Substituted 1-naphthoylguanidines, process for their...

Details Substituted 1-naphthoylguanidines, process for their... Substituted 1-naphthoylguanidines, process for their...

2002-08-14

2003-07-29

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S164000, C514S319000, C514S620000, C546S205000

Reexamination Certificate

active

06600072

ABSTRACT:

The invention relates to substituted 1-naphthoylguanidines of the formula I
in which:
R2, R3, R4, R5, R6, R7 and R8 independently of one another are H, F, Cl, Br, I, CN, NO
2
, CF
3
, C
2
F
5
or X
a
Y
b
Z;
X is O, S, NR(10), CR(11)R(12), C═O, C(═O)NR(10), C(═O)O, SO, SO
2
, SO
2
NR(10), OC═O, NR(10)C═O or NR(10)SO
2
,
where the linkage with the naphthalene ring in each case takes place via the left atom;
R(10), R(11) and R(12) independently of one another are H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
a is zero or 1;
Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 CH
2
groups,
where one of these CH
2
groups can be replaced by O, S, NR(13) or o-, p- or m-phenylene;
R(13) is H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
b is zero or 1;
Z is H, alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, C(═O)R(15), SO
2
R(15), NR(16)R(17) or phenyl,
which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CF
3
, methyl, methoxy and NR(21)R(22);
R(21) and R(22) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;
R(15) is N═C(NH
2
)
2
, NR(18)R(19), N(CH
2
)
c
NR(18)R(19) or OR(20);
c is 2 or 3;
R(18) and R(19) independently of one another are H, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;
or
R(18) and R(19) together are 4 or 5 methylene groups,
of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
, N-benzyl or N-(p-chloro-phenyl);
R(20) is H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
R(16) and R(17) independently of one another are H, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;
or
R(16) and R(17) together are 4 or 5 methylene groups, of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
, N-benzyl or N-(p-chlorophenyl);
or
Z is an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the N-containing heterocycle is linked via N or C and is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CF
3
, methyl, methoxy and NR(21)R(22);
but where, in the case where R(4) is an alkoxy radical, at least one of the substituents R(2), R(3), R(5), R(6), R(7) and R(8) is not equal to hydrogen; and their pharmaceutically tolerable salts.
Preferred compounds of the formula I are those in which all substituents and indices are as defined above, but at least one of the substituents R2, R3, R4, R5, R6, R7 and R8 is not equal to hydrogen; and their pharmaceutically tolerable salts.
Compounds of the formula I are particularly preferred in which R2, R3, R5, R6, R7 and R8 are as defined at the beginning and R4 is H, F, Cl, Br, I, CN, NO
2
, CF
3
, C
2
F
5
or Z where Z is defined as at the beginning, and their pharmaceutically tolerable salts.
Preferred compounds of the formula I are also those in which:
at least one of the substituents R2, R3, R4, R5, R6, R7 and R8 is X
a
Y
b
Z;
X is O, S, NR(10), CR(11)R(12), C═O, C(═O)NR(10), C(═O)O, SO, SO
2
, SO
2
NR(10), OC═O, NR(10) C═O or NR(10)SO
2
,
where the linkage with the naphthalene ring in each case takes place via the left atom;
R(10), R(11) and R(12) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1 or 2 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
a is zero or 1;
Y is alkylene having 1, 2, 3, 4 or 5 CH
2
groups,
where one of these CH
2
groups can be replaced by O, S, NR(13) or o-, p- or m-phenylene;
R(13) is H, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5, or 6 carbon atoms;
b is zero or 1;
Z is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, C(═O)R(15), SO
2
R(15), NR(16)R(17) or phenyl,
which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CF
3
, methyl, methoxy and NR(21)R(22);
R(21) and R(22) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1 or 2 carbon atoms;
R(15) N═C(NH
2
)
2
, NR(18)R(19), N(CH
2
)
c
NR(18(R(19) or OR(20);
R(18) and R(19) independently of one another are H, alkyl having 1, 2, 3, 4 or 5 carbon atoms;
or
R(18) and R(19) together are 4 or 5 methylene groups,
of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
or N-benzyl;
c is 2 or 3;
R(20) is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
R(16) and R(17) independently of one another are H, alkyl having 1, 2, 3, 4 or 5 carbon atoms or perfluoroalkyl having 1 or 2 carbon atoms;
or
R(16) and R(17) together are 4 or 5 methylene groups,
of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
, N-benzyl or N-(p-chlorophenyl);
or
Z is an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
which is linked via N or C and is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, CF
3
, methyl, methoxy and NR(21)R(22);
and the other substituents R2, R3, R4, R5, R6, R7 and R8 in each case, which are still not allocated by the definition given above,
independently of one another are H, F, Cl, Br, I, CN, NO
2
, CF
3
, C
2
F
5
or X
a
Y
b
Z;
X is O, S, NR(10), C═O, C(═O)NR(10), C(═O)O, SO, SO
2
, SO
2
NR(10), OC═O, NR(10) C═O or NR(10)SO
2
,
where the linkage with the naphthalene ring in each case takes place via the left atom;
R(10) is H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms,
a is zero or 1;
b is zero;
Z is H, alkyl having 1, 2, 3, 4 or 5 carbon atoms;
and their pharmaceutically tolerable salts.
Particularly preferred compounds of the formula I are those in which:
at least one of the substituents R2, R3, R4, R5, R6, R7 and R8 is X
a
Y
b
Z;
X is O, NR(10), C(═O)NR(10), C(═O)O, SO
2
NR(10), where the linkage with the naphthalene ring in each case takes place via the left atom;
R(10) is H or methyl;
a is 1;
Y is alkylene having 1, 2, 3, 4 or 5 CH
2
groups,
where one of these CH
2
groups can be replaced by o-, p- or m-phenylene;
b is 1;
Z is C(═O)R(15), NR(16)R(17) or an N-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the N-containing heterocycle is linked via N or C and is unsubstituted;
R(15) is N═C(NH
2
)
2
, NR(18)R(19), or OR(20);
R(18) and R(19) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(18) and R(19) together are 4 or 5 methylene groups,
of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
or N-benzyl;
R(20) is H, alkyl having 1, 2 or 3 carbon atoms;
R(16) and R(17) independently of one another are H or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
or
R(16) and R(17) together are 4 or 5 methylene groups, of which one CH
2
group can be replaced by oxygen, S, NH, N—CH
3
, N-benzyl or N-(p-chlorophenyl);
and the other substituents R2, R3, R4, R5, R6, R7 and R8 in each case, which are still not allocated by the definition given above, independently of one another are H, F, Cl, Br, I, CF
3
or X
a
Y
b
Z;
X is O, NR(10), C(═O)NR(10), C(═O)O, SO
2
, SO
2
NR(10), O C═O or NR(10) C═O,
where the linkage with the naphthalene ring in each case takes place via the left atom;
R(10) is H or alkyl having 1, 2 or 3 carbon atoms;
a is zero or 1;
b is zero;
Z is H or alkyl having 1, 2, 3 or 4 carbon atoms,
and their pharmaceutically tolerable salts.
If the compounds of the formula I contain one or more centers of asymmetry, these can have either the S or the R configuration. The compounds can be present as optical isomers, as diast

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