EP0000488A1 - 3-Oxaloamino-4-oxo-4H-1-benzopyrane compounds, process for their preparation and their pharmaceutical use - Google Patents

Abstract

Process for the preparation of new 3-oxaloamino-4-oxo-4H-1-benzopyran derivatives <IMAGE> in which Ph represents optionally substituted 1,2-phenylene, R represents optionally esterified or amidated carboxy and R1 represents hydrogen or an optionally substituted hydrocarbon radical, in free Form or in salt form with anti-allergic effect.

Description

worin Ph gegebenenfalls substituiertes 1,2-Phenylen darstellt, R gegebenenfalls verestertes oder amidiertes Carboxy darstellt, und R₁ Wasserstoff oder einen gegebenenfalls substituierten Kohlenwasserstoffrest bedeutet, in freier Form oder in Salzform, Verfahren zur Herstellung derselben, diese enthaltende pharmazeutische Präparate und die Verwendung von Verbindungen der Formel I als Pharmazeutikum oder zur Herstellung pharmazeutischer Präparate.The present invention relates to new benzopyran derivatives, in particular 3-oxaloamino-4-oxo-4H-1 _- benzopyran derivatives of the formula I.

wherein Ph represents optionally substituted 1,2-phenylene, R represents optionally esterified or amidated carboxy, and R _{1 represents} hydrogen or an optionally substituted hydrocarbon radical, in free form or in salt form, processes for the preparation thereof, pharmaceutical preparations containing them and the use of Compounds of formula I as a pharmaceutical or for the manufacture of pharmaceutical preparations.

Optionally substituted 1,2-phenylene can be mono- or polysubstituted, with aliphatic radicals, such as lower alkyl, or lower alkylene, acyl radicals, such as, bonded to two adjacent C atoms, for example Lower alkanoyl, optionally etherified or esterified hydroxy, such as lower alkoxy, hydroxy lower alkoxy or lower alkylene dioxy or halogen bonded to two adjacent carbon atoms, and trifluoromethyl.

Optionally esterified or amidated carboxy is, for example, carboxy esterified with an alcohol of an aliphatic character, optionally by at least one optionally substituted aryl or optionally hetero-analogous hydrocarbon radical of aliphatic character, hydroxyl or primary amino.substituted carbamyl or especially free carboxy.

An alcohol of aliphatic character is an alcohol whose C atom connected to the hydroxy group is not part of an aromatic system, for example a lower alkanol which is optionally substituted by optionally substituted phenyl, or a cycloaliphatic alcohol, e.g. a 5- to 8-membered cycloalkanol. Examples of carboxy esterified with an optionally substituted alcohol aliphatic character are: lower alkoxycarbonyl, e.g. Methoxy-, ethoxy-, propoxy-, isopropoxy- and butoxycarbonyl, in the phenyl part optionally substituted phenyl-lower alkoxy-, especially a- and B-phenyl-lower alkoxycarbonyl, e.g. optionally substituted benzyloxy and a- and β-phenethoxycarbonyl, and 5- to 8-membered cycloalkoxycarbonyl, e.g. Cyclopentyloxy, cyclohexyloxy and cycloheptyloxycarbonyl.

In an optionally substituted, optionally hetero-analogous hydrocarbon radical aliphatic in character as a substituent of a carbamyl group, the free valence starts from a non-aromatic carbon atom such a radical is, for example, lower alkyl or lower alkenyl, which can be substituted, for example by optionally substituted phenyl, or, for example, 5- to 8-membered cycloalkyl, such as cyclohexyl, or optionally lower alkylated, optionally monooxa-, aza- or thianalogue 4- to 7-membered alkylene, for example tetra- or pentamethylene or 3-oxa-, 3-aza- or 3-thiapentamethylene. Examples of carbamyl substituted by at least one such radical are: mono- or di-lower alkylcarbamyl, for example N-methyl-, N-ethyl- or N, N-diethylcarbamyl, phenyl-lower alkylcarbamyl optionally substituted in the phenyl part, such as N-benzyl- or N- ( 1- or 2-phenethyl) carbamyl, or pyrrolidino, piperidino, morpholimo, thiomorpholino, piperazino or 4-lower alkyl, for example 4-methylpiperazinocarbonyl.

An optionally substituted hydrocarbon radical R ₁ is, for example, an optionally substituted hydrocarbon radical of aliphatic character or an optionally substituted aromatic hydrocarbon radical.

In an optionally substituted hydrocarbon residue of aliphatic character, the free valence is based on a non-aromatic carbon atom. Such a radical is, for example, an unsubstituted or, in the second place, optionally substituted phenyl-substituted aliphatic hydrocarbon radical, for example lower alkyl, or furthermore a cycloaliphatic hydrocarbon radical, such as 5- to 8-membered cycloalkyl or cycloalkenyl, for example 1-cycloalkenyl. Examples of such radicals include: methyl, ethyl, isopropyl and butyl, and also benzyl, cyclopentyl, cyclohexyl and cycloheptyl.

An optionally substituted aromatic hydrocarbon radical (aryl radical) is, for example, optionally substituted phenyl.

• Mit "nieder" bezeichnete organische Verbindungen oder Reste weisen bis zu 7, vor allem bis zu 4, C-Atome auf und können geradkettig oder verzweigt sein.

Above and below applies:

• Organic compounds or radicals designated with "lower" have up to 7, especially up to 4, carbon atoms and can be straight-chain or branched.

Optionally substituted phenyl and phenyl in optionally substituted phenyl-lower alkyl and phenyl-lower alkoxy is, for example, optionally mono- or polysubstituted phenyl, the substituents being in particular lower alkyl, lower alkoxy and semi-gene, e.g. the following and trifluoromethyl are suitable, such as thenyl, o-, m- or p-tolyl, o-, m- or p-anisyl, o-, m- or p-chlorophenyl or 2,4-, 3, 5- or 2,6-dichlorophenyl.

Lower alkyl is, for example, methyl, ethyl, propyl or n-butyl or isopropyl, sec-, iso- or tert-butyl.

Lower alkoxy and those in lower alkoxycarbonyl are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or amloxy.

Lower alkanoyl is, for example, acetyl, propionyl butyryl, isobutyryl, valeroyl, pivaloyl or caproyl.

Hydroxy-lower alkoxy has up to 3, preferably higher than the a-position, hydroxy groups and is in particular 2- or 3-hydroxy-lower alkoxy, for example 2-hydroxyethoxy.

Lower alkylene is, for example, 3 to 5, especially all 3- or 4-membered lower alkylene, such as 1,3-propylene, 1,4-butylene or 1,5-pentylene.

Lower alkylenedioxy is, for example, 3- to 4-membered lower alkylenedioxy, for example methylene dioxy, ethylenedioxy, ethylenedi, 1,3-propylenedioxy.

Halogen is, for example, halogen up to and including atomic number 35, such as fluorine, chlorine or bromine.

Salts of compounds of the general formula (I), in which R represents carboxy, are salts with bases, primarily corresponding pharmaceutically usable salts, such as alkali metal or alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, also ammonium salts with ammonia or amines such as lower alkyl or hydroxy lower alkyl amines, e.g. Trimethylamine, triethylamine or di- (2-hydroxyethyl-1) amine.

The new compounds show valuable pharmacological properties. In particular, they have anti-allergic effects, e.g. can be shown in the rat in doses of approximately -3 to approximately 100 mg / kg orally or approximately 0.3 to approximately 10 mg intravenously in the passive cutaneous anaphylaxis test (PCA reaction). This is carried out analogously to the method described by Goose and Blair, Immunology, vol. 16, p. 749 (1969), the passive cutaneous anaphylaxis according to that of Ovary, Progr. Allergy, vol. 5, p. 459 (1958). described methods or by inhibiting histamine release, for example from rat peritoneal cells in vitro (cf. Dukor et al., Intern. Arch. Allergy (1976) in print).

The new compounds are known antiallergic agents of similar structure, e.g. the 2-oxaloamino-4-oxo-4H-1-benzopyran derivatives, which are substituted in the 1,2-phenylene radical by alkoxy or hydroxyalkoxy each having up to 6 carbon atoms and which are described in the US Pat. No. 3,937,719, are more effective.

Accordingly, the compounds of the present invention are particularly useful as inhibitors of allergic reactions, e.g. in the treatment and prophylaxis of

allergic diseases, such as asthma, both extrinaic and also intrinsic asthma, or other allergic diseases, such as hay fever, conjunctivitis, urticaria and eczema. The invention relates, for example, to compounds of the formula I in which R is carboxy esterified or amidated with an optionally substituted phenyl-lower alkanol or a cycloaliphatic alcohol and Ph and R _{1 have} the meanings indicated, or in which R _{1 is} an aliphatic hydrocarbon radical which is substituted by optionally substituted phenyl, a cycloaliphatic hydrocarbon radical or represents an optionally substituted aromatic hydrocarbon radical and R and Ph have the meanings indicated, or in which Ph is monosubstituted by acyl, hydroxy-lower alkoxy or trifluoromethyl or by lower alkyl, lower alkoxy, halogen, hydroxy-lower alkoxy and / or hydroxy or on two adjacent C atoms by lower alkylene or lower alkylene dioxy represents disubstituted 1,2-phenylene, and R _{1 have} the meanings given, in each case in free form or in salt form, process for preparing the same, containing pharm pharmaceutical preparations and their use as pharmaceuticals or for the manufacture of pharmaceutical preparations.

The invention relates primarily to compounds of the general formula I in which R is carboxy, carboxy esterified with an alcohol aliphatic character or optionally carbamyl substituted by at least one optionally substituted or hetero-analogous hydrocarbon radical aliphatic, hydroxyl or primary amino, Ph optionally mono- or 1,2-phenylene which is substituted several times by aliphatic radicals, acyl radicals, optionally etherified or esterified hydroxy and / or trifluoromethyl and R _{1 is} hydrogen, an optionally substituted hydrocarbon radical of aliphatic character or aromatic hydrocarbon radical means, the substituents of aromatic groups being in particular lower alkyl, lower alkoxy, halogen and trifluoromethyl, in free form or in salt form.

