6-Aryl-4,5-dihydro-3(2H)-pyridazinones, and their use as anti-hypertensive and anti-thrombocyte agents

6-Aryl-4,5-dihydro-3(2H)-pyridazinones of the formula ##STR1## where R is hydrogen, R.sup.1 is hydrogen or C.sub.1 -C.sub.3 -alkyl, or R and R.sup.1 together are methylene, R.sup.2 and R.sup.3 are identical or different and are each hydrogen or C.sub.1 -C.sub.6 -alkyl, and A is hydroxyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.2 -C.sub.7 -acyloxy, a C.sub.2 -C.sub.7 -carbamic acid ester group, C.sub.1 -C.sub.6 -alkylsulfonyloxy, C.sub.1 -C.sub.6 -alkylmercapto, carboxyl, C.sub.2 -C.sub.7 -alkoxycarbonyl or nitrile, and their preparation are described. The substances are suitable for treating disorders.

The present invention relates to novel 
6-aryl-4,5-dihydro-3(2H)-pyridazinones, processes for their preparation 
and their use in the treatment of disorders. 
A number of phenyl-4,5-dihydro-3(2H)-pyridazinones have been disclosed 
(German Laid-Open Publication Nos. DOS 1,670,158, DOS 2,123,246, DOS 
2,150,436, DOS 2,157,453, DOS 2,304,977, DOS 2,727,481, DOS 2,854,191, DOS 
2,854,475, DOS 3,022,176, DOS 3,022,177 and DOS 3,033,702, Japanese 
Preliminary Published Application No. 53.124-279, and U.S. Pat. Nos. 
3,824,271 and 3,888,901). These compounds are said to possess hypotensive, 
inflammation-inhibiting, cardiovascular, antiphlogistic, coronary dilator, 
anti-allergic, membrane-stabilizing and/or thrombocyte 
aggregation-inhibiting properties. 
We have found that 6-aryl-4,5-dihydro-3(2H)-pyridazinones of the formula 
##STR2## 
where R is hydrogen, R.sup.1 is hydrogen or C.sub.1 -C.sub.3 -alkyl, or R 
and R.sup.1 together are methylene, R.sup.2 and R.sup.3 are identical or 
different and are each hydrogen or C.sub.1 -C.sub.6 -alkyl, and A is 
hydroxyl, C.sub.1 -C.sub.6 -alkoxy, C.sub.2 -C.sub.7 -acyloxy, a C.sub.2 
-C.sub.7 -carbamic acid ester group, C.sub.1 -C.sub.6 -alkylsulfonyloxy, 
C.sub.1 -C.sub.6 -alkylmercapto, carboxyl, C.sub.2 -C.sub.7 
-alkoxycarbonyl or nitrile, possess useful pharmacological properties. 
The compounds in which R is hydrogen, R.sup.1 is hydrogen or methyl, 
R.sup.2 is hydrogen or methyl, R.sup.3 is hydrogen and A is hydroxyl, 
methoxy or nitrile have proved particularly advantageous. 
The numbering of the carbon atoms for substituents A is based on the total 
number of carbon atoms in the particular radical. 
The novel compounds can be prepared by a process wherein 
(a) a compound of the formula II 
##STR3## 
where R and R.sup.1 have the above meanings, is reacted with an acyl 
halide of the formula III 
##STR4## 
where R.sup.2 and R.sup.3 have the above meanings and B is C.sub.1 
-C.sub.6 -alkoxy, C.sub.2 -C.sub.7 -acyloxy, C.sub.1 -C.sub.6 
-alkylmercapto, carboxyl, nitrile or C.sub.2 -C.sub.7 -alkoxycarbonyl, 
and, in the resulting compounds, where relevant, a carboxyl group is 
esterified or an acyloxy group is hydrolyzed and the hydroxy compound 
obtained is reacted, if appropriate, with a reactive derivative of a 
C.sub.1 -C.sub.6 -alkanesulfonic acid or a C.sub.2 -C.sub.7 -alkyl 
isocyanate, or 
(b) where A is C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkylmercapto or 
nitrile, the radical X in a compound of the formula (IV) 
##STR5## 
where R, R.sup.1, R.sup.2 and R.sup.3 have the above meanings and X is 
chlorine, bromine, iodine or alkylsulfonyloxy, is exchanged for a C.sub.1 
-C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkylmercapto or nitrile group, or 
(c) where A is C.sub.1 -C.sub.6 -alkoxy, C.sub.2 -C.sub.7 -acyloxy, C.sub.1 
-C.sub.6 -alkylmercapto, nitrile, carboxyl or C.sub.2 -C.sub.7 
-alkoxycarbonyl, a ketocarboxylic acid of the formula V 
##STR6## 
where R, R.sup.1, R.sup.2, R.sup.3 and B have the above meanings, is 
subjected to a cyclization reaction with hydrazine. 
