boiling point. After cooling in an ice bath 3-p-chlorophenyl-1-phenyl-2-pyrazoline-5-one is obtained with a yield of 84%; F 160.5-161.5.
In accordance with procedure (b) the following 2-pyrazoline-5-ones are obtained:
3-p-methoxyphenyl-1-phenyl-2-pyrazoline-5-one (F 137-138) 3-m-chlorophenyl-1-phenyl-2-pyrazoline-5-one l-phenyl-3-p-tolyl-2-pyrazoline-5-one 3-p-isobutylphenyl-1-phenyl-2-pyrazoline-5-one (F 124.5-125) 3-p-fluorophenyl-1-phenyl-2-pyrazoline-5-one 3-p-bromophenyl-1-phenyl-2-pyrazoline-5-one Example 13 5-Bromo-1,3-diphenyl-pyrazole-4-carbox ldehyde 175 g of fused phosphorus oxitribromide are added dropwise in a period of 75 minutes while stirring and cooling at 10-16 to 306 g of dimethylformamide. To the crystal suspension of the Vilsmeier complex 29 g of 1,3-diphenyl-2-pyrazoline-5-one are added and heating is then carried out for 20 hours at 65 to 70. The product is poured on to 850 g of ice, the p~ is adjusted with 2 n sodium hydroxide solution tc 4-5. Vacuum filtration is carried out and the precipitate is well washed with water. Raw 5-bromo-1,3-diphenyl-pyrazole-4-carboxaldehyde is obtained with a 85 % yield and is purified ~y filtration of a chloroform soiution over silica gel; F 128-128.5.

\

104l~499 .
In a similar manner it is possible to produce ~rom 3-p-chlorophenyl-1-phenyl-2-pyrazoline-5-one 3-p-methox~phenyl-1-phenyl-2-pyrazoline-5-one an~ the Vilsmeier complex from phosphorus oxytribromide and dimethylformamide 5Ibromo-3-p-chlorophen~l-1-phenyl-pyrazole-4-carboxalde-hyde (F 178-179.5) ~ -5-bromo-3-p-methox~phenyl-1-phenyl-~`yrazole-4-carboxal-dehyde. - - -~xample 14 5-Chloro-4-h~drox~ethyl-1,3-diphenyl-~razole ~ o a solution~of 21 g of 5-chloro-1,3-diphenyl-pyrazole -4-carboxaldehyde in 80 ml of dioxan there is added drop-wise at 23 to 27 a solution of 1.11 g of sodium bor~hydride in 35 ml of water. ~he resulting suspension is stirred for a further 30 minutes and on the addition of 200 ml of water 5-chloro-4-hydroxymethyl-1,3-diphenyl-pyrazole is precipita-ted with a 99 % yield, ~ 140.5-141.5 (from toluene).

-- , . .
Example 15 . ~
~.8 g of fiodium borohydride are added to a suspension - of 46.~ g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde in 700 ml of dimethylformamide and 100 ml of water, the temperature possibly rising to 35. After 30 mi-nutes purification is carried out with active charcoal, - precipitation is carried out with 700 ml of water and the - ~recipitate is well washed. 5-Chloro-3-p-chlorophenyl-4-hydroxy~ethyl-1-phenyl-pyrazole is obtained with a 95 ,~ yield;
152.5-153.5 (~rom acetone).

- 36 ~-In a similar manner it is possible to obtain from the corresponding pyrazole-4-carboxaldehydes by reduction S-chloro-4-hydroxymethyl-3-p-methoxyphenyl-1-phenyl-pyrazole (F 126-127) 5-chloro-4-hydroxymethyl-1-phenyl-3-p-tolyl-pyrazole S-chloro-3-m-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole 5-chloro-4-hydroxymethyl-3-p-isobutylphenyl-1-phenyl-pyrazole (F 140-140.5) 5-bromo-4-hydroxymethyl-1,3-diphenyl-pyrazole (F 134-135) 5-bromo-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole S-bromo-4-hydroxymethyl-3-p-methoxyphenyl-1-phenyl-pyrazole 3-p-bromophenyl-5-chloro-4-hydroxymethyl-1-phenyl-pyrazole.

Example 16 5-Chloro-4-chloromethYl-3-p-chlorophenYl-1-phenyl-pyrazole 17.6 g of thionyl chloride are added to a suspension of 45 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole in 45 ml of benzene, there being a consi-derable evolution of gas and solution occurs. Following this heating is carried out for 30 minutes at boiling point for completion of the reaction. The solvent is distilled off in vacuo and this operation is carried out with the addition of benzene. The residue is caused to crystallise with the help of petroleum ether. 5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained with a 98.5 % yield; F 96.5-97.