The invention relates in particular to compounds of the general formula I in which R is carboxy, carboxy esterified with a lower alkanol or optionally monosubstituted by lower alkyl or, secondarily, by lower alkyl, lower alkylene or 3-oxa-, 3-aza- or 3-thia-lower alkylene Carbamyl means Ph, optionally by lower alkyl, such as methyl, 3- or 4-membered lower alkylene, such as 1,3-propylene, hydroxy, lower alkoxy, such as methoxy, hydroxy-lower alkoxy, in which the hydroxy group is bonded at a position higher than a, such as 2-hydroxyethoxy, 3- or 4-membered lower alkylenedioxy, such as methylenedioxy or ethylenedioxy, lower alkanoyl, such as acetyl or butyryl, trifluoromethyl and / or halogen, such as chlorine, substituted 1,2-phenylene, and R _{1 is} hydrogen or in the second line Lower alkyl represents, in free form or in salt form.

The invention relates in particular to compounds of the general formula I in which R denotes carboxy or, secondly, lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, or optionally carbamyl which is mono- or disubstituted by lower alkyl, such as methyl or ethyl, Ph optionally by lower alkyl, such as methyl, 3- or 4-membered lower alkylene, such as 1,3-propylene, hydroxy, lower alkoxy, such as methoxy, 2- or 3-hydroxy-lower alkoxy, such as 2-hydroxyethoxy, 3- or 4-membered lower alkylenedioxy, such as methylenedioxy or ethylenedioxy, lower alkanoyl , such as acetyl or butyryl, and / or halogen, such as chlorine, substituted 1,2-phenylene and R _{1 is} hydrogen or, secondarily, lower alkyl, such as methyl, in free form or in salt form.

The invention. relates primarily to compounds of the general formula I in which R is carboxy or, in the second place, Niedeza lkoxycarbonyl having up to 5 C atoms, such as methoxy or ethoxycarbonyl, Ph in one of the free positions, optionally by lower alkyl having up to 4 C atoms , such as methyl, 3- or 4-membered lower alkylene with up to 4 C atoms, such as 1,3-propylene, lower alkoxy with up to 4 C atom, such as methoxy, 3- or 4-membered lower alkylene dioxide, such as methylenedioxy or Ethylenedioxy, lower alkanoyl with up to 7 carbon atoms, such as acetyl or butyryl, hydroxyl and / or halogen to atom number 35, such as chlorine, substituted 1,2-phenylene, and R _{1 is} hydrogen, lower alkyl with up to 4 carbon atoms, such as methyl, or phenyl, in each case in free form or in salt form.

The invention primarily relates, for example, to compounds of the general formula I in which R is carboxy, Ph is unsubstituted, by lower alkyl having up to 4 carbon atoms, such as methyl, lower alkoxy having up to 4 carbon atoms, such as methoxy, lower alkanoyl by up to 7 carbon atoms, such as butyryl, or halogen to atom number 35, such as chlorine, monosubstituted or by lower alkyl having up to 4 carbon atoms, such as methyl, lower alkyloxy having up to 4 carbon atoms, such as methoxy, halogen to atom number 35, such as Chlorine, and / or lower alkanoyl with up to 7 carbon atoms, such as butyryl, or on two adjacent carbon atoms by 3- or 4-membered lower alkylene with up to 4 carbon atoms, such as 1,3-propylene, disubstituted 1, 2-phenylene means and R _{1 represents} hydrogen, in free form or in salt form.

worin _{R2 C}arboxy bedeutet und R₃ und R₄ unabhängig voneinander Wasserstoff, Niederalkyl mit bis zu 4 C-Atomen, wie Methyl, Niederalkoxy mit bis zu 4 C-Atomen, wie Methoxy; Niederalkanoyl mit bis zu 7, z.B. bis zu 4 C-Atomen, wie Acetyl oder Butyryl, Hydroxy oder Halogen bis Atomnummer 35, wie Chlor, bedeuten oder gemeinsam einen Niederalkylen- oder Niederalkylendioxyrest mit bis zu 4 C-Atomen, wie 1,3-Propylen, Methylendioxy oder Aethylendioxy, darstellen, in freier Form oder in Salzform.The invention particularly relates to compounds of the formula Ia

wherein _{R2 is C} arboxy and R ₃ and R _{4 are} independently hydrogen, lower alkyl having up to 4 C atoms, such as methyl, lower alkoxy having up to 4 C atoms, such as methoxy; Lower alkanoyl with up to 7, for example up to 4 carbon atoms, such as acetyl or butyryl, hydroxy or halogen up to atomic number 35, such as chlorine, or together a lower alkylene or lower alkylene dioxy radical with up to 4 carbon atoms, such as 1,3- Propylene, methylenedioxy or ethylenedioxy, in free form or in salt form.

The invention preferably relates to compounds of the formula Ia, in which R _{2 is} carboxy and R ₃ and. R _{4 is} either hydrogen or, independently of one another, C ₁ -C ₄ -alkyl, such as methyl, or together C ₃ -, or C ₄ -alkylene, such as 1,3-propylene, in free form or in salt form.

The invention relates in particular to the compounds of the formula I mentioned in the examples in free form or in salt form.

The new compounds can be prepared by processes known per se.

oder ein Säureadditionssalz davon mit einer Verbindung der Formel R-X (III) umsetzt, worin X eine gegebenenfalls funktionell abgewandelte Carboxygruppe bedeutet, und gewünschtenfalls eine so erhältliche Verbindung in eine andere Verbindung der Formel I umwandelt und/oder ein erhaltenes Salz in die freie Verbindung oder in ein anderes Salz oder eine erhaltene salzbildende Verbindung in ein Salz überführt.A preferred procedure is characterized, for example, in that a compound of the general formula II

or reacting an acid addition salt thereof with a compound of the formula RX (III), in which X denotes an optionally functionally modified carboxy group, and, if desired, converting a compound thus obtainable into another compound of the formula I and / or a salt obtained into the free compound or into another salt or a salt-forming compound obtained is converted into a salt.

Acid addition salts of compounds of the formula II are, for example, hydrogenides, such as hydrochlorides, the same, and also salts with acids of the formula III.

Functionally modified carboxy groups X are. for example esterified, amidated or anhydridized carboxy groups, such as lower alkoxycarbonyl; optionally substituted carbamyl, e.g. Carbamyl, di-lower alkylcarbamyl or imidazolyl-1-carbonyl, or halocarbonyl, e.g. Chloro- or bromocarbonyl. Examples of starting materials of the formula III include: oxalic acid, oxalic acid diesters, such as lower alkyl oxalic acid and optionally esterified or amidated halo oxalic acids, such as lower alkyl chloro or bromo oxalates or lower alkyl amides, especially diethyl oxalate and ethyl bromate or chloro oxalate.

The reaction of compounds of the formulas II and III can be carried out in a customary manner, for example in the presence of a water-binding agent, such as an acid anhydride, for example phosphorus pentoxide, or of dicyclohexylcarbodiimide, or an, for example acidic or basic, condensing agent, such as a mineral acid, for example Hydrochloric acid, or an alkali metal hydroxide or carbonate, for example sodium or potassium hydroxide, or an organic nitrogen base, for example triethylamine or pyridine. When reacting with an ester halide or amide halide of oxalic acid, an organic nitrogen base is preferably used as the condensing agent. The reaction with oxalic acid is preferably carried out in the presence of a water-binding agent or acidic condensing agent which brings about the dehydration of the primarily formed substituted ammonium salt. If necessary, one works in each case in an inert solvent or diluent, such as a hydrocarbon, for example toluene, N, N-di-lower alkylamide, for example dimethylformamide, or in chloroform or methylene chloride, at normal temperature or with cooling or heating, for example in the temperature range of about 0 ° up to 100 ° C, in a closed vessel and / or under inert gas, eg under nitrogen ..

The starting materials of the formula II are known or can be prepared by methods known per se, for example by customarily employing the nitro group in a corresponding 3-nitro-4-oxo-4H-1-benzopyran derivative. Manner, e.g. by treatment with hydrogen catalytically activated by palladium on activated carbon, e.g. in dimethylformamide at normal pressure, reduced to the amino group.

The 3-nitro-4-oxo-4H-1-benzopyran derivatives mentioned above are themselves known or can be prepared by methods known per se, for example by using a corresponding methylsulfinylacetophenone of the formula HO-Ph-C (= O) -CH ₂ - S (= O) -CH ₃ in the presence of a base, for example potassium carbonate in water, condensed with an aldehyde of the formula R ₁ -CHO, for example formaldehyde, from the 2-R ₁ -3-hydroxymethyl-3-methylsulfinyl obtainable in this way Cleaves -2,3-dihydro-4-oxo-4H-1-benzopyran thermally, for example in boiling toluene, sulfinic acid and the 2-R ₁ -3-hydroxymethyl-4-oxo-4H-benzopyran derivative thus obtained with concentrated, for example 70 % nitric acid, moderately heated, for example to about 40 ° C. A direct mode of formation for the nitro compounds mentioned is that a corresponding a-nitroacetophenone of the formula HO-Ph-C (= O) -CHR ₁ -NO ₂ in the presence of sodium formate with the mixed anhydride of acetic and formic acid, for example Boiling temperature heated.

worin X₁ einen in die gewünschte Gruppe der Formel R-C(=0)-überfuhrbaren Rest bedeutet, X₁ in die Gruppe der Fonnel R-C(=O)- ütierfuhrt und gewünschtenfalls eine so erhältliche Verbindung'in eine andere Verbindung der Formel I umwandelt und/oder ein erhaltenes Salz in die freie Verbindung oder in ein anderes Salz oder eine erhaltene salzbildende Verbindung in ein Salz überführt.The new compounds can also be prepared by working in a compound of formula

in which X ₁ denotes a radical which can be transferred to the desired group of the formula RC (= 0), X _{1 leads} to the group of the Fonnel RC (= O) - and if desired one which is obtainable in this way Converting compound 'into another compound of formula I and / or converting a salt obtained into the free compound or into another salt or a salt-forming compound obtained into a salt.

