Imidazopyridinone derivatives and their use as...

Details Imidazopyridinone derivatives and their use as... Imidazopyridinone derivatives and their use as...

2002-01-16

2003-06-24

Dentz, Bernard (Department: 1625)

Chain, staple, and horseshoe making

C546S118000

Reexamination Certificate

active

06582351

ABSTRACT:

TECHNICAL FIELD
This invention relates to heterocyclic compounds having pharmacological activities, their pharmaceutical compositions and their use as a medicament for treatment or prevention of diseases mediated by cGMP-PDE.
BACKGROUND ART
It is known that a cyclic guanosine-3′,5′-monophosphate (hereinafter referred to as cGMP) derived from a guanosine-5′-triphosphate possesses a relaxant activity of smooth muscle and that a cyclic guanosine-3′,5′-monophosphate phosphodiesterase (hereinafter refereed to as cGMP-PDE) acts to catalyze the degradation of cGMP to a guanosine-5′-monophosphate. cGMP-PDE is a family of enzymes consists from PDE-I, II, V and so on. The compounds having an inhibitory activity of cGMP-PDE are disclosed in European Patent Publication Nos. 579,496; 534,443; 526,004; 636,626; U.S. Pat. Nos. 3,819,631; 5,294,612; 5,488,055; International Patent Publication Nos. 93/07,124; 94/19,351; 95/18,097; 96/32,379; Japan Patent Publication Nos. 05-222,000; 07-330,777; and so on.
Further, some kinds of benzimidazolone compounds having affinity for receptors of vasopressin and/or oxytocin are disclosed in Japanese Patent Kokai No. Hei 8(1996)-73439.
DISCLOSURE OF INVENTION
According to one aspect of this invention, it provides novel heterocyclic compounds represented by the below formula (Ia) and their pharmaceutical compositions.
According to another aspect of the invention, it provides a pharmaceutical composition for treatment or prevention of diseases mediated by cGMP-PDE (especially PDE-V) containing a heterocyclic compound represented by the below formula (I) as an active ingredient.
Specifically, the present invention provides a compound of the formula (Ia):
wherein
X
a
is CH or nitrogen atom;
Y
a
is oxygen atom or sulfur atom;
R
1a
is a halogen atom; cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group,
R
2a
is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and
the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl,
R
3a
, R
4a
and R
5a
are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower-alkoxy-substituted aralkyl group; or two of R
3a
, R
4a
and R
5a
may combine together to form a lower alkylenedioxy group,
m is an integer of 1 or 2,
provided that when R
3a
is hydrogen atom, R
4a
is a lower alkoxy group and R
5a
is hydrogen atom, a halogen atom, cyano group, a lower alkyl group, a lower alkoxy group, a protected carboxy group, carboxy group or nitro group then
1) the lower alkyl group for R
2a
has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl,
2) the cycloalkyl group for R
2a
has one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl,
3) the heterocyclic group for R
2a
is selected from pyrrolidinyl group, dioxanyl group and piperidyl group which groups may be substituted with protected carboxy, acyl, lower alkanesulfonyl, carbamoyl or sulfamoyl,
(4) R
1a
is carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; an acyl group; or a lower alkanesulfonyl group;
(5) X
a
is nitrogen atom;
(6) m is an integer of 2; or
(7) Y
a
is sulfur atom,
its prodrug or a pharmaceutically acceptable salt thereof.
According to the present invention, it also provides a pharmaceutical composition directed to treatment or prevention of diseases mediated by cGMP-PDE which comprises a compound of the formula (I):
wherein
X is CH or nitrogen atom;
Y is oxygen atom or sulfur atom;
R
1
is a halogen atom, cyano group, nitro group, carbamoyl group, a lower alkylcarbamoyl group which may be substituted with a heterocyclic group, carboxy group, a protected carboxy group, a lower alkyl group, a halo(lower)alkyl group, a lower alkoxy group, an acyl group or a lower alkanesulfonyl group,
R
2
is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, carboxy, lower alkanesulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and sulfamoyl; and
the cycloalkyl group and the heterocyclic group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sulfamoylamino, protected carboxy, lower alkanesulfonyl, lower alkyl, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, lower alkylenedioxy, carbamoyl and sulfamoyl,
R
3
, R
4
and R
5
are, the same or different, hydrogen atom, a halogen atom, a lower alkanoyl group, carboxy group, a protected carboxy group, carbamoyl group, nitro group, cyano group, a lower alkyl group optionally substituted by hydroxy, a lower alkoxy group or a lower-alkoxy-substituted aralkyl group, or two of R
3
, R
4
and R
5
may combine together to form a lower alkylenedioxy group,
n is an integer of 1 or 2,
its prodrug or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or diluent.
The present invention further provides an intermediate compound of the following formula (II) or its salt for preparing a compound (I).
wherein
X is CH or nitrogen atom;
Y is oxygen atom or sulfur atom;
R
1
is a halogen atom; cyano group; nitro group; carbamoyl group; a lower alkylcarbamoyl group which may be substituted with a heterocyclic group; carboxy group; a protected carboxy group; a lower alkyl group; a halo(lower)alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group, and
R
2
is a lower alkyl group, a cycloalkyl group or a heterocyclic group, among which the lower alkyl group may have one to three substituents selected from the group consisting of hydroxy, protected hydroxy, acyl, lower-alkoxy-substituted aralkyloxy, amino, lower alkylamino, acylamino, lower alkoxycarbonylamino, lower alkanesulfonylamino, ureido, lower alkylureido, sul

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