Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
63
This application is a division of Application No.
409,072, filed August lO, 1982.
This invention relatefi to novel 2-piperazinoalkyl-1,5
diphenylpyrazolin-3-one compounds and salts thereof, and
to pharm.aceutical preparations containing these compounds
and to a method for preparin~ these compoundsl, a~ well as
intermediate products useful in the method.
It is an object of the invention to provide n~vel
; 1,5-diphenylpyrazolin-3-one compounds with valuab]e
pharmacological properties, and a method for their prepara-
tion.
It has now been found that the novel 1,5-Diphenylpyrazo-
lin-3-oDe compounds have valuable pharmacological properties,
in particular pronounced antiallergic properties, and in
addition also have hypotensive properties and an advantageous
actioD profile with a ~ide therapeutic range and low toxicity.
On the basis of these properties, the new compounds are
suitable as medicament: for the treatment of allergic
illnesses, such as, for example, asthma or hay fever or
allergic origin.
According to one aspect of the present invention
there is provided a 1,5-diphenylpyrazolin-3-one compound
of the general-iormula I
~ . r ~ 76 3
3 -R5
~,
where Rl is a hydrogen or halogen atom, or a lower alkyl,
lower alkoxy, hydroxyl, trifluoromethyl or lower
alkanoyloxy radical, R2 is a hydrogen or halogen atom, or a
lower alkyl or lower alkoxy radical, or Rl and R2 are
bonded to adjacent carbon atoms and together denote a
methylenedioxy or ethylenedioxy radical, R3 is a hydrogen or
halogen atom, or a lower alkyl, lower alkoxy, hydroxyl,
trifluoromethyl or lower alkanoyloxy radical, R4 is a hydro-
gen or halogen atom, or a lower alkyl or lower alkoxy
radical, or R3 and R4 are bonded to adjacent carbon atoms
and together denote a methylenedioxy or ethylenedioxy
radical, Z is an alkylene radical with 2 to 6 carbon atoms,
and R5 is an unsubstituted pyridyl radical, a ~yridyl
radical which is monosubstituted by a halogen atom or a
]ower alkyl or lower alkoxy radical, a thienyl radical, or
an unsubstituted or substituted phenyl radical a
f ~ ~7
~ a
63
~here R6 is a hydrogen or halogen atom, or a lo~er alkyl
lower alkoxy, hydroxyl9 trifluoromethyl or lower alkanoyloxy
radical, and R7 is a hydrogen, or halogen atom, or a lower
alkyl or lower alkoxy radical~ halogen, or R6 and R7 are
bonded to adjacent carbon atoms and together denote a
methylenedioxy or ethylenedioxy radical: and acid
addition salts thereof.
If the substituents Rl to R4 on the phenyl rings
and the substituents contained in the radical R5 in the
compounds of the formula I contain a lower alkyl group,
this can be straight-chain or branched and preferably
contains 1 to 4 carbon atoms. Poss;ble substituents are
thus, in particular, methyl, ethyl, n-propyl, isopropyl,
n-butyl or tert.-butyl, preferably methyl, ethyl, n-propyl
and isopropyl radicals. Preferred alkyl radicals are
ethyl and, in particular, methyl radicals9 especially in ~he
case of disubstitution of the phenyl rings. Lower alkoxy
substituents are preferably methoxy or ethoxy radicals.
Preferred halogen substituents in the phenyl rings
and/or in a pyridyl ring are, fluorine, chlorine and bromine.
If a phenyl ring is su~stituted by a trifluoromethyl radical,
monosubstitution is preferred. Mono- or di-substitution is
advantageous in the case of halogen atoms and/or alkyl or
and1or alkoxy substituents.
The radical Z is a straight or branched alkylene
7~3
chain with 2 to 6 carbon atoms, alkylene chains with 2 to
4 carbon atoms being preferred.
If R5 is a pyridyl group, this can be bonded to
the rest of the molecule in the 2-, 3- or 4-position,
preferably in the 2-position. The pyridyl group can be
unsubstituted or substituted by one of the abovementioned
substituents, in particular lower alkyl or alkoxy,
preferably methyl or methoxy.
If R5 is a thienyl radical, this can be bonded to the
rest of the molecule in the 2- or 3-position, preferably in
the 2-position.
