Substituted coumarin compounds

New benzopyrane derivatives of the general formula ##STR1## in which R is free, esterified or amidated carboxyl, Ph is 1,2-phenylene which contains the group R--CO--NR.sub.3 -- and is otherwise unsubstituted or is substituted, X is a group of the formula --CO--CR.sub.1 .dbd.CR.sub.2 --, in which R.sub.1 and R.sub.2 independently of one another are hydrogen, acyl or a substituted or unsubstituted hydrocarbon radical or a hetero-analogue thereof, or conjointly are 3-membered to 5-membered lower alkylene, and R.sub.2 can also be free or etherified hydroxyl or hydroxyl etherified by an organic carboxylic acid, and R.sub.3 is hydrogen or lower alkyl, are useful as anti-allergic agents.

The invention relates to a process for the preparation of novel benzopyrane 
derivatives of the general formula 
##STR2## 
in which R is free, esterified or amidated carboxyl, Ph is 1,2-phenylene 
which contains the group R--CO--NR.sub.3 -- and is otherwise unsubstituted 
or is substituted, X is a group of the formula --CO--CR.sub.1 
.dbd.CR.sub.2 --, in which R.sub.1 and R.sub.2 independently of one 
another are hydrogen, acyl or a substituted or unsubstituted hydrocarbon 
radical or a hetero-analogue thereof, or conjointly are 3-membered to 
5-membered lower alkylene, and R.sub.2 can also be free or etherified 
hydroxyl or hydroxyl esterified by an organic carboxylic acid, and R.sub.3 
is hydrogen or lower alkyl, in the free form or in the form of a salt, the 
novel compounds themselves, pharmaceutical formulations containing these 
compounds and the use of such formulations. 
Esterified carboxyl is, for example, carboxyl esterified by a substituted 
or unsubstituted alcohol of aliphatic or aromatic character. 
An alcohol of aliphatic character is an alcohol in which the C atom bonded 
to the hydroxyl group is not a member of an aromatic system, for example 
an aliphatic alcohol which is unsubstituted or substituted by substituted 
or unsubstituted aryl or hetero-aryl, for example substituted or 
unsubstituted phenyl or pyridyl, a possible alcohol of this type being, 
for example, a lower alkanol, or is a cycloaliphatic alcohol, for example 
a 5-membered to 8-membered cycloalkanol. Examples which may be mentioned 
of carboxyl esterified by a substituted or unsubstituted alcohol of 
aliphatic character are: lower alkoxy-carbonyl, for example methoxy-, 
ethoxy-, propoxy-, isopropoxy- and butoxy-carbonyl, phenyl-lower 
alkoxy-carbonyl, in particular .alpha.- and .beta.-phenyl-lower 
alkoxy-carbonyl, which is unsubstituted or substituted in the phenyl part, 
possible substituted or unsubstituted phenyl and possible lower alkoxy 
being, in particular, those mentioned below, for example benzyloxycarbonyl 
and .alpha.- and .beta.-phenethoxycarbonyl, and 5-membered to 8-membered 
cycloalkoxycarbonyl, for example cyclopentyloxy-, cyclohexyloxy- and 
cycloheptyloxy-carbonyl. 
An alcohol of aromatic character is an alcohol in which the C atom bonded 
to the hydroxyl group is a member of a carbocyclic or heterocyclic 
aromatic system, for example a phenol which is unsubstituted or 
substituted in the phenyl part or a hydroxypyridine which is substituted 
by lower alkyl, such as methyl, or lower alkoxy, such as methoxy. Examples 
which may be mentioned of carboxyl esterified by a substituted or 
unsubstituted alcohol of aromatic character are: phenoxy-, tolyloxy-, 
anisyloxy- and chlorophenoxy-carbonyl and also 2-, 3- and 
4-pyridyloxycarbonyl. 
Amidated carboxyl contains, as the amino group, for example a free amino 
group or an amino group which is substituted by at least one substituted 
or unsubstituted hydrocarbon radical of aliphatic character, or a 
hetero-analogue thereof, or a substituted or unsubstituted aryl radical. 
In a substituted or unsubstituted hydrocarbon radical of aliphatic 
character, or a hetero-analogue thereof, the free valency emanates from a 
non-aromatic C atom. A radical of this type is, for example, lower alkyl 
or lower alkenyl, which can be substituted by substituted or unsubstituted 
phenyl or naphthyl, or, for example, 5-membered to 8-membered cycloalkyl, 
such as cyclohexyl, or unsubstituted or lower alkylated, for example 
methylated, 4-membered to 7-membered alkylene, or a monooxa-, -aza- or 
-thia-analogue thereof, for example tetramethylene or pentamethylene or 
3-oxa, 3-aza- or 3-thia-pentamethylene. Examples which may be mentioned of 
carbamyl substituted by at least one such radical are: mono- or di-lower 
alkyl-carbamyl, such as N-methyl- and N,N-diethyl-carbamyl, phenyl-lower 
alkyl-carbamoyl which in the phenyl part is unsubstituted or substituted 
as indicated below, such as N-benzyl- or N-(1- or 2-phenethyl)-carbamyl, 
or pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, 
thiomorphininocarbonyl, piperazinocarbonyl or 4-lower 
alkyl-piperazinocarbonyl, for example 4-methyl-piperazinocarbonyl. 
A substituted or unsubstituted aryl radical is, for example, substituted or 
unsubstituted naphthyl, or phenyl which is unsubstituted or substituted as 
indicated below and/or substituted on two adjacent ring atoms by a group 
-OX-, which has the meaning defined. Examples which may be mentioned of 
carbamyl groups substituted by a radical of this type are, for example, 
N-phenyl-, N-tolyl-, N-anisyl-, N-chlorophenyl- and N-naphthyl-carbamyl as 
well as groups of the formula 
##STR3## 
1,2-Phenylene Ph which contains the group R--CO--NR.sub.3 - can also 
contain, in addition to this group, at least one, for example one or two, 
further substituents, examples of possible substituents being lower alkyl, 
such as those mentioned below, for example methyl, lower alkoxy, such as 
those mentioned below, for example methoxy, halogens, such as those 
mentioned below, for example chlorine, and trifluoromethyl. 
Acyl is, for example, acyl derived from an organic carboxylic acid or from 
free, partially esterified or amidated carbonic acid. 
Acyl derived from a carboxylic acid is, for example, lower alkanoyl or 
substituted or unsubstituted benzoyl, for example, acetyl, propionyl, 
butyryl or benzoyl. 
Acyl derived from free, partially esterified or amidated carbonic acid is, 
for example, free, esterified or amidated carboxyl, such as free carboxyl 
or carboxyl esterified or amidated as indicated above, for example 
carboxyl, methoxy- or ethoxy-carbonyl or carbamyl. 
Free or etherified hydroxyl is, for example, free hydroxyl or hydroxyl 
etherified by a lower alkanol or by a substituted or unsubstituted phenol, 
i.e. hydroxyl, lower alkoxy or substituted or unsubstituted phenoxy, for 
example hydroxyl, methoxy, ethoxy or phenoxy. 
Free hydroxyl or hydroxyl esterified by carboxylic acid is, for example, 
free hydroxyl or hydroxyl esterified by a lower alkanecarboxylic acid or 
by a substituted or unsubstituted benzoic acid, i.e. hydroxyl, lower 
alkanoyloxy or substituted or unsubstituted benzoyloxy, especially 
acetoxy, propionyloxy or benzoyloxy. 
A substituted or unsubstituted hydrocarbon radical or a hetero-analogue 
thereof is, for example, a substituted or unsubstituted hydrocarbon 
radical of aliphatic character or a substituted or unsubstituted aromatic 
hydrocarbon radical or a hetero-analogue thereof. 
3-membered to 5-membered lower alkylene can be straight-chain or branched 
and is, for example, 1,3-propylene, 1,4-butylene, 1,5-pentylene or 2- or 
3-methyl-1,4-butylene. 
In a substituted or unsubstituted hydrocarbon radical of aliphatic 
character the free valency emanates from a non-aromatic C atom. A radical 
of this type is, for example, an aliphatic hydrocarbon radical which is 
unsubstituted or substituted by substituted or unsubstituted phenyl, for 
example a lower alkyl radical, or a cycloaliphatic hydrocarbon radical, 
such as adamantyl or monocyclic 5-membered to 8-membered cycloalkyl or 
cycloalkenyl, for example 1-cycloalkenyl. Examples of such radicals which 
may be mentioned in particular are: methyl, ethyl, isopropyl and butyls, 
benzyl and methyl-, methoxy- and chloro-benzyls, cyclopentyl, cyclohexyl, 
1-cyclohexenyl, cycloheptyl and 1-cycloheptenyl. 
A substituted or unsubstituted aromatic hydrocarbon radical or a 
hetero-analogue thereof contains, for example 5 or 6 ring members and up 
to 2 hetero-atoms, such as a nitrogen, oxygen or sulphur atom, and is, for 
example, substituted or unsubstituted phenyl, such as one of those below, 
or a 5-membered or 6-membered hetero-aryl radical containing a nitrogen, 
oxygen or sulphur atom, such as, for example, one of those below. Examples 
are, in particular, phenyl or pyridyl which are unsubstituted or 
substituted by methyl, methoxy or chlorine. 
The following applies in the preceding and following text: 
Substituted or unsubstituted phenyl and naphthyl and also phenyl in 
substituted or unsubstituted benzoyl, benzoyloxy and aromatic alcohols is, 
for example, phenyl or naphthyl which is unsubstituted or monosubstituted 
or polysubstituted, for example monosubstituted or disubstituted, possible 
substituents being, in particular, lower alkyl, lower alkoxy or halogens, 
for example those mentioned below, hydroxyl and also trifluoromethyl, such 
as phenyl, naphthyl, o-, m- or p-tolyl, o-, m- or p-anisyl, o- or 
p-chlorophenyl or 2,4-, 3,5- or 2,6-dichlorophenyl. 
Substituted or unsubstituted hetero-aryl, and substituted or unsubstituted 
hetero-aryl in hetero-aromatic alcohols, preferably has 5 or 6 ring 
members and contains, as the hetero-atom or hetero-atoms up to two 
nitrogen, oxygen and/or sulphur atoms and is, for example, unsubstituted 
or monosubstituted or polysubstituted pyridyl, thienyl or furyl, possible 
substituents being lower alkyl, lower alkoxy and halogens, in particular, 
in each case, those mentioned below, such as 2-, 3- or 4-pyridyl, 
6-methyl-2-pyridyl, 6-methoxy-2-pyridyl or 2- or 3-thienyl. 
Lower alkyl contains, for example, up to 7 and in particular up to 4 C 
atoms and can be straight-chain or branched and bonded in any desired 
position, such as methyl, ethyl, propyl or n-butyl or also isopropyl, 
sec.-butyl or isobutyl. 
