BENZOXAZOLES AND BENZOTHIAZOLES, THEIR PREPARATION AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

BENZOXAZOLES ET BENZOTHIAZOLES, PREPARATION ET UTILISATION COMME PRODUITS PHARMACEUTIQUES

English Abstract

Abstract
Compounds of general formula I,
<IMG> (I)
wherein
R1 represents a hydroxy or mercapto group; an
alkoxy or alkylmercapto group with 1 to 6 carbon atoms;
an alkenyloxy or alkenylmercapto group with 3 to 6
carbon atoms; a phenylalkoxy or phenylalkylmercapto
group wherein the alkyl moiety contains 1 to 3 carbon
atoms and whereln the phenyl nucleus may optionally be
substituted by from 1 to 3 substituents selected from
alkoxy groups with 1 to 3 carbon atoms, halogen atoms and
amino groups; an alkyl group with 1 to 3 carbon-atoms
(optionally substituted by a phenyl group); a phenyl
group (optionally substituted by a methoxy or cyano
group or a halogen atom); or a group of formula
<IMG>,
[in which
R2 represents a hydrogen atom; a straight-chain or
branched alkyl group with 1 to 7 carbon atoms (optionally
substituted by an alkoxy group with 1 to 3 carbon atoms);
a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3

carbon atoms and wherein the phenyl nuclèus may optionally
be substituted by one or two alkoxy groups with 1 to 3
carbon atoms; a phenyl group (optionally substituted by
an alkyl or alkoxy group with 1 to 3 carbon atoms, a
trifluoromethyl, nitro or cyano group or a fluorine,
chlorine or bromine atom, the said mono-substituted
phenyl groups being optionally further substituted by one
or two alkyl groups with 1 to 3 carbon atoms, by an
alkoxy group with 1 to 3 carbon atoms or by a fluorine,
chlorine or bromine atom); or an alkoxycarboxyl group
with 2 to 4 carbon atoms); and
R3 represents a hydrogen atom or an alkyl group
with 1 to 3 carbon atoms'];
R4 and R5, which may be the same or different,
each represents a hydrogen atom or an alkyl group with 1
to 3 carbon atoms; and
X represents an oxygen or sulfur atom,
and salts thereof with inorganic or organic acids or
bases of use as cardiotonic, hypotensive and/or anti-
thrombotic agents.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula I,
<IMG>
(I)
wherein
R1 represents a hydroxy or mercapto group; an alkoxy or alkylmercapto
group with 1 to 6 carbon atoms; an alkenyloxy or alkenylmercapto group with 3
to 6 carbon atoms; a phenylalkoxy or phenylalkylmercapto group wherein the alkyl
moiety contains 1 to 3 carbon atoms and wherein the phenyl nucleus may optionally
be substituted by from 1 to 3 substituents selected from alkoxy groups with 1
to 3 carbon atoms, halogen atoms and amino groups; an alkyl group with 1 to 3
carbon atoms (optionally substituted by a phenyl group); a phenyl group (option-
ally substituted by a methoxy or cyano group or a halogen atom); or a group of
formula
<IMG>,
[in which R2 represents a hydrogen atom; a straight-chain or branched alkyl
group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with
1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein
the phenyl nucleus may optionally be substituted by one or two alkoxy groups
with 1 to 3 carbon atoms; a phenyl group (optionally substituted by an alkyl
42

or alkoxy group with 1 to 3 carbon atoms, a trifluoromethyl, nitro or cyano
group or a fluorine, chlorine or bromine atom, the said mono-substituted phenyl
groups being optionally further substituted by one or two alkyl groups with 1
to 3 carbon atoms, by an alkoxy group with 1 to 3 carbon atoms or by a fluorine,
chlorine or bromine atom); or an alkoxycarboxyl group with 2 to 4 carbon atoms);
and
R3 represents a hydrogen atom or an alkyl group with 1 to 3 carbon
atoms];
R4 and R5, which may be the same or different, each represents a
hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and
X represents an oxygen or sulfur atom,
or a physiologically compatible salt thereof with an inorganic or organic acid
or base, which process comprises
(A) cyclising a compound of formula II,
<IMG> (II)
(wherein R1, R4, R5 and X are as defined above, Y represents a hydrogen atom
or an acyl group and Z represents a nucleophilically exchangeable group) whereby
the desired compound of formula I is obtained;
(B) reacting a carboxylic acid of formula III,
<IMG> (III)
43

(wherein R1, R4, R5 and X are as defined above), or an anhydride, ester, thio-
ester, amide, imidazolide or acid halide thereof, with hydrazine;
(C) for the preparation of a compound of general formula I as defined
above wherein R1 represents an alkoxy or alkylmercapto group with 1 to 6 carbon
atoms; an alkenyloxy or alkenylmercapto group with 3 to 6 carbon atoms; a
phenylalkoxy or phenylalkylmercapto group wherein the alkyl moiety contains 1
to 3 carbon atoms and wherein the phenyl nucleus may optionally be substituted
by from 1 to 3 substituents selected from alkoxy groups with 1 to 3 carbon
atoms, halogen atoms and amino group;; or a group of formula
<IMG>
[in which R2 represents a hydrogen atom; a straight-chain or branched alkyl
group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with
1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein
the phenyl nucleus may optionally be substituted by one or two alkoxy groups
with 1 to 3 carbon atoms; or an alkoxycarbonyl group with 2 to 4 carbon atoms
and R3 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms];
alkylating a compound of formula I wherein R1 represents a hydroxy or mercapto
group or a group of formula
<IMG>
[in which Ra represents a hydrogen atom; a straight-chain or branched alkyl
group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with
1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
44

alkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein
the phenyl nucleus may optionally be substituted by one or two alkoxy groups
with 1 to 3 carbon atoms; or an alkoxycarbonyl group with 2 to 4 carbon atoms]
with a compound of formula IV,
R? - U (IV)
[wherein R? represents an alkyl group with 1 to 3 carbon atoms (optionally
substituted by an alkoxy group with 1 to 3 carbon atoms or by phenyl group
itself optionally substituted by from 1 to 3 substituents selected from alkyl
and alkoxy groups with 1 to 3 carbon atoms, halogen atoms and amino groups);
an alkyl group with 4 to 7 carbon atoms (optionally substituted by an alkoxy
group with 1 to 3 carbon atoms); an alkenyl group with 3 to 6 carbon atoms; or
a cycloalkyl group with 3 to 7 carbon atoms and U represents a nucleophilic-
ally exchangeable group] whereby the desired compound of formula I is obtained;
(D) for the preparation of a compound of formula I as defined above
wherein R4 and R5 are different in the form of an optically active antipode:
resolving a mixture of optically active antipodes thereof, or
(E) for preparing a physiologically compatible salt of a compound of
general formula I as defined above: reacting a compound of formula I with an
appropriate acid or base.
2. A process for the preparation of a compound of general formula I as
defined in claim 1, which comprises cyclising a compound of formula II,
<IMG> (II)

(wherein R1, R4, R5 and X are defined in claim 1, Y represents a hydrogen atom
or an acyl group and Z represents a nucleophilically exchangeable group)
whereby the desired compound of formula I is obtained.
3. A process as claimed in claim 2, wherein, in the compound of formula
II, Z represents a chlorine or bromine atom or a hydroxy, methoxy, ethoxy,
benzyloxy, mercapto, methylmercapto, ethylmercapto, propylmercapto, benzyl-
mercapto, phenylmercapto or imidazolylcarbonyl group.
4. A process as claimed in claim 2 or 3, wherein the reaction is
carried out in the presence of a solvent.
5. A process as claimed in claim 2 or 3, wherein the reaction is
carried out in the presence of a condensing agent.
6. A process as claimed in claim 2 or 3, wherein the reaction is
carried out at the boiling temperature of the reaction mixture.
7. A process as claimed in claim 2, wherein,in the compound of formula
II, Y represents an acetyl, propionyl, benzoyl or p-toluenesulfonyl group.
8. A process as claimed in claim 2 or 3, wherein the compound of
formula II is used as formed in situ.
9. A process as claimed in claim 2, wherein, in the compound of
formula II, Y represents a hydrogen atom and Z represents a mercapto, alkyl-
mercapto, arylmercapto or aralkylmercapto group.
10. A process for the preparation of a compound of general formula I as
defined in claim 1 which comprises reacting a carboxylic acid of formula III,
46

<IMG> (III)
(wherein R1, R4, R5 and X are as defined in claim 1), or an anhydride, ester,
thioester, amide, imidazolide or acid halide thereof, with hydrazine.
11. A process as claimed in claim 10, wherein the reaction is carried
out in the presence of a solvent.
12. A process as claimed in claim 10 or 11, wherein the reaction is
carried out in the presence of an acid as condensing agent.
13. A process as claimed in claim 10 or 11, wherein the reaction is
carried out at temperatures of from 20 to 150°C.
14. A process as claimed in claim 10 or 11, wherein a carboxylic acid of
formula III or an ester, thioester, amide or acid halide thereof is reacted
with hydrazine.
15. A process for the preparation of a compound of general formula I as
defined in claim 1 wherein R1 represents an alkoxy or alkylmercapto group with
1 to 6 carbon atoms; an alkenyloxy or alkenylmercapto group with 3 to 6 carbon
atoms; a phenylalkoxy or phenylalkylmercapto group wherein the alkyl moiety
contains 1 to 3 carbon atoms and wherein the phenyl nucleus may optionally be
substituted by from 1 to 3 substituents selected from alkoxy groups with 1 to
3 carbon atoms, halogen atoms and amino groups; or a group of formula
47

