CH634071A5 - Therapeutically active pyranoquinolones - Google Patents

Description

The present invention relates to new pyrannoquino-leinones, to a pharmaceutical composition containing them and to a process for preparing them.

The subject of the invention is the therapeutically active compounds of formula: c

■>? not

(D

where two of the adjacent symbols R5, R6, R7 and R8 form a chain - COCH = CE — O - and each of the others of these symbols, identical or different, represents a hydrogen or halogen atom or a hydroxyl or alkyl radical , alkenyl or alkoxy or else a radical - NR'R2 where each of the symbols R1 and R2, identical or different, represents a hydrogen atom or an alkyl radical,

Rg represents a hydrogen atom or an alkyl, alkenyl or phenylalkyl radical, and

E represents a carboxyl, 5-tetrazolyl or (N-tetrazol-5-yl) carboxamido radical, as well as their pharmaceutically acceptable derivatives.

To prepare the compounds of formula (I) or their pharmaceutically acceptable derivatives, one of the following methods can be applied:

a) a compound of formula (I) is prepared in which E represents a carboxyl radical by hydrolysis or selective oxidation of a compound of formula:

(II)

where Rs has the meaning indicated above,

R5a, R6a5 R7a R8a have the meanings given for R5, R6, R7 and R8 above, except that two of the adjacent symbols R5a, R6a, R7a and R8a may represent a chain of formula -C0CH = C (D1) 0 -,and

D and / or D1 represent hydrolysable or oxidizable radicals into carboxyl radicals, the other optional of these symbols representing a carboxyl radical,

b) a compound of formula (I) is prepared in which E represents a carboxyl radical by cyclization of a compound or ester of compound of formula:

b5 *>

COOH

B8b lS

R

5b

R

R '

6b

(IV)

X

COOIÏ

COOH

R

8b

R1

S

where Rg has the meaning indicated above, and R5b, R6b, R7b and R8b have the meanings indicated in connection with R5, R6, R7 and R8 above, except that two of the adjacent symbols R5b, R6b, R7b and R8b may represent a hydrogen atom and a -0-C (C00H) = CH-C00H radical,

c) a compound of formula (I) is prepared in which E represents a carboxyl radical by cyclization of a compound or ester of compound of formula:

R O

(V)

COOH

where Rg has the meaning indicated above, and 35 R5c, R60, R7c and R8c have the meanings indicated in connection with Rs, R6, R7 and R8 above, except that two of the adjacent symbols R5c, R60, R7c and R8c do not form not a chain

—COCH = C (COOH) —O—, but represent the pair of radicals:

i) -COCH2CO-COR "or - COCH = C (COOH) —NL1 L2, or 40 a suitable derivative of such a radical, and - OM or a halogen atom, or else ii) - H and - O - C (COR ") = CH - COR"

R "representing a radical - OM or a radical hydrolyzable into such a radical,

45 each of the symbols L1 and L2, identical or different, representing a hydrogen atom or an aryl or alkyl radical, or else these symbols together forming a saturated or unsaturated alkylene chain, and

M representing a hydrogen or alkali metal atom, after which, if the thing is necessary or desired, the radical so - COR "is hydrolyzed to form a radical - COOM,

d) converting into a corresponding compound of formula (I) a compound or ester of compound of formula:

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(III)

(VI)

65 where Rg and E have the meanings indicated above,

R5d, RM, R7d and R8d on (; the meanings given for R5, R6, R7 and R8 above, except that two of the adjacent symbols R5d, RM and R8d may represent the chain —C (RSIR10) = CE— O—,

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at least one of the pairs of radicals R9 and R10 represents a radical = S or else a chain - S (CH2) nS - where n represents 2 or 3, while the other pair of radicals R9, R10 can represent a radical = 0,

e) the A and B radicals are selectively eliminated from a compound or ester of compound of formula:

, 6th

, 8e where Rs and E have the meanings indicated above,

R5e, R6e, R7e and R8e have the meanings given in connection with R5, R6, R7 and R8 above, except that two of the adjacent symbols R5e, R6e, R7e and R8e may represent a chain - COCHA - CBE - O -, and in at least one of the pairs of symbols A and B, both A and B represent a hydrogen atom or one of the symbols A and B represents a hydrogen atom and the other a halogen atom or a hydroxyl radical, however, in the other pair of symbols, A and B may together represent a double bond,

0 a compound of formula (I) is prepared in which E represents a carboxyl radical by cyclization of a compound or ester of compound

of formula:

, 6f

COOH

, 3f where Rs has the meaning given above, and

R5f, R6f, R7f and R8f have the meanings given for R5, R®, R7 and R8 above, except that two of the symbols R5f, R6f, R7f and R8f are adjacent, rather than representing a chain

- COCH = C (COOH) —O—, represent the pair of radicals

- COCH (SOR10) - CH (OH) - COOR "and - OM,

R "and M having the meanings indicated above, and

R10 representing an alkyl radical of 1 to 10 carbon atoms,

g) a compound of formula (I) in which E represents a 5-tetrazolyl radical is prepared by reaction of the corresponding compound of formula (I) in which E represents a cyano radical, with an azide in a solvent which is inert under the reaction conditions , or else h) a compound of formula (I) is prepared in which E represents a (N-tetrazol-5-yl) carboxamido radical by reaction with the 5-amino-tetrazole of the corresponding compound of formula (I) in which E represents a carboxyl radical or else an acid halide, ester or mixed anhydride radical,

after which, if necessary or desired, the ester of the compound of formula (I) is hydrolyzed and / or the compound of formula (I) is converted to a pharmaceutically acceptable derivative.

In process a, the radical D of the formula can be, for example, an ester radical, acid halide, amide or nitrile which can be hydrolyzed to a carboxyl radical. The hydrolysis can be carried out according to conventional techniques, for example under moderately basic conditions, in particular by means of sodium carbonate, sodium hydroxide or sodium bicarbonate, or under acidic conditions, in particular by means of 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 nature of the compounds used. Alternatively, the radical D can be an alkyl radical, for example a lower alkyl radical such as methyl, a hydroxymethyl radical, an aralkenyl radical, for example styryl, an acyl radical, for example lower alkanoyl such as acetyl, or a radical formyl. The oxidation can be carried out under conventional conditions which do not otherwise modify the molecule to the point of rendering the yield of the desired product uneconomic and, for example, an alkyl radical or a hydroxymethyl radical can be oxidized by means of selenium dioxide , for example at reflux in aqueous dioxane, or by means of chromic acid, for example at reflux in aqueous acetic acid. Aralkenyl radicals can be oxidized using, for example, neutral or alkaline potassium permanganate in aqueous ethanol, while acyl radicals can be oxidized using, for example, chromic acid or aqueous hypochlorite , such as sodium hypochlorite. The formyl radical can be oxidized using, for example, chromic acid or silver oxide.

In process b, the cyclization can be carried out by reacting the compound of formula (III) or (IV) with a cyclization agent such as a dehydrating agent such as chlorosulfonic, sulfuric or polyphosphoric acid. The reaction is preferably carried out in an anhydrous medium and can be carried out at a temperature of about 25 to 150 ° C, but preferably from 75 to 150 ° C. The licensee has discovered that the maleic acid derivative of formula (IV) isomerizes to the corresponding fumaric acid derivative of formula (III) when polyphosphoric acid is used for the cyclization of these compounds to the compound of formula (I), which makes it possible to achieve a satisfactory yield of the compound of formula (I) from a mixture which at first sight is not satisfactory of compounds of formulas (III) and (IV). The compounds of formula (III) can also be cyclized under the effect of an elevated temperature, for example from 200 to 250 ° C., optionally in the presence of a solvent with a high boiling point which is inert under the conditions of the reaction, for example diphenyl ether.

