New redox indicators

The invention provides new redox indicators and uses for these redox compounds (I): ##STR1## Wherein X is oxygen or sulphur, R.sub.1 is julolidine or tetrahydroquinoline, which can carry an alkyl radical on the nitrogen atom which, in turn, can be substituted by a sulphuric, phosphonic or carboxylic acid residues, or is (II); wherein R.sub.4 is hydroxyl or a mono- or dialkylated amino group, R.sub.5 and R.sub.6, which can be the same or different, are hydrogen, alkyl or alkoxy, R.sub.2 is hydrogen or alkyl, julolidine or tetrahydroquinoline, which can carry an alkyl on the nitrogen atom which alkyl can be substituted by sulphuric, phosphonic or carboxylic acids, or is III; wherein R.sub.5 and R.sub.6 are the same as in R.sub.1 and R'.sub.4 is hydroxyl, an amino or a mono-or dialkylated amino group, whereby the alkyl radicals can be substituted one or more times by hydroxyl, alkoxy, halogen, morpholine or a sulphuric, carboxylic or phosphonic acid residue, which acids can also be esterified, and R.sub.3 is the same as R.sub.2 or is an alkyl substituted by hydroxyl, alkoxy, dialkylamino or phenyl, or is cycloalkyl, phenyl or pyridyl; as well as the salts thereof.

The present invention is concerned with new redox indicators, with the 
preparation thereof and with reagents containing them. 
The reaction of hydrogen peroxide with oxidation indicators catalysed by 
peroxidase or of peroxidate-active substances plays a special part in 
analytical chemistry because, apart from the detection of hydrogen 
peroxide and peroxidase, it also permits the determination of a series of 
substances which react with oxygen and a series of materials with the 
formation of hydrogen peroxide. In the following, some of these materials 
are listed by way of example and the corresponding oxidases are mentioned 
in brackets: glucose (glucose oxidase), galactose (galactose oxidase), 
L-amino acids (L-amino acid oxidase), cholesterol (cholesterol oxidase), 
uric acid (uricase), sarcosine (sarcosine oxidase), glycerol (glycerol 
oxidase) and pyruvate (pyruvate oxidase). 
As a detection reaction for peroxidases, the method is especially useful 
for the determination of haemoglobin. 
These are, in particular, reactions which are of great importance in 
medical diagnosis and in foodstuff chemistry. 
The detection reactions are carried out either in a cuvette or with the 
help of dry reagents. Quantification thereby takes place in photometers 
via a transmission measurement, with remission photometers via remission 
measurement or with the help of comparative colors by visual comparison. 
The use of dry reagent carriers, i.e. absorbent or swellable carriers, 
which are impregnated with the reagents or in which the reagents are 
incorporated via another step and on which, after moistening with the 
substrate, the detection reaction takes place, has recently achieved ever 
increasing importance. The adjuvants permit, by means of simple handling, 
with a simultaneous great saving of time, a decisive rationalization of 
the analyses in question. The stimulus to develop dry reagents with which 
it is possible to operate with undiluted samples gives the developer the 
problem, with regard to the choice of the indicator or indicator system to 
be used, that serum or plasma (hereinafter referred to as serum) 
considerably disturbs the detection reaction. These disturbances make 
themselves noticeable especially when it is necessary to detect the 
substrates or enzyme activities via coupled reaction steps. As examples of 
substrates, there are here mentioned the detection of creatinine and uric 
acid and, as examples of activity determinations of enzymes, the 
determination of creatine kinase, glutamate-oxalacetate transaminase (GOT) 
and glutamate-pyruvate transaminase (GPT). 
From the literature, there are known numerous compounds which can be used 
as indicators for the detection of hydrogen peroxide with peroxidase as 
catalyst. Such indicators include benzidine and benzidine derivatives, 
various phenols, polyphenols, for example, guaiac resin, leuko dyestuffs, 
for example leuko malachite green, dichlorophenolindophenol, 
aminocarbazoles, triarylimidazoles and 
2,2'-azino-di-[3-ethylbenzthiazole-6-sulphonic acid], as well as dyestuffs 
which result as coupling products of the oxidative coupling of 
aminoantipyrine or related substances with phenols, naphthols, aniline 
derivatives and other coupling components. 
In the case of the detection of hydrogen peroxide in undiluted serum 
samples, the above-mentioned known indicators display more or less great 
disturbances due to reactions with other components of the serum which 
falsify a higher or mostly lower concentration of the substrate to be 
detected. Relatively less disturbed are some triarylimidazoles, such as 
are described in Federal Republic of Germany Patent Specification No. 27 
35 690. However, these imidazoles are only stable in the acidic pH range 
and, as experiments have shown, are, in the case of transfer into a weakly 
acidic to weakly alkaline pH range, such as is necessary in the case of 
almost all enzymatic reactions, i.e. when they are present as free bases, 
spontaneously oxidised by atmospheric oxygen. Therefore, a working up to 
functional dry reagents with these indicators is only possible when they 
are embedded in a protective colloid, for example gelatine. However, this 
can only be carried out in special cases. 
Therefore, it is an object of the present invention to provide coloured 
material formers for the detection reaction of hydrogen peroxide or of 
peroxidate-active substances which do not react with the disturbing 
substances contained in serum, are not spontaneously oxidised by 
atmospheric oxygen in the weakly acidic to weakly alkaline range and thus 
can be used not only in a cuvette test but also in all matrices which can 
be used for dry reagent carriers. 
Thus, according to the present invention, there are provided oxazole and 
thiazole derivatives of the general formula: 
##STR2## 
wherein X is an oxygen or sulphur atom, R.sub.1 is a radical of the 
general formula: 
##STR3## 
in which R.sub.4 is a hydroxyl group or a mono- or dialkylated amino 
group, R.sub.5 and R.sub.6, which can be the same or different, are 
hydrogen atoms, alkyl or alkoxy radicals, which can be substituted by a 
carboxyl group or a julolidine or tetrahydroquinoline radical, which can 
carry an alkyl radical on the nitrogen atom, which in turn can be 
substituted by a sulfo, phosphonic acid or carboxylic acid residue, 
R.sub.2 is a hydrogen atom or an alkyl, julolidine or tetrahydroquinoline 
radical, which can carry an alkyl radical on the nitrogen atom which, in 
turn, can be substituted by a sulfo, phosphonic acid or carboxylic acid 
residue, or a radical of the general formula: 
##STR4## 
in which R.sub.5 and R.sub.6 have the same meanings as given in the 
definition of R.sub.1 and R'.sub.4 is a hydroxyl or amino group or a mono- 
or dialkylated amino group, whereby the alkyl radicals can be substituted 
one or more times by hydroxyl, alkoxy, halogen, morpholine, sulfo, 
carboxylic acid or phosphonic acid, which can also be esterified, and 
R.sub.3 has the same meaning as R.sub.2 or can be an alkyl radical which 
is substituted by hydroxyl, alkoxy, dialkylamino or phenyl, or is a 
cycloalkyl, phenyl or pyridyl radical; as well as the salts thereof. 
The expression alkyl in the definition of the substituents R.sub.2, 
R.sub.3, R.sub.4, R'.sub.4, R.sub.5 and R.sub.6 means radicals with 1 to 6 
and preferably 1-4 carbon atoms, the methyl, ethyl, propyl, butyl and 
tert.-butyl radicals being preferred. The amino groups of the phenyl 
substituents are, as a rule, substituted by alkyl radicals with 1 to 4 
carbon atoms, methyl being preferred. All alkyl radicals can, in turn, be 
substituted one or more times by halogen, hydroxyl, methoxy, carboxyl, a 
sulfo or phosphonic acid residue, which can also be esterified by methanol 
or ethanol, or by a morpholino radical. 
The tetrahydroquinoline radical is a 1,2,3,4-tetrahydroquinoline radical 
and can carry on the nitrogen atom an alkyl radical with 1 to 6 carbon 
atoms, preferably a methyl radical. These alkyl radicals can, in turn, 
carry a carboxyl, phosphonic acid or sulphonic acid residue. 
Cycloalkyl radicals in the definitions of the substituent R.sub.3 are 
radicals with 3 to 7 carbon atoms, the cyclopropyl, cyclopentyl and 
cyclohexyl radicals being preferred. 
By alkoxy radicals in the definitions of the substituents R.sub.2, 
R'.sub.4, R.sub.5 and R.sub.6, alone or as substituents of alkyl radicals, 
are to be understood radicals with 1 to 6 and preferably 1 to 4 carbon 
atoms, methoxy, ethoxy and propoxy radicals being preferred. 
Preferred substituents R.sub.1, R.sub.2 and R.sub.3 include, for example, 
3,5-dimethoxy-4-hydroxyphenyl, 3,5-di-(-tert.-butyl)-4-hydroxyphenyl, 
4-dimathylaminophenyl, 9-julolidino, as well as 
6-N-methyl-1,2,3,4-tetrahydroquinolino, whereby the alkyl substituents can 
carry carboxyl, phosphonic acid or sulfo groups. Furthermore, R.sub.2 and 
R.sub.3 can also preferably signify methyl. Apart from the above-mentioned 
radicals, R.sub.3 means especially hydrogen, n-butyl, tert-butyl, 
3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, cyclohexyl, phenyl, 
benzyl, hydroxymethyl, pyridyl or dimethylaminomethyl. 
The sulfo, phosphonic acid and carboxylic acid residues with which alkyl 
radicals are preponderantly substituted, serve especially for improving 
the solubility. 
The indicators of general formula I can be incorporated into all known 
detection systems. 
With the indicators there can be produced tests which are measured in a 
cuvette. For this purpose, the indicator, together with peroxidase, the 
enzyme or enzymes required for the detection of the particular parameter, 
other reagents and a buffer system and possibly wetting agents and other 
adjuvants are lyophilised, mixed as a powder or pressed into tablets. The 
reagent mixture thus obtained is, before use, dissolved in water and the 
reagent solution is thus prepared. After the addition of the sample 
(substrate solution, enzyme solution, serum or plasma), the resultant 
color is measured in a photometer and the particular concentration or 
enzyme activity calculated via the molar extinction coefficients and the 
added volume of reagent or sample. Not only kinetic but also end point 
measurements are possible. 