A group which can be converted into the group of the formula RC (= 0) is, for example, an oxalo group which is different from an optionally esterified or amidated oxalo group and which can be converted into this functionally modified oxalo group. Such functionally modified oxalo groups are preferably those which have, as the functionally modified α-carbonyl group, thioxomethylene, iminomethylene or an esterified and / or etherified dihydroxymethylene group and / or as the functionally modified carboxy group a functionally modified carboxy group which is different from an esterified or amidated carboxy group. Esterified and / or etherified dihydroxy methyl groups are, for example, dihydroxymethylene groups esterified with a hydrohalic acid, such as hydrochloric acid, and / or etherified with a lower alkanol, such as methanol or ethanol. Examples include, above all, dihalomethylene groups, such as dichloromethylene, lower alkoxyhalomethylene groups, such as methoxy or ethoxychloromethylene, or di-lower alkoxymethylene groups, such as dimethoxy or diethoXymethylene. Functionally modified carboxy groups other than esterified or amidated carboxyl groups are, for example, the cyano group, anhydridized carboxy groups, such as halogen, for example chlorocarbonyl, iminoester, such as imide or amide halide groups, for example iminochloro or aminodichloromethyl, imino ether groups, such as lower alkyloxy or lower alkyleneimino groups, for example methoxy or lower alkyleneimino groups - or Aethoxyininomethyl, 4,4- or 5,5-dimethyloxazolinyl- (2) or 4,4,6-trimethyl-dihydro-oxazinyl- (2), amidino groups, such as amidiho or lower alkyl, for example methylamidino, with a hydrohalic acid, such as hydrochloric acid, esterified and / or ortho acid groups etherified with a lower alkanol; how Tri-lower alkoxy, lower alkoxy dihalogen or trihalomethyl groups, especially trimethoxy or triethoxymethyl, ethoxydichloromethyl or trichloromethyl, or optionally esterified thiocarboxyl groups, such as lower alkylthiocarbonyl groups, for example ethylthiocarbonyl.

Such groups X ₁ can be converted solvolytically into the group of the formula RC (= 0) -, for example hydrolytically into the oxalo group. Functionally modified carboxy as an imino ether, orthoester or Esterhalogenidgruppierung and / or as a functionally modified carbonyl or thioxo minomethylen ^I or an esterified or etherified dihydroxymethylene containing groups X ₁ may be further hydrolyzed to oxalo groups esterified. Similarly, as a functionally modified carboxy group, the cyano group, an amidino or imide or amide halide group and / or as a functionally modified a-carbonyl group, thioxo- or iminomethylene or an etherified or esterified dihydroxymethylene group - .de groups X ₁ can be hydrolyzed to amidated carboxy groups. The hydrolysis can be carried out in a customary manner, if necessary in the presence of a basic or preferably acidic hydrolysis agent, such as an alkali metal hydroxide, such as sodium or potassium hydroxide, or preferably a protonic acid, especially a mineral acid, for example a hydrohalic acid, such as hydrochloric acid, or an organic Carbon or sulfonic acid, e.g. acetic acid or p-toluenesulfonic acid, if necessary in a polar solvent, such as a lower alkanol, ketone or ether, e.g. in ethanol, acetone or dioxane, and / or with cooling or heating, e.g. at about 0 ° C to about 100 ° C.

An anhydride carboxy group, such as halocarbonyl, for example chlorocarbonyl, or a lower alkyleneimino ether group, for example 4,4- or 5,5-dimethyl-oxazolinyl- (2) or 4,4,6-trimethyldihydro-oxazinyl- (2 ), having functionally modified Oxalo groups can also be converted into esterified oxalo groups by conventional alcoholysis, ie reaction with the corresponding alcohol. The alcoholysis of anhydridized carboxy groups is advantageously carried out in the presence of a basic condensing agent, for example pyridine or triethylamine, while the alcoholysis of a lower alkyleneimino ether group is preferably carried out in an acidic manner, for example in the presence of hydrochloric acid, p-toluenesulfonic acid or acetic acid. In an analogous manner, a functionally modified oxalo group having an anhydridized carboxy group can also be amidated by ammonolysis or aminolysis, ie reaction with ammonia or a corresponding primary or secondary amine, preferably in the presence of a basic condensing agent, for example sodium hydroxide, pyridine or triethylamine Oxalo group RC (= O) - transfer.

Further radicals X _{1 which} can be converted into groups of the formula RC (= 0) are, for example, oxidatively convertible into these groups, in particular those which can be converted oxidatively into the oxalo group of the formula RC (= 0) - in which R represents carboxy, optionally hydrated glyoxyloyl group. This can advantageously be formed in situ in the course of the oxidation reaction, for example from the acyl group of an optionally α.β-unsaturated or α, β-dihydroxylated aliphatic or araliphatic carboxylic acid, a glycoloyl group or the glycyl group esterified on the hydroxyl group, or from one of its functional derivatives , for example one of their acetals or imines are set free. Acyl groups of optionally α, β-unsaturated or α, β-dihydroxylated carboxylic acids are, for example, alkanoyl groups, such as lower alkanoyl, for example acetyl, acyl groups of α, β-unsaturated aliphatic mono- or dicarboxylic acids, for example acryloyl, crotonyl or the acyl group of the functionally modified ones Fumaric or maleic acid, acyl groups of α, β-unsaturated ten araliphatic carboxylic acids, for example optionally substituted cinnamoyl, or acyl groups of aliphatic α, β-dihydroxydicarboxylic acids, such as tartaric acid, or monofunctional carboxy derivatives, such as esters or amides. Esterified glycoloyl groups are, for example, glycoloyl groups esterified on the hydroxyl group with a mineral acid, such as a hydrohalic acid, for example with hydrochloric or hydrobromic acid, or with a carboxylic acid, for example with acetic acid or the optionally substituted benzoic acid. Acetalized glyoxyloyl are, for example, lower alkanols or lower alkanediol acetalized Glyox ^y loyl- groups such as dimethoxy, or Diäthoxy- Aethylendioxyacetyl. Imines of glyoxyloyl groups are, for example, optionally substituted N-benzylimines thereof. Further residues that can be oxidatively converted into the oxalo group are, for example, optionally substituted 2-furoyl groups, such as an acetalized formyl group in the 5-position, such as diethoxymethyl. Esterified oxalo groups of the formula RC (= O) -, where R is esterified carboxy, oxidizable groups are etherified glycoloyl groups, such as lower alkoxyacetyl. Residues which can be oxidized or esterified or amidated oxalo groups are furthermore optionally esterified or amidated carboxymethyl groups.

. The oxidation of such groups X ₁ can be carried out in the usual way by reaction with a suitable oxidizing agent. Suitable oxidizing agents are, in particular, oxidizing heavy metal compounds, such as silver compounds, for example silver cutate or silver picolinate, oxygen acids of heavy metals, for example manganese IV and VI, lead IV, chromium VI or iron VI, or halogens or their anhydrides or salts, such as chromic acid, chromium trioxide, potassium dichromate, potassium permanganate, manganese diolide, potassium ferrate, sodium iodate; Sodium periodate or lead tetraacetate. The reaction with these Oxidationsmit agents is carried out in a customary manner, for example in an inert solvent, such as acetone, sulfuric acid, pyridine or water, or in a preferably aqueous, inert solvent mixture, at normal temperature or, if necessary, with cooling or heating, for example at about 0 ° C. to about 100 ° C. The oxidation of optionally etherified glycoloyl groups to optionally esterified oxalo groups is advantageously carried out, for example, with potassium permanganate in aqueous pyridine or acetone at room temperature. Acetalized glyoxyloyl groups and iminoacetyl groups are preferably oxidized acidic, for example with potassium dichromate in sulfuric acid. Acyl groups of α, β-dihydroxylated aliphatic carboxylic acids, such as the acyl residue of tartaric acid, are advantageously oxidized with periodic acid, while for the oxidation of the glycyl group, preferably potassium ferrate in an alkaline medium, for example at P _H = 10-13, for example 11.5, or organic silver salts, like silver picoline used.

The compounds of formula IV mentioned as starting materials are largely new. In addition to their usability as starting materials for the preparation of compounds of the formula I, some of them have further advantageous properties. Thus, compounds of the formula IV in which X ₁ denotes an optionally esterified or etherified glycoloyl group have the same pharmacological properties, with a comparable potency, as the corresponding compounds of the formula I.

Accordingly, the invention also relates to new starting materials, especially compounds of the formula IV, in which X ₁ denotes an optionally esterified or etherified glycoloyl group, processes for their preparation, pharmaceutical preparations containing them and their use as pharmaceuticals or for the production of medicaments.

Esterified glycoloyl groups are understood to mean, for example, glycoloyl groups esterified with a carboxylic acid, such as an aliphatic or aromatic carboxylic acid, e.g. corresponding lower alkanoyloxyacetyl or optionally substituted benzoyloxyacetyl. Lower alkanoyloxyacetyl is e.g. Acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeroyloxy, caproyloxy or pivaloyloxyacetyl. Lower alkyl, such as methyl, lower alkoxy, such as methoxy and / or halogen, such as chlorine, are particularly suitable as substituents for substituted benzoyloxyacetyl groups.

Etherified glycoloyl groups are, for example, glycoloyl groups etherified by an optionally substituted aliphatic or araliphatic alcohol, such as corresponding lower alkoxyacetyl or phenyl-lower alkoxyacetyl groups. Substituents of lower alkoxyacetyl are especially hydroxy, lower alkoxy and / or di-lower alkylamino, and those of phenyl-lower alkoxyacetyl groups e.g. Lower alkyl, such as methyl, lower alkoxy, such as methoxy, and / or halogen, such as chlorine. Lower alkoxy preferably has one of the meanings mentioned at the beginning. Phenyl-lower alkoxyacetyl is especially benzyloxy or 2-phenylethoxyacetyl. The lower alkylamino lower alkoxyacetyl is preferably 2-dimethyl or 2-diethylaminoethoxyacetyl.

The invention relates in particular to those compounds of the formula IV in which Ph and R _{1 have} the meanings given for the respectively preferred connecting groups of the formula I, and X _{1 is} lower alkoxyacetyl, especially with up to 6 carbon atoms, such as methoxy- or ethoxyacetyl, or preferably means glycoloyl.

oder ein Säureadditionssalz davon mit einer Säure der Formel X₁-OH (IVa) oder einem funktionellen Derivat davon umsetzt.The compounds of the formula IV mentioned as starting materials can be prepared by methods known per se, preferably by using a compound of the formula

or reacting an acid addition salt thereof with an acid of the formula X ₁ -OH (IVa) or a functional derivative thereof.