[in which R2 represents a hydrogen atom; a straight-chain or branched alkyl
group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with
1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein
the phenyl nucleus may optionally be substituted by one or two alkoxy groups
with 1 to 3 carbon atoms; or an alkoxycarbonyl group with 2 to 4 carbon atoms
and R3 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms],
which process comprises alkylating a compound of formula I as defined in claim
1 (wherein R1 represents a hydroxy or mercapto group or a group of formula
<IMG>
[in which Ra represents a hydrogen atom; a straight-chain or branched alkyl
group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with
1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein
the phenyl nucleus may optionally be substituted by one or two alkoxy groups
with 1 to 3 carbon atoms; or an alkoxycarbonyl group with 2 to 4 carbon atoms])
with a compound of formula IV,
R? - U (IV)
[wherein R? represents an alkyl group with 1 to 3 carbon atoms (optionally
substituted by an alkoxy group with 1 to 3 carbon atoms or by a phenyl group
itself optionally substituted by from 1 to 3 substituents selected from alkyl
48

and alkoxy groups with 1 to 3 carbon atoms, halogen atoms and amino groups);
an alkyl group with 4 to 7 carbon atoms (optionally substituted by an alkoxy
group with 1 to 3 carbon atoms); an alkenyl group with 3 to 6 carbon atoms; or
a cycloalkyl group with 3 to 7 carbon atoms and U represents a nucleophilically
exchangeable group] whereby the desired compound of formula I is obtained.
16. A process as claimed in claim 15, wherein the alkylation is carried
out in the presence of a solvent and at temperatures up to the boiling tempera-
ture of the reaction mixture.
17. A process as claimed in claim 15 or 16, wherein the reaction is
carried out in the presence of a base.
18. A process as claimed in claim 15 or 16, wherein, in the compound of
formula IV, U represents a halogen atom or a sulfonic acid ester radical.
19. A process for the preparation of a compound as claimed in claim 1
wherein R4 and R5 are different in the form of an optically active antipode,
which comprises resolving a mixture of optically active antipodes thereof.
20. A process for the preparation of a physiologically compatible salt
of a compound of general formula I as defined in claim 1 which comprises reacting
a compound of formula I as defined in claim 1 with an appropriate acid or base.
21. A process as claimed in claim 1 wherein starting compounds are
chosen in which R1 represents a hydroxy or mercapto group; an alkoxy or alkyl-
mercapto group with 1 to 3 carbon atoms; an allyloxy or allylmercapto group; a
hexylmercapto, methoxybenzylmercapto or 2-(amino-dichlorophenyl)-ethyl-mercapto
group; an alkyl group with 1 to 3 carbon atoms (optionally substituted by a
phenyl group); a cyanophenyl, amino or dimethylamino group; an alkylamino group
with 1 to 5 carbon atoms (wherein the alkyl moiety is optionally substituted by
49

a methoxy group); a phenylamino group (wherein the phenyl nucleus is optionally
substituted by a methyl, methoxy, trifluoromethyl, cyano or nitro group or by
a chlorine or bromine atom); or a dichlorophenylamino, dibromophenylamino,
dimethoxyphenylamino, methoxy-nitrophenylamino, trimethylphenylamino, cyclohexyl-
amino, dimethoxyphenylethylamino or ethoxycarbonylamino group;
R4 represents a hydrogen atom or a methyl group; and
R5 represents a methyl group.
22. A process for preparing a compound of general formula Ia,
<IMG> (Ia)
wherein R1 represents a mercapto, methylmercapto, hydroxy, ethoxy, 2-(4-amino-
3,5-dichlorophenyl)-ethylmercapto, amino, dimethylamino, or cyclohexylamino
group; an alkylamino group with 1 to 5 carbon atoms; or a phenylamino group
(optionally substituted by one or two methoxy groups); and
X represents an oxygen or sulfur atom;
or a physiologically compatible salt thereof, which comprises carrying out a
process as claimed in claim 1 utilizing starting compounds in which R1 is as
defined above, X is as defined in claim 1, R4 is methyl and R5 is hydrogen and
where required converting the product to a physiologically compatible salt
thereof.
23. A process as claimed in claim 22, wherein a starting compound is
employed in which X represents an oxygen atom.
24. A process as claimed in claim 23, wherein a starting compound is

employed in which R1 represents a hydroxy, mercapto, ethylamino, n-butylamino,
cyclohexylamino or 4-methoxyphenylamino group.
25. A process for preparing 5-methyl-6-[2'-mercapto-benzoxazole-5'-y1]-
4,5-dihydro-3(2H)-pyridazinone or a physiologically compatible salt thereof,
which comprises refluxing in ethanol 2-amino-4-(5-methyl-4,5-dihydro-3(2H)-
pyridazinone-6-y1)-phenol with potassium ethylxanthogenate, and, if necessary,
neutralizing the potassium salt thus obtained, and where required converting
the product to a physiologically compatible salt thereof.
26. A process for preparing 5-methyl-6-[2'-n-butylamino-benzoxazole-5'-
yl]-4,5-dihydro-3(2H)-pyridazinone or a physiologically compatible acid addition
salt thereof, which comprises cyclizing N-n-butyl-N'-[2-hydroxy-5-(5-methyl-4,5-
dihydro-3(2H)-pyridazinone-6-y1)-phenyl]-thiouria by refluxing with N,N'-dicyclo-
hexyl-carbodiimide in tetrahydrofuran, and, if necessary, converting the product
to a physiologically compatible acid addition salt thereof.
27. A process for preparing a compound of formula I as defined in claim
1 wherein R4 and R5 are different in the form of an optically active antipode,
which comprises carrying out step (D) of claim 1.
28. A process for preparing a physiologically compatible salt of a com-
pound of formula I as defined in claim 1, which comprises reacting a compound
of formula I with a physiologically compatible acid or base.
29. A process according to claim 1, wherein a starting compound is
chosen in which R1 represents a group of formula
<IMG>
51

in which R2 represents a hydrogen atom; a straight-chain or branched alkyl group
with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with 1 to 3
carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenylalkyl group
wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein the phenyl
nucleus may optionally be substituted by one or two alkoxy groups with 1 to 3
carbon atoms; or a phenyl group (optionally substituted by an alkyl or alkoxy
group with 1 to 3 carbon atoms, a trifluoromethyl, nitro or cyano group or a
fluorine, chlorine, or bromine atom, the said mono-substituted phenyl groups
being optionally further substituted by one or two alkyl groups with 1 to 3 car-
bon atoms, by an alkoxy group with 1 to 3 carbon atoms or by a fluorine, chlorine
or bromine atom); one of R4 and R5 represents a hydrogen atom; and X represents
an oxygen atom, and, where required converting the product to a physiologically
compatible salt thereof.
30. A compound of general formula I,
<IMG> (I)
wherein R1 represents a hydroxy or mercapto group; an alkoxy or alkylmercapto
group with 1 to 6 carbon atoms; an alkenyloxy or alkenylmercapto group with 3
to 6 carbon atoms; a phenylalkoxy or phenylalkylmercapto group wherein the
alkyl moiety contains 1 to 3 carbon atoms and wherein the phenyl nucleus may
optionally be substituted by from 1 to 3 substituents selected from alkoxy
groups with 1 to 3 carbon atoms, halogen atoms and amino groups; an alkyl
group with 1 to 3 carbon atoms (optionally substituted by a phenyl group); a
phenyl group (optionally substituted by a methoxy or cyano group or a halogen
52

atom); or a group of formula
<IMG>
[in which R2 represents a hydrogen atom; a straight-chain or branched alkyl
group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with
1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein
the phenyl nucleus may optionally be substituted by one or two alkoxy groups
with 1 to 3 carbon atoms; a phenyl group (optionally substituted by an alkyl
or alkoxy group with 1 to 3 carbon atoms, a trifluoromethyl, nitro or cyano
group or a fluorine, chlorine or bromine atom, the said mono-substituted phenyl
groups being optionally further substituted by one or two alkyl groups with 1
to 3 carbon atoms, by an alkoxy group with 1 to 3 carbon atoms or by a fluorine,
chlorine or bromine atom); or an alkoxycarboxyl group with 2 to 4 carbon atoms);
and
R3 represents a hydrogen atom or an alkyl group with 1 to 3 carbon
atoms];
R4 and R5, which may be the same or different, each represents a
hydrogen atom or an alkyl group with 1 to 3 carbon atoms; and
X represents an oxygen or sulfur atom,
or a physiologically compatible salt thereof with an inorganic or organic acid
or base, whenever prepared by the process defined in claim 1, or by an obvious
chemical equivalent thereof.
31. A compound as claimed in claim 30, wherein R1 represents a hydroxy
or mercapto group; an alkoxy or alkylmercapto group with 1 to 3 carbon atoms;
53

an allyloxy or allylmercapto group; a hexylmercapto, methoxybenzylmercapo or
2-(amino-dichlorophenyl)-ethylmercapto group; an alkyl group with 1 to 3 carbon
atoms (optionally substituted by a phenyl group); a cyanophenyl, amino or
dimethylamino group; an alkylamino group with 1 to 5 carbon atoms (wherein the
alkyl moiety is optionally substituted by a methoxy group); a phenylamino
group (wherein the phenyl nucleus is optionally substituted by a methyl, methoxy,
trifluoromethyl, cyano or nitro group or by a chlorine or bromine atom); or a
dichlorophenylamino, dibromophenylamino, dimethoxyphenylamino, methoxy-nitro-
phenylamino, trimethylphenylamino, cyclohexylamino, dimethoxyphenylethylamino
or ethoxycarbonylamino group;
R4 represents a hydrogen atom or a methyl group; and
R5 represents a methyl group, whenever prepared by the process
defined in claim 21, or by an obvious chemical equivalent thereof.
32. A compound of general formula Ia,
(Ia)
<IMG>
wherein Rl represents a mercapfo, methylmercapto, hydroxy, ethoxy, 2-(4-amino-
3,5-dichlorophenyl)-ethylmercapto, amino, dimethylamino, or cyclohexylamino
group; an alkylamino group with 1 to 5 carbon atoms; or a phenylamino group
(optionally substituted by one or two methoxy groups); and X represents an
oxygen or sulfur atom; or a physiologically compatible salt thereof with an
inorganic or organic acid or base, whenever prepared by the process defined
in claim 22, or by an obvious chemical equivalent thereof.
54