In the same way, the indicators, together with peroxidase, the reagent or 
reagents necessary for the particular parameter to be detected or other 
enzymes, a buffer system, possibly wetting agents and other adjuvants can 
be impregnated on to absorbent reagent carriers, such as papers, fleece or 
the like. For this purpose, one or more impregnation solutions can be 
prepared in the form of aqueous or organic or mixed solutions, depending 
upon how the reagents or adjuvants dissolve, and carriers are impregnated 
or sprayed with these solutions. Subsequently, the carriers are dried. The 
reagent carriers thus obtained can be used as rapid diagnostics for the 
direct determinations of component materials of, for example, body fluids. 
The body fluid is thereby applied directly to the reagent carrier or the 
reagent carrier is dipped into the body fluid. By comparison of the 
resultant colour with comparative colors, a semiquantitative determination 
is possible. By means of remission photometric processes, a quantitative 
evaluation is also possible. It is also possible to prepare a reagent 
solution by eluting with water or buffer the reagents impregnated, as 
above described, on a paper or fleece, with which eluted solution 
substrates and enzymes are determined in a cuvette using a photometer as 
described hereinbefore (cf. Federal Republic of Germany Patent 
Specification No. 2,301,999). 
Another possibility for the use of the indicators according to the present 
invention is the use thereof in reagent films for the quantitative 
determination of enzymes or substrates by means of a remission photometer. 
In this case, the indicator, together with the other necessary reagents 
and adjuvants, is worked up to give a reagent film, for example according 
to the processes described in Federal Republic of Germany Patent 
Specifications Nos. 1,598,153 and 2,910,134. 
Furthermore, the indicators according to the present invention can also be 
successfully combined with stabilisers such as are described, for example, 
in Federal Republic of Germany Patent Specification No. 2,716,060. These 
stabilisers, which are 1-aryl semicarbazides, result in the finished tests 
being insensitive to the influence of light and, with larger amounts, the 
function curves of the remission-photometric measurements can be 
modulated. 
As mentioned above, the indicators according to the present invention can 
be incorporated into all conventional reagent carriers, i.e. absorbent 
carriers, such as filter papers, fleece and the like, or into swellable or 
absorbent reagent films (see Federal Republic of Germany Patent 
Specifications Nos. 1,598,153; 2,910,134 and 3,247,608). 
However, since they are preferably to be used for the detection of enzymes 
and substrates in serum, in FIGS. 1-4 of the accompanying drawings, there 
are shown in cross-section a series of devices which permit, according to 
Federal Republic of Germany Patent Specification No. 3,029,579, on the one 
hand, serum or plasma for the test to be separated from whole blood and, 
on the other hand, on the basis of a special construction of the reagent 
and adjuvant layers, permit a tempering, pre-reaction and directed 
starting of the main reaction.

There is, of course, also the possibility of incorporating the compounds 
according to the present invention into gelatine matrices according to 
Federal Republic of Germany Patent Specification No. 2,735,690, together 
with the reagents and adjuvants necessary for the appropriate detection 
reaction. 
To summarise, it can be said that the compounds of general formula I 
according to the present invention can be used in all test systems, with 
the help of which hydrogen peroxide or peroxidate-active substances can be 
detected directly or after preceding reactions. 
The new compounds of general formula I according to the present invention 
can be prepared in one of the following ways: 
(a) a compound of general formula: 
##STR5## 
in which R.sub.1, R.sub.2 and R.sub.3 have the above-given meanings, is 
reacted with a Lewis acid or pentasulphide; or 
(b) when X is an oxygen atom, a compound of the general formula: 
##STR6## 
in which R.sub.1, R.sub.2 and R.sub.3 have the above-given meanings, is 
reacted with ammonium acetate in glacial acetic acid; or 
(c) when X is a sulphur atom, a thioamide of the general formula: 
##STR7## 
in which R.sub.2 has the above-given meaning, is reacted with an 
.alpha.-halogenoketone of the general formula: 
EQU Hal--CH.sub.2 --CO--R.sub.1 (V) 
in which R.sub.1 has the above-given meaning and Hal is a fluorine, 
chlorine or bromine atom, and subsequently, if desired, the compound 
obtained is converted into another compound of general formula I and also, 
if desired, a base obtained is converted into a salt or a salt obtained is 
converted into a free base. 
More particularly, the preparation of compounds of general formula I takes 
place as follows: 
The reaction of aromatic .alpha.-acyloxyketone (prepared by the acylation 
of acyloins or benzoins with acid halides in pyridine or by the reaction 
of .alpha.-bromoketones with salts of carboxylic acids in 
dimethylformamide) with ammonium acetate in glacial acetic acid by 
Davidson's method, leads, with the introduction of imino nitrogen and ring 
closure, to 2,4-diaryl-substituted 1,3-oxazoles. Corresponding benzoin 
esters can be used for the synthesis of 2,4,5-triaryl-substituted 
1,3-oxazoles. 
The cyclisation of .alpha.-oximinoketones with aromatic aldehydes by the 
action of gaseous hydrogen chloride in glacial acetic acid gives, in the 
case of subsequent reduction of the resultant 1,3-oxazole-N-oxides with 
zinc and acetic acid, depending upon the constitution of the starting 
material, 2,4- or 2,5-diaryl-substituted 1,3-oxazoles. By the condensation 
of appropriately substituted .alpha.-acylaminoketones with polyphosphoric 
acid ethyl ester, 2,5-diaryl- or 2,4,5-triaryl-substituted 1,3-oxazoles 
(Robinson-Gabriel's method) are obtained analogously. 
2,5-Diaryl-substituted 1,3-oxazoles can also be obtained from aldehyde 
cyanohydrins and aldehydes by condensation with ethereal hydrochloric acid 
(Fischer's oxazole synthesis). 
The reaction of a 2-substituted 4-aminophenyl-5-methyl-1,3-oxazole with 
formaldehyde in methanol leads, inter alia to the formation of the 
N,N-bismethyl ether, the reductive methylation of the hydrochloride of 
this compound with formaldehyde in the presence of platinum oxide and 
catalytically-activated hydrogen leading to the N,N-dimethyl compound. 
By alkylation of 2-substituted 4-aminophenyl-5-methyl-1,3-oxazole with 
2,3-epoxypropan-1-ol or epichlorohydrin, there is obtained the 
corresponding aminopropandiol or the aminochloropropanol derivative, 
respectively. 
By substitution of the halogen in the above-mentioned aminochloropropanol 
by reaction with morpholine, there is obtained the corresponding 
morpholine derivative. The reaction of the 2-substituted 
4-aminophenyl-5-methyl-1,3-oxazole with diethyl 
2,3-epoxypropane-phosphonate leads to diethyl 1,3-oxazolephosphonate 
which, by hydrolysis with 6N hydrochloric acid, can easily be converted 
into the phosphonic acid in question. 
Reductive alkylation of the above-mentioned phosphonic acid with 
formaldehyde gives the N-methylated derivative, saponification of which 
with 6N hydrochloric acid gives the free phosphonic acid. 
By the reaction of benzyl bromoacetate with a 2-substituted 
4-aminophenyl-5-methyl-1,3-oxazole, there is obtained the corresponding 
benzyl acetate from which, by catalytic debenzylation, there is obtained 
the aminoacetic acid in question. 
The reaction of 4-dimethylamino-.alpha.-bromoacetophenone with 
4-benzyloxy-3,5-dimethoxyphenylthioamide by Hantzsch's method and 
subsequent hydrolytic acidic debenzylation gives the diaryl-substituted 
1,3-thiazole. 
From diaryl-.alpha.-acylaminoketones, there are obtained, with phosphorus 
pentasulphide, the corresponding 2,4,5-triaryl-substituted 1,3-thiazoles. 
For ease of writing, in the following Examples, the extinctions are given 
as .epsilon.'=.epsilon.10.sup.-3. 
Preferred compounds according to the present invention include the 
following: 
1. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-butyl-1,3-ox 
azole 
2. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-(3-propoxyme 
thyl)-1,3-oxazole 
3. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-(4-n-butoxym 
ethyl)-1,3-oxazole 
4. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-(tert.-butyl 
)-1,3-oxazole 
5. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-cyclohexyl-1 
,3-oxazole 
6. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-benzyl-1,3-o 
xazole 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(1,2,3,4-tetra-hydroquinolino-6-N-methy 
l)-5-methyl-1,3-oxazole 
8. 2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(9-julolidino)-5-methyl-1,3-oxazole 
9. 2,4-bis-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-1,3-oxazole 
10. 2,5-bis-(3,5-dimethoxy-4-hydroxyphenyl)-4-methyl-1,3-oxazole 
11. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-1,3-oxazo 
le 
12. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-butyl-1 
,3-oxazole 
13. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-(3-meth 
oxypropyl)-1,3-oxazole 
14. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-(5-meth 
oxypentyl)-1,3-oxazole 
15. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-(tert.- 
butyl)-1,3-oxazole 
16. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-cyclohe 
xyl-1,3-oxazole 
17. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-benzyl- 
1,3-oxazole 
18. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(1,2,3,4-tetrahydroquinolino-6-N- 
methyl)-5-methyl-1,3-oxazole 
19. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(9-julolidino)-5-methyl-1,3-oxazo 
le 
20. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-methyl-5-(9-julolidino)-1,3-oxazo 
le 
21. 
2-(1,2,3,4-tetrahydroquinolino-6-N-methyl)-4-(3,5-dimethoxy-4-hydroxypheny 
l)-5-methyl-1,3-oxazole 
22. 2-(9-julolidino)-4-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-1,3-oxazole 
23. 
