U.S. patent application number 10/641058 was filed with the patent office on 2004-03-04 for diacyl-substituted guanidines, a process for their preparation, their use as medicament or diagnostic aid, and medicament containing them.
This patent application is currently assigned to Hoechst Aktiengesellschaft. Invention is credited to Albus, Udo, Crause, Peter, Kleemann, Heinz-Werner, Lang, Hans-Jochen, Scholz, Wolfgang, Schwark, Jan-Robert, Weichert, Andreas.
Application Number | 20040044081 10/641058 |
Document ID | / |
Family ID | 6495834 |
Filed Date | 2004-03-04 |
United States Patent
Application |
20040044081 |
Kind Code |
A1 |
Kleemann, Heinz-Werner ; et
al. |
March 4, 2004 |
Diacyl-substituted guanidines, a process for their preparation,
their use as medicament or diagnostic aid, and medicament
containing them
Abstract
Diacyl-substituted guanidines, a process for their preparation,
their use as medicament or diagnostic aid, and medicament
containing them. Diacyl-substituted guanidines of the formula I 1
are described where X(1) and X(2) are 2 T1 is zero, 1, 2, 3 or 4,
R(A) and R(B) are hydrogen, Hal, CN, OR(106), (O)
(cyclo)--(fluoro)alkyl, NR(107)R(108), phenyl or benzyl, or 3 T2a
and T2b are, independently of each other, zero, 1 or 2, where the
double bond can be in the E or Z configuration; or X(1) and X(2)
are 4 as are the pharmaceutically tolerated salts thereof. They are
outstandingly suitable for use as antiarrhythmic pharmaceuticals
possessing a cardioprotective component for the prophylaxis and
treatment of infarction and for the treatment of angina pectoris,
in connection with which they also inhibit or strongly reduce, in a
preventive manner, the pathophysiological processes associated with
the genesis of ischemically induced damage, in particular
associated with the elicitation of ischemically induced cardiac
arrhythmias. On account of their protective effects against
pathological hypoxic and ischemic situations, the compounds of the
formula I according to the invention can, as a consequence of
inhibiting the cellular Na.sup.+/H.sup.+ exchange mechanism, be
used as pharmaceuticals for treating all acute or chronic damage
elicited by ischemia, or diseases induced primarily or secondarily
thereby.
Inventors: |
Kleemann, Heinz-Werner; (Bad
Homburg, DE) ; Lang, Hans-Jochen; (Hofheim, DE)
; Weichert, Andreas; (Egelsbach, DE) ; Crause,
Peter; (Offenbach, DE) ; Scholz, Wolfgang;
(Eschborn, DE) ; Albus, Udo; (Florstadt, DE)
; Schwark, Jan-Robert; (Frankfurt, DE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Assignee: |
Hoechst Aktiengesellschaft
|
Family ID: |
6495834 |
Appl. No.: |
10/641058 |
Filed: |
August 15, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10641058 |
Aug 15, 2003 |
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09534036 |
Mar 24, 2000 |
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6632840 |
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09534036 |
Mar 24, 2000 |
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08837460 |
Apr 18, 1997 |
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6436999 |
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08837460 |
Apr 18, 1997 |
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08293542 |
Aug 22, 1994 |
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Current U.S.
