Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-06-20
2001-03-27
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S300000, C514S397000, C514S414000, C514S418000, C514S419000, C514S443000, C514S466000, C546S277400, C548S311100, C548S453000, C548S467000, C548S484000, C548S485000, C548S492000, C548S493000, C548S496000, C548S497000, C549S053000, C549S058000, C549S441000
Reexamination Certificate
active
06207686
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compound and a pharmaceutically acceptable salt thereof.
More particularly, it relates to novel compound and a pharmaceutically acceptable salt thereof which have pharmacological activities such as endothelin (ET) antagonistic activity and the like, to processes for its preparation, to a pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment and the prevention of endothelin mediated diseases such as hypertension, and the like.
Pharmacological and structural evidence supports the existence of at least two endothelin receptor subtypes, i.e., ET
A
and ET
B
. ET
A
receptors are distributed predominantly in vascular smooth muscle, heart and intestine, whereas ET
B
receptors are found in cerebral cortex, lung and kidney. Recently, it is found that in addition to ET
A
receptors, vasoconstrictor ET
B
receptors are also present on vascular smooth muscle. ET
A
receptors have a higher affinity to ET-1 than ET-3 and sarafotoxin S6c, while ET
B
receptors show nearly the same affinity to all isoforms of ET and sarafotoxin peptides.
The compounds of this invention may have ET
A
and/or ET
B
antagonistic activity.
One object of the present invention is to provide new and useful compound and a pharmaceutically acceptable salt thereof which have pharmacological activities such as endothelin, particularly ET
A
and ET
B
dual antagonistic activity, and the like.
Another object of the present invention is to provide processes for the preparation of said compound and a salt thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said compound or a pharmaceutically acceptable salt thereof.
Still further object of the present invention is to provide a method of using the same for the treatment and the prevention of endothelin mediated diseases such as hypertension, and the like.
DISCLOSURE OF INVENTION
The object compound of the present invention can be represented by the following general formula (I).
in which R
1
is lower alkyl, cyclo(lower)alkyl, optionally substituted aryl, optionally substituted heterocyclic group, cyclo(lower)alkyl(lower)alkyl, or ar(lower)alkyl,
R
2
is hydrogen, hydroxy or protected hydroxy,
R
3
is lower alkyl, aryl, ar(lower)alkyl or optionally substituted heterocyclic(lower)alkyl,
R
4
is carboxy, protected carboxy or lower alkylsulfonylcarbamoyl,
R
5
is hydrogen or lower alkyl,
R
6
is hydrogen or heterocyclic group,
A is a single bond or lower alkylene, and
Ar is optionally substituted aryl,
or pharmaceutically acceptable salts thereof.
The compound having the following formula (IA) is preferable.
Further, the compound having the relative configuration of the following formula (IB) is more preferable.
in which R
1
, R
2
, R
3
, R
4
, R
5
, A and Ar are each as defined above.
According to the present invention, the novel compound (I) and a salt thereof can be prepared by the processes as shown in the following schemes.
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, A and Ar are each as defined above,
R
a
1
is aryl substituted at least by protected carboxy; or heterocyclic group containing at least a protected imino moiety and optionally substituted by suitable substituent(s);
R
b
1
is aryl substituted at least by carboxy; or heterocyclic group containing at least an imino moiety and optionally substituted by suitable substituent(s);
R
a
2
is protected hydroxy,
R
a
3
is heterocyclic(lower)alkyl substituted at least by protected carboxy(lower)alkyl; or heterocyclic(lower)alkyl containing at least a protected imino moiety and optionally substituted by suitable substituent(s);
R
b
3
is heterocyclic(lower)alkyl substituted at least by carboxy(lower)alkyl; or heterocyclic(lower)alkyl containing at least an imino moiety and optionally substituted by suitable substituent(s);
R
c
3
is heterocyclic(lower)alkyl substituted at least by carboxy(lower)alkyl,
R
d
3
is heterocyclic(lower)alkyl substituted at least by protected carboxy(lower)alkyl,
R
e
3
is heterocyclic(lower)alkyl containing at least a thia moiety and optionally substituted by suitable substituent(s),
R
f
3
is heterocyclic(lower)alkyl containing at least thia moiety and its dioxide, and optionally substituted by suitable substituent(s),
R
a
4
is protected carboxy,
Ar
1
is aryl substituted by the group consisting of protected hydroxy and protected carboxy, and optionally by suitable substituent(s), and
Ar
2
is aryl substituted by the group consisting of hydroxy and carboxy, and optionally by suitable substituent(s).
REFERENCES:
Mock et al. Biochemistry Journal (1994) 302, 57-68.*
Fromsen. J. Med. Chem. (1992) 35, 1246-1259.
Hemmi Keiji
Hemmi Mitsue
Kasahara Chiyoshi
Murata Masayoshi
Neya Masahiro
Fujisawa Pharmaceutical Co. Ltd.
Hemmi Mitsue
O'Sullivan Peter
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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