NO154497B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRANOQINOLINON DERIVATIVES. - Google Patents

Description

The present invention relates to the production of new, therapeutic

tically active pyranoquinolinone derivatives with the formula:

where an adjacent pair of the groups Rc , R-, R_ and RD form

_> b / o

a chain -COCH=CE-0-, while the remainder of R,., Rg, R^ and Rg,

which may be the same or different, each representing H, OH, alkyl of 1-6 carbon atoms, halogen, alkenyl of

2-6 carbon atoms, alkoxy with 1-6 carbon atoms or NH ?;

Rg is H or alkyl with 1-6 carbon atoms, E is -COOH, or et

pharmaceutically acceptable salt or lower alkyl ester thereof.

The compounds of formula I are prepared according to the present invention

invention in that one

(a) selectively hydrolyzes or oxidizes a compound of the formula:

where Rg is as defined above, and Rca, R^a, R_a and RDa

DO/O

has the same meaning as R^, Rg, R? and Rg, except that an adjacent pair of the groups R^a, Rg^/ R-^a and Rga may re-

present a chain with the formula -COCH=C(D^)0-, or one or both of the groups D and D, represents a group that can be hydrolyzed or oxidized to a -COOH group,

preferably respectively a lower alkyl ester of carboxyl-

the acid and a methyl group, while the other may represent a

-COOH group,

(b) rinqsluttor a compound of formula: or formula

or an ester of one of these compounds, wherein Rg is as defined above, R^b, Rgb, R^b and Rgb have the same meanings as R^, Rg, R^ and Rg above, except for an adjacent pair of the groups R ^b, Rgb, R^b and Rgb can represent a pair of groups -H and -O-C(COOH)=CH-COOH,

(c) ring-closes a compound of formula:

or an ester thereof, where Rg is as defined above,

R^c, RgC, R^c, and RgC have the same meaning as R^, Rr, R., and RQ, except an adjacent pair of the groups R,-c, RgC, R-yC, and RgC instead of forming a chain

-COCH=C(COOH)-0-, represents a pair of the groups:

(i) -COCH2CO COR" or -COCH=C (COOH) - NL-^I^, or a suitable derivative of such groups, and -OM, or (ii) -H and -O-C(COR")= CH-COR", R" represents -OM, or a group hydrolysable to such a group, and L 2 , which may be the same or different, each is hydrogen or C 1-6 alkyl, and M represents hydrogen or an alkali metal and , if necessary or desired, hydrolyzes the group -COR" to a group -COOM, (d) oxidatively hydrolyzes a compound of the formula: or an ester thereof, wherein Rg and E are as defined above, R1-d, Rgd, R^d and Rgd have the same meaning as R1., Rg, R^ and Rg, except that an adjacent pair of the groups R5d , Rgd, Rjd and Rgd can represent the chain -C(Rg, R1Q)CH=CE-0-, and where at least one of the groups Rg, R1Q forms a =S, and the other pair Rg, R^Q represents =S or =0, to a corresponding compound of formula I, (e) selectively removes groups A and B from a compound of formula:

or an ester thereof, wherein Rg and E are as defined above, R^e, Rge, R^e and Rge have the same meanings as R^, Rg, R^ and Rg above, except that an adjacent pair of the groups R^ e, Rge, R?e and Rge can represent a chain -COCHA-CBE-0-,

and where both A and B in at least one of the pairs of the groups A and B are hydrogen while the other pair A, B together can form a

double bond,

(f) ring-closes a compound of formula:

or an ester thereof, where Rg is as defined above,

R^f, Rgf/ Ryf and Rgf have the same meanings as R,-, Rg, R^ and Rg, except that adjacent pairs of the groups R^f, Rgf/ R7f and Rgf instead of forming a chain -COCH= C(COOH)-O-, represents a pair of the groups -COCH(SOR1Q)-CH(OH)-CO0R" and -OM, R" and M are as defined above, and R^q represents an alkyl group of 1-10 carbon atoms,

(g) reacts a dicarboxylic acid of the formula:

or an ester thereof, wherein Rg has the meaning given above, and an adjacent pair of the groups Rc, R1, R_, and RQ

Db/o forms a chain -C0CH=C(COOH)-0- and the remainder of Rd r, Rb,, R^ and Rg have the meaning given above, with an alkali metal salt or a base to form an alkali metal salt thereof, after which , if necessary or desired, converts an acid or a lower alkyl ester obtained in methods a)-g) into a pharmaceutically acceptable salt, or another lower alkyl ester thereof.

A particularly preferred compound with beneficial therapeutic action is 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2,8-dicarboxylic acid or a pharmaceutical -

zytically acceptable alkali metal salt thereof.

In method (a), the group D can e.g. be an ester, acid halide, amide or nitrile group, which can be hydrolysed to a -COOH group. The hydrolysis can be carried out using conventional techniques, e.g. under weakly basic conditions, one can e.g. use sodium carbonate, sodium hydroxide, sodium bicarbonate or under acidic conditions, e.g. a mixture of aqueous dioxane and hydrochloric acid, or hydrogen bromide in acetic acid. The hydrolysis can be carried out at temperatures from 25 to 120°C, depending on the compounds used. Alternatively, the group D can be an alkyl, e.g. lower alkyl, such as methyl, hydroxymethyl, aralkenyl, e.g. a styryl or acyl, e.g. lower alkanoyl such as acetyl or a formyl. The oxidation can be carried out in a conventional manner, if one

does not otherwise modify the molecule so that the yield of the desired product becomes uneconomical, e.g. an alkyl or a hydroxymethyl group can be oxidized using selenium dioxide, under reflux in aqueous dioxane, or chromic acid, e.g. under reflux in aqueous acetic acid. Aralkenyl groups can be oxidized by e.g. to

use neutral or alkaline potassium permanganate in aqueous ethanol, and acyl groups can be oxidized e.g. by using chromic acid or aqueous hypochlorite, e.g. sodium hypochlorite. The formyl group can be oxidized by using chromic acid or silver oxide.