33. A compound as claimed in claim 32, wherein X represents an oxygen
atom, whenever prepared by the process defined in claim 23, or by an obvious
chemical equivalent thereof.
34. A compound as claimed in claim 32, wherein R1 represents a hydroxy,
mercapto, ethylamino, n-butylamino, cyclohexylamino or 4-methoxyphenylamino
group, whenever prepared by the process defined in claim 24, or by an obvious
chemical equivalent thereof.
35. 5-Methyl-6-[2'mercapto-benzoxazole-5'yl]-4,5-dihydro-3(2H)- pyridazi-
none or a physiologically compatible salt thereof, whenever prepared by the
process defined in claim 25, or by an obvious chemical equivalent thereof.
36. 5-Methyl-6-[2'n-butylamino-benzoxazole-5'-yl]-4,5-dihydro-3(2H)-
pyridazinone or a physiologically compatible acid addition salt thereof, when-
ever prepared by the process defined in claim 26,or by an obvious chemical
equivalent thereof.
37. A compound as claimed in claim 30 or 32, wherein R4 and R5 are
different, in the form of an optically active antipode, whenever prepared by
the process defined in claim 27, or by an obvious chemical equivalent thereof.
38. A physiologically compatible salt of a compound of general formula
I as claimed in claim 1, whenever prepared by the process defined in claim 28,
or by an obvious chemical equivalent thereof.
39. A compound of general formula I as claimed in claim 30, wherein R1
represents a group of formula
<IMG>

in which R2 represents a hydrogen atom; a straight-chain or branched alkyl
group with 1 to 7 carbon atoms (optionally substituted by an alkoxy group with
1 to 3 carbon atoms); a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and wherein
the phenyl nucleus may optionally be substituted by one or two alkoxy groups
with 1 to 3 carbon atoms; or a phenyl group (optionally substituted by an
alkyl or alkoxy group with 1 to 3 carbon atoms, a trifluoromethyl, nitro or
cyano group or a fluorine, chlorine, or bromine atom, the said mono+substituted
phenyl groups being optionally further substituted by one or two alkyl groups
with 1 to 3 carbon atoms, by an alkoxy group with 1 to 3 carbon atoms or by a
fluorine, chlorine or bromine atom); one of R4 and R5 represents a hydrogen
atom; and X represents an oxygen atom; or a physiologically compatible salt
thereof with an inorganic or organic acid, whenever prepared by the process
defined in claim 29, or by an obvious chemical equivalent thereof.
56

Description

- 2 -
This invention relates to new benzoxazoles and
benzothiazoles, to process for their preparation and to
pharmaceutical compositions containing them,
According to one feature of the pre~ent invention
there are provided compounds of general formula I,
R~
~ " ~ ~ ~ H (I)
wherein
Rl represents a hydroxy or mercapto group; an alkoxy
or alkylmercapto group with 1 to 6 carbon atoms; an
alkenyloxy or alkenylmercapto group with 3 to 6 carbon atoms;
a phenylalkoxy or phenylalkylmercapto group wherein the alkyl
moiety contains 1 to 3 carbon atoms and wherein the
phenyl nucleus may optionally be substituted by from 1
to 3 substituents selected from alkoxy groups with 1
to 3 carbon atoms, halogen atoms and amino groups; an
alkyl group with 1 to 3 carbon atoms (optionally sub-
stituted by a phenyl group); a phenyl group (optionally
substituted by a methoxy or cyano group or a halogen
atom); or a group of formula
\ R
~in which
. .

R2 represents a hydrogen atom; a straight-chain or
branched alkyl group with 1 to 7 carbon atoms (optionally
substituted by an alkoxy group with 1 to 3 carbon atoms);
a cycloalkyl group with 3 to 7 carbon atoms; a phenyl-
alkyl group wherein the alkyl moiety contains 1 to 3carbon a~oms and wherein the phenyl nucleus may optionally
be substituted by one or two alkoxy groups with 1 to 3
carbon atoms; a phenyl group (optionally substituted by
an alkyl or alkoxy group with 1 to 3 carbon atoms, a
trifluoromethyl, nitro or cyano group or a fluorine,
chlorine or bromine atom,the said mono-substituted
phenyl groups being optionally further substituted by
one or two alkyl groups with 1 to 3 carbon atoms, by an
alkoxy group with 1 to 3 carbon atoms or by ~ flu~rine,
lS chlorine or bromine atom); or an alkox~carbonyl group
with 2 to 4 carbon atoms ; and
R3 represents a hydrogen atom or an alkyl group
with 1 to 3 carbon atoms~;
R4 and R5, which may be the same or different,
each represents a hydrogen atom or an alkyl group with
1 to 3 carbon atoms; and
X represents an oxygen or sulfur atom,
and salts thereof with inorganic or organic acids
or bases.
~5 The new compounds according to the invention
exhibit interesting pharmacological properties and in
particular cardiovascular activity, i.e. cardiotonic,
hypotensive and/or antithrombotic activity, It will
be appreciated that, for pharmaceutical use, the salts
referred to above will be physiologically compatible,

5~
Other salts may, however, find use for example in the
preparation of compounds of general formula I and their
physiologically compatible salts.
In the compounds according to the invention
Rl may, fbr example, represent a hydroxy, methoxy,
ethoxy, propoxy, isopropoxy, buto~y, i30butoxy, tert~butoxy,
pento~y, neope~toxy, hexoxy, allyloxy, crotylo~y, pe~tenyloxy,
h~enyloxy, be~zylo~y, ~thoxy~be~zyloxy, 1-phen~lethoxy,
2-phe~yl~thoxy, 3-phe~ylpropoxy, ~ercapto, methylmercapto,
ethylmercapto, propylmercapto, isopropylmercapto, butyl
m~rcapto, isobutyl~ercapto, tert~butylmercapto, pentyl
mercapto, neopentylmercapto, tert.pentylmercapto, hexyl-
meroapto, all~lmercapto, crotylmercapto, pentenylmercapto,
;lexenylmercapto, benzylmercapto, methoxybenzylmercapto,
chlorobenzylmercapto, bromobenzylmercapto, dimet~o~ybenzyl-
mercapto, 1-phenylethylmercapto, 2-phenylethylmercapto,
2-(methoxyphenyl)-ethylmeroapto, 2-(dimethoxyphenyl) ethyl
mercapto, 2-(chlorophenyl~-ethylmercapto, 2-(chloro-methoxy~
phenyl)-ethylmercapto, 2-(amino-dichlorophenyl)-ethylmer-
capto, 3-phenylpropylmercapto, methyl, ethyl, propyl,
isopropyl, benzyl, 1-phe~ylethyl, 2--phenylethyl, 1 phenyl-
propyl, 2-phenylpropyl, 3-phenylpropyl, phenyl, methoxy-
phenyl, cyanophenyl, chlorophenyl, bromophe~yl J fluoro-
phenyl, amino, m~thyl~mino, ethylamlno, propylamino,
isopropylamino, butylamino, isobutylamino, tert.butyl-
amlno, pentylamino, isopentylamino, neopentyl~mino,
tert.pentylamino, hexylamino, heptylamino, dimethylamino,
diethylamino, dllsopropylamlno, ~ethyl-ethylamino,
methyl-propylami~o, ethyl-i~opropylamino, methyl-
butylamino, ethyl-pentylamino, methyl-heptylamino,
methoxy-ethylamino, methoxy-propylamino, methoxy~
butylamino, methoxy~pentylamino, methoxy - h2ptyl-
amino 9 ethoxy-ethylamino, propoxy-propylamino,

N-methyl-ethoxyethylam mo, N-ethyl-methoxypropylam mo, cycloprcpylamino, cyclo-
pentylamino, cyclohexylamlno, cycloheptylam mo, N-methyl-cyclohexylamino, N-ethyl-
cyclohexylamino, N-propyl-cyclohexylam mo, phenylamlno, methylphenylamino,
d~rcethylphenylamino, trimlethylphenylam mo, ethylphenylamino, propylphenylamino,
isopropylphenylamino, methoxyphenylamino, dimethoxyphenylamino, isopropoxyphenyl-
amino, fluorophenylamino, difluorophenylamino, chlorophenylamino, dichlorophenyl-
amino, brom~phenylamino, dibromophenylamdno, trifluommethyl phenylamdno, nitro-
phenylamino, cyanophenylamino, methyl-fluorophenylamino, methyl-chlorophenylamino,
methoxy-chlorophenylam mo, methoxy-bromophenylamino, methoxy-cyanophenylamino,
methoxy-trifluorcm~thyl-phenylamdno, methoxy-nitrophenylamino, ethoxy-nitrophenyl-
amino, propQxy-nitrophenylamdno, benzylamdno, l-phenylethylamdno, 2-phenylethyl-
amdno, 3-phenylpropylamdno, methoxybenzylamdno, dimethoxybenzylamino,
2-tdimethoxyphenyl)ethylamino, 2-(diethoxyphenyl)ethylamdno, 2-(dipropoxyphenyl)-
ethylamlno, 2-(methoxy-ethoxyphenyl)ethylamino, N-methyl phenylamino, N-ethyl-
methylphenylamino, N-methyl-methoxyphenylamino, N-ethyl-diimethoxyphenylamino,
N-methyl-benzylamino, N-ethyl-2-phenylethylamino or N-methyl-methoxybenzylamdno
group.
R4 and ~ may each represent a hydrogen atom or a methyl, ethyl, propyl
or isopropyl group. When R4 and R5 are different the compounds according to the
invention may exist in the form of an optically active antipode as well as mix-
tures thereof d~le to the optically active carbon in the 5-position of the
pyridazinone ring. All such fonns are within the scope of the present invention.
Preferred compounds are those wherein:
-- 5 --
~q

Rl represents a hydroxy or mercapto group; an
alkoxy or alkylmercapto group with 1 to 3 carbon atoms;
an allyloxy or allylmecapto group; a hexylmercapto,
methoxybenzylmercapto or 2-(amino-dichlorophenyl)-
ethylmercapto group; an alkyl group with 1 to 3 carbonatoms (optionally substituted by a phenyl group); a
cyanophenyl,amino or dimethylamino group; an alkylamino
group with 1 to 5 carbon atoms (wherein the alkyl moiety
is optionally substituted by a methoxy group); a phenyl-
amino group (wherein the phenyl nucleus is optionallysubstituted by a methyl, methoxy, trifluoromethyl, cyano
or nitro group or by a chlorine or bromine atom~; or a
dichlorophenylamino, dibromophenylamino, dimethoxyphenyl-
amino, methoxy-nitrophenylamino, trimethylphenylamino,
cyclohexylamino, dimethoxyphenylethylamino or ethoxy-
carbonylamino group ;
R4 represents a hydrogen atom or a met.hyl group; and
R5 represents a methyl group:
and more particularly those wherein the pyridazino group
is in position 5 of the benzoxazole or benzothiazole ring.
Especially preferred compounds are those of general
formula Ia,
CH
3 ~ 0
~ ~ ~ N ~ N - H
wherein

