Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-02
2001-03-27
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S395000, C548S304700, C548S306100, C548S237000, C548S238000, C544S403000, C546S198000
Reexamination Certificate
active
06207693
ABSTRACT:
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 Nos. WO 91/05549, WO 95/29152 and WO 96/41795, 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 salt 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 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; protected amino; 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, substituted acyl, aryl or acyl-substituted aryl; 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, acyl(lower)alkoxyimino, aryl or acyl-substituted aryl; 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, substituted acyl(lower)alkoxyimino, acyl(lower)alkoxy, guanidino or N-protected guanidino; and lower alkenyloxy optionally substituted with acyl or substituted acyl;
R
2
is hydrogen; lower alkyl optionally substituted with hydroxy, aryl or acyl; or cyclo(lower)alkyl;
R
3
is hydrogen; halogen; hydroxy; acyloxy; substituted acyloxy; lower alkyl optionally substituted with hydroxy or lower alkoxy; lower alkoxy optionally substituted with aryl, amino, protected amino, acyl, hydroxy, cyano or lower alkylthio; nitro; amino; acyl; substituted acyl; or cyclo(lower)alkyloxy;
A is a single bond, O or NH;
E is lower alkylene, lower alkenylene,
or a group of the formula:
—G—J—
in which G is lower alkylene or
and J is O or
(wherein R
4
is hydrogen or N-protective group);
X is —CH═CH—, —CH═N— or S; and
Y is aryl which may be substituted with acyl, protected amino(lower)alkanoyl, protected amino and nitro, amino and nitro or diamino; or a condensed heterocyclic group which may be substituted with substituent(s) selected from the group consisting of halogen, acyl, lower alkoxy, hydroxy, guanidino, mercapto, acylamino, amino, a heterocyclic group, cyanoamino, amino(lower)alkyl(lower)alkylamino, lower alkylamino, lower alkylamino(lower)alkylamino, substituted-heterocyclic group, lower alkylhydrazino, aryloxy, lower alkylthio, aryl, protected amino, N-protected lower alkylamino(lower)alkylamino, N-protected amino(lower)alkyl(N′-lower alkyl)amino, amino(lower)alkyl(N-lower alkyl)amino, lower alkylamino(lower)alkyl(N-lower alkyl)amino, lower alkoxy(lower)alkylamino and lower alkyl optionally substituted with aryl, ar(lower)alkoxy, cyano, hydroxyimino, mercapto, lower alkylamino, acyloxy, halogen, lower alkoxy, protected hydroxy, hydroxy, lower alkoxyaryl, protected amino, amino, a heterocyclic group or substituted heterocyclic group;
provided that when Y is phenyl which may be substituted with lower alkyl or acyl, then A is a single bond and E is
(wherein R
4
is as defined above);
and pharmaceutically acceptable salt thereof.
The object compound (I) or its salt can be prepared by the processes as illustrated in the following reaction schemes.
wherein
R
1
, R
2
, R
3
, A, E, X and Y are each as defined above,
Ea is
Ya is indolyl,
R
5
is lower alkyl,
Z
1
is an acid residue,
Yb is N-(lower alkyl)indolyl,
Yc is phenyl substituted with amino and nitro,
Yd is phenyl substituted with diamino,
Ye is benzimidazolyl optionally 2-position substituted with aryl, phenoxy, sulfamoylamino, cyanoamino, guanidino, mercapto, amino, lower alkoxycarbonylamino, lower alkoxy or lower alkyl optionally substituted with cyano, mercapto, hydroxy, halogen, protected amino or a heterocyclic group;
Yf is quinoxalinyl or benzotriazolyl,
Yg is N-acylindolyl,
Yh is (N-acyl)acylindolinyl, N-acylindolinyl, (N-acyl)hydroxy(lower)alkylindolinyl, lower alkylamino(lower)alkylamino(N-acyl)indolinyl, (N-lower alkoxyarylmethyl)acylbenzimidazolyl, (N-lower alkoxycarbonyl)phthalimido(lower)alkylindolyl, N-protected lower alkylamino(lower)alkylamino(N-acyl)-benzimidazolyl, (N-acyl)benzimidazolyl, (N-acyl) (lower)-alkylbenzimidazolyl, N-protected amino(lower)alkyl(N-lower alkyl)amino(N-acyl)benzimidazolyl, N-acylindolyl, (N-acyloxymethyl)indolyl, (N-acyl)acylindolyl, (N-arylmethyl)lower alkoxy(lower)alkylbenzimidazolyl or (N-lower alkoxyarylmethyl)acylbenzimidazolyl;
Yi is acylindolinyl, indolinyl, hydroxy(lower)alkylindolinyl, lower alkylamino(lower)alkylaminoindolinyl, acylbenzimidazolyl, phthalimido(lower)alkylindolyl, amino(lower)alkylindolyl, lower alkylamino(lower)alkylaminobenzimidazolyl, benzimidazolyl, lower alkylbenzimidazolyl, amino(lower)alkyl(N-lower alkyl)aminobenzimidazolyl, indolyl, acylindolyl, lower alkoxy(lower)-alkylbenzimidazolyl or acylbenzimidazolyl;
Yj is aryl which is substituted with protected amino and nitro; or a condensed heterocyclic group which is substituted with protected amino or lower alkyl substituted with protected amino;
Yk is aryl which is substituted with amino and nitro; or a condensed heterocyclic group which is substituted with amino or lower alkyl substituted with amino;
Yl is aryl substituted with esterified carboxy, or a condensed heterocyclic group substituted with esterified carboxy,
Ym is aryl substituted with carboxy, or a condensed heterocyclic group substituted with carboxy,
Yn is aryl or a condensed heterocyclic group, each of which is substituted with substituted or unsubstituted N-containing heterocycliccarbonyl, carbamoyl, heterocycliccarbamoyl, or substituted or unsubstituted lower alkylcarbamoyl;
Yo is a condensed (N-acyl)N-containing het
Ohkawa Takehiko
Oku Teruo
Sawada Hitoshi
Sawada Yuki
Setoi Hiroyuki
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Ramsuer Robert W.
Sackey Ebenezer
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