DK158266B - METHOD OF ANALOGY FOR PREPARATION OF PYRANOQUINOLINON DERIVATIVES - Google Patents

Description

The present invention relates to an analogous process for the preparation of novel pyranoquinolinone derivatives of the general formula

.. DK 158266B

, -L · Jl Jl — in COOH

βύϊ; c. nco where R ° and R form a chain -COCH = C (COOH) -O-, and R and R f which may be the same or different, each being hydrogen or alkyl, and Rg being hydrogen or alkyl, or pharmaceutically acceptable salts, alkyl esters or mono- or di-alkylamides thereof, the process of which is characterized by the characterizing part of claim 1.

The compounds of the invention are useful because of their pharmacological activity.

U.S. Patent No. 3,959,289 discloses antiallergically active 4,6-dioxopyrido [3.2-g] quinolines. However, these known compounds have the disadvantage that large doses thereof are required to achieve the desired activity. According to the present invention, there is provided a group of novel pyranoquino-linear having advantageous properties compared to said known compounds, in particular a stronger activity, as documented below.

The compounds of this invention are prepared by (a) a compound of formula II

R5a n R7aJ ^ s, \ -d R83 · where Rg is as defined above, R ^ a and R8a have the same meanings as R ^ and R8 above, and R8a and 7a 1 R represent a chain of the formula -COCH = C (D ) -0- and. In one or both of D and D 'represents a group which can be hydrolyzed or oxidized to a group -COOH, and the other may represent a group -COOH, subjected to selective hydrolysis or oxidation,

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2

(b) a compound of formula III or IV

R5b? 5b r6 ^ J \ hooc. / COOH

R7b4sA JLcOOH R7bJ ^ AN ^ C00H

^ 8b Rg jjeb Rg

III IV

or an ester of each of these, wherein R 9 is as defined above and 5 b 8b 5 8 R 3 and R ° have the same meanings as R and R above, and R 1 and R 2 represent the group pair -H and -O -C (COOH) = CH-COOH, is cyclized,

(c) a compound of formula V

R5C 0

R7cAyJLNJ-COOH

r8c Rg

or an ester thereof, V

where Rg is as defined above, 5C 8c 5 8 R and R have the same meanings as R and R above, and R8c and R4c represent the group pairs: (i) -COCH2COCOR "or -COCHCiCOOHj-NL1.2 or a suitable salt, ester or amide derivative thereof, and -OM or a halogen atom, or (ii) -H and -O-C (COR ") - CH-COR", where R "is -OM or an ester or an amide thereof, 1 2 L and L, which may be the same or different, each being hydrogen, aryl or alkyl, or together forming a saturated or unsaturated alkylene chain, and M being hydrogen or an alkali metal, are cyclized and, if necessary or if desired hydrolysis of the group -COR "to a group -COOM where M is as defined above,

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3

(d) a compound of formula VI

R5a 9 „10» 6d Ax rwii R I8a yoke

or an ester thereof VI

wherein Rg is as defined above, 5d sd 5 8 R3 and R have the same meanings as R and R above and R4 and R4 represent the chain -C (R9R4) CH = C (C00H) -O-, and at least one of the group pairs R9 and R10 together form = S or together form a chain -S (CH 2) S-, where n is 2 or 9 10 2 n 3, and the second pair R, R can represent = 0, is converted into a corresponding (e) groups A and B are selectively removed by dehydration, hydrogenolysis or dehydrohalogenation from a compound of formula VII 5e 'ΑΛΑ / *

^ X-COOH

Γδβ? \ b

K Rg VII

or an ester thereof, wherein R 9 is as defined above, R 1 e and R 2 e have the same meanings as R 2 and R 2 above, and R 2 e and R 2 e represent a chain -COCHA-CB (C00H) -0 -, and in at least one of the group pairs 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 A, B together can form a double bond, or

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4

(f) a compound of formula VIII

R5f O

VYV

. in Jl - COOH

1st I

K Rg VIII

or an ester thereof, wherein R 9 is as defined above and 5 f 8 f 5 8 R and R ° have the same meanings as R and R above, and R 2 f and R 7f represent the group pair -COCH (SOR 2) - CH (OH) ) -COOR "and -OM, where R" and M are as defined above, and 1 1 R is an alkyl group having 1-10 C atoms is cyclized and, if necessary or desired, an ester obtained from a compound of formula I, gg / or a compound of formula I obtained is hydrolyzed to a pharmaceutically acceptable salt, alkyl ester or mono or di-alkylamide derivative thereof and / or such derivative is converted to another pharmaceutically acceptable salt, alkyl ester - or mono- or di-alkylamide derivatives.

In process (a), for example, group D may be an ester, acid halide, amide or nitrile group which can be hydrolyzed to a group -COOH. The hydrolysis can be carried out using conventional techniques, for example under mildly basic conditions, e.g. using sodium carbonate, sodium hydroxide or 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 a temperature of from 25 ° C to 120 ° C depending on the compounds used. Alternatively, the group D may be an alkyl group, e.g. a lower alkyl group such as methyl, a hydroxymethyl, an aralkenyl, e.g. styryl, an acyl, e.g. lower alkanoyl, such as acetyl, or a formyl group. The oxidation can be carried out using conventional techniques that do not otherwise modify the molecule to such an extent that the yield of the desired product is uneconomical. For example, an alkyl or a hydroxymethyl group can be oxidized using selenium dioxide, e.g.

