Piperazinyl carbonyl phenyl pyridazinone derivatives useful as c

Details Piperazinyl carbonyl phenyl pyridazinone derivatives useful as c Piperazinyl carbonyl phenyl pyridazinone derivatives useful as c

1987-03-31

1989-04-18

Berch, Mark L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544238, C07D40310, C07D40514, A61K 3150

Patent

active

048227978

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION

This invention relates to novel pyridazinone derivatives or salts thereof which are useful as cardiotonic and also have vasodilative activity and blood pressure depressing activity.


BACKGROUND OF THE INVENTION

A cardiotonic directly acts on a heart to enhance the contraction thereof and various pharmaceutical drugs have been used in the treatment of cardiac insufficiency.
However, many of these cardiotonics have defects in that their safety margin is extremely narrow, they may cause arrhythmia, their cardiac stimulating activity is transient and they are not suitable for oral administration.
The present inventors have sought for compounds which are of high activity and capable of showing the sufficiently sustained activity as the cardiotonic and have discovered the present invention.


DISCLOSURES OF THE INVENTION

The gist of the present invention resides in pyridazinone derivatives represented by the following general formula (I): ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 represent a hydrogen atom, hydroxy group or alkoxy group of not more than 5 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc., or two of R.sub.1, R.sub.2 and R.sub.3 may be combined together to form a group of --O--CH.sub.2 --O-- or --O--CH.sub.2 --CH.sub.2 --O--, R.sub.4 represents an alkyl group, preferably, an alkyl group of not more than 5 carbon atoms, n represents an integer of 0 to 4 and the dotted line represents a single or double bond, or salts thereof.


BEST EMBODIMENTS OF THE INVENTION

The present invention will be explained more in detail hereinafter.
A pyridazinone derivative according to the present invention may be prepared, for example, by the following reaction route: ##STR3## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 as well as the dotted line are as defined hereinabove.
That is, the compound of the general formula (I) may be produced by an usual amide coupling between the carboxylic acid (II) or derivative thereof and the amine (III).
For instance, there can be mentioned (A) a mixed acid anhydride method, that is, a method of reacting an alkyl halocarboxylic acid with the carboxylic acid (II) to obtain a mixed acid anhydride and then reacting with the amine (III), (B) a carbodiimide method, that is, a method of condensing the carboxylic acid (II) with the amine (III) under the presence of a dehydrating agent such as dicyclohexyl carbodiimide and, in addition, (C) a caboxylic acid halide method, active ester method and the like, the mixed acid anhydride method above being preferred among them.
The mixed acid anhydride may be prepared by reacting the carboxylic acid (II) with the alkyl halocarboxylic acid under the presence of a basic compound (organic base such as triethylamine, pyridine and diazabicycloundecene (DBU); or inorganic salt such as potassium carbonate and sodium carbonate) in a solvent conventionally used for the mixed acid anhydride mehod, for example, tetrahydrofuran, dioxane, toluene, chloroform, ethyl acetate, dimethy formamide and dimethyl acetoamide or a mixed solvent thereof.
The reaction temperature is of about -20.degree. C. to 100.degree. C. and the reaction time is of about 5 minutes to 10 hours. The resultant mixed acid anhydride may directly be reacted with the amine (III) without further isolation. The reaction with the amine is taken place at -20.degree. C. to 100 .degree. C. for about 5 minutes to 10 hours.
The carboxylic acid (II) is a known compound as disclosed in Journal of Medicinal Chemistry, Vol 17, p. 281 -286 (1974). The amine (III) is a well known piperazine derivative.
As the pyridazinone derivative according to the present invention obtained by the reaction as described above, there can be mentioned, for example, the following compound: ##STR4##
Though the compounds indicatively exemplified in the foregoing have the methyl group as the substituent R.sub.4, the compounds in which R.sub.4 is an ethyl, propyl, butyl, pentyl group or the like are also included within the compounds according to the present inv

REFERENCES:
patent: 4631279 (1986-12-01), Robertson
patent: 4636504 (1987-01-01), Rossy et al.
patent: 4639451 (1987-01-01), Katakami et al.
Medicinal Chemistry, Alfred Burger, Interscience Publishers Inc., p. 42.

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