5~
Rl represents a mercapto, methylmercapto 7
hydroxy, et~loxy, 2-(4-amino-3,5-dichloro~ .
phenyl)ethylmercapto~ amino, dimethylamino or cyclo-
hex~lamino group; an alkylamino group with 1 to 5 carbon
. atoms; or a phenylamino group (optionally substituted by
one or two methoxy groups); and
X represents a sulfur atom or more especially an
oxygen atom;
and their salts with acids or bases.
In the above compounds of general formula Ia and
their salts, Rl may more especially represent a hydroxy,
mercapto, ethylamino, n-butylamino, cyclohexylamino or
4-methoxyphenylamino group~
Particularly ?referred compounds according to the
invention are the following:
S-methyl-6-[2'-mercapto-benzoxazole 51-yl]-4,5-
dihydro-3(2H)--pyridazinone and salts thereof, and
5-methyl-6-[2'-n-butylamino-benzoxazole-5'-yl~-
4,5-dihydro-~(2H)-pyridazinone and acid addition salts
thereof.
The compounds of general formula I may, for example,
be prepared by the following processes which processes
constitute further features of the present invention:-
a) Cyclisation of a compound, optionally prepared
in situ in the reaction mixture, of formula II,
Z . R5
R1 ~ C ~ N ~ 4 ~ (II)
Y - X ,1 ~N ,N

(wherein Rl, R~, R5 and ~ are as hereinbefore defined,
Y represents a hydrogen atom or an acyl group and Z
represents a nucleophilically exchangeable group) whereby
the desired compound of formula I is obtained.
Y3 when an acyl group, may for example represent an
acetyl, propionyl, benzoyl or p-toluenesulfonyl group
Z ~ay, for example, represent a chlorine or bromine atom
or a hydroxy, methoxy, ethoxy, benzyloxy, mercapto,
methylmercapto, ethylmercapto, propylmercapto, benzyl-
mercapto, phenylmercapto or imidazolylcarbonyl group,
The cyclisation is conveniently carried out in the
presence of a solvent such as e.g. tetrahydrofuran,
dioxan, benzene, toluene, dimethylformamide, dimethyl
ethylene glycol or sulfoIane and optionally in the
presence of a condensing agent such as e g. N,N'-dicyclo-
hexylcarbodiimide, carbonyldiimidazole, ~-toluenesulfonic
acid, phosphorus oxychloride, thionyl chloride, hydro-
chloric acid, sulfuric acid, phosphoric acid or poly-
phosphoric acid. Reaction temperatures are conveniently
from 25 to 300C, but preferably the boiling temperature
of the reaction mixture, e.g. at temperatures of from 50
to 285C. The cyclisation can however, if desired, be
carried out in the melt.
b~ Reaction of a carboxylic acid of formula III,
~ y ~ C - ~ - CH2 - C00~ (III)

fJ
(wherein Rl, R4, R5 and X are as hereinbefore defined),
or an anhydride, ester, thioester, amide, imidazolide
or acid halide thereof, with hydrazine,
The reaction is conveniently carried out in the
S presence of a solvent such as e.g. methanol, ethanol,
isopropanol, glacial acetic acid, propionic acid and/or
in an excess of hydrazine or hydrazine hydrate. Preferred
temperatures are from O to 200C, e.g. at temperatures of
from 20 to 150C, most preferably, however, at the boiling
temperat~re oE the reaction mixture. Optionally the
reaction may be carried out in the presence of an acid as
condensing agent such as e.g. sulfuric acid or ~-toluene-
sulfonic acid. The reaction can however, if desired, be
carried out without a solvent.
c) For the preparation of compounds of general formula
I wherein Rl represents an alkoxy or alkylmercapto group
with 1 to 6 carbon atoms; an alkenyloxy or alkenylmercapto
group with 3 to 6 carbon atoms; a phenylalkoxy or phenyl-
alkylmercapto group wherein the alkyl moiety contains 1
to 3 carbon atoms and wherein the phenyl nucleus may
optionally be substituted by from 1 to 3 substituents
selected from alkoxy groups with 1 to 3 carbon atoms,
halogen atoms and amino groups~ or a group of
formula
/ R2
-N \
~3
[in which R2 represents a hydrogen atom; a straight-
chain or branched alkyl group with 1 to 7 carbon atoms
(optionally substituted by an alkoxy group with 1 to 3
carbon atoms); a cycloalkyl group with 3 to 7 carbon

.. 10 _
atoms; a phenylalkyl group wherein ~he alkyl moiety
contains 1 to 3 carbon atoms and wherein the phenyl nucleus
may optionally be substituted by one or two alkoxy groups
with l to 3 carbon atoms; or an alkoxycarbonyl group with
2 to 4 carbon atoms and R3 represents a hydrogen atom or
an alkyl group with 1 to 3 carbon atoms]:
Alkylation of a compound of formula I as herein-
before defined (wherein Rl represen-ts a hydroxy or mercapto
group or a group of formula
/ H
-N \
Rà
[in which RA~ represents a hydrogen atom; a straight-
chain or branched alkyl group with 1 to 7 carbon atoms
(optionally substituted by an alkoxy group with 1 to 3
carbon atoms); a cycloalkyl group with 3 to 7 carbon
atoms; a phenylalkyl group wherein the alkyl moiety
contains 1 to 3 carbon atoms and wherein the phe~yl
nucleus may optionally be substituted by one or two
alkoxy groups with 1 to 3 carbon atoms; or an alkoxy-
carbonyl group with 2 to 4 carbon atoms]) with a compound
of formula IV,
1 (IV)
[wherein Rl' represents an alkyl group with 1 to 3 carbon
atoms (optionally substituted by an alkoxy group with l
to 3 carbon atoms or by a phenyl group itself optionally
substituted by from 1 to 3 substituents selected from
alkyl and alkoxy groups with 1 to 3 carbon atoms, halogen

~iS~,2
11
atoms and amino groups); an alkyl group with 4 to 7
carbon atoms (optionally substituted by an alko~y group
with 1 to 3 carbon atoms); an alkenyl group with 3 to 6
carbon atoms; or a cycloalkyl group with 3 to 7 carbon
atoms; and U represents a nucleophilically exchan~eable
group such as, for example, a halogen atom or a sulfonic
acid ester radical, eOg, a chlorine, bromine or iodine
atom or a methanesulfonyloxy, ~toluenesulfonloxy or
methoxysulfonyloxy group, whereby the desired compound
of formula I is obtained.
The alkylation is carried out with an appropriate
alkylating agent of formula IV such as e,g. a phenylalkyl
halide, alkyl halide, dialkyl sulfate or trialkyloxonium-
tetrafluoroborate, Such alkylating agents include for
example benzyl chloride, phenylethyl bromide, methyl
iodide, dimethyl sulfate, diethyl sulfate and ethyl
bromide. The alkylation is conveniently carried out in
the presence of a solvent such as e.g, methanol, ethanol,
methanol/water, dimethylformamide or dioxan and optionally
in the presence of a base such as e.g. sodium carbonate,
sodium bicarbonate, sodium hydroxide, sodium methylate or
potassium carbonate. Preferred temperatures are up to
the boiling temperature of the reaction mi~ture.
Due to the optically active carbon atom in position
5 of the pyridazinone ring, the compounds according to the
invention wherein R4 and R5 are different can, if desired,
be resolved int~ their optically active antipodes. This
resolution is conveniently carried out by fractional
crystallization of salts thereof with optically active
acids such as e.g. tartaric acid, dibenzoyl tartaric acid,

12
malic acid, camphoric acid or camphorsulfonic acid, or
by chromatography using optically active adsorbents,
Morover, the compounds of general formula I can
be converted, if desired, into their salts with inorganic
or organic acids or bases. Suitable acids include for
example hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric acid, fumaric acid, succinic acid, lactic
acid, citric acid, tartaric acid and maleic acidO
The compounds of general formulae II and III, used
as starting materials in the processes d~scribed above,
may be obtained according to methods ~nown from the
literature. Thus, for example a compound of fo~nula II
can be obtained by reaction of a corresponding 3-(nitro-
hydroxybenzoyl)~butyric acid ester with hydrazine,
subsequent reduction of the nitro group followed by
reaction of the thus obtained compound with an appropriate
carboxylic acid derivative,
A compound of fo~nula III may be obtained by
reaction 'of a compound of formula V,
R4
Cl ~ ~0 C - Hal
\=/ '
R5
with malonic ester. The thus obtained compound is
subsequently saponified, decarboxylated, the chlorine
atom is replaced by a hydroxy or mercapto group, the
nltro group is reduced and the thus Gbtained amino cornpound
is cyclisized to the desired benzoxazole or -thiazole
after reaction with an appropriate carboxylic acid derivative,
. . . .

~ 13-
The compoun~ of general formula I as well as
their physiologically compatible salts
exhibit, as already mentioned hereinbefore~ interesting
pharmacological properties and especially a cardiovascular
5 activity, i.e. a cardiotonic, hypotensive and/or anti
thrombotic activity. These compounds are thus suitable
for the treat~ent of chronic heart insufficiency or
angina pectoris and/or for the prophyla~is of arterial
occlusion and thrombosis,
For example the following compounds
A ~ 5 Methyl-6~ ethylamino-benzo~azole-5'-yl7-4,5-dihydro-
3(2H)-pyrlda~inone,
B a 5-Methyl-6- ~ '-cycloh~xylamino-be~zoxazole-5 ~-yl7-
4,5 dihydro-~(2H)-pyridazinone~
C = 5-Methyl-6~ n-butylamlno-be~zoxazole-5'-yl7-4,5-di-
hydro-3~2H)-pyridazinona,
D ~ 5-Meth~1-6~ (4-methoxyphenylamino)-benzoxazole-5'-yl7-
4,5-dihydro-3(2H)-pyridazinone,
E ~ 5-Methyl 6-(2'-mercapto-benzoxazole-5'-yl)-4,5 dihydro-
3(2H)-pyridazlnone,
and
F D 5-Methyl-6-(2'-hydroxy-benzo~azole-5'-yl)-4~5-dlhydro-
3(2H)-pyridazinone
were tested with regard to their biological properties.
The following test~ were per~ormed:

