CS207674B2 - Method of making the derivatives of the pyranochinocarboxyl acid - Google Patents

Description

(54) Production method of pyranoquinolinone carboxylic acid derivatives i

The invention relates to a process for the preparation of novel pyranoquinolinone carboxylic acid derivatives and to compositions containing them.

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

where the adjacent pair of symbols Rg, Rg, R? and Rg forms a chain of formula -COCH = CE-O- and the remaining of Rg, Rg, R? and R 8, which may have the same or different meanings, are hydrogen, hydroxy, alkyl of up to 8 carbon atoms, halogen, alkenyl of up to 8 carbon atoms or alkoxy of up to 8 carbon atoms, or -NR 3 R 8, wherein R 1 and R 8, which may have the same or different meanings, are hydrogen or an alkyl group of up to 8 carbon atoms, R is hydrogen, an alkyl group of up to 8 carbon atoms, an alkenyl group of up to 8 carbon atoms or a phenylalkyl group of up to 8 the carbon atoms in the alkyl and E represents a carboxyl group, and pharmaceutically acceptable salts thereof.

The process for the preparation of the compounds of the formula I or the corresponding pharmaceutically acceptable salts is characterized in that it is selectively hydrolyzed or oxidized with a compound of the formula II

wherein Rg is as defined above, R _a, Rg _and y _and, R₆ _and have the same meanings as Rf, Rg, Ry and Rg are as defined for formula I, except that an adjacent pair of R | j _and t _and Rg, and Rg _and R _{y, and} optionally represents a chain of formula -COCH = C (D) O-, and one or both of D and D represent a group from which can be obtained by hydrolysis or oxidation of the carboxyl group and the second carboxylic acid and, if desired or desired, converting a compound of formula 1 into a pharmaceutically acceptable corresponding salt.

The group D can be, for example, an ester, a halocarbonyl group, an amide or a nitrile group which can be hydrolyzed to a carboxyl group. Hydrolysis can be carried out using conventional procedures, for example in a mildly alkaline medium, for example using sodium carbonate, sodium hydroxide, sodium bicarbonate, or in an acidic medium, for example using a mixture of aqueous dioxane and hydrochloric acid or hydrogen bromide in acetic acid. The hydrolysis can be carried out at a temperature of about 25 to 120 ° C, depending on the compounds used.

Alternatively, D may be an alkyl group such as a lower alkyl group such as a methyl group, a hydroxymethyl group, an aralkenyl group such as a styryl group, an acyl group such as a lower alkanoyl group such as an acetyl group or a formyl group. The oxidation can be carried out using conventional techniques which do not alter the molecule to the extent that the yield of the desired product is economical, for example by oxidizing an alkyl or hydroxymethyl group with selenium dioxide, for example under reflux in aqueous dioxane or with chromic acid. , for example under reflux in aqueous acetic acid. Aralkenyl groups can be oxidized using, for example, neutral or alkaline potassium permanganate in aqueous ethanol, and acyl groups can be oxidized using, for example, chromic acid or an aqueous hypochlorite solution, such as sodium hypochlorite. The formyl group can be oxidized, for example, with chromic acid or silver oxide. ’

The starting materials can be prepared by reacting a compound of formula IX,

(IX) wherein R _g is as defined above and R _b, R g _b, y _b and Rg _b have the same meanings as R,

R 8, R 8 and R 8 as mentioned above, except that the adjacent pair R 8, R 8 _b Ry _b and R 8 _b optionally represent a pair -H and -OC (COOH) = CH-COOH, with a compound of formula X

Da-CSC-Da (X) wherein Da is an ester moiety to form a mixture of compounds of formulas XI and XII,

R,

Rk

Da ^x Y ^x Da ^R 8b ^R g (XI)

R.

^l Rh

N (XII)

Wherein R Da, Da, _b R, _b R g, R _b and Rg _b are as defined above. The Da groups in the compounds of formulas XI and XII can be converted to other D groups using procedures generally known in the art, and the resulting compounds can be cyclized under conventional conditions to give a compound of formula II.

