Note: Descriptions are shown in the official language in which they were submitted.
3Z~7
~ield o~ the I~vention
The invention deals with novel substances relating to pyri-
midoquinazolones, and speci~ically to 2-(o-carboxyphenylamino)-6H-
pyrimido(2,1-b)-quinazolone-6 and derivatives thereof, method of
producing same and application as medicinals.
~ he invention can be utilized in the medical practice.
Summary o~ the Invention
According to the invention, 2-(o-carbo~yphenylamino)-6H-py-
rimido(2,1-b)-quinazolone-6 has the followin~ structural formula:
N
Il CDOH
The above compou~d is a cry~talline light yellow substance,
solu~le in solutions of soda ~nd alkalis, and insoluble in water,
alcohol, acetone, and chloro~orm. Its meltlng point is 290~C
(with decomposition)O
Derivatives of 2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-
quinazolone-6 have ~he following structural ~ormula:
~: ~ ~0~~
where ~ are alkali metals, monoethanolamine, diethyl~mine.
Said compounds are colorless crystalline substances solub~e
in water and lower alcohols~ and insoluble in ethers, chloroform9
dimethyl ~ormamide. Their meltin~ point is 250 to 300C (with
decomposition~ ^
- ' ' , ` .' ' ' ,. ' ' .;
O . , . ' ~.
Still a~other group of derivatives of 2-(o-carboxyphenylami-
no)-6H-pyrimido(2,1-b)-quinazolone-6 have the following structural
formula:
~ H ~ A
where R is OH, alkyloxyl C 1-4,
~HR1 where R1 is ~, alkyl C 1-~ phenyl, aralkyl 9
A are salts of inorganic acids.
Other drivatives o~ 2 (o-carboxyphenylamino) 6H-pyrimido
(2,1-b)-quinazolones-6 have the following structural formula:
~ NH
where R is a~yloxyl C 1-4, ~HP1, where p1 is alk~l C 1-4
~ he a~ove specified compounds are crystalline substance~
which are difficulty soluble in alcohols, dimethyl ~ormamide, in-
soluble in water, acetone, and chloro~orm. ~heir melting point is
240 to 270C (with decomposition).
2-(o-carboxyphenylami~o)-6H pyrimido(2,1-b)-quinazolone-6
and deriva~ive~ thereof posses ph~macological activit~ and can
be success~ully used in medicine for the treatment o$ rheumatism
and other diseases accompanied by an in~lammatory process (arthri-
tis, pol;yserositis e~c. ) O
The invention also consists in a method of producing 2-(o-car-
boxyphenylamino) 6H-pyrimido~2,1-b)-quinazolone-6 and derivative~
thereo~, whereln 2,4-dichlorop~rimidine is brought i~t.o ~terac-
tion with aIlthranilic acid, or a sodium sàlt OI a~thranilic aoid,
' ' , ' ' ' ' ' ' , ' .
l Z(~B~217
or substituted esters, or amides o~ anthranilic acid in an aqueous
medium, or an inorganic solvent at a te~perature of 90 to 120C
and is held at this temperature for 2 to 4 hours, and an end pro-
duct is separa-ted usin~ a conventional method.
The above method allov~s the above novel chemical substances
to be produced at a hi~h yield (70 to 80~o). The method is techno-
lo~ically effective, does not require the application of complica-
ted equipment and allo~Js the products to be prod~lced in one stage.
It is e~edient to carry out interaction betvieen 2,4-dichlo-
ropyrimidine and a sodium salt of anthranilic acid in an aqueous
medium having pH of ~.0 to 8.5.
The above modification o~ the method allows more soluble
compounds to be produced in one stage.
It is most economically to conduct the interaction between
2,4-dichloropyrimidine and substituted esters or amides of an-
thranilic acid with a ratio between the reactive substances
bein~ respectively 1:2 in an organic solvent~
It is possible to additionally neutralize anions of acid
of the product using conven-tional techniques.
Said modi~ication o~ the method allows the range o~ produ-
ced products to be e~panded.
-- ~o accelerate the process and to increase the yield o~ the
end product, it is expedient to utilize alcohols, or dimethyl
formamide, or acetic acid, or mi~tures thereof as an organic sol-
vent.
The invention also consists in the provision of a chemo-
therapeutic antiphlogistic, containing 2-(o-carbo~yphenylamino)-
6H-pyrimido(2~1-b)-quinazolone-6 F derivatives thereof and a
~2~8~17
pharmaceutical basic material as an acting source.
The above specified chemotherapeutic preparation is
intended for treating patients suffering from rheumatoid
arthritis, Bekhterev's disease, Reiter's disease, deform-
- 5 ing asthenoarthrosis, chronic diseases of lungs and biliary
tracts. This preparation can be used independently as
well as in a mixture with other antiphlogistics (being
of both steroid and nonsteroid nature).
