Note: Descriptions are shown in the official language in which they were submitted.
,
~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,
,
~'. - ', ,
1048499
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.
.
~,
.... . - ~` . ..
`., .
.
48499
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.
-- 6 --
1048499
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,
'
1048499
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 - - ~
.
1048499
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
- 12 -
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
- 13 -
1048499
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.
- 14 -
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 _ . .. -
. . - - - . . ~ .
.
.
1048499
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.
- 16 -
1048499
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).
- 17 -
.
~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.
. ' . ' ;
`
1048499
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 _
.
1048499
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 _
1048499
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.
1048499
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.
- 24 -
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).
- 27 -
1048499
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-
- 28 -
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).
- 29 -
~. .,
: 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.
- 34 -
1048499
(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.
-35-
\
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 ~-
1048499
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
- 37 -
~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
- 39 -
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
- 40 -
" ~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,
.
.
.,
--41 -
- ~ . - . . ,
: ~ 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
F 182-183
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-
- 42 -
~ ~ :
.
, . .
-- 1048499
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:
- 46 - -
.
.
1048499
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.
- 47 -