Class: |
514/616 ;
564/147 |
Current CPC
Class: |
C07C 2601/08 20170501;
C07C 279/22 20130101; C07D 233/56 20130101; C07D 295/155 20130101;
A61P 9/10 20180101; C07D 231/12 20130101; C07C 317/44 20130101;
C07C 2601/04 20170501; A61P 9/00 20180101; C07D 249/08 20130101;
C07D 215/54 20130101 |
Class at
Publication: |
514/616 ;
564/147 |
International
Class: |
A61K 031/16; A61K
031/165 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 24, 1993 |
DE |
P 43 28 352.7 |
Claims
1. A diacyl-substituted guanidine of the formula I 127in which:
X(1) and X(2) are 128T1 is zero, 1, 2, 3 or 4, R(A) and R(B) are,
independently, hydrogen, F, Cl, Br, I, CN, OR(106),
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl,
O.sub.zk(CH.sub.2).sub.zlC.sub.zmF.sub.2zm+- 1, NR(107)R(108),
phenyl or benzyl, where the aromatic radicals are not substituted
or are substituted by 1-3 substituents selected from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(109)R(110),
R(109) and R(110) being hydrogen, (C.sub.3-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-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,
(C.sub.1-C.sub.8)-alkyl, (C.sub.1-C.sub.8)-perfluoroalkyl,
(C.sub.3-C.sub.8)-alkenyl, (C.sub.3-C.sub.8)-cycloalkyl, phenyl or
benzyl, where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(111)R(112), R(111) and
R(112) being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl, R(107) and R(108) are,
independently of each other, defined as R(106), or R(107) and
R(108) are together 4 or 5 methylene groups of which one CH.sub.2
group can be replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl, or
X(1) and X(2) are 129T2a and T2b are, independently of each other,
zero, 1 or 2, where the double bond can have the E or Z
configuration; or X(1) and X(2) are 130T3 is zero, 1 or 2, U, YY
and Z are, independently of each other, C or N, where U, YY and Z
can carry the following number of substituents:
8 Bonded to a double Number of permitted U, YY or Z bond in the
ring substituents C yes 1 C no 2 N yes 0 N no 1
R(D) is hydrogen, (C.sub.1-C.sub.8)-alkyl or
(C.sub.1-C.sub.8)-perfluoroal- kyl, R(U1), R(U2), R(Y1), R(Y2),
R(Z1) and R(Z2) are, independently of each other, hydrogen, F, Cl,
Br, I, CN, OR(114), (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl,
O.sub.zka(CH.sub.2).sub.zlaC.sub.zmaF.sub.2- zma+1, NR(115)R(116),
phenyl or benzyl, where the aromatic radicals are not substituted
or are substituted by 1-3 substituents selected from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(117)R(118),
R(117) and R(118) being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-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,
(C.sub.1-C.sub.8)-alkyl, (C.sub.1-C.sub.8)-perfluoroalkyl,
(C.sub.3-C.sub.8)-alkenyl, (C.sub.3-C.sub.8)-cycloalkyl, phenyl or
benzyl, where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(119)R(120), R(119) and
R(120) being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl, R(115) and R(116) are,
independently of each other, defined as R(114), or R(115) and
R(116) are together 4 or 5 methylene groups of which one CH.sub.2
group can be replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl,
where, however, the constitution U is nitrogen (N), YY is nitrogen
(N) and Z is carbon (C) is excepted, R(101), R(102), R(103), R(104)
and R(105) are, independently of each other, hydrogen, F, Cl, Br,
I, --C.ident.N,
X.sub.zoa--(CH.sub.2).sub.zpa--(C.sub.zqaF.sub.2zqa+1),
R(110a)-SO.sub.zbm, R(110b)R(110c)N--CO, R(111a)-CO-- or
R(112a)R(113a)N--SO.sub.2--, where the perfluoroalkyl group is