Functional derivatives of acids of the formula IVa are, for example, an esterified, amidated or anhydridized carboxy group. such as lower alkoxycarbonyl, optionally substituted carbamyl, for example carbamyl, di-lower alkylcarbamyl or imidazolyl-1-carbonyl, or halocarbonyl, for example chloro- or bromocarbonyl, containing acid derivatives. Examples of acids of the formula IVa and their functional derivatives are: for the preparation of compounds of the formula IV in which X ₁ denotes a radical which can be solvolysed to the group RC (= 0) - oxalyl halides, such as oxalyl chloride or oxalyl bromide, tri-lower alkoxy and dihalo-lower alkoxy-acetic acid lower alkyl esters, such as oxalic acid tetra-ethyl ester or dichloroxalic acid diethyl ethyl acetate, oxalic acid ethyl ester Oxalic acid mono- or -diiminodiethyl ester, oxalic acid amidines, such as N-lower alkyloxalic acid ester amidines, oxalic acid dithione lower alkyl, such as dimethyl ester, cyanoformyl chloride and cyanogen, and for the preparation of compounds of formula IV in which X _{1 is} an oxidizable group RC - (= 0) - The remainder means glycolic acid and its lower alkyl ester or the corresponding lactide, mono- or di-lower alkoxyacetic acid and its lower alkyl ester, for example ethyl ethoxy or diethoxyacetic acid ethyl ester, haloacetic anhydrides such as chloroacetic anhydride or chloroacetyl chloride and tartaric acid, furthermore cinnamoyl chloride, acetyl chloride and glycine.

The implementation of compounds of formula II "with Acids of the formula IVa or their derivatives can be carried out in a customary manner, for example in the presence of a water-binding agent, such as an acid anhydride, for example. of phosphorus pentoxide, or of dicyclohexylcarbodiimide, or one, for example acidic or basic, condensing agent, such as a mineral acid, for example hydrochloric acid, or an alkali metal hydroxide or carbonate, for example sodium or potassium hydroxide, or an organic nitrogen base, for example triethylamine or pyridine . When reacting with an acid anhydride such as acid chloride, an organic nitrogen base is preferably used as the condensing agent. The reaction with carboxylic acids is preferably carried out in the presence of a water-binding agent. If necessary, the process is carried out in an inert solvent, at normal temperature or with cooling or heating, for example in the temperature range from about 0 ° C. to about 100 ° C., in a closed vessel and / or under an inert gas, for example nitrogen.

Compounds of the formula IV in which X _{i is} glyoxyloyl can also be prepared by heating a corresponding halogen compound, such as bromoacetyl compound, with hexamethylenetetramine, preferably in an aqueous alcohol. Compounds of the formula IV in which X _{1 is} optionally substituted benzyliminoacetyl can be prepared starting from the corresponding glycyl compounds by reacting them with optionally substituted benzaldehyde and rearranging the benzylidene glycyl compound thus obtainable, preferably under the reaction conditions.

As a functionally modified carboxy group, a functionally modified oxalo having an imino ether group Group-containing compounds of the formula IV can be prepared starting from the corresponding cyanocarbonyl compound by reaction with the corresponding alcohol, cyclic imino ethers by treatment with a lower alkanediol or amino lower alkanol.

worin X₂ einen in die genannte Gruppe X₁ überführbaren Rest bedeutet, den Rest X₂ in einen Rest X₁ überführt und gewünschtenfalls eine so erhältliche Verbindung in eine andere Verbindung der Formel IV, worin X₁ eine gegebenenfalls mit einer Carbonsäure veresterte oder verätherte Glykoloylgruppe bedeutet, überführt.The compounds of the formula IV according to the invention in which X ₁ denotes an optionally etherified or esterified with a carboxylic acid glycoloyl group can also be prepared by reacting in a compound of the formula

in which X ₂ denotes a radical which can be converted into said group X ₁ , the radical X _{2 is converted} into a radical X ₁ and, if desired, a compound thus obtainable into another compound of the formula IV, in which X _{1 is} a glycoloyl group which is optionally esterified or etherified with a carboxylic acid means convicted.

Such groups X ₂ are, for example, esterified glycoloyl groups which are different from the glycoloyl group optionally esterified with a carboxylic acid, such as glycoloyl groups esterified with a mineral acid, for example with a hydrohalic acid, such as chloro, bromine or iodoacetyl. These groups can be hydrolytically, for example in. In the presence of a basic hydrolysis agent, such as sodium hydroxide solution, to the glycoloyl group or by reaction with a salt, for example the sodium salt, a corresponding alcohol or a corresponding carboxylic acid, be converted into etherified or with a carboxylic acid esterified glycoloyl.

More in X ₁ can be converted radicals X ₂ are, for example, radicals which can be converted reductively into the glycoloyl group, such as the optionally hydrated glyoxyl group, which are also formed below the reaction conditions from the oxalo group which may be present in salt or anhydride or ester form or hydrolytically liberated from an acetal such as diethyl or ethylene acetal can be. The reducing agents used are, for example, light or di-light metal hydrides such as borane, diborane, sodium boranate or lithium anilinoborohydride.

A compound of the formula I or IV obtainable according to the invention can be converted into another compound of the formula I or IV in a manner known per se.

For example, a free carboxyl group R can be used in a conventional manner, e.g. by treatment with an optionally substituted phenyl substituted diazo lower alkane or a tri-lower alkyloxonium, tri-lower alkylcarboxonium or di-lower alkylcarbonium salt, such as -hexachloroantimonate or -hexafluorophosphate, or especially by reaction with the corresponding alcohol or a reactive ester, such as a carbon, phosphorus -, sulfurous or carbonic acid esters, e.g. a lower alkane carboxylic acid ester, tri-lower alkyl phosphite, di-lower alkyl sulfite or its carbonate or pyrocarbonate, or a mineral acid or sulfonic acid ester, e.g. esterify the chloro- or hydrobromic acid or sulfuric acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid ester, the corresponding alcohol or an olefin derived therefrom to an esterified carboxyl group R.

The reaction with the corresponding alcohol itself can advantageously be carried out in the presence of an acidic catalyst, such as a protonic acid, for example hydrochloric or hydrobromic, sulfuric, phosphoric, boric, benzenesulfonic and / or toluenesulfonic acid, or a Lewis acid, for example Boron trifluoride etherate, in an inert solvent, in particular an excess of the alcohol used and, if necessary, in the presence of a water-binding agent and / or under more distillative, for example azeotropic, removal of the water of reaction and / or at elevated temperature.

The reaction with a reactive derivative of the corresponding alcohol can be carried out in a conventional manner, in the reaction with a carbonate, phosphorous, sulfurous or carbonic acid ester, for example in the presence of an acid catalyst, such as one of the above, in an inert solvent, such as an aromatic hydrocarbon, e.g. in benzene or toluene, or an excess of the alcohol derivative used or the corresponding alcohol, if necessary under, e.g. azeotropic, distillation of the water of reaction. When reacting with a mineral acid or sulfonic acid ester, the acid to be esterified is advantageously used in the form of a salt, e.g. the sodium or potassium salt, and if necessary works in the presence of a basic condensing agent such as an inorganic base, e.g. of sodium or potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, e.g. of triethylamine or pyridine, and / or in an inert solvent such as one of the above tertiary nitrogen bases or a polar solvent, e.g. in dimethylformamide, and / or at elevated temperature.

The reaction with an olefin can be carried out, for example, in the presence of an acid catalyst, e.g. a Lewis acid, e.g. boron trifluoride, a sulfonic acid e.g. of p-toluenesulfonic acid, or a basic catalyst, e.g. of sodium or potassium hydroxide, advantageously in an inert solvent such as an ether, e.g. in diethyl ether or tetrahydrofuran.

A free carboxyl group R. can also be reacted with ammonia or at least one hydrogen atom containing amine in a conventional manner with dehydration of the intermediate ammonium salt, for example by azeotropic distillation with benzene or toluene or dry heating, into an amidated carboxyl group R.

However, the above-described conversions of free to esterified or amidated carboxyl groups R can also be carried out by adding a compound. of formula (I), wherein R is carboxyl, first in the usual way into a reactive derivative, for example by means of a halide of phosphorus or sulfur, e.g. by means of phosphorus trichloride or. -bromide, phosphorus pentachloride or thionyl chloride, in an acid halide or by reaction with an appropriate alcohol in a reactive ester, i.e. Esters with electron-withdrawing structures, such as the ester with phenol, thiophenol, p-nitrophenol or cyanomethyl alcohol, or with a corresponding amine in a reactive amide, e.g. the amide derived from imidazole or 3,5-dimethylpyrazole. The reactive derivative obtained can then be used in a conventional manner, e.g. as described below for the transesterification, transamidation or mutual conversion of esterified and amidated carboxyl groups R, with an appropriate alcohol, ammonia or the corresponding amine having at least one hydrogen atom to give the desired compound of the formula I.

An esterified carboxyl group R can in the usual way, for example by hydrolysis in the presence of a catalyst, for example a basic or acidic agent, such as a strong base, for example sodium or potassium hydroxide, or a mineral acid, for example hydrochloric acid, sulfuric acid or phosphoric acid free carboxyl group R or, for example, by reaction with ammonia or the corresponding, at least an amine having a hydrogen atom can be converted into an amidated carboxyl group R.

An esterified carboxyl group R can also be used in a conventional manner, e.g. by reaction with a metal salt such as the sodium or potassium salt, a corresponding alcohol or with it itself in the presence of a catalyst, e.g. a strong base, e.g. of sodium or potassium hydroxide, or a strong acid such as a mineral acid, e.g. of hydrochloric acid, sulfuric acid or phosphoric acid, or an organic sulfonic acid, e.g. of p-toluenesulfonic acid, or a Lewis acid, e.g. of boron trifluoride etherate, to be transesterified to another esterified carboxyl group R.

An amidated carboxyl group R can in a conventional manner, for example by hydrolysis in the presence of a catalyst, for example a strong base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide or carbohydrate, or a strong acid, such as a mineral acid , for example of hydrochloric acid, sulfuric acid or phosphoric acid, can be converted into the free carboxyl group _R.

At the rest Ph of a compound obtainable according to the invention, esterified or etherified hydroxyl groups, if appropriate, can also be converted into one another.

