CS207634B2 - Method of preparation of the 3-oxalamino-4-oxo-4h-1-benzopyran derivatives - Google Patents

Description

(54) A method for preparing 3-oxaloamino-4-uxo-4H-1-benzopyian derivatives

The present invention relates to a process for the preparation of novel 3-oxaloamino-4-oxo-4H-1-benzopyran derivatives of the general formula I

H »

Ph if (I) where means

Ph is a 1,2-phenylene group optionally substituted with a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 3 -C 5 alkylene group, a hydroxyl group and / or a halogen atom,

R is a carboxy or liydroxymethyl group; and

R 1 is hydrogen or C 1 -C 4 alkyl, in free form or in salt form.

The optionally substituted 1,2-phenylene group may be substituted by one or more substituents, for example C1 -C4 alkyl, C1 -C4 alkoxy, halogen, or two adjacent carbon atoms as substituents. C 3 -C 5 alkylene.

Examples of the alkyl group having 1 to 4 carbon atoms in the meaning of R1 are methyl, ethyl, isopropyl and butyl.

The term "lower", in each case, means organic compounds or radicals having up to 7 carbon atoms and in particular up to 4 carbon atoms, these compounds or radicals having either straight or branched chains.

C1-C4alkyl means, for example, methyl, ethyl, propyl or n-butyl or isopropyl, sec-butyl, isobutyl or tert-butyl.

C1-C4alkoxy means, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

C3-C5alkylene means, for example, 1,3-propylene, 1,4-butylene or 1,5-pentylene.

By halogen is meant a halogen atom having an atomic number of up to 35, such as a fluorine, chlorine or bromine atom.

207834

Salts of the compounds of formula I in which R is carboxy are bases with bases, in particular the corresponding pharmaceutically usable salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, furthermore ammonium salts with ammonia; with amines such as lower alkylamines or hydroxyalkylamines having 1 to 7 carbon atoms in the alkyl moiety, for example trimethylamine, triethylamine or di- (2-hydroxyethyl amine).

The novel compounds of the formula I have valuable pharmacological properties, in particular they exhibit antiallergic activity, as can be demonstrated, for example, in rats at doses of about 3 to about 100 mg / kg by oral administration or at doses of about 0.3 to about 10 mg / kg by intravenous administration. in a passive cutaneous anaphylaxis test (PCA-reaction). This assay is performed analogously to Goose and Blair, Immunology, Vol. 16, p. 749 (1969), with passive cutaneous anaphylaxis being produced as described by von Ovary, Progr. Allergy, Vol. 5, p. 459 (1958) or by inhibiting histamine release, for example, from rat peritoneal cells in vitro [see Dukor et al. Intern. Sheet. Allergy (1976), in press].

The novel compounds of formula (I) are more effective than known antiallergic agents of a similar structure to those known in the art than, for example, in U.S. Pat. No. 3,937,719, the 2-oxaloamino-4-oxo-4H-1-benzopyran derivatives substituted on the 1,2-phenylene moiety by alkoxy or hydroxyalkoxy having up to 6 carbon atoms each.

Thus, the compounds of formula (I) prepared by the process of the invention are preferably used to inhibit allergic diseases such as asthma, both extrinsic and intrinsic asthma, or other allergic diseases such as hay fever, conjunctivitis, urticaria and eczema.

In particular, the invention relates to a process for the preparation of compounds of the formula I wherein R is a carboxy group, a Ph 1,2-phenylene group optionally substituted by a C 1 -C 4 alkyl group such as a methyl group, a C 3 -C 5 alkylene group, such as 1,3-propylene, hydroxy, C 1 -C 4 alkoxy such as methoxy and / or halogen such as chlorine and R 1 is hydrogen or C 1 -C 4 alkyl such as methyl in the free form or in the form of salts.

In particular, the invention relates to a process for the preparation of compounds of the formula I in which R represents a carboxy or hydroxymethyl group, a Ph 1,2-phenylene group or a monosubstituted C 1 -C 4 alkyl group such as a methyl group, a C 1 -C 4 alkoxy group, such as a methoxy or halogen atom having an atomic number of up to 35, such as a chlorine atom, or an optionally disubstituted C 1 -C 4 alkyl group such as a methyl group, a C 1 -C 4 alkoxy group such as a methoxy group, and / or a halogen atom having an atomic number of up to 35, such as a chlorine atom or two adjacent carbon atoms, an alkylene group having 3 to 4 carbon atoms such as a 1,3-propylene group and R 1 a hydrogen atom, in free or salt form.

More particularly, the invention relates to a process for preparing compounds of formula Ia

where it means

R 6 carboxy and

R3 and R7 independently of one another are hydrogen, C1-C4alkyl, such as methyl, C1-C4alkoxy, such as methoxy, hydroxy or halogen, up to 35, such as chlorine, or together taken together represent a C 3 -C 4 alkylene group, such as a 1,3-propylene group, in free form or in salt form.

In particular, the invention relates to a process for the preparation of the compounds of the formula Ia, in which:

R 6 carboxy and

R 3 and R 6 are either hydrogen or, independently of one another, a C 1 -C 4 alkyl group such as a methyl group or together a C 3 or C 4 alkylene group such as a 1,3-propylene group, the above compounds being prepared in in free form or in the form of its salts.

The invention also relates in particular to the processes for the preparation of the compounds of the formula I in free form or in the form of salts described in the following examples.