~ ~3~ 2
1. Determination o~ the thrombocyte aggregation accordlng
The thrombocyte aggregation wa3 mea~ured in platelet-
rich plasma of healthy test per30n~. The decre~se in
optical d~n~ity wa measured photometrically and re-
corded after addition o~ co~mercial collagen of Me~sr~.
Sigma~ St. Louis, U.S.A., which contai~s 1 mg of collagen-
fibrils per ml. The velocity of aggregation (Vmax) was de-
termined from the angle of inclination of the density ¢ur-
~e . The point o~ the curve where the most light wastransmitted, ~erYed for ~he de~ermi~ation o~ the optical den-
sity ~o.d.). To provoke maximum aggregation approx. 0.01 ~l
of the collagen solution was added to 1 ml o~ platelet-rich
pla~ma.
The following table ~hows the re~ults sbtained:
Tab
Compo~nd ED~o i~ ~lmol/l ..
A 1.4
~ ~ ,
2. Determination of the hypotenxive and positive inotroplc
activity in the cat
The test~ were performed in oats, which were narcotisized
2~ ~ith pentobarbital sodi~m (40 ~g/kg i.p.). The ani~al~
breathed ~pontaneously. The arterial blood pre~sure ~a~

3.~
~ 15
mea~ured in the aorta abdomi~alis by a Statham pre~ure
transducer (P 23 ~c). The positive l~otropic effeot was
determined by mea~uring the pres~ure in the left auricle
by means o~ a catheter tipmanometer (millar PC 350 A).
S The oontractillty parameter dp/dtmaX wa~ registered by
means of an a~alog d$~erentiating circuit~
The sub~tances under test were in~ected lnto the Yena
~emorali~. Physiological saline solution
or polydlol 200 was u~ed as ~olvent. Each sub~tance was
tested ln at lea~t 3 cat~, doAe 0.1 or 2.0 mg/kg i.Y.
The te~ted substancec showed an activity lasting at
least 45 minute~.
The ~ollowing table contain~ the average ~alues:
Te~t Do~e Change of Increase o~
Com- mg¦kg i~v. blood pre~s~re dp/dt
pound in ~m~g in %
A 0.1 -40/~3 ~ 79
B 0.1 -32/32 + 39
C 0.1 -27/27 + 62
D 2.0 -32/42 + 92
E 0.1 - 8/17 + 29
3. A~o',~ t~c~
The acute ~oxicity o~ the te~t compou~d~ was determined
in white mice a~ter oral administration of a ~i~gle dose
(obser~ation time: 14 days)~

- 16, -
Table III~
re~t compound acutc toxicity mg/kg p.o~
A ~ 300 ~2 out o~ 6 animal8 dled~
B ~300 (0 out of 6 a~imal8 dicd)
C ;~300 (1 out o~ 6 animals. died)
D ~ 300 (0 out of 6 animal~ died)
According to a yet further feature of the present
invention there are provided pharmaceutical compositions
comprising as active ingredient, at least one compound of
formula I as hereinbefore defined or a physiogically
compatible salt thereof in association with a pharmaceutical
carrier or excipient.
For pharmaceutical administration the compound of
general fo~nula I and their ph~siologically compatible
salts may be incorporated into the convent-
ional preparations in either solid or liquid form, option-
ally in combination with other active ingredients. The
compositions may, for example, be presented in a form
suitable for oral, rectal or parenteral administration.
Preferred forms include, for example, plain tablets,
coated tablets, powders, suspensions, suppositories and
ampoules.
The active ingredient may be incorporated in
excipients customarily employed in pharmaceutical
compositions such as, for example, talc, gum arabic,
lactose, starch, magnesium stearate, cocoa butter, aqueous

- 17 ~
or non-aqueous vehicles, fatty substances of animal or
vegetable origin, paraffin derivatives, glycols, various
wetting, dispersing or emulsifying agents and/or
preservatives.
Advantageously the compositions may be formulated
as dosage units, each unit being adapted to supply a
fixed dose of active ingredient. Suitable dosage unlts
for adults contain from 10 to 50 mg, preferably from 20
to 40 mg of active ingredient for intravenous administration
and from 50 to 150 mg, preferably from 75 to 100 mg
for oral administration. Such a dosage
may, or example, be administered from 1 to h times per day,
The following non-limiting examples serve to
illustrate the present invention.

N-Ethyl-N'- ~ ^hydro~y 5~(5~ethyl-4,5-dihyd~o-3(2X)-pyrida-
zinone-6-~ he~vl7thiourea
10.8 g ~50 ~ ~ol) of 2-a~i~o-4-(5-~sth~1-4,5-dihydro-3(2H)-
pyridazinone~6-yl)-phe~ol ~ere ~u~pe~dcd i~ 250 ~1 o~ tetra
hydrofuran. The suspension obtained was mixed with 25 ml
(0.29 ~ol) of ethyl isothiocyan~te and the ~esultant mixture
was refluxed for 3.5 hou~s~, whereby a ~leaP solution formed
after a short time. The mixture was then evaporated and the
yellow oily residue obtained was crystallised by addition of
ether. The precipitated product was filtered off with suction,
washed with e~her and dried at room temperature.
Yi81d: 13.0 g (91~5 % o~ theory~
M.p.: 1~7 - 139~C
C14H18N42S (306.4)
Calc.: C 54.88 H 5~92N 18.29S 10.47
Fou~d: 55.10 6.10 17.90 10.30
~a~
3.24 g t1000 ~ mol) of ~-ethyl-N'- ~ -hydroxy-5-(~-methyl-4
oxo-butyric acid-4-yl)-phe~y ~ thlourea ~ere dis~ol~ed i~
15C ml of tetrahydrofuran. The solution obtained was mixed
with 4.17 g (20.0 m mol) of N,N'-dicycloh0xylcarbodiimide
and then refluxed for 5 hours. After refluxing, the resultant
solution was evaporated to half its original volume, boiled
again for a short time then cooled until crystals formed.
The obtained product was filtered off with sUctiOn~
recry3tallized ~rom tetrahydrofuran and dried a~ room temperatu-
re.
Yield: 0.71 g (24.3 % of theory)
M.p.: 160 - 162C.

-- 19 -- , t .7 ~
~a~
5-Meth~1~6~ ethylaml~o-benzoxazole-5'-yl7-4,5-dihydro-.
3.~6 g (11.5 m ~ol) oi N-~thyl-N'- ~ -hydroxy-5-(5-methyl-
4,5 dihydro-3(2H)-pyridazi~o~e-6-yl)-pheny_7thiourea were
dis~olved in 150 ml of tetrahydro~uran~ The ~olution wa~
mixed with 3.13 g (15 m mol) o~ N,N'-dicyclohexylcarbodi~mide
and re~luxed ~or 5 hours. A~ter re~lu2i~g, the reactio~ mix-
tura wa~ evaporated to half its original Yolu~e/ boile~ again
for a short time and cool~d until crystals formed. The
obtained product wag filte~ed off with suction,r~rystallized from
methanol and dried at room temperature.
Yield: 0.84 g (28.3 % o~ theory)
M.p.: 241 - 242C
C1~H14N42 (258.3)
Calc.: C 60.46 H 5.46 ~ 21.6g
Found: 60.28 5.61 21.50
E:CamP1e 2
5-Methyl-6~ n-butylami~o-be~zoxazole-5'-yl7-4,5-dlhydro-
~(2H~- ~ridazl~o~e
Prepared analogou~ly to Example 1 ~rom N ~-butyl-N'- ~ -hydrox~-
5-(5-~ethyl-4,5-dihydro-3(2H) pyridazi~one-6-yl)-phe~yl7thio-
urea.
Yield: 39.7 % o~ theory
M.p.: 186 - 188C
C16H20~42 (30~.4)
Calc.: C 6~.98 H 6,71 N 18.65
Found: 63cg9 6.96 18.54

- 20 ~ ;t~
E ~
5-Methyl 6~ opropylamino-b~nzoxazol~-5'-y ~ -4 9 5-dlhydro-
Prepar~d analogously to Exampl~ 1 ~ro~ N-i~opropyl~
-hydroxy-5-(5-~ethyl-4 9 5 dihydro-~(2H)-py~idazi~o~e-6-yl)-
phenyl7thiourea~
Yield: 52 % of theory
M.p.: 239 - 241C
c15H18N42 (~ 3 )
Calc.: C 62.92 H 6.34 N 19,57
Found: 62.65 6O33 19.25
Exl~r~Le_~
5-Methyl~6~ cyclohe$yla~ino-be~zoxazole-5l-y ~ -4,5-dihydro-
Prepared analogou~ly to Ex~mple 1 fro~ N-cyclohexyl-NI-
-hydroxy-5-(5-~ethyl-4,5-dihydro-3(2H)-pyridazi~one-6-yl)-
phenyl7thiouxea.
Yield: 59.1 % o~ theory
M.p.: 235 - 237C
C18H22N4O2 (326.4)
Calc.: C 66.24 H 6.79 N 17.16
Found: 66.00 6.90 16.99

- -- 21 ~
~a~ ,
5-Methyl-60 ~ '~(~ 9 4-dimethox~phe~ethyla~ino)-benzoxazole-
Prepared analogou~ly to E~a~ple 1 from ~-3,4-dimetho~yphenethyl-
N' ~ -hydroxy-5-(5-methyl~4,5-dihrdro-3(2~)-pyrldazino~e-
6-yl~-phe~l7thiourea.
Yield: 48.2 % Or theory
70 - 72C
C22H24N404 x hydrochlorlc acid (444.93)
Calc.: C 59.39 H 5~87 ~ 12.59 Cl 7.g9
Found: 59.40 5.69 12.89 8.00
Example 6
5-Methyl-6~ phenylamino-benzoxazole~5'-y~-4,5-dihydro-
5 ml of hydrazine hydrate (99 %) were add~d at approx. ~O~C
in portion3 to 20 ml of glacial aoetlc acid whilst ~tlrri~g
a~d ice cooli~. Sub~e~uently 6.5 g (20.0 ~ ~ol) of 2-phenyl-
ami~o~5-(3-methyl-4;oxo-butyric acid-4-yl)-benzo~azole ~ere
added to the reaction ~ixture and the thus obtained ~uspen-
sion ~a~ re~luxed. A~ter 1 hour the su~pensio~ was cooled to
room temperature and diluted with water. Th~ precipitated pro-
duct was ~iltered off with ~uction, washed with ~7~ter an~ ~ried at 80C.
Yield: 2.80 g (4307 % o~ theory)
M.p.: 2'14 - 217C
C1 8H1 6N42 ( 320 . 34 )
Calc .: C 67. 49 H 5 . 03 ~ 1 7 , 49
Fou~d: 67 " 00 ~ . 32 17 . 12

- 2 2
~Z
5-Methyl-6~ (2 chloroanilino)-be~zoxazole~5'~ 4,5-dl-
Prepared analogou~ly to Example 1 ~rom N-2-chloroph~yl-N'-
/~-hydroxy~5-(5~ethyl 4,5-dihydro 3(2~)-pyrldazlnone-6-yl)-
phen~l7thiourea.
Yi~ld: 33.9 ~ of theory
M.p.: 193 - 195~C
N402Cl (354.8)
Calc.;: C 60.93 H 4.26N 15.79 Cl 9.9~
Found: 60.90 4.25 15.93 10.20
5-Methyl-6- ~ '-(4-trliluoromethylphenylami~o)-benzoxazole-
Prepared analogously to Exa~ple 1 ~rom N-4-tri~luoromothyl-
phe~yl~ h~dro~y-5-(5-methyl-4,5-dihydro-3(2H)-pyridazi~one-
6-yl)-phe~yl7thiourea.
Yleld: 57.3 % of theory
M.p.: 249 - 251C
C19 15 4 2 3 (388,~6~
Calc.: C 58.76 H 3.89M 14.42
Found: 5g.00 4.13 14.31
Exampla 9
.
5-Methyl-6- ~ '-(3,4-dichlorophenylamino)-benzo~azole-5'-yl7-
Prepared analogou~ly to Example 1 irom N-3,4-dichloro~Jheny1-
N'- r -hydroxy-5-(5-methyl-4,5-dlhydro-3(2H)-pyridazinone-6-yl)-
pheny ~ thiourea.