One of modifications of the chemotherapeutic anti-
phlogistic is a preparation containing, as an acting source,2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6
hydrochloride in an amount of 0.25 to 0.5 g, and a phar-
maceutical basic material.
A pharmaceutically acceptable filler for tablets is
used as a pharmaceutical basic material. This filler may
be sugar, milk sugar, starch, glucose, sodium hydrocarbonate,
sodium chloride, disubstituted calcium phosphate, kaolin,
dextrin, cacao, acetyl cellulose, methyl cellulose, poly-
vinyl alcohol, talc, calcium stearate, magnesium stearate,
stearic acid, gelatin solution~
A modification of the chemotherapeutic antiphlogistic
is a preparation containing, as an acting source, 2-(o-
carboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6
hydrochloride and a pharmaceutical basic material taken
in the following ratio (percent by weight):
2-(o-carboxyphenylamino)-6H-pyrimido
(2,1-b)-quinazolone-6 hydrochloride 5 to 10
pharmaceutical basic material 90 to 95
The pharmaceutical basic material can be in the
form of an ointment base, e.g. animal fats, fatty oils,
lanolin, wax, spermaceti, fatty acids, higher alcohols,
liquid paraf$in, cellulose
~J
ethers, polysilicone compounds, phgtosterols, bentonite cla~s.
Said ointments were used for external application in nonin-
~ectious burn lesions of skin regions.
Still another modification of the chemotherapeutic anti-
phlogistic is a preparation containing, as a pharmaceutical basic
material, a base for a pastel
The above specified preparation is expedient to be utiliæed
in stomatolo~y for treatment of various inflammatory diseases, par-
ticularly paradontosis. Clinical checkin~ has demonstrated the
efficiency of application of this preparation.
In addition, a modification of the chemotherape~tic anti-
phlogistic is a preparation containin~, as an acting source,
2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-~uinazolo~e-6
hydrochloride in an amount of 0.1 to 0.5 g, and a pharmaceutical
basic material.
~ he pharmaceutical basic material is a pharmaceutical fil-
ler ~or a suppository, e.~. cacao butter or a gelatinous-~lyceric
base.
D~AI~ED EXP~ANATION 0~ THE INV~ION
2-(o-carboxyphenylamino)-6H pyrimido(2,1-b)-qui~azolone-6
and i-ts derivatives were tested for acute toxicity.
Acute toxicity was determined in white mice (18 to 25 g),
rats (150 to 180 g), rabbits (2000 to 3000 g), and cats (2500
to 3200 g).
Acute toxicity of 2~(o-carboxyphenyla~ino)- 6H~pyrimido(2,1-
b)-quinazolone-6 and its derivatives was determined in intra-ab-
dominal and peroral administration; for cats in peroral admini-
stration. The state of the animals was observed ~or 7 days. ~he
..
statistical analysis of obtained data was carried out
in accordance with the method of Litchfield, Wilcockson
and Van der Waerden. The results are given in Table 1.
For the purpose of comparison, the same table shows
the data on acute toxicity of the prior art antiph-
logistics .
-- 8 --
12~ 17
. . . . . .
~ ~U~X ~
~ 0~.~. a ~OU- - - g
~ ~ ,
~ ~ ~ I S ~ o o o
a) ~ ~ ~ ~ I ~ ~ ~ a) o Ln u~ I ~1 ~ I I
o . .,, ,, ~ ~ o ~ .,1 ~ ~ ,~
1~ 1 N ~1 ~ :~,~2 Q~ tq rl
1 1.,.1 1~ 1
1: ~i ~ 'I 'I
,5~ U~ O~ O O ~ ~
Qlrl~ rl
a) E3 U ~ a) ~ 1 u
, I ,.~ 'b
1 ~ ~ O ~ I I ~ Y O
~ 0~ ~ ~ ~0~1 ~ G) O
.Y ~ ~ s~ o
I O ~ rl N :1 0
~ ~I E3 u ~
O ~ I I rl I O O
tn ~ ~ O ~ I R ~ I ~
~ ~ b ~ '~ o ~ I I I I I I
:~ o o~ ~ ~ k~
~, I, ~ a
~o
D ~ 1 R N O O O O O O O
_ o I `-,1
I ~ W ~
I I ~)
~0 0
Q ~ c
~ O o ~ ~ o n o O
C) r~ N r-l ~ ~ O
O ~ ~r~ ~
I ~
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0 ~ 0 ~rl H 0~,1 ~ H 0 ~rl P~ H 0 rl ~ ~
.__ _ .___ _ . _
o ~ ~ _ ~ ~ ~ R
LD50 means hereinafter 1/2 of a lethal dose.
