2-DISUBSTITUTED PHENYL-3,4-DIHYDRO-4-OXO-QUINAZOLINE DERIVATIVES AND PROCESS FOR THEIR PREPARATION

PROCEDE D'OBTENTION DE DERIVES DE PHENYL-3,4-DIHYDRO- 4-OXO-QUINAZOLINE DISUBSTITUE EN 2

English Abstract

ABSTRACT
Novel 2-disubstituted phenyl-3,4-dihydro-4-oxo-quinazolines
and methods for their preparation, the quinazolines exhibiting high
levels of antiallergic activity and are therefore useful in the preparation
and treatment of bronchial asthma, allergic rhinitis, hay fever, urticaria
and dermatosis.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula (I)
<IMG> (I)
the process comprising:
a) cyclizing a compound of formula (II)
<IMG>
(II)
wherein R is esterified or free carboxy; R1 is a) C1-C4 alkyl, optionally
substituted by C1-C2 alkoxy; or b) C3-C4 alkenyl; R2 is hydrogen, methyl or
C1-C2 alkoxy; R3 is a') hydrogen; b') C1-C6 alkoxy, optionally substituted
by C1-C2 alkoxy; c') C2-C4 alkyl; or d') C3-C4 alkenyloxy, wherein one of R2
and R3 is hydrogen and the other is different from hydrogen and wherein, when
R1 is methyl and R2 is hydrogen, R3 is different from unsubstituted methoxy;
or a salt thereof; or
b) oxidizing a compound of formula (III)
<IMG> (III)
22

wherein R is esterified or free carboxy; R1 is a) C1-C4 alkyl, optionally
substituted by C1-C2 alkoxy; or b) C3-C4 alkonyl; R2 is hydrogen, methyl or
C1-C2 alkoxy; R3 is a') hydrogen; b') C1-C6 alkoxy, optionally substituted
by C1-C2 alkoxy; c') C2-C4 alkyl; or d') C3-C4 alkenyloxy, wherein one of R2
and R3 is hydrogen and the other is different from hydrogen and wherein, when
R1 is methyl and R2 is hydrogen, R3 is different from unsubstituted methoxy;
or a salt thereof; and, if desired, converting the compound of formula (I)
into a pharmaceutically acceptable salt.
2. A compound of the formula (I)
(I)
<IMG>
wherein R is esterified or free carboxy; R1 is a) C1-C4 alkyl, optionally sub-
stituted by C1-C2 alkoxy; or b) C3-C4 alkenyl; R2 is hydrogen, methyl or C1-C2
alkoxy; R3 is a') hydrogen; b') C1-C6 alkoxy, optionally substituted by C1-C2
alkoxy; c') C2-C4 alkyl; or d') C3-C4 alkenyloxy, wherein one of R2 and R3
is hydrogen and the other is different from hydrogen and wherein, when R1 is
methyl and R2 is hydrogen, R3 is different from unsubstituted methoxy; and
the pharmaceutically acceptable salts thereof whenever prepared by the process
according to claim 1 or by an obvious chemical equivalent thereof.
3. A process for the preparation of a compound of the formula (I)
<IMG> (I)
23

the process comprising:
a) cyclizing a compound of formula (II)
<IMG> (II)
wherein R is a free carboxy group, a 2-(N,N-diethylamino)-ethoxy-carbonyl
group, a 2-(N,N-dimetllylamino)-ethoxy-carbonyl group, a 2-(1-pyrrolidinyl)-
ethoxy-carbonyl group or a salified carboxy group, R1 is C1-C4 alkyl, R2 is
C1-C2 alkoxy and R3 is hydrogen or a salt thereof; or
b) oxidizing a compound of formula (III)
(III)
<IMG>
wherein R is a free carboxy group, a 2-(N,N-diethylamino)-ethoxy-carbonyl
group, a 2-(N,N-dimethylamino)-ethoxy-carbonyl group, a 2-(1-pyrrolidinyl)-
ethoxy-carbonyl group or a salified carboxy group, R1 is C1-C4 alkyl, R2 is
C1-C2 alkoxy and R3 is hydrogen or a salt thereof; and, is desired converting
the compound of formula (I) into a pharmaceutically acceptable salt.
4. A compound of the formula (I) according to claim 2 wherein R is
a free carboxy group, a 2-(N,N-diethylamino)-ethoxy-carbonyl group, a 2-(N,N-
dimethylamino)-ethoxy-carbonyl group, a 2-(1-pyrrolidinyl)-ethoxy-carbonyl
group or a salified carboxy group, R1 is C1-C4 alkyl, R2 is C1-C2 alkoxy and
R3 is hydrogen, whenever prepared by the process according to claim 3 or by
an obvious chemical equivalent thereof.
24

5. A process according to claim 3 wherein R1 is C1-C2 alkyl.
6. A compound of the formula (I) according to claim 2 wherein R1 is
C1-C2 alkyl whenever prepared by the process according to claim 5 or by an
obvious chemical equivalent thereof.
7. A process according to claim 3 wherein R2 is methoxy.
8. A compound of the formula (I) according to claim 2 wherein R2 is
methoxy whenever prepared by the process according to claim 7 or by an
obvious chemical equivalent thereof.
9. A process according to claim 1a) which comprises cyclizing 4-(2',
3'-dimethoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-(2',3'-
dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
10. A process according to claim 1b) which comprises oxidizing 6-
carbomethoxy-2-(2',3-dimethoxyphenyl)-1,2,3,4-tetrahydro-4-oxo-quinazoline
to give 6-carboxy-2-(2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
11. 6-Carboxy-2-(2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline
and the pharmaceutically acceptable esters and salts thereof, whenever
prepared by the process of claim 9 or 10 or by an obvious chemical equiv-
alent thereof.
12. A process according to claim 1a) which comprises cyclizing 4-(2'-
ethoxy-3'-methoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-
2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
13. A process according to claim 1b) which comprises oxidizing 6-
carbomethoxy-2-(2'-ethoxy-3'-methoxy-phenyl)-1,2,3,4-tetrahydro-4-oxo-
quinazoline to give 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-
dihydro-4-oxo-quinazoline.