3,3L~
- ~3 -
Yield: 7305 % o~ theory
.p.: 25~ - 256~
c18~14N42Cl2 (389.~)
Calc.: C 55.54 H 3063 , Cl 18.22
Found: 55.40 ~83 18.14
E~c~
5~Methyl-6~ (4-bro~ophe~ylami~o)-be~zoxazole-5'-yl7;4,5-
~ ` ` ~
Prepared analogou~ly to Example 1 ~ro~ N-4-bromophenyl~
-hydroxy-5~(5-methyl-4,5-dihydro-3(2H)-pyridazi~o~e-6-yl)-
pheny ~ thlourea.
Yleld: 65~4 % oi theory
M.p.: 243 - 245C
C18H15N402Br (390.27
Calc.: C 55.40H 3~87 N 14.36Br 20.48
Found: 55.00 4.05 13.95 20.76
~ .
5-Methyl-6~ (4-methoxyphenylamino)-benzoxazole-5' -yl7-
Prepared analogu~ly to Example 1 ~rom N-4-methoxyphenyl-
N'- ~ -hydroxy-5-(5-methyl~4,5-dihydro-3(2~) pyridazinone-
6-yl)-phenyl7thiourea.
Yield: 40.3 % o~ theory
M.p.: 220 - 222C
C19H18N43 (350.4)
Calc.: C 65~13 H 5.18 N 15.g9
~ound: 65.30 5.20 15.83

- - 24 ~ ti~ ~
5-Methyl-6~ (2-~ethoxy-4-nitrsphe~ylamino)-benzoxazole-
Prepared analogously to Example 1 ~rom N-2-~ethoxy-4-nltro-
phenyl-N ' -L~-hydro~y-5- ( 5 ~ethyl -4, 5dihydro-3 ( 2H ) -pyridazi-
no~e~6-yl ) -phenyl7thiourea .
Yield: 65 . 6 % o~ theory
M. p ,: 223 - 225C
C1 gH1 7NsOs ( 395 . 4 )
Calc.: C 57.82 ~ 4,33 N 17.71
Found: 58 . 27 4. 25 18. 17
Exam~le 1 3
5-Methyl-6~ (4-methylphenyla~nino ) -benzo~azole-5 t _y~7_
Prepared analogou~ly to Example 1 from N-4-methylphenyl-N'-
~ -hydro~y-5-(5-methyl-4,5-dlhydro-3(2~)-pyridazinone-6-yl~-
phen~l7thlourea~
Yield: 52.1 % o~ theory
M. p .: 273 - 275C
C19H18N402 (334.~9)
Calc .: G 68 ~ 25 ~I 5 ~ 43 N 1 6. 76
Found: 68.10 5.59 16.88
Example 14
5-Methyl-6~ (2,4,6-trlmethylphenylamino)-benzoxazole-
Prepared an~logou~ly to Example 1 from N-2,4,6-trimethyl-
phenyl-N'- ~ -hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyrida-
zinona-6-yl)-phenyl7thiourea.

- 25
Yleld: 76~4 ~ o~ theory
M.p.: 225 - 2Z8C
C21H22N42 (362.4)
Calc~: C 69.59 H 6.12 N 15.46
Fou~d: 69.79 6.37 15.65
5-M~thyl-6~ 4-cyanophenylaml~o)-be~zoxazole-5'-y ~ -
Prepar~d analogously to E~ample 1 fro~ N-4-cyanophenyl-N'-
r -hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinon~6-yl~-
phe~y ~ thiourea.
Yield: 59.7 ~ of theory
M.p.: ~18 - 320C
C19H15~5~t345 37~
Galc.:C 66.08 H 4.38 N 20.28
Fou~d: 66.14 4.58 20.03
~a~
5-Methyl-6~ ethoxycarbonylamino3~be~zoxazole-5'-y ~ -
Prepared analogou~ly to Exa~ple 1 ~ro~ N-etho~ycarbo~yl-N'-
-hydroxy-5-(5-methyl-4,5-dihydro-3(2H)-pyridazinone~6-yl)-
phe~y_7t~iourea.
~ield: 19.8 % o~ theory
M.p.: 235 - 2~9C
C15H16N44 (316.~3)
Calc.: C 56.95 H 5.iO N 17.71
Found: 55081 5.14 17.08

- 26
5-Methyl-6~ -pe~tylamino-be~zoxazole-5'-y ~ -4,5-di~
h dro-~ZH~- idazi~o~e
Prepared analogou~ly to E~ample 1 ~rom N-n-pentyl-N'-
~ -hydroxy-5-(5-~ethyl-4,5-dihydro-3(2H)-pyridazlnone-6-yl)-
phe~y ~ thiourea.
Yield: 52.3 % o~ theory
M.p~: 154 155C
C17H2~N4Q2 (314.4)
Calc.: C 64.95 ~ 7.05 N 17.82
~ound: 65.26 7.12 17.88
Ex~mple 18
5-Methyl-6- ~ '-ethylamino-benzoxa20le-5'-y ~ -4,5-dihydro-
Prepared analogously to Exa~ple 1 ~rom N-ethyl-N'- ~ -hydroxy-
5-(5-methyl-4,5-dihydro-3(2H)~pyrldazino~e-6-yl)-phenyl7thio-
urea.
Yield: 71.9 % of theory
M.p.: 244 - ~46C
C14H16N402 (272.3~
Calc.: C 61.75 H 5.92 N 20.57
Found: 61.95 5.98 20.85
xam~le 12
5-Methyl-6- ~ '-(3 methoxypropylamino)-benzoxazole-5'-y ~ -
4 dih dro ~2H~- idazinone
Prepared analogously to Example 1 fro~ N-~-methoxypropyl-N'-
-hydroxy-5-(5-methyl-4,5~dihydro-3(2H)-pyridazinone6-yl)-
phenyl7thiourea0

- 27 -
Yield: 55.5 % o~ theory
M,p.: 153 - 154C
C16H20N43 (~16.4)
Cal~ C 60.75 H 6.37 N 17.71
Found: 61.00 6.40 17.56
Exa~ple 20
5~Methyl-6~ am~no-benzoxazole 5' yl7-4,5-dihydro-3(2~)-
~vridazinone
Prepared analogously to E~a~ple 1 ~rom ~ hydroxy-5-(5~methy
4,5-dihydro-3(2H)-pyridazino~e-6-yl)-phenyl7thiourea.
Yield: 42.1 % of theory
M.p.: 285 - 287C
~Q~ .
5,5-Dimethyl-6~ phenylethyl)-benzoxazole-5'-y ~ -4,5-di-
a) ~
30 g (0.6~8 ~ol) of sodium hydride (50 % oil suspen~ion)
were added at room temperature to 1200 ~1 of absolute
tetrahydrofuran and the mixture wa~ stirred for 15 mlnutes.
After addition o~ 52 g ~0.228 mol) of 4-(4-chlorophenyl)-
3-methyl-4-oxo butyric acid in 3mall portions, the reaction
mixture was refluxed for 2 hour~. Subsequently the mixture
was cooled to 40C and 64 ml ~1.02 mol) of methyl iod~de
were added dropwise. After reiluxing for a further 3 hours
and sub~que~t cooll~g to room temperature, the reaction
mixture wa~ added to water with stirring and the orga~ic
phases were distilled off in a rota~y evaporator. The
aqueous alkaline solution was wash~d twice with petroleum
ether and then acidified by means o~ conc. hydrochloric
acid. The o~l thus obtai.ned crystallised on further

28 -
stirring. The crystals Were filtered off with suction,
washed with water and dried.
Yield: 52 g (94.7 % of theory)
M.p.: 95 - 97C.
b) 4-(4-Chloro-3-nltrophenyl)-3,~-dimethyl 4-oxo butyric
acid
48 g (0.2 ~ol) o~ 4-(4-chlorophsnyl)-3,3 dimethyl-4-oxo-
butyric acid were added in portions at -15C and -104C
to 500 ~l oi ~uming nitric acid whil~t ~tirring. After
stirring for 30 ~i~ute~ at -10~C, the reaction mixture
wqs poured on ice water. The precipitate~ product wa~
filtered off with suction, washed neutral with ~at~r and dried.
Yield: 47.5 g (83.1 % of t~ory)
M.p.: 118 - 120C.
c) 2-Nltro-4-(5,5-dimethyl-4,5 dihydro-3(2H)-pyridaz~none-
6 1~ chlorobe~zene
43 ml of hydrazi~ hydrate (99 %) were added in portions
at approx. 20C to 400 ml of glacial acetic acid whilst
stirring and ice-cooling. Sub~equently 43 g (0.15 mol)
of 4-(4-chloro-3-nltrophenyl)-5,5-dlmethyl-4-oxo-butyric
acid were added a~d the reactio~ mixture was re~luxed
~or 1 hour. After cooling, the reaction mixture waq dilu-
ted wlth water. The precipitated produc~ was filter~d
off with suction,washed-ayain with water and dried.
Yield: 33 g (78.1 % o~ theory)
M.p.: 193 - 194C.
d) 2-Nitro-4-(5,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone-
6 l~ henol
28 g (0.1 mol) of 2-nltro-4-(5,5-dimethyl-4,5-dihydro
3(2H)-pyridazinore-6-rl)-chlorobenzene were suspended
in 750 ml of glycol and the su~pen~ion was mixed with a