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5 under reflux in aqueous dioxane, or of chromic acid, e.g. 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, e.g. sodium hypochlorite. The formyl group can be oxidized using, for example, chromic acid or silver oxide.

In process (b), the cyclization can be carried out by treating the compound of formula III or IV with a cyclizing 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 a temperature of from 25 ° C to 150 ° C and preferably from 75 ° C to 150 ° C. It has been found that isomerization 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 cyclize these compounds to a compound of formula I, thereby obtaining a satisfactory yield of the compound of formula In view of an unsatisfactory mixture of compounds of formulas III and IV. Compounds of formula III can also be cyclized by subjecting the compound to an elevated temperature, 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.

When one of the groups is -OM, the cyclization process (c) (i) can be carried out by heating, or under basic or neutral conditions. However, it is preferred to carry out the cyclization 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 from 20 ° to 150 ° C. The group -COR "is preferably an ester group, with R" e.g. may be a lower alkoxy group. When one of the groups is -COCH = C (COOH) -NL L, the derivative of the group -COOH can be a group -CONL L, where L and L are as defined above. It is preferred that L and L are hydrogen, phenyl, alkyl of 1-6 C atoms or together form a 4- or 5-membered alkylene chain, e.g. together with the nitrogen atom forms a piperidine ring. When one of the groups is halogen, the cyclization can be carried out in a solvent which is inert under the reaction conditions, preferably a high boiling polar solvent, e.g. pyridine, dimethylformamide or hexamethylphosphoramide. The reaction gene

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6 is preferably carried out by means of a strong base, e.g. an alkali metal hydride such as sodium hydride. The reaction is preferably carried out at a temperature of from 80 ° to 200 ° C in the absence of free oxygen, e.g. under an inert atmosphere such as nitrogen.

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

9 10

In processes (d), when R and R together form a chain -S- (C C) -S-, the conversion may comprise oxidative hydrolysis and may be carried out in an aqueous polar organic solvent, e.g. aqueous ethanol, acetone or tetrahydrofuran. The oxidative hydrolysis may be carried out in the presence of an oxidizing agent, for example mercuric chloride, an N-halo succinimide such as N-bromo or N-chloro succinimide, a peracid such as periodic acid, or p-toluene sulfone chloramide or a salt. thereof. When mercuric chloride is used, the reaction can be carried out in the presence of a base, e.g. mercuric oxide, cadmium carbonate or calcium carbonate. N-Halogen succinimides can be used alone or in the presence of a silver salt, e.g. silver perchlorate or silver nitrate. The reaction may conveniently be carried out at a temperature of from -15 ° to 100 ° C.

When R and R together form a group = S, the conversion may comprise (oxidative) hydrolysis and may be carried out in the presence of a heavy metal compound, e.g. a compound of group Ib, Ilb or Hib in the periodic system of Mendeleef as catalyst. 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 and an organic solvent system such as acetone-acetic acid, alpha-channels, tetrahydrofuran / methanol or tetrahydrofuran. Alternatively, the reaction may be carried out by alkylation followed by hydrolysis.

In such cases, the reaction may be carried out with (i) an alkyl halide or sulfonate (e.g., methyl iodide) in a moist solvent, e.g. acetone, (ii) an alkyl fluorosulfonate and water in sulfur dioxide, or (iii) a trialkyloxonium fluoroborate followed by water.

DK 158266 B

7 deg sodium hydroxide.

When both A and B are hydrogen, process (s) is a dehydrogenation and can be carried out by oxidation using a mild oxidizing agent, e.g., selenium dioxide, palladium black, chloranil, lead tetraacetate or triphenylmethyl perchlorate. Alternatively, the dehydrogenation of a compound of formula VII wherein both A and B are hydrogen can be indirectly carried out by halogenation followed by dehydrohalogenation, e.g. by treatment with N-broitisuccinimide or pyridinium bromide perbromide to form a compound of formula VII wherein A is halogen and B is hydrogen which is then dehydrobrominated. When one of A and B is hydroxy, the dehydration can be catalyzed with an acid, e.g. sulfuric or oxalic acid, a base, e.g. potassium hydroxide, or a salt, e.g. potassium bisulfate, 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 can be carried out at elevated temperature, e.g. from 20 to 150 ° C.

The cyclization process (f) can 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 temperature of from 10 to 120 ° C in the presence of an organic base, e.g. piperidine.

The starting materials of process (b) can be prepared by reacting a compound of formula IXj5b% ix R7b / ss> NN NHRg j8b wherein Rg, R ^ * 5, r ^ * 3, ^ 7b R8b are as defined above, with a compound of formula X:

Da-C = C-Da X

wherein Da is an ester group to form a mixture of compounds of formulas XI and XII

8

DK 1 58266 B

R5b R5b VS c Vin • 'viV V? V'

XI XII

wherein Rg, Da, R ^ b, R ^ b, R ^ b and R ^ b are as defined above.

