COMPOSES A BASE D'ACIDES 4-HYDROXY-2-QUINOLINONE-3- CARBOXYLIQUES

4-HYDROXY-2-QUINOLINONE-3-CARBOXYLIC ACID COMPOUNDS

Abrégé anglais

Abstract of the Disclosure
The invention provides pharmaceutical compositions
comprising 4-hydroxy-2-quinolinone-3-carboxylic acid
esters, useful in the treatment of allergic conditions
such as allergic asthma. There is also provided a process
for the preparation of certain novel compounds of this
type. The novel compounds have the formula I,
<IMG> I

Revendications

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
formula I,
<IMG> I
in which either
a) R° is cycloalkyl of 3 to 6
carbon atoms, cycloalkylalkyl
in which the cycloalkyl part
is of 3 to 6 carbon atoms and
the alkyl part is of 1 or 2
carbon atoms, alkenyl or
alkynyl of 3 to 6 carbon
atoms in which the
unsaturation is on other than
the alpha carbon atom, or
<IMG>
in which n is 0 or 1 and
Y and Y' are independently
hydrogen, fluorine, chlorine,
bromine, alkyl of 1 to 3
carbon atoms, alkoxy of 1 to
3 carbon atoms,
trifluoromethyl or nitro with
the proviso that only one of
Y and Y' can be from the
group consisting of nitro and
trifluoromethyl,
13

R is alkyl of 1 to 4 carbon
atoms, and
R1 and R2 are independently hydrogen,
fluorine, chlorine, bromine, alkyl
of 1 to 4 carbon atoms, alkoxy of 1
to 4 carbon atoms, nitro or trifluor-
omethyl, with the proviso that only
one of R1 and R2 can be from the
group consisting of nitro and
trifluoromethyl,
b) R° is hydrogen, alkyl of 1 to 6 carbon
atoms, cycloalkyl of 3 to 6 carbon
atoms, cycloalkylalkyl in which the
cycloalkyl part is of 3 to 6 carbon
atoms and the alkyl part is of 1 or
2 carbon atoms, alkenyl or alkynyl
of 3 to 6 carbon atoms in which the
unsaturation is on other than the
alpha carbon atom, or
<IMG>
in which n is 0 or 1 and
Y and Y' are independently
hydrogen, fluorine, chlorine,
bromine, alkyl of 1 to 3
carbon atoms, alkoxy of 1 to
3 carbon atoms, trifluoro-
methyl or nitro with the
proviso that only one of Y
and Y' can be from the group
consisting of nitro and
trifluoromethyl,
14

R is alkyl of 1 to 4 carbon atoms and
R1 and R2 together form a methylenedioxy
group or c) R° is alkyl of 1 to 6 carbon atoms
R is alkyl of 1 to 4 carbon atoms and
R1 and R2 are independently alkoxy of 1 to 4
carbon atoms,
characterised by reacting a compound of the
formula II
<IMG> II
in which R°, R1 and R2 are as defined above, with
a compound of formula III
<IMG> III
in which R is as defined above, and
M is an alkali metal,
in an inert organic solvent,
and optionally converting the free acid form or the salt
of the compound of the formula I thus obtained into or
into another pharmaceutically acceptable base salt.
2. A process as claimed in Claim 1 when carried
out at a temperature of from 0°C to 150°C.
3. A process as claimed in Claim 1 when carried
out at a temperature of from 60°C to 120°C.
4. A compound of the formula I as defined in Claim
1 or a pharmaceutically acceptable base salt thereof
whenever prepared by a process as claimed in Claim 1 or by
an obvious chemical equivalent thereof.
5. A process as claimed in Claim 1 wherein R° is
allyl.

6. A compound as claimed in Claim 4 wherein in the
formula I R° is allyl whenever prepared by a process as
claimed in Claim 5 or by an obvious chemical equivalent
thereof.
7. A process as claimed in Claim 1 wherein R1
and R2 are methoxy.
8. A compound as claimed in Claim 4 wherein in the
formula I R1 and R2 are alkoxy whenever prepared by a
process as claimed in Claim 7 or by an obvious chemical
equivalent thereof.
9. A process as claimed in Claim 1 wherein R1
and R2 are methoxy.
10. A compound as claimed in Claim 4 wherein in the
formula I R1 and R2 are methoxy whenever prepared by a
process as claimed in Claim 9 or by an obvious chemical
equivalent thereof.
11. A process as claimed in Claim 1 wherein R1
and R2 are methoxy in the 6- and 7-positions.
12. A compound as claimed in Claim 4 or Claim 5
wherein in the formula I R1 and R2 are methoxy in the
6- and 7-positions whenever prepared by a process as
claimed in Claim 11 or by an obvious chemical equivalent
thereof.
13. A process for producing 1-allyl-4-hydroxy-6,7-
dimethoxy-2-quinolinone-3-carboxylic acid ethyl ester or a
pharmaceutically acceptable base salt thereof which
comprises reacting 1-allyl-6,7-dimethoxyisatoic anhydride
with sodio-diethyl malonate and when required converting
the free acid form obtained into a pharmaceutically
acceptable base salt.
16