2,4-bis-(4-dimethylaminophenyl)-5-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxaz 
ole 
24. 2-(9-julolidino)-4,5-bis-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxazole 
25. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-phenyl- 
1,3-oxazole 
26. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4,5-bis(9-julolidino)-1,3-oxazole 
27. 2,4,5-tris-(3,5-di-tert.-butyl-4-hydroxyphenyl)-1,3-oxazole 
28. 
2-(4-dimethylaminophenyl)-4,5-bis-(3,5-di-tert.-butyl-4-hydroxyphenyl)-1,3 
-oxazole 
29. 
2-(1,2,3,4-tetrahydroquinolino-6-N-methyl)-4,5-bis-(3,5-di-tert.-butyl-4-h 
ydroxyphenyl)-1,3-oxazole 
30. 
2-(9-julolidino)-4,5-bis-(3,5-di-tert.-butyl-4-hydroxyphenyl)-1,3-oxazole 
31. 
2-(4-dimethylaminophenyl)-4-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl- 
1,3-oxazole 
32. 
2-(1,2,3,4-tetrahydroquinolino-6-N-methyl)-4-(3,5-di-tert.-butyl-4-hydroxy 
phenyl)-5-methyl-1,3-oxazole 
33. 
2-(9-julolidino)-4-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-1,3-oxazo 
le 
34. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis-(1,2,3,4-tetrahydroquinolino-6-N 
-methyl)-1,3-oxazole 
35. 2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis-(9-julolidino)-1,3-oxazole 
36. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-phenyl-1,3-o 
xazole 
37. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis-(3,5-di-tert.-butyl-4-hydroxyphe 
nyl)-1,3-oxazole 
38. 
2-(1,2,3,4-tetrahydroquinolino-6-N-methyl)-4,5-bis(3,5-dimethoxy-4-hydroxy 
phenyl)-1,3-oxazole 
39. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-4-(N-2,3-dihydroxypropyl)-aminophenyl- 
5-methyl-1,3-oxazole 
40. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-4-(N-2,3-dihydroxypropyl)-methylaminop 
henyl-5-methyl-1,3-oxazole 
41. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-phenyla 
mino}-methane-phosphonic acid 
42. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-methylp 
henylamino}-methanephosphonic acid 
43. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-phenyla 
mino}-ethanesulch-onic acid 
44. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-phenyla 
mino}-ethanephosphonic acid 
45. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-phenyla 
mino}-methanephosphonic acid 
46. 
N{-4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-methylp 
henylamino}-methanesulphonic acid 
47. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-54-methyl-(1,3)-oxazolyl]-methylph 
enylamino}-ethanephosphonic acid 
48. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-54-methyl-(1,3)-oxazolyl]-phenylam 
ino}-acetic acid 
49. 
N,N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-54-methyl-(1,3)-oxazolyl]-phenyl 
amino}-bis-ethanesulphonic acid 
50. 
N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-phenyla 
mino}-bis-methanephosphonic acid 
51. 
N,N-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-pheny 
lamino}-bis-acetic acid 
52. 
{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl-]1,2,3,4-t 
etrahydroquinolino}-6-N-ethanesulphonic acid 
53. 
{2-[4-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl-]1,2,3,4-t 
etrahydroquinolino}-6-N-ethanesulphonic acid 
54. 
{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2,3,4-t 
etrahydroquinolino}-6-N-ethanephosphonic acid 
55. 
{2-[4-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2,3,4-t 
etrahydroquinolino}-6-N-ethanephosphonic acid 
56. 
{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2,3,4-t 
etrahydroquinolino}-6-N-acetic acid 
57. 
{2-[4-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2,3,4-t 
etrahydroquinolino}-6-N-acetic acid 
58. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-hydroxymethy 
l-1,3-oxazole 
59. 
{5-[2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-(1,3)-oxaz 
olyl]-methyl}-trimethylammonium chloride 
60. 
-{5-[2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-(1,3)-oxa 
zolyl]-methyl}pyridinium chloride 
61. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-N-3-chloro-2-hydroxypropylamin 
ophenyl)-5-methyl-1,3-oxazole 
62. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-[4-(N-2,3-dihydroxypropyl)-aminop 
henyl]-5-methyl-1,3-oxazole 
63. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-[4-(N-2,3-dihydroxypropyl)-methyl 
aminophenyl]-5-methyl-1,3-oxazole 
64. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-ph 
enylamino}-methanephosphonic acid 
65. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-me 
thylphenylamino}-methanephosphonic acid 
66. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-[4-(3-N-morpholino-2-hydroxypropy 
l)-aminophenyl-]5-methyl-1,3-oxazole 
67. diethyl 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-ph 
enylamino-2-hydroxypropyl}-phosphonate 
68. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-ph 
enylamino-2-hydroxypropyl}-phosphonic acid 
69. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-me 
thylphenylamino-2-hydroxypropyl}-phosphonic acid 
70. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-ph 
enylamino}-ethanesulphonic acid 
71. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-ph 
enylamino}-ethanephosphonic acid 
72. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-ph 
enylamino}-methanephosphonic acid 
73. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-me 
thylphenylamino}-methanesulphonic acid 
74. 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-me 
thylphenylamino}-ethanephosphonic acid 
75. 
N,N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]- 
phenylamino}-bis-ethanesulphonic acid 
76. 
N,N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]- 
phenylamino}-bis-methanephosphonic acid 
77. 
N,N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]- 
phenylamino}-bis-acetic acid 
78. 
{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2, 
3,4-tetrahydroquinolino-6-N-ethanesulphonic acid 
79. 
{2-[4-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2, 
3,4-tetrahydroquinolino-}6-N-ethanesulphonic acid 
80. 
{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2, 
3,4-tetrahydroquinolino}-6-N-ethanephosphonic acid 
81. 
{2-[4-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2, 
3,4-tetrahydroquinolino}-6-N-ethanephosphonic acid 
82. 
{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-1,2, 
3,4-tetrahydroquinolino-}6-N-acetic acid 
83. 
{2-[4-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-(1,3)-oxazolyl]-1,2,3, 
4-tetrahydroquinolino}-6-N-acetic acid 
84. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-hydroxy 
methyl-1,3-oxazole 
85. 
{5-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-(1,3) 
-oxazolyl]-methyl}-trimethylammonium chloride 
86. 
1-{5-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-(1, 
3)-oxazolyl]-methyl}pyridinium chloride 
87. 
{5-[4-(4-dimethylaminophenyl)-5-methyl-2-(1,3)]-oxazolyl]-2-hydroxy-3-meth 
oxy}-phenyloxyacetic acid 
88. 
{5-[4-(4-dimethylaminophenyl)-5-methyl-2-(1,3)-oxazolyl-2-hydroxy-3-tert.- 
butyl}-phenoxyacetic acid 
89. 
{5-[2-(4-dimethylaminophenyl)-5-methyl-4-(1,3)-oxazolyl]-2-hydroxy-3-metho 
xy}-phenoxyacetic acid 
90. 
{5-[2-(4-dimethylaminophenyl)-5-methyl-4-(1,3)-oxazolyl]-2-hydroxy-3-tert. 
-butyl}-phenoxyacetic acid 
91. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4,5-bis-(1,2,3,4-tetrahydroquinolin 
o-6-N-methyl)-1,3-oxazole. 
The following Examples are given for the purpose of illustrating the 
present invention: 
EXAMPLE 1 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-1,3-oxazole 
hydrochloride 
(a) 
4-N,N-Dimethylamino-.alpha.-[(3,5-dimethoxy-4-hydroxy)-benzyloxy]-acetophe 
none. 
A suspension of 48 g. (0.2 mol) 4-dimethylamino-.alpha.-bromoacetophenone 
and 48.4 g. (0.22 mol) sodium syringate in 1.2 liters of anhydrous 
dimethylformamide is heated for 2 hours at 130.degree. C., while stirring. 
After evaporating the solvent in a vacuum to about one third of its 
volume, 1 liter of ice water is added thereto, the crystals formed are 
filtered off with suction, the filter cake is washed with 500 ml. water 
and the crude product is recrystallised from 400 ml. acetic acid. After 
suction filtration, the crystals are washed with 200 ml. water and 200 ml 
acetone. Subsequently, the product is dried in a vacuum at 40.degree. C. 
to give 42.1 g. (55% of theory) of the title compound in the form of 
beige-coloured crystals; m.p. 208.degree.-210.degree. C. (b) 36 g. (0.1 
mol) of the ester obtained in (a) above are heated in 500 ml. glacial 
acetic acid with 38.6 g. (0.5 mol) ammonium acetate for 2 hours at 
130.degree. C. while stirring. After cooling, the reaction mixture is 
poured into 2 liters of ice water and the crystals are filtered off with 
suction and washed with water and diethyl ether to give 15.1 g. of 
beige-coloured crystals. The crude product is purified column 
chromatographically on silica gel with chloroform-methanol (9:1 v/v). The 
appropriate fraction gives, upon evaporation, 7.3 g. (20.6% of theory) of 
the title compound; m.p. 202.degree.-204.degree. C. (decomp ); 
.lambda..sub.max =498 nm, .epsilon.'=20.5 cm.sup.2 .mu.mol.sup.-1. 
The following compounds are obtained analogously: 
1.1. 2,4-Bis-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxazole 
(a) 
3,5-Dimethoxy-4-hydroxy-.alpha.-[(3,5-dimethoxy-4-hydroxy)-benzoyloxy]-ace 
tophenone; yield 94% of theory: m.p. 147.degree./153.degree. C. 
(b) Title compound (base); yield 29% of theory; m.p. 
168.degree.-172.degree. C. Hydrochloride; m.p. 132.degree.-134.degree. C. 
(decomp.); .lambda..sub.max 470 nm; .epsilon.' =14.4 cm.sup.2 
.mu.mol.sup.-1. 
1.2. 
2-(4-Dimethylaminophenyl)-4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxazole hy 
drochloride 
(a) 
4-Benzyloxy-3,5-dimethoxy-.alpha.-(4-dimethylaminobenzoyloxy)-acetophenone 
; yield 53% of theory; m.p. 114.degree. C. 
