Note: Descriptions are shown in the official language in which they were submitted.
8159
4-12400/CGC 893/+
2-Aryl-pyrazolo[~,3-c]quinolin-3-(1~1 and 5H)-one compounds, process
for their preparation-
2-Aryl-pyrazolo[4,3-c]quinolin-3-ones have not been descrlbed
in the chemical literature yet. However, 2-unsubstituted 4-phenyl-
pyrazolo[4,3-c]quinolin-3-ones, or 3-hydroxy-tautomers thereof respec-
tively, are describet in Monatsh. 57, 52 (1931~. In contrast, 2-phenyl-
pyrazolo[4,3-c]isoquinolin-3-ones (or 3-ols) are described in J, Chem.
Soc. l9S9, 599; and European Patent Application 5,745 discloses anti-
infl G atory, CNS-depressant and anti-anxiety 3-phenyl-pyrazolot3,4-c]-
isoquinolin-5-one~.
The present invention relates to 2-aryl-pyrazolo[4,3-c]quinolin-
3-(1 and 5H)-one compounds, in particular of the general Formulae I
and II
~ R R~ R
R3~ 1 i1 (I) and R3~ 1 ¦ (I1)
wherein R3 is hydrogen, lower alkyl, lower alkoxy, halogen and tri-
fluoromethyl; R is phenyl which may be substituted with lower alkyl,
lower alkoxy, lower alkylthio, hydroxy, one or two halogen atoms,
trifluoromethyl, nitro, amino, mono-lower alkylamino, di-lower alkyl-
amino, cyano, carbamoyl, mono-lower alkylcarbamoyl, di-lower alkyl-
carbamoyl, and carboxy, or R is pyridyl which may be substituted by
lower alkyl or halogen; Rl is hydrogen, lower alkyl, di-lower alkyl-
amino-lower alkyl, and phenyl lower alkyl wherein the phenyl group may
.' ~
.
~8~59
-- 2 --
be substituted with halogen; and R2 is hydrogen and lower alkyl; their
3-hy~lroxy tautomers; lower alkanoyl, carbamoyl, mono- or di-lower
alkylcarbamoyl derivatives of the compounds, in which R is amino-
phenyl; or salts,especially pharmaceutically acceptable salts thereof;
process for their manufacture, pharmaceutical preparations containing
these psychoactive compounds and their therapeutic application.
The 1,2-phenylene group is preferably unsubstituted, or
substituted by one substituent R3 selected from the following
groups: lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl;
lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy;
halogeno, e.g. fluoro, chloro or bromo or trifluoromethyl.
The phenyl radical R in 2 position is preferably unsubstituted
or substituted with lower alkyl, lower alkoxy, lower alkylthio,
hydroxy, one or two halogen atoms, trifluoromethyl, nitro, amino,
mono-lower alkylamino, di-lower alkylamino, cyano, carbamoyl, mono-
lower alkylcarbamoyl, di-lower alkylcarbamoyl, and carboxy, or R is
pyridyl which may be substituted by lower alkyl or halogen.
The radical Rl, in either the 1- or preferably 5-position, is
advantageously hydrogen, but also one of said alkyl groups, or
(di-lower alkylamino or phenyl)-lower alkyl group, which preferably
separates adjacent hetero-atoms by at least 2 carbon atoms, such as
2-(dimethylamino or diethylamino)-ethyl, 2- or 3-(dimethylamino)-
propyl; benzyl, 1- or 2-phenethyl.
The radical R2 in 4-position is preferably also hydrogen, or
one of said alkyl groups, advantageously methyl.
~''
'1~48~5~
- 3
One account of said 1- or 5-substituents Rl the compounds of
this invention are correctly depicted as 3-ones, or 3-oxo-derivatives
respectively. But in case Rl = H, they may also form a minor amount of
3-hydroxy-tautomers, depending on milieu and substitution. In general,
however, they are weak bases or acids, forming acyl-derivatives only
with compounds having an amino-phenyl group R, and salts with either
strong acids or bases. Said acyl derivat *es are the lower alkanoyl,
carbamoyl, mono- or di-lower alkylcarbamoyl derivatives of the above
amino-phenyl compounds, e.g. the acetyl, propionyl, pivaloyl; (methyl
or ethyl)-carbamoyl derivatives; and the salts are preferably alkali
metal, e.g. sodium or potassium salts of the 1- or 5-unsubstituted
compounds (Rl = H) and/or the carboxy-phenyl compounds; or addition
salts of all of said compounds with acids, especially with the pharma-
ceutically acceptable acids listed below.
.. . ..
The term "lower", referred to above or hereinafter in connec-
tion with organic radicals or compounds respectively, defines suchwith up to 4, and advantageously those with one or two carbon atoms.
The compounds of the invention exhibit valuable pharmacological
properties, i.e. psychoactive effects, primarily antidepress~nt or
anxiolytic properties. They are demonstrable by in vitro and in vivo
tests, using advantageously mammals, e.g. mice, rats, or monkeys, as
test objects. Said compounds can be applied to them enterally or
parenterally, advantageously orally or subcutaneously, intravenously
or intraperitoneally, for example, within gelatin capsules or in the
form of starchy suspensions or aqueous solutions or suspensions
respectively. The applied dosage may range between about O.Ol and
100 mg~kg/day, preferably between about 0.05 and 5 mg/kg/day, advan-
tageously between about O.l and 0.5 mg~kg/day.
C .~
8~59
-- 4 --
Said antidepressant properties can be shown in mice according
to the Behavioral Despair test (Arch. Int. Pharmacodyn. Ther. 229
(2) : 327-336, Oct. 1977). It induces a depressed state therein by
forcing them to swim in a narrow cylinder from which they cannot
escape. After a brief period of vigorous activity the mice adopt a
characteristic immobile posture, which is readily identifiable.
Immobility is reduced by the compounds of this invention, other
tricyclic antidepressants, monoamine oxidase inhibitors, atypical
antidepressants and electroconvulsive shock.
Anxiolytic effects are routinely observed, for example,
accorting to theclassical metrazole antagonism test in rats, or
according to thè Cook-Davitson conflict proceture, using male Wistar
rats which are maintainet at 80 % of normal body weight by dietary-,
but not water-restriction. They are trained to press a lever within
a conditioning chamber, also containing a liquid dipper, a house light,
a speaker and a grid-floor. Both lever and grid are connected to an
electrical shock source and the chamber is situated in a sound-
attenuated room in which a white noise-source is activated during
testing, in order to mask any extraneous auditory cues. Each session
of 47 minutes duration consists of two alternating schedules. The
first is a Variable Interval (VI) schedule of 30 seconds, lasting
for 5 minutes, during which a sweetened, condensed milk reinforcement
is delivered following the first lever-press after the 30 seconds have
elapsed, and a drug-induced decrement of this performance is taken as
an indication of a neurological deficit. Immediately following the VI-
schedule both a 1000 Hæ tone and a light-cue are activated, indicating
the commencement of the second, Fixed Ration (FR) schedule, lasting
for 2 minutes, wherein the milk reinforcement is delivered concomitant
. .~
59
-- 5 --
with an electric foot shock immediately following the tenth response,
thereby establishing a conflict situation. The intensity of said
shoc'~ ranges between 2.0 and 3.6 mA, varying with each animal, in
order to adjust them to about 25-100 responses during this schedule
over the entire session. A drug-induced enhancement of performance
during the FR-schedule is taken as indication of antianxiety effects,
as exhibited by said compounds of this invention.
