NZ187156A - Dioxodihydropyranoquinolinedicarboxylic acid derivatives and analogs - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 87156 1 87156 | Priority Dxici?}: 4r'r>.'77,/.. {'."7.7 ... } r. . 3 *S • ~7% I <* f.- w.w Hi t m vlJt F» r» I I 0 . ..: 3O rt^19W t \&S(a AMENDED under Section _JL/. of th Patonts Act 1953 from ASSISTANT CQt-lK^^^F^^^TENTS ^ ?$• F% ga mt < NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION "COMPOUNDS" J:/We, FISOHG LIIIITED a British company of Fison House, 9 Grosvenor Street, London, England hereby declare the invention for which / we pray that a patent may be granted to ihk/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - \ J&/WT 18715 6 £A-tS95777r This invention relates to new pyranoquinolinone derivatives, ^ , , _ . . . oac^ "tieuT use ^ j P & S. compositions containing them and methods for their preparation^ ^ ^ According to our invention we provide compounds of formula I, ?S ■V in which an adjacent pair of Rg, R^, and Rg form a chain -COCH^CE-O-, and the remainder of Rg, Rg, R^ and Rg, which may be the same or different, each represent hydrogen, hydroxy, alkyl, halogen, alkenyl, alkoxy, or -NR^ in which and R2, which are the sane or different, are each hydrogen or alkyl, Rg is hydrogen, alkyl, alkenyl or phenyl-alkyl, and ■> u>kvcJ^ rroujUe ite Scx/we ckC^-fer A. J. P. & S. -<2-£^kE^is -OOOH, a 5-tetrazolyl group or an (N-tetrazol-5-yl) cj.-j _£o carboxamido group, and pharmaceutically acceptable derivatives thereof. According to our invention we also provide a process for the 20 production of a compound of formula I, or a pharmaceutically acceptable derivative thereof, which comprises, (a) producing a compound of formula I in which/Eis -COCH by J - & S. '1w ' selectively hydrolysing or oxidising a compound of-formula II, 187156 ii i,n which Rg is "as defined above", - R5a, Rga, R.?a and Rga have the same significances as R5, Jtg, R^ and Rg above, save than an adjacent pair of R^a, Rga, R^a and R^a instead of forming a chain -C0CE=C(E)0- represents a chain of formula -COCH=C(D^)0- and D and D1 which may be the same or different, each represents a -COOH group or a group hydrolysable or oxidisable to a -COOH group, provided that only one of D and D-l represents a -COOH group, (b) producing a compound of formula I in which_ each E is -COOH cyclising a compound of formula III or IV, fcb COOH III V Rg or an ester of either thereof, COOH COOH IV V JKUWr 18715 6 in which Rg is as defined above, oad- Rgb, Rgb, Ryb and Rgb have the same significances as Rg, Rg, R- and Rg above, save that an adjacent pair of R^b, R*b, R-b and 8«.^* ccxn cdto Rgb nam represent the pair of groups -H and -O-C((XX3H)<H-00CH, # h . ^ecxciv (c) producing a compound of formula I in which^E is -COOH by cyclising a compound of fornula V, COOH V Rg or an ester thereof, in which Rg is as defined above, RgC, RgC, RyC and RgC have the same significances as Rg, Rfi, 15 R^ and Rg above save that an adjacent pair of RgC, R^c, R^c and RgC, instead of forming a chain -Q0CH=C(C0CH)-O-, represent the pairs of groups: * (i) -OOO^GO-COR" or -aXH=C(C00H) -NL^, or a suitable derivative thereof; and -CM or a halogen atom, or 20 (ii) -H and -0-C(C0R")=CH-C0R" R" represents -CM, or a group which" is hydrolysable thereto, Lj and which may be the same or different are each hydrogen, aryl or alkyl, or together form a saturated or unsaturated alkylene chain, and 25 M represents hydrogen or an alkali metal, NOW AMENDED and if necessaiy or desired hydrolysing the group a group -OOQM, (d) conversion of a compound of formula VI, 187156 V Ryd' 1.p-* s' i-ju-*9-- or an ester thereof, in which Rg and E ayfe as defined a ove, R«jd, R^d, Ryd andyftgd have the s^xne significances as R^, R^, that an'.^djacent pair of Rgd, Rgd, and Rg above ave form an -a\CH0) S- 4 Tl Rutland RgdLcan also CtndL the pairs of jgroups R„ an ' R1Q/ which pairs of grouns may be the same or/different, t; >gether and form =S or = 0 or together fh in which n is 2 or 3, orovided that only oneypair R^, R, may represent =0, to fa. correspon fng compound of formula I, (e) /Selectively y1 moving the groups A and B from a compound of fibrmula VII, >R", to the chain -C(R9R10)=CE-0-, VII rester thereof, lich Rg and E are as defined above, NOW AMENDED - AS AMENDED 18715b and if necessary or desired hydrolysing the groiip -COR", to a group -COOM, (d) conversion of a compound of formula VI, or an ester thereof in which Rg and £ are as defined above, Rjd, R^d, R7d and R,d have the same significances as Rj, Re, R,, and R, above save that an adjacent pair of Rjd, R6d, R,d and Rgd can also represent the chain -C(R9R10)CH=CE-O-, and the pairs of groups R, and R10, which pairs of groups may be the same or different, together form =S or =0 or together form an -S^H^S- chain in which n is 2 or 3, provided that only one pair R^ and R10 may represent =0, to a corresponding compound of formula I, (e) selectively removing the groups A and B from a compound of formula VII, h K '6 VI * -Rg RSe 0 A H E VII V Rg B or an ester thereof in which Rg and E are as defined above, 187156 Rge, Rge, R^e and Rge havejthe same significances as R5, Rg, R? and Rg above save that j an adjacent pair of R,.e, Rge, R7e and Rge can also represent a chain -COCHA-CBE-p-, , and in the pairs of groups A and B, which pairs of groups may be same or different, both A and B are hydrogen, or one of A and B is hydrogen and the other is halogen or hydroxy, or A and B together form a double bond, provided that both pairs of A and B do not form double bonds, (f) producing a compound of formula I in which each E is -COOH by cyclising a compound of formula VIII, VIII COOH or an ester thereof, in which Rg is as defined above, Rgf/ Rgf, R?f and Rgf have the same significances as Rg, Rg, R7 and Rg above save that an adjacent pair of R^f, Rgf» R^f and Rgf/ instead of forming a chain -COCH=C(COOH)-O-, represent the pair of groups -COCHtSORj Q)-CH(OH)-COOR" and -0M, R" and M are as defined above, and R10 represents an alkyl C 1 to 10 group, (g) producing a compound of formula I in which each E is a 5-tetrazolyl group by reacting a corresponding compound of formula I in which each E is -CN, ;r 187156 vdth an azide in a solvent which is inert under the reaction conditions, or (V) . -€A.cjL ^ p. -09- producing a compound of formula I in which^E is an (N-tetrazol~ j2Ack - £e> 5-yl)carboxamido group by reacting a corresponding compound of formula I in which^E is -COOH, or an acid halide, ester or mixed anhydride thereof, with 5-aminotetrazole, and if necessary or desired hydrolysing the ester of the compound of formula I and/or converting the compound of 10 formula I to a pharmaceutically acceptable derivative thereof.

In process (a) the group D may be, for example an ester, acid halide, amide or a nitrile group, which may be hydrolysed to a -COOH group. The hydrolysis may be carried out using conventional techniques, for example under mildly basic 15 conditions, e.g. using sodium carbonate, sodium hydroxide, sodium bicarbonate, or under acidic conditions, e.g. a mixture of aqueous dioxan and hydrochloric acid, or hydrogen bromide in acetic acid. The hydrolysis may be carried out at a temperature of from about 25° to 120°C depending on the compounds used. 20 Alternatively the group D may be an alkyl, e.g. a lower alkyl such as methyl, a hydroxymethyl, an aralkenyl, e.g. styryl, an acyl, e.g. a lower alkanoyl such as acetyl, or a fonnjrl group. The oxidation may be carried out using conventional techniques which do not otherwise modify the molecule to such an extent that 25 the yield of the desired product is uneconomical , for example an 187156 alkyl or a hydroxymethyl group may be oxidised using selenium dioxide, e.g. under reflux in aqueous dioxan; or chromic acid, e.g. under reflux in aqueous acetic acid. Aralkenyl groups may be oxidised using, for exanple neutral or alkaline potassium 5 permanganate in aqueous ethanol, and acyl groups may be oxidised using, for exanple chromic acid or an aqueous hypochlorite, e.g. sodium hypochlorite. The formyl group may be oxidised using, for exanple chronic acid or silver oxide.

In process (b) the cyclisation may be carried out by treating 10 the conpound of formula III or IV, vdth a cyclising agent, for exanple a dehydrating agent such as chlorosulphonic, sulphuric or polyphosphoric acid. The reaction is preferably carried out tinder anhydrous conditions and may be carried out at a tenperature of from about 25° to 150°, and preferably from 75° to 150°C. We 15 have found that isomerisation of the maleic acid derivative of formula IV to the corresponding fumaric acid derivative of formula III takes place when polyphosphoric acid is used to cyclise these compounds to a conpound of formula I, thus enabling a satisfactory yield of -the conpound of fonnula I to be obtained 20 from a prima facie unsatisfactory mixture of compounds of formulae III and IV. Compounds of formula III may also be cyclised by subjecting the conpound to an elevated tenperature, e.g. of from 200 to 250°C, optionally in the presence of a high boiling solvent which is inert under the reaction conditions, e.g. diphenyl ether. 25 When one of the groups is -CM the cyclisation of process •09/B/B7 187156 (c) (i) may be carried out by heating, or under basic or neutral conditions. It is however preferred to carry out the cyclisation in the presence of an acid, e.g hydrochloric acid, and in a solvent which is inert under the reaction conditions, e.g ethanol. 5 The reaction may be carried out at from about 20° to 150°C. The group -COR" is preferably an ester grot?), e.g R" may be a lower alkoxy group. When one of the groups is -CQCH=»C(000H)-NL-^ the derivative of the -COOH group may be a group -CONLjl^ in which and are as defined above. It is preferred that and are 10 hydrogen, phenyl, alkyl C 1 to 6 or together form a 4 or 5 membered alkylene chain, e.g. together with the nitrogen atom form a piperidine ring. When one of the groups is halogen the cyclisation may be carried out in a solvent which is inert under the reaction conditions, preferably a high boiling polar solvent, 15 e.g pyridine, dime thy lfomaraide orhexamethylphosphorand.de. The reaction is preferably carried out with the aid of a strong base, for exanple an alkali metal hydride, e.g sodium hydride. The reaction is preferably carried out at a tenperature of from about 80° to 200°C, in the absence of free oxygen, e.g under an inert 20 atmosphere such as nitrogen.

Hie cyclisation of process (c)Cii)~may be carried out by treating the conpound of formula V with a cyclising agent, for example a dehydrating agent such as chlorosulphonic, polyphosphoric or inilphuric acid. Ihe reaction is preferably carried out under 25 anhydrous conditions and may be carried out at a tenperature of ^10/D/87 - 187156 from 0° to 100°C. Alternatively cyclisation may be achieved by converting the free carboxy groins of the cojnpound of fornula V to acyl halide groups and subjecting the resulting acyl halide to an intramolecular Friedel-Crafts reaction.

In processes (d), when Rg and together form a chain -S- (GH^^-S-, the conversion may comprise oxidative hydrolysis and may be carried out in an aqueous polar organic solvent, for exanple aqueous ethanol, acetone or te tr ahydTO fur an. The oxidative hydrolysis may be carried out in the presence of an 10 oxidising agent, for exanple mercuric chloride, an N-halosuccin-imide such as N-bxomo- or N-chloro-succinimide, a per-acid such as periodic add; or £-toluenesulphonchloramide or a salt thereof. When mercuric chloride is used the reaction may be carried out in the presence of a base, e.g. mercuric oxide, 15 cadmium carbonate or calcium carbonate. N-halosuccinimides may be used alone or in the presence of a silver salt, e.g. ilver perchlorate, or silver nitrate. The reaction may conveniently be carried out at a tenperature of from about 15° to 100°C.

When Rg and R^g together form a =S group the conversion may 20 comprise (oxidative) hydrolysis and may be carried out in the p £$. presence of a heavy metal compound, e.g. a conpound of group lb, go lib or Illb of the Periodic Table of Mendeleef, as catalyst * Suitable compounds include mercury, thallium and silver compounds, e.g. mercury (II) acetate or chloride, thallium (III) trifluoro-25 acetate, or silver oxide. The reaction may be carried out in the <ufmr 187156 presence o£ water and an organic solvent system such as acetone-acetic acid, alkanols, tetrahydrofuran/methanol, or tetrahydro-furan. Alternatively the reaction may be carried out by alkylation followed by hydrolysis. In such cases the reaction may be effected 5 by (i) an alkyl halide or sulphonate (e.g. methyl iodide), in a moist solvent, e.g. acetone, (ii) an alkylfluorosulphonate and water in sulphur dioxide, or (iii) a trialkyl oxonium fluoroborate followed by aqueous sodium hydroxide.

When both A and B are hydrogen process (e) is a 10 dehydrogenation and may be carried out by oxidation using a mild oxidising agent, for exanple selenium dioxide, palladium black, chloranil, lead tetraacetate or triphenyl methyl perchlorate. Alternatively the dehydrogenation of a conpound of fomula VII in which both A and B are hydrogen may be carried out indirectly by 15 halogenation followed by dehydrohalogenation, e.g. by treatment vdth N-bromosuccinimide or pyridinium bromide perbronri.de to yield a conpound of fornula VII in which A is halogen and B is hydrogen, which is subsequently dehydrobrominated. When one of A and B is hydroxy the dehydration may be catalysed by an acid, e.g. sulphuric 20 or oxalic acid; a base, e.g. potassium hydroxide; or a salt, e.g. potassium hydrogen sulphate; or N-bromosuccinimide. The reaction may be carried out in a solvent which is inert under the reaction conditions, e.g. a halogenated hydrocarbon, xylene, or glacial acetic acid. The reaction may be carried out at an 25 elevated tenperature, e.g. from 20 to 150°C. -12/D/C7 187156 The cyclisation of process CO may be carried out in a solvent which is inert under the reaction conditions, e.g. diethyl ether or benzene. The reaction may also, if desired, be carried out in the presence of a Lewis acid, e.g. boron trifluoride. The reaction is preferably carried out at a tenperature of from 10 to 120°C in presence of an organic base, . P & S. pi'perrdine.