In a similar manner it is possible to obtain from the corresponding 4-hydroxymethyl-pyrazoles the following 4-chlo-romethyl-pyrazoles S-chloro-4-chloromethyl-1,3-diphenyl-pyrazole (F 67.5-68.5) 5-chloro-4-chloromethyl-3-p-methoxyphenyl-1-phenyl-pyrazole (F 129-129.5) 5-chloro-4-chloromethyl-1-phenyl-3-p-tolyl-pyrazole 5-chloro-4-chloromethyl-3-m-chlorophenyl-1-phenyl-pyrazole ~048499 5-chloro-4-chloromethyl-3-p-isobutylphenyl-1-phenyl-pyrazole (F 87-87.3) 5-bromo-4-chloromethyl-1,3-diphenyl-pyrazole (F 83.5-84) 5-bromo-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole 5-bromo-4-chloromethyl-3-p-methoxyphenyl-1-phenyl-pyrazole 3-p-bromophenyl-5-chloro-4-chloromethyl-1-phenyl-pyrazole.

Example 17 S-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole Hydrogen chloride gas is introduced into a mixture of 15 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole and 25 ml of concentrated hydrochloric acid and heating is carried out for 4 hours at boiling point. Follow-ing this 25 ml of toluene are mixed in. The layers are sepa-rated and the aqueous phase with toluene is removed. The or-ganic layers are reduced in bulk by evaporation in vacuo, toluene is again added and reduction in bulk is repeated.
5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained with a quantitative yield; F 96.5-97 (from pe-troleum ether).

Example 18 5-Chloro-3-p-chloroPhenyl-1-phenyl-pYrazole-4-acetonitrile 35 g of 5-chloro-4-chloromethyl-3-p-chlorophenyl-pxra-zole are added while stirring and slight cooling at 25 to a mixture of 6.15 g of sodium cyanide in 150 ml of dimethyl-sulfoxide. Stirring is carried out for 2 to 5 hours at this temperature until the reaction is determinated. The solution is mixed with 200 ml of water and 200 ml of trichloroethylene 1~8499 or benzene. ~he layers are separated. Washing is carried out with the organic solvent. Drying is carried out with sodium sulfate and the organic phase is purified with Tonsil. By reducing in bulk in vacuo 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile is obtained with a yield equal to 99 % of the theoretical amount; F 129.5-130.5 (from aceto-nitrile).

In a similar manner it is possible to obtain for the corresponding 4-chloromethyl-pyrazoles the following pyrazole-4-acetonitriles:
5-chloro-1,3-diphenyl-pyrazole-4-acetonitrile (F 78.5-79.5) 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile (F 91.5-92.5) 5-chloro-1-phenyl-3-p-tolyl-pyrazole-4-acetonitrile 5-chloro-m-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetonitrile (F 98-98.5) 5-bromo-1,3-diphenyl-pyrazole-4-acetonitrile (F 99-100.5) 5-bromo-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile 3-p-bromophenyl-5-chloro-1-phenyl-pyrazole-4-acetonitrile 1~)48499 Example 19 EthYl ~ _nl~r~ chlorophenyl-1-phe~y~-pYrazole-4-acetate 10 g of 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 at boiling point. The liquid is pured on to ice, made alkaline with sodium bicarbonate solution extracted with ether and reduced in bulk. After recrystallisation from ethanol and water ethyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate is obtained with a 69 ~ yield; F 51.5-52.5 (from ether/pe-troleum ether).
In a similar manner with the corresponding alcohols the following esters are produced:
methyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate (F 66-67.5) n-butyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate (Kp~o 0001 210-215 ) n-hexyl 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate.

Example 20 Ethyl 5-chloro-3-p-chlorophenYl-1-phenyl-pyrazole-4-acetate

6.9 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid, 70 ml of ethanol and 4 g of concentrated sulfu-ric acid are heated at boiling for 8 hours. The liquid is re-duced in volume, pured into water and ice, extracted with ether, washed with sodium carbonate solution, the organic " ~048499 - `
solution is dried and reduced in volume..~thyl 5-chloro-3--p-chlorophenyl-1-phenyl-pyrazole-4-acetate is obtained with a yield of 85 %; F 51.5-52.5.
.

