IE44886B1 - Quinoline carboxylic acid esters - Google Patents

Abstract

The preparation of compounds of the formula I <IMAGE> is described. The process is based on reaction of the corresponding compounds of the formulae II and III <IMAGE> The compounds are used as pharmaceuticals, especially as antiallergics. [GB1572920A]

Description

* «'^ββ IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS This invention relates to 4-hydroxy-2-guinolinone-3-carboxylic acid esters.

The invention provides pharmaceutical compositions 5 comprising compounds of formula Ip R° lp R1 — COOR Ip R2 OH in which R° is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which the 10 ' 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 15 carbon atom, or -‘-"•’i'GC in which n is 0 or 1 and Y and Y* are independently _ 3 - 44886 hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl 5 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 10 Rj and R^ 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 R^ 15 and R2 can be from the group consisting of nitro and trifluoromethyl,or R^ and R2 together form a methylenedioxy group.

The compounds of formula Ip possess pharmacological activity. In particular they possess disodium chromoglycate 20 (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 g) are sensitised 25 by subcutaneous administration of 1 mg of egg albumin 44886 - '4 - (Merck Nr. 967) and 200 mg Λ1(OH)^ in 1 ml of physiological saline and 0.5 ml of Haemophiluspertussis vaccine (Schwei-zerisches Serum and Impfinstltut, Bern; Nr. 115 325; 4 x 1010 organism/ml) intraperitoneally. Fourteen days later, the 5 animals are exsanguinated,the blood centrifuged, the serum collected and deep frozen. The serum thus obtained (antiserum) is injected intradermally (0.1 ml of 1:200 diluted serum per injection site) at four sites on the backs of untreated,female rats. Twenty-four hours later each rat 10 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 15 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 20 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 - 5 - 44885 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 5 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 inhibition 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 15 cells by centrifugation at 350 x g and 4°C, the sediments are taken up in 1 ml of Hank's balanced salt solution (HESS) (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 20 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 2.24/3? of compound 48/80 (N-methylhomoanisylamineformaldehyde condensate; a histamine liberator from Burroughs Wellcome and Co. Inc., 25 Tuckahoe, N.Y. USA), to determine the 48/80 induced histamine release, or 2 ml of HBSS with 2.24/ig of 48/80 _ 6 _ 4 4 8 a β 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 5 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 10 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 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 acceptable base salts, which salt forms have the same order of activity as the free 20 acid forms. Suitable salts include the sodium, potassium and lithium salts.

The compounds of formula Ip may be admixed with conventional pharmaceutically acceptable diluents or carriers and, optionally, other excipients, and administered 25 in such forms as tablets or capsules. 4 4 8 0 6 -Is - The invention further provides novel compounds within the scope of formula ϊρ above. Such novel compounds are those of formula I • R° R1 — COOR I *2 OH 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, 10 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 15 γ and Y* are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl 20 or nitro with the proviso that ‘•^SSq - 8 - only one of Y and Y' can be from the group consisting of nitro and trifluoromethyl, and R, R^ and R2 have the same significances as 5 in formula Xp above, provided that R^ and R^ do not together form a methylenedioxy group, b) R° and R have the same significances as R^ and R in formula Ip above, and R^ and R2 ^ together form a methylenedioxy group, or c) R° is' alkyl of 1 to 6 carbon atoms, R has the same significance as in formula Ip above, and R^ and R2 are independently alkoxy of 1 to 15 4 carbon atoms.

The invention also provides a process for the preparation of compounds of formula I, characterised by reacting a compound of the formula II: R° ·φ>· R2 0 20 in which R°, R^ and R2 are as defined above, with a compound of formula III ^.COOR MCH III- '^COOR 4 48 8 6 - S - 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 5 temperature of from 0°C to 150°C, preferably 60°C to 120°C.