14. 6-Carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 12 or 13 or by an obvious chemical
equivalent thereof.
15. A process according to claim 1a) which comprises cyclizing 4-(2'-
isopropoxy-3'-methoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-
(2'-isopropoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
16. 6-Carboxy-2-(2'-isopropoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 15 or by an obvious chemical
equivalent thereof.
17. A process according to claim 1a) which comprises cyclizing 4-(2'-
butoxy-3'-methoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-(2'-
butoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
18. 6-Carboxy-2-(2'-butoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 17 or by an obvious chemical
equivalent thereof.
19. A process according to claim 1a) which comprises cyclizing 4-(2',
3'-diethoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-(2',3'-di-
ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
20. A process according to claim 1b) which comprises oxidizing 6-
carbomethoxy-2-(2',3'-diethoxy-phenyl)-1,2,3,4-tetrahydro-4-oxo-quinazoline
to give 6-carboxy-2-(2',3'-diethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
21. 6-Carboxy-2-(2',3'-diethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline
and the pharmaceutically acceptable esters and salts thereof, whenever
prepared by the process of claim 19 or 20 or by an obvious chemical
equivalent thereof.
26

22. A process according to claim 1a) which comprises cyclizing 2-(2'-
ethoxy-3'-methyl-benzoylamino)-5-carbomethoxybenzamide to give the hydrolysed
product, 6-carboxy-2-(2'ethoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazo-
line.
23. A process according to claim 1b) which comprises oxidizing 6-
carbomethoxy-2-(2'-ethoxy-3'-methyl phenyl)-1,2,3,4-tetrahydro-4-oxo-
quinazoline to give 6-carboxy-2-(2'-ethoxy-3'-methyl-phenyl)-3,4-dihydro-
4-oxo-quinazoline.
24. 6-Carboxy-2-(2'-ethoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 22 or 23 or by an obvious chemical
equivalent thereof.
25. A process according to claim 1a) which comprises cyclizing 4-(2'-
ethoxy-5'-methoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-(2'-
ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
26. A process according to claim 1b) which comprises oxidizing 6-
carbomethoxy-2-(2'-ethoxy-5'-methoxy-phenyl)-1,2,3,4-tetrahydro-4-oxo-
quinazoline to give 6-carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-
4-oxo-quinazoline.
27. 6-Carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 25 or 26 or by an obvious chemical
equivalent thereof.
28. A process according to claim 1a) which comprises cyclizing 2-(2'-
ethoxy-5'-propoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-(2'-
ethoxy-5'-propoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
27

29. 6-Carboxy-2-(2'-ethoxy-5'-propoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 28 or by an obvious chemical
equivalent thereof.
30. A process according to claim la) which comprises cyclizing 4-
(2'-methoxy-5'-ethoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-
(2'-methoxy-5'-ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
31. 6-Carboxy-2-(2'-methoxy-5'-ethoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 30 or by an obvious chemical
equivalent thereof.
32. A process according to claim 1a) which comprises cyclizing 4-
(2'methoxy-5'-allyloxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-
(2'-methoxy-5'-allyloxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
33. 6-Carboxy-2-(2'-methoxy-5'-allyloxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 32 or by an obvious chemical
equivalent thereof.
34. A process according to claim 1a) which comprises cyclizing 2-(2'-
ethoxy-5'-isopropoxy-benzoylamino)-isophthalamic acid to give 6-carboxy-2-
(2-ethoxy-5'-isopropoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
35. 6-Carboxy-2-(2'-ethoxy-5'-isopropoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharamaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 34 or by an obvious chemical
equivalent thereof.
36. A process according to claim 1a) which comprises cyclizing 4-(2'-
ethoxy-5'-ethyl-benzoylamino)-isophthalamic acid to give 6-carboxy-2-(2'-
28

ethoxy-5'-ethyl-phenyl)-3,4-dihydro-4-oxo-quinazoline.
37. A process according to claim 1b) which comprises oxidizing 6-
carbomethoxy-2-(2'-ethoxy-5'-ethyl-phenyl)-1,2,3,4-tetrahydro-4-oxo-
quinazoline to give 6-carboxy-2-(2'-ethoxy-5'-ethyl)-3,4-dihydro-
4-oxo-quinazoline.
38. 6-Carboxy-2-(2'-ethoxy-5'-ethyl-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 36 or 37 or by an obvious chemical
equivalent thereof.
39. A process according to claim 11 which further comprises esteri-
fication with 2-(N,N-diethylamino)-ethanol to give 6-[2-(N;N-diethylamino)-
ethoxy-carbony] -2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazo-
line.
40. 6-[2-N,N-diethylamino)-ethoxy-carbonyl]-2-(2'-ethoxy-3'-methoxy-
phenyl)-3,4-dihydro-4-oxo-quinazoline and the pharmaceutically acceptable
salts thereof, whenever prepared by the process of claim 39 or by an
obvious chemical equivalent thereof.
41. A process according to claim 12 or 13 which further comprises esteri-
fication with 2-(N,N-dimethylamino)-ethanol to give 6-[2-(N,N-dimethylamino)-
ethoxy-carbonyl] -2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazo-
line.
42. 6-[2-(N,N-dimethylamino)-ethoxy-carbony]-2-(2'-ethoxy-3'-methoxy-
phenyl)-3,4-dihydro-4-oxo-quinazoline and the pharmaceutically acceptable
salts thereof, whenever prepared by the process of claim 41 or by an obvious
chemical equivalent thereof.
43. A process according to claim 12 or 13 which further comprises
esterification with 2-(1-pyrrolidinyl)-ethanol to give 6-[2-(1-pyrrolidinyl)-
ethoxy-carbonyl]-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
29