8a -
~1 '
12~8~
Chronic toxicity of 2-(o-carboxyphenylamino)-6H-
pirimido(2,1-b)-quinazolone-6 and its derivatives
was determined in rats and guinea pigs. The above
substances were administered daily, once a day,
perorally through a gastric tube in a conditionally
therapeutic dose (100 mg/kg of mass) dissolved in
0.5 ml distilled water. Apricot gum, gum arabic,
gelatose, starch were used as an emulgator.
The results of investigations prove that
2-(o-carboxyphenylamino~-6H-pyrimido (2,1-b~-qui-
nalozone-6 and its derivatives, when administered
perorally in a selected dose (100 mg/kg), have not
exerted appreciable effect for 10 days on the compo-
sition of peripheric blood in experimental animals.
lS In the daily administration of said compound during
2 months, the results were obtained indicating the
fact that general analysis of blood, differential
blood count, and thrombocytes, which had been
determined in dynamics during the whole experiment
once a day, remained within the limits of physio-
logical variations for the given kind of animals.
This circumstance differentiates advantageously
2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-qui-
nazolone-6 and its derivatives from other nonsteroid
antiphlogistics which, when being administered for a
long time, adversely effect to a variable degree
the composition of peripheric blood in patients.
To reveal the effect of 2-(o-carboxyphenyl-
amino)-6H-pyrimido(2,1-b)-quinaæolone-6 and its
derivatives on the organism in prolonged adminis-
tration, the morphologic studies were conducted on
the internal organs of experimental animals
(rats), i.e. lungs, heart, liver, kidneys,
adrenal glands, mucous coats of stomach and
intestine.
_ g _
- ~2~2~L7
2-(o-carboxyphenylamino)-6H-pyrimido(2,1~b)-
quinazolone-6 or its derivatives were administered
daily, perorally through a gastric tube for 3 months
in the above specified dose. The animals were killed
after 5, 30, and 90 days. In total, during 3 months
the animals have received more than 3LD50. The tissues
were fixed in formol and Carnois liquid. Paraffin and
frozen sections were prepared. Histologic and histo-
chemical methods of investigation were used.
In the thorough morphologic study of organs of
animals which for a long time received 2-(o-carboxy-
phenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 and its
derivatives in a conditionally therapeutic dose, no
pathologic changes were noticed as against the norm.
Antl-inflarnmatory effect of 2-(o-carboxyphenyl-
A amino)-6~-pyrimido(2,1-b)~quinazolone-6 and its deri-
vatives was evaluated from anti-exudative and anti_
proliferative efficiency and from its influence on the
formation of necrotic processes within the inflammation
focus.
Anti-exudative effect of 2-(o-carboxyphenylamino)-
6H-pyrimido(2,1-b)-quinazolone-6 and its derivative was
studied using a model of foot edema in a rat, caused by
various phlogogenic stimuli (formalin, carrageenin,
ovalbumin, serotonin, trypsin, and hyaluronidase).
The growth of foot edema in the rat was registered
in dynamics after each hour from the moment of subplantar
administration of a stimulus during S hours. Percentage
of inhibition of the foot edema in the rat was calculated
from the following formula: V - V
percentage of inhibition = k V -~100,
where Vk is the volume of a control edematic foot minus
the initial volume of the same foot prior to
edema,
VO is the volume of the tested edematic foot minus
the initial volume of the same foot prior to
edema.
-- 10 --
17~
8~
The development of the edema in the formalin in-
flammation was characterized by a moderate growth o~
the edema, the maximum magnitude of its acuteness being
3 to 4 hours after subplantar administration o~ a
stimulus (2% solution of formalin, 0.1 ml to each foot).
By this time, a classical local inflammation developed
in the animals, said inflammation accompanied by the
formation of an edema, hyperemia, and considerable
painfulness. The inflammation of a foot is maintained
for 7 and more days, and after 3 to 4 days necrosises
are often formed in the place of injection of formalin.