In method c (i), when one of the adjacent radicals represented by two of the symbols R5c, R6c, R7c and R8c is an —OM radical, the cyclization can be carried out by heating in basic or neutral medium. It is however preferable to carry out the cyclization in the presence of an acid such as hydrochloric acid and in a solvent which is inert under the reaction conditions, such as ethanol. The reaction can be carried out at a temperature of about 20 to 150 ° C. The radical - COR "is preferably an ester radical and, for example, R" can represent a lower alkoxy radical.

When one of the adjacent radicals is a —COCH = C (COOH) —NL1L2 radical, the derivative of the carboxyl radical can be a radical - CONL1L2 where L1 and L2 have the meanings indicated above. It is preferable that L1 and L2 represent hydrogen atoms or phenyl or alkyl radicals of 1 to 6 carbon atoms or else together represent an alkylene chain with 4 or 5 atoms, for example form a piperidine ring with the atom nitrogen. When one of two adjacent symbols represents a halogen atom, the cyclization can be carried out in a solvent inert under the reaction conditions, which is preferably a polar solvent with high boiling point such as Pyridine, dimethylformamide or hexamethylphosphoramide. The reaction is preferably carried out using a strong base, such as an alkali metal hydride, for example sodium hydride. The reaction is preferably carried out at a temperature of about 80-200 ° C in the absence of free oxygen, for example in an inert atmosphere such as a nitrogen atmosphere.

The cyclization of process c (ii) can be carried out by reaction of the compound of formula V with a cyclization agent such as an agent

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dehydration such as chlorosulfonic, polyphosphoric or sulfuric acid. The reaction is preferably carried out in an anhydrous medium and can be carried out at a temperature from 0 to 100 ° C. As a variant, cyclization can be ensured by conversion of the free carboxyl radicals of the compound of formula V to acyl halide radicals, then by a Friedel-Crafts intramolecular reaction of the resulting acid halide.

In process d, when R9 and R10 together represent a chain - S— (CH2) n — S—, the conversion can comprise an oxidative hydrolysis and be carried out in an aqueous polar organic solvent such as ethanol, acetone or aqueous tetrahydrofuran. Oxidative hydrolysis can be carried out in the presence of an oxidizing agent such as mercuric chloride, an N-halo-succinimide such as N-bromosuccinimide or N-chlorosuccin-imide, a peracid such as periodic acid or p -toluènesulfone-chloramide possibly salified. In the case of mercuric chloride, the reaction can be carried out in the presence of a base, such as mercuric oxide, cadmium carbonate or calcium carbonate. N-halogenosuccinimides can be used alone or in the presence of a silver salt, such as silver perchlorate or silver nitrate. The reaction can advantageously be carried out at a temperature of about 15 to 100 ° C.

When R9 and R10 together represent a radical = S, the conversion can comprise a hydrolysis (oxidizing) and be carried out in the presence, as catalyst, of a heavy metal compound such as a compound of a metal of group Ib, IIb or Illb of periodic table of elements. Suitable compounds are the mercury, thallium and silver compounds, for example 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, for example acetone and acetic acid, alkanols, tetrahydrofuran and methanol or else tetrahydrofuran. As a variant, the conversion can be ensured by alkylation, then hydrolysis. In such cases, the conversion can be carried out using: i) an alkyl sulfonate or halide (such as methyl iodide) in a wet solvent such as acetone, ii) a fluorosulfonate alkyl and water in sulfur dioxide, or iii) a trialkyloxonium fluoroborate, then aqueous sodium hydroxide.

In process e, when A and B both represent hydrogen atoms, the reaction is dehydrogenation and can be carried out by oxidation using a moderate oxidizing agent, such as selenium dioxide, palladium black, chloranil, lead tetracetate or triphenylmethyl perchlorate. As a variant, the dehydrogenation of a compound of formula (VII) where A and B both represent hydrogen atoms can be carried out indirectly by halogenation, then dehydrohalogenation, for example by reaction with N-bromosuccinimide or pyridinium bromide perbrominated leading to a compound of formula (VII) where A represents a halogen atom and B a hydrogen atom, which is then subjected to dehydrobromation. When one of the symbols A and B represents a hydroxyl radical, dehydration can be catalyzed using an acid, such as sulfuric or oxalic acid, using a base, such as potassium hydroxide, using a salt, such as potassium hydrogen sulfate, or by means of N-bromosuccinimide. The reaction can be carried out in a solvent inert under the reaction conditions, for example in a halogenated hydrocarbon, xylene or glacial acetic acid. The reaction can be carried out at an elevated temperature, for example 20 to 150 ° C.

The cyclization of process f can be carried out in an inert solvent under the reaction conditions, for example in diethyl ether or benzene. If desired, the reaction can also be carried out in the presence of a Lewis acid, such as boron trifluoride. The reaction is preferably carried out at a temperature of 10 to 120 ° C in the presence of an organic base, such as piperidine.

Suitable solvents which are inert under the reaction conditions of process g are in particular those which dissolve the two reactants, as is the case with N, N-dimethylformamide. Other suitable solvents are dimethyl sulfoxide, tetrahydrofuran, diethyl glycol and ethyl methyl glycol. The reaction is preferably carried out at a temperature of about 20 to 130 ° C for about 1 to 20 hours. The azide for the reaction is preferably ammonium azide or an alkali metal azide, such as sodium or lithium azide; however, other azides, for example aluminum azide or azides of nitrogenous bases such as demono-, di-, tri- and tetramethylammonium, anilinium, morpholi-nium and piperidinium azides can also be used, if the thing is desired. When the azide is not an alkali metal azide, it can be prepared in the reaction mixture by double decomposition. If desired, the reaction can be carried out in the presence of an electron acceptor, such as aluminum chloride, boron trifluoride, ethylsulfonic acid or benzenesulfonic acid. Rather than being carried out under the above conditions, the reaction can be carried out using hydrazoic acid (or hydrogen azide) at a temperature of about 20 to 150 ° C in a suitable solvent under higher pressure. to that of the atmosphere. When the azide is not hydrazoic acid and is, for example, sodium azide, the reaction product is the corresponding tetrazole salt. This salt can easily be converted to the free acid by reaction with a strong acid, such as hydrochloric acid.

In process h, the anhydride is preferably a mixed anhydride of the type which preferentially splits to give, as main product, the chromonecarboxamidotetrazole sought during the reaction with 5-aminotetrazole. Examples of suitable acids from which mixed anhydride can be derived are sulfonic acids, such as benzenesulfonic acid, sterically hindered carboxylic acids, such as pivalic, isovaleric acid, diethylacetic or triphenylacetic acid, and alkoxyformic acids, such as alkoxyformic acid with a lower alkoxy radical such as ethoxyformic or isobutoxyformic acid. When the reaction is carried out with an acid halide, this is advantageously an acid chloride. The reaction is preferably carried out in an anhydrous medium in a solvent which reacts neither with 5-aminotetrazole, nor with the mixed anhydride or the acid halide, for example in pyridine or dimethylformamide. However, when the reaction is carried out in a non-basic solvent such as dimethylformamide, the mixture preferably also comprises in adequate proportion an acid acceptor such as triethylamine. The reaction is preferably carried out at a temperature of about -15 to + 20 ° C. When the reaction is carried out with an ester, the holder prefers to take a lower alkyl ester and carry out the reaction in a solvent which is inert under the reaction conditions, for example in glacial acetic acid, at a temperature of about 100 to 150 ° C. When the reaction is carried out starting from a compound of formula (I) where E represents a carboxyl radical, it can be carried out by heating the compound of formula (I) and 5-aminotetrazole in a solvent which is inert under the conditions reaction, for example in dimethylacetamide, at a temperature of 100 to 200 ° C. Alternatively, the reaction can be carried out in the presence of a condensing agent, such as N, N'-carbonyldiimidazole or dicyclohexylcarbodiimide, in a aprotic solvent, such as dimethylformamide, at a temperature of about 10 to 40 ° C.