44. 6-[2-(1-pyrrolidinyl-ethoxy-carbonyl]-2-(2'-ethoxy-3'-methoxy-
phenyl-3,4-dihydro-4-oxo-quinazoline and the pharmaccutically acceptable
salts thereof, whenever prepared by the process of claim 43 or by an
obvious chemical equivalent thereof.
45. A process according to claim 1a) which comprises cyclizing 4-(2'-
isopropoxy-5'-methoxy-benzoylamino)-isophthalic acid to give 6-carboxy-2-(2'-
isopropoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
46. 6-Carboxy-2-(2'-isopropoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-
quinazoline and the pharmaceutically acceptable esters and salts thereof,
whenever prepared by the process of claim 45 or by an obvious chemical equiv-
alent thereof.
47. A process according to claim 1a) which comprises cyclizing 4-(2',
5'-diethoxy-benzoylamino)-isophthalic acid to give 6-carboxy-2-(2',5'-di-
ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
48. 6-Carboxy-2-(2',5'-diethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline
and the pharmaceutically acceptable esters and salts thereof, whenever pre-
pared by the process of claim 47 or by an obvious chemical equivalent
thereof.

Description

~3~
The present invention relates to 2-disubsti~uted phenyl-3,4-dihydro-
4-oxo-quinazoline derivatives, to a process for th0ir preparation and to
pharmaceutical compositions containing them. The present invention p~ovides
compounds of the following formula ~I)
4 11 3
R ~ ~
N ~ ~ R2 ~I)
8 1 6' ~ 4'
R3,
wherein
R is esterified or free carboxy;
Rl is a) Cl-C4 alkyl, optionally substitu~ed by Cl-C2 alkoxy;
or
b) C3-C~ alkenyl;
R2 is hydrogen, methyl or Cl-C2 alkoxy;
R3 is a') hydrogen;
b) Cl-C6 alkoxy, optionally substituted by Cl-C2 alkoxy;
c~ C2-C4 alkyl; or
d~ C3-C4 alkenyloxy;
wherein one of R2 and R3 is hydrogen and the other is different from hydrogen
and wherein, when Rl is methyl and R2 is hydrogen, R3 is different from un-
substituted methoxy; and the pharmaceutically acceptable salts thereof.
It is to be noted that the above definition of the compounds of the
invention includes all the possible isomers and stereoisomers as well as
their mix~ures.
The alkyl~ alkenyl, alkoxy and alkenyloxy groups may be branched or
straight chain.
When R is an esterified carboxy group, it is preferably a C2-C12

carbalkoxy group, in particular a C2-C7 carbalkoxy group, which may be unsub-
stituted or substituted by a -N group, wherein each of R4 and R5 is in-
dependently hydrogen or Cl-CI~ alkyl5, preferably Cl-C2 alkyl, or Rl, and R5,
taken together with the nitrogen atom, form a N-pyrrolidinyl, piperidino, or
morpholino radical.
When R3 is C2-C4 alkyl, it is preferably e-thyl; when R3 is Cl-C6
alkoxy, it is preferably Cl-C3 alkoxy.
When R3 is C3-C4 alkenyloxy, it is preferably allyloxy. R is pre-
ferably a free carboxy group or a 2-(N,N-diethylamino)-ethoxy-carbonyl group
or a 2-~N,N-dimethylamino)-ethoxy-carbonyl group or a 2-(1-pyrrolidinyl)-
ethoxy-carbonyl group or a salified carboxy group.
Particularly preferred compounds of the invention are those of for-
mula (I) wherein R is a free carboxy group, a 2-(N,N-diethylamino)-ethoxy-
carbonyl group, a 2-(N,N-dimethylamino)-ethoxy-carbonyl group, a 2-(1-
pyrrolidinyl)-ethoxy-carbonyl group or a salified carboxy group, Rl is Cl-C4
alkyl, preferably Cl-C2 alkyl, R2 is Cl-C2 alkoxy, preferably methoxy, and R3
is hydrogen.
Examples of pharmaceutically acceptable salts are in particular
those either with inorganic bases, such as sodium, potassium, calcium and
aluminium hydroxides, or with organic bases, such as, lysine, triethanol-
amine, triethylamine, dibenzylamine, procaine, diethanolamine, N,N'-dibenzyl~
ethylenediam;ne, N-methyl-N-benzylamine, N,N-di-(2-ethyl-hexyl)-amine, N-
ethylpiperidine, N-ethylmorpholine, piperidine, 2-(N,N-diethylamino)-ethyl-
amine, ~-phenethylamine, N-benzyl-~-phenethylamine, N-benzyl-N,N-dimethyl-
amine and the other acceptable organic amines. Also the salts with inorganic
acids, e.g. hydrochloric, hydrobromic and sulphuric acids as well as those
with organic acids, e.g. citric, tartaric, maleic, fumaric, malic, methane-
sulphQnic and ethanesulphoni~c acids are included in the present invention.
Preferred salts~ are the sodrum and potass~ium salts of the compounds of for-
mula (I) uherein R is a free carboxy group, as well as the hydrochlorides ofthe basic esters, e.g. the 2-(N,N-diethylamino)-ethyl and 2-(N,N-dimethyl-
amino)-ethyl esters.
-- 2 --

