USE OF INHIBITORS OF THE CELLULAR NA+/H+ EXCHANGER (NHE) FOR PRODUCTION OF A MEDICAMENT FOR THE NORMALIZATION OF SERUM LIPIDS

UTILISATION D'INHIBITEURS DE L'ECHANGEUR CELLULAIRE NA+/H+ (NHE) POUR LA PRODUCTION D'UN MEDICAMENT VISANT LA NORMALISATION DE LIPIDES SERIQUES

English Abstract

The active substances identified as inhibitors of the cellular Na+/H+
exchanger (NHE) are used to prepare a medicament for normalizing serum lipids.
They are used in the preparation of a medicament which reduces lipid levels in
the blood and can be administered for treating diseases caused by lipid levels
which are too high, and for alleviating the endothelial dysfunctional syndrome
and for treating diseases caused thereby.

French Abstract

Les principes actifs identifiés comme inhibiteurs de l'échangeur cellulaire Na<+>H<+> (NHE) sont utilisés pour préparer un médicament servant à normaliser les lipides sériques. Ils s'utilisent dans la préparation d'un médicament permettant d'abaisser le taux de lipides dans le sang et par conséquent de traiter les maladies induites par des taux trop élevés, et de réduire le syndrome dysfonctionnel endothélial de traiter les maladies qu'il induit.

Claims

181
claims

1. Use of an Na+/H+ exchange inhibitor for the production of a medicament
for the treatment of raised blood lipid levels.

2. The use I as claimed in claim 1, which comprises employing as Na+/H+
exchange inhibitor:
I. a) benzoylguanidines of the formula I


Image

in which:
R(1) or R(2)
is R(6)-S(O)n- or R(7)R(8)N-O2S-;
and the other substituent R(1) or R(2) in each case
is H, F, Cl, Br, (C1-C4)-alkyl, (C1-C4)-alkoxy or phenoxy,
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of fluorine, chorine, methyl
and methoxy;
or the other substituent R(1) or R(2) in each case
is R(6)-S(O)n or R(7)R(8)N-;
n is zero, 1 or 2;
R(6) is (C1-C6)-alkyl, (C5-C7)-cycloalkyl, cyclopentylmethyl,
cyclohexylmethyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
R(7) and R(8)
identically or differently are H or (C1-C6)-alkyl;
or
R(7) is phenyl-(CH2)m;
m is 1 - 4;
or





182
R(7) is phenyl,
which is unsubstituted or substituted by 1 - 2
substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
or
R(7) and R(8)
together are a straight-chain or branched (C4-C7)-chain,
where the chain can additionally be interrupted by O, S or
NR(9);
R(9) is H or methyl;
or
R(7) and R(8)
together with the nitrogen atom to which they are bonded, are
a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline
system;
R(3), R(4) and R(5)
independently of one another are H or (C1-C2)-alkyl,
or
R(3) and R(4)
together are a (C2-C4)-alkylene chain;
or
R(4) and R(5)
together are a (C4-C7)-alkylene chain;
and their pharmaceutically tolerable salts;

b) benzoylguanidines of the formula I
Image
in which:
R(1) is R(4)-SO m or R(5)R(6)N-SO2-;
m is zero, 1 or 2;





183
R(4) and R(5)
are C1-C8-alkyl, C3-C6-alkenyl or-Cn H2n-R(7);
n is zero, 1, 2, 3 or 4;
R(7) is C5-C7-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
or
R(5) is H;
R(6) is H or C1-C4-alkyl,
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by an O, S, NH, N-CH3 or N-benzyl;
R(2) is hydrogen, F, Cl, Br, (C1-C4)-alkyl-, O-(CH2)m C p F2p+1 or-X R(10);
m is zero or 1;
p is 1, 2 or 3;
X is O, S or NR(11);
R(10) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl or-Cn H2n-R(12);
n is zero, 1,2,3 or 4;
R(12) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy und NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
R(11) is hydrogen or C1-C3-alkyl;
or
R(10) and R(11)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by O, S, NH, N-CH3 or





184
N-benzyl;
R(3) is defined as R(1), or is C1-C6-alkyl, nitro, cyano, trifluoromethyl, F,
Cl, Br, I or -X-R(10);
X is O, S or NR(11);
R(10) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl or-Cn H2n-R(12);
n is zero to 4;
R(12) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy und NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
R(11) is C1-C3-alkyl,
or
R(10) and R(11)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by O, S, NH, N-CH3 or
N-benzyl;
and their pharmaceutically tolerable salts;

c) ortho-substituted benzoylguanidines of the formula I
Image
in which:
R(1) is F, Cl, Br, I, C1-C6-alkyl or -X-R(6);
X is O, S, NR(7) or Y-ZO;
Y is O or NR(7);

185
Z is C or SO;
R(6) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl,-(CH2)m Cp F2p+1 or -Cn H2n-R(8);
m is zero or 1;
p is 1 -3;
n is zero to 4;
R(8) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of the groups F, Cl, CF3, methyl, methoxy and
NR(9)R(10);
R(9) and R(10)
are H or C1-C4-alkyl;
R(7) is H or C1-C3-alkyl;
or
R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by O, S, NH, N-CH3 or N-benzyl;
R(3) is H or -X-R(6);
X is O, S, N R(7) or Y-ZO;
R(7) is H or C1-C3-alkyl;
Y is O or NR(7);
where Y is bonded to the phenyl radical of the formula
I,
Z is C or SO;
R(6) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl,-(CH2)m Cp F2p+1 or -Cn H2n-R(8);
m is zero or 1;
p is 1 -3;
n is zero to 4;
R(8) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of the groups F, Cl, CF3, methyl, methoxy and





186
NR(9)R(10);
R(9) and R(10)
are H or C1-C4-alkyl;
or
R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by O, S, NH, N-CH3 or N-benzyl;
R(2) and R(4)
identically or differently are R(11)-SO q- or R(12)R(13)N-SO2-;
q is zero - 2;
R(11) is C1-C4-alkyl,
which is unsubstituted or carries phenyl as a substituent,
where phenyl is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or C1-C4-alkyl;
R(12) and R(13)
are defined as R(6) and R(7);
or one of the two radicals R(2) or R(4)
is hydrogen or is defined as R(1);
R(5) is H, methyl, F, Cl or methoxy,
and their pharmaceutically tolerable salts;

d) benzoylguanidines of the formula I

Image

in which:
R(1) or R(2)
is an amino group -NR(3)R(4);
R(3) and R(4)





187
identically or differently are H, C1-C6-alkyl or
C3-C7-cycloalkyl;
or
R(3) is phenyl-(CH2)p-;
p is 0, 1,2,3 or 4;
or
R(3) is phenyl,
where the phenyl in each case is unsubstituted or carries one to two
substituents selected from the group consisting of fluorine, chlorine,
methyl and methoxy;
or
R(3) and R(4)
together can be a straight-chain or branched
C4-C7-methylene chain, where one -CH2- member of the
methylene chain can be replaced by oxygen, S or NR(5);
R(5) is H or lower alkyl;
the other substituent R(1) or R(2) in each case
is H, F, Cl, C1-C4-alkyl, C1-C4-alkoxy. CF3, Cm F2m+1 -CH2-, benzyl or
phenoxy,
where the respective phenyl radical is unsubstituted or carries
one to two substituents selected from the group consisting of
methyl, methoxy, fluorine and chlorine;
m is 1, 2 or 3;
and their pharmaceutically tolerable salts;

e) benzoylguanidines of the formula I

Image
in which:
R(1) is R(4)-SO m or R(5) R(6)N-SO2-;





188
m is zero, 1 or 2;
R(4) and R(5)
are C1-C8-alkyl, C3-C6-alkenyl or-Cn H2n-R(7);
n is zero, 1, 2, 3 or 4;
R(7) is C5-C7-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
or
R(5) is H;
R(6) is H or C1-C4-alkyl;
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by an O, S, NH, N-CH3 or N-benzyl;
R(2) is hydrogen, straight-chain or branched (C5-C8)-alkyl,
-CR(13)=CHR(12) or-C~-CR(12);
R(12) is phenyl,
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
are H or (C1-C4)-alkyl;
or
R(12) is (C1-C9)-heteroaryl,
which is unsubstituted or substituted as phenyl,
or
R(12) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3 OH,
or
R(12) is (C3-C8)-cycloalkyl;
R(13) is hydrogen or methyl,


189
or
R(12) is (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, phenyl,
C6H5-(C1-C4)-alkyl, naphthyl, biphenylyl, 1,1-diphenyl-(C1-C4)-alkyl,
cyclopentadienyl, pyridyl, pyrrolyl, furanyl, thienyl,
thiazolyl, oxazolyl, indenyl, quinolyl, indolyl, benzofuranyl,
benzothienyl, benzothiazolyl, benzoxazolyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,
pyrazinyl, pyrimidinyl, pyridazinyl, indazolyl, isoquinolyl,
phthalazinyl, quinoxalinyl, quinazolinyl or cinnolinyl;
R(3) is defined as R(2);
and where the aromatic substituents R(2) and R(3) are unsubstituted or
substituted by 1 - 3 substituents from the groups F, Cl, CF3, (C1-C4)-alkyl
or -alkoxy, or NR(10)R(11) with R(10) and R(11) being H or (C1-C4)-alkyl;
and their pharmaceutically tolerable salts;

f) benzoylguanidines of the formula I

Image
in which:
R(1) or R(2)
is R(3)-S(O)n- or

Image
the other substituent R(1 ) or R(2) in each case
is H, OH, F, Cl, Br, I, C1-C4-alkyl, C1-C4-alkoxy, benzyloxy or
phenoxy,
which is unsubstituted or carries one to three substituents
selected from the group consisting of fluorine, chlorine,
methyl, methoxy, hydroxyl or benzyloxy,

190
R(3)-S(O)n, -NR4)R(5) or 3,4-dehydropiperidine
R(3) is C1-C6-alkyl, C5-C7-cycloalkyl, cyclopentylmethyl,
cyclohexylmethyl or phenyl,
which is unsubstituted or substituted by one to three
substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
R(4) and R(5)
identically or differently, are H or C1-C6-alkyl;
or
R(4) is phenyl-(CH2)m-;
m is 1,2,3 or 4;
or
R(4) is phenyl,
which is unsubstituted or carries one to two
substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
or
R(4) and R(5)
together are a straight-chain or branched C4-C7-chain, where the
chain can additionally be interrupted by O, S or NR(6),
R(6) is H or methyl;
or
R(4) and R(5)
together with the nitrogen atom to which they are bonded, are
a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline
system;
n is zero, 1 or 2;
and their pharmaceutically tolerable salts;
g) isoquinolines of the formula I

191


Image



in which:
R(1) is hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl, substituted
aminoalkyl or an aryl or heteroaryl ring;
where the rings are unsubstituted or substituted by 1 - 3
groups selected from the group consisting of halogen, nitro,
amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower
alkyl, lower alkoxy, benzyloxy, phenoxy, hydroxyl,
trifluoromethyl,
R(2) is hydrogen, halogen, alkyl or aryl;
which is unsubstituted or substituted by 1 - 3 groups selected
from the group consisting of halogen, nitro, amino,
mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl,
lower alkoxy, benzyloxy, phenoxy, hydroxyl,

G is

Image


X(2), X(3) and X(4)
independently of one another are hydrogen, halogen, nitro, amino,
alkyl, sulfonamide, mono(lower alkyl)amino, di(lower alkyl)amino,
lower alkyl, benzyloxy, hydroxyl;
X(1) is hydrogen, oxygen, sulfur or NR(7);
R(7) is hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl, substituted
aminoalkyl or an aryl or a heteroaryl ring;
which rings are unsubstituted or substituted by 1 - 3
groups selected from the group consisting of halogen,

192
nitro, amino, mono(lower alkyl)amino, di(lower
alkyl)amino, lower alkyl, lower alkoxy, benzyloxy,
phenoxy, hydroxyl and trifluoromethyl;
in which substituents each alkyl chain or alkenyl chain can be
interrupted by oxygen, sulfur or NR(8);
R(8) is hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl,
substituted aminoalkyl or an aryl or heteroaryl ring,
which rings are unsubstituted or substituted by
1 - 3 groups selected from the group consisting
of halogen, nitro, amino, mono(lower
alkyl)amino, di(lower alkyl)amino, lower alkyl,
lower alkoxy, benzyloxy, phenoxy, hydroxyl and
trifluoromethyl;
and their pharmaceutically acceptable salts;

h) compounds of the formula I


Image

in which:
R(1) is hydrogen, F, Cl, Br, I, -NO2, -C~N, -CF3, R(4)-SO m or
R(5)R(6)N-SO2-;
m is zero, 1 or 2;
R(4) and R(5)
are (C1-C8)-alkyl, (C3-C6)-alkenyl, -C n H2n-R(7) or CF3;
n is zero, 1, 2, 3 or 4;
R(7) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting

193
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
or
R(5) is H;
R(6) is H or (C1-C4)-alkyl;
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is -SR(10), -OR(10), -NHR(10), -NR(10)R(11), -CHR(10)R(12),
-[CR(12)R(13)0R(13')], -(C-[CH2-OR(13')]R(12)R(13)} or
-[CR(18)R(17)]p-(CO)-[CR(19)R(20)]q-R(14);
R(10), R(11)
identically or differently
are -[CHR(16)]s-(CH2)p-(CHOH)q-(CH2)r-(CHOH)t-R(21) or
-(CH2)p-O-(CH2-CH2O)q-R(21),
R(21) is hydrogen, methyl,
p, q, r identically or differently
are zero,1, 2, 3 or 4;
s is zero or 1;
t is 1,2,3 or 4;
R(12) and R(13)
identically or differently are hydrogen, (C1-C6)-alkyl or,
together with the carbon atom carrying them, are a
(C3-C8)-cycloalkyl,
R(13') is hydrogen or (C1-C4)-alkyl;
R(14) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -C aH2a-R(15);
a is zero,1, 2, 3 or 4;
R(15) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)

194
are H or (C1-C4)-alkyl;
or
R(15) is(C1-C9)-heteroaryl,
which is unsubstituted or substituted as phenyl,
or
R(15) is(C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3
OH;
R(16), R(17), R(18), R(19) and R(20)
are hydrogen or (C1-C3)-alkyl;
R(3) is defined as R(1),
or
R(3) is (C1-C6)-alkyl or-X-R(22);
X is oxygen, S or NR(16);
R(16) is H or (C1-C3)-alkyl;
or
R(22) and R(16)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
R(22) is defined as R(14);
and their pharmaceutically tolerable salts;

i) benzoylguanidines of the formula I


Image


in which:
R(1) is hydrogen, F, Cl, Br, I, -NO2, -C~N, R(16)-C pH2p-O q'R(4)-SO m or
R(5)R(6)N-SO2-;
m is zero, 1 or 2;

195
p is zero or 1;
q is zero, 1, 2 or 3;
R(16) is C r F2r+1;
r is 1, 2 or 3;
R(4) and R(5)
are (C1-C8)-alkyl, (C3-C6)-alkenyl, -C n H2n-R(7) or CF3;
n is zero, 1, 2, 3 or 4;
R(7) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
or
R(5) is H;
R(6) is H or (C1-C4)-alkyl;
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
R(2) is (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(2) is -SR(10), -OR(10), -NR(10)R(11), -CR(10)R(11)R(12);
R(10) is -C aH2a-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
a is zero, 1 or 2;
R(11) and R(12)

196
independently of one another are defined as R(10) or are
hydrogen or (C1-C4)-alkyl;
R(3) is defined as R(1), or is (C1-C6)-alkyl or -X-R(13);
X is oxygen, S, or NR(14);
R(14) is H or (C1-C3)-alkyl;
R(13) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -C bH2b-R(15);
b is zero, 1, 2, 3 or 4;
or
R(13) and R(14)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(15) isphenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or (C1-C4)-alkyl;
and their pharmaceutically tolerable salts;

k) benzoylguanidines of the formula I



Image



in which:
one of the substituents R(1), R(2), R(3) or R(4):
is an amino group
Image ;

197
R(5) is hydrogen or C(1-6)-alkyl;
n is zero, 1, 2, 3 or 4;
R(6) is H or C(1-4)-alkyl;
in which one CH2 group can be replaced by 1 sulfur atom or a group
NR(7);
R(7) is hydrogen, methyl or ethyl;
or
R(6) is C(3-8)-cycloalkyl or phenyl,
which is unsubstituted or carries 1, 2 or 3 substituents
selected from the group consisting of F, Cl, Br, methyl,
methoxy, -NR(8)R(9);
R(8) and R(9)
are H, methyl or ethyl;
or
R(5) and R(6)
together with the nitrogen atom are a 5-, 6- or 7-membered
ring, in which 1 carbon atom can be replaced by oxygen, S or
NR(10);
R(10) is H, C(1-3)-alkyl or benzyl;
and the other substituents R(1), R(2), R(3), R(4) in each case are:
hydrogen, F, Cl, Br, I, CN, CF3, NO2, CF3-O-, C m F2m+1-CH2-O- or
R(11)-C q H2q-Xp-;
m is 1, 2 or 3;
q is zero, 1, 2, 3 or 4;
p zero or 1;
X is oxygen or NR(12);
R(12) is H or C(1-3)-alkyl;
R(11) is hydrogen, C(1-6)-alkyl, C(3-8)-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1, 2 or 3
substituents selected from the group consisting of F,
Cl, CH3, CH3-O- and NR(13)R(14);
R(13), R(14)
are H, methyl or ethyl;
and their pharmaceutically tolerable salts;

98
I) benzoylguanidines of the formula I

Image

in which
R(1) is R(4)R(5)N-C(X)-;
X is oxygen, S or N-R(6);
R(4) and R(5)
identically or differently, are H, (C1-C8)-alkyl, (C3-C6)-alkenyl
or -C n H2n-R(7);
n is zero, 1, 2, 3 or 4;
R(7) is (C5-C7)-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methoxy and (C1-C4)-alkyl;
or
R(4) and R(5)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(6) is defined as R(4) or is amidine;
R(2) is H, F, Cl, Br, I, (C1-C8)-alkyl, 1-alkenyl or 1-alkynyl,
(C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, phenyl,
C6H5-(C1-C4)-alkyl, naphthyl, biphenylyl, 1,1-diphenyl-(C1-C4)-alkyl,
cyclopentadienyl, pyridyl, thiopyridyl, pyrrolyl, furanyl, thienyl,
thiazolyl, oxazolyl, indenyl, quinolyl, indolyl, benzofuranyl,
benzothienyl, benzothiazolyl, benzoxazolyl or-W-R(8);
W is oxygen, S or NR(9);
R(8) is H, (C1-C6)-alkyl, (C5-C7)-cycloalkyl,
cyclohexylmethyl, cyclopentylmethyl, -(CH2)m C p F2p+1
or -C q H2q-R(10);
m is zero or 1;
p is 1, 2 or 3;
q is zero, 1, 2, 3 or 4;

199
R(10) is phenyl,
which is unsubstituted or substituted by
1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl,
methoxy and NR(11)R(12);
R(11) and R(12)
are H or (C1-C4)-alkyl;
R(9) is H or (C1-C3)-alkyl;
or
R(8) and R(9)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
R(3) is H, F, Cl, Br, I, (C1-C6)-alkyl or -W-R(8) as defined for R(2),
and their pharmaceutically acceptable salts;

m) benzoylguanidines of the formula I

Image

in which:
R(1), R(2), R(3)
are hydrogen, F, Cl, Br, I or (C1-C12)-alkyl;
one of the substituents R(1), R(2) or R(3)
is N3, CN, OH or (C1-C10)-alkyloxy, if at least one of the remaining
substituents R(1), R(2) or R(3) is a sufficiently lipophilic alkyl radical
having 3 to 12 carbon atoms;
or
one of the substituents R(1), R(2) and R(3)
is R(4)-C n H2n-Om-;

200
m is zero or 1;
n is zero, 1, 2 or 3;
R(4) is C p F2p+1;
p is 1, 2 or 3, if n is zero or 1;
or
R(4) is (C3-C12)-cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl,
where the aromatic and heteroaromatic ring systems are
unsubstituted or substituted by a substituent selected from
the group consisting of F, Cl, CF3, methyl, methoxy and
NR(5)R(6);
R(5) and R(6)
are hydrogen or (C1-C4)-alkyl;
or one of the substituents R(1), R(2) and R(3)
is -C~CR(5) or-C[R(6)] = CR(5);
R(5) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy, hydroxyl, amino,
methylamino and dimethylamino,
(C1-C9)-heteroaryl,
which is unsubstituted or substituted as phenyl,
or
R(5) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3 OH;
or
R(5) is (C3-C8)-cycloalkyl,
R(6) is hydrogen or methyl;
and their pharmacologically acceptable salts;

201
o) benzoylguanidines of the fommula I

Image

in which:
R(1) is hydrogen, F, Cl, Br, I, -NO2, -C~N, X o-(CH2)p-(CF2)q-CF3,
R(5)-SO m, R(6)-CO- or R(6)R(7)N-SO2-, where
X is oxygen, S or NR(14);
m is zero, 1 or 2;
o is zero or 1;
p is zero, 1 or 2;
q is zero, 1, 2, 3, 4, 5 or 6;
R(5) and R(6)
are (C1-C8)-alkyl, (C3-C6)-alkenyl, -C n H2n-R(3) or CF3;
n is zero, 1, 2, 3 or 4;
R(8) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or C1-C4-alkyl;
or
R(6) is H;
R(7) is H or (C1-C4)-alkyl;
or
R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;

202

Image

or Image


or Image


Y is oxygen, -S- or -NR(12)-;
R(11) and R(12)
are hydrogen or (C1-C3)-alkyl;
h is zero or 1;
i, j and k
independently are zero, 1, 2, 3 or 4;
but where h, i and k are not simultaneously zero,
R(3) is defined as R(1), or is (C1-C6)-alkyl or-X-R(13);
X is oxygen, S or NR(14);
R(14) isHor (C1-C3)-alkyl;
R(13) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -C b H2b-R(15);
b is zero, 1, 2, 3 or 4;
or
R(13) and R(14)
together are 4 or 5 methylene groups, where one CH2
group can be replaced by oxygen, S, NH, N-CH3 or
N-benzyl;
R(15) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)

203
are H or (C1-C4)-alkyl;
R(4) is hydrogen, -OR(16) or-NR(16)R(17);
R(16) and R(17)
independently are hydrogen or (C1-C3)-alkyl;
and their pharmaceutically tolerable salts;

p) benzoylguanidines of the formula I

Image

in which:
R(1) is R(6)-CO or R(7)R(8)N-CO;
R(6) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-C n H2n-R(9);
n is zero, 1, 2, 3 or 4;
R(9) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(10)R(11);
R(10) and R(11)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-C n H2n-R(12);
n is zero, 1, 2, 3 or 4;
R(12) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(13)R(14);

204
R(13) and R(14)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(8) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is defined [lacuna] R(1), or is H, F, Cl, Br, I, CN, NO2, (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -C n H2n R(15);
n is zero 1, 2, 3, 4;
R(15) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(2) is (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(2) is SR(18), -OR(18), -NR(18)R(19), -CR(18)R(19)R(20);
R(18) is-C a H2a-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
a is zero,1 or 2;
R(19) and R(20)

205
independently of one another are defined as R(18) or are
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(2) is R(21)-SO m or R(22)R(23)N-SO2-;
m is 1 or 2;
R(21) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl,
-C n H2n-R(24),
n is zero, 1, 2, 3 or 4;
R(24) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);
R(27) and R(28)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(22) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl,
-C n H2n-R(29);
n is zero, 1, 2, 3 or 4;
R(29) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(30)R(31 );
R(30) and R(31)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(23) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(22) and R(23)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or

206
R(2) is R(33)X-;
X is oxygen, S, NR(34), (D=O)A-, NR(34)C=MN(*)R(35)-;
M is oxygen or S;
A is oxygen or NR(34);
D is C or SO;
R(33) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)b C d F2d+1, -C n H2n-
R(36),
b is zero or 1;
d is 1, 2, 3, 4, 5, 6 or 7;
n is zero, 1, 2, 3 or 4;
R(36) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(37)R(38);
R(37) and R(38)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(34) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(35) is defined as R(33);
or
R(33) and R(34)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent structure;
or
R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42),
-C[R(42)R(43)OH], -C-CR(45), -CR(46)=CHR(45),
-[CR(47)R(48)]u-(CO)-[CR49)R(50)]v-R(44);
R(40), R(41)
identically or differently are -(CH2)p-(CHOH)q-(CH2)r-
(CHOH)t-R(51) or -(CH2)p-O-(CH2-CH2O)q-R(51);

207
R(51) is hydrogen or methyl;
u is 1, 2, 3 or 4;
v is zero, 1, 2, 3 or 4;
p, q, r
identically or differently are zero, 1, 2, 3 or 4;
t is 1, 2, 3 or 4;
R(42) and R(43)
identically or differently are hydrogen or (C1-C6)-alkyl;
or
R(42) and R(43)
together with the carbon atom carrying them form a (C3-C8)-cycloalkyl;
R(44) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or-C e H2e-R(45);
e is zero, 1, 2, 3 or 4;
R(45) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(52)R(53) where
R(52) and R(53) are H or (C1-C4)-alkyl, or
R(45) is (C1-C9)-heteroaryl,
which is unsubstituted or substituted as phenyl;
or
R(45) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3 OH;
R(46), R(47), R(48), R(49) and R(50)
are hydrogen or methyl;
or
R(2) is R(55)-NH-SO2-;
R(55) is R(56)R(57)N-(C=Y)-;
Y is oxygen, S or N-R(58);
R(56) and R(57)
identically or differently are H, (C1-C8)-alkyl, (C3-C6)-alkenyl
or -C f H2f-R(59);
f is zero,1, 2, 3 or 4;

208
R(59) is (C5-C7)-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1
- 3 substituents selected from the group
consisting of F, Cl, CF3, methoxy and
(C1-C4)-alkyl;
or
R(56) and R(57)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
R(58) is defined as R(56) or is amidine;
R(3), R(4) and R(5)
independently of one another are defined as R(1) or R(2);
and their pharmaceutically tolerable salts;

q) benzoylguanidines of the formula I

Image

in which:
R(1) is hydrogen, F, Cl, Br, I, -NO2, -C=N, -X o-(CH2)p-(CF2)q-CF3,
R(5)-SO m-, R(6)-CO-, R(6)R(7)N-CO- or R(6)R(7)N-SO2-;
X is oxygen, -S- or NR(14);
m is zero, 1 or 2;
o is zero or 1;
p is zero, 1 or 2;
q is zero, 1, 2, 3, 4, 5 or 6;
R(5) and R(6)

209
are (C1-C8)-alkyl, (C3-C6)-alkenYI, -C n H2n-R(8) or CF3;
n is zero, 1, 2, 3 or 4;
R(8) is (C3-C7)-cycloalkyl, phenyl,
which is not substituted or is substituted by 1 to
3 substituents selected from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(9)R(10);
R(9) and R(10)
are H or (C1-C4)-alkyl;
or
R(6) is hydrogen;
R(7) is hydrogen or (C1-C4)-alkyl;
or
R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is

Image , Image or Image

R(11) is (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 to 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino, dimethylamino and
benzyl;
Y is oxygen, -S- or NR(12);
R(12) is H or (C1-C4)-alkyl;
R(3) is defined as R(1);
or
R(3) is (C1-C6)-alkyl or -X-R(13);
X is oxygen, -S- or NR(14);
R(14) is H or (C1-C3)-alkyl;
R(13) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -C b H2b-R(15);

210
b is zero, 1, 2, 3 or 4;
or
R(13) and R(14)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
R(15) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or (C1-C4)-alkyl;
R(4) is hydrogen, -OR(16), -NR(1 6)R(17) or C r F2r+1;
R(16) and R(17)
independently are hydrogen or (C1-C3)-alkyl;
r is 1, 2, 3 or 4;
and their pharmaceutically tolerable salts;

r) benzo-fused 5-membered ring heterocycles of the formula I

Image

in which:
X is N or CR(6);
Y is oxygen, S or NR(7);
A, B together are a bond
or
A, B are both hydrogen, if X is simultaneously CR(6) and Y is NR(7);
one of the substituents R(1 ) to R(6) is a -CO-N=C(NH2)2 group;
the other substituents R(1) to R(6) in each case

211
are hydrogen, F, Cl, Br, I or (C1-C6)-alkyl;
up to two of the other substituents R(1 ) to R(6)
are CN, NO2, N3, (C1-C4)-alkyloxy or CF3;
up to one of the other substituents
is R(8)-C n H2n-z-;
n is zero to 10;
where the alkylene chain -C n H2n- is straight-chain or
branched and where one carbon atom can be replaced by an
oxygen or sulfur atom or by a nitrogen atom;
R(8) is hydrogen, (C2-C6)-alkenyl or (C3-C10)-cycloalkyl,
which is unsubstituted or substituted by 1 to 4 methyl
groups or an OH group, or can contain an ethylene
group -CH=CH-, and in which one methylene group
can be replaced by an oxygen or sulfur atom or by a
nitrogen atom;
or
R(8) is phenyl,
which is unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of F,
Cl, Br, I, CF3, CH3-S(O)s- or R(9)-W y-;
s is zero, 1 or 2;
R(9) is H, methyl, ethyl,
W is oxygen or NR(10);
R(10) is H or methyl;
y is zero or 1;
or
R(8) is C m F2m+1;
m is 1 to 3;
or
R(8) is 1- or 2-naphthyl, pyridyl, quinolyl or isoquinolyl;
Z is -CO-, -CH2- or -[CR(11)(OH)]q-;
q is 1, 2 or 3;
R(11) is H or methyl;
or

212
Z is oxygen or -NR(12)-;
R(12) is H or methyl;
or
Z is-S(O)s-;
s is zero, 1 or 2;
or
Z is -SO2-NR(13)-;
R(13) is H or (C1-C4)-alkyl;
R(7) is hydrogen, (C1-C10)-alkyl, (C2-C10)-alkenyl or R(8)-C n H2n-;
and their pharmaceutically tolerable salts;

s) benzoylguanidines of the formula I

Image

in which:
R(1), R(3) or R(4)
is-NR(6) C=X NR(7)R(8);
X is oxygen or S;
R(6) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl,
(C3-C8)-alkenyl or -C n H2n-R(9);
n is zero, 1, 2, 3 or 4;
R(9) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(10)R(11);
R(10) and R(11)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

213
R(7) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl,
(C3-C8)-alkenyl or-coH2o-R(12);
o is zero, 1, 2, 3 or 4;
R(12) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(13)R(14);
R(13) and R(14)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(8) is defined as R(7);
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
the remaining substituents R(2), R(3), R(4), R(5) or R(1), R(2), R(4), R(5)
or R(1), R(2), R(3), R(5) in each case
independently of one another are hydrogen, F, Cl, Br, I, -O ta(C1-C8)-alkyl,
-O tb(C3-C8)-alkenyl,
O tc(CH2)b C d F2d+1, -O td C p H2p R(18),
or up to 2 groups CN, NO2, NR(16)R(17),
b is zero or 1;
d is 1, 2, 3, 4, 5, 6 or 7;
ta is zero or 1;
tb is zero or 1;
tc is zero or 1;
td is zero or 1;
p is zero, 1, 2, 3 or 4;
R(18) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are

214
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(19)R(20);
R(19) and R(20)
are hydrogen or (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(16) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl,
-C q H2q-R(21),
q is zero, 1, 2, 3 or 4;
R(21) is (C3-C8)-cycloalkyl, phenyl, biphenylyl ornaphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
F, Cl, CF3, methyl, methoxy or NR(22)R(23),
R(22) and R(23) are hydrogen, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(17) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl,
-C r H2r-R(24);
r is zero, 1, 2, 3 or 4;
R(24) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(25)R(26);
R(25) and R(26)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(16) and R(17)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
and their pharmaceutically tolerable salts;

t) diacyl-substituted guanidines of the formula I

215

Image

in which:
X(1) and X(2) are


Image


T1 is zero, 1, 2, 3 or 4;
R(A) and R(B)
independently of one another are hydrogen, F, Cl, Br, I, CN,
OR(106), (C1-C8)-alkyl, (C3-C8)-cycloalkyl, O zk(CH2)zl C zm F2zm+1,
NR(107)R(108), phenyl or benzyl,
where the aromatics are not substituted or are substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(109)R(110);
R(109) and R(110)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
zl is zero, 1, 2, 3 or 4;
zk is zero or 1;
zm is 1, 2, 3, 4, 5, 6, 7 or 8;
R(106)
is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(111)R(112);
R(111) and R(112)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

216

R(107) and R(108)
independently of one another are defined as R(106),
or
R(107) and R(108)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
X(1) and X(2) are

Image

T2a and T2b
independently of one another are zero, 1 or 2;
where the double bond can have the (E)- or (Z)-configuration;
or
X(1) and X(2) are


Image

T3 is zero, 1 or 2;
U, YY and Z
independently of one another are C or N,
where U, YY, Z can carry the following number of
substituents:

217

U, YY or Z Bonded in the ring to Number of pemmitted
a double bond substituents
C yes 1
C no 2
N yes 0
N no 1

R(D) is hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl,
R(U1), R(U2), R(Y1), R(Y2), R(Z1), R(Z2)
independently of one another are hydrogen, F, Cl, Br, I, CN,
OR(114), (C1-C8)-alkyl, (C3-C8)-cycloalkyl,
O zka(CH2)zla C zma F2zma+1, NR(115)R(116), phenyl or benzyl,
where the aromatics are not substituted or are substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy, NR(117)R(118),
R(117) and R(118)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
zka is zero or 1;
zla is zero, 1, 2, 3 or 4;
zma is 1, 2, 3, 4, 5, 6, 7 or 8;
R(114)
is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(119)R(120);
R(119) and R(120)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(115) and R(116) independently of one another are defined as
R(114);
or

218
R(115) and R(116)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
but where the constitution of U is nitrogen (N), YY is nitrogen (N)
and Z is carbon (C) is excluded,
R(101), R(102), R(103), R(104) and R(105)
independently of one another are hydrogen, F, Cl, Br, I, -C-N,
X zoa-(CH2)zpa-(C zqa F2zqa+1), R(110a)-SO zbm, R(110b)R(110c)N-CO,
R(111a)-CO- or R(112a)R(113a)N-SO2-,
where the perfluoroalkyl group is straight-chain or branched,
X is oxygen, S or NR(114a);
R(114a)
is H or (C1-C3)-alkyl;
zoa is zero or 1;
zbm is zero, 1 or 2;
zpa is zero, 1, 2, 3 or 4;
zqa is 1, 2, 3, 4, 5, 6, 7 or 8;
R(110a), R(110b), R(111a) and R(112a)
independently of one another are (C1-C8)-alkyl,
(C3-C8)-alkenyl, -C zn H2zn-R(115a) or (C1-C8)-perfluoroalkyl;
zn is zero, 1, 2, 3 or 4;
R(115a)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(116a)R(117a);
R(116a) and R(117a)
are hydrogen, (C1-C4)-perfluoroalkyl or
(C1-C4)-alkyl;
or
R(110b), R(111a) and R(112a)
are hydrogen;
R(110c) and R(113a)

219
independently are hydrogen, (C1-C4)-perfluoroalkyl or
(C1-C4)-alkyl;
or
R(110b) and R(110c) and R(112a) and R(113a)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are (C1-C8)-alkyl, -C zal H2zal R(118a) or
(C3-C8)-alkenyl,
zal is zero, 1, 2, 3 or 4;
R(118a)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy or
NR(119a)R(119b);
R(119a) and R(119b)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents from the group consisting of
F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are -C-C-R(193);
R(193)
is phenyl which is not substituted or is substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3, methyl,

220
methoxy or NR(194)R(195);
R(194) and R(195)
are hydrogen or CH3;
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are
-Y-para-C6H4-(CO)zh-(CHOH)zi-(CH2)zj-(CHOH)zk-R(123),
-y-meta-C6H4-(CO)zad-(CHOH)zae-(CH2)zaf-(CHOH)zag-R(124)
or
Y ortho-C6H4-(CO)zah-(CHOH)zao-(CH2)zap-(CHOH)zak-R(125);
Y is oxygen, -S- or-NR(122d)-;
zh, zad, zah
independently are zero or 1;
zi, zj, zk, zae, zaf, zag, zao, zap and zak
independently are zero, 1, 2, 3 or 4;
but where in each case
zh, zi and zk are not simultaneously zero,
zad, zae and zag are not simultaneously zero, and
zah, zao and zak are not simultaneously zero,
R(123), R(124) R(125) and R(122d)
independently are hydrogen or (C1-C3)-alkyl;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are SR(129), -OR(130),
-NR(131)R(132) or -CR(133)R(134)R(135);
R(129), R(130), R(131) and R(133)
independently are -C zab H2zab-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
zab is zero, 1 or 2;
R(132), R(134) and R(135)
independently of one another are defined as R(129) or are

221
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are -W-para-(C6H4)-R(196),
-W-meta-(C6H4)-R(197) or -W-ortho-(C6H4)-R(198);
R(196), R(197) and R(198)
independently are (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 to 3 substituents from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl,
amino, methylamino, dimethylamino and benzyl;
W is oxygen, S or NR(136)-;
R(136)
is hydrogen or (C1-C4)-alkyl;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are R(146)X(1a)-;
X(1a)
is oxygen, S, NR(147), (D=O)A-, NR(148)C=MN(*)R(149)-;
M is oxygen or sulfur;
A is oxygen or NR(150);
D is C or SO;
R(146)
is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)zbz C zdz F2zdz+1 or
-C zxa H2zxa-R(151);
zbz is zero or 1;
zdz is 1, 2, 3, 4, 5, 6 or 7;
zxa is zero, 1, 2, 3 or 4;
R(151)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(152)R(153);

222
R(152) and R(153)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(147), R(148) and R(150)
independently are hydrogen, (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl;
R(149) is defined as R(146),
or
R(146) and R(147), or R(146) and R(148)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the alkanoyl
parent structure;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are -SR(164), -OR(165), -NHR(166),
-NR(167)R(168), -CHR(169)R(170), -CR(154)R(155)OH,
-C~CR(156), -CR(158)=CR(157) or
-[CR(159)R(160)]zu-(C=O)-[CR(161)R(162)]zv-R(163);
R(164), R(165), R(166), R(167), R(169)
identically or differently are -(CH2)zy-(CHOH)zz-(CH2)zaa-
CHOH)zt-R(171) or -(CH2)zab-O-(CH2-CH2O)zac-R(172);
R(171) and R(172)
are hydrogen or methyl;
zu is 1, 2, 3 or4;
zv is zero, 1, 2, 3 or 4;
zy, zz, zaa, zab, zac
identically or differently are zero,1, 2, 3 or 4;
zt is 1, 2, 3 or4;
R(168), R(170), R(154), R(155)
identically or differently are hydrogen or (C1-C6)-alkyl,
or
R(169) and R(170), or R(154) and R(155)

223
together with the carbon atom carrying them are a (C3-C8)-cycloalkyl;
R(163)
is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or
-C zeb H2zeb-R(173);
zeb is zero, 1, 2, 3 or 4;
R(156), R(157) and R(173)
independently are phenyl which is unsubstituted or is
substituted b y 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(174)R(175);
R(174) and R(175)
are hydrogen or (C1-C4)-alkyl;
or
R(156), R(157) and R(173)
independently are (C1-C9)-heteroaryl,
which is unsubstituted or substituted as phenyl;
R(158), R(159), R(160), R(161) and R(162)
are hydrogen or methyl,
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are R(176)-NH-SO2-;
R(176)
is R(177)R(178)N-(C=Y')-;
Y' is oxygen, S or N-R(179);
R(177) and R(178)
identically or differently are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or-C zfa H2zfa-R(180);
zfa is zero, 1, 2, 3 or 4;
R(180)
is (C5-C7)-cycloalkyl or phenyl,
which [lacuna] unsubstituted [lacuna] by
1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methoxy

224
or (C1-C4)-alkyl;
or
R(177) and R(178)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, sulfur, NH,
N-CH3 or N-benzyl;

R(179)
is defined as R(177) or is amidine,
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are NR(184a)R(185), OR(184b),
SR(184c) or -C znx H2znx-R(184d);
znx is zero, 1, 2, 3 or 4;
R(184d)
is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
methyl, methoxyand NR(116k)R(117k);
R(116k) and R(117k)
are hydrogen or C1-C4-alkyl;
R(184a), R(184b), R(184c), R(185)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl or (CH2)zao-R(184g);
zao is zero, 1, 2, 3 or 4;
184g
is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or substituted by 1 - 3
substituents from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(184u)R(184v);
R(184u) and R(184v)
are hydrogen or C1-C4-alkyl;
or
R(184a) and R(185)

225
together are 4 or 5 methylene groups, of
which one CH2 group can be replaced by
oxygen, sulfur, NH, N-CH3 or N-benzyl;
and their pharmaceutically tolerable salts;

u) benzoylguanidines of the formula I

Image

in which:
R(1) is H, F, Cl, Br, I, CN, N02, (C1-C8)-alkyl, (C3-C8)-cycloalkyl or
X a-(CH2)b-(CF2)c-CF3;
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, (C1-C4)-alkyl or -C d H2d R(6);
d is zero, 1, 2, 3 or 4;
R(6) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 to 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(7)R(8);
R(7) and R(8)
independently are H or (C1-C4)-alkyl;
or

226
R(1) is -SR(10), -OR(10) or -CR(10)R(11)R(12);
R(10) is-C f H2f-(C3-C8)-cycloalkyl,-(C1-C9)-heteroarylorphenyl~
where the aromatic systems are unsubstituted or
substituted by one to 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
f is zero, 1 or 2;
R(11) and R(12)
independently of one another are defined as R(10) or are
hydrogen or (C1-C4)-alkyl;
or
R(1) is phenyl, naphthyl, biphenylyl or (C1-C9)-heteroaryl,
the latter linked via C or N,
and which are unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
or
R(1) is -SR(13), -OR(13), -NHR(13), -NR(13)R(14), -CHR(13)R(15),
-C[R(15)R(16)]OH, -C~CR(18), -C[R(19)]=CR(18), -[CR(20)R(21)]k-
(CO)-[CR(22)R(23)R(24)];
R(13) and R(14)
identically or differently are -(CH2)g-(CHOH)h-(CH2)i-(CHOH)j-
R(17),
R(17) is hydrogen or methyl;
-(CH2)g-O-(CH2-CH2O)h-R(24),
g, h, i
identically or differently are zero, 1, 2, 3 or 4;
j is 1, 2, 3 or 4;
R(15) and R(16)
identically or differently are hydrogen, (C1-C6)-alkyl or
together with the carbon atom carrying them are a (C3-C8)-cycloalkyl;


227

R(18) isphenyl,which is unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(25)R(26);
R(25) and R(26)
are H or (C1-C4)-alkyl;
or
R(18) is(C1-C9)-heteroaryl,
which is unsubstituted or substituted as phenyl;
or
R(18) is(C1-C6)-alkyl,
which is unsubstituted or substituted by 1 to 3 OH;
or
R(18) is(C3-C8)-cycloalkyl;
R(19), R(20), R(21), R(22) and R(23)
are hydrogen or methyl;
k is zero, 1, 2, 3 or 4;
l is zero, 1, 2, 3 or 4;
R(24) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -C m H2m-R(18);
m is 1, 2, 3 or 4;
R(2) and R(3)
independently of one another are defined as R(1);
R(4) is (C1-C3)-alkyl, F, Cl, Br, I, CN or -(CH2)n-(CF2)o-CF3;
n is zero or 1;
o is zero, 1 or 2;
and their pharmaceutically tolerable salts;

228
v) acylguanidines of the formula I

Image

in which:
X is carbonyl, sulfonyl,
R(1 ) is H, (C1-C8)-alkyl,
unsubstituted or substituted by hydroxyl,
(C3-C8)-cycloalkyl, phenyl,
which is unsubstituted or substituted by 1 - 3 substituents
from the group F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino or dimethylamino,
R(2) is H, (C1-C4)-alkyl,
and their pharmaceutically tolerable salts;

w) phenyl-substituted alkycarboxylic acid guanidides, carrying
perfluoroalkyl groups, of the formula I