Lower alkoxy, and also lower alkoxy in lower alkoxy-carbonyl, contains, for 
example, up to 7 and in particular up to 4 C atoms and can be 
straight-chain or branched and bonded in any desired position, such as 
methoxy, ethoxy, propoxy, isopropoxy, butoxy or amyloxy. 
Lower alkanoyl, and also lower alkanoyl in lower alkanoyloxy, contains, for 
example, up to 7 and in particular up to 4 C atoms and can be 
straight-chain or branched, such as acetyl, propionyl, butyryl or 
isobutyryl. 
Halogen is, for example, halogen having an atomic number of up to and 
including 35, such as fluorine, chlorine or bromine. 
Salts of compounds of the general formula (I), in which R, R.sub.1 and/or 
R.sub.2 is carboxyl, are salts with bases, in particular corresponding 
salts which can be used pharmaceutically, such as alkali metal salts or 
alkaline earth metal salts, for example sodium salts, potassium salts, 
magnesium salts or calcium salts, and also ammonium salts with ammonia or 
amines, such as lower alkyl-amines or hydroxy-lower alkyl-amines, for 
example trimethylamine, triethylamine or di- or 
tri-(2-hydroxyethyl)-amine. 
The novel compounds show valuable pharmacological properties. In 
particular, they show anti-allergic actions, which can be demonstrated, 
for example, on rats in doses of about 1 to about 100 mg/kg on oral 
administration in the passive cutaneous anaphylaxis test (PCA reaction), 
which is carried out analogously to the method described by Goose and 
Blair, Immunology, Volume 16, page 749 (1969), passive cutaneous 
anaphylaxis being produced by the procedure described by Ovary, Progr. 
Allergy. Volume 5, page 459 (1958). They also effect inhibition of the 
immunologically induced release of hystamine, for example from the 
peritoneal cells of rats infested with Nippostrongylus brasiliensis, in 
vitro, (cf. Dukor et al., Intern. Arch. Allergy (1976), to be published). 
Furthermore, they are highly active in various bronchoconstrictions 
induced artificially, as can be shown, for example, in the dosage range of 
about 1 to about 3 mg/kg, administered intraveneously, with the aid of the 
bronchoconstriction produced by IgE antibodies in rats and in the dosage 
range of from about 1 mg/kg, administered intraveneously, with the aid of 
the bronchoconstriction induced by IgG antibodies in guinea pigs. The 
compounds of the present invention are useful as inhibitors of allergic 
reactions, for example in the treatment and prophylaxis of allergic 
diseases, such as asthma, including both extrinsic and intrinsic asthma, 
or other allergic diseases, such as hayfever, conjunctivitis, urticaria 
and eczema. 
The invention relates, in particular, to compounds of the general formula I 
in which R is carboxyl, carbamyl esterified by an alcohol of aliphatic or 
aromatic character or carbamyl which is unsubstituted or substituted by at 
least one substituted or unsubstituted hydrocarbon radical of aliphatic 
character, or a hetero-analogue thereof, or by a substituted or 
unsubstituted aryl radical, Ph is 1,2-phenylene which contains the group 
R--CO--NR.sub.3 -- and is otherwise unsubstituted or is substituted, X is 
a group --CO--CR.sub.1 .dbd.CR.sub.2 --, in which R.sub.1 and R.sub.2 
independently of one another are hydrogen, lower alkanoyl, benzoyl, free 
carboxyl, carboxyl esterified or amidated as indicated above for R or a 
substituted or unsubstituted hydrocarbon radical of aliphatic character or 
an aromatic hydrocarbon radical, or a hetero-analogue thereof, or 
conjointly are 1,3-, 1,4- or 1,5-lower alkylene, and R.sub.2 can also be 
free hydroxyl or hydroxyl etherified by a lower alkanol or esterified by a 
lower alkanecarboxylic acid, and R.sub.3 is hydrogen or lower alkyl, 
possible substituents of aromatic and heteroaromatic groups being, in each 
case, in particular lower alkyl, such as methyl, lower alkoxy, such as 
methoxy, halogen, such as chlorine, hydroxyl and trifluoromethyl, in the 
free form or in the form of a salt. 
The invention relates, in particular, to compounds of the general formula I 
in which R is carboxyl, carboxyl esterified by a lower alkanol which is 
unsubstituted or substituted by substituted or unsubstituted phenyl or 
carboxyl esterified by a substituted or unsubstituted phenol, or carbamyl 
which is unsubstituted, monosubstituted by lower alkyl, substituted or 
unsubstituted phenyl-lower alkyl or substituted or unsubstituted phenyl, 
for example a group 
##STR4## 
in which Ph and X are as defined below, or disubstituted by lower alkyl or 
by lower alkylene or a hetero-analogue thereof, Ph is 1,2-phenylene which 
contains the group R--CO--NR.sub.3 -- and is otherwise unsubstituted or is 
substituted, X is a group --CO--CR.sub.1 .dbd.CR.sub.2 --, in which 
R.sub.1 and R.sub.2 independently of one another are hydrogen, lower 
alkanoyl, such as acetyl, free carboxyl or carboxyl esterified by a lower 
alkanol, such as methanol, lower alkyl which is unsubstituted or 
substituted by phenyl, which, in turn, can be substituted, or substituted 
or unsubstituted phenyl or 5-membered to 6-membered heteroaryl containing 
a nitrogen, oxygen or sulphur atom, or conjointly are tri-, tetra- or 
penta-methylene and R.sub.2 can also be free hydroxyl or hydroxyl 
etherified by a lower alkanol, such as methanol, or esterified by a lower 
alkanecarboxylic acid, such as acetic acid, and R.sub.3 is hydrogen or 
lower alkyl, possible substituents of phenyl, phenol, 1,2-phenylene Ph and 
heteroaryl being lower alkyl, such as methyl, lower alkoxy, such as 
methoxy, halogen, such as chlorine, hydroxyl and trifluoromethyl, in the 
free form or in the form of a salt. 
The invention relates especially, on the one hand, to compounds of the 
general formula Ia 
##STR5## 
and, on the other hand, to compounds of the general formula Ib 
##STR6## 
in which, in each case, R.sub.o is carboxyl, lower alkoxy-carbonyl, such 
as methoxy- or ethoxy-carbonyl, phenyl-lower alkoxy-carbonyl which in the 
phenyl part is unsubstituted or substituted as indicated below, such as 
benzyloxycarbonyl, or free carbamyl, carbamyl monosubstituted or 
disubstituted by lower alkyl, such as methyl or ethyl, or carbamyl 
disubstituted by tetra- or penta-methylene or 3-oxa-, 3-aza- or 
3-thia-pentamethylene, Ph' is 1,2-phenylene which contains the group 
R.sub.o --CO--NH-- and, in addition, is otherwise unsubstituted or is 
substituted as indicated below, R.sub.1 ' and R.sub.2 ' conjointly are 
tri-, tetra- or penta-methylene, or R.sub.1 ' is hydrogen, lower alkanoyl, 
such as acetyl, carboxyl, lower alkoxy-carbonyl, such as methoxy- or 
ethoxy-carbonyl, lower alkyl, such as methyl, or phenyl or pyridyl which 
are unsubstituted or substituted as indicated below, and R.sub.2 ' has one 
of the meanings given for R.sub.1 ' or is hydroxyl, lower alkoxy, such as 
methoxy, or lower alkanoyloxy, such as acetoxy, possible substituents of 
substituted phenyl-lower alkoxy-carbonyl R' or additionally substituted 
1,2-phenylene Ph' and of substituted phenyl and pyridyl R.sub.1 ' and/or 
R.sub.2 ' being, lower alkyl, such as methyl, lower alkoxy, such as 
methoxy, halogen, such as chlorine, hydroxyl and trifluoromethyl, in each 
case in the free form or in the form of a salt. 
The invention relates primarily on the one hand to compounds of the general 
formula Ia in which R.sub.o is carboxyl or lower alkoxy-carbonyl having up 
to 5 C atoms, such as methoxy- or ethoxy-carbonyl, Ph' is 1,2-phenylene 
which contains the group R.sub.o --CO--NH, for example bonded in the 
4-position or 5-position, and is otherwise unsubstituted or substituted in 
one of the free positions by lower alkyl or lower alkoxy having, in each 
case, up to 4 C atoms, such as methyl or methoxy, or hydroxyl or halogen, 
such as chlorine, R.sub.1 ' is hydrogen or lower alkyl or lower alkanoyl, 
having, in each case, up to 4 C atoms, such as methyl or acetyl, or is 
phenyl or pyridyl and R.sub.2 ' has one of the meanings given for R.sub.1 
' or is hydroxyl or lower alkoxy having up to 4 C atoms, such as methoxy, 
and, on the other hand, to compounds of the general formula Ib in which 
R.sub.o and Ph' are as defined above and R.sub.1 ' and R.sub.2 ' 
independently of one another are hydrogen, lower alkyl having up to 4 C 
atoms, such as methyl, or phenyl, in each case in the free form or in the 
form of a salt. 
The invention relates very particularly to compounds of the formula Ic 
##STR7## 
in which one of the radicals R.sub.6 and R.sub.7 is a group of the formula 
R.sub.o '--CO--NH, in which R.sub.o ' is carboxyl or, less preferentially, 
lower alkoxy-carbonyl having up to 5 C atoms, such as methoxy- or 
ethoxy-carbonyl, and the other is hydrogen and R.sub.3 and R.sub.4 
independently of one another are hydrogen or lower alkyl having up to 4 C 
atoms, such as methyl, in the free form or in the form of a salt. 
The novel compounds can be prepared according to process which are known 
per se. 
A preferred procedure comprises, for example, the reaction of a compound of 
the general formula II 
##STR8## 
in which Ph, R.sub.3 and X have the defined meanings, or a salt thereof, 
with a functionally modified oxalic acid of the formula R-Y in which Y is 
an esterified carboxyl group or a carboxyl group which has been converted 
to an anhydride with a hydrogenhalide acid and, if desired, the conversion 
of a compound thus obtained into another compound of the general formula 
(I) and/or the conversion of a resulting salt-forming compound into a salt 
or of a resulting salt into the free compound. 
Salts of compounds of the formula II are, for example, hydrohalides, such 
as hydrochlorides, thereof and also salts with oxalic acid or monoester or 
monoamide thereof. 
Functional derivatives of oxalic acid are for example symmetrical oxalic 
acid diesters, such as di-lower alkyl esters, and esterified 
halogenooxalic acids of the formula R-CO-Hal, in which Hal is chlorine or 
bromine. 