According to the process of the invention, the compounds of formula (I) are prepared by preparing a compound of formula (II)

where it means

X is hydrolytically convertible to the desired group of formula

R — C—

II o

and

R1 and Ph are as defined above, the group X hydrolyzes to the group of the formula

R — C—

And optionally converting the compound of formula (I) thus obtained into another compound of formula (I) and / or converting the obtained salt into a free compound or other salt, or converting the salt-forming compound into a salt.

A group convertible to an oxalo group of the formula

R — C — II o

is a functionally modified esterified or amidated oxal group. Such functionally modified oxal groups are preferably groups having as a functionally altered α-carbonyl group, a thioxomethylene, iminomethylene or esterified and / or etherified dihydroxymethylene group and / or as a functionally modified carboxyl group from an esterified or amidated carboxy group .

The esterified or amidated carboxy group is, for example, an aliphatic alcohol, an esterified carboxy group, optionally with at least one optionally substituted aryloivine residue, or an optionally heteroanalohydric hydrocarbon residue of an aliphatic nature, a hydroxy group or a primary amino substituted carbamoyl group or particularly a free carboxy group.

An aliphatic alcohol is an alcohol in which the hydroxy-bonded carbon atom is not a member of the aromatic system, for example an optionally substituted phenyl-substituted lower alkanol, or a cycloaliphatic alcohol, for example a 5- to 8-membered cycloalkanol. Examples of optionally substituted aliphatic alcohols of the esterified carboxy group are lower alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl, propoxy.

carbonyl, isopropoxycarbonyl and butoxycarbonyl, optionally substituted phenyl (lower alkoxy) in phenyl, especially α-phenyl (lower alkoxy) carbonyl and β-phenyl (lower alkoxy) carbonyl, for example optionally substituted benzyloxycarbonyl, α-phenethoxycarbonyl, as well as also a 2-phenethoxycarbonyl group and a 5- to 8-membered cycloalkoxycarbonyl group, for example cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl.

In the case of a substituted, optionally heteroanalogical hydrocarbon radical of aliphatic character, as a carbamoyl substituent, the free bond is based on a non-aromatic carbon atom. Such a radical is, for example, a lower alkyl or lower alkenyl group substituted with an optionally substituted phenyl group, or a 5- to 6-membered cycloalkyl group such as a cyclohexyl group, or an optionally low alkylated optionally monooxa analog, monoazaanalog or monothiaanalog 3-oxapentamethylene, 3-azapentamethylene or 3-thiapentamethylene. Examples of at least one such substituted carbamoyl radical are mono (lower alkyl) carbamoyl and di (lower alkyl) carbamoyl such as, for example, N-methylcarbamyol, N-ethylcarbamoyl or N, N-diethylcarbamoyl, optionally substituted phenyl ( lower alkyl is carbamoyl such as N-benzylcarbamoyl, N- (1-phenylethylcarbamoyl and N- (2-phenylethyl) carbamoyl or pyrrolidinecarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl or 4-lower alkylcarbonyl or 4-lower alkylcarbonyl methylpiperazinocarbonyl.

Esterified and / or etherified dihydroxymethyl groups are, for example, dihydroxymethyienic groups esterified with, for example, hydrohalic acids, such as hydrochloric acid and / or etherified with a lower alkanol such as methanol, or ethanolein. Examples which may be mentioned are, in particular, dihalomethylene groups, such as dichloromethylene, lower alkoxy halomethylene, such as methoxychloromethylene or ethoxychloromethylene or di (lower alkoxy) methylene groups such as dimethoxymethylene or diethioxymethylene.

For example, cyano, anhydride carboxy such as halocarbonyl, for example chlorocarbonyl, iminoester, such as imide halide or amide halide, for example iminochloromethyl or aminodichloromethyl, lower alkyl, imino or lower alkyl, imino-chloroethyl, lower alkyl, imino, an alkyleniminoethyl group, for example a methoxyiminomethyl or ethoxyiminomethyl group, 4,4-dimethyloxazolinyl- (2) or 5,5-dimethyloxazolinyl- (2) or

4,4,6-trimethyldihydroxazinyl- (2) -, amidino, such as amidino or lower alkylamidino, such as ethylamidino; furthermore, orthoacidic groups esterified with hydrohalic acids such as hydrochloric acid and / or etherified with a lower alkanol such as a tri (lower alkoxy) group, a lower alkoxydihalogen group or a trihalomethyl group, in particular trimethoxymethyl, triethoxymethyl, ethoxydichloromethyl or trichloromethyl or optionally esterified lower alkylthiocarbonyl, for example ethylthiocarbonyl.

For example, to hydroxymethyl R the hydrolyzable groups are optionally a carboxylic acid such as a lower alkanoic acid or a mineral acid such as a hydrohalic acid of an esterified glycoloyl group such as an acetoxyacetyl, chloroacetyl, bromoacetyl or iodoacetyl group.

The hydrolysis may be carried out in a manner known per se, optionally in the presence of a basic or preferably acidic hydrolyzing agent, such as an alkali metal hydroxide, e.g. sodium hydroxide or potassium hydroxide, or preferably in the presence of a protonic acid, in particular a mineral acid such as for example a hydrohalic acid such as hydrochloric acid or in the presence of an organic carboxylic or sulfonic acid such as acetic acid, p-toluenesulfonic acid, optionally in a polar solvent such as a lower alkanol, a ketone or an ether such as ethanol, acetone or dioxane; or with cooling or heating, for example at a temperature of about 0 to about 100 ° C.