The compounds of formula XI and XII can be hydrolyzed to form compounds of formulas IV and III. Alternatively, the groups Da of the compounds of formula XI and XII can be converted, using prior art, into other groups D, and the resulting compounds may be cyclized, using the same conditions as in process (b) above, to forming a compound of formula II. As a further and preferred alternative, the compounds of formula XI and XII can be cyclized, using the same conditions as in process (b) above, to form a compound of formula II wherein D is an ester group and the resulting compound of formula II is itself used for process (a), or the D group is converted to another group D, e.g. an acid halide, amide or nitrile group, using techniques known in the art.

The fumarate isomer of formula XII (or the corresponding compound where Da has been converted to D) is the only isomer capable of cyclization to form the desired compounds of formula II. The amounts of the two isomers can be readily determined by NMR spectroscopy, and it has been found that the desired fumaric acid derivative generally constitutes only a minor part of the mixture of isomers obtained in the reaction.

The compounds of formula V wherein R6c and 7c R represent the groups -COCH2COCOR "and -OM or halo

gene, can be prepared by reacting a compound of formula XIII

R59 0

'plumbing

-7 J-C00H

Η79γ \ Ν / ~

^ 8g Rg XIII

or an ester thereof, wherein

DK 158266 B

9

R 9 is as defined above and R 2, R 2, R 2 and R 2 have the same meanings as R 1, R 2, R 2 and R 2 above, except that R 6 and R 7, instead of forming a chain -COCH = CH (COOH) -O-, the groups represent -COCH 2 and -OM or halogen, where M is as defined above, with a compound of formula XIV:

R'CZ-CZR "XXV

wherein R "is as defined above, R 1 is a suitable leaving group, for example, an alkoxy, halogeno, amino, alkylamino, substituted amino (e.g., an aryl sulfonylamino group) or substituted alkylamino group which can react with the carbanion of the group -COCH 2 from the compound of formula 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 hydrolyzing the resulting compound to a compound of formula V. The preferred compounds of formula XIV are dialkyloxalates, for example diethyl oxalate.

Compounds of formula V bearing a group 1 2 -COCH = C (COOH) -NL L, or a derivative thereof, can be prepared from known compounds in one or more steps using methods known per se.

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

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

The compounds of formula V bearing substituents -H and -O-C (COR ") = CH-COR" can be prepared by reacting a compound of formula XV 5h λ R ir

r7AJ ^^ - C00H

j ^ h Rg XV

.. DK 158266B

Or an ester thereof, wherein R ~ f f R ^ h Qg R8h ^ are gamma meanings such as, R ^, R ^ and R ^ above, except that R ^^ 1 and R ^ * 1, instead of forming a chain -COCH = C (C00H) -O-, the groups -H and -OH, with a dialkylacetylene dicarboxylate, are represented in the usual manner followed, if necessary, by hydrolysis of the reaction product.

The compounds of formula VIII can be prepared by reacting a compound of formula XVI

R5i O

ΟΛ .nAjJU »»

I 8i I

R Rg or an ester thereof, where

Rg is as defined above, R '**, R ^, R ^ and R ^ have the same meanings as R ^, R ^, R ^ and R above, except that Rbl and R71, instead of forming a chain - COCH = C (COOH) -O-, represents the group-paired -OH and -COO-Alkyl, with a methyl alkyl sulfoxide anion, e.g. the anion of dimethyl sulfoxide, and reacting the resulting o-hydroxy-2-alkylsulfinyl compound with glyoxalic acid or an ester thereof.

Compounds of formulas VI, VII, IX, XIII, XIV, XV and XVI are either known or can be prepared from known compounds using techniques known per se.

The compounds of formula I and their intermediates can be isolated from their reaction mixtures using conventional techniques.

Suitable pharmaceutically acceptable salts of the compounds of formula I 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 , eg. salts with hydroxylamine, lower alkylamines such as methylamine or ethylamine, with substituted lower alkylamines, e.g. hydroxy-substituted alkylamines, such as tris (hydroxymethyl) methylamine, or with simple monocyclic nitrogen-heterocyclic compounds, e.g. piperidine or morpholine.

. DK 158266B

In general, it is preferred to form the pharmaceutically acceptable salt by treating the free acid of formula I with a suitable base, e.g. with an alkaline earth metal or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution or by a metathetic process with an appropriate salt. When a strongly basic compound is used, e.g. by keeping the temperature sufficiently low, care is taken to ensure that the compound of formula I is not hydrolyzed or otherwise degraded. The pharmaceutically acceptable salt can be recovered from the reaction mixture by, for example, precipitation with solvent and / or removal of the solvent by evaporation, e.g. by freeze drying.

Suitable pharmaceutically acceptable esters include simple lower alkyl esters, e.g. ethyl ester. The esters can be prepared by conventional techniques, e.g. esterification or transesterification. Suitable pharmaceutically acceptable mono- or di-alkylamides may be those wherein alkyl has 1-6 C atoms and can be prepared by conventional techniques, e.g. by reacting an ester of the corresponding acid with an appropriate amine.