14. 1-Allyl-4-hydroxy-6,7-dimethoxy-2-quinolinone-3-
carboxylic acid ethyl ester or a pharmaceutically
acceptable base salt thereof whenever prepared by a
process as claimed in Claim 13 or by an obvious chemical
equivalent thereof.
17

Description

This invention relates to 4-hydroxy-2-quinolinone-
3-carboxylic acid esters.
The invention provides pharmaceutical compositions
comprising compounds of formula I
,R
D ` ~A~ I
in which either
a) R is cycloalkyl of 3 to 6 carbon atoms,
cycloalkylalkyl in which the cycloalkyl
part is of 3 to 6 carbon atoms and the
alkyl part is of 1 or 2 carbon atoms,
alkenyl or alkynyl of 3 to 6 carbon
atoms in which the unsaturation is on
other than the alpha carbon atom, or
~Y
~CH2)n~
in which n is O or 1 and
Y and Y' are independently
hydrogen, fluorine, chlorine,
bromine, alkyl of 1 to 3 carbon
atoms, alkoxy of 1 to 3 carbon
atoms, trifluoromethyl or nitro with
the proviso that only one of Y and
Y' can be from the group consisting
of nitro and trifluoromethyl,
is alkyl of 1 to 4 carbon atoms, and

59~
2 --
Rl and R2 are independently hydrogen,
fluorine, chlorine, bromine, alkyl
of 1 to 4 carbon atoms, alkoxy of 1
to 4 carbon atoms, nitro or trifluor-
omethyl, with the proviso that only
one of Rl and R2 can be from the
group consisting of nitro and
trifluoromethyl,
b) R is hydrogen, alkyl of 1 to 6 carbon
atoms, cycloalkyl of 3 to 6 carbon
atoms, cycloalkylalkyl in which the
cycloalkyl part is of 3 to 6 carbon
atoms and the alkyl part is of 1 or
2 carbon atoms, alkenyl or alkynyl
of 3 to 6 carbon atoms in which the
unsaturation is on other than the
alpha carbon atom, or
( 2)n ~
in which n is O or 1 and
Y and Y' are independently
hydrogen, fluorine, chlorine,
bromine, alkyl of 1 to 3
carbon atoms, alkoxy of 1 to
3 carbon atoms, trifluoro-
methyl or nitro with the
proviso that only one of Y
and Y' can be from the group
consisting of nitro and
trifluoromethyl,
.

~s~
R is alkyl of l to 4 carbon atoms and
Rl and R2 together forrn a methylenedioxy
group or c) R is alky:L of l to 6 carbon atoms
R is alkyl of l to 4 carbon atoms and
Rl and R2 are independently alkoxy of l to 4
carbon atoms.
The compounds of formula I possess pharmacological
activity. In particular they possess disodium
chromoglycate (DSCG)-like activity, in particular
histamine release inhibiting activity, and are therefore
indicated for use in the treatment of allergic conditions,
such as allergic asthma, as indicated in the passive
cutaneous anaphylaxis test in the rat. Female rats
(180-200 9) are sensitised by subcutaneous administration
of 1 mg of egg albumin

~,~g~g~
(~lerck Nr. 967) and 200 mg ~l(OH)3 in 1 ml of physiolo~
saline and 0. 5 ml o~ Haernophiluspertussis vaccine (Sch~ei-
zerisches Serum and Impfinstitut, Bern; ~r. 115 325; 4 x 10
organism/ml) intraperitoneally. Fourteen days later, the
animals are exsanguinated,the blood centrifuged, the serum
collected and deep frozen. The serum thus obtained (anti-
serum) is injected intradermally (0.1 ml of 1:200 diluted
serum per injection site) at four sites on the backs of
untreated,female rats. ~wenty-four hours later each rat
~ is administered 0.1 to 5.6 m~kg i.v. or 0.1 to 100 mg~k~ p.o. of the
test compound, and either immediately or 5 to 30 minutes
afterwards, in the case of intravenous administration, or 15
or 60 minutes afterwards, in the case of oral administration,
egg albumin (5 mg/ml i.v.) dissolved in physiological
saline containing 0.25% Evans Blue dye (Merck Nr. 3169).
The egg albumin elicits a cutaneous anaphylatic reaction,
the intensity of which is proportional to the extent to
~hich the Evans Blue dye diffuses into the tissue sur-
rounding each of the four sensitisation sites. Thirty
2 ~ minutes after the administration of the egg albumin,
the rats are killed with ether, the underside of the skin
of the back of each animal is exposed and the diameter
r~
~ , .