Image

in which:
R(A) is hydrogen, F, Cl, Br, I, CN, OR(6), (C1-C8)-alkyl, (C3-C8)-cycloalkyl,
O r(CH2)a C b F2b+1 or NR(7)R(8);
r is zero or 1;
a is zero, 1, 2, 3 or 4;
b is 1 , 2, 3, 4, 5, 6, 7 or 8;
R(6) is hydrogen, (C1-C8)-alkyl, (C3-C8)-alkenyl, (C3-C8)-cycloalkyl,


229
phenyl or benzyl,where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(9)R(10);
R(9) and R(10)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8)
independently of one another are defined as R(6);
R(B) independently is defined as R(A);
X is 1, 2 or 3;
R(1) is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, -O t(CH2)d C e F2e+1, F,
Cl, Br, I or CN;
t is zero or 1;
d is zero, 1, 2, 3 or 4;
e is 1 , 2, 3, 4, 5, 6, 7 or 8;
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1);
but with the condition
that at least one of the substituents R(1), R(2), R(3), R(4), R(5), R(A) and
R(B) is an -O t(CH2)d C e F2e+1 or an O r(CH2)a C b F2b+1 group,
and their pharmaceutically tolerable salts;

x) heteroaroylguanidines of the formua I

Image


in which:
HA is SO m, O or NR(5);
m is zero, 1 or 2;
R(5) is hydrogen, (C1-C8)-alkyl or -C am H2am R(81);

230
am is zero, 1 or 2;
R(81) is (C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted
by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl,
methoxy and N R(82)R(83);
R(82) and R(83)
is H or CH3;
or
R(81) is (C1-C9)-heteroaryl,
which is linked via C or N and which is
unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
one of the two substituents R(1) and R(2)
is -CO-N=C(NH2)2;
and the other in each case
is hydrogen, F, Cl, Br, I, (C1-C3)-alkyl, -OR(6), C r F2r+1,
-CO-N=C(NH2)2 or -NR(6)R(7);
R(6) and R(7)
independently are hydrogen or (C1-C3)-alkyl;
r is 1, 2, 3 or 4;
R(3) and R(4)
independently of one another are hydrogen, F, Cl, Br, I, -C~N,
X-(CH2)p-(Cq-F2q+1), R(8)-SO bm, R(9)R(10)N-CO, R(11)-CO- or
R(12)R(13)N-SO2-,
where the perfluoroalkyl group is straight-chain or branched,
X is oxygen, S or NR(14);
R(14) is H or(C1-C3)-alkyl;
bm is zero, 1 or 2;
p is zero, 1 or 2;

231
q is zero, 1, 2, 3, 4, 5 or 6;
R(8), R(9), R(11) and R(12)
independently are (C1-C8)-alkyl, (C3-C6)-alkenyl,
-C n H2n-R(15), CF3;
n is zero, 1, 2, 3 or 4;
R(15) is (C3-C7)-cycloalkyl or phenyl;
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy or NR(16)R(17);
R(16) and R(17)
are H or C1-C4-alkyl;
or
R(9), R(11) and R(12)
are H;
R(10) and R(13)
independently are H or (C1-C4)-alkyl;
or
R(9) and R(10), and R(12) and R(13)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
or
R(3) and R(4)
independently of one another are (C1-C8)-alkyl or -C al H2al R(18);
al is zero, 1 or 2;
R(18) is (C3-C8)-cycloalkyl or phenyl;
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(19)R(20);
R(19) and R(20)
are H or CH3;
or
R(3) and R(4)

232
independently of one another are (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(3) and R(4)
independently of one another are

Image


or Image

or Image

Y is oxygen, -S- or -NR(22)-;
h, ad, ah independently are zero or 1;
i, j, k, ae, af, ag, ao, ap and ak independently are zero, 1, 2, 3, 4,
but where in each case
h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero,
ah, ao and ak are not simultaneously zero,
R(23), R(24) R(25) and R(22)
independently are hydrogen or (C1-C3)-alkyl;
or
R(3) and R(4)
independently of one another are hydrogen, F, Cl, Br, I, CN,
(C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or-C g H2g R(26);
g is zero, 1, 2, 3 or 4;

233
R(26) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(27)R(28);
R(27) and R(28)
are H, (C1-C4)-alkyl or (C1-C4)-pefluoroalkyl;
or
R(3) and R(4)
independently of one another are SR(29), -OR(30), -NR(31)R(32) or
-CR(33)R(34)R(35);
R(29), R(30), R(31) and R(33)
independently are -C a H2a-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
a is zero, 1 or 2;
R(32), R(34) and R(35)
independently of one another are defined as R(29) or are
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3) and R(4)
independently of one another are

Image , Image or Image


R(96), R(97) and R(98)
independently are (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted
or substituted by 1 to 3 substituents selected from the

234
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino, dimethylamino or
benzyl;
W is oxygen, S or NR(36)-;
R(36) is H or (C1-C4)-alkyl;
or
R(3) and R(4)
independently of one another are R(37)-SOcm or R(38)R(39)N-SO2-;
cm is 1 or 2;
R(37) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-C s H2s R(40);
s is zero, 1, 2, 3 or 4;
R(40) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(41)R(42);
R(41) and R(42)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(38) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-C w H2w-R(43);
w is zero, 1, 2, 3 or 4;
R(43) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(44)R(45);
R(44) and R(45)
are H, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(39) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;


235
or
R(38) and R(39)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
R(3) and R(4)
independently of one another are R(46)X(1)-;
X(1) is oxygen, S, NR(47), (D=O)A-, NR(48)C=MN(*)R(49)-,
M is oxygen or S;
A is oxygen or NR(50);
D is C or SO;
R(46) is (C1-C8)-alkyl. (C3-C8)-alkenyl, (CH2)b C d F2d+1 or -C x H2x-
R(51);
b is zero or 1;
d is 1, 2, 3, 4, 5, 6 or 7;
x is zero, 1, 2, 3 or 4;
R(51) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(52)R(53);
R(52) and R(53)
are H, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(47), R(48) and R(50)
independently are hydrogen, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(49) is defined as R(46);
or
R(46) and R(47), or R(46) and R(48)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3

236
or N-benzyl,
where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent structure;
or
R(3) and R(4)
independently of one another are -SR(64), -OR(65), -NHR(66),
-NR(67)R(68), -CHR(69)R(70), -C(OH)R(54)R(55), -C~CR(56),
-CR(58)=CHR(57), -[CR(59)R(60)]u-(CO)-[CR(61)R(62)]v-R(63);
R(64), R(65), R(66), R(67) and R(69)
identically or differently are -(CH2)y-(CHOH)z-(CH2)aa-
(CH2OH)t-R(71) or -(CH2)ab-O-(CH2-CH2O)ac-R(72),
R(71) and R(72)
are hydrogen or methyl;
u is 1, 2, 3 or 4;
v is zero, 1, 2, 3 or 4;
y, z, aa
identically or differently are zero, 1, 2, 3 or 4;
t is 1, 2,3 or 4;
R(68), R(70), R(54) and R(55)
identically or differently are hydrogen, (C1-C6)-alkyl;
or
R(69) and R(70), or R(54) and R(55)
together with the carbon atom carrying them are a
(C3-C8)-cycloalkyl;
R(63)
is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -C e H2e-R(73);
e is zero, 1, 2, 3 or 4;
R(56), R(57) and R(73)
independently are phenyl,
which are unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(74)R(75);

237
R(74) and R(75)
are H or (C1-C4)-alkyl;
or
R(56), R(57) and R(73)
independently are (C1-C9)-heteroaryl,
which is unsubstituted or substitued as phenyl;
R(58), R(59), R(60), R(61) and R(62)
are hydrogen or methyl,
or
R(3) and R(4)
independently of one another are R(76)-NH-SO2-;
R(76) is R(77)R(78)N-(C=Y')-;
Y' is oxygen, S or N-R(79);
R(77) and R(78)
identically or differently are H, (C1-C8)-alkyl, (C3-C6)-alkenyl,
-C f H2f-R(80);
f is zero, 1, 2, 3 or 4;
R(80) is (C5-C7)-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methoxy and (C1-C4)-alkyl;
or
R(77) and R(78)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
R(79)
is defined as R(77) or is amidine;
or
R(3) and R(4)
independently of one another are NR(84)R(85);
R(84) and R(85)
independently of one another are H, (C1-C4)-alkyl, or together

238
are 4 or 5 methylene groups,
of which one CH2 group can be replaced by oxygen, S,
NH, N-CH3 or N-benzyl; or of which one or two CH2
groups can be replaced by CH-C dm H2dm+1
and their pharmaceutically tolerable salts;

y) bicyclic heteroaroylguanidines of the formula I

Image

in which:
T, U, V, W, X, Y and Z
independently of one another are nitrogen or carbon;
but with the restriction
that X and Z are not simultaneously nitrogen,
and that T, U, V, W, X, Y and Z carry no substituents if they are
nitrogen,
and that no more than four of them are simultaneously nitrogen,
R(1) and R(2)
independently of one another are hydrogen, F, Cl, Br, 1, (C1-C3)-alkyl,
(C1-C3)-perfluoroalkyl, OR(8), N R(8)R(9) or C(=O)N=C(NH2)2;
R(8) and R(9)
independently of one another are hydrogen or (C1-C3)-alkyl,
or
R(8) and R(9)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NHI N-CH3 or N-benzyl;
R(3), R(4), R(5), R(6) and R(7)

239
independently of one another are hydrogen, F, Cl, Br, l, -C~N,
X k-(CH2)p-(C q F2q+1), R(10a)-SO bm, R(10b)R(10c)N-CO, R(11)-CO- or
R(12)R(13)N-SO2-,
where the perfluoroalkyl group is straight-chain or branched;
X is oxygen, S or NR(14);
R(14) is H or (C1-C3)-alkyl;
bm is zero,1 or 2;
p is zero,1 or 2;
k is zero or 1;
q 1,2,3,4,5 or 6;
R(10a), R(10b), R(11) and R(12)
independently of one another are (C1-C8)-alkyl,
(C3-C6)-alkenyl, -C n H2n-R(15) or (C1-C8)-perfluoroalkyl;
n is zero, 1, 2, 3 or 4;
R(15) is (C3-C7)-cycloalkyl or phenyl, which is not substituted
or is substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are H or C1-C4-alkyl;
or
R(10b), R(11) and R(12)
are hydrogen;
R(10c) and R(13)
independently are hydrogen or (C1-C4)-alkyl;
or
R(10b) and R(10c) and R(12) and R(13)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
or
R(3), R(4), R(5), R(6) and R(7)

240
independently of one another are (C1-C8)-alkyl, -C al H2al R(18) or
(C3-C8)-alkenyl;
al is zero, 1 or 2;
R(18) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where
the aromatics are not substituted or are substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(19a)R(19b);
R(19a) and R(19b)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are (C1-C9)-heteroaryl, which is linked
via C or N and which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino or dimethylamino;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are

Image


or Image

or Image


Y is oxygen, -S- or -NR(22)-;

241
h, ad, ah
independently of one another are zero or 1;
i, j, k, ae, af, ag, ao, ap and ak
independently of one another are zero, 1, 2, 3 or 4;
but where in each case
h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero, and
ah, ao and ak are not simultaneously zero,
R(23), R(24) R(25) and R(22)
independently of one another are hydrogen or (C1-C3)-alkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are SR(29), -OR(30), -NR(31)R(32) or
-CR(33)R(34)R(35);
R(29), R(30), R(31) and R(33)
independently of one another are -C a H2a-(C1-C9)-heteroaryl, which
is unsubstituted or substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
a is zero, 1 or 2;
R(32), R(34) and R(35)
independently of one another are defined as R(29) or are
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are

Image , Image or Image


R(96), R(97) and R(98)
independently of one another are (C1-C9)-heteroaryl, which is

242
linked via C or N and which is unsubstitued or substituted by
1 to 3 substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino, dimethylamino
or benzyl;
W is oxygen, S or NR(36)-;
R(36) is H or (C1-C4)-alkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(46)X(1)-;
X(1) is oxygen, S, NR(47), (D=O)A- or NR(48)C=MN(*)R(49)-;
M is oxygen or sulfur;
A is oxygen or NR(50);
D is C or SO;
R(46) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)b C d F2d+1 or -C x H2x-R(51);
b is zero or 1;
d is 1, 2, 3, 4, 5, 6 or 7;
x is zero, 1, 2, 3 or 4;
R(51) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(52)R(53);
R(52) and R(53)
are hydrogen, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(47), R(48) and R(50) independently
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(49) is defined as R(46);
or
R(46) and R(47), or R(46) and R(48)
together are 4 or 5 methylene groups, of which one CH2

243
groups can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the
heteroaroylguanidine parent structure;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are -SR(64), -OR(65), -NHR(66),
-NR(67)R(68), -CHR(69)R(70) or -CR(54)R(55)OH, -C~CR(56),
-CR(58)=CR(57) or -[CR(59)R(60)]u-CO-[CR(61)R(62)]v-R(63);
R(64), R(65), R(66), R(67) and R(69)
identically or differently are
-(CH2)y-(CHOH)z-(CH2)aa-(CHOH)t-R(71) or
-(CH2)ab-O-(CH2-CH2O)ac-R(72);
R(71) and R(72)
independently of one another are hydrogen or methyl;
u is 1, 2, 3 or 4;
v is zero, 1, 2, 3 or 4;
y, z, aa identically or differently
are zero, 1, 2, 3 or 4;
t is 1, 2, 3 or 4;
R(68), R(70), R(54) and R(55)
identically or differently are hydrogen or (C1-C6)-alkyl;
or
R(69) and R(70), or R(54) and R(55)
together with the carbon atom carrying them are
(C3-C8)-cycloalkyl;
R(63)
is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or
-C e H2e-R(73);
e is zero, 1, 2, 3 or 4;
R(56), R(57) and R(73) independently
are phenyl, which is unsubstituted or substituted by 1 - 3

244
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(74)R(75);
R(74) and R(75)
are hydrogen or (C1-C4)-alkyl;
or
R(56), R(57) and R(73) independently
are (C1-C9)-heteroaryl, which is unsubstituted or substituted
as phenyl;
R(58), R(59), R(60), R(61) and R(62)
are hydrogen or methyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(76)-NH-SO2-;
R(76) is R(77)R(78)N-(C=Y')-;
Y' is oxygen, S or N-R(79);
R(77) and R(78)
identically or differently are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or -C f H2f-R(80);
f is zero, 1, 2, 3 or 4;
R(80) is (C5-C7)-cycloalkyl or phenyl, which [lacuna]
unsubstituted [lacuna] by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3,
methoxy and (C1-C4)-alkyl;
or
R(77) and R(78)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, sulfur, NH,
N-CH3 or N-benzyl;
R(79) is defined as R(77) or is amidine;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are NR(84a)R(85), OR(84b), SR(84c)

245
or -C n H2n-R(84d);
n is zero, 1, 2, 3 or 4;
R(84d) is (C3-C7)-cycloalkyl or phenyl, which is not
substituted or is substituted by 1 - 3 substituents from
the group consisting of F, Cl, CF3, methyl, methoxy
and NR(16)R(17);
R(16) and R(17)
are hydrogen or C1-C4-alkyl;
R(84a), R(84b), R(84c) and R(85)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl or (CH2)ax-R(84g);
ax is zero, 1, 2, 3 or 4;
R(84g) is (C3-C7)-cycloalkyl or phenyl, which is not
substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and
NR(84u)R(84v);
R(84u) and R(84v)
are hydrogen or C1-C4-alkyl;
or
R(84a) and R(85)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl,
and their pharmaceutically tolerable salts;

246
z) benzoylguanidines of the formula I


Image

in which:
R(1) is R(6)-SO m;
m is zero, 1 or 2;
R(6) is perfluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which
is straight-chain or branched;
R(2) and R(3)
independently of one another are hydrogen, F, Cl, Br, I, alkyl having
1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms
or phenoxy,
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, methyl and
methoxy;
or
R(2) and R(3)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 to 4
substituents selected from the group consisting of F, Cl, Br, I,
CN, alkanoyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
alkoxycarbonyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
formyl, carboxyl, CF3, methyl and methoxy;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2 or 3
carbon atoms, F, Cl, Br, I, CN, OR(7), NR(8)R(9) or -(CH2)n-(CF2)o-
CF3;

247
R(7), R(8) and R(9)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
n is zero or 1;
o is zero, 1 or 2;
and their pharmacologically acceptable salts;

ab) phenyl-substituted alkenylcarboxylic acid guanidides, carrying
perfluoroalkyl groups, of the formula I


Image


in which:
R(A) is hydrogen, F, Cl, Br, I, CN, OH, OR(6), (C1-C8)-alkyl,
O r(CH2)a C b F2b+1, (C3-C8)-cycloalkyl or NR(7)R(8);
r is zero or 1;
a is zero, 1, 2,3 or 4;
b is 1, 2, 3, 4, 5, 6, 7 or 8;
R(6) is (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methloxy and
NR(9)R(10);
R(9) and R(10)

248
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8)
independently of one another are defined as R(6);
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
R(B) independently is defined as R(A);
x is zero, 1 or 2;
y is zero, 1 or 2;
R(C) is hydrogen, F, Cl, Br, I, CN, OR(12), (C1-C8)-alkyl, Op(CH2)f C g F2g+1
or (C3-C8)-cycloalkyl;
p is zero or 1;
f is zero, 1, 2, 3 or 4;
g is 1, 2, 3, 4, 5, 6, 7 or 8;
R(12)
is (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatics phenyl or benzyl are not
substituted or are substituted by 1 - 3 substituents
from the group consisting of F, Cl, CF 3, methyl,
methoxy and NR(13)R(14);
R(13) and R(14)
independently of one another are H, (C1-C4)-alkyl
or (C1-C4)-perfluoroalkyl;
R(D) independently is defined as R(C),
R(1) is hydrogen, (C1-C8)-alkyl, -O t(CH2)d C e F2e+1 (C3-C8)-cycloalkyl, F,
Cl, Br, I or CN;
t is zero or 1;
d is zero, 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5, 6, 7 or 8;

249
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1);
but with the condition
that at least one of the substituents R(A), R(B), R(C), R(D), R(1), R(2), R(4)
or R(5) is a O r(CH2)a C b F 2b+1, O p(CH2)f C g F2g+1 or O t(CH2)d C e F2e+1 group
and R(3) is not a O t(CH2)d C e F2e+1 group;
and their pharmaceutically tolerable salts;

ac) ortho-amino-substituted benzoylguanidines of the formula I

Image


in which:
R(1) is NR(50)R(6),
R(50) and R(6)
independently of one another are hydrogen, (C1-C8)-alkyl or
(C1-C8)-perfluoroalkyl;
R(2), R(3), R(4) and R(5)
independently of one another are R(10)-SO a-, R(11)R(12)N-CO-,
R(13)-CO- or R(14)R(15)N-SO2-;
a is zero, 1 or 2,
R(10), R(11), R(12), R(13), R(14) and R(15)
independently of one another are (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl, (C3-C6)-alkenyl or -C ab H2ab-R(16);
ab is zero, 1, 2, 3 or 4;
R(16) is (C3-C7)-cycloalkyl, phenyl,
which is not substituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy or NR(17)R(18);
R(17) and R(18)

250
independently of one another are H, CF3 or
(C1-C4)-alkyl;
or
R(11), R(12), and also R(14) and R(15)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
or
R(11), R(12), R(14) and R(15)
independently of one another are hydrogen;
or
R(2), R(3), R(4) and R(5)
independently of one another are SR(21), -OR(22), -NR(23)R(24) or
-CR(25)R(26)R(27);
R(21), R(22), R(23) and R(25)
independently of one another are -C b H2b-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, CH3,
methoxy, hydroxyl, amino, methylamino and dimethylamino;
b is zero, 1 or 2;
R(24), R(26) and R(27)
independently of one another are hydrogen, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
or
R(2), R(3), R(4) and R(5)
independently of one another are hydrogen, F, Cl, Br, I, CN,
-(Xa)dg-C da H2da+1, -(Xb)dh-(CH2)db-C de F2de+1, (C3-C8)-alkenyl or
-C df H2df R(30);
(Xa) is O, S or NR(33);
R(33)
is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
dg is zero or 1;

251
(Xb) is O, S or NR(34);
R(34)
is H, (C1-C4)-alkyl or (C1-C4)-perfiuoroalkyl;
dh is zero or 1;
da is zero, 1, 2, 3, 4, 5, 6, 7, 8;
db is zero, 1, 2, 3, 4;
de is zero, 1, 2, 3, 4, 5, 6, 7;
df is zero, 1, 2, 3, 4;
R(30)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where
the aromatics phenyl, biphenylyl or naphthyl are not
substituted or are substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3, methyl, methoxy and
NR(31 )R(32);
R(31) and R(32)
are H, (C1-C4)-alkyl or (C1-C4)-perfiuoroalkyl;
or
R(2), R(3), R(4) and R(5)
independently of one another are NR(40)R(41) or -(Xe)-
(CH2)eb R(45);
R(40) and R(41)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C1-C8)-perfiuoroalkyl or (CH2)e-R(42);
e is zero, 1, 2, 3 or 4;
R(42)
is (C3-C7)-cycloalkyl, phenyl, which is not substituted
or is substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(43)R(44);
R(43) and R(44)
independently of one another are H, CF3 or
(C1-C4)-alkyl;

252
or
R(40) and R(41)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
(Xe) is O, S or NR(47);
R(47)
is H, (C1-C4)-alkyl or (C1-C4)-plerfluoroalkyl;
eb is zero, 1, 2, 3 or 4;
R(45) is (C3-C7)-cycloalkyl, phenyl, which is not substituted or is
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3,methyl, methoxy, NR(50)R(51) and
-(Xfa)-(CH2)ed-(Xfb)R(46);
Xfa is CH2, O, S or NR(48);
Xfb is O, S or NR(49);
ed is 1, 2, 3 or 4;
R(46)
is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(48), R(49), R(50) and R(51)
independently of one another are H or (C1-C4)-alkyl or
(C1 -C4)-perfluoroalkyl;
where R(3) and R(4), however, cannot be hydrogen,
and their pharmaceutically tolerable salts;

ad) benzoylguanidines of the formula I



Image

253
in which:
one of the three substituents R(1), R(2) and R(3)
is (C1-C9)-heteroaryl-N-oxide,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
one of the three substituents R(1), R(2) and R(3)
is -SR(10), -OR(10), -NR(10)R(11) or -CR(10)R(11)R(12);
R(10)
is -C a H2a-(C1-C9)-heteroaryl-N-oxide,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
[lacuna] F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
a is zero, 1 or 2;
R(11) and R(12)
independently of one another are defined as R(10),
are hydrogen or (C1-C4)-alkyl;
and the other substituents R(1), R(2) and R(3) in each case
independently of one another are (C1-C8)-alkyl, (C2-C8)-alkenyl or
-C m H2m R(14);
m is zero, 1 or 2;
R(14) is (C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and
NR(15)R(16),
R(15) and R(16)
are hydrogen or CH3;
or

254
the other substituents R(1), R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, I, -C~N,
X-(CH2)p-(C q F2q+1), R(22)-SO u, R(23)R(24)N-CO, R(25)-CO- or
R(26)R(27)N-SO2-,
where the perfluoroalkyl group is straight-chain or branched;
X is a bond, oxygen, S or NR(28);
u is zero, 1 or 2;
p is zero, 1 or 2;
q is zero, 1, 2, 3, 4, 5 or 6;
R(22), R(23), R(25) and R(26)
independently are (C1-C8)-alkyl, (C2-C6)-alkenyl,
-C n H2n-R(29) or CF3;
n is zero, 1, 2, 3 or 4;
R(28) is hydrogen or (C1-C3)-alkyl;
R(29) is (C3-C7)-cycloalkyl or phenyl;
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and
NR(30)R(31);
R(30) and R(31)
are hydrogen or C1-C4-alkyl,
or
R(23), R(25) and R(26)
are also hydrogen;
R(24) and R(27)
independently of one another are hydrogen or (C1-C4)-alkyl;
or
R(23) and R(24), and also R(26) and R(27) together are 4 or 5
methylene groups, of which one CH2 group can be replaced by
oxygen, S, NH, N-CH3 or N-benzyl;
or
the other substituents R(1), R(2) and R(3) in each case

255
independently of one another are OR(35) or NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or (C1-C6)-alkyl;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
R(4) and R(5)
independently of one another are hydrogen, (C1-C4)-alkyl, F, Cl,
-OR(32), -NR(33)R(34) or C r F2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or (C1-C3)-alkyl;
r is 1, 2, 3 or 4;
and their pharmaceutically tolerable salts;

ad) benzoylguanidines of the formula I



Image



in which:
R(1) is hydrogen, F, Cl, Br, I, CN, NO2, OH, (C1-C8)-alkyl,
(C3-C8)-cycloalkyl, O a-(CH2)b-(CF2)c-CF3;
a is zero or 1;
b is zero, 1 or 2;
c is zero, 1, 2 or 3;
or
R(1) is R(5)-SO m or R(6)R(7)N-SO2-;
m is zero, 1 or 2;

256
R(5) and R(6) independently of one another
are (C1-C8)-alkyl, (C3-C6)-alkenyl, CF3 or-C n H2n-R(8);
n is zero, 1, 2, 3 or 4;
R(7) is hydrogen or (C1-C4)-alkyl;
R(8) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10) independently of one another
are hydrogen or (C1-C4)-alkyl;
or
R(6) is H;
or R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
or
R(1) is -SR(11), -OR(11) or -CR(11)R(12)R(13);
R(11) is -C p H2p-(C3-C8)-cycloalkyl, -(C1-C9)-heteroaryl or phenyl,
where the aromatic systems are unsubstituted
or substituted by 1 - 3 substituents selected
from the group consisting of Fl, Cl, CF3, CH3,
methoxy, hydroxyl, amino, methylamino and
dimethylamino;
R(12), R(13) independently of one another
are defined as R(11) or are hydrogen or
(C1-C4)-alkyl;
p is zero, 1 or 2;
or
R(1) is phenyl, naphthyl, biphenylyl or (C1-C9)-heteroaryl, the latter linked
via C or N,
which are unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, CH3,

257
methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(2) is -CF2R(14), -CF[R(1 5)][R(16)], -CF[(CF2)q-CF3)][R(15)],
-C[(CF2)r-CF3]=CR(15)R(16);
R(14) is (C1-C4)-alkyl or (C3-C6)-cycloalkyl;
R(15) and R(16) independently of one another
are hydrogen or (C1-C4)-alkyl;
q is zero, 1 or 2;
r is zero, 1 or 2;
R(3) is defined as R(1 );
R(4) is hydrogen, (C1-C3)-alkyl, F, Cl, Br, I, CN, -(CH2)s-(CF2)t-CF3;
s is zero or 1;
t is zero, 1 or 2;
and their pharmaceutically tolerable salts;

af) benzoylguanidines of the formula I



Image


in which:
one of the three substituents R(1), R(2) and R(3)
is -Y4-[(CH2)k-CHR(7)-(C=O)R(8)]-phenyl,
-Y-3-(CH2)k-CHR(7)-(C=O)R(8)]-phenyl or
Y-2-[(CH2)k-CHR(7)-(C=O)R(8)]-phen
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group F, Cl, -CF3, methyl,
hydroxyl, methoxy, or -NR(37)R(38);
R(37) and R(38)
independently of one another are hydrogen or -CH3;

258
Y is a bond, oxygen, -S- or -NR(9);
R(9) is hydrogen or -(C1-C4)-alkyl;
R(7) is -OR(10) or -NR(10)R(11);
R(10) and R(11)
independently of one another are hydrogen, -(C1-C8)-alkyl,
-(C1 -C8)-alkanoyl, -(C1-C8)-alkoxycarbonyl,
benzyl, benzyloxycarbonyl;
or
R(10) istrityl;
R(8) is -OR(12) or-NR(12)R(13);
R(12) and R(13)
independently of one another are hydrogen, -(C1-C8)-alkyl
or benzyl;
k is zero, 1, 2, 3 or 4;
and the other radicals R(1), R(2) and R(3) in each case
independently of one another are -(C1-C8)-alkyl, -(C2-C8)-alkenyl or
-(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, -CF3, methyl,
methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or -CH3;
or
the other radicals R(1), R(2) and R(3) in each case
independently of one another are R(18)R(19) N-(C=Y')-NH-SO2-;
Y' is oxygen, -S- or -N-R(20);
R(18) and R(19)
independently of one another are hydrogen, -(C1-C8)-alkyl,
-(C3-C6)-alkenyl or -(CH2)t-R(21);
t is zero, 1, 2, 3 or 4;

259
R(21) is -(C5-C7)-cycloalkylorphenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the groups consisting of F,
Cl, -CF3, methoxy and -(C1-C4)-alkyl;
or
R(18) and R(19)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -N-CH3 or -N-
benzyl;
R(20)
is defined as R(18) or is amidine;
or
the other radicals R(1), R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, I, -C~N,
X-(CH2)p-(C q F2q+1), R(22)-SO u-, R(23)R(24)N-CO-, R(25)-CO- or
R(26)R(27)N-SO2-, where the perfluoroalkyl group is straight-chain
or branched;
X is a bond, oxygen, -S- or -NR(28);
u is zero,1 or 2;
p is zero, 1 or 2;
q is 1, 2, 3, 4, 5 or 6;
R(22), R(23), R(25) and R(26)
independently of one another are -(C1-C8)-alkyl,
-(C3-C6)-alkenyl, -(CH2)n-R(29) or -CF3;
n is zero, 1, 2, 3 or 4;
R(28) is hydrogen or -(C1-C3)-alkyl;
R(29) is -(C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, -CF3, methyl, methoxy and -NR(30)R(31);
R(30) and R(31)
are hydrogen or -(C1-C4)-alkyl;

260
or
R(23), R(25) and R(26)
are hydrogen;
R(24) and R(27)
independently of one another are hydrogen or -(C1-C4)-alkyl;
or
R(23) and R(24), and also R(26) and R(27)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, - N-CH3 or
-N-benzyl;
or
the other radicals R(1), R(2) and R(3) in each case
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or -(C1-C6)-alkyl;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -N-CH3 or -N-benzyl;
R(4) and R(5)
independently of one another are hydrogen, -(C1-C4)-alkyl, F, Cl,
-OR(32), -NR(33)R(34) or -C r F2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or -(C1-C3)-alkyl;
r is 1, 2, 3 or 4;
and their pharmaceutically tolerable salts;

261
ag) benzoylguanidines of the formula I


Image


in which:
R(1) is R(6)-CO or R(7)R(8)N-CO;
R(6) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl
or -C n H2n-R(9),
n is zero, 1, 2, 3 or 4;
R(9) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(10)R(11),
R(10) and R(11)
are H, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(7) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl,
(C3-C8)-alkenyl or -C n H2n-R(12);
n is zero, 1, 2, 3 or 4;
R(12) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(13)R(14);


262
R(13) and R(14)
are H, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(8) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(7) and R(8) together
are 4 or 5 methylene groups, of which one CH2 group
can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is defined as R(1), or is H, OH, F, Cl, Br, l, CN, NO2, (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -C n H2n R(15);
n is zero,1, 2, 3 or 4;
R(15) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(16)R(17);
R(16) and R(17)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(2) is (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(2) is SR(18), -OR(18), -NR(18)R(19) or -CR(18)R(19)R(20);
R(18) -is C a H2a-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino,
dimethylamino;
a is zero,1 or 2;
R(19) and R(20)


263
independently of one another are defined as R(18) or
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(2) is R(21)-SO m or R(22)R(23)N-SO2-;
m is 1 or 2;
R(21) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-C n H2n-R(24);
n is zero, 1, 2, 3 or 4;
R(24) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);
R(27) and R(28)
are H, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(22) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-C n H2n-R(29);
n is zero, 1, 2, 3 or 4;
R(29) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(30)R(31);
R(30) and R(31)
are H, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(23) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(22) and R(23)
together are 4 or 5 methylene groups, of which one CH2


264
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
R(2) is R(33)X-;
X is oxygen, S, NR(34), (D=O)A- or NR(34)C=MN(*)R(35)-;
M is oxygen or S;
A is oxygen or NR(34);
D is C or SO;
R(33) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)b C d F2d+1 or
-C n H2n-R(36);
b is zero or 1;
d is 1, 2, 3, 4, 5, 6 or 7;
n is zero, 1, 2, 3, or 4;
R(36) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(37)R(38);
R(37) and R(38)
are H, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
R(34) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(35) is defined as R(33);
or
R(33) and R(34)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent structure;
or
R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42),


265
-CR(42)R(43)OH, -C~CR(45), -CR(46)=CR(45) or
-[CR(47)R(48)]u-CO-[C(R49)R(50)]v-R(44);
R(40) and R(41)
independently of one another are -(CH2)p-(CHOH)q-(CH2)r-
(CHOH)t-R(51) or -(CH2)p-O-(CH2-CH2O)q-R(51);
R(51) is hydrogen or methyl;
u is 1, 2, 3 or 4;
v is zero, 1, 2, 3 or 4;
p, q and r
independently of one another are zero, 1, 2, 3 or 4;
t is 1, 2, 3 or 4;
R(42) and R(43)
independently of one another are hydrogen or (C1-C6)-alkyl;
or
R(42) and R(43)
together with the carbon atom carrying them are a
(C3-C8)-cycloalkyl;
R(44) is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, -C e H2e-R(45);
e is zero, 1, 2, 3 or 4;
R(45) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(52)R(53);
R(52) and R(53)
are H or (C1-C4)-alkyl;
or
R(45) is (C1-C9)-heteroaryl,
which is unsubstituted or substituted as phenyl;
or
R(45) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3 OH;
R(46), R(47), R(48), R(49) and R(50)


266
independently of one another are hydrogen or methyl;
or
R(2) is R(55)-NH-SO2-;
R(55) is R(56)R(57)N-(C=Y)-;
Y is oxygen, S or N-R(58);
R(56) and R(57)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or -C f H2f-R(59);
f is zero, 1, 2, 3 or 4;
R(59) is (C5-C7)-cycloalkyl, phenyl,
which is unsubstituted or substituted by
1 - 3 substituents selecled from the
group consisting of F, Cl, CF3, methoxy
and (C1-C4)-alkyl;
or
R(56) and R(57)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(58)
is defined as R(56) or is amidine;
R(3), R(4) and R(5) are independently of one another defined as R(1) or
R(2), but where at least one of the substituents R(2), R(3), R(4) and R(5)
must be OH;
and their pharmaceutically tolerable salts;

ah) benzoylguanidines of the formula I

Image


267
in which:
one of the three substituents R(1), R(2) and R(3)
is R(6)-A-B-D-;
R(6) is a basic protonatable radical, i.e. an amino group
-NR(7)R(8), an amidino group R(7)R(8)N-C[=N-R(9)]- or a
guanidino group

Image

R(7), R(8), R(9) and R(10)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
or
R(7) and R(8)
together are C a H2a;
a is 4, 5, 6 or 7;
where if a = 5, 6 or 7 a methylene group of the group
C a H2a can be replaced by a heteroatom group O, SO m
or NR(11),
or
R(8) and R(9) or R(9) and R(10) or R(7) and R(10)
are a group C a H2a;
a is 2, 3, 4 or 5;
where if a = 3, 4 or 5 a methylene group of the
group C a H2a can be replaced by a heteroatom
group O, SO m or NR(11);
m is zero, 1 or 2;
R(11) is hydrogen or methyl;
or


268
R(6) is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is C b H2b;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
where in the group C b H2b one or two methylene
groups can be replaced by one of the groupings
selected from the group consisting of -O-, -CO-,
-CH[OR(20)]-, -SO m-, -NR(20)-, -NR(20)-CO-,
-NR(20)-CO-NH-, -NR(20)-CO-NH-SO2-

Image

and -SO aa[NR(19)]bb-;
and where in the group C b H2b a methylene group can
be replaced by -CH-R(99), where R(99) together with
R(7) forms a pyrrolidine or piperidine ring;
aa is 1 or 2;
bb is 0 or 1;
aa + bb = 2;
R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon
atoms;
R(20) is hydrogen or methyl;
B is a phenylene or naphthylene radical
Image Image

R(12) and R(13)
independently of one another are hydrogen, methyl, F,


269
Cl, Br, l, CF3 or -SO w-R(14);
R(14) is methyl or NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
alkyl having 1, 2, 3 or 4 carbon atoms;
w is zero, 1 or 2;
D is -C d H2d-X f-;
d is zero, 1, 2, 3 or 4;
X is -O-, -CO-, -CH[OR(21)]-, -SO m- or -NR(21)-;
f is zero or 1;
R(21) is hydrogen or methyl;
m is zero,1 or 2;
and the other substituents R(1) and R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, I, -CN,
-(C1-C8)-alkyl, -(C2-C8)-alkenyl, -NR(35)R(36) or R(17)-C g H2g-Z h-;
g is zero,1, 2, 3 or 4;
h is zero or 1;
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
Z is -O-, -CO-, -SO v-, -NR(18)-, -NR(18)-CO-, NR(18)-CO-NH-
or -NR(18)-SO2-;
R(18) is hydrogen or methyl;
v is zero, 1 or 2;
R(17) is hydrogen, cycloalkyl having 3, 5 or 6 carbon atoms or
C k F2k+1-;
k is 1, 2 or 3,
or


270
R(17) is pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4
substituents selected from the groupl consisting of F,
Cl, Br, I, -CN, (C2-C8)-alkanoyl,
(C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl and
methoxy;
or
R(17) -is (C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, hydroxyl, methoxy,
-NR(37)R(38), CH3SO2- and H2NO2S-;
R(37) and R(38)
are hydrogen or -CH3;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or -C r F-2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
r is 1 , 2, 3 or 4;
and their pharmacologically tolerable salts;

ai) indenoylguanidines of the formula I

Image

in which:


271
R(1) and R(2)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3, 4, 5 or 6
carbon atoms, O-alkyl having 1, 2, 3 or 4 carbon atoms,
O-C(=O)-alkyl having 1, 2, 3 or 4 carbon atoms or C m H2m-NR(12)R(13);
R(12) and R(13)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
m is zero, 2, 3 or 4;
NH-C(=O)-NH2, C(=O)-O-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-NH2, C(=O)-NH-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-N(alkyl)2 having 1, 2, 3 or 4 carbon atoms in each alkyl
group, alkenyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms,
alkynyl having 2, 3, 4, 5, 6, 7, 8, 9 or 1 0 carbon atoms, alkylaryl
having 1, 2, 3 or 4 carbon atoms in the alkyl group, alkenylaryl
having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the alkenyl group,
alkynylaryl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the
alkynyl group, C1-C4-alkyl-substituted aryl, C1-C4-alkylheteroaryl,
C1-C4-alkenylheteroaryl, aminoalkylaryl having 1, 2,, 3 or 4 carbon
atoms in the alkyl group, substituted aryl, heteroaryl and substituted
heteroaryl;
R(3), R(4), R(5) and R(6)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, O-alkyl having 1, 2, 3, 4, 5, 6, 7, 8,
9 or 10 carbon atoms, halogen, (such as F, Cl, Br, I), OH, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, O-lower alkyl,
O-aryl, O-lower alkylaryl, O-substituted aryl, O-lower
alkyl-substituted aryl, O-C(=O)-C1-C4-alkylaryl, O-C-(=O)-NH-C1-C4-alkyl,
O-C(=O)-N(C1-C4-alkyl)2, NO2, CN, CF3, NH2, NH-C(=O)-C1-C4-alkyl,
NH-C(=O)-NH2, COOH, C(=O)-O-C1-C4-alkyl, C(=O)-NH2,
C(=O)-NH-C1-C4-alkyl, C(=O)-N(C1-C4-alkyl)2, C1-C4-COOH,
C1-C4-alkyl-C(=O)-O-C1-C4-alkyl, SO3H, SO2-alkyl, SO2-alkylaryl,



272
SO2-N-(alkyl)2, SO2-N(alkyl)(alkylaryl), C(=O)-R(11), C1-C10-alkyl-C(=O)-R(11),
C2-C10-alkenyl-C(=O)-R(11), C2-C10-alkynyl-C(=O)-R(11),
NH-C(=O)-C1-C10-alkyl-C(=O)-R(11), O-C1-C11-alkyl-C(=O)-R(11);
R(11) is C1-C4-alkyl, C1-C4-alkynyl, aryl, substituted aryl, NH2,
NH-C1-C4-alkyl, N-(C1-C4-alkyl)2, SO3H, SO2-alkyl, SO2-alkylaryl,
SO2-N-(alkyl)2, SO2-N(alkyl)(alkylaryl);
X is O, S or NH;
R(7), R(8), R(9) and R(10)
independently of one another are hydrogen, alkyl, cycloalkyl, aryl,
alkylaryl;
or
R(8) and R(9)
together are part of a 5, 6 or 7-membered heterocyclic ring;
A is absent or is a nontoxic organic or inorganic acid.

ak) benzyloxycarbonylguanidines of the formula I

Image
in which:
R(1), R(2) and R(3)
independently of one another are -Y-[4-R(8)-phenyl],
-Y-[3-R(8)-phenyl] or -Y-[2-R(8)-phenyl],
where the phenyl is in each case unsubstituted or substituted
by 1 - 2 substituents from the group consisting of F, Cl, -CF3,
methyl, hydroxyl, methoxy and -NR(96)R(97);
R(96) and R(97)
independently of one another are hydrogen or -CH3;


273

Y is a bond, CH2, oxygen, -S- or-NR(9);
R(9) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(8) is SO a[NR(98)]b NR(99)R(10);
a is 1 or 2;
b is 0 or 1;
a + b = 2;
R(98), R(99) and R(10)
independently of one another are hydrogen,
-(C1-C8)-alkyl, benzyl, -(C2-C8)-alkylene-NR(11)R(12),
(C2-C8)-alkylene-NR(13)-(C2-C8)-alkylene-NR(37)R(38) or
(C0-C8)-alkylene-CR(39)R(40)CR(41)R(42)(C0-C8)-
alkylene-NR(43)R(44);
R(11), R(12), R(13), R(37), R(38), R(43) and R(44)
independently of one another are hydrogen,
-(C1-C8)-alkyl or benzyl:
R(39), R(40), R(41) and R(42)
independently of one another are hydrogen,
-(C1-C8)-alkyl or -(C0-C3)-alkylenephenyl,
where the phenyl is not substituted or is
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, -CF3,
methyl and methoxy;
or
R(99) and R(10)
together are 4 - 6 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -N-CH3 or
-N-benzyl;
or
R(8) is SO a[NR(98)]b NR(95)-C[=N-R(94)]-NR(93)R(92);
R(92), R(93), R(94) and R(95)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;


274
or
R(1), R(2) and R(3)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, I, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl, methoxy;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, -(C1-C8)-alkyl,
-(C2-C8)-alkenyl or -(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and -Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
R(1), R(2) and R(3)
independently of one another are -Q-4-[(CH2)k-CHR(17)-
(C=O)R(20)]-phenyl, -Q-3-(CH2)k-CHR(17)-(C=O)R(20)]-phenyl or
-Q-2-[(CH2)k-CHR(17)-(C=O)R(20)]-phenyl.
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group F, Cl, -CF3, methyl,
hydroxyl, methoxy and -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or-CH3;
Q is a bond, oxygen, -S- or-NR(18);
R(18) is hydrogen or-(C1-C4)-alkyl;
R(17) is -OR(21) or -NR(21)R(22);


275
R(21) and R(22)
independently of one another are hydrogen,
-(C1-C8)-alkyl, -(C1-C8)-alkanoyl, -(C1-C8)-alkoxycarbonyl,
benzyl, benzyloxycarbonyl;
or
R(21) is trityl;
R(20) is -OR(23) or -NR(23)R(24);
R(23), R(24) independently of one another are
hydrogen, -(C1-C8)-alkyl or benzyl;
k is zero, 1, 2, 3 or 4;
or
R(1), R(2) and R(3)
independently of one another are (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents from the group F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
or
R(1), R(2) and R(3)
are -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is -C f H2f-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents from the group F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
f is zero, 1 or 2;
R(26) and R(27)
independently of one another are defined as R(25) or
are hydrogen or (C1-C4)-alkyl,
or
R(1), R(2) and R(3)
independently of one another are (C1-C9)-heteroaryl-N-oxide,
which is linked via C or N and which is unsubstituted or