The compounds of formula I and pharmaceutically acceptable salt, alkyl ester and mono- or di-alkylamide derivatives thereof are useful as mentioned, because of their pharmacological effect on animals. They are particularly useful because they inhibit the release and / or action of pharmacological mediators derived from the in vivo combination of certain types of antibody and specific antigen, e.g. the combination of reagent antibody with specific antigen (see Example 27 of British Patent No. 1,292,601).

To document this activity of the compounds of the present invention, the following comparative experiments were performed.

Charles River France / Fisons-reared rats (male or female) weighing from 100 to 150 g were subcutaneously infected at weekly intervals with N. brasiliensis larvae at doses increasing from ca. 2000 larvae per animals to 12,000 larvae per animals to establish the infection. After 8 weeks, the rats were blood drawn at cardiac puncture and 15-20 ml of blood were collected from each animal. The blood samples were then centrifuged at 3500 rpm for 30 minutes to remove the blood cells from the blood plasma. The serum was collected and used to provide a serum containing

DK 158266 B

12 N. brasiliensis antibody. An experimental sensitivity test was performed to determine the minimum amount of serum required to provide a skin strip of 2 cm in diameter in control animals by the test described below. It was found that optimum sensitivity in rats in the body weight range of 100-130 g is obtained using a serum diluted with eight parts of physiological saline solution. This diluted solution is termed antibody serum A.

The antigen to react with the antibody in serum A was prepared by removing N. brasiliensis worms from the intestine of infected rats, centrifuging the homogenate and collecting the supernatant fluid. This liquid was diluted with saline to give a protein content of 1 mg / ml and is known as solution B.

Charles River France / Fisons-reared rats with body weight range 100 to 130 g were sensitized by intradermal injection of 0.1 ml of serum A in the right flank. Sensitivity was allowed to develop for 24 hours and the rats were then given intravenous injection with 1 ml / 100 g body weight of a mixture of solution B (0.25 ml), Evans Blue dye solution (0.25 ml) and the solution of the test compound. (0.5 ml with varying percentages of active materials). For each percent level of active material in the test solution, five rats were injected. Five rats were used as controls in each test. The dosage of the test compound was chosen such that a range of inhibition values were obtained.

Thirty minutes after injection of Solution B, the rats were killed and the skin removed and incised. The intensity of the anaphylactic reaction was assessed by comparing the size of the characteristic blue streak produced by dispersing the Evans Blue dye from the site of sensitization to the size of the streak of the control animals. The size of the strip was given a value from 0 (no detected strip, ie 100% inhibition) to 4 (no difference in strip size, ie no inhibition), and the percent inhibition for each dose level was calculated as: (Control group number - Treatment group number) x 100% inhibition = -

Kontrolgruppetal

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13

The percent inhibitions for the different dose levels were plotted graphically for each compound. From these charts, the dose required to achieve a 50% inhibition of the anaphylactic reaction (ID ^ q) was determined. The results are shown in the table below.

Table

Compound, IDq mg / kg

Compound of Example 2 Disodium 4,6-dioxo-9-ethyl-10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylate 0.02

Compound of US No. 3,959,289 (Ex.3)

Disodium 1,4,6,9-tetrahydro-10-methyl-4,6-dioxypyrido [3,2-g] quinoline-2,8-dicarboxylate 0.056

These test results clearly demonstrate the superior ability of the compounds of this invention to inhibit anaphylactic reaction in rats compared to the compounds known from the above-mentioned patent specification No. 3,959,289.

The novel compounds have also been shown to interfere with the reflex pathways of laboratory animals and humans, and in particular the reflexes associated with lung function. In humans, both subjective and objective changes resulting from the inhalation of specific antigen by sensitized individuals are inhibited by prior administration of the novel compounds. Therefore, the novel compounds are disclosed for use in the treatment of reversible, airway obstruction and / or to prevent excessive mucus secretion. The novel compounds are allotted for the treatment of allergic asthma, so-called "internal" asthma (where no sensitivity to external antigen can be detected), bronchitis, cough and nasal and bronchial obstructions associated with common colds. The novel compounds may also be of value in the treatment of other conditions in which antigen-antibody responses or excessive mucus secretion are responsible for or are a bioavailability of disease, e.g. hay fever, certain eye conditions, e.g. trachoma, nutritional allergy, e.g. urticaria and atopic eczema, and conditions of the gastrointestinal tract, e.g. gastrointestinal allergies, especially in children, e.g. milk allergy, or ulcerative colitis.

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14

Of course, for the above applications, the dose used will vary with the compound used, the mode of application and the treatment desired. Generally, however, satisfactory results are obtained when the compounds are used at a dose of from 0.001 to 50 mg per day. in the test described in Example 27 of British Patent Specification No. 1,292,601. For humans, the prescribed total daily dose is within the range of 0.01 mg to 1,000 mg, preferably from 0.01 mg to 200 mg, and in particular from 1 mg to 60 mg, which may be administered in divided doses from 1 to 6 times daily. or in a delayed release form. Thus, unit dosage forms suitable for applications (by inhalation or through the esophagus) comprise from 0.01 mg to 50 mg, preferably 0.01 to 20 mg, and especially from 0.01 mg to 19 mg of the compound, preferably in admixture with solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.