The reaction can be carried out in a customary manner, especially in the 
manner known from the literature for analogous reactions, if necessary in 
the presence of a condensing agent, for example in the presence of a basic 
condensing agent, such as a tertiary organic nitrogen base, for example 
triethylamine or pyridine, or of an alkali metal hydroxide or alkali metal 
carbonate, for example of sodium hydroxide or potassium hydroxide, in the 
case of the reaction with an ester-halide of oxalic acid, and/or in an 
inert solvent, preferably an inert polar solvent, such as a 
N,N-dialkylamide, for example in N,N-dimethylformamide or 
N,N-dimethylacetamide. 
With this reaction, oxalic acid ester-amides and/or symmetrical oxalic acid 
diamides of the general formula (I) can be obtained, in accordance with 
the particular molar ratios and concentration ratios of the oxalic acid 
component used and on the reaction conditions. If, for example, the 
equimolar amount of an oxalic acid ester-halide is added to a solution of 
the amine component of the general formula (II) and a tertiary organic 
nitrogen base at a moderate reaction temperature, for example at 0.degree. 
to 80.degree. and preferably 15.degree. to 50.degree., or if the equimolar 
amount of an oxalic acid diester is initially introduced and the amine 
component is added, oxalic acid ester-amides of the general formula (I) 
are preferentially obtained. Conversely, when an excess of the amine 
component is used under more drastic reaction conditions and/or the amine 
component is initially introduced, symmetrical oxamides of the general 
formula (I) are preferentially obtained from the reaction with oxalic acid 
diesters. 
The novel compounds can also be prepared by converting in a compound of the 
formula 
##STR9## 
a radical R' of the formula X.sub.1 --NR.sub.3 -- in which X.sub.1 denotes 
a halogenooxalyl group, into a group of the formula R--CO--NR.sub.3 -- by 
solvolysis, or a radical R' of the formula X.sub.2 --NR.sub.3 -- in which 
X.sub.2 denotes a glyoxyloyl group or an optionally etherfied glycoloyl 
group, into an optionally esterified oxaloamino group R--CO--NR.sub.3 -- 
by oxidation and, if desired, converting a compound which is thus 
obtainable into another compound of the formula I and/or converting a 
resulting salt into the free compound or into another salt or converting a 
resulting salt-forming compound into a salt. 
In this context, halogenooxalyl X.sub.1 is especially chlorooxalyl and 
solvolysis means hydrolysis, alcoholysis (reaction with the alcohol 
corresponding to the desired esterified carboxyl group R--) and/or ammono- 
or aminolysis (reaction with ammonia or an amine corresponding to the 
desired amidated carboxyl group). 
Thus, for example, a halogenooxalyl group X.sub.1 can be converted into the 
free oxalo group by hydrolysis, for example in the presence of an acid or 
basic agent, such as of a mineral acid, for example hydrochloric acid, or 
of an alkali metal hydroxide, for example sodium hydroxide solution or 
potassium hydroxide solution, the reaction preferably being carried out 
under acid conditions and/or in the presence of an oxidising agent, for 
example hydrogen peroxide, in the case of the hydrolysis of cyanocarbonyl 
groups or of thiooxalo groups of the oxalo group. The reaction is, if 
necessary, carried out in a polar solvent, such as a lower alkanol, ketone 
or ether, for example in ethanol, acetone or dioxane, and/or with cooling 
or warming, for example at about 0.degree. C. to about 100.degree. C. 
A halogenooxalyl group X.sub.1 can also be converted into esterified oxalo 
groups by conventional alcoholysis, i.e. by reaction with the 
corresponding alcohol. The reaction is advantageously carried out in the 
presence of a basic condensing agent, for example of pyridine or 
triethylamine. In an analogous manner, a halogenooxalyl group X.sub.1 can 
be converted into an amidated oxalo group R--C(.dbd.O)-- by ammonolysis or 
aminolysis, i.e. by reaction with ammonia or a corresponding primary or 
secondary amine, preferably in the presence of a basic condensing agent, 
for example of sodium hydroxide, pyridine or triethylamine. 
A glyoxyloyl group X.sub.2 which can be hydrated can advantageously be 
formed in situ in the course of the oxidation reaction, for example from 
the acyl group of an aliphatic or araliphatic carboxylic acid which can be 
.alpha.,.beta.-unsaturated or .alpha.,.beta.-dihydroxylated, a glycoloyl 
group, which can be esterified on the hydroxyl group, or the glycyl group, 
or can be set free from one of its functional derivatives, for example 
from one of its acetals or imines. Acyl groups of carboxylic acids which 
can be .alpha.,.beta.-unsaturated or .alpha.,.beta.-dihydroxylated are, 
for example, alkanoyl groups, such as lower alkanoyl, for example acetyl, 
acyl groups of .alpha.,.beta.-unsaturated aliphatic monocarboxylic or 
dicarboxylic acids, for example acryloyl, crotonyl or the acyl group of 
free or functionally modified fumaric acid or maleic acid, acyl groups of 
.alpha.,.beta.-unsaturated araliphatic carboxylic acids, for example 
substituted or unsubstituted cinnamoyl, or acyl groups of aliphatic 
.alpha.,.beta.-dihydroxydicarboxylic acids, such as of tartaric acid, or 
monofunctional carboxy derivatives, such as esters or amides, thereof. 
Esterified glycoloyl groups are, for example, glycoloyl groups esterified 
on the hydroxyl group by a mineral acid, such as a hydrogen halide acid, 
for example by hydrochloric acid or hydrobromic acid, or by a carboxylic 
acid, for example by acetic acid or substituted or unsubstituted benzoic 
acid. Acetalised glyoxyloyl groups are, for example, glyoxyloyl groups 
acetalised by lower alkanols or a lower alkane-diol, such as dimethoxy-, 
diethoxy- or ethylenedioxy-acetyl. Imines of glyoxyloyl groups are, for 
example, substituted or unsubstituted N-benzylimines or 
N-(2-benzothiazolyl)-imines thereof or imines with 
3,4-di-tert.-butyl-o-quinone. 
The oxidation can be carried out in a customary manner by reaction with a 
suitable oxidising agent. Suitable oxidising agents are, especially, 
oxidising heavy metal compounds, such as silver compounds, for example 
silver nitrate or silver picolinate, oxy-acids of heavy metals, for 
example of manganese-IV, manganese-VII, chromium-VI and iron-VI, or of 
halogens, or their anhydrides or salts, such as chromic acid, chromium 
dioxide, potassium dichromate, potassium permanganate, manganese dioxide, 
potassium ferrate, sodium iodate, sodium periodate or lead tetraacetate. 
The reaction with these oxidising agents is effected in a customary 
manner, for example in an inert solvent, such as acetone, acetic acid, 
pyridine or water, or a mixture, preferably an aqueous mixture, of inert 
solvents, at normal temperature or, if necessary, with cooling or warming, 
for example at about 0.degree. C. to about 100.degree. C. The oxidation of 
free or etherified glycoloyl groups to free or esterified oxalo groups is, 
for example, advantageously carried out with potassium permanganate in 
aqueous pyridine or acetone at room temperature. Acetalised glyoxyloyl 
groups and imino-acetyl groups are preferably oxidised under acid 
conditions, for example with potassium dichromate in sulphuric acid. Acyl 
groups of .alpha.,.beta.-dihydroxylated aliphatic carboxylic acids, such 
as the acyl radical of tartaric acid, are advantageously oxidised with 
periodic acid, whilst potassium ferrate in an alkaline medium, for example 
at pH=10 to 13, for example 11.5, or organic silver salts, such as silver 
picolinate, are preferably used for the oxidation of the glycyl group. 
Groups of the formula R--CH.dbd.N-- are preferably oxidised with an 
organic per-acid, for example with peracetic acid or m-chloroperbenzoic 
acid, in an inert solvent, for example methylene chloride, chloroform or 
benzene. 
A compound of the general formula I which is obtainable according to the 
invention can be converted into another compound of the general formula I 
in a manner which is known per se. 
Thus, for example, a free carboxyl group R can be esterified to an 
esterified carboxyl group R in a customary manner, for example by 
treatment with a diazo-lower alkane, which is unsubstituted or substituted 
by substituted or unsubstituted aryl or hetero-aryl, or a tri-lower 
alkyl-oxonium, tri-lower alkyl-carboxonium or di-lower alkyl-carbonium 
salt, such as hexachloroantimonate or hexafluorophosphate, or, in 
particular, by reaction with the corresponding alcohol or a reactive 
derivative, such as a carboxylic acid ester, phosphorous acid ester, 
sulphurous acid ester or carbonic acid ester, for example a lower 
alkane-carboxylic acid ester, a tri-lower alkyl phosphite, di-lower alkyl 
sulphite or the pyrocarbonate, or a mineral acid ester or sulphonic acid 
ester, for example the hydrochloric acid ester or hydrobromic acid ester 
or sulphuric acid ester, benzenesulphonic acid ester, toluenesulphonic 
acid ester or methanesulphonic acid ester, of the corresponding alcohol, 
or with an olefin derived therefrom. 
The reaction with the corresponding alcohol itself can advantageously be 
carried out in the presence of an acid catalyst, such as a proton-acid, 
for example hydrochloric acid or hydrobromic acid, sulphuric acid, 
phosphoric acid, boric acid, benzenesulphonic acid and/or toluenesulphonic 
acid, or a Lewis acid, for example boron trifluoride-etherate, in an inert 
solvent, especially an excess of the alcohol employed, and, if necessary, 
in the presence of a water-binding agent and/or with removal of the water 
of reaction by distillation, for example as an azeotrope, and/or at 
elevated temperature. 
The reaction with a reactive derivative of the corresponding alcohol can be 
carried out in a customary manner and, when starting from a carboxylic 
acid ester, phosphorous acid ester, sulphurous acid ester or carbonic acid 
ester, can be carried out, for example, in the presence of an acid 
catalyst, such as one of those mentioned above, in an inert solvent, such 
as an aromatic hydrocarbon, for example in benzene or toluene, or in an 
excess of the alcohol derivative employed or of the corresponding alcohol, 
the water of reaction being distilled off if necessary, for example as an 
azeotrope. Starting from a mineral acid ester or sulphonic acid ester, the 
acid to be esterified is advantageously employed in the form of a salt, 
for example the sodium or potassium salt, and the reaction is carried out, 
if necessary, in the presence of a basic condensing agent, such as an 
inorganic base, for example sodium hydroxide or sodium carbonate, 
potassium hydroxide or potassium carbonate or calcium hydroxide or calcium 
carbonate, or of a tertiary organic nitrogen base, for example 
triethylamine or pyridine, and/or in an inert solvent, such as one of the 
above tertiary nitrogen bases or a polar solvent, for example 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, for example a Lewis acid, for example boron 
trifluoride, or a sulphonic acid, for example p-toluenesulphonic acid, or, 
in particular, of a basic catalyst, for example sodium hydroxide or 
potassium hydroxide, advantageously in an inert solvent, such as an ether, 
for example in diethyl ether or tetrahydrofurane. 
