Note: Descriptions are shown in the official language in which they were submitted.
1 1 ~G~56
The invention relates to a process for the preparation of novel
pharmacologically valuable pyrimidyl-qu m azolines of the formula I
NH O
CH30 ~ N ~ ~ N l o (I)
and acid addition salts, thereof, where Rl and R2 denote hydrogen, aIkyl hav-
ing 1 to 6 C atoms, alkenyl having 2 to 6 C atoms, cycloaIkyl having 5 to 7
C atoms, phenyl or benzyl and R3 denotes hydrogen, alkyl having 1 to 6 C
atoms, alkenyl having 2 to 6 C atoms, phenyl, phenalkyl having 1 to 4 C
atoms in the aLkyl radical, halogen, nitro, amlno, alkylcarbonylamino having
1 to 6 C atoms in the alkyl radical, phenylcarbonylamino or formyl.
Compounds of the formula I in which Rl is the same as R~ are part-
icularly preferred, as are the acid addition salts of these compounds. m e
alkyl and aIkenyl groups represented by Rl, R2 and R3 can be straight-chain
or branched. In the case of the cycloalkyl radical represented by Rl and R2,
cyclopentyl and cyclohexyl are preferred. In the case of the phenalkyl
radical, benzyl and phenethyl are preferred. Halogen denotes, in particular,
chlorine, fluo~ine or bromune. In the case of the aIkylcarbonylamino
radical, aoe tylamino is preferred.
The following are examples of suitable alkyl and aIkenyl radicals:
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec.-butyl, tert.-butyl,
n-pPntyl, i-pentyl, n-hexyl, allyl and methallyl. ~Iethyl, e~hyl, n propyl,
n-butyl, brQmlne or amino are preferred for R3. Cbmpounds of the formula I
and/or acid addition salts thereof which æe very particularly preferred are
those in which R1 = R2 = methyl and R3 denotes hydrogen or nitro.
Provided that at least one of ~he substituents Rl, R2 or R3 de-
notes hydrogen, the compounds of the fon~ula I can also exist in oth~r
tautcmeric forms~
~ `
5 ~ ~
The ccmpounds of the formula I can be prepared by reacting a com~
pound of the formula II
NH2
CH8 ~ (II)
3 ~N ~LX
X in formula II denoting a mercapto radical or in particular a halogen atom,
preferably chlorine or bromine, with a oampound of the formula III
R ~N - R2
HN ~ ~ N ~ O ~III)
R , R2 and R3, in formula III, having the meaning already indicated. This
reaction is normally carried out in a sultable solvent or disparsing agent m
which the reactants are dissolved or suspended, respectively, such as, for
example, a hydrocarbon, for example benzene, toluene or xylene, a halogenated
hydrocarbon, such as, for exa~,ple, chloroform, methylene chloride, carbon
tetrachloride or chlorobenzene, an ether, such as, for e~ample, dioxane
diethyl ether or tetrahydrofuran, and also water, dime-thyl sulphoxide, di-
methylforn~mide, N-methylpyrrolido.ne or an alcohol, such as, for example,
methanol, ethanol, amyl alcohol, isoam~l alcohol and the like. m e reaction
can ke carried out at normal temFerature or at elevated temperature, for
exa~,ple between 20 and 160 C. Normally, the reaction temFerature is between
80 and 140 &. At a lower boiling point of the solvent or dispersant e~ployed,
the reactio~ takes place in a closed pressure vessel. In general, the molar
ratio between the cc~pounds of the formMlae II and III is 1 : 1. If equi-
mDlar quantities are employed, it is advisable, in the case of a compound II
wherein X denotes halogen being employed, to carry out the reaction in the
presence of at least equimolar quantities of an acid-binding agent, such as,
for example, potassium earbonate, sodium carbonate, triethylamine or the like.
Otherwlse, in the absence of acid-binding agents, the hydrohalides of the com-
pounds of the general formula I are usually obtained. If one of the com-
pounds II or III is employed in a m~lar excess, the excess of the compound
can act as an acid-binding agent.
The starting compound of the formula II can be prepared in accord-
ance with kncwn specifications (for example Soc. 1948, page 1764 or US Patent
Specification 3,511,836).