In method (b), the cyclization can be carried out by treating the compound of formula III or IV with a cyclization agent, e.g. a dehydrating agent such as chlorosulfonic acid, sulfuric acid or polyphosphoric acid. The reaction is preferably carried out under anhydrous conditions and can be carried out at temperatures from 25 to 150°C, preferably from 75 to 150°C. It has been found that the isomerization of the maleic acid derivative of the compound of formula IV to the corresponding fumaric acid derivative of formula III takes place when polyphosphoric acid is used to ring-close these compounds to a compound of formula I, thereby obtaining a satisfactory yield of the compound of formula I from an initially unsatisfactory mixture of compounds of formulas III and IV. Compounds of formula III can also be ring-closed by subjecting the compounds to elevated temperature, e.g. from 200 to 250°C, possibly in the presence of a high-boiling solvent which is inert under the reaction conditions, e.g. diphenyl ether.

When one of the groups is -OM, the cyclization (c) (i) can be carried out by heating under basic or neutral conditions. However, it is preferred to carry out the ring closure in the presence of an acid, e.g. hydrochloric acid, and in a solvent which is inert under the reaction conditions, e.g. ethanol. The reaction can be carried out at temperatures from 20 to 150°C. The group -COR" is preferably an ester group, and R" can be a lower alkoxy group. When one of the groups -COOH=C(COOH)-NL1L2, then the derivative of the -COOH group will be a group -CONL^I^, where and I^ are as defined above.

The cyclization in process (c) (ii) can be carried out by treating the compound of formula V with a cyclization agent, e.g. a dehydrating agent such as chlorosulphonic acid, polyphosphoric acid or sulfuric acid. The reaction is preferably carried out under anhydrous conditions and can be carried out at a temperature from 0 to 100°C. Alternatively, the ring closure can be performed by converting the free carboxy groups in the compound of formula V into acyl halide groups, and then subjecting the resulting acyl halide to intramolecular Friedel-Craft reaction.

In method (d), when Rg and R-^q together form an =S-group, the oxidative hydrolysis can be carried out in the presence of a heavy metal compound, e.g. a compound from group Ib, Ilb or Illb in the periodic table, as catalysts. Suitable compounds include mercury, thallium and silver compounds, e.g. mercury (II) acetate or chloride, thallium (III) trifluoroacetate or silver oxide. The reaction can be carried out in the presence of water, alkanols, tetrahydrofuran/methanol

or tetrahydrofuran.

Process (e) is a dehydrogenation and can be carried out by oxidation using a weak oxidizing agent, e.g. selenium dioxide, palladium on charcoal, chloranil, lead tetraacetate or triphenylmethyl perchlorate.

The cyclization in method (f) can be carried out in a solvent which is inert under the reaction conditions, e.g. diethyl ether or benzene. The reaction can also, if desired, be carried out in the presence of a Lewis acid, e.g. boron trifluoride. The reaction is preferably carried out at temperatures from 10 to 120°C in the presence of an organic base, e.g. piperidine.

In method (g), preparation of a pharmaceutically acceptable salt of a compound of formula I includes treatment of a compound of formula I or an ester thereof

where Rg is as defined above, and an adjacent pair of R5, Rg, R7 and Rg can form a chain -O-C(COOH)=CHC0-, the rest of R,-, Rg, R^ and Rg have the above meaning, with a compound containing an available pharmaceutically acceptable cation and capable of converting the group COOH or an ester thereof, into a pharmaceutically acceptable salt of an E group.

Compounds capable of converting the group COOH or an ester thereof to a pharmaceutical salt of an E group include compounds such as bases or ion exchange resins containing pharmaceutically acceptable cations such as sodium, potassium, calcium, ammonium and suitable nitrogen-containing organic cations. In general, it is preferred to prepare pharmaceutically acceptable salts by treating the free acid of formula I with a suitable base, e.g. an alkaline earth metal or alkali metal hydroxide, carbonate or bicarbonate in an aqueous solution or by a metathetic process with a suitable salt. When using a strongly basic compound, care must be taken to keep the temperature sufficiently low to ensure that the compound of formula I is not hydrolyzed or broken up. The pharmaceutically acceptable alkali salt can be recovered from the reaction mixture by solvent precipitation and/or removal of the solvent by evaporation, e.g. freeze drying.

The starting compounds for method (b) can be prepared by reacting a compound with formula:

where Rg, R^b, Rgb, R^b and Rgb are as defined above, with a compound of formula:

Da-C=C-Da

where Da is an ester group, to form a mixture of compounds of formulas VI and XII

where Rg, Da, R5b, Rgb, R?b and Rgb are as defined above.

Compounds of formula XI and XII can be hydrolyzed to compounds of formula IV and III. Alternatively, the groups Da in the compounds of the formulas XI and XII can be converted using commonly known techniques to other groups D, and the resulting compounds can then be ring-closed using the same conditions as for method (b) above, whereby a compound with formula II. As a further and preferred alternative, the compounds of formula XI and XII can be cyclized using the same conditions as for method (b) above, whereby a compound of formula II is obtained where D is an ester group, after which the resulting compound of formula II itself itself can be used in method (a), or the D group can be converted into another D group, e.g. an acid halide, amide or nitrile group using techniques known per se.

The fumarate isomer of formula XII (or the corresponding compound where Da has been converted to D) is the only isomer which can be cyclized to the desired compounds of formula II. The amount of the two isomers can be easily determined by nuclear magnetic resonance spectroscopy, and it has been found that in general the desired fumaric acid derivative will only form a minor part of the prepared mixture of isomers.

Compounds of formula V, wherein an adjacent pair of R^c, RgC, R7c and RgC represent the groups -COCH2COCOR" or

-OM, can be produced by reacting a compound with formula:

or an ester thereof, where Rg is as defined above,

and where R5g, Rgg, R?g and Rgg have the same meaning as R5,

Rg, R7 and Rg above, except that adjacent pairs

of R5g, Rgg and Rgg instead of forming a -COCH=CH(COOH)-0 chain, represent the groups -COCH3 and -OM where M is as defined above, with a compound of formula:

where R" is as defined above, R' is a suitable leaving group, e.g. an alkyl group, halogen, amino, alkylamino, substituted amino (e.g. an arylsulfonylamino group) or a substituted alkylamino group, which is reactive with carbon the -ion of the -COCH^ group in the compound of formula XIII, and each of the groups Z is a carbonyl oxygen atom, or one of the Z groups may represent two halogen atoms, while the other is a carbonyl oxygen atom, and if necessary, hydrolyze the resulting compound to a compound of formula V. The preferred compounds of formula XIV are dialkyl oxalates, eg diethyl oxalate.