The starting compounds of the formula II mentioned can be prepared by methods known per se, preferably by reacting the compound of formula III or an acid addition salt thereof with an acid of formula IV

X - OH (IV) wherein

Ph, R 1 and X are as defined above, or with a functional derivative thereof.

Functional derivatives of acids of the formula IV are, for example, acid derivatives containing, for example, an esterified or amidated carboxyl group or an anhydride carboxyl group such as a lower alkoxycarbonyl group, an optionally substituted carbamoyl group such as carbamoyl group, di (lower alkyl) carbamoyl group or imidazolyl-1 a carbonyl group or a halocarbonyl group, for example a chlorocarbonyl or bromocarbonyl group. Examples of acids of formula IV and their functional derivatives are in particular: oxalyl halides such as oxalyl chloride or oxalyl bromide, tri lower alkoxyacetic acid in the form of diethyl ester and dihalogen (lower alkoxy) acetic acid in the form of lower alkyl ester such as tetraethyl ester of oxalic acid or diethyl ester dichloroxalic acids, iminodialkyl oxalic acid ester such as monoiminoethyl oxalic acid ester and diiminodiethyl oxalic acid ester, dithio (lower alkyl) oxalic acid ester such as dithiodimethyl oxalic acid ester, cyanoformyl chloride and dicyano.

The reaction of compounds of formula III with acids of formula IV or derivatives thereof is carried out in a manner known per se, for example in the presence of a water-binding agent such as an acid anhydride such as phosphorus pentoxide or dicyclohexylcarbodiimide or in the presence of an acidic or basic condenser such as a mineral acid such as hydrochloric acid or an alkali metal hydroxide or carbonate such as sodium hydroxide and potassium hydroxide or an organic nitrogen base such as triethylamine or pyridine.

In the reaction with an acid anhydride, for example an acid chloride, an organic nitrogen base is preferably used as a condensing agent. The reaction with the carboxylic acids is preferably carried out in the presence of a water-binding agent. Optionally, an inert solvent is always used at room temperature or with cooling or heating, for example at a temperature of about 0 ° C to about 100 ° C, in a closed vessel and / or in an inert gas atmosphere such as nitrogen.

As a compound of formula (II) containing a functionally modified carboxyl group, a functionally modified oxal group with an iminoether group,

It can be prepared from the corresponding cyanocarbonyl compound by reaction with the corresponding alcohol, cyclic imino ether by treatment with a lower alkanediol or amino (lower alkanol).

The compound of the formula I prepared by the process according to the invention can be converted into another compound of the formula I in a manner known per se.

On the Ph residue of the compound of formula (I) prepared by the process of the invention, optionally esterified or etherified hydroxyl groups may be interchanged.

Thus, for example, the free hydroxyl group can be etherified to an etherified hydroxyl group, for example, to a lower alkoxy group, a hydroxyf lower alkoxy group, or a lower alkylenedioxy group, by reaction with an etherifying agent such as a lower alkylating agent.

Etherifying agents are, for example, reactive esterified alcohols, such as a mineral acid, for example hydroiodic, hydrobromic or hydrochloric acid or sulfuric acid, or organic sulfonic acids, for example p-toluenesulfonic, p-bromobenzene, benzenesulfonic, methanesulfonic, ethanesulfonic or ethersulfonic ester, or lower alkanols or lower alkanediols as well as diazo (lower alkanes).

Particular etherification agents include, in particular, lower alkyl chlorides, lower alkyl bromides, or lower alkyl iodides, for example methyl iodide, lower alkylene halohydrins such as ethylene chlorohydrin, di (lower alkyl) sulfates such as dimethyl sulfate or diethyl sulfate, methyl fluorosulfonate, lower alkyl sulfonates such as methyl methanesulfonate or ethyl methanesulfonate , p-toluenesulfonate or p-bromobenzenesulfonate, epoxy (lower alkanes) such as propylene oxide and diazoalkanes such as diazomethane.

The reaction with etherifying agents, for example the etherifying agents mentioned above, can be carried out in a manner known per se; in the case of reaction with a diazo (lower alkane), for example in an inert solvent such as an ether, for example tetrahydrofuran, or using a reactive esterified alcohol, for example in the presence of a basic condensing agent such as an inorganic base such as sodium, potassium or calcium hydroxide or carbonate; in the presence of a tertiary or quaternary nitrogen base such as pyridine, triethylamine or tetraethylammonium hydroxide or benzyleriethylammonium hydroxide; and / or in the presence of an appropriate solvent for the reaction, which may also be an excess to etherify, for example, the lower alkyl halide or alkyl sulfate used and / or an excess of a tertiary nitrogen base such as triethylamine or pyridine as base condensation agent; elevated temperatures. Methyl iodide methylation in amyl alcohol / potassium carbonate at boiling point is particularly recommended.

Conversely, an etherified hydroxy group can be converted to a hydroxy group in a known manner, for example in the presence of an acidic agent such as a hydrohalic acid, for example hydroiodic acid, in an inert solvent such as ethanol or acetic acid.

In a similar manner, an esterified hydroxy group such as a halogen may also be converted to an etherified hydroxy group by reaction with a corresponding metal alcoholate, such as a lower alkali metal alkanolate, for example by reaction with sodium methoxide.