According to another aspect of the present invention9
the aforesaid 1~5-diphenylpyrazolin-3-one compound of
formula I, or an acid addition salt thereof, is prepared by
a method in which, in a manner which is known per se,
either a) a compound of formulaeII or III
" ~ ~
R R4-
R3 R3
Il
1 1
.` ~2~763
where Rls R2, R3, R4 and Z have the above defined
meanings, Y is a radical which can be split off by
aminolysis, Z' is an alkylene chain with 2 to 4 carbon
atoms, and Y' is a halogen atom, or a mixture of such
compounds is reacted with a compound of formula V
H 1`1~, - R5 V
/
where R5 has the above defined meaning, or
b) in order to prepare a compound of formula Ia
R1
R~ z_~ R ' la
R4-- --
~3
where Rl, R2- R3~ R4 and Z have the above defined meanings
and R5' is a substituted phenyl group a'
where R6' is a trifluoromethyl radical in the ortho- or
para-positionS a compound of the formula IV
~ ' ~lZ~ 63
- ~ lV
R4 R~
~here Rl, R2, R3, R4 and Z have the above defined meanings,
is reacted with a compound of formula VI
~ ~I
where R6' has the above defined meaning and U is 8 halogen
atom. If the compound of formula I is obtained in the form
of the free compound it may be subsequently converted into
an acid addition salt or if the compound of iormula I is
obtaiDed in the form of an acid addition salt it may be
subsequently converted into the free compound.
Detailed description of the invention
The reaction of the compoundSof formulae II or III
or the mixture thereof with a compound of formula V
according to process variant a) can be carried out by
methods ~hich are customary per se for the alkylation of
amines.
` 12~(~7~;3
The reaction is advantageously carried out under
basic conditions in an organic solvent which is inert under
the reaction conditions. Possible radicals which can be
split off by aminolysis from a compound of formula II are,
S in particular, halogens, such as chlorine, bromine or iodine,
preferably chlorine or bromine. Examples of suitable
solvents which may be used include aromatic hydrocarbons,
such as benzene, toluene or xylene, cyclic ethers, such as
dioxane, dimethylformamide, 1,3-dimethyl-2-imidazolidinone,
hexamethylphosphoric acid triamide, sulpholane,
dimethylsulphoxide, tetramethylurea and lowe} alkanols, for
example isopentanol. The temperature can be from room
temperature up to 150 C, el~vated temperature, for example
a temperature of from 50 to 150 C, in particular from 90
to 150 C, advantageously being used if a compound of
formula II is employed, whilst a temperatbre from room
temperature to the boiling point of the solvent can be used
if a compound of formula III is employed. If desired, the
reaction of the compound of formulae II or III with the
compound of formula Y can, however, also take place in themelt
without a solvent. The reaction can advantageously be
carried out with the addition of an organic or inorganic
base. However, it is also possible to employ an excess
of the compound of formula V and to use this as an
internal base. Particularly suitable organic bases include
~ Z~S~763
alkali metal carbonates Dr bicarbonates, ~uch as sodium
carbonate, s~dium bicarbonate or potassium carbonate.
Suitable organic bsses include tertiary organic amines,
iD particular tertiary lower alkylamines, such as
triethylamine, n-tripropylamine, n-tributylamine, 1,4-
dimethylpiperazine or pyridine.
If the comp~un~ of ~ormulae II, III
or V containfree hydroxyl groups ~s sub~tituents, these
are advantageously provided with a protective group, in a
manner which is known per se, during the reaction. Suitable
protective groups which can easily be split off again
after the reaction are kDown from, for example E. McOmie
"Protective Groups in Organic Chemistry" Plenum Press 1971.
For example, ethers, in particular tetrahydropyranyl
ethers, are suitable for protecting a hydroxyl group. These
protective groups can easily be removed again in a known
manner after the reaction.
The reaction of a compound of formula IV with a
compound of formula VI can likewise be carried out in a
manner which is known per se, under the conditions customary
for al~ylation of amines, for example the conditions mentioned
above for the reaction of a compound of formula lI ~ith a
compound of formula V. The substituted halogenated
phenyl compounds are sufficiently activated by the presence
of a second order substituent to be capable of reaction with
` ~lZ1~71~3
the pipera~ine derivstive of formul~ IV.
The compound of formula I can be isolated from
the reaction mixture, and purified, in a manner which is
known per se. If the compound is obtained in the form of
an acid addition salt, this salt can be converted into the
free base in the customary manner9 and, uhere desired, the
base can be converted into a pharmacologically acceptable
acid addtion salt in known manner.