A preferred variation is the possibility of cyclizing compounds of formulas XI and XII to form a compound of formula II wherein D is an ester group, using the compound of formula II thus obtained as such or converting D to another D group, e.g. to an acid halide, amide or nitrile group, in each case using otherwise conventional and known methods.

The pumarate isomer of the compound of formula XII (or the corresponding compound in which Da was converted to group D) is the only isomer that can be cyclized to the expected compound of formula II. The proportion of the two possible isomers can be readily determined by nuclear magnetic resonance spectroscopy and it has been found that the fumaric acid derivative is only a minor proportion of the mixture of the two isomers obtained by the reaction.

The compounds of formula (II) may be prepared by a known method for preparing similar known compounds.

Alternatively, compounds of formula II, for example in the case of an acid halide, amide or nitrile, can be prepared from compounds of formula I using conventional procedures, for example by reacting an ester of a compound of formula I with ammonia to form an amide, followed by dehydration of the amide to give the nitrile.

Compounds of formula (IX) are either known or can be prepared from known compounds using conventional procedures known per se.

The compound of formula (I) or a salt thereof may be prepared as described above. It is also within the scope of the present invention to treat any salt so formed to give the free compound of formula (I), or to convert one salt into another salt.

The compounds of formula I and intermediates thereof can be isolated from the corresponding reaction mixtures using conventional procedures.

Pharmaceutically acceptable salts of the compounds of formula (I) include salts of pharmaceutically acceptable acids and, when E is a carboxyl group, 2-carboxylic acid esters and amides. Suitable salts in this context include ammonium salts, alkali metal salts such as sodium, potassium and lithium, alkaline earth metal salts such as calcium or magnesium, and salts of suitable organic bases such as hydroxylamine salts, lower alkylamines such as methylamine or ethylamine, salts of substituted lower alkylamines, for example hydroxyalkylamines, such as tris (hydroxymethyl) methylamine, or salts of simple monocyclic nitrogen heterocyclic compounds, for example piperidine or morpholine.

Suitable esters include simple lower alkyl esters, for example ethyl esters, esters derived from basic group alcohols, for example lower dialkylamino substituted alkanols, such as a beta- (diethylamino) ethyl ester, and acyloxyalkyl esters, for example lower acyloxyalkyl esters such as pivaloyloxymethyl ester or bis-esters, derived from dihydroxy compounds such as a lower di (hydroxyalkyl) ether, for example bis-2-oxapropane-1,3-diyl ester. It is also possible to use pharmaceutically acceptable acid addition salts of basic esters as well as those compounds in which one of R R, Rg, R ^ and Rg is -NR ^, for example the corresponding hydrochloride, hydrobromide, oxalic, maleic or fumaric acid salt. Esters can be prepared by conventional methods, for example by esterification or reesterification. Suitable amides are unsubstituted amides, or they may be monoalkylamides or dialkylamides having 1 to 6 carbon atoms, and these are prepared by conventional methods, for example by reacting the corresponding acid ester with ammonia or a suitable amine.

The compounds of formula (I) and suitable derivatives thereof are pharmaceutically useful because of their pharmacological activity in animals; in particular, they are useful because they prevent the release and / or action of pharmacological mediators which in vivo combine certain types of antibodies with a specific antigen, for example a combination of a reagent antibody with a specific antigen (see Example 27 of British Patent Specification 292 601 ). It has also been found that the novel compounds abolish the reflex pathways of both experimental animals and humans, and especially those associated with lung function.

In humans, administration of the novel compounds avoids both subjective and objective changes resulting from inhalation of the specific antigen by sensitive patients.