straight-chain or branched, X is hydrogen, S or NR(114a), zoa is
zero or 1, R(114a) being H or (C.sub.1-C.sub.3)-alkyl, 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) are, independently,
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-alkenyl,
--C.sub.znH.sub.2zn--R(115a) or (C.sub.1-C.sub.8)-perfluoroalkyl,
zn is zero, 1, 2, 3 or 4, R(115a) is (C.sub.3-C.sub.8)-cycloalkyl,
phenyl, biphenylyl or naphthyl, where the aromatic radicals are not
substituted or are substituted by 1-3 substituents selected from
the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(116a)R(117a), R(116a) and R(117a) being hydrogen,
(C.sub.1-C.sub.4)-perfluoroalkyl or (C.sub.1-C.sub.4)-alkyl, or
R(110b), R(111a) and R(112a) are also hydrogen, R(110c) and R(113a)
are, independently, hydrogen, (C.sub.1-C.sub.4)-perfluoroalkyl or
(C.sub.1-C.sub.4)-alkyl, or R(110b) and R(110c) and also R(112a)
and R(113a) are together 4 or 5 methylene groups of which one
CH.sub.2 group can be replaced by oxygen, sulfur, NH, N--CH.sub.3
or N-benzyl, or R(101), R(102), R(103), R(104) and R(105) are,
independently of each other, (C.sub.1-C.sub.8)-alkyl,
--C.sub.zalH.sub.2zalR(118a) or (C.sub.3-C.sub.8)-alkenyl, zal is
zero, 1, 2, 3 or 4, R(118a) is (C.sub.3-C.sub.8)-cycloalkyl,
phenyl, biphenylyl or naphthyl, where the aromatic radicals are not
substituted or are substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(119a)R(119b),
R(119a) and R(119b) being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl, or R(101), R(102), R(103), R(104)
and R(105) are, independently of each other,
(C.sub.1-C.sub.9)-heteroaryl which is linked via C or N and which
is unsubstituted or is substituted by 1-3 substituents from the
group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl,
amino, methylamino and dimethylamino, or R(101), R(102), R(103),
R(104) and R(105) are, independently of each other,
--C.ident.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, CF.sub.3, methyl, methoxy or NR(194)R(195), R(194) and R(195)
being hydrogen or CH.sub.3, or R(101), R(102), R(103), R(104) and
R(105) are, independently of each other,
--Y-para-C.sub.6H.sub.4--(CO).sub.zh--(CHOH).sub.zi--(CH.sub.2).sub.zj--(-
CHOH).sub.zk--R(123),
--Y-meta-C.sub.6H.sub.4--(CO).sub.zad--(CHOH).sub.za-
e--(CH.sub.2).sub.zaf--(CHOH).sub.zag--R(124) or
--Y-ortho-C.sub.6H.sub.4--
-(CO).sub.zah--(CHOH).sub.zao--(CH.sub.2).sub.zap--(CHOH).sub.zak--R(125),
Y is oxygen, --S-- or --NR(122d)-, zh, zad and zah are,
independently, zero or 1, zi, zj, zk, zae, zaf, zag, zao, zap and
zak are, independently, zero, 1, 2, 3 or 4, where, however, in each
case, zh, zi and zk are not simultaneously zero, zad, zae and zag
are not simultaneously zero, zah, zao and zak are not
simultaneously zero, R(123), R(124), R(125) and R(122d) are,
independently, hydrogen or (C.sub.1-C.sub.3)-alkyl, or R(101),
R(102), R(103), R(104) and R(105) are, independently of each other,
SR(129), --OR(130), --NR(131)R(132) or --CR(133)R(134)R(135),
R(129), R(130), R(131) and R(133), are, independently,
--C.sub.zabH.sub.2zab--(C.sub.1-C.sub.9)-heteroaryl which is
unsubstituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino,
methylamino and dimethylamino, zab is zero, 1 or 2, R(132), R(134)
and R(135) are, independently of each other, defined as R(129), or
hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl, or R(101), R(102), R(103), R(104)
and R(105) are, independently of each other,
--W-para-(C.sub.6H.sub.4)--R(196),
--W-meta-(C.sub.6H.sub.4)--R(197) or
--W-ortho-(C.sub.6H.sub.4)--R(198), R(196), R(197) and R(198) are,
independently, (C.sub.1-C.sub.9)-heteroaryl which is linked via C