Compounds of formula V having a COCH=C (COOH)-NI^I^ group, or a derivative of such a compound, can be prepared from known compounds in one or more steps by means of known methods.

Compounds of formula II can be prepared as described above or by a method analogous to method (c) (i).

Alternatively, the compounds of formula II, e.g. if one has an acid halide, an amide or a nitrile, is prepared from compounds of formula I using conventional techniques, e.g. a reaction between an ester of a compound of formula I and ammonia, whereby the amide is obtained, followed by a dehydration of this nitrile.

Compounds of formula V having substituents -H and

-0-C(COR")=CH-COR", can be prepared by reacting a compound of formula:

or an ester thereof, where Rg has the above meaning, R^h, Rgh, R7h and Rgh have the same meaning as R,-, Rg,

R^ and Rg above, except that adjacent pairs of R^h, Rb ,h, R_/ h and Ro„h, instead of forming an OCH=C(COOH)-0 chain, represent the groups -H and -OH, with a dialkylacetylene dicarboxylate in a conventional manner, and if necessary, carry out a hydrolysis of the reaction product.

Compounds of formula VIII can be prepared by reacting a compound of formula:

or an ester thereof, where Rg is as defined above,

R^i, Rgi/ R-yi and Rgi have the same meaning as R^, Rg, R^ and

Rg above, except that adjacent pairs of R^i, Rgi'

R^i and RDi instead of forming a chain -COOH=C (COOH)-O-, represent the pair of groups -OH and COO-alkyl, with a methyl alkyl sulfoxide anion, e.g. the anion of dimethylsulfoxide, after which the resulting o-hydroxy-2-alkylsulfonyl compound is reacted with glyoxal acid or an ester thereof.

Compounds of formula VI, VII, IX, XIII, XIV, XV and

XVI are either known or can be prepared from known compounds using conventional techniques.

The methods described above can give the compound of formula I or derivative thereof.

The invention also includes treatment of any derivative thus formed, to release the free compound of formula I or conversion of one derivative into another.

Compounds of formula I and their intermediates can therefore be isolated from their reaction mixtures by means of conventional

technique.

Pharmaceutically acceptable derivatives of compounds with

formula I includes pharmaceutically acceptable salts and lower alkyl esters 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 hydroxylamine, lower alkylamines, such as methylamine or ethylamine, with lower substituted alkylamines, e.g. hydroxy-substituted alkylamines, such as tris(hydroxymethyl)methylamine, or with simple monocyclic nitrogen heterocyclic compounds, e.g. piperidine or morpholine. Suitable esters include simple lower alkyl esters, e.g. the ethyl ester, esters derived from alcohols containing basic groups, e.g. di-lower alkylamino-substituted alkanols such as |3-(diethylamino)-ethyl ester, and acyloxyalkyl esters, e.g. a lower alkoxy-lower alkyl ester, such as the pivaloyloxymethyl ester, or a bis ester derived from a dihydroxy compound, e.g.

a di(hydroxy-lower alkyl) ether, e.g. the bis-2-oxypropane-1,3-diyl ester. Pharmaceutically acceptable acid addition salts of the basic esters can also be used, and the same applies to compounds where one of the groups Rc, , R_ and R_ is a group -NI^ e.g. the hydrochloride, hydrobromide, oxalate, maleate or fumarate salt. The ester can be prepared in a conventional manner, e.g. by an esterification or a transesterification.

Compounds of formula I and said pharmaceutically acceptable salts and esters of such compounds are very valuable because they have pharmacological activity in animals, in particular they can be used because they inhibit the release of and/or the action of pharmacological preparations arising from an in vivo combination of certain types of antibody and specific antigen, e.g. the combination of reaginic antibody with specific antigen (see Example 27 of British Patent No. 1,292,601). It has also been found that the new compounds affect the reflexes in animals and humans, especially the reflexes associated with lung function. In humans, both subjective and objective changes that occur when a specific antigen is inhaled in sensitized patients will be inhibited by a prior supply of the new compounds. Thus, the new compounds can be used in the treatment

of reversible airway obstructions and/or to prevent secretion of too much mucus. The new compounds can thus be used for the treatment of allergic asthma, so-called "intrinsic" asthma (where no sensitivity to extrinsic antigen can be demonstrated), bronchitis, cough and nasal and bronchial congestion associated with common colds. The new compounds may also be valuable in the treatment of other conditions, where one has antigen-antibody reactions or excessive secretion from the mucous membrane, or similar disorders, e.g. in hay fever, certain eye conditions, e.g. trachoma, allergy in the intestinal tract, e.g. urticaria and atopic eczema, and gastrointestinal conditions, e.g. gastrointestinal allergy, especially in children, e.g. milk allergy, or ulcerative colitis.

For the above purposes, the doses administered will of course vary with the compound used, the route of administration and the treatment desired."However, satisfactory results will usually be obtained when the compound is administered in amounts of 0.001-50 mg per kg of body weight in the test indicated in Example 27 of British Patent No. 1,292,601 For humans, the indicated total dose will be 0.01-1000 mg, preferably 0.01-200 mg, more preferably 1-600 mg, which may be administered in divided doses from 1 to 6 times a day or in a slow-release form. Unit dosage forms suitable for administration (by inhalation or oesophagus) may thus include 0.01-50 mg, preferably 0.01-20 mg, and more preferably 0.01-10 mg of the compound, preferably mixed with a solid or liquid pharmaceutically acceptable carrier.

Compounds of formula I and pharmaceutically acceptable derivatives of such compounds have the advantage that they are more effective than certain pharmacological models, or act longer than compounds of similar structure. Furthermore, compounds of formula I and said pharmaceutically acceptable salts and esters thereof will be advantageously used because they are more effective in that they affect the reflexes and inhibit the secretion of such by the mucous membranes, and they constitute this more effectively and more strongly than compounds of similar structure.

