Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-01-30
2001-04-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S253130, C514S255010, C514S332000, C514S333000, C514S336000, C514S346000, C514S352000, C514S353000, C514S354000, C514S355000, C544S364000, C544S365000, C544S390000, C546S256000, C546S260000, C546S261000, C546S280400, C546S281400, C546S297000, C546S305000, C546S309000, C546S316000, C546S323000
Reexamination Certificate
active
06211242
ABSTRACT:
This application is a 371 of PCT/JP95/00788, filed Apr. 21, 1995.
TECHNICAL FIELD
This invention relates to new benzamide derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some benzamide derivatives have been known as vasopressin antagonist, for example, in PCT International Publication No. WO 91/05549 and EP Application Publication No. 0620216.
DISCLOSURE OF INVENTION
This invention relates to new benzamide derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to new benzamide derivatives and pharmaceutically acceptable salts thereof which possess activities as vasopressin antagonistic activity, vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibiting growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity, oxytocin antagonistic activity and the like, to a pharmaceutical composition comprising the same and to a method for the treatment and/or prevention of hypertension, heart failure, renal insufficiency, edema, ascites, vasopressin parasecretion syndrome, hepatocirrhosis, hyponatremia, hypokalemia, diabetic, circulation disorder, cerebrovascular disease (e.g. cerebral edema, cerebral infarction, etc.), Meniere's syndrome (e.g. Meniere's disease, etc.), motion sickness and the like in human beings or animals.
One object of this invention is to provide new and useful benzamide derivatives which possess aforesaid activities.
Another object of this invention is to provide processes for the preparation of said benzamide derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said benzamide derivatives and pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said benzamide derivatives and pharmaceutically acceptable salts thereof.
The object benzamide derivatives of this invention are new and can be represented by the following general formula (I):
wherein
R
1
is lower alkyl, aryl, cyclo(lower)alkyl or a
heterocyclic group, each of which may be substituted with substituent(s) selected from the group consisting of halogen; hydroxy; nitro; amino; acyl; substituted acyl; acyl(lower)alkylsulfinyl; acyl(lower)alkylsulfonyl; acyloxy; lower alkylamino(lower)alkylcarbamoyloxy; aryl; cyano; a heterocyclic group; lower alkenyl optionally substituted with acyl or substituted acyl; lower alkynyl optionally substituted with amino, acylamino or substituted acylamino; lower alkyl optionally substituted with halogen, amino, lower alkylamino, acylamino, substituted acylamino, hydroxy, acyloxy, acyl(lower)alkanoyloxy, acyl, substituted acyl or acyl(lower)alkoxyimino; lower alkylthio optionally substituted with acyl or substituted acyl; alkoxy optionally substituted with aryl, substituted aryl, hydroxy, acyloxy, amino, lower alkylamino, protected amino, a heterocyclic group, acyl-substituted pyridyl, substituted acyl-substituted pyridyl, halogen, acyl(lower)alkylamino, N-protected-acyl(lower)alkylamino, N-acyl(lower)alkyl-N-lower alkylamino, acyl, substituted acyl, acylamino, substituted acylamino, lower alkylhydrazinocarbonylamino, hydroxyimino, acyl(lower)alkoxyimino or substituted acyl(lower)alkoxyimino; and lower alkenyloxy optionally substituted with acyl or substituted acyl;
R
2
is lower alkyl optionally substituted with hydroxy, aryl or acyl; or cyclo(lower)alkyl;
R
3
is hydrogen, halogen, lower alkyl, lower alkoxy, nitro or amino;
R
4
is lower alkyl; aryl; or substituted aryl;
X is CH or N, and
Y is CH or N, and pharmaceutically acceptable salts thereof.