A free carboxyl group R can, furthermore, be converted into an amidated 
carboxyl group R by reaction with ammonia or an amine containing at least 
one hydrogen atom, in the customary manner, with dehydration of the 
ammonium salt formed as an intermediate, for example by azeotropic 
distillation with benzene or toluene or by dry heating. 
The conversions, described above, of free carboxyl groups R into esterified 
or amidated carboxyl groups R can, however, also be carried out by first 
converting a compound of the formula I, in which R is carboxyl, into a 
reactive derivative in a customary manner, for example into an acid halide 
by means of a halide or phosphorus or sulphur, for example by means of 
phosphorus trichloride or phosphorus tribromide, phosphorus pentachloride 
or thionyl chloride, or into a reactive ester, i.e. esters having 
electron-attracting structures, such as the esters with phenol, 
thiophenol, p-nitrophenol or cyanomethyl alcohol, or a reactive amide, for 
example the amide derived from imidazole or 3,5-dimethylpyrazole, by 
reaction with a corresponding alcohol or amine, and then reacting the 
resulting reactive derivative in a customary manner, for example as 
described below for the transesterification, trans-amidation and 
inter-conversion of esterified and amidated carboxyl groups R, with a 
corresponding alcohol, ammonia or the corresponding amine containing at 
least one hydrogen atom, to give the desired group R. 
An esterified carboxyl group R can, in a customary manner, be converted to 
a free carboxyl group R, for example by hydrolysis in the presence of a 
catalyst, for example of a basic or acid agent, such as a strong base, for 
example sodium hydroxide or potassium hydroxide, or a mineral acid, for 
example hydrochloric acid, sulphuric acid or phosphoric acid, or to an 
amidated carboxyl group R, for example by reaction with ammonia or the 
corresponding amine containing at least one hydrogen atom. 
An esterified carboxyl group R can also be transesterified to another 
esterified carboxyl group R in a customary manner, for example by reaction 
with a metal salt, such as the sodium or potassium salt, of a 
corresponding alcohol or with the alcohol itself, in the presence of a 
catalyst, for example of a strong base, for example sodium hydroxide or 
potassium hydroxide, or of a strong acid, such as a mineral acid, for 
example hydrochloric acid, sulphuric acid of phosphoric acid, or of an 
organic sulphonic acid, for example p-toluenesulphonic acid, or of a Lewis 
acid, for example boron trifluoride etherate. 
An amidated carboxyl group R can be converted to the free carboxyl group R 
in a customary manner, for example by hydrolysis in the presence of a 
catalyst, for example of a strong base, such as an alkali metal hydroxide 
or alkali metal carbonate or an alkaline earth metal hydroxide or alkaline 
earth metal carbonate, for example sodium hydroxide or sodium carbonate or 
potassium hydroxide or potassium carbonate, or of a strong acid, such as a 
mineral acid, for example hydrochloric acid, sulphuric acid or phosphoric 
acid. 
Furthermore, in a compound obtainable according to the invention, free, 
esterified or etherified hydroxyl groups R.sub.2 can be converted into one 
another. 
Thus, for example, a free hydroxyl group R.sub.2 can be esterified to a 
hydroxyl group R.sub.1 and/or R.sub.2 esterified by a carboxylic acid, by 
reaction with a preferably functionally modified carboxylic acid, such as 
a lower alkanecarboxylic acid, for example acetic acid, or etherified to 
an etherified hydroxyl group, for example a lower alkoxy group, R.sub.1 
and/or R.sub.2, by reaction with an etherifying agent, for example with a 
lower alkylating agent. 
A functionally modified carboxylic acid is, for example, an anhydride, such 
as the symmetrical anhydrides thereof, or an anhydride with a hydrogen 
halide acid, such as hydrochloric acid or hydrobromic acid, a reactive 
ester, i.e. an ester having electron-attracting structures, for example 
the phenyl, (p-nitro)-phenyl, or cyanomethyl ester of a lower 
alkanecarboxylic acid, or a reactive amide, for example a N-lower 
alkanoylimidazole or a N-lower alkanoyl-3,5-dimethylpyrazole. 
Etherifying agents are, for example, reactive esterified alcohols, such as 
alcohols esterified by a mineral acid, for example by hydriodic acid, 
hydrochloric acid or hydrobromic acid or sulphuric acid, or an organic 
sulphonic acid, for example by p-toluenesulphonic acid, 
p-bromobenzenesulphonic acid, benzenesulphonic acid, methanesulphonic 
acid, ethanesulphonic acid or ethenesulphonic acid, or fluorosulphonic 
acid, and also diazoalkanes. Etherifying agents which may be mentioned in 
particular are lower alkyl chlorides, lower alkyl iodides and lower alkyl 
bromides, for example methyl iodides, di-lower alkyl sulphates, for 
example dimethyl sulphate or diethyl sulphate, or methyl fluorosulphonate, 
lower alkyl sulphonates, such as lower alkyl, for example methyl, 
p-toluenesulphonate, p-bromobenzenesulphonate, methanesulphonate or 
ethanesulphonate, and also diazo-alkanes, for example diazomethane. 
The reactions with acids, preferably functionally modified acids, and with 
etherifying agents, for example those singled out above, can be carried 
out in a customary manner, for example in an inert solvent, such as an 
ether, for example in tetrahydrofurane, in the case of the reaction with a 
diazoalkane or, when reactive esterified alcohols are used, for example in 
the presence of a basic condensing agent, such as of an inorganic base, 
for example sodium hydroxide or sodium carbonate, potassium hydroxide or 
potassium carbonate or calcium hydroxide or calcium carbonate, or of a 
tertiary or quaternary nitrogen base, for example pyridine, 
.alpha.-picoline, quinoline or triethylamine, or tetraethyl-ammonium 
hydroxide or benzyltriethyl-ammonium hydroxide, and/or of a solvent 
customary for the particular reaction, which solvent can also comprise an 
excess of the functional acid derivative used for the esterification, for 
example of a lower alkanoic acid anhydride or acid chloride, or the lower 
alkyl halide or lower alkyl sulphate used, for example, for the 
etherification, and/or a tertiary nitrogen base used as the basic 
condensing agent, for example triethylamine or pyridine, if necessary at 
elevated temperature. Methylation by means of acyl iodide in amyl 
alcohol/potassium carbonate at the boiling point and also acylation by 
means of a lower alkanoic acid anhydride at 50.degree.-150.degree. or by 
means of a lower alkanoyl chloride in pyridine or pyridine-triethylamine 
at temperatures between -20.degree. and +100.degree. C. are especially to 
be recommended. 
Conversely, etherified or, in particular, esterified hydroxyl R.sub.2 can 
also be converted into hydroxyl in a customary manner, for example in the 
presence of an acid agent, such as a hydrogen halide acid, for example 
hydriodic acid, in an inert solvent, for example in ethanol or acetic 
acid. 
Furthermore, in a compound obtainable according to the invention, acyl 
R.sub.2 and/or, in particular, R.sub.1 can be replaced by hydrogen. Thus, 
a carboxyl group R.sub.2 and/or, in particular, R.sub.1 can be 
decarboxylated in a customary manner, for example by the action of heat, 
or the acyl group R.sub.1 of a carboxylic acid can be split off in a 
customary manner, such as by the action of basic agents, such as alkalis, 
for example dilute sodium hydroxide solution or, in particular, sodium 
carbonate solution, preferably about 5% strength sodium carbonate 
solution. 
Depending on the choice of the starting materials and procedures, the novel 
compounds can be in the form of one of the possible isomers or in the form 
of a mixture thereof, for example in the form of isomers in respect of the 
orientation of X, and also, depending on the number of asymmetrical carbon 
atoms, in the form of pure optical isomers, such as antipodes, or in the 
form of mixtures of isomers, such as racemates, mixtures of diasteromers 
or mixtures of racemates. 
Resulting mixtures of isomers in respect of the orientation of X, mixtures 
of diasteromers and mixtures of racemates can be separated on the basis of 
the physical/chemical differences between the constituents into the pure 
isomers, diasteromers or racemates in a known manner, for example by 
chromatography and/or fractional crystallisation. 
Resulting racemates can also be resolved into the optical antipodes by 
known methods, for example by recrystallisation from an optically active 
solvent, with the aid of nitro organisms or by reaction of an acid end 
product with an optically active base which forms salts with the racemic 
acid and separation of the salts obtained in this way, for example on the 
basis of their different solubilities, into the diasteromers, from which 
the antipodes can be set free by the action of suitable agents. 
Advantageously, the more active of the two antipodes is isolated. 
Resulting free compounds of the formula I, for example those in which R, 
R.sub.1 and/or R.sub.2 is carboxyl, can be converted into salts in a 
manner which is known per se, inter alia by treatment with a base or with 
a suitable salt of a carboxylic acid, usually in the presence of a solvent 
or diluent. 
Resulting salts can be converted into the free compounds in a manner which 
is known per se, for example by treatment with an acid reagent, such as a 
mineral acid. 
The compounds, including their salts, can also be obtained in the form of 
their hydrates or can incorporate the solvent used for crystallisation. 
Because of the close relationship between the novel compounds in the free 
form and in the form of their salts, the free compounds or their salts, in 
the preceding and following text, are, where appropriate, also to be 
understood to include the corresponding salts or free compounds, in 
respect of general sense and intended use. 
The invention also relates to those embodiments of the process in which a 
compound obtainable as an intermediate at any stage of the process is used 
as the starting material and the missing steps are carried out, or a 
starting material is used in the form of a salt and/or racemate or 
antipode or, especially, is formed under the reaction conditions. 
The starting materials are known or, if they are novel, can be prepared 
according to methods which are known per se. 
Thus, the starting materials of the general formula (II) can be prepared, 
for example, when, in a compound of the formula 
##STR10## 
in which Ph and X have the defined meanings and R" is nitro or an acylated 
amino group which differs from a group of the formula RCONR.sub.3 --, the 
nitro group R" is converted by conventional reduction, for example 
catalytically or using a metal and a acid, for example using iron and 
hydrochloric acid, or sodium hyposulphite in aqueous ammonia, into primary 
amino, or an acylated amino group R" is converted by conventional 
hydrolysis, preferably in the presence of an acid, such as a mineral acid, 
for example hydrochloric acid or sulphuric acid, or of an inorganic base, 
for example sodium hydroxide solution or potassium hydroxide solution, 
into an amino group --NHR.sub.3. Primary amino which is first formed can 
easily be alkylated to --NHR.sub.3, for example using a lower alkyl 
halide. 