The anxiolytic effects of said new compounds can also be
estimated by the Diazepam Receptor Binding Assay in vitro, e.g. as
described in Nature 266, 732 (1977) or Proc. Nat. Acad. Sci. USA 74,
3805 (1977). Diazepam binds specifically and with high affinity to
crude synaptosomal membrane preparations from rat fore-brain. This
binding is inhibited by other anxiolytic compounds, e,g. other pharma-
cologically more active benzo-diazepines. When tritiated diazepam
is use-l, the interaction of other drugs with said receptor can be
readily assessed thus: Membranes from rat fore-brain are incubated
at 0-5 with tritiated diazeFam and various concentrations of the
test substances in a physiological medium at the pH = 7.5. The mem-
branes, containing the receptors with various amounts of tritiated
diazepam, are filtered onto glass fiber filters, which are then
shaken in a liquid scintillation counter. The concentration of the
compounds of this invention, required to inhibit the specific
binding of 2 nM tritiated diazepam by 50 %, i.e. the IC50 (Inhibitory
Concentration) is determined graphically and ranges down to about
0.6 nM, what is an order of magnitude lower than the value for
diazepam (5 nM) and almost four orders lower than the value for
hlordiazepoxide (400 nM).
Accordingly, the compounds of this invention are useful in
the treatment of mental depression and preferably for combatting
81S9
anxiety problems similar to those treated with diazepam. In contrast
to dia~epam, said compounds of the invention appear to be devoid of
neurological deficit liability at doses where antianxiety effects
are already established. Finally, the compounds of the invention are
also valuable intermediates in the preparation of other useful pro-
ducts, especially of corresponding pharmaceutical compositions.
The most preferred compounds of the invention are those of
Formula III
~./~
H
wherein R3 i8 hydrogen, lower alkyl, lower alkoxy, fluoro, chloro,
bromo or trifluoromethyl; ant R' is phenyl, o- or m-fluorophenyl;
or it i9 p-fluorophenyl when R3 is chloro; or salts, especially
pharmaceutically acceptable acid addition salts thereof, for their
predominant antidepressant activity.
The compounds of the invention are prepared according to con-
ventional methods, which consists in
1) ring-closing compounds of formula IV
X
R3--+- 1; i (IV)
~ 2
... ..
114~159
-- 7 --
wherein X is -NH-NH-R and Y is hydroxy or lower alkoxy; or X is
halogen and Y is H2N-N-R; or X is lower alkoxy-amino or azido, and Y
is NH-R; and, if required, reacting a resulting compound, or an alkali
metal salt thereof, with a reactive ester of the alcohol Rl-OH, or
2) condensing compounds of formula V
/.~ /W
R3~ (v)
wherein both W and Rl are hydrogen Z is R2-~= ~\ X
and Rl is lower alkyl; or W i8 ~ ~CH-COR2 and Z is hydrogen;
or W is X ~CH2 and Z is R2-CO and
a) if a compound is required in which Rl in l-position differs from
hydrogen, reacting a resulting compound in which Rl is hydrogen, with
a reactive ester of the alcohol Rl-OH, in which Rl is a residue
defined above, and,
b) if a compound is required in which Rl in 5-position differs from
hydrogen, reacting an alkali metal salt of a resulting compound in
which Rl is hydrogen, with a reactive ester of the alcohol Rl-OH, in
which Rl is a residue defined above, and,
c) if a compound is required in which the phenyl group R is substi-
tuted by hydroxy, hydrolysing a lower alkoxy substituent of the
phenyl group R, and,
i ~.
.
.
~81S9
-- 8 --
d) if a compound is required in which the phenyl group R is substi-
tuted by the amino group, hydrogenating the nitro substituent of the
phenyl group R, and,
e) if a compound is required in which the phcnyl group R is substituted
by mono- or di-lower alkylamino group, alkylating the amino substi-
tuent of the phenyl group R, and,
f) if a compound is required in which the phenyl group R i5 substi-
tuted by an acylamino group, acylating the amino substituent of the
phenyl group R by the acyl groups named above, and,
g) if a compound is required in which the phenyl group R is substituted
by the carbamoyl group, converting the cyano substituent of the phenyl
group R into carbamoyl, and,
h) if a compound is required in which the phenyl group R is substi-
tuted by the carboxy group, hydrolysing the cyano substituent of the
phenyl group R, and, if required, converting a resulting free compound
into a salt or a resulting salt into the free compound or into
another salt.
The ring-closure of said acids or esters IV occurs by heating
them to temperatures between about 80 and 180, advantageously in
the presence of inert solvents, such as aliphatic or aromatic hydro-
carbons and/or ethers, e.g. toluene, ~ylenes, biphenyls and/or
diphenyl ethers, while distilling off the water or alkanols generated.
Said hydrazides IV are similarly ring-closed, but advantageously
under basic conditions, in order to neutralize the generated hydro-
halic acids, for example in the presence of aqueous alkali me~al
hydroxides. The ring-closure of said amides IV occurs by heating
them to temperatures between about 120 and 300, preferably between
200 and 250, advantageously also in the presence of said inert sol-
11~8~5~
g
vents.
Some of the starting material of Formula IV is new, but caneasily be prepared from the known precursors with ~ = OH, e.g. as
illustrated by the examples herein or described in J. 'Ied. Chem. 12,
1096 (1969) or C.R. Acad. Sc. Paris, t. 280, C, 1385 (1975), by con-
densation with corresponding aryl-hydrazines, Said hydrazides are pre-
pared by condensing 4-chloroquinolin-3-carboxylic acid chlorides and
~-acylated aryl-hydrazines, e.g. the trifluoroacetates, which
hydrolyze under ring-closing conditions. Said amides are preferably
obtained by condensing 4-haloquinolin-3-carbo~ylic acid halides with
R-amines, and subsequently with O-lower alkylhydroxylamines or alkali
metal azides.
Said condensation of the W - H compounds is
preferably carried out with strong aprotic condensation agents, such
as polyphosphoric acid lo~ter alkyl esters. In case the compounds with
Z = H are ring-closed, the water generated is advantageously removed
azeotropically, preferably in said hydrocarbons and/or ethers, if
desired, in the presence of conventional molecular sieves, and/or
a catalytic amount of acid, e.g. hydrochloric acid.
Lastly, compounds V with carbon containing W and Z are ring-
closed under neutral conditions, optionally in the presence of de-
hydrating agents, such as thionyl halides, phosphorus oxyhalides or
lower alkyl polyphosphate esters.