Examples of suitable pharmacologically acceptable
acid addition salts of the compounds of formula I are
their salts with hydrochloric acid, hydrobromic acid,
sulphuric acid, phosphoric acid, methanesulphonic acid,
ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic
acid, citric acid, acetic acid~ lactic acid, succinic acid,
maleic acid, fumaric acid, malic acid, tartaric acid,
benzoic acid, phenylacetic acid and mandelic acid.
The compounds of formula I contain two or if R5
denotes an optionally substituted pyridyl group, three
basic centres and can thus form acid addition salts with
one, two or three equivalents of acid. Mono-acid salts
are particularly suitable for tbe preparation of
pharmaceutical compositions. Salts which contain several
equivalents-of acid can, if desired, be converted into
mono-acid salts in a manner which is known per se~ for
example by conversion into the free base and subsequent
763
reaction of the base with an equivalent amount of acid.
Compounds of formula I in which Z is a branched
alkylene chain are obtained, in the synthesis, in the form
of their racemates. The racemic mixtures as well as the
optically active forms of these compounds fall within the
scope of this invention. The racemic mixtures can be
separatPd into their optically active antipodes in a manner
which is known per se, by reaction with suitable optically
active acids, such as, for example, 0,0'-dibenzoyl-tartaric
acid, mandelic acid or di-0-isopropylidene-2-oxo-L-gulonic
acid, and s~bsequent fractional crystallisation of the salts
obtained (Tetrahedron 33, (1~77) 2725 - 2736).
Compounds of formulae II and III have not yet been
described in the Literature, and represent new, valuable
intermediate products for the preparation of pharmacologic-
al]y active ccmpounds, for example the compounds of formula
I.
Compounds of formulae II and III can be obtained
by processes which are known per se. Thus, in particular,
compounds of formula II where Y is a halogen atom and
compounds of formula III can be obtaioed by reacting alkali
metal salts, prepared _ situ, of a 1,5-diphenylpyrazolin-3-
one compound of formula VIII
` ~l21(~763
-
R2 ~
~NH VIII
R4
~3
where Rl, R2, R3 and R4 have the above defined meanings,
with a compound of formula VII
Y Z Y VII
where Z and Y have the above defined meanings and Y'
is a halogen atom, Y' preferably being chlorine or bromine.
The reaction is advantageously carried out in a
solvent which is inert under the reaction conditions, at
a temperature of from 0 C to the boiling point of the
solvent. In general, a temperature of from 0 C to 100 C
is preferred. Examples of suitable solvents are lower
alcohols, such as methanol, ethanol, ispropancl, butanol
and tert-butanol, as well as aromatic hydrocarbons, such as
benzene and toluene, dimethylformamide, sulpholane,
hexamethylphosphoric acid triamide, tetramethylurea and
cyclic ethers, such as, for example dioxane and
tetrahydrofuran.
Possible alkali metal salts of the l,S-diphenyl-
;~ 763
13
pyrazolin~3-one compounds are the lithium, sodium or
potassium salts, preferably the sodium salt, and these 6alts
may be obtained in situ by reacting the compound of
formula VIII with an alkali metal alcoholate or alkali
metal hydride.
If ~ in the compound of formula VIII is an
alkylene chain with 2 to 4 carbon atoms, cyclic alkylation
products of formula III are obtained in the reaction in
addition to the open-chain alkylation products of formula
II. The reaction mixture contains varying proportions of
the compounds II and III, depending upon the solvents and
alkali metal compounds used, the reaction time and the
par~icular meanings of the individual substituents. Thus,
for example, if a lower alcohol and the corresponding
alkali metal alcoholate are used and the reaction times
are relatively long, for example 12 to 35 hours, the
cyclic compounds III are predominantly formed, ~hilst the
compounds II are predominantly formed if dimethylforma~ide
and alkali metal hydrides are used and the reaction times
are, for example, 1 to 5 hours. Since both the compounds
II and III or mixtures thereof can be used iD the
subsequent reaction, it is not necessary to separate the
t~o compounds before further reaction. The cyclic
compounds III can, however, of course be separated from
the open-chain products by crystallisation in a manner which
~Z~7~i3
14
i6 known per se. Thus, the cyclic immonium salts III
can easily be crystallised frbm, for example, aromatic
andlor halogenated hydrocarbons, such as benzene, toluene
or chloroform.