Starting materials of the general formula (II) can also be prepared when a 
compound of the general formula 
##STR11## 
is subjected to a condensation reaction with an ester of an acid of the 
formula R.sub.2 COCHR.sub.1 COOH, or a compound of the formula 
##STR12## 
is subjected to a condensation reaction with an anhydride, for example 
with a carboxylic acid or hydrochloric acid, of an acid of the formula 
R.sub.2 COOH, R''' in the formulae being hydrogen or a group --NHR.sub.3 
or R", hydrogen R''' is replaced by nitro by conventional nitration, nitro 
is reduced to amino and, if necessary, acylamino is hydrolysed to amino 
and/or amino is alkylated to --NHR.sub.3. The reaction is carried out in a 
conventional manner, for example in the presence of a strongly acid 
condensing agent, such as a mineral acid, for example sulphuric acid, 
hydrochloric acid or hydrobromic acid, phosphoric acid or polyphosphoric 
acid, or of an aprotic acid condensing agent, such as an acid anhydride, 
for example phosphorus pentoxide or phosphorus oxychloride, or of a Lewis 
acid, for example aluminium trichloride, when starting from compounds IIb, 
or in the presence of a basic condensing agent, for example of an alkali 
metal carboxylate, such as sodium acetate in excess anhydride, or of 
potassium carbonate in acetone, when starting from compounds of the 
formula IIc. The compounds of the formula IIa, which have been mentioned 
above as starting materials, can also be prepared in an analogous manner. 
Most of the compounds of the formula III which have been mentioned as 
starting materials are novel. In addition to the fact that they can be 
used as starting materials for the preparation of compounds of the formula 
I, some of them show further advantageous properties. Thus, compounds of 
the formula III in which R' is a free or etherified glycoloylamino group, 
and also related compounds in which R' is an esterified glycoloylamino 
group show the same pharmacological properties, in an activity of 
comparable strength, as the corresponding compounds of the formula I. 
The invention accordingly also relates to novel starting materials, in 
particular compounds of the formula III in which R' is a group of the 
formula R.sub.o --NHR.sub.3 and R.sub.o is a free or etherified glycoloyl 
group or a glycoloyl group esterified by a carboxylic acid, processes for 
their preparation, pharmaceutical formulations containing these compounds 
and the use of these formulations as pharmaceuticals or for the 
preparation of medicaments. 
Glycoloyl groups esterified by a carboxylic acid are to be understood as 
meaning, for example, glycoloyl groups esterified by an aliphatic or 
aromatic carboxylic acid, for example corresponding lower 
alkanoyloxy-acetyl or substituted or unsubstituted benzoyloxy-acetyl. 
Lower alkanoyloxyacetyl is, for example, acetoxy-, propionyloxy-, 
butyryloxy-, isobutyryloxy-, valeroyloxy-, caproyloxy- or 
pivaloyloxyacetyl. Possible substituents of substituted benzoyloxyacetyl 
groups are, in particular, lower alkyl, such as methyl, lower alkoxy, such 
as methoxy, and/or halogen, such as chlorine. 
Etherified glycoloyl groups are, for example, glycoloyl groups etherified 
by a substituted or unsubstituted, aliphatic or araliphatic alcohol, such 
as corresponding lower alkoxyacetyl or phenyl-lower alkoxy-acetyl groups. 
Substituents of lower alkoxy-acetyl are, in particular, hydroxyl, lower 
alkoxy and/or di-lower alkyl-amino and substituents of phenyllower 
alkoxy-acetyl groups are, for example, lower alkyl, such as methyl, lower 
alkoxy, such as methoxy, and/or halogen, such as chlorine. Lower alkoxy 
preferably has one of the meanings defined initially and phenyl-lower 
alkoxy-acetyl is especially benzyloxyacetyl or 2-phenylethoxyacetyl. 
Dilower alkyl-amino-lower alkoxyacetyl is preferably 2-dimethyl- or 
2-diethyl-aminoethoxyacetyl. 
The invention relates especially to those compounds of the formula III in 
which Ph and R.sub.1 have the meanings defined for the particular 
preferred catagories of the formula I, R' is a group R.sub.o --NHR.sub.3 
and R.sub.o is lower alkoxy-acetyl, in particular having up to 6 carbon 
atoms, such as methoxyacetyl or ethoxyacetyl, or, preferably, glycoloyl. 
The compounds of the formula III, which have been mentioned as starting 
materials, can be prepared by methods which are known per se, preferably 
by reacting a compound of the formula 
##STR13## 
or an acid addition salt thereof, with a corresponding acid, for example 
of the formula X.sub.1 --OH (IIIa), X.sub.2 --OH (IIIb) or R.sub.o --OH 
(IIIc), or a functional derivative thereof, and, if desired, converting a 
compound which is thus obtainable into another compound of the formula III 
in which R' is a group R.sub.o --NHR.sub.3. 
Functional derivatives of acids of the formula IIIa to IIIc are, in 
particular, acid derivatives which contain an esterified or amidated 
carboxyl group or a carboxyl group in the form of an anhydride, such as 
lower alkoxy-carbonyl, substituted or unsubstituted carbamyl, for example 
carbamyl or imidazolyl-1-carbonyl, or halogenocarbonyl, for example 
chlorocarbonyl or bromocarbonyl. Examples which may be mentioned in 
particular of acids of the formula IIIa to IIIc and functional derivatives 
thereof are: oxalyl halides, such as oxalyl chloride or oxalyl bromide as 
functional derivatives of acids of the formula IIIa, as acids of the 
formulae IIIb and IIIc and functional derivatives thereof, glycollic acid 
and its lower alkyl esters and the corresponding lactide, or lower alkyl 
mono-lower alkoxy-acetates, such as ethyl mono-lower alkoxy-acetates, for 
example ethyl ethoxyacetate or ethyl diethoxyacetate, and for the 
preparation of precursors of compounds of the formula III in which R' is a 
group X.sub.2 --NR.sub.3 -- and X.sub.2 denotes glyoxyloyl, lower alkyl 
di-lower alkoxyacetates, halogenoacetic anhydrides, such as chloroacetic 
anhydride or chloroacetyl chloride and tartaric acid, or 
2,3-diacetoxysuccinic anhydride, and also cinnamoyl chloride, acetyl 
chloride and glycine. 
The reaction of compounds of the formula II with the above-mentioned acids 
and derivatives thereof can be carried out in a conventional manner, for 
example in the presence of a water-binding agent, such as an acid 
anhydride, for example phosphorus pentoxide, or dicyclohexylcarbodiimide, 
or of a condensing agent, for example an acid or basic condensing agent, 
such as a mineral acid, for example hydrochloric acid, or an alkali metal 
hydroxide or alkali metal carbonate, for example sodium hydroxide or 
potassium hydroxide, or of an organic nitrogen base, for example 
triethylamine or pyridine. In the case of the reaction with an acid 
anhydride, such as an 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 reaction is in each case carried out in an inert 
solvent, at normal temperature or with cooling or warming, for example in 
the temperature range from about 0.degree. C. to about 100.degree. C., in 
a closed vessel and/or under an inert gas, for example nitrogen. 
Compounds of the formula III in which R' is a group --NHR.sub.3 --X.sub.2 
and X.sub.2 is glyoxyloxy can also be prepared when a corresponding 
halogenoacetyl compound, such as a bromoacetyl compound, is heated with 
hexamethylenetetramine, preferably in an aqueous alcohol, or is oxidised 
with silver tetrafluoborate in dimethylsulphoxide. Analogously, a 
chloroacetyl compound can also be oxidised with potassium dichromate in 
hexamethylphosphoric acid triamide in the presence of 
dicyclohexyl-18-crown-6-ether. Compounds of the formula III in which R' is 
a group X.sub.2 --NHR.sub.3 -- and X.sub.2 is an iminoacetyl group, for 
example substituted or unsubstituted benzyliminoacetyl, can be prepared 
starting from the corresponding glycyl compounds by reacting these with 
the corresponding carbonyl compound, for example with benzaldehyde, and 
rearranging the intermediate which is thus obtainable, for example a 
benzylideneglycyl compound, preferably under the reaction conditions. The 
compounds, according to the invention, of the formula III in which R' is a 
group of the formula R.sub.o --NHR.sub.3 -- and R.sub.o is a free or 
esterified glycoloyl group or a glycoloyl group esterified by a carboxylic 
acid can also be prepared by converting the radical R' in a compound of 
the formula III, in which R' is a radical which can be converted into the 
group R.sub.o NHR.sub.3 --, into the desired group R.sub.o --NHR.sub.3 -- 
and, if desired, converting a compound which is thus obtainable into 
another compound of the formula III in which R' is a group R.sub.o 
NHR.sub.3 --. 
Radicals which can be converted into a group R.sub.o --NHR.sub.3 -- are 
those of the formula X.sub.1 '--NHR.sub.3 --, in which X.sub.1 ' is an 
esterified glycoloyl group which differs from a glycoloyl group which can 
be free or esterified by a carboxylic acid, for example a glycoloyl group 
esterified by a mineral acid, for example by a hydrogen halide acid, such 
as cycloacetyl or bromoacetyl. Groups X.sub.1 ' of this type can be 
converted to a glycoloyl group by hydrolysis, for example in the presence 
of a basic hydrolysing agent, such as sodium hydroxide solution, or into 
esterified glycoloyl groups or glycoloyl groups esterified by a carboxylic 
acid by reaction with a salt, such as an alkali metal salt, for example 
the sodium salt, of a corresponding alcohol or, respectively, of a 
corresponding carboxylic acid. 
Further radicals R' which can be converted into groups of the formula 
R.sub.o --NHR.sub.3 -- are those of the formula X.sub.2 '--NHR.sub.3 --, 
in which X.sub.2 ' is a radical which can be converted by reduction into 
the glycoloyl group, such as the glycoloyl group, which can be in the form 
of a hydrate. This group can also be formed under the reduction conditions 
from an oxalo group, for example from an oxalo group in the free form or 
in the form of a salt, such as in the form of the sodium salt, or in the 
form of an anhydride or ester, such as halogenooxalyl, for example 
chlorooxalyl or bromooxalyl, or a mixed anhydride with diphenylphosphoric 
acid, or in the form of a lower alkyl ester, for example in the form of 
the methyl or isopropyl ester. The reduction of such groups is effected in 
a conventional manner. Starting from halogenooxalyl, catalytically 
activated hydrogen, for example hydrogen catalytically activated by 
palladium on a support, such as barium sulphate, if necessary in the 
presence of a sulphur-containing co-catalyst, such as thiourea, is 
preferably used. Anhydrides with diphenylphosphoric acid are 
advantageously reduced with an excess of sodium boronate. Oxalo groups in 
the form of a salt are advantageously reduced with a borane, such as 
diborate or a borane/ether complex, for example with borane in 
tetrahydrofurane, whilst oxalo groups in the form of an ester are 
advantageously reduced with sodium anilino-borohydride, which is 
obtainable by the reaction of sodium borohydride and acetanilide in 
pyridine. 