The free compounds of the formula I prepared according to the process of the invention wherein R is carboxy can be converted into salts in a manner known per se, for example by treatment with a base or a suitable carboxylic acid salt, usually in the presence of a solvent or diluent.

The salts of the compounds of the formula I prepared according to the invention can be converted into the free compounds in a manner known per se, for example by treatment with an acid reagent, such as treatment with a mineral acid.

The compounds of formula I and their salts may also be in the form of their hydrates or may include solvents used to crystallize them.

For the close relationship between the compounds of formula I in free form and in the form of salts, in the foregoing and hereinafter, the term free compounds or salts thereof according to the meaning and purpose is to be understood as meaning the corresponding salts or corresponding free compounds.

The process according to the invention also relates to embodiments starting from a compound obtained as an intermediate from any stage of the process or in which the process is interrupted at any stage or in which the starting material is formed under the reaction conditions or in which the reactants are also present in the process. in the form of its derivatives, for example salts.

The invention also relates to such embodiments of the process starting from racemates or from antipodes.

Preference is given to starting materials which lead to the aforementioned particularly preferred compounds of the general formula (I).

The invention also relates to pharmaceutical compositions comprising compounds of formula I or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions include topical, enteral, oral and rectal administration, parenteral administration, and inhalation for warm-blooded individuals, said compositions comprising the pharmacologically active substance alone or in admixture with pharmaceutically acceptable carriers. The dosage of the active ingredient depends on the species of the warm-blooded individual, the age and individual condition as well as the route of administration.

The novel pharmaceutical compositions contain, for example, about 10 to about 95%, preferably about 20 to about 90%, of the active ingredient. The pharmaceutical compositions of the invention are, for example, compositions in aerosol and spray form, or in the form of dosage units such as dragees, tablets, capsules or suppositories and ampoules.

The pharmaceutical compositions of the invention are prepared by methods known per se, for example by conventional methods of mixing, granulating, drageing, preparing solutions or lyophilizing. Thus, pharmaceutical compositions for oral administration can be prepared by combining the active ingredient with solid carriers, optionally granulating the resulting mixture and / or granulating the mixture or granulate into tablets or dragee cores, if appropriate.

Suitable carriers are, in particular, fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates such as calcium phosphate or dibasic phosphate, as well as binders such as starch glue such as corn starch, wheat starch, rice or potato and glue thereof, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone and / or optionally disintegrants such as the above-mentioned starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidone, agar, alginic acid and its salts such as sodium alginate .

The auxiliaries are preferably flow control agents and glidants such as silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and / or polyethylene glycol.

Dragee cores are provided with suitable gastric-resistant coatings using, for example, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or in suitable mixtures For example, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methylcellulose phthalate are used to prepare gastric juice-resistant coatings.

The tablets or dragee coatings may contain coloring agents or pigments, for example, to identify or indicate a different dose of the active ingredient.

Other orally administrable formulations are gelatin insertion capsules as well as soft, sealed gelatin and plasticizer capsules, such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers such as lactose, binders such as starches and / or in admixture with lubricants such as talc or magnesium stearate and optionally in admixture with stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, optionally with the addition of stabilizers.

Suppositories which consist of a combination of the active ingredient and a suppository matrix are suitable as rectally usable pharmaceutical compositions. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules containing a combination of the active ingredient with a matrix may also be used; suitable as matrix are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Particularly suitable for parenteral use are aqueous solutions of the active ingredient in water-soluble form, for example in the form of a water-soluble salt, as well as suspensions of the active ingredient corresponding to oil injections for injection, wherein suitable lipophilic solvents or carriers are fatty oils such as sesame, oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides. Alternatively, aqueous suspensions containing viscosity enhancers, for example carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers, may be used for injection.

Inhalants for treating the respiratory tract by nasal or oral administration are, for example, aerosols or sprays which contain the pharmacologically active substance in powder form or in the form of drops of a solution or suspension. The powdered active ingredient compositions generally contain, in addition to the active ingredient, a liquid propellant and a boiling point below room temperature and optionally carriers such as liquid or solid non-ionic or anionic surfactants and / or contain solid diluents. Formulations which contain the active ingredient in solution form contain a suitable propellant, optionally an additional solvent and / or a stabilizer. Compressed air may also be used in place of the propellant, these means being produced with a suitable sealing device and a voltage release device.

For example, topical pharmaceutical compositions are lotions and creams suitable for the treatment of the skin containing liquid or semi-solid oil-in-water and water-in-oil and ointment emulsions, such compositions preferably containing preservatives; eye drops which contain the active substance in an aqueous or oily solution and eye ointments, which are preferably produced in sterile form, are suitable for treating the eyes; nasal powders, aerosols and sprays similar to those described above for the airways as well as coarse powders which are administered by rapid inhalation through the nostrils and nasal drops containing the active substance in an aqueous or oily solution are suitable for the treatment of the nose; suitable for the treatment of the mouth are succulent sweets which contain an active substance in a mass consisting of sugar, acacia or tragaut and to which flavorings may be added, as well as pastilles which contain the active substance in an inert mass, which consists, for example, of: gelatine and glycerin or sugar and acacia.

The invention also relates to the use of the novel compounds of the formula (I) in the form of their salts as pharmacologically active substances, in particular as anti-allergic drugs, preferably in the form of pharmaceutical compositions. The daily dose for a warm-blooded individual weighing about 70 kg is about 200 to about 1200 mg.