In general, alkylation of 1,5-diphenylpyrazolin-3-
one compound of formula VIII with the compound of formula
~II gives a mixture of the desired N-alkylated product
and the corresponding isomeric 0-alkylated product.
The r~-alkylated product can be separated off from the
mixture by chromatography or crystallisation.
The 0-alkylated by products can be rearranged into
the corresponding ~-alkylated products II and the cyclic
immonium salts lII simply by heating. The rearrangement
temperature is advantageously from 60 C to 200 C. If
desired, the rearrangement can be carried out in the
presence of an inert solvent, advantageously at the boiling
point of the solvent. Suitable solvents are lower alcohols
with boiling points within the range given, for example
methanol, butanol or isopentanol, and aromatic hydrocarbons
with boiling points within the range given, such as benzene,
toluene or xylene. The mixture of cyclic immonium compound
III, N-alkylated product II and isomeric 0-alkylated product,
obtained during alkylation~ can also be employed directly
without prior separation9 for the rearrangement reactioD
under the influence of heat.
~Z1~763
Compounds of formula IV have not yet been
described in the I.iterature, and are also new valuable
intermediate products for the preparation of pharmacologically
active compounds, for example the compounds of formula I.
Compounds of formula I~ can be obtained by methods
which are known per se, for example by reacting a compound
of formulae II or III with an excess of piperazine. The
reaction can be carried out by methods which are customary
per se for the alkylation of amines, for example under the
conditions described above for the reaction of a compound
of formulae II or III with a compound of formula V.
Compounds of iormula IV can also be obtained from
compounds of formula IX
15 ~ Q
R
R~,
where Rl, R2, R3, R4 and Z have the above defined meanings
and Q represents an amine-protecting group, by splitting
off the amine-protecting group in a manner which is known
per se. Possible amine-protecting groups are the customary
protecting groups which are known per se for the protection
1.2~ 763
l6
of an amino group, for example acyl groups which can be
split off by hydrolysis or benzyl groups which can be split
off by hydrogenolysis. Suitable pro~ective groups are known
from, for example, E. McOmie "Protective Groups in Organic
Chemisty"; Plenum Press, London (1971), page 44 et seq.,
the formyl group and lower carbalkoxy protecting groups being
particularly suitable. These groups can be split off by
acid or alkaline hydrolysis in a manner which is known per
se.
Compounds of formula IX can be obtained in a manner
which is known per se, for example by reacting a compound
of formulae II or III with a compound of formula X
~'
H ~ -Q X
where Q has the above defined meanings. The reaction can
be carried out by methods which are customary for the
alkylation of amines, for example under the reaction
conditîons described for the reaction of a compound of
formulae II or III with a compound of formula V.
The 1,5-diphenyl-pyrazolin-3-ones of formula VIII
are known, or they can be prepared by methods which are
known per se, for example by the methods described by
Michaelis and Rassmann (Ann. 352, (1907) 158) and by
Michaelis and Willert (Ann. 358, (1908) 159j, for example
starting from correspondingly substituted benzoylacetic
763
17
acid esters and correspDndingly substituted ~-acetyl-
phenyl-hydra~ines.
Compounds of formula V are known, or they can be
prepared by methods which are known per se, for example
by reacting an amine of formula XI
H2N-R5 XI
where R5 has the above defined meaning, with a corresponding
di-~haloalkyl)amine, under conditions which are customary
for the alkylation of amines.
The compounds of formula I and their pharmacologic-
ally acceptab]e acid addition salts are distinguished by
interesting pharmacological properties, and in particular
have antiallergic actions. In addition, the compounds are
well tolerated and are only slightly toxic, and, in particular,
there is a wide interval between their therapeutically
effective dose and the toxic dose.
On the basis of their antiallergic actions, the
compounds of formula I and their pharmacologically acceptable
acid addition salts are suitable as antiallergic agents for
the treatment of allergic illnesses, such as, for example,
bronchial asthma or allergic rhinitis.
The antiallergic properties of the compounds of
formula I can be demonstrated in standard pharmacological
tests on small animals. ~or example, the substances have
an inhibiting action on the re]ease of endogenic mediators
lZlQ763
-
from mast cells or basophilic leucocyte6 which leads to
allergic reactions. The doses to be used vary, of course,
depending on the nature of the substance used, on the
mode of administration and OD the coDdition to be treated.