A compound, according to the invention, of the formula III which is thus 
obtainable can be converted into another compound, according to the 
invention, of the formula III. 
Thus, for example, the inter-conversions of free, esterified or etherified 
hydroxyl groups R.sub.2 and the separation of isomers in respect of the 
orientation of X can be applied to the compounds according to the 
invention. 
Furthermore, glycoloyl groups R.sub.o can be esterified by reaction with an 
esterifying agent, such as a corresponding carboxylic acid anhydride, for 
example a lower alkanoic acid anhydride or acid chloride, advantageously 
in the presence of a base, such as triethylamine or pyridine. Glycoloyl 
groups R.sub.o can also be etherified, for example by conversion into an 
alkali metal salt, such as the sodium salt, and reaction with a reactive 
derivative of the particular alcohol, such as a lower alkyl halide, for 
example a lower alkyl bromide, or a di-lower alkyl sulphate. Furthermore, 
glycoloyl groups R.sub.o esterified by a carboxylic acid can be hydrolysed 
to glycoloyl, for example in the presence of a hydrolysing agent, such as 
a base, such as sodium hydroxide solution. 
In the process of the present invention, the starting materials used are 
preferably those which lead to the compounds described initially as being 
particularly valuable. 
The present invention also relates to pharmaceutical formulations which 
contain one of the compounds, according to the invention, of the formula I 
or II or a salt thereof which can be used pharmaceutically. The 
pharmaceutical formulations according to the invention are those which are 
intended for topical and local application and for enteral, such as oral 
or rectal, and parenteral administration to, and for inhalation by, 
warm-blooded animals and contain the pharmacological active compound on 
its own or together with an excipient which can be used pharmaceutically. 
The dosage of the active compound depends on the species of warm-blooded 
animal, the age and the state of health of the individual and also on the 
mode of administration. 
The novel pharmaceutical formulations contain, for example, from about 10% 
to about 95%, and preferably from about 20% to about 90%, of the active 
compound. Pharmaceutical formulations according to the invention are, for 
example, those in the form of an aerosol or spray or in dosage unit forms, 
such as dragees, tablets, capsules or suppositories, and also ampoules. 
The pharmaceutical formulations of the present invention are prepared in a 
manner which is known per se, for example by means of conventional mixing, 
granulating, dragee-making, dissolving or lyophilising processes. Thus, 
pharmaceutical formulations for oral use can be obtained by combining the 
active compound with solid excipients, granulating a resulting mixture if 
desired and processing the mixture or granules, after adding suitable 
auxiliaries if desired or necessary, to give tablets or dragee cores. 
Suitable excipients are, especially, fillers, such as sugars, for example 
lactose, sucrose, mannitol or sorbitol, cellulose formulations and/or 
calcium phosphates, for example tricalcium phosphate or calcium hydrogen 
phosphate, as well as binders, such as starch pastes using, for example, 
maize starch, wheat starch, rice starch or potato starch, gelatine, 
tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or, if 
desired, disintegrating agents, such as the abovementioned starches, and 
also carboxymethyl-starch, crosslinked polyvinylpyrrolidone, agar or 
alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, 
in particular, flow-regulating agents and lubricants, for example silica, 
talc, stearic acid or salts thereof, such as magnesium stearate or calcium 
stearate, and/or polyethylene glycol. Dragee cores are provided with 
suitable coatings, which, if desired, are resistant to gastric juices, and 
for this purpose, inter alia, concentrated sugar solutions, which can 
contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or 
titanium dioxide, lacquer solutions in suitable organic solvents or 
solvent mixtures or, in order to produce coatings resistant to gastric 
juices, solutions of suitable cellulose formulations, such as 
acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are 
used. Dyestuffs or pigments can be added to the tablets or dragee 
coatings, for example for identification or in order to characterise 
different doses of the active compound. 
Other pharmaceutical formulations which can be used orally are push-fit 
capsules made of gelatine, as well as soft, sealed capsules made of 
gelatine and a plasticiser, such as glycerol or sorbitol. The push-fit 
capsules can contain the active compound in the form of granules, for 
example mixed with fillers, such as lactose, binders, such as starches, 
and/or lubricants, such as talc or magnesium stearate, and can contain 
stabilisers. In soft capsules, the active compound is preferably dissolved 
or suspended in suitable liquids, such as fatty oils, liquid paraffin or 
liquid polyethylene glycols, it also being possible to add stabilisers. 
Possible pharmaceutical formulations which can be used rectally are, for 
example, suppositories, which consist of a combination of the active 
compound with a suppository base. Suitable suppository bases are, for 
example, natural or synthetic triglycerides, paraffin hydrocarbons, 
polyethylene glycols or higher alkanols. In addition it is also possible 
to use gelatine rectal capsules which contain a combination of the active 
compound with a base; bases which can be used are, for example, liquid 
triglycerides, polyethylene glycols or paraffin hydrocarbons. 
Formulations suitable for parenteral administration are, in particular, 
aqueous solutions of an active compound in the water-soluble form, for 
example of a water-soluble salt, and also suspensions of the active 
compound, such as corresponding oily injection suspensions, in which case 
suitable lipophilic solvents or vehicles, such as fatty oils, for example 
sesame oil, or synthetic fatty acid esters, for example ethyl oleate or 
triglycerides, are used, or aqueous injection suspensions which contain 
substances which increase the viscosity, for example sodium 
carboxymethylcellulose, sorbitol and/or dextran, and can also contain 
stabilisers. 
Inhalation formulations for the treatment of the respiratory passages by 
nasal or buccal administration are, for example, aerosols or sprays which 
can disperse the pharmacological active compound in the form of a powder 
or in the form of drops of a solution or suspension. Formulations which 
have powder-dispersing properties usually contain, in addition to the 
active compound, a liquid propellant gas which has a boiling point below 
room temperature and also, if desired, excipients, such as liquid or solid 
non-ionic or anionic surface-active agents and/or solid diluents. 
Formulations in which the pharmacological active compound is in solution 
contain, in addition to this active compound, a suitable propellant and 
also, if necessary, an additional solvent and/or a stabiliser. In place of 
the propellant gas, it is also possible to use compressed air and this can 
be produced as required by means of a suitable compression and pressure 
release device. 
Pharmaceutical formulations for topical and local use are, for example, 
lotions and creams which contain a liquid or semi-solid oil-in-water or 
water-in-oil emulsion, and ointments(such formulations preferably 
containing a preservative) for the treatment of the skin, eyedrops which 
contain the active compound in aqueous or oil solution and eye ointments, 
which are preferably prepared in a sterile form, for the treatment of the 
eyes, powders, aerosols and sprays (similar to those described above for 
the treatment of the respiratory passages) and also coarse powders, which 
are administered through the nostrils by rapid inhalation, and nosedrops, 
which contain the active compound in aqueous or oily solution, for the 
treatment of the nose, or lozenges, which contain the active compound in a 
composition generally consisting of sugar and gum arabic or tragacanth, to 
which flavourings can be added, as well as pastilles, which contain the 
active compound in an inert composition, for example consisting of 
gelatine and glycerol or sugar and gum arabic, for the local treatment of 
the mouth. 
The invention also relates to the use of the novel compounds of the formula 
(I) and salts thereof, as pharmacologically active compounds and 
especially as anti-allergic agents, preferably in the form of 
pharmaceutical formulations. The daily dose which is administered to a 
warm-blooded animal weighing about 70 kg is from about 200 mg to about 
1,200 mg. 
The examples which follow illustrate the invention described above; 
however, they are not intended to restrict the scope of the invention in 
any way. Temperatures are given in degrees centigrade.

EXAMPLE 1 
35 g of 7-amino-4-methyl-coumarin and 24.5 g of triethylamine are initially 
introduced into 400 ml of dimethylformamide. A solution of 29.5 g of 
oxalic acid monomethyl ester-chloride in 100 ml of dimethylformamide is 
added dropwise to this mixture in the course of 15 minutes. The reaction 
temperature is kept below 35.degree. by external cooling. The yellow, 
thick suspension is stirred overnight at room temperature and then poured 
into 2 liters of ice-water. The suspension is filtered with suction and 
the precipitate is recrystallised from acetone. This gives 
7-methoxyoxalylamino-4-methyl-coumarin with a melting point of 
248.degree.-51.degree.. 
EXAMPLE 2 
13.2 g of 7-amino-4,6-dimethyl-coumarin and 7 g of triethylamine are 
initially introduced into 250 ml of dimethylformamide and the mixture is 
warmed to 45.degree.. Virtually everything goes into solution. 9.5 g of 
oxalic acid monomethyl ester-chloride in 100 ml of dimethylformamide are 
now added dropwise. The internal temperature is kept below 45.degree. by 
external cooling. Everything goes into solution at the start of the 
dropwise addition and a slight precipitate then separates out. The 
resulting suspension is stirred overnight at room temperature. The 
dimethylformamide is stripped off in vacuo and the residue is diluted with 
water and extracted by shaking with chloroform. The chloroform phase is 
separated off, washed with water, dried over anhydrous sodium sulphate and 
evaporated to dryness in vacuo. This gives crude 
4,6-dimethyl-7-methoxyoxalyl-amino-coumarin which, after recrystallisation 
from chloroform, melts at 222.degree.-5.degree.. 
EXAMPLE 3 
3 g of 7-methoxyoxalylamino-4-methyl-coumarin are suspended in 50 ml of N 
sodium hydroxide solution and the suspension is stirred for 21/2 hours at 
30.degree.-35.degree.. A clear solution is obtained and this is acidified 
with dilute hydrochloric acid. The precipitate formed is filtered off with 
suction and recrystallised from acetone. This gives 2.6 g of 
4-methyl-7-oxaloamino-coumarin with a melting point of 
236.degree.-38.degree. (decomposition). The sodium salt melts above 
300.degree.. 
EXAMPLE 4 
The following compounds can also be prepared in a manner analogous to that 
described in Examples 1 to 3: 8-methoxyoxalylamino-4-methyl-coumarin, 
7-methoxyoxalylamino-3-phenyl-coumarin, melting point 
250.degree.-252.degree., 7-methoxyoxalylamino-3-(3-pyridyl)-coumarin, 
4-hydroxy-7-methoxyoxalylaminocoumarin, 
6-methoxy-7-methoxyoxalylamino-coumarin, 6-methoxyoxalylamino-coumarin, 
6-methoxyoxalylamino-4-methyl-coumarin, 
3-acetyl-7-methoxyoxalylamino-coumarin, 
3,4-dimethyl-7-methoxyoxalylamino-coumarin, melting point 
258.degree.-260.degree., 2,3-dimethyl-6-methoxyoxalylamino-chromone, 
7-methoxyoxalylamino-3-methyl-flavone, 
6-chloro-8-methoxyoxalylamino-4-methylcoumarin, 
4,6-dimethyl-8-methoxyoxalylamino-coumarin, 
4,5-dimethyl-8-methoxyoxalylamino-coumarin, 
3-acetyl-4-hydroxy-7-methoxyoxalyl-amino-coumarin, melting point 
205.degree.-206.degree., 6-methoxy-5-methoxyoxalyl-amino-coumarin and 
4-methyl-7-(4-methyl-7-cumaryl)-aminooxalyl-amino-coumarin. 