(b) 
2-(4-Dimethylaminophenyl)-4-(4-benzyloxy-3,5-dimethoxyphenyl)-1,3-oxazole; 
yield 16% of theory; m.p. 157.degree. C. 
(c) 4.3 g. (0.01 mol) of the oxazole derivative obtained in (b) are 
hydrogenated in 100 ml. ethanol, by the addition of 0.3 g. 10% palladium 
on active charcoal, at 25.degree. C. under normal pressure. After 
filtering off the catalyst and evaporating the filtrate, there are 
obtained 2.7 g. of the title compound; yield 65% of theory; m.p. 
185.degree. C.; .lambda..sub.max =512 nm, .epsilon.'=5.3 cm.sup.2 
.mu.mol.sup.-1. 
1.3. 
2-(4-Dimethylaminophenyl)-4-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-1,3-o 
xazole hydrochloride 
(a) 
3,5-Dimethoxy-4-hydroxy-.alpha.-(4-dimethylaminobenzoyloxy)propiophenone; 
yield 40.5% of theory; m.p. 152.degree.-155.degree. C. (decomp.). 
(b) Title compound; yield 20.5% of theory: m.p. 128.degree. C.; 
.lambda..sub.max 327 nm, .epsilon.'=78.9 cm.sup.2 .mu.mol.sup.-1. 
1.4. 2-(9-Julolidino)-4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxazole 
hydrochloride 
(a) 3,3-Dimethoxy-4-hydroxy-.alpha.-(9-julolidinocarboxy)acetophenone, 
purification by chromatography on silica gel, elution agent: chloroform; 
yield 42.8% of theory, amorphous powder TLC: silica gel plate, elution 
agent: n-heptanemethyl ethyl ketone (1:1 v/v). RF value: 0.48 
(b) Title compound; yield 25.6% of theory; colourless crystals; m.p. 
231.degree.-233.degree. C. .lambda..sub.max 540 nm, .epsilon."=21.6 
cm.sup.2 .mu.mol.sup.-1. 
1.5. 
2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-4-(4dimethylaminophenyl)-5-methyl-1 
,3-oxazole 
(a) 4-Dimethylamino-.alpha.-[(3,5-di-tert.-butyl-4-hydroxy)benzoyloxy] 
-propiophenone; yield 85.6% of theory; m.p. 172.degree. C. 
(b) Title compound yield 95% of theory; m.p. 125.degree. C. (decomp.). 
.lambda..sub.max 488 nm, .epsilon.'=46.4 cm.sup.2 .mu.mol.sup.-1. 
1.6. 
2-(3,4-Di-tert.-butyl-4-hydroxyphenyl)-4-(3,5-dimethoxy-4-hydroxyphenyl)-5 
-methyl-1,3-oxazole 
(a) 
4-(3,5-Dimethoxy-4-hydroxyphenyl)-.alpha.-(3,5-di-tert.-butyl-4-hydroxyben 
zyloxy)-propiophenone; yield 90.5% of theory; amorphous yellowish powder. 
TLC silica gel plate, elution agent: toluene-ethyl acetate (5:1 v/v); RF 
value=0.425. 
(b) Title compound: yield 82.4% of theory; m.p. 83.degree.-85.degree. C. 
.lambda..sub.max =486 nm; .epsilon.'=31.1 cm.sup.2 .mu.mol.sup.1. 
1.7. 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-phenyl-1,3-o 
xazole 
(a) 4-Dimethylamino-0-(4-benzyloxy-3,5-dimethoxybenzoyl)benzoin; m.p. 
126.degree.-128.degree. C. 
(b) 
2-(3,5-Dimethoxy-4-benzyloxyphenyl)-4-(4-dimethylaminophenyl)-5-phenyl-1,3 
-oxazole (worked up directly). 
(c) Instead of the catalytic debenzylation mentioned in Example 1.2.c), the 
0-benzyl protective group is here split off, after ring closure of (a) to 
give the 1,3-oxazole (b), by boiling with 6N hydrochloric acid for 30 
minutes to give the title compound; yield 40% of theory; m.p. 167.degree. 
C. (decomp ); .lambda..sub.max 582 nm, .epsilon.'=36.4 cm.sup.2 
.mu.mol.sup.-1. 
1.8. 
2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-4-(9-julolidino)-5-methyl-1,3-oxazo 
le 
(a) 9-Julolidino-.alpha.-bromomethyl ketone 
From julolidine aldehyde, there is obtained, by a Grignard reaction with 
ethyl magnesium bromide, the corresponding carbonol; m.p. 
74.degree.-77.degree. C. An Oppenauer oxidation of this product gives 
9-julolidinoethyl ketone (m.p. 68.5.degree.-69.5.degree. C.) from which, 
by bromination in glacial acetic acid, there is obtained 
9-julolidino-.alpha.-bromoethyl ketone; m.p. 82.degree.-84.degree. C. 
(b) 9-Julolidino-.alpha.-(3,5-di-tert.-butyl-4-hydroxybenzoyloxy)-ethyl 
ketone; m.p. 165.degree.-170.degree. C. 
(c) Title compound: yield 34% of theory; m.p. 135.degree. C. (decomp.). 
.lambda..sub.max =490 nm, .epsilon.'=35.2 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 2 
2,4,5-Tris-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxazole 
(a) 3,3',5,5'-tetramethoxy-4,4'-dibenzyloxybenzoin. 
81.7 g. (0.3 mol) 4-Benzyloxy-3,5-dimethoxybenzaldehyde are suspended in 
300 ml. ethanol, 6 g. potassium cyanide are added thereto and the reaction 
mixture is heated under reflux for 3 hours, the aldehyde thereby going 
into solution. The reaction mixture is then poured into 1.5 liters ice 
water and stirred for 2 hours, while cooling with ice. The crude product 
obtained is taken up with 2.times.300 ml. dichloromethane, dried with 
anhydrous sodium sulphate and evaporated in a vacuum. The residue, 87.3 g. 
of oily material, is purified by chromatography on silica gel. The 
appropriate fraction is evaporated to give 52.4 g of yellowish crystals of 
the title compound; yield 63.2% of theory; m.p. 149.degree.-150.degree. C. 
(b) 
3,3',5,5'-tetramethoxy-4,4'-dibenzyloxy-0-(4-benzoyloxy-3,5-dimethoxybenzo 
yl)-benzoin 
15.8 g. (0.029 mol) of the above-mentioned benzoin derivative are suspended 
in 40 ml. pyridine and, while stirring, a solution of 13.4 g. (0.0435 mol) 
4-benzyloxy-3,5-dimethoxybenzoyl chloride in 80 ml. anhydrous pyridine is 
added dropwise thereto. After 8 hours at ambient temperature, the reaction 
mixture is evaporated in a vacuum on a rotary evaporator, the residue is 
taken up in 100 ml. dichloromethane, the solution is successively shaken 
with 2N hydrochloric acid, water, 2N aqueous sodium carbonate solution and 
water and then evaporated in a vacuum. There are obtained 25 g. of the 
oily title compound. TLC: silica gel 60, elution agent: 
isopropanol/n-butyl acetate/water/ammonia (5:2:1.5:0.5 v/v/v/v). 
(c) 2,4,5-Tris-(4-benzyloxy-3,5-dimethoxyphenyl)-1,3-oxazole 
20 g. (0.0245 mol) of the compound obtained under (b) are heated with 28.4 
g. (0.37 mol) ammonium acetate in 250 ml. glacial acetic acid for 5 hours 
under reflux, thereafter the reaction mixture is poured into a mixture of 
500 ml. water and 250 ml. concentrated ammonia and the precipitated 
crystalline crude product is filtered off, washed with water and dried. 
Yield 24.6 g. For purification, the product is chromatographed on silica 
gel; elution agent: toluene-ethyl acetate (4:1 v/v). There are obtained 13 
g. (yield 66.4% of theory) of beige-coloured crystals of the title 
compound; m.p. &gt;80.degree. to 120.degree. C. (no sharp melting point). 
TLC: silica gel, elution agent: toluene-ethyl acetate (4:1 v/v); RF 
value=0.64. 
(d) 11 g. (0.014 mol) of the above oxazole are dissolved in 300 ml. 
methanol and, after the addition of 1.1 g. palladium on charcoal (10%), 
hydrogenated at normal pressure. After the take up of the calculated 
amount of hydrogen, the catalyst is filtered off and the filtrate is mixed 
with 7.5 ml. 5N ethereal hydrochloric acid and evaporated in a vacuum. 
There are obtained 7 g. (yield 82.1% of theory) of the title compound in 
the form of colourless crystals; m.p. 205.degree.-207.degree. C. 
(decomp.); .lambda..sub.max 632 nm, .epsilon.'=22.2 cm.sup.2 
.mu.mol.sup.-1. 
The following compound is obtained in an analogous way: 
2.1. 
2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-4,5-bis-(3,5-dimethoxy-4-hydroxyphe 
nyl)-1,3-oxazole 
(a) 
3,3',5,5'-Tetramethoxy-4,4'-dibenzyloxy-.alpha.-(4-hydroxy-3,5-di-tert.-bu 
tyl)-benzoyloxybenzoin Yield: 42.5% of theory; yellowish amorphous powder. 
TLC silica gel 60, elution agent: toluene-ethyl acetate (5:1 v/v); RF 
value=0.61. 
(b) 
2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-4,5-bis-(3,5-dimethoxy-4-benzyloxyp 
henyl)-1,3-oxazole. Yield: 62.5% of theory; reddish oil TLC: silica gel 60; 
elution agent: toluene-ethyl acetate (5:1 v/v): RF value=0.56. 
(c) Title compound: yield 81.5% of theory; m.p. 120.degree. C. (decomp.); 
.lambda..sub.max 587 nm, .epsilon.'=40.2 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 3 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-(4-aminophenyl)-5-methyl-1,3-oxazole 
hydrochloride 
(a) 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-acetaminophenyl-5-methyl-1,3-oxazole N 
-oxide. 
50 g. (0.227 mol) 4-acetaminophenyl-1-oximino-2-propanone and 41.35 g. 