Anti-inflammatory effect of 2-(o-carboxyphenyl-
amino)-6H-pyrimido-(2,1-b)-quinazolone-6 hydrochloride
is given in Table 2 as against that of the prior art
15 antiphlogistics~
Table 2
Dose, Way of Number Percen- Thera-
Preparation mg/kg Admin- of tage of peutic-
istra- tests inhibi- al
_ _ _ tion __ tion _dex
1 2 3 4 5 6
2-~o-carboxyphenyl- 5 Intra- 5 28 59.8
amino)-6H-pyrimido10 abdo- 5 47 59.8
(2,1-b)-quinazolone-49 minal 5 55 59.8
6 98 5 70 59.8
2-(o-carboxyphenyl- 5 Intra- 5 31 61.2
amino)-6H-pyrimido10 abdo- 5 50 51.2
(2,1-b)-quinazolone-49 minal 5 57 61.2
6 hydrochloride 98 5 71 61.2
Mephenamine acid-~-9 Intra- 5 22 1.5
(2,3-dimethylphenyl) 18 abdo- 5 24 1.5
anthranilic acid36 minal 5 31 1.5
72 5 33 1.5
Phenylbutazone-1,2-21 Intra- 5 17 2.8
diphenyl-4-butyl 42 abdo- 5 40 2.8
pyrasolidone-dion-82 minal 5 51 2.8
3,5
Sodium salicylate-65 Intra- 5 14 1.8
6-oxybenzoic acid,130 abdo- 5 24 1.8
sodium salt 260 minal 5 41 1.8
~ . _
-- 11 --
3Z~7
Therapeutical index is hereinafter determined as
LD50
E~ , where ED50 is a dose allowing the effect to
be achieved in 50% cases out of 100%.
The obtained results indicate that the development
of a formalin edema of a foot in the rat was the most
actively depressed by 2-(o-carboxyphenylamino)-6H-
pyrimido(2,1-b)-quinazolone-6, and by 2-to-carboxy-
phenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 hydro-
chloride. The advantages of 2-(o-carboxyphenylamino)-
6H-pyrimido(2,1-b)-quinazolone-6 and those of its
derivative are also confirmed by pharmacotherapeutic
width of effect (evaluated from therapeutical index).
Simultaneously with the inhibition of formalin
edema, 2-(o-carboxyphenylamino~-6H-pyrimido(2,1-b)
quinazolone-6 and its derivative decreased other
symptoms of inflammation, i.e. hyperemia and painful~
ness, and prevented subsequent formation of necrotic
foci at the location of injection of formalin, which
fact is almost noncharacteristic of mephenamine acid,
- 20 butadiene and sodium salicylate.
Similar results have been obtained for other deri-
vatives of 2-(o-carboxyphenylamino~-6H-pyrimido(2,1-b)-
quinazolone-6.
Taking into account that nonsteroid antiphlogistics
produce different influences on inflammatory edemas of
various genesis, the action of 2-(o-carboxyphenylamino)-
6H-pyrimido(2,1-b)-quinazolone-6 and its derivatives on
other types of edemas has been studied.
~2~ 17
A carrageenin edema was induced by subplantar
administration in rats of 0.1 ml 1% solution of
carrageenin (polysaccharide prepared from Iceland or
pearl moss).
In the control test, the edema grew quickly and
reached the maximum magnitude (201%) after 3 to 4 hours
following the injection of carxageenin. Table 3 gives
the data on the inflammatory action of 2-(o-carboxy-
phenylamino)-6H-pyrimido(2,1-b)-quinazolone-6, and
2-(o-carboxyphenylamino)-6H-pyrimido(2,l-b)-quinazolone-
6 hydrochloride. For the purpose of comparison, this
table also gives the data on the inflammatory action of
the prior art antiphlogistics.
Table 3
.. . ...... _ .
Dose,. Way of Num- Percen- Thera-
Preparation mg/kg admin~ ber tage of peutic-
istra- of inhibi- al
tion tests tion index
1 2 3 4 5 6
_
2-(o-carboxyphenyl- 25 Intra- 5 11 9.8
amino)-6H-pyrimido 49 abdo~ 5 25
(2,1-b)-quinazolone-98 minal 5 54
2-(o-carboxyphenyl- 25 Intra- 5 12 10.9
amino)-6H-pyrimido 49 abdo- 5 26
(2,1-b)-quinazolone- 98 minal 5 55
6 hydrochloride
- 13 -
82~1 7
- 1 2 3 _ 4 5 _6
Mephenamine acid-N-(2,3- 25 Intra- 5 33 148
dimethyl phenyl) anthra-50 abdomin- 5
nilic acid 100 al 5 50
Phenylbutazone-1,2-diphe- 21 Intra- 5 27 3.5
nyl-4-butyl pyxasolidine- 42 abdomin- 5 44
dion-3,5 84 al 5 51
Sodium salicylate-6 oxy- 65 Intra- 5 14 5.6
benzoic acid, sodium 90 abdomin- 5 32
salt ~30 al 5 56
It follows fxom the above Table that 2-(o-carboxyphenylamino)-
6H-pyrimido(2,1-b)-quinazolone-6 and its derivative possess a
higher antiinflammatory activity.