~ 29 ~ ~ 3~'
- solution o~ 40 g o~ powdered potas~ium hydroxide in
250 ml o~ glycol. The ~olution thu~ obtained wa~ heated
for 2 hour~ at 160C. A~ter cooling to room temperature
the ~olution wa~ poured into approx. 3 1 of lce-water and
acidi~ied b~ ~ean~ o~ conc. hydrochloric acid. T~e
precipitated product was filtered off wlth suctlon. The.'iltrate
was extracted 4 times wlth 250 ml aliquots of ethyl acetate,
The organic phaYe was dri~d with 30dium ~ul~ate and
e~aporated. The residue and the solid product were o~b~
triturated with water, ~lt~r.ed with suction and dried.
Yield: 20 g (76 % o~ theory)
M.p.- 211 - 213VC~
e) 2-Amino-4~5 9 5-dimethyl-4,5-dihydro-3(2~)-pyridaæinone-
20 g (0.076 mol) o~ 2-nitro-4-(5,5-dimethyl-4,5-dihydro-
3(2H)-pyrldazinoae 6-yl)-phenol i~ 600 ml of dimethyl
forma~ide were reduced in a Parr apparatus at room te~-
perature with hydrogen (5 bar) and 2 g of palladium/char-
coal (10 %) a~ cataly~t. When the hydrogen absorption wa~
fi~i~hed the catalyst wa~ filtered off with suction and the fil-
trate was evaporated. A solld product was obtained, which
wa~ triturated with ether. After flltering o~ with suction, the
product wa~ wa~hed with ether and dried.
Yield: 17 g (96 % of theory)
~.p.: 260 - 263C.
f ) 2- ( 2-Phenylpropionylamino)-4-(5,5-dimethyl-4,5-dihydro-
3 ( 2~ ) -PYridazinone-6-Yl ) -~n~
208 g (O.012 mol) oi 2-amino-4-(5,5-dimethyl-4,5-dihydro-
3(2H)-pyridazinone-6-yl)~phenol were suapended in 40 ~l
o~` absolute tetrahydrofura~ and 40 ml of absolute dimethyl-
formamide. 3.03 g (0.018 mol) o~ 2-phenylpropionic acid
chloride were added dropwi~e at room temperature~ A~ter
1~5 hours the reaction ~ixture waa atlrred into water
and extracted several times with ethyl acetate. ~he

~` - 30 ~
organic phase~ were dried with 30dium sul~ate and evaporated.
The product obtained wa~ purified by column ch~omato-
graphy (~ilica gel, ~ram size: 0.05 - 0...~0 m~,
eluant: chloroform/ethanol 1 %). The product thu~ obtained
wa~ reacted further in crude form.
Yield: 1.7 g (38.8 ~ o~ th~ory.
g) 5,5-Dimethyl-6~ phenylethyl)-benzoxazole 5~-yl7-
1.7 g (O.0046 mol) o~ 2-(2-phenylpropionylamino)-4-
(5,5-dimethyl~4,5-dihydro-3(2H)-pyridazinone-6-yl)-
phenol were su3pended in 12 ml o~ sulfolane and the su~-
pension was refluxed ~or 5 hours. Subsequently the hot
reaction ~ixture was stirred into ice-water. The preci-
pitated oily product wa~ extracted with ethyl aoetate~
The organic phase was dried with sodlum sul~ate and eva-
porat~d. The obtained residue was purified by-means o~
col~mn chromatography (silica gel, grain size: 0.05
to 0.20 mm., eluant: chloro~orm/ethanol 1 %). The corres-
pondi~g fractions were combined, ~iltered via charcoal
and evaporated. The residue was an-oil, which was crystal-
lized with petroleum ether.
Yield: 1 g ~62.5 % o~ theory)
M.p.: 131 - 135C
C21H21N32 (347.4)
Cslc.:C 72.61 H 6.09 N 12.10
Found:72,18 6.30 11.91
Exampl~ 22
5,5-Dimethyl-6-(2'-amino-benzoxazole-5'-yl)-4,5-dihydro-
~ a _ " . _. . .
2.1 g (0.0072 mol) of N- ~ -hydroxy-5-(5,5-dim~thyl-4,5-di
hydro-3(2H)-pyridazinone-6-yl)-phenyl7thiourea (prepared
by alkaline hydroly~is of N'-benzoyl-M-~ -hydroxy-5-(5,5-di

~ - 31 ~ ;t;~ ~
methyl-4,5-dihydro-3(2H)-pyridazino~0-6-yl)-pheny ~ -thio-
urea) were dissol~ed i~ 40 ml o~ ab~olute tetrahydro~uran~
2.05 g (0.01 ~ol~ of N,N'-dicyclohexylc~rbodiimide were
added and the r~action mi~ture wa~ re~luxed for 2 hours
whil~t ~tirring. After cooling to roo~ temperature 7 the
precipltated product wa~ filtered off ~i.th suction and washed
wlth tetrahydrofuran. The reaction product was ~uspsnded
i~ 1 N ~mmo~ia, ~irred for 30 mi~ute~ ~ e~Uoff~th suction,
wa~hed with water a~d dried.
Yield: 1.0 g (54 % o~ theory)
M.p.: ~ 250C
C13H14N42 (258.3)
Calc.: C 60.45 H 5,46 N 21.69
Found: 60 9 ~7 5.41 21.44
Example 2~
5-Methyl-6-L2'-dimethylamino-benzothiazole-5'-yl7-4 7 5-di
a)
27 g (0.1 mol) of 4-(3-nitro-4-chlorophenyl)-3-methyl-
4-oxo-butyric acid were added to a olution of 72 g
(0.3 mol) oi ~odium sulfide x 9 H20 in 500 ml o~ water
and the mixture was heated for ~5 hours on a steam
bath. A~tsr coolin~ to 10C, the reaction mixture was
ad~u~ted to pH 4.5 by mean~ of glacial acetic acid. Sub-
~eque~tly the reaction mixture was extracted several
tlmes with ~thyl acetate. The organic pha~e was dried
with sodium sulfate and evaporated. The residue obtai-
ned was reacted ~urther in crude form.
Yield: 27.5 (approx. 100 % o~ theory).
b) 5-Methyl 6~ dimethylaminobenzothi~zole-5'-y ~ -4,5-di-
2.2 g (0.01~ mol) of dimethylthiocarbamoyl chloride were
added at roo~ temperature to a solution of 2.8 g (0.012 mol)

- 32 -
of 2-ami~o-4-(5-methyl-4,5-dihydro-3~2H)-pyrida7i~o~e-
6-yl)-thiophenol (prepared by reaction o~ 4-(3-amino-
4-mercaptophe~yl)-3-~ethyl-4-oxo-butyric acid and hydra-
zine) in 40 ~1 of absolute tetrahydro~uran whilst stirring~
A~ter 20 hours the precipltated product w~ ~iltered o~
Th~ ~iltrate wa~ dlluted with water and extracted t~lce
with ethyl acetate. Subse~e~tly the aqueou~ pha~e wa~
made alkaline by means of 2 N ~odium hydr~xide solution
and extracted with chloroform. The organic ph~e was
dried with ~odium ~ulfate and evaporated. An olly pro-
duct wa~ obtai~ed~ which cry3tallized ~hile ~ta~di~g
o~ernight~ The obtai~ed crude product (1 g) was puri
fied by column chromatography (sillca gel,grain size:
O,05 to 0.20 mm, eluant: chloro~orm/athanol 1 %).
Yield: 550 mg (16 ~ o~ theory)
M.p.: 177 - 184C
C14H16N4S (288.4)
Calc.: C 58.31 H 5.59 N 19.43 S 11.12
Found: 58.41 5.69 19.12 11.02
~2a~
5-Methyl-6- ~ '-(4 cya~ophenyl)-benzoxazole-5'-y ~ -
2.07 g (5.3 m mol) of 1-acetoxy-2-~4'-cyanobenzoylamino)-
4-(5-methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-benzene
in 50 ml of sulfolane were mixed with 0.5 ml of 10 ~ hy-
drochloric acid~ After hesting for 4 hours to 240C, the
mixture was ~tlrred into 150 ml of water and the precipi-
tate obtained wa~ filter~d off with suc~ion. Ihe produc~ was puri-
fied by column chromatography (silica gel, ohloroform
+ 1 % ethanol).
Yield: 145 mg (8.3 % of theory)
M~pr 278 ~ 280C~
C1 gH1 4N402 ( 33 35 )
Calc.: C 69.08 H 4.27 N 16.96
Found: 68.24 4.~4 16.86

~~ 33 ~ 2
5-Methyl-6-(2'-hydroxy-benzoxazole-5'-yl)-4,5-dihydro-3(2~)-
~ridazlnone
1.08 g (0.005 ~ol) o~ 2-ami~o-4-(5-methyl-4~5-dihydro-3(2H)-
pyridazinone-6-yl)-phe~ol ~ere su~pe~ded in 50 ml of abs
te t~trahydro~uran ~nd the sw p~n~io~ ~a~ mixed wlth 1 g
(0.006 mol) o~ N,N'-carbonyld~dazole whilst stirring,
A~ter reflu~ing ior 45 minute~ the reaction ~lxture wa~
evaporated a~d the r¢sidue ~a~ ~tirred with water. The
obtained crystals w~re ~lltered:of~ w~th~suction, washRd ~ith ~ter
and dried. Subsequently the crude product wa~ dissolved in
chloroform:methanol . 9~ iltered hot vla acti~ated char-
coal, and the ~iltrate ~as e~aporated u~til cry~tals
formed. The reaction product was cooled in an ice bath,
The precipitated product was filtered off with suction, w~shed with
ether and drled.
Yield: 0.55 g (44.7 % o~ theory)
. p .: 2go - 253C
C12H11N303 (245.2)
Calc.: C 58.77 H 4.52 N 17.13
Found: 58.77 4.46 17.22
Example 26
5-Methyl 6-(2'-ethoxy-benzoxazole-5'-yl)~4,5-dihydro-3(2H)-
ridazinone
2.19 g (O.01 mol) of 2-a~ino-4-(5-methyl-4,5-dihydro-3(2H)-
pyridazinone-6-yl)-phenol wére uspended in 10 ml o~ tetra-
ethyl carbonate and 3 ml o~ dimethylformamide were added.
A~er heating ~or 1 hour at 180C (oil bath), the reaction
mixture wa~ cooled to room temperature.- ~he precipi~ated
product wa~ filtered of~,~ith sllction and washRd with e-ther. Sub-
sequently the reaction product was recrystallized twice
~rola 100 ml of ethanol by addition of activated char-
coal.

