[0001] This invention-relates to 4-hydroxy-2-quinolinone-3-carboxylic acids and their salts.
[0002] The invention provides pharmaceutical compositions comprising compounds of formula
Ip
in which R
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0002)
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
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0003)
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
and
Rlp and R2p are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms,
alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl, with the proviso that only
one of Rlp and R2p can be from the group consisting of nitro and trifluoromethyl, or R1p and R2p together form a 6,7-methylenedioxy group.
[0003] The compounds of formula I
p possess pharmacological activity. In particular they possess disodium chromoglycate
(DSCG)-like actiivity, in particular histamine release inhibiting activity, and are
therefore indicated for use in the prophylactic treatment of allergic conditions,
such as allergic asthma, as indicated in the passive cutaneous anaphylaxis test in
the rat. Female rats (180-200 g) are sensitised by subcutaneous administration of
1 mg of egg albumin (Merck Nr. 967) and 200 mg Al(OH)
3 in 1 ml of physiological saline and 0.5 ml of Haemophiluspertussis vaccine (Schwei-
zerisches Serum and Impfinstitut, Bern; Nr. 115 325; 4 x 10
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 f diluted serum per injection
site) at four sites on the backs of untreated, female rats. Twenty-four hours later
each rat is administered 0.1 to 5.6 mg/kg i.v. or 0.1 to 100 mg/kg 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 which the Evans Blue dye diffuses
into the tissue surrounding each of the four 'sensitisation sites. Thirty 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 of the areas of
blue dye surrounding each of the four sensitisation sites are measured. Each 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.
[0004] The DSCG-like activity, in particular histamine release inhibiting activity, can
be confirmed by inhibition of histamine release fn 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 4°C, the sediments are taken up in 1 ml of Hank's balanced salt solution
(HBSS) (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 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 HBSS and 2.24/ug of compound 48/80 (N-methyl-
homoanisylamineformaldehyde condensate; a histamine liberator from Burroughs Wellcome
and Co. Inc., Tuckahoe, N.Y. USA), to determine the 48/80 induced histamine release,
or 2 ml of HBSS with 2.24 µg of 48/80 and from 18 to 180 µg/ml of the test compound,
to determine the 48/80 induced histamine release in the presence of the test compound.
[0005] 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 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 indicated suitable daily dosage is from 20 to 800 mg preferably
administered in divided dosages of from 5 to 400 mg 2 to 4 times a day, or in retard
form.
[0006] The compounds may be used in free acid form or in the form of their pharmaceutically
acceptable mono- or di-base salts, which salt forms have the same order of activity
as the free acid forms. Suitable salts include the sodium, potassium and lithium mono-
and disalts.
[0007] 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.
[0008] The compound l-methyl-4-hydroxy-2-quinoline-3-carboxylic acid has been described
in Mitscher et al., "Heterocycles" Vol. 3, No. 11, pp 913-919 (1975), but to our knowledge
no useful pharmacological activity has been given for this compound.
[0009] Accordingly, the invention further provides novel compounds within the scope of formula
I
p above. Such novel compounds are those of formula I
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0004)
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'
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0005)
in which n, Y and Y' are as defined above, and R1 and R2 have the same significance as R1p and R2p above, provided that R1 and R2 do not together form a 6,7-methylenedioxy group,
b) R° is hydrogen, R1 is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy
of 1 to 4 carbon atoms and R2 is fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon
atoms, nitro or trifluoromethyl,
c) R° is alkyl of 1 to 6 carbon atoms and R1 and R2 are independently alkoxy of 1 to 4 carbon atoms,
or d) R° has the same significance as R
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0006)
above, and R1 and R2 together form a 6,7-methylenedioxy group.
[0010] Preferred significances of R° are hydrogen, alkyl or alkenyl, more preferably alkyl
or alkenyl, particularly allyl.Preferred significances of R
1 and R
2 are dialkoxy, more preferably 6,7-dialkoxy, particularly 6,7-dimethoxy. Combinations
of these preferred significances are especially advantageous.
[0011] Preferably the compounds of formula I are in the free acid or disalt form, more preferably
the free acid form.
[0012] The invention also provides a process for the preparation of compounds of formula
I, characterised by hydrolysing a compound of formula II
in which R°, R1 and R2 are as defined above,
R is alkyl of 1 to 6 carbon atoms,
and M is hydrogen or a pharmaceutically acceptable cation.
[0013] When it is desired to obtain the compound of formula I in the disalt form, a suitable
procedure is alkaline hydrolysis of the compound of formula II in an aqueous medium
at a temperature of 40-150°C, preferably 80-120°C, followed by recovery under conditions
avoiding acidification, which can lead to decarboxylation of the product. Preferably
M is hydrogen and at least 2 mole equivalents of base are used, preferably sodium
or potassium hydroxide to give the disodium or dipotassium salt. When M is itself
a cation, mixed disalts may be prepared.