An ovalbumin edema was induced by subplantax administration
in rats of egg albumin (0.1 ml per ioot). The edema developed very
intensely, i.e. reached the maximum magnitude (191~) as soon as after
1 hour following the injection of ovalbumin, and completely disap-
peared by the end o~ the da~.
~ he preparations under studies were administered in the given
~nvestigations in a dose corresponding to 1/10~D50 for the rats in
the intra-abdominal administration.
Antiexudative e~fect o~ 2-(o-carboxyphenylamino)-6H-pyrimido
(2,1-b)-quinasolone-6 and its derivatives with the given type of
edema corresponds to the level of mephenamine acid and sodium
sa~icylate. At the moment o~ ma2imum deuelopment of an ovalbumin ede-
ma (1 to 2 hours after injection o~ ovalbumin), its mani~estation
was inhibited by 27 to 30%. During subsequent hours, the antiin- -
~lammatory effect o-f 2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-
quinazolone-6 and its derivatives of mephenamine acid and sodium
.
.
salicylate increased With the gi~en kind of aseptic inflammation,
phenylbutazone did not produce antiedematic effect.
Antiproliferative pxoperties of 2-(o-carboxyphen~lamino)-6H-
pyrimido(2,1-b)-quinazolone-6 and its derivatives have been studied
as against other nonsteroid preparations in the experimeIlts ~lith
"cotton granuloma".
The term "cotton granuloma" means hereinafter the formation of
a granular-fibrous tissue a:round cotton balls implanted into expe-
rimental animals.
'~he influence o~ these nonsteroid antiinflammatory preparations
on theformation of a "cotton granuloma" i5 shown in ~able 4.
~able 4
.. . .. . _ _ . . _ _ .. . v .. . .. . _
Dose, Number Percen- ~herapeuti-
Preparation mg/kg o~ tage of cal index
tests inhibi-
tion
2~(o-~carbo~;yphenylamino)- 48 5 17 20.5
6H-pyrimido(2,1-b) quina- 95 9 25
zolone-6 190 7 ~50
2-(o-ca~boxyphen;ylamino) ~ 48 5 18 22.3
6E~-p~yrimido(2,1-b)-quina-95 9 24
2010ne-6 hydrochloride 190 7 52
Mephenamine acid N-(2,~- 13 9 33 7.43
dimethyl phenyl) anthra-52 7 42
nilic acid 78 5 52
Phenylbutazone-1,2-diphe- 18 10 6 8.27
nyl-4-butyl pyrasolidine 72 7
-dion-3,5 108 5 58
Sodium salicylate-6-oxy- 60 8 8 7~27
benzoic acid, sodium salt 80 20 20
160 36 ~36
2~0 52 52
,
15 -
2~
As can be seen from the above data, the most effective among
the given preparations were those of 2-(o-carboxyphenylamino)-6H-
pyrimido(~ b)-quinazolone~6, 2-(o-carboxyphenylamino)-6H-pyrimido
(2,1-b)-quinazolone-6 hydrochloride, and mephenamine acid.
At the same time, pharmacotherapeutic ~idth of effect of 2-(o-
carboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 and its deriva-
tive 2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 hyd-
rochloride is three times that of mephenamine acid, sodium salicyl-
ate, and phenylbutazone. '~he inhibition of proliferative processes
of other derivative of 2-(o-carbox~phenylamino)-6H pyrimido(2,1-b)-
quinazolone-6 is at the level of inhibition o~ 2-(o-carboxyphenyl-
amino)6H-pyrimido(2,1-b)-quinazolone-6 hydrochloride.
The analgetic activity of 2-(o-carboxyphenylamino) 6H-pyrimido
(2,1-b)-quinazolone-6 and its derivativès ~as judged from the vari-
ation of the threshold o~ pain sensitivity in the contact-heat sti-
mulation~
Table 5 gives the data on ~he analgetic activity of 2-(o-carbo-
xyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 ~nd its derivative
2-(o-carboxyphenylamino)~6~-pyrimido(2,1-b)-quinazolone-6 hydro-
chloride in the contact-heat stimulation. For the purpose o~ com-
parison, this table also gives the data on the analgetic activity
of the prior art antiphlogistics.
Table 5
. .
Dose, Number Increase in Therapeu-
Preparationmg/kg of latent pe- tical index
tests riod of pai~
reaction in
_ mice, %
-
_ 1 2_~~ 4 5
2-(o-carboxyphenylaminoj- 52 7 30 10.8
6H-pyrimido(2,1-b)-~uina- 10510 51
zolone-6 1578 60
` --16 -
.
.