(0.227 mol) 3,5-dimethoxy-4-hydroxybenzaldehyde are suspended in 600 ml. 
glacial acetic acid and, while stirring, dry hydrogen chloride gas is 
passed through the reaction mixture for 5 hours, whereafter the reaction 
mixture is evaporated to one half in a vacuum. After the addition of 200 
ml. ethanol, the mixture is filtered and the filter cake is washed with 
150 ml. ethanol. Yield 75.6 g. (80% of theory) of the title compound; 
brownish crystals; m.p. &gt;200.degree. C. (decomp.). TLC: silica gel; 
elution agent: chloroform-methanol (8:1 v/v); RF value=0.31. 
(b) 75.62 g. (0.182 mol) of the above-mentioned product are suspended in 
900 ml. glacial acetic acid and, while stirring, 220 g. (3.35 g. atom) 
zinc dust are added thereto portionwise. Thereafter, the reaction mixture 
is heated under reflux for 2 hours, filtered while hot and the filtrate 
evaporated in a vacuum and boiled under reflux for 30 minutes with 500 ml. 
6N hydrochloric acid. The reaction mixture is cooled with ice and the 
crystals formed are filtered off with suction and the filter residue is 
washed with 150 ml. acetone. The zinc-containing crude product is 
dissolved in 1.2 liters hot water, mixed with a solution of 55 g. 
Titriplex III in 1.5 liters water and the base liberated by the addition 
of 50 ml. concentrated aqueous ammonia solution. After filtering off and 
washing the filter residue with water, it is recrystallised from 6N 
hydrochloric acid and, after filtering off, washing the hydrochloride with 
acetone and drying in a vacuum at 40.degree. C., there are obtained 60.2 
g. (79.8% of theory) of the title compound; m.p. 253.degree.-255.degree. 
C. (decomp.); .lambda..sub.max 540 nm, .epsilon.'=29 cm.sup.2 
.mu.mol.sup.-1. 
The following compounds are obtained in an analogous manner: 
3.1. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-amino-3-methoxyphenyl)-5-methyl-1,3 
-oxazole hydrochloride from 
4-acetamino-3-methoxyphenyl-1-oximino-2-propanone and 
3,5-dimethoxy-4-hydroxybenzaldehyde; m.p. &gt;227.degree. C. (decomp.); 
yellowish crystals; .lambda..sub.max 546 nm, .epsilon.'=21.6 cm.sup.2 
.eta.mol.sup.-1. 
3.2. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-methyl-5-(4-dimethylaminophenyl)-1,3-o 
xazole hydrochloride from 4-dimethylaminophenyl-2-oximino-1-propanone and 
3,5-dimethoxy-4-hydroxybenzaldehyde; m.p. 168.degree.-170.degree. C. 
(decomp.); colourless crystals; .lambda..sub.max 494 nm, .epsilon.'=5.7 
cm.sup.2 .mu.mol.sup.-1. 
3.3. 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-aminophenyl)-5-methyl-1,3-oxaz 
ole hydrochloride from 4-acetaminophenyl-1-oximino-2-propanone and 
3,5-di-tert.-butyl-4-hydroxybenzaldehyde via the oxime; (oxime m.p. 
215.degree. C. (decomp.)); colourless crystals; m.p. 238.degree. C.; TLC: 
silica gel 60, elution agent: chloroform-methanol (19:1 v/v); RF value: 
0.65 (base); .lambda..sub.max 514 nm; .epsilon.'=41.6 cm.sup.2 
.mu.mol.sup.-l. 
3.4. 
2-(4-Dimethylaminophenyl)-bis-4,5-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxaz 
ole hydrochloride. 
(a) Bis-(3,3',5,5')-tetramethoxy-4,4'-benzyloxybenzil monoxime 27.13 g. 
(0.05 mol) bis-(3,3',5,5'-tetramethoxy-4,4'-benzyloxybenzil are suspended 
in 350 ml. dry pyridine, 6.35 g. (0.1 mol) hydroxylamine hydrochloride are 
added thereto and the reaction mixture is stirred for 4.5 hours at ambient 
temperature, thereafter evaporated in a vacuum and the residue is 
separated chromatographically on the silica gel column; elution agent: 
toluene-ethyl acetate (2:1 v/v). The appropriate fraction contains 17.3 g. 
(62% of theory) of oxime; reddish oil. TLC: silica gel 60; elution agent: 
toluene-ethyl acetate (2:1 v/v); RF value=0.64. 
(b) 14.49 g. (0.026 mol) of the above compound are dissolved in 50 ml. 
glacial acetic acid, together with 3.88 g. (0.026 mol) 
4-dimethylaminobenzaldehyde, and dry hydrogen chloride is passed in at 
15.degree. to 20.degree. C., while stirring, for 3.5 hours. Thereafter, 
the reaction mixture is substantially evaporated in a vacuum, the residue 
is stirred with diethyl ether and the crude product obtained is purified 
on silica gel; elution agent: dichloromethane-acetone-methanol (20:10:2 
v/v/v). There are obtained 3.1 g. (21.1% of theory) of beige-coloured 
crystals: m.p. 212.degree.-215.degree. C. (decomp.}: .lambda..sub.max 619 
nm, .epsilon.'=25.9 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 4 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4,5-bis-(4-dimethylaminophenyl)-1,3-oxazo 
le 
(a) 4,4'-Bis-(dimethylamino)-benzil monoxime. 
74 g. (0.25 mol) 4,4'-bis-(dimethylamino)-benzil are stirred with 20.8 g. 
(0.3 mol) hydroxylamine hydrochloride in 1.2 liters pyridine for 30 hours 
at ambient temperature. The reaction mixture is then evaporated to dryness 
in a vacuum, stirred with 500 ml. water, subsequently with 500 ml. of a 
mixture of methanol and water (1:3 v/v) and finally with 500 ml. toluene, 
filtered off with suction and dried. There are obtained 69.6 g. (89.2% of 
theory) 4,4'-bis-(dimethylamino)-benzil monoxime; m.p. 179.degree. C. 
(decomp ). (b) 4,4'-Bis-(dimethylamino)-2-aminodesoxybenzoin hydrochloride 
10 g. (0.032 mol) of the compound obtained in (a) are hydrogenated in 60 
ml. 6N methanolic hydrochloric acid at ambient temperature in the presence 
of 1.93 g. palladium on charcoal. After ending of the take up of hydrogen, 
the catalyst is filtered off with suction and the filtrate is evaporated 
in a vacuum. After recrystallisation of the residue from methanol, there 
are obtained 9.1 g. (84% of theory) of yellowish crystals of the title 
compound: m.p. 218.degree.-220.degree. C. (decomp.). 
(c) 
4,4'-Bis-(dimethylamino)-2-(4-benzyloxy-3,5-dimethoxybenzamino)-desoxybenz 
oin. 
33.64 g. (0.11 mol) 4-benzyloxy-3,5-dimethoxybenzoyl chloride are dissolved 
in 250 ml. anhydrous pyridine, then a suspension of 33.4 g. (0.1 mol) of 
the compound obtained under (b) in 300 ml. anhydrous pyridine is added 
thereto dropwise at 5.degree. to 10.degree. C. and the reaction mixture is 
stirred for 8 hours at 40.degree. C. and evaporated in a vacuum. The 
residue is taken up in 200 ml. dichloromethane, shaken up three times in 
each case with 100 ml. 2N hydrochloric acid, 100 ml. water, 100 ml. 
aqueous sodium bicarbonate solution and 100 ml. water, dried over 
anhydrous sodium sulphate and evaporated. The crude product, 53.2 g. of 
semicrystalline material, is dissolved hot in a mixture of 650 ml. 
toluene-methanol (12:1 v/v) and the oily product obtained is brought to 
crystallisation by trituration with diethyl ether. There are obtained 33.1 
g. (58.3% of theory) of beige-coloured crystals; m.p. 207.degree. C. 
(decomp.) of the title compound. 
(d) 
2-(3,5-Dimethoxy-4-benzyloxyphenyl)-4,5-bis-[4-(dimethylaminophenyl]-1,3-o 
xazole. 
28.3 g. (0.05 mol) of the above-mentioned compound are heated under reflux 
for 7 hours with 243 g. (0.75 mol) polyphosphoric acid ethyl ester in 300 
ml. anhydrous chloroform, thereafter neutralised by the addition of 6N 
ammonia solution and the reaction product is extracted with 
dichloromethane and the organic phase is shaken up with water, dried over 
anhydrous sodium sulphate and evaporated. The title compound, 30 g. of 
brown oil, is used directly, without purification, for the next step. TLC: 
silica gel 60; elution agent: chloroform-ethyl acetate (4:1 v/v); RF 
value=0.66. (e) 28 g. (0.05 mol) of the crude product obtained according 
to (d) are boiled under reflux for 1 hour with 200 ml. 6N hydrochloric 
acid. Thereafter, the reaction mixture is evaporated in a vacuum and the 
residue is recrystallised twice from methanol-acetone (2:1 v/v). The pale 
yellow title compound is filtered off and the filter cake is washed with 
acetone and dried in a vacuum at 50.degree. C. Yield 16.1 g. (35.1% of 
theory) of colourless crystals; m.p. 232.degree.-234.degree. C. (decomp.); 
.lambda..sub.max 550 nm, .epsilon.'=8.57 cm.sup.2 .mu.mol.sup.-1. 
4.1. 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-5-(4-dimethylaminophenyl)-1,3-oxazole hy 
drochloride. 
(a) 4-Dimethylamino-.omega.-aminoacetophenone hydrochloride. 
6 g. (0.03 mol) 4-Dimethylamino-.omega.-hexamethylenetetraminium 
acetophenone bromide are suspended in 28 ml. ethanol and, after the 
addition of 14 ml. concentrated hydrochloric acid, stirred for 3 days at 
ambient temperature, thereafter filtered off and the filtrate evaporated 
in a vacuum. There are obtained 5 g. 