The compounds of formula I, and pharmaceutically acceptable salt, alkyl ester and mono- or di-alkylamide derivatives thereof, have the advantage that they are more effective in certain pharmacological models, or are longer effective than compounds of similar structure to the compounds of In addition, the compounds of formula I and said pharmacologically acceptable derivatives thereof are advantageous in that they are more effective in interfering with reflex pathways and in inhibiting mucus secretion than in compounds of similar structure to the compounds. of formula I.

5 8

It is preferred that each of R and R, when alkyl, contains up to 8 C atoms and preferably up to 4 C atoms. Preferably, the 6 7 of R and R formed -COCH = C (C00H) -O- is bonded to the benzene ring in such a way that the part -0- of the chain is in position R7.

Pharmaceutical compositions contain (preferably in an amount of less than 80% by weight and especially less than 50% by weight) a compound of formula I, or a pharmaceutically acceptable salt, alkyl ester or mono or di-alkylamide derivative thereof, in combination with a pharmaceutically acceptable excipient, diluent or carrier. Examples of suitable aids, diluents or carriers are for tablets, capsules and dragees: microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid,

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15 starch, sodium bicarbonate and / or gelatin, for suppositories: natural or hardened oils or waxes, and for inhalation compositions: coarse lactose. The compound of formula I, or said pharmaceutically acceptable salt, ester or amide derivative thereof, is preferably in a form having an average particle diameter of from 0.01 to 10 microns. The compositions may also contain suitable preservative, stabilizing and wetting agents, solubilizers, sweeteners, coloring agents and fragrances / flavors. The compositions may, if desired, be worked up in a delayed release form. Preferred compositions intended for ingestion through the esophagus and. to release their contents into the gastrointestinal tract.

The process according to the invention is further described by the following examples.

Example 1 4,6-Dioxo-10-propyl ~ 4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.

(a) 4-Acetamido-2-allyloxyacetophenone.

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

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

The above allyl ether (18.4 g) was heated at 200-210 ° C for 4 hours. 17.1 g of the thermally rearranged subtitle product was obtained as a brown solid. The structure was again confirmed by NMR and mass spectroscopy.

(c) 4-Acetamido-2-hydroxy-3-propyl-acetophenone.

The product of step (b) (17 g) was dissolved in glacial acetic acid and hydrogenated in the presence of Adams catalyst until hydrogen uptake ceased. The catalyst was filtered off through a diatomaceous earth filter and the filtrate was evaporated to give 13.0 g of almost colorless solid as the evaporation residue. The mass and NMR spectra confirmed the structure of the product.

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(D) Ethyl 7-acetamido-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate.

A mixture of diethyl oxalate (19.3 g, 17.9 ml) and the above product from step (c) (12.4 g) in dry ethanol (100 ml) was added to a stirred solution of sodium ethoxide in ethanol (prepared by dissolving sodium (6.1 g) in dry ethanol (200 ml). The reaction mixture was refluxed for 3 hours and then poured into dilute hydrochloric acid and chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated to give 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 product was extracted into ethyl acetate which was washed with water and dried. The solvent was evaporated to give 10 g of a sticky solid having mass and NMR spectra consistent with the expected product.

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

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

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

The aminobenzopyran from step (e) (2.0 g) and dimethylacetylene dicarboxylate (1.24 g, 1.01 ml) was 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 small amount of ethanol and dried to give 2.0 g of a product which was a mixture of maleic and fumaric acid esters obtained by Michael addition of the amine to the acetylene.

This mixture of esters (2.0 g) was treated with polyphosphoric acid (30 ml) and heated on a 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.

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17

The solvent was evaporated to give 1.6 g of a yellow-orange solid. Recrystallization of this ethyl acetate solid gave the desired product as fluffy orange needles, m.p. 187-188 ° C.

Analysis:

Found: C: 62.0%, H: 5.1%, H: 3.7%

Calculated for C 20 H 19 NO 7: C: 62.3%, H: 4.9%, N: 3.6% (g) 4,6-Dioxo-10-propyl-4H, 6H-pyrano [3,2-g] quinoline -2,8-dicarboxylic acid.

The above bis ester (2.5 g) was refluxed with sodium bicarbonate (1.64 g) in ethanol (100 ml) and water (50 ml) for 1½ hours. The whole was poured into water and acidified to precipitate a gelatinous solid. This was collected by filtration and refluxed with ethanol and the product was separated by centrifugation (1.4 g), mp, 303-304 ° C (dec). The structure of the product was confirmed by mass and NMR spectra.

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

The bis acid from step (g) (1.35 g) and sodium bicarbonate (0.661 g) in water (150 ml) was heated and stirred until a clear solution was available. This solution was filtered and the filtrate was lyophilized to give 1.43 g of the desired disodium salt.

Analysis:

Found: C: 46.1%, H: 4.0%, N: 2.9%

Calculated for C17H11NO7Na2'12'5% H2O: C: 46'1% 'H: 3'8%' N: 3.15%

Example 2 4,6-Dioxo-9-ethyl ~ 10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.

(a) 4- (N-Acetyl-N-ethyl) amino-2-allyloxyacetophenone.

