Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-09-17
2001-07-17
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S307000, C514S311000, C514S357000, C546S145000, C546S175000, C546S329000, C564S170000, C564S176000
Reexamination Certificate
active
06262123
ABSTRACT:
DESCRIPTION
The invention relates to benzoylguanidines of the formula I
in which:
R(1) is H, F, Cl, Br, I, CN, NO
2
, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkoxy having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkoxy having 3, 4, 5, 6, 7 or 8 carbon atoms or X
a
—(CH
2
)
b
—(CF
2
)
c
—CF
3
;
X is oxygen, S or NR(5),
a is zero or 1;
b is zero, 1 or 2;
c is zero, 1, 2 or 3;
R(5) is H, alkyl having 1, 2, 3 or 4 carbon atoms or —C
d
H
2d
R(6);
d is zero, 1, 2, 3 or 4;
R(6) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl, biphenylyl or naphthyl,
where the aromatic radicals phenyl, biphenylyl or naphthyl are unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
methyl, methoxy and NR(7)R(8);
R(7) and R(8) are, independently, H or alkyl having 1, 2, 3 or 4 carbon atoms; or
R(1) is —SR(10), —OR(10) or —CR(10)R(11)R(12);
R(10) is —C
f
H
2f
-cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms in the cycloalkyl ring, or phenyl,
where phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
methoxy, hydroxyl, amino, methylamino and dimethylamino;
f is zero, 1 or 2;
R(11) and R(12) are, independently of each other, defined as R(10), or hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(1) is phenyl, naphthyl, biphenylyl or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, with the latter being linked by a C atom or an N atom of the ring,
which are in each case unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino,
or
R(1) is —SR(13), —OR(13), —NHR(13), —NR(1 3)R(14), —CHR(13)R(15), —C[R(15)R(1 6)OH], —C≡CR(18), —C[R(19)]═CHR(18) or —C[R(20)R(21 )]
k
—(CO)— [(CR(22)R(23)]
l
—R(24),
k is zero, 1, 2, 3 or 4;
l is zero, 1, 2, 3 or 4;
R(13) and R(14) are, identically or differently, —(CH
2
)
g
—(CHOH)
h
—(CH
2
)
i
—(CHOH)
j
—R(17) or —(CH
2
)
g
—O—(CH
2
—CH
2
O)
h
—R(24);
R(17) is hydrogen or methyl,
g, h and i are, identically or differently, zero, 1, 2, 3 or 4;
j is 1, 2, 3 or 4;
R(15) and R(16) are, identically or differently, hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or are, together with the carbon atom carrying them, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;
R(18) is phenyl,
which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, methyl, methoxy and NR(25)R(26);
R(25) and R(26) are H or alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(18) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or substituted as phenyl;
or
R(18) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which is unsubstituted or substituted by 1-3 OH;
or
R(18) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;
R(19), R(20), R(21), R(22) and R(23) are, identically or differently, hydrogen or methyl;
R(24) is H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or —C
m
H
2m
—R(18);
m is 1, 2, 3or 4;
one of the two substituents R(2) and R(3) is hydroxyl;
and
the other of the substituents R(2) and R(3) in each case is defined as R(1);
R(4) is alkyl having 1, 2, 3 or 4 carbon atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CN, I or —(CH
2
)
n
—(CF
2
)
o
—CF
3
;
n is zero or 1;
o is zero or 1;
and the pharmaceutically tolerated salts thereof.
Compounds of the formula I are preferred in which:
R(1) is H, F, Cl, Br, I, CN, NO
2
, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkoxy having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkoxy having 3, 4, 5, 6, 7 or 8 carbon atoms or X
a
—(CF
2
)
c
—CF
3
;
x is oxygen;
a is zero or 1;
c is zero, 1, 2 or 3;
or
R(1) is —SR(10) or—OR(10);
R(10) is —C
f
H
2f
-cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms in the cycloalkyl ring, or phenyl,
where phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino;
f is zero or 1;
or
R(1) is phenyl, naphthyl, biphenylyl or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, with the latter being linked via a C atom or N atom of the ring, which are unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino,
or
R(1) is —SR(13), —OR(13), —NHR(13), —NR(13)R(14), —C≡CR(18) or —C[R(19)]═CHR(18);
R(13) and R(14) are, identically of differently, —(CH
2
)
g
—(CHOH)
h
—(CH
2
)
i
—(CHOH)
j
—R(17) or —(CH
2
)
g
—O—(CH
2
—CH
2
O)
h
—R(24);
R(17) is hydrogen or methyl, g, h and i are, identically or differently, zero, 1 or 2;
is 1 or 2;
R(18) is phenyl,
which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, methyl, methoxy and NR(25)R(26);
R(25) and R(26) are H or alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(18) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or substituted as phenyl;
or
R(18) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which is unsubstituted or substituted by 1-3 OH;
or
R(18) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;
R(19) is hydrogen or methyl;
one of the substituents R(2) and R(3) is hydroxyl;
and
the other of the substituents R(2) and R(3) in each case is defined as R(1);
R(4) is alkyl having 1 or 2 carbon atoms, methoxy, F, Cl, Br, CN or —(CH
2
)
n
—(CF
2
)
o
—CF
3
;
n is zero or 1;
o is zero or 1
and the pharmaceutically tolerated salts thereof.
Compounds of the formula I are very particularly preferred in which:
R(1) is H, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, cycloalkoxy having 5 or 6 carbon atoms or —Xa—(CF
2
)
c
—CF
3
;
X is oxygen;
a is zero or 1;
c is zero or 1;
or
R(1) is —SR(10) or —OR(10);
R(10) is cycloalkyl having 4, 5 or 6 carbon atoms, or phenyl, where phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or
R(1) is quinolyl, isoquinolyl or pyridyl, which are linked via a C atom or N atom of the ring; and which are unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino,
or
R(1) is phenyl, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, CH
3
, methoxy, hydroxyl, amino, methylamino and dimethylamino, or
R(1) is —C≡CR(18);
R(18) is phenyl or cycloalkyl having five or 6 carbon atoms;
one of the two substituents R(2) and R(3) is hydroxyl;
and the other of the substituents R(2) and R(3) in each case is defined as R(1);
R(4) is methyl, methoxy, F, Cl or CF
3
;
and the pharmaceutically tolerated salts thereof.
Compounds of the formula I are especially preferred in which
R(1) is H, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, cycloalkoxy having 5 or 6 carbon atoms or CF
3
;
one of the substituents R(2) and R(3) is hydroxyl,
and
the other of the substituents R(2) and R(3) in each case is defined as R(1);
R(4) is methyl, methoxy, F, Cl or CF
3
;
and the pharmaceutically tolerated salts thereof.
A special preference is given to the compounds of the formula I which are selected from the group consisting of 2,6-dichlorobenzoylguanidine hydrochloride, 3-chloro-2,6-dimethoxybenzoylguanidine hydrochloride, 4-hydroxy-2, 3,5,6-tetrafluorobenzoylguanidine hydrochloride, 4-hydroxy-2,5-trifluoromethylbenzoylguanidine hydrochloride and 4-hydroxy-2-methyl-5-trifluoromethylbenzoylguanidine hydrochloride.
Heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon
Albus Udo
Brendel Joachim
Kleemann Heinz-Werner
Lang Hans Jochen
Scholz Wolfgang
Aventis Pharma Deutschland GmbH
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
Kumar Shailendra
LandOfFree
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