4-dimethylamino-.omega.-aminoacetophenone hydrochloride; m.p. 185.degree. 
C. (decomp.). 
(b) 
4-Dimethylamino-.omega.-(4-benzyloxy-3,5-dimethoxybenzamido)-acetophenone. 
4.81 g. of the above compound from (a) are suspended in 50 ml. anhydrous 
pyridine and a solution of 7.56 g. (0.025 mol) 
4-benzyloxy-3,5-dimethoxybenzoyl chloride in 70 ml. anhydrous pyridine is 
added dropwise thereto, while cooling with ice. After 6 hours, the 
reaction mixture is filtered and the filtrate evaporated in a vacuum. 
After taking up the residue in dichloromethane, it is shaken up with water 
and 2N hydrochloric acid, the organic phase is dried and evaporated in a 
vacuum and the residue is triturated with 50 ml. diethyl ether. There are 
obtained 7.11 g of the title compound; m.p. 128.degree.-131.degree. C. 
(decomp.). (c) 5 g. (0.01 mol) of the compound from (b) are heated under 
reflux with 54.4 g. (0.16 mol) polyphosphoric acid ethyl ester in 300 ml. 
anhydrous chloroform for 5 hours under an atmosphere of argon. 
Subsequently, the reaction mixture is evaporated on a rotary evaporator. 
There is obtained a light brownish oil which is boiled under reflux with 
150 ml 6N hydrochloric acid for 20 minutes, evaporated in a vacuum and 
purified chromatographically on a silica gel column, first with 
heptane-acetone (1:1 v/v) and then with methanol-acetone (1:1 v/v). There 
are obtained 2.6 g. of amorphous, beige-coloured compound. TLC silica gel 
plate: elution agent: chloroform-methyl ethyl ketone-methanol-glacial 
acetic acid-water (7.5/2.5/3.5/0.5/0.9 v/v/v/v/v); .lambda..sub.max 353 
nm, .epsilon.'=8.7 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 5 
2,5-Bis-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-oxazole 
(a) 3,5-Dimethoxy-4-hydroxybenzaldehyde cyanhydrin. 
10 g. (0.055 mol) 3,5-Dimethoxy-4-hydroxybenzaldehyde are warmed, while 
stirring with 10 g. (0.1 mol) sodium hydrogen sulphite in 100 ml. water, 
dissolving thereby taking place. Thereafter, while stirring, 2.7 g. (0.055 
mol) sodium cyanide in 13 ml. water are added dropwise thereto within the 
course of 30 minutes, stirring is continued for 30 minutes and the 
cyanhydrin formed is then extracted by shaking out three times with 50 ml. 
amounts of diethyl ether. After drying the ethereal phase over anhydrous 
sodium sulphate, the solution is used directly in step (b). TLC silica 
gel; elution agent: chloroform-methanol (5:1 v/v), RF value=0.88; elution 
agent chloroform-tetrahydrofuran (1:1 v/v), RF value=0.8. ((b) The 
ethereal solution from 5(a) is mixed with 2.2 g. (0.014 mol) 
3,5-dimethoxy-4-hydroxybenzaldehyde and, while cooling, hydrogen chloride 
is passed through until the solution is saturated. Upon standing, 1.06 g. 
(25% of theory) of the title compound crystallises out, which is obtained 
in pure form by taking up in water and shaking out with dichloromethane. 
The colourless crystals melt at 260.degree. C. (decomp.). .lambda..sub.max 
586 nm, .epsilon.'=29.2 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 6 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-(N,N-bis-methoxymethylaminophenyl)-5-me 
thyl-1,3-oxazole 
5 g. (0.0153 mol) of the compound of Example 3 (free base) are dissolved in 
300 ml. methanol, 20 ml. 27% formaldehyde solution are added thereto, the 
reaction mixture is left to stand for 16 hours at ambient temperature and 
then evaporated. The residue is triturated with 200 ml. diethyl ether. 
There are obtained 3 g. (60.2% of theory) of pale grey, amorphous title 
compound. TLC silica gel; elution agent: chloroform-methanol (19:1 v/v). 
RF value=0.58; .lambda..sub.max 536 nm, .epsilon.'=33.5 cm.sup.2 
mol.sup.-1. 
EXAMPLE 7 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-5-methyl-1,3-ox 
azole hydrochloride 
3.2 g. (0.0084 mol) of the compound of Example 3 (free base) are dissolved 
in 110 ml. methanol-water (10:1 v/v), 1.9 ml. 37% formaldehyde solution, 1 
ml. concentrated hydrochloric acid, as well as 0.5 g. platinum oxide, are 
added thereto and hydrogenation is carried out for 4 hours to 5.degree. to 
8.degree. C. under normal pressure. After filtering off the catalyst, the 
filtrate is concentrated to 50 ml. and, upon cooling, with ice, there are 
obtained 2 g. (51% of theory) of colourless crystals of the title 
compound; m.p. 250.degree. C. (decomp.); .lambda..sub.max 510 nm, 
.epsilon.'=30 cm.sup.2 .mu.mol.sup.-1. 
7.1. 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-(3-methoxy-4-dimethylaminophenyl)-5-me 
thyl-1,3-oxazole hydrochloride. 
In a manner analogous to that described in Example 7, from the 
hydrochloride of the base of Example 3.1, there is obtained, with 
formaldehyde solution and platinum oxide as catalyst, a yield of 82% of 
theory of the title compound in the form of colourless crystals; m.p. 
230.degree.-235.degree. C. (decomp.); .lambda..sub.max 499 nm, 
.epsilon.'=29.2 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 8 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4[-4-(2,3-dihydroxypropyl)-aminophenyl]-5 
-methyl-1,3-oxazole 
15.9 g. (0.049 mol) of the compound of Example 3 (free base) are suspended 
in 320 ml. ethanol and, after the addition of 19.1 ml. (0.29 mol) 
2,3-epoxypropanol, boiled under reflux for 5 hours, thereafter evaporated 
in a vacuum and the crude product is purified by chromatography on silica 
gel. Elution agent: chloroform-methanol (12:1 v/v). The appropriate 
fraction gives 3.32 g. (26.5% of theory) of the pale pink-coloured title 
compound; m.p. 165.degree.-167.degree. C. (decomp.); .lambda..sub.max 491, 
.epsilon.'=21.6 cm.sup.2 .mu.mol.sup.-2. 
8.1. 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-[4-bis-(2,3-dihydroxypropyl)-aminophen 
yl-]5-methyl-1,3-oxazole 
By the reaction of 3.8 g. (0.01 mol) 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-aminophenyl)-5-methyloxazole with 
1.41 ml. (0.029 mol) 2,3-epoxypropanol by boiling under reflux for 5 
hours, there is obtained, besides the mono- compound of Example 8, also 
the desired bis-compound. Purification takes place by column 
chromatography on silica gel 60 (column 4.5 cm. diameter, filling height 
70 cm.; elution agent: methylene chloride-methanol (8:1 v/v). The 
appropriate fractions give 2.1 g. (40% of theory) of the title compound in 
the form of colourless crystals; m.p. 187.degree.-189.degree. C. 
(decomp.). TLC finished plate silica gel 60 F 254; elution agent: 
methylene chloride-methanol (8:1 v/v). RF value=0.31. .lambda..sub.max 510 
nm, .epsilon.'=23.6 cm.sup.2 .mu.mol.sup.-1 (at pH 6) .lambda..sub.max 505 
nm, .epsilon.'=33.3 cm.sup.2 .mu.mol.sup.-1 (at pH 8). 
8.2. 
2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-4-(4-bis-2,3-dihydroxypropyl)-amino 
phenyl]-5-methyl-1,3-oxazole from the compound of Example 3.3 and 
2,3-epoxypropanol analogously to Example 8 (a). Title compound: yellowish 
oil; TLC silica gel plate 60; elution agent: dichloromethane-chloroform 
(8:1 v/v); RF value: 0.31 .lambda..sub.max 552 nm, .epsilon.'=30.3 
cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 9 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-[N-3-chloro-2-hydroxypropyl]-(aminophen 
yl)-5-methyl-1,3-oxazole 
3.26 g. (0.01 mol) of the compound of Example 3 (free base) are heated 
under reflux for 6 hours in 65 ml. ethanol with 1.12 ml. (0.14 mol) 
epichlorohydrin, thereafter the reaction mixture is evaporated in a vacuum 
and the residue is stirred with 25 ml. water and thereafter with diethyl 
ether. There is obtained 1.6 g. (38.2% of theory) of colourless crystals 
of the title compound; m.p. 120.degree.-123.degree. C. (decomp.); 
.lambda..sub.max 554 nm, .epsilon.'=37.2 cm.sup.2 .mu.mol.sup.-2. 
EXAMPLE 10 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-[N-3-morpholino-2-hydroxypropyl]-(amino 
phenyl)-5-methyl-1,3-oxazole 
4.2 g. (0.01 mol) of the compound obtained in Example 9 are heated under 
reflux for 1.5 hours with 50 ml. morpholine. Thereafter, the reaction 
mixture is evaporated in a vacuum, the residue is stirred with acetone, 
the resultant morpholine hydrochloride is filtered off, this is washed 
with acetone and the filtrate is again evaporated. The residue, 8 g. of a 
brownish oil, is thereby purified chromatographically with silica gel 60 
with isopropanol/n-butyl acetate/water (5/3/2 v/v/v). There is obtained 
1.7 g. (36.4% of theory) of the title compound in the form of a 
honey-coloured oil. TLC: silica gel plate; elution agent: as in the column 
separation. RF value=0.51. .lambda..sub.max 551 nm, .epsilon.'=10 cm.sup.2 
.mu.mol.sup.-1. 
EXAMPLE 11 
{{3-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-1,3)-oxazolyl]-phenyla 
mino}-2-hydroxypropyl}}phosphonic acid 
(a) Diethyl 2,3-epoxypropane phosphonate. 