276
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(1), R(2) and R(3)
independently of one another are -SR(28), -OR(28), -NR(28)R(29)
or -CR(28)R(29)R(30);
R(28) is -Cg H29-(C1-C9)-heteroaryl-N-oxide,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
g is zero, 1 or 2;
R(29), R(30)
independently of one another are defined as R(28),
hydrogen or (C1-C4)-alkyl;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, F, Cl, Br, I, -C~N,
T-(CH2)n-(C i F2i+1), R(31)SO ~-, R(32)R(33)N-CO-, R(34)-CO- or
R(45)R(46)N-SO2, where the perfluoroalkyl group is straight-chain
or branched;
T is a bond, oxygen, -S- or -NR(47);
is zero, 1 or 2;
h is zero,1 or 2;
is 1, 2, 3, 4, 5 or 6;
R(31), R(32), R(34) and R(45)
independently of one another are -(C1-C8)-alkyl,
-(C3-C6)-alkenyl, (CH2)n R(48) or -CF3;
n is zero, 1, 2, 3 or 4;
R(47) is hydrogen or alkyl with 1, 2 or 3 carbon atoms;
R(48) is -(C3-C7)-cycloalkyl or phenyl,


277
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy and
-NR(49)R(50);
R(49) and R(50)
are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(32), R(34) and R(45)
are hydrogen;
R(33) and R(46)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(32) and R(33), and R(45) and R(46)
together are 5 or 6 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -NCH3 or
-N-benzyl;
or
R(1), R(2) and R(3)
independently of one another are R(51)-A-G-D-;
R(51) is a basic protonatable radical, i.e. an amino group
-NR(52)R(53), an amidino group R(52)R(53)N-C[=N-R(54)]-
or a guanidino group R(52)R(53)N-C[=N-R(54)]-NR(55)-;
R(52), R(53), R(54) and R(55)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(52) and R(53) are
a group C.alpha.H2.alpha.;
a is 4, 5, 6 or 7;
where if .alpha. = 5, 6 or 7 a carbon atom of the group
C.alpha.H2.alpha. can be replaced by a heteroatom group O, SO d


278
or NR(56),
or
R(53) and R(54) or R(54) and R(55) or R(52) and R(55) are
a group C y H2y;
y is 2, 3, 4 or 5;
where if y = 3, 4 or 5 a carbon atom of the group
C y H2y can be replaced by a heteroatom group O, SO d
or NR(56);
d is zero, 1 or 2;
R(56) is hydrogen or methyl;
or
R(51) is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is a group C e H2e;
e is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
where in the group C e H2e a carbon atom can be replaced by
one of the groupings -O-, -CO-, -CH[OR(57)]-, -SO r-,
-NR(57)-, -NR(57)-CO-, -NR(57)-CO-NH-, -NR(57)-CO-NH-
SO2- or -NR(57)-SO2-;
r is zero, 1 or 2;

G is a phenylene radical

Image

R(58) and R(59)
independently of one another are hydrogen, methyl,
methoxy, F, Cl, Br, I, CF3 or -SO s-R(60);
R(60) is methyl or NR(61)R(62);
R(61) and R(62)
independently of one another are


279
hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
D is -C v H2v-E w-;
v is zero, 1, 2, 3 or 4;
E is -O-, -CO-, -CH[OR(63)]-, -SO aa- or -NR(63)-;
w is zero or 1;
aa is zero, 1 or 2
R(63) is hydrogen or methyl,
or
R(1), R(2) and R(3)
independently of one another are -CF2R(64), -CF[R(65)][R(66)],
-CF[(CF2)q-CF3][R(65)], -C[(CF2)p-CF3]=CR(65)R(66);
R(64) is alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having
3, 4, 5, 6 or 7 carbon atoms;
R(65) and R(66) independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
q is zero, 1 or 2;
p is zero, 1 or 2;
or
R(1), R(2) and R(3)
independently of one another are -OR(67) or -NR(67)R(68);
R(67) and R(68)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(67) and R(68)
together are 4, 5, 6 or 7 methylene groups, of which one CH2
group can be replaced by oxygen, -S- SO2. -NH-, -NCH3 or
-N-benzyl;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(69), -NR(70)R(71) or -CzF2z+1;


280
R(69), R(70) and R(71)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
z is 1 , 2, 3 or 4;
R(6) and R(7)
independently of one another are hydrogen or alkyll having 1, 2, 3 or
4 carbon atoms;
X is oxygen or NR(72);
R(72) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;

al) alkenylcarboxylic acid guanidides, carrying fluorophenyl groups, of the
formula I

Image
in which:
R(6) is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl or phenyl,
where the phenyl group is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) independently is defined as R(6);
R(1), R(2), R(3), R(4) and R(5)
independently of one another are hydrogen or F;
where, however, at least one of the radicals R(1), R(2), R(3), R(4)
and R(5) must be fluorine;
and their pharmaceutically tolerable salts;


281
am) benzoylguanidines of the formula I

Image

in which:
R(1) is R(4)-SO m
or R(5)R(6)N-SO2-;
m is 1 or 2;
R(4) and R(5)
independently of one another are alkyl having 1, 2, 3, 4, 5, 6,
7 or 8 carbon atoms, alkenyl having 3, 4, 5 or 6 carbon
atoms, CF3 or -C n H2n-R(7);
n is zero, 1, 2, 3 or 4;
R(6) is H or alkyl having 1, 2, 3 or 4 carbon atoms;
R(7) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or
phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or alkyl having 1, 2, 3 or 4 carbon
atoms;
or
R(5) is also hydrogen;
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which a CH2 group
can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or


282
R(1) is -O p-(CH2)q-(CF2)r-CF3;
p is zero or 1;
q is zero, 1 or 2;
r is zero, 1, 2 or 3;
or
R(1) is -SR(10), -OR(10) or-CR(10)R(11)R(12);
R(10), R(11) and R(12)
independently of one another are hydrogen, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
-C sH2s-(C3-C8)-cycloalkyl or an aromatic system
selected from the group consisting of pyridyl, pyrrolyl,
quinolyl, isoquinolyl, imidazolyl or phenyl;
s is zero, 1 or 2;
where the aromatic systems pyridyl, pyrrolyl, quinolyl,
isoquinolyl, imidazolyl and phenyl are unsubstituted or
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
R(2) is -(CH2)u-(CF2)t-CF3;
t is zero, 1, 2 or 3;
u is zero or 1;
R(3) is hydrogen or independently is defined as R(1);
and their pharmaceutically tolerable salts;

an) substituted cinnamic acid guanidides of the formula I

Image

in which:


283

at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is
-X a-Y b-L n-U;
X is CR(16)R(17), O, S or NR(18);
R(16), R(17) and R(18)
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;
a is zero or 1;
Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
alkylene-T having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the
alkylene group, T, T-alkylene having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms in the alkylene group;
T is NR(20), O, S or phenylene,
where the phenylene is not substituted or is
substituted by 1 - 3 substituentsi selected from
the group consisting of F, Cl, CF-3, methyl,
methoxy and NR(21)R(22);
R(20), 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;
b is zero or 1;
L is O, S, NR(23) or C kH2k;
k is 1, 2, 3, 4, 5, 6, 7, 8;
n is zero or 1;
U is NR(24)R(25) or an N-containing heterocycle having 1, 2, 3,
4, 5, 6, 7, 8 or 9 carbon atoms;
R(24) and R(25)
independently of one another are hydrogen, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon


284
atoms;
or
R(24) and R(25)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where the N-containing heterocycles are N- or C-bridged and
are not substituted or are substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);
R(23), R(27) and R(28)
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;
and the other substituents R(1), R(2), R(3), R(4) and R(5) in each case
independently of one another are H, F, Cl, Br, I, CN, -On-C m H2m+1,
-O p-(CH2)s-C q F2q+1 or -C r H2rR(10);
n is zero or 1;
m is zero 1, 2, 3, 4, 5, 6, 7 or 8;
p is zero or 1;
q is 1, 2, 3, 4, 5, 6, 7 or 8;
s is zero, 1, 2, 3 or 4;
r is zero, 1, 2, 3 or 4;
R(10)
is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
where the phenyl is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of
F, Cl, CF3, methyl, methoxy and NR(11)R(12);
R(11) and R(12)
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;


285
R(6) and R(7)
independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
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;
and their pharmaceutically tolerable salts;

ao) benzoylguanidines of the formula I

Image

in which:
at least one of the substituents R(1), R(2) and R(3)
is R(6)-C(OH)2-;
R(6) is perfluoroalkyl having 1, 2 or 3 carbon atoms, which is
straight-chain or branched;
and the other substituents R(1), R(2) and R(3)
independently of one another are hydrogen, OH, F, Cl, Br, I, alkyl
having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5 or 6
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or phenoxy,
which is unsubstituted or is substituted by 1 - 3 substituents


286
selected from the group consisting of F, Cl, methyl and
methoxy;
or
the other substituents R(1), R(2) and R(3)
independently of one another are alkyl-SO x, -CR(7)=CR(8)R(9) or
-C~CR(9);
x is zero, 1 or 2;
R(7) is hydrogen or methyl;
R(8) and R(9)
independently of one another are hydrogen, alkyl having 1, 2,
3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms or phenyl,
which is unsubstituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl and methoxy;
or
the other substituents R(1), R(2) and R(3)
independently of one another are phenyl, C6H5-(C1-C4)-alkyl,
naphthyl, biphenylyl, quinolinyl, isoquinolinyl or imidazolyl,
where quinolinyl, isoquinolinyl or imidazolyl are bonded via C
or N and where phenyl, C6H5-(C1-C4)-alkyl, naphthyl,
biphenylyl, quinolinyl, isoquinolinyl and imidazolyl are
unsubstituted or are substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
or
the other substituents R(1), R(2) and R(3)
independently of one another are SR(10), -OR(10),
-CR(10)R(11)R(12);
R(10)
is -C f H2f(C3-C8)-cycloalkyl, quinolinyl, isoquinolinyl, pyridinyl,
imidazolyl or phenyl,


287
where the aromatic systems quinolinyl, isoquinolinyl,
pyridinyl, imidazolyl and phenyl are unsubstituted or
are substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
f is zero, 1 or 2;
R(11) and R(12)
independently of one another are defined as R(10), hydrogen
or alkyl having 1, 2, 3 or 4 carbon atoms;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2 or 3
carbon atoms, F, Cl, Br, I, CN, OR(13), NR(14)R(15),
-(CH2) n-(CF2)o-CF3;
R(13), R(14) and R(15)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
n is zero or 1;
o is zero, 1 or 2;
and their pharmacologically acceptable salts;

ap) sulfonimidamides of the formula I

Image
in which:
at least one of the three substituents R(1), R(2) and R(3)
is a benzoylguanidine,

Image


288
which is unsubstituted or substituted in the phenyl moiety by
1 - 4 radicals selected from the group consisting of alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2,
3, 4, 5, 6, 7 or 8 carbon atoms, -(CH2)m-R(14), F, Cl, Br, I,
-C~N, CF3, R(22)SO2-, R(23)R(24)N-CO-, R(25)-CO-,
R(26)R(27)N-SO2, -OR(35), -SR(35) or-NR(35)R(36);
m is zero, 1 or 2;
R(14)
is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F and Cl, -CF3, methyl, methoxy and
-NR(15)R(16);
R(15) and R(16)
independently of one another are
hydrogen or -CH3;
R(22), R(23), R(25) and R(26)
independently of one another are alkyl having 1, 2, 3,
4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5,
6, 7 or 8 carbon atoms, (CH2)n R(29) or -CF3;
n is zero, 1, 2, 3 or 4;
R(29) is -(C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy and
-NR(30)R(31);
R(30) and R(31)
are hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
or
R(23), R(25) and R(26)
are hydrogen;


289
R(24) and R(27)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
or
R(23) and R(24), and also R(26) and R(27)
together are 5 or 6 methylene groups, of which one
CH2 group can be replaced by oxygen, -S-, -NH-,
-NCH3 or-N-benzyl;
R(35) and R(36)
independently of one another are hydrogen or alkyl
having 1, 2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -NCH3 or
-N-benzyl;
or
R(35)
is phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy, SO2R(5),
SO2NR(6)R(7) and -NR(32)R(33);
R(5) is alkyl having 1, 2, 3, 4, 5 or 6 carbon
atoms
R(6) and R(7)
independently of one another are
hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
R(32) and R(33)
independently of one another are
hydrogen or alkyl having 1, 2, 3 or 4


290
carbon atoms;
or
R(35)
is C1-C9-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
and the other substituents R(1), R(2) and R(3) in each case
independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms, (CH2)p R(10)
p is zero, 1, 2, 3 or 4;
R(10) isphenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, -CF3, methyl, methoxy, -SO2NR(17)R(8) and
-SO2R(9);
R(17) and R(8)
independently of one another are hydrogen or
alkyl having 1, 2, 3 or 4 carbon atoms;
R(9) is alkyl having 1, 2, 3 or 4 carbon atoms;
orthe other radicals R(1) and R(3) in each case
are hydrogen,
R(4) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;


291
aq) benzoylguanidines of the formula I

Image

in which:
R(1) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or NR(7)R(8);
R(7) and R(8)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(2) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-SO2R(9);
R(9) independently is defined as R(1);
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26) or -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25)
is -(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are delined as R(25) or


292
are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms;
R(4) is hydrogen, F, Cl, Br, l, OH, -C-N, CF3, alkyl having 1, 2, 3, 4, 5, 6,
7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon
atoms or -(CH2)m R(14);
m is zero, 1 or 2;
R(14) is-(C3-C8)-cycloalkylorphenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;
R(5) and R(6)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;

ar) benzenedicarboxylic acid diguanidides of the formula I
Image
in which:
one of the radicals R(1), R(2), R(3) and R(4)
is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F-, Cl, Br, I,


293
-OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) and R(4)
independently of one another are hydrogen, F, Cl, Br, l, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or -CH3;
or
R(2) and R(4)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or
pyrrol-3-yl,
each of which is not substituted or is substituted by 1 - 4
substituents selected from the group consisting of F, Cl, Br, I,
-CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl,
carboxyl,-CF3, methyl, methoxy;
or
R(2) and R(4)
independently of one another are R(22)-SO2-, R(23)R(24)N-CO-,
R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;

294
or
R(2) and R(4)
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X-(CH2)y-CF3
or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F and Cl, -CF3, methyl,
methoxy and -NR(6)R(7);
R(6) and R(7)

295

independently of one another are hydrogen or -CH3;
X is a bond or oxygen;
y is zero, 1 or 2;
and their pharmaceutically tolerable salts;

as) benzenedicarboxylic acid diguanidides of the formula I

Image

in which:
one of the radicals R(1), R(2), R(3) and R(5)
is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(5) in each case are:
R(1) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) is hydrogen, F, Cl, Br, I, OH, -C~N, CF3, -CO-N=C(NH2)2, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5,
6, 7 or 8 carbon atoms or -(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;

296

or
R(2) is R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
R(2) is -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or ,3 carbon atoms;
R(4) is CF3, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl

297
having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, -(C3-C8) cycloalkyl or
-(CH2)mR(14);
m is 1 or 2;
R(14) is-(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;
or
R(4) is phenyl,
which is substituted by 2, 3, 4 or five substituents selected
from the group consisting of F, Cl, CF3, methyl, methoxy and
-NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
CH3;
and their pharmaceutically tolerable salts;

at) diaryldicarboxylic acid diguanidides of the formula I


Image

in which:
one of the radicals R(1), R(2), R(3), R(4) and R(5)
is -CO-N=C(NH2)2;
the other radicals R(1) and R(5) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;


298
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
the other radicals R(2) and R(4) in each case
independently of one another are hydrogen, F, Cl, Br, I, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or -CH3;
or
the other radicals R(2) and R(4) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or
pyrrol-3-yl.
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, I, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl, methoxy;
or
the other radicals R(2) and R(4) in each case
are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
the other radicals R(2) and R(4) in each case

299

independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
the other radical R(3) in each case
is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
one of the radicals R(6), R(7), R(8), R(9) and R(10)
is -CO-N=C(NH2)2;
the other radicals R(6) and R(10) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;
R(132), R(133) and R(134)
independently of one another are hydrogen or alkyl having 1,

300

2, 3 or 4 carbon atoms;
the other radicals R(7) and R(9) in each case
independently of one another are hydrogen, F, Cl, Br, I, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mm R(114);
mm is zero, 1 or 2;
R(114)
is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(115)R(116);
R(115) and R(116)
are hydrogen or -CH3;
or
the other radicals R(7) and R(9) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, I, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl and methoxy;
or
the other radicals R(7) and R(9) in each case
are R(122)-SO2-, R(123)R(124)N-CO-, R(128)-CO- or
R(129)R(130)N-SO2;
R(122) and R(128)
independently of one another are methyl or -CF3;
R(123), R(124), R(129) and R(130)
independently of one another are hydrogen or methyl;
or

301

the other radicals R(7) and R(9) in each case
independently of one another are -OR(135) or -NR(135)R(136);
R(135) and R(136)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(135) and R(136)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
the other radical R(8) in each case
is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or
-CR(125)R(126)R(127);
R(125)
is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(125)
is -(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(126) and R(127)
independently of one another are defined as R(125) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-,
-NR(17)-CO-NR(18)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-,
-SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;

302

R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms
and their pharmaceutically tolerable salts;

au) substituted thiophenylalkenylcarboxylic acid guanidides of the formula I

Image


in which:
at least one of the substituents R(1), R(2) and R(3)
is -O p-(CH2)s-Cq F2q+1, R(40)CO or R(31)SO k-;
p is zero or 1;
s is zero, 1, 2, 3 or 4;
q is 1, 2, 3, 4, 5, 6, 7 or 8;
k is zero, 1 or 2;
R(40) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl and methoxy;
R(31) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl or methoxy;
or

303


R(31) is NR(41)R(42);
R(41) and R(42)
independently of one another are hydrogen, alkyl
having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having
1, 2, 3 or 4 carbon atoms,
or
R(41) and R(42)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
and the other substituents R(1), R(2) and R(3) in each case
independently of one another are H, F, Cl, Br, I, CN,
O na-C ma H2ma+1 or -O ga C ra H2ra R(10);
na is zero or 1;
ma is zero, 1, 2, 3, 4, 5, 6, 7 or 8;
ga is zero or 1;
ra is zero, 1, 2, 3 or 4;
R(10) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
where the phenyl is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of
F, Cl, CF3, methyl and methoxy;
R(4) and R(5)
independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
independently of one another are H, alkyl having 1, 2,
3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or

304

4 carbon atoms;
and their pharmaceutically tolerable salts;

av) ortho-substituted benzoylguanidines of the formula I

Image

in which:
R(2) and R(3)
independently of one another are hydrogen, Cl, Br, I, (C1-C8)-alkyl,
(C3-C8)-cycloalkyl or -OR(5);
R(5) is (C1-C8)-alkyl or -C d H2d-(C3-C8)-cycloalkyl;
d is zero, 1 or 2;
where one of the two substituents R(2) and R(3) is always hydrogen but
both substituents R(2) and R(3) are not simultaneously hydrogen,
and their pharmaceutically tolerable salts;

ax) benzoylguanidines of the formula I

Image

in which:
R(1) is H, F, Cl, Br, I, CN, NO2, 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-(CH2)b-(CF2)C-CF3;
X is oxygen, S, NR(5),
a is zero or 1;

305

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 H2d 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 aromatics phenyl, biphenylyl
or naphthyl are not substituted or are
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(7)R(8);
R(7) and R(8)
independently are 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 H2f-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, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
f is zero, 1 or 2;
R(11) and R(12)
independently of one another are defined as R(10) or are
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 via a carbon atom
or a nitrogen atom of the ring,
which are in each case unsubstituted or substituted by 1 - 3

306

substituents selected from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino,
or
R(1) is -SR(13), -OR(13), -NHR(13), -NR(13)R(14), -CHR(13)R(15),
-C[R(15)R(16)OH], -C~CR(18), -C[R(19)]=CHR(18),
-C[R(20)R(21)]k-(CO)-[CR(22)R(23)]~-R(24),
k is zero, 1, 2, 3 or 4;
is zero, 1, 2, 3 or 4;
R(13) and R(14)
identically or differently are -(CH2)g-(CHOH)h-(CH2)i-
(CHOH)j-R(17) or -(CH2)9-O-(CH2-CH2O)h-R(24);
R(17)is hydrogen or methyl,
g, h and i
identically or differently are zero, 1, 2, 3 or 4;
is 1, 2, 3 or 4;
R(15) and R(16)
identically or differently are hydrogen, alkyl having 1, 2,3, 4,
5 or 6 carbon atoms or. together with the carbon atom
carrying them, are 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, CF3, 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

307

R(18) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,
which is unsubstituted or substituted by 1 - 3 O H;
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)
identically or differently are 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 H2m-R(18);
?? very broad with all R(18)s
m is 1, 2, 3 or 4;
R(2) and R(3)
are defined as R(1);
R(4) is alkyl having 1, 2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;

ay) ortho-substituted benzoylguanidines of the formula I

Image

in which:
R(1) is H, F, Cl, Br, I, CN, NO2, 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-(CH2)b-(CF2)C-CF3;
X is oxygen, S, 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

308

-C d H2d 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 aromatics phenyl, biphenylyl
or naphthyl are unsubstituted or
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, C F3,
methyl, methoxy and NR(7)R(8);
R(7) and R(8)
independently are 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 H2f-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, C F3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
f is zero, 1 or 2;
R(11) and R(12)
independently of one another are defined as R(10), or are
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 via a carbon atom
or a nitrogen atom of the ring,
which are in each case unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino,

309

or
R(1) is -SR(13), -OR(13), -NHR(13), -NR(13)R(14), -CHR(13)R(15),
-C[R(15)R(16)OH], -C-CR(18), -C[R(19)]=CHR(18),
-C[R(20)R(21)]k-(CO)-[CR(22)R(23)]~-R(24),
k is zero, 1, 2, 3 or 4;
is zero, 1, 2, 3 or 4;
R(13) and R(14)
identically or differently are -(CH2)g-(CHOH)h-(CH2)i-
(CHOH)j-R(17) or -(CH2)g-O-(CH2-CH2O)h-R(24);
R(17) is hydrogen or methyl,
g, h and i
identically or differently are zero, 1, 2, 3 or 4;
is 1, 2, 3 or 4;

R(15) and R(16)
identically or differently are hydrogen, alkyl having 1, 2, 3, 4,
5 or 6 carbon atoms or, together with the carbon atom
carrying them, are 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, CF3, 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;

310

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)
identically or differently are 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 H2m-R(18);
m is 1, 2, 3 or 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, I or -(CH2)n-(CF2)o-CF3;
n is zero or 1;
o is zero or 1;
and their pharmaceutically tolerable salts.

Il. Compounds of the formula

Image

in which:
W, Y and Z
are a nitrogen atom or a carbon atom substituted by R(2) or R(3) or
R(4),
R(1) is hydrogen, A, Hal, -CF3, -CH2F, -CHF2, -CH2CF3, -C2F5, -CN,
-NO2, -ethynyl, or an X-R';
A is alkyl having 1 to 6 carbon atoms;

311

Hal is F, Cl, Br or I;
X is oxygen, S or NR'';
R'' is hydrogen, A or a cyclic methylene chain having 3 to
7 carbon atoms;
R' is H, A, HO-A-, HOOC-A-, (C3-C7)-cycloalkyl,
(C6-C8)-cycloalkylalkyl, CF3, CH2F, CHF2, CH2-CF3, Ph, -CH2-Ph or
Het;
Ph is phenyl, naphthyl or biphenylyl, which is
unsubstituted or mono-, di- or trisubstituted by A, OA,
NR'R'', Hal, CF3;
Het is a mono- or binuclear saturated, unsaturated or
aromatic heterocycle having 1 to 4 nitrogen, oxygen
andtor sulfur atoms,
which is unsubstituted or mono-, di- or
trisubstituted by Hal, CF3, A, OH, OA, -X-R',
-CN, -NO2, and/or carbonyl oxygen,
where Het is bonded via N or an alkylene chain C m H2m
where m = zero to 6;
or
R' and R''
together are alkylene having 4 - 5 carbon atoms, in which one
CH2 group can also be replaced by oxygen, S, NH, N-A,
N-Ph and N-CH2-Ph;
R(2) and R(3)
independently of one another are hydrogen, Hal, A, HO-A-, X-R',
-C(=N-OH)-A, A-O-CO-(C1-C4)-alkyl-, CN, NO2, COOH,
halogen-substituted A, in particular CF3, CH2F, CHF2, C2F5, CH2CF3, or
S(O)nR''';
R''' is A, Ph or-Het;
n is zero, 1 or 2;
or
R(2) and R(3)

312

independently of one another are SO2NR'R'', Ph or -O-Ph,
-O-CH2-Ph, -CO-A, -CHO, -COOA, -CSNR'R'', CONR'R'',
-CH=CH-COOH,-CH=CH-COOA, indenyl, indanyl,
decahydronaphthyl, cyclopentenyl, dihydrothienyl, dihydrofuryl,
heterobicyclyl, alkylthienyl, halothienyl, haloalkylthienyl, acylthienyl,
halofuryl, haloalkylfuryl or pyrrolyl;
or
R(2) and R(3)
independently of one another are R(5)-O-;
R(5) is hydrogen, A, (C1-C6)-alkenyl or (C3-C7)-cycloalkyl;
R(4) is Ph, Het, -O-Het; CF3, S(O)nR''', -SO2NR'R'', alk;

Image

or
two of the substituents R(1) to R(4)
together are a group -O-CR(6)R(7)-CO-NR(8)-,

or Image or Image

where R(2) has the meaning indicated;
R(6), R(7), R(8) and R(9)
independently of one another are H or A;
or
R(8) is (C5-C7)-cycloalkyl;
or
R(9) is cyano;
alk is straight-chain or branched (C1-C8)-alkyl or (C3-C8)-cycloalkyl,
which is unsubstituted or mono-, di- or trisubstituted by A;
or
alk is an ethenyl or ethynyl radical which is substituted by H, A, Ph or
Het.

313

III. Indoloylguanidine derivatives of the formula


Image


in which
R(2) is hydrogen, unsubstituted or substituted (C1-C8)-alkyl,
(C3-C7)-cycloalkyl, OH, (C1-C6)-alkyl-O-, an aromatic radical or a group
-CH2-R(20);
R(20) is (C2-C6)-alkenyl or (C2-C6)-alkynyl;
R(1) is 1 to 5 identical or different substituents, which are:
hydrogen, unsubstituted or substituted (C1-C8)-alkyl,
(C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, halogen,
-NO2 (C2-C8)-alkanoyl, arylalkanoyl having up to 10 carbon atoms, aroyl having
up to 11 carbon atoms, -COOH, (C2-C6)-alkoxycarbonyl, an
aromatic group or one of the following mentioned groups: -OR(3),
-NR(6)R(7) or -S(O)n R(40);
R(3) is hydrogen, (C1-C8)-alkyl, substituted (C1-C8)-alkyl,
(C3-C7)-cycloalkyl, an aromatic radical or a group -CH2-R(30)
R(30) is alkenyl or alkynyl;
R(6) and R(7)
independently of one another are hydrogen, unsubstituted or
substituted (C1-C8)-alkyl, (C3-C7)-cycloalkyl,
(C2-C8)-alkanoyl, an arylalkanoyl group having up to 10 carbon
atoms, an aroyl group having up to 11 carbon atoms, an
aromatic group or -CH2-R(60);
R(60) is (C2-C6)-alkenyl or (C2-C6)-alkynyl;
or
R(6) and R(7)
together with the nitrogen atom are a 5 - 7-membered cyclic
amine, which can additionally contain further heteroatoms in

314

the ring;
n is zero, 1 or 2;
R(40) is unsubstituted or substituted (C1-C8)-alkyl, or an aromatic
group, or a group Image

A is oxygen, -S(O)n- or -N(R50)-;
R(50) is hydrogen or (C1-C8)-alkyl;
R' is hydrogen, unsubstituted or substituted (C1-C8)-alkyl,
in which the ring represents a saturated 3 - 8-membered
heterocycle having a nitrogen atom,
said substituted alkyl carries one or more groups selected from the
group consisting of halogen, -OH, (C1-C6)-alkoxy, -CN, -COOH,
(C2-C6)-alkoxycarbonyl, (C2-C8)-alkanoyl, arylalkanoyl having up to
10 carbon atoms, aroyl having up to 11 carbon atoms, an aromatic
group, -CONR(4)R(5),
R(4) and R(5)
identically or differently are hydrogen or (C1-C8)-alkyl;
or
R(4) and R(5)
are connected to one another and together form a
5 -7-membered cyclic amine which can additionally contain
further heteroatoms in the ring,
or said substituted alkyl carries a group

Image

in which:
E is a nitrogen atom or a CH group;
R'' is hydrogen, (C1-C8)-alkyl which is unsubstituted or
substituted by OH, (C1-C6)-alkoxy, -CN, -COOH,
(C2-C6)-alkoxycarbonyl, (C2-C8)-alkanoyl, aralkanoyl having up to
10 carbon atoms, aroyl having up to 11 carbon atoms, an
aromatic group, -NR(6)R(7), -CONR(4)R(5);
R(4) and R(5)

315

independently of one another are hydrogen or
(C1-C8)-alkyl;
where the cyclic system of the formula Image

is a 3 - 8-membered saturated aliphatic or heterocyclic ring system
having a nitrogen atom,

and where the aromatic groups mentioned are an aryl radical having up to
10 carbon atoms, a 5- or 6-membered heteroaryl radical having
1 - 4 nitrogen atoms, a 5- or 6-membered heteroaryl group containing 1 or
2 nitrogen atoms and a heteroatom which is oxygen or sulfur, or furyl,
and where the aryl radicals mentioned can be unsubstituted or substituted
by unsubstituted (C1-C8)-alkyl or substituted (C1-C8)-alkyl, halogen, -NO2,
(C2-C6)-alkoxycarbonyl, COOH, -OR(3), NR(6)R(7), -CONR(4)R(5),
-SO2NR(6)R(7) or S(O)n R(40),
where R(1) and the guanidinocarbonyl radical can be in any desired
position of the 5- or 6-membered ring of the indole system,
and the appropriate pharmaceutically tolerable salts.

IV. Heterocyclic guanidine derivatives of the formula


Image


in which:
X is -O-, -S-, -NH-, -N[(C1-C4)-alkyl]- or -N(phenyl)-;
R(1), R(2) and R(3)
are hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, phenyl,
benzyl;
or
two of the substituents R(1), R(2) and R(3)

316

together with one side of the benzo system are a 4 - 6-membered
carbocyclic ring;
R(4) and R(5)
independently of one another are hydrogen, (C1-C12)-alkyl,
benzhydryl, aralkyl,
which is unsubstituted or substituted by one or more
substituents from the groups halogen, (C1-C4)-alkyl,
(C1-C4)-alkyl-O- or -CF3, -(CH2)m-CH2-T,
m is zero to 3;
T is -CO-O-T(1);
T(1) is hydrogen or (C1-C4)-alkyl;
Cy is a benzo-fused unsaturated or dihydro-5-membered ring
heterocycle
Image

a pyrazole or imidazole ring of the formula Image or

Image

a naphthyl radical or a dihydro- or tetrahydronaphthyl radical

Image

a 2-, 3- or 4-pyridyl radical
Image

Z is N- or CH;
a thienyl radical Image

R(6) is hydrogen, halogen, hydroxyl, (C1-C10)-alkyl, (C1-C10)-alkyl-O-,
phenoxy, (C1-C10)-alkyloxymethyloxy- or -(O)n S-R(9);
R(9) is (C1-C10)-alkyl, thienyl, pyridyl, thiazolyl, thiadiazolyl,

317
imidazolyl, pyrazolyl or phenyl,
each of which is unsubstituted or mono- or
disubstituted by halogen, (C1-C4)-alkyl or
(C1-C4)-alkyl-O-;
R(7) and R(8)
is hydrogen, halogen, hydroxyl, (C1-C10)-alkyl,
(C1-C10)-alkyl-O-, phenyl, phenoxy or
(C1-C10)-alkoxymethyloxy;
or
Cy is phenyl,
which is unsubstituted or mono- or disubstituted by halogen,
(C1-C4)-alkyl or (C1-C4)-alkyl-O-;
or
Cy is -Gr-Am;
Gr is -R(13)-R(12)-(CH2)q-C[W][W(1)]-(CH2)q-; R(13)R(14)- or
-R(15)-;
R(12) is a single bond, -O-, -(O)nS-, -CO- or -CONH-;
R(13) is a single bond, phenyl, thienyl, pyridyl, thiazolyl,
thiadiazolyl, imidazolyl or pyrazolyl;
R(14) is a single bond or SO2-;
R(15) is (C2-C10)-alkenyl- or (C2-C10)-alkynyl;
W and W(1)
independently of one another are hydrogen, (C1-C4)-
alkyl;
or
W and W(1)
cyclically connected to one another are a
(C3-C8)-hydrocarbon ring;
q and q'
are zero to 9;
Am is -NR(10)R(11);
R(10) is hydrogen, (C1-C4)-alkyl or benzyl,

318

R(11) is (C1-C4)-alkyl, phenyl or benzyl;
or
R(10) and R(11)
together are a (C3-C10)-alkylene group,
which is unsubstituted or substituted by -COOH,
(C1-C5)-alkoxycarbonyl,
(C2-C4)-hydroxyl-alkylene or benzyl;
or
Am is pyrrolyl, pyridyl, pyrazolyl, morpholinyl, dihydropyridyl,
tetrahydropyridyl, quinuclidinyl, imidazolyl,
3-azabicyclo[3.2.1]octyl,
which is unsubstituted or substituted by (C1-C4)-alkyl,
or
Am is azabicyclo[3.2.2]nonyl;
or
Am is a piperazine group of the formula Image


R(16) is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, phenyl,
tolyl, methoxyphenyl, halophenyl, diphenylmethylene,
benzyl or pyridyl;
or
Am is an azido group -(O)t-(CH2)q-C[W][W(1)]-(CH2)q'-N3;
t is zero or 1;
where W and W(1) have the previously indicated meaning;
and the optical enantiomers and the pharmacologically tolerable salts.

3. The use as claimed in claim 1, which comprises using:
r) benzo-fused heterocycles, having a 5-membered ring, of the formula I

319

Image

in which:
X is N or CR(6);
Y is oxygen, S or NR(7);
A, B together are a bond
or
A, B are both hydrogen, if X is CR(6) and Y is simultaneously NR(7);
one of the substituents R(1) to R(6) is a -CO-N=C(NH2)2 group;
the other substituents R(1) to R(6) in each case
are hydrogen, F, Cl, Br, I or (C1-C6)-alkyl;
up to two of the other substituents R(1) to R(6)
are CN, NO2, N3, (C1-C4)-alkyloxy or CF3;
up to one of the other substituents
is R(8)-C n H2n-Z-;
n is zero to 10;
where the alkylene chain -C n H2n- is straight-chain or
branched and where a carbon atom can be replaced by an
oxygen or sulfur atom or by a nitrogen atom;
R(8) is hydrogen, (C2-C6)-alkenyl or (C3-C10)-cycloalkyl,
which is unsubstituted or substituted by 1 to 4 methyl
groups or an OH group, or can contain an ethylene
group -CH=CH-, and where a methylene group can be
replaced by an oxygen or sulfur atom or by a nitrogen
atom;
or
R(8) is phenyl,

320
which is unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of F,
Cl, Br, I, CF3, CH3-S(O)s- or R(9)-Wy-;
s is zero, 1 or 2;
R(9) is H, methyl, ethyl,
W is oxygen or NR(10);
R(10) is H or methyl;
y is zero or 1;
or
R(8) is C m F2m+1;
m is 1 to 3;
or
R(8) is 1- or 2-naphthyl, pyridyl, quinolyl or isoquinolyl;
Z is -CO-, -CH2- or -[CR(11)(OH)]q-;
q is 1, 2 or 3;
R(11) is H or methyl;
or
Z is oxygen or -NR(12)-;
R(12) is H or methyl;
or
Z is -S(O)s-;
s is zero, 1 or 2;
or
Z is -SO2-NR(13)-;
R(13) is H or (C1-C4)-alkyl;
R(7) is hydrogen, (C1-C10)-alkyl, (C2-C10)-alkenyl or R(8)-C n H2n;
and their pharmaceutically tolerable salts;

321
v) acylguanidines of the formula I

Image

in which:
X is carbonyl, sulfonyl,
R(1) is H, (C1-C8)-alkyl,
unsubstituted or substituted by hydroxyl,
(C3-C8)-cycloalkyl, phenyl,
which is unsubstituted or substituted by 1 - 3 substituents
from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino or dimethylamino,
R(2) is H, (C1-C4)-alkyl,
and their pharmaceutically tolerable salts;

w) phenyl-substituted alkylcarboxylic acid guanidides, carrying
perfluoroalkyl groups, of the formula I

Image

in which:
R(A) is hydrogen, F, Cl, Br, I, CN, OR(6), (C1-C8)-alkyl, (C3-C8)-
cycloalkyl, O r(CH2)a C b F2b+1 or NR(7)R(8);
r is zero or 1;
a is zero, 1, 2, 3 or 4;
b is 1 , 2, 3, 4, 5, 6 , 7 or 8;
R(6) is hydrogen, (C1-C8)-alkyl, (C3-C8)-alkenyl,


322
(C3-C8)-cycloalkyl, phenyl or benzyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(9)R(10);
R(9) and R(10)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8)
independently of one another are defined as R(6);
R(B) independently is defined as R(A);
X is 1, 2 or 3;
R(1) is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, -O t(CH2)d C e F2e+1, F,
Cl, Br, I or CN;
t is zero or 1;
d is zero, 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5, 6, 7 or 8;
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1);
but with the condition
that at least one of the substituents R(1), R(2), R(3), R(4), R(5), R(A) and
R(B) is an -O t(CH2)d C e F2e+1 or an O r(CH2)a C b F2b+1-group,
and their pharmaceutically tolerable salts;

y) bicyclic heteroaroylguanidines of the formula I

Image

in which:
T, U , V, W, X, Y and Z

323

independently of one another are nitrogen or carbon;
but with the restriction
that X and Z are not simultaneously nitrogen,
and that T, U, V, W, X, Y and Z carry no substituents when they are
nitrogen,
and that no more than four of them are simultaneously nitrogen,
R(1) and R(2)
independently of one another are hydrogen, F, Cl, Br, I,
(C1-C3)-alkyl, (C1-C3)-perfluoroalkyl, OR(8), NR(8)R(9) or C(=O)N=C(NH2)2;
R(8) and R(9)
independently of one another are hydrogen or (C1-C3)-alkyl,
or
R(8) and R(9)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(3), R(4), R(5), R(6) and R(7)
independently of one another are hydrogen, F, Cl, Br, I, -C~N,
X k-(CH2)p-(C q F2q+1), R(10a)-SO b m, R(10b)R(10c)N-CO,
R(11)-CO- or R(12)R(13)N-SO2-,
where the perfluoroalkyl group is straight-chain or branched;
X is oxygen, S or NR(14);
R(14) is H or (C1-C3)-alkyl;
bm is zero, 1 or 2;
p is zero, 1 or 2;
k is zero or 1;
q is 1 , 2, 3, 4, 5 or 6;
R(10a), R(10b), R(11) and R(12)
independently of one another are (C1-C8)-alkyl,
(C3-C6)-alkenyl, -C n H2n-R(15) or (C1-C8)-perfluoroalkyl;
n is zero, 1, 2, 3 or 4;
R(15) is (C3-C7)-cycloalkyl or phenyl, which is not substituted
or is substituted by 1 - 3 substituents selected from the

324
group consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are H or C1-C4-alkyl;
or
R(10b), R(11) and R(12)
are hydrogen;
R(10c) and R(13)
independently are hydrogen or (C1-C4)-alkyl;
or
R(10b) and R(10c) and also R(12) and R(13)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are (C1-C8)-alkyl, -C al H2 al R(18) or
(C3-C8)-alkenyl;
al is zero, 1 or 2;
R(18) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where
the aromatics are not substituted or are substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(19a)R(19b);
R(19a) and R(19b)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are (C1-C9)-heteroaryl which is linked
via C or N and which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino or dimethylamino;
or

325

R(3), R(4), R(5), R(6) and R(7)
independently of one another are

Image



or Image

or Image


Y is oxygen, -S- or -NR(22)-;
h, ad, ah
independently of one another are zero or 1;
i, j, k, ae, af, ag, ao, ap and ak
independently of one another are zero, 1, 2, 3 or 4;
but where in each case
h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero, and
ah, ao and ak are not simultaneously zero,
R(23), R(24) R(25) and R(22)
independently of one another are hydrogen or (C1-C3)-alkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are SR(29), -OR(30), -NR(31)R(32) or
-CR(33)R(34)R(35);
R(29), R(30), R(31) and R(33)
independently of one another are -C a H2a-(C1-C9)-heteroaryl, which

326
is unsubstituted or substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
a is zero, 1 or 2;
R(32), R(34) and R(35)
independently of one another are defined as R(29) or
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are

Image ~ or
Image Image


R(96), R(97) and R(98)
independently of one another are (C1-C9)-heteroaryl, which is
linked via C or N and which is unsubstituted or substituted by
1 to 3 substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino, dimethylamino
or benzyl;
W is oxygen, S or NR(36)-;
R(36) is H or (C1-C4)-alkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(46)X(1)-;
X(1) is oxygen, S, NR(47), (D=O)A- or NR(48)C=MN(*)R(49)-;
M is oxygen or sulfur;
A is oxygen or NR(50);
D is C or SO;
R(46) is (C1-C8)-alkyl. (C3-C8)-alkenyl, (CH2)b C d F2d+1 or
-C x H2x-R(51);
b is zero or 1;

327
d is 1, 2, 3, 4, 5, 6 or 7;
x is zero, 1, 2, 3 or 4;
R(51) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1-3 substituents selected from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(52)R(53);
R(52) and R(53)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(47), R(48) and R(50) independently
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(49) is defined as R(46);
or

R(46) and R(47), or R(46) and R(48)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the
heteroaroylguanidine parent structure;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are -SR(64), -OR(65), -NHR(66),
-NR(67)R(68), -CHR(69)R(70) or-CR(54)R(55)OH, -C~CR(56),
-CR(58)=CR(57) or-[CR(59)R(60)]u-CO-[CR(61)R(62)]v-R(63);
R(64), R(65), R(66), R(67) and R(69)
identically or differently
are-(CH2)y-(CHOH)z-(CH2)aa-(CHOH)t-R(71) or
-(CH2)ab-O-(CH2-CH2O)ac-R(72);
R(71) and R(72)
independently of one another are hydrogen or methyl;

328
u is 1, 2, 3 or 4;
v is zero, 1, 2, 3 or 4;
y, z, aa identically or differently
are zero, 1, 2, 3 or 4;
t is 1, 2, 3 or 4;
R(68), R(70), R(54) and R(55)
identically or differently are hydrogen or (C1-C6)-alkyl;
or
R(69) and R(70), or R(54) and R(55),
together with the carbon atom carrying them, are a
(C3-C8)-cycloalkyl;
R(63)
is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or
-C e H2e-R(73);
e is zero, 1, 2, 3 or 4;
R(56), R(57) and R(73) independently
are phenyl, which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(74)R(75);
R(74) and R(75)
are hydrogen or (C1-C4)-alkyl;
or
R(56), R(57) and R(73) independently
are (C1-C9)-heteroaryl, which is unsubstituted or substituted
as phenyl;
R(58), R(59), R(60), R(61) and R(62)
are hydrogen or methyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(76)-NH-SO2-;
R(76) is R(77)R(78)N-(C=Y')-;
Y' is oxygen, S or N-R(79);

329
R(77) and R(78)
identically or differently are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or-C f H2f-R(80);
f is zero, 1, 2, 3 or 4;
R(80) is (C5-C7)-cycloalkyl or phenyl, which is
unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methoxy and (C1-C4)-alkyl;
or
R(77) and R(78)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, sulfur, NH,
N-CH3 or N-benzyl;
R(79) is defined as R(77) or is amidine;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are NR(84a)R(85), OR(84b), SR(84c)
or -C n H2n-R(84d);
n is zero, 1, 2, 3 or 4;
R(84d) is (C3-C7)-cycloalkyl or phenyl, which is not substituted
or is substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are hydrogen or C1-C4-alkyl;
R(84a), R(84b), R(84c) and R(85)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl or (CH2)ax-R(84g);
ax is zero, 1, 2, 3 or 4;
R(84g) is (C3-C7)-cycloalkyl or phenyl, which is not
substituted or is substituted by 1 - 3
substituents selected from the group consisting