Each of the groups Rg, R^, Rg, R? and Rg when containing carbon atoms, contains up to 6, preferably up to 4 carbon atoms. In particular, it is preferred that R^, Rg, R^ and Rg are selected from the group consisting of hydrogen, methoxy, propyl, allyl, methyl, ethyl, chlorine, bromine and hydroxy. The -COCH=CE-0 chain may be attached to the benzene ring in any manner, and at any of the adjacent positions R,-, Rg, R^ and Rg. However, it is preferred that the chain is bound in positions Rg and R^, and that the -0 part of the chain is in position R^.

Pharmaceutical preparations contain (preferably less than 80% and more preferably less than 50% by weight) a compound of formula I or said pharmaceutically acceptable salts or esters of such a compound, in combination with a pharmaceutically acceptable carrier. Examples of suitable carriers for tablets, capsules and the like are micro-crystalline cellulose, calcium phosphate, diatomaceous earth and a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin, while for suppositories natural or hardened oils or waxes, and for inhalation preparations, crude lactose. The compound of formula I or said pharmaceutically acceptable salt or ester thereof is preferably in a form having an average diameter of from 0.01 to 10 µm. The preparations may also contain suitable preservatives, moisturizing and flavoring agents. The preparations can, if desired, be worked up in a form that ensures slow release. One prefers preparations that are designed so that they can be taken through the esophagus and release their contents in the intestinal tract.

The following examples illustrate the connection.

Example 1

6, 9- dihydro- 4, 6- dioxo- 4H- pyrano[ 3, 2- g] quinoline- 2, 8- dicarboxylic acid (and disodium salt)

(a) 4-acetamido-2-allyloxyacetophenone

19.3 g of 4-acetamido-2-hydroxyacetophenone, 12.1 ml of allyl bromide and 21.5 g of anhydrous potassium carbonate were stirred in 250 ml of dry dimethylformamide at room temperature for 24 hours. The reaction mixture was poured into water and the product extracted with ethyl acetate. The organic solution was washed with water, dried over magnesium sulfate and evaporated to dryness. The desired product was obtained as a beige colored solid weighing 20.5 g. The structure of the product was confirmed by NMR and mass spectroscopy.

(b) 4-acetamido-3-allyl-2-hydroxyacetophenone

18.4 g of the above allyl ether was heated at 300

to 210°C for 4 hours. 17.1 g of the heat-replaced desired product was obtained as a brown solid. Again, the structure was confirmed by NMR and<1> mass spectroscopy.

(c) 4-acetamido-2-hydroxy-3-propylacetophenone

17 g of the product from step (b) was dissolved in glacial acetic acid and hydrogenated in the presence of Adams catalyst until hydrogen absorption stopped. The catalyst was filtered off using diatomaceous earth, and the filtrate was evaporated to give 13.0 g of a colorless solid. The structure of the product was confirmed by mass spectroscopy and NMR spectra.

(d) Ethyl-7-acetamido-4-oxy-8-propyl-4H-1-benzopyran-2-carboxylate

A mixture of 19.3 g (17.9 ml) of diethyl oxalate and product

tet from step (c) weighing 12.4 g in 100 ml of dry ethanol,

was added to a stirred solution of sodium ethoxide in ethanol prepared by dissolving 6.1 g of sodium in 200 ml of dry ethanol. The reaction mixture was refluxed for 3 hours, then poured into dilute hydrochloric acid and chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated, and a brown solid was obtained which was dissolved in 300 ml of ethanol containing 3 ml of concentrated hydrochloric acid, and the mixture was refluxed for 1 hour. The reaction mixture was then poured into water, and the product extracted into ethyl acetate, which was washed with water and dried. Evaporation of the solvent gave 10 g of a sticky substance which had mass spectra and NMR spectra in accordance with the expected product.

(e) Ethyl-7-amino-4-oxy-8-propyl-4H-1-benzopyran-2-carboxylate

A solution of 10 g of the amide from step (d) in 300 ml of ethanol containing 5 ml of concentrated hydrochloric acid was refluxed for 8 hours. The reaction mixture was diluted with water and extracted into ethyl acetate. The extract was washed with water, dried, after which the solvent was evaporated, and a dark brown semi-solid was obtained. This was chromatographed on a silica gel column, using ether as an eluent, to give 4.8 g of the desired product, the structure of which was confirmed by mass spectroscopy and NMR spectra. Melting point 84-87°C.

(f) 2-ethoxycarbonyl-8-methoxycarbonyl-10-propyl-4H-pyrano[3,2-g]-quinoline-4,6(9H)dione

2.0 g of the aminobenzopyran from step (e) and 1.24 g of dimethyl acetylene dicarboxylate were refluxed in 30 ml of ethanol for 26 hours. The reaction mixture was de-

cooled to -0°C, and insoluble tan solid was collected by filtration and washed with a little ethanol and dried to give 2.0 g of a product which was a mixture of maleic and fumaric esters prepared by Michael addition of the amine to acetylene .

2.0 g of this mixture of esters was treated with 30 ml of polyphosphoric acid and heated on a steam bath with stirring.

for 20 minutes. The mixture was then poured into ice and stirred with ethyl acetate. The organic layer was separated, and washed with water and dried. The solvent was evaporated,

and 1.6 g of a yellow-orange solid was obtained. The recrystallization of this compound from ethyl acetate gives the desired product as orange needles, melting point 187-188°C.

Analysis

Found: C, 62.0%; H, 5.1%; H, 3.7% <C2>0<H>19NO7 Theoretical: C, 62.3%; H, 4.9%; H, 3.6% (g) 6,9-dihydro-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-carboxylic acid

2.5 g of the above bisester was boiled under reflux

run with sodium bicarbonate weighing 1.64 g in 100 ml of ethanol and 50 ml of water for 1 1/2 hours. The whole thing was then poured into acidified water so that a gelatinous solid was precipitated. This was filtered off, refluxed with ethanol, and the product separated by centrifugation, weighing 1.4 g and melting at 303-304°C with decomposition. The structure of the product was confirmed by mass spectroscopy and NMR.

(h) Disodium- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H-pyrano[ 3, 2-g] quinoline- 2, 8- dicarboxylate

1.35 g of the bisic acid from step (g) and 0.661 g of sodium bicarbonate in 150 ml of water were heated and stirred until a clear solution was obtained. The solution was filtered, and the filtrate freeze-dried to 1.43 g of the desired disodium salt.