EXAMPLE 5 
The following compounds can also be prepared in a manner analogous to that 
described in Examples 1 to 3: 7-ethoxyoxalylamino-4-methyl-coumarin, with 
a melting point of 218.degree.-220.degree., starting from 8.7 g of 
7-amino-4-methyl-coumarin and 3,4-dimethyl-7-oxaloamino-coumarin, with a 
melting point of 233.degree., starting from 5.5 g of 
3,4-dimethyl-7-methoxyoxalylamino-coumarin. 
EXAMPLE 6 
10.5 g of 7-amino-4-methyl-coumarin are dissolved in 6 g of triethylamine 
and 70 ml of dimethylformamide and the solution is treated dropwise with 
3.8 g of oxalyl chloride, with external cooling and while stirring. The 
mixture is stirred overnight at room temperature and poured into ice 
water, the resulting mixture is acidified to pH 5 to 6 with 2 N 
hydrochloric acid and the precipitate is filtered off with suction. The 
crystalline material is suspended in ethanol, the suspension is digested 
warm and the precipitate is filtered off with suction. This gives 
4-methyl-7-(4-methyl-7-cumaryl)-aminooxalylamino-coumarin. This product is 
again digested with dimethylformamide and again filtered off with suction. 
It melts above 300.degree.. 
EXAMPLE 7 
7-Methoxyoxalylamino-3-phenyl-coumarin with a melting point of 
250.degree.-252.degree. can be prepared in a manner analogous to that 
described in Examples 1 and 2, starting from 6 g of 
7-amino-3-phenyl-coumarin. 
The starting material can be prepared as follows: 40 g of 
2-methoxy-4-acetyl-amino-benzaldehyde and 223.2 g of benzyl cyanide are 
dissolved in 525 ml of ethanol, with warming. A mixture of 19.7 ml of 50% 
strength potassium hydroxide solution and 105 ml of ethanol is then added 
dropwise at 30.degree.-35.degree.. After stirring for 30 minutes at 
40.degree.-45.degree., the mixture is left to stand overnight. The 
reaction solution is then diluted with water, the ethanol is stripped off 
in vacuo and the aqueous phase is extracted thoroughly with ether. The 
dried ether solution is evaporated to dryness in vacuo and the residual 
oil is distilled under 0.1 mm Hg. 
.alpha.-Phenyl-2-methoxy-4-acetylamino-cinnamonitrile passes over at 
62.degree.. 63 g of .alpha.-phenyl-2-methoxy-4-acetylamino-cinnamonitrile 
are dissolved in 500 ml of warm toluene. A little nitrile precipitates 
again on cooling to 50.degree.. 150 g of aluminium chloride are then added 
in 6 portions, and the internal temperature rises to 68.degree.. The dark 
green mixture is kept at 80.degree. for 6 hours. It is then poured on to a 
mixture of 800 g of ice and 100 ml of concentrated hydrochloric acid, the 
toluene is stripped off in vacuo and the product which has precipitated is 
filtered off with suction, 700 ml of 85% strength acetic acid and 120 ml 
of concentrated hydrochloric acid are poured over the product and the 
mixture is heated under reflux overnight. After cooling, crystalline 
7-amino-3-phenyl-coumarin, which has separated out, is filtered off with 
suction and recrystallised from ethanol/ethyl acetate. It melts at 
205.degree.-208.degree.. 
EXAMPLE 8 
N-Ethyl-7-methoxyoxalylamino-4-methyl-coumarin with a melting point of 
136.degree.-8.degree. can be prepared in a manner analogous to that 
described in Examples 1 and 2, starting from 25.2 g of 
7-ethylamino-4-methyl-coumarin. 
7-Ethylamino-4-methyl-coumarin, which is used as the starting material, is 
obtained from 50 g of 3-ethylaminophenol by heating this with 55.5 g of 
ethyl acetoacetate and 39.7 g of zinc chloride in 190 ml of ethanol for 12 
hours under reflux. For working up, the reaction mixture is poured into 
3,000 ml of water, the resulting mixture is stirred for 2 hours and 
7-ethylamino-4-methyl-coumarin is filtered off with suction. After 
recrystallisation from ethanol, it melts at 154.degree.-155.degree.. 
EXAMPLE 9 
N-Ethyl-7-oxaloamino-4-methyl-coumarin with a melting point of 142.degree. 
is obtained in a manner analogous to that described in Example 3, starting 
from 14 g of N-ethyl-7-methoxyoxalylamino-4-methyl-coumarin. 
EXAMPLE 10 
N-Methyl-7-methoxyoxalylamino-4-methyl-coumarin with a melting point of 
164.degree.-165.degree. is obtained in a manner analogous to that 
described in Examples 1 and 2, starting from 10.6 g of 
7-methylamino-4-methylcoumarin. 
The starting material is prepared from 67.4 g of 3-methylamino-phenol in a 
manner analogous to that described in Example 7 for 
7-ethyl-amino-4-methyl-coumarin. 7-Methylamino-4-methyl-coumarin melts at 
193.degree.-4.degree.. 
EXAMPLE 11 
N-Methyl-7-oxaloamino-4-methyl-coumarin with a melting point of 
162.degree.-164.degree. is obtained in a manner analogous to that 
described in Example 3, starting from 13.5 g of 
N-methyl-7-methoxyoxalylamino-4-methyl-coumarin. 
EXAMPLE 12 
8-Methoxyoxalylamino-7-methoxy-4-methyl-coumarin with a melting point 
228.degree.-229.degree. can be prepared in a manner analogous to that 
described in Examples 1 and 2, starting from 9.7 g of 
8-amino-7-methoxy-4-methyl-coumarin. 
The starting material can be prepared as follows: 
A mixture of 16.3 ml of 65% strength nitric acid and 17 ml of concentrated 
sulphuric acid is added slowly dropwise to a solution of 45.5 g of 
.beta.-methylumbelliferone in 100 ml of concentrated sulphuric acid with 
external cooling (internal temperature below 5.degree.). After the 
dropwise addition has ended, the ice bath is removed and the mixture is 
stirred further at room temperature. As soon as the internal temperature 
has reached 20.degree., the mixture is poured into 1,200 ml of ice water 
and the product which has separated out is filtered off with suction. A 
mixture of 6-nitro- and 8-nitro-.beta.-methylumbelliferone with a melting 
point of 223.degree.-229.degree. is obtained. This mixture is heated in 
acetone with 123.9 g of methyl iodide in the presence of 139.6 g of 
potassium carbonate for 19 hours under reflux. The acetone is stripped off 
in vacuo and the evaporated residue is treated with 400 ml of water. The 
material which has not dissolved is filtered off with suction. This gives 
8-nitro-7-methoxy 4-methyl-coumarin with a melting point of 233.degree.. 
6-Nitro-.beta.-methylumbelliferone with a melting point of 243.degree. can 
be isolated, as the single product, from the filtrate by acidifying with 
concentrated acid. 
8-Amino-7-methoxy-4-methyl-coumarin with a melting point of 
152.degree.-155.degree. is obtained from 
8-nitro-7-methoxy-4-methylcoumarin by reducing the nitro group with sodium 
hyposulphite. 
EXAMPLE 13 
The following compounds can also be prepared in a manner analogous to that 
described in Examples 1 to 3: 8-oxaloamino-7-methoxy-4-methyl-coumarin 
starting from 8-methoxyoxalylamino-7-methoxy-4-methyl-coumarin, 
6-methoxyoxalylamino-7-hydroxy-4-methyl-coumarin starting from 
6-amino-.beta.-methylumbelliferone (obtainable by reduction of the nitro 
group) and 6-oxaloamino-7-hydroxy-4-methyl-coumarin starting from 
6-methoxyoxalylamino-7-hydroxy-4-methyl-coumarin. 
EXAMPLE 14 
4,6-Dimethyl-7-oxaloamino-coumarin, melting point 250.degree.-251.degree. 
(decomposition), 7-methoxyoxalylamino-3,4-tetramethylene-coumarin, melting 
point 231.degree.-232.degree., and 
7-oxaloamino-3,4-tetramethylene-coumarin monohydrate, melting point 
235.degree. (decomposition), can also be prepared in a manner analogous to 
that described in Examples 1 to 3. 
EXAMPLE 15 
2,3-Dimethyl-6-methoxyoxalylamino-4-oxo-4H-1-benzopyrane with a melting 
point of 242.degree.-244.degree. can be obtained in a manner analogous to 
that described in Examples 1 to 3, starting from 12 g of 
2,3-dimethyl-6-amino-4-oxo-4H-1-benzopyrane. 
The starting material can be prepared as follows: 
150 g of phosphorus pentoxide are added to 100 g of ethyl 
2-methylacetoacetate and 100 g of phenol in 300 ml of toluene, while 
stirring. After briefly warming to 40.degree., an exothermic reaction 
starts and the internal temperature rises up to 40.degree.. The mixture is 
then warmed at an internal temperature of about 100.degree. for 2 hours, 
cooled somewhat (about 80.degree.) and, after adding a further 100 g of 
phenol and 100 g of phosphorus pentoxide, again heated at 100.degree. for 
2 hours. The reaction mixture is diluted with 300 ml of toluene and 
poured, while still hot, into 1,500 ml of ice-water. The resulting mixture 
is rendered alkaline with concentrated sodium hydroxide solution and 
saturated with sodium chloride. It is then stirred vigorously for 45 
minutes and the organic phase is separated off, washed with 400 ml of 2 N 
sodium hydroxide solution and then with 600 ml of a saturated solution of 
sodium chloride, dried and evaporated to dryness. The residual oil is 
subjected to fractional distillation in vacuo and the fractions which pass 
over at 170.degree./13 mm are collected and crystallised from 
isopropanol/petroleum ether. The resulting 
2,3-dimethyl-4-oxo-4H-1-benzopyrane with a melting point of 
91.degree.-3.degree. is nitrated in 70 ml of concentrated sulphuric acid 
at below 5.degree. with 6.9 ml of fuming nitric acid and 
6-nitro-2,3-dimethyl-4-oxo-4H-1-benzopyrane, which is thus obtainable, is 
reduced, in dimethylformamide, with hydrogen in the presence of Raney 
nickel. 6-Amino-2,3-dimethyl-4-oxo-4H-1-benzopyrane, which is thus 
obtained, melts at 202.degree.-204.degree.. 