Examples of particularly preferred compounds of the invention are:
6-carboxy-2~2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-~2'-i.sopropoxy-3'-methoxy-phenyl)-3,4-di.hydro-4-oxo-quinazoline;
6-carboxy-2-(2'~butoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2',3'-diethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'ethoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-ethoxy-5'-propoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-methoxy-5'-ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-methoxy-5'-allyloxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'--ethoxy-5'-isopropoxy-phenyl)-3,4-dihydro-4-oxo-quillazoline;
6-carboxy-2-(2'-ethoxy-5'-ethyl-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6- L-(N,N-diethylamino)-ethoxy-carbon ~ -2-(2'-ethoxy-3'-methoxy-phenl)-3,4-
-dihydro-4-oxo-quinazoline;
6- ~ (N,N-dimethylamino)-ethoxy-carbon ~ -2-(2~thoxy-3'-methoxy-phenyl)-3,4-
-dihydro-4-oxo-quinazoline;
6- ~-(1-pyrrolidinyl)-ethoxy-carbonyl¦-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-
-dihydro-4-oxo,~quinazoline, as well as the pharmaceutically acceptable salts
thereof, in particular, the sodium salts and the hydrochlorides of the basic
esters (in particular of those with 2-(N,N-diethylamino)-ethanol, 2-(N,N-dime-
thylamino~ethanolJ 2-(1-pyrrolidinyl~ethanol and the esters, in particular the
ethyl, isopropyl, t-butyl, hexyl esters.
The compounds of the invention are prepared by a process comprising:
a) cyclizing a compound of formula (II)
Q
R ~ C 'NH2 ORl
N~ -C0 ~ R2 (II)
R3
-- 3 --

wherein
R, Rl, R2, R3 are as defined above, or a salt thereof; or
b~ oxidizing a compound of formula (III~
o
R ~ NH OR
l~ N ~ R2
H
R3
wherein
R, Rl, R2, R3 are as defined above, or a sal~ thereof; and, if desired, con-
verting a compound of formula (I~ into another compound of formula (I~ by
known methods and/or, if desired, converting a compound of formula (I~ into
a pharmaceutically acceptable salt and/or, if desired, converting a salt into
a free compound and/or, if desired, resolving a mixture of isomers into the
single isomers.
The cyclization of the compounds of formula (II~ may be carried out,
e.g., at a temperature ranging from room temperature to about 200C, by treat-
ment with a basis such as, for example, ammonium, sodium or potassium hydroxide,
either in the absence of solvents or in the presence of a solvent such as, for
example, tetrahydrofuran, dioxane, dimethylformamide and their mixtures.
Alternatively, the cyclization of the compounds of formula (II~ may
be carried out by treatment with a dehydrating agent such as, for example,
acetic anhydride, PC13, POC13, polyphosphoric acid, dicyclohexylcarbodiimide,
either in the absence of solvents or in the presence of a solvent, such as,
for example, benzene, toluene, xylene, pyridine, tetrahydrofuran, dioxane, ace-
tic acid, dimethylformamide, at a temperature ranging from about 0C to about
200C. The oxidation of the compounds of formula (III~ may be carried out,
for example, with potassium permanganate in acetone or with chromium trioxide
in acetic acid at a temperature ranging from about 0C to about 30C.
As stated above, a compound of formula ~I) may be converted into

~21~8
another compound of formula (I~ by known methods. For example, a compound of
formula ~I), wherein R is an esterified carboxy group, may be converted into
a compound of formula (I), wherein R is carboxy, by basic hydrolysis, using,
e.g., sodium or potassium hydroxide, in a solvent such as water or a lower
aliphatic alcohol, and operating at a temperature ranging from the room tem-
perature to about 150C; the same reaction may be carried out by treatment
with lithium bromide in dimethylformamide at a temperature higher than 50C.
A compound of formula ~I) wherein R is carboxy, may be converted in-
to a compound of formula (I) wherein R is an esterified carboxy group, e.g.,
a carbalkoxy group, by esterification, for example, by reaction of the alka-
line salt of the acid with the suitable alkyl halide, in an inert solvent
such as acetone, dioxane, dime~hylformamide, h~xamethylphosphorotriamide at
a temperature ranging from about 0C to about 100C.
Also the optional salification of a compound of formula (I) as well
as the conversion of a salt into the free compound and the resolution of a
mixture of isomers into the single isomers may be effected by conventional
methods.
The compounds of formula (II) may be prepared, for example:
(a') by reaction of a compound of formula (IV)
R ~ ~ ORI (IV)
R3
wherein R, Rl, R2 and R3 are as defined above, with ammonium hydroxide; this
reaction is preferably performed at a temperature ranging from the room tem-
perature to 200C, either in the absence of solvents or in an inert organic
solvent such as lower aliphatic alcohols, dioxane and dimethylformamide;
(b') by reaction of a compound of formula (V)

R 11
\~ C ~ (V)
~ NH2
wherein R is as defined above, with a compound of formula (VI)
ORl
ZOC ~__ R2
IJ ~(.VI )
R3
wherein Rl, R2 and R3 are as defined above and Z is chlorine or bromine; this
reaction is preferably performed a~ a temperature ranging from the room tem-
perature to 150C, using a basis such as, for example, sodium bicarbonate,
sodium carbonate, pyridine, triethylamine as acid acceptor, operating either
in the presence of a solvent such as, e.g., benzene, toluene, xylene, pyridine,
dioxane, dimethylformamide or in the absence of solvents.
The compounds of formula (III) may be prepared, for example, by
reaction of the compounds of formula (V) with an aldehyde of formula (VII)
ORl
OHC ~ R2 (VII)
R3
wherein Rl, R2 and R3 are as defined above, in an inert solvent such as, for
example, benzene, tolueneJ xylene, dioxane, e~hanol, dimethoxyethane, bis-
(2-methoxyethyl)ether, dimethylformamide and in the presence of a basic or
acid catalyst such as piperidine, hydrochloric acid, sulphuric acid, p-toluene-
sulphonic acid, at a temperature ranging from the room temperature to about
150C.
The compounds of formula (IV) may be in turn prepared, for example,
30 by heating a compound of formula (VIII)
- 6 -