For example, a free hydroxyl group can be obtained by reaction with an etherifying agent, e.g. with a lower alkylating agent to an etherified hydroxy group, e.g. etherify a lower alkoxy, hydroxy lower alkoxy or lower alkylene dioxy group.

Etherifying agents are, for example, reactive esterified alcohols, such as with a mineral acid, for example with iodic, chlorine or hydrobromic or sulfuric acid, or organic sulfonic acid, for example with p-toluene, p-bromobene zol, benzene ,. Methane, ethane or ethene sulfonic acid, or fluorosulfonic acid esterified lower alkanols or lower alkane diols, as well as diazo lower alkanes. As etherifying agents are in particular lower alkyl chlorides, bromides or iodides, for example methyl iodide, lower alkylene halohydrins, for example ethylene chlorohydrin, di-lower alkyl sulfates, for example dimethyl or diethyl sulfate, or methyl fluorosulfonate, lower alkyl sulfonates, such as methyl or ethyl methane, p-toluene - or p-bromobenzenesulfonates, epoxy lower alkanes, for example propylene oxide, and diazoalkanes, for example diazomethane.

The implementations with etherification agents, e.g. the ones highlighted above can be carried out in a conventional manner, e.g. when reacting with a diazo lower alkane in an inert solvent such as an ether, e.g. in tetrahydrofuran, or when using a reactive esterified alcohol e.g. in the presence of a basic condensing agent such as an inorganic base e.g. of sodium, potassium or calcium hydroxide or carbonate, or a tertiary or quaternary nitrogen base, e.g. of pyridine, triethylamine, or tetraethyl- or benzyltriethylammonium hydroxide, and / or a solvent customary for the respective reaction, which can also be obtained from an excess of the lower alkyl halide or sulfate used for the etherification and / or a tertiary nitrogen base used as basic condensing agent, e.g. Triethylamine or pyridine, if necessary, at elevated temperature. In particular, methylation using methyl iodide in amyl alcohol / potassium carbonate at boiling temperature is recommended.

Conversely, etherified hydroxy can be used in a conventional manner, for example in the presence of an acidic agent such as a hydrohalic acid, e.g. of hydroiodic acid, in an inert solvent, e.g. convert to ethanol or acetic acid, to hydroxy.

In an analogous manner, esterified hydroxy, such as halogen, can also be reacted with a corresponding metal alcoholate, such as an alkali metal lower alkanolate, e.g. with sodium methoxide, convert to etherified hydroxy.

Furthermore, in a compound of the formula IV obtainable according to the invention, glycoloyl X ₁ can be esterified by reaction with an esterifying agent, such as a lower alkanoic acid or benzoic anhydride or chloride, or by conversion into an alkali metal salt and reaction with a corresponding halogen compound, such as a lower alkyl halide. etherify. Conversely, esterified or etherified glycoloyl, for example acid catalytically, can be hydrolyzed to glycolöyl.

Free compounds of the formula I obtainable according to the invention, in which R represents carboxy, can be converted into salts in a manner known per se, i.a. by treatment with a base or with a suitable salt of a carboxylic acid, usually in the presence of a solvent or diluent.

Salts obtainable according to the invention can be converted into the free compounds in a manner known per se, e.g. by treating with an acidic reagent such as a mineral acid.

The compounds including their salts can also be obtained in the form of their hydrates or include the solvent used for the crystallization.

Due to the close relationship between the new compounds in free form and in the form of their salts are in the preceding and below to be understood by the free compounds or their salts as appropriate and appropriate also the corresponding salts or free compounds.

The invention also relates to those embodiments of the process according to which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt and / or racemate or antipode or in particular forms under the reaction conditions .

In each case, preference is given to using starting materials which lead to the target compounds initially mentioned as the preferred subject matter of the invention.

The present invention also relates to pharmaceutical preparations which contain compounds of the formula (I) or pharmaceutically acceptable salts thereof. The pharmaceutical preparations according to the invention are those which are intended for topical and local as well as enteral, such as oral or rectal, and parenteral administration to and for inhalation by warm-blooded animals and which contain the pharmacologically active substance alone or together with a pharmaceutically usable carrier material. The dosage. of the active ingredient depends on the warm-blooded species, the age and the individual condition, as well as on the mode of administration.

The new pharmaceutical preparations contain e.g. from about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient. Pharmaceutical preparations according to the invention are e.g. such aerosol or spray form or in unit dosage forms, such as dragées, tablets, capsules or suppositories, and also ampoules.

The pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. produced by conventional mixing, granulating, coating, solution or lyophilization processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, into tablets or dragee cores after adding suitable auxiliaries .

Suitable carriers are, in particular, fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparation and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as steel hexister, for example of maize, wheat, rice or potato sticks, gelatin , Tragacanth, methyl cellulose and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, optionally gastric juice-resistant coatings, including concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings , Solutions of suitable Cel Lulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, are used. Dyes or pigments can be added to the tray or dragée coatings, for example for identification or for labeling different doses of active ingredient.

Other pharmaceutical preparations which can be used orally are plug-in capsules made of gelatin, and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and, if appropriate, 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, stabilizers also being able to be added.

As rectally applicable pharmaceutical preparations, e.g. Suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material; the basic bulk materials are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration, primarily aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and suspensions of the active ingredient, such as corresponding oily injection suspensions, are suitable, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.

Inhalation preparations for the treatment of the respiratory tract by nasal or buccal administration are e.g. Aerosols or sprays, which can distribute the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension. In addition to the active ingredient, preparations with powder-distributing properties usually contain a liquid propellant with a boiling point below room temperature, and, if desired, carriers, such as liquid or solid nonionic or anionic surface-active agents and / or solid diluents. Preparations in which the pharmacological active ingredient is present in solution contain, in addition to this, a suitable propellant, and, if necessary, an additional solvent and / or a stabilizer. Instead of the propellant gas, compressed air can also be used, which can be generated as required by means of a suitable compression and expansion device.

Pharmaceutical preparations for topical and topical use are, for example, for the treatment of the skin lotions and creams which contain a liquid or semi-solid oil-in-water or water-in-oil emulsion and ointments (those preferably containing a preservative) , for the treatment of the eyes eye drops, which contain the active compound in aqueous or oily solution, and eye ointments, which are preferably produced in sterile form, for the treatment of the nose, powders, aerosols and sprays (similar those described above for the treatment of the respiratory tract), as well as coarse powder, which is administered by rapid inhalation through the nostrils, and nasal drops, which contain the active compound in aqueous or oily solution, or for the local treatment of the mouth, lollipop bonbons, which the active Contain compound in a mass which is generally formed from sugar and gum arabic or tragacanth, to which flavorings can be added, and pastilles which contain the active substance in an inert mass, for example from gelatin and glycerol or sugar and gum arabic.

The invention also relates to the use of the new compounds of the formula (I) 'and their salts as pharmacologically active compounds, in particular as antiallergics, preferably in the form of pharmaceutical preparations. The daily dose administered to a warm-blooded animal is administered from about 70 _'kg, is from about 200 mg to about 1200 mg.

The following examples illustrate the invention described above; however, it should not restrict the scope of this in any way. Temperatures are given in degrees Celsius.

example 1

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 is added dropwise 4.5 g of oxalic acid monomethyl chloride with stirring in an anhydrous atmosphere at 10 °. After the addition has ended, the mixture is stirred for 90 minutes at room temperature. The reaction solution is then partitioned between 3 times 50 ml of chloroform and 50 ml of 2N hydrochloric acid. The organic phases are washed neutral, dried over sodium sulfate and concentrated in vacuo. After adding ether to the concentrated solution, the 3-methoxyoxalylamino-4-oxo-4H-1-benzopyran crystallizes from mp 200-201 °.

Example 2

35 ml of n-sodium hydroxide solution and then 1.3 l of water are added to a suspension of 7.6 g of 3-methaxyoxalylamino-4-oxo-4H-1-benzopyran in 200 ml of ethanol. Now the mixture is heated to 70 ° with stirring for 15 minutes. The now clear solution is adjusted to P _H = 2 with concentrated hydrochloric acid and slowly cooled to room temperature. The 3-oxaloamino-4-oxo-4H-1-benzopyran crystallized from a melting point of 200 ° (dec.).

Example 3

• 6-Hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-Chlor-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Chlor-3-oxalcamino-4-oxo-4H-1-benzopyran, F. 213-215°,
• 6-Mathoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, F. 174-175°,
• 6-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran, F. 230°,
• 5,8-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzapyran,
• 5,8-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-Methoxyoxalylamino-6,7-trimethylen-4-oxo-4H-1-benzopyran, F. 185-186° und
• 3-Oxaloamino-6,7-trimethylen-4-oxo-4H-1-benzopyran,F. 185°.

In an analogous manner - as described in Examples 1 and 2, one can also produce:

• 6-hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-chloro-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-chloro-3-oxalcamino-4-oxo-4H-1-benzopyran, mp 213-215 °,
• 6-mathoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, mp 174-175 °,
• 6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran, mp 230 °,
• 5,8-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzapyran,
• 5,8-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-methoxyoxalylamino-6,7-trimethylene-4-oxo-4H-1-benzopyran, mp 185-186 ° and
• 3-oxaloamino-6,7-trimethylene-4-oxo-4H-1-benzopyran, F. 185 °.

Example 4

1.36 g of monoethyl ester chloride of oxalate are added dropwise 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. The reaction solution is stirred at 90 ° for 90 minutes and evaporated to dryness under reduced pressure. The yellowish, solid evaporation residue is digested with water, filtered off, dried and recrystallized from ethanol. 3-Aethoxy-oxalylamino-6-chloro-4-oxo-4H-1-benzopyran of mp 161-162 ° is obtained.

Example 5

In an analogous manner to that described in Example 4, starting from 20 g of 3-amino-4-oxo-4H-1-benzopyran, 3-ethoxyoxalylamino-4-oxo-4H-1-benzopyran of melting point 146.5-148 " .

Example 6

In an analogous manner to that described in Example 4, starting from 2.0 g of 3-amino-2-methyl-4-oxo-4H-1-benzopyran, 3-ethoxyoxalylamino-2-methyl-4-oxo-4H-1- benzopyran, mp 100-104 °.