The starting compounds for process b can be obtained by reaction of a compound of formula:

R *

.6b

NHR

, 8b

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where Rs, R5b, R6b, R7b and R8b have the meanings indicated above, with a compound of formula:

Da — C = C — Da (X)

where Da represents an ester radical, for the formation of a mixture of compounds of formulas:

(XI)

(XII)

where Rs, Da, R5b, R6b, R7b and R8b have the meanings indicated above.

The compounds of formulas (XI) and (XII) can be hydrolyzed into compounds of formulas (IV) and (III). As a variant, it is possible to convert the Da radicals of the compounds of formulas (XI and XII) according to conventional techniques into various D radicals and to cyclize the resulting compounds under the conditions indicated with regard to process b above to obtain a compound of formula (II). According to another variant which is preferred, the compounds of formulas (XI) and (XII) can be cyclized under the conditions mentioned in connection with process b above to obtain a compound of formula (II) where D represents an ester radical, then use the resulting compound of formula (II) itself in process a or else convert the radical D into another radical D, for example into an acid halide, amide or nitrile radical, according to conventional techniques.

The isomer fumarate of formula (XII) (or the corresponding compound in the formula of which the radical Da has been converted into a radical D) is the only isomer capable of cyclizing to give the desired compounds of formula (II). The proportion between the two isomers can be easily determined by nuclear magnetic resonance spectroscopy and the licensee has discovered that, in general, the fumaric acid derivative sought is only a minor proportion of the mixture of isomers formed during the reaction.

The compounds of formula (V) where two of the symbols R5c, R6c, R7e and R8c adjacent represent a radical - COCH2COCOR "and a radical - OM or a halogen atom can be obtained by reaction of a compound or ester of compound of formula:

35

where Rs has the meaning indicated above, and

R5s, R6s, R7s and R8s have the meanings given for Rs, R6, R7 and R8 above, except that two of the symbols R5s, R6s, R7g and R8s are adjacent, rather than representing a chain —COCH = CH ( COOH) —O—, represent a radical - COCH3 and a radical - OM or a halogen atom, M having the meaning indicated above,

with a compound of formula:

R'CZ-CZR "(XIV)

where R "has the meaning indicated above,

R 'represents a suitable labile substituent, for example a halogen atom or an alkoxy, amino, alkylamino, substituted amino (for example arylsulfonylamino) or substituted alkylamino radical, reacting with the carbanion of the radical - COCH3 of the compound of formula (XIII) , and each symbol Z represents an oxygen atom of carbonyl function or else one of the symbols Z represents two halogen atoms and the other represents an oxygen atom of carbonyl function,

after which, if necessary, the resulting compound is hydrolyzed to obtain a compound of formula (V). The preferred compounds of formula (XIV) are dialkyl oxalates, such as diethyl oxalate.

The compounds of formula (V) comprising a —COCH = C (COOH) —NLJL2 radical or one of its derivatives can be obtained from known compounds in one or more stages according to known methods.

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

As a variant, the compounds of formula (II), for example the acid halides, amides and nitriles, can be obtained from compounds of formula (I) according to conventional techniques, for example by reaction of an ester of compound of formula (I) with ammonia for the formation of the amide, then by dehydration of the amide for the formation of the nitrile.

The compounds of formula (V) carrying in adjacent positions a hydrogen atom and a radical - O — C (COR ") = CH — COR" can be obtained by reaction of a compound or ester of compound of formula:

(XV)

COOH

where R5h, R6h, R7h and R8h have the meanings given in connection with Rs, R6, R7 and R8 above, except that two of the symbols R5h R6h, R7h and R8h are adjacent, rather than representing a chain —COCH = C ( COOH) —O—, represent a hydrogen atom and a hydroxyl radical,

with a dialkyl acetylenedicarboxylate in a conventional manner, then, if necessary, by hydrolysis of the reaction product.

The compounds of formula (VIII) can be obtained by reaction of a compound or ester of compound of formula:

60

(XIII)

COOH

COOH

(XVI)

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where RS has the meaning indicated above, and

R5i, R6 ', R7' and R8i have the meanings given for R5R6, R1 and R8 above, except that two of the symbols R5i, R6i, R7 'and R8' are adjacent, rather than representing a chain

—COCH = C (COOH), represent a hydroxyl radical and a radical - COO — alkyl,

with a methylalkylsulfoxide anion, for example the dimethylsulfoxide anion,

and reacting the resulting O-hydroxy-2-alkylsulfinylated derivative with glyoxalic acid or one of its esters.

The compounds of formula (I) where E represents a cyano radical can be obtained by dehydration of the pyrannoquinoline lineamide corresponding by means, for example, of phosphorus oxychloride as dehydrating agent. The reaction is preferably carried out in a mixture comprising at least 1 molar equivalent of dehydrating agent per mole of pyrannoquinoline lineamide. When the dehydrating agent reacts with one of the radicals represented by R5, R6, R7 and R8 (for example when one of these radicals comprises a hydroxyl radical), it is advisable to take sufficient dehydrating agent to allow the reaction secondary as well as the main reaction. If desired, the reaction can be carried out in the presence of an acid acceptor, such as triethylamine. The reaction can be carried out in the presence of a solvent, such as N, N-dimethylformamide, dimethylsulfoxide, pyridine, benzene or hexamethylphosphoramide, or else in an excess of the dehydrating agent, as the reaction. The reaction can be carried out at a temperature of about 0 to 200 ° C depending on the nature of the dehydrating agent. In the case of phosphorus oxychloride, the temperature is preferably from 0 to 100 ° C.

The starting chromoneamides can be obtained by reaction of a corresponding pyrannoquinoline ester with ammonia according to conventional techniques for the production of amides from esters, for example in an alkanol as solvent at a temperature of 0 at 120 ° C.

The compounds of formulas (VI) (VII), (IX), (XIII), (XIV), (XV) and (XVI) are known or else can be prepared from known compounds according to conventional techniques.

The methods described above make it possible to obtain the compounds of formula (I) and their derivatives. The derivatives thus obtained can be treated in order to release the free compound of formula (I) thereof or else to convert one derivative into another.

The compounds of formula (I) and the intermediates for their synthesis can be isolated from the reaction mixtures according to the usual techniques.