4- (N-Acetyl-N-ethyl) amino-2-hydroxyacetophenone (92.6 g), allyl bromide (51 ml) and anhydrous potassium carbonate (90.4 g) were stirred in dry dimethylformamide (500 ml) for 17 hours. . The reaction mixture was poured into water and the product extracted with ether. The organic solution was then washed well with water, dried over magnesium sulfate and evaporated to dryness. The product was obtained as an oil (102.5 g). The structure of the product was confirmed by NMR and mass.

DK 158266 B

18 spectroscope !.

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

The allyl ether product of step (a) (100.5 g) was refluxed in diethylaniline (300 ml) for 3 hours. The reaction mixture was cooled and poured into dilute hydrochloric acid and extracted into ether which was washed with dilute hydrochloric acid and then with water. The organic solution was extracted with 10% sodium hydroxide solution which was then acidified. The precipitated product was extracted with ether which was dried over magnesium sulfate. The resulting ether solution was evaporated to dryness to give a tan oil (78.7 g). 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 ethanol (500 ml) and glacial acetic acid (20 ml) and hydrogenated in the presence of Adams catalyst until hydrogen uptake was stopped. The catalyst was filtered through diatomaceous earth and the filtrate was evaporated to give 79.9 g of brown oil. This brown oil was a mixture and was partitioned by high pressure liquid chromatography using ether / petroleum ether (1: 1) as the solvent to give 44.2 g of the subtitle product and 23.8 g of 6- (N-acetyl-N -ethyl) amino-3-propyl-2-hydroxyacetophenone.

(c) 4-N-Ethylamino-3-propyl-2-hydroxyacetophenone.

4- (N-Acetyl-N-ethyl) amino-3-propyl-2-hydroxyacetophenone (44 g) was refluxed in 48% hydrogen bromide in glacial acetic acid (100 ml), glacial acetic acid (500 ml) and water (20 ml) in 6 hours. The reaction mixture was poured onto ice-water and extracted with ethyl acetate, washed with water, sodium bicarbonate solution, then again with water and dried over magnesium sulfate. The organic solvent was evaporated to dryness to give the subtitle compound as a red oil (34 g). The structure was confirmed by NMR and mass spectroscopy.

(d) Methyl 6-acetyl-1-ethyl-7-hydroxy-4-oxo-8-propyl-4H-quinoline-2-carboxylate.

The amine product of step (c) (17 g) and dimethacetylene dicarboxylate (11.3 ml) was refluxed in ethanol (300 ml) for 17 hours. The reaction mixture was cooled and evaporated to dryness to give a deep red oil. This oil was chromatographed on a silica gel.

DK-158266 B

19 column column using ether / petroleum ether (1: 1) as eluent to give 19.1 g of dimethyl-1- (4-acetyl-3-hydroxy-2-propyl-phenyl) -N-ethylamino maleate, m.p. 83-87 ° C.

The maleic ester (5 g) was heated and stirred in polyphosphoric acid (100 ml) on a steam bath for 10 minutes. The reaction mixture was cooled and poured onto 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 subtitle compound, m.p. 121-123 ° C.

Analysis:

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

Calcd for c18 H21 NO5: C: 65.3%, H: 6.34%, N: 4.23%.

Methyl 6-acetyl-1-ethyl-5-hydroxy-4-oxo-4H-quinoline-2-carboxylate was recovered from the purification as a pale yellow solid (100 mg).

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

The hydroxyketone product of step (d) (1.0 g) and diethyl oxalate (3.3 ml) in dry dimethylformamide (25 ml) was added to ether washed 50% sodium hydride (0.581 g) in dry dimethylformamide (20 ml) and the reaction mixture was stirred. for 4 hours. The reaction mixture was then poured into water, acidified and extracted with ethyl acetate, then washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give an oil which was dissolved in ethanol (100 ml) and concentrated hydrochloric acid (a few drops) added. The solution was refluxed for ½ hour, cooled, poured into water and extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated to dryness to give an oil which solidified by grating with 40-60 ° petroleum ether (1.2 g). The structure of the compound was confirmed by NMR.

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

The above bis ester (1.0 g) and sodium bicarbonate (0.787 g) in ethanol (85 ml) and water (32 ml) were refluxed for 4 hours. The reaction mixture was poured into water and acidified, and the precipitate was collected by filtration and dried. The product was purified

DK 158266 B

20 by grating with boiling ethanol, then twice with boiling acetone. After each grating, the mixture was centrifuged and the supernatant removed by decantation. The residual solid was dried to give 0.547 g of the desired diacid as a yellow powder, m.p. 298-300 ° C (dec.).

Analysis:

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

Calculated for C C ^HHNO ^: C: 61.5%, H: 4.6%, N: 3.79%.

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

The above diacid (4.098 g) was suspended in water (100 ml) and treated with sodium bicarbonate (1.82 g). The resulting solution was filtered and the filtrate was treated with acetone until complete precipitation of the product had taken place.

The desired disodium salt was filtered off and dried to yield 3.39 g of a pale yellow powder.

Analysis:

Found: C: 51.1%, H: 4.3%, N: 3.0%

Calcd for C 19 H 15 NN 2 O 7 (6'9% water): C: 51.1%, H: 4.1%, N: 3.1%.