or N and which is unsubstituted or is substituted by 1 to 3
substituents from the group consisting of F, Cl, CF.sub.3,
CH.sub.3, methoxy, hydroxyl, amino, methylamino, dimethylamino and
benzyl, W is oxygen, S or NR(136)-, R(136) being hydrogen or
(C.sub.1-C.sub.4)-alkyl, or R(101), R(102), R(103), R(104) and
R(105) are, independently of each other, R(146)X(1a)-, X(1a) is
oxygen, S, NR(147), (D=O)A- or NR(148)C=MN(*)R(149)-, M is oxygen
or sulfur, A is oxygen or NR(150), and D is C or SO, R(146) is
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-alkenyl,
(CH.sub.2).sub.zbz--C.sub.zdzF.sub.2zdz+1 or
--C.sub.zxaH.sub.2zxa--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
(C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or naphthyl, where
the aromatic radicals are not substituted or are substituted by 1-3
substituents from the group consisting of F, Cl, CF.sub.3, methyl,
methoxy and NR(152)R(153), R(152) and R(153) being hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-perfluoroalkyl,
R(147), R(148) and R(150) are, independently, hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-perfluoroalkyl, R(149)
is defined as R(146), or R(146) and R(147), or R(146) and R(148),
respectively, are together 4 or 5 methylene groups of which one
CH.sub.2 group can be replaced by oxygen, sulfur, NH, N--CH.sub.3
or N-benzyl, where A and N(*) are bonded to the phenyl nucleus of
the alkanoyl parent substance, or R(101), R(102), R(103), R(104)
and R(105) are, independently of each other, --SR(164), --OR(165),
--NHR(166), --NR(167)R(168), --CHR(169)R(170), --CR(154)R(155)OH,
--C.ident.CR(156), --CR(158)=CR(157) or
--[CR(159)R(160)].sub.zt-(C.ident.O)--[(CR(161)R(162-
)].sub.zv-R(163), R(164), R(165), R(166), R(167) and R(169) are
identical or different and are
--(CH.sub.2).sub.zy--(CHOH).sub.zz--(CH.sub.2).sub.z-
aa--(CHOH).sub.zt--R(171) or
--(CH.sub.2).sub.zab--(CH.sub.2--CH.sub.2O).s- ub.zac--R(172)
R(171) and R(172) being hydrogen or methyl, zu is 1, 2, 3 or 4, zv
is zero, 1, 2, 3 or 4, zy, zz, zaa, zab and zac are identical or
different and are zero, 1, 2, 3 or 4, zt is 1, 2, 3 or 4, R(168),
R(170), R(154) and R(155) are identical or different and are
hydrogen or (C.sub.1-C.sub.6)-alkyl, or R(169) and R(170), or
R(154) and R(155), respectively, are, together with the carbon atom
carrying them, a (C.sub.3-C.sub.8)-cycloalkyl, R(163) is hydrogen,
(C.sub.1-C.sub.6)-alkyl- , (C.sub.3-C.sub.8)-cycloalkyl or
--C.sub.zebH.sub.2zeb--R(173), zeb is zero, 1, 2, 3 or 4, R(156),
R(157) and R(173) are, independently, phenyl which is unsubstituted
or is substituted by 1-3 substituents from the group consisting of
F, Cl, CF.sub.3, methyl, methoxy and NR(174)R(175), R(174) and
R(175) being hydrogen or (C.sub.1-C.sub.4)-alkyl, or R(156), R(157)
and R(173) are, independently, (C.sub.1-C.sub.9)-heteroaryl which
is unsubstituted or is 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) and R(105) are, independently of each other,
R(176)-NH--SO.sub.2--, R(176) is R(177)R(178)N--(C.dbd.Y')--, Y, is
oxygen, S or N--R(179), R(177) and R(178) are identical or
different and are hydrogen, (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.6)-alkenyl or --C.sub.zfaH.sub.2zfa--R(180) zfa is
zero, 1, 2, 3 or 4, R(180) is (C.sub.5-C.sub.7)-cycloalkyl or
phenyl which is unsubstituted or substituted by 1-3 substituents
from the group consisting of F, Cl, CF.sub.3, methoxy or
(C.sub.1-C.sub.4)-alkyl, or R(177) and R(178) are together 4 or 5
methylene groups of which one CH.sub.2 group can be replaced by