The following examples illustrate the process of the invention and do not limit it in any way. Temperatures are given in ° C.

Example 1

To a suspension of 7.6 g of 3-methoxyoxalylamino-4-oxo-4H-1-benzopyran in 200 ml of ethanol is added 35 ml of sodium hydroxide solution and then 1.3 liters of water are added. Heat to 70 ° C with stirring for 15 minutes. Celsius. The pH of the now clear solution was adjusted to 2 with concentrated hydrochloric acid and slowly cooled to room temperature. 3-Oxaloamino-4-oxo-4H-1-benzopyran, m.p. 200 DEG C. (dec.), Crystallized.

The starting material can be prepared in the following manner:

To a solution of 3.7 g of triethylamine and 5 g of 3-amino-4-oxo-4H-1-benzopyran in 100 ml of chloroform was added dropwise under stirring in a water-free atmosphere at 10 ° C.

4.5 g of oxalic acid monomethyl ester chloride. After the addition was complete, it was stirred for 90 minutes at room temperature. The reaction solution was partitioned between chloroform (3 x 50 ml) and 2N hydrochloric acid (50 ml). The organic phase is washed neutral, dried over sodium sulfate and concentrated in vacuo. After addition of ether to a concentrated solution of 3-methoxyoxalylamino-4-oxo-4H-1-benzopyran crystallized, m.p. 200 DEG-201 DEG.

Example 2

To a solution of 2.7 g of 3-ethoxyoxalylamino-6-chloro-4-oxo-4H-1-benzopyran in 200 ml of 50% ethanol, 0.1 N sodium hydroxide solution was added dropwise while heating on a steam bath, until a slightly basic reaction. The color of the reaction mixture first switched to orange and then to white. An additional 0.1 N sodium hydroxide solution was added until a pale orange color persisted. The precipitate was filtered off, washed with N hydrochloric acid and then with water, filtered off with suction, dried and recrystallized from methanol. 6-chloro-3-oxaloainmo-4-oxo-4H-1-benzopyran, m.p. 213 DEG-215 DEG C. is obtained.

The starting material can be prepared as follows:

To a solution of 1.95 g of 3-amino-6-chloro-4-oxo-4H-1-benzopyran in 1.58 g of pyridine and 100 ml of methylene chloride was added dropwise 1.36 g of monoethyl ester of oxalic acid chloride. After the addition was complete, it was stirred for 90 minutes at 90 ° C and evaporated to dryness under reduced pressure. The yellowish solid evaporation residue is dispersed with water, filtered, dried and recrystallized from ethanol. 3-Ethoxyoxalylamino-6-chloro-4-oxo-4H-1-benzopyran is obtained, m.p. 161-162 ° C.

In a similar manner as described above, 3-oxaloamino-4-oxo-4H-1-benzopyran is obtained from 3-ethoxyoxalylamino-4-oxo-4H-1-benzopyran, m.p. 195-197 ° C (from ethanol). and 1 g of 3-ethoxyoxalylamino-2-methyl-4-oxo-4H-1-benzopyran 2-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran, m.p. 208 DEG-209 DEG C. (from ethanol).

The starting material can be prepared as follows:

A solution of 5.0 g of 2-methyl-3-nitro-4-oxo-4H-1-benzopyran in 250 ml of ethanol is mixed with 0.75 g of 10% palladium on carbon and hydrogenated at room temperature and under normal pressure for a period of time. 40 minutes.

The catalyst was then filtered off and the solvent was removed under reduced pressure. The yellow evaporation residue is recrystallized from benzene. There was obtained 3-amino-2-methyl-4-oxo-4H-1-benzopyran, m.p. 118-120 ° C.

Example 3

In a similar manner to that described in Example 2, 5 g of 3-amino-7-methoxy-4-oxo-4H-1-benzopyran is obtained, despite 3-ethoxyoxalylamino-7-methoxy-4-oxo-4H-1-benzopyran mp 218-220 ° C 7-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran mp 236-238 ° C.

The starting material can be prepared as follows:

1.85 g of 4-hydroxy-7-methoxy-3-nitrocoumarin are stirred in 60 ml of 5% aqueous sodium hydroxide solution for 20 hours at room temperature. The reaction mixture was filtered, sucked dry and recrystallized from ethanol. 2-Hydroxy-4-methoxy- (3'-nitroacetophenone), m.p. 138-140 ° C, is obtained.

2.11 g of 2-hydroxy-4-methoxy-p-nitroacetophenone are added to a stirred mixture of 0.68 g of sodium formate and 25 ml of mixed acetic anhydride and formic anhydride. Warm to 80 ° C, allow to cool to room temperature, stir for 1 hour at room temperature, add 100 mL of ice water, filter off with suction, wash with water, filter to dryness and recrystallize from ethyl acetate. 185 DEG-187 DEG C., 7-methoxy-3-nitro-4-oxo-4H-1-benzopyran.

To a suspension of 7 g of 7-methoxy-3-nitro-4-oxo-4H-1-benzopyran in 80 ml of ethanol and 30 ml of water stirred under a nitrogen atmosphere is added 20 g of sodium dithionite. Stir 20 minutes, evaporate under reduced pressure, dissolve the solid residue in water and extract with chloroform. The chloroform extract was dried over sodium sulfate and evaporated. 3-Amino-7-methoxy-4-oxo-4H-1-benzopyran is obtained, m.p. 143-146 ° C.