Pharmaceutically acceptable derivatives of the compounds of formula (I) are in particular the pharmaceutically acceptable salts and, when E in the formula represents a carboxyl radical, the esters and amides of the carboxylic acid radical in position 2. Suitable salts are the ammonium salts , alkali metals (eg sodium, potassium and lithium) and alkaline earth metals (eg calcium or magnesium), as well as the salts formed with suitable organic bases such as the salts formed with hydroxylamine , lower alkylamines such as methylamine or ethylamine, substituted lower alkylamines such as hydroxylated alkylamines such as tri- (hydroxymethyl) methylamine or simple monocyclic nitrogen heterocyclic compounds such as piperidine or morpholine. Suitable esters are in particular simple lower alkyl esters such as the ethyl ester, esters obtained from alcohols containing basic radicals such as di (lower alkyl) aminoalkanols, such as the P- (diethylamino) ethyl ester and the acyloxy esters -alkyls such as (lower acyloxy) esters (lower alkyls) such as the pivaloyloxymethyl ester, in addition to the bisesters derived from dihydroxy compounds, for example from a di (lower hydroxyalkyl) ether such as the bis-2-oxapropane-1 ester , 3-diylic. The pharmaceutically acceptable acid addition salts of basic esters as well as compounds in the formula of which one of the symbols R5, R6, R7 and R8 represents a radical —NR'R2, for example hydrochlorides, hydrobromides, Oxalates, maleates or fumarates are also suitable. The esters can be prepared in a conventional manner, namely by esterification or transesterification. The amides can, for example, be unsubstituted or carry one or two alkyl radicals of 1 to 6 carbon atoms and can be obtained according to conventional techniques, for example by reaction of an ester of the corresponding acid with the ammonia or a suitable amine.

The compounds of formula (I) and their pharmaceutically acceptable derivatives are useful because of their pharmacological activity in animals and in particular because they inhibit the release and / or the effect of pharmacological mediators which result from the combination in vivo. certain types of antibodies and specific antigens, for example the combination of a reactin antibody with a specific antigen (see example 27 of English patent No. 1292601). The new compounds have also been shown to have an effect on the reflex arc in experimental animals and humans and, in particular, reflexes associated with the functioning of the lungs. In humans, both subjective and objective changes resulting from the inhalation of a specific antigen by a sensitized subject are inhibited during the prior administration of the new compounds. Thus, these new compounds are indicated for the treatment of reversible obstructions of the airways and / or to prevent the secretion of an excess of mucus. The new compounds are also suitable for the treatment of allergic asthma also called intrinsic asthma (for which no sensitivity to an extrinsic antigen could be demonstrated), bronchitis, cough and nasal and bronchial obstructions associated with colds currents. The new compounds may furthermore be useful for the treatment of other conditions for which an antigen-antibody reaction or an excessive secretion of mucus are responsible for or promote a disease, as is the case with hay fever. , for certain eye conditions, for example trachoma, for food allergy such as hives and atopic eczema and for gastrointestinal conditions such as gastrointestinal allergy, especially in children, in particular l allergy to milk, besides ulcerative colitis.

For the purposes mentioned above, the dose administered obviously varies with the nature of the compound, with the mode of administration and with the treatment required. However, in general, satisfactory results are obtained by administering the compounds in an amount of 0.001 to 50 mg / kg of body weight in the test mentioned in example 27 of English patent No. 1292601. For humans, the total daily dose indicated is from 0.01 to 1000 mg and preferably from 0.01 to 200 mg, but more advantageously from 1 to 60 mg which can be administered in several doses, from 1 to 6 once a day, or in a spread-out form. Thus, unit dosage forms suitable for administration (by inhalation or by the esophagus) comprise 0.01 to 50 mg and preferably 0.01 to 20 mg, but more advantageously 0.01 to 10 mg of the compound, preferably as a mixture with a pharmaceutically acceptable solid, diluent or adjuvant carrier or liquid.

The compounds of formula (I) and their pharmaceutically acceptable derivatives offer the advantage of being more effective on certain pharmacological models or of having a longer lasting effect than compounds of analogous structure. In addition, the compounds of formula (I) and their pharmaceutically acceptable derivatives are advantageous in that they are involved in the transmission of reflexes and the inhibition of mucus secretion more effectively than do the structural compounds. similar.

The licensee prefers that, in the compound formula, each of the symbols Rs, R5, R6, R7 and R8, when they represent radicals containing carbon atoms, have up to 8 carbon atoms and preferably up to 4 carbon atoms. Specifically, the holder prefers that R5, R6, R7 and R8 are chosen from hydrogen, chlorine and bromine atoms and the methoxy, propyl, allyl, methyl, ethyl and hydroxyl radicals. Chain

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—COCH = CE — O - can be attached to the benzene ring in any direction and in any two adjacent positions of the substituents Rs, R6, R7 and R8. However, the licensee prefers that this chain be united at the positions carrying the substituents R6 and R7 so that the terminal oxygen atom of this chain occupies the position of the substituent R7. The licensee further prefers that E represents a carboxyl radical.

A pharmaceutically acceptable salt of a compound of formula (I) can be produced, when the latter contains a salifiable radical.

Compounds suitable for converting the compound of formula (I) into a pharmaceutically acceptable salt are in particular compounds such as bases and ion exchange resins which contain pharmaceutically acceptable cations, for example sodium, potassium, calcium or ammonium cations or suitable nitrogenous organic cations. As a general rule, the holder prefers to form the pharmaceutically acceptable salt by reaction of the free acid of formula (I) with an appropriate base, such as an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate in aqueous solution or by a double decomposition reaction with an appropriate salt. When using a strongly basic compound, care should be taken, for example by maintaining a sufficiently low temperature, that the compound of formula (I) does not undergo hydrolysis or other degradation. The pharmaceutically acceptable salt can be separated from the reaction mixture, for example by precipitation in solvent and / or by removal of the solvent by evaporation, for example lyophilization.

The invention further relates to a pharmaceutical composition which comprises (preferably in an amount of less than 80% and more advantageously less than 50% by weight) a compound of formula (I) or one of its pharmaceutically acceptable derivatives , in combination with a vehicle, a pharmacologically acceptable thinner or adjuvant. Examples of suitable vehicles, diluents or adjuvants are: for tablets, capsules and dragees, microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, l stearic acid, starch, sodium bicarbonate and / or gelatin; for suppositories, natural or hardened oils and waxes and, for inhalation compositions, coarse lactose. The compound of formula (I) or its pharmaceutically acceptable derivative is preferably in a form having a mass median diameter of 0.01 to 10 | i. The compositions may also contain preservatives, stabilizers and wetting agents, solubilizers, sweeteners, colorants and suitable flavorings. The compositions may, if desired, be presented in a spread-out form. The incumbent prefers the compositions to be administered by the esophagus which release their content in the gastrointestinal system.

The aforementioned 5-tetrazoyl and (N-tetrazol-5-yl) carboxamido radicals correspond respectively to the formulas:

/ —N N — N

- C - CONÏÏ —C '

N N "

I I

H H

(XVII) (XVIII)

The radicals of formulas (XVII) and (XVIII) can exist in tautomeric forms and the various tautomeric compounds which result therefrom fall within the scope of the definition of the compounds of formula (I).

The preparation of the compounds of formula (I) is illustrated by the following examples.

Example 1:

4,6-dioxo-10-propyl-4H, 6H-pyranno- [3,2-g] -quinoline-2,8-di-carboxylic acid a) 4-Acetamido-2-allyloxyacetophenone

Stirred at room temperature for 24 h in 250 ml of dry dimethylformamide 19.3 g of 4-acetamido-2-hydroxyaceto-phenone, 12.1 ml of allyl bromide and 21.5 g of anhydrous potassium carbonate. The reaction mixture is poured into water and the product is extracted with ethyl acetate. The organic solution is washed thoroughly with water, dried over magnesium sulfate and evaporated to dryness. The desired product is obtained in an amount of 20.5 g in the form of a beige solid. The structure of the compound is confirmed by nuclear magnetic resonance spectroscopy and mass spectroscopy.