Analysis

Found: C, 46.1%; H, 4.0%; N, 2.9% C17H11N07Na212.5%H2° Theoretical: C, 46.1%; H, 3.8%; N, 3.15%

Example 2

9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano[ 3, 2- g]- quinoline- 2, 8- dicarboxylic acid (and esters and disodium salt)

(a) 4-(N-acetyl-N-ethyl)amino-2-allyloxyacetophenone

92.6 g of 4-(N-acetyl-N-ethyl)amino-2-hydroxyacetophenone,

51 ml of allyl bromide and 90.4 g of anhydrous potassium carbonate were stirred in 500 ml of dry dimethylformamide for 17 hours. The reaction mixture was poured into water and the product extracted with ether. The organic solution was washed with water, dried over magnesium sulfate and evaporated to dryness. 102 g of an oil was obtained. The structure of the product was confirmed by NMR and mass spectroscopy.

(b) 4-( N- acetyl- N- ethyl) amino- 3- propyl- 2- hydroxyacetophenone

100.5 g of the allyl ether product from step (a) was refluxed in 300 ml of diethylaniline for 3 hours. The reaction mixture was cooled and poured into dilute hydrochloric acid and extracted with ether, the latter being washed with dilute hydrochloric acid and then with water. The organic solution was extra-

hardened with 10% sodium hydroxide solution and then acidified.

The precipitated product was extracted with ether which had been dried over magnesium sulfate. The remaining ether solution was evaporated to dryness, and 78.7 g of a yellow-brown oil was obtained. This oil was a mixture of 4-(N-acetyl-N-ethyl)amino-3-allyl-2-hydroxyacetophenone and 6-(N-acetyl-N-ethyl)amino-3-allyl-2-hydroxyacetophenone.

This mixture was dissolved in 500 ml ethanol and 20 ml glacial acetic acid and hydrogenated in the presence of Adams catalyst until hydrogen absorption stopped. The catalyst was filtered off through diatomaceous earth, and the filtrate evaporated to 79.9 g of a brown oil. The oil was a mixture and was separated by high pressure liquid chromatography using ether/petroleum ether (1:1) as a solvent to give 44.2 g of the desired compound and 23.8 g of 6-(N-acetyl -N-ethyl)amino-3-propyl-2-hydroxyacetophenone.

(c) 4-N-ethylamino-3-propyl-2-hydroxyacetophenone

44 g of 4-(N-acetyl-N-ethyl)amino-3-propyl-2-hydroxyacetophenone was refluxed in 48% hydrogen bromide in 100 ml of glacial acetic acid, 500 ml of glacial acetic acid and 20 ml of water for 6 hours. The mixture was then poured into ice water and extracted with ethyl acetate which was then washed with water, sodium bicarbonate solution and then again with water and dried over magnesium sulfate. The organic solvent was evaporated to dryness to give the desired compound as 34 g of a red oil. The structure was confirmed by NMR and mass spectroscopy. (d) Methyl-6-acetyl-1-ethyl-7-hydroxy-4(1H)-oxo-8-propyl-quinoline-2-carboxylate 17 g of the amine product from step (c) and 11.3 ml of dimethacetylene dicarboxylate was refluxed in 300 ml of ethanol for 17 hours. The reaction mixture was cooled and evaporated to dryness, and a deep red oil was obtained. This was chromatographed on a silica gel column, using ether/petroleum (1:1) as eluent, and 19.1 g of dimethyl-1-(4-acetyl-3-hydroxy-2-propylphenyl)-N-ethyl was obtained -aminomaleate. Melting point 83.87°C. 5 g of the maleic acid ester were heated and stirred in 100 ml of polyphosphoric acid on a steam bath for 10 minutes. The reaction mixture was cooled and poured into a mixture of ice water and ethyl acetate. The organic solution was separated, washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give a pale yellow solid. This product was purified by high pressure liquid chromatography to give 2.6 g of the desired compound, mp 121-123°C.

Analysis

Found: C: 65.5%; H, 6.6%; N, 4.2% C18H21N05 Requirements: C: 65.3%; H, 6.34%; N, 4.23%

100 mg of methyl 6-acetyl-1-ethyl-5-hydroxy-4-oxy-4H-quinoline-2-carboxylate was obtained from the purification as a pale yellow solid.

(e) Diethyl-6,9-dihydro-4,6-dioxo-9-ethyl-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylate

To 1.0 g of the hydroxyketone product from step (d) and 3.3 ml of diethyl oxalate in 25 ml of dry dimethylformamide was added ether washed with 50% sodium hydride (0.581 g) in 20 ml of dimethylformamide, and the mixture was stirred for 4 hours. It was then completely soaked in water, acidified and extracted with ethyl acetate,

which was then washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness, and an oil was obtained which was dissolved in 100 ml of ethanol, to which a couple of drops of concentrated hydrochloric acid were added. The resolution was

refluxed for half an hour, cooled, poured into water and extracted with ethyl acetate, the latter being washed with water and then dried over magnesium sulfate. The solvent was evaporated to dryness, and an oil was obtained which solidified on treatment with 1.2 g of 40 to 60 C petroleum ether. The structure of the compound was confirmed by NMR.

(f) 9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano-[ 3, 2-g] quinoline- 2, 8- dicarboxylic acid

1.0 g of the above bisester and 0.787 g of sodium bicarbonate in 85 ml of ethanol and 32 ml of water were refluxed for 4 hours. The reaction mixture was poured into water, acidified, after which the precipitate was collected by filtration and dried. The product was purified by treatment with boiling ethanol, and then twice with boiling acetone. After each treatment, the treatment was centrifuged, and the overlying liquid was removed by decanting. The remaining solid was dried to give 0.547 g of the desired diacid as a yellow powder, m.p. 298-300°C decomposition.