S I~ general, however, satisfactory results are achieved in
animal experiments ~ith doses of from 0.05 to 75 mg. per
kg of body weight. Thus, the new compo~nds exhibit a
specific inhibiting action in the PCA test (Passive
Cutaneous Anaphylaxis test) on rats which is described
below.
Description of the test method to determine the inhibition
of passive cutaneous anaphylaxis (PCA test, see
15 Arch.int. pharmacology 252 (1981) 316-326).
To prepare the IgE-antiovoalbumin serum, ~sed in
the test, by the method Df Mota (Immunology 7, (1964) 6~1)
and J. Goose (Immunology 16 (1969j 749), msle Wistar rats
of 200-250 g. body weight were senfiitised by subcutaneous
injection of 1 mg~ of ovoalbumin and 1 ml. of Bordatella
pertussis suspension ~"Vaxicoq" Merieux 3.101 organisms/ml.~.
After 14 days, the animals are exsanguinated and ~he blood
is centrifuged. The antiserum thus obtained is stored at
20C.
~on-sensitised rats are injected, in each case, with
12~763
19
0.1 ml. of antiserum into the skin at four different p1aces
on their shaven backs. After 72 hours, a solution of the
test compound or, for comparison, only the solvent, is
administered orally, and 10 minutes later, 5 mg. of ovo-
albumin and 5 mg. of blue dyestuff (Evans blue) in 0.9%strength NaCl solution are administered intraperitoneally.
After 30 minutes, the animals a-re sacrificed and the
diameters of the blue spots formed at the sites
injected with antiserum are measured. The inhibiting effect
of the test substance is determined from the size of the
blue spots which appear.
The table which follows shows the results obtained
in the test described above. The example numbers given
for the compounds of the formula I relate to the
preparation Examples below.
Test substance PCA inhibition
of formula I ED50 mg/kg p.o.
Example No.
1 0.8
13 8.5
22 9.8
27 8.2
Determination of the minimum toxic dose in mice: it was
763
2~
not possible to detect sny toxic sy~peOms on oral
administration of the ~bove substsDce~ in doses of up
to 300 mg¦kg.
As medicines, the compounds of the formula I and
their pharmacologic~lly acceptable salts can be compounded
~s conventional pharmaceutical prepsrat;ons, such as,
for example, tablets, capsules~ suppositories or solutions,
together with the customary solid or liquid diluents or
carriers, together w;th any necessary or desirable
pharmaceutical auxiliaries. These pharmaceutical
preparations can be made by methods which are known per
se, using the customary solid excipients, such as, for
example, talc, lactose or starch, or liquid diluents,
such as, for example, water, fatty oils or liquid
paraffins.
The compounds of formula I can be administered
in pharmaceutical use forms which contain about 0.5 to
100 mg. preferably 0.5-25 mg., of active substance per
-- individual dose. The dosage to be used will, of course, vary ~e-
pending on the species to be treated and the individual
requirements. Parenteral formulations will in general
contain less active substance than preparations for oral
administration.
The Examples which follow are non-limiting Examples
intended to illustrate the preparation of the new compounds
~2~(~763
21
of formula I and of the new intermediate products in
more detail.
The structures of the new compounds were
confirmed by spectroscopic investigations, in particular
by precise analysis of the IR and ~MR spectra.
The IR spectra of the 1,5-diphenylpyrazolin-3-one
compounds show the carbonyl absorption band of the
pyrazolin-3-one ring at about 1630 - 1680 cm , and
are free from -C=~ bands9 which can be observed in
pyrazole derivatives.
Exa~ple 1:
1~5-Diphenyl-2- {3-[4-(2-pyridyl)-piperazin-l-y~ -
propyl~ - pyrazolin-3-one.
A) 47.2 g. (200 mmols) of 1,5-diphenylpyrazolin-3-
one are dissolved in 350 ml. of dimethylformamide. 6.6 g.
of sodium hydride (80% pure, 220 mmols) are added in
portions to the solution at 80 C, whilst stirring. The
resulting suspension is allowed to cool to 60 C, and a
" solution of 34.7 g. (220 mmols) of 1-bromo-3-chloro-
propane in 150 ml. of
~Zi~763
, .