Example 4

In a similar manner to that described in Example 1, it was obtained from 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyran via 5,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran mp 186 DEG-187 DEG C. 5,7-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran, m.p. 224 DEG C. (from water / ethanol, with decomposition).

For example, the starting material is prepared from 5,7-dimethyl-4-hydroxycoumarin by treatment with nitric acid in acetic acid at 80 ° C to give 5,7-dimethyl-4-hydroxy-3-nitrocoumarin which is treated for 24 hours sodium hydroxide solution and subsequent acidification under decarboxylation to 4,6-dimethyl-2-hydroxy- (S-nitroacetophenone) analogously to J. Am. Chem. Soc., 67, 99 (1945) or by reaction with 5,7-dimethyl- 4-hydroxy-3-nitrocoumarin with mixed formic and acetic anhydride to give 5,7-dimethyl-3-nitro-4-oxo-4H-1-benzopyran, m.p. -amino-5,7-dimethyl-4-oxo-4H-1-benzopyran (m.p. 120-121 ° C) similar to that described in Tetrahedron Letters 1976, 719. The product is then purified over the hydrochloride.

Example 5

In a similar manner to that described in Example 4, 2-hydroxy-5-methoxy- [1-nitroacetophenone] is obtained from 4-hydroxy-6-methoxycoumarin via hydroxy-6-methoxy-3-nitrocoumarin, m.p. 172-174 ° C. 143-144 ° C (from methylene chloride / petroleum ether), 6-methoxy-3-nitro-4-oxo-4H-1-benzopyran, mp 149-150 ° C, and from 3-amino-6-methoxy-4; -oxo-4H-11

174 DEG-175 DEG C. 6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran, m.p. 230 DEG C. 6-methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran; . Celsius.

Example 6

In a similar manner to that described in Example 4, from 6,7-dimethyl-4-hydroxycoumarin via 6,7-dimethyl-4-hydroxy-3-nitrocoumarin, m.p. 205 DEG-207 DEG C. (dec.), 4.5. -dimethyl-2-hydroxy-; 3-nitroacetophenone, m.p. 142-144 ° C (from methylene chloride / petroleum ether), 6,7-dimethyl-3-nitro-4-oxo-4H-1-benzopyran, m.p. 155 DEG-157 DEG C. and over 3-amino-6,7-dimethyl-4-oxo-4H-1-benzopyran, m.p. 150 DEG-152 DEG C. (from chloroform / toluene) and 6,7-dimethyl-3; 6-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran, m.p. 222 DEG-224 DEG C .;

Example 7

In a similar manner to that described in Example 4, 2-hydroxy-5-methyl-4-methyl-4-methylcoumarin was obtained via 4-hydroxy-6-methyl-3-nitrocoumarin, m.p. 178 DEG C. (dec.). -nitroacetophenone, m.p. 137-138 ° C (from ethanol), 6-methyl-3-nitro-4-oxo-4H-1-benzopyran, mp 97-99 ° C, 3-amino-6-methyl-4 -oxo-4H-1-benzopyran, m.p. 96-98 ° C (from ethyl acetate / petroleum ether); and 3-methoxyoxalylamino-6-methyl-4-oxo-4H-1-benzopyran, mp 179.5 ° C 6 methyl 3-oxaloamino-4-oxo-4H-1-benzopyran, m.p. 199.5 ° C.

Example 8

In a similar manner to that described in Example 4, 4-hydroxy-4,6,7,8-tetrahydro-2-oxocyclopenta [g] -1-benzopyran was obtained via 4-hydroxy-3-nitro-4,6,7, 8-tetrahydrocoumarin, m.p. 215 DEG-217 DEG C. (decomposition of 5- (2-nitroacetyl) -6-liydroxyindane, m.p. 115 DEG-117 DEG C. (from methylene chloride / petroleum ether), 3-nitro-4-oxo) -4,6,7,8-tetrahydrocyclopenta [g] -1-benzopyran, m.p. 145 ° C (dec.), 3-amino-4-oxo-4,6,7,8-tetrahydrocyclopenta [g] -1 -benzopyran, m.p. 151-152 ° C (from ethyl acetate / petroleum ether) and 3-methoxyoxalylamino-4-oxo-4,6,7,8-tetrahydrocyclopenta [g] -1-benzopyran, mp 185-186 ° C 185 DEG C. (dec.) 3-oxaloamino-4-oxo-4,6,7,8-tetrahydrocyclopenta [g] -1-benzopyran.

Example 9

To a mixture heated to 60 ° C with 50 ml of ethanol and 0.5 ml of 2 N sodium hydroxide solution was added 0.5 g of 3-chloro-oxalylamino-5,7-dimethyl-17;

20783,4 thyl-4-oxo-4H-1-benzopyran. It is mixed with 300 ml of water, warmed to 60 ° C and acidified to pH 1 with 2 N hydrochloric acid. The precipitate is filtered off, washed with a small amount of ethanol and dried. 5,7-Dimethyl-3-oxaloamino-4-oxo-1-benzopyran, m.p. 222 DEG C. (dec.).

The starting material can be prepared as follows:

A solution of 0.5 g of 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyran in 5 ml of chloroform is slowly added dropwise to 5 ml of oxalyl chloride under a nitrogen atmosphere. Stir for one hour, evaporate to dryness under reduced pressure, dissolve the residue in 30 ml of chloroform, filter and re-evaporate to dryness. 3-Chloro-oxalylamino-5,7-dimethyl-4-oxo-4H-1-benzopyran, m.p.