Thus, the novel compounds may be indicated as being suitable for use in the treatment of reversible airway problems and / or preventing the secretion of excessive mucus. Thus, the novel compounds are indicated for use in the treatment of allergic asthma, the so-called. internal asthma (when susceptibility to external antigens cannot be demonstrated), bronchitis, cough, nasal and bronchial problems associated with common colds. The novel compounds are also of value in the treatment of other conditions where antigen responses to the antibody or excessive mucus secretion are responsible for or contribute to certain diseases, such as hay fever, some eye problems, such as trachoma, food-related allergies such as urticaria and atypical eczema, and gastrointestinal disorders such as gastrointestinal allergies, especially in children, such as milk allergies or ulcerative colitis.

For the above purposes, the dosage administered will, of course, vary with respect to the agent employed, the mode of administration and the expected outcome of the treatment. Usually, however, satisfactory results are obtained when the subject compounds are administered at a dosage of from 0.001 to 50 mg per kg body weight in the test described in Example 27 of British Patent Specification No. 5,940,519.

292 601. For humans, the total daily dose is in the range of 0.01 mg to 1,000 mg, preferably 0.01 mg to 200 mg, and most preferably 1 mg to 60 mg, and may be administered in divided doses of one to six times a day or in sustained release dosing. Unit dosage forms suitable for administration (by inhalation or oesophageally) contain from 0.01 to 50 mg, preferably 0.01 mg to 20 mg, and most preferably 0.01 mg to 10 mg of the compound, preferably in admixture with a solid or liquid pharmaceutically acceptable a carrier, diluent or adjuvant.

The compounds of formula (I) and their pharmaceutically acceptable salts have the advantage of being more active in some pharmacological models or acting longer than compounds of similar structures as compared to the compounds of formula (I). advantageous in that they are more effective at canceling reflex pathways and inhibiting mucus secretion compared to compounds of similar structures as compared to compounds of formula I.

It is preferred that each of R _; , ^R g> ^S 5 ' ^R g> ^{and R} g> P ^octide contain carbon, containing up to 4 carbon atoms. It is particularly preferred that R 6, R 8, Ry and δ be selected from the group consisting of hydrogen, methoxy, propyl, allyl, methyl, ethyl, chloro, bromo, or hydroxyl. The chain - CCCH-CE-O- can be bonded to the novel ring in any manner and at any adjacent positions to R 1, R g, Ry and R g. However, it is preferred that the chain be bound at the Rg and Ry positions of the oxygen portion of the chain that is at the Ry position.

The present invention also provides a process for the preparation of a pharmaceutically acceptable salt of a compound of formula (I), comprising:

(c) ^R wherein R 8i my abovementioned meanings, ^R 5j'_ ^R 6j>

Ryj, Rgj have the same meanings as R ^, the pair R ^ j] Rgj, Ryj and Rgj optionally form a chain

Rg, Ry and Rg, provided that the adjacent O-C (X) = CHCO- and X represents a carboxyl group (or the corresponding ester, or a salt thereof), a nitrile group, a halocarbonyl group or an amide group, cation and capable of converting the group X to a pharmaceutically acceptable salt of acid E.

Compounds capable of converting the group X to a pharmaceutically acceptable salt of group E include compounds such as bases and ion exchange resins containing pharmaceutically acceptable cations such as sodium, potassium, calcium, ammonium and suitable nitrogen-containing organic cations. It is generally believed to be advantageous to prepare a pharmaceutically acceptable salt by treating the free acid of formula I with a corresponding base, for example an alkaline earth or alkali metal hydroxide, a similar carbonate or bicarbonate in aqueous solution or by double decomposition using a suitable salt. If a 3-base base compound is used, care should be taken to keep the temperature low enough that the compound of formula I is not hydrolyzed or otherwise degraded. The pharmaceutically acceptable salt may be isolated from the reaction mixture by, for example, solvent precipitation and / or solvent distillation, for example, by lyophilization.