•J- ' e.g./pxparidonoi Suitable solvents which are inert under the reaction conditions of process (g) include those in which both the reagents are soluble, 10 e.g. N,N-dimethylformandde. Other solvents which may be mentioned include dimethylsulphoxide, tetrahydrofuran, diethyl glycol and ethyl methyl glycol. Ihe reaction is preferably carried out at a temperature of from about 20° to 130°C for from about 1 to 20 hours. The azide used in the reaction is preferably ammonium or an alkali 15 metal azide, e.g. sodium or lithium azide, but other azides, e.g. aluminium azide or the azides of nitrogen containing bases, e.g. mono-, di-, tri-, and tetra- methyl- ammonium, anilinium, morpholinium and piperidinium azides, may also be used if desired. Vihere an azide other than that of an alkali metal is used this 20 azide may be prepared in the reaction mixture by double decomposition. Hie reaction may, if desired, be carried out in the presence of an electron acceptor, e.g. aluminium chloride, boron trifluoride, ethyl sulphonic acid or benzene sulphonic acid. As an alternative -to the reaction conditions set out above, the reaction may be 25 carried out using hydrazoic acid (hydrogen azide) at a tenperature <13/B/S7- 187156 of from about 20° to 150°C in a suitable solvent, under greater than atmospheric pressure. When an azide other than hydrazoic acid is used, e.g. sodium azide, the product of the reaction -will be the corresponding tetrazole salt. This salt may readily be 5 converted to the free acid by treatment vdth strong acid, e.g. hydrochloric acid.

In process (h) the anhydride is preferably a mixed anhydride of such a type that it vdll cleave preferentially, to give the desired chromone carboxamidotetrazole, as the major product when 10 reacted with the 5-aminotetrazole. Examples of suitable acids from which the mixed anhydride may be derived are sulphonic acids e.g. benzene sulphonic acid, sterically hindered carboxylic acids, e.g. pivalic, isovaleric, diethylacetic or triphenylacetic acid, and alkoxy formic acids, e.g. a lower alkoxy formic acid 15 such as ethoxy or isobutoxy formic acid. When an acid halide is used it may conveniently be an acid chloride. The reaction is preferably carried out under anhydrous conditions in a solvent which vdll not react vdth either the 5-aminotetrazole or the mixed anhydride or acid halide, e.g. pyridine or dimethylformamide. 20 However when the reaction is carried out in a non-basic solvent, e.g. dimethylformamide, an adequate proportion of an acid acceptor, e.g. triethylandne, should also preferably be present. The reaction is preferably carried out at a tenperature of from . & S. about -15° to +20°C. When an ester is used we. prefer to use a if aJUiSjl ^ .^. .25. lowerester and to carry out the reaction in a solvent 187156 which is inert under the reaction conditions, e.g. glacial acetic acid, at a tenperature of from about 100 to 150°C. When a conpound of fornula I in which E is -COOH is used as starting material the reaction nay be carried out by heating the conpound 5 of fornula I and the 5-aminotetrazole in a solvent which is inert under the reaction conditions, e.g. dimethylacetamide, at a tenperature of from 100 to 200°C. Alternatively the reaction may be carried out in the presence of a condensation agent, e.g. N,N'-carbonyl-diimidazole or dicyclohexyl carbodiimide, in an 10 aprotic solvent, e.g. dimethylformamide, at a tenperature of from about 10 to 40°C.

The starting materials for process (b) may be made by reacting a conpound of formula IX, hh NHRg in which Rg, R^b, R^b, R^b and Rgb are as defined above, with 20 a conpound of formula X, Da-C^C-Da X in which Da is an ester group, to produce a mixture of compounds of formulae XI and XII, Azf&rsr 187156 XI Ryb in which Rg, Da, Rgb, R^b, R?b and Rgb are as defined above. The conpounds of formula XI and XII may be hydrolysed to give compounds of formulae IV and III. Alternatively the groups Da in the conpounds of formulae XI and XII may be converted using 10 conventional techniques known per se, to other groups D and the resulting conpounds cyclised, using the same conditions as for process (b) above, to yield a conpound of fomula II. As a further and preferred alternative the conpounds of formula XI and XII may "be cyclised, using the same conditions as for process (b) above, 15 to give a conpound of fornula II in which D is an ester group, and the resulting conpound of formula II is used itself in process (a), or the D grovp converted to another group D, e.g an acid halide, amide or nitriie group, using techniques known per se. conpound in which Da has been converted to D) is the only isomer which can cyclise to give the required conpounds of fomula II. The proportion of the two isomers may be readily determined by nuclear magnetic resormance spectroscopy and we have found that, in general, the desired fumaric acid derivative is only a minor 25 proportion of the mixture of isomers obtained from the reaction.

The fumarate isomer of fornula XII (or the corresponding 187156 The compounds of fonnula V, in which an adjacent pair of R^c, I^c, RyC and RgC represent the groups -COQ^COCOR" and -CM or halogen, may be made by reacting a conpound of fornula XIII, XIII :ooh i or an ester thereof, in which Rg is as defined above, and Rgg, Rgg, Ryg and Rgg have the same significances as Rg, Rg, Ry and Rg above, save that an adjacent pair of Rgg, Rgg, R^g and Rgg, instead of forming a -C0CH=CH(COOH)-0- chain, represent the groups -GOCHj and -CM or halogen, in which M is as defined above, 15 vdth a compound of fomula XIV, R'CZ-CZR" XIV in vfoich R" is as defined above, R' is a suitable leaving group, e.g an alkoxy, halo, amino, 20 alkylanino, substituted amino (e.g an axylsulphonylamino group) or substituted alkylamino group, reactive vdth the carbanion of the -OOCHj group of the compound of fornula XIII, and each Z is a carbonyl oxygen atom, or one Z may represent two halogen atoms and the other a carbonyl oxygen atom, and if necessary hydrolysing the resulting conpound to a • •■■17/D/07' 187156 conpound of formula V. The preferred conpounds of formula XIV are dialkyl oxalates, e.g diethyl oxalate.

Conpounds of formula V bearing a -C0CHaC(COOH)~NL-jL2 group, or a derivative thereof, may be made from known conpounds in one 5 or more steps using processes known per se.

The conpounds of formula II may be made as described above or by a process analogous to process (c)(i).

Alternatively the conpounds of formula II may, for exanple in the case of the acid halide, the amide and the nitrile, be 10 made from conpounds of formula I using conventional techniques, e.g reaction of an ester of the conpound of formula I with ammonia to produce the amide, followed by dehydration of the amide to form the nitrile.

The conpounds of formula V carrying substituents -H and 15 -O-C (COR") =CH-C0R" may be made by reacting a conpound of formula XV, tah O XV COOH or an ester thereof, (U- o0 ka is cs*>o^e, aj\& in which^Rgh, Rgh, Kfi and Rgh have the same significances as Rg, Rg, Ry and Rg above, save that an adjacent pair of Rgh, Rgh, Ryh and Rgh, instead of forming a -CX)CH»C(C0OH)-O- chain, iQ/D/87— 187156 represent the groups -H and -OH, vdth a dialkyl acetylene dicarboxylate, in conventional manner, followed if necessary by hydrolysis of the reaction product.

Conpounds of formula VIII may be made by reacting a conpound of formula XVI, or an ester thereof, in which Rg is as defined above, Rgi, Rgi, Ryi and Rgi have the sane significances as Rg, Rg, 15 Ry and Rg above, save that an adjacent pair of Rgi, Rgi, Ryi and Rgi, instead of forming a chain -COCH=C(COOH)-0-, represent the pair of groups -OH and -COOAlkyl, vdth a methyl alkyl sulphoxide anion, e.g. the anion of dimethyl sulphoxide, and reacting the resulting £-hydroxy-2 -alkylsulphiny 1 compound with glyoxalic acid or an ester thereof. 1 The conpounds of formula I in which E is -CN may be made by dehydrating the corresponding pyranoquinolinone amide using, for example, phosphorus oxychloride, as dehydrating agent. The reaction is 25 preferably carzled out using at least one molar equivalent of ^te/B/87 18715 6 dehydrating agent per mole of the pyranoquinolinone amide. Where the dehydrating agent reacts vdth one of Rg, Rg, R^ or Rg (e.g. a siibstituent comprising an -OH group) sufficient dehydrating agent should be used to satisfy the side reaction as well as the main 5 reaction. The reaction may, if desired, be carried out in the presence of an acid binding agent, e.g. triethylamine. The reaction may be carried out in the presence of a solvent, e.g. N,N-dimethyl-formandde, dimethyl sulphoxide, pyridine, benzene or hexamethyl phosphoramide, or an excess of the dehydrating agent may be used 10 as the reaction medium. The reaction may be carried out at a tenperature of from about 0° to 200°C depending on the dehydrating agent used. When phosphorus oxychloride is used a tenperature of from 0° to 100°C is preferred.

The chromone amide starting materials may be made by 15 reacting a corresponding pyranoquinolinone ester vdth ammonia, using techniques conventional in the production of amides from esters, e.g. using an alkanol as solvent at a temperature of 0° to 120°C.

Conpounds of formulae VI, VII, IX, XIII, XIV, XV and XVI are either known or may be made from known conpounds vising conventional 20 techniques known per se.

The processes as described above may produce the conpound of fornula I or a derivative thereof. It is also within the scope of this invention to treat any derivative so produced to liberate the free compound of fornula I, or to convert one derivative into 25 another. 187156 The conpounds of fornula I and the intermediates therefore may be isolated from their reaction mixtures using conventional techniques.

Pharmaceutically acceptable derivatives of the conpounds of 5 formula I include pharmaceutically acceptable salts, and when E is a -COOH group, esters and amides of the 2-carboxylic acid group. Suitable salts include ammonium, alkali metal (e.g sodium, potassium and lithium) and alkaline earth metal (e.g. calcium or magnesium) salts, and salts with suitable organic bases, e.g. salts with . 10 hydroxyl amine, lower alkylaraines such as methylamine or ethyl amine, with substituted lower alkylamines, e.g hydroxy substituted alkylamines such as tris (hydroxymethyl) me thy lamine, or with simple monocyclic nitrogen heterocyclic conpounds, e.g piperidine or morpholine. Suitable esters include sinple lower alkyl esters, 15 e.g the ethyl ester, esters derived from alcohols containing basic groups, e.g di-lower alkyl amino substituted alkanols such as the fr(diethylamino)-ethyl ester, and acyloxy alkyl esters, e.g a lower acyloxy-lower alkyl ester such as the pivaloyloxymethyl ester, or a bis-ester derived from a di-hydroxy conpound, e.g a di(hydroxy-lower 20 alkyl) ether, e.g the bis-2-oxapropan-l,3-diyl ester. The pharmaceutically acceptable acid addition salts of the basic esters, and also of those compounds in which one of Rg, Rg, R^ and Rg is a group -NR^, e.g the hydrochloride, the hydrobromide, the oxalate, the male ate or the fumarate salts, may also be used. The esters 25 may be made by conventional techniques, e.g esterificatiom or - ^l/B/87 187156 transesterifi cation. The amides may be, for exanple, unsubstituted or mono- or di- C 1 to 6 alkyl amides and may be made by conventional techniques, e.g reaction of ?n ester of the corresponding acid vdth ammonia or an appropriate amine. 5 The conpounds of fornula I and pharmaceutically acceptable derivatives thereof are useful because they possess pharmacological activity in animals; in particular they are useful because they inhibit the release and/or action of pharmacological mediators which result from the in vivo conbination of certain types of 10 antibody and specific antigen, e.g the combination of Teaginic antibody vdth specific antigen (see Exanple 27 of British Patent Specification No 1,292,601). The new conpounds have also been found to interfere vdth reflex pathways in experimental animals and man and in particular those reflexes associated with lung 15 function. In man, both subjective and objective changes which result from the inhalation of specific antigen by sensitised siibjects are inhibited by prior administration of the new conpounds. Thus the new conpounds are indicated for use in the treatment of reversable airway obstruction and/or to prevent the secretion of 20 excess nucous. 1he new compounds are thus indicated for the treatment of allergic asthma, so-called 'intrinsic' asthma (in which no sensitivity to extrinsic antigen can be demonstrated), bronchitis, coughs and the nasal and bronchial obstructions associated with the common colds. The new conpounds may also be of value in the 25 treatment of other conditions in which antigen-antibody reactions or 1 871 5 6 'xwxr excess mucous secretion are responsible for, or are an adjunct to, disease, for exanple, hay fever; certain eye conditions, e.g trachoma; alimentary allergy, e.g urticaria and atopic eczema; and gastrointestinal conditions, for exanple gastrointestinal allergy, 5 especially in children, e.g milk allergy, or ulcerative colitis.

For the above mentioned uses the dosage administered mil, of course, vary vdth the conpound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds aTe 10 administered at a dosage of from 0.001 to 50 mg per kg of animal body weight in the test set out in Exanple 27 of British Patent Specification No 1,292,601. For man the indicated total daily dosage is in the range of from 0.01 mg to 1,000 mg preferably from u k0 .-.3. 0.01 mg to 200 mg and more preferably from 1 mg tomg, which may be administered in divided doses from 1 to 6 times a day or in sustained release form. Thus unit dosage forms suitable for administration (by inhalation or oesophageally) comprise from 0.01 mg to 50 mg, preferably 0.01 mg to 20 mg and more preferably from 0.01 mg to 10 mg of the compound preferably admixed vdth a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.

The conpounds of formula I, and pharmaceutically acceptable derivatives thereof, have the advantage that they are more efficacious in certain pharmacological models, or are longer 25 acting than conpounds of similar structure to the conpounds of 187156 --23 - formula I. Furthermore the compounds of formula I, and pharmaceutically acceptable derivatives thereof, are advantageous in that they are more efficaceous in interfering with reflex pathways and in inhibiting the secretion of mucous than are compounds of similar structure to the compounds of formula I.

We prefer each of those of Rg, R,., Rg, R^ and Rg, which do not form part of the ~C0CF=CE-0- chain, when they contain carbon,to contain up to 8, and preferably up to 4 carbon atoms. Specifically we prefer those of Rg, Rg, R? and Rg which do not fori part of the -C0CH=CE-0- chain to be selected from hydrogen, metho: propyl, allyl, methyl, ethyl, chlorine, bromine and hydroxy. The -C0CH=CE-0- chain may be bonded to the benzene ring in any sense and in any of the adjacent positions Rg, R^, Rg. However, we prefer the chain to be bonded in the positions Rg and Ry the -0-part of the chain being in position R^. We also prefer the group E to be a -COOH group.