.
Exam?le 21 5-Chloro-3-~-cklorophenyl-1-phen~ razole-4-acetamide 5g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile and 10 ml of ~6 /~ sulfuric acid are stirred for 4 hours at room temperature. The batch is added to 50 g o~ ice, the precipitate is separated by vacuum filtering and washed with water. 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide is obtained with a 59 % yield; F 192-193.
, .
Example 22 5-Chloro -~-3 -c~lo~o~hen~l-1-phenvl-p~razole-4-acetanilide .
(a) 1.1 ~ of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid, 15 ml of benzene and 0.5 g of . phosphorus oxitrichloride are heated for 2 hours at boiling and 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetyl chloride is obtained.
~ . ` (b) To the solution of the acid chloride in ben-- zene 0.31 ml of aniline is added drop~lise and stirring -- ` is carried out for 1 hour at room temperature. Filtra-` tion is carried.out folh~ed by recrystallisation. 5-- Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetani-lide is obtained.-F 201-202. --In a similar manner from 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-ace Gyl chloride and ammonia morpholine, piperidine, .

.
., - ~ . - . . , : ~ i - ~0484~9 ethylamine, 2-aminoethanol and phenylhydrazine the follo-- -~ng pyrazole-4-acetic acid derivates are obtained:
5-chloro-3-p-chlorophenyl-1-phenyl-pyxazole-4-acetamide F 192_195 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetmorpholide 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetpiperidide $-chloro-3-p-chlorophen~l-1-phenyl-pyrazole-4-acetic acid ethylamide $-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid (2-hydroxyeth~l)-amide ~
5-chloro-~-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid 2'-phenyl-hydrazide . .
xample 23 .5-Chloro-3-p-chlorophen;yl-1-phenyl-F)~yrazole-4-thioacetmorpholide 1.5 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetmorpholide, 8 ml of pyridine and 0.8 g of phosphorus pen-tasulfide are heated for 5 hours under re~lux. Then 30 g of ice are added to the solution and the precipitate is vacuum~
filtered. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-thio-acetmorpholide is obtained; F 204-205.5 (from dimethylformamide, H20 ) . . - - . - . . ' -.
Example 24 5-Chloro-3-~_ ~ nyl-~razole-4-acetamidoxime To a hot solution of 1.0 g ol 5-chloro-3-p-chlorophenyl-1-phenyl-~razole-4-acetonitrile in 75`ml of ethanol a solu-~ion of 0.42 g of hydroxylamine hydrochloride in 6.05 ~l of 1 N sodium bicarbonate solution is added and heating is car-r~ed out at boiling for 11 hours under reflux. The so-~ ~ :
.
, . .

lution is evaporated to dryness and recrystallised from ~etha-nol/water. 5-chloro-3-p-chloropherlyl-1-phen~l-pyrazole-4-acet amidoxime is obtained with a yield of 86%; F 184-186 (from toluene).

Example 25 ¦ 10,000 tablets are produced with an active substance content of 50 mg from the following components:
500 g 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid - 700 g maize starch - 1 450 g lactose 30 g amorphous silicic acid 40 g sodium lauryl sulfate 50 g polyvinyl~yrrolidone 160 g pectin 50 g talc 20 g magnesium stearate .
2~000 g The ~drug constituent, the maize starch, the lactose, the amorphous silicic acid and the sodium lauryl sulfate are mixed and sieved. This mixture is moistened with a so-lution of the polyvinylpyrrolidone in 320 ml of alcohol and granulated through a sieve with a mesh width of 1,25 mm.
~he granules are dried at 40 and mixed with pectin, talc and magnesium stearate. ~he mixture is pressed to 200 mg tablets wlth a diameber of 8 mm.

.
Example 26 - 10,000 capsules with a drug constituentcontent of - 50 mg are prepared from the following com~onents: -- - -- ~~43 ~
-- .

. . . .
. ~ . . . . .

- i~)48499 - `
- ~ 500 g 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-- - acetic acid . `
- ` 495 g microcrystalline cellulose . 5 g amorphous silicic acid .
1,000 g ~ he drug constituent in a finely powdered .orm, the ~icrocrystalline cellulose and the unpressed a~orp~ous si~icic acid are thoroughly mixed and filled off in hard ` lèlatine capsules, size 4. ' .