Example 3

The following compounds are also prepared by the procedures described above: (i) 6,9-Dihydro-4,9-dioxo-4H-pyrano [2,3-q] quinoline-2,7-dicarboxylic acid NMR: delta (DMSO) , 6.6 (1H, s), 6.9 (1H, s), 7.6 (1H, s), 8.6 (1H, s).

(ii) 9- (3-Methylbutyl) -4,6-dioxo-4H, 6H-pyrano (3,2-g] -quinoline-2,8-dicarboxylic acid, mp 302-304 ° C (dec).

(iii) 10-Methyl-4,6-dioxo-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid, m.p. 302 ° C.

(iv) 4,6-Dioxo-10-propyl-4H, 6H-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid. Diethyl ester has m.p. 211-212eC.

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21

Example 4 9-Ethyl-6,9-dihydro-4,4-dioxo-1Q-propylTH-pyrano [3,2-g] quinoline-2,8-dicarboxylic acid.

(a) 6-Acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-9-propylquinoline-2-carboxylic acid.

Methyl 6-acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylate (20 µl was heated under reflux in glacial acetic acid (150 ml) containing the 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 identified as the subtitle compound (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 of step (a) (14.2 g) 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 at reflux for 5 hours and then cooled and poured into chloroform (1 liter). 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 give the title compound (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 [3,2-g] quinoline-2,8-dicarboxylic acid,

The product of step (b) was hydrolyzed by the process of step (a) to give a product (1.1 g) which, by comparison by thin layer chromatography, was identical to the product of Example 2.

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22

Example 5 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 hydrogen chloride, under ice-cooling, was introduced into the mixture until saturation. The mixture was heated to 75 ° C for 8 hours, then cooled and poured into water and extracted with ethyl acetate. The organic phase was dried and evaporated and the residue was chromatographed (SiC 2 / ethyl acetate) to give the subtitle compound (0.8 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) (0.75 g) was heated under reflux with selenium dioxide (1.5 g) in glacial acetic acid.

(50 ml) for 48 hours. Filtration through "Celite" gave a clear filtrate which was treated with concentrated hydrochloric acid (25 ml) and heated at reflux for 12 hours.

Upon cooling and pouring into water, a precipitate (0.1 g) was obtained which, when compared by thin layer chromatography, proved identical to the product of Example 2.

Example 6 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-dione acid.

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

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23

Concentrated hydrochloric acid (4 ml) was added and the solvent was evaporated. The residue was dried in vacuo and extracted into ether. The ether was evaporated to give the subtitle compound (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.

in

The product of step (a) (3.55 g) was added in small portions with stirring to chlorosulfonic acid (100 ml) cooled to -78 ° C. The solution was allowed to slowly warm to room temperature and then heated to 50 ° C for 1 hour. The reaction mixture was gently 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 title compound (0.2 g), which was chromatographically identical to the product of Example 2.

Example 7 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 heated together in an autoclave for 12 hours at 100 ° C, after which the volatiles were evaporated at 60 ° C. The residue was triturated with ether to give the subtitle compound (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 [3,2-g] quinoline-2,8-dicarboxylic acid.

The product of 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 an evaporation residue which was separated by high pressure liquid chromatography to give the title compound

DK 158266 B

24 (.0.2 g) which was chromatographically identical to the product of Example 2.

Example 8 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylic acid.

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

Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylate (10 g) and pen-taphosphorus decasulfide (20 g ) was fused at 160 ° C for 6 hours and then cooled, and the product mixture was extracted into ethyl acetate. Chromatography (silica gel / ethyl acetate) afforded the subtitle compound (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] guinoline-2,8-dicarboxylic acid,

The diester from step (al 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 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 solid was purified by high-pressure liquid chromatography to give the title compound (2.1 g), which was chromatographically identical to the product of Example 2.

Example 9 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylic acid.

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

Diethyl 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g] guinoline-2,8-dicarboxylate (5 g) in glacial acetic acid (100 ml) was hydrogenated over Adams catalyst (0.5 g) at 4 atmospheres until hydrogen uptake ceased. Ka

DK 158266 B

The talysator 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 evaporation residue gave the subtitle 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 cymene (10 ml) and treated with 10% Pd / C catalyst at reflux for 6 hours. Filtration and evaporation gave a gum which was purified by high pressure liquid chromatography to give the title compound (0.15 g) which was chromatographically identical to the product of Example 2.

Example 10 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-6,8-dihydro-4,6-dioxo-10-propyl-4H-pyranot3,2-g] quinoline-2,8-dicarboxylate (4.27 g) and sodium hydroxide (1.6 g ) in water (10 ml) was heated to reflux for 24 hours, then the water was evaporated and the residue was suspended in ethanol (50 ml) saturated with gaseous hydrogen chloride and refluxed for 1 hour. Evaporation of the solvent gave a residue which was chromatographed (silica gel / ether) to give 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 formed which by NMR and mass spectroscopy was shown to be the desired product (0.93 g).