Example 10

Reaction of 3-oxaloamino-4-oxo-4H-1-benzopyran with an equimolar amount of 2 N sodium hydroxide solution gives the sodium salt thereof and reaction of the acid dissolved in hot dimethylformamide with 0.1 M calcium chloride solution to give calcium salt 3. oxaloamino-4-oxo-4H-1-benzopyran, m.p.

Example 1 a d 11

In a similar manner to that described in Example 1, 3-oxaloamino-4-oxo-2,6,7-trimethyl-4H- was obtained from 3-methoxyoxalylamino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran. l-Benzopyran, m.p. > 200 DEG C. (dec.). The starting material can be prepared in a manner known per se from 6,7-dimethyl-4-hydroxy-3-nitrocoumarin by treatment with sodium hydroxide solution and acid decarboxylation to 2-hydroxy-4,5-dimethyl- (S-nitroacetophenone), by reaction with acetic anhydride in the presence of formic acid, 3-nitro-4-oxo-2,6,7-trimethyl-4H-1-benzopyran is obtained with a melting point of 175-177 ° C and its hydrogenation in the presence of palladium on calcium carbonate in dimethylformamide.

In a similar manner to that described in Example 1, it is obtained by reacting 3-amino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran with oxalic acid methyl ester of 3-methoxyoxalylamino-4-oxo-2,6, 7-trimethyl-4H-1-benzopyran, m.p. 210-211 ° C.

Example 12

In a manner similar to that described in Examples 1 to 11, the following compounds can be prepared:

6-hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,

5,8-dimethyl-3-oxaloamine (4'-oxo-4H-1-benzopyran),

6,7-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran, mp 205 ° C,

6-chloro-7-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran;

6-chloro-7-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran; and

3-hydroxyamethylamino-4-oxo-4H-1-benzopyran, m.p. 199-200 ° C.

Example 13

Tablets containing 0.1 g of 3-oxaloamino-4-oxo-4H-1-benzopyran are prepared as follows:

Ingredients (for 1000 tablets)

3-Oxaloamino-4-oxo-4H-1-

-benzopyran 100 g lactose 50 g wheat starch 73 g colloidal silicic acid 13 g magnesium stearate 2 g talc 12 g water q.s.

3-Oxaloamino-4-oxo-4H-1-benzopyran is mixed with a portion of wheat starch, lactose and colloidal silica and the mixture is rubbed through a sieve. Another portion of wheat starch is boiled with five times water in a water bath and the above powder mixture is kneaded with this gel until a slightly plastic mass is formed. This plastic is rubbed through a sieve with a mesh size of about 3 mm, dried and the dry granulate is rubbed again with a sieve. The rest of the wheat starch, talc and magnesium stearate are then admixed and the mixture is compressed into tablets weighing 0.25 g.

Tablets containing in each case 0.1 g of a substance selected from the group consisting of "

6-hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran;

6-chloro-3-oxaloamino-4-oxo-4H-1-benzopyran;

6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran;

5,8-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran;

3-Oxaloamino-6,7-trimethylene-4-oxo-4H-1-benzopyran.

7 (6 3 4 *)

Example 14

A suitable solution for inhalation of about 2% of the active compound according to the invention in free form or in the form of a sodium salt is prepared, for example, in the following composition:

Composition of the active substance 3 _r pxalQamino-4-oxo-4H-benzopyran 2000 mg of a stabilizer, such as ethylenediaminetetraacetic acid disodium salt 10 mg of the preservative benzalkonium chloride 10 mg Distilled water to fresh 100 ml

Preparation

The active substance is dissolved by the addition of an equimolar amount of a 2N sodium hydroxide solution in freshly distilled water. A stabilizer and a preservative are then added. After all components have been completely dissolved, the solution obtained is made up to 100 ml, filled into vials and sealed.

Similarly, 2% aqueous inhalation solutions can be prepared which contain

6-Hydroxy-3-oxaloamino-4-oxo-4H-1. -benzopyran,

6-chJor ^{pxjaJoa-3-imino-4-axo-4H-benzopyran,}

6-Methoxy-3-oxaloamino-4-oxo-4H-1. -benzopyran,

5,8-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran

3-Oxalpamino-6,7-trimethylene-4-Qxo-4H-1-bonzopyran.

Example 15

For the insufflation of about 25 mg of the active ingredient of the present invention containing capsules can be prepared, for example, as follows:

Ingredients:

active ingredient, for example

3-oxaloamime 4-oxo-4H-1-benzopyran 25 mg lactose finely ground 25 mg

Preparation

The active ingredient and lactose are intimately mixed. The powder obtained is then sieved and filled in portions of 50 mg each. up to 1000 gelatin capsules.

Similarly, a capsule containing 25 mg of each is prepared

6-hydroxy-3-pxalkylamino-4-oxo-4H-1. -benzopyran,

6-chloro-3-oxaloamino-4-oxo-4H-1-benzopyran,

6-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran

5,8-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,

3-Oxaloamino-6,7-trimethylene-4-oxo-4H-1-benzopyran.

