CA1095914A - 4-hydroxy-2-quinolinone-3-carboxylic acid compounds - Google Patents
4-hydroxy-2-quinolinone-3-carboxylic acid compoundsInfo
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- CA1095914A CA1095914A CA272,682A CA272682A CA1095914A CA 1095914 A CA1095914 A CA 1095914A CA 272682 A CA272682 A CA 272682A CA 1095914 A CA1095914 A CA 1095914A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Quinoline Compounds (AREA)
Abstract
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,
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~
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
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.~
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
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~
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.
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.~
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
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~
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.
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:
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~. --
~ . . .
~ 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.)
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.
~,
~,
Claims (14)
1. A process for the preparation of a compound of formula I, 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 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, 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 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, 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
II
in which R°, R1 and R2 are as defined above, with a compound of formula III
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.
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 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, 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 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, 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
II
in which R°, R1 and R2 are as defined above, with a compound of formula III
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.
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66214876A | 1976-02-27 | 1976-02-27 | |
| US662,148 | 1991-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095914A true CA1095914A (en) | 1981-02-17 |
Family
ID=24656562
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA272,682A Expired CA1095914A (en) | 1976-02-27 | 1977-02-25 | 4-hydroxy-2-quinolinone-3-carboxylic acid compounds |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS52118475A (en) |
| AT (1) | AT368993B (en) |
| AU (1) | AU516052B2 (en) |
| BE (1) | BE851866A (en) |
| CA (1) | CA1095914A (en) |
| CH (1) | CH626347A5 (en) |
| DE (1) | DE2706752A1 (en) |
| DK (1) | DK73677A (en) |
| ES (1) | ES456325A1 (en) |
| FI (1) | FI770536A (en) |
| FR (1) | FR2342067A1 (en) |
| GB (1) | GB1572920A (en) |
| IE (1) | IE44886B1 (en) |
| IL (1) | IL51548A (en) |
| NL (1) | NL7701925A (en) |
| NZ (1) | NZ183443A (en) |
| PT (1) | PT66238B (en) |
| SE (1) | SE7701834L (en) |
| ZA (1) | ZA771148B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4187309A (en) * | 1977-06-20 | 1980-02-05 | Sandoz, Inc. | 4-Hydroxy-2-quinolinone-3-carboxylic acids and salts thereof |
| JPS54130587A (en) * | 1978-03-30 | 1979-10-09 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
| US4215123A (en) * | 1979-05-07 | 1980-07-29 | American Home Products Corporation | Antisecretory 4-oxy-3-carboxy or cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives |
| DE3420116A1 (en) * | 1984-05-30 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | IMMUNTIMULATING AGENTS |
-
1976
- 1976-02-25 ES ES456325A patent/ES456325A1/en not_active Expired
-
1977
- 1977-02-15 CH CH184477A patent/CH626347A5/en not_active IP Right Cessation
- 1977-02-17 DE DE19772706752 patent/DE2706752A1/en not_active Withdrawn
- 1977-02-18 SE SE7701834A patent/SE7701834L/en unknown
- 1977-02-18 DK DK73677A patent/DK73677A/en not_active Application Discontinuation
- 1977-02-18 FI FI770536A patent/FI770536A/fi not_active Application Discontinuation
- 1977-02-21 GB GB7154/77A patent/GB1572920A/en not_active Expired
- 1977-02-23 NL NL7701925A patent/NL7701925A/en not_active Application Discontinuation
- 1977-02-25 IE IE424/77A patent/IE44886B1/en unknown
- 1977-02-25 BE BE175296A patent/BE851866A/en not_active IP Right Cessation
- 1977-02-25 FR FR7705514A patent/FR2342067A1/en active Granted
- 1977-02-25 CA CA272,682A patent/CA1095914A/en not_active Expired
- 1977-02-25 NZ NZ183443A patent/NZ183443A/en unknown
- 1977-02-25 JP JP1942077A patent/JPS52118475A/en active Pending
- 1977-02-25 ZA ZA00771148A patent/ZA771148B/en unknown
- 1977-02-25 AU AU22716/77A patent/AU516052B2/en not_active Expired
- 1977-02-25 IL IL51548A patent/IL51548A/en unknown
- 1977-02-25 AT AT0126877A patent/AT368993B/en not_active IP Right Cessation
- 1977-02-25 PT PT66238A patent/PT66238B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE851866A (en) | 1977-08-25 |
| AU516052B2 (en) | 1981-05-14 |
| CH626347A5 (en) | 1981-11-13 |
| IL51548A0 (en) | 1977-04-29 |
| JPS52118475A (en) | 1977-10-04 |
| FR2342067A1 (en) | 1977-09-23 |
| IL51548A (en) | 1980-06-30 |
| DE2706752A1 (en) | 1977-09-01 |
| DK73677A (en) | 1977-08-28 |
| PT66238B (en) | 1978-10-13 |
| IE44886B1 (en) | 1982-05-05 |
| ATA126877A (en) | 1982-04-15 |
| AT368993B (en) | 1982-11-25 |
| NL7701925A (en) | 1977-08-30 |
| NZ183443A (en) | 1979-07-11 |
| GB1572920A (en) | 1980-08-06 |
| ZA771148B (en) | 1978-09-27 |
| ES456325A1 (en) | 1978-05-01 |
| FI770536A (en) | 1977-08-28 |
| IE44886L (en) | 1977-08-27 |
| SE7701834L (en) | 1977-08-28 |
| PT66238A (en) | 1977-03-01 |
| FR2342067B1 (en) | 1980-01-11 |
| AU2271677A (en) | 1978-08-31 |
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| MKEX | Expiry |