• Eine Lösung von 5,0 g 2-Methyl-3-nitro-4-oxo-4H-1-benzopyran in 250 ml Aethanol wird mit 0,75 g 10%-iger Palladiumkohle versetzt und bei Raumtemperatur und Normaldruck 40 Minuten lang hydriert. Der Katalysator wird abfiltriert und das Lösungsmittel unter vermindertem Druck abgezogen. Der gelbe EindampfrUckstand wird aus Benzol umkristallisiert. Man erhält das 3-Amino-2-methyl-4-oxo-4H-1-benzopyran vom F. 118-120°.

The starting material can be produced as follows, for example:

• 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-carbon and hydrogenated at room temperature and normal pressure for 40 minutes. The catalyst is filtered off and the solvent is removed under reduced pressure. The yellow evaporation residue is recrystallized from benzene. The 3-amino-2-methyl-4-oxo-4H-1-benzopyran of mp 118-120 ° is obtained.

Example 7

To a solution of 2.7 g of 3-ethoxyoxalylamino-6-chloro-4-oxo-4H-1-benzopyran in 200 ml of 50% aqueous ethanol is added dropwise with occasional heating on a steam bath until the reaction is weakly basic. 1-n sodium hydroxide solution added. The color of the reaction _- mix proposes initially to to orange and then white. A further 0.1 l sodium hydroxide solution is added until a weak orange color remains. The precipitate is filtered off, washed with n-hydrochloric acid and then with water, filtered off with suction, dried and recrystallized from methanol. 6-Chloro-3-oxaloamino-4-oxo-4H-1-benzopyran of mp 213-215 ° is obtained.

Example 8

In an analogous manner to that described in Example 7, starting from 15.5 g of 3-ethoxyoxalylamino-4-oxo-4H-1-benzopyran, 3-oxaloamino-4-oxo-4H-1-benzopyran of mp 195-197 ° is obtained (from ethanol) and starting from 1 g of 3-ethoxyoxalylamino-2-methyl-4-oxo-4H-1-benzopyran the 2-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran of F. 208-209 ° (from ethanol).

Example 9

In an analogous manner to that described in Example 4, starting from 5 g of 3-amino-7-methoxy-4-oxo-4H-1-benzopyran, 3-ethoxyoxalylamino-7-methoxy-4-oxo-4H-1-benzopyran was obtained from F. 218-220 ° (from ethyl acetate).

• 1,85 g 4-Hydroxy-7-methoxy-3-nitro-cumarin werden in 60 ml5%-iger wässriger Natronlauge 20 Stunden bei Raumtemperatur gerührt. Die Reaktionsmischung wird abfiltriert, trockengesaugt.und aus Aethanol umkristallisiert. Man erhält das 2-Hydroxy-4-methoxy-β-nitro-acetophenon vom F. 138-140°.
• 2,11 g 2-Hydroxy-4-methoxy-_ß-nitro-acetophenon werden zu einem gerührten Gemisch von 0,68 g Natriumformat und 25 ml des gemischten Anhydrides von Essig- und Ameisensäure hinzugefügt.. Man erwärmt auf 80°, lässt auf Raumtemperatur abkühlen, rührt 1 Stunde bei Raumtemperatur nach, fügt 100 ml Eiswasser hinzu, saugt ab, wäscht mit Wasser nach, saugt trocken und kristallisiert aus Essigsäureäthylester um. Man erhält 7-Methoxy-3-nitro-4-oxo-4H-1-benzopyran vom F. 185-187°..
• Zu einer unter Stickstoff gerührten Suspension von 7 g 7-Methoxy-3-nitro-4-oxo-4H-1-benzopyran in 80 ml Aethanol und 30 ml Wasser werden 20 g Natriumdithionit hinzufügt. Man lässt 20 Minuten rühren, dampft unter vermindertem Druck ein, löst den festen Eindampfrückstand in Wasser und extrahiert mit Chloroform. Der Chloroformauszug wird über Natriumsulfat getrocknet und eingedampft. Man erhält das 3-Amino-7-methoxy-4-oxo-4H-1-benzopyran vom F. 143-146°.

The starting material can be produced as follows, for example:

• 1.85 g of 4-hydroxy-7-methoxy-3-nitro-coumarin are stirred in 60 ml of 5% aqueous sodium hydroxide solution for 20 hours at room temperature. The reaction mixture is filtered off, sucked dry and recrystallized from ethanol. The 2-hydroxy-4-methoxy-β-nitro-acetophenone of mp 138-140 ° is obtained.
• 2.11 g of 2-hydroxy-4-methoxy- _ß- nitro-acetophenone are added to a stirred mixture of 0.68 g of sodium format and 25 ml of the mixed anhydride of acetic and formic acid. The mixture is heated to 80 ° and left to cool Cool to room temperature, stir for 1 hour at room temperature, add 100 ml of ice water, suction, wash off with water, suction dry and recrystallized from ethyl acetate. 7-Methoxy-3-nitro-4-oxo-4H-1-benzopyran of mp 185-187 ° is obtained.
• 20 g of sodium dithionite are added 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, which is stirred under nitrogen. The mixture is stirred for 20 minutes, evaporated under reduced pressure, the solid evaporation residue is dissolved in water and extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated. The 3-amino-7-methoxy-4-oxo-4H-1-benzopyran of mp 143-146 ° is obtained.

Example 10

In an analogous manner to that described in Example 7, starting from 2.1 g of 3-ethoxyoxalylamino-7-methoxy-4-oxo-4H-1-benzopyran, 7-methoxy-3-oxaloamino-4-oxo-4H-1- benzopyran of mp 236-238 ° (from ethanol).

Example 11

In an analogous manner to that described in Example 1, starting from 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyran, 5,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1- Prepare benzopyran with a melting point of 186-187 ° (from ethanol). The starting material can, for example, starting from 5,7-dimethyl-4-hydroxy-coumarin by reaction with nitric acid in acetic acid at 80 ° for 5,7-dimethyl-4-hydroxy-3-nitro-coumarin, treating the same with sodium hydroxide solution for 24 hours and excluding acid with decarboxylation to 4,6-dimethyl-2-hydroxy- _ß - nitro-acetophenone in analogy to that in J. Am. Chem. Soc. 67, 99 (1945) described method and reaction of the same with the mixed anhydride of formic and acetic acid to 5,7-dimethyl-3-nitro-4-oxo-4H-1-benzopyran of mp 120-125 ° and reduction thereof with sodium dithionite to give 3-amino-5,7-dimethyl-4-oxo-4H-1-benzopyran (mp 120-121 °) in analogy to the process described in Tetrahedron Letters 1976, 719 and purification thereof via the hydrochloride .

Example 12

Analogously to the process described in Example 11, starting from 4-hydroxy-8-methyl-coumarin via 4-hydroxy-8-methyl-3-nitro-coumarin of mp 178-180 ° (dec.), 2-hydroxy -3-methyl-β-nitro-acetophenone, mp 126-128 ° (from ethanol), 8-methyl-3-nitro-4-oxo-4H-1-benzopyran, mp 85-95 ° and 3-amino -8-methyl-4-oxo-4H-I-benzopyran, melting point 151-152 °, the 3-methoxyoxalylamino-8-methyl-4-oxo-4H-1-benzopyran, melting point 164.5 °.

Example 13

In an analogous manner to that described in Example 11, starting from 4-hydroxy-6-methoxy-coumarin via 4-hydroxy-6-methoxy-3-nitro-coumarin of mp 172-174 °, 2-hydroxy-5-methoxy - _β- nitro-acetophenone with a melting point of 143-144 ° (from methylene chloride / petroleum ether), 6-methoxy-3-nitro-4-oxo-4H-1-benzopyran with a melting point of 149-150 ° and 3-amino-6 -methoxy-4-oxo-4H-1-benzopyran the 6-methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran of mp 174-175 ° (from ethanol / chloroform).

Example 14

In an analogous manner to that described in Example 11, starting from 6,7-dimethyl-4-hydroxy-coumarin via 6,7-dimethyl-4-hydroxy-3-nitro-coumarin with a melting point of 205-207 ° (dec.) , 4,5-Dimethyl-2-hydroxy-β-nitro-acetophenone of mp 142-144 ° (from methylene chloride / petroleum ether), 6,7-dimethyl-3-nitro-4-oxo-4H-1-benzopyran of F. 155-157 ° and 3-amino-6,7-dimethyl-4-oxo-4H-1-benzopyran of F. 150-152 ° (from chloroform / toluene) the 6,7-dimethyl-3-methoxyoxalylamino 4-oxo-4H-1-benzopyran, mp 222-224 ° (from chloroform / ethanol).

Example, ₁₅

In an analogous manner to that described in Example 11, starting from 4-hydroxy-6-methyl-coumarin via 4-hydroxy-6-methyl-3-nitro-coumarin with a melting point of 178 ° (dec.), 2-hydroxy-5 -methyl-β-nitro-acetophenone with a melting point of 137-138 ° (from ethanol), 6-methyl-3-nitro-4-oxo-4H-1-benzopyran with a melting point of 97-99 ° and 3-amino-6 -methyl-4-oxo-4H-1-benzopyran of F. 96-98 ° (from ethyl acetate / petroleum ether) the 3-methoxyoxalylamino-6-methyl-4-oxu-4H-L-benzopyran of F. 179.5 ° (from chloroform / ethanol).

Example 16

In an analogous manner to that described in Example 11, starting from 4-hydroxy-4,6,7,8-tetrahydro-2-oxocyclopenta [g] -1-benzopyran via 4-hydroxy-3-nitro-4, 6, 7,8-tetrahydro-coumarin, mp 215-217 ° (dec.), 5- (2-nitroacetyl) -6-hydroxy-indane, mp 115-117 ° (from methylene chloride / petroleum ether), 3- Nitro-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran, melting point 145 ° (dec.) And 3-amino-4-oxo-4,6,7,8- tetrahydro-cyclopentajgl-1-benzopyran of F. 151-152 ° (from ethyl acetate / petroleum ether) the 3-meth _Q xyoxalylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -l-benzopyran der Formula from F. 185-186 °.