~9;~3L~13
COOH
R ~ NH-CO ~ R2 (VIII~
R3
wherein R, Rl, R2 and R3 are as defined above, in acetic anhydri~e at a tem-
perature varying between the room temperature and the reflux temperature.
The compounds of formula (VIII) may be prepared for example by
reaction of a compound of formula (IX)
R ~ COOR6
(IX)
~ NH2
wherein R is as defined above and R6 is hydrogen or alkyl, in particular Cl-
C4 alkyl, with a compound of for~ula (VI), at a temperature varying between
room temperature and 150C, either in the presence of a solvent such as
benzene, toluene, dioxane, pyridine or in the absence of solvents, using a
basis such as sodium bicarbonate, sodium carbonate, pyridine, triethylamine,
as acid acceptor, and by subsequent basic hydrolysis of the ester group, i.e.,
when R6 is alkyl, wi~h sodium or potassium hydroxide in a solvent such as
water, lower aliphatic alcohols, in particular ethanol, dioxane and their mix-
tures at a temperature ranging from 10C to 100C.
The compounds of formula (V) may be prepared by known methods, for
example, by reduction of the corresponding nitro-derivatives or by reaction of
a compound of formula (X)
R ~ C0~OI (X~
N 5
H
wherein R is as defined above, with ammonium hydroxide, either in the absence

~z~
of solvents or in the presence of organic solvents such as methanol, ethanol,
dioxane, dimethylformamide, tetrahydrofuran~ at a temperature ranging from
-30C to 200C.
The compounds of formula (VI) are known compounds and they may be
prepared by conventional methods.
The compounds of formula ~X~ may be in turn prepared from a compound
of formula (IX), wherein R6 is hydrogen, by one of the following methods:
(a") by reaction with phosgene at room temperature in an acidic aqueous medium;
(b") by reaction with ethyl chloroformate, at a temperature ranging from 50C
to 120C, either in the absence or in the presence of sol~ents such as,
dioxane, benzene, toluene, xylene, to obtain the corresponding N-carbe-
thoxy derivative, and by subsequent cyclization, which may be carried out
by using an excess of ethyl chloroformate or with acetyl chloride or with
PBr3, at a temperature ranging from 50C to 150C.
The compounds of formula (IX) are known compounds and may be prepared
by known methods, for example, by reduction, in a conventional manner, of the
corresponding nitro-derivatives.
Also the compounds of formula (VII) are known compounds. The com-
pounds of the invention possess anti-allergic activity, as is shown by the
fact that they are active in the passive cutaneous anaphylaxis (PCA) test in
rats, according to Goose Y. and Blair A.M.Y.N. (Immunology, 1969, 16:749).
They can be therefore used in prevention and treatment of bronchial
asthma, allergic rhinitis, hay fever, urticaria and dermatosis.
An important peculiarity of the compounds of the invention is that
they exhibit high levels of antiallergic activity also when orally administer-
ed, as is shown in the following Table, where the potency ratio of a number
of compounds of the invention, reported with respect to the compounds 6-car-
boxy-2-(2'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline (K 11695) and 6-car-
boxy-2-~2'-methoxy-5'-methyl-phenyl)-3~4-dihydro-4-oxo-quinazoline (K 11963),
which compounds are two active quinazoline derivatives among those described in
- 8 ~

~O~Z~
German Offenlegungsschrift No. P26 54 215-4-
To the antiallergic activity of the compound k 11695 the convention-
al value 1 was given.
In ~he following Table the compounds of the invention are identified
by the codes:
K 13261 : 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3~4-dihydro-4-oxo-quinazo-
line;
K 13323 : 6-carboxy-2-~2'-methoxy-5'-allyloxy-phenyl)-3J4-dihydro-4-oxo-quina-
zoline;
K 11944 : 6-carboxy-2-(2~thoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazo-
line;
K i3300 : 6-carboxy-2-(2',3l-dimethoxy-pheny1}3,4-dihydro-4-oxo-quinazoline;
13251 : 6-carboxy-2-(2'-ethoxy-5'-isopropoxy-phenyl)-3,4-dihydro-4-oxo-
-quinazoline;
K 13330 : 5-carboxy-2-(2'-methoxy-5'-ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazo-
line;
K 13336: 6-carboxy-2-(2',3'-diethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
K 11966 : 6-carboxy-2-(2'-ethoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazo-
line;
K 13349 : 6- ~ (N,N-diethylaminoethoxy)carbony~ -2-~2'-ethoxy-3'-methoxy-
-phenyl)-3,4-dihydro-4-oxo-quinazoline.

T ~A B L E
_ _ ~
Compound Potency ratio Fiducial limits
for P = 0.95
. _ _ ,
K 11695 1
K 11963 1.91 I.10 - 3.37
K 13261 38.90 26.44 - 58.20
K 13323 10.16 6.90 - 15.06
K 11944 13.54 9.25 - 20.51
K 13300 5.70 3.58 - 9.23
K 13251 5.28 3.36 - 8.42
K 13330 8.04 4.30 - 15.72
K 13336 6.66 3.57 - 12.89
K 11966 4.25 2.75 - 6.73
K 13349 51.76 33.48 - 82.32
- 10 -