~Z~8Z~7
_ 1 2 _ 3 _ 4 5
2-(o-carboxyphenyla~ino)- 52 7 31 11.0
6H-pyrimido(2,1-b)-quina- 105 10 52
zolone-6 hydI~ochloride 157 8 62
~Iephenamine acid-N-(2,3-di- 3.5 9 18 8.3
methyl phenyl) anthranilic7.0 8 36
acid 15 9 43
Phenylbutazone-1,2-diphenyl- 25 6 8 4-7
4-butyl pyrasolidine-dion-~,550 7 43
100 9 92
Sodium salicylate-6-oxyben~ 32 8 28 5.9
zoic acid, sodium salt 65 8 38
130 7 59
,,
It follows from ~able 5 that in the contact-heat stimulation,
mephenamine acid possessed the most expressed analgetic effect. The
analgetic activity of 2 (o-carboxyphenylamino)-6H-pyrimido(2,1-b)
quinazolone 6 and its derivative is considerably lower in this kind
of stimu~ation than that of mephenamine acid and phenylbutazone,and
is higher than that of sodium salicylate. However, 2-(o-carboxy-
phenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 and its derivatives
have greatest width of analgetic activity. Similar res~lts ~lave
been obtained in other derivatives o~ 2-(o-carboxypheny~amino)-6H-
pyrimido(2,1-b)-quinazolone-6. Antipyretic e~fect of 2-(o-carboxy-
phenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 and its derivatives
has been investigated in rats suffering from pyrogena~ fever. ~axi-
mum decrease in the temperature (degrees) was determined. In all
the tests, 2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6
was used in a dose constituting 5Y0 of ~D50, while the other prepara-
tions were used in a dose constituting 70% of ~D50.
Table 6 gives the data of antipyretic effect of 2-(o-carboxy-
- - 17 -
.,, '. ~
~B~7
phenylamino)-6H-pyrimido(2,1-b)-quinazolone-6 and its derivative. ~or
the p~rpose of comparison, this table also gives the data on antipy
retic effect of the prior art antiphlogistics.
Table 6
.
Antipyretic effect
Preparation (maximum decrease in
t emperature ?, C
-
2-(o-carboxyphenylamino)-6H-pyrimido 1.
(2,1-b)-quinazolone-6
2-(o-carboxyphenylamino)-6H-pyrimido 1.4
(2,1-b)-quinazolone-6 hydrochloride
Indometacin 1-(para-chlorobenzoyl)5- 0O7
metoxy-2-methyl-indole-3-acetic acid
Bruphen-2-(para-isobutyl phenyl)-prQ- 1.3
pionic acid
~J.ephenamine acid-~-(2,3-dimethyl phe- 1
nyl) anthranilic acid
According to the obtained data, antipyretic activity of 2-(o-
carboxyphenylamino)-6H-pyrimido(~,1-b)-quinazolone-6 and its deriva-
tive is at the level of such preparations as bruphen and mephenami-
ne acid, and considerably exceeds that o~ indometacin.
Extensive clinical studies of the preparation made in the
form of table-ts containin~ 2-(o-carboxyphenylamino)-6H-pyrimido
(2,1-b)-quinazolone-6 hydrochloride ha~e been conducted. More than
400 patients of different agen were observed, suffering from active
rheumatism, rhe~matoid arthritis, Bekh~erev's disease, Reiterls
disease, deforming asthenoarthrosis, chronic diseases of l~ngs and
biliary tracts.
The preparation ~as used in a daily dose of from 1.5-3.0 to
,
.
.
17
5.0 g. The duration of the treatment course ~as from two weeks to
three months. Subjective improvement was observed by the 2nd-'Ith
day, while objective improvement was registered after 7 to 10 days
from the beginning of the treatment.
~ he chemotherapeutic preparation in the form of a paste ~as
applied in stomatology for the treatment of paradontosis.
~ he method of trea-tment ~itn the utilization of a paste con-
taining 2-(o-carboxyphenylamino-6H-pyrimido(2,1-b)-quinazolone-6
hydrochloride as an acting source consisted in the ~ollowing:
Pathologic tooth-gingival pockets were washed with a solu-
tion of antiseptics (nitrofurazone, rivanol) with subsequent intro-
duction of the inventive paste into said pockets. ~o prolong the
curative effect7 the introduced paste was covered with a hardena~le
bandage.
The course of treatment, depending on the passage and degree
of development of a dystrophic-inflammatory form of paradontosis,
included 3 to 10 sessions conducted dail~ or every other day.
~ he above specified method of treat~ent is simple and can be
conducted both in a hospital or under ambulatory conductions. 175
patients were subjected to the treatment o~ parandontosis with the
use of said paste, the treatment being success~ul in all the cases.
A positive effect was also o~tained in the case bf utiliza-
tion of said chemotherapeutical preparation having an ointment base
and a base for suppository.
