Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
-- 1 --
RAN 4044/50-2
The present invention relates to novel quinazoline
5 compounds in D-Form or as racemates or the formula
~ ~ J ~
wherein Rl is bromo and R2 is methyl or chloro,
or Rl is methoxy and R2 is chloro,
their tautomers and salts thereof with mineral acids,
to a process for the manufacture thereof and pharmaceu-
tical preparations containing same.
Hence, the group of compoundsof formula I comprises
7-bromo-1,5-dihydro-3,6-dimethyl-imidazo[2,1-b]quinazolin-
2(3H)-one, 7-bromo-6-chloro-1,5-dihydro-3-methyl-imidazo
[2,1-b]quinazolin-2(3H)-one and 6-chloro-1,5-dihydro-7-
26 methoxy-3-methyl-imidazo[2,1-b]quinazolin-2(3H)-one.
Among the compounds of formula I there are preferred
D,L-7-bromo-1,5-dihydro-3,6-dimethyl~imidazo[2,1-
b]quinazolin-2(3H)-one and, particularly,
D-7-bromo-1,5-dihydro-3,6-dimethyl-imidazo[2,1-b]qui-
nazolin-2(3H)-one, their tautomers and salts thereof with
mineral acids.
The compounds of formula I can exist in various tau-
3S tomeric forms. The invention lS therefore not restrlcted
to compounds of formula I reproduced hereinbefore, but
also includes the tautomers, for example those of the
Mé/24.4.~30
31~3~
-- 2
formulae
. I i ,
10 and
H
~ ~ N
R1 ~ N ~
I CH3
wherein Rl and R2 have the significance given
earlier.
The compounds of formula I and their tautomers (e.g.
of formulae Ia and Ib) can exist in the form of racemates
25 or in optically active form, the racemaies and the com-
pounds in D-form forming part of the present invention.
Examples of mineral acid salt~ of the sompounds provi-
ded by the present invention are physiologically compa-
30 tible salts,such as hydrochlorides, hydrobromides, sul-
phates and phosphates.
According to the process provided by the present
invention, the compounds of formula I, tautomQrs and salts
35 thereof are manufactured bv
a) brominating a compound of the formula
~3~
-- 3 --
~CH=3
R21
wherein R21 is methyl or chloro,
ln the 7-position, or,
b) reacting a compound of the formula
,~,,NH2
11 111
R1 ~ CH2NH~HCooR3
R2 CH3
wherein Rl and R2 are as above and R3 is lower alkyl,
with cyanogen bromide, or
~5
c) treating a compound of the formula
R~ H CooR3 IV
2 CH3
R
3~
~L31~3~
, . . .
-- 4
wherein R -R are as above,
with ammonia and
isolating an obtained compound of formula I or a
tautomer thereof in that form or in form of a salt with
a mineral acid.
The bromination of a compound of formula II in 7-
position can conveniently be performed in acetic acid by
10 about room temperature.
The reaction of a compound of formula III with cya-
nogen bromide according to embodiment (b) of the process
is conveniently carried out while warming in a solvent,
15 such as a lower alkanol, e.g. ethanol.
The treatment Or a compound of formula IV with am-
monia according to embodiment (c) of the process is con-
veniently carried out while warming in a solvent such as
a lower alkanol, e.g. ethanol, and water.
The starting materials of formulae II, III and IV
belong to a generically ~nown class of compounds and
can be prepared in analogy to known compounds, e.g.
according to the methods given in the nublished german
patent application 2832138.
The compounds of formula I in D-form or as racemates,
their tautomers and the physiologically compatible salts
thereof with mineral acids inhibit the aggregation of
blood platelets and can therefore be used for the pro-
phylax~s of thromboses.
The compounds of formula I in D-form or as racemates,
~5 their tautomers and the physiologically compatible salts
thereof with mineral acids can be used as medicaments.
For example, they can be used in the form of pharmaceu-
~ 5 --
tical p.eparations which contain them in association witha compatible pharmaceutical carrier material. Such carrier
material can be an organic or inorganic inert carrier
material suitable for enteral or parenteral administration
such as, for example, water, gelatin, gum arabic, lactose,
starch, magnesium stearate, talc, vegetable oils, poly-
alkyleneglycols, petroleum jelly, and the like. The phar-
maceutical preparations can be made up in solid form, for
example, as tablets, dragees, supnositories or capsules,
or in a liquid form, for example, as s~lutions, suspen-
sions or emulsions. The pharmaceutical preparations may be
sterilized and/or may contain adluvants, such as pre-
serving, stabilizing, wetting or emulsifying agents, salts
for varying the osmotic pressure or buffers. The pharma-
ceutical preparations can also contain still other thera-
peutically valuable substances. The compounds privided by
the invention are preferably administered orally. A daily
dosage of O.5 ~g/kg to 30 mg/kg may be administered to
warm-blooded animals orally and a d~ily dosage of
o.o5 mg/kg to 10 mg/kg may be administered parenterally.