1~481S9
-- 10 --
The starting material of Formula V is also new, but can be
prepared according to known methods, e.g. by condensing an l-aryl
pyrazolidin-3,5-dione with ethyl orthoformate and an aniline. Said
second starting material V can be prepar2d analogous to the process
described in Izv. Akad. ~auk. Latv. S.S.R. 1965, 587, but chosing
analogs with an o-nitro group, which is subsequently reduced with
catalytically activated hydrogen. Said final starting material V is
similarly prepared from said common l-R-3-(o-nitrophenyl)-5-pyrazol-
ones, by reducing and N-acylating.
The resulting compounds of the invention can be converted into
each other according to conventional methods. For example, compounds
with Rl = H can be l-substituted with reactive esters of Rl-OH,
e,g. such of hydrohalic, aliphatic or aromatic sulonic acids, such
as Rl-(halides, sulfates, aliphatic or aromatic sulfonates), e.g.
methyl iodide, dimethyl sulfate, benzyl chloride or methyl mesylate
or tosylate, in order to yield the l-substituted compounds of Formula
II. Those of Formula I are similarly obtained from the corresponding
alkali metal salts, e.g. with Rl being sodium or potassium, whereby
5-substitution occurs. Furthermore, resulting lower alkoxy compounds
may be hydrolyzed to the corresponding phenols withstrong hydrohalic
acids, e.g. hydrobromic acid. Resulting nitro compounds may be hydro-
genated to the corresponding amines with catalytically activated or
nascent hydrogen, e.g. hydrogen in the presence of noble metal cata-
lysts, such as nickel, palladium or platinum; or generated by the
action of reactive metals on alcohols or acids, such as zinc on hydro-
halic acids. Said amines may be alkylated as shown for the compounds
with Rl = H, or by reductive alkylation; or acylated, for example,
with the use of corresponding reactive acid derivatives, e.g.
~L~48~S~
anhydrides, halides or isocyanates. Resultant nitriles can be con-
verted into the corresponding amides in a manner known per se, e.g.
by treatment with aqueous alkali metal hydroxides, e.g. aqueous
sodium hydroxide, ethanol and hydrogen peroxide, or into the corre-
sponding acids by hydrolysis, e.g. with aqueous alkali metal hydrox-
ides, such as sodium hydroxide.
Finally, a resulting compound can either be converted into
its alkali metal salts, advantageously with the use of alkali metal
hydrides, hydroxides or lower alkoxides; or into its acid addition
salts (especially if amino-substituted compounds are involvedj,
preferably with the use of pharmaceutically acceptable inorganic or
organic acids, such as strong inorganic acids, for example, hydro-
halic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric,
nitric or perchloric acid; aliphatic or aromatic carboxylic or sul-
fonic acids, e.g. formic, acetic, propionic, succinic, glycollic,
lactic, malic tartaric, citric, maleic, hydroxymaleic, pyruvic, phenyl-
acetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic,
salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic,
ethane-sulfonic, hydroxyethanesulfonic, ethylenesulfonic; halogeno-
benzene sulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic
or cyclohexylsulfamic acid; or ascorbic acid. These or other salts,
for example the picrates, can also be used for purification of the
amino-bases obtained; these are converted into salts, the salts are
separated and the free compounds liberated from the salts. In view
of the close relationship between the free compounds and the compounds
in the form of their salts, whenever a compound is referred to in
this context, a corresponding salt is also intended, provided such is
possible or appropriate under the circumstances. Acid addition salts
of compounds devoid of basic substituents, e.g. an amino group, usually
hydrolyse in about neutral aqueous media.
~48~59
- 12 -
The above-mentioned reactions are carried out according to
standard methods, in the presence or absence of diluents, preferably
such as are inert to the reagents and are solvents thereof, of cata-
lysts, condensing or said other agents respectively and/or inert at-
mospheres, at low temperatures, room temperatureor elevated tempera-
tures, preferably at the boiling point of the solvents used, at
atmospheric or superatmospheric pressure.
Resulting mixtures of isomers can be separated into the single
isomers by methods in themselves known, e.g. by fractional distilla-
tion, crystallization and~or chromatography.
The invention further includes any variant of the above
processes in which an intermediate product, obtainable at any stage
thereof is used as starting material, and any remaining steps are
carried out, or said process is discontinued at any stage thereof,
or in which the starting materials are ormed under the reaction
conditions, e.g. those of Formula IV with X = NH-NH-R, from their
precursors with X = Cl, or in which the reaction components are used
in the form of their salts.
Mainly those starting materials should be used in the reactions
of the invention that lead to tbe formation of those compounds indi-
cated above as being especially valuable, e.g. those of Formula III.
The pharmacologically active compounts of the invention are
useful in the manufacture of pharmaceutical composi~ions comprising
an effective amount thereof in conjunctionoradmixturewith excipients
suitable for either enteral or parenteral application. Preferred are
tablets and gelatin capsules comprising the active ingredient together
with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,
cellulose, and~or glycine, ant lubricants, e.g. silica, talcum, stearic
acid, its magnesium or calcium salt and/or polyethyleneglycol; for
11~;L8159
- 13 -
tablets also binders, e.g. magnesium aluminium silicate, starch paste,
gelatin, tragacanth, methylcellulose, sotium carboxymethylcellulose
ant/or polyvinylpyrrolidone, if desired, disintegrants, e.g. searches,
agar, alginic acid or its salts, enzymes of the binders or effervescent
mixtures and/or atsorbents, colorants, flavors and sweeteners.
Injectable compositions are preferably aqueous isotonic solutions or
suspensions, ant suppositories are advantageously prepared from fatty
emulsions or suspensions. Said compositions may be sterilized and/or
contain adjuvants, such as preserving, stabilizing, wetting or
emulsifying agents, solution promoters, salts for regulating the
osmoti-c pressure and/or buffers. They may also contain other
therapeutically valuable substances. Said pharmaceutical compositions
are preparet according to conventional m~xing, granulating or coating
methods respectively and contain about 0.1 to 75 ~, preferably about
1 to 50 ~ of the active ingredient.~
The following examples, illustrating the invention, are not
to be construed as being limitations thereon. Temperatures are given
in degrees Centigrade, all parts wherever given are parts by weight
and, if not otherwise stated, all evaporations are carried out under
reduced pressure, e.g. between about 0.1 and 15 mmHg.
The compounds named in the following examples having too high
a melting point, are characterized by their IR or NMR spectral data.
59
- 14 -
Example 1: The mixture of 1681 g of ethyl 4-chloro-quinoline-3-
carboxylate, 1017 g of p-chlorophenylhydrazine and 25000 ml of
xylene is heated to 105 for 24 hours while stirring Imder nitrogen.