.
Example 27 , 100,000 tablets are produced with a content of a compound of this invention of 100 mg from the following - components:

10.000 kg 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid - ~ 4.500 kg dex*ropropxyphen hydrochloride 5.300 kg potato starch 0.500 kg polyvinylpyrrolidone (mean molecular weight of 25.000) . 1.800 kg carboxymethyl cellulose 0.200 kg magnesium stearate ~ -:
- . 5 1 wat.er `

. : The drug constituent of this invention, the dextro-propoyphen hydrochloride and the potato starch are - : . .. .. .
`, ' ' . - ' `- - ~ '~.
- ,- . , ' - . ' - - - .: ~ 44 ~ - ` . :
~' ', - . `-! - - ` .
, ` ~` ~' ' ' ' , ' - ' .
1. , ~ -.. . -`

1~)48499 `

sprayed in a fluid bed granulator with a solution of the polyvinylpyrrolidon in 5 l of water. The granules are dried to up to a relative humidity of 50 - 60 %, then the carboxymethyl cellulose and the magnesium stearate are added and the mixture is homogenized.
After sieving the granulate is pressed to 170 mg tablets with a diameter of 8 mm.

Example 28 1,000 suppositories are produced with a drug constituent content of 100 mg from the following components:

0.106 kg 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-ace`tic acid, sodium salt 2.393 kg suppocire ~ BM

The suppocire ~ BM is heated up to 40 - 50 C. The sodium salt is stirred into this melt. The batch is homogenized and poured into molds.

..
Example 29 A gel with a drug constituent content of 1 % is prepared from the following components:

1.00 kg 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid 1.50 kg carbopol ~ 934 0.30 kg cremophor ~ EL
~ ~ 40 kg sodium hydroxide solution 20.00 kg propylenglycol ad 100.00 kg water _ 45 _ r . , ~ .
.

.

~g)48499 The carbopol ~ 934 is suspended in the water under .vigorous stirring. The mixture is left for 1 hour, then the drug constituent, the cremophor ~ EL and the propylenglycol are added, followed by slow addition of the sodium hydroxide solution under agitation until a pH of 8 is reached.

Example 30 A suspension with a drug constituent content of 50 mg per 5 ml is produced from the following componehts:

1.00 kg 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid 2.70 kg tylose ~ C30 0.11 kg sodium cyclamate o.o8 kg sorbic acid ad 100 1 water The tylose ~ C 30 is put into 90 1 of water under ~igorous stirring; the drug constituent of this invention,- the cyclamate and the sorbic acidjare -added, the volume is completed up to 100 1. The mixture is passed through corundum disk crusher, vented and filled up into 5 ml fractions.

Exam~le 31 : . A batch for 100 1 of an injection solution is produced from the f~llowing components:

.

.

4.152 kg 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-- 4-aceticacid,sodium salt 0.150 kg prednisolone 0.200 kg sodium di~ulfite 0.025 kg cystein hydrochloride 26.ooo kg 1,2-propylenglycol ad 100 l water 65 1 of destilled water are heated up to ~0 C bubling nitrogen through the fluid, the drug constituent of this invention and the prednisolone are added. After complete dissolution of the added compounds the solution is cooled down to room temperature. The sodium disulfite, the cystein hydrochloride and the propylenslycol are added, the volume is completed up to 100 1 and the mixture is agitated for complete dissolution.
.

Example 32 A batch for 100 l of an injection solution is produced in analogy to the procedure described in example 31 but replacing 0.150 kg prednisolone with 0.0~0 kg dexamethasone.

Following the procedure described in examples 27 to 32 pharmaceutical compositions containing 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid and -4-sodium acetate, respectively, are produced replacing 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid and -4-sodium acetate, respectively with the correspondin~ 5-chloro-1,3-diphenyl-pyrazole derivative in the same amount.

Claims (31)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS::

1. A process for the preparation of pyrazole-4-acetic acid derivatives of the general formula I

and their pharmaceutically acceptable salts, in which Ph1 and Ph2 are the same or different phenyl radicals, and ha1 denotes fluorine, chlorine or bromine, which comprises hydrolysing a corresponding compound of the formula II
wherein B denotes in which X is oxygen, sulfur or an imino group, and Y is a hydroxy, amino, alkylamino, arylamino, hydroxyamino hydrazino, hydrazobenzene, 2-hydroxyethylamino, mercapto, azido, morpholino or piperidino group, or a chlorine or bromine atom, provided that Y is not -OH when X is = 0 and where required converting a compound of formula I in the free acid form into a pharmaceutically acceptable salt thereof, or a salt of a compound of formula I into the corresponding free acid.