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 dn 10 inert organic solvent, e.g. dimethyl acetamide. The compounds of formula II are either known or may be produced in conventional manner from available materials. For example, l-allyl-6,7-dimethoxyisatoic anhydride may be prepared according to the following reaction scheme: 15 CH,0 _ Ob ^ ’XX CH3° ννΌ0ΟΗ CH3O^^NoOCH3 70% HN03 CH, COOH Y J 0830 W"2 < Hz CH3°YY"N02 % Pd/C AA CH 0 COOCH CH 0 COOCH 3 3 3 3 1) NaOH 2) C0C1 H„0 z " A0 CH30 1) NaH/DMA ^3° ch3o Ay 2|κ·"2·"4 «AV a 4 a 8 e -ΐ.α - 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 inter- Λ converted in conventional manner, and where the salt form is the salt derived from the alkali metal M in the compound 10 of formula XXI, 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 Ip. 75 Preferred groups of compounds of formula I are: a) those in which R° is allyl b) those in which R and R2 are alkoxy, preferably methoxy, preferably in the 6- and 7-positions c) those in which R^ and R^ form a 6,7-methylene- 20 dioxy group.

Particularly preferred is 1-ally1-4-hydroxy- 6,7-dimethoxy-2-quinolinone-3-carboxylic acid ethyl ester. - 11 - . ii»88 Preferred pharmaceutical compositions, other than those comprising a compound of formula I, are those comprising a compound of formula Ip in which R^ and are each alkoxy and R° is hydrogen. R1 and R2 are prefer-5 ably both methoxy, particularly in the 6- and 7-positions.

The following Examples illustrate the invention: - 34886 - 12 - EXAMPLE 1: l-Allyl-4-hydroxy-G , 7-dimothoxy-2-quinolinone- 3-carboxylic acid ethyl ester.

A solution of 5.0 g of l-allyl-6,7-dimethoxyisatoic anhydride, in 50 ml of dimethylacetamide is added, dropwise, 5 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 (57¾ in mineral oil) - first at room temperature and then briefly at 120DC). She resulting mixture is heated at 120°C for 4 hours. The dimethyl 10 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 evaporated in vacuo. The residue is recrystaliised from 15 methylene chloride/diethyl ether, to yield the heading compound, m.p. 165-166°C.

EXAMPLES 2-11 In manner analogous to Example 1, employing appropriate starting materials in approximately equivalent amounts, the 20 following compounds of formula I may be obtained. 2) l-allyl‘-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p. 88-91°C. 3) l-cyclopentyl-4~hydroxy-2"quinolinone-3-carboxylic-acid ethyl ester. 4) l"cyclopropylmethyl-4-hydroxy-2-quinolinone-3- carboxylic acid ethyl ester. „ -13 - 4*88θ 5) 1- io-nitrobenzyl)-4-hydroxy-2-quinoiinone-3-carboxylic acid ethyl ester, m.p. 148-151°C. 6) 1-propargy1-4-hydroxy-2-quinolinone-3-carboxylie acid ethyl ester, m.p. 171-174°C. 7) 1-(p-fluorobenzyl)-4-hydroxy-2-quinolinone-3~ carboxylic acid ethyl ester, m.p. 126-129°C. 8) l-phenyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p. 180-183°C. 9) l-methyl-4*-hydroxy-6,7~methylenedioxy-2-quinolinone- ^ 3-carboxylic acid ethyl ester, m.p. 212-215°C. ) l-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.