According to the invention there is also provided a process for the production of a pharmaceutically acceptable salt of a compound of fornula I, which comprises treating a compound of fornula Ic, ?S3 o v- *7* ~" x V Rg in which Rg is as defined above, Rgj, Rgj, Ryj and Rgj have the same significances as H. v Kj and Rg above, save that an adjacent pair of Rgj, Rgj, R^j and Ic 1 871 56' -Q3/B/30 h>' ££•'* P Rgj may form a chain -0-C(X)»CHC0-, and y I-JUICL ivvo-vj Ue tLe S3cuv\e or cAeffC/eyv/Tj X^is a 5-tetrazolyl group, an (N-tetrazol-5-yl)carboxamido group, a carboxylic acid group (or an ester thereof, or another salt thereof), a nitrile group, an acid halide group or an amide 5 group, vdth a conpound containing an available pharmaceutically acceptable cation and capable of converting the group X to a pharmaceutically acceptable salt of an E group.

Compounds capable of converting the group X to a 10 pharmaceutically acceptable salt of an E group include conpounds, e.g bases and ion exchange resins, containing pharmaceutically acceptable cations, e.g sodium, potassium, calcium, ammonium and appropriate nitrogen containing organic cations. In general we prefer to form the pharmaceutically 15 acceptable salt by treating the free acid of formula I vdth an appropriate base, e.g vdth an alkaline-earth or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution or by a metathetical process vdth an appropriate salt. When a strongly basic conpound is used care should be taken, e.g by keeping the 20 tenperature sufficiently low, to ensure that the conpound of formula I is not hydrolysed or otherwise degraded. Hie pharmaceutically acceptable salt may be recovered from the reaction mixture by, for exanple, solvent precipitation and/or removal of the solvent by evaporation, e.g by freeze drying. 25 According to our invention we also provide a pharmaceutical composition comprising (preferably less than 80%, and more preferably less than 50% by weight) of a confound of formula I, or a pharmaceutically acceptable derivative thereof, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are:- for tablets capsules and dragees; nicrocrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories, natural or hardened oils or waxes; and for inhalation compositions, coarse lactose. The conpound of formula I, or the pharmaceutically acceptable derivative thereof, preferably is in a form having a mass median diamster of from 0.01 to 10 microns. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilizers, sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form. We prefer compositions which are designed to be taken oesophageally and to release their contents in the gastrointestinal tract.

The 5-tetrazolyl and (N-tetrazol-5-yl)carboxamido groups are of formulae XVII and XVIII respectively, N N N M XVII c \ N N XVIII H 187156 'ilie groups of formulae XVII and XVIII may exist in tautomeric forms find swell t;uitumeric forms are included within the definition of the conpounds of fornula I.

In this specification the term 'lower' when applied to a carbon containing group is used to mean such a group containing up to and including 10 carbon atoms.

Hie inventiou is illustrated, but in no way limited by the following I:Xc'iiii|)lc*s- Example 1 4,6-l)io.\o-]<) propy 1 -4M.f)H-pyranoZr3t2-g^quinolinc-2,8-dic,arboxylic acid (a) 4 - Acc t arii di>- 2 - a 11 yloxyacetophenone 4-;\cetaiui «lo-2-hydroxyacetophenone (19.3g) allyl bromide (12.1 ml) and anhydrous jiotassium carbonate (21.Sg) were stirred in dry dimethylforinaniidc (250 ml) at room tenperature for 24 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. 'Hie organic solution was then washed well with water dried uvor magnesium sulphate and evaporated to dryness. The sub-title product was obtained as buff coloured solid (20.5g). The structuio of the product was confirmed by NMR and mass spectroscopy. (b) 4-Acctamido-3-allyl-2-hydroxyacetophenone Ihc above allyl ether (18.4g) was heated at 200-210°C for 4 hours. 17.1^ of the thermally rearranged sub-title product was obtained as a brown solid. Again the structure was confirmed by MIR and miss sjiectroscopy. (c) 4-Acctamido-2-hydroxy-3-propyl acetophenone The product of step (b) (17g) was dissolved in glacial acetic acid and hydrogenated in the presence of Adams catalyst until hydrogen uptake had ceased. The catalyst was filtered off through T-oefBrsS" 187156 a kieselguhr filter and the filtrate was evaporated to leave 13.Og of almost colourless solid. The mass and NMR spectra confirmed the structure of the product. (d) Ethyl 7-acetainido-4-oxo-8-propyl-4H-l-benzopyrari-2-carboxylate 5 A mixture of diethyl oxalate (19.3g; 17.9 ml) and the above product of step (c) (12.4g) in dry ethanol (100 ml) was added to a stirred solution of sodium ethoxide in ethanol (prepared by dissolving sodium (6.1g) in dry ethanol (200 ml)). The reaction mixture was refluxed for 3 hours and then poured into dilute 10 hydrochloric acid and chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated to leave a brown solid which was dissolved in ethanol (300 ml) containing concentrated hydrochloric acid (3 ml) and the whole was refluxed for 1 hour. The reaction mixture was poured into water and the 15 product was extracted into ethyl acetate which was washed with water and dried. The solvent was evaporated to leave 10 g of a sticky solid which had mass and NMR spectra consistent with the expected product. (e) Ethyl 7-amino-4-oxo-8-propyl-4H-l-benzopyran~2-carboxylate A solution of the amide of step (d) (lOg) in ethanol (300 mL), containing concentrated hydrochloric acid (5 ml), was refluxed for 8 hours. The reaction mixture was diluted with water and extracted into ethyl acetate. The extract was washed with water, dried and the solvent was evaporated to leave a dark brown semi-25 solid. This was chromatographed on a silica gel column, using 187156 ether as eluant to give 4.8g of the required product whose structure was confirmed by mass and NMR spectral evidence; mp 84-87°C. (f) 8-Ethoxycarbonyl-2 -methoxycarbonyl-4,6-dioxo-l0-propyl-4H, 6H-pyrano/T3,2-g^7quinoline The amino benzopyran of step (e) (2.0g) and dimethyl acetylene dicarboxylate (1.24g; 1.01 ml) were refluxed in ethanol (30 ml) for 26 hours. The reaction mixture was cooled to 0°C and the insoluble yellow-brown solid was collected by filtration and washed with a little ethanol and dried to give 2.0g of a product which was a mixture of maleic and fumaric esters obtained by Michael addition of the amine to the acetylene.

This mixture of esters (2.0g) was treated with polyphosphoric acid (30 ml) and heated on the steam bath with stirring for 20 minutes. The reaction mixture was then poured onto ice and stirred with ethyl acetate. The organic layer was separated, washed with water and dried. The solvent was evaporated to leave 1.6g of a yellow orange solid. Recrystallisation of this solid from ethyl acetate gave the required product as fluffy orange needles np 187-188°C.

Analysis Found: C, 62.0%;-H, 5.1%; H, 3.7% C2C^iL9N07 c 62.3%; H, 4.9%; N, 3.6% (g) 4,6-Dioxo-10-propyl-4H>6H-pyranoZ73 t2-gJ7quinoline-2,8-dicarboxylic acid The above bis ester (2.5g) was refluxed with sodium bicarbonate V.Q8/B/3Q 187156 (1.64g) in ethanol (100 ml) and water (50 ml) for 1J hours. The whole was poured into water and acidified to precipitate a gelatinous solid. This was collected by filtration, refluxed with ethanol and the product was separated by centrifugatian (1.4g) 5 np 303-304°C dec. The structure of the product was confirmed by mass and NMR evidence. (h) Disodium 4,6-dioxo-10-propyl-4Ht6H-pyranoP ,2-gl7quinoline-2,8-dicarboxylate The bis acid from step (g) (1.35g) and sodium bicarbonate 10 (0.661g) in water (150 ml) were warmed and stirred until a clear solution was obtained. This solution was filtered and the filtrate was freeze dried to give 1.43g of the required disodium salt. Analysis Found: C, 46.1%; H, 4.0%; N, 2.9% 15 12,5% ^0 required: C, 46.1%; H, 3.8%; N, 3.15% Exanple 2 4,6-Dioxo-l-ethyl-10-propyl-4H>6H-pyrano£r3,2-gL7quinoline-2,8-dicarboxylic acid (a) 4- (N-Acetyl-N-ethyl) amino-2 -allyloxyace tophenone 20 4- (N-acetyl-N-ethyl) amino-2-hydroxyacetophenone (92.6g), allyl bromide (51 mis) and anhydrous potassium carbonate C90.4g) were stirred in dry dime thy Ifomtamide (500 mis) for 17 hours. The reaction mixture was poured into water and the product was extracted with ether. The organic solution was then washed well 25 with water, dried over magnesium sulphate and evaporated to 187156 £9/6/30- c\- dryness. The product was obtained as an oil (102.5g). The structure of the product was confirmed by NMR and mass spectroscopy. (b) 4- (N-Acetyl-N-ethyl) amino-3-propyl-Z -hydroxyace tophenone 5 The allyl ether product of step (a) (100.5g) was refluxed in ^ o S. diethylaniline (300 mis) for 3 hours. The reaction mixture was ^ 01 \ cooled and poured into dilute hydrochloric acid and extracted into ether, vMch latter was washed with dilute hydrochloric acid, and then with water. The organic solution was extracted with 101 10 sodium hydroxide solution which was then acidified. The precipitated product was extracted vdth ether which was dried over magnesium sulphate. The resulting ethereal solution was evaporated to dryness to give a yellow-brown oil (78.7g). This oil was a mixture of 4- (N-acetyl-N-ethyl) amino-3-allyl~2-15 hy droxyace tophenone and 6-(N-acetyl-N-ethyl) amino-3-allyl-2-hydroxyace tophenone.

This mixture was dissolved in ethanol (500 mis) and glacial acetic acid (20 nils) and hydrogenated in the presence of Adams catalyst until hydrogen uptake had ceased. The catalyst was 20 filtered off through kieselgiihr and the filtrate evaporated to leave 79.9g of brown oil. This brown oil was a mixture and was separated by high pressure liquid chromatography using ether/petroleum ether (1:1) as solvent to give 44.Zg of the sub-title conpound and 23.8g of 6- (N-acetyl-N-ethyl) amino-3-25 propyl-2-hydroxyacetophenone.

' , -£Q/£/30— 6 (c) 4-N-Ethylamino-3-propyl-2-hydroxyace tophenone 4- (N-Acetyl-N-ethyl) amino-3-propyl-2-hydroxyacetophenone (44g) was refluxed in 48% hydrogen bromide in glacial acetic acid (100 mis), glacial acetic acid (500 mis) and water (20 mis) for 5 6 hours. The reaction mixture was poured on to ice-water and extracted with ethyl acetate which was washed with water, sodium bicarbonate solution, then water again and dried over magnesium sulphate. The organic solvent was evaporated to dryness to leave the sub-title conpound as a red oil (34g). The structure was 10 confirmed by NMR and mass spectroscopy. (d) Methyl 6-acetyl-l-ethyl-7-hydroxy-4-oxo-8-propy 1 -4H-quinoline-2-carboxylate The amine product of step (c) (17g) and dimethacetylenedi-carboxylate (11.3 mis) were refluxed in ethanol (300 mis) for 17 hrs. 15 The reaction mixture was cooled and evaporated to dryness to leave a deep red oil. This oil was chrcmatographed on a silica gel column using ether/petroleum ether (1:1) as eluant to give 19.lg of dimethyl 1- (4-acetyl-3-hydroxy-2-propylphenyl)-N-ethylainino-maleate m.p. 83-87°C.

The maleic ester (5g) was heated and stirred in polyphosphoric acid (100 mis) on the steam bath for 10 minutes. The reaction mixture was cooled and poured on to a mixture of ice-water and ethyl acetate. The organic solution was separated, washed with water and dried over magnesium sulphate. The solvent was 25 evaporated to dryness to leave a pale yellow solid. This 187156 jxm^r product was purified by high pressure liquid chromatography to give 2.6g of the sub title compound m.p. 121-123°C.

Analysis Found: C: 65.51 H; 6.6% N; 4.2% ^S^l^S Recluired: C: 65.3% H; 6.34% N; 4.23% Methyl 6-acetyl-l-ethyl-5-hydroxy-4~oxo-4H-quinoline-2-carboxylate was obtained from the purification as a pale yellow solid (100 mgs). (e) Diethyl 4,6-dioxo-1-ethy 1 -10-propy 1 -4H-6H-pyranoZT3,2-gI7-10 quinoline-2,8-dicarboxylate The hydroxy ketone product of step (d) (l.Og) and diethyl oxalate (3.3 mis) in dry dime thylformamide (25 mis) were added to ether washed 50% sodium hydride (0.581g) in dry dimethylformamide (20 mis) and the reaction mixture stirred for 4 hours. The 15 reaction mixture was then poured into water,acidified and extracted with ethyl acetate, which was then washed with water and dried over magnesium sulphate. The solvent was evaporated to dryness to give an oil which was dissolved in ethanol (100 mis) and concentrated hydrochloric acid (a few drops) added. The 20 solution was refluxed for J hr, cooled, poured into water and extracted with ethyl acetate, which was washed with water and dried over magnesium sulphate. The solvent was evaporated to dryness to leave an oil which solidified on trituration with 40-60° petroleum ether (1.2g). The structure of the conpound was 25 confirmed by NMR. ■ 1 C7156 (f) 6,9-Dihydro-4,6-dioxo-9-ethyl-10-propyl-4H-pyrano/" 3,2-q 7quinoline-2,8-dicarfaoxylic acid The above bis ester (l.Og) and sodium bicarbonate (0.787g) in ethanol (85 mis) and water (32 mis) were refluxed for 4 hours. The reaction mixture was poured into water, acidified and the precipitate was collected by filtration and dried. The product was purified by triturating with boiling ethanol, then twice with boiling acetone.

After each trituration the mixture was centrifuged and the supernatant liquid was removed by decantation. The residual solid was dried to give 0.547g of the required di-acid as a yellow powder m.p. 298-300° dec.

Analysis; Found: C: 61.3% H; 5.0% N; 3.6% C19H17N07 Ret3uired: Cj 61'5% H' 4-6% N? 3-79% (g) Disodium 6,9-diliydro-4,6-dioxo-9-ethyl-10-propyl-4H-pyrano/ 3,2-q / quinoline-2,8-dicarboxylate Ifre above di-acid (4.098g) was suspended in water (100 mis) and was treated with sodium bicarbonate (1.82g). The resulting solution was filtered and the filtrate was treated with acetone until aonplete precipitation of the product had occurred. The required di-sodium.salt was filtered off arid dried to give 3.39g . of a pale yellow pcwler.