- 22 -
di~ethyl~orlamide is added dropwise ~uring this addition,
the temperature drops to about ~0 C. Stirring is continued
at this temperature ~or 12 hours~ As much as possible o~
the dimethyl~ormamide is then strippect o~ ur-der reduted
pressure toil pump), during ~hich unreacted bromochloro-
propane is also re~oved ~rom the reaction mixture The
residue is taken up in r~ethylene chloride and the fnixture
is stirred Sodium bromide and unreacted diphenyLpyrazoli-
none are thereby precipitated, and ~an be ~iltered of~
uith suction The methylene chloride soîution is ~ashed
uith ~ater, dr;ed over sodium sulphate and ~iltered and the
solvent is stripped o~ under reduced pressure 60 9 o~ a
viscous, light yellou oil ~hich contains a mixture of the
isomers 1,5-diphenyl-2-(3-chloropropyl)-pyrazolin-3-one and
1,5-diphenyl-3-(3--thloropropoxy)-pyra20le rer.ain The
lat1er is rearranged into 1,5-diphenyl-Z-(3-chloropropyl)-
pyrazolin-3-one by heating the mixture 1.o 170 C ~or or,e
hour. The resulting product can be employed in the next
reaction stage uithout ~urther puri~ication
B) 31 3 g o~ 1,5-diphenyl-2-(3-chloropropy~)-pyrazo-
lin-3-one are dissolved in 300 ml o~ tolucne, and 16 3 q
o~ N-(2-pyridyl)-piperazine and 15.9 9 o~ potassium carbon-
ate are added to the solution. The suspension is heated
under re~lux ~or 20 hours, uhilst stirring A~ter the reac-
tion mixture has bren cooled, ;t is extracted by shakinguith uater, the organic phase is concentrated as far as
possible under reduced pressure, the residue is takcn up
in d;lute hydrochloric acid and the suspension thus Gbtaincd
is exlracted uith n,ethy-crle chloride lhe nou clear aqueous
`7~3
- 23 -
phase is rendered alkaline uith dilute sodium hydroxide
solution and extracted ~ith ethyl acelaten ~he organic
extract is dried over sodium sulphate and filtered and the
- filtrate is evaporated under reduced pressure. 42 4 9 of
the title compound remain as the re5idue, as a Light yello~
oi l .
To forr the trihydrochloride of the title compound;
this residue is dissolved in isopropyl alcohol, and a
saturated solution of hydrogen chloride in diethyl ether
is added drop~ise to the 50lution~ uhilst stirring. The
trihydrochloride crystals uhich have precipitated are fiL-
tered oif ~ith suction and rinsed uith isopropyl alcohol
and ether. Yie~d~ ~1.6 9. ~elting point: 1~6-198 C.
Exarnple 2:
_ _
1,5-Diphenyl-2-~3-~4-(2-pyridyl)-piperazin-1-yl~-propyl}-
pyrazolin-3-one.
A~ 118 9 o~ 1,5-diphenylpyrazolin-3-one are suspended
in 1 l of methanol~ and a solution of 99 9 of sodium methyl-
ate in methanol (30% strength solution) is acTded, uhilst
20 stirring. After 15 minutes, 54 ml of 1-bromo-3-chloropro-
pane are added dropwise to the resulting clear solution,
and the solution is heated under reflux for 48 hours. Most
of the solvent is then distilled off under reduced pressure,
the residue is dissolved in 1 1 of ~,ethylene chl~ride and
25 the organic solution is~ashed uith t~o 250 ml portions of
uater The uash uater is extracted once more uith 3ûO ml
of methylene chloridæ and the organic phases are combined,
dried over sodium su(phate and filtered. After the solvent
l~as bern s~ripped o~f un(3er reduced pressure, ~50 9 of
121~763
~ 74 -
trude 1,5-diphenylpyra20 o-L2~3-b~-dihydro-1,3-oxazinium
chloride remain as a yel o~ish crystalline residue. ~his
residue is suspended in 20D rl o~ acetone and the suspen-
sion is heated under reflux lor 5 rinutes and then coo ed,
5 ~hilst stirring. The crystals are ~iltered o~ and uashed
again, ~ith 25~ ml o~ ethyl acetate, in the same way. ~he
crystals are then dried at 60 C in a drying chamber for 5-
hours. ~elting point: 2û8-210 C, yield: 102 9.