The resulting suspension is cooled to 20, combined with 1400 ml
of 2N aqueous sodium hydroxide, stirred for 15 minutes and diluted
with 30000 ml of water. Stirring is continued for 1 hour, the
aqueous phase separated, washed five times with 8000 ml of diethyl
ether each, filtered and the filtrate treated with the solution of
1600 g of ammonium chloride in 800 ml of water while stirring under
nitrogen. The resulting suspension is stirred overnight at room tem-
perature, filtered and the residue washed 5 times with 12000 ml of
hot water. This residue is dried at 5 mmHg and 90 and 1665 g
thereof are dissolved in 8400 ml of dimethylformamide at 130. The
solution is filtered and allowed to cool to room temperature while
stirring. The resulting suspension is filtered, washed twice with
500 ml of cold dimethylformamide each, four times with 1000 ml of
diethyl ether and the residue i8 dried at 0.1 mmHg and 100, to
yield the 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one of
the formula
./-~.
c
.~ \.~ \./ ~o
! I! I!
H
melting at 324 - 327 with decomposition.
The starting material is prepared according to the following
(generally applicable) method: To 1272 g of aniline 2953 g of
diethyl ethoxymethylenemalonate are added during 20 minutes while
stirring, and stirring is continued for 135 minutes at 90 - 92.
Thereafter the generated ethanol is distilled off during 4 hours at
10 mmHg and 80. The residual oil is allowed to crystallize on trays,
it is pulverized and dried at 5 mmHg and room temperature to yield
the diethyl phenylaminomethylenemalonate melting at 45 - 463
~8159
- 15 -
1085 g thereof are added during 45 minutes to 10850 ml of
the eutectic diphenyl ether-biphenyl mixture (73.5 : 26.5 parts by
weight) at 215-220, while stirring under nitrogen. After completed
addition the temperature is raised to 238 and the generated mixture
of ethanol and diphenyl ether is collected in a trap during 4 hours
(about 390 ml). The mixture is allowed to cool to room temperature
while stirring, the resulting suspension is filte-ed, the residue
washed twice with 500 ml of diethyl ether each and dried at 0.1 mmHg
and 85, to yield the ethyl 4-hydroxyquinolin-3-carboxylate melting
at 276-280.
1630 g thereof are added to 2463 ml of phosphorus oxychloride
during 30 minutes while stirring under nitrogen. The mixture is
stirred for 15 minutes at 70 and for 2 hours at 95, whereupon the
liquid i8 distilled off at ll mm Hg and 60. The residue is dissolved
in 8000 ml of methylene chloride, the solution is cooled to 0 and
treated with 5000 g of crushed ice. The mixture is stirred, combined
with 3000 ml of 50 % aqueous sodium hydroxide below 15 , and when
Lhe pH = 12 is reached the organic layer is separated. It is washed
twice with 2000 ml of water each, once with 2000 ml of saturated
aqueous sodium chloride, dried and evaporated. The residual oil is
allowed to crystallize on trays, it is pulverized and dried at
0.1 mmHg and room temperature, to yield the ethyl 4-chloro-quinolin-
3-carboxylate melting at 44-46.
To the solution of 1445 g of p-chloroaniline in 3375 ml of
38 % hydrochlorid acid and 5650 ml of water the solution of 793 g
of sodium nitrite in 3300 ml of water is added during 1 hour at -5 to
-8 while stirring under nitrogen. After 15 minutes 7617 g of
stannous chloride in 9000 ml of 38 % hydrochloric acid are added
during 30 minutes below 25. The resulting suspension is stirred
in an ice bath for one hour, filtered, the residue suspended in
30000 ml of water, and 5000 g of solid sodium hydroxide are added
1148159
- 16 -
during 1 hour at a - 25, while stirring under nitrogen. The mi~ture
is extracted twice with 8000 ml of diethyl ether, the combined
extracts washed twice ~ith 4000 ml of water and o~ce with saturated
aqueous sodium chloride, dried, filtered, evaporated and the residue
dried at 5 mmHg and room temperature, to yield the p-chlorophenyl-
hydrazine melting at 82 - 87.
Example 2: The mixture of 1 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]-
quinolin-3(5H)-one and 3.38 ml of N aqueous sodium hydroxide is
stirred under nitrogen at room temperature overnight. The resulting
solution is filtered, evaporated and the residue dried under reduced
pressure, to yield the corresponding sodium salt melting at 280 - 284.
Example 3: The mixture of 1 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]-
quinolin-3(5H!-one, 20 ml of trifluoroacetic acid and 0.325 g of
methanesulfonic acid is stirred at room temperature for 1 hour and
evaporated. The re3i~ue L8 trituratet with diethyl ether and filtered
off, to yield the corresponding mesylate melting at 250 - 255.
Example 4: The mixture of 3 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]-
quinolin-3(5H)-one and lO0 ml of dimethyl sulfate is stirred at 110 -
130 for 2 hours and evaporated. The residue is dissolved in N aqueous
sodium hydroxide, the solution extracted with methylene chloride and
the extract evaporated. The residue is recrystallized from diethyl
ether, to yield the l-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]-
quinolin-3-one melting at 158 - 161.
Example 5: The mixture of 5 g of 2-(p-chlorophenyl)-pyrazolo-[4,3-c]-
quinolin-3(5H)-one, 0.81 g of 50 % sodium hydride in mineral oil and
lO0 ml of anhydrous tetrahydrofuran is refluxed for 2 hours. It is
cooled to room temperature, combined with 3 g of methyl iodide while
stirring and another 1 g thereof is added after one hour. The mixture
is stirred overnight at room temperature, filtered and the residue
8~S9
- 17 -
recrystallized from tetrahydrofuran-heptane, to yield the 5-methyl-2-
(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 322 - 323.
Example 6: The mixture of 10 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]-
quinolin-3(5H)-one, 1,8 g of 50 ~ sodium hydride in mineral oil and
250 ml of 1,2-dimethoxyethane is stirred at 100 until dissolution.
It is cooled to room temperature and 15 g of 3-dimethylaminopropyl
chloride in 10 ml of 1,2-dimethoxyethane are added. The mixture is
stirred at 150 overnight, cooled, the supernatant solution decanted
off and the residue treated with said solvent, to yield the 5-(3-di-
methylaminopropyl)-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one
melting at 189 - 191.
Similarly the 5-(2-dimethylaminoethyl)-2-(p-chlorophenyl)-
pyrazolo[4,3-c]quinolin-3-one is obtained, m.p. 184 - 186.
Example 7: The mixture of 2 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]-
quinolin-3(5H)-o~e, 0.33 g of 50 ~ sodium hydride in mineral oil and
50 ml of 1,2-dimethoxyethane is stirred at 100 until dissolution.
It is cooled to room temperature, combined with 3.9 g cf o-fluoro-
benzyl chloride in 2 ml of 1,2-dimethoxyethane and the mixture
refluxed for 4 hours. It is cooled to room temperature, filtered,
the residue washed with diethyl ether, slurried in 10 ml of N aqueous
sodium hydroxide, filtered again, washed with water and dried, to
yield the 5-(o-fluorobenzyl)-2-~p-chlorQphenyl)-pyrazolo[4,3-c]-
quinolin-3-one melting at 338 - 339.