The invention is further explained in terms of specific exam~
ples of embodiments thereof.
Example 1
Anthranilic acid in an amount of 27.4 g was dissolved in 200 ml
of 1h solution of sodium hydroxide. ~o thls solution was added
19
'
82~L~
2,4-dichloropyrimidine in an amount of 14.9 g,following
which the resulting mixture was heated with stirring to
a temperature of 100C. The reaction mass was held at
this temperature for 3 hours, cooled, and the formed
S precipitate of 2-(o-carboxyphenylamino)-6H-pyrimido(2,1-
b)-quinazolone-6 was filtered. Then the precipitate
thus obtained was purified by recrystallization from
dimethyl sulfoxide, acetic acid, or reprecipitated from
an alkali solution using an acid. The melting point of
the precipitate was 290C (with decomposition). The yield
of the end product was 75%.
Example 2
Anthranilic acid in an amount of 27.4 g was dissolved
in 200 ml of lh solution of sodium hydroxide. The result-
ing solution was heated to a temperature of 90C, and asolution of 14.9 g 2,4-dichloropyrimidine in 50 ml dimethyl
formamide was added thereto gently with stirring~ Follow-
ing this, the temperature was raised to 100C, and the
resulting mixture was held for 2 hours. A precipitate
thus formed of 2-(o-carboxyphenylamino)-6H-pyrimido-
(2,1-b)-quinazolone-6 was filtered after cooling and
treated similarly to the method described in Example 1.
Example 3
To a solution of 27.4 g anthranilic acid in 200 ml of
lh solution of sodium hydroxide heated to a temperature of
90C, was added a solution of 14.9 g 2,4-dichloropyrimidine
in 50 ml alcohol. The reaction mixture was stirred at a
temperature of 100C and held for 4 hours. Then the mix-
ture was treated as specified in Example 1.
Example 4
Anthranilic acid in an amount of 3.0 g was dissolved
in 300 ml
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;~ .
of O.lh solution of sodium hydroxide. To this solution
was added 2,4-dichLoropyrimidine in an amount of 1.5 g,
and the resulting mixture was heated to a temperature of
100C and held with stirring for 2 hours. Then 200 ml
of the solution were evaporated, a precipitate of a
sodium salt of 2-(o-carboxyphenylamino)-6H-pyrimido
(2,1-b)-quinazolone-6, which precipitated after cooling,
was filtered, and purified by recrystallization from
alcohol.
Example 5
2-(o-Carboxyphenylamino)-6H-pyrimido(2,1-b)-
quinazolone-6 in an amount of 3.32 g (Example 1) was
added to a solution of 0.4 g sodium hydroxide in 50 ml
absolute alcohol. The resulting mixture was left for
dissolution, following which a sodium salt of 2-(o-
carboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6
was separated by adding 200 ml ether to the solution,
and purified by recrystallization from alcohol.
Example 6
To a suspension of 3.32 g 2-(o-carboxyphenyl-
amino)-6H-pyrimido(2,1-b)-quinazolone-6 in 10 ml
alcohol was added with stirring 2-aminoethanol in an
amount of 0.65 g. First, the starting substances were
dissolved, following which a novel precipitate formed,
said precipitate being an ethanol ammonium salt of
2-(o-~arboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-
6, a crystalline substance soluble in water. The melt-
ing point of this substance was 255C (with decomposi-
tion). The yield of the end product was 80%.
Example 7
2-(o-carboxyphenylamino)-6H-pyrimido(2,1 b)-
quinazolone-6 in an amount of 3.32 g was mixed with 10
ml alcohol, and diethyl amine in an amount of 0O75 g
was added thereto. The resulting solution of diethyl
ammonium salt of 2-~o-carboxyphenylamino)-6H-pyrimido
-21-
(2,1-b)quinazolone-6 was treated as specified in Example 6. The
melting point of this substance was 270C (with decomposition).
The yield of the end product was 8270.
Example 8
Anthranilic acid in an amount of 27.5 g and 14.9 g 2,4-di-
chlorop~rimidine dissol~ed in 200 ml acetic acid were heated with
stirring to a temperat~re of 105C and held at this temperature
for 3 hours. A precipitate thus formed was filtered after cooling,
washed with alcohol and ether. The resulting substance was 2-(o-
carboxyphenylamino)-6H-pyrimido(2,1-b)-~uinazolone-6 hydrochloride,
a crystalline substance having the melting point of 85 to ~87C
(with decomposition). The yield of the end product was 80jo~
Example 9
2,4-dichloropyrimidine in an amount of 14.9 g and 30.2 g me-
thyl ether of anthranilic acid were dissolved in 100 ml butanol.