Analysis; Found: C: 51.1% H; 4.3% N; 3.0% C19H15NNa2°7 Ret3uired: C: 51.1% H? 4.1% (6.9% water) 187156 Exarnole 3 The following compounds may also be made by the processes described above:- (i) 5-2thyl-5,8-dilv, dro-4,8-dioxo-10-propyl-4H-py r ano [ 2,3-h) -quinoline-2,6-dicarboxylic acid l.l(3H,t), 1.6(2H,m), 2.2(2H,t), 6.6(18,5), 6.8(LH,S), 7.8 (lH,s). (i i) 7,10-D ihydro-4,10-dioxo-4H-pyrano [2,3-f ] quinoline-2,8-dicarbcxylic acid 6.6(111,5), 6.8 (lH,s), 7.6 dH,d,J=8H2), 8.1(lH,d),J=8H2). (iii) 6,9-Dihydro-5-hydroxy-4,6-dioxo-10-propy1-4H-pyrano£3,2-g7-quinoline-2,8-dicarboxylic acid l.l(3H,t), 1.6 (2H,m), 2.2(2H,t), 6.3(lH,s), 6.9(lH,s). (iv) 6,9-Dihydro-4,9-dioxo-4H-pyrano[2,3-g]quinoline-2,7-dicarboxylic acid 6.0 (lH,s), 6.9 (lH,s), 7.6 (lH,s), 8.6(lH,s), (v) 7,10-Dihydro-4,10-dioxo-4H-pyrano ^/2,3-f/ quinoline--2,8-di/N- (fcetrazol-5-yl)_/-carboxainide (vi) 10-Bromo-6,9-dihydro-4,6-dioxo-2,8-di-(tetrazol-5-yl)-4H-pyrano-£3,2-c|7 quinoline. ^ ^n-iscr 127156 Exanple 4 Disodium 7-ethyl-7,10-dihydro-4,10-d.icixo-4H-pyrano/~2,3-f 7quinoline- 2,8-dicarboxylate (a) Methyl 6-acetyl-l-ethyl-5-hydroxy - 4 (J H) -oxo-quinoline-2-carboxylate A mixture of dimethyl acetylene dicarboxylate (13g; 91.5 rmole) and 4-ethylamino-2-hydroxyacetcphenone (16.lg, 89.8 irmoles) in ethanol (250 ml) was refluxed on a steambath for 7 hours. The mixture was cooled before being poured into water. The mixture was concentrated by removing sate Of the ethanol and was then extracted with ethyl acetate. The organic extract was washed with a large volume of water and then was dried (anhydrous sodium sulphate) . Solvent was removed by evaporation to give a light brown oil. When triturated with petroleum ether/ether mixture a yellow solid was obtained. Both NMR and MS showed it to be consistent with the expected structure.

The above dimethyl acetylene dicarboxylate adduct of 4-ethylamino 2-hyaroxy acetophenane (5.5g, 17.1 ntnoles) was cyclised by heating with polyphosphoric acid (190g) for 20 minutes. The dark viscous solution was treated with ice/water mixture and the resulting suspension was extracted with ethylacetate. Itie organic layer was washed with large volume of water, and this was then dried (anhydrous sodium sulphate).

Solvent was removed to give a light brown solid. NMR and MS showed this ocntpound to be a mixture, the sub-title compound \ 187156 being the main product. A pure sample was obtained by chromatography on silica gel using petroleum ether/ether as eluent. A yellow solid vdth MP *= 155-58°C and NMR and MS consistent with the desired structure was obtained. (b) Diethyl 7-ethyl-7, lO-dihydro-4,10-dioxo-4H-pyrano/~2,3-f 7quinoline 2,8 -dicarboxylate A mixture of the product of step (a) (2.6g, 8.99 nxnoles) and diethyl oxalate (11 mis, 75.3 nmoles) in dry dims thylforxnamide (70 mis) was added to a stirred suspension of 57% sodium hydride (1.8g, 43.48 nmoles) under nitrogen at roam tenperature. After addition, the mixture was left stirred at room tenperature for 28 hours.

The mixture was then acidified vdth 10% hydrochloric acid. A bright yellow precipitate was obtained. The mixture was extracted with ethyl acetate which was dried and evaporated to give a yellow solid. This solid was redissolved in an ethanol/hydrochloric acid mixture. This solution was refluxed cn a stearribath for 2 hours and cooled before pouring into an ice/water mixture. The mixture was extracted vdth ethyl acetate, dried, and evaporated to give a brown oil which when triturated vdth a petroleun ether/ether mixture yielded a brown solid whose NMR ancl MS spectra were consistent with the desired structure. (c) 7-Ethyl-7,10-dihydro-4,10-dioxo-4H-pyrano/~2,3-f 7qui"oline~2,8-dicarboxylic acid 0.IN Sodium hydroxide (75ml; 7.4815 irmoles) was added slowly to a boiling solution of the product of step (b) (1.440g; T0SEP19S1 127 i 56 3.7402 mmoles) in methanol (50 mis). After addition the mixture was allowed to reflux for 2 hours, then cooled, and acidified with 10% hydrochloric acid. A light brown precipitate was obtained, which was filtered off and dried in vacuo. NMR and MS were consistent with the desired structure.

Elemental Analysis: C = 58.8% H = 3.37% N = 4.25% Containing 11.9% HjO (d) Disodium 7-ethyl-7,10-dlhydro-4,10-dioxo-4H-pyrano/ 2,3-f /quinoline-2,8-dicarboxylate Excess acetone was added to a solution of the product of step (c) (0.755g, 2.2948 mmoles) and sodium bicarbonate (0.3856g, 4.5892 mmoles) in water (5 mis). A pale yellow precipitate was obtained and was dried in vacuo. NMR was consistent with the desired structure.

Elemental Analysis: C = 51.49% H = 2.43% N = 3.75% Found: C = 44".1% H = 3.7% N = 3.2% Cbntaining 14.4% 1^0 Exanple 5 Disodium 6,9-dihydro-9- (3-snethylbutyl) -4,6-dioxo~4H-pyrano/~3,2-g 7quiiioline' 2,8-decarboxylate (a) Methyl 6-aoetyl-7-hydroxy-l- (3-methylbutyl) - 4 (lli) -oxo-quinoline-2-carboxylate Polyphosphoric acid (50 ml) was added to E-dimethyl 2-/~N-(4-acetyl-3-hydroxyphenyl) -N- (3-methylbutyl) amino 7-but-2-ene-l, 4- Found: C = 51.8 H = 4.3 N = 3.7 1 £711-6 dioate, (10.89g) and the resulting viscous dark red oil was stirred on a steambath for ten minutes, then poured into an iced water/ ethyl acetate mixture and stirred vigorously for one hour. Hie resulting mixture was extracted into ethyl acetate, dried using magnesium sulphate, filtered and the volatiles were removed in vacuo affording a mixture (8.0g) of the required sub-title ocitipound and methyl 6-acetyl-5-hydxoxy-l- (3-methylbutyl)-4 (1H) -oxo-quinoline-2-carboxylate.

Separation of the isomers was achieved using column chromatography with silica gel as the stationary phase and eluting primarily with ether, then chloroform. This process removed sore of the unwanted isomer, the required sub-title conpound being adsorbed on the silica-gel. Hie silica gel was removed from the column, refluxed with ethyl acetate, filtered off and the filtrate evaporated yielding a crude sample of the required sub-title conpound (2.7g).

This was further pruified vising high pressure liquid chranatgraphy affording 0.5g of the sub-title compound. MP 108-110°C.

Cigl^jNOs Requires: C, 65.3%: H, 6.3%: N, 4.2% NMR spectroscopy and mass spectroscopy confirmed the structure, (b) Diethyl 6,9-dihydro-9- (3-^rethylbutyl) -4,6-dioxo--4H-pyrano/~3,2-q 7 quinoline-2,8-dicarboxylate A solution of the product of step (a) (2.3g) and diethyl oxalate (7.5 ml) in dry dimethylformamide (60 ml) was added to a stirred Analysis Found C, 65.4%: H, 6.3%: N, 3.9% j suspension of ether washed sodium hydride (0.65g) in dry dimethylfomiamide (75 ml) under nitrogen. The whole was then stirred at ambient temperature for twenty four hours, then poured into iced water and extracted into ethyl acetate. This solution was dried using magnesium sulphate, filtered and volatiles removed in vacuo, affording an oil.

To this oil was added saturated ethanolic hydrogen chloride (300 ml) and the whole heated under reflux for two hours, then poured into iced water and extracted into ethyl acetate, which was washed with water, saturated aqueous sodium chloride solution and then dried using magnesium sulphate. The organic solution was filtered and volatiles were removed in vacuo. The resulting oil was subjected to column chromatography with silica gel as the stationary phase and diethyl ether as eluant affording a solid, which was triturated with light petroleum ether, washed with a little ether, and dried under reduced pressure over phosphorus pentoxide at 100°C for three hours yielding 1.2g of sub-title compound. MP 149-150°C.

Analysis Found: C, 64.2%: H, 6.01: N, 3.01 C23H25NO7 Requires: C, 64.6%: H, 5.9%: N, 3.3% NMR spectroscopy and mass spectroscopy confirmed the structure, (c) 9- (3-Methylbutyl)-4,6-dioxo-4Ht6H-pyranoZr3,2-gI7quinoline;2,8-dicarboxylic acid The product of step (b) (l.OOOg) was dissolved in methanol (150 ml) and heated to reflux. 0.1 M NaOH (46.8 ml) was then added and the whole 187156 heated at reflux for three minutes. The solution was cooled, acidified, and the precipitated product collected and dried under reduced pressure over phosphorus pentoxide at 80°C for two hours, and then at 100°C for one and one half hours, affording the sub-title conpound (0.7g) MP 302-304°C.

Analysis Found: C, 59.7%: H, 4.9%: N, 3.5% CL9H17N07 Requires: C, 59.7%: H, 4.6%: N, 3.6% 2.9% H20 Hemihydrate requires: C, 60,0%: H, 4.5%: N, 3.7% (d) Disodium 6,9-dihyd±P-9- (3-inethylbutyi) -4,6-dioxo~4H-pyrano/3,2-q 7 quinoline-2,8-dicarboxylate The product of step (c) 2.9% H20 (0.5g) was suspended in distilled water (100 ml). Sodium bicarbonate (0.243g) was added and the whole mixture was shaken vigorously. The resulting solution was filtered and freezed dried affording 0.7 g of the title ocnpound. Analysis Found: C, 45.4%: H, 5.2%: N, 2.95% G^^NNa^ Requires: C, 45.4%: H,-4.9%: N, 2.8% 17.2% H20 NMR spectroscopy confirmed the structure. '£7156 Example 6 Disodium 7 >10-dihydro-7-(3-fnethylbutyl) —4,10^dioxo^4H-pyrano f~2,3-f 7quinoIine-2,8-dicarboxylate (a) N- (3-Methoxypheny 1)-N- (3-methylbutyl) e thanamide Sodium hydride (14.4gm) was washed with dry ether, then suspended in dry dimethylformand.de (100 ml) under dry nitrogen. N- (3-Methoxy-phenyl)ethanoarride (74.3g) was dissolved in dry dimethylformarrri.de (400 ml) and added to the WaH suspension. The resulting suspension was cooled to 0°C and stirred until hydrogen evolution ceased. 3-Methylbutyl bromide (88.5g) was then added dropwise and the vfoole stirred at roam tenperature for two hours. The mixture was then poured into water containing a little ethanol, extracted into ether, washed with water, dried using magnesium sulphate, filtered and the volatiles were removed in vacuo. The resulting oil was subjected to a vacuum distillation, accepting the fraction at 126-146°C and 0.5 ntn Hg pressure, yielding 95.5 gm of the sub-title conpound. NMR spectroscopy and mass spectroscopy confirmed the structure. (b) N- (3-Hydroxyphenyl) -N- (3-methylbutyl) ethanairu.de'-; To a stirred solution of the product of step (a) (10.8g) in dry dichloroethane (100 ml) at -10°C was added boron tribrcmide (18.4g). The tenperature was alleged to rise to roan tenperature and the mixture was stirred at this tenperature for 1% hours, then poured into water, extracted into chloroform, dried using magnesium sulphate, filtered and the volatiles were removed in vacuo, affording (10.4g) of the sub-title compound. NMR spectroscopy and mass spectroscopy 127 IS£ confirmed the structure. (c) N-Acetyl-N- (5-methylbutyl) -aminophenyl-ethanoate To the product of step (b) (92.2g) in dry toluene (2L) was added acetyl chloride (49.Ig) and pyridine (2 ml). The resulting solution was refluxed for five hours, poured into water and the organic layer was separated, washed with more water, dried using magnesium sulphate, filtered and the volatiles were removed in vacuo, affording (102g) of the sub-title conpound.

NMR spectroscopy and mass spectroscopy confirmed the structure. (d) N- (4 -Acetyl - 3-hydroxyphenyl) -N- (3-methylbutyl) -ethanoamide The product of step (c) (11.3g) was mixed with aluminium chloride (18g) and sodium chloride (2.5g) and then heated at 160°C for two hours. Iced water was added cautiously and the resulting mixture was extracted with 101 sodium hydroxide solution, which was then washed with ether. The alkaline extracts were acidified, extracted into ether, cried using magnesium sulphate, filtered and the volatiles were renoved in vacuo, affording 7.5g of the sub-title compound.

NMR spectroscopy and mass spectroscopy confirmed the structure. (e) l-ZI2-Hydroxy-4- (5-methylbutyl) amino-phenyQ-ethanone To the product of step (d) (49.9g) in glacial acetic acid (550 ml) was added 48$ aqueous hydrogen bromide solution (110 ml). The mixture was refluxed for two hours, poured into water and extracted into diethyl ether. The ether was washed well with water, then with saturated sodium bicarbonate solution, dTied using magnesium sulphate, j filtered and finally the volatiles were removed in vacuo, affording 38.Og of the sub-title compound.