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

18.4 g of the above allyl ether are heated for 4 h at 200-210 ° C. 17.1 g of the desired compound having undergone thermal transposition are obtained in the form of a brown solid. Again, the structure is confirmed by nuclear magnetic resonance spectroscopy and mass spectroscopy.

c) 4-Acetamido-2-hydroxy-3-propylacetophenone

17 g of the product obtained in b are dissolved in glacial acetic acid and the solution is hydrogenated in the presence of Adams catalyst until the absorption of hydrogen is complete. The catalyst is separated by filtration through kieselguhr and the filtrate is evaporated to obtain 13.0 g of an almost colorless solid. The structure of the product is confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.

d) ethyl 7-Acetamido-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate

A mixture of 19.3 g (17.9 ml) of diethyl oxalate and 12.4 g of the product obtained in c above in 100 ml of dry ethanol is added to a stirred ethanolic solution of ethyl ethylate. sodium prepared by dissolving 6.1 g of sodium in 200 ml of dry ethanol. The reaction mixture is heated at reflux for 3 h, then poured into dilute hydrochloric acid and chloroform. The chloroform phase is separated, washed with water and dried. The solvent is evaporated to obtain a brown solid which is dissolved in 300 ml of ethanol containing 3 ml of concentrated hydrochloric acid, then the whole is heated under reflux for 1 h. The reaction mixture is poured into water and the product is extracted with ethyl acetate, then the extract is washed with water and dried. The solvent is evaporated off to obtain 10 g of the desired product in the form of a sticky solid, the structure of which is confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.

e) ethyl 7-Amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate

A solution of 10 g of the amide obtained in d above in 300 ml of ethanol containing 5 ml of concentrated hydrochloric acid is heated at reflux for 8 h. The reaction mixture is diluted with water and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and the solvent is removed by evaporation to obtain a dark brown semi-solid. This is chromatographed on a column of silica gel with elution with ether to obtain 4.8 g of the desired product, the structure of which is confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy and which melts at 84-87 °. vs.

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

The mixture is heated at reflux for 26 h in 30 ml of ethanol 2.0 g of the aminobenzopyranne obtained in e and 1.24 g (1.01 ml) of dimethyl acetylenedi-carboxylate. The reaction mixture is cooled to

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0 ° C and the insoluble yellow brown solid is collected by filtration, which is washed with a little ethanol and dried so as to isolate 2.0 g of a product which consists of a mixture of the fumaric ester and maleic ester formed by Michael addition of the amine on acetylene.

30 ml of polyphosphoric acid are added to 2.0 g of this mixture of esters and the new mixture is heated in a steam bath with stirring for 20 min. The mixture is then poured onto ice and the new mixture is stirred in the presence of ethyl acetate. The organic phase is separated, washed with water and dried. The solvent is evaporated to obtain 1.6 g of an orange-yellow solid. By recrystallization of this solid from ethyl acetate, the desired product is obtained in the form of light orange needles, melting at 187-188 ° C.

Analysis for C20H19NO7:

Calculated: C62.3 H 4.9 N3.6%

Found: C62.0 H 5.1 N3.7%

g) 4,6-dioxo-10-propyl-4H, 6H-pyranno- [3,2-g] -quinoline-2,8-dicarboxylic acid

2.5 g of the above bisester is refluxed for 90 min in the presence of 1.64 g of sodium bicarbonate in 100 ml of ethanol and 50 ml of water. The mixture is poured into water and acidified to precipitate a gelatinous solid. This solid is collected by filtration, it is heated to reflux in the presence of ethanol, and then 1.4 g of the desired compound are separated by centrifugation, melting at 303-304 ° C with decomposition. The structure of the product is confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.

h) 4,6-Dioxo-10-propyl-4H, 6H-pyranno- [3,2-g] -quinolein-2,8-di-carboxylic acid disodium

The mixture is heated and stirred until a clear solution is obtained 1.35 g of the bisacid obtained in g above and 0.661 g of sodium bicarbonate in 150 ml of water. The solution is filtered and the filtrate is lyophilized to obtain 1.43 g of the desired disodium salt.

Analysis for CnHnN07Na2.12.5% H2O:

Calculated: C46, W H 3.8 N 3.15%

Found: C46, W H 4.0 N 2.90%

Example 2:

4,6-dioxo-1-ethyl-10-propyl-4H, 6H-pyranno [3,2-g] -quino-2,8-dicarboxylic acid a) 4-fN-Acetyl-N-ethyl) amino-2-allylacetophenone

The mixture is stirred for 17 h in 500 ml of dry dimethylformamide 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 . The reaction mixture is poured into water and the product is extracted with ether. The organic solution is washed thoroughly with water, then dried over magnesium sulfate and evaporated to dryness. 102.5 g of the desired compound are thus obtained in the form of an oil. The structure of the product is confirmed by nuclear magnetic resonance spectroscopy and mass spectroscopy.

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

The mixture is refluxed for 3 h in 300 ml of diethylaniline

100.5 g of the allyl ether obtained in stage a. The reaction mixture is cooled and poured into dilute hydrochloric acid, then the new mixture is extracted with ether, after which the ether extract is washed with dilute hydrochloric acid and then with water. The organic solution is extracted with a 10% solution of sodium hydroxide, then the extract is acidified. The product thus precipitated is extracted with ether and the ether extract is dried over magnesium sulfate. The resulting ethereal solution is evaporated to dryness to obtain 78.7 g of a yellow-brown oil. This oil consists of a mixture of 4- (N-acetyl-N-ethyl) amino-3-allyl-2-hydroxyaceto-phenone and 6- (N-acetyl-N-ethyl) amino-3-allyl-2- hydroxyaceto-phenone.

This mixture is dissolved in 500 ml of ethanol and 20 ml of glacial acetic acid, then the solution is hydrogenated in the presence of Adams catalyst until the absorption of hydrogen is complete. The catalyst is separated by filtration on kieselguhr and the filtrate is evaporated to obtain 79.9 g of a brown oil. This brown oil consists of a mixture and is separated by high pressure liquid chromatography using a 1: 1 mixture of ether and petroleum ether as 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

Heated at reflux for 6 h 44'g of 4- (N-acetyl-N-ethyl) -amino-3-propyl-2-hydroxyacetophenone in 100 ml of 48% hydrogen bromide in glacial acetic acid , 500 ml of glacial acetic acid and 20 ml of water. The reaction mixture is poured into ice water and the new mixture is extracted into ethyl acetate, then the extract is washed with water, with sodium bicarbonate solution and again with water before drying it over magnesium sulfate. The organic solvent is evaporated to dryness to obtain 34 g of the desired compound in the form of a red oil. The structure of the compound is confirmed by nuclear magnetic resonance spectroscopy and mass spectroscopy.

d) 6-Acetyl-1-ethyl-7-hydroxy-4-oxo-8-propyl-4H-methyl carboxylate

Heated at reflux for 17 h in 300 ml of ethanol 17 g of the amine obtained in c and 11.3 ml of dimethyl acetylenedicarboxylate. The reaction mixture is cooled and evaporated to dryness to obtain a deep red oil. This oil is chromatographed on a column of silica gel with elution using a 1: 1 mixture of ether and petroleum ether to obtain 19.1 g of 1- (4-acetyl-3-hydroxy-2). -propylphenyl) -N-dimethylethylaminomaleate melting at 83-87 ° C.