g~
J - 5 _
of the areas of blue dye surrounding each of the four
sensitisation sites are measured. ~ach dose of test
compound is investigated in between four and six rats
and the mean diameter compared with the Mean value
obtained in four solvent-treated control rats. The
percentage inhibition is taken as the percentage of the
mean diameter in the test animals relative to the mean
diameter in the controls.
The DSCG-like activity, in particular histamine
release inhibiting activity, can be confirmed by in-
hibition of histamine release in the rat peritoneal mast
cell test, basically as described by Kusner et al.,
J. Pharmacol. Exp. Therap. 184, 41-46 (1973), with the
following modification: after sedimentation of the mast
cells by centrifugation at 350 x g and 4C, the sediments
are taken up in 1 ml of Hank's balanced salt solution
(~IBSS) (buffered to a pH of 6.9) and pooled. The
resulting suspension is centrifuged, washed again with
HBSS and sedimented. The thus purified mast cells are
9 ~ prepared as 2 ml suspensions in HBSS. To these are added
either 2 ml of HBSS, to determine the spontaneous histamine
release, or 2 ml of HsSS and 2.24/ug of compound 48/80
(N-methylhomoanisylamineformaldehyde condensate; a
histamine liberator from Burroughs Wellcome and Co. Inc.,
Tuckahoe, N.~'. USA), to determine the 48/80 induced
histamine release, or 2 ml of HBSS with 2.24 ~g of 48/80

Si9~
) 6~
and from 18 to 180 ug/ml of the test compound, to
determine the 48/80 induced histamine release in the
presence of the test compound.
The 48/80 induced histamine release minus the
spontaneous histamine release is taken as 100% histamine
release. The 48/80 induced histamine release in the
presence of the test compound minus the spontaneous
histamine release is then compared with the 100~ value
to determine the percentage inhibition by the test
-a compound. [The histamine determination is effected in
conventional manner, for example as described in the
above-mentioned Kusner et al. article, or in Kusner
and Herzig, Advances in Automated Analysis, 429 (1971)].
An indica ed su~takle daily dosage is from 20 to 400 mg
preferably administered in divided dosages of from
5 to 200 mg 2 to 4 times a day, or in retard form.
The compounds may be used in free acid form or in
the form of their pharmaceutically acceptablebase salts,~hich
salt forms have the same order of activity as the free
2 ~ acid forms. Suitable salts include the sodium, potassium
and lithium salts.
The compounds of formula I may be admixed with
conventional pharmaceutically acceptable diluents or
carriers and, optionally, other excipients, and administered
in such forms as tablets or capsules.

S~
The invention also provides a process for the
preparation of compounds of formula I, characterised by
reacting a compound of the formula II:
I o
~ ~ II
in which R, Rl and R2 are as defined above, with
a compound of formula III
/ COOR
MCH III
\ COOR
b.~

-- 8 --
in which R is as defined above, and
M is an alkali metal.
The process is suitably carried out in an inert
organic solvent, e.g. dimethyl acetamide, and at a
temperature of from 0C to 150C, preferably 60C to
120C.
The compounds of formula III may be produced from
the corresponding dialkyl malonates by reaction with a
strong alkali metal base, e.g. sodium hydride, and in an
t ~ inert organic solvent, e.g. dimethyl acetamide. The compounds
of formula II are either known or may be produced in con-
ventional manner from available materials. For example,
l-allyl-6,7-dimethoxyisatoic anhydride may be prepared
according to the following reaction scheme:
CH30 ~\ HCl CH30 ~\COOCH3
¦70% HN03
~,CH3 COOH
3 ~ 2 2 3 ~ NO 2
5% Pd/C
CH30 COOCH3 CH30 COOCH3
1) NaOH 2) C'OC12
H~O
~ ' H
CEI30 ~ ~ ~/ O l)Nali/D~ C~i30
3 ~0 2)Br C~2 CH C~2 C'H
r ~
- l )

The compound of formula I may be isolated from the
reaction medium in conventional manner, for example,
comprising treatment with a proton source such as water or
an aqueous mineral acid.
Compounds of formula I may exist in the form shown,
having a free acidic hydroxyl group, or in the form of
their base salts. Salts and free acid forms may be
interconverted in conventional manner, and where the salt
form is the salt derived from the alkali metal M in the
compound of formula III, it may be obtained from the
reaction mixture without isolation of the free acid form.
The same process, with appropriate starting materials,
may also be used to prepare the other compounds of formula
I.
Preferred groups of compounds of formula I are:
a) those in which R is allyl
b) those in which Rl and R2 are alkoxy, preferably
methoxy, preferably in the 6- and 7-positions
c) those in which Rl and R2 form a 6,7-methylene-
dioxy group.
Particularly preferred is l-allyl-4-hydroxy-6,7-
dimethoxy-2-quinolinone-3-carboxylic acid ethyl ester.
The following examples illustrate the invention:
,~
.