The aggregation-inhibiting activity was demonstrated
according to the aggregometer method of BORN [Nature 194,
927 (1962J] and MICHAL and BORN [Nature 231, 220 ~1971)].
The maximum aggregation velocity was taken as the test
parameter and the effective concentration (~C50) was as-
certained from dosage-activity curves.
Human platelet enriched plasma was obtained ~y cen-
trifugation from citrated venous blood. The tests wereperformed with suspensions of the test substance in O,9%
NaCl or with a solution of the test substance in DMSO.
A. Test substance suspended in O,9% NaCl:
o,l8 ml OL citrated plasma was treated with 10 ~1
of an aqueous suspension of the test substance and the
3~
-- 6
mixture was incubated at 37C for 10 minutes, whereupon
the aggregation was initiated by the addition of 10 ~1
of collagen-fibril suspension.
6 B. Test substance dissolved in DMS0:
0,5 ml of citrated plasma was treated with 5 ~1 of
test solution and the mixture was incubated at 37C for
10 minutes, whereupon the aggregation was initiated by
10 the addition of 5 ~1 of collagen-fibril suspension or of
5 ~1 of a 10 4 M adenosine diphosphate (ADP) solution.
Plasma incubated with DMS0 serYed as the control.
Platelet enriched rabbit plasma was obtalned by
15 centrifugation frpm arterial blood tre~ted wi~h citrate
(9 mM). 0,6 ml of plasma was treated with 5 ~1 of test
solution and the mixture was incubated at 37C for 10
minutes, whereupon the a~gregation was initiated by the
addition of 5 ~1 of collagen-fibril suspension or of 5 ul
20 of a 10-4 adenosine diphosphate (ADP) solution. Plasma
incubated wlth dimethylsulfoxide served as the control.
The results are gi~ren tn the Table hereinafter.
~5
~L~33~
..,
-- 7
N
~ o CO U~ " O
~ U7
r~ O O ~: O
E ~
~1 o ............ ~
Q ~ ~ In ~ o o
C '1 W 1 ~ ~ ~
r~
E _
;C
~ ~ o ,
o ~ Ll~ ~ In o
O C~ X O O O
_ ~, _ ...
C ,1 o ~ CO
o ~ ~ ~n
,, e
~ ~ ¢ ~ ~ o ~ O
O Q
~ V
~ ~ ~ o'~ CO ~
a) p ~o ~ o ~ o ,
a~ _ _ _ .
~ .
Q
a) .~ o
~1 ~ Q ~ ~ N
,4 oo I I i O
E~ ,-1 ` ` ` ,a .,,
1~ ~ ) 6
~:1 O O O E3
a~ N N N ~-1 a) ~1 a)
O (5 (~ >1 ~
~1 ~ J
~:: E E E ~ O a~ O
.,, .,, .,, .,, ~ ~ e ~
~ ' ' a~ ' e ~ ' s
a~ I o I o
o ~ o
C E e ~ 6 Q h SS ~
,~ rl S rl h
t)
l I I O I o 5:1 c E ~
C ~u~ h ~ ~ -I OI O
O ` ` ~ `
o "~
~: I I S I ,C m ~o ::C
O o o ~ 7 Z:
L~ ~--
O U~ ~ ~ I N:~ ~ ~.
~_) ~ >1 0 ~ O ~ O O I .C I
~ ~ I S I ~ I ~ O
U~ ~ 0 -1 ~'~ U~ O
s:: o m o
Ul 11~ --!tl ~ h~ -- C) N ~ N .
a
E~ ~ ~ D C I ~ ~1
~ 1 0 -1 ;~
0 -1 0 ~ O rl 0 3 s~ ::5 1: rl
1~ ~iE ~ ~ t~ O ~ O o~
O O O o O O o~ ~ ~1
~ N h N ~ N ~ Q Q ~) a~
m m ~m I ~ I ~ Q~
.. - r ~ I~ r ~ O :~
I
1~3~;3~
-- 8
Example 1
A solution of 52 g of bromide in 200 ml of ~lacial
acetic acid is added to 64 g of D-1,5-dihydro-3,6-dimethyl-
imidazo[2,1-b]quinazolin-2(3H)-one in 400 ml of glacial
acetic acid. After 2 hours, the reaction mixture is fil-
tered and the precipitate (97.4 g, m.p. 250-255C) is
washed with glacial acetic acid, dried and recrystallized
from methanol and diethylether to yield 64.8 g of D-7-bro-
10 mo-1,5-dihydro-3,6-dimethyl-imidazo~2,1-b]quinazolin-2(3H)-
one hydrobromide, m.p. 277-279C (decomposition), [a]25 =
-21,3 (c = 1%, DMSO).
25 g of this salt are pulverized and susper.ded in
15 2 1 of water. The suspension is stirred 5 hours, then
filtered, the residue washed with water and dried. There
are obtained 17,25 g of D-7-bromo-1,5-dihydro-3,6-dimethyl-
imidazo[2,1-b]quinazolin-2(3H)-one, m.p. above 300C,
[a]D = -38C (in trifluoroacetic acid).