The starting compound of the formula II in which X = Cl is kncwn,
cGmpare German Offenlegungsschrift 1,620,138, column 7 and US Patent Speei-
fication 3,511,836, Example 1. me starting compounds of the formula II in
which X denotes a halogen atom other than chlorine, can be prepared corres-
pondingly. Thus, for example, 2,4-dihydroxy-6,7-dimethoxyquinazoline, which
is known, can be converted by means of phosphorus oxybromide into 2,4-dibromo- ~
6,7-dimethoxyquinazoline and the latter can be converted by means of ``
anhydrous ammonia into 2-bromD-4-amino-6,7-dimethoxyquinazoline.
me st~rting eompound of the formula II wherein X represents -SC~3
is also known, ef. Cerman Offenlegungsschrift 1,620,138, cols, 7 and 8.
m e starting ccmpaunds of the formula III can be obtaLned by reaet-
ing the pyrimidines of the formula V
R3 ~ N - R
Il I (V) ~ `
Hal I O
Rl
wherein Hal denotes a halogen atom, preferably ehlorine, with piperazine.
The reaction of a pyrimidine of the formula V with pipexazine is normally
carried out in a suitable solvent or dispersing agent in which the reactants
are dissolved or suspended, respectively, such as, for example, a hydrocarbon,
: ~ :
1 1 5Q~6~B
for example benzene, toluene or xylene, a halogenated hydro Æ bon, such as,
for example, chloroform, methylene chloride, carbon tetrachloride or chloro-
benzene, an ether, such as, for example, dioxane, diethyl ether or tetra-
hydrofuran, and also water, dimethyl sulphoxide, dimethylformamide, N-methyl-
pyrrolidone or an alcohol, such as, for example, methanol, ethanol, amyl
alcohol, isoamyl alcohol or the like. m e reaction can be carried out at
normal temperature or at elevated temperature, for example between 20 and
140C. Normally, the reaction temperature is between 80 and 120& . At a
lcwer boiling point of the solvent or dispersant used, the reaction takes
pla oe in a closed pressure vessel. m e molar ratio between the pyrimidine
of the formula V and piperazine can be 1:(1 to lO) and even more, if appro-
priate. If equimolar quantities are em loyed, it is advisable to carry out
the reaction in the presence of at least equimolar quantities of an acid-
binding agent, such as, for exa~,ple, potassium carbonate, sodium carbonate,
triethylamine or the like. In the absence of acid-binding agents, the
hydrohalides of the compcunds of the formula III are usually obtained.
Ccmpounds of the formula I can also be prepared by reacting
2-piperazinyl-4-am mo-6,7-dlmethoxyquinazoline of the formula rv
CH3O ~ N
CH3O ~ N ~ ~ (IV)
with a compound of the formula V. m e reaction of the quinazoline derivative
of the formula IV with a pyrimidine of the formula V is normally carried out
in a suitable solvent or dispersing a~ent in which the reactants are dis-
solved or suspanded, respectively, such as, for example, a hydrocarbon, for
exa~ple benzene, toluene or xylene, a halogenated hydrocarbon, such as, for
example, chloroform, methylene chloride, carbon tetrachloride or chloro-
banzene, an ether, such as, for example, dioxane, diethyl e-ther or te-tra-
-- 4 --
hydrofuran, and also water, dimethyl sulphoxide, dimethylformamide, N-methyl-
pyrrolidone or an alcohol, such as, for example, methanol, e~hanol, amyl
alcohol, isoamyl alcohol or the like. m e reaction can be carried out at
normal temperature or at elevated temperature, or example between 20 and
160C. Normally, tbe reaction temperature is between 80 and 140C. At a
lcwer boiling point of the solvent or dispersant used, the reaction takes
place in a closed pressure vessel.
In general, the molar ratio between the two compounds is 1:1. If
equimolar quantities are employed, it is advisable to carry out the reaction
in the presence of at least equimolar quantities of an acid-binding agent,
such as, for example, potassium c æbonate, sodium carbonate, triethylamine or
the like. Gtherwise, in the absence of acid~binding agents, tbe hy~ro-
halides of the compounds of the formula I are usually obtained. If a molar
excess of the formula IV is employed, this exoe ss can act as the acid-binding
agent.