NMR spectroscopy and mass spectroscopy confirmed the structure. (f) E-Dimethyl N- (4-acetyl-3-hydroxyphenyl)-N- C3-methylbutyl)-anrino-1,4-but-2-enedioate To the product of step (e) (38.Og) in dry ethanol (300 ml) was added dimethyl acetylene dicarboxylate (31.8g). The resulting solution was heated under reflux for seven hours, after which time the volatiles were removed in vacuo, affording (76 gm) of crude sub-title compound. The crude sample was subjected to column chromatography using silica-gel as the stationary phase and a 1:1 mixture of petroleum ether and diethyl ether as eluant. This process afforded (41.4 gm) of pure sub-title compound.

NMR spectroscopy and mass spectroscopy confirmed the structure and that of the isomeric form of the product. (g) Methyl 6-Acetvl-5-hydroxy-l~ (3-methylbutyl) -4-oxo-4H-quinoline-2-carboxylate The product of szsrp (f) (3.3g) was added to stirred viscous polyphosphoric acid (15 ml) and the mixture was heated on a steam bath for fifteen minutes. The whole was then poured onto an iced water, ethyl acetate mixture and vigorously stirred for one hour. The organic layer was separated, washed well with water, dried using magnesium sulphate, filtered and volatiles were removed in vacuo affording a crude sample (1.7g) sub-title compound, 0.7g of which was recrystallised from methanol to give 0.3g of the pure -43 1^7/6"^ sub-title compound. MP 140-141°C.

Analysis Found: C, 65.21: H, 6.5%: N, 4.1% C18H21N05 c> 65.31: H, 6.3%: N, 4.2% NMR spectroscopy and mass spectroscopy confirmed preparation of the sub-title compound. (h> Diethyl 7 - (3-methylbutyl) -4,10-dioxo-4H, 10H-pyranoiQ, 3- f ~7 -ciulnoline-2,8-dicarboxylate To sodium hydride (0.26g), which had been washed with dry ether, was added dry dime thyl formamide (20 ml) under nitrogen, with stirring. The product of step (g) (0.9g) and diethyl oxalate (3.18g) in dry dimethylformamide (20 ml) were added to the above Natl suspension and the whole was stirred at room temperature for twenty four hours, then heated on a steam bath for two hours. The reaction mixture was cooled, poured into water, acidified and extracted into ethyl acetate. The organic layer was dried using magnesium sulphate, filtered and volatiles were removed in vacuo. The residue was dissolved in saturated ethanolic HC1 (200 ml) and refluxed for 15 minutes. The whole was poured into water, extracted into ethyl acetate and dried. Evaporation gave a sticky solid which was crystallised from aqueous ethanol to give 0.5g of a light brown crystalline solid. This was further purified using column chromatography with silica gel as the stationary phase and ethyl acetate as eluant, affording 0.26g of sub-title compound. MP 144-146°C. 44 187156 Analysis .* Pound:C, 64.2%: H, 6.2%: N, 3.37% C23H25N07 ^ecSJL^reSiCf 64.6%: H, 5.9%: N, 3.3% NMR spectroscopy and mass spectroscopy confirmed preparation of the sub-title caipound. (i) 7,10-Dihydro-7- (3-nethylbutyl) -4,10-dioxo-4H-pyrano/~2 / 3-f 7quinollne-2,8-dicarboxylic acid 'Ihe product of step (h) (0.918g) was dissolved in methanol (50 ml) and heated to reflux. O/lM NaCH (43 ml) was added and the whole was refluxed for five minutes. The resulting solution was then acidified with 0.1NHC1 and allowed to cool. A yellow solid crystallised out of solution, was filtered off, washed with ether and dried under a reduced pressure of 0.2mm Hg at 70°C over phosphorus pentoxide, affording 0.67g of sub-title caipound.

.Analysis Found: C, 55.7%: H, 4.9%: N, 3.0% ClgH17N07 9.4% H20 Requires: C, 55.7%: H, 5.2%: N, 3.4% Dihydrate Requires: C, 56.0%: H, 5.16%: N, 3.4% (j) Disodium 7,10-dihydro07-(3-methylbutyl)-4,10-diooto-4H-pyrano/"2>3-f 7~ quinoline-2,8-dicarboxylate The product of step (i) 9.4% 1^0 (0.5568g) was suspended in distilled water (40 ml). Sodiun bicarbonate (0.23g) was then added and the whole vigorously shaken until solution was achieved. The solution was then filtered, and the filtrate freeze-dried, to give 0.59g of the title caipound.

SEP 1981 / Analysis Found: C, 46.7%: H, 4.7%: N, 2.8% C19HlSNNa2°7 Recluirts: c» 46.7%: H, 4.7%: N, 2.8% 14.9% H20 NMR spectroscopy confirmed preparation of the title compound. 187156 w/b/25 Exanple 7 Disodium S-methoxy-4,7-dioxo-4H,7H-pyranoZ3 r ?-h"7gmnoline-2,9-dicaiboxylate (a) N- C 3-Acetyl - 2 -hydroxy- 4 -me thoxypheny11 acetamide 1- (3-Amijio-2-hydroxy-6-inethoxy-phenyl)ethanone (12.9g) was added to a mixture of acetic acid (3 mis) and water (20 mis) and heated to 60°C. Acetic anhydride (9.5 mis) was then added and the whole heated on a steam bath for thirty minutes. The reaction mixture was poured into water and extracted into ether, which was 10 dried using magnesium sulphate, and after filtration the volatiles were removed in vacuo, affording a golden brown solid vfaich was triturated with chloroform and dried under reduced pressure, yielding 3.7g of the sub title conpound, mp 160-162°C. (b) Ethyl 8-amino-6-methoxy-4-oxo-4H-l-benzopyTan-2-caTboxylate Sodium (1.4g) was reacted with ethanol (150 mis). The resultant solution was cooled and stirred vigorously, and to this solution was added a slurry of the product of step (a) (3.5g) and diethyl oxalate (5.4 mis) in ethanol (50 mis). The mixture was heated under reflux for three hours, poured into water and the aqueous solution was 20 extracted into ethyl acetate, which was washed with a little water and dried using magnesium sulphate. After filtration the solvent was removed in vacuo. This procedure yielded an oil to which was added concentrated hydrochloric acid (3 mis) and ethanol (100 mis). This solution was heated under reflux overnight. The volatiles were 25 removed in vacuo, to afford the sub title conpound (2.3g). N.M.R. - 47 - MJZ.FATEMTOFHCE • 12 OCT 1979 * w, / received 1 87 I 'j6 and Mass Spectroscopy confirmed the structure. (c) Dimethyl 2-/ N-(5-nethaxy-2-ethaxycaJbcnyl-4-oxo-4H-l-toenzopyran-8-yl) -amino 7 -but-2-ene-l, 4 -dioate lb the product of step (b) (2.3g) was', added ethanol (200 mis) and dimethyl acetylenedicarboxylate (1.3 mis). The whole was heated under reflux for twenty four hours. The volatiles were then removed in vacuo to afford a sticky yellow-orange solid which was triturated with a petroleum ether-diethyl ether mixture. Hie resulting solid was filtered off vender reduced pressure affording (1.8gm) of the sub-title caipound. N. M. R. Spectroscopy and Mass Spectroscopy confirmed the structure. (d) Methyl 2-ethoxycarbonyl-7,10-dlhydro-5-*nethoxy--4,7-dioxo-4H-pyrano / 3,2-h 7~quinoline-9-carboxylate To refluxing diphenyl ether (50 mis) was added the product of step (c) (1.8gm). Refluxing was continued for five minutes, and the mixture was then allovred to cool. Light petroleum ether was added and the precipitated product was filtered off under reduced pressure, and washed with a little diethyl ether, affording l.Og of crude sub title caipound. This solid was triturated with a mixture of hot ethyl acetate and chloroform, filtered under reduced pressure and dried. The material was recrystallised from toluene, and dried in vacuo at 89°C over phosphorus pentoxide for four hours, resulting in 0.2g of the sub title caipound, np 260-261°C. 187156 -09/b/zs (e) 5-Methoxy-4,7-dioxo-4H,7H-pyranoZT3.2-hI7quinoline-2.9-dicarfaoxylic acid To a stirred suspension of methyl 2-ethoxycarbony 1 -5-mathor/-4,7-dioxo-4H, 7H-pyrano£T3,2-hJ7quinoline-9-carboxylate (2g) in 5 glacial acetic acid (16 mis) was added concentrated hydrochloric acid (4 mis). Ihe Whole was heated on a steam bath for two hours, cooled and the resultant solid was filtered off under reduced pressure. Ihe solid was washed with acetic acid and ether, and then dried under reduced pressure over phosphorus pentoxide and 10 sodium hydroxide at 80°C, yielding (0.8g) of the sub-title conpound, up 294-6°C (dec).

Analysis Found: C, 49.1; H, 3.4; N, 3.6* CjjHgNOg.g.et ly) Requires: C, 49.1; H, 3.5; N, 3.81 15 MR spectroscopy and mass spectroscopy confirm the structure. (f) Disodium 5-msthoxy-4,7-dioxo-4H, 7H-pyTanoZ3,2-hI7quinoline- % 2,9-dicaTboxylate -Methoxy-4,7-dioxo-4H,7H-pyrano£3,2-h~7quinoline-2,9-dicarboxylic acid (0.6231g) was suspended in distilled water (50 mis). 20 Sodium bicarbonate (0.286 gm) was adcbd, and the whole was vigorously shaken. Ihe resultant solution was filtered and the filtrate was freeze dried, affording (0.6g) of the title conpound.

Analysis Found: C, 41.07; H, 2.7; N, 3.31 25 C^HyNNajOg.M^t 1^0 Requires: C, 41.07; H, 3.1; N, 3.21 kz.patemt off.ce f .12 oct 1979 , recav"r:i 187156 ***** ) P.&S. ^ <\ • Example 8 4 t6-Dioxo-10- Cprop-2-enyl)-4H.6H-pyranoQ .2-gI7quinoline-2,8-dicarboxylic acid (a) Ethyl 7-amino-4-oxo-8- (prop-2-enyl) -4H-benzopyTan-2-carboxylate 1- (4-Acetylanrino-2-hydroxy-3- (prop-2-enyl) -phenyl) ethanane (20g) and diethyl oxalate (30.95g; 28.7 ml) were added to a previously formed solution o£ sodium ethoxide (from addition of sodium (9.7g) to dry ethanol (243.4 ml)) with stirring.

The reaction mixture was stirred under reflux for 3 hours, cooled and then poured into water. The precipitated product was extracted into chloroform, dried and evaporated to dryness under reduced pressure. The yellow residual solid was dissolved in fresh, dry ethanol (324.5 ml), concentrated hydrochloric acid (3.25 ml) added and the reaction mixture refluxed for 17 hours. The whole was poured into water (1.5 litre), extracted into ethyl acetate, washed with water and dried over magnesium sulphate. Ihe solvent was evaporated to dryness and the residue triturated with 40-60 petroleum ether to give 19.6g of brown crystalline solid. A l.Og sample of the crude product was recrystallised from ethanol to give a crystalline solid, rap 142.5-143°C. (b) Dimethyl N- (2-ethoxycarbonyl-4-oxo-8- (prop-2-enyl)-4H-1-benzopyran-7-yl) -2-aminobut-2-ene-l ,4-dioate The product of step (a) (18.6g) and dime thy ^acetylene-dicarboxylate (11.95g; 10.86 ml) in ethanol (148 ml) were refluxed together for 17 hours. The reaction mixture was cooled to 10°C and - 50 - h.z.patentofflcg 12 OCT 1979 ? RECEIVED ■11/D/ftr 187156 the precipitate was collected by filtration, washed with a little ethanol and dried to give 15.8g of product. A 0.9g sample was recrystallised from ethanol to give a crystalline solid, mp 148-148.5°C. (c) Ethyl 8 -roethoxycarb ony 1 - 4,6-dioxo-10- (prop-2-eny 1) -4H.6H-5 pyranoZ3,2-gZ7quinoline-2-caTboxylate The product of step (b) (14. Og) was added to diphenyl ether (200 ml) under reflux with stirring. The reaction mixture was refluxed for a further 5 minutes, cooled and poured into 60-80 petroleum ether (2.0 1). The precipitated product was collected by 10 filtration, dried and Tecrystallised from ethyl acetate to give 3.5g of yellow solid. (d) 4,6-Dioxo-lO- (prop-2-enyl)-4H,6H-pyrano/3,2-g~7quinoline-2,8-dicarboxylic acid The product of step (c) was hydrolysed by the method of 15 Exanple 9(c) to afford the title conpound. Structure was confirmed by N.M.R.

Example 9 4 t10-Dioxo-4Ht10H-pyranoZr^ ,3-h_7quinoline-2,8-dicaiboxylic acid (a) Ethyl 5-amino-4-oxo-4H-benzopyran-2-cart>oxylate 20 Ethyl 5-nitro-4-oxo-4H-benzopyran-2-caTboxylate (lOg, 38.022 mmoles) in ethanol (250 mis) was added to 5% Pd/C (lg) in ethanol (50 ml) in a hydrogenation vessel. TWo drops of concentrated hydrochloric acid were then added to the above mixture. The mixture was then hydrogcnated at 3 atmospheres pressure at room tenperature for 2 hours. 25 The catalyst was filtered off through a filter aid which was _ 51 _ NZ. PATBfi* OFFICE 12 OCT 1979 f?tc=7vh> 18 /1 b 6 washed with chloroform. Hie filtrate was evaporated to give a yellow solid (8.1g, 91.51). NMR and mass spectra confirmed that the desired conpound had been made. (b) 8-Ethoxyeaibonyl-2-niethoxy carbonyl-4,10-dioxo-4H, lOH-pyrano-Zj2,3-h "7-quinoline The product of step (a) (6.1g, 26.18 mmole) and dimethyl acetylene-dicaiboxylate (llg; 77.46 mnole) were heated in ethanol (180 ml) for 7 hours. The reaction mixture was cooled and was diluted with water. Half of the original volume of ethanol was removed and the concentrated mixture was extracted with ethyl acetate. The organic layer was washed with a large volume of water, dried and evaporated to give a yellow solid (8.5g, 861).