EXAMPLES 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: 20 12) l-hexyl~4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p. 64°-66°C. 13) l-ethyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, m.p. 68°-71°C. 14) l-butyl-7-chloro-4-hydroxy-2-quinolinone-3-carboxylic 25 acid ethyl ester, m.p. 54°-55°C. 4 ·3 8 8 S ) l-methyl-4-hydroxy-6-n\ethoxy-2-quinolinone-3~ carboxylic acid ethyl ester, m.p. 130° to 133°C. 16) l-methyl-4-hydroxy-6-chloro-2-quinolinone-3-carboxylic acid ethyl ester, m.p. 132°-135°C. 17) 1-methy1-4-hydroxy-2-quinolinone-3-carboxylie acid ethyl ester, m.p. 100°-102°C. 18) 4-hydroxy-6-methyl-2-quinolinone~3-carboxylic acid ethyl ester. 19) 4-hydroxy-6,7-dimethoxy-2~quinolinone-3-carboxylic 10 acid ethyl ester. ) 4-hydroxy-6"chloro-2-quinolinone-3-carboxylic acid ethyl ester.

EXAMPLES 21, 22: pharmaceutical Compositions Representative pharmaceutical compositions comprising 15 compounds of formula Ip and formula I respectively are capsules prepared by standard techniques to contain the following: Example active ingredient wt.active wt.Kaolin No. ingredient (mg.) 20 _ _ (mg.) _ 21) l-methyl-4-hydroxy-2-quino- 70 210 linone-3-carboxylic acid ethyl estet 22) l-allyl-4-hydroxy-6,7-dimethoxy- 5 275 25 2-quinolinone-3~carbOxylic acid ethyl ester Such capsules may be administered 4 times daily for the treatment of allergic asthma.

Claims (6)

1. A pharmaceutical, composition comprising a compound of formula Ip ft % — COOR Ip R2 OH 5 in which R® is hydrogen, alkyl of 1 to G carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in Which the cycloalkyl part is of 3 to G carbon atoms and the alkyl part is of 1 or 10 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 1 in which n is 0 or 1 and Y and Y' are independently ύ 4 8 8 β - ιε - hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl 5 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 10 R and R are independently hydrogen, fluorine, J· a 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 R, 15 and R2 can be from the group consisting of*nitro and trifluoromethyl,or R^ and R^ together form· a methylenedioxy group , in free acid or pharmaceutically acceptable base salt form, in association with a pharmaceutically acceptable 20 diluent or carrier.

2. A pharmaceutical composition as claimed in Claim 1 in which, in the compound of formula Ip, and R2 do not together form a methylenedioxy group.

3. A pharmaceutical composition as claimed in 25 Claim 1 or Claim 2 in which, in the compound of formula Ip, 44βββ - 17 - R° is hydrogen and R. and R, are each alkoxy. P &, £t