The quinazoline of the formula IV can be prepared in accordance
with known specifications (for example Germ~n Offenlegungsschrift 1,620,138).
A further process for the preparation of the compounds, accordlng to the
invention, of the formula I in which R3 is not hydrogen, consists in using as
starting material the compounds of the formula Vl
NH2 o
C~301~NJ--N/~ ~J~
which are unsubstituted in the 5-position of the pyrimidine ring and introduc-
ing, in a manner which is in itself known, the substituents R into the .
5-position, for example introducing the formyl group by reacting VI with
acetic acid/formic anhydride, the nitro group by careful nitration with
nitric acid, the amino group and the aLkylcæbonylamino or phenylcarbonyl-
-- 5 --
1 1 5~G5~
amino group by reducing the nitro group and, if necessary, acylating with
acylating agents which introduce the aIkylcarbonyl or phenylcarbonyl, respect-
ively, and the bromine radical by careful bromination and so on.
Inorganic and organic acids are suitable for the formation of acid
addition salts with the ccmpounds of the formula I, for example hydrogen
chloride, hydrogen bromide, naphthalene-1,5-disulphonic acid, phosphoric acid,
nitric acid, sulphuric acid, oxalic acid, lactic acid, tartaric ad d, acetic
acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid,
diethylacetic acid, m~lonic acid, succinic acid, pimelic acid, fumaric acid,
maleic acid, malic acid, sulphamic acid, phenylpropionic acid, gluconic acid,
ascorbic acid, isonicotinic acid, methanesulphonic acid, p-toluenesulphonic
acid, citric acid or adipic acid. Pharmaceutically acceptable acid addition
salts are preferred. The acid addition salts can be obtained in the
customary manner by combining the ccmponents, appropriately in a suitable
diluent or dispersing agent. Examples of suitable diluents and dispersing
agents are ether, water, alcohols, hydrocarbons and the like.
The com~ounds, according to the invention, of the formu~a I and
their pharmaceutically acceptable acid addition salts possess valuable
pharmacological properties. In particular, they possess a strongly marked
action for the reduction of blood pressure and are therefore suitable for the
treatment of hypertension. Surprisingly, the campounds of the formula I are
markedly superior to the known ccmpounds of similar structure of US Patent
Specification 3,511,836. The quinazolyl-pyrimidines according to the inven-
tion can, therefore, be administered to humans on their own, in mixtures with
one another or in pharmaceutical formulations which contain, as the active
constituent, an effective dose of at least one quinazolyl-pyrimidine accord-
ing to the invention or an acid addition salt thereof together with customary
pharmaceutically acceptable excipients and additives. Examples of suitable
excipients are water, vegetable oils, starch, gelatine, lactose, magnesium
stearate, waxes, petroleum jelly and the like. Examples of additives which
-- 6 --
5 6
can be used are wetting agents, disintegrants, preservatives and the like.
The pharma oeutical formulations can be present in the form of, for example,
tablets, capsules, aqueous or oily solutions or suspensions, emulsions,
injectable aqueous or oily solutions or suspensions, dispersible powders or
aerosol mixtures. Besides the compcunds of the formula I, the pharmaceutical
formulations can also ~ontain, in addition, one or more other pharmaceutic-
ally active substances, for example tranquillisers, such as, for example,
luminal, meprobamate, chlorpromazine and benzodiazepine sedatives, such as, ~ -
for example, diazepam or chlordiazepoxide, vasodilators, such as, for example,
glycerol trinitrate, pentaerythritol tetranitrate and carbochrQmene, agents
which tonicise the heart, such as, for example, digitalis formulations,
~-blockers, such as, for example, propranolol, bronchodilators and sympathomi-
metic agents, such as, for example, isoprenaline, orciprenaline and the like
~-adrenergic block.~ng agents, such as, or example, phentolamine, and
diuretics, such as, or example, furosemide.
The preparation of the co~pounds of the formula I is illustrated by
means of the follcwing examples:
Example 1
2.9 g of 2-piperaz.inyl-4-am~lo-6,7-dimethoxyquinazoline are stirred
for 24 hours at room temperature in 50 ml of ethanol to which are added 4 g
of potassium carbonate and 2.2 g of 1,3-di~.ethyl-5-nitro-6-chloropyrimidine-
2,4-dione. The mixture is then filtered and the residue is digested in 20 ml
of 0.5 N aqueous hydrochloric acid.