~S9~
-- 10--
EXA~IPL~ Allyl-4-h~droxy-~,7-dimethoxy-2-quinolinone-
3-carboxylic acid e~hyl ester.
A solution of 5.0 g of 1-allyl-6,7-dimethoxyisatoic
anhydride in 50 ml of dimethylacetamide is added, dropwise,
to a solution of sodio-diethyl malonate (prepared by reacting
3.1 g of diethyl malonate in 75 ml of dimethylacetamide with
0.9 g of sodium hydride (57% in mineral oil) - first at
room temperature and then briefly at 120C). The resulting
mixture is heated at 120C for 4 hours. The dimethyl
t ~ acetamide is evaporated off, water is added and the mixture
is washed once with methylene chloride, acidified with
2N hydrochloric acid, and extracted with methylene chloride-.
The organic phase is dried over sodium sulphate and eva-
porated in vacuo. The residue is recrystallised from
met`nylene chloride/diethyl ether, to yield the heading
compound/ m.p. 165-166C.
EX~IPL~S 2-11
-
In manner analogous to Example 1, employing appropriate
starting materials in approximately equivalent amounts, the
2 ~ following compounds of formula I may be obtained.
2) 1-allyl-4-hydroxy-2-quinolinone-3-carboxylic acid
ethyl ester, m.p. 88-91C.
3) 1-cyclopentyl-4-hydroxy-2-quinolinone-3-carboxylic-
acid ethyl ester.
4) 1-cyclopropylmethyl-4-hydroxy-2-quinolinone-3-
carboxylic acid ethyl ester.
. .~ .,.. ~

5) 1-(o-nitrobenzyl)-4-hydro~y-2-quinolinone-3-
carboxylic acid ethyl ester, m.p. 148-151C.
6) 1-proparc3yl-4-hydroxy-2-quinolinone-3-carboxylic
acid ethy] ester, m.p. 171-174C.
7) 1-(p-fluorobenzyl)-4-hydroxy-2-quinolinone-3-
carboxylic acid ethyl ester, m.p. 126-129C.
8) 1-ph~nyl-4-hydroxy-2-quinolinone-3-carboxylic
acid ethyl ester, m.p. 180-183C.
9) 1-~ethvl-4-hydroxy-6,7-methylenedioxy-2-quinolinone- .;~
t ~3-carboxylic acid ethyl ester, m.p. 212-215C.
10) 1-allyl-4-hydroxy-6,7-methylenedioxy-2-quinolinone-
3-carboxylic acid ethyl ester.
11) 1-methyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-
carboxylic acid ethyl ester.
EXP~PLES 12-20
.
- In manner analogous to Example 1, employing
appropriate starting materials in approximately equivalent
amounts, the following additional compounds of formula Ip
may be obtained:
12) 1-hexyl-4-hydroxy-2-quinolinone-3-carboxylic acid
ethyl ester, m.p. 64-66C.
13) 1-ethyl-4-hydroxy-2-quinolinone-3-carboxylic acid
ethyl ester, m.p. 68-71C.
14) 1-butyl-7-chloro-4-hydroxy-2-quinolinone-3-carboxylic
acid ethyl ester, m.p. 54-55C.
~ . . .

~ gss~
~ 1~. --
15) 1-methyl-4-ilydroxy-6-rnethoxy-2-quinolinone-3-
carboxylic acid ethyl ester, m.p. 130 to 133C.
16) 1-methyl-4-hydroxy-6-chloro-2-quinolinone-3-
carboxylic acid ethyl ester, m.p. 132-135C.
17) 1-methyl-4-hydroxy-2-quinolinone-3-carboxylic
acid ethyl ester, m.p. 100-102C.
18) 4-hydroxy-6-methyl-2-quinolinone-3-carboxylic
acid ethyl ester.
19) 4-hydroxy-6,7-dimethoxy-2-quinolinone-3-carboxylic
acid ethyl ester.
20) 4-hydro~y-6-chloro-2-quinolinone-3-carboxylic
acid ethyl ester.
EXAMPLES 21, 22: Pharmaceutical Compositions
Representative pharmaceutical compositions
comprising compounds of formula I are capsules prepared by
standard techniques to contain the following:
Example active ingredient wt.active wt.Kaolin
No. ingredient (mg.)
(mg.)
21) 1-methyl-4-hydroxy-2-quino- 70 210
linone-3-carboxylic acid
ethyl ester
22) 1-allyl-4-hydroxy-6,7- 5 275
dimethoxy-2-quinolinone-
3-carboxylic acid ethyl
ester
Such capsules may be administered 4 times daily
Eor the treatment of allergic asthma.
~,