Yield: 900 ~g (33 ~ of theory),
M.p.: 193 194C.
C14 15 3 3 (27~.3~
Calc.: C 61~5~ H 5.5~N 15.38
Found: 61.59 5.5215.65
~:Z
5-Methyl-6-(2'-mercapto-be~zoxazole-5'-yl)-4~5-dihydro-
22 g (0.1 mol) o~ 2-amino-4-(5-methyl-4,5-dihydro-3(2H)-
pyridazinone-6-yl)-phenol ~ere suspended in 500 ml of
ethanol a~d 24 ~ (0.15 mol) of potas~ium ethylxanthogenate
were added whilst stirri~g. A~ter re~luxing for 3 hours,
the reaction mixture wa~ cooled to room temperature. The
precipitated product was filtered of with suction ~ washed
with cold ethanol and ether. The pota~sium salt thus ob-
tained wa~ dissolved in 1000 ml of water 7 ~lltered via
activated charcoal and the ~iltrate was neutralized with
2 N acetic acid. The precipitated product was fil-
tered o~ wlth suctlon, ~d with water and dried in a va~um shelf dryer.
Yield:-15 g (57.7 % of theory)
M.p.: ~250C
C12H11N3~2S (26103)
Calc.: C 55.16 H 4.24N 16,08S 12.27
Found: 55.09 . 4.16 15.9~ 12.10
Example 28
5-Methyl-6-(2'-methylmercapto-be~zoxazole-5'-yl)-4,5-di-
h~
65~ mg (0.0025 mol) 5 methyl-6-(2'-mercapto-benzoxazole~5'
yl)-~,5-dihydro-3(2H)-pyridazinon0 were dissol~ed in 10 ml

- 35 ~ .P~
o~ absolute dimethyl~or~amide and the 501utio~ was mlxed
with 210 mg ~0.0025 mol~ o~ ~odium bicarbonate. A~ter
additio~ of 2 ml of methyl iodide the reaction mixture was
~t~rred ~or 15 hour~ at 40C~ The reaction mixture ~as
stirred i~to wat~r and e~tracted with ethyl acetate. The
organlo phase was dried with odium sulfate and evapora-
ted. The obtained solid re~idue was recrystallized from
ethanol.
Yield: 340 mg ~49.4 % of theory)
.p .: 178 - 180C.
C13H13N32S (275.3~
Calc.: C 56,71 ~ 4.76 N 15.26 S 11.65
Found: 56~20 4.78 15.41 11.57
5-Methyl-6-(2'~n-hexylm~rcapto-benzoxazole-5'-yl)-4,5-dihydro-
2.99 g (0.01 mol) o~ 5-methyl-6-(2'-mercapto-benzo~azole~5'-yl)-
4,5-dihydro-3(2H)-pyrida2inone-potassium salt were dissol~ed
in 20 ml of absolute dimethylformamide. 1.5 ml of n-hexyl
bromide were added whilst stirring and the reaction mixture
w~s stirred for 1 hour at 40C. Sub~eque~tly the reaction
mixture was stlrred into water and extracted with ethyl ace-
tate. The organic phase was dr1ed with sodium sulfate7 and
e~aporatedO The obtained residue was recrystalllzed from
ethanol.
Yield: 2.4 g (69.6 % of theory)
M.p.: 119 - 121C
C18H23N32S (~45.5)
Calc.: C 62.57 H 6.71 N 12.16 S 9.28
Fo~nd: 62.65 6.79 12.17 9.05

~ 36 ~
5-Methyl-6-(2'-allylmercapto-benzoxazole-5'-yl)-4,5-dihydro-
Prepared analogou~ly to Exa~ple 29 ~rom 5-methyl-6-(2'-mer-
capto-benzoxazole-5l-yl)~4,5-dihydro 3(2H)-pyridazinone-
potassium salt and allyl bromide.
Yield: 73 % of theory
M.p,: 113 - 114C
C15H15N32 ~301.4)
Cal~.: C 59.78 H 5.02N 13.94 S 10.63
Found: 60.01 5.21 14.28 10050
~a~ . .
5-Methyl-6~(2'-p-methoxybenzylmercapto~benzoxazole 5'-yl)-
Prepared analogously to Example 29 from 5-methyl-6-(2 7 -mer-
capto-benzoxazole-5'-yl)-4~5-dihydro-3(2H)-pyridazinone-
potas~ium ~alt and ~-methoxybenzyl bromide.
Yield: 66.6 % o~ theory
M.p.: 174 - 176C
C20H19 3 3 (381.5)
Calc.: C 62.97 H 5.02N 11~02 S 8.41
Found: 63.47 5.08 11.34 8.63

~ 37 ~ r~
5-Methyl~ 4-amino-3,5-dichlorophenyl)-ethylmercapt ~ -
benzoxazole-5'-~11-4,5-dihydro-~(2H)-pyridazinone
Prepared analogously to Example 29 from 5-methyl-6-(2'-mer-
capto-benzoxazole-5'-yl)-4,5-dihydro-3(2~)-pyridazinone
potassium salt and 2-(4-amino-3,5-dichlorophenyl)-ethyl
bromide.
Yield: 52 % o~ theory
M. p.: 205 - 208C.
~xample ~3
5-Methyl- ~ '-methylbenzoxazole-5'~17-4,5-dlhydro-3(2~)-
p"yridazinone ___ , _
Prepared analogously to Example 21g from 2-acetylamino-4-(5-
methyl-4,5-dihydro-3(2H)-pyridazinone-6-yl)-phenol by hea-
ting in sulfolane.
Yleld: 75.3 % of theory
M.p.: 210 - 213C.
Example ~L~
5-Methyl- ~ '-isopropylbenzoxazole-5'-y ~ -4,5-dihydro~3(2H)-
pyridazinone
Prepared analogously to Example 21g from 2-isobutyrylamino-
4-(5-methyl-4,5-dihydro-3(2~1)-pyridazinone-6-yl)-phenol by
heating in sulfolane.
Yield: 52.5 % of theory
M.p.: 160 - 162C.

- - 38 ~
~a~
Tablets co~tai~ing 100 mg of 5 methyl-6~ ethylami~o-
Co~poqition:
1 tablet contai~s:
Active ingredient 100.0 mg
Lacto~e 50.0 mg
Polyvinyl pyrrolidone 5.0 mg
Carboxymethyl cellulose 19i0 mg
Mag~esium stearate 1.O mg
175.0 mg
The active ingredient and the lacto~e were homogeneously
moistened with an aqueou~ ~olution o~ the polyvinyl pyrro-
lidone.
Moist screening: 1.5 m~
Drying: in a circulat~on air drler at 50C
Dry screening: 1 mm
The granulate and the remaining auxiliary products were
mixed and pressed into tablets.
Weight of tablet: 175 mg
Punch: 8 mm 0
Example B
Coated tablets containing 50 mg o~ 5-methyl-6~ ethylamino-
1 coated tablet core contains:
Active ingredient 50.0 mg
Corn starch dried 20.0 mg
Soluble ~tarch 2.0 mg
Carboxymethyl cellulose 7.0 mg
Magnesium stearate 1.O mg
80.0 mg
,

3~
The active ingredie~t and the starch were homoge~eously
moi~tsned with a~ aqueous solution of the soluble starch~
Moist scrQe~ing: 1.O m~
Dry screening: 1.0 mm
Drying: in a circulation air drier at 50~
The granulate a~d the re~aining au~iliary product~ wer~
mixed and pres~ed into cores.
Weight o~ core: 80 mg
Punch: 6 ~m
Radius oY survature: 5 ~m
The iinished cores were covered with a sugar coating ln
conventional manner,
Weight of coated tablet: 120 mg
E~ le C
Suppositorles containing 75 mg o~ 5-methyl-6~ ethyl-
1 suppoQitory contains:
Active ingredient: ~ 75.0 mg
Suppository mass (e.g. Witepsol H 19
and Witepsol W 45) 1625.0 mg
1700.0 mg
Method o~ preparation:
The suppository ma~s was melted. At 38C the pulverized
active ingredient was homogeneously dispersed in the melt.
The suppository mass was cooled to ~5C and poured into
pre-cooled moulds.
Welght of suppository: 1.7 g
~rr~d e- ~VI Q ~I~

_a~
Ampoules containing 25 mg o~ 5-meth~l-6-L2'-ethylamino-
Compo~ition:
1 ampoule contain~:
Active ingredient 25.0 mg
Sodium chloride 45.0 mg
Polyethylene glycol 600 1.0 ml
Di~solving intermediary (e.g. hy-
droxy-ethylated hydrated castor oil) 015 ml
Water ~or in~ection purpo~es ad 5.0 ~1
Method of pre~aration~
The active ingredient was di~ol~ed in a mixture o~
polyethylene glycol, dissolving intermediary and approx.
hal~ of the water in a suitable volume-calibrated ~e~sel
whilst ~tirring. The solution wa~ mi2ed with the sodium
chloride ~nd made up with water to the gi~7e~ :volume.
Example E
Suspension containing 75 mg of 5-methyl-6- ~ ' ethylamino-
100 ml of ~uspension contain:
Active ingredient 1.5 g
Carboxymethyl cellulose 0.1 g
Methyl p-hydroxybe~zoate 0.05 g
Propyl p-hydroxybenzoate 0.03 g
Cane ~ugar 10.0 g
Glycerine 5.0 g
Sorbit ~olution 70 % 20.0 g
Aroma 0-3 g
Water dist. 100.0 ~l

gf~
,. -- 'I 1
Di tilled water wa~ heated up to 70C9 a~d methyl ~-hydroxy-
be~zoate, propyl p-hydroxybe~zoate, glycerine, and carbo~y
methyl cellulose were dissolved therein ~hilst stirring.
This olution was cooled to roo~ temperature, the active
ingredie~t wa~ added whilst stirri~g a~d homogeneouæly
disperæed. Subsequently, the sugar, the sorbit solution,
and the aroma were added and dis~olved and the suspensio~
wa~ evaporated i~ vacuo whilst ~tirri~g.