The solid (8.5g, 22.66 ninole) was added slowly to preheated diphenyl ether (90 ml, 240°C) under N2 with stirring. After addition the mixture was brought to Teflux for 15 minutes. The mixture was cooled and poured into petroleum ether (40-60°C, 200 ml) to give the subtitle product as a light grey solid (4g, 51.31) np « 166-70°C. (c) 4<10-Djoxo-4H,10H-pyranoZ72t3-hJ7quinoline-2,8-dicarboxylic acid Sodium hydroxide solution (0.1N, 58.27 ml; 5.8267 mmole) was added slowly to a boiling methanolic solution of the product of step (b). After addition, the reaction was heated to reflux for 25 minutes. The mixture was cooled and was acidified vdth dilute hydrochloric acid (101) to give a very fine precipitate. This was filtered off and was collected as a light brown solid and dried - 52 - H-Z. PATENT OFrtCS 12 OCT 1979 RECEIVED 127156 in vacuo over P2°5 at overnight to give the sub-title product (0.4617g) up 200°C.

Analysis Found: C, 50.9; H, 2.78? N, 4.12% 8.8% 1.0 H2O Requires: C, 50.9 W,3.1; N, 4.2% (d) Disodium 5,7-dihydro-4,8-dioxo-4H-pyrano /~2,3-h 7quinoline-2,6-dicarboxylate The product of step (c) (0.4117g, 1.2462 imole) was dissolved with sodium bicarbonate (0,2094g, 2.4922 mmole) in water (30 ml).

This was filtered to ramove any insoluble particles. The solution was then freeze "dried to give the sub-title product as a brown solid (0.4137g).

Analysis Bound: C, 41.82; H, 2.96; N, 3.44% 14.14% 1.0 HjO Requires: C, 41.82; H, 2.82; N,3.49% Exanple 10 (a) 3-EthoKycarbonyl-10-hydroxy-8 -methoxycarbony1-1-oxo-lH-pyrano-/ 3,2-f 7quinoli"e Ethyl 6-arrrincj-4-axo-4H-l-benzqpyran-2-carboxylate (3.9g; 16.7 mtole) in ethanol (70 ml) and dimethyl acetylene-dicarboxylate (2.84g; 20 mmole) were heated tinder reflux for 2 hrs. The solution was cooled and the solvent removed on the rotary evsporator to give a green solid.

Hie solid was added all at once to refluxing diphenyl ether (50 ml) and heating was continued for 25 mins. The mixture was allowed to cool.. and then poured into a mixture of diethyl ether (25 ml) and 187156 petroleum ether (bp 40-60°C) (40 ml) and the brown solid was filtered off and recry stallised from chloroform to give the title conpcund as a dark green solid (2.9g ; 50.6%), np 247-8.^C. (b) Disodium 10-hydroxy-l-oxiO-lH-pyrano/"*3,2-f 7ouinoline-3,8-dicarfaoocylate The product of step (a) was hydrolysed by the method of Example 11 (d) to afford the disodium salt.

Analysis C14H14NNa207.6.11% H20 requires: C 45.74% H 2.1% N 3.8% Exanple 11 Disodiun 7,10-dihydro-4,10-dio?oo-4H-pyrano/~2,3-f 7qui"oli"e~2,8-dicarboxylate (a) Ethyl 7-aminc>-4-axo-4H-l-benzopyran-2-carboxylate A solution of sodium mstal, (18.4g, 0.8 gatcm), in dry ethanol (1200 ml), was treated with N-(4-acety 1-3-hydxoxyphenyl)acetamide, (30.88g, 0.16 mole). This mixture was stirred for 15 mins then diethyl oxalate (58.4g, 54.3 ml, 0.4 mole) was added dropwise over 30 mins. The resulting mixture was heated and stirred at 60°C for 2 hrs, allowed to cool and poured into a mixture of chloroform (600 ml) f ccnc HCl (85 ml), and water (2000 ml). The organic layer was isolated and combined with a chloroform wash of the aqueous layer. The combined chloroform extracts were washed well with water then evaporated to dryness. The residue was taken up into ethanol (400 ml), and ooanc. HCl (10 ml), was added. The solution was heated at reflux for 30 minutes then evaporated to dryness. The found: C 45.74% H 2.45% N 3.6% 187156 residue was treated with ether and ethanol was added drcpwise until the residue began to solidify. Insoluble material -was filtered off, washed again with ether and the required sub-title product was recovered as a brown solid (20.5g), (55%), np 192-194°CJ. NMR and mass spectra confirmed the structure. (b) Dimethyl 2-/~N- (2-ethoxycartioriyl-4-oxo-4H-l-benzopyran-7-yl) amino 7~ but-2-ene-l, 4-dioate A solution of the product of step (a) (4.2g, 0.018 mole), and dimethyl acetylenedicarboxylate, (7.68g, 6.6 ml, 0.054 mole) in ethanol (200 ml), was heated at reflux for 3*s hrs. Solvent was evaporated off and the residue was triturated with ether. Insoluble material was filtered off and washed with ether to give the required product as a buff coloured solid (4.3g), (64%), up 147-51'c. NMR and mass spectra confirmed the structure. (c) 2-Ethoxycarbcnyl-7,10-dihydro-8-niethoxycarfaonyl-4, lO-dioxo-4H-pyrano / 2,3-f 7quinoline Diphenyl ether (140 ml), was heated to 240°C and the product of step (b) (3.85g, 0.01027 mole), was added quickly but in small portions. The resulting solution was heated at reflux for 5 minutes then allowed to cool, when a gel-like percipitate formed. This was added to a mixture of ether and 40-60°C petroleum ether and allowed to stand. Insoluble material was filtered off, washed well with ether and dried in vacuo to leave the required product as a pale brown pow3er (3.25g), 92%, np 239-41°C. The structure was confirmed hy NMR and mass spectra. 18/156 "eW4ft (d) Disodium 4.10-dioxo-4H,10H-pyranoZI2 t3-JC7quinoline-2,8-dicarboxylate A solution of the product of step (c) (0.517g, 1.506 mmole) in methanol (100. ml), was stirred and heated at reflux during the dropwise 5 addition of 0.1015M sodium hydroxide solution (29.7 ml, 3.012 nmole)« The addition was complete after 15 minutes. After continuing at reflux for 5 minutes the mixture was evaporated to dryness, the residue was re dissolved in water. This solution was filtered and the filtrate was swamped with acetone. After standing overnight the precipitated 10 solid was filtered off, washed with acetone and dried in vacuo to leave the required disodium salt as a dark yellow powder (0.45g), 86.51. The structure was confirmed by JWR spectrum and elemental analysis: Found: C, 44.36% : H, 2.181 : N, 3.54* 15 required for C^HjNNa^^O: C, 44.1* : H, 2.38* : N, 3.67* HZ. PATTriTOrRCE - 56 - 12OCT 1979 RECFJV5D 1871 jo EXAMPLE 12 (a) 2- (2-Carbaxy-3,4-dihvdtro-8-^Tiet±iyl-4-oxo-quinolin--7-yloxy) but-2-en- 1,4-dioic acid Dimethyl acetylenedicarboxylate (12.3 ml) was added dropwise to 3-amino-2-nethylphenol (12.4g) in ethanol (100 ml), at rocm tenperature.

After 0.5h, N-benzyltrimethylarrmonium hydroxide (0.5 ml), and dims thyl acetylenedicarboxylate (12.3 ml) ware added, and the reaction mixture was refluxed for 4h. Ihe solution was cooled, poured into chloroform (500 ml) and washed with water (5 x 200 ml). The chloroform layer was dried over magnesium sulphate, and concentrated iii vacuo to give a dark oil, to which was added polyphosphoric acid (70g). The whole was stirred on a steam bath for 0.5h, then poured onto ice and extracted with ethyl acetate (2 x 200 ml). The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo to give a dark oil (27.4g). This oil was dissolved in ethanol (200 ml) which contained sodium hydroxide (12g) in water (100 ml), and refluxed for 5h. The clear solution was cooled, the ethanol removed by distillation in vacuo, and the residue was acidified with 5-IJiydrochloric acid, to give on standing overnight the sub-title conpound (12.7g). N.m.r. and i.r. spectra were consistent with the proposed structure. (b) 6,9-Dihydro lQ-methyl-4,6-dioxo-4H-pyrano/~3,2-g 7quinoline-2,8- dicarbaxylic acid . ' ■ — Ihe product of step (a) above (5.8g; 17.4 mole) was added portionwise to chlorosulpbonic acid (20 ml) with stirring while cooling in an ice bath. Ihe mixture was allowed to warm to rocm tenperature and stirred for 1 hour, when it was added dropwise to a mixture of PATENT OF and water with rapid stirring. Ihe brawn solid was filtered off arjd .16 DEC 19 recrystallised from dime thy lformamide to yield a light brown crvst^ffijjjjyj^|^^ solid (2.82g; 51%) containing 1 molar equivalent of dimethylformainide*"^^™™"* of crystallisation, m.p. = 302°C.

I a 71 L' 6 Example 13 6-Amino-7,10-dihydro-5-raethoxy-4 >7-dioxo-4H-pyrano[3,2-h]-quinoline-2,9-dicarboxylic acid (a) Diethyl 7 >10-dihvdro-5-methoxy-6-nitro-4,7-dioxo~4R-5 pyrano[3,2-h]quinoline-2,9-dicarboxylate Diethyl 7,10-dihydro-5-methoxy-4,7-dioxo-4H-pyrano~ [3,2-h]quinoline-2,9-dicarboxylate (0.82g) was dissolved in a mixture of concentrated sulphuric acid (5ml) and concentrated nitric acid (1ml) and heated at 75°C for 36 10 hours. The mixture was poured into water (100ml)/ and the precipitate was collected, and dried to afford the title I compound (O.llOg) as a brown powder. The structure was confirmed by n.m.r. and mass spectroscopy. (b) Diethyl 6-amino-7,10-dihydro-5-methoxy-4,7-dioxo-4H-15 pyrano-[3,2-h]quinoline-2,9-dicarboxylate The product of step (a) (0.105g) was dissolved in glacial acetic acid (5ml) and hydrogenated over 5% Pd/C catalyst at 1 atmosphere and room temperature until hydrogen uptake ceased. Filtration removed the catalyst 20 and dilution with water afforded a yellow precipitate which was collected and dried. Separation by high pressure liquid chromatography afforded the sub-title compound (0.033g) as an off-white solid. The structure was confirmed by n.m.r. and mass spectroscopy. ■ 16DEC198I i I c 716 6 (c) 6-Amino-7 ,10-dihydro-5-inethoxy-4, 7-dioxo-4H-pyrano-[3,2-h3quinoline-2,9-dicarboxylic acid The product of step (b) (0.03g) in glacial acetic acid refluxed 18 hours. The reaction mixture was poured into water (10ml) and an off-white solid was filtered off. Drying afforded the title compound (0.018g).

NMR c DMSO: 3.95(3H,s); 6.95(lH,s); 7.4(lH,s); 9.6(brs-4H). Example 14 -Bromo-6,9-dihydro-4,6-dioxo-4H-pyrano[3,2-q]quinoline-2,8-dicarboxylic acid I (a) Diethyl 10-bromo-6,9-dihydro-4,6-dioxo-4H-pyrano--[3,2-g)quinoline-2,8-dicarboxylate Ethyl 7-amino-8-bromo-4-oxo-4H-l-benzopyran-2-carboxy-late (5.3g) and dimethyl acetylenedicarboxylate (3.35g) in methanol (50ml) were heated under reflux for 18 hours. The solvent was evaporated iji vacuo, and the oil residue was poured into refluxing diphenyl ether (150ml) in one portion. After 10 minutes continued refluxing, the mixture was cooled and poured into petroleum ether (40-60°C, 1 litre). The precipitated solid was collected, washed w.ith petroleum ether and dried. The solid was separated into its components by high pressure liquid chromatography, and the sub-title compound was obtained as a fluffy yellow solid (0.28g). The structure (lmlj was treated with 48% aqueous HBr (2 drops) and 59 '£7156 was confirmed by n.m.r. and mass spectroscopy. (b) 10-Bromo-6,9-dihydro-4,6-dioxo-4H-pyrano[3,2-q)- quinoline-2,8-dicarboxylic acid ■ihe product of step (a) (0.27g) was heated under 5 reflux in glacial acetic acid (5ml) containing 48% HBr (10 drops) for 18 hours; the reaction mixture was then poured into water (100ml) and the precipitate was collected.

Drying afforded the title compound (O.llg) as an amorphous powder.

NMR^DMSO: 6.95 (1H,s) ; 7.0(lH,s); 8.6(lH,s).

Example 15 .

N,N*-Di-(tetrazol-5-yl)-9-(but-3-enyl)-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-q]quinoline-2,8-dicarboxamide (a) 6-Acetyl-3-(but-3-enyl)amino-2-propylphenyl 15 6-Acetyl-3-acetylamino-2-propylphenol (23.5g) was added to a stirred solution of lithium diisopropylamide (21.4g) in dry tetrahydrofuran (500ml) under a nitrogen atmosphere at 0°C. After stirring for 2 hours, but-3-enylbromide (13.5g) was added. The reaction was allowed 20 to warm to ambient temperature, and was then left for 7 2 hours.