This reaction of II with III is carried out under the conditions 
conventionally employed for an N-acylation reaction; as a rule, not less 
than an equimolar amount of the acid halide is used, advantageously in the 
presence of a solvent, in the presence or absence of an acid acceptor, and 
at a suitable temperature of as a rule not more than 100.degree. C., 
preferably not more than 70.degree. C., if appropriate at the boiling 
point of the reaction mixture and if appropriate under superatmospheric 
pressure. 
Preferred solvents for use on an industrial scale are ketones, e.g. 
acetone, diethyl ketone or methyl ethyl ketone, aromatic hydrocarbons, 
e.g. benzene, toluene, xylene, cyclic ethers, e.g. tetrahydrofuran or 
dioxane, aliphatic or aromatic chlorohydrocarbons, e.g. methylene 
chloride, ethylene chloride or chlorobenzene, and dialkylformamides, e.g. 
dimethylformamide. 
Advantageously, the reaction is carried out in the presence of an acid 
acceptor. Suitable acid acceptors are weak inorganic bases, e.g. sodium 
carbonate, potassium carbonate, sodium bicarbonate or potassium 
bicarbonate, or organic bases, e.g. tertiary amines. 
A possible method for the preparation of the novel compounds in which A is 
alkoxycarbonyl comprises esterifying a compound I, in which A is carboxyl, 
in a conventional manner. The esterification is advantageously carried out 
in an excess of the alcohol as a solvent. 
The novel compounds (I) in which A is hydroxyl can be obtained by 
hydrolyzing an ester. 
The novel compounds (I), in which A is an alkylsulfonyloxy group 
--O--SO.sub.2 --R.sup.4 or a carbamic acid ester group --O--CO--NHR.sup.4 
can be obtained from one of the above alcohols in a conventional manner, 
i.e. in a reaction with an alkanesulfonyl halide R.sup.4 --SO.sub.2 --Hal 
or with an alkanesulfonic anhydride (SO.sub.2 R.sup.4).sub.2 O, or from an 
isocyanate R.sup.4 --N.dbd.C.dbd.O in a conventional manner. 
In accordance with process (b), the radical X can be exchanged for an 
alkoxy or alkylmercapto radical by reaction with a suitable alcohol or a 
suitable alkylmercaptan in the presence of an auxiliary base as an acid 
acceptor, under conventional conditions, for example using not less than 
equimolar amounts of the reagent and of the auxiliary base, advantageously 
in the presence of a solvent, at from 0.degree. to 80.degree. C., if 
appropriate at the boiling point of the reaction mixture, and if 
appropriate under superatmospheric pressure. 
Suitable solvents are those which are inert under the reaction conditions, 
for example aromatic hydrocarbons, such as toluene, aliphatic or aromatic 
chlorohydrocarbons, such as methylene chloride, ethylene chloride or 
chlorobenzene, ketones, such as acetone or methyl ethyl ketone, or 
dialkylformamides, such as dimethylformamide. The reagent itself may also 
be employed as the solvent. 
Auxiliary bases as acid acceptors are advantageously inorganic bases, e.g. 
sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate 
or potassium bicarbonate, or tertiary organic amines, e.g. triethylamine. 
The exchange of the radical X for an alkoxy radical can also be effected by 
reaction with a suitable sodium alcoholate or potassium alcoholate in a 
conventional manner, for example using not less than an equimolar amount 
of the alcoholate, in a solvent, i.e. in the corresponding alcohol or in a 
solvent which is inert under the reaction conditions, such as an aromatic 
hydrocarbon, e.g. toluene, an open-chain or cyclic aliphatic ether, e.g. 
diethyl ether, tetrahydrofuran or dioxane, or a dialkylformamide, e.g. 
dimethylformamide, at from 0.degree. to 100.degree. C., if appropriate at 
the boiling point of the reaction mixture, and if appropriate under 
superatmospheric pressure. 
The radical X can be exchanged for a nitrile group by treatment with sodium 
cyanide or potassium cyanide, either in a suitable solvent, for example a 
lower alcohol, such as methanol, ethanol, propanol, dimethylformamide, or 
a mixture of water with one of the above lower alcohols, or in a two-phase 
system comprising water and a water-immiscible solvent, such as an 
aromatic hydrocarbon, e.g. toluene, or an aliphatic or aromatic 
chlorohydrocarbon, e.g. methylene chloride, ethylene chloride or 
chlorobenzene. In the lastmentioned procedure, i.e. the phase-transfer 
method, it is advantageous to add an appropriate catalyst, such as a 
quaternary ammonium halide, e.g. tetrabutylammonium iodide. 
The compounds (IV) used as starting materials are known, or can be prepared 
under the conditions described in German Laid-Open Application Nos. DOS 
2,727,481 and DOS 2,854,475. 