60 g. (0.44 mol) Epibromohydrin are mixed with 66.5 g. (68.6 ml.; 0.4 mol) 
triethyl phosphate and heated for 3 hours at 110.degree. C. The resultant 
ethyl bromide is distilled off using a descending cooler and the crude 
product obtained is subsequently fractionally distilled. There are 
obtained 39.8 g. (51.2% of theory) of ester; b.p..sub.0.7 
93.degree.-95.degree. C. (GC 96.5%). 
(b) Diethyl 
{{3-{4-[2-(3,5-dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl-phenyl 
amino-2-hydroxypropyl}}-phosphonate 
3.26 g. (0.01 mol) of the compound of Example 3 (free base) are suspended 
in 100 ml. ethanol, 11.65 g. (0.06 mol) of the epoxide compound from step 
(a) above are added thereto and the reaction mixture is heated under 
reflux for 7 hours. After evaporating off the solvent, there is obtained a 
pale brown oil which is purified chromatographically on silica gel 60. 
Column: filling height 73 cm., elution agent: chloroform-methanol (19:1 
v/v). Working up of the appropriate fraction gives 3.5 g. (67.3% of 
theory) of the pale yellow coloured title compound; m.p. 188.degree. C. 
TLC finished plate: silica gel 60 F 254, elution agent: 
chloroform-methanol (8:1 v/v), RF value=0.313, .lambda..sub.max 517 nm, 
.epsilon.'=10.5 cm.sup.2 .mu.mol.sup.-2. 
(c) 
{{3-{4-[2-(3,5-Dimethoxy-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-pheny 
lamino}-2-hydroxypropyl }}phosphonic acid hydrochloride 
2.3 g. (0.044 mol) of the phosphonic acid ester of Example 11 (b) are 
heated under reflux for 3 hours with 25 ml. 6N hydrochloric acid and 
thereafter evaporated in a vacuum. The crude product obtained, 2.3 g. of 
semi-crystalline material, is stirred with 15 ml. isopropanol, filtered 
off with suction and dried. There is obtained 1.76 g. (88.8% of theory) of 
beige-coloured crystals of the title compound; m.p. 
170.degree.-182.degree. C. (decomp.); .lambda..sub.max 583 nm, 
.epsilon.'=10.5 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 12 
{{3-{4-[2-(3,5-Dimethoxy-4-hydroxyphenyl)]-5-methyl-4-(1,3)-oxazolylphenylm 
ethylamino}-2-hydroxyphenyl}}phosphonic acid 
(a) Title compound: diethyl ester. 
1 g. (1.9 mmol) of the compound of Example 11 (b) is hydrogenated in 100 
ml. methanol with 0.1 g. platinum oxide in the presence of 0.5 ml. 
formaldehyde solution and 0.2 ml. concentrated hydrochloric acid for 4 
hours at ambient temperature. After filtering off the catalyst with 
suction, the filtrate is evaporated in a vacuum. There is obtained 1.1 g. 
of reddish oil, which is purified chromatographically on a silica gel 60 
column (4 cm. diameter, 70 cm. filling height). After evaporation of the 
appropriate fraction, there is obtained 0.31 g. (30.2% of theory) of 
amorphous, colourless powder. TLC finished plate: silica gel 60 F 254, 
elution agent: chloroform-methanol (19:1 v/v), RF value=0.34, 
.lambda..sub.max 589 nm, .epsilon.'=67.3 cm.sup.2 .mu.mol.sup.-1. (b) 0.3 
g. (0.56 g. of the compound from Example 12 a) is heated under reflux in 
10 ml. 6N hydrochloric acid for 2 hours, thereafter evaporated to dryness 
in a vacuum and the residue enriched with isopropanol. There are obtained 
2.73 g. (57.1% of theory) of the title compound as a yellowish, amorphous 
powder. TLC finished plate: silica gel 60 F 254; elution agent: 
chloroform-methanol (19:1 v/v), RF value=0.26, .lambda..sub.max 593 nm, 
.epsilon.'=9.7 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 13 
2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-4-{4-[N,N-bis(2,3-dihydroxypropyl)]- 
aminophenyl}-5-methyl-1,3-oxazole 
3.8 g. (0.01 mol) 
2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-4-(4-aminophenyl)-5-methyl-1,3-oxaz 
ole (Example 3.3) are boiled under reflux for 8 hours with 3.7 g. (3.3 ml.; 
0.05 mol) 2,3-epoxypropan-1-ol in 500 ml. ethanol. Thereafter, the 
reaction mixture is evaporated in a vacuum and the residue is purified 
column chromatographically. Column diameter 4.5 cm., filling height 70 
cm., silica gel 60; elution agent: methylene chloride-methanol (8:1 v/v). 
By evaporation of the appropriate fractions, there are obtained 2.4 g. 
(45.6% of theory) of amorphous, light reddish powder. TLC finished plate: 
silica gel 60 F 254, elution agent: methylene chloride-chloroform (8:1 
v/v), RF value =0.31, .lambda..sub.max 395 nm, .epsilon.'=22.2 cm.sup.2 
.mu.mol.sup.-1. 
EXAMPLE 14 
N-{4-[2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-phe 
nylamino}-acetic acid 
(a) Benzyl 
N-{4-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)-5-methyl-4-(1,3)-oxazolyl]-ph 
enylamino}-acetate. 
3.78 g. (0.01 mol) 
2-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-4-(4-aminophenyl)-5-methyl-1,3-oxaz 
ole are stirred under argon for 2.5 hours with 2.52 g. (0.011 mol) benzyl 
bromoacetate in 50 ml. anhydrous dimethylformamide in the presence of 2.36 
g. (0.011 mol) 1,8-bis-dimethylaminonaphthalene, thereafter evaporated in 
a vacuum and the residue is taken up in 100 ml. methylene chloride, shaken 
up several times with water and the organic phase is dried with anhydrous 
sodium sulphate and evaporated. There are obtained 5.94 g. of a reddish, 
amorphous crude product which is purified column chromatographically. 
Column diameter 4.5 cm., filling height 85 cm., silica gel 60; elution 
agent: chloroform and 1% ethyl acetate. By evaporation of the appropriate 
fraction, there are obtained 3.11 g. (71.4% of theory) of the title 
compound as an amorphous, light reddish powder. TLC finished plate: silica 
gel 60 F 254, elution agent: chloroform and 1% ethyl acetate, RF 
value=0.29. (b) 2.3 g. (4.4 mol) of the above benzyl ester are dissolved 
in 100 ml. methanol and, after the addition of 0.2 g. palladium on active 
charcoal (10%), hydrogenated for 30 minutes at ambient temperature. After 
filtering off the catalyst with suction, the filtrate is evaporated in a 
vacuum to give 1.92 g. (98% of theory) of bright red, amorphous title 
compound. TLC finished plate: silica gel 60 F 254, elution agent: 
isopropanol-n-butyl acetate-water (5/3/2 v/v/v), RF value=0.53; 
.lambda..sub.max 510 nm, .epsilon.'=32.3 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 15 
2-(3,5-Dimethoxy-4-hydroxyphenyl)-4-(4-dimethylaminophenyl)-1,3-thiazole 
(a) 
2-(3,5-Dimethoxy-4-benzyloxyphenyl)-4-(4-dimethylaminophenyl)-1,3-thiazole 
. 
3.7 g. (0.012 mol) 3,5-dimethoxy-4-benzyloxyphenyl-thioamide and 2.94 g. 
(0.012 mol) 4-dimethylamino-.alpha.-bromoacetophenone are heated under 
reflux for 3 hours in 120 ml. anhydrous ethanol. After cooling and placing 
in an ice bath, there are obtained 5.21 g. (97.3% of theory) of pale 
yellow crystals of the title compound; m.p. 205.degree.-207.degree. C. 
(decomp.). (b) The above-mentioned product is dissolved in 250 ml. 
methanol and hydrogen chloride passed into the boiling solution for 2 
hours. After evaporating in a vacuum, the residue is dissolved in 150 ml. 
water and the thiazole liberated by the addition of ammonia. After taking 
up in dichloromethane and working up, there are obtained, after 
recrystallisation from ethanol, 3.1 g. (65.7% of theory) of the title 
compound as pale yellowish crystals; m.p. 219.degree.-221.degree. C. 
(decomp.), .lambda..sub.max 541 nm, .epsilon.'=12.2 cm.sup.2 
.mu.mol.sup.-1. 
EXAMPLE 16 
2-(3,5 
-Dimethoxy-4-hydroxyphenyl)-4,5-bis-(4-dimethylaminophenyl)-1,3-thiazole 
hydrochloride 
(a) 
2-(3,5-Dimethoxy-4-benzyloxyphenyl)-4,5-bis-(4-dimethylaminophenyl)-1,3-th 
iazole. 
5.68 g. (0.01 mol) of the title compound of Example 4 (c) are dissolved in 
60 ml. anhydrous chloroform and, with the addition of 3.3 g. (0.015 mol) 
phosphorus pentasulphide, heated under reflux for 2 hours, while stirring. 
Thereafter, the reaction mixture is poured on to a mixture of ammonia and 
ice and the organic phase is separated off and shaken up several times 
with water. After drying and evaporating, one obtains 5.8 g. of the title 
compound 16 (a) as a brown oil. TLC silica gel plate 60, elution agent: 
ethyl acetate, RF value=0.88. (b) The above-mentioned product is heated 
under reflux for 30 hours with 30 ml. 6N hydrochloric acid, after the 
addition of ammonia extracted 3 times with 30 ml. amounts of 
dichloromethane, worked up and purified column chromatographically on 
silica gel. Elution agent: methanol/chloroform (6/1 v/v). The appropriate 
fractions contain 2.2 g. (46.2% of theory) of the title compound; 
yellowish crystals; m.p. 218.degree. C. (decomp.); .lambda..sub.max 552 
nm, .epsilon.'=10.8 cm.sup.2 .mu.mol.sup.-1. 