The solvent was evaporated in vacuo, and concentrated hydrochloric acid (100ml), water (100ml) and glacial acetic acid (50ml) were added. This mixture was heated 25 under reflux for 18 hours, then cooled, basified with - eo - 'C7 T 56 anunonia, and ether extracted. Drying and evaporation yielded the sub-title compound (19.7g). The structure was confirmed by n.m.r. and mass spectroscopy. (b) Methyl 6-acetyl-l-(but-3-enyl)-1,4-dihydro-7-hydroxy-4-5 oxo-8-propylquinoline-2-carboxylate The product of step (a) (19.5g), dimethyl acetylenedi-carboxylate (13.5g) and methanol (100ml) were heated under reflux for 24 hours and then the solvent was evaporated in vacuo. The residue was added to stirred polyphosphoric 10 acid (150ml) heated to 95°C. After 2 hours the reaction was poured into ice (1 litre) and ether exracted. The i ethereal extract was washed well with dilute hydrochloric acid, brine and sodium bicarbonate solution, and then dried. Evaporation afforded a gum which solidified 15 partially. The solid was collected and shown to be the sub-title compound (3.3g) by n.m.r. and mass spectroscopy. (c) 9- (But-3-enyl) -6,9-dihydro-4,6-di'pxo-10-propyl-4H-pyrano-[3,2-g1quinoline-2,8-dicarboxylic acid The product of step (b) (3.2g) was added to a solution 20 of sodium (1.15g) in dry ethanol (50ml) and diethyl oxalate (3.5g) was added. After stirring at room temperature for 18 hours, gaseous hydrogen chloride was passed into the ice-cooled mixture until saturated. The mixture was heated to reflux for 1 hour, then evaporated, and the 25 residue was taken up into glacial acetic acid (50ml) and - 6i 6 187156 48% aqueous HBr (lml). The mixture was heated to reflux • overnight, then cooled and poured into water (1 litre). Filtration and dry'.ng afforded a fawn solid (1.8g) which was Shown to be the sub-title compound by n.m.r. and mass spectroscopy. (d) N,N'-Di(tetrazol-5-yl)-9-(but-3-enyl)-6,9-dihydro"4,6-di oxo-10-propyl-4H-pyrano{3,2-g]quinoline-2,8-dicarboxamide The product of step (c) (1.75g), thionyl chloride (.'l.D'6g.).3* 2-dicKLoroe thane (20ml) and dry dimethyl formamide (1 drop) were heated under reflux for 4 hours. On cooling a precipitate appeared which was collected and dried 1 in vacuo« The solid was added to a solution of 5-aminotetrazole (1.5g) in dry dimethylacetamide (20ml). After 48 hours at room temperature the mixture was poured into water (150ml) and the precipitated solid was collected. Drying jin vacuo afforded the title compound (0.8g) as an off-white powder. NMR^DMSO: 1. 0 (3H, t) ; 1.8(2H,m); 2.2(2H,m); 3.8(4H,m); 4.65(2H,m); 5.3(lH,m); 7.0(lH,s); 8.6(lH,s); 8.7(lH,s); 10.3(br). 187156 1 s; ) Example 16 9-Ethy1-6,9-dihydro-4,6-dioxo-lQ-propyl-4H-pyrano[3,2-ql-quinoline-2,8-dicarboxylic acid guinoline-2-carboxylic acid Methyl 6-acetyl-l-ethyl-l,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylate (20g) was heated under reflux in glacial acetic acid (150ml) containing 48% aqueous HBr (20ml). After 18 hours the mixture was cooled and poured into water. Ammonia was added until pH3. The precipitate was collected and dried i_n vacuo, and was identified as the sub-title compound (14.3g) by n.m.r. and mass spectroscopy. (b) 2-Ethoxycarbonyl-9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-q]quinoline-8-carboxylic acid The product of step (a) (14.2g) was added to a solution of sodium (5.2g) in ethanol (200ml), and then diethyl oxalate (16g) was added. The mixture was heated under reflux for 5 hours then cooled and poured into chloroform (1 litre). The mixture was shaken with dilute hydrochloric acid (150ml), then the organic phase was dried and evaporated in vacuo. The residue was dissolved in ethanol (200ml) containing concentrated hydrochloric acid (2ml) and refluxed for 18 hours. The solvent was evaporated, and the residue was recrystallised from (a) 6-Acetyl-l-ethyl-l,4-dihydro-7-hydroxy-4-oxo-9-propyl- 63 • 187156 ) ethanol to afford the sub-title compound (3.2g). The structure was confirmed by n.m.r. and mass spectroscopy, (c) 9-Ethyl~6 ,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-ig]quinoline-2,8-dicarboxylic acid The product of step (b) was hydrolysed by the process of step (a) to afford a product (l.lg) identical with that of Example 2 by thin layer chromatographic comparison. Example 1*7' 9-Ethyl-6,9-dihydro-4 t6-dioxo-10-propyl-4H-pyrano[3,2-q]-quinoline-2,8-dicarboxylic acid (a) Methyl 9-ethyl-6,9-dihydro-2-methyl-4,6-dloxo-10- propyl-4H-pyrano[3,2-g]quinoline-8-carboxylate 6-Acetyl-l-ethyl-7-hydroxy-4(1H)-oxo-8-propylquinoline-2-carboxylic acid (3.15g) was dissolved in dry dimethyl-formamide (50ml) containing washed sodium hydride (1.05g) and then ethyl acetate (4.4g) was introduced. After stirring overnight gaseous hydrogen chloride was passed into the mixture with ice cooling until saturated. The mixture was warmed to 75°C for 8 hours, then cooled, poured into water and the mixture was extracted with ethyl acetate. The organic phase was dried and evaporated and the residue was chromatographed (Si02/ethyl acetate) to provide the sub-title compound (0.8g). The structure was confirmed, by n.m.r. and mass spectroscopy. 64 > 187156 (b) 9-5thyl-6,9-dihydra-4,6-dioxo-10-propyl-4H-pyrano-f3,2-g]guinoline-2,8-dicarboxylic acid The product of step (a)' (0.75g) was heated under reflux with selenium dioxide (1.5g). in glacial acetic acid a clear filtrate which was treated with concentrated hydrochloric adid (25ml) and heated under reflux for 12 hours. On cooling and pouring into water a precipitate was obtained (0.lg) which was identical to the product of Example 2 by thin layer chromatographic comparison. Example 18 9-Ethyl-6,9-dihydro-4 t6-dioxo-10-propyl-4H-pyrano[3,2-q]-guinoline-2,8-dicarboxylic acid (a) N-[3-(1,2-dicarboxyethenyloxy)-2-propylphenyl]-N-ethyl-2-amino-but-2-ene-l,4-dioic acid 3-Ethylamino-2-propylphenol (17.9g) , dimethyl acetyl-enedicarboxylate (35g), potassium hydroxide (0.56g) , water (50ml) and ethanol (100ml) were heated under reflux for 24 hours. Potassium hydroxide (1.65g) was added and refluxing was continued for another 24 hours.

Concentrated hydrochloric acid (4ml) was added and the solvent was evaporated. The residue was dried in vacuo and extracted into ether. The ether 'was evaporated to afford the sub-title compound (3.6g). The structure was confirmed by n.m.r. and mass spectroscopy. (50ml) for 48 hours. Filtration through "Celite" afforded 65 I 87156 (b) 9-Ethyl-6,9-dihydro-4y6-dioxo-10-propyl-4H-pyrano~ [3,2-g]quinoline-2/8-dicarboxyllc acid The product of step (a) (3.55g) was added in small portions to chlorosulphonic acid (100ml) cooled to -78°C 5 with stirring. The solution was allowed to warm slowly to room temperature and was then warmed to 50°C for 1 hour. The reaction mixture was cautiously poured onto ice (1 litre) and extracted into ethyl acetate. After drying the ethyl acetate was evaporated and the residue was 10 separated by high pressure liquid chromatography to afford the title compound (0.2g) chromatographically idential to I the product of Example 2.

Example ^ 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-q]-15 quinoline-2,8-dicarboxylic acid (a) l-Ethyl-6-(3-carboxy-3-diethylamino-l-oxo-prop-2-enyl)-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylic acid 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-20 (3,2-g]quinoline-2,8-dicarboxylic acid (lg) and diethyl-amine (5ml) were heated together Tn an autoclave for 12 hours at 100°C, then the volatile materials were evaporated at 60°C. The residue was triturated with ether to afford the sub-title compound (0.78g). Structure was 25 confirmed by n.m.r. and mass spectroscopy. '87156 i (b) 9-Ethy1-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-qjquinoline-2,8-dicarboxylic acid The product of step (a) (0.77g) was suspended in ethaholic hydrogen chloride (20ml) and heated under reflux residue which was separated by high pressure liquid chromatography to give the title compound (0.2g) which was chromatographically identical to the product of Example 2. Example 20 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-iH-pyrano-[3,2-q]quinoline-2,8-dicarboxylic acid (a) Diethyl 9-ethyl-6,9-dihydro-10-propyl-4,6-dithioxo-4H-pyrano[3,2-gjquinoline-2y 8-dicarboxylate Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (lOg) and penta-phosphorus decasulphide (20g) were fused together at 160°C for 6 hours, then cooled and the product mixture was extracted into ethyl acetate. Chromatography (silica gel/ethyl acetate) afforded the sub-title compound (5.6g). The structure was verified by n.m.r. and mass spectroscopy. (b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-q]quinoline-2,8-dicarboxylic acid The diester from step (a) was heated at 100°C in glacial acetic acid (50ml) containing concentrated hydro- for 24 hours. Evaporation of the solvent afforded a 67 187156 chloric acid (5ml) for 24 hours. The acetic acid solvent was evaporated and the residue was triturated with ether. The solid residue was dissolved in acetonitrile (50ml) containing water (1ml), and was stirred vigorously with 5 mercuric chloride (2g). After 48 hours the solution was filtered, and the filtrate was diluted with water (250ml) and then acidified. The precipitated solid was purified by high pressure liquid chromatography to afford the title compound (2.1g) which was chromatographically identical 10 with the product of Example 2.

Example 21 l 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-q) -quinoline-2,8-dicarboxylic acid (a) 9-Ethyl-2,3,6,9-tetrahydro-4,6-dioxo-10-propyl-4H-15 pyrano[3,2-q]quinoline-2,8-dicarboxylic acid Diethyl 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylate (5g) in glacial acetic acid (100ml) was hydrogenated over Adams catalyst (0.5g) at 4 atmospheres until hydrogen uptake ceased. The 20 catalyst was removed and concentrated hydrochloric acid (5ml) was added. The solution was refluxed for 24 hours then evaporated. High pressure liquid chromatography of the residue gave the sub-title compound (0.9g). The structure was supported by n.m.r. and mass spectroscopy. 187)56 (b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-q]quinoline-2,8-dicarboxylic acid The product of step (a) (0.85g) was suspended in cymene (10ml) and treated with 10% Pd/C catalyst at reflux 5 for 6 hours. Filtration and evaporation afforded a gum which was purified by high pressure liquid chromatography to give the title compound (0.15g) chromatographically identical with the product of Example 2.

Example 22 - 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-q]-quinoline-2,8-dicarboxylic acid i (a) 1-Ethyl-l,4-dihydro-7-hydroxy-6-methoxycarbonyl-4-oxo-8-propylquinoline-2-carboxylic acid Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-15 pyrano[3,2-g]quinoline-2,8-dicarboxylate (4.27g) and sodium hydroxide (1.6g) in water (10ml,) were heated to reflux for 24 hours, then the.water was evaporated and the residue was suspended in ethanol (50ml) saturated with hydrogen chloride gas and refluxed for 1 hour. Evaporation 20 of the solvent afforded a residue which was chromato-graphed (silica gel/ether) to afford a diester (1.3g) which was boiled with a solution of sodium hydroxide (0.139g) in water (20ml). On acidification a precipitate was formed which was shown to be the desired product 25 (0.93g) by n.m.r. and mass spectroscopy. 187156 (b) 9-3thy1-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-q)quinoline-2,8-dicarboxylic acid The product of step (a) (0.9g) dissolved in dry dimethyl sulphoxide (10ml) was added to a solution of dimsyl under N2- After 48 hours the reaction mixture was poured into water (500ml) and ether extracted. Drying and evaporation afforded a red oil which was suspended in toluene (20ml) and treated with piperidine (l.lg) and gly-10 oxylic acid hydrate (1.5g). After refluxing for 5 hours, the mixture was cooled, poured into ethyl acetate (100ml) and washed with saturated sodium bicarbonate solution. The sodium bicarbonate solution was acidified and extracted with ethyl acetate. Drying and evaporation gave a gum 15 which was separated by high pressure liquid chromatography to give the title compound (0.13g) which was identical chromatographically to the product of Example 2.

Example 23 9-Ethyl-10-propyl-2,8-di-tetrazol-5-yl-4H-pyrano[3,2-q]-20 quinoline-4,6(9H)-dione (a) 9-Ethyl-6,9-dihydro-4,6-dioxo-i0-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarbonitrile 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarbonyl chloride (lOg) was added 25 dropwise to cooled aqueous ammonia solution (100ml) with sodium (lg) in dry dimethyl sulphoxide (50ml) at 40°C 70 J 18715S\ stirring. The insoluble material was collected and washed well with water, then dried in vacuo at 80°C.

The solid was added to a solution of phosphoryl chloride (20g) in dry dimethyl formamide (100ml) and "warmed to 60°C for 48 hours. The reaction mixture was cooled and poured into water (1 litre), and extracted into ether. Drying and evaporation afforded an oil which was chromatographed (silica gel/ether) to afford the sub-title compound (3.7g). The structure was supported by n.m.r. and mass spectroscopy. (b) 9-Ethyl-10-propyl-2,8-di-tetrazol-5-yl-4H-pyrano-[3,2-g]quinoline-4,6(9H)-dione The product of step (a) (3.6g) and ammonium azide (1.3g) in dry dimethyl formamide (100ml) were heated to 140°C for 16 hours then cooled and poured into water. On acidification a precipitate was obtained which was chromatographed (silica gel/ethyl acetate) to produce the title compound (1.6g).

NMR<S~DMSO: 1. 0 (3H, t) ; l.l(3H,t); 1.8(2H/m); 3.8(2H,m); 4.5(2H,m); 7.1(1H,s); 8.65(1H„S); 8.8(lH,s); 10.1(2Hbrs). -ai/e/ias.