The object compound (I) for its salt can be prepared by the processes as illustrated in the following reaction schemes.
wherein
R
1
, R
2
, R
3
, R
4
, X and Y are each as defined above,
R
a
1
is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with esterified carboxy; lower alkenyl substituted with esterified carboxy; lower alkyl substituted with esterified carboxy, esterified carboxy(lower)alkanoyloxy or esterified carboxy(lower)alkoxyimino; lower alkylthio substituted with esterified carboxy; alkoxy substituted with esterified carboxy-substituted aryl, esterified carboxy-substituted pyridyl, esterified carboxy(lower)alkylamino, N-protected-esterified carboxy(lower)alkylamino, N-esterified carboxy(lower)alkyl-N-lower alkylamino, esterified carboxy or esterified carboxy(lower)alkoxyimino; or lower alkenyloxy substituted with esterfied carboxy;
R
b
1
is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with carboxy; lower alkenyl substituted with carboxy; lower alkyl substituted with carboxy, carboxy(lower)alkanoyloxy or carboxy(lower)alkoxyimino; lower alkylthio substituted with carboxy; alkoxy substituted with carboxy-substituted aryl, carboxy-substituted pyridyl, carboxy(lower)alkylamino, N-protected-carboxy(lower)alkylamino, N-carboxy(lower)alkyl-N-lower alkylamino, carboxy or carboxy(lower)alkoxyimino; or lower alkenyloxy substituted with carboxy;
R
c
1
is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with acyloxy; lower alkyl substituted with acyloxy or acyl(lower)alkanoyloxy; or alkoxy substituted with acyloxy;
R
d
1
is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with hydroxy; lower alkyl substituted with hydroxy;
or alkoxy substituted with hydroxy;
R
e
1
is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with alkoxy substituted with protected amino, N-protected-acyl(lower)alkylamino, N-protected-N-containing heterocycliccarbonylamino or N-protected-N-containing heterocyclicsulfonyl-substituted aryl;
R
f
1
is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with alkoxy substituted with amino, acyl(lower)alkylamino, N-containing heterocycliccarbonylamino or N-containing heterocyclicsulfonyl-substituted aryl;
R
g
1
is lower alkyl, aryl, haloaryl, cyclo(lower)alkyl or a heterocyclic group, each of which is substituted with substituted or unsubstituted N-containing heterocycliccarbonyl; carbamoyl; substituted or unsubstituted lower alkylcarbamoyl; lower alkenyl substituted with substituted or unsubstituted N-containing heterocycliccarbonyl, carbamoyl or substituted or unsubstituted lower alkylcarbamoyl; lower alkyl substituted with substituted or unsubstituted N-containing heterocycliccarbonyl, carbamoyl, substituted or unsubstituted lower alkylcarbamoyl, substituted or unsubstituted N-containing heterocycliccarbonyl(lower)alkanoyloxy, carbamoyl(lower)alkanoyloxy, substituted or unsubstituted lower alkylcarbamoyl(lower)alkanoyloxy, substituted or unsubstituted N-containing heterocycliccarbonyl(lower)alkoxyimino, carbamoyl-(lower)alkoxyimino or substituted or unsubstituted lower alkylcarbamoyl(lower)alkoxyimino; lower alkylthio substituted with substituted or unsubstituted N-containing heterocycliccarbonyl, carbamoyl or substituted or unsubstituted lower alkylcarbamoyl; alkoxy substituted with substituted or unsubstituted N-containing heterocycliccarbonyl-substituted aryl, carbamoyl-substituted aryl, substituted or unsubstituted lower alkylcarbamoyl-substituted aryl, substituted or unsubstituted N-containing heterocycliccarbonyl-substituted pyridyl, carbamoyl-substituted pyridyl, substituted or unsubstituted lower alkylcarbamoyl-substituted pyridyl, substituted or unsubstituted N-containing heterocycliccarbonyl(lower)alkylamino, carbamoyl(lower)alkylamino, substituted or unsubstituted lower alkylcarbamoyl(lower)alkylamino, N-protected-(substituted or unsubstituted N-containing heterocyclic)carbonyl(lower)alkylamino, N-protected-carbamoyl(lower)alkylamino, N-protected
Hemmi Keiji
Hemmi Yusuke
Ohkawa Takehiko
Setoi Hiroyuki
Tanaka Hirokazu
Fujisawa Pharmaceutical Co. Ltd.
Hemmi Yusuke
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Raymond Richard L.
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