330
of F, Cl, CF3, methyl, methoxy and
NR(84u)R(84v);
R(84u) and R(84v)
are hydrogen or C1-C4-alkyl;
or
R(84a) and R(85)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl,
and their pharmaceutically tolerable salts;

ab) phenyl-substituted alkenylcarboxylic acid guanidides, carrying
perfluoroalkyl groups, of the formula I


Image

in which:
R(A) is hydrogen, F, Cl, Br, I, CN, OH, OR(6), (C1-C8)-alkyl,
O r(CH2)a C b F2b+1. (C3-C8)-cycloalkyl or NR(7)R(8);
r is zero or 1;
a is zero, 1, 2, 3 or 4;
b is 1, 2, 3, 4, 5, 6, 7 or 8;
R(6) is (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatics are not substituted or are

331
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(9)R(10);
R(9) and R(10)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8)
independently of one another are defined as R(6);
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
R(B) independently is defined as R(A);
X is zero, 1 or 2;
Y is zero, 1 or 2;
R(C) is hydrogen, F, Cl, Br, I, CN, OR(12), (C1-C8)-alkyl, O p(CH2)f C g F2g+1
or (C3-C8)-cycloalkyl;
p is zero or 1;
f is zero, 1, 2, 3 or 4;
g is 1, 2, 3, 4, 5, 6, 7 or 8;
R(12)
is (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatics phenyl or benzyl are not
substituted or are substituted by 1 - 3 substituents
from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(13)R(14);
R(13) and R(14)
independently of one another are H,
(C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(D) independently is defined as R(C),
R(1) is hydrogen, (C1-C8)-alkyl, -O t(CH2)d C e F2e+1, (C3-C8)-cycloalkyl, F,

332
Cl, Br, I or CN;
t is zero or 1;
d is zero, 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5, 6, 7 or 8;
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1);
but with the condition
that at least one of the substituents R(A), R(B), R(C), R(D), R(1), R(2), R(4)
or R(5) is a O r(CH2)a C b F2b+1, O p(CH2)f C g F29+1 or O t(CH2)d C e F2e+1 group
and R(3) is not a O t(CH2)d C e F2e+1 group;
and their pharmaceutically tolerable salts;

ah) benzoylguanidines of the formula I

Image

in which:
one of the three substituents R(1), R(2) and R(3)
is R(6)-A-B-D-;
R(6) is a basic protonatable radical, i.e. an amino group
-NR(7)R(8), an amidino group R(7)R(8)N-C[=N-R(9)]- or a
guanidino group

Image

R(7), R(8), R(9) and R(10)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;

333
or
R(7) and R(8)
together are C a H2a;
a is 4, 5, 6 or 7;
where if a = 5, 6 or 7 a methylene group of the group
C a H2a can be replaced by a heteroatom group O, SO m
or NR(11),
or
R(8) and R(9) or R(9) and R(10) or R(7) and R(10)
are a group C a H2a;
a is 2, 3, 4 or 5;
where if a = 3, 4 or 5 a methylene group of the
group C a H2a can be replaced by a heteroatom
group O, SO m or NR(11);
m is zero, 1 or 2;
R(11) is hydrogen or methyl;
or
R(6) is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is C b H2b;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
where in the group C b H2b one or two methylene
groups can be replaced by one of the groupings
selected from the group consisting of -O-, -CO-,
-CH[OR(20)]-, -SO m-, -NR(20)-, -NR(20)-CO-,
-NR(20)-CO-NH-, -NR(20)-CO-NH-SO2-


Image


and -SO aa[NR(19)]bb-;
and where in the group C b H2b a methylene group can

334
be replaced by -CH-R(99), where R(99) together with
R(7) forms a pyrrolidine or piperidine ring;
aa is 1 or 2;
bb is 0 or 1;
aa + bb = 2;
R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon
atoms;
R(20) is hydrogen or methyl;
B is a phenylene or naphthylene radical,


Image
Image

R(12) and R(13)
independently of one another are hydrogen, methyl, F,
Cl, Br, I, CF3 or-SO w-R(14);
R(14) is methyl or NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
alkyl having 1, 2, 3 or 4 carbon atoms;
w is zero, 1 or 2;
D is-C d H2d-X f-;
d is zero, 1, 2, 3 or 4;
X is -O-, -CO-, -CH[OR(21)]-, -SOm- or -NR(21)-;
f is zero or 1;
R(21) is hydrogen or methyl;
m is zero, 1 or 2;
and the other substituents R(1) and R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, I, -CN,

335
-(C1-C8)-alkyl, -(C2-C8)-alkenyl, -NR(35)R(36) or R(17)-C g H2g-Z h-;
g is zero, 1, 2, 3 or 4;
h is zero or 1;
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
Z is -O-, -CO-, -SO v- , -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH-
or -NR(18)-SO2-;
R(18) is hydrogen or methyl;
v is zero, 1 or 2;
R(17) is hydrogen, cycloalkyl having 3, 5 or 6 carbon atoms or
C k F2k+1-;
k is 1, 2 or 3,
or
R(17) is pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4
substituents selected from the group consisting of F,
Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl,
formyl, carboxyl, -CF3, methyl and
methoxy;
or
R(17) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, hydroxyl, methoxy,
-NR(37)R(38), CH3SO2- and H2NO2S-;
R(37) and R(38)
are hydrogen or -CH3;

336
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or -C r F2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
r is 1, 2, 3 or 4;

and their pharmacologically tolerable salts;

ai) indenoylguanidines of the formula I

Image

in which:
R(1) and R(2)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3, 4, 5 or 6
carbon atoms, O-alkyl having 1, 2, 3 or 4 carbon atoms, O-C(=O)-alkyl
having 1, 2, 3 or 4 carbon atoms or C m H2m-NR(12)R(13);
R(12) and R(13)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
m is zero, 2, 3 or 4;
NH-C(=O)-NH2, C(=O)-O-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-NH2, C(=O)-NH-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-N(alkyl)2 having 1, 2, 3 or 4 carbon atoms in each alkyl
group, alkenyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms,
alkynyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, alkylaryl

337
having 1, 2, 3 or 4 carbon atoms in the alkyl group, alkenylaryl
having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the alkenyl group,
alkynylaryl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the
alkynyl group, C1-C4-alkyl-substituted aryl, C1-C4-alkylheteroaryl,
C1-C4-alkenylheteroaryl, aminoalkylaryl having 1, 2, 3 or 4 carbon
atoms in the alkyl group, substituted aryl, heteroaryl and substituted
heteroaryl;
R(3), R(4), R(5) and R(6)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, O-alkyl having 1, 2, 3, 4, 5, 6, 7, 8,
9 or 10 carbon atoms, halogen, (such as F, Cl, Br, I), OH, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, O-lower-alkyl,
O-aryl, O-lower-alkylaryl, O-substituted aryl, O-lower-alkyl-
substituted aryl, O-C(=O)-C1-C4-alkylaryl, O-C(=O)-NH-C1-C4-alkyl,
O-C(=O)-N(C1-C4-alkyl)2, NO2, CN, CF3, NH2, NH-C(=O)-C1-C4-alkyl,
NH-C(=O)-NH2, COOH, C(=O)-O-C1-C4-alkyl, C(=O)-NH2,
C(=O)-NH-C1-C4-alkyl, C(=O)-N(C1-C4-alkyl)2, C1-C4-COOH,
C1-C4-alkyl-C(=O)-O-C1-C4-alkyl, SO3H, SO2-alkyl, SO2-alkylaryl, SO2-N-(alkyl)2,SO2-N(alkyl)(alkylaryl), C(=O)-R(11), C1-C10-alkyl-C(=O)-R(11),
C2-C10-alkenyl-C(=O)-R(11), C2-C10-alkynyl-C(=O)-R(11),
NH-C(=O)-C1-C10-alkyl-C(=O)-R(11), O-C1-C11-alkyl-C(=O)-R(11);
R(11) is C1-C4-alkyl, C1-C4-alkynyl, aryl, substituted aryl, NH2,
NH C1-C4-alkyl, N-(C1-C4-alkyl)2 SO3H, SO2-alkyl,
SO2-alkylaryl, SO2-N-(alkyl)2, SO2-N(alkyl)(alkylaryl);
X is O, S or NH;
R(7), R(8), R(9) and R(10)
independently of one another are hydrogen, alkyl, cycloalkyl, aryl,
alkylaryl;
or
R(8) and R(9)
together are part of a 5, 6 or 7-membered heterocyclic ring;
A is absent or is a nontoxic organic or inorganic acid

338
ak) benzyloxycarbonylguanidines of the formula I

Image
in which:
R(1), R(2) and R(3)
independently of one another are -Y-[4-R(8)-phenyl],
-Y-[3-R(8)-phenyl] or -Y-[2-R(8)-phenyl],
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group consisting of F, Cl, -CF3,
methyl, hydroxyl, methoxy and -NR(96)R(97);
R(96) and R(97)
independently of one another are hydrogen or -CH3;
Y is a bond, CH2, oxygen, -S- or -NR(9);
R(9) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(8) is SO a[NR(98)]b NR(99)R(10);
a is 1 or 2;
b is 0 or 1;
a + b = 2;
R(98), R(99) and R(10)
independently of one another are hydrogen,
-(C1-C8)-alkyl, benzyl, -(C2-C8)-alkylene-NR(11)R(12),
(C2-C8)-alkylene-NR(13)-(C2-C8)-alkylene-NR(37)R(38) or
(C0-C8)-alkylene-CR(39)R(40)CR(41)R(42)(C0-C8)-
alkylene-NR(43)R(44);
R(11), R(12), R(13), R(37), R(38), R(43) and R(44)
independently of one another are hydrogen,
-(C1-C8)-alkyl or benzyl:
R(39), R(40), R(41) and R(42)

339
independently of one another are hydrogen,
-(C1-C8)-alkyl or-(C0-C3)-alkylenephenyl,
where the phenyl is not substituted or is
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, -CF3,
methyl and methoxy;
or
R(99) and R(10)
together are 4 - 6 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -N-CH3 or
-N-benzyl;
or
R(8) is SO a[NR(98)]b NR(95)-C[=N-R(94)]-NR(93)R(92);
R(92), R(93), R(94) and R(95)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
or
R(1), R(2) and R(3)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or
pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, I, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl, methoxy;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, -(C1-C8)-alkyl,
-(C2-C8)-alkenyl or -(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F

340

and CI, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
R(1), R(2) and R(3)
independently of one another are -Q-4-[(CH2)k-CHR(17)-
(C=O)R(20)]-phenyl, -Q-3-(CH2)k-CHR(17)-(C=O)R(20)]-phenyl or
-Q-2-[(CH2)k-CHR(17)-(C=O)R(20)]-phenyl,
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group consisting of F, CI, -CF3,
methyl, hydroxyl, methoxy and -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or -CH3;
Q is a bond, oxygen, -S- or-NR(18);
R(18) is hydrogen or -(C1-C4)-alkyl;
R(17) is -OR(21) or -NR(21)R(22);
R(21) and R(22)
independently of one another are hydrogen, -(C1-C8)-alkyl,
-(C1-C8)-alkanoyl, -(C1-C8)-alkoxycarbonyl,
benzyl, benzyloxycarbonyl;
or
R(21) is trityl;
R(20) is -OR(23) or -NR(23)R(24);
R(23), R(24) independently of one another are hydrogen,
-(C1-C8)-alkyl or benzyl;
k is zero, 1, 2, 3 or 4;
or
R(1), R(2) and R(3)
independently of one another are (C1-C9)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents from the group consisting of
F, CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino and

341
dimethylamino;
or
R(1), R(2) and R(3)
are -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is-C f H2f-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
f is zero, 1 or 2;
R(26) and R(27)
independently of one another are defined as R(25) or
are hydrogen or (C1-C4)-alkyl,
or
R(1), R(2) and R(3)
independently of one another are (C1-C9)-heteroaryl-N-oxide,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(1), R(2) and R(3)
independently of one another are -SR(28), -OR(28), -NR(28)R(29)
or -CR(28)R(29)R(30);
R(28) is-Cg H29-(C1-C9)-heteroaryl-N-oxide,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
g is zero, 1 or 2;
R(29), R(30)
independently of one another are defined as R(28), or

342
are hydrogen or (C1-C4)-alkyl;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, F, Cl, Br, I, -C~N,
T-(CH2)h-(C i F2i+1), R(31)SOl-, R(32)R(33)N-CO-, R(34)-CO- or
R(45)R(46)N-SO2, where the perfluoroalkyl group is straight-chain
or branched;
T is a bond, oxygen, -S- or-NR(47);
l is zero, 1 or 2;
h is zero, 1 or 2;
i is 1, 2, 3, 4, 5 or 6;
R(31), R(32), R(34) and R(45)
independently of one another are -(C1-C8)-alkyl,
-(C3-C6)-alkenyl, (CH2)n R(48) or -CF3;
n is zero, 1, 2, 3 or 4;
R(47) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R(48) is -(C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy and
-NR(49)R(50);
R(49) and R(50)
are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(32), R(34) and R(45)
are hydrogen;
R(33) and R(46)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(32) and R(33) and also R(45) and R(46)
together are 5 or 6 methylene groups, of which one CH2

343
group can be replaced by oxygen, -S-, -NH-, -NCH3 or
-N-benzyl;
or
R(1), R(2) and R(3)
independently of one another are R(51)-A-G-D-;
R(51) is a basic protonatable radical, i.e. an amino group
-NR(52)R(53), an amidino group R(52)R(53)N-C[=N-R(54)]- or
a guanidino group R(52)R(53)N-C[=N-R(54)]-NR(55)-;
R(52), R(53), R(54) and R(55)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(52) and R(53)
are a group C.alpha.H2.alpha.;
.alpha. is 4, 5, 6 or 7;
where if .alpha. = 5, 6 or 7 a carbon atom of the group
C.alpha.H2.alpha. can be replaced by a heteroatom group O, SO d
or NR(56),
or
R(53) and R(54) or R(54) and R(55) or R(52) and R(55)
are a group C yH2y;
y is 2, 3, 4 or 5;
where if y = 3, 4 or 5 a carbon atom of the group
C y H2y can be replaced by a heteroatom group O, SO d
or NR(56);
d is zero, 1 or 2;
R(56) is hydrogen or methyl;
or
R(51) is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is a group C e H2e;
e is zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

344
where in the group C e H2e a carbon atom can be replaced by
one of the groupings -O-, -CO-, -CH[OR(57)]-, -SO r-,
-NR(57)-, -NR(57)-CO-, -NR(57)-CO-NH-, -NR(57)-CO-NH-
SO2- or -NR(57)-SO2-;
r is zero, 1 or 2;
G is a phenylene radical,

Image
R(58) and R(59)
independently of one another are hydrogen, methyl,
methoxy, F, Cl, Br, I, CF3 or-SO s-R(60);
R(60) is methyl or NR(61)R(62);
R(61) and R(62)
independently of one another are
hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
D is -C v H2v-E w-;
v is zero, 1, 2, 3 or 4;
E is -O-, -CO-, -CH[OR(63)]-, -SO aa- or -NR(63)-;
w is zero or 1;
aa is zero, 1 or 2
R(63) is hydrogen or methyl,
or
R(1), R(2) and R(3)
independently of one another are -CF2R(64), -CF[R(65)][R(66)],
-CF[(CF2)q-CF3)][R(65)]. -C[(CF2)p-CF3]=CR(65)R(66);
R(64) is alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having
3, 4, 5, 6 or 7 carbon atoms;
R(65) and R(66) independently of one another are hydrogen or alkyl

345
having 1, 2, 3 or 4 carbon atoms;
q is zero, 1 or 2;
p is zero, 1 or 2;
or
R(1), R(2) and R(3)
independently of one another are -OR(67) or -NR(67)R(68);
R(67) and R(68)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(67) and R(68)
together are 4, 5, 6 or 7 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, SO2, -NH-, -NCH3 or
-N-benzyl;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(69), -NR(70)R(71) or-C z F2z+1;
R(69), R(70) and R(71)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
z is 1, 2, 3 or 4;
R(6) and R(7)
independently of one another are hydrogen or alkyl having 1, 2, 3 or
4 carbon atoms;
X is oxygen or NR(72);
R(72) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;

346
al) alkenylcarboxylic acid guanidides, carrying fluorophenyl groups, of the
formula I


Image

in which:
R(6) is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl or phenyl,
where the phenyl group is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) independently is defined as R(6);
R(1), R(2), R(3), R(4) and R(5)
independently of one another are hydrogen or F;
where, however, at least one of the radicals R(1), R(2), R(3), R(4)
and R(5) must be fluorine;
and their pharmaceutically tolerable salts;

an) substituted cinnamic acid guanidides of the formula I

Image

in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5)
is -X a-Y b-L n-U;

347
X is CR(16)R(17), O, S or NR(18);
R(16), R(17) and R(18)
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;
a is zero or 1;
Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
alkylene-T having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the
alkylene group, T, T-alkylene having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms in the alkylene group;
T is NR(20), O, S or phenylene,
where the phenylene is not substituted or is
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(21)R(22);
R(20), 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;
b is zero or 1;
L is O, S, NR(23) or C k H2k;
k is 1, 2, 3, 4, 5, 6, 7, 8;
n is zero or 1;
U is NR(24)R(25) or an N-containing heterocycle having 1, 2, 3,
4, 5, 6, 7, 8 or 9 carbon atoms;
R(24) and R(25)
independently of one another are hydrogen, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms;
or

348
R(24) and R(25)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where the N-containing heterocycles are N- or C-bridged and
are not substituted or are substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);
R(23), R(27) and R(28)
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;
and the other substituents R(1), R(2), R(3), R(4) and R(5) in each case
independently of one another are H, F, Cl, Br, I, CN, -O n C m H2m+1,
-O p-(CH2)s-C q F2q+1 or -C r H2r R(10);
n is zero or 1;
m is zero 1, 2, 3, 4, 5, 6, 7 or 8;
p is zero or 1;
q is 1, 2, 3, 4, 5, 6, 7 or 8;
s is zero, 1, 2, 3 or 4;
r is zero, 1, 2, 3 or 4;
R(10)
is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
where the phenyl is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of
F, Cl, CF3, methyl, methoxy and NR(11)R(12);
R(11) and R(12)
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(6) and R(7)
independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl

349
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
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;
and their pharmaceutically tolerable salts;

ar) benzenedicarboxylic acid diguanidides of the formula I

Image

in which:
one of the radicals R(1), R(2), R(3) and R(4)
is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I,
-OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) and R(4)
independently of one another are hydrogen, F, Cl, Br, I, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)m R(14);

350
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
R(2) and R(4)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl,
each of which is not substituted or is substituted by 1 - 4
substituents selected from the group consisting of F, Cl, Br, I,
-CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl,
carboxyl, -CF3, methyl, methoxy;
or
R(2) and R(4)
independently of one another are R(22)-SO2-, R(23)R(24)N-CO-,
R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
R(2) and R(4)
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group

351
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is -(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X-(CH2)y-CF3
or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F and Cl, -CF3, methyl,
methoxy and -NR(6)R(7);
R(6) and R(7)
independently of one another are hydrogen or -CH3;
X is a bond or oxygen;
y is zero, 1 or 2;
and their pharmaceutically tolerable salts;

352
as) benzenedicarboxylic acid diguanidides of the formula I


Image


in which:
one of the radicals R(1), R(2), R(3) and R(5)
is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(5) in each case are:
R(1) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) is hydrogen, F, Cl, Br, I, OH, -C o N, CF3, -CO-N=C(NH2)2, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5,
6, 7 or 8 carbon atoms or -(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;
or
R(2) is R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)

353
independently of one another are hydrogen or methyl;
or
R(2) is -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;

R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(4) is CF3, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl
having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, -(C3-C8)-cycloalkyl or
-(CH2)m R(14);
m is 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,

354
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;
or
R(4) is phenyl,
which is substituted by 2, 3, 4 or five substituents selected
from the group consisting of F, Cl, CF3, methyl, methoxy and
-NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
CH3;
and their pharmaceutically tolerable salts;

at) diaryldicarboxylic acid diguanidides of the formula I


Image


in which:
one of the radicals R(1), R(2), R(3), R(4) and R(5)
is -CO-N=C(NH2)2;
the other radicals R(1) and R(5) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
the other radicals R(2) and R(4) in each case

355
independently of one another are hydrogen, F, Cl, Br, I, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)m R(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
the other radicals R(2) and R(4) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-
yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, I, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl, methoxy;
or
the other radicals R(2) and R(4) in each case
are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
the other radicals R(2) and R(4) in each case
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;

356
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
the other radical R(3) in each case
is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is -(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
one of the radicals R(6), R(7), R(8), R(9) and R(10)
is -CO-N=C(NH2)2;
the other radicals R(6) and R(10) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;
R(132), R(133) and R(134)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
the other radicals R(7) and R(9) in each case
independently of one another are hydrogen, F, Cl, Br, I, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon

357
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mm R(114);
mm is zero, 1 or 2;
R(114)
is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(115)R(116);
R(115) and R(116)
are hydrogen or -CH3;
or
the other radicals R(7) and R(9) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, I, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl and methoxy;
or
the other radicals R(7) and R(9) in each case
are R(122)-SO2-, R(123)R(124)N-CO-, R(128)-CO- or
R(129)R(130)N-SO2;
R(122) and R(128)
independently of one another are methyl or -CF3;
R(123), R(124), R(129) and R(130)
independently of one another are hydrogen or methyl;
or
the other radicals R(7) and R(9) in each case
independently of one another are -OR(135) or -NR(135)R(136);
R(135) and R(136)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;



358
or
R(135) and R(136)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
the other radical R(8) in each case
is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or
-CR(125)R(126)R(127);
R(125)
is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(125)
is -(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(126) and R(127)
independently of one another are defined as R(125) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-,
-NR(17)-CO-NR(18)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-,
-SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;
R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms
and their pharmaceutically tolerable salts;




359
au) substituted thiophenylalkenylcarboxylic acid guanidides of the formula I

Image

in which:
at least one of the substituents R(1), R(2) and R(3)
is -O p-(CH2)s-C q F2q+1, R(40)CO- or R(31)SO k-;
p is zero or 1;
s is zero, 1, 2, 3 or 4;
q is 1, 2, 3, 4, 5, 6, 7 or 8;
k is zero, 1 or 2;
R(40) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl and methoxy;
R(31) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl or methoxy;
or
R(31) is NR(41)R(42);
R(41) and R(42)
independently of one another are hydrogen, alkyl
having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having




360
1, 2, 3 or 4 carbon atoms,
or
R(41) and R(42)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
and the other substituents R(1), R(2) and R(3) in each case
independently of one another are H, F, Cl, Br, I, CN,
-O na-C maH2ma+1 or -O gaC ra H2ra R(10);
na is zero or 1;
ma is zero, 1, 2, 3, 4, 5, 6, 7 or 8;
ga is zero or 1;
ra is zero, 1, 2, 3 or 4;
R(10) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
where the phenyl is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of
F, Cl, CF3, methyl and methoxy;
R(4) and R(5)
independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
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;
and their pharmaceutically tolerable salts;




361
4. The use of an Na+/H+ exchange inhibitor as claimed in claims 1 to 3 for
the production of a medicament for the treatment of hypercholesterolemiarelated
disorders of the cardiovascular system.

5. The use of an Na+/H+ exchange inhibitor as claimed in claims 1 to 3 for
the production of a medicament for the prevention and treatment of
endothelial dysfunction syndrome.

6. The use of an Na+/H+ exchange inhibitor as claimed in claims 1 to 3 for
the production of a medicament for the prevention and treatment of cardiac
hypertrophies and cardiomyopathies.

7. The use of an Na+/H+ exchange inhibitor as claimed in claims 1 to 3 for
the production of a medicament for the prevention and treatment of
coronary vascular spasms and myocardial infarcts, which are caused as a
result of increased lipid levels and endothelial dysfunction syndrome.

8. The use of an Na+/H+ exchange inhibitor as claimed in claims 1 to 3 for
the production of a medicament for the prevention and treatment of
thromboses which are caused by increased lipid levels and endothelial
dysfunction syndrome.

9. The use of an Na+/H+ exchange inhibitor as claimed in claims 1 to 3 for
the production of a medicament for the prevention and treatment of high
blood pressure which is caused by increased lipid levels and endothelial
dysfunction syndrome.

10. The use of an Na+/H+ exchange inhibitor as claimed in claims 1 to 3 for
the production of a medicament for the prevention and treatment of
peipheral vascular disorders which are caused by increased lipid levels
and endothelial dysfunction syndrome.




362
11. The use of an Na+/H+ exchange inhibitor for the production of a
medicament as claimed in claims 1 to 10 in combination with a hypotensive
medicament.

12. The use of an Na+tH+ exchange inhibitor for the production of a
medicament as claimed in claims 1 to 10 in combination with an
angiotensin converting enzyme (ACE) inhibitor.

13. The use of an Na+/H+ exchange inhibitor for the production of a
medicament as claimed in claims 1 to 10 in combination with an
angiotensin receptor antagonist.

14. The use of an Na+/H+ exchange inhibitor for the production of a
medicament as claimed in claims 1 to 10 in combination with a blood lipid
level-lowering active compound.

15. The use of an Na+/H+ exchange inhibitor for the production of a
medicament as claimed in claims 1 to 10 in combination with an HMG-CoA
reductase inhibitor.

16. The use of an Na+/H+ exchange inhibitor for the production of a
medicament as claimed in claims 1 to 10 in combination with lovastatin or
pravastatin.

Description

CA 022~7299 1998-12-03

WO 97/46226 PCT/EP97/02548
Description

Use of inhibitors of the cellular Na+/H+ exchanger (NHE) for the production
of a medicament for the normalization of serum lipids




The invention relates to the use of NHE inhibitors for the production of a
medicament for the normalization of serum lipids. This applies to all
substances which show NHE inhibitor action.

10 The active compounds which are known and identified as NHE inhibitors
are guanidine derivatives, preferably acylguanidines, inter alia such as
described in the following publications and patent disclosures: Edward J.
Cragoe, Jr., "DIURETICS, Chemistry, Pharmacology and Medicine",
J. WILEY & Sons (1983), 303 - 341, additionally compounds of the
15 following formulae:
I. (HOE 89/F 288 - US 5 292 755)
a) benzoylguanidines of the formula I
R(1)~ p~5J

20 R(2~ ~\~N\ R(4)
H
in which:
R(1) or R(2)
is R(6)-S(O)n- or R(7)R(8)N-O2S-;~5 and the other substituent R(1) or R(2) in each case
is H, F, Cl, Br, (C1-C4)-alkyl, (C1-C4)-alkoxy or phenoxy,
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of fluorine, chorine, methyl
and methoxy;~0 or the other substituent R(1) or R(2) in each case
is R(6)-S(O)n or R(7)R(8)N-;
n is zero,1 or 2;
R(6) is (C1-C6)-alkyl, (C5-C7)-cycloalkyl, cyclopentylmethyl,
cyclohexylmethyl or phenyl,

CA 022~7299 1998-12-03


which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
R(7) and R(8)
identically or differently are H or (C1-C6)-alkyl;
or
R(7) is phenYl-(cH2)m;
m is1-4;
or
R(7) isphenyl,
which is unsubstituted or substituted by 1 - 2
substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
or
R(7) and R(8)
together are a straight-chain or branched (C4-C7)-chain,
where the chain can additionally be interrupted by O, S or
NR(9);
R(9) is H or methyl;
or
R(7) and R(8)
together with the nitrogen atom to which they are bonded, are
a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline
system;
R(3), R(4) and R(5)
independently of one another are H or (C1-C2)-alkyl,
or
R(3) and R(4)
together are a (C2-C4)-alkylene chain;
or
R(4) and R(5)
together are a (C4-C7)-alkylene chain;
and their pharmaceutically tolerable salts;
(HOE 92/F 34 - US 5 373 924)

CA 022~7299 1998-12-03


b) benzoylguanidines of the formula I
R ( 2 )~1~

J~ N~ N H 2

~ NH2
in which:
R(1) is R(4)-SOm or R(5)R(6)N-SO2-;
m is zero, 1 or 2;
R(4) and R(5)
are C1-C8-alkyl, C3-C6-alkenyl or-CnH2n-R(7);
n is zero, 1, 2, 3 or 4;
R(7) is C5-C7-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or C~-C4-alkyl;
or
R(5) is H;
R(6) is H or C1-C4-alkyl,
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by an O, S, NH, N-CH3 or N-benzyl;
R(2) is hydrogen, F, Cl, Br, (C1-C4)-alkyl-, O-(CH2)mCpF2p+1 or X R( 0);
m is zero or 1;
p is 1, 2 or 3;
X isO, SorNR(11);
R(10) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl or-CnH2n-R(12);
n is zero, 1, 2, 3 or 4;
R(12) is phenyl,
which is unsubstituted or substituted by 1 - 3

CA 022~7299 1998-12-03


substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy und NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
R(11) is hydrogen or C1-C3-alkyl;
or
R(10) and R(11)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by O, S, NH, N-CH3 or
N-benzyl;
R(3) is defined as R(1), or is C1-C6-alkyl, nitro, cyano, trifluoromethyl, F,
Cl, Br, l or-X-R(10);
X is O, S or NR(11);
R(10) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl or -CnH2n-R(12);
n iszeroto4;
R(12) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy und NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
R(11) is C1-C3-alkyl,
or
R(10) and R(11)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by O, S, NH, N-CH3 or
N-benzyl;
and their pharmaceutically tolerable salts;
(HOE 92/F 035 EP- Offenlegungsschrift 556 673)

CA 022~7299 1998-12-03


c) ortho-substituted benzoylguanidines of the formula I
R ( 2 )


~; N ~N H 2

o NH2
R ( S )
I




10 in which:
R(1 ) is F, Cl, Br, I, C~-C6-alkyl or -X-R(6);
X is O, S, NR(7) or Y-ZO;
Y is O or NR(7);
Z is C or SO;
R(6) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl~-(CH2)mCpF2p+1 or-CnH2n-R(3);
m iszeroor1;
p is 1 -3;
n iszeroto4;
R(8) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of the groups F, Cl, CF3, methyl, methoxy and
NR(9)R(1 0);
R(9) and R(10)
are H or C1-C4-alkyl;
R(7) is H or C1-C3-alkyl;
or
R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by O, S, NH, N-CH3 or N-benzyl;
R(3) is H or-X-R(6);
X is O, S, N R(7) or Y-ZO;
R(7) is H or C1-C3-alkyl;

CA 022~7299 1998-12-03


Y isOorNR(7);
where Y is bonded to the phenyl radical of the
formula 1,
Z is C or SO;
R(6) is H, C1-C6-alkyl, C5-C7-cycloalkyl, cyclohexylmethyl,
cyclopentylmethyl~-(cH2)mcpF2p+l 0r~CnH2n~R(8);
m iszeroor1;
p is 1 - 3;
n iszeroto4;
R(8) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or C1-C4-alkyl;
or
R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by O, S, NH, N-CH3 or N-benzyl;
R(2) and R(4)
identically or differently are R(1 1 )~SOq~ or R(1 2)R(1 3)N-SO2-;
q iszero-2;
R(1 1 ) is C1-C4-alkyl,
which is unsubstituted or carries phenyl as a substituent,
where phenyl is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or C1-C4-alkyl;
R(12) and R(13)
are defined as R(6) and R(7);
or one of the two radicals R(2) or R(4)
is hydrogen or is defined as R(1 );
R(5) is H, methyl, F, Cl or methoxy,

CA 022~7299 1998-12-03


and their pharmaceutically tolerable salts;
(HOE 92/F 036 - US 5 364 868)
d) benzoylguanidines of the formula I
R ( 1 ) ~


R ( 2 ) 'J"--''''~ N H 2 ( I )

~ NH2
in which:
R(1) or R(2)
is an amino group -NR(3)R(4);
R(3) and R(4)
identically or differently are H, C1-C6-alkyl or
C3-C7-cycloalkyl;
or
R(3) is phenyl-(CH2)p-;
p is 0, 1, 2, 3 or 4;
or
R(3) is phenyl,
where the phenyl in each case is unsubstituted or carries one to two
substituents selected from the group consisting of fluorine, chlorine,
methyl and methoxy;
or
R(3) and R(4)
together can be a straight-chain or branched
C4-C7-methylene chain, where one -CH2- member of the
methylene chain can be replaced by oxygen, S or NR(5);
R(5) is H or lower alkyl;
the other substituent R(1) or R(2) in each case
is H, F, Cl, Cl-c4-alkyl~ C1-C4-alkoxY, CF3, CmF2m+1~CH2~~ benzyl or
phenoxy,
where the respective phenyl radical is unsubstituted or carries
one to two substituents selected from the group consisting of
methyl, methoxy, fluorine and chlorine;

CA 022~7299 1998-12-03


m is1,20r3;
and their pharmaceutically tolerable salts;
(92/F 197 K - NZ 248 013)
e) benzoylguanidines of the forrnula I
R( l )
R ( 2 ) ~

R ( 3 )/~/N~NH2 ( I )
~ NH2
in which:
R(1 ) is R(4)-SOm or R(5)R(6)N-S02-;
m is zero, 1 or 2;
R(4) and R(5)
are C1-C8-aîkyl, C3-C6-alkenyl or-CnH2n-R(7);
n is zero,1, 2, 3 or 4;
R(7) is C5-C7-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
or
R(5) is H;
R(6) is H or Cl-C4-alkyl;
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by an 0, S, NH, N-CH3 or N-benzyl;
R(2) is hydrogen, straight-chain or branched (C5-C8)-alkyl,
-CR(13)=CHR(12) or-C--CR(12);
R(12) is phenyl,
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,

CA 022~7299 1998-12-03


methoxy and NR(14)R(15);

R(14) and R(15)
are H or (C1-C4)-alkyl;
or
R(12) is (C1 -C9)-heteroaryl,
which is unsubstituted or substituted as phenyl,
or
R(12) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3 OH,
or
R(12) is(C3-C8)-cycloalkyl;
R(13) is hydrogen or methyl,
or
R(12) is (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1 -C4)-alkyl, phenyl,
C6H5-(C1-C4)-alkyl, naphthyl, biphenylyl,1,1-diphenyl-
(C1-C4)-alkyl, cyclopentadienyl, pyridyl, pyrrolyl, furanyl,
thienyl, thiazolyl, oxazolyl, indenyl, quinolyl, indolyl,
benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,
isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indazolyl,
isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl or
cinnolinyl;
R(3) is defined as R(2);
and where the aromatic substituents R(2) and R(3) are unsubstituted or
substituted by 1 - 3 substituents from the groups F, Cl, CF3, (C1-C4)-alkyl
or -alkoxy, or NR(10)R(11) with R(10) and R(11) being H or (C1-C4)-alkyl;
and their pharmaceutically tolerable salts;
(HOE 92/F 303 K - EP- Offenlegungsschrift 589 336, NZ 248 703)
f) benzoylguanidines of the formula I

CA 022~7299 1998-12-03


R ( 1 )~C~C~C / N H 2




,C~ ,C~ ~N= C~
R ( 2 ) C C NH2

o

in which:
R(1) or R(2)
is R(3)-S(O)n- or
R ( 4 )\
N ~ ~ 2 S -
R ( 5 )
15 the other substituent R(1) or R(2) in each case
is H, OH, F, Cl, Br, I, C1-C4-alkyl, C1-C4-alkoxy, benzyloxy or
phenoxy,
which is unsubstituted or carries one to three substituents
selected from the group consisting of fluorine, chlorine,
methyl, methoxy, hydroxyl and benzyloxy,
R(3)-S(O)n, -NR(4)R(5) or 3,4-dehydropiperidine
R(3) is C1-C6-alkyl, C5-C7-cycloalkyl, cyclopentylmethyl,
cyclohexylmethyl or phenyl,
which is unsubstituted or substituted by one to three
substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
R(4) and R(5)
identically or differently, are H or C1-C6-alkyl;
or
R(4) is phenYl-(cH2)m-;
m is 1, 2, 3 or4;
or
R(4) is phenyl,
which is unsubstituted or carries one to two

CA 022~7299 1998-12-03


substituents selected from the group consisting of
fluorine, chlorine, methyl and methoxy;
or
R(4) and R(5)
together are a straight-chain or branched C4-C7-chain, where the
chain can additionally be interrupted by O, S or NR(6),
R(6) is H or methyl;
or
R(4) and R(5)
together with the nitrogen atom to which they are bonded, are
a dihydroindole, tetrahydroquinoline or tetrahydroisoquinoline
system;
n is zero, 1 or 2;
and their pharmaceutically tolerable salts;
15 (92/F 304 - US 5 416 094)
g) isoquinolines of the formula I
X(l )


X(3)~ (2)
X ( 2 ) COG

in which:
R(1) is hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl, substituted
aminoalkyl or an aryl or heteroaryl ring;
where the rings are unsubstituted or substituted by 1 - 3
groups selected from the group consisting of halogen, nitro,
amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower
alkyl, lower alkoxy, benzyloxy, phenoxy, hydroxyl,
trifluoromethyl,
R(2) is hydrogen, halogen, alkyl or aryl;
which is unsubstituted or substituted by 1 - 3 groups selected
from the group consisting of halogen, nitro, amino,
mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl,

CA 022~7299 1998-12-03


lower alkoxy, benzyloxy, phenoxy, hydroxyl,

G is /R ( 3 )
/ ~ R(4) Vl I
- N--C\N~ R ( 5 )
~ R(6)

X(2), X(3) and X(4)
independently of one another are hydrogen, halogen, nitro, amino,
alkyl, sulfonamide, mono(lower alkyl)amino, di(lower alkyl)amino,
lower alkyl, benzyloxy, hydroxyl;
X(1 ) is hydrogen, oxygen, sulfur or NR(7);
R(7) is hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl, substituted
aminoalkyl or an aryl or a heteroaryl ring;
which rings are unsubstituted or substituted by 1 - 3
groups selected from the group consisting of halogen,
nitro, amino, mono(lower alkyl)amino, di(lower
alkyl)amino, lower alkyl, lower alkoxy, benzyloxy,
phenoxy, hydroxyl and trifluoromethyl;
in which substituents each alkyl chain or alkenyl chain can be
interrupted by oxygen, sulfur or NR(8);
R(8) is hydrogen, alkyl, cycloalkyl, arylalkyl, alkenyl,
substituted aminoalkyl or an aryl or heteroaryl ring,
which rings are unsubstituted or substituted by
1 - 3 groups selected from the group consisting
of halogen, nitro, amino, mono(lower
alkyl)amino, di(lower alkyl)amino, lower alkyl,
lower alkoxy, benzyloxy, phenoxy, hydroxyl and
trifluoromethyl;
and their pharmaceutically acceptable salts;
(92/F 404 - EP 602 522, NZ 250 438)
h) compounds of the formula I

CA 022~7299 1998-12-03


R(l )
R(2)
~\~ (I)

~ Nq/ N H 2
R ( 3 )
O NH2

in which:
10 R(1) is hydrogen, F, Cl, Br, l, -NO2, -C-N, -CF3, R(4)-SOm or
R(5)R(6)N-SO2-;
m is zero,1 or 2;
R(4) and R(5)
are (C1-C8)-alkyl, (C3-C6)-alkenyl, -CnH2n-R(7) or CF3;
n iszero,1,2,30r4;
R(7) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
or
R(5) is H;
R(6) is H or (C1-C4)-alkyl;
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is -SR(10), -OR(10), -NHR(10), -NR(10)R(11), -CHR(10)R(12),
-[CR(12)R(13)0R(13')], -{C-[CH2-OR(13')]R(12) (R(13)} or
-[CR(18)R(17)]p-(CO)-[CR(19)R(20)]q-R(14);
R(10), R(11)
identically or differently
are -[CHR(16)]s-(CH2)p-(CHOH)q-(CH2)r-(CHOH)t-R(21) or

CA 022~7299 1998-12-03



~(CH2)p~0~(CH2~CH20)q~R(21 )~
R(21) is hydrogen, methyl,
p, q, r identically or differently
are zero,1, 2, 3 or 4;
s iszeroor1;
t is1,2,30r4;
R(12) and R(13)
identically or differently are hydrogen, (C1-C6)-alkyl or,
together with the carbon atom carrying them, are a
1 0 (C3-C8)-cycloalkyl,
R(13') is hydrogen or (C1-C4)-alkyl;
R(14) is H, (C~-C6)-alkyl, (C3-C8)-cycloalkyl or-CaH2a-R(15);
a is zero,1, 2, 3 or 4;
R(15) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or (C1-C4)-alkyl;
or
R(15) is (C1-Cg)-heteroaryl,
which is unsubstituted or substituted as phenyl,
or
R(15) is(C1-C6)-alkYI,
which is unsubstituted or substituted by 1 - 3
OH;
R(16), R(17), R(18), R(19) and R(20)
are hydrogen or (C1-C3)-alkyl;
R(3) is defined as R(1),
or
R(3) is (C1-C6)-alkyl or-X-R(22);
X is oxygen, S or NR(16);
R(16) .is H or (C1-C3)-alkyl;
or

CA 022~7299 1998-12-03


R(22) and R(16)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
R(22) is defined as R(14);
and their pharmaceutically tolerable salts;
(HOE 92/F 405 - EP 602 523, NZ 250 437)
i) benzoylguanidines of the formula I
R(l )

~N~ N H

O NH2
15 in which:
R(1) is hydrogen, F, Cl, Br, l, -NO2, -C-N, R(16)~CpH2p~Oq~ R(4)-SOm or
R(5)R(6)N-SO2-;
m is zero,1 or 2;
p is zero or 1;
q iszero,1, 2 or3;
R(16) is CrF2r+1;
r is 1, 2 or 3;
R(4) and R(5)
are (c1-c8)-alkyl~ (C3-C6)-alkenYI, ~CnH2n~R(7) or CF3;
n is zero,1, 2, 3 or 4;
R(7) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, r"ethoxy and NR(8)R(9);
R(8) and R(9)
are H or C1-C4-alkyl;
or
R(5) is H;
R(6) is H or (C1-C4)-alkyl;

CA 022~7299 1998-12-03


or
R(5) and R(6)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
R(2) is (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
10 or
R(2) is -SR(10), -OR(10), -NR(10) R(11), -CR(10)R(11)R(12);
R(10) is-CaH2a-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
a is zero, 1 or 2;
R(11) and R(12)
independently of one another are defined as R(10) or are
hydrogen or (C1-C4)-alkyl;
R(3) is defined as R(1), or is (C1-C6)-alkyl or -X-R(13);
X is oxygen, S, or NR(14);
R(14) is H or (C1-C3)-alkyl;
R(13) is H~ (C1-C6)-alkyl, (c3-c8)-cycloalkyl or-cbH2b-R(15);
b iszero,1, 2, 3 or4;
or
R(13) and R(14)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(15) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
.CI, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)

CA 022~7299 1998-12-03


are H or (C1-C4)-alkyl;
and their pharmaceutically tolerable salts;
(HOE 92/F 411 - NZ 250 450, EP 603 650)

5 k) benzoylguanidines of the formula I
R ( l )
R ( 2 ~

R ( 3 ) /~f N~ N H 2 t I )
R ( 4 ) ~ NH2

in which:
one of the substituents R(1), R(2), R(3) or R(4)
~R ( S )
15 is an amino group _ N
\CnH2n-R ( 6 )

R(5) is hydrogen or C(1 6)-alkyl;
n is zero,1, 2, 3 or 4;
R(6) is H or C(1 4)-alkyl;
in which one CH2 group can be replaced by 1 sulfur atom or a group
NR(7);
R(7) is hydrogen, methyl or ethyl;
or
R(6) is C(3 8)-cycloalkyl or phenyl,
which is unsubstituted or carries 1, 2 or 3 substituents
selected from the group consisting of F, Cl, Br, methyl,
methoxy, -NR(8)R(9);
R(8) and R(9)
are H, methyl or ethyl;
or
R(5) and R(6)