The cyclization reaction (c) with hydrazine, which is preferably employed 
as the hydrate, is advantageously carried out in a solvent, in particular 
a lower alcohol, e.g. methanol, ethanol or propanol, a cyclic ether, e.g. 
tetrahydrofuran or dioxane, or dimethylformamide, at from 50.degree. to 
150.degree. C., preferably from 80.degree. to 100.degree. C. In this 
procedure, as a rule 1 mole of hydrazine or hydrazine hydrate is used per 
mole of (V). 
The compounds (V) are obtained when an amino acid (VI) 
##STR7## 
where R and R.sup.1 have the above meanings, is acylated with III. 
The compounds of the formulae II and VI which are used as starting 
materials are known (cf. German Laid-Open Application Nos. DOS 1,670,158, 
DOS 2,150,436 and DOS 2,854,475, and U.S. Pat. Nos. 3,824,271 nd 
3,888,901), or can be prepared under the conditions described in U.S. Pat. 
Nos. 3,324,271 and 3,888,901. 
Typical examples of compounds which are obtained by the above processes are 
6-[p-(2-acetoxyacetylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone 
, 6-[p-(2-propionyloxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyrid 
azinone, 
6-[p-(2-acetoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazi 
none, 6-[p-(2-acetoxybutyrylamino]-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 
6-[p-(2-acetoxyacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-propionyloxyacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-acetoxypropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-acetoxybutyrylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-hydroxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinon 
e, 
6-[p-(2-hydroxybutyrylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinon 
e, 6-[p-(2-hydroxyacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-hydroxypropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-hydroxybutyrylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-methoxy- 
2-methylpropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 
6-[p-(2-methoxyacetylamino)-phenyl] -4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-methoxy-2-methylpropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazi 
none, 6-[p-(2-methoxybutyrylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-ethoxypropionylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazino 
ne, 
6-[p-(2-ethoxy-2-methylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazin 
one, 
6-[p-(2-ethoxybutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinon 
e, 6-[p-(2-ethoxyacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-ethoxypropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-ethoxy-2-methylpropionylamino)phenyl]-4,5-dihydro-3(2H)-pyridazino 
ne, 6-[p-(2-ethoxybutyrylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-propoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazi 
none, 6-[p-(2-propoxypropionylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-methylmercaptopropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-p 
yridazinone, 
6-[p-(2-methylmercapto-2-methylpropionylamino)-phenyl]-4,5-dihydro-5-methy 
l-3(2H)-pyridazinone, 6-[ 
p-(2-methylmercaptobutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyrida 
zinone, 
6-[p-(2-methylmercaptoacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-methylmercaptopropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazino 
ne, 
6-[p-(2-methylmercapto-2-methylpropionylamino)-phenyl]-4,5-dihydro-3(2H)-p 
yridazinone, 
6-[p-(2-methylmercaptobutyrylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone 
, 6-[p-(2-ethylmercaptoacetylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-ethylmercaptopropionylamino-phenyl]-4,5-dihydro-3(2H)-pyridazinone 
, 6-[p-(2-ethylmercapto-2-methylpropionylamino)-phenyl]-4,5-dihydro-3(2H)-p 
yridazinone, 
6-[p-(2-ethylmercaptobutyrylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-ethylmercaptoacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyrid 
azinone, 
6-[p-(2-ethylmercaptopropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-py 
ridazinone, 
6-[p-(2-ethylmercapto-2-methylpropionylamino)phenyl]-4,5-dihydro-5-methyl- 
3(2H)-pyridazinone, 
6-[p-(2-ethylmercaptobutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyri 
dazinone, 
6-[p-(2-cyano-2-methylpropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-p 
yridazinone, 
6-[p-(2-cyano-2-methylpropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazino 
ne, 6-[p-(2-cyanobutyrylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-carboxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinon 
e, 
6-[p-(2-carboxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazi 
none, 6-[p-(2-carboxyacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-carboxypropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-methoxycarbonylpropionylamino)-phenyl]-4,5 
-dihydro-5-methyl-3(2H)-pyridazinone, 
6-[p-(2-methoxycarbonylacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone 
, 6-[p-(2-methoxycarbonylpropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazi 
none, 
6-[p-(2-methylsulfonyloxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-p 
yridazinone, 