Analysis

Found: C: 61.3% H: 5.0% N: 3.6% C19H17N07 Required: C: 61.5% H: 4.6% N: 3.79% (g) Disodium- 6, 9- dihydro- 4, 6- dioxo- 9- ethyl- 10- propyl-4H-pyrano- [ 3, 2-g] quinoline- 2, 8- dicarboxylate

4.098 g of the above diacid was suspended in 100 ml of water and treated with 1.82 g of sodium bicarbonate. The resulting solution was filtered, after which the filtrate was treated with acetone until complete precipitation of the product was obtained. The desired disodium salt was filtered off, and 3.39 g of a pale yellow powder was obtained.

Analysis

Found: C: 51.1% H: 4.3% N: 3.0% C19H15Na2°7 Required: C: 51.5% H: 4.1% N: 3.1%

Example 3

(i) 5-ethyl-5,8-dihydro-4,8-dioxo-10-propyl-4H-pyrano-[2,3-h]-quinoline-2,6-dicarboxylic acid,

N<MR6>DMSQ: 1.1 (3H, t), 1.6 (2H, m), 2.2 (2H, t),

6.8 (1H, s) , 7.8 (1H, s) . (ii) 7,10-dihydro-4,10-dioxo-4H-pyrano[2,3-f ]-quinoline-2,8-dicarboxylic acid,

NMR6 MC_: 6.6 (1H, s), 6.8 (1H, s), 7.6 (1H, d, J=8Hz),

DMSO

8.1 (1H, d, J=8Hz).

(iii) 6,9-dihydro-5-hydroxy-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2,8-dicarboxylic acid,

NMRS : 1.1 (3H, t), 1.6 (2H, m), 2.2 (2H, t), 6.3 (1H,

DMSO

s) , 6.9 (1H, s) .

(iv) 6,9-dihydro-4,9-dioxo-4H-pyrano[2,3-g]quinoline-2,7-dicarboxylic acid,

NMR<SDMS0: 6.6 (1H, s) , 6.9 (1H, s) , 7.6 (1H, s),

8.6 (1H, s) .

Example 4

(i) 7,10-dihydro-7-(3-methylbutyl)-4,10-dioxo-4H-pyrano-[2,3-f]-quinoline-2,8-dicarboxylic acid, m.p. 246-248°C

(decomp.)

(ii) 6,9-dihydro-9-(3-methylbutyl)-4,6-dioxo-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylic acid, m.p. 302-304°C (decomp.) (iii) Disodium 7-ethyl-7,10-dihydro-4,10-dioxo-4H-pyrano-[3,2-f]quinoline-2,8-dicarboxylate,

Analysis

Found: C 44.1%, H 3.5%, N 3.3%

C16HgNNa2O7, 14.4%, H2O

Requires: C 44.1%, H 3.7%, N 3.2%

Example 5

(a) 7,10-dihydro-5-methoxy-4,7-dioxo-4H-pyrano-[3,2-h]-quinoline-2,9-dicarboxylic acid, m.p. 294-296°C (decomp.), (b) 6,9-dihydro-4,6-dioxo-10-(prop-2-enyl)-4H-pyrano-[3,2-g]quinoline-2, 8-carboxylic acid, (structure confirmed by NMR). (c) 7,10-dihydro-4,10-dioxo-4H-pyrano[2,3-h]quinoline-2,8-dicarboxylic acid, m.p. 200°C (d) 10-hydroxy-1-oxo-1H-pyrano[3,2-f]quinoline-2,8-dicarboxylic acid, disodium salt.

Analysis

C14<H>15NNaO,7.6 11 H20 requires C 45.74% H 2.1% N 3.8%

found: C 45.74% H 2.45% N 3.6% (e) 7,10-dihydro-4,10-dioxo-4H-pyrano[3,2-f]-quinoline-2,8-dicarboxylic acid , disodium salt

Analysis

Found: C 44.36% H 2.18% N 3.54% C14H5N<Na>207.2H20 requires: C 44.1% H 2.38% N 3.67%

(f) 6,9-dihydro-10-methyl-4,6-dioxo-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylic acid, m.p. 302°C. (g) Diethyl 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylate, m.p. 211-212°C. (h) 6-amino-7,10-dihydro-5-methoxy-4,7-dioxo-4-pyrano-3,2-h]quinoline-2,9-dicarboxylic acid

NM R 0 .DMSO: 3.95(3H, s); 6.95 (1H, s); 7.4 (1H, s); 9.6 (brs-4H).

(i) 10-bromo-6,9-dihydro-4,6-dioxo-4H-pyrano[3,2-g]-quinoline-2,8-dicarboxylic acid

NMRgDMSO: 6.95 (1H, s); 7.0 (1H, s); 8.6 (1H, p).

Example 6

9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano% 3, 2]-quinoline- 2, 8- dicarboxylic acid

(a) 6-acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-8-propyl-quinoline-2-carboxylic acid

Methyl 6-acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-8-propyl-quinoline-2-carboxylate (20 g) was heated under reflux in glacial acetic acid (150 ml) containing 48% aqueous HBr (20 mL). After 18 hours, the mixture was cooled and poured into water. Ammonia was added until pH 3. The precipitate was collected and dried in vacuo and was identified as the compound under (a) above (14.3 g) by NMR and mass spectroscopy.

(b) 2-ethoxycarbonyl-9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-8-carboxylic acid

The product from step (a) (14.2) was added to a solution of sodium (5.2 g) in ethanol (200 ml) and then diethyl oxalate (16 g) was added. The mixture was heated under reflux for 5 hours and then cooled and poured into chloroform

(1 litre). The mixture was shaken with dilute hydrochloric acid (150 ml), and then the organic phase was dried and evaporated in vacuo. The residue was dissolved in ethanol (200 ml) containing concentrated hydrochloric acid (2 ml) and refluxed for 18 hours. The solvent was evaporated and the residue was recrystallized from ethanol to obtain the compound under (b) (3.2 g). The structure was confirmed by NMR and mass spectroscopy.

(c) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-13,2-g]quinoline-2,8-dicarboxylic acid

The product from step (b) was hydrolysed by the method

in step (a) and gave a product (1.1 g) identical to that of Example 2 by comparison by thin layer chromatography.

