Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
  • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
  • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
  • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings

Definitions

• the present invention relates to new benzopyran derivatives, in particular 3-oxaloamino-4-oxo-4H-1 - benzopyran derivatives of the formula I.
• Ph represents optionally substituted 1,2-phenylene
• R represents optionally esterified or amidated carboxy
• R 1 represents hydrogen or an optionally substituted hydrocarbon radical, in free form or in salt form
• 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.
• aliphatic radicals such as lower alkyl, or lower alkylene
• acyl radicals such as, bonded to two adjacent C atoms
• 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.
• 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.
• 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.
• 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
• 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.
• 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) carb
• 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.
• the free valence is based on a non-aromatic carbon atom.
• 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.
• aromatic hydrocarbon radical is, for example, optionally substituted phenyl.
• 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.
• 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.
• 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).
• PCA reaction passive cutaneous anaphylaxis test
• 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.
• the compounds of the present invention are particularly useful as inhibitors of allergic reactions, e.g. in the treatment and prophylaxis of
• 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 disub
• 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
• 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
• 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
• 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.
• 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.
• 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.
• 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.
• a water-binding agent such as an acid anhydride, for example phosphorus pentoxide, or of dicyclohexylcarbodiimide
• 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.
• 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.
• a water-binding agent or acidic condensing agent which brings about the dehydration of the primarily formed substituted ammonium salt.
• 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.
• a base for example potassium carbonate
• Such functionally modified oxalo groups are preferably those which have, as the functionally modified ⁇ -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.
• a hydrohalic acid such as hydrochloric acid
• a lower alkanol such as methanol or ethanol.
• dihalomethylene groups such as dichloromethylene
• lower alkoxyhalomethylene groups such as methoxy or ethoxychloromethylene
• 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
• Functionally modified carboxy as an imino ether, orthoester or Esterhalogenidgrupptechnik 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.
• 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.
• 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
• 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.
• halocarbonyl for example chlorocarbonyl
• 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.
• a basic condensing agent for example pyridine or triethylamine
• 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.
• This can advantageously be formed in situ in the course of the oxidation reaction, for example from the acyl group of an optionally ⁇ . ⁇ -unsaturated or ⁇ , ⁇ -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 ⁇ , ⁇ -unsaturated or ⁇ , ⁇ -dihydroxylated carboxylic acids are, for example, alkanoyl groups, such as lower alkanoyl, for example acetyl, acyl groups of ⁇ , ⁇ -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 ⁇ , ⁇ -unsaturated ten araliphatic carboxylic acids, for example optionally substituted cinnamoyl, or acyl groups of aliphatic ⁇ , ⁇ -dihydroxydicarboxylic acids, such as tartaric acid, or monofunctional carboxy derivatives, such as esters or amides.
• alkanoyl groups such as lower alkanoyl
• 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.
• a mineral acid such as a hydrohalic acid, for example with hydrochloric or hydrobromic acid
• 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.
• 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.
• 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.
• 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.
• an inert solvent such as acetone, sulfuric acid, pyridine or water
• 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.
• 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.
• 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.
• 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.
• 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 .
• 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 triethyl
• 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.
• 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.
• a corresponding halogen compound such as bromoacetyl compound
• X 1 is optionally substituted benzyliminoacetyl
• 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.
• a functionally modified oxalo having an imino ether group 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.
• 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.
• a basic hydrolysis agent such as sodium hydroxide solution
• 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.
• 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.
• 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
• an inert solvent in particular an excess of the alcohol used and, if necessary, in the
• 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.
• an acid catalyst such as one of the above
• an inert solvent such as an aromatic hydrocarbon, e.g. in benzene or toluene
• an excess of the alcohol derivative used or the corresponding alcohol if necessary under, e.g. azeotropic, distillation of the water of reaction.
• 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.
• 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.
• 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
• 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.
• 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.
• 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.
• a catalyst for example a basic or acidic agent, such as a strong base, for example sodium or potassium hydroxide, or
• 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.
• 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,
• 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.
• 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
• a strong acid such as a mineral acid , for example of hydrochloric acid, sulfuric acid or phosphoric acid
• esterified or etherified hydroxyl groups can also be converted into one another.
• 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.
• an etherifying agent e.g. with a lower alkylating agent
• 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 ,.
• a mineral acid for example with iodic, chlorine or hydrobromic or sulfuric acid
• organic sulfonic acid for example with p-toluene, p-bromobene zol, benzene
• 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.
• lower alkyl chlorides bromides or iodides
• lower alkylene halohydrins for example ethylene chlorohydrin
• di-lower alkyl sulfates for example dimethyl or diethyl sulfate, or methyl fluorosulfonate
• 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.
• 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.
• methylation using methyl iodide in amyl alcohol / potassium carbonate at boiling temperature is recommended.
• 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.
• an acidic agent such as a hydrohalic acid, e.g. of hydroiodic acid
• an inert solvent e.g. convert to ethanol or acetic acid
• esterified hydroxy such as halogen
• a corresponding metal alcoholate such as an alkali metal lower alkanolate, e.g. with sodium methoxide
• 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.
• 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.
• 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 .
• 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.
• compositions of the present invention are manufactured in a manner known per se, e.g. produced by conventional mixing, granulating, coating, solution or lyophilization processes.
• 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.
• fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparation and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate
• binders such as steel hexister
• 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 .
• 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.
• compositions 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.
• 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.
• suppositories into consideration 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.
• aqueous solutions of an active ingredient in water-soluble form for example a water-soluble salt
• suspensions of the active ingredient such as corresponding oily injection suspensions
• suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides
• 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.
• 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.
• compressed air can also be used, which can be generated as required by means of a suitable compression and expansion device.
• compositions 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
• 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 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.
• 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.
• 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.
• 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:
• 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.
• Capsules suitable for insufflation containing about 25 mg of an active ingredient according to the invention can e.g. are manufactured as follows:
• 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.
• 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.).
• 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.
• 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 °.
• 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.
• 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.).

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