:~J921~llS
The antiallergic activity was determined by the inhibition of the
IgE-mediated PCA according to Goose J. and Blair A.M.J.N. tloc. cit.~ using
homocytotropic antibodies raised in rats following the method of Mota I., Im-
munology, 7, 681, (1964).
The tested compounds were administered per os 15 minutes before the
administration of the antigen: at least 6 rats were used for each dose.
The potency ratios were calculated according to the method of
Finney, D.J. ~1952), Statistical Method in Biological Assay, C. Griffin, London,
page 118.
Seven days indicative acute toxicity after oral administration was
assessed for the compounds of the invention. For example, the following LD50
values were obtained:
K 13261 : LD50 ~ 400 mg/kg in rats;
K 11944 : LD50 > 800 mg/kg in rats;
~13300 : LD50 > 800 mg/kg in mice;
K 11966 : LD50~ 800 mg/kg in mice-
The codes K 13261, K 11944, K 13300 and K 11966 were used to identify
the compounds of the invention as specified above.
The compounds of the invention may be administered in conventional
manner, for instance, orally and parenterally at a daily dosage preferably of
0.5 to 15 mg/kg~ or by inhalation, preferably at a daily dosage of 0.5 to
100 mg, preferably 0.5 to 25 mg, or by topical application.
The nature of the pharmaceutical compositions containing the com-
pou~sof this invention in association with pharmaceutically acceptable car-
riers or diluents will, of course, depend upon the desired mode of adminis*ra-
tion.
The compositions may be formulated in the conventional manner with
the usual ingredients. For example, the compounds of the invention may be
administered in the form of aqueous or oily solutions or suspensions, aerosols,
as well as powders, tablets, pills, gelatine capsules, syrups, or creams, or

Z~B
lotions for topical use.
Thuss for oral administration, the pharmaceutical compositions con-
taining the compounds of this invention, are preferably tablets, pills or ge-
latine capsules which contain the active substance together with diluents,
such as, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellu-
lose; lubricants, for instance, silica, talc, stearic acid, magnesium or cal-
cium stearate, and/or polyethylene glycols; or they may also contain binders,
such as, for example, starches, gela~ine, methylcellulose, carboxymethylcel-
lulose, gum-arabic, tragacanth, polyvinylpyrrolidone, disintegrating agents,
such as, for instance, starches, alginic acid, alginates, sodium starch gly-
colate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as,
for instance, lecithin, polisorbates, laurylsulphates; and, in generalJ non-
toxic and pharmacologically inactive substances used in pharmaceutical for-
mulations. Said pharmaceutical preparations may be manufactured in known
manner~ for example, by means of mixing, granulating, tabletting, sugar-coat-
ing, or film-coating processes.
For the treatment of allergic asthma, the compounds of the invention
are also administered by inhalation. For such use, suitable compositions may
comprise a suspension or solution of the active ingredient, preferably in the
form of a salt, such as the sodium salt, in water, for administration by means
of a conventional nebulizer. Alternatively, the compositions may comprise a
suspension or a solution of the active ingredient in a conventional liquified
propellant, such as, dichlorodifluoromethane or dichlorotetrafluoroethane to
be administered from a pressurized container, i.e., an aerosol dispenser.
When the medicament is not soluble in the propellant, it may be necessary to
add a co-solvent, such as, ethanol, dipropylene glycol, isopropyl myristate,
and/or a surface-active agent to the composition, in order to suspend the me-
dicament in the propellant medium and such surface-active agents may be any
of those commonly used for this purpose, such as non-ionic surface-active
agents, e.g., lecithin.

~2~1~
The compounds of the invention may also be administered in the form
of powders by means of a suitable insuf~lator device and in this case the
fine particle sized powders of the active ingredient may be mixed with a di-
luent material such as a lac-tose.
Furthermore, the compounds of this invention may also be adminis-
tered by intradermal or intravenous in3ec-tion in the conventional manner or
by suppositories.
In addition to the internal administration, -the compounds o~ this
invention may find use in compositions for topical application, e.g. as
creams, lotions or pastes for use in dermatological treatments. For these
compositions the active ingredient may be mixed with conventional oleaginous
or emulsifying excipients.
The following examples illustrate but do not limit the present in-
vention.
Example 1
Dimethyl-4~amino-isophthalate (5 g) in 50 ml of dioxane and 10 ml
of anhydrous pyridine is treated with 7.5 g of 2-ethoxy-3-methoxy-benzoyl
chloride at room temperature, overnight. After dilution with water, the pre-
cipitate is collected, dissolved in ethyl acetate, and washed with 5% ~aHC03
and then with ~ater. After evaporation to dryness under vacuum, the material
is crystallized from isopropyl ether, yielding dimethyl-4-(2'-ethoxy-3'-
methoxy-benzoylamino)-isophthalate (9 g; m.p. 113-115C), which is dissolved
in 80 ml of dioxane and treated with 70 ml of 1 ~ ~aOH at room temperature
for 4 hours. After acidification with diluted HCl, the precipitate is col-
lected under vacuum and washed with water until neutral. The yield is 7.4 g
of 4-(2'ethoxy-3'-methoxy-benzoylamino)-isophthalic acid (m.p. = 244-246C),
which are treated with 10 ml of acetic anhydride at the reflux temperature
for 10'.
After cooling, dilute with 60 ml of isopropyl ether and filter.
The yield is 5 g of 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)4H-
3,1-benzoxazin-4-one (m.p. = 175-177 C), which are reacted at room temperature

1~'92~ 1~
first with 70 ml of 32% ammonium hydroxide for 4 hours and then with 20 ml of
2N NaO}I overnight. After acidification wi~h 4N IICl, the precipitate is ~ilter-
ed off and crystallized from ethanol to give G-carboxy-2-(2'-ethoxy-3'-methoxy-
-phenyl)-3,4-dihydro-4-oxo-quinazoline (3 g; m.p. = 228~229C).
Analogously, the following compounds were obtained:
6-carboxy-2-(2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p. 269-
271C;
6-carboxy-2-(2'-isopropoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline,
m.p. 278-230C;
6-carboxy-2-(2'-butoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
211-212C;
6-carboxy-2-~2'~2-ethoxyethoxy)-3'-methoxy-phenyl~-3,4-dihydro-4-oxo-quinazo-
line, m.p. 206-20;7C.
Example 2
Proceeding as described in Example 1, starting from the suitable 2-
-alkoxy-3-ethoxy-benzo~yl-chlorides, the following compounds were prepared:
6-carboxy-2-(2'-methoxy-3'-ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
272-3C;
6-carboxy-2-~2',3'-diethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p. 233-
234C.
Example 3
Proceeding as described in Example l, starting from the suitable 2-
-alkoxy-5-methoxy-benzoyl-chlorides, the following compounds were prepared:
6-carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
269-271C;
6-carboxy-2-(2'isopropoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline,
m.p. 280-282C;
6-carboxy-2-(2'-but~y-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
244-245C.
- 14 -