Pharmaceutical compositions comprise (preferably below 80% by weight, and more preferably below 50%) compounds of Formula I or a pharmaceutically acceptable derivative in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers include:

for tablets, capsules and dragees: microcrystalline cellulose, calcium phosphate, diatomaceous earth, carbohydrates such as lactose, glucose or mannitol, talc, stearic acid, starch, sodium bicarbonate and / or gelatin; for suppositories of natural or hardened oils or waxes and for inhalants, coarse-grained lactose. The compound of formula (I) or a pharmaceutically acceptable derivative is preferably in a form characterized by a weight average diameter of 0.01 to 10 microns. The composition may also contain suitable preservatives, stabilizers, and wetting agents, solubilizers, sweeteners, coloring agents and flavors. The composition may be formulated, if desired, into a sustained release form. Preference is given to compositions which are intended to be administered oesophagally and to be released in the gastrointestinal tract.

The invention is illustrated by the following non-limiting examples.

Example

4,6-Dioxo-10-propyl-4H, 6H-pyrano (3,2-g) quinoline-2,8-dicarboxylic acid (e) 4-Acetemido-2-allyloxyacetophenone

A mixture of 19.3 g of 4-acetamido-2-hydroxyaeetophenone, 12.1 ml of allyl bromide and 21.5 g of anhydrous potassium carbonate was stirred in 250 ml of dry dimethylformamide for 24 hours at room temperature. After pouring the reaction mixture into water, the product is extracted into ethyl acetate, the organic solution is washed well with water, dried over anhydrous magnesium sulphate and, after filtration, the filtrate is evaporated to dryness. The sub-title product was obtained in a yield of 20.5 g as a yellowish-colored solid. The structure was confirmed by NMR spectra and mass spectroscopy.

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

18.4 g of the above allyl ether were heated at 200-210 ° C for 4 hours. 17.1 g of a thermally rearranged product, the composition of which is given in the subtitle, is obtained in the form of a brown color. The structure was also confirmed by NMR spectra and mass spectroscopy.

(c) 4-Acetamido-2-hydroxy-3-propylacetophenone g of the product of step (b) is dissolved in glacial acetic acid and the solution is hydrogenated in the presence of Adams catalyst until the consumption of hydrogen ceases. The catalyst was filtered through a silica gel filter and the filtrate was concentrated to give 13.0 g of an almost colorless solid. Mass and NMR spectra confirm the structure of the product.

(d) 7-Acetamido-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid ethyl ester

A mixture of 19.3 g, ie 17.9 ml of diethyl oxalic acid ester, with 12.4 g of the above product from step (c) in 100 ml of dry ethanol is added with stirring to a solution of sodium ethoxide in absolute ethanol; prepared by dissolving 6.1 g of sodium in 200 ml of absolute ethanol. The reaction mixture was heated to reflux for 3 hours, then poured into dilute hydrochloric acid / chloroform solution, the chloroform layer was separated and washed with water and dried. Distilling off the solvent gave a brown solid as a residue, which was dissolved in 300 ml of ethanol containing 3 ml of concentrated hydrochloric acid, and the reaction mixture was heated under reflux for one hour. The reaction mixture is poured into water, the product is extracted into ethyl acetate, the solution in this solvent is washed with water, and 10 g of sticky solid is isolated by distilling off the solvent after drying; mass spectra and NMR spectra were consistent with the expected structure.

(e) 7-Amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid ethyl ester

A solution of 10 g of the amide of step (d) in 300 ml of ethanol containing 5 ml of concentrated hydrochloric acid is refluxed for 8 hours. The reaction mixture is diluted with water and after extraction with ethyl acetate, the organic solution is washed with water, dried and distilling off the solvent gave a dark brown semisolid as a residue. This was chromatographed on a silica gel column using ether to elute. 4.8 g of the expected product are obtained, m.p. 84 DEG-87 DEG C .; the structure was confirmed by mass and NMR spectra.