5 g of the maleic ester are heated and stirred in 100 ml of polyphosphoric acid in a steam bath for 10 min. The reaction mixture is cooled and poured into a mixture of water and ice, as well as ethyl acetate. The organic phase is separated, washed with water and dried over magnesium sulfate. The solvent is evaporated to dryness to obtain a pale yellow solid. This product is purified by high pressure liquid chromatography to isolate 2.6 g of the desired compound, melting at 121-123 ° C.

Analysis for C18H2iN05:

Calculated: C65.3 H 6.34 N4.23%

Found: C65.5 H 6.60 N 4.20%

Methyl 6-acetyl-1-ethyl-5-hydroxy-4-oxo-4H-quinoline-2-carboxylate is obtained after purification in the form of a pale yellow solid, at a rate of 100 mg.

e) 4,6-Dioxo-1-ethyl-10-propyl ~ 4H, 6H-pyranno- [3,2-g] -quinoline-2,8-dicarboxyIate

1.0 g of the hydroxyketone obtained in d and 3.3 ml of diethyl oxalate in 25 ml of dry dimethylformamide are added to 0.581 g of 50% sodium hydride washed with ether in 20 ml of dimethylformamide dry, then stir the reaction mixture for 4 h. The mixture is then poured into water, the new mixture is acidified and extracted with ethyl acetate, then the extract is washed with water and dried over magnesium sulfate. The solvent is evaporated to dryness to obtain an oil which is dissolved in 100 ml of ethanol and which a few drops of concentrated hydrochloric acid are added. The solution is heated at reflux for 30 min, cooled, poured into water and the new mixture is extracted with ethyl acetate, then the extract is washed with water and washed. dry on

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magnesium sulfate. The solvent is evaporated to dryness to obtain an oil which is made to solidify by trituration in the presence of boiling petroleum ether in the range from 40 to 60 ° C so as to isolate 1.2 g. The structure of the compound is confirmed by nuclear magnetic resonance spectroscopy.

f) Acid 4,6-dioxo-1-ethyl-10-propyl-4H, 6H-pyranno- [3,2-g] -quino-lenin-2,8-dicarboxylic

1.0 g of the above bisester and 0.787 g of sodium bicarbonate in 85 ml of ethanol and 32 ml of water are heated at reflux for 4 h. The reaction mixture is poured into water, the new mixture is acidified and the precipitate is collected by filtration and dried. The product is purified by tritration in the presence of ethanol at the boil, then twice in the presence of acetone at the boil. After each trituration, the mixture is centrifuged and the supernatant liquid is removed by decantation. The residual solid is dried to obtain 0.547 g of the desired diacid, in the form of a yellow powder melting at 298-300 ° C with decomposition.

Analysis for C1S) H17N07:

Calculated: C61.5 H 4.6 N3.79%

Found: C61.3 H 5.0 N3.60%

gj 4,6-Dioxo-1-ethyl-10-propyl-4H, 6H-pyranno- [3,2-g] -quinoline-2,8-dicarboxylate disodium

Reacted with 1.82 g of sodium bicarbonate 4.098 g of the diacid obtained above suspended in 100 ml of water. The resulting solution is filtered and acetone is added to the filtrate until the precipitation of the product has ended. The desired disodium salt is then separated by filtration and dried to isolate 3.39 g of a pale yellow powder.

Analysis for C19H15NNa207 (6.9% of H20):

Calculated: C 51.1 H 4.1 N3, l%

Found: C51.1 H 4.3 N 3.0%

Example 3:

The following compounds can also be obtained by applying the procedures described above:

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

ii) 4,10-dioxo-4H, 10H-pyranno [2,3-f] -quinoline-2,8-di-carboxylic acid;

iii) 10-bromo-4,6-dioxo-4H, 6H-pyranno- [3,2-g] -quino-lein-2,8-dicarboxylic acid;

iv) 5-hydroxy-4,6-dioxo-10-propyl-4H, 6H-pyranno- [3,2-

g] quinoline-2,8-dicarboxylic;

v) 4,9-dioxo-4H, 9H-pyranno- [2,3-g] -quinoline-2,8-dicar-boxylic acid;

vi) 4,10-dioxo-4H, 10H-pyranno- [2,3-f] -quinoline-2,8-di- [N- (tetrazol-5-yl)] carboxamide;

vii) 10-bromo-4,6-dioxo-2,8-di (tetrazol-5-yl) -4H, 6H-pyranno- [3,2-g] -quinoline.

Example 4:

The following compounds can be prepared by the methods described above:

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

ii) 9- (3-methylbutyl) -4,6-dioxo-4H, 6H-pyranno- [3,2-g] -quinoline-2,8-dicarboxylic acid m.p. 302-304 ° C (dec.)

iii) Disodium 7-Ethyl-4,10-dioxo-4H, 10H-pyranno- [2,3-f] -quinoelin-2,8-dicarboxylate

Analysis for C, cHQNNa207.14.4%, H2O:

Calculated: C44, W H 3.7 N 3.2%

Found: C44, W H 3.5 N 3.3%

Example 5:

The following compounds can be prepared by the methods described above:

a) 5-Methoxy-4,7-dioxo-4H, 7H-pyranno- [3,2-h] -quino-lein-2,9-dicarboxylic acid, m.p. 294-6 ° C (dec.)

b) 4,6-dioxo-10- (prop-2-enyl) -4H, 6H-pyranno- [3,2-g] -qui-noline-2,8-dicarboxylic acid, structure confirmed by NMR

c) 4,10-dioxo-4H, 10H-pyranno- [2,3-h] -quinoline-2,8-di-carboxylic acid, m.p. 200 ° C

d) 10-hydroxy-1-oxo-1 H-py ranno- [3,2-f] -quinoline-3,8-dicar-boxylate disodium

Analysis for C14H15NNa207.6.11 H20:

Calculated: C 45.74 H 2.10 N 3.8%

Found: C 45.74 H 2.45 N3.6%

e) 4,10-dioxo-4H, 10H-pyranno- [2,3-f] -quinoline-2,8-dicarboxy-late disodium

Analysis for: C14H5NNa207.2H20:

Calculated: C 44.10 H 2.38 N 3.67%

Found: C 44.36 H 2.18 N3.54%

f) 10-methyl-4,6-dioxo-4H, 6H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid, m.p. 302 ° C

g) 4,6-dioxo-10-propyl-4H, 6H-pyranno- [3,2-g] -quino-lein-2,8-dicarboxylic acid, m.p. diethyl ester: 211-212 ° C.

h) 6-amino-7,10-dihydro-5-methoxy-4,7-dioxo-4H-py-ranno- [3,2-h] -quinoline-2,9-dicarboxylic acid NMR 5 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-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid 5 NMR DMSO: 6.95 (1H, s) ; 7.0 (1H, s); 8.6 (1H, s).

j) N, N'-Di (tetrazol-5-yl) -9- (but-3-enyl) -6,9-dihydro-4-oxo-10-propyl-4H-pyranno- [3,2-g ] -quinoline-2,8-dicarboxamide NMR S DMSO: 1.0 (3H, t); 1.8 (2H, m); 2.2 (2H, m); 3.8 (4H, m); 4.65 (2H, m); 5.3 (1H, m); 7.0 (1H, s); 8.6 (1H, s); 8.7 (1H, s); 10.3 (br).

k) 9-Ethyl-10-propyI-2,8-di-tetrazol-5-yl-4H-pyranno- [3,2-g] -quinoline-4,6 (9H) -dione NMR 5 DMSO: 1, 0 (3H, t); 1.1 (3H, t); 1.8 (2H, m); 3.8 (2H, m); 4.5 (2H, m); 7.1 (1H, s); 8.65 (1H, s); 8.8 (1H, s): 10.1 (2H, brs).