The mixture is filtered again and the residue is suspended in ..
aqueous sodium carbonate solution and filtered off and recrystallised fron
aqueous dimethylformamide.
This gives 4-~4-amino-6,7-dimethoxyquinazolin-2-yl)-1-~1,3-dimethyl-
2,4-dioxo-5-nitro-pyrimidin-6-yl~-piperazine of the formula
.. .
~ 15~6~6
NH2
CH30 ~ ~ ~ 3
CH30 N ~ N 1 0
Melting point 300&.
Analysis: (C20H24N8&)
C H N 0
calculated: 50.8 5~1 23.7 20.3
found: 50.9 5.1 23.5 20.4
Yield: 87% of theory.
The 1,3-d~nethyl-5-nitro-6-chloropyrimidine-2,4-dione used as the
starting material can be prepared as follows:
17 g of 1,3-d~nethyl-6-chloropyrimidine-2,4-dione are added in por-
tions at 15C to 50 ml of concentrated sulphuric acid. The m~xture is then
cooled to 3 to 5C and 17 ml of fuming nitric acid are added dropwise slowly
to the mixture, while stirring. The solution is then poured onto ice, while
stirring, whereupon a semi-solid precipitate is deposited. The mixture is
extracted with methylene chloride, the organic phasa is dried with magnesium
sulphate and the solution is concentrated at 25C under a water-pump vacuum.
This leaves as rasidue an oil which solidifies after a short t~ne. The sub,
stance is racrystallised onca from ligroin/ethyl acetate. This givas 1,3-
dimethyl-5-nitro-6-chloropyrimidine-2,4-dione in a yield of 95% of theory. `;
Melting point: 92&.
The 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline used as the
starting material can be prepared as follows:
2.5 g of 2 chloro-4-amino-6,7-dime~hoxyquinazoline are added to a
solution of 5 g of anhydrous piperazine in 50 ml of dio~ane and the mixture
is then heated at 95& for 12 hours. It is then concentrated, the residue is
dissolved in water and the pH of the solution is adjus-ted -to 2.5 with hydro-
- 8 -
"~
1 1~6~56
chloric acid. The acid aqueous solution is extracted with methylene chloride
and the aqueous phase is then rendered aIkaline with sodium hydroxide solu-
tion. A precipitate is deposited and is recrystallised frcm ethanol. This
gives 2-piperazinyl-4-amino-6,7-di~thoxyquinazoline in a yield of 83% of
theory.
Melting point: 235 C.
Example 2
2.4 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline, together with
4.5 y of 1,3-~imethyl-6-piperazinylpyrimidine-2,4~io~e and 50 ml of ethanol
are heated in an autoclave for 8 hours at 130C. me mixture is then cooled
and concentrated under a water-pump vacuum. The residue is digested with
water and is then recrystallised from dimethylformamide. ~his gives 4-(4-
a~ino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-dioxo-pyrimidin-6-yl)-
piperazine.
NH O
3 ~ N ~ N - CH
C 3 ~ N ~ ~ ~ N 1 O
CH3
Melting point: 273C.
Analys~S: (C2oH25N7 4)
C H N o
calculated: 56.2 5.9 23.0 15.0
found: 56.0 6.0 23.0 14.7
Yield: 81% of theory.
The 1,3-dimethyl-6-piperazinylpyrimidine-2,4-dione used as the
starting material can be prepared as follows:
20 g of 1,3-di~ethyl-6-chloropyrimidine-2,4-dione are added to a
mlxture of 30 g of piperazine and 500 ml of toluene and the mixture is boiled
under reflux for 3 hours. It is then filtered and the filtrate is concen-
11~8~5~
trated under a water-pump vacuum. The residue which remains after concentra-
tion is recrystallised from ethyl acetate. This gives 1,3-dimethyl-6-
piperazinylpyrimidine-2,4-dione
~\N ~N ~0
CH3
in a yield of 75% of theory.
Melting point: 117 C.
