Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1989-10-04
1992-05-05
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544238, 544239, 514247, 514250, C07D23726
Patent
active
051109255
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
1. Technical Field
The present invention relates to new pyridazinone derivatives and the process for the production of such compounds.
2. Background Art
Several drugs under development are known as cardiotonic drugs. The following compounds are typical examples: ##STR3##
The purpose of the present invention is to seek a new substance that has an excellent cardiotonic action and that is safe and free from side effects. It is also to offer the method in which this new substance can be manufactured in a commercially advantageous manner.
DISCLOSURE OF INVENTION
The present invention relates to a compound having the formula below, and the processes for the production of such compound: ##STR4## wherein Y represents C.sub.1-4 alkylene which may be substituted by C.sub.1-18 alkyl, C.sub.1-5 alkoxy, C.sub.1-5 alkylthio, C.sub.1-5 alkyl, C.sub.1-5 alkoxycarbonyl or benzyl, or ##STR5## (where each r.sup.1 and r.sup.2 represents hydrogen, C.sub.1-18 alkyl, C.sub.1-5 alkoxy, C.sub.1-5 alkylthio C.sub.1-5 alkyl, C.sub.1-5 alkoxycarbonyl or benzyl); and C.sub.1-5 alkoxy, acetyl or C.sub.2-5 alkenyl; and alkyl, or C.sub.1-5 alkoxy; and hydroxy; and
Compared to milrinone and CI-914, the compounds of the present invention exhibit a potent and selective inhibition of the phosphodiesterase III, have an excellent cardiotonic activity, are safe, non-toxic and orally effective, and are useful for the treatment of congestive heart failure. In addition, the compounds of the present invention inhibit a platelet aggregation and have an antithrombotic activity. The compounds of the present invention have a bronchodilatory activity and are useful for the treatment of chronic obstructive pulmonary disease such as asthma and bronchitis.
Moreover, the compounds of the present invention are useful for the treatment of various diseases (hypertension, ulcer, diabetes, cancer, etc.) which are associated with the intracellular level of cyclic AMP.
BEST MODE FOR CARRYING OUT THE INVENTION
The compounds under the present invention can be manufactured in the methods specified below.
(a) when R.sub.1 is not acetyl; ##STR6## wherein R'.sub.1 is hydrogen, C.sub.1-5 alkyl which may be substituted by C.sub.1-5 alkoxy, or C.sub.2-5 alkenyl.
The reaction is carried out in an inert organic solvent, preferably in such a solvent as benzene, toluene, xylene, a lower alcohol or DMF, in the presence of an acid catalyst, preferably such a catalyst as hydrochloric acid, sulfuric acid, acetic acid or paratoluene sulfonic acid, at room temperature or by heating to a temperature above room temperature to 200.degree. C. The reaction may be performed more efficiently if formed water is removed by such a means as azeotropic dehydration during the reaction.
(b) when R.sub.1 is acetyl: ##STR7## Wherein R".sub.1 is acetyl, and X is C.sub.1-5 alkoxy.
The reaction is carried out in an inert organic solvent, preferably in such a solvent as a lower alcohol or DMF, at room temperature or by heating to a temperature above room temperature to 200.degree. C. After the reaction is completed, a usual post-treatment gives the intended product.
The structure of the compounds of this invention has been determined from IR, NMR, MASS spectra, etc.
The compounds of this invention are expressed as pyridazinone-3(2H)-one compounds. However, the pyridazinone part can be a tautomer of pyridazinol, and if R.sub.2 is hydrogen, the cycloacetylamino part be a tautom of enol form or keto form shown below. ##STR8## In addition, if R.sub.5 is a methyl group and is a single bond in the compound of this invention, an optical isomer is present. This invention includes all these isomers.
Furthermore, each raw material having the formula (II), (III) or (IV) can be a similar tautomer.
The following Examples illustrate the present invention.
EXAMPLE 1
4,5-Dihydro-6-((4-(3-oxo-1-cyclopentenyl)amino)phenyl)-3(2H)-pyridazinone
(Compound No. 2) ##STR9##
430 mg of 4,5-dihydro-6-(4-aminophenyl)-3(2H)-pyridazinone and 220 mg of cyclopentane-1,3-dione were suspended in 4 ml of ethanol,
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Kusase You
Mochizuki Nobuo
Murakata Masatoshi
Takebayashi Michinori
Daus Donald G.
Mason, Jr. Joseph C.
Nippon Soda Co. Ltd.
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