6-[p-(2-methylsulfonyloxyacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazino 
ne, 
6-[p-(2-methylsulfonyloxypropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridaz 
inone, 
6-[p-(2-methylaminocarbonyloxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3( 
2H)-pyridazinone, 6-[p-(2-methylaminocarbonyloxyacetylamino)-phenyl] 
-4,5-dihydro-3(2H)-pyridazinone, 
6-[p-(2-methylaminocarbonyloxypropionylamino)-phenyl]-4,5-dihydro-3(2H)-py 
ridazinone, 
6-[p-(2-ethylaminocarbonyloxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2 
H)-pyridazinone, 
6-[p-(2-ethylaminocarbonyloxyacetylamino)-phenyl]-4,5-dihydro-3(2H)-pyrida 
zinone, 
6-[p-(2-ethylaminocarbonyloxypropionylamino)-phenyl]-4,5-dihydro-3(2H)-pyr 
idazinone, 
6-[p-(2-ethylaminocarbonyloxypropionylamino)-phenyl]-4,5-dihydro-5-methyl- 
3(2H)-pyridazinone, 
2-[p-(2-acetoxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one 
, 2-[p-(2-propionyloxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en 
-5-one, 
2-[p-(2-propionyloxypropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2- 
en-5-one, 
2-[p-(2-acetoxybutyrylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-on 
e, 
2-[p-(2-acetoxybutyrylamino)-phenyl]-3,4-diazabicyclo-[4.1.0]hept-2-en-5-o 
ne, 
2-[p-(2-hydroxyacetylamino)phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one, 
2-[p-(2-hydroxypropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]-hept-2-en-5 
-one, 2-[p-( 
2-hydroxybutyrylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one, 
2-[p-(2-methoxypropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5- 
one, 
2-[p-(2-methoxy-2-methylpropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hep 
t-2-en-5-one, 
2-[p-(2-methoxybutyrylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-on 
e, 
2-[p-(2-ethoxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one, 
2-[p-(2-ethoxypropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-o 
ne, 2-[p-(2-ethoxy-2-methylpropionylamino)-phenyl]-3,4-diazabicyclo[ 
4.1.0]hept-2-en-5-one, 
2-[p-(2-ethoxybutyrylamino)-phenyl]-3,4-diazabicyclo[4.1.0]-hept-2-en-5-on 
e, 
2-[p-(2-methylmercaptoacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-e 
n-5-one, 
2-[p-(2-methylmercaptopropionylamino)-phenyl]-3,4-diazabicyclo-[4.1.0]hept 
-2-en-5-one, 
2-[p-(2-methylmercapto-2-methyl-propionylamino)-phenyl]-3,4-diazabicyclo[4 
.1.0]hept-2-en-5-one, 
2-[p-(2-methylmercaptobutyrylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2- 
en-5-one, 
2-[p-(2-ethyl-mercaptoacetylamino)phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en 
-5-one, 
2-[p-(2-ethylmercaptopropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2 
-en-5-one, 
2-[p-(2-ethylmercapto-2-methylpropionylamino)-phenyl]-3,4-diazabicyclo-[4. 
1.0]hept-2-en-5-one, 
2-[p-(2-ethylmercaptobutyrylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-e 
n-5-one, 
2-[p-(2-cyano-2-methylpropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept- 
2-en-5-one, 
2-[p-(2-cyanobutyrylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5 
-one, 2-[p-(2-carboxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en 
-5-one, 
2-[p-(2-carboxypropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5- 
one, 
2-[p-(2-methoxycarbonylacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2- 
en-5-one, 
2-[p-(2-methoxycarbonylpropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept 
-2-en-5-one, 
2-[p-(2-ethoxycarbonylacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-e 
n-5-one, 
2-[p-(2-ethoxycarbonylpropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept- 
2-en-5-one, 
2-[p-(2-methylsulfonyloxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept- 
2-en-5-one, 
2-[p-(2-methylsulfonyloxypropionylamino)-phenyl]-3,4-diazabicyclo[4.1.0]he 
pt-2-en- 5-one, 
2-[p-(2-methylaminocarbonyloxyacetylamino)phenyl]-3,4-diazabicyclo[4.1.0]h 
ept-2-en-5-one, 
2-[p-(2-methylaminocarbonyloxypropionylamino)-phenyl]-3,4-diazabicyclo[4.1 
.0]hept-2-en-5-one, 
2-[p-(2-ethyl-aminocarbonyloxyacetylamino)-phenyl]-3,4-diazabicyclo-[4.1.0 
]hept-2-en-5-one and 
2-[p-(2-ethylaminocarbonyloxy-propionylamino)-phenyl]-3,4-diazabicyclo[4.1 
.0]hept-2-en-5-one. 
The compounds I in which R is hydrogen (4,5-dihydro-3(2H)-pyridazinones) 
possess an asymmetric carbon atom in the 5-position, and are therefore 
usually obtained in the form of their racemates. The invention also 
relates to the enantiomers; these are advantageously isolated in a 
conventional manner as early as the stage of compound (II), provided that 
in this compound R is hydrogen, for example by formation of diastereomeric 
salts with an optically active carboxylic acid, e.g. dibenzoyltartaric 
acid or camphor-10-sulfonic acid, and the optically active intermediates 
are converted separately to the desired enantiomers. 
Owing to the presence of the asymmetric carbon atoms 1 and 6 of the 
3,4-diazabicyclo[4.1.0]hept-2-en-5-one ring, the compounds I in which R 
and R.sup.1 together are methylene(3,4-diazabicyclo[4.1.0]-heptenones 
likewise form racemates. The invention also relates to the enantiomers 
obtainable from these. 
Corresponding statements apply where the meaning of A differs from that of 
B. 