B) 156.3 9 of 1,5-diphenylpyra20lo-[2,3-b~-dihydro-
10 1,3-oxazinium chtoride are suspended in 1.5 1 ol toluene,
165 g of potassium carbonate are added and the suspension
is heated to 50C. 77 ml o~ 1-(2-pyridyl)-piperazine are
added dropwise in the course o~ 10 minutes, ~hilst stirring,
and the reaction mixture is then heated under re~lux ~or 5
15 hours. After it has been cooled, it is acidi~ied with 650
ml of 15% strength aqueous hydrochloric acid and the aqueous
phase ;s separated o~ irom the organic phase and ~ashed
uith 300 ml of ethyl acetate. The brganic phases are dis-
carded. A solution o~ 175 9 o~ sodium hydroxide in 175 ml
20 o~ ~ater is added to the aqueous phase and the ~ixture i5
cxtracted ~ith three 250 ml portions o~ methylene chloride.
The combined methylene chloride phases are dried over
sod;um sulphate and ~iltered. After the solvent has been
removed under reduced pressure, 225 9 of crude 1~5-diphenyl-
25 2-{3-~4-(2-pyridyl)-p;perazin-1-yl~-propyl3-pyra70lin-3-
one remain as a yello~ oiL. This is dissolved in 4.5 1 o~
isopropanol. An cxcess of hydroocn chloride gas is then
passed in, whilst stirring, and the rixture is stirred ~or
1 hour. The crystalline prec;pitate for~ed is ~iliered s~f,
123~'~?~63
~ 25 -
vashed ~ith two 250 ml portions o1 isopropanol and dried
at 6Qt in a drying chamber for lZ hours. 212 9 of the tri-
hydrochloride of the title tompound o~ meltinQ point 196-
198C are obtained.
~) tonversion of the trihydrochloride o~ the title
compound into the monohydroch~oride: 212 9 of the tri-
hydroctlloride are dissolved in 500 ml o~ uater, a solution-
of 55 9 of sodium hydroxide in 55 ml of ~ater is added and
the mixture is extracted ~ith three 250 mL portions of
lO methylene chloride The orga-nic phase is dr;ed over sodium
sulphate and ~iltered. After the solvent has been removed
under reduced pressure, the base remains as a colourless
oily residue. This is dissolved in 2.5 ml of ;sopropanol
The solution is mixed, ~hilst stirring, ~ith a previously
15 prepared solution of 9 9 of gaseous hydrogen chloride in
500 ml of isopropanol. The precipitate ~hich thereby forms
consists of the monohydrochloride of the title compound. Stir-
ring is ~ontinued for 1 hour, and the crystals are then
filtered off, uashed uith three 200 ml portions of iso-
20 propanol and dried at 60C in a drying chamber lor 12 hours.Melting point: 206-208C, yield~ 164 9
Exan,ple 3:
1,5-D;phenyl-2-~3-(4-phenylpiperazin-1-yl)-propyl~-pyrazo-
lin-3-one.
31.3 9 of 1,5-diphenyl-2-(3-chloropropyl)-pyrazo-
lin-3-one (prepared anaLogousLy to Example 1A) are dissolved
;n 300 ml of toluene, and 18.6 9 oS N-ph~nylpiper~Zine ~nd
15.9 9 o~ potass;um carhonate are added to the solution.
The suspcnsion formed is heated under reflux ior 20 hours,
~lZ~L~763
- 26 -
uhilst stirring. After the rcaction so(ution has been
ccoled, it is extracted by shakiny uitil water and the
organic phase is separated o~ and concentrated as ~ar as
possible under reduced pressure. Dilute hydrochloric atid
5 is added to the residue, and the suspension thereby obtained
is extracted with methylene chlcride Dilute sodium hydr-
oxide solution is added to he no~ clear aqueous phase
until the mixture has an alkaline reaction, and the mixture
is extracted ~ith ethyl acetateA The organic extract is
lO separated of~, dried over sodium sulphate and filtered and
the filtrate is evaporated under reduced pressure. The
crude 1,5-diphenyl-2-[3-(4-phenylpiperazin-1-yl)-propyl~-
pyrazolin-3-one rer,ains as a light yellow oil (41.2 9).