(f) 8-Ethoxycarbonyl-2-methoxycarbonyl-4,6-dioxo-10-propyl-4H, 6H-pyrano (3,2-g) quinoline.

A mixture of 2.0 g of the eminobenzopyran derivative of step (e) and 1.24 g, i.e. 1.01 ml of dimethyl acetyldicarboxylic acid ester, is heated under reflux for 30 hours in an atmosphere of 30 ml. After cooling the reaction mixture to 0 ° C, the insoluble yellow-brown solid is filtered off, washed with a small amount of ethanol and dried to isolate 2.0 g of the product, a mixture of maleic and fumaric esters obtained by Michael addition of the amine to the acetylene derivative.

This mixture of esters (2.0 g) was mixed with 30 ml of polyphosphoric acid and heated on a steam bath for 20 minutes with stirring. The reaction mixture is then poured onto ice, ethyl acetate is added, the reaction mixture is stirred, the organic layer is separated, washed with water and dried. After distilling off the solvent, 1.6 g of a yellow-orange solid is obtained, and by recrystallization of this solid from ethyl acetate, the expected product is isolated as loose orange needles of m.p. 187-188 ° C.

Analysis: 19 ° ^θ20 Η ^Ν 7 Calculated: 62.3% C 4.9% H 3.6% N;

Found:% C, 62.0;% H, 5.1;% N, 3.7%.

(g) 4,6-Dioxo-10-propyl-4H, 6H-pyrano (3,2-g) quinoline-2,8-dicarboxylic acid

In a medium of 1.64 g of sodium bicarbonate in a mixture of 100 ml of ethanol and 50 ml of water, 2.5 g of the above bisester are heated under reflux for 1.5 hours. The reaction mixture was poured into water, followed by acidification to precipitate a gelatinous solid which was filtered off, heated to reflux with ethanol, and then separated by centrifugation in a yield of 1.4 g; mp 303-304 ° C (dec.). The structure was confirmed by mass and NMR spectra.

(h) 4,6-Dioxo-10-propyl-4H, 6H-pyrano (3,2-g) quinoline-2,8-dicarboxylic acid disodium salt

A solution of 0.661 g of sodium bicarbonate in 150 ml of water was heated to a clear dissolution after addition of 1.35 g of the bis-acid from step (g), then the solution was filtered and the filtrate lyophilized to give 1.43 g of the disodium salt.

Analysis: σ, γΗ, JnO Na ^ 1 ^ 2, 5% H ₂ O Calculated: 46, and% C, 3.8% H, 3.15% N;

Found: C, 46.1; H, 4.0; N, 2.9.

Example 2

4,6-Dioxo-1-ethyl-10-propyl-4H, 6H-pyrano (3,2-g) quinoline-2,8-dicarboxylic acid (a) 4- (N-Acetyl-N-ethyl) amino- 2-allyloxyacetophenone

A mixture of 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 was stirred in 500 ml of dry dimethyl formamide for 17 hours, then the reaction mixture was poured. into water and the product was extracted into ether. The organic solution was washed well with water, dried over anhydrous magnesium sulfate, and concentrated to dryness to afford 102.5 g of an oily product.

The structure of this product was confirmed by NMR spectra and mass spectrum.

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

A mixture of 100.5 g of the allyl ether product of step (a) and 300 ml of dlethylaniline was heated to reflux for 3 hours, then the reaction mixture was cooled and poured into dilute hydrochloric acid. After extraction with ether, the organic solution is washed with dilute hydrochloric acid solution, water, the organic solution is extracted with 10% sodium hydroxide solution, this solution is then acidified, the precipitated product is extracted with ether and the ether solution is dried over anhydrous magnesium sulfate. The resulting ether solution is concentrated to dryness to give 78.7 g of a tan oil which is 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 is dissolved in 500 ml of ethanol and, after addition of 20 ml of glacial acetic acid, the solution is hydrogenated in the presence of Adams catalyst until the consumption of hydrogen ceases. The catalyst was filtered off through silica gel and the filtrate was concentrated to dryness to give 79.9 g of a brown oil. This is a mixture which is separated by HPLC using a 1: 1 mixture of ether and petroleum ether to give 44.2 g of the sub-title compound and 23.8 g of 6- (N-). acetyl-N-ethyl) amino-3-propyl-2-hydroxyacetophenone.