(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 sulfoxide (10 ml) was added to a solution of dimsyl sodium (1 g) in dry dimethyl sulfoxide (50 ml) at 40 ° C under N 2 · After For 48 hours, the reaction mixture was poured into water (500 mL) and extracted. Drying and evaporation

Claims (10)

1. Analogous Process for Preparation of Pyranoquinolinone Derivatives of General Formula I R5O Process according to claim 1, part (a), characterized in that the group D is an ester, amide or nitrile group and that the hydrolysis is carried out under mildly basic or under acidic conditions. Process according to claim 1, part (a), characterized in that the group D is an alkyl, aralkenyl, acyl or formyl group and the process comprises oxidation. Process according to claim 1, part (a) or claim 3, characterized in that the group D is an alkyl group and that the oxidation is carried out using selenium dioxide. Process according to claim 1, part (b) or (c) (ii), characterized in that the reaction is carried out under anhydrous conditions and in the presence of a dehydrating agent. Process according to claim 1, part (b), characterized in that a compound of formula III is cyclized by subjecting it to an elevated temperature. Process according to claim 1, part (c) (i), characterized in that one group of the group pairs is a group -OM and that the ring closure is carried out under acidic conditions at a temperature of from 20 ° to 150 ° C. 7. In rVV ^ n, - - cooh R8 Rg where R8 and R7 form a chain -COCH = C (C00H) -0-, and R8 and R8 may be the same or different, each is hydrogen or alkyl and, Rg is hydrogen or alkyl, or pharmaceutically acceptable salts, alkyl esters or mono- or di-alkylamides thereof, characterized in that (a) a compound of formula IIa 8a Rg wherein Rg is as defined above, 5 cl 8 cl 5 8 R and R have the same meanings as R and R 6¾ 7a above, and R and R represent a chain of the formula -COCH = C (D1) 0-, and in DK 158266 B one or both of D and D represents a group which can be hydrolyzed or oxidized to one group -COOH, and the other may represent a group -COOH, subjected to selective hydrolysis or oxidation, (b) a compound of formula III or IV '5b R6b JsHOOCk 7hÅ ^ J COOH 111 R? b ^ j ^ b Rg R5b R6b in ^ COOH \ II IV R COOH R8b LR Rg or an ester of each of these, wherein Rg is as defined above and R8b and R8b have the same meanings as R8 o and R and R represent the group pair -H and -O-C (COOH) = CH-COOH, are subjected to cyclization, (c) a compound of formula V R5c o <yCA J-COOH r8c Rg or a ester thereof, wherein Rg is as defined above, 5c 8c 5 fl R and R have the same meanings as R and R above, 6c 7c and R and R represent the group pairs: (i) -COCH2COCOR 'or -COCH = C (COOH) - NL1L2, or a suitable salt, ester or amide derivative thereof, and -OM or a halogen atom, or DK 158266B (ii) H and -0-C (COR ") = CH-COR", where R "is - OM or an ester or an amide thereof, T, 1 2 '9 L in which may be the same or different, each being hydrogen, aryl or alkyl, or together forming a saturated or unsaturated alkylene chain and M being hydrogen or an alkali metal , is cyclized and, if necessary or desired, hydrolysis of the group -COR "to a group -COOM where M is as defined above, (d) a compound of formula R5d 9" 10 K \ AX II II VI R7aA-ANA -C00H R8d Rg or an ester thereof, wherein Rg is as defined above, cj qj 58 Roa and R u have the same meanings as R and R above, and R6d and R7d represent the chain -C (R9R1 °) CH = C (C00H) -0- and 9 10 at least one of the group pairs R and R together form = S or together form a chain -S (CH9) S-, where 9 10 Δ nn is 2 or 3, and the other pair R, R can represent = 0, is converted to a corresponding compound of formula I by hydrolysis or oxidative hydrolysis, (e) groups A and B are selectively removed by dehydration, hydrogenolysis or dehydrohalogenation from a compound of formula VII or an ester thereof wherein R 9 is as defined above, 5e bark co R and R have the same meanings as R and R above, and R 2 e and R 2 e represent a chain -COCHA-CB (COOH) -O-, and in at least one of the group pairs A and B are 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 A, B together can then is a double bond, or (f) a compound of formula VIII 5f R 0 "tY 1 - C00H 188 in K Rg or an ester thereof, wherein Rg is as defined above and 5f 8f S 8 R and R have the same meanings as R and R 6 £ 7 f above, and R and R represent the group pair -COCH (SOR11) -CH (OH) -CO00R "and -OM, where R" and M are as defined above and 11 R is an alkyl group having 1- 10 C atoms are cyclized and, if necessary or desired, an obtained ester of a compound of formula I is hydrolyzed and / or an obtained compound of formula I is converted to a pharmaceutically acceptable salt, alkyl ester or mono or di-alkylamide derivative thereof, and / or such derivative is converted to another pharmaceutically acceptable salt, alkyl ester or mono or di-alkylamide derivative. Process according to claim 1, part (c) (i), characterized in that one group of the group pairs is halogen and that the reaction is carried out in a high boiling polar solvent and in the presence of a strong base. Process according to any one of claims 1-8, characterized in that each 5 of 8 and R, when alkyl, contains up to 8 carbon atoms. Process according to claim 9, characterized in that R and R, when alkyl, contain up to 4 carbon atoms.