Example 7

9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano[ 3, 2- g]-quinoline- 2, 8- dicarboxylic acid

(a) Methyl-9-ethyl-6,9-dihydro-2-methyl-4,6-dioxo-10-propyl

4H-pyrano[3,2-g]quinoline-8-carboxylate

6-Acetyl-1-ethyl-7-hydroxy-4(1H)-oxo-8-propylquinoline-2-carboxylic acid (3.15 g) was dissolved in dry dimethylformamide (50 ml) containing washed sodium hydride (1.05 g) and then ethyl acetate (4.4 g) was introduced. After stirring overnight, gaseous hydrochloride was introduced into the mixture with ice-cooling until saturation. The mixture was heated 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 (SiO 2 / ethyl acetate) to obtain the compound under point (a)

(0.8g). The structure was confirmed by NMR and mass spectroscopy.

(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylic acid

The product from step (a) (0.75 g) was heated under reflux with selenium dioxide (1.5 g) in glacial acetic acid (50 ml) for 48 h. Filtration through "Celite" gave a clear filtrate which was treated with concentrated hydrochloric acid (25 mL) and heated under reflux for 12 hours. Upon cooling and pouring into water, a precipitate (0.1 g) was obtained which was identical to the product in example 2 when compared by thin-layer chromatography.

Example 8

9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano[ 3, 2- g]-quinoline- 2, 8- dicarboxylic acid

(a) N-[3-(1,2-dicarboxyethenyloxy)-2-propylphenyl]-N-ethyl-2-amino-but-2-ene-1,4-dioic acid

3-Ethylamino-2-propylphenol (17.9 g) dimethyl acetylene dicarboxylate (35 mg), potassium hydroxide (0.56 g), water (50 ml) and ethanol (100 ml) were heated under reflux for 24 hours. Potassium hydroxide (1.65 g) was added and reflux was continued for a further 24 hours.

Concentrated hydrochloric acid (4 ml) was added and the solution evaporated. The residue was dried in vacuo and extracted into ether. The ether was evaporated to give the desired compound under (a) (3.6 g). The structure was confirmed by NMR

and mass spectroscopy.

(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g)quinoline-2,8-dicarboxylic acid

The product from step (a) (3.55 g) was added in small amounts to chlorosulfonic acid (100 ml) cooled to -78°C with stirring. The solution was allowed to warm slowly to room temperature and was then heated to 50°C for 1 hour. The reaction mixture was carefully poured onto ice (1 liter) and extracted into ethyl acetate. After drying, the ethyl acetate was evaporated and the residue was separated by high pressure liquid chromatography to give the desired compound (0.2 g) which by chromatographic comparison was found to be identical to the product of Example 2.

Example 9

9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano[ 3, 2- g]-quinoline- 2, 8- dicarboxylic acid

(a) 1-ethyl-6-(3-carboxy-3-diethylamino-1-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[3,2-g]-quinoline-2,8-dicarboxylic acid (1 g) and diethylamine (5 mL) were combined heated in an autoclave for 12 hours at 100°C, and then the volatiles were evaporated at 60°C. The residue was triturated with ether to give the desired compound under (a) (0.78 g). The structure was confirmed by NMR and mass spectroscopy.

(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2g]quinoline-2,8-dicarboxylic acid

The product from step (a) (0.77 g) was suspended in ethanolic hydrogen chloride (20 ml) and heated under reflux for 24 hours. Evaporation of the solvent gave a residue which was separated by high pressure liquid chromatography to give the desired compound under (b) (0.2 g) which by chromatographic comparison was found to be identical to

)

the product in example 2.

Example 10

9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano- [ 3, 2- g]-quinoline- 2, 8- carboxylic acid

(a) Diethyl 9-ethyl-6,9-dihydro-10-propyl-4,6-dithioxo-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate

Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylate (10 g) and pentaphosphorus decasulphide (20 g) became. fused at 160°C for 6 hours, then cooled, and the product mixture was extracted into ethyl acetate. Chromatography (silica gel/ethyl acetate) gave the desired compound under (a) (5.6 g). The structure was confirmed by NMR and mass spectroscopy.

(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylic acid

The diester from step (a) was heated at 100°C in glacial acetic acid (50 ml) containing concentrated hydrochloric acid (5 ml) for 24 hours. The acetic acid solvent was evaporated and the residue was triturated with ether. The solid residue was dissolved in acetonitrile (50 ml) containing water (1 ml), and was stirred vigorously with mercuric chloride (2 g). After 48 hours, the solution was filtered and the filtrate was diluted with water (250 mL) and then acidified. The precipitated substance was purified by high-pressure liquid chromatography, and this gave the desired compound (2, 1g) with the product of Example 2.

Example 11

9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano [ 3, 2- g]-quinoline- 2, 8- dicarboxylic acid

(a) 9-ethyl-2,3,6,9-tetrahydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]-2,8-dicarboxylic acid

Diethyl 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]-quinoline-2,8-dicarboxylate (5 g) in glacial acetic acid (100 ml) was hydrogenated over an Adams catalyst (0.5 g) at 4 atmospheres until hydrogen uptake ceased. The catalyst was removed and concentrated hydrochloric acid (5 mL) was added. The solution was refluxed for 24 hours and then evaporated. High pressure liquid chromatography of the residue gave the desired compound (0.9 g). The structure was confirmed by NMR and mass spectroscopy.

(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylic acid

The product of step (a) (0.85 g) was suspended in cyme (10 ml) and treated with 10% Pd/C catalyst at reflux for 6 h. Filtration and evaporation gave a gum which was purified by high pressure liquid chromatography and this gave the desired compound (0.15 g) which by chromatographic comparison was found to be identical to the product of Example 2.

Example 12

, 9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano[ 3, 2- g]-quinoline- 2, 8- dicarboxylic acid

(a) 1-ethyl-1,4-dihydro-7-hydroxy-6-methoxycarbonyl-4-oxo-8-propylquinoline-2-carboxylic acid Diethyl-9-ethyl-6,9-dihydro-4,6-dioxo- 10-propyl-4H-pyrano

[3,2-g]quinoline-2,8-dicarboxylate (4.27) and sodium hydroxy (1.6 g) in water (10 mL) were heated to reflux for 24 h, then the water was evaporated and the residue suspended in ethanol (50 ml) saturated with hydrogen chloride gas and refluxed for 1 hour. Evaporation of the solvent gave a residue which was chromatographed (silica gel/ether),

and this gave a diester (1.3 g), which was boiled with a solution of sodium hydroxide (0.139 g) in water (20 ml). Upon acidification, a precipitate was formed which proved to be the desired product (0.93 g) by NMR analysis and mass spectroscopy.