~he mixture was heated at a temperature of 120C and held for 4
ho~rs. ~ollowing this, the mixture was cooled, the ~ormed precipi-
tate was ~iltered, washed with acetone and then with ether. ~qethyl
ester of 2~(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-quinazolone-6
hydrochloride was recrystallized from methanol. ~he melting point
was of` 254 to 255C (with decomposition~. ~he yield of the end
product was 70~v~
Example 10
Ethyl ester of 2-(o-caxboxyphenylamino)-6H-pyrimido(2,1-b3-
quinazolone-6 hydrochloride was prepared from 14.9 g of 2,4-dichlo-
ropyrimidine and 33 g of ethyl ester of anthranilic acid using the
method specified in Example 9. ~he melting point was o~ 242 to
244C (with deco~po~ition). The yield o~ the end product was 67%.
.
~2()~32~!L7
Example 11
Hydrochloride of propyl ester of 2-(o-carboxyphenylamino)-
6H-pyrimido(2,1-b)~quinazolone-6 was prepared from 1409 g of di-
chloropyrimidine and 35.8 g of~propyl ester of anthranilic acid
similaxly to the method specified in ~xample 9. The melting point
was of 233 to 235C (with decomposition). The yield of the end pro
duct was 67%.
Example 12
Hydrochloride of isopropyl ester of 2-(o-carboxyphenylamino)-
6E-pyrimido(2,1-b)-quinazolone-6 was prepared similarly to the meth-
od specified in EXample 11. The melting point was of 241 to 242C
(with decomposition). The yield of the end product VJas 65~.
Example 13
Hydrochloride of butyl ester of 2 (o-carboxyphenylamino)-6H-
pyrimido(2,1~b)-quinazolone-6 was prepared from 14.9 g o~ 2,4-di-
chloropyrimidine and 38.6 g of butyl ester of anthranilic acid
using the method described above (~ample 9). The melting point was
of 243 to 245C (with decomposition). r~he yield of the end product
was 71~o~
Example 14
2,4-dichloropyrimidine in an amount of 7.45 g and 13.6 g of
o-aminobenzamide were dissolved in 50 ml of dimethyl formamide, and
the resulting solution was heated to a temperature of 100C. A~ter
15 minutes9 a precipitate of 2-(o-carboxyphe~ylamino)-6H-pyrimido
(2,1-b)-quinaæolone-6 began to form. Said mixture was held at a
temperature of 100C for one more hour, rollowing v~hich the reac-
tion mass was cooled to the room temperature, the precipitate was
filtere~, washed with dimethyl formamide, and then with ether. ~he
` ~æ~2~7
melting point was of 241 to ~42C (with decomposition). ~he yield
of the end product was 80i'o~
E~amp~e 15
Hydrochloride of 2-(o-methylcarbamide phe~ylamino)-6H-pyrimi-
do(2,1-b)-quinazolone-6 was prepared from 7.45 g of 2,4-dichloropy-
rimidine and 15.0 g of o-methyl aminobenzamide according to the
method specified in Example 14. The meltin~ point was of 252 to
253C (with decomposition)O The yield of the end product ~as Sio.
Example 16
Hydrochloride o~ 2-(o-phenylcarbamide phenylamino)-6H-pyri-
mido(2,1-b)-quinazolone-6 was prepared from 7.45 g of 294~dichloro-
pyrimidine and 21.2 g of phenyl amide of anthranilic acid similar-
ly to the method described in E~ample 14. ~he melting point was of
257C (with decomposition). The yield of the end product was 60~.
~xample 17
Hydrochloride of 2-(o-benzylcarbamide phenylamino)-6H-pyri-
mido(2,1-b)-quinazolone-6 was formed in the interaction between
7.45 g o~ 2,4-dichloropyrimidine and 22.6 g 0~ benzylamide of anthra-
nilic acid using the method specified in Example 14. ~he melting
point was of 2~ to 255C (with decomposition). ~he yield of the end
product was 76%.
Example 18
Hydrochloride of 2-(o-carboxyphenylamino)-6H-pyrimido(2,1-b)-
quinazolone-6 in an amount of 3.7 g was added to 50 ml of 0.2h solu-
tion of sodium hydroxide, agitated for 5 to 10 minutes, and ~iltered.
The precipitate left on the filter was washed with water u~til the
filtrate was free from chlorides. ~he melting point was of 290C
(with deoompositlon). ~he-yield of the end product was 95%.
While particular embodiments of the invention have been
shown and described, various modifications thereof wi~l be apparent
to those skilled in the art and therefore it is not intended that
the invention be li~ited to the disclosed e~bodiments or to the
details thereof and the departures may be made therefrom within
the spirit and scope of the invention as defined in the claims.
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