9~
Example 4
4-amino-isophthalic acid (17 g) is refluxed in 800 ml of methanol
and 39 ml of BF3 etherate for 18 hours. Af-ter concentrat-lon under vacuum,
dilute with water and filter. The precipitate is partitioned between 250 ml
of ethyl acetate and 250 ml of 5% NaHC03. The aqueous phase is separated off
and acidified and the precipitate filtered out and washed with water until
neutral. This yields 12 g of 2-amino-5-carbomethoxybenzoic acid, which are
then reacted with 60 ml of ethyl chlorocarbonate in 80 ml of dioxane under
reflux for 20 hours. Add 48 ml of acetyl chloride and reflux for 72 hours.
Concentrate the suspension obtained under vacuum,dilute with ethyl ether and
filter. This gives 10 g of 5-carbomethoxy-isatoic anhydride (m.p. 275-278 C)
which are treated with 25 ml of 32% ammonium hydroxide in 25 ml of dimethyl-
formamide at room temperature for 30'. After dilution with water, the pre-
cipitate is filtered off and washed until neutral. 2-amino-5-carbomethoxy-
benæamide (8.1 g) is obtained, which is dissolved in 80 ml of dioxane and 10
- ml of pyridine and reacted with 14 g of 2-ethoxy-3-methyl-benzoyl-chloride at
room temperature for 16 hours. After dilution with water, filter the precip-
itate and wash it until neutral. Crystallize from ethanol, yielding 9.4 g of
2-(2'-ethoxy-3'-methyl-benzoylamino)-5-carbomethoxybenzamide, which are
treated with 45 ml of 2N sodium hydroxide in 45 ml of dioxane at room temper-
ature for 8 hours.
After dilution with water and acidification, the precipitate is
filtered and washed with hot ethanol to yield 7.4 g of 6-carboxy-2-(2'- ,
ethoxy-3'-methyl~phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p. 240-241C.
Analogously the following compound was obtained:
6-carboxy-2-(2'-methoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
252-253C.
Example 5
Proceeding as described in Example 1, starting from the suitable
2,5-dialkoxy-benzoyl-chlorides, the following compounds were prepared:
6-carboxy-2-(2',5'-diethoxy-phenyl-3,4-dihydro-4-oxo-quinazoline, m.p.

291-292C;
6~carboxy-2-(2'~methoxy-5'-ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
274-5C;
6-carboxy-2-(2'-methoxy-5'-isopropoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline,
m.p. 279-280C;
6-carboxy-2-(2'-ethoxy-5'-isopropoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline,
m.p. 225-227C;
6-carboxy-2-(2',5'-diisopropoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
216-217C;
6-carboxy-2-(2l-methoxy-5l-propoxy-phenyl)-3~4-dihydro-4-oxo-quinazoline~ m.p.
275-277C;
6-carboxy-2-(2'ethoxy-5'-propoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
258-260C;
6-carboxy-2-(2'-methoxy-5'-allyloxy-phenyl)-3,4-dih`ydro-4-oxo-quinazoline,
m.p. 251-253C;
6-carboxy-2-(2'-ethoxy-5'-allyloxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
244-245C;
6-carboxy-2- ~ -methoxy-5'-(2-ethoxyethoxy)-phen~ -3,4-dihydro-4-oxo-quinazo-
line, m.p. 239-240C.
Example 6
Proceeding as described in Example 1, starting from the suitable 2-
-ethoxy-5-alkyl-benzoyl-chlorides, the following compounds were prepared:
6-carboxy-2-(2'-ethoxy-5'ethyl-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p. 272-
274C;
6-carboxy-2-(2'-ethoxy-5'-propyl-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
280-282C;
6-carboxy-2-(2~-ethoxy-5'-butyl-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
; 24~-251C.
Example 7
2-amino-5-carbomethoxy-benzamide (4 g), obtained as described in
- 1~ -

Example 4, is reacted with 4.5 g of 2-ethoxy-3-methoxy-benzaldehyde in the
presence of 0.2 ml of piperidine in 150 ml of xylene and refluxed for 4 hours.
After cooling, the precipitate is filtered out and washed with ben-
zene. The yield is 3.9 g of 6-carbomethoxy-2-(2'-ethoxy-3'-methoxyphenyl)-1,
2, 3, 4-tetrahydro-~-oxo-quinazoline, which are dissolved in 250 ml of acetone
and oxidized at 0-5C for 3 hours by a gradual addition of 2.3 g of finely
powdered potassium permanganate. An excess of sodium bisulfite is added and
after one hour the inorganic precipitate is filtered out and the acetone so-
lution evaporated to dryness to give a residue which is crystallized from
ethanol. The yield is 2.6 g of 6-carbomethoxy-2-(2'-ethoxy-3'-methoxy-phenyl)-
-3,4-dihydro-4-oxo-quinazoline, m.p. 165-167C, which are treated with 12 ml
of lN NaOH in 25 ml of dioxane at room temperature for 16 hours.
After dilution with water and acidification, 6-carboxy-2-~2'-ethoxy-
-3'-methoxyphenyl)-3,4-dihydro-4 oxo-quinazoline (2.1 g; m.p. 228-229C), is
obtained.
Analogously, the following compounds were obtained:
6-carboxy-2-(2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p. 269-
271C;
6-carboxy-2-(2',3'-diethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p. 233-
4C;
6-carboxy-2-(2l-ethoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
240-241C;
6-carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
269,271C;
6-carboxy-2-(2'-ethoxy-5'-ethyl-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
272-274C.
Example 8
6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazo-
line (5.8 g), obtained as described in Example 1, is treated with an excess
(2 moles/mole) of thionyl chloride in dioxane at reflux temperature for 4