Example 17

• 5,7-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran vom F. 224 (Zers., aus Wasser/Aethanol), ausgehend von 5,7-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6,7-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran vom F. 205° (aus Wasser/Aethanol), ausgehend von 6,7-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran vom F. 230° (aus Wasser/Aethanol), ausgehend von 6-Methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Methyl-3-oxaloamino-4-bxo-4H-1-benzopyran vom - F. 199,5° (aus Wasser/Aethanol), ausgehend von 3-Methoxyoxalylamino-6-methyl-4-oxo-4H-1-benzopyran und
• 3-Oxaloamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta[g]-1-benzopyran vom F. 185° (Zers.), ausgehend von 3-Methoxy- oxalylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta[g]-1-benzopyran.

An analogous manner to that described in Example 2 is obtained

• 5,7-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran of F. 224 (dec., From water / ethanol), starting from 5,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H -1-benzopyran,
• 6,7-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran with a melting point of 205 ° (from water / ethanol), starting from 6,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1 -benzopyran,
• 6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran with a melting point of 230 ° (from water / ethanol), starting from 6-methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-methyl-3-oxaloamino-4-bxo-4H-1-benzopyran from - mp 199.5 ° (from water / ethanol), starting from 3-methoxyoxalylamino-6-methyl-4-oxo-4H-1- benzopyran and
• 3-oxaloamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran with a melting point of 185 ° (dec.), Starting from 3-methoxy-oxalylamino-4-oxo-4, 6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran.

Example 18

A suspension of 9 g of 3-amino-4-oxo-4H-1-benzopyran in 3.6 g of dimethyl acid and 300 ml of xylene is heated to boiling in a nitrogen atmosphere with stirring. About 200 ml of xylene are distilled off within 24 hours. Now allowed to cool to 90 ° and the precipitate of a by-product formed is filtered off and evaporated to dryness. The 3-methoxyoxalylamino-4-oxo-4H-1-benzopyran of mp 200-201 ° is obtained from ethanol / petroleum ether from the evaporation residue.

Example 19

• 6-Chlor-3-methoxyoxalylamino-7-methyl-4-oxo-4H-1-benzopyran,
• 6-Chlor-7-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran, 6-Chlor-3-methoxyoxalylamino-8-methyl-4-oxo-4H-1-benzopyran und
• 6-Chlor-8-methyl-3-oxaloamino-l-benzopyran.

An analogous manner to that described in Examples 1 to 18 also gives

• 6-chloro-3-methoxyoxalylamino-7-methyl-4-oxo-4H-1-benzopyran,
• 6-chloro-7-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran, 6-chloro-3-methoxyoxalylamino-8-methyl-4-oxo-4H-1-benzopyran and
• 6-chloro-8-methyl-3-oxaloamino-l-benzopyran.

Example 20

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

Composition (for 1000 tablets):

The 3-methoxyoxalylamino-4-oxo-4H-1-benzopyran is mixed with part of the wheat starch, with the lactose and the colloidal silica and the mixture is passed through a sieve. Another part of the wheat starch is gelatinized with five times the amount of water on the water bath and the above powder mixture is kneaded with this paste until a weak plastic mass has formed. The plastic mass is pressed through a sieve with a mesh size of approximately 3 mm, dried and the dry granules are again passed through a sieve. Then the remaining wheat starch, the talc and the magnesium stearate are mixed in and the mixture obtained is compressed into tablets of 0.25 g.

• 3-Oxaloamino-4-oxo-4H-1-benzopyran,
• 6-Hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-Chlor-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Chlor-3-oxaioamino-4-oxo-4H-1-benzopyran,
• 6-Methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,8-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 5,8-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-Methoxyoxalylamino-6,7-trimethylen-4-oxo-4H-l-benzopyran und
• 3-Oxaloamino-6,7-trimenthylen-4-oxo-4H-1-benzopyran hergestellt werden.

In an analogous manner, tablets containing 0.1 g each can also be used

• 3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-chloro-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-chloro-3-oxaioamino-4-oxo-4H-1-benzopyran,
• 6-methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,8-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 5,8-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-methoxyoxalylamino-6,7-trimethylene-4-oxo-4H-1-benzopyran and
• 3-oxaloamino-6,7-trimenthylene-4-oxo-4H-1-benzopyran can be prepared.

Example 21

An approximately 2% aqueous solution of an active ingredient according to the invention which is water-soluble in free form or in the form of the sodium salt can be inhaled, e.g. are manufactured in the following composition:

composition

Manufacturing

The active ingredient is dissolved in freshly distilled water with the addition of the equimolecular amount of 2N sodium hydroxide solution. Then the stabilizer and the preservative are added. After all components have completely dissolved, the solution obtained is made up to 100 ml, filled into vials and sealed in a gastight manner.

• 3-Methoxyoxalylamino-4-oxo-4H-1-benzopyran
• 6-Hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-Chlor-3-methoxyoxalylamino-4-oxo-4H-1benzopyran,
• 6-Chlor-3-oxaloamino-4-oxo-4H-l-benzopyran,
• 6-Methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,8-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 5,8-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-Methoxyoxalylamino-6,7-trimethylen-4-oxo-4H-1-benzopyran und
• 3-Oxaloamino-6,7-trimethylen-4-oxo-4H-1-benzopyran herstellen.

In an analogous manner, one can also contain 2% aqueous inhalation solutions

• 3-methoxyoxalylamino-4-oxo-4H-1-benzopyran
• 6-hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-chloro-3-methoxyoxalylamino-4-oxo-4H-1benzopyran,
• 6-chloro-3-oxaloamino-4-oxo-4H-l-benzopyran,
• 6-methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,8-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 5,8-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-methoxyoxalylamino-6,7-trimethylene-4-oxo-4H-1-benzopyran and
• Prepare 3-oxaloamino-6,7-trimethylene-4-oxo-4H-1-benzopyran.

Example 22

Capsules suitable for insufflation containing about 25 mg of an active ingredient according to the invention can e.g. are manufactured as follows:

Composition -

Manufacturing

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

• 3-Oxaloamino-4-oxo-4H-1-benzopyran,
• 6-Hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-Chlor-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Chlor-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-Methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,8-Dimetyyl-3-methoxyoxulylamino-4-oxo-4H-1-benzopyran,
• 5,8-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-Methoxyoxalylamino-6,7-trimethylen-4-oxo-4H-1-benzopyran und
• 3-Oxsloamino-5,7-trimethylen-4-oxo-4H-1-banzopyran herstellen.

In an analogous manner, insufflation capsules containing 25 mg each can also be used

• 3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-hydroxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-chloro-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-chloro-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6-methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,8-dimetyyl-3-methoxyoxulylamino-4-oxo-4H-1-benzopyran,
• 5,8-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 3-methoxyoxalylamino-6,7-trimethylene-4-oxo-4H-1-benzopyran and
• Prepare 3-oxsloamino-5,7-trimethylene-4-oxo-4H-1-banzopyran.

Example 23

• 3-Aethoxyoxalylamino-6-chlor-4-oxo-4H-1-benzopyran,
• N-(6,7-Dimethyl-4-oxo-4H-benzopyran-3-yl)-oxamid,
• 2-Methyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 7-Methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,7-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 3-Methoxyoxalylamino-8-methyl-4-oxo-4H-1-benzopyran,
• 6,7-Dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 5,7-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6,7-Dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran
• 3-Methoxyoxalylamino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran,
• 3-Oxaloamino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran,
• 3-Glycoloylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta[g]-1-benzopyran,
• 3-Acetoxyglycoloylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta[g]-1-benzopyran und
• 6-Methyl-3-oxaloamino-4-oxo-4H-1-benzopyran als Wirkstoff hergestellt werden.

In an analogous manner as described in Examples 20-22, pharmaceutical preparations can contain

• 3-ethoxyoxalylamino-6-chloro-4-oxo-4H-1-benzopyran,
• N- (6,7-dimethyl-4-oxo-4H-benzopyran-3-yl) oxamide,
• 2-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 7-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 5,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 3-methoxyoxalylamino-8-methyl-4-oxo-4H-1-benzopyran,
• 6,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran,
• 5,7-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran,
• 6,7-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran
• 3-methoxyoxalylamino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran,
• 3-oxaloamino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran,
• 3-glycoloylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran,
• 3-acetoxyglycoloylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran and
• 6-Methyl-3-oxaloamino-4-oxo-4H-1-benzopyran can be prepared as an active ingredient.

Example 1.24

15 ml of saturated methanolic ammonia solution are added to a solution of 0.2 g of 6,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran in 30 ml of methanol and 20 ml of methylene chloride. The precipitating N- (6,7-dimethyl-4-oxo-4H-1-berizopyran-3-y1) -oxamide is filtered off, washed with a little methanol and dried; it melts at 280-282 °.

Example 25

0.5 g of 3-chloro-oxalylamino-5,7-dimethyl-4-oxo-4H-1-benzopyran is added to a mixture of 50 ml of ethanol and 0.5 ml of 2N sodium hydroxide solution heated to 60 °. 300 ml of water are added, the mixture is warmed to 60 ° and then acidified to pH = 1 with 2N hydrochloric acid. The precipitate which precipitates is filtered off, washed with a little ethanol and dried. 5,7-Dimethyl-3-oxaloamino-4-oxo-1-benzopyran of mp. 222 ° (dec.) Is obtained.

• Zu 5 ml Oxalylchlorid wird unter Stickstoff langsam die Lösung von 0,5 g 3-Amino-5,7-dimethyl-4-oxo-4H-1-benzopyran in 5 ml Chloroform zugetropft. Man lässt eine Stunde nachrühren, dampft unter vermindertem Druck zu Trockne ein, löst den Eindampfruckstand in 30 ml Chloroform, filtriert und dampft erneut zur Trockne ein. Man erhält das 3-Chloroxalylamino-5,7-dimethyl-4-oxo-4H-1-benzopyran vom Smp. 150-153°.

The starting material can be produced as follows:

• The 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 nitrogen. The mixture is stirred for one hour, evaporated to dryness under reduced pressure, the evaporation pressure is dissolved in 30 ml of chloroform, filtered and again evaporated to dryness. The 3-chloroxalylamino-5,7-dimethyl-4-oxo-4H-1-benzopyran of mp 150-153 ° is obtained.