The starting material can be prepared as follows:
A solution of 302 g of 3-nitro-o xylene in 200 ml
of carbon tetrachloride is added under stirring to 391 g
25 of N-bromosuccinimide and 10 g of dibenzoylperoxide in
1000 ml carbon tetrachloride. The mix~ure is heated to
reflux for 3-4 hours, then cooled to room temperature and
filtered. The filtrate is evaporated to dryness, yielding
480 g of a mixture of the isomers, 2-methyl-6-nitrobenzyl-
30 bromide and 2-methyl-3-nitrobenæylbromide.
A solution of 900 ml of triethylamine in 1000 ml of
ethanol is added dropwise to a solution of 380 g of D-
alanine ethyl ester hydrochloride in 1500 ml of ethanol.
~5 The mixture is warmed to 70C and treated with the above-
mentioned 480 g of bromides in 1000 ml of ethanol. The
mixture is heated to reflux for 3-4 hours, evaporated to
dryness, treated with 1500 ml of water and extracted with
methylene chlo~ide. The extracts are washed with water,
dried and evaporated, yielding 534 g of a mixture of the
isomers, N-(2-methyl-6-nitrobenæyl)-D-alanine ethyl ester
5 and N-(2-methyl-3-nitrobenzyl)-D-alanine ethyl ester.
A solution of this mixture in 1000 ml of ethanol is
hydrogenated over 50 g of a palladium/carbon catalyst.
After the catalyst is filtered off, 186 g of cyanogen
~0 bromide are added to the filtrate, containing N-(2-amino-
6-methylbenzyl)- and N-(2-amino-3-methylbenzyl)-D-alanine
ethyl ester. The mixture is stirred for 48 hours, then made
alkaline by addition of 300 ml of concentrated ammonium
hydroxide and stirred for 1-2 hours. The precipita~e is
15 filtered, washed with water and drled, yielding 54.4 g
of D-1,5-dihydro-3,6-dimethylimidazoC2,1-b]quinazolin-
2(3H)-one.
Example 2
In analogy to the procedure of Example 1, there are
obtained:
D,L-7-bromo-1,5-dihydro-3,6-dimethyl-imidazo[2,1-b]
quinazolin-2(3H)-one, m.p. 305C, (decomposition), m.p.
25 o~ the hydrobromide 272-276C, m.p. of the hydrochloride
above 300C;
D-7-bromo-6-chloro-1,5-dihydro-3-methyl-imidazo[2,1-
b]quinazolin-2(3H!one, m.p. of the hydrochloride 290C
(decomposition).
N-(2-Amino-G-chloro-5-methoxybenzyl)-D-alanine ethyl
ester, prepared from 2-chloro-3-meihoxy-6-nitrotoluene via
35 2-chloro-3-methoxy-6-nitrobenzylbromide and N-(6-chloro-
5-methoxy-2-nitrobenzyl)-D-alanine ethyl ester, is con-
verted, in anaJogy to the procedure of Example 1 for the
,,
"
,
~ 3~ 3~
. .
-- 10 --
conversion o~ N-(2-amino-6-methylbenzyl)-D-alanine ethyl
ester to D-1,5 dihydro-3,6-dimethyl-imidazo[2,1-b]quina-
zolin-2(3H)-one, to D-6 chloro 1,5 dihydro-7-methoxy-3-
methyl-imidazo~2,1-b]chinazolin-2(3H)-one, m.p. o~ the
hydrochloride 280C.
ExamPle 4
Tablets containing the following ingredients were
10 manu~actured in the usual manner:
D-7-bromo-1,5-dihydro-3,6-dimethyl-
imidazo[2,1-b]quinazolin-2(3~)-
one hydrochloride 185.0 mg
Lactose 15~0 mg
Maize starch 37.5 mg
Water-soluble poly~inylpyrrolidone 10.0 mg
Magnesium stearate 2.5 m~
Total weight per tablet 250.0 mg
Example 5
Interlocking gelatin capsules containing the follo-
wing ingredients were manu~actured in the usual manner:
26
D-7-bromo-1,5-dihydro-3,6-dimethyl-
imidazo[2,1-dJquinazolin-2(3H)-
one hydrochloride 200.0 mg
Water-soluble polyvinylpyrrolidone 2.0 mg
Maize starch 43.0 mg
Talc 4.5 mg
Magnesium stearate 0.5 mg
Total weight per capsule 250.0 mg
3~
11 --
Example 5
An injection solution containing the following inqre-
dients was manufactured in the usual manner:
D-7-bromo-1,5-dihydro-3,6-dimethyl-
imidazo~2,1-b]quinazolin-2(3H)-one
hydrochloride 114.0 mg
Glycerinformal 2.4 ml
Water . 4.0 ml