The novel dihydropyridazinones of the formula (I) inhibit thrombocyte 
aggregation and possess hypotensive properties. They are suitable as 
antihypertensive agents and for the prophylaxis and therapy of thrombotic 
disorders. 
The following methods were used to examine the pharmacodynamic properties 
of the products according to the invention: 
1. Inhibition of the collagen-induced aggregation of rat thrombocytes ex 
vivo. 
The substances are administered orally to groups of 10-15 male 
Sprague-Dawley rats weighing 200-250 g. 1 hour after administration, blood 
is taken under ether anesthesia, and thrombocyte-rich plasma is obtained 
by centrifuging. The photometric measurement of the thrombocyte 
aggregation is carried out with addition of MgCl.sub.2 (final 
concentration 10 millimoles/liter) and of collagen Stago (final 
concentration 0.02 mg/ml) in a Born Mk3 aggregometer. The maximum 
extinction change per second is used as a measure of the aggregation. 
The ED 33% is determined at the dose which inhibits the collagen-induced 
thrombocyte aggregation by 33%. 
2. Antihypertensive effect on spontaneously hypertonic rats. 
The substances are administered orally to groups of 4-8 male spontaneously 
hypertonic Okamoto rats weighing 270-340 g. Before, and 2 hours after, the 
administration, the systolic blood pressure is measured nonsurgically by 
means of piezoelectric crystal sensors. 
The ED 20% is determined at the dose which lowers the systolic pressure by 
20%, taking into account the values found with untreated control animals. 
The effective doses were calculated from the linear relationships between 
the logarithm of the dose and the logarithm of the effect, by means of 
regression analysis. 
Amipizone 
(6-[p-(2-chloropropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazi 
none, German Laid-Open Application No. DOS 2,727,481) was used as the 
reference substance for the inhibition of thrombocyte aggregation and the 
hypotensive action. 
The experiments showed (cf. Table 1) that the novel compounds, when 
administered orally, possess an antihypertensive action and inhibit the 
aggregation of thrombocytes. The antihypertensive effect is observed for 
doses which are from 1.2 to 6.7 times smaller than in the case of the 
reference substance Amipizone. In respect of the inhibition of thrombocyte 
aggregation, the effect of the novel substances is superior to that of the 
reference substance by a factor of 1.4. 
TABLE 1 
______________________________________ 
Inhibition of thrombocyte aggregation and anti- 
hypertensive effect after oral administration 
Inhibition of Anti- 
thrombocyte hypertensive 
Example aggregation.sup.1 
action.sup.2 
No. Ed 33% R.E. ED 20% R.E. 
______________________________________ 
2 &gt;10 &lt;0.063 0.42 2.86 
3 1.8 0.35 1.0 1.20 
5 0.85 0.74 0.36 3.33 
10 5.4 0.12 1.0 1.20 
13 3.0 0.21 0.18 6.67 
14 0.45 1.40 &gt;1.0 -- 
15 0.54 1.12 0.46 2.61 
Amipizone 0.63 1.00 1.2 1.00 
______________________________________ 
.sup.1 Rat, oral administration; ED 33% = dose which inhibits the 
collageninduced aggregation by 33%; R.E. = relative effect; Amipizone = 
1.00. 
.sup.2 Spontaneously hypertonic rat, oral administration; ED 20% (mg/kg) 
dose which reduces the blood pressure in comparison with the control grou 
by 20%; R.E. Amipizone = 1.00. 
Accordingly, the present invention also relates to therapeutic agents or 
formulations which in addition to conventional pharmaceutical carriers and 
diluents contain a compound of the formula I as the active compound, and 
the use of these compounds for therapeutic purposes in the treatment of 
high blood pressure or thrombo-embolic disorders. 
The therapeutic agents or formulations are prepared in a conventional 
manner, using an appropriate dose with the conventional pharmaceutical 
carriers or diluents and the conventional pharmaceutical auxiliaries, in 
accordance with the desired route of administration. Suitable daily doses 
for humans are from 1 to 100, preferably from 5 to 50, mg per patient for 
oral administration, and from 0.1 to 10, preferably from 0.5 to 5, mg per 
patient for parenteral administration. Oral administration is preferred. 
Examples of formulations which are suitable for oral administration are 
tablets, film tablets, coated tablets, capsules, pills, powders, 
solutions, suspensions and depot forms. 
For practical use, the compounds employed according to the invention are 
formulated with the carriers conventionally used in pharmaceutical 
production. For example, appropriate tablets can be obtained by mixing the 
active compound with conventional auxiliaries, for example inert diluents, 
such as dextrose, sugar, sorbitol, polyvinylpyrrolidone, mannitol, calcium 
carbonate, calcium phosphate or lactose, desintegrating agents, e.g. corn 
starch, alginic acid or polyvinylpyrrolidone, binders, e.g. starch or 
gelatine, lubricants, e.g. magnesium stearate or talc, and/or agents for 
achieving a depot effect, e.g. carboxypolymethylene, 
carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. 