(c) 4-N-Ethylamino-3-propyl-2-hydroxyacetophenone g of 4- (N-acetyl-N-ethyl) amino-3-propyl-2-hydroxyacetophenone is heated in a mixture of 100 ml of a 48% solution of hydrogen bromide in ice acetic acid, 500 ml glacial acetic acid and 20 ml water were refluxed for 6 hours. The reaction mixture is poured onto ice-water, extracted with ethyl acetate, the organic solution obtained is washed with water, sodium bicarbonate solution, again with water, and dried over anhydrous magnesium sulfate. The organic solvent is concentrated to dryness and 34 g of the subtitle compound is isolated as a red oil. The structure was confirmed by NMR spectra and mass spectrum.

(d) 6-Acetyl-1-ethyl-7-hydroxy-4-oxo-8-propyl-4H-quinoline-2-carboxylic acid methyl ester

A mixture of 17 g of the amine product of step (c) and 11.3 ml of acetylene dicarboxylic acid dimethyl ester was heated to reflux in 300 ml of ethanol for 17 hours, then the reaction mixture was cooled and concentrated to dryness to give a deep red residue. oil This oil is chromatographed on a silica gel column using a 1: 1 mixture of ether and petroleum ether to give 19.1 g of 1- (4-acetyl-3-hydroxy-2-propylphenyl) -N- Mp 83-87 ° C.

The obtained maleic ester of 5 g was heated with stirring in 100 ml of polyphosphoric acid on a steam bath for 10 minutes. The reaction mixture was cooled and poured onto a mixture of ice and water with ethyl acetate. The organic solution was separated, washed with water and dried over anhydrous magnesium sulfate. Concentration of the organic solution to dryness gave a pale yellow solid as a residue, and was purified by HPLC. Yield: 2.6 g (m.p. 121-123 ° C).

H, 6.34; N, 4.23. Found: C, 65.3;

Found: C 65.5, H 6.6, N 4.2%.

6-Acetyl-1-ethyl-5-hydroxy-4-oxo-4H-quinoline-2-carboxylic acid methyl ester was obtained after purification in a yield of 100 mg as a pale yellow solid.

(e) 4,6-Dioxo-1-ethyl-10-propyl-4H, 5H-pyrano (3,2-g) quinoline-2,8-dicarboxylic acid diethyl ester

A mixture of 1.0 g of hydroxyketone product of step (d), 3.3 ml of diethyl oxalic acid ester in 25 ml of dry dimethylformamide was added to 0.581 g of 50% ether-washed sodium hydride in 20 ml of dry dimethylformamide, and the reaction mixture was stirred for 4 hours. clock. The reaction mixture was then poured into water, acidified and extracted with ethyl acetate to give an organic solution which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off to dryness.

The residual oil is dissolved in 100 ml of ethanol, a few drops of concentrated hydrochloric acid are added, the solution is heated under reflux for 30 minutes, cooled, poured into water and extracted with ethyl acetate, washed with water and dried over sulphate magnesium. By distilling off the solvent to dryness an oil is obtained as a residue which solidifies by trituration with petroleum ether (b.p. 40-60 ° C). The yield of the product, confirmed by NMR spectra, was 1.2 g.

(F) 4,6-Dioxo-1-ethyl-10-propyl-4H, 6H-pyrano- (3,2-g) quinoline-2,8-dicarboxylic acid

A mixture of 1.0 g of the above ester, 0.787 g of sodium bicarbonate, 85 ml of ethanol and 32 ml of water was refluxed for 4 hours. The reaction mixture is poured into water, the solution is acidified, the precipitate is filtered off and dried. The product was purified by trituration with boiling ethanol, then twice with boiling ethanol, then twice with boiling acetone, centrifuging the reaction mixture and separating the supernatant by decanting. Drying of the remaining solid gave 0.547 g of the expected diacid as a yellow powder of m.p.