CA 022~7299 1998-12-03


together with the nitrogen atom are a 5-, 6- or 7-membered
ring, in which 1 carbon atom can be replaced by oxygen, S or
NR(10);
R(10) is H, C(1 3)-alkyl or benzyl;
5 and the other substituents R(1), R(2), R(3), R(4) in each case are:
hydrogen, F, Cl, Br, l, CN, CF3, NO2, CF3-O-, CmF2m+1-CH2-O- or
R(11)~CqH2q~Xp~;
m is1,2Or3;
q is zero,1, 2, 3 or 4;
p iszeroor1;
X is oxygen or NR(12);
R(12) is H or C(1 3)-alkyl;
R(11) is hydrogen, C(1 6)-alkyl, C(3 8)-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1, 2 or 3
substituents selected from the group consisting of F,
Cl, CH3, CH3-O- and NR(13)R(14);
R(13), R(14)
are H, methyl or ethyl;
and their pharmaceutically tolerable salts;
(HOE 92/F 422 - EP 604 852)
I) benzoylguanidines of the formula I
R(2)~R(3)

N~l ~
H ~ o NH

in which:
R(1) is R(4)R(5)N-C(X)-;
X is oxygen, S or N-R(6);
R(4) and R(5)
identically or differently, are H, (C1-C8)-alkyl, (C3-C6)-alkenyl
or -CnH2n-R(7);
n .is zero,1, 2, 3 or 4;
R(7) is (C5-C7)-cycloalkyl or phenyl,

CA 022~7299 1998-12-03


which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methoxy and (C1-C4)-alkyl;
or
R(4) and R(5)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(6) is defined as R(4) or is amidine;
R(2) is H, F, Cl, Br, I, (C1-C8)-alkyl, 1-alkenyl or 1-alkynyl,
(C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, phenyl,
C6H5-(C1-C4)-alkyl, naphthyl, biphenylyl, 1,1-diphenyl-(C1-C4)-alkyl,
cyclopentadienyl, pyridyl, thiopyridyl, pyrrolyl, furanyl, thienyl,
thiazolyl, oxazolyl, indenyl, quinolyl, indolyl, benzofuranyl,
benzothienyl, benzothiazolyl, benzoxazolyl or-W-R(8);
W is oxygen, S or NR(9);
R(8) is H, (C1-C6)-alkyl, (C5-C7)-cycloalkyl,
cyclohexylmethyl, cyclopentylmethyl, -(CH2)mCpF2p+
or ~CqH2q~R(1 0);
m iszeroor1;
p is1,20r3;
q is zero, 1, 2, 3 or 4;
R(10) is phenyl,
which is unsubstituted or substituted by
1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl,
methoxy and NR(1 1 )R(12);
R(11) and R(12)
are H or (C1-C4)-alkyl;
R(9) is H or (C1-C3)-alkyl;
or
R(8) and R(9)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;

CA 022~7299 1998-12-03


R(3) is H, F, Cl, Br, l, (C1-C6)-alkyl or-W-R(8) as defined for R(2),
and their pharmaceutically acceptable salts;
(93/F 054 - NZ 250 919, EP- Offenlegungsschrift 612 723)
m) benzoylguanidines of the fommula I
R(1 )
R ( 2 )~J~

R ( 3 ) ~b--N'~ N H 2
~ NH2

in which:
R(1), R(2), R(3)
are hydrogen, F, Cl, Br, l or (C1-C12)-alkyl;
one of the substituents R(1), R(2) or R(3)
is N3, CN, OH or (C~-C~0)-alkyloxy, if at least one of the remaining
substituents R(1), R(2) or R(3) is a sufficiently lipophilic alkyl radical
having 3 to 12 carbon atoms;
or
one of the substituents R(1), R(2) and R(3)
is R(4)-cnH2n-om-;
m iszeroor1;
n is zero,1, 2 or 3;
R(4) is CpF2p+1;
p is 1, 2 or 3, if n is zero or 1;
or
R(4) is (C3-C12)-cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl,
where the aromatic and heteroaromatic ring systems are
unsubstituted or substituted by a substituent selected from
the group consisting of F, Cl, CF3, methyl, methoxy and
NR(5)R(6);
R(5) and R(6)
.are hydrogen or (C1-C4)-alkyl;
or one of the substituents R(1), R(2) and R(3)

CA 022~7299 1998-12-03


is -C-CR(5) or-C[R(6)] = CR(5);
R(5) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy, hydroxyl, amino,
methylamino and dimethylamino,
(C1 -Cg)-heteroaryl,
which is unsubstituted or substituted as phenyl,
or
R(5) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3 OH;
or
R(5) is (C3-C8)-cycloalkyl,
R(6) is hydrogen or methyl;
and their pharmacologically acceptable salts;
(93/F 153 - EP- Offenlegungsschrift 627 413, NZ 260 660)
o) benzoylguanidines of the formula I
R(l )
R(2)
\~



~ N H
in which:
R(1) is hydrogen, F, Cl, Br, l, -NO2, -C-N, Xo-(CH2)p-(CF2)q-CF3,
R(5)-SOm, R(6)-CO- or R(6)R(7)N-SO2-, where
X is oxygen, S or NR(14);
m iszero,1 or2;
o iszeroor1;
p is zero,1 or 2;
q is zero,1, 2, 3, 4, 5 or 6;
R(5) and R(6)

CA 022~7299 1998-12-03


are (c1-c8)-alkyl~ (C3-C6)-alkenYI, ~CnH2n~R(3) or CF8;
n is zero, 1, 2, 3 or 4;
R(8) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or C1-C4-alkyl;
or
R(6) is H;
R(7) is H or (C1-C4)-alkyl;
or
R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;


R(2) is - y~3( C ) h - ( C H O H ) ~ - ( C H 2 ) j - ( C H O H ) k - R ( 1 1 )

~
or -r ( C )h-( CHOH ) I-( CH2) I-( CHOH )k-R ( l l )


or ~(C)h-(CHOH)I-(CH2) j-(CHOH)k-R( l l )


Y is oxygen, -S- or-NR(12)-;
R(1 1 ) and R(12)
are hydrogen or (C1-C3)-alkyl;
h is zero or 1;
i, j and k
independently are zero, 1, 2, 3 or 4;
but where h, i and k are not simultaneously zero,

CA 022~7299 1998-12-03


R(3) is defined as R(1), or is (C1 -C6)-alkyl or -X-R(13);
X is oxygen, S or NR(14);
R(14) is H or (C1-C3)-alkyl;
R(13) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or-CbH2b-R(15);
b is zero,1, 2, 3 or 4;
or
R(13) and R(14)
together are 4 or 5 methylene groups, where one CH2
group can be replaced by oxygen, S, NH, N-CH3 or
N-benzyl;
R(15) isphenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or (C1-C4)-alkyl;
R(4) is hydrogen, -OR(16) or -NR(16)R(17);
R(16) and R(17)
independently are hydrogen or (C1-C3)-alkyl;
20 and their pharmaceutically tolerable salts;
(HOE 93/F 154 - EP- Offenlegungsschrift 628 543, NZ 260 681)
p) benzoylguanidines of the formula I
R(l )

R ( 2 )~ --N H 2


R(4) 0
in which:
30 R(1) is R(6)-CO or R(7)R(8)N-CO;
R(6) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-CnH2n-R(9);
n is zero,1, 2, 3 or 4;
R(9) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,

CA 022~7299 1998-12-03

24
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(10)R(11);
R(10) and R(11)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoro-
alkyl;
R(7) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-CnH2n-R(12);
n iszero,1,2,3Or4;
R(12) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(13)R(14);
R(13) and R(14)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoro-
alkyl;
R(8) is H, (C1 -C4)-alkyl or (C1 -C4)-perfluoroalkyl;
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is defined as R(1), or is H, F, Cl, Br, l, CN, NO2, (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or-CnH2nR(15);
n iszero1,2,3,4;
R(15) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoro-
alkyl;

CA 022~7299 1998-12-03


or
R(2) is (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(2) is SR(18), -OR(18), -NR(18)R(19), -CR(18)R(19)R(20);
R(18) is -CaH2a-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
a is zero,1 or 2;
R(19) and R(20)
independently of one another are defined as R(18) or are
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(2) is R(21)-SOm or R(22)R(23)N-SO2-;
m is1Or2;
R(21) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl, -
-CnH2n-R(24),
n is zero,1,2,3 or 4;
R(24) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);
R(27) and R(28)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoro-
alkyl;
R(22) is H, (C~-C8)-alkyl, (C~-C8)-perfluoroalkyl, (C3-C8)-alkenyl,
-CnH2n-R(29);
n is zero,1,2,3 or 4;

CA 022~7299 1998-12-03

26
R(29) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(30)R(31);
R(30) and R(31)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoro-
alkyl;
R(23) is H, (C1 -C4)-alkyl or (C1 -C4)-perfluoroalkyl;
or
R(22) and R(23)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
R(2) is R(33)X-;
X is oxygen, S, NR(34), (D=O)A-, NR(34)C=MN(*)R(35)-;
M is oxygen or S;
A is oxygen or NR(34);
D is C or SO;
R(33) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1, ~CnH2n~
R(36),
b is zero or 1;
d is 1, 2, 3, 4, 5, 6 or 7;
n is zero, 1, 2, 3 or 4;
R(36) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(37)R(38);
R(37) and R(38)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoro-
alkyl;
.R(34) is H, (C~-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(35) is defined as R(33);

CA 022~7299 1998-12-03


or
R(33) and R(34)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent structure;
or
R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42),
-C[R(42)R(43)0H], -C-CR(45), -CR(46)=CHR(45),
-[CR(47)R(48)]U-(CO)-[CR49)R(50)]V-R(44);
R(40), R(41)
identically or differently are ~(CH2)p~(CHOH)q~(CH2)r~
(CHOH)t-R(51) or -(CH2)p-O-(CH2-CH2O)q-R(51);
R(51) is hydrogen or methyl;
u is 1, 2, 3 or 4;
v is zero,1, 2, 3 or 4;
p, q, r
identically or differently are zero,1,2, 3 or 4;
t is 1, 2, 3 or4;
R(42) and R(43)
identically or differently are hydrogen or (C1-C6)-alkyl;
or
R(42) and R(43)
together with the carbon atom carrying them form a (C3-C8)-
cycloalkyl;
R(44) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or-CeH2e-R(45);
e is zero,1, 2, 3 or 4;
R(45) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(52)R(53) where
R(52) and R(53) are H or (C1-C4)-alkyl, or
R(45) is (C~-Cg)-heteroaryl,

CA 022~7299 1998-12-03

28
which is unsubstituted or substituted as phenyl;
or
R(45) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 - 3 OH;
R(46), R(47), R(48), R(49) and R(50)
are hydrogen or methyl;
or
R(2) is R(55)-NH-SO2-;
R(55) is R(56)R(57)N-(C=Y)-;
Y is oxygen, S or N-R(58);
R(56) and R(57)
identically or differently are H, (C1-C8)-alkyl, (C3-C6)-
alkenyl or-CfH2f-R(59);
f is zero,1, 2, 3 or 4;
R(59) is (C5-C7)-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1
- 3 substituents selected from the group
consisting of F, Cl, CF3, methoxy and
(C1-C4)-alkyl;
or
R(56) and R(57)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
R(58) is defined as R(56) or is amidine;
R(3), R(4) and R(5)
independently of one another are defined as R(1) or R(2);
and their pharmaceutically tolerable salts;
(HOE 93/F 220 - EP- Offenlegungsschrift 640 593, NZ 264 117)


CA 022~7299 1998-12-03

29
q) benzoylguanidines of the formula I

R(l )
R(2)
\~\,




in which:
R(1) is hydrogen, F, Cl, Br, I, -NO2, -C-N, -Xo-(CH2)p-(CF2)q-CF3,
R(5)-SOm-, R(6)-CO-, R(6)R(7)N-CO- or R(6)R(7)N-SO2-;
X is oxygen, -S- or NR(14);
m iszero, 1 or2;
o iszeroor1;
p is zero, 1 or 2;
q is zero, 1, 2, 3, 4, 5 or 6;
R(5) and R(6)
are (c1-c8)-alkyl~ (C3-C6)-alkenYI. ~CnH2n~R(3) or CF8;
n is zero, 1, 2, 3 or 4;
R(8) is (C3-C7)-cycloalkyl, phenyl,
which is not substituted or is substituted by 1 to
3 substituents selected from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(9)R(1 0);
R(9) and R(10)
are H or (C1-C4)-alkyl;
or
R(6) is hydrogen;
R(7) is hydrogen or (C1-C4)-alkyl;
or
R(6) and R(7~
together are 4 or 5 methylene groups, of which one CH2

CA 022~7299 1998-12-03


group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is
-- Y ~ R(l 1 ), ~ R(l 1 ) or ~ R(l 1 )


R(11) is (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 to 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino, dimethylamino and
benzyl;
Y is oxygen, -S- or NR(12);
R(12) is H or (C1-C4)-alkyl;
R(3) is defined as R(1);
or
R(3) is (C1-C6)-alkyl or-X-R(13);
X is oxygen, -S- or NR(14);
R(14) isHor(C1-C3)-alkyl;
R(13) is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or-CbH2b-R(15);
b is zero,1, 2, 3 or 4;
or
R(13) and R(14)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
R(15) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are H or (C1-C4)-alkyl;
R(4) is hydrogen, -OR(16), -N R(16) R(17) or C,F2,+1;
R(16) and R(.17)
independently are hydrogen or (C1-C3)-alkyl;

CA 022~7299 1998-12-03


r is1,2,30r4;
and their pharmaceutically tolerable salts;
(HOE 93/F 223 K - EP 639 573, NZ 264 130)
r) benzo-fused 5-membered ring heterocycles of the formula I
R(2)

R(3)~ 3 X


R ( S ) ( I ) -

in which:
X is N or CR(6);
Y is oxygen, S or NR(7);
A, B together are a bond
or
A, B are both hydrogen, if X is simultaneously CR(6) and Y is NR(7);
one of the substituents R(1) to R(6) is a -CO-N=C(NH2)2 group;
the other substituents R(1) to R(6) in each case
are hydrogen, F, Cl, Br, l or (C1-C6)-alkyl;
up to two of the other substituents R(1) to R(6)
are CN, NO2, N3, (C1-C4)-alkyloxy or CF3;
up to one of the other substituents
is R(8)-cnH2n-z-;
n is zero to 10;
where the alkylene chain -CnH2n- is straight-chain or
branched and where one carbon atom can be replaced by an
oxygen or sulfur atom or by a nitrogen atom;
R(8) is hydrogen, (C2-C6)-alkenyl or (C3-C10)-cycloalkyl,
which is unsubstituted or substituted by 1 to 4 methyl
groups or an OH group, or can contain an ethylene
group -CH=CH-, and in which one methylene group
. can be replaced by an oxygen or sulfur atom or by a
nitrogen atom;

CA 022~7299 1998-12-03


or
R(8) is phenyl,
which is unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of F,
Cl, Br, l, CF3, CH3-S(O)s- or R(9)-Wy~;
s is zero,1 or 2;
R(9) is H, methyl, ethyl,
W is oxygen or NR(10);
R(10) is H or methyl;
y is zero or 1;
or
R(8) is CmF2m+1;
m is 1 to 3;
or
R(8) is 1 - or 2-naphthyl, pyridyl, quinolyl or isoquinolyl;
Z is -CO-, -CH2- or -[CR(11)(OH)]q-;
q is 1, 2 or 3;
R(11) is H or methyl;
or
Z is oxygen or-NR(12)-;
R(12) is H or methyl;
or
Z is-S(O)s-;
s is zero,1 or 2;
or
Z is -SO2-NR(13)-;
R(13) is H or (C1-C4)-alkyl;
R(7) is hydrogen~ (C1-C10)-alkyl~ (C2-C10)-alkenyl or R(8)-CnH2n;
and their pharmaceutically tolerable salts;
(HOE 93/F 236 - EP- Offenlegungsschrift 638 548, NZ 264 216)

CA 022~7299 l998-l2-03


s) benzoylguanidines of the formula I
R ( 2 )


R ( ~ ) ~ ~ H ( I )
R(S) 0

in which:
R(1), R(3) or R(4)
is -NR(6) C=X NR(7)R(8);
X is oxygen or S;
R(6) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl,
(C3-C8)-alkenyl or-CnH2n-R(9);
n iszero, 1,2,30r4;
R(9) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(1 O)R(1 1 );
R(10) and R(1 1 )
are H, (C1-C4)-alkyl or (C~-C4)-
perfluoroalkyl;
R(7) is hydrogen, (C1-C8)-alkyl, (C~-C8)-perfluoroalkyl,
(C3-C8)-alkenyl or-coH2o-R(12);
o is zero, 1, 2, 3 or 4;
R(12) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and

CA 022~7299 1998-12-03

34
NR(13)R(14);
R(13) and R(14)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(8) is defined as R(7);
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
the remaining substituents R(2), R(3), R(4), R(5) or R(1), R(2), R(4), R(5)
or R(1), R(2), R(3), R(5) in each case
independently of one another are hydrogen, F, Cl, Br, l, -Ota(C1-C8)-
alkyl, -Otb(C3-C8)-alkenyl,
-OtC(cH2)bcdF2d+1, -OtdCpH2pR(18),
or up to 2 groups CN, NO2, NR(16)R(17),
b is zero or 1;
d is 1,2, 3,4, 5,6 or 7;
ta is zero or 1;
tb iszero or 1;
tc is zero or 1;
td iszeroor1;
p is zero,1,2, 3 or 4;
R(18) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(19)R(20);
R(19) and R(20)
are hydrogen or (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(16) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-
alkeny~, ~CqH2q~R(21)~
q is zero,1,2, 3 or 4;

CA 022~7299 1998-12-03


R(21) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
F, Cl, CF3, methyl, methoxy or NR(22)R(23),
R(22) and R(23) are hydrogen, (C1-C4)-alkyl or
(Cl -C4)-perfluoroalkyl;
R(17) is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-
alkenyl, -CrH2r-R(24);
r is zero,1, 2, 3 or 4;
R(24) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(25)R(26);
R(25) and R(26)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
or
R(16) and R(17)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
and their pharmaceutically tolerable salts;
(HOE 93/F 249 - EP- Offenlegungsschrift 640 587, NZ 264 282)
t) diacyl-substituted guanidines of the formula I
X ( 1 ) ~,NH NH X ( 2 )
Il lf 1~ I
~ NH ~
in which:
30 X(1) and X(2) are

CA 022~7299 l998-l2-03

36
R( 101 )
R( l 02) ~ {Cl R(A)R(B)I }T1
1~
R( 1 03) '~ R( 1 05)
R(10~)

T1 is zero,1, 2, 3 or 4;
R(A) and R(B)
independently of one another are hydrogen, F, Cl, Br, l, CN,
OR(106), (C1-C8)-alkyl, (C3-C8)-cycloalkyl, Ozk(CH2)zlCzmF2zm+
NR(107)R(108), phenyl or benzyl,
where the aromatics are not substituted or are substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(109)R(110);
R(109) and R(110)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
zl is zero,1, 2, 3 or 4;
zk is zero or 1;
zm is 1, 2, 3, 4, 5, 6, 7 or 8;
R(106)
is hydrogen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-
alkenyl, (C3-C8)-cycloalkyl, phenyl or benzyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(111)R(112);
R(111) and R(112)
are hydrogen, (C1-C4)-alkyl or (C~-C4)-
perfluoroalkyl;
R(107) and R(108)
independently of one another are defined as R(106),
or
R(107) and R(108)
together are 4 or 5 methylene groups, of which one CH2

CA 022~7299 1998-12-03


group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
X(1 ) and X(2) are
R(101) R(~)
R(102)~ ~ CCIR(~)R(~ T2
~ ' CCIR(~)R(~ T2
R(103) ~ R(105) R(~)
R(10~)

T2a and T2b
independently of one another are zero, 1 or 2;
where the double bond can have the (E)- or (Z)-configuration;
or
X(1) and X(2) are

( \ / ~R(Z1)
R(103) ~ Z- R(Z2)

R(102) ~ ~ ~ -{CIR(A)R(B)1~3
R(101 / R(U2) R(D)
R(Ul)
T3 is zero, 1 or 2;
U, YY and Z
independently of one another are C or N,
where U, YY, Z can carry the following number of
substituents:
U, YY or Z Bonded in the ring to Number of permitted
a double bond substituents
C yes
C no 2
N yes 0
N no

CA 022~7299 1998-12-03

38
R(D) is hydrogen, (C1-C8)-alkYI or (C1-c8)-Perfluoroa
R(U1), R(U2), R(Y1), R(Y2), R(Z1), R(Z2)
independently of one another are hydrogen, F, Cl, Br, l, CN,
OR(114), (C1-C8)-alkyl, (C3-C8)-cycloalkyl,
~zka(CH2)zlaCzmaF2zma+l, NR(115)R(116), phenyl or benzyl,
where the aromatics are not substituted or are substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy, NR(117)R(118),
R(117) and R(118)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl,
zka is zero or 1;
zla is zero,1, 2, 3 or 4;
zma is1,2,3,4,5,6,7Or8;
R(114)
is hydrGgen, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-
alkenyl, (C3-C8)-cycloalkyl, phenyl or benzyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(119)R(120);
R(119) and R(120)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(115) and R(116) independently of one another are defined as
R(114);
or
R(115) and R(116)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
but where the constitution of U is nitrogen (N), YY is nitrogen (N)
and Z is carbon (C) is excluded,
R(101), R(102), R(103), R(104) and R(105)
independently of one another are hydrogen, F, Cl, Br, l, -C-N,
Xzoa~(CH2)zpa~(CzqaF2zqa+1)~ R(110a)-SOzbm, R(110b)R(110c)N-CO,

CA 022~7299 1998-12-03


R(111a)-CO- or R(112a)R(113a)N-SO2-,
where the perfluoroalkyl group is straight-chain or branched,
X is oxygen, S or NR(114a);
R(114a)
is H or (C1-C3)-alkyl;
zoa is zero or 1;
zbm is zero,1 or 2;
zpa is zero,1, 2, 3 or 4;
zqa is 1,2, 3, 4, 5, 6, 7 or 8;
R(110a), R(110b), R(111a) and R(112a)
independently of one another are (C1-C8)-alkyl,
(C3-C8)-alkenyl, -CznH2zn-R(115a) or (Cl-C8)-perfluoroalkyl;
zn is zero,1, 2, 3 or 4;
R(115a)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(116a)R(117a);
R(116a) and R(117a)
are hydrogen, (C1-C4)-perfluoroalkyl or
(C1 -C4)-alkyl;
or
R(11 Ob), R(111 a) and R(112a)
are hydrogen;
R(110c) and R(113a)
independently are hydrogen, (C1-C4)-perfluoroalkyl or
(C1 -C4)-alkyl;
or
R(110b) and R(110c) and R(112a) and R(113a)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
or

CA 022~7299 1998-12-03


R(101), R(102), R(103), R(104), R(105)
independently of one another are (C1-C8)-alkyl, -CzalH2zalR(118a) or
(c3-c8)-alkenyl~
zal is zero, 1, 2, 3 or 4;
R(118a)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy or
NR(119a)R(119b);
R(119a) and R(119b)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents from the group consisting of
F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are -C--C-R(193);
R(193)
is phenyl which is not substituted or is substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3, methyl,
methoxy or NR(194)R(195);
R(194) and R(195)
are hydrogen or CH3;
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are
-Y-para-C6H4.-(CO)zh-(CHOH)zi-(CH2)zj-(CHOH)zk-R(123),
-y-meta-c6H4-(co)zad-(cHoH)zae-(cH2)zaf-(cHoH)za9-R(124)

CA 022~7299 1998-12-03


or
Y ortho-c6H4-(co)zah-(cHoH)zao-(cH2)zap-(cHoH)zak-R(125);
Y is oxygen, -S- or-NR(122d)-;
zh, zad, zah
independently are zero or 1;
zi, zj, zk, zae, zaf, zag, zao, zap and zak
independently are zero,1, 2, 3 or 4;
but where in each case
zh, zi and zk are not simultaneously zero,
zad, zae and zag are not simultaneously zero, and
zah, zao and zak are not simultaneously zero,
R(123), R(124) R(125) and R(122d)
independently are hydrogen or (C1-C3)-alkyl;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are SR(129), -OR(130),
-NR(131)R(132) or -CR(133)R(134)R(135);
R(129), R(130), R(131) and R(133)
independently are -CzabH2zab-(C1-C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
zab is zero,1 or 2;
R(132), R(134) and R(135)
independently are defined as R(129) or are hydrogen, (C1-
C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are -W-para-(C6H4)-R(196), -W-meta-
(C6H4)-R(197) or -W-ortho-(C6H4)-R(198);
R(196), R(197) and R(198)
independently of one another are (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or


. ~ . . _ _ ~ .

CA 022~7299 l998-l2-03

42
substituted by 1 to 3 substituents from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl,
amino, methylamino, dimethylamino and benzyl;
W is oxygen, S or NR(136)-;
R(136)
is hydrogen or (C1-C4)-alkyl;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are R(146)X(1a)-;
X(1a)
is oxygen, S, NR(147), (D=O)A-, NR(148)C=MN(*)R(149)-;
M is oxygen or sulfur;
A is oxygen or NR(150);
D is C or SO;
R(146)
is (C1-C8)-alkyl~ (C3-Cg)-alkenyl, (CH2)zbzCzdzF2zdz+l or
~CzxaH2zxa~R(151);
zbz is zero or 1;
zdz is 1, 2, 3, 4, 5, 6 or 7;
zxa is zero,1, 2, 3 or 4;
R(151)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(152)R(153);
R(152) and R(153)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(147), R(148) and R(150)
independently are hydrogen, (C1-C4)-alkyl, (C,-C4)-
perfluoroalkyl;
R(149~ is defined as R(146),
or

CA 022~7299 1998-12-03

43
R(146) and R(147), or R(146) and R(148)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the alkanoyl
parent structure;
or
R(101), R(102), R(103), R(104) and R(105)
independently of one another are -SR(164), -OR(165), -NHR(166),
-NR(167)R(168), -CHR(169)R(170), -CR(154)R(155)0H,
-C-CR(156), -CR(158)=CR(157) or
-[CR(159)R(160)]zu-tC=O)-[CR(161)R(162)]zv-R(163);
R(164), R(165), R(166), R(167), R(169)
identically or differently are -(CH2)zy~(CHOH)zz~(CH2)zaa~
(CHOH)zt-R(171) or ~(CH2)zab~O-(cH2-cH2o)zac-R(172);
R(171) and R(172)
are hydrogen or methyl;
zu is1,2,3cr4;
zv is zero,1,2,3 or 4;
zy, zz, zaa, zab, zac
identically or differently are zero,1, 2, 3 or 4;
zt is 1, 2, 3 or 4;
R(168), R(170), R(154), R(155)
identically or differently are hydrogen or (C1-C6)-alkyl,
or
R(169) and R(170), or R(154) and R(155)
together with the carbon atom carrying them are a (C3-C8)-
cycloalkyl;
R(163)
is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or
~CzebH2zeb~R(173);
zeb is zero,1, 2, 3 or 4;
R(156), R(157) and R(173)
independently are phenyl which is unsubstituted or is


.,

CA 022~7299 1998-12-03


substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(174)R(175);
R(174) and R(175)
are hydrogen or (C1-C4)-alkyl;
or
R(156), R(157) and R(173)
independently are (C1-Cg)-heteroaryl,
which is unsubstituted or substituted as phenyl;
R(158), R(159), R(160), R(161) and R(162)
are hydrogen or methyl,
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are R(176)-NH-SO2-;
R(176)
is R(177)R(178)N-(C=Y')-;
Y' is oxygen, S or N-R(179);
R(177) and R(178)
identically or differently are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or-CZfaH2Zfa-R(180);
zfa is zero,1, 2, 3 or 4;
R(180)
is (C5-C7)-cycloalkyl or phenyl,
which is unsubstituted or substituted by
1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methoxy
or (C1-C4)-alkyl;
or
R(177) and R(178)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, sulfur, NH,
N-CH3 or N-benzyl;

R(179)


, .. .

CA 022~7299 1998-12-03


is defined as R(177) or is amidine,
or
R(101), R(102), R(103), R(104), R(105)
independently of one another are NR(184a)R(185), OR(184b),
SR(184c) or ~CznxH2znx~R(184d);
znx is zero,1, 2, 3 or 4;
R(184d)
is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(116k)R(117k);
R(116k) and R(117k)
are hydrogen or C1-C4-alkyl;
R(184a), R(184b), R(184c), R(185)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C~-C8)-perfluoroalkyl or (CH2)zaO-R(184g);
zao is zero,1, 2, 3 or 4;
R(184g)
is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or substituted by 1 - 3
substituents from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(184u)R(184v);
R(184u) and R(184v)
are hydrogen or C1-C4-alkyl;
or
R(184a) and R(185)
together are 4 or 5 methylene groups, of
which one CH2 group can be replaced by
oxygen, sulfur, NH, N-CH3 or N-benzyl;
and their pharmaceutically tolerable salts;




.

CA 022~7299 l998-l2-03

46
(HOE 93/F 254 - EP-Offenlegungsschrift 640 588, NZ 264 307)
u) benzoylguanidines of the formula I
R(l )



( 3 )~ N H 2
R ( 4 ) ~
10 in which:
R(1) is H, F, Cl, Br, l, CN, NO2, (C1-C8)-alkyl, (C3-C8)-cycloalkyl or
Xa-(cH2)b-(cF2)c-cF3;
X is oxygen, S or NR(5);
a iszeroor1;
b iszero,1 or2;
c is zero,1, 2 or 3;
R(5) is H, (C1-C4)-alkYI 0r-cdH2dR(6);
d is zero,1, 2, 3 or 4;
R(6) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 to 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(7)R(8);
R(7) and R(8)
independently are H or (C~-C4)-
alkyl;
or
R(1) is -SR(10), -OR(10) or -CR(10)R(11)R(12);
R(10) is -CfH2f-(C3-C8)-cycloalkyl, -(C1-Cg)-heteroaryl or phenyl,
where the aromatic systems are unsubstituted or
substituted by one to 3 substituents selected from the
.group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;

CA 022~7299 1998-12-03


f is zero, 1 or 2;
R(11) and R(12)
independently of one another are defined as R(10) or are
hydrogen or (C1-C4)-alkyl;
or
R(1) is phenyl, naphthyl, biphenylyl or (C1-Cg)-heteroaryl,
the latter linked via C or N,
and which are unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
or
R(1) is-SR(13),-OR(13),-NHR(13),-NR(13)R(14),-CHR(13)R(15),
-C[R(15)R(16)]0H,-C-CR(18),-C[R(19)]=CR(18),-[CR(20)R(21 )]k-
(CO)-[CR(22)R(23)R(24)];
R(13) and R(14)
identically or differently are -(CH2)9-(CHOH)h-(CH2)j-(CHOH)j-
R(17),
R(17)is hydrogen or methyl;
-(CH2)9-O-(CH2-CH2O)h-R(24),
9, h, i
identically or differently are zero, 1, 2,3 or 4;
j is1,2,3 or 4;
R(15) and R(16)
identically or differently are hydrogen, (C1-C6)-alkyl or
together with the carbon atom carrying them are a (C3-C8)-
cycloalkyl;
R(18)is phenyl,
which is unsubstituted or substitu.~3d by 1 to 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(25)R(26);
R(25) and R(26)
are Hor(C1-C4)-alkyl;
or

CA 022~7299 1998-12-03

48
R(18) is (C1-Cg)-heteroaryl,
which is unsubstituted or substituted as phenyl;
or
R(18) is (C1-C6)-alkyl,
which is unsubstituted or substituted by 1 to 3 OH;
or
R(18) is(C3-C8)-cycloalkyl;
R(19), R(20), R(21), R(22) and R(23)
are hydrogen or methyl;
k iszero, 1,2,3cr4;
is zero,1, 2, 3 or 4;
R(24) is H~ (C1-C6)-alkyl, (c3-c8)-cycloalkyl or
R(18);
m is 1, 2, 3 or4;
15 R(2) and R(3)
independently of one another are defined as R(1);
R(4) is (C1-C3)-alkyl, F, Cl, Br, l, CN or-(CH2)n-(CF2)O-CF3;
n iszeroor1;
o is zero,1 or 2;
20 and their pharmaceutically tolerable salts;
(HOE 93/F 436 - EP-Offenlegungsschrift 659 748), NZ 270 264)
v) acylguanidines of the formula I


R ( 1 )~ N~NH2 ( I )
8 ~ NH2

in which:
X is carbonyl, sulfonyl,~0 R(1) is H, (C1-C8)-alkyl,
unsubstituted or substituted by hydroxyl,
(C3-C8)-cycloalkyl, phenyl,
which is unsubstituted or substituted by 1 - 3 substituents
from the group F, Cl, CF3, CH3, methoxy, hydroxyl, amino,

FEB-23-99 11 25 FROM CA 02257299 1998-12-03~ PAGE 2

49
methylamino or dime~hy1amino,
R~2) is H, (C1-C4)-alkyl,
and the;r Ph8nn~CeUt;CaIIY tObrabIe ~ t~;
tHO~ 94/~ 01~ K EP Offenb~Un~9~Ch~t 666 ~Z, NZ 270 37~)
W) PhenYI-SUb8titUted alkYCarbOX~YI;C aC;d ~Uan;d;deS, C8nY;n~
P~rflUOrO~IkYI 3r~UP~, Of the fOrrnUI~ I
R ~ ~ ) R ~ ~ )
~1) \ /
R ~ C ) I,~N ~ 2 ( I )
R ( 5 ) R ~ 5 ~ o h~
R ( ~ )

In wnich:
R(A) is h~clrvyen. F, Cl, Br, I, CN, OP~(B), (C1'C~ alkYI, ~C3-C8)-
cycloalkyi, Or(cHz)acbF2b~l ~r NR~7~R(8);
r i~zeroorl
a i~ z~ro, 1, 2, 3 or 4;
b is1,2,3,4,S,6,7~r8;
R(6~ i~ hydro~en, lCl-C8)-alkyl, (C3-C~)-alkenyl. ~C3 Ce~)-cycloalkyl.
phenyl or benzyl~
1~ where the aron~atlcs are not substituted or a~e
substltuted by 1 - 3 ~ub~tl~u~nt3 selects ~ from th~
~roup consistin~ of F, Cl, CF3, methyl, m~thoxy ana
NR(Y~R~1 C);
F~(9) snd R(10)
2D ~re H, (Ct-C4)-alkYI Or ~C~-C~)~PerflUOrOal~YI;

~t7) ~nd R1~)
;ndeP~ ntlY Of One anOthOr are def;n~ aS R(BJ;
R(B) indePendentlY jS dOf;ned a~ R~A~;
~5 X jS 1, 20r3;
R~1) ;5 hYdrOgen, (C1-CB)-alkYI. (C3~C~)~YCIOaIkYI~ ~Ot(CHZ)d~eFZe+h F~
C:l, Br, I Or C~;
t ;8Z~rOOr1;

CA 022~7299 1998-12-03


d is zero, 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5, 6, 7 or 8;
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1);
5 but with the condition
that at least one of the substituents R(1), R(2), R(3), R(4), R(5), R(A) and
R(B) is an ~Ot(CH2)dCeF2e+1 or an ~r(CH2)aCbF2b+1 group~
and their pharmaceutically tolerable salts;
(HOE 94/F 094 - EP-Offenlegungsschrift 676 395, NZ 270 894)
10 x) heteroaroylguanidines of the formua I

R(3) R(2)
~ I
R(~) HA R( l )
in which:
HA is SOm~ O or NR(5);
m is zero, 1 or 2;
R(5) is hydrogen, (C1-Cg)-alkyl or~CamH2amR(81);
am iszero, 1 or2;
R(81 ) is (C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted
by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl,
methoxy and NR(82)R(83);
R(82) and R(83)
Is H or CH3;
or
R(81) is (C1-Cg)-heteroaryl,
which is linked via C or N and which is
unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;

CA 022~7299 1998-12-03

51
one of the two substituents R(1 ) and R(2)
is -CO-N=C(NH2)2;
and the other in each case
is hydrogen, F, Cl, Br, I, (C1-C3)-alkyl, -OR(6), CrF2r+1, -CO-
N=C(NH2)2 or -NR(6)R(7);
R(6) and R(7)
independently are hydrogen or (C1-C3)-alkyl;
r is 1, 2, 30r4;
R(3) and R(4)
independently of one another are hydrogen, F, Cl, Br, I, -C-N, X-
(CH2)p~(Cq~F2q+1 ). R(8)-SObm, R(9)R(1 O)N-CO, R(1 1 )-CO- or
R(1 2)R(1 3)N-S02-.
where the perfluoroalkyl group is straight-chain or branched,
X is oxygen, S or NR(14);
R(t4) is H or (C1-C3)-alkyl;
bm is zero, 1 or 2;
p is zero, 1 or 2;
q iszero, 1,2,3,4,50r6;
R(8), R(9), R(11) and R(12)
independently are (C1-C8)-alkyl, (C3-C6)-alkenyl,
-CnH2n-R(15). CF3;
n is zero, 1, 2, 3 or 4;
R(15) is (C3-C7)-cycloalkyl or phenyl;
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy or NR(16)R(17);
R(16) and R(17)
are H or C1-C4-alkyl;
or
R(9), R(11) and R(12)
are H;
R(10) and R(13)
independently are H or (C1-C4)-alkyl;
or

CA 022~7299 1998-12-03

52
R(9) and R(10), and R(12) and R(13)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
or
5 R(3) and R(4)
independently of one another are (C1-C8)-alkyl or -CalH2alR(18);
al is zero, 1 or 2;
R(18) is (C3-C8)-cycloalkyl or phenyl;
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(19)R(20);
R(19) and R(20)
are H or CH3;
or
R(3) and R(4)
independently of one another are (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(3) and R(4)
independently of one another are
o




~ Y~3 ( C ) h ~ ( C H 0 H ) i ~ ( C H 2 ) i ~ ( C H 0 H ) k ~ R ( 2 3 )


or ~(C)o~-(CHOH)o,-(CH2)o,-(CHOH)o9-R(24)
-r

~ r ~ ( C ) o h - ( C H 0 H ) 0 0 - ( C H 2 ) 0 p - ( C H 0 H ) 0 k - R ( 2 S )



CA 022~7299 1998-12-03

53
Y is oxygen, -S- or-NR(22)-;
h, ad, ah independently are zero or 1;
i, j, k, ae, af, ag, ao, ap and ak independently are zero,1, 2, 3, 4,
but where in each case
h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero,
ah, ao and ak are not simultaneously zero,
R(23), R(24) R(25) and R(22)
independently are hydrogen or (C1-C3)-alkyl;
10 or
R(3) and R(4)
independently are hydrogen, F, Cl, Br, l, CN, (C1-C8)-alkyl, (C1-C8)-
perfluoroalkyl, (C3-C8)-alkenyl or-CgH29R(26);
g is zero,1, 2, 3 or 4;
R(26) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(27)R(28);
R(27) and R(28)
are H, (C1-C4)-alkyl or (C1-C4)-pefluoroalkyl;
or
R(3) and R(4)
independently of one another are SR(29), -OR(30), -NR(31)R(32) or
-CR(33)R(34)R(35);
R(29), R(30), R(31) and R(33)
independently of one another are -CaH2a-(C1-Cg)-heteroaryl~
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
a is zero,1 or 2;
R(32), R(34) and R(35)
independently of one another are defined as R(29) or are

CA 022~7299 1998-12-03

54
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3) and R(4)
independently of one another are

-- W ~R ( 9 6 ) , ~R ( 9 7 ) o r ~R ( 9 8 )

--W W--
R(96), R(97) and R(98)
independently are (Cl-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 to 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino, dimethylamino or
benzyl;
W is oxygen, S or NR(36)-;
R(36) is H or (C1-C4)-alkyl;
or
R(3) and R(4)
independently of one another are R(37)-S0cm or R(38)R(39)N-S02-;
cm is 1 or 2;
R(37) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-CsH2sR(40);
s iszero,1,2,30r4;
R(40) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(41)R(42);
R(41) and R(42)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(38) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-CWH2w-R(43);
w is zero,1, 2, 3 or 4;

CA 022~7299 1998-12-03


R(43) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(44)R(45);
R(44) and R(45)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(39) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(38) and R(39)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
R(3) and R(4)
independently of one another are R(46)X(1)-;
X(1) is oxygen, S, NR(47), (D=O)A-, NR(48)C=MN(~)R(49)-,
M is oxygen or S;
A is oxygen or NR(50);
D is C orSO;
R(46) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1 ~r-CxH2x-
R(51);
b iszeroor1;
d is 1, 2, 3, 4, 5, 6 or 7;
x iszero,1, 2, 3 or4;
R(51) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(52)R(53);
R(52) and R(53)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(47), R(48) and R(50)

CA 022~7299 1998-12-03

56
independently are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(49) is defined as R(46);
or
R(46) and R(47), or R(46) and R(48)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl,
where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent structure;
or
R(3) and R(4)
independently of one another are -SR(64), -OR(65), -NHR(66), -
NR(67)R(68), -CHR(69)R(70), -C(OH)R(54)R(55), -C -CR(56),
-CR(58)=CHR(57), -[CR(59)R(60)]U-(CO)-[CR(61)R(62)]v-R(63);
R(64), R(65), R(66), R(67) and R(69)
identically or differently are -(CH2)y~(CHOH)z~(CH2)aa~
(CH20H)t-R(71) or-(CH2)ab-O-(CH2-CH20)ac-R(72),
R(71) and R(72)
are hydrogen or methyl;
u is 1, 2, 3Or4;
v is zero,1, 2, 3 or 4;
y, z, aa
identically or differently are zero,1, 2, 3 or 4;
t is 1, 2, 3 or4;
R(68), R(70), R(54) and R(55)
identically or differently are hydrogen, (C1-C6)-alkyl;
or
R(69) and R(70), or R(54) and R(55)
together with the carbon atom carrying them are a (C3-C8)-
cycloalkyl;
R(63)
is H~ (C1-C6)-alkyl, (C3-C8)-cycloalkyl or-ceH2e-R(73);
e is zero,1, 2, 3 or 4;

CA 022~7299 1998-12-03


R(56), R(57) and R(73)
independently are phenyl,
which are unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(74)R(75);
R(74) and R(75)
are H or (C1-C4)-alkyl;
or
R(56), R(57) and R(73)
independently are (C1 -Cg)-heteroaryl,
which is unsubstituted or substitued as phenyl;
R(58), R(59), R(60), R(61) and R(62)
are hydrogen or methyl,
or
R(3) and R(4)
independently of one another are R(76)-NH-SO2-;
R(76) is R(77)R(78)N-(C=Y')-;
Y' is oxygen, S or N-R(79);
R(77) and R(78)
identically or differently are H, (C1-C8)-alkyl, (C3-C6)-alkenyl, -
C,H2,-R(80);
f is zero,1, 2, 3 or 4;
R(80) is (C5-C7)-cycloalkyl or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methoxy and (C1-C4)-alkyl;
or
R(77) and R(78)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
R(79)
is defined as R(77) or is amidine;
or
R(3) and R(4)

CA 022~7299 1998-12-03


independently of one another are NR(84)R(85);
R(84) and R(85)
independently of one another are H, (C1-C4)-alkyl, or together
are 4 or 5 methylene groups,
of which one CH2 group can be replaced by oxygen, S,
NH, N-CH3 or N-benzyl; or of which one or two CH2
groups can be replaced by CH-CdmH2dm+1,
and their pharmaceutically tolerable salts;
(HOE 94/F 123 - EP-Offenlegungsschrift 682 017, NZ 272 058)
10 y) bicyclic heteroaroylguanidines of the formula I

R(~) R(3)

R ( S ) ~v~w~,X~y~R ( 2 )
~U~l~z~Nq~ N H 2

R ( 7 ) R ( l ) ~ NH2

in which:~0 T, U, V, W, X, Y and Z
independently of one another are nitrogen or carbon;
but with the restriction
that X and Z are not simultaneously nitrogen,
and that T, U, V, W, X, Y and Z carry no substituents if they are
nitrogen,
and that no more than four of them are simultaneously nitrogen,
R(1) and R(2)
independently of one another are hydrogen, F, Cl, Br, l, (C1-C3)-
alkyl, (C1-C3)-perfluoroalkyl, OR(8), NR(8)R~9) or C(=O)N=C(NH2)2;
R(8) and R(9)
independently of one another are hydrogen or (C1-C3)-alkyl,
or
R(8) and R(9)
together are 4 or 5 methylene groups, of which one CH2

CA 022~7299 1998-12-03

59
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(3), R(4), R(5), R(6) and R(7)
independently of one another are hydrogen, F, Cl, Br, l, -C-N, Xk-
(CH2)p-(CqF2q+1)t R(10a)-SObm, R(10b)R(10c)N-CO, R(11)-CO- or
R(12)R(13)N-s02-~
where the perfluoroalkyl group is straight-chain or branched;
X is oxygen, S or NR(14);
R(14) is H or (C1-C3)-alkyl;
bm is zero,1 or 2;
p iszero,1 or2;
k iszeroor1;
q 1,2,3, 4, 5 or 6;
R(10a), R(10b), R(11) and R(12)
independently of one another are (C1-C8)-alkyl,
(c3-C6)-alkenyl, -CnH2n-R(15) or (C1-Cg)-PerflU~r~alkyl;
n is zero,1, 2, 3 or 4;
R(15) is (C3-C7)-cycloalkyl or phenyl, which is not substituted
or is substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are H or C1-C4-alkyl;
or
R(1 Ob), R(11) and R(12)
are hydrogen;
R(10c) and R(13)
independently are hydrogen or (C1-C4)-alkyl;
or
R(10b) and R(10c) and R(12) and R(13)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
or
R(3), R(4), R(5), R(6) and R(7)


.