Example 26

0.2 g of potassium permanganate is added to a solution of 0.2 g of 3-glycoloylamino-4-oxo-4,6,7; 8-tetrahydro-cyclopenta [g] -1-benzopyran in 40 ml of acetone and 40 ml of water and allowed to stir for 40 hours at room temperature. The precipitate formed is filtered off, the filtrate is acidified with 2N hydrochloric acid and the precipitate which has separated out is filtered off. This gives 3-0xaloamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran with a melting point of 185 ° (dec.).

• Zu 6 g 3-Amino-4-oxo-4,6,7,8-tetrahydro-cyclo- penta[g]-1-benzopyran werden 7 g Glycolsäure hinzugefügt. Die Reaktionsmischung wird 1 Stunde auf 120° erwärmt. Man lässt auf Raumtemperatur abkühlen, digeriert mit Wasser, filtriert ab, trocknet und kristallisiert aus 400 ml Aethanol und anschliessend aus wenig Essigsäureäthylester um. Man erhält das 3-Glycoloylamino-4-oxo-4,6,7,8-tetrahydro- cyclopenta[g]-1-benzopyran vom Smp. 199-200°.

The starting material can be produced as follows, for example:

• 7 g of glycolic acid are added to 6 g of 3-amino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran. The reaction mixture is heated to 120 ° for 1 hour. It is allowed to cool to room temperature, digested with water, filtered off, dried and crystallized from 400 ml of ethanol and then from a little ethyl acetate. The 3-glycoloylamino-4-oxo-4,6,7,8-tetrahydrocyclopenta [g] -1-benzopyran of mp 199-200 ° is obtained.

From this, the 3-acetoxyglycoloylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran of mp 199-200 ° can be prepared by customary acetylation with acetic anhydride.

Example 27

The sodium salt is obtained by reacting 3-oxaloamino-oxo-4H-1-benzopyran with the equimolecular amount of 2N sodium hydroxide solution, and by reacting the acid mentioned, dissolved in hot dimethylformamide with 0.1 II calcium chloride solution, the calcium salt of 3-oxaloamino-4 -axo-4H-1-benzopy- rans, which do not melt up to 300 °.

Example 28

The 3-methoxyoxalylamino-4-oxo-2,6,7 is obtained in an analogous manner to that described in Example 1 by reacting 3-amino-4-oxo-2,6,7-trimethyl-4H-1benzopyran with methyl oxalate chloride -trimethyl-4H-1 benzopyran from Mp 210-211 °. The starting material can in the usual way starting from 6,7-dimethyl-4-hydroxy-3-nitro-coumarin by treatment with sodium hydroxide solution and acidic decarboxylation to give 2-hydroxy-4,5-dimethyl-ß-nitro-acetophenone, reaction with the same Acetic anhydride in the presence of formic anhydride to give 3-nitro-4-oxo-2,6,7-trimethyl-4H-1benzopyran of mp. 175-177 ° and hydrogenation thereof in the presence of palladium on calcium carbonate in dimethylformamide.

Example 29

In a manner analogous to that described in Example 2, 3-oxaloamino-4-oxo-2,6,7-trimethyl is obtained starting from 3-methoxyoxalylamino-4-oxo-2,5,7-trimethyl-4H-1-benzopyran -4H-1-benzopyran, mp over 200 ° (dec.).

Claims (19)

1. 3-oxaloamino-4-oxo-4H-l-benzopyran derivatives

wherein Ph represents optionally substituted 1,2-phenylene, R represents optionally esterified or amidated carboxy and R _{1 represents} hydrogen or an optionally substituted hydrocarbon radical, in free form or in salt form. 2. Compounds according to claim 1, in which R denotes carboxy, carboxy esterified with an alcohol of an aliphatic character or carbamyl optionally substituted by at least one optionally substituted or hetero-analogous hydrocarbon residue of aliphatic character or optionally substituted aryl residue, Ph optionally one or more times by aliphatic residues, acyl residues, optionally etherified or esterified hydroxy and / or trifluoromethyl substituted 1,2-phenylene and R _{1 is} hydrogen, an optionally substituted hydrocarbon radical of aliphatic character or aromatic hydrocarbon radical, lower alkyl, lower alkoxy, halogen and trifluoromethyl being suitable as substituents for aromatic groups. 3. Compounds according to claim 1, wherein R is carboxy, lower alkoxycarbonyl or carbamyl mono- or disubstituted by lower alkyl, Ph optionally by lower alkyl, 3- or 4-membered lower alkylene, hydroxy, lower alkoxy, 2- or 3-hydroxy-lower alkoxy, 3- or 4-membered lower alkylenedioxy, lower alkanoyl and / or halogen, substituted 1,2-phenylene and R _{1 is} hydrogen or lower alkyl, in each case in free form or in salt form. 4. Compounds according to claim 1, wherein R is carboxy or lower alkoxycarbonyl having up to 5 carbon atoms, Ph in one of the free positions, optionally by lower alkyl having up to 4 carbon atoms, 3- or 4-membered lower alkylene having up to 4 carbon atoms -Atoms, lower alkoxy with up to 4 carbon atoms, 3- or 4-membered lower alkylenedioxy, lower alkanoyl with up to 7 carbon atoms, hydroxyl and / or halogen to atom number 35 is substituted 1,2-phenylene and R _{1 is} hydrogen, lower alkyl with up to 4 carbon atoms or phenyl, in free form or in salt form. 5, compounds of formula Ia

wherein R _{2 is} carboxy and R ₃ and R ₄ independently of one another are hydrogen, lower alkyl having up to 4 carbon atoms, lower alkoxy having up to 4 carbon atoms, lower alkanoyl having up to 7 carbon atoms, hydroxyl or halogen to atom number 35 or together . represent a 3- or 4-membered lower alkylene or lower alkylenedioxy radical having up to 4 carbon atoms, in free form or in the form of a pharmaceutically acceptable salt. 6. Compounds according to claim 5, in which R _{2 is} carboxy and R ₃ and R _{4 are} hydrogen or in which R _{2 is} carboxy, R3 is hydrogen and R _{4 is} hydroxy, lower alkoxy having up to 4 C atoms or halogen to atom number 35, in free form or in the form of a pharmaceutically acceptable salt. 7. Compounds according to claim 5, wherein R _{2 is} carboxy and R ₃ and R ₄ independently of one another are C ₁ -C ₄ -alkyl or together are C ₃ - or C ₄ -alkylene, in free form or in salt form. 8. 3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof. 9. 3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, 6-hydroxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, 6-hydroxy-3-oxoaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 6-chloro-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, 6-chloro-3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 6-methoxy-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, 6-methoxy-3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 5,8-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, 5,8-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 3-methoxyoxalylamino-6,7-trimethylene-4-oxo-4H-1-benzopyran or 3-oxaloamino-6,7-trimethylene-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof. 10. 5,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, 3-methoxyoxalylamino-8-methyl-4-oxo-4H-1-benzopyran, 6,7-dimethyl-3-methoxyoxalylamino-4-oxo-4H-1-benzopyran, 3-methoxyoxalylamino-6-methyl-4-oxo-4H-benzopyran, 6,7-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 6-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 6-chloro-3-methoxyoxalylamino-7-methyl-4-oxo-4H-1-benzopyran, 6-chloro-7-methyl-3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 6-chloro-8-methyl-3-oxaloamina-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, 6-chloro-3-methoxyoxalylamino-8-methyl-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof, N- (6,7-dimethyl-4-oxo-4H-1-benzopyran-3-yl) oxamide, 3-methoxyoxalylamino-4-oxo-2,6,7-trimethyl-4H-1-benzopyran or 3-oxaloamino-4-oxo-2,6,7-trimethyl-411-1-benzopyran or a pharmaceutically acceptable salt thereof. 11. 5,7-dimethyl-3-oxaloamino-4-oxo-4H-1-benzopyran or a pharmaceutically acceptable salt thereof. 12. 3-glycoloylamino-4-oxo-4H-1-benzopyran derivatives of the formula

wherein Ph represents optionally substituted 1,2-phenylene, R 'represents an optionally esterified or etherified hydroxymethyl group and R _{1 represents} hydrogen or an optionally substituted aliphatic hydrocarbon radical, in free form or in salt form. 13. 3-Glycoloylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran. 14. 3-Acetoxyglycoloylamino-4-oxo-4,6,7,8-tetrahydro-cyclopenta [g] -1-benzopyran. 15. Process for the preparation of new 3-0xaloamino-4-oxo-4H-1-benzopyran derivatives of the formula I.

in which Ph represents optionally substituted 1,2-phenylene, R represents optionally esterified or amidated carboxy and R _{1 represents} hydrogen or an optionally substituted hydrocarbon residue, in free form or in salt form, characterized in that a) a compound of the general formula II

or an acid addition salt thereof with a compound of the formula RX (III) in which X denotes an optionally functionally modified carboxy group, or or an acid addition salt thereof with an acid of the formula R'-COOH (IIIa) or a functional derivative thereof or in a compound of the formula

wherein X ₂ denotes a radical which can be converted into the group R ', or in a salt thereof, X _{2 transfers} into the group R' and, if desired, converts a compound obtained into another compound of the formula I 'and / or a free compound obtained into one Salt or a salt obtained is converted into the free compound or into another salt. 17. Pharmaceutical preparations containing one of the compounds claimed in one of claims 1 to 14 in free form or in the form of a pharmaceutically usable salt. 18. Use of compounds claimed in any one of claims 1-14 as a medicament or for the production of such in a non-chemical way. 19. Compounds according to any one of claims 1-14 as a medicament. b) in a compound of the formula

wherein X _{1 means} a radical which can be converted into the desired group of the formula RC (= O), X ₁ converts into the group of the Fortnel RC (= O) - and, if desired, converts a compound obtainable in this way into another compound of the formula I and / or Converts a salt obtained into the free compound or another salt or a salt-forming compound obtained into a salt. 16. Process for the preparation of new 3-glycoloyl-amino-4-oxo-4H-1-benzopyran derivatives of the formula

wherein Ph is optionally substituted 1,2-phenylene, R 'represents an optionally esterified or etherified hydroxymethyl group and R _{1 is} hydrogen or an optionally substituted hydrocarbon radical, in free form or in salt form, characterized in that a compound of the formula