The tablets can also consist of a plurality of layers. 
Accordingly, coated tablets may be prepared by coating cores, prepared 
similarly to the tablets, with agents conventionally used in tablet 
coatings, e.g. collidone, shellac, gum arabic, talc, titanium dioxide or 
sugar. The tablet shell can also consist of a plurality of layers, in 
which the auxiliaries mentioned above in connection with tablets may be 
used.

EXAMPLE 1 
20.3 g (100 millimoles) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 18.0 g (120 millimoles) of 2-acetoxypropionyl chloride and 400 ml of 
absolute acetone for 10 hours at room temperature. The product was 
filtered off under suction at 10.degree. C., washed with cold acetone and 
dried at 70.degree. C. under reduced pressure. 28.1 g (88.6%) of 
6-[p-(2-acetoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazi 
none were obtained. Mp.: 198.degree.-200.degree. C. 
(dimethylformamide/water). 
EXAMPLE 2 
6.13 g (19.3 millimoles) of 
6-[p-(2-acetoxypropionylamino]-4,5-dihydro-5-methyl-3(2H)-pyridazinone 
(see Example 1) were dissolved in 20 ml of methanol. The solution was 
poured into 60 ml of 1N NaOH, the mixture was stirred for 20 minutes at 
room temperature, the pH was brought to 6 with 2N HCl, 100 ml of water 
were added and after 2 hours the product was filtered off under suction 
and dried at 60.degree. C. under reduced pressure. 3.7 g (69.8%) of 
6-[p-(2-hydroxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazi 
none were obtained. Mp.: 181.degree.-182.degree. C. (n-propanol). 
EXAMPLE 3 
6.0 g (29.5 millimoles) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 3.9 g (35.9 
millimoles) of methoxyacetyl chloride in 150 ml of absolute 
tetrahydrofuran were refluxed for 2 hours, while stirring. The product was 
filtered off under suction at 10.degree. C., washed with water and 
recrystallized from dimethylformamide/water. 3.6 g (44%) of 
6-[p-(methoxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone 
were obtained as colorless crystals. Mp.: 212.degree. C. 
EXAMPLE 4 
20.3 g (107 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone 
were stirred with 14.7 g (0.12 mole) of 2-methoxypropionyl chloride and 
400 ml of absolute acetone for 10 hours at room temperature. The product 
was filtered off under suction at 10.degree. C., washed with cold acetone 
and dried at 70.degree. C. under reduced pressure. 20.8 g (76%) of 
6-[p-(2-methoxypropionylamino)-phenyl]4,5-dihydro-3(2H)-pyridazinone were 
obtained. Mp.: 245.degree.-247.degree. C. 
EXAMPLE 5 
5.0 g (24.6 millimoles) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 3.6 g (29.4 
millimoles) of 2-methoxypropionyl chloride in 150 ml of absolute 
tetrahydrofuran were refluxed for 2 hours, while stirring. The mixture was 
evaporated down, the residue was stirred with water and the product was 
filtered off under suction, washed with water, dried, and recrystallized 
from propanol. 4.0 g (56%) of 
6-[p-(2-methoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazi 
none were obtained as colorless crystals. Mp.: 193.degree.-194.degree. C. 
EXAMPLE 6 
20.3 g (0.1 mole) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 18.1 g (0.12 mole) of 2-methoxybutyryl chloride and 10.1 g (0.1 mole) 
of triethylamine in 200 ml of absolute acetone for 3 hours at room 
temperature. 100 g of ice were added, the crystals were filtered off under 
suction and recrystallized from dimethylformamide/water, and the resulting 
product was dried at 50.degree. C. under greatly reduced pressure. 18.9 g 
(63%) of 
6-[p-(2-methoxybutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazino 
ne were obtained. Mp.: 151.degree.-152.degree. C. 
EXAMPLE 7 
6.0 g (29.8 millimoles) of 2-(p-aminophenyl)- 
3,4-diazabicyclo[4.1.0]hept-2-en-5-one and 3.9 g (35.9 millimoles) of 
methoxyacetyl chloride in 150 ml of absolute tetrahydrofuran were refluxed 
for 4 hours, while stirring. The product was filtered off under suction at 
10.degree. C., washed first with tetrahydrofuran and then with water and 
recrystallized from propanol. 3.5 g (43%) of 
2-[p-(methoxyacetylamino)-phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one 
were obtained as colorless crystals. Mp.: 206.degree. C. 
EXAMPLE 8 
20.3 g (0.1 mole) of 
6-(p-aminophenyl)-4,5-dihydro5-methyl-3(2H)-pyridazinone were stirred with 
14.7 g (0.12 mole) of ethoxyacetyl chloride and 400 ml of absolute acetone 
for 10 hours at room temperature. The product was filtered off under 
suction at 10.degree. C., washed with cold acetone and dried at 70.degree. 
C. under reduced pressure. 14.8 g (51%) of 
6-[p-(ethoxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone 
were obtained. Mp.: 195.degree.-197.degree. C. 