2~ ~8
hours. After cooling and concentrating to dryness under vacuum, the residue
is reacted with an excess of absolute ethanol at 50C for 2 hours. After cool-
ing, the precipitate îs filtered and washed with ethanol and water. The yield
is 5.1 g of 6-carbethoxy-2-~2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
-quinazoline, m.p. 168-169C.
Analogously, the following compounds were obtained:
6-carbethoxy-2-~2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carbethoxy-2-~2'-methoxy-5'-allyloxy-phenyl)-3,4-dihydro-4-oxo-quinazoline.
Example 9
6-carboxy-2-~2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazo-
line (3.6 g) is treated with hot aqueous solution of 800 mg of sodium bicar-
bonate. After cooling and clearing the solution by filtration, it is concen-
trated to a small volume and diluted with 4 volumes of acetone. Filter the
precipitate and wash it with acetone. The yield is 3.4 g of the sodium salt
of 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline,
m.p.~ 320C.
Analogously, the sodium salts of the following compounds were obtain-
ed:
6-carboxy-2-(2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-~2',3'-diethoxy-phenyl)-3~4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, m.p.
320C;
6-carboxy-2-(2'-e~hoxy-5'-ethyl-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-methoxy-5'-allyloxy-phenyl)-3,4-dihydro-4-oxo-quinazoline,
m.p.~ 310C;
6-carboxy-2-(2'-ethoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazoline.
Example 10
Proceeding as described in Example 8 and using the suitable aliphatic
alcohols, the isopropyl-, tert-bu~yl, octyl-, hexyl-, undecyl-esters of the
following compounds were obtained:
- 18 -

2.~
6-carboxy-2-(2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-qwinazoline;
6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-isopropoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-methoxy-5'-allyloxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-methoxy-3'-ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carb~xy-2-(2'-me~hoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-ethoxy-5'-ethyl-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
Example 11
6-chlorocarbonyl-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
-quinazoline (6.1 g) obtained as described in Example ~, is suspended in 60 ml
of dioxane and treated with 4.2 ml of 2-(N,N-diethylamino)-ethanol and 1 ml of
triethylamine at room temperature for 18 hours. After dilution with water and
alkalinization with K2C03, the precipitate is filtered and washed until neutral,then crystallized from ethanol. The yield is 5.5 g of the 2-(N,N-diethylamino)-
-ethyl ester of 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
-quinazoline, m.p. 93-94C.
Analogously, the 2-~N,N-diethylamino)-ethyl esters of the following
compounds were obtained:
6-carboxy-2-(2',3'-dimethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-methoxy-3i-ethoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-isopropoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2- ~1-(2-ethoxyethoxy)-3'-methoxy-phenyl~-3,4-dihydro-4-oxo-quinazo-
line;
6-carboxy-2-(2'-methoxy-5'-allyloxy'-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-methoxy-3'-methyl-phenyl)-3,4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-ethoxy-5'-methoxy-phenyl)-3/4-dihydro-4-oxo-quinazoline;
6-carboxy-2-(2'-ethoxy-5'-ethyl-phenyl)-3,4-dihydro-4-oxo-quinazoline.
Example 12
Proceeding as described in Example 11, and using as reagents either
- 19 -

2~ ~
2-(N,N-dimethylamino)-ethanol or 2-(1-pyrrolidinyl)-ethanol, the following
esters were obtained:
6- ~-(N,N-dimethylamino)-ethoxy-carbony~ -2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-
-dihydro-4-oxo-quinazoline, m.p. 137-138C:
. .
6- 2-~N,N-dimethylamino)-ethoxy-carbon ~ -2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-
-dihydro-4-oxo-quinazoline;
6- ~ (N,N-dimethylamino)-ethoxy-carbon ~ -2-(2'-methoxy-5'-allyloxy-phenyl)-
-3,4-dihydro-4-oxo-quinazoline;
6- ~ (l-pyrrolidinyl)-ethoxy-carbon ~ -2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-
-dihydro-4-oxo-quinazoline, m.p. 144-146C;
6- ~ (l-pyrrolidinyl)-ethoxy-carbony~ -2-(2'-ethoxy-5'-methoxy-phenyl)-3,4-
-dihydro-4-oxo-quinazoline;
6- ~ (l-pyrrolidinyl)-ethoxy-carbon ~ -2-(2'-methoxy-5'-allyloxy-phènyl)-3,4-
-dihydro-4-oxo-quinazol~ine.
Example 13
Tablets, each weighing 150 mg and containing 50 mg of the active
substance are manufactured as follows:
Composition (for 10,000 tablets)
6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
20 -quinazoline 500 g
lactose 710 g
corn starch 237.5 g
talc powder 37.5 g
magnesium stearate 15 g
; 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline, lac-
tose and a half of the corn starch are mixed; the mixture is then forced
through a sieve of 0.5 mm openings. Corn starch (18 g~ is suspended in warm
water (1~0 ml). The resulting paste is used to granulate the powder. The
granules are dried, comminuted on a sieve size 1.4 mm, then the remaining
quantity of starch, talc and magnesium stearate is added, carefully mixed, and
- 20 -

1~2 ~
processed into tablets using punches of 8 mm diameter.
Example 14
Aerosol formulation:
6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-
-quinazoline 2 %
ethanol 10 %
lecithin 0.2 %
mixture of dichlorodifluoromethane and
dichlorotetrafluoroethane (70:30 mixture) ad100 %
- 21 -