4. A pharmaceutical composition as claimed in Claim 3' in which, in the compound of formula Xp, and R2 are methoxy in the 6- and 7-positions. 5 5. A pharmaceutical composition as claimed in any one of the preceding claims, in unit dosage form. 6. A pharmaceutical composition as claimed in Claim 5 in which the unit dosage forms comprise 5-200 mg of compound of formula Ip. 10 7. A pharmaceutical composition as claimed in Claim 5 or Claim 6, in the form of a capsule. 8. A pharmaceutical composition substantially as described in Example 21 or 22. 9. A process for the preparation of a compound 15 of formula I R°^ Ri — COOR I R2 ' OH in which either a) R° is cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which the cycloalkyl 20 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 «'i 8 8 6 - 18 - atoms in which the unsaturation is on other than the alpha carbon atom, or in which n is 0 or 1 and 5. and Y' are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl 10 or nitro with the proviso that only one of Y and Y' can be from the group consisting of nitro and trifluoromethyl, and R, and R2 have the same significances as in 15 formula Ip, stated in Claim 1, provided that and R2 do not together form a methylenedioxy group, b) R° and R have the same significances as R° and P R.in formula Ip, stated in Claim 1, and R^ 20 and R2 together form a methylenedioxy group, or c) R° is alkyl of 1 to 6 carbon atoms, R has the same significance as in formula Ip, stated in Claim 1, and and R2 are independently alkoxy of 1 to 25. carbon atoms, characterised by reacting a compound of the formula ΪΙ: - 19 _ 44886 R° R2 Ο in which R°, R^ and R2 are as defined above, with a compound of formula III ^.COOR MCH III Nv^coor 5 in which R is as defined above, and M is an alkali metal, in an inert organic solvent. 10. A process as claimed in Claim 9, substantially as described in any one of Examples 1-19. 10 11. A compound of formula I, stated in Claim 9, whenever prepared by the process of Claim 9 or Claim 10. 12. A compound of formula I, stated in Claim 9. 13. A compound of formula I, stated in Claim 9, in which R° is cycloalkyl of 3 to 6 carbon atoms, cyclo-15 alkylalkyl 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 a-!8 8G — 20 - 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 5. and Y* are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 % carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluororr.ethyl 10 ’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 15 R^ and Rj -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 R^ 20 and R^ can be from the group consisting of nitro and trifluoromethyl. - 21 - 41 4 8 8 θ « 14. A compound as claimed in Claim 13 in which R° is allyl. ' 15. A compound as claimed in Claim 13 or Claim 14 in which R^ and are both alkoxy. 5 16. A compound as claimed in Claim 15 in which R^ and Rj are methoxy in the 6- and 7-positions. 17. l-Allyl-4-hydroxy-6,7-dimethoxy-2-quinolinone-3-carboxylic acid ethyl ester. 18. 1-Ally1-4-hydroxy-2-quinolinone-3-carboxylic 10 acid ethyl ester.> . 19. l-Cyclopentyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester. . 20. l-Cyclopropylmethyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester. 15 21. 1-(o-Nitrobenzyl)-4-hydroxy-2-quinolinone-3- carboxylic acid ethyl ester. 22. l-Propargyl-4-hydroxy-2-quinolinone-3-carboxylie acid ethyl ester. 23. 1-(p-Fluorobenzyl)-4-hydroxy-2-quinolinone-3- 20 carboxylic acid ethyl ester. 24. l-Phenyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester. 25. A compound of formula I, stated in Claim 9, .-22- ί-ϋθΒβ in which 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 5 atoms and the alkyl part is of 1 Or 2 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms in which the un-saturation is on other than the alpha carbon atom, or 10 in which n is 0 or 1 and- Y and Y’ are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 15 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 20 nitro and trifluoromethyl, R is alkyl of 1 to 4 carbon atoms, and and R2 together form a methylenedioxy group. 26. A compound as claimed in Claim 25 in which the methylenedioxy group bridges the 6- and 7-positions. - 23 - 4488* 27. A compound as claimed in Claim 25 or 26 in which R° is allyl. 25. A compound as claimed in Claim 25 or 26 in which R° is alkyl. 5 29. 1-Allyl-4-hydroxy-6,7-methylenedioxy-2- quinolinone-3-carboxylic acid ethyl ester. 30. l-Methyl-4-hydroxy-6,7-methylenedioxy-2-quinolinone-3-carboxylic acid ethyl ester. 31. A compound of formula I, stated in Claim 9, TO in which R° is alkyl of 1 to 6 carbon atoms R is alkyl of 1 to 4 carbon atoms and R1 and R£ are each alkoxy of 1 to 4 carbon atoms. 32. A compound as claimed in Claim 31 in which R° is methyl. 15 33. A compound as claimed in Claim 31or 32 in which R^ and Rj are methoxy in the 6- and 7-positions. 34. l-Methyl-4-hydroxy-6,7-dimethoxv-2-quinolinone-3-carboxylic acid ethyl ester. 35. A compound as claimed in any one of Claims 20 11-34 in base salt form. 36. A pharmaceutical composition comprising a compound as claimed in any one of Claims 11-34, in free acid or pharmaceutically acceptable, base salt form, in association with a pharmaceutically acceptable diluent 25 or carrier. Dated this 25th day of February, 1977. BY: TOMKINS &(\C0., Appl 1 cants regents, (Signed) 4-J88G - 15 -

5. Dartmouth Road, DUBLIN

6.