EXAMPLE 9 
13.75 g (50 millimoles) of 
6-[p-(2-hydroxyproionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazio 
ne were stirred with 3.1 g (55 millimoles) of methyl socyanate and 250 ml 
of absolute tetrahydrofuran for 5 ours at room temperature, with the 
addition of 0.2 ml of riethylamine. The solvent was removed, after which 
the esidue was partitioned between ethyl acetate and water, he organic 
phase was separated off, dried and evaporated own, and the residue was 
recrystallized from dimethylformamide/water. 16.6 g (69%) of 
6-[p-(2-methylaminocarbonyloxypropionylamino)-phenyl]-4,5-dihydro-5-methyl 
3(2H)-pyridazinone were obtained. Mp.: 96.degree.-98.degree. C. 
EXAMPLE 10 
27.5 g (135 millimoles) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 13.7 g (0.12 mole) of methanesulfonyl chloride and 400 ml of absolute 
acetone for 10 hours at room temperature. The product was filtered off 
under suction at 10.degree. C., washed with cold acetone and dried at 
70.degree. C. under reduced pressure. 24 g (95%) of 
6-[p-(2-methylsulfonyloxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H 
)-pyridazinone were obtained. Mp.: 110.degree.-112.degree. C. 
EXAMPLE 11 
20.3 g (0.1 mole) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 14.9 g (0.12 mole) of 2-methylmercaptoacetyl chloride and 400 ml of 
absolute acetone for 10 hours at room temperature. The product was 
filtered off under suction at 10.degree. C., washed with cold acetone and 
dried at 70.degree. C. under reduced pressure. 12.5 g (43%) of 
6-[p-(2-methylmercaptoacetylamino)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyrid 
azinone were obtained. Mp.: 220.degree.-222.degree. C. 
EXAMPLE 12 
5.9 g (57.0 millimoles) of cyanoacetyl chloride were added dropwise to 6.0 
g (31.7 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone in 
150 ml of absolute tetrahydrofuran at room temperature, while stirring. 
After the addition was complete, stirring was continued for a further 10 
minutes at 50.degree. C. The product was filtered off under suction at 
10.degree. C., washed first with tetrahydrofuran and then with water and 
recrystallized from dimethylformamide/water. 4.4 g (54%) of 
6-[p-(cyanoacetylamino)-phenyl]-4.5,-dihydro-3(2H)-pyridazinone were 
obtained as pale beige crystals. Mp.: 270.degree. C. (decomposition). 
EXAMPLE 13 
5.5 g (53.1 millimoles) of cyanoacetyl chloride were added dropwise to 6.0 
g (29.5 millimoles) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 150 ml of 
absolute tetrahydrofuran at room temperature, while stirring. After the 
addition was complete, stirring was continued for a further 10 minutes at 
50.degree. C. The product was filtered off under suction at 10.degree. C., 
washed first with tetrahydrofuran and then with water and recrystallized 
from dimethylformamide/water. 2.2 g (27%) of 
6-[p-(cyanoacetylamino)-phenyl]-4,5-dihydro-5-methyl3(2H)-pyridazinone. 
0.5 H.sub.2 O were obtained as colorless crystals. Mp.: 263.degree. C. 
(decomposition). 
EXAMPLE 14 
18.9 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone were 
stirred with 16.0 g (0.12 mole) of 2-cyanopropionyl chloride and 10.1 g 
(0.1 mole) of triethylamine in 200 ml of absolute acetone for 3 hours at 
room temperature. 100 g of ice were added, after which the pale yellow 
crystals were filtered off under suction, and the product was 
recrystallized from dimethylformamide/water. 19.0 g (70.3%) of 
6-[p-(2-cyanopropionylamino)-phenyl-]- 4,5-dihydro-3(2H)-pyridazinone. 
0.25 H.sub.2 O were obtained as colorless crystals. Mp.: 
235.degree.-238.degree. C. 
EXAMPLE 15 
20.3 g (0.1 mole) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 16.0 g (0.12 mole) of 2-cyanopropionyl chloride and 10 g (0.1 mole) 
of triethylamine in 200 ml of absolute acetone for 3 hours at room 
temperature. 100 g of ice were added, after which an oil/crystal mixture 
was obtained. The product was recrystallized from dimethylformamide/water, 
and 18.6 g (65.5%) of 
6-[p-(2-cyanopropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazino 
ne. 0.2 H.sub.2 O were obtained as pale yellow crystals. Mp.: 
130.degree.-132.degree. C. 
EXAMPLE 16 
20.3 g (0.1 mole) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 15.8 g (0.12 mole) of 2-cyanobutyryl chloride and 10.1 g (0.1 mole) 
of triethylamine in 200 ml of absolute acetone for 3 hours at room 
temperature. 100 g of ice were added, after which the crystals were 
filtered off under suction, and the product was recrystallized from 
dimethylformamide/water and dried at 50.degree. C. under greatly reduced 
pressure. 14.9 g (50%) of 
6-[p-(2-cyanobutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone 
were obtained. Mp.: 225.degree.-227.degree. C. 