EXAMPLE 16 
7.4 g of 2,3-dimethyl-6-methoxyoxalylamino-4-oxo-4H-1-benzopyrane and 
warmed for 5 minutes at 70.degree. with 26.9 ml of N sodium hydroxide 
solution in 100 ml of water. A solution forms. After stirring for 90 
minutes at room temperature, the crystalline sodium salt of 
2,3-dimethyl-6-oxaloamino-4-oxo-4H-1-benzopyrane, which has separated out 
and has a melting point about 265.degree., is filtered off. 
EXAMPLE 17 
7-Methoxyoxalylamino-2,3-dimethyl-4-oxo-4H-benzopyrane with a melting point 
of 228.degree.-29.degree. can be prepared in a manner analogous to that 
described in Example 1 and 2, starting from 17.2 g of 
7-amino-2,3-dimethyl-4-oxo-4H-1-benzopyrane. 
The starting material can be prepared as follows: 
30 g of 2-hydroxy-4-acetylamino-propiophenone are heated with 14.3 g of 
anhydrous sodium acetate in 25.5 ml of acetic anhydride for 6 hours under 
reflux, the warm suspension is poured into ice-water, the resulting 
mixture is stirred for 30 minutes and the precipitate is filtered off with 
suction. 7-Acetylamino-2,3-dimethyl-4-oxo-4H-1-benzopyrane melts at 
259.degree.-61.degree.. Saponification to give 
7-amino-2,3-dimethyl-4-oxo-4H-1-benzopyrane (melting point 
224.degree.-26.degree.) is effected by boiling under reflux in 
concentrated hydrochloric acid for 90 minutes. 
EXAMPLE 18 
7-Oxaloamino-2,3-dimethyl-4-oxo-4H-1-benzopyrane with a melting point of 
234.degree.-40.degree. can be obtained in a manner analogous to that 
described in Example 3, starting for 9 g of 
7-methoxyoxalylamino-2,3-dimethyl-4-oxo-4H-1-benzopyrane. 
EXAMPLE 19 
7-Methoxyoxalylamino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane with a 
melting point of 239.degree. is obtained in a manner analogous to that 
described in Example 1 and 2, starting from 11 g of 
7-amino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane. 
The starting material can be prepared as follows: 
35 g of 2-hydroxy-4-acetylaminopropiophenone, 23.8 g of benzoyl chloride 
and 169.1 g of potassium carbonate are heated in 3,800 ml of acetone for 8 
hours under reflux. The acetone is stripped off in vacuo and the residue 
is treated with 1,200 ml of water. The resulting mixture is stirred well 
and the material which has not dissolved in filtered off with suction, 
washed successively with 5% strength sodium hydroxide solution and water 
and dried in vacuo. The resulting material is then heated with 420 ml of 
saturated methanolic hydrochloric acid for 1 hour under reflux. The 
methanol is distilled off in vacuo and the residue is treated with 
concentrated ammonia solution. The product which separates out is filtered 
off with suction and digested with toluene and 
7-amino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane with a melting point of 
204.degree.-206.degree., which remains undissolved, is filtered off. 
7-Oxaloamino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane with a melting point 
of 243.degree. can be obtained in a manner analogous to that described in 
Example 3, starting from 7.5 g of 
7-methoxyoxalylamino-2-phenyl-3-methyl-4-oxo-4H-1-benzopyrane. 
EXAMPLE 20 
1 g of 7-hydroxyacetamido-4-methyl-coumarin is dissolved in 60 ml of 
acetone and the solution is stirred with 1 g of potassium permanganate in 
50 ml of water for 40 hours at room temperature. 
7-Oxalo-amino-4-methylcoumarin is extracted with 2 N sodium hydroxide 
solution and precipitated by acidifying. It melts at 
236.degree.-238.degree. with decomposition. 
The starting material can be prepared as follows: 
8.7 g of 7-amino-4-methyl-coumarin are stirred, under nitrogen, in a 
round-bottomed flask, together with 7.6 g of glycollic acid at an oil bath 
temperature of 150.degree.-160.degree.. The reaction mass becomes 
crystalline after about 30 minutes. It is diluted with water and the 
product is filtered off with suction and recrystallised from 200 ml of 
dimethylformamide and 100 ml of ethanol. 
7-Hydroxyacetamido-4-methyl-coumarin with a melting point of 
253.degree.-254.degree. is obtained. 
EXAMPLE 21 
The following compounds can also be prepared in a manner analogous to that 
described in Examples 1 to 20: 
6-methoxyoxalylamino-4-oxo-4H-1-benzopyrane, 
6-oxaloamino-4-oxo-4H-1-benzopyrane, 
6-methoxyoxalylamino-2-methyl-4-oxo-4H-1-benzopyrane, 
6-oxaloamino-2-methyl-4-oxo-4H-1-benzopyrane, 
6-oxaloamino-3-(2-pyridyl)-coumarin, 
8-methoxyoxalylamino-3-(2-pyridyl)-coumarin, 
8-oxaloamino-3-(2-pyridyl)-coumarin, 6-methoxy-5-oxaloamino-coumarin, 
8-methoxyoxalylamino-coumarin, 8-oxaloamino-coumarin, 
5-methoxyoxalylamino-coumarin, 5-oxaloaminocoumarin-coumarin, 
6-methoxy-5-methoxyoxalylamino-4-methyl-coumarin, 
6-methoxy-4-methyl-5-oxaloamino-coumarin, 
6-hydroxy-4-methyl-5-oxaloamino-coumarin, 
6-hydroxy-4-methyl-5-oxaloamino-coumarin, 
7-methoxy-4-methyl-8-oxaloamino-coumarin, melting point 214.degree. and 
7-methoxy-8-methoxyoxalylamino-4-methyl-coumarin, melting point 
216.degree.. 7-Methoxyoxalylaminocoumarin, 6-oxaloaminocoumarin, 
7-oxaloaminocoumarin, 4-methyl-6-oxaloamino-coumarin, 
4-hydroxy-6-methoxyoxalylaminocoumarin, 
6-methoxyoxalylamino-3-(2-pyridyl)-coumarin, melting point 
240.degree.-242.degree. (decomposition) and 
4-hydroxy-6-oxaloaminocoumarin. 
EXAMPLE 22 
Tablets containing 0.1 g of 7-oxaloamino-4-methylcoumarin are prepared as 
follows: 
______________________________________ 
Composition (for 1,000 tablets): 
______________________________________ 
7-Oxaloamino-4-methyl-coumarin 
100 g 
Lactose 50 g 
Wheat starch 73 g 
Colloidal silica 13 g 
Magnesium stearate 2 g 
Talc 12 g 
Water q.s. 
______________________________________ 
The 7-oxaloamino-4-methyl-coumarin is mixed with a portion of the wheat 
starch and with the lactose and the colloidal silica and the mixture is 
forced through a sieve. A further portion of the wheat starch is mixed to 
a paste with five times the amount of water on a water bath and the above 
pulverulent mixture is kneaded with this paste until a slightly plastic 
mass has formed. The plastic mass is passed through a sieve of about 3 mm 
mesh width and dried and the dry granules are again forced through a 
sieve. The remainder of the wheat starch, the talc and the magnesium 
stearate are then mixed in and the resulting mixture is pressed to give 
tablets weighing 0.25 g (with a breaking groove). 
Tablets containing, in each case, 100 mg of one of the compounds, of the 
general formula I, mentioned in Examples 1 and 2 can also be prepared in 
an analogous manner. 
EXAMPLE 23 
An approximately 2% strength aqueous solution, which is suitable for 
inhalation, of a water-soluble active compound according to the invention, 
in the free form or in the form of the sodium salt, can, for example, be 
prepared in the following composition: 
______________________________________ 
Composition 
______________________________________ 
Active compound, for example 
4-methyl-7-oxaloamino-coumarin 
2,000 mg 
Stabiliser, for example the disodium salt 
of ethylenediaminetetraacetic acid 
10 mg 
Preservative, for example benzalkonium 
chloride 10 mg 
Freshly distilled water to make up 
to 100 ml 
______________________________________ 
Preparation 
The active compound is dissolved in freshly distilled water with the 
additive of the equimolecular amount of 2 N sodium hydroxide solution. The 
stabiliser and the preservative are then added. After all of the 
components have dissolved completely, the resulting solution is made up to 
100 ml and filled into small bottles and these are sealed gas-tight. 
2% strength inhalation solutions containing, as the active compound, a 
compound which is the object of the preparation in one of Examples 1, 2 
and 4 can also be prepared in an analogous manner. 
EXAMPLE 24 
An approximately 2% strength aqueous solution, which is suitable for 
inhalation, of a water-soluble active compound according to the invention, 
in the free form or in the form of the sodium salt, can, for example, be 
prepared in the following composition: 
______________________________________ 
Composition 
______________________________________ 
Active compound, for example the sodium salt of 
3,4-dimethyl-7-oxaloamino-coumarin 
2,000 mg 
Stabiliser, for example the disodium salt of 
ethylenediaminetetraacetic acid 
10 mg 
Preservative, for example benzalkonium chloride 
10 mg 
Freshly distilled water to make up 
to 100 ml 
______________________________________ 
Preparation 
The active compound is dissolved in freshly distilled water. The stabiliser 
and the preservative are then added. After all of the components have 
dissolved completely, the resulting solution is made up to 100 ml and 
filled into small bottles and these are sealed gas-tight. 
2% strength inhalation solutions containing, as the desired compound, 
another compound which is the object of the preparation in one of Examples 
5 to 21 can also be prepared in an analogous manner. 
EXAMPLE 25 
Capsules suitable for insufflation and containing about 25 mg of an active 
compound according to the invention can, for example, be prepared in the 
following composition: 
______________________________________ 
Composition 
______________________________________ 
Active compound, for example 7-methoxyoxyalyl- 
amino-4-methyl-coumarin 25 g 
Very finely ground lactose 25 g 
______________________________________ 
Preparation 
The active compound and the lactose are intimately mixed. The resulting 
powder is then sieved and filled in 50 mg portions into 1,000 gelatine 
capsules. 
Insufflation capsules containing, in each case, a compound which is the 
object of the preparation according to one of Examples 2 to 4 can also be 
prepared in an analogous manner. 
EXAMPLE 26 
Capsules suitable for insufflation and containing about 25 mg of an active 
compound according to the invention can, for example, be prepared in the 
following composition: 
______________________________________ 
Composition 
______________________________________ 
Active compound, for example 3,4-dimethyl-7- 
oxaloamino-coumarin 25 g 
Very finely ground lactose 25 g 
______________________________________ 
Preparation 
The active compound and the lactose are intimately mixed. The resulting 
powder is then sieved and filled in 50 mg portions into 1,000 gelatine 
capsules. 
Insufflation capsules containing, in each case, another compound which is 
the object of the preparation according to one of Examples 5 to 19 can 
also be prepared in an analogous manner.