298-300 ° (dec.).

Analysis: for Ο, ^ Η ^ ΝΟ?

calculated: 61.5% C, 4.6% H, 3.79% N;

Found: C 61.3%, H 5.0%, N. 3.6%.

(g) 4,6-Dioxo-1-ethyl-10-propyl-4H, 6H-pyrano (3,2-g) quinoline-2,8-dicarboxylic acid disodium salt

To a suspension of 4.098 g of the above diacid in 100 ml of water was added 1.82 g of sodium bicarbonate, the solution obtained was filtered and acetone was added to the filtrate until the product precipitated completely. The expected disodium salt was filtered off and dried to give 3.39 g of a pale yellow powder.

Analysis for Cj ^H HNNNajO ^ . 6.9% H ₂ O calculated: 51.1% c, 4.1% H, 3.1 % M; * found: 51.1% c, 4.3% H, 3.0 % N.

Example 3

The following compounds may also be prepared as described hereinabove:

1. 7- (3-methylbutyl) -4,10-dioxo-4H, 10H-pyrano [2,3-b] quinoline-2,8-dicarboxylic acid, m.p. 246 DEG-248 DEG C. (dec.);

2. 9- (3-methylbutyl) - (4,6-dioxo-4H, 6H-pyrano [3,2-gD quinoline-2,8-dicarboxylic acid), mp 302-304 ° C (dec.),

3. 7-Ethyl-4,10-dioxo-4H, 1OH-pyrano- [2,3-f] quinoline-2,8-dicarboxylic acid disodium salt.

Analysis for C 8 H 9 NNagO ?, 14.4% H ₂ O calculated: 44.1% C, 3.5% H, 3.3 found: 44.1% C, 3.7% H, 3.2 PŘE D M

% Nj

Claims (3)

OF THE INVENTION A process for the preparation of pyranoquinolinone carboxylic acid derivatives of the general formula I, ^R e R E (I) where the adjacent pair Rg, Rg, R? and Rg is -COCH = CE-O- and the other Rg, Rg, Ry and Rg, the meanings of which may be the same or different, are hydrogen, hydroxyl, alkyl of up to 8 carbon atoms, halogen, alkenyl of up to C 8-C, alkoxy or C až-C zbytek alkoxy or a radical of the formula -NR, R ₂ , wherein R, ^{and R} 2, which may be the same or different, are hydrogen or alkyl of up to 8 carbon atoms, R, is hydrogen, alkyl of up to 8 carbon atoms, alkenyl of up to 8 carbon atoms or phenylalkyl of up to 8 carbon atoms in alkyl, and E is carboxyl, or the corresponding pharmaceutically acceptable salts, characterized in that it is selectively hydrolyzed or oxidizes a compound of formula IX; R (II) _N J_D ^R 9 wherein R is as defined above, _And Rg, Rg _and R ^ _a and R g _and R have the same meanings as Rg, Rg, Rg and R, with the proviso that an adjacent pair of R g _and R, R g _and R? _a and R 8 _and optionally denote a chain of the formula -00011 = O (O, O) -, and day or both D and D represent a group which can be hydrolyzed or oxidized to a carboxyl group and the other can be a carboxyl group and If desired or desired, the compound of formula I is converted to the corresponding pharmaceutically acceptable salt. 6a n, 2. A process according to claim 1, wherein D is an ester, amide or nitrile group and the hydrolysis is carried out in a slightly alkaline or slightly acidic medium. 3. A process according to claim 1, wherein the starting material is a compound of formula (II) wherein D is an alkyl group and the oxidase is carried out using selenium dioxide.