[0014] When it it desired to obtain the free acid form of compounds of formula I, a suitable
procedure is mild acid hydrolysis of a compound of formula II in which R is an acid-labile
group such as t-butyl. The temperature is suitably from -20° to 60°C, preferably from
-10° to 35°C in order to avoid decarboxylation of the product. Suitable acid catalysts
are sulphuric acid, hydrochloric acid and perchloric acid, preferably the latter.
The reaction medium is suitably a water-miscible non-hydroxylic organic solvent, for
example acetonitrile.
[0015] Compounds of formula I in free acid form may be treated with base in conventional
manner to obtain the monosalt form, in which the salt-forming cation is. associated
with both the 4-hydroxy and the 3-carboxyl functions, and the disalt form.
[0016] The same process, with appropriate starting materials, may be used to prepare the
other compounds of formula I .
[0017] The compounds of formula II are described and claimed in our German DOS 2 706 752,
and may be prepared by the methods disclosed therein.
[0018] The following Examples illustrate the invention:
EXAMPLE 1: 1-Allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid
A:1-Allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3- carboxylic acid t-butyl ester
[0019] To a solution of 8.3 g of di-t-butyl malonate in 75 ml of dimethylacetamide is added
portionwise 1.9 g of pentane-washed 50% sodium hydride. The resulting solution is
stirred at room temperature for 30 minutes and there is then added 10.0 g of l-allyl-6,7-dimethoxyisatoic
anhydride in 100 ml of dimethylacetamide. The resulting solution is heated at 120°C
for 3 hours, the dimethylacetamide removed in vacuo, water added, the resulting mixture
washed with methylene chloride, acidified with 2 N. hydrochloric acid and extracted
with methylene chloride. The organic phase is dried and evaporated in vacuo to an
oil which is crystallized from ether to obtain l-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic
acid t-butyl ester.
B: 1-Allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3- carboxylic acid
[0020] To a solution of 3.1 g of l-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic
acid t-butyl ester in 30 ml of acetonitrile at 0°C is added 0.75 ml of 60% aqueous
perchloric acid. The resulting precipitate is recovered by filtering and washed with
ether to obtain 1-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid which
melts at 169-170°C and decarboxylates at 185-195°C.
EXAMPLES 2-26:
[0021] In manner analogous to Example 1, employing appropriate starting materials in approximately
equivalent amounts, the compounds of formula I listed in Table I below may be obtained.
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0009)
EXAMPLE 27: Preparation of Disodium salt of compound of Example 1
[0022] The compound of Example 1 (1-allyl-6,7-dimethoxy-4-hydroxy-7-quinolinone-3-carboxylic
acid) (3.0 g) and 800 mg of sodium hydroxide are placed in 75 ml of water and the
resulting suspension heated to 50°C until a solution is formed. The water is then
evaporated in vacuo and the resulting residue oven dried under high vacuum to obtain
1-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid disodium salt, m.p.
320°C with decomposition.
1. A pharmaceutical composition comprising compounds of formula I
p
in which R
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0011)
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
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0012)
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
and
R1p and R2p are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl, with the proviso that
only one of R1p and R2p can be from the group consisting of nitro and trifluoromethyl, or R1p and R2p together form a 6,7-methylenedioxy group,
in free acid or pharmaceutically acceptable mono- or di-base salt form, in association
with a pharmaceutically acceptable diluent or carrier.
2. A pharmaceutical composition according to Claim 1 in unit dosage form, each unit
dosage comprising 5-400 mg of compound of formula Ip.
3. A process for the prepartion of a compound of formula I,
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0013)
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
![](https://data.epo.org/publication-server/image?imagePath=1979/02/DOC/EPNWA1/EP78100168NWA1/imgb0014)
in which n, Y and Y' are as defined above, and R1 and R2 have the same significance as R1p and R2p above, provided that R1 and R2 do not together form a 6,7-methylenedioxy group,
b) R° is hydrogen, R1 is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy
of 1 to 4 carbon atoms and R2 is fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon
atoms, nitro or trifluoromethyl,
c) R° is alkyl of 1 to 6 carbon atoms and R1 and R2 are independently alkoxy of 1 to 4 carbon atoms,
or d) R° has the same significance as R° above, and R1 and R2 together form a 6,7-methylene-dioxy group,
characterised by hydrolysing a compound of formula II
in which R°, R1 and R2 are as defined above,
R is alkyl of 1 to 6 carbon atoms,
and M is hydrogen or a pharmaceutically acceptable cation,
provided that when hydrolysis is carried out under acid conditions, R is an acid-labile
alkyl group.
4. A compound of formula I, stated in Claim 3, whenever prepared by the process of
Claim 3.
5. A compound of formula I, stated in Claim 3.
6. A compound according to Claim 5, in which R° is hydrogen, alkyl or alkenyl.
7. A compound according to Claim 6, in which R° is allyl.
8. A compound according to Claim 5, in which R1 and R2 are dialkoxy.
9. A compound according to Claim 8 in'which R1 and R2 are 6,7-dimethoxy.
10. l-Allyl-6,7-dimethoxy-4-hydroxy-2-quinoline-3-carboxylic acid, in free acid, mono-
or di-salt form.