EXAMPLE 17 
20.3 g (0.1 mole) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 15.8 g (0.12 mole) of 2-cyano-2-methylpropionyl chloride in 100 ml of 
pyridine for 3 hours at 0.degree. C. 100 g of ice were added, after which 
the crystals were filtered off under suction, and the product was 
recrystallized from dimethylformamide/water and dried at 50.degree. C. 
under greatly reduced pressure. 20.5 g (57%) of 
6-[p-(2-cyano-2-methylpropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-p 
yridazinone were obtained. Mp.: 225.degree.-227.degree. C. 
EXAMPLE 18 
5.6 g (54.1 millimoles) of cyanoacetyl chloride were added dropwise to 6.0 
g (29.8 millimoles) of 
2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one in 150 ml of 
absolute tetrahydrofuran at room temperature, while stirring. After the 
addition was complete, stirring was continued for a further 10 minutes at 
50.degree. C. The product was filtered off under suction at 10.degree. C., 
washed first with tetrahydrofuran and then with water and recrystallized 
from dimethylformamide/water. 3.6 g (44%) of 
2-[p-(cyanoacetylamino)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one 
hemihydrate were obtained as pale beige crystals. Mp.: 284.degree. C. 
(decomposition). 
EXAMPLE 19 
20.1 g (0.1 mole) of 
2-(p-aminophenyl)-3,4-diazabicyclo[4.1.0]hept-2-en-5-one were refluxed 
with 16.0 g (0.12 mole) of 2-cyanopropionyl chloride and 10.1 g (0.1 mole) 
of triethylamine in 200 ml of absolute acetone for 3 hours, while 
stirring. 100 g of ice were added, after which the crystals were filtered 
off under suction and the product was recrystallized from 
dimethylformamide/water. 24.2 g (85.2%) of 
2-[p-(2-cyanopropionylamino)-phenyl]- 
3,4-diazabicyclo[4.1.0]hept-2-en-5-one. 0.25 H.sub.2 O were obtained. Mp.: 
238.degree.-240.degree. C. 
EXAMPLE 20 
20.3 g (100 millimoles) of 
6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred 
with 16.4 g (120 millimoles) of methyl chloroformylacetate and 400 ml of 
absolute acetone for 10 hours at room temperature. The product was 
filtered off under suction at 10.degree. C., washed with cold acetone and 
dried at 70.degree. C. under reduced pressure. 15.6 g (52%) of 
6-[p-(methoxycarbonylacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyrid 
azinone were obtained. Mp.: 228.degree.-230.degree. C. 
EXAMPLE 21 
2.9 g (0.01 mole) of 
6-[p-(2-chloropropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazin 
one in 10 g of dimethylformamide were stirred with 2.64 g (0.02 mole) of 
potassium cyanide for 4 hours at 80.degree. C., the reaction mixture was 
cooled to room temperature and then poured onto 100 g of ice, the crystals 
formed were filtered off under suction, and the product was recrystallized 
from ethanol. 1.9 g (67%) of 
6-[p-(2-cyanopropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazino 
ne. 0.2 H.sub.2 O were obtained. Mp.: 130.degree.-132.degree. C. 
FORMULATION EXAMPLES 
______________________________________ 
1. Tablets 
______________________________________ 
Active compound 10 mg 
Polyvinylpyrrolidone (mean molecular weight 
170 mg 
25,000) 
Polyethylene glycol (mean molecular weight 4,000) 
14 mg 
Hydroxypropylmethylcellulose 
40 mg 
Talc 4 mg 
Magnesium stearate 2 mg 
240 mg 
______________________________________ 
The active compound was moistened with a 10% strength aqueous solution of 
polyvinylpyrrolidone, and forced through a sieve of 1.0 mm mesh size, and 
the granules were dried at 50.degree. C. They were then mixed with 
polyethylene glycol (mean molecular weight 4,000), 
hydroxypropylmethylcellulose, talc and magnesium stearate, and the mixture 
was pressed to give tablets weighing 250 mg. 
______________________________________ 
2. Coated tablets 
______________________________________ 
Active compound 10 mg 
Lactose 90 mg 
Corn starch 60 mg 
Polyvinylpyrrolidone 6 mg 
Magnesium stearate 1 mg 
167 mg 
______________________________________ 
The active compound, lactose and corn starch were mixed, moistened with an 
8% strength aqueous solution of the polyvinylpyrrolidone, and granulated 
by being passed through a 1.5 mm mesh sieve. The granules were dried at 
50.degree. C., and were forced through a 1.0 mm sieve. The grannules thus 
obtained were mixed with magnesium stearate, and the mixture was pressed 
to form cores. These were coated in a conventional manner with a shell 
consisting essentially of sugar and talc.