To ~orm ~he dihydrochloride, this residue is dis-
15 solved in isopropanol, and a saturated solution o~ hydrogen
chloride gas in diethyl ether is added dropuise to the
solution, ~hilst stirring. ~he dihydrochloride, uhich has
precipitated as crystals, is ~iltered o~ u'ith suction and
rinsed with isopropanol and ether Melting point: 227-
20 23û C, yield: 38~7 9.~xa~ple 4:
1,5-Diphenyl-2-~3-t4-t4-tri~luoron,ethylp1lenyl)-piperazin-
1-yl~-propyl3-pyrazolin-3-one.
A) 24.2 9 ot the 1,5-diphenylpyra70lo-t2,3-b]-dihyclro-
25 oxazinium chloride prepared according to Example 2A areheated under reflux in ~ûO ml o~ isopropanol ~ith ZZ.8 9
of N-~ormylpiperazine and 2.5 9 o~ potassium'bromide ~or
12 hours. The isopropanol is then distilled o~ in vacuo
and the residue is taken up in toluene. The toluene phase
12~ i3
- 27 -
is extracted uith dilute hydrochloric acid, dilute sodium
hydroxide solution is added to the hydrochloric atid ex-
tracts until the mixture has an alkal;ne reaction, and the
rixture i5 extracted ~ith methylene chloride. ~he methylene
chloride phase is separated off, washed neutral, dried over
sodium sulphate and evaporated 7n vacuo. 1,5 Diphenyl-2-[3-
(4-~ormylpiperazin-1-yl)-propyl~-pyrazolin-3-one is obtained
as the residue.
B) 19 2 9 o~ 1,5-diphenyl-2-r3-t4-~ormylpiperazin-1-
yl)-propyl~-pyrazolin-3-one are dissolved in ~00 ml o~ a
mixture o~ ethanol and 2~X strength hydrochloric acid ~1:1).
~he solution is le~t to stand at room temperature ~or 12
hours and is then heated under reflux for another 2 hours,
and the ethanol is then distilled o~f i vacuo. Toluene and
dilute sodium hydroxide solution are added to the rrsidue.
The toluene phase is separated off, uashed ~ith uater,
dried over sodium sulphate and evaporated n vacuo. 1,5-
Diphenyl-2-[3-(piperazin-1-yl)-propyl~-pyrazolin-3-one is
obta;ned as the residue.
C) 13.3 9 of the piperazine compound obtained above
are dissolved in 150 ml o~ dimethylformamide, 7 9 of potas-
sium carbonate and 8.5 9 o~ 4-tri~luoromethyl-bromoben~ene
are added to the solution, and the mixture is heated at
12ûC ~or 16 hours, uhilst stirring. ~he solvent is then
substantially stripped off under reduced pressure, the dark
broun residue is taken up in di(ute hydrochloric acid and
the m;xture is extratted uith ethyl acrtate, uhich can then
be cdiscarded. The aqueous phase is subsequently rendered
alkaline aga;n ancd is extracted with methylene chloride.
`7~;3
~ 2~ -
~he organic phase is dried over sodium sulphate and ~iL-
tered over a short silica gel column. A~ter the solvent
has bcen evaporated o~ the title compound rema;ns as a
colourless viscous oiL
The 1 5-diphenyl-2-~(piperazin-1-yL~-alkyL]-pyrazo-
lin-3-one compounds o~ the ~ormula I listed in the tablé
uhich ~olLous can also be prepared ~rom corresponding com--
po~nds of the ~ormula II III or IV by the processes des-
cribed in ExampLes 1-4.
- 23
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Example ¦ ~ablets
Tablets having the ~ol~o~iny torposition per tablet
are prepared:
1,5-Diphenyl-2-~3-[4-~2-pyr;dyl)-pipera2in-
-propyl3-pyra701in-3-one ronohydrochlDride 25 mg
corn starch 60 mg
Lactose ~30 mg
Gelatine solution (1ûX strength solution) ~ mg
The active compound, the maize starch and the lac-
tose are thickened ~ith the lDX strength gelagine solution.
The paste is comminuted and the granules ~ormed are placed
on a suitable metal sheet and dried at 4D~t. The dried
granules are passed through a comminuting rachine, and
~ixed ~ith the further ~ollo~ing auxiliaries in a mixer:
~alc 9
Y.agnesium stearate 5 ~9
cor~ starch 9 mg
and the r.ixture ;s then pressed to tablets ueighing 240 mg.