oxygen, sulfur, NH, N--CH.sub.3 or N-benzyl, R(179) is defined as
R(177) or is amidine, or R(101), R(102), R(103), R(104) and R(105)
are, independently of each other, NR(184a)R(185), OR(184b),
SR(184c) or --C.sub.znxH.sub.2znx--R(184d), znx is zero, 1, 2, 3 or
4, R(184d) is (C.sub.3-C.sub.7)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(116k)R(117k),
R(116k) and R(117k) being hydrogen or (C.sub.1-C.sub.4)-alkyl,
R(184a), R(184b), R(184c) and R(185) are, independently of each
other, hydrogen, (C.sub.1-C.sub.8)-alkyl,
(C.sub.1-C.sub.8)-perfluoroalkyl or (CH.sub.2).sub.zao--R(184g),
zao is zero, 1, 2, 3 or 4, 184g is (C.sub.3-C.sub.7)-cycloalkyl or
phenyl which is not substituted or is substituted by 1-3
substituents from the group consisting of F, Cl, CF.sub.3, methyl,
methoxy and NR(184u)R(184v), R(184u) and R(184v) being hydrogen or
(C.sub.1-C.sub.4)-alkyl, or R(184a) and R(185) are together 4 or 5
methylene groups of which one CH.sub.2 group can be replaced by
oxygen, sulfur, NH, N--CH.sub.3 or N-benzyl, and also
pharmaceutically tolerated salts thereof, where, however, the
following compounds are excepted: 131and where, additionally, the
compounds are excepted in which the radicals R(1) to R(5) are
combined as follows:
9 R(101) R(102) R(103) R(104) R(105) R(105) R(104) R(103) R(102)
R(101) [X(1)] [X(1)] [X(1)] [X(1)] [X(1)] [X(2)] [X(2)] [X(2)]
[X(2)] [X(2)] H Cl Cl H H H H Cl Cl H H H NH.sub.2 H H H H NH.sub.2
H H H H H H H H H H H H Cl H H H H H H H H Cl H H Cl H H H H Cl H H
H H CH.sub.3 H H H H CH.sub.3 H H H H NH.sub.2 H H H H H H H H H Cl
H H H H H H H H H CH.sub.3 H H H H H H H
2. A compound of the formula I as claimed in claim 1, wherein X(1)
is identical to X(2) and wherein the remaining substituents are
defined as in claim 1.
3. A compound of the formula I as claimed in claim 1, wherein: X(1)
and X(2) are 132T1 is zero or 2, R(A) and R(B) are, independently,
hydrogen, F, Cl, CN, OR(106), (C.sub.1-C.sub.4)-alkyl,
(C.sub.5-C.sub.6)-cycloalkyl- , CF.sub.3 or NR(107)R(108), R(106)
is hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3, phenyl or benzyl,
where the aromatic radicals are not substituted or are substituted
by 1-3 substituents selected from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy and NR(111)R(112), R(111) and R(112)
being hydrogen, CH.sub.3 or CF.sub.3, R(107) and R(108) are,
independently of each other, defined as R(106), or R(107) and
R(108) are together 4 or 5 methylene groups of which one CH.sub.2
group can be replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl, or
X(1) is 133where the double bond can be in the E or Z
configuration, or X(1) is 134U, YY and Z are, independently of each
other, C or N; with, however, the restriction that only one of the
positions U, YY and Z can be nitrogen; where U, YY and Z can carry
the following number of substituents:
10 U, YY Bonded to a double Number of permit- or Z bond in the ring
ted substituents C yes 1 C no 2 N yes 0 N no 1
R(D) is hydrogen, R(U1), R(U2), R(Y1), R(Y2), R(Z1) and R(Z2) are,
independently of each other, hydrogen, F, Cl, CN, OR(114),
CH.sub.3, CF.sub.3 or NR(115)R(116) R(114) is hydrogen,
(C.sub.1-C.sub.4)-alkyl, CF.sub.3, phenyl or benzyl, where the
aromatic radicals are not substituted or are substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(119)R(120), R(119) and R(120) being
hydrogen, CH.sub.3 or CF.sub.3, R(115) and R(116) are,
independently of each other, defined as R(114), or R(115) and
R(116) are together 4 or 5 methylene groups of which one CH.sub.2
group can be replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl,