(b) 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]quinoline-2,8-dicarboxylic acid

The product of step (a) (0.9 g) dissolved in dry dimethyl sulphoxide (10 ml) was added to a solution of dimethyl sodium (1 g)

1 dry dimethylsulfoxide (50 ml) at 40°C under N2. After

After 48 hours, the reaction mixture was poured into water (500 mL) and extracted with ether. Drying and evaporation gave a red oil which was suspended in toluene (20 mL) and treated with piperidine (1.1 g) and glycosylic acid hydrate (1.5 g). After refluxing for 5 hours, the mixture was cooled, poured into ethyl acetate (100 mL) and washed with saturated sodium bicarbonate solution. The sodium bicarbonate solution was acidified and extracted

with ethyl acetate. Drying and evaporation gave a gum which was separated by high pressure liquid chromatography, and this gave the desired compound (0.13 g) which by chromatographic comparison was found to be identical to the product of Example 2.

Example 13

Disodium- 9- ethyl- 6, 9- dihydro- 4, 6- dioxo- 10- propyl- 4H- pyrano-[ 3, 2-g] quinoline- 2, 8- dicarboxylate

Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2,8-dicarboxylate (11.3 kg) was suspended in meta -nol (113 L) and treated with sodium hydroxide solution (2.113 kg in 26.4 L water) for 3 min. The mixture was then refluxed for 4 hours and filtered while hot. Acetone (565 L) was added and after cooling overnight the product was isolated on a centrifuge and dried for 24 hours at 50°C >98% by HPLC.

Claims (2)

1. Analogy method for the preparation of therapeutically active compounds of the formula: where an adjacent pair of the groups R1, Rg, R7 and Rg form a chain -COCH=CE-0-, while the remainder of R1-, Rg, R^ and Rg, which may be the same or different, each represent H, OH, alkyl with 1-6 carbon atoms, halogen, alkenyl with 2-6 carbon atoms, alkoxy with 1-6 carbon atoms or NH2; Rg is H or alkyl down 1-6 carbon atoms, E is -COOH, or a pharmaceutically acceptable salt or lower alkyl ester thereof, characterized in that one: (a) selectively hydrolyzes or oxidizes a compound of the formula: where Rg is as defined above, and R^a, R^a, R^a and Rga have the same meanings as R,., Rg, R^ and Rg, except that an adjacent pair of the groups R^a, R^ a, R-^a and Rga can represent a chain with the formula -C0CH=C(D^)0-, or one or both of the groups D and represent a group that can be hydrolyzed or oxidized to a -COOH group, preferably respectively a lower alkyl ester of the carboxylic acid and a methyl group, while the other may represent a -COOH group, (b) ring-closing a compound of formula: or formula: or an ester of one of these compounds, wherein Rg is as defined above, R^b, Rgb, R^b and Rgb have the same meanings as R^, Rg, Ry and Rg above, except for an adjacent pair of the groups R^ b, Rgb, Ryb and Rgb can represent a pair of groups -H and -0-C(COOH)=CH-COOH, (c) ring-closing a compound of formula: or an ester thereof, where Rg is as defined above, R5°' R6C' R7°°^ R8° ^is the same meaning as R5, Rg, R7 and Rg, except an adjacent pair of the groups R5c, RgC, R^c and RgC instead of forming a chain -COCH= C(COOH)-0-, represents a pair of the groups: (i) -COCH2CO COR" or -COCH=C(COOH)- NL^L9, or a suitable derivative of such groups, and -OM, or (ii) -H and -O-C(COR")=CH-COR", R" represents -OM, or a group hydrolyzable to such a group, and L2 which may be the same or different, each being hydrogen or C1- 6 alkyl, and M represents hydrogen or an alkali metal, and, if necessary or desired, hydrolyzes the group -COR" to a group -COOM, (d) oxidatively hydrolyzes a compound of the formula: or an ester thereof, wherein Rg and E are as defined above, Rj-d, Rgd, Ryd and Rgd have the same meanings as R^, Rg, R^ and Rg, except that an adjacent pair of the groups R1-d, Rgd, R^d and Rgd can represent the chain -C(Rg, Rj_q) CH=CE-0-, and where at least one of the groups Rg, R^Q forms a =S, and the other pair Rg, R, Q represents =S or =0, to a corresponding compound of formula I, (e) selectively removes groups A and B from a compound of formula: or an ester thereof, where Rg and E are as defined above, Rj_e, R^e, R7e and Rge have the same meaning as R^, Rg, R? and Rg above, except that an adjacent pair of the groups Rce, R,e, R_,e and R„e can represent a chain -COCHA-CBE-0-, D 0 / O and where both A and B in at least one of the pairs of the groups A and B are hydrogen while the other pair A, B together can form a double bond, (f) ring-closing a compound with formula: or an ester thereof, wherein Rg is as defined above, R^f, Rgf # R-yf and Rgf have the same meaning as R5, Rg, R7 and Rg, except that adjacent pairs of the groups R^f, Rgf/ R- yf and Rgf instead of forming a chain -COCH=C(COOH)-0-, represent a pair of the groups -COCH(SOR1Q)-CH(OH)-COOR" and -OM, R" and M are as defined above, and R^q represents an alkyl group of 1-10 carbon atoms, (g) reacts a dicarboxylic acid of the formula: or an ester thereof, where R has the meaning given above, and an adjacent pair of the groups R^, Rg, R^ and Rg form a chain -COCH=C(COOH)-O- and the remainder of R5, Rg, R^ and Rg have the meaning given above, with an alkali metal salt or a base for forming an alkali metal salt thereof, after which, if necessary or desired, an acid or lower alkyl ester obtained in methods a)-g) is converted into a pharmaceutically acceptable salt or other lower alkyl ester thereof. 2. Analogous method according to claim 1, for the production of 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano-[3,2-g]-quinoline-2,8-dicarboxylic acid, or a pharmaceutically acceptable alkali metal salt thereof, characterized in that the corresponding starting material in one of the process alternatives a)-c) and g) is used.