Example-8: The mixture of 3.5 g of ethyl 4-(2,4-dichlorophenyl-
hydrazino)-quinolin-3-carboxylate and 40 ml of eutectic diphenyl
ether-biphenyl is heated to 175 for 4 hours, cooled to room tem-
perature and diluted with diethyl ether. The resulting suspension is
filtered, the residue washed with diethyl ether and dissolved in N
aqueous sodium hydroxide. The solution is washed with diethyl ether,
its pH adjusted to 8.5 with ammonium chloride and the precipitate
l~B~59
- 18
formed collected. It is washed successively with hot water, methanol
and diethyl ether, to yield the 2-(2,4-dichlorophenyl)-pyrazolo[4,3-c]-
quinolin-3(5H)-one, showing peaks in the IR-spectrum at 890, 867, 845,
832, 816, 796, 775, 767, 756, 730 and 701 cm 1.
The starting material is prepared as follows: The mixture of
2.8 g of ethyl 4-chloroquinolin-3-carboxylate, 2.1 g of 2,4-dichloro-
phenylhydrazine and 40 ml of eutectic diphenyl ether-biphenyl is
heated to 80 - 90~ overnight while stirring. It is cooled to room
temperature, diluted with diethyl ether and the precipîtate collected.
It is taken up in N aqueous sodium hydroxide, the solution extracted
with diethyl ether, the extract washed with water, dried, filtered,
concentrated and the precipitate collected, to yield the ethyl 4-(2,4-
dichlorophenyl hydrazino)-quinolin-3-carboxylate, melting at
151 - 153.
Example 9: The mixture of 3,6 g of ethyl 4-chloro-2-methyl-quinolin-3-
carboxylate, 1.8 g of phenylhytrazine and 40 ml of xylene is refluxed
for 4 hours, cooled to room temperature, diluted with diethyl ether
and filtered. The residue is dissolved in 50 ml of 2N aqueous sodium
hydroxide, the solution washed with diethyl ether and its pH adjusted
to 8.5 with ammonium chloride. The precipitate formed is collected,
washed successively with hot water, methanol and diethyl ether, to
yield the 4-methyl-2-phenyl-pyrazolo[4,3-c]quinolin-3(5H)-one,
showing in the IR-spectrum peaks at 874, 867, 858, 850, 822, 780,
765, 756, 750, 740 and 722 cm
Analogously the 4-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]-
quinolin-3(5H)-one is prepared, melting at 349 - 350.
Example 10: The mixture of 2,7 g of ethyl 4-chloro-6-methoxy-quinolin-
3-carboxylate, 1,4 g of p-fluorophenylhydrazine and 20 ml of eutectic
diphenyl ether-biphenyl is heated to 160 - 165 for 4 hours, then
-
~48159
-- 19 --
cooled to room temperature and diluted with diethyl ether The preci-
pital:ed crystalline product is collected, washed thoroughly with
ai.ethyl ether and dried, to yield the 2-(p-fluorophenyl)-8-methoxy-
pyrazolo[4,3-c]quinolin-3(5H)-one hydrochloride melting at 322 - 324.
Example 11: The mixture of 4 g of ethyl 4-chloroquinolin-3-carboxylate,2.04 g of 2-hydrazinopyridine and 50 ml of eutectic diphenyl ether-
biphenyl is stirred at 110 - 130 for 3 hours under nitrogen. After
cooling to room temperature it is diluted with diethyl ether, filtered,
the solids washed with diethyl ether and dissolved in 100 ml of
aqueous sodium hydroxide. The solution is washed with diethyl ether
and the pH thereof adjusted to 8.5 by addition of ammonium chloride.
The precipitate fonmed is collected, washed successively with water,
methanol and diethyl ether, to yield the 2-(2-pyridyl)-pyrazolo-
[4,3-c]quinolin-3(5H)-one showing in the IR-spectrum peaks at 887,
865, 853, 788, 780, 765, 756, 737 and 726 cm 1.
Analogously the 8-fluoro-2-(2-pyridyl)-pyrazolo-[4,3-c]quinolin-
3(5~)-one is prepared,showing IR-peaks at 895, 868, 826, 792, 776,
758 and 725 cm 1,
The starting material for the latter is prepared as follows:
The mixture of 28.9 g of ethyl 6-fluoro-4-hydroxy-quinolin-3-carboxyl-
ate [J.A.C.S., 69, 371 (1947)] and 240 ml of phosphorus oxychloride
is refluxed under nitrogen for 3 hours. After cooling to room tempera-
ture, the solution is evaporated and the residue treated with ice-
water and chloroform. The organic layer is dried and evaporated. The
residue is taken up in aqueous sodium bicarbonate and diethyl ether,
the ethereal layer is dried and evaporated, to yield the ethyl 4-
chloro-6-fluoro-quinolin-3-carboxylate melting at 55 - 57.
Example 12: The mixture of 3 g of 2-(p-methoxyphenyl)-pyrazolo[4,3-c]-
quinolin-3(5H)-one and 260 ml of 48 % hydrobromic acid is refluxed for
1 hour and concentrated to about 50 ml. The concentrate is cooled to
~48~S9
- 20 -
room temperature, the precipitate collected, washed with methanol and
diethyl ether, and dissolved in diluted aqueous sodium hydroxide.
The solution is washed wi~h diethyl ether, then its pH adjusted to
8.5 by addition of ammonium chloride, precipipating a solid which is
collected, washed with methanol, then with diethyl ether and dried,
to yield to 2-(p-hydroxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one
melting at 294 - 296.
Example 13: The solution of 1.9 g of 2-(p-nitrophenyl)pyrazolo[4,3-c~-
quinolin-3(5H)-one in the mixture of 18.6 ml of 2N aqueous sodium
hydroxide and 75 ml of ethanol is hydrogenated over 0 2 g of platinum
oxide at 2.7 atm. for 6 hours. The mixture is filtered, the filtrate
evaporated, the residue taken up in water and the solution washed
with diethyl ether. The pH thereof is adjusted to about 8.5 by
addition of aqueous ammonium chloride, the precipitate collected,
washed successively with methanol and diethyl ether and dried, to
yield the 2-(p-aminophenyl) pyrazolo[4,3-c]quinolin-3(5H)one,
showing IR-peaks at 896, 885, 865, 840, 820, ~15, 782, 776, 761, 740,
736 and 720 cm l.
Example 14: To the mixture of 1.4 g of 2-(p-aminophenyl)-pyrazolo-
[4,3-c]quinolin-3(5H)-one, 4.1 ml of 37 ~ aqueous formaldehyde, 1 g
of sodium cyanoborohydride and 20 ml of acetonitrile, 0,6 g of
glacial acetic acid are added while stirring. Stirring is continued
overnight at room temperature and the mixture di~uted with water.