Example 6:

9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid a) 6-acetyl-1-ethyl- acid 1,4-dihydro-7-hydroxy-4-oxo-9-propyl-quinoline-2-carboxylic.

20 g of methyl 6-acetyl-1-ethyl-1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylate were heated to reflux in 150 ml of glacial acetic acid containing 20 ml 48% aqueous HBr. After 18 h, the mixture was cooled, and poured into water. The pH was brought to 3 by addition of ammonia. The precipitate was collected and dried in vacuo and identified by NMR and mass spectroscopy as the subtitle compound (14.3 g).

b) 2-Ethoxycarbonyl-9-ethyl-6,9-dihydro-4,6-dioxo-10-propyi-4H-pyranno [3,2-g] -quinoline-8-carboxylic acid.

The product from step a (14.2 g) was added to a solution of 5.2 g of sodium in 200 ml of ethanol, then 16 g of diethyl oxalate was added. The mixture was heated at reflux for 5 h, then cooled and poured into 11 of chloroform. The mixture was shaken with 150 ml of dilute hydrochloric acid, then the organic phase was dried and evaporated in vacuo. The residue was dissolved in 200 ml of ethanol containing 2 ml of concentrated hydrochloric acid and heated at reflux for 18 h. The solvent was evaporated and the residue was recrystallized from ethanol to obtain the subtitle compound (3.2 g). The structure was confirmed by NMR and by mass spectroscopy.

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c) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

The product from step b was hydrolyzed by the process from step a and 1.1 g of a product which was found to be identical to that of Example 2 was obtained by layer chromatographic comparison.

Example 7:

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

a) Methyl 9-Ethyl-6,9-dihydro-2-methyl-4,6-dioxo-10-propyl-4H-py-ranno- [3,2-g] -quinoline-8-carboxylate.

6-acetyl-1-thyl-7-hydroxy-4 (1H) -oxo-8-propylquinoline-2-carboxylic acid (3.15 g) was dissolved in 50 ml of dry dimethylformamide containing 1.05 g washed sodium hydride, then 4.4 g of ethyl acetate were introduced. After stirring overnight, hydrochloric gas was passed through the mixture to saturation by refrigerating with ice. The mixture was heated at 75 ° C for 8 h, then cooled, poured into water and the mixture was extracted with ethyl acetate. The organic phase was dried, evaporated and the residue was chromatographed (SiO2 / ethyl acetate), which provided 0.8 g of the subtitle compound. The structure was confirmed by NMR and mass spectroscopy.

b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

The product from step a (0.75 g) was heated at reflux with 1.5 g of selenium dioxide in 50 ml of glacial acetic acid for 48 h. By filtering through celite, a clear filtrate was obtained which was treated with 25 ml of concentrated hydrochloric acid and heated at reflux for 12 h. After cooling, the mixture was poured into water and 0.1 g of a precipitate was obtained which was found to be identical to the product of Example 2 by thin layer chromatographic comparison.

Example 8:

9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [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.

17.9 g of 3-ethylamino-2-propylphenol, 35 g of dimethyl acetylenedicarboxylate, 0.56 g of potassium hydroxide, 50 ml of water and 100 ml of ethanol were heated at reflux for 24 h. . 1.65 g of potassium hydroxide was added and heating under reflux continued for another 24 h.

4 ml of concentrated hydrochloric acid were added and the solvent was evaporated. The residue was dried in vacuo and extracted with ether. The ether was evaporated and 3.6 g of the subtitle compound were obtained. The structure was confirmed by NMR and mass spectroscopy.

b) 9-Ethyl-6,9-dihydro-4,6-dioxo-1 0-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

3.55 g of the product from step a was added in small portions to 100 ml of chlorosulfonic acid cooled to -78 ° C, with stirring. The solution was allowed to warm slowly to room temperature, then heated to 50 ° C for 1 h. The reaction mixture was poured carefully onto 11 ice and extracted with ethyl acetate. After drying, the ethyl acetate was evaporated and the residue was separated by high pressure liquid chromatography to give 0.2 g of the title compound, chromatographically identical to the product of Example 2.

was heated together in an autoclave for 12 h at 100 ° C, then the volatiles were evaporated at 60 ° C. The residue was triturated in ether and obtained 0.78 g of the subtitle compound. The structure was confirmed by NMR and mass spectroscopy.

B) 9-ethyl-6,9-dihydro-4,6-dioxo-l 0-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

The product from step a (0.77 g) was suspended in 20 ml of ethanolic hydrochloric gas and heated under reflux for 24 h. After evaporation of the solvent, a residue was obtained which was separated by high pressure liquid chromatography, thus obtaining 0.2 g of the title compound, chromatographically identical to the product of Example 2.

Example 10:

9-Ethyl-6,9-dihydro-4,6-dioxo-1,0-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

a) Diethyl 9-Ethyl-6,9-dihydro-10-propyl-4,6-dithioxo-4H-pyranno- [3,2-g] -quinoline-2,8-dicarboxylate.

Diethyl 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno- [3,2-g] -20 quinoline-2,8-dicarboxylate (10 g) and decasulfide of pentaphosphorus (20 g) were melted together at 160 ° C for 6 h, then cooled, and the mixture was extracted with ethyl acetate. Chromatography (silica gel / ethyl acetate) gave 5.6 g of the subtitle compound. The structure was verified by NMR and mass spectroscopy.

b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

The diester from step a was heated to 100 ° C in 50 ml of glacial acetic acid containing 5 ml of concentrated hydrochloric acid for 24 h. The acetic acid, used as a solvent, was evaporated and the residue was triturated with ether. The solid residue was dissolved in 50 ml of acetonitrile containing 1 ml of water and stirred vigorously with 2 g of mercuric chloride. After 48 h, the solution was filtered, then the filtrate was diluted with 250 ml of water and acidified. The solid precipitate was purified by high pressure liquid chromatography to provide 2.1 g of the title compound, chromatographically identical to the product of Example 2.

Example 11:

40 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

a) 9-Ethyl-2,3,6,9-tetrahydro-4,6-dioxo-10-propyl-4H-py-ranno- [3,2-g] -quinoline-2,8-dicarboxylic acid.

Diethyl 6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno- [3,2-g] -quino-45 lein-2,8-dicarboxylate (5 g) in acid glacial acetic acid (100 ml) was hydrogenated on 0.5 g of Adams catalyst under 4 atm until the absorption of hydrogen was stopped.

The catalyst was removed and 5 ml of concentrated hydrochloric acid was added. The solution was heated to reflux for 24 h and evaporated. By residue high pressure liquid chromatography, 0.9 g of the subtitle compound was obtained. The structure was confirmed by NMR and mass spectroscopy.

b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

The product from step a (0.85 g) was suspended in 10 ml of cymene and treated with a 10% Pd / C catalyst at reflux for 6 h. After filtration and evaporation, a gum was obtained which was purified by high pressure liquid chromatography, thus obtaining 0.15 g of the title compound, chromatographically identical to the product of Example 2.