R(101) is hydrogen, F, Cl, CH.sub.3, OH, NH.sub.2 or CF.sub.3,
R(102) is hydrogen, F, Cl, Br, --C.ident.N,
--C.sub.zqaF.sub.2zqaCF.sub.3, R(110a)-SO.sub.2R(110b)R(110c-
)N--CO--, R(111a)-CO-- or R(112a)R(113a)N--SO.sub.2--, R(110a),
R(110b), R(111a) and R(112a) are, independently,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-alkenyl,
--C.sub.znH.sub.2zn--R(115a) or CF.sub.3, zn is zero or 1, zqa is
zero, 1, 2, 3, 4 or 5, R(115a) is (C.sub.3-C.sub.6)-cycloalkyl or
phenyl which is not substituted or is substituted by 1-2
substituents from the group consisting of F, Cl, CF.sub.3, methyl,
methoxy and NR(116a)R(117a), R(116a) and R(117a) being hydrogen or
methyl, or R(110b), R(111a) and R(112a) are also hydrogen, R(110c)
and R(113a) are, independently, hydrogen or methyl, R(103) is
--Y-para-C.sub.6H.sub.4--(CO).sub.zh--(CHOH).sub.zi--(CH.sub.2).sub.zj--(-
CHOH).sub.zk--R(123),
--Y-meta-C.sub.6H.sub.4--(CO).sub.zad--(CHOH).sub.za-
e--(CH.sub.2).sub.zaf--(CHOH).sub.zag--R(124) or
--Y-ortho-C.sub.6H.sub.4--
-(CO).sub.zah--(CHOH).sub.zao--(CH.sub.2).sub.zap--(CHOH).sub.zak--R(125),
Y is oxygen, S or --NR(83), R(123), R(124), R(125) and R(83) are,
independently, hydrogen or methyl, zh, zad and zah are,
independently, zero or 1, zi, zk, zae, zag, zao and zak are,
independently, zero, 1, 2 or 3,3 zj, zaf and zap are,
independently, zero or 1, where, however, 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, or R(103) is hydrogen, F, Cl, Br, CN,
(C.sub.1-C.sub.8)-alkyl, CF.sub.3, (C.sub.3-C.sub.8)-alkenyl or
--C.sub.zalH.sub.2zalR(118a), zal is zero, 1 or 2, R(118a) is
(C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not substituted or
is substituted by 1-2 substituents selected from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(119a)R(119b),
R(119a) and R(119b) being hydrogen or CH.sub.3, or R(103) is
(C.sub.1-C.sub.9)-heteroaryl which is linked via C or N and which
is unsubstituted or is substituted by 1-2 substituents from the
group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl,
amino, methylamino and dimethylamino, or R(103) is
--W-para-(C.sub.6H.sub.4)--R(- 196),
--W-meta-(C.sub.6H.sub.4)--R(197) or
--W-ortho-(C.sub.6H.sub.4)--R(1- 98), R(196), R(197) and R(198)
are, independently, pyrrolyl, imidazolyl, pyrazolyl or pyridyl
which in each case is unsubstituted or substituted by 1 to 2
radicals selected from the group consisting of F, Cl, CF.sub.3,
CH.sub.3, methoxy, dimethylamino and benzyl, W is oxygen, --S-- or
NR(136)--, R(136) being hydrogen or methyl, or R(103) is --SR
(129), --OR (130), --NR (131)R(132) or --CR(133)R(134)R(135),
R(129), R(130), R(131) and R(133) are, independently of each other,
--C.sub.zabH.sub.2zab--(C.su- b.1-C.sub.9)-heteroaryl which is
unsubstituted or substituted by 1-2 substituents selected from the
group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl,
amino, methylamino and dimethylamino, zab is zero or 1, R(132),
R(134) and R(135) are, independently of each other, hydrogen or
CH.sub.3, or R(103) is R(110a)-SO.sub.2 or
R(112a)R(113a)N--SO.sub.2--, R(110a) is (C.sub.1-C.sub.4)-alkyl,
CF.sub.3, (C.sub.3-C.sub.4)-alkenyl or
--C.sub.znH.sub.2zn--R(115a), zn is zero or 1, R(115a) is
(C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not substituted or
is substituted by 1-2 substituents selected from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(116a)R(117a),
R(116a) and R(117a) being hydrogen or CH.sub.3, R(112a) is
hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3,
(C.sub.3-C.sub.4)-alkenyl or --C.sub.zaH.sub.2za--R(115a), za is
zero or 1, R(115a) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which