The precipitate formed is dissolved in diluted sodium hydroxyde, the
aqueous solution washed with diethyl ether and its pH adjusted to
8.5 by addition of aqueous ammonium chloride. The precipitate formed
is collected, washed with methanol, then with diethyl ether and dried
to yield the 2-(p-methylaminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-
one melting at 302 - 304.
~1~8159
- 21 -
Exa~ple 15: The mixture of 0.7 g of 2-(p-aminophenyl)-pvrazolo[4,3-c]-quinolin-3(5H)-one, 1.4 g of methylisocyanate and 25 ml of methanol
is refluxed for 7 hours and allowed to stand at room temperature over-
night. It is evaporated, the residue treated with diluted aqueous
sodium hydroxide and diethyl ether, the aqueous solution separated,
washed with diethyl ether and its pH adjusted to 8.5 with a~monium
chloride. The precipitate formed is collected, washed with methanol,
then with diethyl ether and dried, to yield the 2-(p-methylcarbamoyl-
aminophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing IR-peaks of
895, 869, 850, 816, 812, 785, 780, 767 and 738 cm 1.
Example 16: 38,5 ml of a 0,17 M solution of ethyl 4-chloro-quinoline-
3-carboxylate in xylene, and 0,96 g of p-cyanophenylhydrazine in 30 ml
of xylene are mixed and heated at 115 to 120 for 3 hours. The mixture
is then cooled to room temperature, and stirred with 20 ml of lN
aqueous sodium hydroxide and sufficient water to dissolve all solids.
The aqueous layer is separated, washed twice with diethyl ether, then
treated with an aqueous solution of 1.07 g ammonium chloride, and the
resulting precipitate is collected, washed with water and dried to
yield the 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, showing
peaks in the IR-spectrum at 885, 830, 780, 755 and 730 cm 1.
~xample 17: One gram of 2-(p-cyanophenyl)-pyrazolo~4,3-c]quinolin-3-
(5H)-one, 3~50 ml of lN aqueous sodium hydroxide and 10 ml of ethanol
are mixed and stirred at room temperature until the solid has dis-
solved. The solution is then treated with 1.4 ml of 30 % hydrogen
peroxide, giving an immediate precipitate. After stirring for 2 hours
at room temperature, the mixture is filtered, and the solid is
crystallized from dimethylformamide, to yield the 2-(p-carbamoyl-
p'nenyl)-pyrazolol4,3-c]quinolin-3(5H)-one, showing peaks in the IR-
spectrum at 885, 853, 830, 785, 775, 752 and 732 cm 1
~1~8~59
- - 22 -
Example 18: One gram of 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3-
(5H)-one and 50 ml of 2N aqueous sodium hydroxide are mixed and
refluxed for 3 hours. The solution is acidified with 50 ml of hydro-
chloric acid, filtered, and the collected precipitate dried. It is
taken up in 25 ml of 1~ aqueous sodium hydroxide, and the solution
neutralized to pH=6-7 with lN hydrochlorid acid. The resulting solid
is filtered off, triturated with water and dried, to give the 2-(p-
carboxyphenyl)-pyrazolo~4,3-c]quinolin-3(5H)-one 3/2 hydrate, showing
IR-peaks at 886, 858, 820, 780, 770, 760 and 730 cm 1.
Example l9: The pH of the solution of 1 g of 4-chloro-quinoline-3-
(N-phenyl-N-trifluoroacetamido)-carboxamide in the minimum amount of
50 ~ aqueous tetrahydrofuran is adjusted to 10 by the addition of
lithium hydroxide. The mixture is stirred at room temperature for 48
hours, concentrated to remove most of the tetrahydrofuran, washed with
dichloromethane, and acidified to pH=3 by addition of diluted hydro-
chloric acid. The precipitate formed is collected by suction filtra-
tion, and purified by preparative thin layer chromatography using
toluene: ethanol: conc. a~monium hydroxide (70:30:3) as developing
solvent on silica gel, to obtain the 2-phenyl-pyrazolo[4,3-c]-
quinolin-3(5H)-one melting at 326 - 328,
The starting material is prepared as follows:
To the ice-cooled solution of 10.8 g of phenylhydrazine in 120 ml
of diethyl ether, 10.5 g of trifluoroacetic anhydride in 25 ml of
diethyl ether are added dropwise over the period of 15 minutes. The
mixture is stirred at 0-5 for 15 minutes, then at room temperature
for 2 hours, whereupon it is filtered. The filtrate is washed with
water, dried, evaporated and the residue crystallized from diethyl
ether: n-heptane, to yield the ~-trifluoroacetylphenylhydraæine
melting at 119-121.
The mixture of 1~5 g thereof in 100 ml of tetrahydrofuran and
0.06 g of lithium hydride is stirred under moisture exclusion for
.. .. .. . . ..
~8159
- 23 -
5 hours at room temperature, to form a solution. Separately, 1.9 g of
4-ch].oro-3-chlorocarbonylquinoline hydrochloride are stirred in 100 ml
of tetrahydrofuran with 0.06 g of lithium hydride under moisture
exclusion for one minute at 10, and the solution is added to the
former in 10 ml portions. The mixture is stirred at room temperature
for 18 hours, then refluxed for 8 hours and concentrated under reduced
pressure, obtaining the 4-chloroquinoline-3-(N-phenyl-N-trifluoro-
acetamido)-carboxamide, which is used without further purification.
Example 20: The mixture of 0.211 g of 4-(0-methylhydroxylamino)-
quinoline-3-(N-p-chlorophenyl)-carboxamide, and lS ml of eutectic
diphenyl ether-biphenyl is heated to 240 for 2 hours under nitrogen.
It is cooled to room temperature, diluted with 150 ml of petroleum
ether, and the resultant precipitate is collected. It is washed with
petroleum ether, stirred with 15 ml of diethyl ether and 3 ml of 2N
aqueous sodium hydroxide for 1 hour, filtered to remove insoluble
material, and the layers of the ~iltrate are separated. The aqueous
phase is treated with 0,32 g of ammonium chloride, to give a yellow
precipitate, which is collected and recrystallized from ethanol, to
yield the 2-(p-chlorophenyl)-pyrazolo~4,3-c]quinolin-3(5H)-one melting
at 327; it is identical with that of Example 1.
The starting material is prepared as follows:
The mixture of 11,62 g of 4-hydroxyquinoline-3-carboxylic acid
[M. Hamana et al., Chem. Pharm. Bull., 26, 3856 (1978)], 7.84 g of
p-chloroaniline, 17.59 g of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydro-
quinoline, and 150 ml of dimethylformamide is heated at 60-70 for
2 hours, to obtain a clear solution. It is cooled, filtered and
evaporated in a rotary evaporator. The residue is triturated with
diethyl ether, filtered, and the collected solid is washed with di-
ethyl ether, to yield a mixture containing starting acid. It is
stirred in 100 ml of 2N aqueous sodium hydroxide for 1.5 hour,
filtered, washed with water, and dried to obtain the 4-hydroxy-
3~4815~
- 24 -
quinoline-3-(N-p-chlorophenyl)-carboxamide, sho~ing IR-peaks at
3450, 3260 and 3210 cm 1.