Example 9:

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

a) 1-Ethyl-6- (3-carboxy-3-diethylamino-1-oxoprop-2- 65 enyl) -1,4-dihydro-7-hydroxy-4-oxo-8-propylquinoline-2-carboxylic acid.

9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno- [3,2-g] -quinoline-2,8-dicarboxylic acid and diethylamine (5 ml ) have

Example 12:

9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [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-pyranno- [3,2-g] -quinoline-2,8-dicarboxylate (4.27 g) and hydroxide

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sodium (1.6 g) were heated to reflux in 10 ml of water for 24 h, then the water was evaporated and the residue was suspended in 50 ml of ethanol saturated with hydrochloric gas and heated to reflux for 1 h. Evaporation of the solvent left a residue which was chromatographed (silica gel / ether), which gave 1.3 g of a diester, which was boiled in a solution of 0.139 g of sodium hydroxide in 20 ml of water. Upon acidification, a precipitate formed which was found to be the desired product (0.93 g) by NMR and mass spectroscopy.

b) 9-Ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid.

The product from step a (0.9 g) dissolved in 10 ml of dry dimethyl sulfoxide was added to a solution of 1 g of the sodium salt of dimethyl sulfoxide in 50 ml of dry dimethyl sulfoxide at 40 ° C under nitrogen. After 48 h, the reaction mixture was poured into 500 ml of water and extracted with ether. After drying and evaporation, a red oil was obtained, which was suspended in 20 ml of toluene and treated with 1.1 g of piperidine and 1.5 g of hydrated glyoxylic acid. After heating at reflux for 5 h, the mixture was cooled, poured into 100 ml of ethyl acetate and washed with saturated sodium bicarbonate solution. The sodium bicarbonate solution was acidified and extracted with ethyl acetate. After drying and evaporation, a gum was obtained which was separated by high pressure liquid chromatography, which provided 0.13 g of the title compound, chromatographically identical to the product of Example 2.

Claims (25)

634071 2 CLAIMS 1. Therapeutically active compounds, of formula: R5 0 where two of the adjacent symbols R5, R6, R7 and R8 form a chain —COCH = CE — O - and each of the others of these symbols, identical or different, represents a hydrogen or halogen atom or a hydroxyl or alkyl radical , alkenyl or alkoxy or else a radical —NR'R2 where each of the symbols R1 and R2, identical or different, represents a hydrogen atom or an alkyl radical, Re represents a hydrogen atom or an alkyl, alkenyl or phenylalkyl radical, and E represents a free or esterified carboxyl radical, 5-tetrazolyl or (N-tetrazol-5-yl) carboxamido, and its pharmaceutically acceptable derivatives. 2. Compound according to claim 1, in the formula in which each of the radicals represented by Rs, R6, R7 and R8, when they include carbon atoms, has up to 8. 3. Compound according to claim 2, in the formula of which each of the radicals represented by R5, R5, R7 and R8, when they include carbon atoms, has up to 4. 4. Compound according to one of claims 1 to 3, in the formula of which the chain - COCH = CE — O - is fixed at the positions occupied by the symbols R6 and R7, the terminal oxygen atom of the chain being united at the position occupied by R7. 5. Compound according to one of claims 1 to 4, in the formula of which R5, R6, R7 and R8 represent substituents chosen from hydrogen, chlorine and bromine atoms and methoxy, propyl, allyl, methyl radicals , ethyl and hydroxyl. 6. Compound according to one of claims 1 to 5, in the formula of which E represents a carboxyl radical. 7. 4,6-Dioxo-10-propyl-4H, 6H-pyranno- [3,2-g] -quino-lein-2,8-dicarboxylic acid as a compound according to claim 1. 8. 4,6-Dioxo-1-ethyl-10-propyl-4H, 6H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic acid as a compound according to claim 1. 9. 5-Ethyl-4,8-dioxo-10-propyl-4H, 8H-pyranno [2,3-h] -quinoline-2,6-dicarboxylic acid as a compound according to claim 1. 10. 4,10-Dioxo-4H, 10H-pyranno- [2,3-f] -quinoline-2,8-dicarboxylic acid as a compound according to claim 1. 11. 10-Bromo-4,6-dioxo-4H, 6H-pyranno- [3,2-g] -quino-lein-2,8-dicarboxylic acid as a compound according to claim 1. 12. 5-Hydroxy-4,6-dioxo-10-propyl-4H, 6H-pyranno [3,2-g] -quinoline-2,8-dicarboxylic as a compound according to claim 1. 13. 4,9-Dioxo-4H, 9H-pyranno- [2,3-g] -quinoline-2,7-di-carboxylic acid as a compound according to claim 1. 14. 4,10-dioxo-4H, 10H-pyranno- [2,3-f] -quinoline-2,8-di- [N- (tetrazol-5-yl)] carboxamide as a compound according to claim 1. 15. 10-Bromo-4,6-dioxo-2,8-di (tetrazol-5-yl) -4H, 6H-py-ranno- [3,2-g] -quinoline as a compound according to claim 1. 16. The ethyl ester of a compound according to one of claims 1 to 15. 17. The sodium salt of a compound according to one of claims 1 to 15. 18. Compound according to one of claims 1 to 17, characterized in that it is in a form having a mass median diameter of 0.01 to 10 p .. 19. Pharmaceutical composition, characterized in that it comprises a compound according to one of claims 1 to 18 in combination with a pharmaceutically acceptable vehicle, diluent or adjuvant. 20. Composition according to claim 19, characterized in that it comprises less than 80% by weight of active agent. 21. Composition according to claim 19, characterized in that it is in the form of unit doses containing 0.01 to 50 mg of a compound according to one of claims 1 to 18 as active agent. 22. Composition according to Claim 21, characterized in that the unit doses comprise 0.01 to 20 mg of active agent, in particular 0.01 to 10 mg of active agent. 23. Process for the preparation of the compounds according to claim 1, in the formula of which E represents a carboxyl radical, characterized by the selective hydrolysis of a compound of formula: B5a O where Rs has the meaning indicated above, R5a, R6a, R7a and R8a have the meanings indicated in connection with Rs, R6, R7 and R8 above, or else two of the adjacent symbols R5a, R6a, R7a and R8a represent a chain of formula - COCH = C (D1) 0—, and D and / or D1 represent hydrolysable radicals into carboxyl radicals, the other possible of these symbols representing a carboxyl radical. 24. The method of claim 23, characterized in that, in the formula, D represents an ester, amide or nitrile radical and the hydrolysis is carried out under moderately basic conditions or under acidic conditions. 25. Process for preparing the compounds according to claim 1, characterized by the oxidative hydrolysis of a compound of formula: , 10 , 6d , 8d where Rs and E have the meanings indicated above, R5d, R6d, R7d and R8d have the meanings indicated in connection with R5, R6, R7 and R8 above, or two of the symbols R5d, R6d, R7d and R8d adjacent represent the chain - C (R9R1 °) = CE — O—, 5 10 15 20 25 30 35 40 45 50 55 60 65 3 634,071 at least one of the pairs of radicals RQ and R10 represents a radical = S or else a chain - S (CH2) nS - where n represents 2 or 3, while the other pair of radicals R9, R10 can represent a radical = 0.