is not substituted or is substituted by 1-2 substituents selected
from the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(116a)R(117a), R(116a) and R(117a) being hydrogen or CH.sub.3,
R(113a) is hydrogen or CH.sub.3, or R(112a) and R(113a) are
together 4 or 5 methylene groups of which one CH.sub.2 group can be
replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl, or R(103) is
R(146)X(1a)-, X(1a) is oxygen, S, NR(147), (C.dbd.O)A- or
NR(148)C=MN(%)R(149)-, M is oxygen, and A is oxygen or NR(150),
R(146) and R(147) are, independently, hydrogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.4)-alkenyl,
(CH.sub.2).sub.zbzC.sub.zdzF.sub.2zdz+1 or
C.sub.zxaH.sub.2zxa--R(151), zbz is zero or 1, zdz is 1, 2, 3, 4,
5, 6 or 7, zxa is zero or 1, R(151) is (C.sub.3-C.sub.6)-cycloalkyl
or phenyl which is not substituted or is substituted by 1-2
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy or NR(152)R(153), R(152) and R(153) being hydrogen
or CH.sub.3, R(148) is hydrogen or (C.sub.1-C.sub.4)-alkyl, R(149)
is defined as R(146), or 20 R(146) and R(147), or R(146) and
R(148), respectively, are together 4 or 5 methylene groups of which
one CH.sub.2 group can be replaced by oxygen, S, NH, N--CH.sub.3 or
N-benzyl, where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent substance, or R(103) is --SR(164),
--OR(165), --NHR(166), --NR(167)R(168), --CHR(169)R(170),
--[CR(154)R(155)OH], --C.ident.CR(156), --CR(158)=CR(157) or
--[CR(159)R(160a)].sub.zz-(CO)-[CR(161)R(162)].sub.zv-R(163),
R(164), R(165), R(166), R(167) and R(169) are identical or
different and are
--(CH.sub.2).sub.zy--(CHOH).sub.zz--(CH.sub.2).sub.zaa--(CHOH).sub.zt--R(-
171) or
--(CH.sub.2).sub.zab--O--(CH.sub.2--CH.sub.2O).sub.zac--R(172),
R(171) and R(172) are hydrogen or methyl, zu is 1 or 2, zv is zero,
1 or 2, zy, zz, zaa, zab and zac are identical or different and are
zero, 1 or 2, zt is 1, 2 or 3, R(168), R(170), R(154) and R(155)
are identical or different and are hydrogen or methyl, or R(169)
and R(170), or R(154) and R(155), respectively, together with the
carbon atom carrying them, are a (C.sub.3-C.sub.6)-cycloalkyl,
R(163) is hydrogen, (C.sub.1-C.sub.4)-alkyl- ,
(C.sub.3-C.sub.6)-cycloalkyl or --C.sub.zebH.sub.2zeb--R(173), zeb
is zero, 1 or 2, R(156), R(157) and R(173) are, independently of
each other, phenyl which is unsubstituted or is substituted by 1-2
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(174)R(175), R(174) and R(175) being hydrogen
or CH.sub.3, or R(156), R(157) and R(173) are, independently of
each other, (C.sub.1-C.sub.9)-heteroaryl which is unsubstituted or
is substituted as phenyl, R(158), R(159), R(160), R(161) and R(162)
are hydrogen or methyl, or R(103) is R(176)-NH--SO.sub.2--, R(176)
is R(177)R(178)N--(C.dbd.Y')--- , Y' is oxygen, S or N--R(179),
R(177) and R(178) are identical or different and are hydrogen,
(C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-alkenyl or
--C.sub.zfaH.sub.2zfa--R(180), zfa is zero or 1, R(180) is
(C.sub.5-C.sub.7)-cycloalkyl or phenyl which is unsubstituted or
substituted by 1-2 substituents selected from the group consisting
of F, Cl, CF.sub.3, methoxy or methyl, or R(177) and R(178) are
together 4 or 5 methylene groups of which one CH.sub.2 group can be
replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl, R(179) is
defined as R(177), R(104) is hydrogen, CF.sub.3
(C.sub.1-C.sub.8)-alkyl or --C.sub.zalH.sub.2zalR(118a), zal is
zero or 1, R(118a) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which
is not substituted or is substituted by 1-2 substituents selected