CA 022~7299 1998-12-03


independently of one another are (C1-C8)-alkyl, -CalH2alR(18) or
(C3-C8)-alkenyl;
al is zero, 1 or 2;
R(18) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where
the aromatics are not substituted or are substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(1 9a)R(1 9b);
R(19a) and R(19b)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
10 or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are (C1-Cg)-heteroaryl, which is linked
via C or N and which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino or dimethylamino;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are
o




-Y~( C ) h- ( CHOH ) j - ( CH2 ) I - ( CHOH ) k-R ( 2 3 )


o r - r ( C ) a d - ( C H o H ) O, - ( C H 2 ) a, - ( c H o H ) a 9 -



o r ~ ( C ) O h - ( C H O H ) O O - ( C H 2 ) O p - ( C H O H ) O k - R ( 2 5 )

Y is oxygen, -S- or-NR(22)-;
h, ad, ah
independently of one another are zero or 1;
i, j, k, ae, af, ag, ao, ap and ak
independently of one another are zero, 1, 2, 3 or 4;

CA 022~7299 1998-12-03

61
but where in each case
h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero, and
ah, ao and ak are not simultaneously zero,
R(23), R(24) R(25) and R(22)
independently of one another are hydrogen or (C1-C3)-alkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are SR(29), -OR(30), -NR(31)R(32) or
-CR(33)R(34)R(35);
R(29), R(30), R(31) and R(33)
independently of one another are -CaH2a-(C1-Cg)-heteroaryl, which
is unsubstituted or substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
a is zero,1 or 2;
R(32), R(34) and R(35)
independently of one another are defined as R(29) or are
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
20 or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are

-- W ~R(96) , ~R(97) or ~R(98)

--W W--

R(96), R(97) and R(98)
independently of one another are (C1-Cg)-heteroaryl, which is
linked via C or N and which is unsubstitued or substituted by
1 to 3 substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino, dimethylamino
or benzyl;
W is oxygen, S or NR(36)-;
R(36) is H or (C1-C4)-alkyl;

CA 022~7299 1998-12-03

62
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(46)X(1)-;
X(1) is oxygen, S, NR(47), (D=O)A- or NR(48)C=MN(~)R(49)-;
M isoxygen orsulfur;
A is oxygen or NR(50);
D is C or SO;
R(46) is (C1-C8)-alkyl, (C3-Cg)-alkenyl, (CH2)bCdF2d+1 ~r-CxH2x-
R(51);
b is zero or 1;
d is1,2,3,4,5,60r7;
x is zero,1,2, 3 or 4;
R(51) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(52)R(53);
R(52) and R(53)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(47), R(48) and R(50) independently
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(49) is defined as R(46);
or
R(46) and R(47), or R(46) and R(48)
together are 4 or 5 methylene groups, of which one CH2
groups can be replaced by oxygen, sulfur, NH, N-CH3 or N-
benzyl;
where A and N(~) are bonded to the phenyl nucleus of the
heteroaroylguanidine parent structure;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are -SR(64), -OR(65), -NHR(66), -
NR(67)R(68), -CHR(69)R(70) or-CR(54)R(55)0H, -C-CR(56), -

CA 022~7299 1998-12-03


CR(58)=CR(57) or-[CR(59)R(60)]u-CO-[CR(61)R(62)]v-R(63);
R(64), R(65), R(66), R(67) and R(69)
identically or differently are
~(CH2)y-(cHoH)z-(cH2)aa-(cHoH)t-R(71) or
-(cH2)ab-o-(cH2-cH2o)ac-R(72);
R(71) and R(72)
independently of one another are hydrogen or methyl;
u is 1, 2, 3Or4;
v is zero,1, 2, 3 or 4;
y, z, aa identically or differently
are zero,1, 2, 3 or 4;
t is 1, 2, 3 or4;
R(68), R(70), R(54) and R(55)
identically or differently are hydrogen or (C1-C6)-alkyl;
or
R(69) and R(70), or R(54) and R(55)
together with the carbon atom carrying them are (C3-C8)-
cycloalkyl;
R(63)
is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl or
-CeH2e-R(73);
e is zero,1, 2, 3 or 4;
R(56), R(57) and R(73) independently
are phenyl, which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(74)R(75);
R(74) and R(75)
are hydrogen or (C1-C4)-alkyl;
or
R(56), R(57) and R(73) independently
are (C1-Cg)-heteroaryl, which is unsubstituted or substituted
as phenyl;
R(58), R(59),.R(60), R(61) and R(62)
are hydrogen or methyl;

CA 022~7299 1998-12-03

64
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(76)-NH-SO2-;
R(76) is R(77)R(78)N-(C=Y')-;
Y' is oxygen, S or N-R(79);
R(77) and R(78)
identically or differently are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or-CfH2f-R(80);
f is zero, l, 2, 3 or 4;
R(80) is (C5-C7)-cycloalkyl or phenyl, which is
unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methoxy and (C1-C4)-alkyl;
or
R(77) and R(78)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, sulfur, NH,
N-CH3 or N-benzyl;
R(79) is defined as R(77) or is amidine;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are NR(84a)R(85), OR(84b), SR(84c)
or -CnH2n-R(84d);
n is zero,1, 2, 3 or 4;
R(84d) is (C3-C7)-cycloalkyl or phenyl, which is not
substituted or is substituted by 1 - 3 substituents from
the group consisting of F, Cl, CF3, methyl, methoxy
and NR(16)R(17);
R(16) and R(17)
are hydrogen or C1-C4-alkyl;
R(84a), R(84b), R(84c) and R(85)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C1-C8)-perfluoroalkyl or (CH2)ax-R(84g);
ax is zero, 1, 2, 3 or 4;

CA 022~7299 1998-12-03


R(84g) is (C3-C7)-cycloalkyl or phenyl, which is not
substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and
NR(84u)R(84v);
R(84u) and R(84v)
are hydrogen or C1-C4-alkyl;
or
R(84a) and R(85)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl,
and their pharmaceutically tolerable salts;
(HOE 94/F 134 - EP-Offenlegungsschrift 686 627, NZ 272 103)
z) benzoylguanidines of the fommula I
R(l )


R ( 3 )~;~ N H 2
R(4) 0
in which:
R(1) is R(6)~S0m;
m is zero, 1 or 2;
R(6) is perfluoroalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which
is straight-chain or branched;
R(2) and R(3)
independently of one another are hydrogen, F, Cl, Br, l, alkyl having
1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or
phenoxy,
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, methyl and
methoxy;
or

CA 022~7299 1998-12-03

66
R(2) and R(3)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-
yl,
which is not substituted or is substituted by 1 to 4
substituents selected from the group consisting of F, Cl, Br, I,
CN, alkanoyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
alkoxycarbonyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
formyl, carboxyl, CF3, methyl and methoxy;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2 or 3
carbon atoms, F, Cl, Br, I, CN, OR(7), NR(8)R(9) or-(CH2)n-(CF2)O-
CF3;
R(7), R(8) and R(9)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
n iszeroor1;
o is zero, 1 or 2;
and their pharmacologically acceptable salts;
(HOE 94/F 168 - EP-Offenlegungsschrift 690 048, NZ 272 373)
20 ab) Phenyl-substituted alkenylcarboxylic acid guanidides, carrying
perfluoroalkyl groups, of the formula I
R(2) R(1 )

R(3)~~

R(4) ~ " C ~ N~, NH2


R(A ) R(B )

in which:
R(A) is hydrogen,.F, Cl, Br, I, CN, OH, OR(6), (C1-C8)-alkyl,
Or(CH2)aCbF2b+1, (C3-C8)-cycloalkyl or NR(7)R(8);

CA 02257299 199~-12-03

67
r iszeroor1;
a is zero, 1, 2, 3 or 4;
b is 1, 2, 3, 4, 5, 6, 7 or 8;
R(6) is (C1-C8)-alkyl, (Cl-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(9)R(1 0);
R(9) and R(10)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8)
independently of one another are defined as R(6);
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
R(B) independently is defined as R(A);
20 x iszero, 1 or2;
y is zero, 1 or 2;
R(C) is hydrogen, F, Cl, Br, I, CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF29+
or (C3-C8)-cycloalkyl;
p is zero or 1;
f iszero, 1, 2, 3 or4;
g is1,2,3,4,5,6,70r8;
R(1 2)
is (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatics phenyl or benzyl are not
substituted or are substituted by 1 - 3 substituents
from the group consisting of F, Cl, CF3, methyl,
.methoxy and NR(13)R(14);
R(13) and R(14)

CA 022~7299 1998-12-03

68
independently of one another are H, (C1-C4)-
alkyl or (C1-C4)-perfluoroalkyl;
R(D) independently is defined as R(C),
R(1) is hydrogen, (C1-C8)-alkyl~ -Ot(CH2)dCeF2e+l~ (C3-Cg)-cycloalkyl, F~
Cl, Br, l or CN;
t iszeroor1;
d is zero,1, 2, 3 or 4;
e is 1, 2, 3, 4, 5, 6, 7Or8;
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1);
but with the condition
that at least one of the substituents R(A), R(B), R(C), R(D), R(1), R(2), R(4)
or R(5) is a ~r(CH2)~cbF2b+l, Op(CH2)fCgF2~+1 or Ot(CH2)dCeF2e+1 group
and R(3) is not a Ot(cH2)dceF2e+1 group;
15 and their pharmaceutically tolerable salts;
(HOE 94/F 182 - EP-Offenlegungsschrift 690 048, NZ 272 449)
ac) oftho-amino-substituted benzoylguanidines of the formula I

R(2)
R ( 3 ) ~ R ( 1 )

R ( ~ N H 2
R ( 5 ) ~ NH2
in which:
R(1) is NR(50)R(6),
R(50) and R(6)
independently of one another are hydrogen, (C1-C8)-alkyl or
(Cl -C8)-perfluoroalkyl;
R(2), R(3), R(4) and R(5)
independently of one another are R(10)-SOa-, R(11)R(12)N-CO-,
R(13)-CO- or R(14)R(15)N-SO2-;
a is zero, 1 or 2,
R(10), R(11)rR(12), R(13), R(14) and R(15)
independently of one another are (C1-C8)-alkyl, (C1-C8)-


,

CA 022~7299 1998-12-03

69
perfluoroalkyl, (C3-C6~-alkenYI or ~CabH2ab~R(16);
ab is zero,1, 2, 3 or 4;
R(16) is (C3-C7)-cycloalkyl, phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(17)R(18);
R(17) and R(18)
independently of one another are H, CF3 or
(Cl-C4)-alkyl;
or
R(11), R(12), and also R(14) and R(15)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
or
R(11), R(12), R(14) and R(15)
independently of one another are hydrogen;
or
R(2), R(3), R(4) and R(5)
independently of one another are SR(21), -OR(22), -NR(23)R(24) or
-CR(25)R(26)R(27);
R(21), R(22), R(23) and R(25)
independently of one another are -CbH2b-(C1-Cg)-heteroaryl~
which is unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, CH3,
methoxy, hydroxyl, amino, methylamino and dimethylamino;
b is zero,1 or 2;
R(24), R(26) and R(27)
independently of one another are hydrogen, (C1-C4)-alkyl or
(C1-C4)-perfluoroalkyl;
or
R(2), R(3), R(4) and R(5)
independently of one another are hydrogen, F, Cl, Br, l, CN,
(Xa)dg CdaH2da+1~ -(Xb)dh-(CH2)db-CdeF2de+1~ (C3-C8)-alkenyl or


,

CA 022~7299 1998-12-03


-CdfH2dfR(30);
(Xa) is O, S or NR(33);
R(33)
is H, (Cl-C4)-alkyl or (C1-C4)-perfluoroalkyl;
dg iszero or 1;
(Xb) is O, S or NR(34);
R(34)
is H~ (Cl-C4)-alkyl or (Cl-C4)-perfluoroalkyl;
dh is zero or 1;
da iszero,1,2,3,4,5,6,7,8;
db is zero, 1, 2, 3, 4;
de iszero,1,2,3,4,5,6~7;
df is zero, 1, 2, 3, 4;
R(30)
is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where
the aromatics phenyl, biphenylyl or naphthyl are not
substituted or are substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3, methyl, methoxy and
NR(31)R(32);
R(31) and R(32)
are H, (Cl-C4)-alkyl or (Cl-C4)-perfluoroalkyl;
or
R(2), R(3), R(4) and R(5)
independently of one another are NR(40)R(41) or -(Xe)-
(CH2)ebR(45);
R(40) and R(41)
independently of one another are hydrogen, (Cl-C8)-alkyl,
(C1-C8)-perfluoroalkyl or (CH2)e-R(42);
e is zero, 1, 2, 3 or 4;
R(42)
is (C3-C7)-cycloalkyl, phenyl, which is not substituted
or is substituted by 1 - 3 substituents selected from the
.group consisting of F, Cl, CF3, methyl, methoxy and
NR(43)R(44);

CA 022~7299 1998-12-03


R(43) and R(44)
independently of one another are H, CF3 or
(Cl -C4)-alkyl;
or
R(40) and R(41)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
(Xe) is O, S or NR(47);
R(47)
is H~ (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
eb is zero,1, 2, 3 or 4;
R(45) is (C3-C7)-cycloalkyl, phenyl, which is not substituted or is
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, methyl, methoxy, NR(50)R(51) and
~(Xfa)~(CH2)ed~(Xfb)R(46);
Xfa is CH2, O, S or NR(48);
Xfb is O, S or NR(49);
ed is 1, 2, 3 or 4;
R(46)
is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(48), R(49), R(50) and R(51)
independently of one another are H or (C1-C4)-alkyl or
(C1 -C4)-perfluoroalkyl;
where R(3) and R(4), however, cannot be hydrogen,
and their pharmaceutically tolerable salts;




.

CA 022~7299 1998-12-03

72
(HOE 94/F 265 - NZ 272 946, EP-Offenlegungsschrift 700 904)
ad) benzoylguanidines of the formula I
R(l )


R ( 3 )~ --N H 2
R(4) ~

10 in which:
one of the three substituents R(1), R(2) and R(3)
is (C1-Cg)-heteroaryl-N-oxide,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
one of the three substituents R(1), R(2) and R(3)
is -SR(10), -OR(10), -NR(10)R(11) or -CR(10)R(11)R(12);
R(10)
is -CaH2a-(C1 -Cg)-heteroaryl-N-oxide,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
a is zero,1 or 2;
R(11) and R(12)
independently of one another are defined as R(10),
are hydrogen or (C1-C4)-alkyl;~0 and the other substituents R(1), R(2) and R(3) in each case
independently of one another are (C1-C8)-alkyl, (C2-C8)-alkenyl or
-CmH2mR(14);
m .is zero, 1 or 2;
R(14) is (C3-C8)-cycloalkyl or phenyl,

CA 022~7299 1998-12-03


which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and
NR(15)R(16),
R(15) and R(16)
are hydrogen or CH3;
or
the other substituents R(1), R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, l, -C-N,
X~(CH2)p~(CqF2q+1)~ R(22)-SOu~ R(23)R(24)N-CO, R(25)-CO- or
R(26) R(27) N-SO2-,
where the perfluoroalkyl group is straight-chain or branched;
X is a bond, oxygen, S or NR(28);
u is zero,1 or 2;
p iszero,1 or2;
q iszero,1,2,3,4,5Or6;
R(22), R(23), R(25) and R(26)
independently are (C1-C8)-alkyl, (C2-C6)-alkenyl,
-CnH2n-R(29) or CF3;
n is zero,1, 2, 3 or 4;
R(28) is hydrogen or (C1-C3)-alkyl;
R(29) is (C3-C7)-cycloalkyl or phenyl;
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and
NR(30)R(31);
R(30) and R(31)
are hydrogen or C1-C4-alkyl,
or
R(23), R(25) and R(26)
are also hydrogen;
R(24) and R(27)
independently of one another are hydrogen or (C1-C4)-alkyl;
or

CA 022~7299 1998-12-03


R(23) and R(24), and also R(26) and R(27) together are 4 or 5
methylene groups, of which one CH2 group can be replaced by
oxygen, S, NH, N-CH3 or N-benzyl;
or
the other substituents R(1), R(2) and R(3) in each case
independently of one another are OR(35) or NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or (C1-C6)-alkyl;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
R(4) and R(5)
independently of one another are hydrogen, (C1-C4)-alkyl, F, Cl,
-OR(32), -NR(33)R(34) or CrF2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or (C1-C3)-alkyl;
r is 1, 2, 3 or 4;
and their pharmaceutically tolerable salts;
(HOE 94/F 266 - EP-Offenlegungsschrift 702 001, NZ 272 948)
ae) benzoylguanidines of the formula I
R(l )

R ( 2 )~ N H2

J~ ~N=(
R(3) 1~ 1I NH2
R(4) ~
30 in which:
R(1) is hydrogen, F, Cl, Br, l, CN, NO2, OH, (C1-C8)-alkyl, (C3-C8)-
cycloalkyl~ Oa-(cH2)b-(cF2)c-cF3;
a iszero.or1;
b is zero,1 or 2;


.. . . ~ .

CA 022~7299 1998-12-03


c is zero, 1, 2 or 3;
or
R(1) is R(5)-SOm or R(6)R(7)N-SO2-;
m is zero, 1 or 2;
R(5) and R(6) independently of one another
are (C1-C8)-alkyl, (C3-C6)-alkenyl, CF3 or-CnH2n-R(8);
n is zero, 1, 2, 3 or 4;
R(7) is hydrogen or (C1-C4)-alkyl;
R(8) is (C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10) independently of one another
are hydrogen or (C1-C4)-alkyl;
or
R(6) is H;
or R(6) and R(7)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl,
or
R(1 ) is -SR( 1 1), -OR(1 1 ) or -CR(1 1 )R(1 2)R(13);
R(11 ) is -cpH2p-(c3-c8)-cycloalkyl~ -(C1-Cg)-heteroaryl or phenyl,
where the aromatic systems are unsubstituted
or substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3, CH3,
methoxy, hydroxyl, amino, methylamino and
dimethylamino;
R(12), R(13) independently of one another
are defined as R(11 ) or are hydrogen or
(C1-C4)-alkyl;
p is zero, 1 or 2;
or
R(1 ) is phenyl, naphthyl, biphenylyl or (C1-C9)-heteroaryl, the latter linked
via C or N,

CA 022~7299 1998-12-03

76
which are unsubstituted or substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, CH3,
methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(2) is -CF2R(14), -CF[R(15)][R(16)], ~CF[(CF2)q~CF3)][R(15)],
-C[(CF2)r-CF3]=CR(15)R(16);
R(14) is (C1-C4)-alkyl or (C3-C6)-cycloalkyl;
R(15) and R(16) independently of one another
are hydrogen or (C1-C4)-alkyl;

q iszero,1 or2;
r is zero,1 or 2;
R(3) is defined as R(1);
R(4) is hydrogen, (Cl-C3)-alkyl, F, Cl, Br, l, CN, -(CH2)s-(CF2)t-CF3;
s is zero or 1;
t iszero,1 or2;
and their pharmaceutically tolerable salts;
(HOE 94/F 267 - EP-Offenlegungsschrift 700 899, NZ 272 947)
af) benzoylguanidines of the formula I
R(l )
R ( 2 )~,~,R ( 5 )

R ( 3 )~ --N H2
R(4) 0
in which:
one of the three substituents R(1), R(2) and R(3)
is -Y-4-[(CH2)k-CHR(7)-(C=O)R(8)]-phenyl,
-Y-3-(CH2)k-CHR(7)-(C=O)R(8)]-phenyl or
-Y-2-[(CH2)k-CHR(7)-(C=O)R(8)]-phenyl,
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group F, Cl, -CF3, methyl,
hydroxyl, methoxy, or-NR(37)R(38);
R(37) and R(38)

CA 022~7299 1998-12-03


independently of one another are hydrogen or -CH3;
Y is a bond, oxygen, -S- or-NR(9);
R(9) is hydrogen or -(C1-C4)-alkyl;
R(7) is -OR(10) or -NR(10)R(11);
R(10) and R(11)
independently of one another are hydrogen, -(C1-C8)-
alkyl, -(C1 -C8)-alkanoyl, -(C1 -C8)-alkoxycarbonyl,
benzyl, benzyloxycarbonyl;
or
R(10) is trityl;
R(8) is-OR(12) or-NR(12)R(13);
R(12) and R(13)
independently of one another are hydrogen, -(C1-C8)-
alkyl or benzyl;
k iszero,1,2,3Or4;
and the other radicals R(1), R(2) and R(3) in each case
independently of one another are -(C1-C8)-alkyl, -(C2-C8)-alkenyl or
-(CH2)mR(14);
m is zero,1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, -CF3, methyl,
methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
the other radicals R(1), R(2) and R(3) in each case
independently of one another are R(18)R(19)N-(C=Y')-NH-SO2-;
Y' is oxygen, -S- or-N-R(20):
R(18) and R(19)
independently of one another are hydrogen, -(C1-C8)-alkyl,
-(C3-C6)-alkenyl or-(CH2)t-R(21);
t .is zero,1, 2, 3 or 4;
R(21) is -(C5-C7)-cycloalkyl or phenyl,

CA 022~7299 1998-12-03

78
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, -CF3, methoxy and -(C1-C4)-alkyl;
or
R(18) and R(19)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -N-CH3 or -N-
benzyl;
R(20)
is defined as R(18) or is amidine;
or
the other radicals R(1), R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, l, -C-N,
X~(CH2)p~(CqF2q+1)~ R(22)-SOU-, R(23)R(24)N-CO-, R(25)-CO- or
R(26)R(27)N-SO2-, where the perfluoroalkyl group is straight-chain
or branched;
X is a bond, oxygen, -S- or -NR(28);
u is zero,1 or 2;
p is zero,1 or 2;
q is 1, 2, 3,4, 5 or 6;
R(22), R(23), R(25) and R(26)
independently of one another are -(C1-C8)-alkyl,
-(C3-C6)-alkenyl, -(CH2)n-R(29) or-CF3;
n is zero,1, 2, 3 or 4;
R(28) is hydrogen or-(C1-C3)-alkyl;
R(29) is -(C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, -CF3, methyl, methoxy and -N R(30) R(31);
R(30) and R(31)
are hydrogen or-(C1-C4)-alkyl;
or
R(23), R(25) and R(26)
are hydrogen;

CA 022~7299 1998-12-03

79
R(24) and R(27)
independently of one another are hydrogen or -(C1-C4)-alkyl;
or
R(23) and R(24), and also R(26) and R(27)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, - N-CH3 or -
N-benzyl;
or
the other radicals R(1), R(2) and R(3) in each case
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or -(C1-C6)-alkyl;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -N-CH3 or-N-benzyl;
R(4) and R(5)
independently of one another are hydrogen, -(C1-C4)-alkyl, F, Cl,
-OR(32), -NR(33)R(34) ~r~CrF2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or -(C1-C3)-alkyl;
r is 1, 2, 3 or 4;
and their pharmaceutically tolerable salts;
(HOE 94tF 352 - EP-Offenlegungsschrift 713 684, NZ 280 517)
25 ag) benzoylguanidines of the formula I
R(l )
R ( 2 ) ~ "R ( 5 )

R ( 3 )~ =N H 2
R(4) 0
in which:
R(1) is R(6)-CO or. R(7)R(8)N-CO7
R(6) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl

CA 022~7299 1998-12-03


or -CnH2n-R(9),
n is zero, 1, 2, 3 or 4;
R(9) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(10)R(11),
R(10) and R(11)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(7) is H~ (C1-Cg)-alkyl, (C1-C8)-perfluoroalkyl~ (C3-C8)-
alkenyl or-CnH2n-R(12);
n is zero,1, 2, 3 or 4;
R(12) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(13)R(14);
R(13) and R(14)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(8) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(7) and R(8) together
are 4 or 5 methylene groups, of which one CH2 group
can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(2) is defined as R(1), or is H, OH, F, Cl, Br, l, CN, NO2, (C1-C8)-alkyl,
(Cl-C8)-perfluoroalkyl, (C3-C8)-alkenyl or-CnH2nR(15);
n is zerQ,1, 2, 3 or 4;
R(15) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,

CA 022~7299 1998-12-03


where the aromatics are not substituted or are substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(16)R(17);
R(16) and R(17)
are H, (Cl-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(2) is (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(2) is SR(18), -OR(18), -NR(18)R(19) or-CR(18)R(19)R(20);
R(18) -is CaH2a-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino,
dimethylamino;
a is zero, 1 or 2;
R(19) and R(20)
independently of one another are defined as R(18) or
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(2) is R(21 )-S~m or R(22)R(23)N-SO2-;
m is 1 or2;
R(21) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-CnH2n-R(24);
n is zero, 1, 2, 3 or 4;

R(24) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);


.

CA 022~7299 1998-12-03

82
R(27) and R(28)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(22) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or
-CnH2n-R(29);
n is zero,1, 2, 3 or 4;
R(29) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatics are not substituted
or are substituted by 1 - 3 substituents
selected from the group consisting of F,
Cl, CF3, methyl, methoxy and
NR(30)R(31);
R(30) and R(31)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(23) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(22) and R(23)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
R(2) is R(33)X-;
X is oxygen, S, NR(34), (D=O)A- or NR(34)C=MN(*)R(35)-;
M is oxygen or S;
A is oxygen or NR(34);
D is C or SO;
R(33) is (C~-C8)-alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1 or
-CnH2n-R(36);
b iszeroor1;
d is 1, 2, 3, 4, 5, 6 or 7;
n is zero,1, 2, 3, or 4;
R(36) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
where the aromatics are not substituted or are

CA 022~7299 1998-12-03

83
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(37)R(38);
R(37) and R(38)
are H, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(34) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(35) is defined as R(33);
or
R(33) and R(34)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent structure;
or
R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42),
-CR(42)R(43)0H, -C--CR(45), -CR(46)=CR(45) or
-[CR(47)R(48)]U-CO-[C(R49)R(50)]V-R(44);
R(40) and R(41)
independently of one another are ~(CH2)p~(CHOH)q~(CH2)r~
(CHOH)t-R(51) or ~(CH2)p~O~(CH2~CH2O)q~R(51);
R(51) is hydrogen or methyl;
u is 1, 2, 3 or4;
v is zero,1, 2, 3 or 4;
p, q and r
independently of one another are zero,1, 2, 3 or 4;
t is 1, 2, 3 or 4;
R(42) and R(43)
independently of one another are hydrogen or (C1-C6)-alkyl;
or
R(42) and R(43)
together with the carbon atom carrying them are a (C3-C8)-
cycloalkyl;

CA 022~7299 1998-12-03

84
R(44) is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, -CeH2e-R(45);
e is zero,1, 2, 3 or 4;
R(45) is phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl, methoxy and NR(52)R(53);
R(52) and R(53)
are H or (C1-C4)-alkyl;
or
R(45) is(C1-Cg)-heteroaryl,
which is unsubstituted or substituted as phenyl;
or
R(45) is (C1-C6)-alkYI,
which is unsubstituted or substituted by 1 - 3 OH;
R(46), R(47), R(48), R(49) and R(50)
independently of one another are hydrogen or methyl;
or
R(2) is R(55)-NH-SO2-;
R(55) is R(56)R(57)N-(C=Y)-;
Y is oxygen, S or N-R(58);
R(56) and R(57)
independently of one another are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or-CfH2f-R(59);
f is zero,1, 2, 3 or 4;
R(59) is (C5-C7)-cycloalkyl, phenyl,
which is unsubstituted or substituted by
1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methoxy
and (C1-C4)-alkyl;
or
R(56) and R(57)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(58)

CA 022~7299 1998-12-03


is defined as R(56) or is amidine;
R(3), R(4) and R(5) are independently of one another defined as R(1) or
R(2), but where at least one of the substituents R(2), R(3), R(4) and R(5)
must be OH;
5 and their phammaceutically tolerable salts;
(HOE 95/F 007 K - EP-Offenlegungsschrift 723 956, NZ 280 887)
ah) benzoylguanidines of the formula I

R(l )
R ( 2 ) ~ R ( 5 )
R(3) ~N~NH2

R(~) ~ NH2
15 in which:
one of the three substituents R(1), R(2) and R(3)
is R(6)-A-B-D-;
R(6) is a basic protonatable radical, i.e. an amino group
-NR(7)R(8), an amidino group R(7)R(8)N-C[=N-R(9)]- or a
guanidino group

R ( 7 ) R ( 1 0 )

R ( 8 ) --N~fN~

R(9)

R(7), R(8), R(9) and R(10)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
or
R(7) and R(8)
together are CaH2a;
a is4, 5, 6 or7;
where if a = 5, 6 or 7 a methylene group of the group

CA 022~7299 1998-12-03

86
CaH2a can be replaced by a heteroatom group O, S~m
or NR(11),
or
R(8) and R(9) or R(9) and R(10) or R(7) and R(10)
are a group CaH2a;
a is2,3,4Or5;
where if a = 3, 4 or 5 a methylene group of the
group CaH2a can be replaced by a heteroatom
group O, S~m or NR(11);
m is zero,1 or2;
R(11) is hydrogen or methyl;
or
R(6) is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is CbH2b;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
where in the group CbH2b one or two methylene
groups can be replaced by one of the groupings
selected from the group consisting of -O-, -CO-,
-CH[OR(20)]-, ~SOm~~ -NR(20)-, -NR(20)-CO-,
-NR(20)-CO-NH-, -NR(20)-CO-NH-SO2-
llo)oo
-R ( 20 ) N-S-
I N R ( l 9 ) l bb
and -SOaa[NR(1 9)]bb-;
and where in the group CbH2b a methylene group can
be replaced by -CH-R(99), where R(99) together with
R(7) forms a pyrrolidine or piperi~line ring;
aa is 1 or2;
bb isOor1;
aa + bb = 2;
R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon
atoms;

CA 022~7299 1998-12-03

87
R(20) is hydrogen or methyl;
B is a phenylene or naphthylene radical
R(12) R(12)


5 /$
R( l 3)
R ( l 3 )

R(12) and R(13)
independently of one another are hydrogen, methyl, F,
Cl, Br, l, CF3 or-SOw-R(14);
R(14) is methyl or NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
alkyl having 1,2, 3 or 4 carbon atoms;
w is zero,1 or 2;
D is-CdH2d-Xf-;
d is zero,1, 2, 3 or 4;
X is -O-, -CO-, -CH[OR(21)]-, ~SOm~ or-NR(21)-;
f is zero or 1;
R(21) is hydrogen or methyl;
m is zero,1 or 2;
and the other substituents R(1) and R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, l, -CN,
-(C1-C8)-alkyl, -(C2-C8)-alkenyl, -NR(35)R(36) or R(17)-CgH29~Zh~;
g is zero,1, 2, 3 or 4;
h is zero or 1;
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or

CA 022~7299 1998-12-03


R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
Z is -O-, -CO-, -SOv- ,-NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH-
or -NR(18)-SO2-;
R(18) is hydrogen or methyl;
v iszero,10r2;
R(17) is hydrogen, cycloalkyl having 3, 5 or 6 carbon atoms or
CkF2k+1-;
k is1,20r3,
or
R(17) is pyrrol-1 -yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4
substituents selected from the group consisting of F,
Cl, Br, l, -CN, (C2-C8)-alkanoyl, (C2-C8)-
alkoxycarbonyl, formyl, carboxyl, -CF3, methyl and
methoxy;
or
R(17) -is (C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, hydroxyl, methoxy,
-NR(37)R(38), CH3SO2- and H2NO2S-;
R(37) and R(38)
are hydrogen or-CH3;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or-CrF2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
r is 1, 2, 3 or 4;
and their pharmacologically tolerable salts;
(HOE 95/F 072 - EP-Offenlegungsschrift 738 712, NZ 286 380)

CA 022~7299 1998-12-03

89
ai) indenoylguanidines of the formula I

R ( 3 )R ( 2 ) ~ -R ( 8 )
( 5 ) ~NlN/ R ( 9 ) x A

R(6)R(l) R(7) R(lO)




in which:
R(1) and R(2)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3, 4, 5 or 6
carbon atoms, O-alkyl having 1, 2, 3 or 4 carbon atoms, O-C(=O)-
alkyl having 1, 2, 3 or 4 carbon atoms or CmH2m-NR(12)R(13);
R(12) and R(13)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
m is zero, 1, 2, 3 or 4;
NH-C(=O)-NH2, C(=O)-O-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-NH2, C(=O)-NH-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-N(alkyl)2 having 1, 2, 3 or 4 carbon atoms in each alkyl
group, alkenyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms,
alkynyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, alkylaryl
having 1, 2, 3 or 4 carbon atoms in the alkyl group, alkenylaryl
having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the alkenyl group,
alkynylaryl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the
alkynyl group, C1-C4-alkyl-substituted aryl, C1-C4-alkylheteroaryl,
C1-C4-alkenylheteroaryl, aminoalkylaryl having 1, 2, 3 or 4 carbon
atoms in the alkyl group, substituted aryl, heteroaryl and substituted
heteroaryl;
R(3), R(4), R(5) and R(6)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, O-alkyl having 1, 2, 3, 4, 5, 6, 7, 8,

CA 022~7299 1998-12-03


9 or 10 carbon atoms, halogen, (such as F, Cl, Br, I), OH, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, O-lower alkyl, O-aryl, O-lower
alkylaryl, O-substituted aryl, O-lower alkyl-substituted aryl, O-C(=O)-C1-C4-
alkylaryl, O-C(=O)-NH-C~-C4-alkyl, O-C(=O)-N(C1-C4-alkyl)2, NO2, CN,
CF3, NH2, NH-C(=O)-C1-C4-alkyl, NH-C(=O)-NH2, COOH, C(=O)-O-C1-C4-
alkyl, C(=O)-NH2, C(=O)-NH-C~-C4-alkyl, C(=O)-N(C1-C4-alkyl)2, C1-C4-
COOH, C1-C4-alkyl-C(=O)-O-C1-C4-alkyl, SO3H, SO2-alkyl, SO2-alkylaryl,
SO2-N-(alkyl)2, SO2-N(alkyl)(alkylaryl), C(=O)-R(11), C1-C10-alkyl-C(=O)-
R(11), c2-clo-alkenyl-c(=o)-R(11), C2-Clo-alkYnyl-c(=o)-R(11)~ NH-
C(=O)-Cl-C1O-alkyl-C(=O)-R(11), O-Cl-Cl l-alkyl-C(=O)-R(11 );
R(11 ) is C1-C4-alkyl, C1-C4-alkynyl, aryl, substituted aryl, NH2, NH-C1-C4-
alkyl, N-(C1-C4-alkyl)2, S03H, SO2-alkyl, SO2-alkylaryl, SO2 N
(alkyl)2, SO2-N(alkyl)(alkylaryl);
X isO, SorNH;
R(7), R(8), R(9) and R(10)
independently of one another are hydrogen, alkyl, cycloalkyl, aryl,
alkylaryl;
or
R(8) and R(9)
together are part of a 5, 6 or 7-membered heterocyclic ring;
A is absent or is a nontoxic organic or inorganic acid.
(HOE 95/F 109 - EP 748 795, NZ 286 583)
ak) benzyloxycarbonylguanidines of the formula I

R ( l )
R ( 2 ) ~ R ( S )
R ( 3 ) J~X~N~ N H 2

R ( 4 ) R ( 6 )\ ~ N H 2
R(7)
in which:
R(1), R(2) and R(3)
independently of one another are -Y-[4-R(8)-phenyl], -Y-[3-R(8)-
phenyl] or-Y-[2-R(8)-phenyl],

CA 022~7299 1998-12-03

91
where the phenyl is in each case unsubstituted or substituted
by 1 - 2 substituents from the group consisting of F, Cl, -CF3,
methyl, hydroxyl, methoxy and -NR(96)R(97);
R(96) and R(97)
independently of one another are hydrogen or -CH3;
Y is a bond, CH2, oxygen, -S- or-NR(9);
R(9) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(8) is SOa[NR(98)]bNR(99)R(10);
a is 1 or 2;
b isOor1;
a + b = 2;
R(98), R(99) and R(10)
independently of one another are hydrogen, -(C1-C8)-
alkyl, benzyl, -(C2-C8)-alkylene-NR(11)R(12), (C2-C8)-
alkylene-NR(13)-(C2-C8)-alkylene-NR(37)R(38) or
(CO-C8)-alkylene-CR(39)R(40)CR(41 )R(42)(Co-C8)-
alkylene-NR(43)R(44);
R(11), R(12), R(13), R(37), R(38), R(43) and R(44)
independently of one another are hydrogen,
-(C1-C8)-alkyl or benzyl:
R(39), R(40), R(41) and R(42)
independently of one another are hydrogen,
-(C1-C8)-alkyl or-(CO-C3)-alkylenephenyl,
where the phenyl is not substituted or is
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl,-CF3,
methyl and methoxy;
or
R(99) and R(10)
together are 4 - 6 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -N-CH3 or
-N-benzyl;
or
R(8) is SOa[NR(98)]bNR(95)-C[=N-R(94)]-NR(93)R(92);

CA 022~7299 1998-12-03

92
R(92), R(93), R(94) and R(95)
independently of one another are hydrogen or alkyl
having 1,2, 3 or 4 carbon atoms;
or
R(1), R(2) and R(3)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-
yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, l, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -
CF3, methyl, methoxy;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, -(C1-C8)-alkyl, -(C2-C8)-
alkenyl or-(CH2)mR(14);
m is zero,1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and -Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
R(1), R(2) and R(3)
independently of one another are -Q-4-[(CH2)k-CHR(17)-

(C=O)R(20)]-phenyl, -Q-3-(CH2)k-CHR(17)-(C=O)R(20)]-phenyl or
-O-2-[(CH2)k-CHR(17)-(c=O)R(2o)]-phenyl~
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group F, Cl, -CF3, methyl,
hydroxyl, methoxy and -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or -CH3;
Q is a bQnd, oxygen, -S- or-NR(18);
R(18) is hydrogen or-(C1-C4)-alkyl;

CA 022~7299 1998-12-03

93
R(17) is -OR(21) or -NR(21)R(22);
R(21) and R(22)
independently of one another are hydrogen, -(C1-C8)-
alkyl, -(C1 -C8)-alkanoyl, -(C1 -C8)-alkoxycarbonyl,
benzyl, benzyloxycarbonyl;
or
R(21) is trityl;
R(20) is-OR(23) or-NR(23)R(24);
R(23), R(24) independently of one another are
hydrogen, -(C1-C8)-alkyl or benzyl;
k is zero,1, 2, 3 or 4;
or
R(1), R(2) and R(3)
independently of one another are (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents from the group F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
or
R(1), R(2) and R(3)
are -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is-CfH2f-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents from the group F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
f is zero,1 or 2;
R(26) and R(27)
independently of one another are defined as R(25) or
are hydrogen or (C1-C4)-alkyl,
or
R(1), R(2) and R(3)
independently of one another are (C1-Cg)-heteroaryl-N-oxide,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group

CA 022~7299 1998-12-03

94
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(1), R(2) and R(3)
independently of one another are -SR(28), -OR(28), -NR(28)R(29)
or -CR(28)R(29)R(30);
R(28) is-CgH29-(C1-Cg)-heteroaryl-N-oxide,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
g is zero,1 or 2;
R(29), R(30)
independently of one another are defined as R(28),
hydrogen or (C1-C4)-alkyl;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, F, Cl, Br, l, -C-N,
T-(CH2)h-(CjF2j+1), R(31)SOI-, R(32)R(33)N-CO-, R(34)-CO- or
R(45)R(46)N-SO2, where the perfluoroalkyl group is straight-chain
or branched;
T is a bond, oxygen, -S- or-NR(47);
is zero,1 or 2;
h is zero,1 or 2;
is 1, 2, 3, 4, 5 or 6;
R(31), R(32), R(34) and R(45)
independently of one another are -(C1-C8)-alkyl, -(C3-C6)-
alkenyl, (CH2)nR(48) or-CF3;
n is zero,1, 2, 3 or 4;
R(47) is hydrogen or alkyl with 1, 2 or 3 carbon atoms;
R(48) is -(C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy and

CA 022~7299 1998-12-03


-NR(49)R(50);
R(49) and R(50)
are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(32), R(34) and R(45)
are hydrogen;
R(33) and R(46)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(32) and R(33), and R(45) and R(46)
together are 5 or 6 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -NCH3 or
-N-benzyl;
or
R(1), R(2) and R(3)
independently of one another are R(51)-A-G-D-;
R(51) is a basic protonatable radical, i.e. an amino group
-NR(52)R(53), an amidino group R(52)R(53)N-C[=N-R(54)]-
or a guanidino group R(52)R(53)N-C[=N-R(54)]-NR(55)-;
R(52), R(53), R(54) and R(55)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(52) and R(53) are
a group CaH2a;
a is4,5,60r7;
where if ~ = 5, 6 or 7 a carbon atom of the group
CaH2a can be replaced by a heteroatom group 0, S~d
or NR(56),
or
R(53) and R(54) or R(54) and R(55) or R(52) and R(55) are
.a group CyH2y;
y is2,3,40r5;

CA 022~7299 1998-12-03

96
where if y = 3,4 or 5 a carbon atom of the group
CVH2v can be replaced by a heteroatom group O, S~d
or NR(56);
d is zero, 1 or 2;
R(56)is hydrogen or methyl;
or
R(51)is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is a group CeH2e;
e is zero, 1, 2,3,4,5,6,7,8,9 or 10;
where in the group CeH2e a carbon atom can be replaced by
one of the groupings -O-, -CO-, -CH[OR(57)]-,-SOr-,-
NR(57)-,-NR(57)-CO-,-NR(57)-CO-NH-,-NR(57)-CO-NH-

SO2- or-NR(57)-SO2-;
r is zero, 1 or 2;
G is a phenylene radical
~ R ( 5 8 )


R ( S 9 )
R(58) and R(59)
independently of one another are hydrogen, methyl,
methoxy, F, Cl, Br, I, CF3 or-SOs-R(60);
R(60)is methyl or NR(61)R(62);
R(61) and R(62)
independently of one another are
hydrogen or alkyl having 1, 2,3 or 4
carbon atoms;
D is-cvH2v-Ew-;
v is zero, 1, 2,3 or 4;
E is-O-,-CO-,-CH[OR(63)]-,-SOaa- or -NR(63)-;
w is zero or 1;
aa .is zero, 1 or 2
R(63) is hydrogen or methyl,