The mixture of 1 g thereof and 25 ml of phosphorus oxychloride
is heated at 80 for 3 hours to obtain a clear solution. It is
evaporated, the residue treated with 400 ml of a l:l mixture of ice
and 2N aqueous sodium hydroxide, stirred with 200 ml of dichlorometha-
ne, filtered and the layers separated. The organic phase is dried
and evaporated, to yield the 4-chloroquinoline-3-(N-p-chlorophenyl)-
carboxamide, melting at 229-234. (It may also be prepared by treating
said acid with phosphorus oxychloride first, and the resulting di-
chloride with said aniline second).
The mixture of O.S g thereof, 1 g of 0-methylhydroxylamine
hydrochloride and 1.65 g of diisopropylethylamine is heated to 100
in a small pressure vessel for 18 hours. The coolet mixture is then
triturated with water, dissolved in tetrahydrofuran, dried, evaporated
and the residue recrystallized from methanol, to yield the 4-(0-
methylhydroxylamino)-quinoline-3-(N-p-chlorophenyl)-carboxamide
melting at 210-212.
Example 21: The solution of 308 mg of 1-(p-chlorophenyl)-4-hydroxy-
methylene-3-(o-nitrophenyl)-4,5-dihydropyrazol-S-one in 80 ml of
tetrahydrofuran is hydrogenated over S0 mg of 5 % platinum on charcoal
at room temperature and 3 atmospheres for O.S hour. The mixture is
filtered, the filtrate evaporated and the residue taken up in 150 ml
of toluene. To the solution, 0.1 ml of conc. hydrochloric acid is
added, and the mixture refluxed at a water separator for 18 hours.
It is cooled, the precipitate formed filtered off and purified by
preparative thin layer chromatography, using ethyl acetate: ethanol:
conc. ammonium hydroxide (17:3:3) as developing solvent on silica gel,
to yield the 2-(p-chlorophenyl)-pyra7O1O[4,3-c~quinolin-3tSH)-one
melting at 327, it is identical with that of Example 1.
3159
- 25 -
The starting material is prepared as follows:
The solution of 39.6 g of monoethyl malonate, 50 mg of 2,2-bipyridyl
(indicator) and 650 ml of tetrahydrofuran is cooled to -70, whereupon
305 ml of 1.97 M n-butyl lithium in hexane are added slowly under
nitrogen while stirring. The temperature is allowed to rise to about
-5 near the end of addition, after the pink color of the indicator
persists. The mixture is recooled to -65, and the solution of 31.7 g
of o-nitrobenzoyl chloride in 50 ml of tetrahydrofuran is added drop-
wise within 10 minutes. The resultant mixture is stirred at room tem-
perature for 1 hour and then poured onto a mixture of 650 ml of lN
hydrochloric acid and 1100 ml of diethyl ether. The organic layer is
separated, washed successively with 350 ml of saturated aqueous sodium
bicarbonate, 400 ml of water and 200 ml of saturated aqueous sodium
chloride solution, dried and evaporated, to yield the ethyl 2-(o-nitro-
benzoyl)-acetate, as a colorless oil.
The solution of 3.55 g thereof and 1.7 g of p-chlorophenyl-
hydrazine in 65 ml of toluene is refluxed for 3 hours at a water
separator. The mixture is evaporated, the residue chromatographed on
silica gel with 15 Z ethyl acetate in toluene as eluent, to yield the
l-(p-chlorophenyl)-3-(o-nitrophenyl)-4,5-dihydropyrazol-5-one,
melting at 138-141.
0.7 g thereof is stirred in 10 ml of dimethylformamide dimethyl-
acetal at room temperature for 18 hours. The dark reaction mixture
is poured onto ice-water, the precipitate is collected by suction
filtration, taken up in ethyl acetate, washed with water, dried and
evaporated to leave the l-(p-chlorophenyl)-4-dimethylaminomethylene-
3-o-nitrophenyl-4,5-dihydropyrazol-5-one, melting at 208-210
(decomposition).
2.5 g thereof are stirred in the mixture of 20 ml of tetra-
hydrofuran and 20 ml of 20 Z aqueous hydrochloric acid, at 60 for
8~59
- 26 -
3 hours, then at room temperature for 18 hours. It is diluted with
saturated aqueous sodium chloride solution, the precipitate collected
and washed with ethyl acetate, leaving the l-(p-chlorophenyl)-4-hydro-
xymethylene-3-(o-nitrophenyl)-4,5-dihydropyrazol-5-one, melting at
155-157.
Example 22: The mixture of 650 mg of 1-(p-chlorophenyl)-2-methyl-4-
anilinomethylidene-pyrazolidin-3,5-dione, 2 g of ethyl polyphosphate
and 10 ml of 1,1,2,2-tetrachloroethane is refluxed for 24 hours. The
solution is poured onto 10 ml of 2N aqueous sodium hydroxide and the
organic layer chromatographed on silica gel plates, using toluene:
ethanol:conc. ammonium hydroxide (80:20:1) as eluent, to yield the 1-
methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one with an Rf-
0.48. When using dichloromethane:methanol (19:1) as eluent, said
compound has the Rf = 0.33. The compound is identical with that of
example 4.
The starting material is prepared as follows:
20 g of diethyl malonate are added to 5.8 g of sodium metal dissolved
in 100 ml of absolute ethanol. After stirring for 15 minutes, 17.8 g
of p-chlorophenylhydrazine are added, and the resulting mixture is
stripped to remove excess ethanol. The residue is heated at 110 to
120 for 4.5 hours, then quenched with 500 ml of ice-water. The
resulting mixture is washed twice with diethyl ether and the aqueous
layer is acidified with conc. hydrochlorid acid to a pH below 2. The
resulting solid is recrystallized from toluene, to give the l-(p-
chlorophenyl)-pyrazolidin-3,5-dione melting at 189-193.
The mixture of 2 g thereof, 2.81 g of triethyl orthoformate,
0.97 g of aniline and 30 ml of ethanol is refluxed for 16 hours. It
is cooled, filtered and the residue washed with water, to yield the
l-(p-chlorophenyl)-4-anilinomethylidene-pyrazolidin-3,5-dione,
melting at 288-290.
1148~9
- 27 -
The mixture of 500 mg thereof, lS mg of lithium hydride and
2 ml of dimethylformamide is heated at 70 for 3 hours. The solution
is then cooled to 5, and 700 mg of methyl iodide are added. The
mixture is stirred for 16 hours at room temperature and evaporated.
The residue is taken up in water and dichloromethane, the organic
phase separated, dried and evaporated, to yield the l-(p-chlorophenyl)-
2-methyl-4-anilinomethylidene-pyrazolidin-3,5-dione, showing NMR-peaks
at 3,14, 7,47, 8,42, 10,92 and 10,98 ppm.
