Benzo[h]cinnoline compound, a method of preparing said compound

Details Benzo[h]cinnoline compound, a method of preparing said compound Benzo[h]cinnoline compound, a method of preparing said compound

1986-03-25

1988-11-01

Daus, Donald G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544234, 562462, 562490, 568328, C07D23736, A61K 3150

Patent

active

047820578

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE ART

The present invention relates to novel and pharmaceutically useful benzo[h]cinnoline compounds, methods of preparing said compounds and pharmaceutical compositions containing said compounds.


PRIOR ART

Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 14, p. 262 (1971) discloses 2-substituted-benzo[h]cinnolin-3(2H)-ones. This literature reports that all the compounds were found to be devoid of significant biological activity, although all the compounds were evaluated for analgesic, hypotensive, antiinflammatory, and CNS activities.
European Patent Application No. 124314 discloses 3H-indeno-pyridazin-3-one derivatives with cardiotonic and antihypertensive activities.


DISCLOSURE OF THE INVENTION

The present inventors have made intensive studies in order to develop useful drugs. As a result of such investigations, the present inventors have found that novel benzo[h]cinnoline compounds have potent affinity for benzodiazepine receptor and antianxiety activity. The present invention, relates to benzo[h]cinnoline compounds represented by the formula: ##STR2##
In the formula, each of X and Y is hydrogen, halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, hydroxy, alkyl having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl or isobutyl), alkoxy having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, propoxy or butoxy), amino, alkanoylamido having 2 to 4 carbon atoms (e.g. acetamido, propionamido or butyrylamido), nitro, cyano, alkanoyl having 2 to 4 carbon atoms (e.g. acetyl, propionyl or butyryl); Ar is phenyl or pyridyl which may be optionally substituted by at least one substituent selected from the group consisting of halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, hydroxy, alkyl having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl or isobutyl), alkoxy having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, propoxy or butoxy), amino, alkanoylamido having 2 to 4 carbon atoms (e.g. acetamido, propionamido or butyrylamido), nitro and cyano; and the bond position indicated by dotted line is single bond or double bond.
The compounds of formula (I) of the present invention can be, for example, prepared by the following Methods 1, 2 and 3.
(1) Method 1
The compound of the formula (I) can be prepared by reacting a compound of the formula: ##STR3## wherein R is hydrogen or alkyl having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl or isobutyl) and other symbols are as defined above, with a hydrazine compound of the formula: hydrochloric acid salt), and then subjecting the thus obtained compound of the formula: ##STR4## wherein each symbol is as defined above, to a ring closure reaction.
The reaction of the compound of the formula (II) with the compound of formula (III) is carried out by refluxing under heating for 5 to 20 hours in a suitable solvent, for example, in an alcoholic solvent such as methanol, ethanol or propanol. In case the hydrazine compound of formula (III) is used as an acid addition salt, the above reaction is carried out in the presence of an acid scavenger (e.g. sodium acetate, potassium acetate, sodium hydrogencarbonate, sodium carbonate or potassium carbonate).
The ring closure reaction of the obtained compound of formula (IV) is carried out by refluxing under heating for 5 to 10 hours in acetic acid.
(2) Method 2
The compound of the formula (I), wherein the bond position indicated by dotted line is double bond, can be synthesized by adding bromine in acetic acid dropwise to the compound wherein the bond position indicated by dotted line is single bond [Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 14, p. 262 (1971)], and preferably by adding 1 to 1.5 times moles of bromine dropwise to the compound of the formula: ##STR5## wherein each symbol is as defined above, at 20.degree.-60.degree. C. in acetic acid.
The compound of the formula (I) wherein the bond position indicated by the dotted line is a double bond can also be prepared by reacting the compound wherein the bond position indicated by a d

REFERENCES:
patent: 3464988 (1969-09-01), Holava et al.
patent: 4602019 (1986-07-01), Sircar et al.
Curran, Ross; J. Med. Chem., 17, p. 273 (1974).
Cignarella et al. I, Il Farmaco, Ed. Sci., 37(2), p. 133 (1981).
Yamada et al., J. Med. Chem., 25, p. 975 (1982).
Tebib et al., Chemical Abstracts, vol. 108, No. 31317m (1988).

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