NOW AMENDED 1 87/1 56 What we claim is; 1. A process for the production of a conpound *5 0 V fornula I, in which an adjacent pair of R^, Rg, Ry and/Rg, form a chain -OOCH^CE-O-, and the remainder of Rg, R^, R^ aiftl Rg, which may be the same or different, each represent hydrogen, hydroxy, alkyl, // halogen, alkenyl, alkoxy, or -NR-^ in v£iich and R2, which are / the same or different, are each hydrogen or alkyl, / / Rg is hydrogen, alkyl, alkenyl/or phenyl-alkyl, and _ujLvcJL be SCXc^C /or differ ^o-cU. E/is -OOfflf, a 5-tetrazolyl^group or an (N-tetrazol-5-yl) carboxamido ,group, / or ar/phannaceuticall)y^icceptable derivative thereof, which comprises, (a)/ production of Compound of formula I in which^E is -COOH by ilectively hydrol) Ing or oxidising a coirpound of formula II, 20/ / *5® 0 v7iTil V 1 II r in which Rg is as defined above, 3% 4% 7*- NOW AMENDED NOW AMENDEO 187156 tx... i. p. &S- R^a, Rga, R^a and Rga have the same significances as R^., Rg, R^ and Rg above, save than an adjacent pa&r of R^a, and Rga instead of forming a chain -C0CH=C6E)0- represents a/ chain of formula -COCH=C (D) O-, and D and^D^, which may bef the same or different, each represents a -COOH group or a group / / hydrolysable or oxidisable to a -COOlS group, provided that only one of D and represents a -COOl^group, ^ (b) producing a compound of formula I in which each E is -COOH / or by cyclising a compound of formula III IV, / III IV or an esteir of either thereof, in which/R is as defined above, and / g Rgb, R£b, R^b and Rgb have the same significances as R^, Rg, R_ and above, save than an adjacent pair of Rcb, Rcb, R_b and 7 / o d c 7 also represent the pair of groups -H and -0-C(COOH)=CH-C0l (c) /producing a compoxznd of formula I in which each E is^G^blf^t (r NOW AWEMde0 - JS& -7* % ^3/8/136—, cyclising a conpound of fomula V, r5c NOW AMEND' 1/871 56 or an ester thereof, 0 in which Rg is as defined above RgC, RgC, RyC and RgC have^the sane significance as Rg, Rg, Ry and Rg above save that an adjacent pair of RgC^ RgC, R^c and RgC, instead of forming a cliain -CCCH=C(OOOHVO-, represent the //' pairs of groups: /> (i) -COO^CO Cm."'or -COCH^GCGOOH^^NL^, or a suitable derivative thereof;/and -CM or a halogen atom, or Cii) -H and/0-C(CDR")'<H-CX)R>,/ / / R" represents -CM, or a group which is hydrolysable thereto, and/L^ which may be tile same or dif hydrogen/aryl or allcyl, or^together form a saturated or unsaturated alkylene chain, and / / M represents hydrogen or an alkali metal, and if necessary or desired hydrolysing the group -GORV, to a group -COGM, (d) conversion of a compound of fornula VI, different are each NOW AMENDED / t'w 1* V * 187156 NOW AMENDED VI or an ester thereof, in which Rg and E are as define^ above, Rgd, Rgd, R^d and Rgd have the same significances as Rg, Rg, Ry and Rg above save that an. 'adjacent paixf of Rgd, Rgd, R?d and Rfld can also represent/the chain -C,(RgRlo)=CE-0-^ Ch^ji the pairs of groups Rg and R^g, which pairs of groups may ^ c be the same or different,/together and, form =S or = 0 or / / together form an -SlCH^^S- chain in which n is 2 or 3, provided that only on^ pair Rq, R1Q may represent = 0, / to a corresponding compound of formula I, (e) selectively removing the groups A and B from a compound of VII or an ester thereof, in which Rg and E are as defined above, /' R_e/ R.e, R_e and R_e have the same significances as Rc, ^/ w * w 5 Rg, R^/and Rg above save that an adjacent pair of Rge* R6e' R^e/and Rge can also represent a chain -C0CHA-CBE-0-, and in thfe pairs of groups A and B, which pairs of groups jjiay be same or different, both A and B IC ■"SSL - WOW AMEN DEO NOW AMENDED 187156 are hydrogen, or one of A and B is hydrogen- and the otlter is f / halogen or hydroxy, or A and B together form a doubl^ bond, i provided that both pairs of A and B do not form double bonds % / / (f) producing a compound of formula if in which ^fich E is -COOH by cyclising a .compound of formula VIIl/ VIII V' or an ester thereof, in which Rg is as defined aboy4, R^f, an^ Rgf have the same significance as R,., Rgj/Ry and Rg above save than an adjacent pair of R^f, Rgf# R^f/and Rgf# instead of forming a chain -C0CH=C(COOH)-0-, represent ifhe pair of groups -COCH (SOR^g) -CH (OH) -COOR" and' -0M, R" and M aire as defined above, and '10 / represents an alkyl C 1 to 10 group, (g) producing a comp9<ind of formula I in which each E is a -tetrazplyl group/£>y reacting a corresponding compound of formula /* // I in which each jj/is -CN, with an az$ie in a solvent which is inert under the reaction conditions, h) producing a compound of formula I in which each E is an (N-tetrazdl-5-yl) carboxamido group by reacting a corresponding compounor of fcjow amended iQ -6s-- row 187156 formula I in which each E is -COOH, or an acid halide, ester or mixed anhydride thereof, with 5-aniinotetrazole, / / / * / and if necessary or desired hydrolysing , the ester of/uie '• / ' conpound of fonnula I and/or converting the coirpound of, fornula I to a pharmaceutically acceptable derivative/thereof, ' 2. ~ A process according to part (a) ^od/ciaim 1, Wf^srem the group D is an ester, amide or nitrile group and the hydrolysis is carried out under mildly basic or under acidic conditi 3. A process according to part? (a) of Clai^fl, wherein the group D is an alkyl, aralkenyl, acyl or fornyl groyp and the process comprises oxidation. 4. A process according to part (a) o4 Claim 1 or to Claim 3, vihere in the group D is an alkyl group and the oxidation is carried * • * * out using selenium dioxide. / t . A process according to part/ (b) or (c)(ii) of Claim 1, wherein the reaction is parried out un&r anhydrous conditions and in the presence of a ^dehydrating agent. 6. A process according tb part (b) of Claim 1, wherein a compound of fornula III is cyclised by subjecting it to an elevated temperaptire. / | 7. A process acceding Nto part (c)(i) of Claim 1,/wherein one/of the groy£s is halogen and the cyclisation is carried out under acidic conditions at a temperature of ^rom 20° tc/l50°C. 8. A. process according to part (c) (j.) of Claim 1, wherein one of jthe groups is halogen and the reaction is carried out in a High boiling polar IS 77 ®OW AMEND! 187156 OW AM EN DEO solvent and in the presence of a strong base. /. / 9. A process for the production of a pharmaceutically- acceptable salt of a coirpound of formula I, as defined in Claim 1, "Which coirjvrises treating a conpound of fornula Ic, V 0 / / Ic . & S. in which Rg is as defined in Claim 1, Rgj* R^j and Rgj have the same^significances as Rg, R7 and Rg in Claim 1, save that an adjacent pair of R^j^ R^j and Rgj nay £ycm p. chain -0-COQ"CHOO-# each. X, which may be the Sane/6r different, is a 5-tetrazolyl group, // ' an (N-tetrazol-5-yl) carboxamido group, a carboxylic acid crroup (or an ester thereof, or another salt thereof), a nitrile group, an acid halide group or An amide group, with a compound -containing an available pharmaceutically acceptable' cation ana/capable of converting the group X to a pharmacejutically. a^^ptable salt of group E.

. A/'process according to any one Of the preceding claims, wherein each/of those ox/R,., Rg, and Rg, which do not form part of the -C9CH=CE-0- cl^in^ when they contain carbon, contain up to 8 carbon process according to Claim 10, wherein each of those of Re., Rc, Ji/j and Rg, which do not form part of the -C0CH=CE-0- chain, fey contain carbon, contain up to 4 carbon atoms. . rocess according to any one of the preceding claims. [* foJUNl98Q It fjoW A :cp IV" 187156 NOW AMENDED wherein each of those of , Rg, and which do not form part of the -C0CH=CE-0- chain, are selected from hydrogen, methoxy, propyl, allyl, methyl, ethyl, chlorine, bromine and hydroxy. 13. A process according to any one of the preceding claimsj wherein each E is -COOH. 14. A process according to Claim 1 an^substantially a/ hereinfcefc described.

. A process according to Claim V and substantially as hereinbefc described in any one of the Examples, 16. A compound of formula I, as defined in Cla^m 1, or a pharmaceutically acceptable derivative thereof* whenever prepared by a process according to any one of the preceding claims.

JL 17. A compound of formula I, as defined in Claim 1, or a pharmaceutically acceptable derivative ^hereof. 18. A compound acco/ding to Claim 17/ wherein each of those , which do not form part of the -C0CH=CE-0- chain, when they/contain carbon, contain up to 8 carbon atoms. 19. A compound according to Claipn 18, wherein each of those of R^, Rg, R? and Rg, lich do not form jfart of the -C0CH=CE-0-chain, when they contain carbon, contains up to 4 carbon atoms. 20. A compound accordingA:o any one of Claims 17 to 19, wherein beii fg in position R?. pari/ of the chain 2V. A compound according to any one of Claims 17 to 20, wherein ach of those of Rg, R^ and Rg which do not form part of the -C0CH=CE-0- chajoi are selected from hydrogen, methoxy, propyl, allyl, methyl/ ethyl, chlorine, bromine and hydroxy. 22. A compound according to any one of Claims 17 to 21, wherein ach E is/a -COOH group.

MOW AMENDE© h* tejuh;9sc 7*1 - ** - NOW AMENDED 23. 6,9-Dihydro-4,6-diaxo-10-prcpyl-4H-pyrano^ dicarboxylic acid. 24. 9-Ethyl-6,9-dib^dro-4,6-^iioxo-lO-pTOpyl 2,8-dicarbaxylic acid. . 5-Ethyl-5,8-dihydro-4,8-diaxo-lO-p: 2,6-dicarboxylic acid. 26. 7, lCHDihydro-4,10-diaxo-4H acid. 27. 10-Braix>-6,9-dihydro-4,6-diax3o-4H-pyrano< tricarboxylic acid. 28. 6,9-Dihydro-5-hydraxy-4 , 6-dioxo-lO-f), 187156 2,8-dicarbaxylic acid. 29- 6,9-Dihydro-4,9-diaxo-4H-pyrano( acid. / . 7,10-Dihydro^4,10-dioxo-4H-^rano/_2,3-f J7quinoline-2,8-di^~N- (tetrazol- 6-dioxo-2,8-di- (tetrazol-5-yl) -4H-pyrano- ccnpound according to any one of Claims conpound according to any one of Claims any cne of Claims 17 to 33 in a form of from 0.01 to 10 microns. oanpositicn comprising a conpound according to combination - row amended *}> 91 187]5t NOW AME vdth a pharmaceutically acceptable adjuvan^j diluent or ( trier. 36. A conposition according to Claim 35/comp rising les<£ than 801 by weight of active ingredient. 37. A conposition comprising from $.01 mg to 5 ^ of a conpound according to any one o£ Claims 1/to 34, as ac£ e ingredient, in unit dosage form. 38. A conposition according to Claim 37 c iprising from 0.01 mg to 20 mg of active ingredient. 39. A conposition according to Claii/ 38 conprising from 0.01 mg to 10 mg of active ingredient. j/ 40. A compositions according to/Claim 35 and substantially as / hereinbefore described. 41. A conpqyfod of fbrnula/II, / defined iz/ Claim 1. / V, VI, VII. or VIII as 42. / A compound" as claimed in claim 17 as defined in oif whenever prepared by a process as described In any /one of Examples 7 to 12. dated this day of ouee*nbw A. J. PARK & SON psb @lhjdsu. agents for the applicants NOW AMENDED N.Z. PATENT OFFICE 12dec1983 PEGEiVED 1S715I

Claims (10)

WHAT WE CLAIM IS: AS AMENDED

1. A pharmaceutically acceptable salt of 9-ethyl-6,9-dihydro-4, 6-dioxo- 10-propyl-4H-pyrano[3,2-g]quinolin-2, 8-dicarboxylic acid.

2. A compound of claim 1 wherein the salt is the disodium salt.

3. A pharmaceutical composition comprising a compound as claimed in claim 1 or claim 2 in combination with a pharmaceutically acceptable adjuvent, diluent or carrier.

4. A composition as claimed in claim 3 comprising less than 80% by weight of active ingredient

5. A pharmaceutical composition comprising from 0.01 mg to 50 mg of a compound as claimed in Claim 1 or Claim 2, as active ingredient, in unit dosage form.

6. A composition as claimed in Claim 5 comprising from 0.01 mg to 20 mg of active ingredient

7. A composition as claimed in Claim 6 comprising from 0.01 mg to 10 mg of active ingredient

8. A compound as claimed in Claim 1 or Claim 2 when prepared by a process substantially as hereinbefore described.

9. A compound as claimed in Claim 8 when prepared by a process substantially as hereinbefore described with reference to any Example thereof whether for the specific compound or otherwise.

10. A process for the production of a compound of formula I o o COOH ch2ch2ch3 which comprises: (1) a) selectively hydrolysing or oxidising a compound of formula II -72- AS AMENDED 187156 ch2ch3 ch3ch2ch3 in which one or both of D and D, represents a group hydrolysable or oxidiSable to a -COOH group and the other may represent a -COOH group; b) cyclising a compound of formula HI, nia IVa, IVb, IVc or JVd hooc"\ COOH hooc chzchj chjchjjck^ COOH COOH CH2CH3 ch2ch^h3 hooc HOOC IVa COOH CH2CH3 ch^chich3 HOOC COOH HOOC IVb HOOC COOH CH2CH3 ch2ch2ch3 hooc COOH COOH CH2CH3 CH2CH2CH3 vd HOOC -73 COOH _ HOOC COOH ch2ch3 CH2CH2CH3 AS AMENDED c) cyclising a compound of formula V 18 7 15 6 o V COOH ch^hjchj or an ester thereof in which R7o represent the pair of groups: (i) -COCH2COCORn, -COCH=C(COOH) -NL, L 2, or COCH=C(CONL, L 2) -NL,Lj and -OM, or, when a group -COCF| COCOR" is involved a halogen atom, or (ii) -H and -0-C(C0R")=CH-C0R" R" represents -OM or a group which is hydrolysable thereto, Lt and L which may be the same or different, are each hydrogen, aiyl or alkyl, or together form a saturated or unsaturated alkylene chain, and M represents hydrogen or an alkali metal, and, if necessary or desired, hydrolysing the group -COR", to a group -COOM; (d) conversion of a compound of formula VI, or an ester thereof in which R*, and may represent the chain -C(R9R10)CH=C(COOH)-o-, at least one of the pairs of groups R$ and Rj0 together form a =S or together form an -S(CH2)aS- chain in which n is 2 or 3 and the other pair Rg and R10 may represent = O, to a compound of formula I; VI ch2ph2ch3 -74- >1 IS?15b AS AMENDED (e) selectively removing the groups A and B from a compound of formula VII COOH CH2CH3 ch2ch2ch3 VII or an ester thereof in which and R,e may represent the chain -C0CHA-CB(C00H)-0- or the chain C0CH=C(C00H)-0-, in which in at least one of the pairs of groups A and B both A and B are hydrogen, or one of A and B is hydrogen and the other is halogen or hydroxy, and the other pair of A and B may together form a double bond; or (f) producing a compound of formula I by cyclising a compound of formula VIII o r. vra COOH CH2CH3 chjchjch3 or an ester thereof, in which and R* represent the pair of groups -COCH^SOI^, )- CH(OH)-COOR" and -OM, R" and M are as defined above and R10 represents an alkyl CI to 10 group; and if desired, (II) conversion of die compound of formula I to a pharmaceutically acceptable salt there0f" DATED this 1th omoejllw A.J.iWy& SON ^ agewlfo^e -75-