2. A process according to claim 1 wherein in the compound of formula II, B represents in which X is oxygen, sulfur, imino, alkylimino or hydroxyimino, and Y is amino, monoalkylamino, dialkylamino, phenylamino, alkoxy, alkylthio, chlorine or bromine.

3. A process according to claim 1 wherein the compound of formula II
is a pyrazole-4-acetonitrile or a pyrazole-4-acetamide.

4. A process according to claim 1 wherein the compound of formula II
is an alkyl pyrazole-4-acetate.

5. A process according to claim 1, 3 or 4 wherein in the compound of formula II
Ph1 is phenyl, and Ph2 is phenyl, halophenyl, p-lower alkoxyphenyl or p-lower alkyl phenyl.

6. A process according to claim 2 wherein in the compound of Formula II
Ph1 is phenyl, and Ph2 is phenyl, halophenyl, p-lower alkoxyphenyl or p-lower alkyl phenyl.

7. A process ac¢ording to claim 1, 3 or 4 wherein in the compound of formula II
Ph1 is phenyl, and Ph2 is phenyl, p-chlorophenyl, p-methoxyphenyl or p-isobutylphenyl.

8. A process according to claim 1, 3 or 4 wherein in the compound of formula II
Ph1 is phenyl, Ph2 is phenyl, and hal is chlorine.

9. A process according to claim 1, 3 or 4 wherein in the compound of formula II
Ph1 is phenyl, Ph2 is p-chlorophenyl, and hal is chlorine.

10. A process according to claim 1, 3 or 4 wherein in the compound of formula II
Ph1 is phenyl, Ph2 is p-methoxyphenyl, and hal is chlorine.

11. A process according to claim 1, 3 or 4 wherein in the compound of formula II
Ph1 is phenyl, Ph2 is p-isobutylphenyl, and hal is chlorine.

12. A process according to claim 1, 3 or 4 wherein in the compound of formula II
Ph1 is phenyl, Ph2 is phenyl, and hal is bromine.

13. A process according to claim 1 for the preparation of 5-chloro-1,3-diphenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-1,3-diphenyl-pyrazole-4-acetonitrile in the presence of sulfuric acid.

14. A process according to claim 1 for the preparation of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile in the presence of sulfuric acid.

15. A process according to claim 1 for the preparation of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetate in the presence of sodium hydroxide.

16. A process according to claim 1 for the preparation of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile in the presence of sodium hydroxide.

17. A process according to claim 1 for the preparation of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5S-chloro-3-p-chlorophenyl-1 phenyl-pyrazole-4-zcetamide in the presence of sulfuric acid.

18. A process according to claim 1 for the preparation of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-thioacetmorpholide in the presence of hydrochloric acid.

19. A process according to claim 1 for the preparation of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide in the presence of nitrous acid.

20. A process according to claim 1 for the preparation of 5-chloro-3-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile in the presence of sulfuric acid.

21. A process according to claim 1 for the preparation of 5-chloro-3-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing ethyl-5-chloro-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetate in the presence of sodium hydroxide.

22. A process according to claim 1 for the preparation of 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-chloro-3-p-isobutylphenyl-1-phenyl-pyrazole-4-acetonitrile in the presence of sulfuric acid.

23. A process according to claim 1 for the preparation of 5-bromo-3-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing 5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetonitrile in the presence of sulfuric acid.

24. A process according to claim 1 for the prepartaion of 5-bromo-3-methoxyphenyl-1-phenyl-pyrazole-4-acetic acid which comprises hydrolysing ethyl-5-bromo-3-p-methoxyphenyl-1-phenyl-pyrazole-4-acetate in the presence of sodium hydroxide.

25. The process of claim 14, 15 or 16 which includes the step of con-verting the product into its sodium salt.

26. The process of claim 17, 18 or 19 which includes the step fo con-verting the product into its sodium salt.

27. The process of claim 14, 15 or 16 which includes the step fo con-verting the product into its calcuim salt.

28. The process of claim 17, 18 or 19 which includes the step fo con-verting the product into its calcuim salt.

29. The process of claim 14, 15 or 16 which includes the step fo con-verting the product into its morpholine salt.

30. The process of claim 17, 18or 19 which includes the step fo con-verting the product into its morpholine salt.

31. Compounds of formula I defined in claim 1 and their pharmaceutically acceptable salts, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.