EXAMPLE 17 
Survey of the optical properties of compounds of general formula (I) 
The following procedure is used for determining the molar extinction 
coefficients: 2.times.10.sup.-2 mol of indicator of general formula (I) 
are dissolved in 100 ml. 0.1M hydrochloric acid. If the compound does not 
dissolve quantitatively, then it is dissolved in a mixture of hydrochloric 
acid/methanol (9:1 v/v). 0.1 ml. of this solution are diluted with 10 ml. 
0.1M phosphate buffer (pH 6.0). 10 .mu.l. of the indicator solution thus 
obtained are pipetted into a mixture consisting of 10 .mu.l diluted. 
hydrogen peroxide solution (100 .mu.l. 30% hydrogen peroxide are diluted 
with water to 100 ml.), 10 .mu.l peroxidase solution (600 U peroxidase are 
dissolved in 1 ml. water) and 10 ml. 0.1M phosphate buffer (pH 6.0). The 
indicator is oxidised and the solution becomes coloured. After 60 seconds, 
a spectrum is recorded of the coloured solution and from the extinction 
values there are calculated the molar extinction coefficients (if the 
coloured material formed precipitates out, then a mixture of buffer, 
acetone or methanol (9:1 v/v) is used). 
According to the same process, the hydrogen peroxide concentrations can be 
determined from samples or the concentrations of substrates from which 
hydrogen peroxide results as reaction product by a preceding enzymatic 
reaction. 
EXAMPLE 18 
Test system for the detection of uric acid in aqueous solutions 
On to a polyester film precoated with gelatine there is poured, with a wet 
film thickness of 300.mu., a gelatine matrix of the composition given 
hereinafter and subsequently dried. Into 47.5 ml. trisphosphate buffer 
(0.5M, pH 7.2) are introduced 8.4 g. gelatine, 0.25 g. Tween 20, 0.5 kU 
uricase, 5 kU peroxidase and 100 mg. indicator substance of Example 3 
(2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(4-aminophenyl)-5-methyl-1,3-oxazole 
hydrochloride). The reagent film so produced is worked up to give a test 
system corresponding to FIG. 1 of the accompanying drawings. 35 .mu.l. 
uric acid solution are applied to the dosing zone. By pressing the reagent 
zone and the fabric on to the transport zone, the reaction is started. 
After 2 minutes, measurement is made in a remission photometer (the fabric 
has the function of equalizing the unevennesses of the glass fibre 
fleece). 
The calibration curve obtained with the abovedescribed system is given in 
the following Table: 
______________________________________ 
uric acid 
concentration % remission 
______________________________________ 
3 mg./dl. 54.9 
5 mg./dl. 48.8 
7 mg./dl. 43.2 
9 mg./dl. 38.7 
11 mg./dl. 33.6 
14 mg./dl. 30.9 
______________________________________ 
EXAMPLE 19 
Test system for the detection of creatinine in serum 
An absorbent paper (stencil paper of the firm Scholler & Hosch, surface 
weight 12 g./m.sup.2 ; absorbency 50 ml./m.sup.2) is impregnated with a 
solution of 200 kU peroxidase and 1.2 g. collagen hydrolysate dissolved in 
100 ml. phosphate buffer (0.1M, pH 8.0) and dried. In a second 
impregnation step, the pre-impregnated paper is post-impregnated with a 
solution consisting of 2 mmol indicator substance of Example 8 (a) 
(2-(3,5-dimethoxy-4-hydroxyphenyl)-4-[4-bis-(2,3-dihydroxypropyl)-aminophe 
nyl]-5-methyl-1,2-oxazole) in 100 ml. methanol and dried. Reagent paper (a) 
is thus obtained. 
For the production of reagent paper (b), the above-mentioned carrier is 
impregnated with a solution of 5 kU sarcosine oxidase, 30 kU creatinine 
amidohydrolase, 40 kU creatinine amidinohydrolase and 0.5 g. 
Triton.times.100 in 100 ml. 0.1M phosphate buffer (pH 8.0) and dried. 
Both papers are incorporated into a test system according to FIG. 2 of the 
accompanying drawings. 
For the detection of creatinine in serum, 30 .mu.l. of serum are pipetted 
on to the dosing zone. The reaction is started by pressing the enzyme and 
indicator paper on to the transport zone. After one minute, the colour 
formed is measured remission photometrically. Evaluation takes place by 
means of a calibration curve. 
The following Table gives the values for a calibration curve for creatinine 
in serum. 
______________________________________ 
creatinine 
concentration % remission 
______________________________________ 
0.1 mg./dl. 68.1 
0.5 mg./dl. 59.9 
1.5 mg./dl. 48.2 
5.0 mg./dl. 35.0 
10.0 mg./dl. 30.7 
______________________________________ 
EXAMPLE 20 
Test system for the detection of uric acid in blood 
From the components set out hereinafter, there is prepared a coating mass 
and this is raked out with a wet film thickness of 200.mu. on to a 
transparent film and then dried. 18 g. of a synthetic resin dispersion of 
a mixed polymer of vinyl acetate and vinyl propionate, 1.5 g. of alginate, 
68 ml. of 0.5M tris-citrate buffer (pH 7.5), 0.7 g. of the indicator 
substance according to Example 3, 2 kU uricase, 100 kU peroxidase, 0.5 g. 
Triton.times.100 and 12 g. diatomaceous earth are stirred until 
homogeneous. 
On to the layer so produced, there is raked on a second layer as optical, 
white background, which has the composition given hereinafter, with a 
layer thickness of 200.mu. and dried. 52 ml. 0.1M tris-citrate buffer (pH 
7.0), 5.5 g. titanium dioxide, 2.7 g. diatomaceous earth, 0.4 g. alginate, 
1.4 g. of a synthetic resin dispersion of a mixed polymer of vinyl acetate 
and vinyl propionate and 0.2 g. Triton.times.100. 
The test film thus produced is worked up to give tests according to FIG. 3 
of the accompanying drawings. 
For the detection of uric acid in blood, 30 .mu.l. of blood are applied to 
the dosing zone, after one minute pressure is applied in the reagent flap 
and after a further 2 minutes the colour formed is measured with a 
remission photometer and the uric acid value determined from a previously 
produced calibration curve. 
The following Table gives the values for a calibration curve: 
______________________________________ 
uric acid 
concentration % remission 
______________________________________ 
4.6 mg./dl. 58.0 
6.0 mg./dl. 50.6 
7.9 mg./dl. 43.1 
9.0 mg./dl. 40.5 
10.6 mg./dl. 36.1 
13.5 mg./dl. 31.8 
15.6 mg./dl. 28.7 
______________________________________ 
EXAMPLE 21 
Test system for the detection of GPT in blood 
Absorbent papers (stencil papers of the firm Scholler & Hosch, surface 
weight 12 g./m.sup.3 ; absorbency 50 ml./m.sup.2) are impregnated with one 
of the solutions 1 and 2 described hereinafter and then dried. 
Solution 1 
In one liter of a 0.2M buffer of potassium hydroxide solution and 
2-(N-morpholino)-ethanesulphonic acid of pH 6.7 are dissolved 0.03 mol 
.alpha.-ketoglutarate, 0.8 mol alanine, 0.01 mol magnesium chloride, 
0.0001 mol ascorbic acid, 0.009 mol of the substance of Example 7, i.e. 
2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(dimethylamino- 
phenyl)-5-methyl-1,3-oxazole hydrochloride, and 5 g. octyl pyranoside. 
This is used to produce reagent paper (a). 
Solution 2 
In one liter of the above-described buffer are dissolved 0.003 mol thiamine 
pyrophosphate, 500 kU pyruvate kinase, 500 kU peroxidase and 100 kU 
ascorbate oxidase. This is used to produce reagent paper (b). 
These reagent papers are worked up to give a test system according to FIG. 
2 of the accompanying drawings. 
For the determination of the enzyme activity, 30 .mu.l. of blood are 
pipetted on to the dosing zone, after 1 minute the covering film and the 
reaction papers are pressed together and the colour development is 
followed with a remission photometer. Evaluation takes place via a two 
point measurement from a reference curve. The reference curve is produced 
by making a series of dilutions with enzyme activities of from 10 to 1000 
U/liter and the remission values determined via fixed time measurements in 
a remission photometer. 
EXAMPLE 22 
Process for the detection of glucose concentrations in blood for the 
diagnosis of hypoglycaemia 
A raw film mass is produced in the following manner: 10 g. of 1.7% alginate 
swelling in a 0.5M phosphate buffer (pH 5.0), 15 g. aqueous synthetic 
dispersion of a co-polymer of vinyl acetate and vinyl propionate, 5 g. of 
a 15% aqueous solution of 4-dodecylbenzenesulphonate, 25 kU glucose 
oxidase, 200 kU peroxidase, 270 mg. of substance according to Example 3, 
10 g. diatomaceous earth and 0.4 ml. hexanol are stirred up to give a 
homogeneous slurry and this is then raked with a wet film thickness of 
150.mu. on to a multifilar fabric (2 F/964 of the firm Schwiezer 
Seidengaze Fabrik) and subsequently dried. 
This film is worked up to give a test system according to FIG. 4 of the 
accompanying drawings. For the determination of glucose, 30 .mu.l. of 
blood are pipetted on to the dosing zone, the covering film and the 
reagent film are pressed on to the transport zone and the resulting 
reaction colour is measured with a remission photometer. The glucose 
concentrations are determined on the basis of a calibration curve which 
has the following appearance: 
______________________________________ 
mg. glucose/dl. 
% remission 
______________________________________ 
20 37.2 
40 22.6 
60 18.6 
80 12.8 
______________________________________ 
List of references: 
1. reagent zone carrier (transparent) 
2. reagent zone 
3. fabric 
4. transport zone of glass fibres 
5. separation zone of glass fibres 
6. fixing fabric 
7. covering film (transparent) 
8. reagent paper (a) 
9. reagent paper (b) 
10. optically white background (porous) 
11. multifilar fabric 
12. carrier foil 
13. point of adhesion. 
It will be understood that the specification and examples are illustrative 
but not limitative of the present invention and that other embodiments 
within the spirit and scope of the invention will suggest themselves to 
those skilled in the art.