Example 23: The solution of 50 m~ of 1-(p-chlorophenyl)-3-(o-formyl-
aminophenyl)-4,5-dihydropyrazol-5-one in 10 ml of dichloromethane
is evaporated, leaving a thin film on the flask wall. This is heated
at 190-200 for 30 minutes under a gentle stream of nitrogen. The
reaction product is chromatographed on silica gel plates, using ethyl
acetate:ethanol:conc. ammonium hydroxide (17:3:3) as eluent, to yield
the 2-(p-chlorophenyl)-pyrazolo[4,3-c3quinolin-3(5H)-one with an
Rf ~ 0.16. When using 5 % methanol in dichloromethane, said compound
has the Rf ~ 0.07, and with toluene:ethanol:conc. ammonium hydroxide
(70:30:3), the Rf ~ 0.32.
The starting material is prepared thus: 2 g of l-(p-chloro-
phenyl)-3-(o-nitrophenyl)-4,5-dihydropyrazol-5-one are catalytically
hydrogenated in 100 ml of ethanol over 200 mg of 5 % platinum on
carbon at room temperature and 3 atmospheres. Since the product
crystallizes from the mixture as it is formed, the mixture is diluted
with dichloromethane to dissolve said crystalline product. It is
filtered, the filtrate evaporated, and the dried residue recrystallized
from ethanol, affording the 3-(o-aminophenyl)-1-(p-chlorophenyl)-4,5-
dihydropyrazcl-5-one melting at 199-201.
0.3 g thereof are added to 10 ml of 97 % formic acid under ice
cooling while stirring under nitrogen, to give a colorless solution.
1 ml of acetic anhydride is added and the mixture stirred overnight
~14~159
- 28 -
at room temperature, then poured into 300 ml of saturated aqueous
sodium chloride solution. The white precipitate is collected, dissolved
in 200 ml of diethyl ether, dried and evaporated, leaving the l-(p-
chlorophenyl)-3-(o-formylaminophenyl)-4,5-dihydropyrazol-5-one,
melting at 170-172.
Example 24: According to the methods illustrated by the previous
examples, advantageously Examples 1 and 8-11, the following compounds
of Formula II are prepared: Rl R2 = H.
No. Ph Rm.p. C or IP-peaks cm
1 8-CH30-C6H3 2-pyridyl 319 - 323
2 7-CF -C6H 2-pyridyl 348 - 350
3 C6H4 4-CH3-2-pyridYl342 - 344
4 C6H4 5-Cl-2-pyridyl886, 835, 828, 797, 778, 756
C6H4 2,5-C12-phenyl337 - 338
6 C6H4 3,4-C12-phenyl890, 878, 867, 823, 818, 795
7 C6H4 3,5-cl2-phenYl890, 871, 847, 830, 806, 788
As well as compounds of formula III:
jNo. R~ R'm.p. C or IR-peaks cm
8 H -CH3 349 - 350 (HCl-salt)
9 H p-CH3 338 - 340
H p-OCH3 268 - 270
11 H p-SCH3 307 - 309
12 H p-F 342 - 346
13 H m-F 335 - 338
14 H o-F 338 - 340
H o-Cl 336 - 339
16 H m-Cl 336 - 337
17 H p-Br 328 - 330
18 H p-CF3 315 - 320
.. . _
~L~48~5~
- 29 -
Example 24: (Continued)
No. R~ R'm.p. C or IR-peaks cm
_.
19 H P-N02886, 853, 818, 780, 758, 749
7-Cl H872, 851, 830, 818, 798, 770
21 7-Cl p-Cl865, 852, 823, 795, 768, 7C2
22 7-Cl p-F890, 858, 835, 804, 770, 731
23 7-Cl m-Cl 333 - 335
24 8-CH3 H860, 810, 785, 770, 750, 730
8-CH3 p-CH3 340 - 342
26 8-CH3 p-Cl 335 - 337
27 8-OCH3 H 321 - 325
28 8-OCH3 p-OCH3 313 - 315
29 8-OCH3 o-F 344 - 347
8-OCH3 m-Cl 324 - 327
31 8-OCH3 p-Cl 347 - 349
32 8-F H 327 - 328
33 8-F p-OCH3 289 - 292
34 8-F p-F884, 868, 827, 767, 715, 708
8-F m-F900, 881, 865, 839, 827, 774
36 8-F o-F868, 850, 815, 782, 750, 724
37 8-F p-Cl 342 - 345
38 8-F m-Cl870, 810, 800, 775, 760, 714
39 8-Cl H894, 871, 845, 812, 787, 770
8-Cl o-F895, 875, 858, 820, 814, 782
41 8-Cl m-F892, 884, 867, 860, 815, 771
42 8-Cl p-F898, 890, 870, 855, 832, 820
43 8-Cl o-Cl896, 885, 880, 848, 823, 789
44 8-Cl p-Cl890, 842, 820, 806, 782, 768
8-Cl m-Cl890, 865, 815, 790, 777, 740
46 8-Cl P-N02895, 882, 849, 834, 808, 784
47 8-F P-N02896, 884, 869, 860, 828, 821
48 8-OCH3P-N02 338 - 340
~1~8159
- 30 -
E Iple 24: (Continued)
_
N~. R' mp. C or IR-peaks cm
49 6-Cl p-Cl 825, 806, 762, 736, 720
7-CF3 H 324 - 327
51 7-CF3 p-F 331 - 334
52 7-CF3 m-Cl 317 - 320
1 7-CF3 p-Cl 890, 854, 826, 800, 770, 756
Example 25: Tablets each containing 5 mg of the active ingredient:
Formula (for 10 000 tablets)
tp-chlorophenyl)-pyrazolo~4,3-c]-quinolin-3(5H)-one 50 g
LactosP 1157 g
Corn Starch 75 g
Polyethylene glycol 6,000 75 g
Talcum powder 75 g
Magnesium stearate 18 g
Purified water q.s.
All the powders are passed through a screen with openings of
0 6 mm. Then the drug substance, lactose, talcum, magnesium stearate
and half of the starch are mixed in a suitable mixer. The other half
of the starch is suspended in 40 ml of water and the suspension added
to the boiling solution of the polyethylene glycol in 150 ml of
water. The paste formed is added to the powders which are granulated,
if necessary, with an additional amount of water. The granulate is
dried overnight at 25, broken on a screen with 1.2 mm openings and
compressed into tablets using concave punches with 6,4 mm diameter,
uppers bisected.
~4131~9
- 31 -
le 26: Capsules each containing 10 mg of the active ingredient:
Formula (for 10 000 capsules)
2-phenyl-pyrazolo[4,3-c] quinolin-3(5H)-one 100 g
Lactose 1800 g
Talcum powder 100 g
All the powders are passed through a screen with openings of
0.6 mm. Then the drug substance is placed in a suitable mixer and
mixed first with the talcum, then with the lactose until homogenous.
No. 3 capsules are filled with 200 mg each, using a capsule L;lling
machine.
Analogously tablets or capsules are prepared from the
remaining compounds of the invention, e.g. those illustrated by
the previous examples.