E ~
5.2 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dibutyl-
2,4-dioxo-pyrimidin-6-yl)-piperazine
NH~ 0
3 ~ N ~ N - C4Hg
CH30 ~ ~ N ~ N 1 o
c4Hg
are dissolved in 20 ml of glacial acetic acid. A mixture of 1.7 g of bromlne
and 20 ml of glacial aoe tic acid is then added dropwise, while chilling, and
cooling with ice. me mixture is then stirred for a further 2 hours at room
te~perature. me product is then filtered off and recrystallised from
ethanol. This gives 1-(4-amino-6,7_dimethoxyquinazolLn-2-yl)-1-(1,3-dibutyl-
2,4-dioxo-5-brcmopyrimidin-6-yl)-piperazine hydrobromide
~ O
CH30 ~ N ~ ~ - C4H9
CH30 ~ ~ --"`N 0 . HBr
C~Hg
Melting point: above 300C, de ~ ~position.
~ 10 ~
'.~
656
Analysis: (C26H37Br2N704)
C H Br N O
calculated: 46.5 5.5 23.8 14.6 9.5
found: 46.7 5.3 23.5 14.7 9.8
Yield: 61% of theory.
Example 4
5.6 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dicyclo-
hexyl-2,4-dioxo-pyrlmidin-6-yl)-piperazine
NH2 o
3 ~ ~ ~ ~ - C6Hll
C6 11 ;
are added to a mixture of 24 ml of acetic anhydride and 12 ml of formic acid
and the mix*ure is stirred for 5 hours at 80C. It is then concentrated
under a water-pump vacuum. me residue is treated wlth 0.5 N aqueous sodium
hydroxide solution and is filtered off and recrystallised from dimethylform~
amide. This gives 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dihexyl- ,
2,4-dioxo-5-formyl-pyrimidin-6-yl)-piperazine
NH2 0
CH3 ~ ~ ~ N - C6H
3 ~ I O
6 11
Melting point: 314 C, decomposition.
Analysis: (C31H41N705)
C H N O
calculated: 62.96.9 16.6 13.5
found: 62.8 6.6 16.5 13.2
Yield: 81% of theory.
5 B
Example 5
4.7 g of 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-
2,4-dioxo-5-nitro~yrimidin-6-yl)-piperazine
NEI2
CH30 ~ N 2 ~ N - CH3
3 ~ N ~ ~ ~ N 1 0
C 3
are suspended in 300 ml of etha~ol, 0.4 g of 10% strength Pd-on-charcoal are
added and the mixture is hydrogenated by shaking with hydrogen for 20 hours
at room temperature and normal pressure. m e mixture is then filtered, the
residue is immediately digested under hot conditions with dimethylformamide
and the catalyst is filtered off while the dimethylformamide solution is
still hot. The dimethylformamide solution is then con oentrated under a water-
pump vacuum and the residue is recrystallised from aqu~ous dimethylformamide.
This gives 4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-1-(1,3-dimethyl-2,4-
dioxs-5-amino-pyrimidin-6-yl)-piperazine
NH2 0
C~I30 ~ M ~ ~ - CH
C1130~NJ_ ~ Nlo
C 3
~lelting point: 327C.
Analysis: (C20H26N7 4)
C H N 0
calculated: 54.3 5.9 25.3 14.5
found: 54.0 6.1 25~0 14~7
Yield: 78% of theory.
m e following substances were prepared analogously to Examples 1 to
5:
- 12 -
`~.
6 ~ ~
NH 0
CH3~ ~ 2N R3 ~ N - R2
CH30 ~ N ~ ~ ~ N ~ o
Rl :
Rl = R2 R3 p~L~t.
.
3 3 317C
/ 3
C~I3 -C4H9 325 C
H H 297C
-CH3 -N~I-C0 C2H5 314C
-C3H7 -CH2 ~ 331C
CH -CH-CH2- ~ 319 &
n 6 13 322C
-c~3 -C~2-CH-CH2 328 C
H 316 C
-CH2 ~ H 324 &
-C2H5 H 311C
-C4Hg H 309C
cyclohexyl H 323 &
-C2H5 N02 318C
-C3H7 CH0 331 C
-C3H7 H 314C
Rl R2 R3Meltin
. .