Example 16 and 16

In a similar manner to that described in Examples 12 to 14, pharmaceutical compositions containing the active ingredient can be prepared

2-Methyl-3-oxaloamino-4-oxo-4H-1-benzopyran

7-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran

5.7 _i - _1- dimethyl-3-oxalqamino-4-oxo-4H-i-benzopyran,

3-Oxalqamino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran

3-hydroxyacetylamino-4-oxo-4,6,7,8. -tetrahydrocyclopenta [g] -1-benzopyran,

6 'methyl-3-ioxalolamino-4-ioxo: -4H-1-benzopyran

6,7-3-dijnethyl _oxalqa) min'0-4-oxo-4H-benzopyran-L.

Claims (22)

SUBJECT VYNALEZU A process for the preparation of 3-oxaloamino-4-oxo-4H-1-benzopyran derivatives of the general formula I wherein: Ph is a 1,2-phenylene group optionally substituted with a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 3 -C 5 alkylene group, a hydroxyl group and / or a halogen atom, R is carboxy or hydroxymethyl; and R @ 1 is hydrogen or C1 -C4 alkyl, in free form or in the form of a salt, characterized in that in the compound of the formula II: NH-X where is X is hydrolytically convertible to the desired group of formula R — C— II o and R 1 and Ph are as defined above, the group X hydrolyzes to the group of the formula R-CII o and optionally converting the salt thus obtained into the free compound or another salt, or converting the obtained salt-forming compound into a salt. 2. A process according to claim 1, wherein X is hydrolyzable to a carboxy group, Ph is optionally a C1-C4 alkyl group, a C3-C5 alkylene group. Carbon, C 1 -C 4 alkoxy, hydroxy and / or halogen substituted 1,2-phenylene, R 1 is hydrogen or C 1 -C 4 alkyl. 3. The method according to claim 2, characterized, in that starting from a compound of the formula II ¹ wherein X is functionally modified oxaloskupinu, for example, esterified or amidated carboxy, imino ether, orthoester or esterhalogenidovou group amidinohalogenidovou, imidhalogenidovou or amidhalogenidovou. 4. A process according to any one of claims 1 to 3, wherein X is as defined in item 1, 2 or 3, wherein Ph is optionally C 1 -C 4 alkyl at one of the free positions. , a C1-C4 alkylene group, a C1-C4 alkoxy group, a hydroxy group and / or a halogen atom having an atomic number of up to 35 substituted 1,2-phenylene and R1 represents a hydrogen atom or a C1-C4 alkyl group . 5. A process according to any one of Claims 1 to 3, wherein X is as defined in (1), (2) or (3), Ph is (C1-C4) alkyl, (C1-C4) alkoxy. carbon atoms, a halogen atom having an atomic number of up to 35 or on two adjacent carbon atoms a C1-C4 alkylene group substituted with a 1,2-phenylene group and R1 a hydrogen atom. 6. A process according to any one of claims 2 and 3, wherein the compound is of formula (IIa) X as defined in points 2 and 3, R 3 and R 6 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy or halogen of up to 35, or together form an C 3 -C 4 alkylene group. 7. A process according to claim 6, wherein X is as defined in 2 or 3, R3 and R1 are hydrogen or R3 is hydrogen and R4 is hydroxy, C1-4 alkoxy. carbon atoms or halogen atoms having an atomic number of up to 35. 8. The process of claim 6, wherein X is as defined in point 2 or 3, wherein R5 and Rd are each independently C1-C4alkyl or together are alkylene. 3 or 4 carbon atoms. 9. A process according to claim 2, wherein the X-hydrolyzable group is a X-amino-convertible group. 10. The process of claims 2 and 3, wherein the starting material is 6-hydroxy-3-O-amino-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to an oxalo group. 11. The process of claims 2 and 3, wherein the starting material is 6-chloro-3-X-amino-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to an oxalo group. 12. The process of claims 2 and 3, wherein the starting material is 6-methoxy-3-X-amino-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to an oxalo group. 13. The process of claims 2 and 3, wherein the starting material is 5,8-dimethyl-3-X-amino-4-oxo-4H-1-benzopyran, wherein X is a hydrolytically-convertible group. 14. A process according to rolls 2 and 3, wherein X is hydrolytically convertible to oxalkoxy, starting from 3-X-amino-6,7-trimethylene-4-oxo-4H-1-benzopyran. 15. A process according to any one of claims 1 to 3, wherein the starting material is 5,7-dimethyl-3-X-amino-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to oxalo. 16. A process according to any one of claims 1 to 3, wherein the starting material is 3-X-amino-8-methyl-4-oxo-4H-1-benzopyran, wherein X is hydrolytically convertible to oxalo. 17. A process according to any one of claims 1 to 3, starting from 6,7-dimethyl-3-X-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to an oxalo group. 18. A process according to any one of claims 1 to 3, wherein the starting material is 3-X-amino-6-methyl-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to an oxalo group. 19. A process according to any one of claims 1 to 3, wherein the starting material is 6-chloro-7-methyl-3-X-amino-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to an oxalo group. 20. A process according to any one of claims 1 to 3, wherein the starting material is 6-chloro-8-methyl-3-X-amino-4-oxo-4H-1-benzopyran, wherein X is hydrolyzable to an oxalo group. 21. A process according to any one of claims 1 to 3, wherein the starting material is 3-X-amino-4-oxo-2,6-7-trimethyl-4H-1-benzopyran, wherein X is a hydrolyzable oxalo group. 22. The process of claim 1, wherein said X-amino-4-oxo-4H-1-benzopyran is X-hydrolyzable.