Fused pyridazine compounds

Details Fused pyridazine compounds Fused pyridazine compounds

1998-09-29

2001-04-17

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S234500, C544S119000, C544S237000

Reexamination Certificate

active

06218392

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel fused pyridazine compound. In particular, the present invention relates to a novel fused pyridazine compound which is useful as drug.
DESCRIPTION OF RELATED BACKGROUND ART
Recently, studies on compounds exhibiting inhibitory activity against cyclic GMP phosphodiesterase (hereinafter referred to as “cGMP-PDE”) have proceeded and attempts have been made to apply such compounds to the prevention and treatment of circulatory failures such as hypertension, angina pectoris and myocardial infarct.
Known examples of the compound usable in the prevention and treatment of circulatory failures include quinazoline compounds disclosed in JP-A-29582/1975, 4H-3,1-benzoxazin-4-one compounds disclosed in WO 88/09790, 1H-2,3,4,5-tetra-hydroimidazo[2,1-b)quinazolin-2-one and 1,2,3,4,5,6-hexahydropyrimido[2,1-b]quinazolin-2-one disclosed in JP-A-86894/1973, nitrogenous heterocyclic compounds disclosed in WO 93/07124 and 4-aminoquinazoline derivatives disclosed in EP 579496.
However, most of the compounds described above are not on the market and many of them have problems of solubility, in vivo dynamics and toxicity which must be solved prior to the use as drugs.
DISCLOSURE OF THE INVENTION
Under the above circumstances, the inventors of the present invention have started their studies for the purpose of finding a compound which exhibits an excellent cGMP-PDE inhibiting activity, has such a high water solubility as to be well absorbed into the living body, and is less toxic.
As a result of the studies, they have found that the above object can be attained by a fused pyridazine compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof. The present invention has been accomplished on the basis of this finding.
{wherein ring C represents a five- or six-membered ring which may contain a heteroatom;
n is an integer of 0 to 4;
R
1
represents a halogen atom, an optionally substituted lower alkyl group, optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, a nitro group, a cyano group, —NR
2
R
3
(wherein R
2
and R
3
represent each independently a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or alternatively R
2
and R
3
together with the nitrogen atom to which they are bonded may form a ring which may be substituted), —O—R
9
(wherein R
9
represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), —S—R
10
(wherein R
10
represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group),
(wherein R
11
represents a hydrogen atom, a lower alkyl group or an amino group; and m is an integer of 0 to 2), or an optionally protected carboxyl group, with the proviso that when n is 2 to 4, R
1
's represent each independently a substituent selected from among those described above;
A represents a hydrogen atom, a halogen atom, —NR
4
R
5
(wherein R
4
and R
5
represent each independently a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or alternatively R
4
and R
5
together with the nitrogen atom to which they are bonded may form a ring which may be substituted), an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group;
X represents —NR
6
— (wherein R
6
represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group) or —N═;
Y represents —CO— or —CB═ (wherein B represents a hydrogen atom, a halogen atom, —NR
7
R
8
(wherein R
7
and R
8
represent each independently a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or alternatively R
7
and R
8
together with the nitrogen atom to which they are bonded may form a ring which may be substituted), —O—R
12
(wherein R
12
represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), —S—R
13
(wherein R
13
represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group), an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group]; and the symbol {overscore (--------)}
represents a double bond or a single bond, with the proviso that the cases wherein C represents a benzene ring and n is 0) are excepted.}
In the above definition of the general formula (I), the lower alkyl group constituting the optionally substituted lower alkyl as defined with respect to R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
and R
13
may be a linear or branched lower alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl. The substituent constituting it includes a hydroxyl group, a nitro group, an amino group, a cyano group, acyl groups such as an acetyl group and a benzoyl group; lower alkoxy groups such as a methoxy group and an ethoxy group; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and an optionally protected carboxyl group. One or more of these substituents may be bonded to one or more carbon atoms of the lower alkyl group.
The lower alkoxy group constituting the optionally substituted lower alkoxy group as defined with respect to R
1
may be one derived from the above lower alkyl group, and examples thereof include a methoxy group, an ethoxy group and a propoxy group.
The substituent constituting it includes a hydroxyl group, a nitro group, an amino group, a cyano group, acyl groups such as an acetyl group and a benzoyl group; lower alkoxy groups such as a methoxy group and an ethoxy group; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and an optionally protected carboxyl group. One or more of these substituents may be bonded to one or more carbon atoms of the lower alkoxy group.
The cycloalkyl group constituting the optionally substituted cycloalkyl group as defined with respect to R
1
may be one having 3 to 8 carbon atoms, while the substituent constituting it includes a hydroxyl group, a nitro group, an amino group, a cyano group, an acyl groups such as an acetyl group and a benzoyl group; lower alkoxy groups such as a methoxy group and an ethoxy group; halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and an optionally protected carboxyl group. One or more of these substituents may be bonded to one or more carbon atoms of the cycloalkyl group.
The acyl group as defined with respect to R
2
, R
3
, R
4
, R
5
, R
7
, R
8
, R
9
, R
10
, R
12
and R
13
may be one derived from an aliphatic, aromatic or acyl group derived from heterocyclic ring, and examples thereof include lower alkanoyl groups such as a formyl group, an acetyl group, a propionyl group, a butyryl group, a valeryl group, an isovaleryl group and a pivaloyl group; aroyl groups such as a benzoyl group, a toluoyl group and a naphthoyl group; and heteroaroyl groups such as a furoyl group, a nicotinoyl group and an isonicotinoyl group. In short, the group may be one derived from a

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