CA 022~7299 1998-12-03

97
or
R(1), R(2) and R(3)
independently of one another are -CF2R(64), -CF[R(65)][R(66)],
~CF[(CF2)q~CF3][R(65)]1 -C[(CF2)p-CF3]=CR(65)R(66);
R(64) is alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having
3, 4, 5, 6 or 7 carbon atoms;
R(65) and R(66) independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
q is zero, 1 or 2;
p is zero, 1 or 2;
or
R(1), R(2) and R(3)
independently of one another are -OR(67) or -NR(67)R(68);
R(67) and R(68)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(67) and R(68)
together are 4, 5, 6 or 7 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, SO2, -NH-, -NCH3 or
-N-benzyl;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(69), -NR(70)R(71) or-CzF2z+l;
R(69), R(70) and R(71)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
z is 1, 2, 3 or 4;
R(6) and R(7)
independently of one another are hydrogen or alkyl having 1, 2, 3 or
4 carbon atoms;
X is oxygen or NR(72);
R(72) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
and their pharmaceuticaliy tolerable salts;

CA 022~7299 1998-12-03

98
(HOE 95/F 115 - EP 744 397, NZ 286 622)
al) alkenylcarboxylic acid guanidides, carrying fluorophenyl groups, of the
formula I
) R ( l )
R ( 3 ) ~ / R ( 6 ) H
R ( ~ ) ~N~N~
R ( S ) ~ H~N~
R ( 7 )

in which:
R(6) is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl or phenyl,
where the phenyl group is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) independently is defined as R(6);
R(1), R(2), R(3), R(4) and R(5)
independently of one another are hydrogen or F;
where, however, at least one of the radicals R(1), R(2), R(3), R(4)
and R(5) must be fluorine;
and their pharmaceutically tolerable salts;
(HOE 95/F 167 - NZ 299 015)
ak) benzoylguanidines of the formula I
R(l )
R ( 2 ) ~
R ( 3 ) ~f~ NH2
~ NH2
in which:
R(1) is R(4)-SOm .
or R(5)R(6)N-SO2-;

CA 022~7299 1998-12-03


m is 1 or 2;
R(4) and R(5)
independently of one another are alkyl having 1, 2, 3, 4, 5, 6,
7 or 8 carbon atoms, alkenyl having 3, 4, 5 or 6 carbon
atoms, CF3 or-CnH2n-R(7);
n is zero, 1, 2, 3 or 4;
R(6) is H or alkyl having 1, 2, 3 or 4 carbon atoms;
R(7) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or
phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and NR(8)R(9);
R(8) and R(9)
are H or alkyl having 1, 2, 3 or 4 carbon
atoms;
or
R(5) is also hydrogen;
or
R(5) and R(6)
together are 4 or 5 methylene groups, of which a CH2 group
can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
or
R(1 ) is -Op-(CH2)q-(CF2)r-CF3;
p iszeroor1;
q iszero,10r2;
r is zero, 1, 2 or 3;
or
R(1 ) is -SR(10), -OR(10) or -CR(1 O)R(1 1 )R(12);
R(10), R(1 1 ) and R(12)
independently of one another are hydrogen, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
-CsH2s-(C3-C8)-cycloalkyl or an aromatic system
. selected from the group consisting of pyridyl, pyrrolyl,
quinolyl, isoquinolyl, imidazolyl or phenyl;

CA 022~7299 1998-12-03

100
s is zero, 1 or 2;
where the aromatic systems pyridyl, pyrrolyl, quinolyl,
isoquinolyl, imidazolyl and phenyl are unsubstituted or
substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
R(2) is-(cH2)u-(cF2)t-cF3;
t is zero, 1, 2 or 3;
u iszeroor1;
R(3) is hydrogen or independently is defined as R(1);
and their pharmaceutically tolerable salts;
(HOE 95/F 173 - NZ 299 052)
an) substituted cinnamic acid guanidides of the formula I
R ( 2 )
R ( 3 ) ~R (Rl()6 )

R ( ~ ) ~N~,~ NH2
R ( S )R ( 7 )~ NH2

in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is
-X -Yb-L -U;
X is CR(16)R(17), O, S or NR(18);
R(16), R(17) and R(18)
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;
a is zero or 1;
Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
alkylene-T having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the
alkylene group, T, T-alkylene having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms in the alkylene group;
T .is NR(20), O, S or phenylene,
where the phenylene is not substituted or is

CA 022~7299 1998-12-03

101
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(21)R(22);
R(20), 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;
b iszeroor1;
L is O, S, NR(23) or CkH2k;
k is 1, 2, 3, 4, 5, 6, 7, 8;
n iszeroor1;
U is NR(24)R(25) or an N-containing heterocycle having 1, 2, 3,
4, 5, 6, 7, 8 or 9 carbon atoms;
R(24) and R(25)
independently of one another are hydrogen, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms;
or
R(24) and R(25)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where the N-containing heterocycles are N- or C-bridged and
are not substituted or are substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);
R(23), R(27) and R(28)
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;
and the other substituents R(1), R(2), R(3), R(4) and R(5) in each case
independently of one another are H, F, Cl, Br, l, CN, ~On-CmH2m+

CA 022~7299 1998-12-03

102
~op-(cH2)s-cqF2q+1 0r~CrH2rR(1~);
n is zero or 1;
m is zero 1, 2, 3, 4, 5, 6, 7 or 8;
p iszeroorl;
q is 1, 2, 3, 4, 5, 6, 7 or 8;
s is zero, 1, 2, 3 or 4;
r is zero, 1, 2, 3 or 4;
R(1 0)
is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
where the phenyl is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of
F, Cl, CF3, methyl, methoxy and NR(11)R(12);
R(1 1 ) and R(12)
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(6) and R(7)
independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
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;~nd their pharmaceutically tolerable salts;

CA 022~7299 1998-12-03

103
(HOE 95/F 220 - NZ 299 052)
ao) benzoylguanidines of the formula I

R(l )
R ( 2 ) ~ R ( 5 )

R ( 3 ) ~N~NH2
R ( ~ ) ~ N H 2

in which:
at least one of the substituents R(1), R(2) and R(3)
is R(6)-C(OH)2-;
R(6) is perfluoroalkyl having 1, 2 or 3 carbon atoms, which is
straight-chain or branched;
and the other substituents R(1), R(2) and R(3)
independently of one another are hydrogen, OH, F, Cl, Br, I, alkyl
having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5 or 6
carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms or phenoxy,
which is unsubstituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, methyl and
methoxy;
or
the other substituents R(1), R(2) and R(3)
independently of one another are alkyl-SOx, -CR(7)=CR(8)R(9) or
-C -CR(9);
x is zero, 1 or 2;
R(7) is hydrogen or methyl;
R(8) and R(9)
independently of one another are hydrogen, alkyl having 1, 2,
3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms or phenyl,
which is unsubstituted or is substituted by 1 - 3
.substituents selected from the group consisting of F,
Cl, CF3, methyl and methoxy;

CA 022~7299 1998-12-03

104
or
the other substituents R(1), R(2) and R(3)
independently of one another are phenyl, C6H5-(C1-C4)-alkyl,
naphthyl, biphenylyl, quinolinyl, isoquinolinyl or imidazolyl,
where quinolinyl, isoquinolinyl or imidazolyl are bonded via C
or N and where phenyl, C6H5-(C1-C4)-alkyl, naphthyl,
biphenylyl, quinolinyl, isoquinolinyl and imidazolyl are
unsubstituted or are substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
or
the other substituents R(1), R(2) and R(3)
independently of one another are SR(10), -OR(10),
-CR(10)R(11)R(12);
R(10)
is-CfH2f-(C3-C8)-cycloalkyl, quinolinyl, isoquinolinyl, pyridinyl,
imidazolyl or phenyl,
where the aromatic systems quinolinyl, isoquinolinyl,
pyridinyl, imidazolyl and phenyl are unsubstituted or
are substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
f is zero,1 or 2;
R(11) and R(12)
independently of one another are defined as R(10), hydrogen
or alkyl having 1,2,3 or 4 carbon atoms;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1,2 or 3
carbon atoms, F, Cl, Br, l, CN, OR(13), NR(14)R(15),
~(CH2)n-(CF2)o~CF3;
R(13), R(14) and R(15)
independently of one another are hydrogen or alkyl having 1,
2,3 or.4 carbon atoms;
n iszeroor1;

CA 022~7299 1998-12-03

105
o is zero,1 or 2;
and their pharmacologically acceptable salts;
(HOE 95/F 253 - NZ 299 682)
ap) sulfonimidamides of the formula I
N,R1
O= S--R2
.N~

in which:
at least one of the three substituents R(1), R(2) and R(3)
is a benzoylguanidine,

~'~NYNH2

O NH2

which is unsubstituted or substituted in the phenyl moiety by
1 - 4 radicals selected from the group consisting of alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2,
3, 4, 5, 6, 7 or 8 carbon atoms, -(CH2)m-R(14), F, Cl, Br, l,
-C-N, CF3, R(22)SO2-, R(23)R(24)N-CO-, R(25)-CO-,
R(26)R(27)N-SO2, -OR(35), -SR(35) or-NR(35)R(36);
m is zero,1 or 2;
R(14)
is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F and Cl, -CF3, methyl, methoxy and
-NR(15)R(16);
R(15) and R(16)
independently of one another are
hydrogen or-CH3;
R(22),. R(23), R(25) and R(26)
independently of one another are alkyl having 1, 2, 3,

CA 022~7299 1998-12-03

106
4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5,
6, 7 or 8 carbon atoms, (CH2)nR(29) or -CF3;
n is zero, 1, 2, 3 or 4;
R(29) is -(C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy and
-NR(30)R(31);
R(30) and R(31)
are hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
or
R(23), R(25) and R(26)
are hydrogen;
R(24) and R(27)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
or
R(23) and R(24), and also R(26) and R(27)
together are 5 or 6 methylene groups, of which one
CH2 group can be replaced by oxygen, -S-, -NH-, -
NCH3 or-N-benzyl;
R(35) and R(36)
independently of one another are hydrogen or alkyl
having 1, 2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -NCH3 or
-N-benzyl;
or
R(35)
.is phenyl,
which is not substituted or is substituted by 1 - 3

CA 022~7299 1998-12-03

107
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy, SO2R(5),
SO2N R(6) R(7) and -N R(32) R(33);
R(5) is alkyl having 1, 2, 3, 4, 5 or 6 carbon
atoms
R(6) and R(7)
independently of one another are
hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
R(32) and R(33)
independently of one another are
hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
or
R(35)
is Cl-Cg-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
and the other substituents R(1), R(2) and R(3) in each case
independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms, (CH2)pR(10)
p is zero, 1, 2, 3 or 4;
R(10) isphenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, -CF3, methyl, methoxy, -SO2NR(17)R(8) and
-SO2R(9);
R(17) and R(8)
independently of one another are hydrogen or
alkyl having 1, 2, 3 or 4 carbon atoms;
. R(9) is alkyl having 1, 2, 3 or 4 carbon atoms;
or the other radical R(1 ) and R(3) in each case

CA 022~7299 1998-12-03

108
are hydrogen,
R(4) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;
(HOE 95/F 265 - NZ 299 739)
ao) benzoylguanidines of the formula I
R




O= S--R1
R2-N
R3~, R6

R4~ N~, NH2
R5 O NH2
in which:
R(1) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or NR(7)R(8);
R(7) and R(8)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(2) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-SO2R(9);
R(9) independently is defined as R(1);
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26) or -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25)
is -(C1 -C9)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
.CI, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;

CA 022~7299 1998-12-03

109
R(26) and R(27)
independently of one another are defined as R(25) or
are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms;
R(4) is hydrogen, F, Cl, Br, I, OH, -C-N, CF3, alkyl having 1, 2, 3, 4, 5, 6,
7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon
atoms or-(CH2)mR(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;
R(5) and R(6)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;
(HOE 95/F 269 K)
ar) benzenedicarboxylic acid diguanidides of the formula I
R2
R3 l R1
~' Il' I
R4~N~yNH2
R5 O NH2
in which:
one of the radicals R(1), R(2), R(3) and R(4)
is -CO-N=C(NH2)2;
and the other radicaJs R(1), R(2), R(3) and R(4) in each case are:
R(1 ) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I,

CA 022~7299 1998-12-03

110
-OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) and R(4)
independently of one another are hydrogen, F, Cl, Br, l, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mR(14);
m is zero,1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
R(2) and R(4)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or
pyrrol-3-yl,
not which is not substituted or is substituted by 1 - 4
substituents selected from the group consisting of F, Cl, Br, l,
-CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl,
carboxyl, -CF3, methyl, methoxy;
or
R(2) and R(4)
independently of one another are R(22)-SO2-, R(23)R(24)N-CO-,
R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
R(2) and R(4)

CA 022~7299 1998-12-03

111
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, l, X-(CH2)y~CF3
or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F and Cl, -CF3, methyl,
methoxy and -NR(6)R(7);
R(6) and R(7)
independently of one another are hydrogen or -CH3;
X is a bond or oxygen;
y is zero,1 or 2;
and their pharmaceutically tolerable salts;

CA 022~7299 1998-12-03

112
(HOE 95/F 269 BK)
as) benzenedicarboxylic acid diguanidides of the formula I
R2
R3~R1

R4~hf N~ NH2
R5 O NH2
in which:
one of the radicals R(1), R(2), R(3) and R(5)
is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(5) in each case are:
R(1) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) is hydrogen, F, Cl, Br, l, OH, -C-N, CF3, -CO-N=C(NH2)2, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5,
6, 7 or 8 carbon atoms or -(CH2)mR(14);
m is zero,1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;
or
R(2) is R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24),. R(29) and R(30)
independently of one another are hydrogen or methyl;

CA 022~7299 1998-12-03

113
or
R(2) is -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(4) is CF3, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl
having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, -(C3-C8)-cycloalkyl or
-(CH2)mR(14);
m is 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
.and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)

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114
independently of one another are hydrogen or
-CH3;
or
R(4) is phenyl,
which is substituted by 2, 3, 4 or five substituents selected
from the group consisting of F, Cl, CF3, methyl, methoxy and
-NR(1 5)R(1 6);
R(15) and R(16)
independently of one another are hydrogen or
CH3;
and their pharrnaceutically tolerable salts;
(HOE 96/F 013)

CA 022~7299 1998-12-03

115
at) diaryldicarboxylic acid diguanidides of the formula I

R3~R,~ R3


R5 R6
in which:
one of the radicals R(1), R(2), R(3), R(4) and R(5)
is -CO-N=C(NH2)2;
the other radicals R(1 ) and R(5) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
the other radicals R(2) and R(4) in each case
independently of one another are hydrogen, F, Cl, Br, I, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mR(1 4);
m is zero, 1 or 2;
R(14) is-(C3-C8)-cycloalkylorphenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(1 5)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
the other radicals R(2) and R(4) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or
pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, I, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,

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116
-CF3, methyl, methoxy;
or
the other radicals R(2) and R(4) in each case
are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
the other radicals R(2) and R(4) in each case
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
the other radical R(3) in each case
is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are

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117
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
one of the radicals R(6), R(7), R(8), R(9) and R(10)
is -CO-N=C(NH2)2;
the other radicals R(6) and R(10) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;
R(132), R(133) and R(134)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
the other radicals R(7) and R(9) in each case
independently of one another are hydrogen, F, Cl, Br, l, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mmR(114);
mm is zero,1 or 2;
R(114)
is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(115)R(116);
R(115) and R(116)
are hydrogen or-CH3;
or
the other radicals R(7) and R(9) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-
yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, l, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl and methoxy;
or
the other radicals R(7) and R(9) in each case
are R(122)-SO2-, R(123)R(124)N-CO-, R(128)-CO- or
R(129)R(130)N-so2;

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118
R(122) and R(128)
independently of one another are methyl or -CF3;
R(123), R(124), R(129) and R(130)
independently of one another are hydrogen or methyl;
or
the other radicals R(7) and R(9) in each case
independently of one another are -OR(135) or -NR(135)R(136);
R(135) and R(136)
independently of one another are hydrogen or alkyl having 1,
2, 3,4, 5 or 6 carbon atoms;
or
R(135) and R(136)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
the other radical R(8) in each case
is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or
-CR(125)R(126)R(127);
R(125)
is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(125)
is -(C1 -Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(126) and R(127)
independently of one another are defined as R(125) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

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119
A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-,
-NR(17)-CO-NR(18)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-,
-SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;
R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms
and their pharmaceutically tolerable salts;
(HOE 96/F 026)
au) substituted thiophenylalkenylcarboxylic acid guanidides of the formula I
R(2 R(5)

R(1 S ~ ~ ~ N~ / NH2


R(4) ~ NH2
in which:
at least one of the substituents R(1), R(2) and R(3)
~~P~(CH2)s~CqF2q+1 ~ R(40)CO or R(31)SOk;
p iszeroor1;
s is zero,1, 2, 3 or 4;
q is 1, 2, 3, 4, 5, 6, 7 or 8;
k is zero,1 or 2;
R(40) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl and methoxy;
R(31) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl or methoxy;

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120
or
R(31) is NR(41)R(42);
R(41) and R(42)
independently of one another are hydrogen, alkyl
having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having
1, 2, 3 or 4 carbon atoms,
or
R(41) and R(42)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
and the other substituents R(1), R(2) and R(3) in each case
independently of one another are H, F, Cl, Br, I, CN,
~~na~CmaH2ma+1 0r~~gaCraH2raR(1~);
na is zero or 1;
ma is zero, 1, 2, 3, 4, 5, 6, 7 or 8;
ga is zero or 1;
ra is zero, 1, 2, 3 or 4;
R(10) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
Where the phenyl is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of
F, Cl, CF3, methyl and methoxy;
R(4) and R(5)
independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
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;

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121
and their pharmaceutically tolerable salts;
(HOE 96/F 032)
av) ortho-substituted benzoylguanidines of the formula I
F~ F

R(2) ~,~

R(3) J~ N~ NH2
Cl O NH2
In whlch:
R(2) and R(3)
independently of one another are hydrogen, Cl, Br, I, (C1-Cg)-alkyl,
(C3-Cg)-cycloalkyl or-OR(5);
R(5) is (C1-Cg)-alkyl or-CdH2d-(C3-C8)-CYcl~alkYl;
d is zero, 1 or 2;
where one of the two substituents R(2) and R(3) is always hydrogen but
both substituents R(2) and R(3) are not simultaneously hydrogen,
and their pharmaceutically tolerable salts;
(HOE 96/F 042)
ax) benzoylguanidines of the formula I
R(1 )
R(2~

R(3) 'J~ N ~ NH2
R(4) ~ NH2
in which:
R(1) is H, F, Cl, Br, I, CN, NO2, 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 Xa-(CH2)b-(CF2)C-CF3;
X is oxygen, S, NR(5),
a iszeroor1;
b is zero, 1 or 2;
c is zerQ, 1, 2 or 3;
R(5) is H, alkyl having 1, 2, 3 or 4 carbon atoms or

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122
-CdH2dR(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 aromatics phenyl, biphenylyl
or naphthyl are not substituted or are
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(7)R(8);
R(7) and R(8)
independently are 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 ~CfH2f-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, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
f is zero,1 or 2;
R(11) and R(12)
independently of one another are defined as R(10) or are
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 via a carbon atom
or a nitrogen atom of the ring,
which are in each case unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino,
or
R(1) is -SR(13), -OR(13), -NHR(13), -NR(13)R(14), -CHR(13)R(15),

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123
-C[R(15)R(16)0H], -C-CR(18), -C[R(19)]=CHR(18),
-C[R(20)R(21)]k-(CO)-[CR(22)R(23)]i-R(24),
k is zero,1, 2, 3 or 4;
iszero,1,2,30r4;
R(13) and R(14)
identically or differently are -(CH2)g-(CHOH)h-(CH2)j-
(CHOH)j-R(17) or -(CH2)g~0~(CH2~CH20)h~R(24);
R(17) is hydrogen or methyl,
g, h and i
identically or differently are zero,1, 2, 3 or 4;
is 1, 2, 30r4;
R(15) and R(16)
identically or differently are hydrogen, alkyl having 1, 2, 3, 4,
5 or 6 carbon atoms or, together with the carbon atom
carrying them, are 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, CF3, 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)
identically or differently are hydrogen or methyl;

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124
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 -CmH2m-R(18);
m is 1, 2, 3 or 4;
R(2) and R(3)
are defined as R(1);
R(4) is alkyl having 1, 2, 3 or 4 carbon atoms;
and their pharmaceutically tolerable salts;
(HOE 96/F 043)
av) ortho-substituted benzoylguanidines of the formula I
R(1 )
R(2~

R(3) J~ N~y NH2
R(4) ~ NH2

in which:
R(1 ) is H, F, Cl, Br, I, CN, NO2, 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 Xa-(CH2)b-(CF2)C-CF3;
X is oxygen, S, NR(5),
a iszeroor1;
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
-CdH2dR(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 aromatics phenyl, biphenylyl
or naphthyl are unsubstituted or
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(7)R(8);

CA 022~7299 1998-12-03

125
R(7) and R(8)
independently are 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);
Rt10) is -CfH2f-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, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
f is zero,1 or 2;
R(11) and R(12)
independently of one another are 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 via a carbon atom
or a nitrogen atom of the ring,
which are in each case unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino,
or
R(1) is -SR(13), -OR(13), -NHR(13), -NR(13) R(14), -CHR(13)R(15),
-C[R(15)R(16)0H], -C-CR(18), -C[R(19)]=CHR(18),
-C[R(20)R(21)]k-(CO)-[CR(22)R(23)]l-R(24),
k is zero,1, 2, 3 or 4;
is zero,1, 2, 3 or 4;
R(13) and R(14)
identically or differently are -(CH2)9-(CHOH)h-(CH2)j-
(CHOH)j-R(17) or -(CH2)9-O-(CH2-CH2O)h-R(24);
R(17) is hydrogen or methyl,
g, h and i

CA 022~7299 1998-12-03

126
identically or differently are zero,1, 2, 3 or 4;
is1,2,30r4;
R(15) and R(16)
identically or differently are hydrogen, alkyl having 1, 2, 3, 4,
5 or 6 carbon atoms or, together with the carbon atom
carrying them, are 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, CF3, 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)
identically or differently are 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 -CmH2m-R(18);
m is 1, 2, 3 or 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

CA 022~7299 1998-12-03

127
carbon atoms, F, Cl, Br, l or-(CH2)n-(CF2)O-CF3;
n is zero or 1;
o iszeroor1;
and their pharmaceutically tolerable salts.

(DE 195 02 895, DE 44 30 212, EP 667 341, DE 44 04 183, EP 708 088,
EP 723 963, EP O 694 537, DE 44 21 495, EP 699 660, EP 699 663,
EP 699 666, DE 43 37 611, EP 0719 766, WO 94/26709, WO 96 04 241,
EP 726 254, US 4 251 545, DE 35 02 629, WO 84/00875, Kumamoto et
al., Pharm. Bull. [1966], 7 - 13; US 3 780 027, JP 8225513)
Il. Also suitable are compounds of the formula
R(3) R(2)


R(4) ~ NH2
in which:
W, Y and Z
are a nitrogen atom or a carbon atom substituted by R(2) or R(3) or
R(4);
R(1) is hydrogen, A, Hal, -CF3, -CH2F, -CHF2, -CH2CF3, -C2Fs, -CN,
-NO2, -ethynyl, or an X-R';
A is alkyl having 1 to 6 carbon atoms;
Hal is F, Cl, Br or l;
X is oxygen, S or NR";
R" is hydrogen, A or a cyclic methylene chain having 3 to
7 carbon atoms;
R' is H, A, HO-A-, HOOC-A-, (C3-C7)-cycloalkyl, (C6-C8)-
cycloalkylalkyl, CF3, CH2F, CHF2, CH2-CF3, Ph, -CH2-Ph or
Het;
Ph is phenyl, naphthyl or biphenylyl which is unsubstituted
or mono-, di- or trisubstituted by A, OA, NR'R", Hal,
.CF3;
Het is a mono- or binuclear saturated, unsaturated or

CA 022~7299 1998-12-03

128
aromatic heterocycle having 1 to 4 nitrogen, oxygen
and/or sulfur atoms,
which is unsubstituted or mono-, di- or
trisubstituted by Hal, CF3, A, OH, OA, -X-R',
-CN, -NO2, and/or carbonyl oxygen,
where Het is bonded via N or an alkylene chain CmH2m
wherem=zeroto6;
or
R' and R"
together are alkylene having 4 - 5 carbon atoms, in which one
CH2 group can also be replaced by oxygen, S, NH, N-A, N-
Ph and N-CH2-Ph;
R(2) and R(3)
independently of one another are hydrogen, Hal, A, HO-A-, X-R',
-C(=N-OH)-A, A-O-CO-(C1-C4)-alkyl-, CN, NO2, COOH, halogen-
substituted A, in particular CF3, CH2F, CHF2, C2Fs, CH2CF3, or
S(O)nR"';
R"' is A, Ph or -Het;
n is zero, 1 or 2;
or
R(2) and R(3)
independently of one another are SO2NR'R", Ph or -O-Ph,
-O-CH2-Ph, -CO-A, -CHO, -COOA, -CSNR'R", CONR'R",
-CH=CH-COOH, -CH=CH-COOA, indenyl, indanyl,
decahydronaphthyl, cyclopentenyl, dihydrothienyl, dihydrofuryl,
heterobicyclyl, alkylthienyl, halothienyl, haloalkylthienyl, acylthienyl,
halofuryl, haloalkylfuryl or pyrrolyl;
or
R(2) and R(3)
independently of one another are R(5)-0-;
R(5) is hydrogen, A, (C1-C6)-alkenyl or (C3-C7)-cycloalkyl;
R(4) is Ph, Het, -O-Het; CF3, S(O'~nR"', -SO2NR'R", alk;
Rl ;
~N~
N~

CA 022~7299 1998-12-03

129
or
two of the substituents R(1) to R(4)
together are a group -O-CR(6)R(7)-CO-NR(8)-,


R(~ R(g) [R(2)] 0 to 4
where R(2) has the meaning indicated;
R(6), R(7), R(8) and R(9)
independently of one another are H or A;
or
R(8) is (C5-C7)-cycloalkyl;
or
R(9) is cyano;
alk is straight-chain or branched (C1-C8)-alkyl or (C3-C8)-cycloalkyl,
which is unsubstituted or mono-, di- or trisubstituted by A;
or
alk is an ethenyl or ethynyl radical which is substituted by H, A, Ph or
Het:
[DE 41 27 026, DE 4337609, JP 07025768, Edward J. Cragoe, Jr.,
DIURETICS (Chemistry, Pharmacology and Medicine), J. Wiley & Sons
(1983), 303-341]
Ill. Compounds of the formula
Z~N ~ Y

X J~N ~ N~ N H2
O NH2
in which:
X is H, Hal, (Hal)3c, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, substituted
phenyl, (C~-C5)-alkyl-S- or (C~-C5)-alkyl-SO2;
Y is NH2 or substituted amino;
or
X and Z
together are a -(CH2)4- or a 1,3-butadienylene chain;
or

CA 022~7299 1998-12-03

130
Z is H, Hal, OH, HS, (C1-C5)-alkyl, (C3-C6)-cycloalkyl, substituted
phenyl;
or
Z is an amino group -NR(1)R(2);
R(1 ) is H, straight- or branched-chain, optionally substituted
(C1-Cg)-alkyl,
which can be interrupted by oxygen;
or
R(1) is (C3-C8)-alkenyl, (C3-C8)-alkynyl, (C3-C7)-cycloalkyl or OH-
substituted phenyl or OH-substituted phenyl-(C1-C4)-alkyl or
OH-substituted (C3-C7)-cycloalkyl;
R(2) is 1-morpholino, hydrogen or a straight or branched (C1-C8)-
alkyl chain,
which can be interrupted by oxygen or an amino
group,
which straight or branched (C1-C8)-alkyl chain is
unsubstituted or substituted by
a substituted or unsubstituted mono- or polynuclear
heterocycle which contains nitrogen, oxygen or sulfur
atoms;
or
which alkyl chain is substituted by phenyl,
optionally mono- or polysubstituted by (C1-C4)-alkoxy,
optionally substituted by OH, alkylamino, alkyl or
phenyl;
or
by an aminocarbonyl group
or
by hydroxyl or (C1-C4)-alkoxy groups,
or
R(2) is phenyl,
unsubstituted or substituted by alkyl, alkoxy, an amino
group, which as substituents carries:
H, a mono- or polynuclear heterocycle which

CA 022~7299 1998-12-03

131
contains nitrogen, oxygen or sulfur atoms,
which is unsubstituted or substituted by
H, Hal or (C1-C4)-alkyl;
a phenyl radical,
unsubstituted or substituted by a
substituent selected from the group
consisting of (C,-C4)-alkYI, (C1-C4)-
alkoxy, Hal and OH;
or
R(2) is 1 -piperidino,
unsubstituted or substituted in the 4-position by an
acyl radical of an aliphatic, alicyclic, aromatic or
heteroaromatic carboxylic acid, (C1-C8)-alkyl, which for
its part can be substituted by OH or (C1-C4)-alkoxy or
a (C1-C4)-alkoxy-substituted phenyl radical;
or
R(2) is amidino,
which is unsubstituted or substituted by phenyl,
which is unsubstituted or substituted by Hal or
alkyl;
or
R(2) is an acyl radical of an aliphatic, alicyclic, aromatic or
heteroaromatic carboxylic acid,
or
R(2) is a (C1-C8)-alkyl chain, which can be substituted by a phenyl
radical carrying OH, alkoxy or alkyl radicals,
or
R(1) and R(2)
together with the nitrogen atom to which they are bonded, are
a piperazine ring,
which is unsubstituted or via a (C1-C6)-methylene
chain carries a mono- or polynuclear heterocycle,
which contains nitrogen, oxygen or sulfur,
Hal is F, Cl, Br or 1.
-


CA 022~7299 1998-12-03

132
( EP 708 091, EP 622 356, JP 5-125085)
IV. Likewise suitable are indoloylguanidine derivatives of the formula

[R(1)]5~ , N~ NH2

R(2) ~ NH2
in which
R(2) is hydrogen, unsubstituted or substituted (C1-C8)-alkyl, (C3-C7)-
cycloalkyl, OH, (C1-C6)-alkyl-O-, an aromatic radical or a group
-CH2-R(20);
R(20) is (c2-c6)-alkenyl or (C2-C6)-alkYnYI;
R(1) is 1 to 5 identical or different substituents, which are:
hydrogen, unsubstituted or substituted (C1-C8)-alkyl, (C2-C6)-
alkenyl, (C2-C6)-alkynyl, (C3-C7)-cycloalkyl, halogen, -NO2 (C2-C8)-
alkanoyl, arylalkanoyl having up to 10 carbon atoms, aroyl having up
to 11 carbon atoms, -COOH, (C2-C6)-alkoxycarbonyl, an aromatic
group or one of the following mentioned groups: -OR(3), -NR(6)R(7)
or -S(O)nR(40);
R(3) is hydrogen, (C1-C8)-alkyl, substituted (C1-C8)-alkyl, (C3-C7)-
cycloalkyl, an aromatic radical or a group -CH2-R(30)
R(30) is alkenyl or alkynyl;
R(6) and R(7)
independently of one another are hydrogen, unsubstituted or
substituted (C1-C8)-alkyl, (C3-C7)-cycloalkyl, (C2-C8)-alkanoyl,
an arylalkanoyl group having up to 10 carbon atoms, an aroyl
group having up to 11 carbon atoms, an aromatic group or
-CH2-R(60);
R(60) is (c2-c6)-alkenyl or (C2-C6)-alkYnYI;
or
R(6) and R(7)
together with the nitrogen atom are a 5 - 7-membered cyclic
amine, which can additionally contain further heteroatoms in
the ring;
n is zero,1 or 2;

CA 02257299 1998-12-~3

133
R(40) is unsubstituted or substituted (C1-C8)-alkyl, or an aromatic
group, or a group -A ~ R'

A is oxygen, ~S(O)n~ or-N(R50)-;
R(50) is hydrogen or (C1-C8)-alkyl;
R' is hydrogen, unsubstituted or substituted (C1-C8)-alkyl,
in which the ring represents a saturated 3 - 8-membered
heterocycle having a nitrogen atom,
said substituted alkyl carries one or more groups selected from the
group consisting of halogen, -OH, (Cl-C6)-alkoxy, -CN, -COOH,
(C2-C6)-alkoxycarbonyl, (C2-C8)-alkanoyl, arylalkanoyl having up to
10 carbon atoms, aroyl having up to 11 carbon atoms, an aromatic
group, -CONR(4)R(5),
R(4) and R(5)
identically or differently are hydrogen or (C1-C8)-alkyl;
or
R(4) and R(5)
are connected to one another and together form a 5 -
7-membered cyclic amine which can additionally contain
further heteroatoms in the ring,
or said substituted alkyl carries a group ~-R~

in which:
E is a nîtrogen atom or a CH group;
R" is hydrogen, (C1-C8)-alkyl or substituted (C1-C8)-alkyl which is
unsubstituted or substituted by OH, (C1-C8)-alkoxy, -CN,
-COOH, (C2-C6)-alkoxycarbonyl, (C2-C8)-alkanoyl, aralkanoyl
having up to 10 carbon atoms, aroyl having up to 11 carbon
atoms, an aromatic group, -NP~(6)R(7), -CONP~(4)R~5);
R(4) and R(~)
independently of one another are hydrogen or (Cl-C8)-
alkyl;
where the cyclic system of the formula ~3



. . .

CA 022~7299 1998-12-03

134
is a 3 - 8-membered saturated aliphatic or heterocyclic ring system
having a nitrogen atom,

and where the aromatic groups mentioned are an aryl radical having up to
10 carbon atoms, a 5- or 6-membered heteroaryl radical having
1 - 4 nitrogen atoms, a 5- or 6-membered heteroaryl group containing 1 or
2 nitrogen atoms and a heteroatom which is oxygen or sulfur, or furyl,
and where the aryl radicals mentioned can be unsubstituted or substituted
by unsubstituted (C1-C8)-alkyl or substituted (C~-C8)-alkyl, halogen, -NO2,
(C2-C6)-alkoxycarbonyl, COOH, -OR(3), NR(6)R(7), -CONR(4)R(5),
-SO2NR(6)R(7) or S(O)nR(40),
where R(1) and the guanidinocarbonyl radical can be in any desired
position of the 5- or 6-membered ring of the indole system,
and the appropriate pharmaceutically tolerable salts.

(WO 95 04052)
V. Additionally suitable are heterocyclic guanidine derivatives of the
formula
R~



R(:~ N~N~
in which:
X is -O-, -S-, -NH-, -N[(C1 -C4)-alkyl]- or -N(phenyl)-;
R(1), R(2) and R(3)
are hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-alkyl-O-, phenyl,
benzyl;
or
two of the substituents R(1), R(2) and R(3)
together with one side of the benzo system are a 4 - 6-membered
carbocyclic ring;
R(4) and R(5)
independently of one another are hydrogen, (C1-C12)-alkyl,

CA 022~7299 1998-12-03

135
benzhydryl, aralkyl,
which is unsubstituted or substituted by one or more
substituents from the groups halogen, (C1-C4)-alkyl, (C1-C4)-
alkyl-O- or-CF3, -(CH2)m-CH2-
m iszeroto3;
T is -CO-O-T(1 );
T(1 ) is hydrogen or (C1-C4)-alkyl;
Cy is a benzo-fused unsaturated or dihydro-5-membered ring
heterocycle ~,

R(6)
a pyrazole or imidazole ring of the formula ~N or

~ ~ R(6) R(7) R(a)
R(6) R(7) R(8)

a naphthyl radical or a dihydro- or tetrahydronaphthyl radical


R(6)
a 2-, 3- or 4-pyridyl radical R(8) ~
~,, ~ R(6)
R(7)
Z is N- or CH;
a thienyl radical ~6)
~ R~7)

R(6) is hydrogen, halogen, hydroxyl, (C1-C10)-alkyl, (C1-C10)-alkyl-
O-, phenoxy, (C1-C10)-alkyloxymethyloxy- or-(O)nS-R(9);
R(9) is (C1-C10)-alkyl, thienyl, pyridyl, thiazolyl, thiadiazolyl,
imidazolyl, pyrazolyl or phenyl,
each of which is unsubstituted or mono- or
disubstituted by halogen, (C1-C4)-alkyl or
(C1 -C4)-alkyl-O-;
R(7) and R(8~
is hydrogen, halogen, hydroxyl, (C1-C10)-alkyl,

CA 022~7299 1998-12-03

136
(C1-C10)-alkyl-O-, phenyl, phenoxy or
(C1 -Cl 0)-alkoxymethyloxy;
or
Cy is phenyl,
which is unsubstituted or mono- or disubstituted by halogen,
(C1-C4)-alkyl or (C1-C4)-alkyl-O-;
or
Cy is -Gr-Am;
Gr is -R(1 3)-R(1 2)~(CH2)q~C[W][W(1 )]~(CH2)q~~; R(1 3)R(14)- or
-R(1 5)-;
R(12) is a single bond, -O-, -(O)nS-, -CO- or-CONH-;
R(13) is a single bond, phenyl, thienyl, pyridyl, thiazolyl,
thiadiazolyl, imidazolyl or pyrazolyl;
R(14) is a single bond or SO2-;
R(15) is (c2-clo)-alkenyl- or (C2-C10)-alkynYI;
W and W(1 )
independently of one another are hydrogen, (C1-C4)-
alkyl;
or
W and W(1)
cyclically connected to one another are a (C3-C8)-
hydrocarbon ring;
q and q'
are zero to 9;
Am is -NR(1 0)R(1 1 );
R(10) is hydrogen, (C1-C4)-alkyl or benzyl,
R(11) is (C1-C4)-alkyl, phenyl or benzyl;
or
R(10) and R(1 1 )
together are a (C3-C10)-alkylene group,
which is unsubstituted or substituted by -COOH,
(Cl-C5)-alkoxycarbonyl, (C2-C4)-hydroxyl-
alkylene or benzyl;
or

CA 022~7299 1998-12-03

137
Am is pyrrolyl, pyridyl, pyrazolyl, morpholinyl, dihydropyridyl,
tetrahydropyridyl, quinuclidinyl, imidazolyl,
3-azabicyclo[3.2.1]octyl,
which is unsubstituted or substituted by (C1-C4)-alkyl,
or
Am is azabicyclo[3.2.2]nonyl;
or
Am is a piperazine group of the formula ~N~R('
~NJ
R(16) is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, phenyl,
tolyl, methoxyphenyl, halophenyl, diphenylmethylene,
benzyl or pyridyl;
or
Am is an azido group -(O)t-(CH2)q-C[W][W(1)]-(CH2)q'-N3;
t iszeroor1;
where W and W(1) have the previously indicated meaning;
and the optical enantiomers and the pharmacologically tolerable salts.