CH3 C2H5 H 303 C
H C2H5 H 298 C
- 13 -
~;~
1 ~56~6
The pharmacological efficacy of the compounds of the invention was tested as
follows:
1. Measurement of Blood Pressure in normotonic anesthetlzed Rats
Male IV~NOV~S rats (300 - 340 g) of the SIV 50 phylum were anesthetized
by administering 66 mg/kg of ~-chloralose (1.1 percent solution, 0.6 ml/
100 g) and 20 mg/kg of aprobarbital into the tail vein. The trachea was
cannulated in order to facilitate the spontaneous respiration. The blood
pressure was measured conventionally by a surgical method via a PE tube
inserted into the right carotid artery. A three way cock per~itted the
use of this PE tube for the intraarterial administration of the test sub-
stan oes, a volume of 0.1 ml having been injected in each case. By rinsing
with 0.9 percent NaCl the test substan oe s were also transferred towards
the central nervous system via the vertebral artery before distribution
in the general circulation started.
The maximum systolic and diastolic lowering of the blood pressure as well
as the maximIm change of the cardiac rate were evaluated quantitatively.
The time passed between the beginning of the change and the reaching of
the initial value was regarded as the duration of efficacy. The values
given in the following Table 1 were obtained:
- 14 -
5 ~
T a b 1 e
Formulation BPs - BPd CR
and Dose ~ mmHg min Q ni~Ig ~ s/mln
(mg~kg) x x x
0.01 - 30 36 - 27 + 5
Prazosin
_ - 20 60 . .... .. _ . . .
BPS = systoLic blood pressure
BPd = diastolic blood pressure
DE = duration of efficacy
CR = cardiac rate
x = mean value
* = 4-(4-amino-6,7-dimethaxychinazoline-2-yl)-1-(1,3-dimethyl-2,4-dioxo-
5-nitro-pyrimidine-6-yl)-piperazine
Prazosin = camparison formulation according to US Patent 3,511,836
2. Effect of Blood Pressure in normotonic anesthetized Dogs :
The investigations were carried out on mongrel dogs of both sexes under
pentobarb.ital anesthesia (30 - 40 mg/kg administered intravenously).
Ar~ificial respiration of the animals was effected by means of a Bird Mark
7 respirator. me final expiratory carbon dioxide content (measured with ~;
a Uras machine was between 4.5 and 5% by volum~.
In order to ensure a constant depth of the narcosis -the animals we~e given
a continuous intravenous infusion of pentobarbital = 4 m~/kg/6 ml/h during
the entire experiment.
The systolic and diastolic blood pressure were measured peripherally in
the femoral artery via a Statham pressure recorder.
- 15 -
5 0~
The parameters were continuously recorded on a Brush Mark 6 direct re-
corder via preamplifiers.
The test substances were injected intravenously in the form of boluses.
The values obtamed are disclosed in the following Table 2:
T a b 1 e 2
Formulation BPS BPd
and Dose ~ m~g min Q mmH~ ~ s/mln
(m~/kg) x ~ x x _
0.1 - 40 60 - 42 - 17
Prazosin
0.5 - 15 10 - 10 0
(m e abbreviations are identical with those used in Table 1)
The pharmaceutical formulations can contain, for example, 0.1 to 50 mg, pre~
ferably 0.5 to 40 m~, per dose of the active substance. Per kg of body
weight, for example, 0.002 to 1 mg, preferably 0.02 to 0.5 mg of the active
substance can ke administered daily.
Example 6
Pills can ke prepared according to ~he following formulation:
4-(4-amino-6,7-dimetho~ychinazoline-2-yl)-1-(1,3_dimethyl-2,4-dioxo-5-nitro-
pyrimidine-6-yl)-piperazine 2 m~
Co m starch 100 m~
Lactose 60 m~
Sec. calcium phosphate 30 m~
Soluble starch 2 mg
~agnesium stearate 2 m~
Colloidal silicic acid 4 mg
~ . .
200 m~
- 16 -
~ ,..
,
~ . . :
1 15~
Example 7
Tablets can be prepared according to the following formulation:
4-(4-amino-6,7-dimethoxychinazoline-2-yl)-1-(1,3-dimethyl-2,4-dioxo-
pyrimidine-6-yl)-pipera2ine 2 mg
Lactose 60 mg
Cornstarch 30 ~g ~`
Soluble starch 4 mg
Magnesium stearate 4 m~
100
~.~