Preferably, NHE exchange inhibitors of subtype 3 are used:
(HOE 93/F 223 K - EP 639 573, NZ 264 130)
r) benzo-fused 5-membered ring heterocycles, of the formula I
R ( 2 ) 9



\R ( 1 )
R ( 5 )

in which:
X is N or CR(6);
Y is oxygen, S or NR(7);
A, B together are a bond
or
A, B are both hydrogen, if X is CR(6) and Y is simultaneously NR(7);

CA 022~7299 1998-12-03

138
one of the substituents R(l) to R(6) is a -CO-N=C(NH2)2 group;
the other substituents R(1 ) to R(6) in each case
are hydrogen, F, Cl, Br, I or (C1-C6)-alkyl;
up to two of the other substituents R(1 ) to R(6)
are CN, NO2, N3, (C1-C4)-alkyloxy or CF3;
up to one of the other substituents
is R(8)-cnH2n-z-;
n iszeroto 10;
where the alkylene chain -CnH2n- is straight-chain or
branched and where a carbon atom can be replaced by an
oxygen or sulfur atom or by a nitrogen atom;
R(8) is hydrogen, (C2-C6)-alkenyl or (C3-C10)-cycloalkyl,
which is unsubstituted or substituted by 1 to 4 methyl
groups or an OH group, or can contain an ethylene
group -CH=CH-, and wherein a methylene group can
be replaced by an oxygen or sulfur atom or by a
nitrogen atom;
or
R(8) is phenyl,
which is unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of F,
Cl, Br, I, CF3, CH3-S(O)s- or R(9)-Wy~;
s is zero, 1 or 2;
R(9) is H, methyl, ethyl,
W is oxygen or NR(10);
R(10) is H or methyl;
y is zero or 1;
or
R(8) is CmF2m+l;
m is 1 to 3;
or
R(8) is 1- or 2-naphthyl, pyridyl, quinolyl or isoquinolyl;
Z . is -CO-, -CH2- or -[CR(11 )(OH)]q-;
q is 1, 2 or3;

CA 022~7299 1998-12-03

139
R(11) is H or methyl;
or
Z is oxygen or -NR(12)-;
R(12) is H or methyl;
or
Z is-S(O)s-;
s is zero,1 or 2;
or
Z is -SO2-NR(13)-;
R(13) is H or (C1-C4)-alkyl;
R(7) is hydrogen, (C1-C~0)-alkyl, (C2-C10)-alkenyl or R(8)-CnH2n-;
and their pharmaceutically tolerable salts;

(HOE 93/F 436 - EP-Offenlegungsschrift 659 748), NZ 270 264)
v) acylguanidines of the formula I


R ( 2 )~3~",N~NH2 ( I )
8 ~ NH2

in which:
X is carbonyl, sulfonyl,
R(1) is H, (C1 -C8)-alkyl,
unsubstituted or substituted by hydroxyl,
(C3-C8)-cycloalkyl, phenyl,
which is unsubstituted or substituted by 1 - 3 substituents
from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino or dimethylamino,
R(2) is H, (C1-C4)-alkyl,
and their pharmaceutically tolerable salts;
(HOE 94/F 014 K - EP-Offenlegungsschrift 666 252, NZ 270 370)
w) phenyl-substituted alkylcarboxylic acid guanidides, carrying
perfluoroalkyl groups, of the formula I



,

CA 022~7299 1998-12-03

140
R(8) R(~)
R(l ) \ /
R ( 2 )~( C ) ~Nq/N H 2 ( I )

R ( 3 ) R ( 5 ) ~ NH2
R(~)

in which:
R(A) is hydrogen, F, Cl, Br, I, CN, ORt6), (C1-C8)-alkyl, (C3-C8)-
cycloalkyl, Or(CH2)aCbF2b+1 or NR(7)R(8);
r iszeroor1;
a is zero, 1, 2, 3 or 4;
b is 1, 2, 3, 4, 5, 6, 70r8;
R(6) is hydrogen, (C1-C8)-alkyl, (C3-C8)-alkenyl, (C3-C8)-cycloalkyl,
phenyl or benzyl,
where the aromatics are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(9)R(1 0);
R(9) and R(10)
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8)
independently of one another are defined as R(6);
R(B) independently is defined as R(A);
X is 1, 2 or 3;
R(1) is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, -0t(CH2)dCeF2e+1, F,
Cl, Br, I or CN;
t is zero or 1;
d is zero, 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5, 6, 7 or 8;
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1 );
but with the condition
that at least one of the substituents R(1), R(2), R(3), R(4), R(5), R(A) and
R(B) is an -0t(CH2)dCeF2e+1 or an ~r(CH2)aCbF2b+1 group~

CA 022~7299 1998-12-03

141
and their pharmaceutically tolerable salts;

(HOE 94/F 123 - EP-Offenlegungsschrift 682 017, NZ 272 058)
y) bicyclic heteroaroylguanidines of the formula I
R(~) R(3)

R ( S ) ~v~w~,X~y~R ( 2 )
~u~l~z~Nq~ N H 2

R ( 7 ) R ( l ) ~ N H 2
in which:
T, U, V, W, X, Y and Z
independently of one another are nitrogen or carbon;
but with the restriction
that X and Z are not simultaneously nitrogen,
and that T, U, V, W, X, Y and Z carry no substituents when they are
nitrogen,
and that no more than four of them are simultaneously nitrogen,
R(1) and R(2)
independently of one another are hydrogen, F, Cl, Br, l, (C1-C3)-
alkyl, (C1-C3)-perfluoroalkyl, OR(8), NR(8)R(9) or C(=O)N=C(NH2)2;
R(8) and R(9)
independently of one another are hydrogen or (C1-C3)-alkyl,
or
R(8) and R(9)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;
R(3), R(4), R(5), R(6) and R(7)
independently of one another are hydrogen, F, Cl, Br, l, -C-N,
Xk-(CH2)p-(CqF2q+1), R(10a)-SObm, R(10b)R(10c)N-CO, R(11)-CO-
or R(12)R(13)N-SO2-,
where the perfluoroalkyl group is straight-chain or branched;
X is oxygen, S or NR(14);
R(14) is H or (C1-C3)-alkyl;

CA 022~7299 1998-12-03

142
bm is zero,1 or 2;
p is zero,1 or 2;
k iszeroor1;
q is1,2,3,4,50r6;
R(1 Oa), R(1 Ob), R(11) and R(12)
independently of one another are (C1-C8)-alkyl,
(c3-c6)-alkenyl~ -CnH2n-R(15) or (C1-Cg)-PerflU~r~alkyl;
n is zero,1,2, 3 or 4;
R(15) is (C3-C7)-cycloalkyl or phenyl, which is not substituted
or is substituted by 1 - 3 substituents selected from the
group consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are H or C1-C4-alkyl;
or
R(1 Ob), R(11) and R(12)
are hydrogen;
R(10c) and R(13)
independently are hydrogen or (C1-C4)-alkyl;
or
R(10b) and R(10c) and also R(12) and R(13)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
25 or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are (C1-C8)-alkyl, -CalH2alR(18) or
(C3-C8)-alkenyl;
al is zero,1 or 2;
R(18) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where
the aromatic are not substituted or are substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyL, methoxy and NR(19a)R(19b);
R(19a) and R(19b)

CA 022~7299 1998-12-03

143
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are (C1-Cg)-heteroaryl which is linked
via C or N and which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3, CH3, methoxy,
hydroxyl, amino, methylamino or dimethylamino;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are
o




-Y~( C ) h- ( CHOH)j-(CH2)j-(CHOH)k-R(23)


or _r (C)Od_(CH~H)OO-(CH2)0f-(CHOH)O9-R(24)




Or ~ (C)Qh_(CH~H)OO-(CH2)CP-(CHOH)~-R(2S)




Y is oxygen, -S- or-NR(22)-;
h, ad, ah
independently of one another are zero or 1;
i,j,k,ae,af,ag,ao,apandak
independently of one another are zerG, 1, 2, 3 or 4;
but where in each case
h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero, and
ah, ao and ak are not simultaneously zero,
R(23), R(24) R(25) and R(22)

CA 022~7299 1998-12-03

144
independently of one another are hydrogen or (C1-C3)-alkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are SR(29), -OR(30), -NR(31)R(32) or
-CR(33) R(34) R(35);
R(29), R(30), R(31) and R(33)
independently of one another are -CaH2a-(C1-Cg)-heteroaryl, which is
unsubstituted or substituted by 1 - 3 substituents selected from the group
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
a is zero,1 or 2;
R(32), R(34) and R(35)
independently of one another are defined as R(29) or
hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are

-- W ~R(96) ~ ~R(97) or ~R(98)

--W W--

R(96), R(97) and R(98)
independently of one another are (C1-Cg)-heteroaryl, which is
linked via C or N and which is unsubstituted or substituted by
1 to 3 substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino, dimethylamino
or benzyl;
W is oxygen, S or NR(36)-;
R(36) is H or(C1-C4)-alkyl;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(46)X(1)-;
X(1) is oxygen, S, NR(47), (D=O)A- or NR(48)C=MN(*)R(49)-;
M is oxygen orsulfur;

CA 022~7299 1998-12-03

145
A is oxygen or NR(50);
D is C or SO;
R(46) is (C1-Cg)-alkyl~ (C3-C8)-alkenYI, (CH2)bCdF2d+1 or
-CXH2X-R(51 );
b iszeroor1;
d is 1, 2, 3, 4, 5, 6 or 7;
x is zero,1, 2, 3 or 4;
R(51) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl,
where the aromatic are not substituted or are
substituted by 1 -3 substituents selected from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(52)R(53);
R(52) and R(53)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-
perfluoroalkyl;
R(47), R(48) and R(50) independently
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(49) is defined as R(46);
or
R(46) and R(47), or R(46) and R(48)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
where A and N(*) are bonded to the phenyl nucleus of the
heteroaroylguanidine parent structure;
or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are -SR(64), -OR(65), -NHR(66),
-NR(67)R(68), -CHR(69)R(70) or-CR(54)R('5)0H, -C-CR(56),
-CR(58)=CR(57) or-[CR(59)R(60)]u-CO-[CR(61)R(62)]v-R(63);
R(64), R(65), R(66), R(67) and R(69)
identically or differently
are -(cH2)y-(cHoH)z-(cH2)aa-(cHoH)t-R(71) or
-(cH2)ab-o-(cH2-cH2o)ac-R(72);

CA 022~7299 1998-12-03

146
R(71) and R(72)
independently of one another are hydrogen or methyl;
u is 1,2, 30r4;
v is zero, 1, 2, 3 or 4;
y, z, aa identically or differently
are zero, 1, 2, 3 or 4;
t is 1, 2, 3 or 4;
R(68), R(70), R(54) and R(55)
identically or differently are hydrogen or (C1-C6)-alkyl;
or
R(69) and R(70), or R(54) and R(55)
together with the carbon atom carrying them, are a (C3-C8)-
cycloalkyl;
R(63)
is hydrogen, (C~-C6)-alkyl, (C3-C8)-cycloalkyl or
-CeH2e-R(73);
e is zero,1, 2, 3 or 4;
R(56), R(57) and R(73) independently
are phenyl, which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F, Cl, CF3,
methyl, methoxy and NR(74)R(75);
R(74) and R(75)
are hydrogen or (C1-C4)-alkyl;
or
R(56), R(57) and R(73) independently
are (C1-Cg)-heteroaryl, which is unsubstituted or substituted
as phenyl;
R(58), R(59), R(60), R(61) and R(62)
are hydrogen or methyl;
30 or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are R(76)-NH-SO2-;
R(76) is R(77.)R(78)N-(C=Y')-;
Y' is oxygen, S or N-R(79);

CA 022~7299 1998-12-03

147
R(77) and R(78)
identically or differently are hydrogen, (C1-C8)-alkyl,
(C3-C6)-alkenyl or-C~H2f-R(80);
f is zero, 1, 2, 3 or 4;
R(80) is (C5-C7)-cycloalkyl or phenyl, which is
unsubstituted or substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methoxy and (C~-C4)-alkyl;
or
R(77) and R(78)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, sulfur, NH,
N-CH3 or N-benzyl;
R(79) is defined as R(77) or is amidine;
15 or
R(3), R(4), R(5), R(6) and R(7)
independently of one another are NR(84a)R(85), OR(84b), SR(84c)
or -CnH2n-R(84d);
n is zero, 1, 2, 3 or 4;
R(84d) is (C3-C7)-cycloalkyl or phenyl, which is not substituted
or is substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
NR(16)R(17);
R(16) and R(17)
are hydrogen or C1-C4-alkyl;
R(84a), R(84b), R(84c) and R(85)
independently of one another are hydrogen, (C1-C8)-alkyl,
(Cl-C8)-perfluoroalkyl or (CH2)aX-R(84g);
ax is zero, 1, 2, 3 or 4;
R(84g) is (C3-C7)-cycloalkyl or phenyl, which is not
substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, CF3, methyl, methoxy and
N R(84u) R(84v);

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148
R(84u) and R(84v)
are hydrogen or C1-C4-alkyl;
or
R(84a) and R(85)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl,
and their pharmaceutically tolerable salts;
(HOE 94/F 168 - EP-Offenlegungsschrift 690 048, NZ 272 373)
ab) phenyl-substituted alkenylcarboxylic acid guanidides, carrying
perfluoroalkyl groups, of the formula I
R(2) R(1 )

R(3) " :" / R,~D)R~) R(B)
- E ~ ~c
N~ NH2

R(5) R(C)
R(A ) R(B)

in which:
R(A) is hydrogen, F, Cl, Br, l, CN, OH, OR(6), (C1-C8)-alkyl,
15~r(CH2)aCbF2b+1, (C3-C8)-cycloalkyl or NR(7)R(8);
r is zero or 1;
a is zero,1, 2, 3 or 4;
b is 1, 2, 3, 4, 5, 6, 7 or 8;
R(6) is (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatic are not substituted or are
substituted by 1 - 3 substituents from the group
consisting of F, Cl, CF3, methyl, methoxy and
. NR(9)R(10);
R(9) and R(10)

CA 022~7299 1998-12-03

149
are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) and R(8)
independently of one another are defined as R(6);
or
R(7) and R(8)
together are 4 or 5 methylene groups, of which one CH2
group can be replaced by oxygen, sulfur, NH, N-CH3 or
N-benzyl;
R(B) independently is defined as R(A);
10 X iszero, 1 or2;
Y is zero, 1 or 2;
R(C) is hydrogen, F, Cl, Br, I, CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF29+
or (C3-C8)-cycloalkyl;
p iszeroor1;
f iszero, 1, 2, 3 or4;
g is 1, 2, 3, 4, 5, 6, 7 or 8;
R(1 2)
is (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl,
(C3-C8)-cycloalkyl, phenyl or benzyl;
where the aromatics phenyl or benzyl are not
substituted or are substituted by 1 - 3 substituents
from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(13)R(14);
R(13) and R(14)
independently of one another are H, (C1-C4)-
alkyl or (C1-C4)-perfluoroalkyl;
R(D) independently is defined as R(C),
R(1) is hydrogen, (C1-C8)-alkyl, -Ot(CH2)dCeF2e+1~ (C3-Cg)-cycloalkyl~ F~
Cl, Br, I or CN;
t iszero or 1;
d is zero, 1, 2, 3 or 4;
e is 1, 2, 3, 4, 5, 6, 7 or 8;
R(2), R(3), R(4) and R(5)
independently of one another are defined as R(1);

CA 022~7299 1998-12-03

150
but with the condition
that at least one of the substituents R(A), R(B), R(C), R(D), R(1), R(2), R(4)
or R(5) is a ~r(CH2)aCbF2b+1- Op(CH2)fCgF29+1 or Ot(CH2)dCeF2e+~ group
and R(3) is not a Ot(CH2)dCeF2e+1 group;
and their pharmaceutically tolerable salts;
(HOE 95/F 007 K - EP-Offenlegungsschrift 723 956, NZ 280 887)
ah) benzoylguanidines of the formula I
R(l)
R(2) ~ R(S)
R(3) ~ N ~ NH2

R(~) ~ NH2
in which:
one of the three substituents R(1), R(2) and R(3)
is R(6)-A-B-D-;
R(6) is a basic protonatable radical, i.e. an amino group
-NR(7)R(8), an amidino group R(7)R(8)N-C[=N-R(9)]- or a
guanidino group
R(7) R(lO)
~N N~
R(8)
R(9)~

R(7), R(8), R(9) and R(10)
independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
or
R(7) and R(8)
together are CaH2a;
a is4,5,60r7;
where if a = 5, 6 or 7 a methylene group of the group
CaH2a can be replaced by a heteroatom group O, S~m
.or NR(11),
or

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151
R(8) and R(9) or R(9) and R(10) or R(7) and R(10)
are a group CaH2a;
a is2,3,4Or5;
where if a = 3,4 or 5 a methylene group of the
group CaH2a can be replaced by a heteroatom
group O, S~m or NR(11);
m is zero,1 or 2;
R(11) is hydrogen or methyl;
or
R(6) is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is CbH2b;
b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
where in the group CbH2b one or two methylene
groups can be replaced by one of the groupings
selected from the group consisting of -O-, -CO-,
-CH[OR(20)]-, ~SOm~~ -NR(20)-, -NR(20)-CO-,
-N R(20)-CO-N H-, -N R(20)-CO-N H-SO2-
1(1 ~ ) ~ ~
- R ( 2 0 ) N -S -
I N R ( l 9 ) I b b
and -SOaa[NR(1 9)]bb-;
and where in the group CbH2b a methylene group can
be replaced by CH-R(99), where R(99) together with
R(7) forms a pyrrolidine or piperidine ring;
aa is 1 or 2;
bb is 0 or 1;
aa + bb = 2;
R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon
atoms,
R(20) is hydrogen or methyl;

CA 022~7299 1998-12-03

152
B is a phenylene or naphthylene radical,
R( l 2) R( l 2)


R ( l 3 ) ~
R( l 3)
R(12) and R(13)
independently of one another are hydrogen, methyl, F,
Cl, Br, l, CF3 or -SOW-R(14);
R(14) is methyl or NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
alkyl having 1, 2, 3 or 4 carbon atoms;
w is zero,1 or2;
D is -CdH2d-Xf-;
d is zero,1, 2, 3 or 4;
X is -O-, -CO-, -CH[OR(21)]-, ~SOm~ or -NR(21)-;
f iszeroor1;
R(21) is hydrogen or methyl;
m is zero,1 or 2;
and the other substituents R(1) and R(2) and R(3) in each case
independently of one another are hydrogen, F, Cl, Br, l, -CN,
-(C1-C8)-alkyl, -(C2-C8)-alkenyl, -NR(35)R(36) or R(17)-CgH29~Zh~;
g is zero,1, 2, 3 or4;
h is zero or 1;
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
Z is -O-, -CO-, -SOv- ,-NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH-

CA 022~7299 1998-12-03

153
or -NR(18)-SO2-;
R(18) is hydrogen or methyl;
v is zero,1 or 2;
R(17) is hydrogen, cycloalkyl having 3, 5 or 6 carbon atoms or
CkF2k+1-;
k is 1,2Or3,
or
R(17) is pyrrol-1 -yl, pyrrol-2-yl or pyrrol-3-yl,
which is not substituted or is substituted by 1 - 4
substituents selected from the group consisting of F,
Cl, Br, l, -CN, ~C2-C8)-alkanoyl, (C2-C8)-
alkoxycarbonyl, formyl, carboxyl, -CF3, methyl and
methoxy;
or
R(17) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, rnethyl, hydroxyl, methoxy, -
NR(37)R(38), CH3SO2- and H2NO2S-;
R(37) and R(38)
are hydrogen or-CH3;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or-CrF2r+1;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
r is 1, 2, 3 or 4;
and their pharmacologically tolerable salts;
(HOE 95/F 072 - EP-Offenlegungsschrift 738 712, NZ 286 380
ai) indenoylguanidines of the formula I

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154
R ( 3 )R ( 2 ) N-R ( 8 )

( 4 ) ~ ~ / R ( 9 ) ~ A

R(6)R(1) R(7) R(lO)

in which:
R(1) and R(2)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, cycloalkyl having 3, 4, 5 or 6
carbon atoms, O-alkyl having 1, 2, 3 or 4 carbon atoms, O-C(=O)-
alkyl having 1, 2, 3 or 4 carbon atoms or CmH2m-NR(1 2)R(13);
R(12) and R(13)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
m is zero, 2, 3 or 4;
NH-C(=O)-NH2, C(=O)-O-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-NH2, C(=O)-NH-alkyl having 1, 2, 3 or 4 carbon atoms,
C(=O)-N(alkyl)2 having 1, 2, 3 or 4 carbon atoms in each alkyl
group, alkenyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms,
alkynyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, alkylaryl
having 1, 2, 3 or 4 carbon atoms in the alkyl group, alkenylaryl
having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the alkenyl group,
alkynylaryl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the
alkynyl group, C1-C4-alkyl-substituted aryl, C1-C4-alkylheteroaryl,
C1-C4-alkenylheteroaryl, aminoalkylaryl having 1, 2, 3 or 4 carbon
atoms in the alkyl group, substituted aryl, heteroaryl and substituted
heteroaryl;
R(3), R(4), R(5) and R(6)
independently of one another are hydrogen, alkyl having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms, O-alkyl having 1, 2, 3, 4, 5, 6, 7, 8,
9 or 10 carbon atoms, halogen, (such as F, Cl, Br, I), OH, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, O-lower-alkyl,
O-aryl, O-lower-alkylaryl, O-substituted aryl, O-lower-alkyl-

CA 022~7299 1998-12-03

155
substituted aryl, O-C(=O)-C1-C4-alkylaryl, O-C(=O)-NH-C1-C4-alkyl,
~~C(=~)-N(c1-c4-alkyl)2~ NO2, CN, CF3, NH2, NH-C(=O)-C1-C4
alkyl, NH-C(=O)-NH2, COOH, C(=O)-O-C1-C4-alkyl, C(=O)-NH2,
C(=o)-NH-c1-c4-alkyl~ C(=o)-N(c1-c4-alkyl)2~ C1-C4-C~~H~ C1-C4
alkyl-C(=O)-O-C1-C4-alkyl, SO3H, SO2-alkyl, SO2-alkylaryl, SO2-N-
(alkyl)2, SO2-N(alkyl)(alkylaryl), C(=O)-R(11), C1-C10-alkyl-C(=O)-
R(11), C2-C10-alkenyl-C(=O)-R(11), C2-C10-alkynyl-C(=O)-R(11),
NH-C(=O)-C1 -C10-alkyl-C(=O)-R(11), O-C1-C11 -alkyl-C(=O)-R(11);
R(11) is C1-C4-alkyl, C1-C4-alkynyl, aryl, substituted aryl, NH2,
NH-C1-C4-alkYI, N-(C1-C4-alkyl)2, S03H, SO2-alkyl,
SO2-alkylaryl, SO2-N-(alkyl)2, SO2-N(alkyl)(alkylaryl);
X isO, SorNH;
R(7), R(8), R(9) and R(10)
independently of one another are hydrogen, alkyl, cycloalkyl, aryl,
alkylaryl;
or
R(8) and R(9)
together are part of a 5, 6 or 7-membered heterocyclic ring;
A is absent or is a nontoxic organic or inorganic acid.
(HOE 95/F 109 - EP 748 795, NZ 286 583)
ak) benzyloxycarbonylguanidines of the formula I
R(l )
R ( 2 ) ~,~ R ( 5 )

R(3) J~X~N~NH2
R ( 4 ) R ( 6 )\ ~ N H 2
R ( 7 )
in which:
R(1), R(2) and R(3)
independently of one another are -Y-[4-R(8)-phenyl],
-Y-[3-R(8)-phenyl] or-Y-[2-R(8)-phenyl],
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group consisting of F, Cl, -CF3,
methyl, hydroxyl, methoxy and -NR(96)R(97);

CA 022~7299 1998-12-03

156
R(96) and R(97)
independently of one another are hydrogen or -CH3;
Y is a bond, CH2, oxygen, -S- or-NR(9);
R(9) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(8) is SOa[NR(98)]bNR(99)R(10);
a is 1 or 2;
b isOor1;
a + b = 2;
R(98), R(99) and R(10)
independently of one another are hydrogen, -(C1-C8)-
alkyl, benzyl, -(C2-C8)-alkylene-NR(11)R(12), (C2-C8)-
alkylene-NR(13)-(C2-C8)-alkylene-NR(37)R(38) or
(CO-C8)-alkylene-CR(39)R(40)CR(41 )R(42)(Co-C8)-
alkylene-NR(43)R(44);
R(11), R(12), R(13), R(37), R(38), R(43) and R(44)
independently of one another are hydrogen,
-(C1-C8)-alkyl or benzyl:
R(39), R(40), R(41) and R(42)
independently of one another are hydrogen,
-(C1-C8)-alkyl or-(CO-C3)-alkylenephenyl,
where the phenyl is not substituted or is
substituted by 1 - 3 substituents selected
from the group consisting of F, Cl, -CF3,
methyl and methoxy;
or
R(99) and R(10)
together are 4 - 6 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -N-CH3 or
-N-benzyl;
or
R(8) is SOa[NR(98)]bNR(95)-C[=N-R(94)]-NR(93)R(92);
R(92), R(93), R(94) and R(95)
.independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;

CA 022~7299 1998-12-03

157
or
R(1), R(2) and R(3)
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-
yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, l, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl, methoxy;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, -(C1-C8)-alkyl, -(C2-C8)-
alkenyl or-(CH2)mR(14);
m is zero,1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
R(1), R(2) and R(3)
independently of one another are -Q-4-[(CH2)k-CHR(17)-
(C=O)R(20)]-phenyl, -Q-3-(CH2)k-CHR(17)-(C=O)R(20)]-phenyl or
-Q-2-[(CH2)k-CH R(17)-(C=o) R(20)]-phenyl,
where the phenyl in each case is unsubstituted or substituted
by 1 - 2 substituents from the group consisting of F, Cl, -CF3,
methyl, hydroxyl, methoxy and -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or -CH3;
Q is a bond, oxygen, -S- or -NR(18);
R(18) is hydrogen or-(C1-C4)-alkyl;
R(17) is -OR(21) or -NR(21)R(22);

CA 022~7299 1998-12-03

158
R(21) and R(22)
independently of one another are hydrogen, -(C1-C8)-
alkyl, -(C1 -C8)-alkanoyl, -(C1 -C8)-alkoxycarbonyl,
benzyl, benzyloxycarbonyl;
or
R(21) istrityl;
R(20) is-OR(23) or-NR(23)R(24);
R(23), R(24) independently of one another are hydrogen,
-(C1-C8)-alkyl or benzyl;
k iszero,1,2,30r4;
or
R(1), R(2) and R(3)
independently of one another are (C1-Cg)-heteroaryl,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents from the group consisting of
F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
or
R(1), R(2) and R(3)
are-SR(25),-OR(25),-NR(25)R(26),-CR(25)R(26)R(27);
R(25) is-CfH2f-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents from the group consisting of F, Cl, CF3,
CH3, methoxy, hydroxyl, amino, methylamino and
dimethylamino;
f is zero,1 or 2;
R(26) and R(27)
independently of one another are defined as R(25) or
are hydrogen or (C1-C4)-alkyl,
30 or
R(1), R(2) and R(3)
independently of one another are (C1-Cg)-heteroaryl-N-oxide,
which is linked via C or N and which is unsubstituted or
substituted by 1 - 3 substituents selected from the group

CA 022~7299 1998-12-03

159
consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino,
methylamino and dimethylamino;
or
R(1), R(2) and R(3)
independently of one another are -SR(28), -OR(28), -NR(28)R(29)
or -CR(28)R(29)R(30);
R(28) is-CgH29-(C1-Cg)-heteroaryl-N-oxide,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
g is zero,1 or 2;
R(29), R(30)
independently of one another are defined as R(28), or
are hydrogen or (C1-C4)-alkyl;
or
R(1), R(2) and R(3)
independently of one another are hydrogen, F, Cl, Br, l, -C-N,
T-(CH2)h-(CjF2j+1), R(31)SOI-, R(32)R(33)N-CO-, R(34)-CO- or
R(45)R(46)N-SO2, where the perfluoroalkyl group is straight-chain
or branched;
T is a bond, oxygen, -S- or -NR(47);
is zero,1 or 2;
h is zero,1 or 2;
i is 1, 2, 3, 4, 5 or 6;
R(31), R(32), R(34) and R(45)
independently of one another are -(C1-C8)-alkyl,
-(C3-C6)-alkenyl, (CH2)nR(48) or-CF3;
n is zero,1, 2, 3 or 4;
R(47) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R(48) is -(C3-C7)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting
of F, Cl, -CF3, methyl, methoxy and

CA 022~7299 1998-12-03

160
-NR(49)R(50);
R(49) and R(50)
are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
or
R(32), R(34) and R(45)
are hydrogen;
R(33) and R(46)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(32) and R(33) and also R(45) and R(46)
together are 5 or 6 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, -NH-, -NCH3 or
-N-benzyl;
15 or
R(1), R(2) and R(3)
independently of one another are R(51)-A-G-D-;
R(51) is a basic protonatable radical, i.e. an amino group
-NR(52)R(53), an amidino group R(52)R(53)N-C[=N-R(54)]-
or a guanidino group R(52)R(53)N-C[=N-R(54)]-NR(55)-;
R(52), R(53), R(54) and R(55)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
or
R(52) and R(53)
are a group C~H2a;
a is4,5,60r7;
where if a = 5, 6 or 7 a carbon atom of the group
CaH2~ can be replaced by a heteroatom group 0, S~d
or NR(56),
or
R(53) and R(54) or R(54) and R(55) or R(52) and R(55)
are a group CyH2y;
y is2,3,40r5;

CA 022~7299 1998-12-03

161
where if y = 3, 4 or 5 a carbon atom of the group
CyH2y can be replaced by a heteroatom group O, S~d
or NR(56);
d is zero,1 or 2;
R(56) ishydrogenormethyl;
or
R(51) is a basic heteroaromatic ring system having 1 - 9 carbon
atoms;
A is a group CeH2e;
e is zero,1, 2, 31 4, 5, 6, 7, 8, 9 or 10;
where in the group CeH2e a carbon atom can be replaced by
one of the groupings -O-, -CO-, -CH[OR(57)]-, -SO,-, -
NR(57)-, -NR(57)-CO-, -NR(57)-CO-NH-, -NR(57)-CO-NH-
SO2- or-NR(57)-SO2-;
r iszero, 1 or2;
G is a phenylene radical,
R(58)


R ( S 9 )

R(58) and R(59)
independently of one another are hydrogen, methyl,
methoxy, F, Cl, Br, l, CF3 or-SOs-R(60);
R(60) is methyl or NR(61)R(62);
R(61) and R(62)
independently of one another are
hydrogen or alkyl having 1, 2, 3 or 4
carbon atoms;
D is-cvH2v-Ew-;
v iszero,1,2,3Or4;
E is -O-, -CO-, -CH[OR(63)]-, -SOaa- or -NR(63)-;
w .is zero or 1 ;
aa is zero,1 or 2

CA 022~7299 1998-12-03

162
R(63) is hydrogen or methyl,
or
R(1), R(2) and R(3)
independently of one another are -CF2R(64), -CF[R(65)][R(66)],
-CF[(CF2)q~CF3)][R(65)]~ -c[(cF2)p-cF3]=cR(65)R(66);
R(64) is alkyl having 1,2, 3 or 4 carbon atoms or cycloalkyl having
3, 4, 5, 6 or 7 carbon atoms;
R(65) and R(66) independently of one another are hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
q is zero,1 or2;
p is zero,1 or 2;
or
R(1), R(2) and R(3)
independently of one another are -OR(67) or -NR(67)R(68);
R(67) and R(68)
independently of one another are hydrogen or alkyl having 1,
2, 3,4, 5 or 6 carbon atoms;
or
R(67) and R(68)
together are 4, 5, 6 or 7 methylene groups, of which one CH2
group can be replaced by oxygen, -S-, SO2, -NH-, -NCH3 or
-N-benzyl;
R(4) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(69), -NR(70)R(71) or-CzF2z+1;
R(69), R(70) and R(71)
independently of one another are hydrogen or alkyl having 1,
2 or 3 carbon atoms;
z is 1, 2, 3 or 4;
R(6) and R(7)
independently of one another are hydrogen or alkyl having 1, 2, 3 or
4 carbon atoms;
X is oxygen or NR(72);
R(72) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

CA 022~7299 1998-12-03

163
and their pharmaceutically tolerable salts;

(HOE 95/F 115 - EP 744 397, NZ 286 622)
al) alkenylcarboxylic acid guanidides, carrying fluorophenyl groups, of the
5 formula I
R ( 2 ) R ( l )
R ( 3 ) ~/ R ( 6 ) 7
R ( ~ ) ~N~ N~

R(5) ~ H~N~
R ( 7 )
in which:
R(6) is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl or phenyl,
where the phenyl group is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of F, Cl,
CF3, methyl, methoxy and NR(9)R(10);
R(9) and R(10)
are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;
R(7) independently is defined as R(6);
R(1), R(2), R(3), R(4) and R(5)
independently of one another are hydrogen or F;
where, however, at least one of the radicals R(1), R(2), R(3), R(4)
and R(5) must be fluorine;
and their pharmaceutically tolerable salts;


CA 022~7299 1998-12-03

164
(HOE 95/F 173 -NZ 299 052)
an) substituted cinnamic acid guanidides of the formula I
R ( 2 )
R ( 3 ) ~R (Rl()6 )

R(~) ~N~NH2
R ( S )R ( 7 )~ NH2

in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5)
iS -Xa~Yb~Ln-u;
X is CR(16)R(17), O, S or NR(18);
R(16), R(17) and R(18)
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;
a is zero or 1;
Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
alkylene-T having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the
alkylene group, T or T-alkylene having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms in the alkylene group;
T is NR(20), O, S or phenylene,
where the phenylene is not substituted or is
substituted by 1 - 3 substituents selected from
the group consisting of F, Cl, CF3, methyl,
methoxy and NR(21)R(22);
R(20), 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;
b iszeroor1;
L is O, S, NR(23) or CkH2k;
k is 1, 2, 3, 4, 5, 6, 7, 8;


.

CA 022~7299 1998-12-03

165
n iszeroor1;
U is NR(24)R(25) or an N-containing heterocycle having 1, 2, 3,
4, 5, 6, 7, 8 or 9 carbon atoms;
R(24) and R(25)
independently of one another are hydrogen, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms;
or
R(24) and R(25)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
where the N-containing heterocycles are N- or C-bridged and
are not substituted or are substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(27)R(28);
R(23), R(27) and R(28)
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;
and the other substituents R(1), R(2), R(3), R(4) and R(5) in each case
independently of one another are H, F, Cl, Br, l, CN, -On CmH2m+1,
~~p-(cH2)s-cqF2q+1 or-CrH2~R(10);
n is zero or 1;
m is zero 1, 2, 3, 4, 5, 6, 7 or 8;
p iszeroor1;
q is 1, 2, 3, 4, 5, 6, 7 or 8;
s is zero,1, 2, 3 or 4;
r is zero,1, 2, 3 or 4;
R(10)
is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
.where the phenyl is not substituted or is substituted by
1 - 3 substituents selected from the group consisting of

CA 022~7299 1998-12-03

166
F, Cl, CF3, methyl, methoxy and NR(11)R(12);
R(11) and R(12)
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(6) and R(7)
independently of one another are hydrogen, F, Cl, Br, l, CN, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
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;
and their pharmaceutically tolerable salts;
(HOE 95/F 269 K)
20 ar) benzenedicarboxylic acid diguanidides of the formula I
R2
R3~T~R1

R4~N~NH2
R5 ~ NH2
in which:
one of the radicals R(1), R(2), R(3) and R(4)
is -CO-N=C(N H2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, l,
-OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;

CA 022~7299 1998-12-03

167
R(2) and R(4)
independently of one another are hydrogen, F, Cl, Br, l, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mR(14);
m is zero,1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
R(2) and R(4)
independently of one another are pyrrol-1 -yl, pyrrol-2-yl or pyrrol-3-
yl,
each of which is not substituted or is substituted by 1 - 4
substituents selected from the group consisting of F, Cl, Br, l,
-CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl,
carboxyl, -CF3, methyl, methoxy;
or
R(2) and R(4)
independently of one another are R(22)-SO2-, R(23)R(24)N-CO-,
R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
30 R(2) and R(4)
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;

CA 022~7299 1998-12-03

168
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, l, X-(CH2)y~CF3
or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F and Cl, -CF3, methyl,
methoxy and -NR(6)R(7);
R(6) and R(7)
independently of one another are hydrogen or-CH3;
X is a bond or oxygen;
y is zero,1 or 2;
30 and their pharmaceutically tolerable salts;
(HOE 95/F 269 BK)
as) benzenedicarboxylic acid diguanidides of the formula I

CA 022~7299 1998-12-03

169
R2
R3~,~ R1
R4 ~1/ ~ N y NH2
R5 ~ NH2
in which:
one of the radicals R(1), R(2), R(3) and R(5)
is -CO-N=C(N H2)2;
and the other radicals R(1), R(2), R(3) and R(5) in each case are:
R(1) and R(5)
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) is hydrogen, F, Cl, Br, l, OH1 -C-N, CF3, -CO-N=C(NH2)2, alkyl
having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5,
6, 7 or 8 carbon atoms or -(CH2)mR(14);
m is zero,1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;
or
R(2) is R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
R(2) is -OR(35) or -NR(35)R(36);
-


CA 022~7299 1998-12-03

170
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(4) is CF3, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl
having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, -(C3-C8)-cycloalkyl or
-(CH2)mR(1 4);
m is 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
independently of one another are hydrogen or
-CH3;


,

CA 022~7299 1998-12-03

171
or
R(4) is phenyl,
which is substituted by 2, 3, 4 or five substituents selected
from the group consisting of F, Cl, CF3, methyl, methoxy and
-NR(1 5)R(16);
R(15) and R(16)
independently of one another are hydrogen or
CH3;
and their pharmaceutically tolerable salts;
10 (HOE 96/F 013)
at) diaryldicarboxylic acid diguanidides of the formula I
R2 R9


R4~R,~ R8
R5 R6
in which:
one of the radicals R(1), R(2), R(3), R(4) and R(5)
is -CO-N=C(NH2)2;
20 the other radicals R(1 ) and R(5) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
the other radicals R(2) and R(4) in each case
independently of one another are hydrogen, F, Cl, Br, I, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mR(1 4);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl,
.which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F

CA 022~7299 1998-12-03

172
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16)
are hydrogen or-CH3;
or
5 the other radicals R(2) and R(4) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-
yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, l, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl, methoxy;
or
the other radicals R(2) and R(4) in each case
are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28)
independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30)
independently of one another are hydrogen or methyl;
or
the other radicals R(2) and R(4) in each case
independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(35) and R(36)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
the other radical R(3) in each case
is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
.which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,

CA 022~7299 1998-12-03

173
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
or
R(25) is-(C1-Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(26) and R(27)
independently of one another are defined as R(25) or are
hydrogen or alkyl having 1, 2, 3,4, 5, 6, 7 or 8 carbon atoms;
one of the radicals R(6), R(7), R(8), R(9) and R(10)
is -CO-N=C(NH2)2;
the other radicals R(6) and R(10) in each case
independently of one another are hydrogen, alkyl having 1, 2, 3 or 4
carbon atoms, F, Cl, -OR(132), -NR(133)R(134) or CF3;
R(132), R(133) and R(134)
independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
20 the other radicals R(7) and R(9) in each case
independently of one another are hydrogen, F, Cl, Br, l, OH, -CN,
CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
-(CH2)mmR(114);
mm iszero,1 or2;
R(114)
is -(C3-C8)-cycloalkyl or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(115)R(116);
R(115) and R(116)
are hydrogen or-CH3;
or



.

CA 022~7299 1998-12-03

174
the other radicals R(7) and R(9) in each case
independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-
yl,
which is not substituted or is substituted by 1 - 4 substituents
selected from the group consisting of F, Cl, Br, l, -CN,
(C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl,
-CF3, methyl and methoxy;
or
the other radicals R(7) and R(9) in each case
are R(122)-SO2-, R(123)R(124)N-CO-, R(128)-CO- or
R(129)R(130)N-SO2;
R(122) and R(128)
independently of one another are methyl or -CF3;
R(123), R(124), R(129) and R(130)
independently of one another are hydrogen or methyl;
or
the other radicals R(7) and R(9) in each case
independently of one another are -OR(135) or -NR(135)R(136);
R(135) and R(136)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5 or 6 carbon atoms;
or
R(135) and R(136)
together are 4 - 7 methylene groups, of which one CH2 group
can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
the other radical R(8) in each case
is hydrogen, -SR(125), -OR(125), -NR(125)R(126) or
-CR(125)R(126)R(127);
R(125)
is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
or phenyl,
which is unsubstituted or substituted by 1 - 3
.substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino

CA 022~7299 1998-12-03

175
and dimethylamino;
or
R(125)
is -(C1 -Cg)-heteroaryl,
which is unsubstituted or substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino
and dimethylamino;
R(126) and R(127)
independently of one another are defined as R(125) or are
hydrogen or alkyl having 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms;
A is absent or is -NR(11)-CO-, -NR(12)-CO-NR(13)-,
-NR(17)-CO-NR(18)-SO2-, -NR(19)-SO2-, -SO2-NR(19)-SO2-,
-SO2-NR(19)-CO-, -O-CO-NR(19)-SO2- or -CR(20)=CR(21)-;
R(11), R(12), R(13), R(17), R(18), R(19), R(20) and R(21)
independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms
and their phammaceutically tolerable salts;
(HOE 96/F 026)
au) substituted thiophenylalkenylcarboxylic acid guanidides of the formula I

R(2; ~, R(3) R(5)


R(1 S ~ N\~ NH2

R(4) ~ NH2
in which:
at least one of the substituents R(1), R(2) and R(3)
is -~p~(CH2)s-cqF2q+1, R(40)CO- or R(31)SOk;
p iszeroor1;
s iszero,1,2,3Or4;
q is 1, 2,.3, 4, 5, 6, 7 or8;
k is zero,1 or 2;

CA 022~7299 1998-12-03

176
R(40) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl and methoxy;
R(31 ) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
perfluoroalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl,
which is not substituted or is substituted by 1 - 3
substituents selected from the group consisting of F,
Cl, CF3, methyl or methoxy;
or
R(31 ) is NR(41 )R(42);
R(41) and R(42)
independently of one another are hydrogen, alkyl
having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having
1, 2, 3 or 4 carbon atoms,
or
R(41) and R(42)
together are 4 or 5 methylene groups, of which one
CH2 group can be replaced by oxygen, S, NH, N-CH3
or N-benzyl;
and the other substituents R(1), R(2) and R(3) in each case
independently of one another are H, F, Cl, Br, I, CN,
-ona-CmaH2ma+1 ~r~~gaCraH2raR(1~);
na is zero or 1;
ma is zero, 1, 2, 3, 4, 5, 6, 7 or 8;
ga is zero or 1;
ra is zero, 1, 2, 3 or 4;
R(10) is cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
where the phenyl is not substituted or is substituted by
.1 - 3 substituents selected from the group consisting of
F, Cl, CF3, methyl and methoxy;


-

CA 022~7299 1998-12-03

177
R(4) and R(5)
independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl
having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8
carbon atoms or phenyl,
which is not substituted or is substituted by 1 - 3 substituents
selected from the group consisting of F, Cl, CF3, methyl,
methoxy and NR(14)R(15);
R(14) and R(15)
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;
and their pharmaceutically tolerable salts.

15 For inhibitors of Na+/H+ exchange of this type, numerous medicinal uses
have already been described, such as, for example, forms of illness which
occur due to chronic or acute undersupply of blood to an organ (ischemia),
in particular of the heart. They are therefore suitable, for example, for the
treatment of ischemically induced arrhythmias, different forms of angina
20 pectoris, in heart transplants, in cardiac surgery and in angioplastic surgical
interventions. Other indications described for NHE inhibitors are stroke and
cerebral edema, shock and proliferation-related diseases, such as
atherosclerosis, diabetic late damage, fibrotic disorders and organ
hypertrophy.
It has now surprisingly been found that NHE inhibitors have a favorable
effect on serum lipoproteins. It is generally recognized that for the
formation of arteriosclerotic vascular changes, in particular of coronary
heart disease, excessively high blood lipid values, so-called
30 hyperlipoproteinemias, are a significant risk factor. For the prophylaxis and regression of atherosclerotic changes, the lowering of raised serum
lipoproteins therefore has extreme importance. Beside the reduction of
serum total cholesterol, the lowering of the proportion of specific
atherogenic lipid fractions of this total cholesterol, in particular of the low

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density lipoproteins (LDL) and of the very low density lipoproteins (VLDL)
has particular importance, since these lipid fractions are an atherogenic
risk factor. However, the high density lipoproteins are ascribed a protective
function against coronary heart disease. Accordingly, hypolipidemics
5 should be able to lower not only total cholesterol, but in particular the VLDLand LDL serum cholesterol fractions. It has now surprisingly been found
that NHE inhibitors have valuable therapeutically utilizable properties with
respect to affecting the serum lipid level. Thus they significantly reduce the
raised serum concentration of LDL and VLDL, such as is to be observed,
10 for example, as a result of increased dietetic uptake of a cholesterol- and
lipid-rich diet or in the case of pathological metabolic changes, for example
genetically related hyperlipidemias. They can therefore be used for the
prophylaxis and for the regression of atherosclerotic changes by
eliminating a causal risk factor. These include not only the primary
15 hyperlipidemias, but also certain secondary hyperlipidemias, such as
occur, for example, in diabetes. Moreover, the NHE inhibitors lead to a
marked reduction in the infarcts induced by metabolic anomalies and in
particular to a significant reduction in the induced infarct size and its
degree of severity. Furthemmore, NHE inhibitors result in effective
20 protection against endothelial damage induced by metabolic anomalies.
With this protection of the vessels against the endothelial dysfunction
syndrome, NHE inhibitors are valuable pharmaceuticals for the prevention
and treatment of coronary vascular spasms, of atherogenesis and of
atherosclerosis, of left ventricular hypertrophy and of dilated
25 cardiomyopathy, and thrombotic disorders.

This antihyperlipidemic action is shown for an NHE inhibitor, 4-isopropyl-
3-methylsulfonylbenzoylguanidine methanesulfonate (Hoe 642), in the
following table, male New Zealand white rabbits (n = 28) having a weight of
30 3 - 4 kg being used and divided into four groups of 7 animals in each case
randomized as described below: 1) standard rabbit feed ((~)Altromin 2834),
2) atherogenic diet having a content of 0.25% cholesterol and 3% coconut
oil, 3) standard rabbit feed + Hoe 642 (0.1 %), 4) atherogenic diet +
Hoe 642 (0.1 %).

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Blood samples were taken once after 30 days feeding by puncture of the
auricular artery. Serum was obtained from the blood. The total cholesterol
was measured from the serum by means of the CHOD (cholesterol
oxidase)-PAP method (Merckotestt Merck Diagnostics, E. Merck, 64271
5 Darmstadt, Germany). The separation of the lipoproteins was carried out,
likewise from the serum, by FPLC (fast protein liquid chromatography)
method (Marz et al.1993, Clin. Chem. 39/11 :2276-2281).

Results
10 Total cholesterol values, and the subfractions VLDL, LDL and HDL from
the rabbit sera:

(mmol/l) Cholesterol VLDL LDL HDL

Normal diet 0.65 + 0.08 0.05 + 0.01 0.12 + 0.02 0.48 + 0.06

Normal diet
+ HOE 642 0.69 + 0.1 0.05 + 0.02 0.23 + 0.04 0.41 + 0.17

Che'e Is,uidiet 17.85+3.71 5.68+ 1.38 9.31 + 1.88 2.86+0.73

Cholesterol diet
+ HOE 642 7.95 + 0.89~ 4.6 + 0.6 2.1 + 0.2~ 1.8 + 0.2

25 The values are indicated as mean values + SEM (standard error of the
mean).
Significances: *pc0.05 cholesterol diet + HOE 642 vs cholesterol diet.
There are no significant differences between the two normal diet groups.
Both normal diet groups are significantly different from the two cholesterol
30 groups.

The compounds used according to the invention are therefore
advantageously used for the production of a medicament for the treatment
of hypercholesterolemia; for the production of a medicament for the
35 prevention of atherQgenesis; for the production of a medicament for the
prevention and treatment of atherosclerosis, for the production of a

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medicament for the prevention and treatment of illnesses which are caused
by increased cholesterol levels, for the production of a medicament for the
prevention and treatment of illnesses which are caused by endothelial
dysfunction, for the production of a medicament for the prevention and
5 treatment of atherosclerosis-induced hypertension, for the production of a
medicament for the prevention and treatment of atherosclerosis-induced
thromboses, for the production of a medicament for the prevention and
treatment of hypercholesterolemia- and endothelial dysfunction-induced
ischemic damage and postischemic reperfusion damage, for the
10 production of a medicament for the prevention and treatment of
hypercholesterolemia- and endothelial dysfunction-induced cardiac
hypertrophies and cardiomyopathies, for the production of a medicament
for the prevention and treatment of hypercholesterolemia- and endothelial
dysfunction-induced coronary vascular spasms and myocardial infarcts, for
15 the production of a medicament for the treatment of the conditions
mentioned in combination with hypotensive substances, preferably with
angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor
antagonists, a combination of an NHE inhibitor with a blood lipid level-
lowering active compound, preferably with an HMG-CoA reductase
20 inhibitor, e.g. Iovastatin or pravastatin, the latter causing a hypolipidemicaction and thereby increasing the hypolipidemic properties of the NHE
inhibitor, proving to be a favorable combination with increased action and
reduced use of active compound.

25 The administration of sodium/proton exchange inhibitors as novel
pharmaceuticals for lowering increased blood lipid levels is claimed, as well
as the combination of sodium/proton exchange inhibitors with
pharmaceuticals having a hypotensive and/or hypolipidemic action.




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