from the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(119a)R(119b), R(119a) and R(119b) being hydrogen or CH.sub.3, or
R(104) is quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl
which are linked via C or N and which are unsubstituted or
substituted by 1-2 substituents selected from the group consisting
of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino, methylamino
and dimethylamino, or R(104) is R(110a)-SO.sub.2 or
R(112a)R(113a)N--SO.sub.2--, R(110a) is (C.sub.1-C.sub.4)-alkyl or
CF.sub.3, R(112a) is hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3 or
--C.sub.zaH.sub.2za--R(115a), za is zero or 1, R(115a) is phenyl
which is not substituted or is substituted by 1-2 substituents
selected from the group consisting of F, Cl, CF.sub.3, methyl,
methoxy and NR(116a)R(117a), R(116a) and R(117a) being hydrogen or
CH.sub.3, R(113a) is hydrogen or CH.sub.3, or R(104) is
--C.ident.CR(193), R(193) is phenyl which is unsubstituted or
substituted by 1-2 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(194)R(195), R(194) and
R(195) being hydrogen or CH.sub.3, R(105) is hydrogen.
4. A process for preparing a compound I as claimed in claim 1,
wherein a) two equivalents of the compounds of the formula II are
reacted with one equivalent of the guanidine, 135where X(1) and
X(2) have the given meaning and L is a leaving group which can
readily be substituted nucleophilically, or b) a compound of the
formula Ia 136is reacted with a compound of the formula III 137with
the participation of a base, where X(1) and X(2) have the given
meaning and L is a leaving group which can readily be substituted
nucleophilically, and wherein conversion takes place, where
appropriate, into a pharmaceutically tolerated salt.
5. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment of arrhythmias.
6. A method for treating arrhythmias, wherein an effective quantity
of a compound I as claimed in claim 1 is treated with the customary
additives and administered in a suitable form for
administration.
7. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment or prophylaxis of cardiac
infarction.
8. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment or prophylaxis of angina pectoris.
9. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment or prophylaxis of ischemic conditions
of the heart.
10. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment or prophylaxis of ischemic conditions
of the peripheral and central nervous system and of stroke.
11. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment or prophylaxis of ischemic conditions
of peripheral organs and limbs.
12. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment of shock conditions.
13. The use of a compound I as claimed in claim 1 for preparing a
medicament for employment in surgical operations and organ
transplantations.
14. The use of a compound I as claimed in claim 1 for preparing a
medicament for the preservation and storage of transplants for
surgical procedures.
15. The use of a compound I as claimed in claim 1 for preparing a
medicament for the treatment of diseases in which cell
proliferation represents a primary or secondary cause, and
consequently its use as an anti-atherosclerotic agent, or as an
agent against diabetic late complications, cancerous diseases,
fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or
renal fibrosis, and against hyperplasia of the prostate.
16. The use of a compound I as claimed in claim 1 for preparing a
scientific tool for inhibiting the Na.sup.+/H.sup.+ exchanger and
for diagnosing hypertension and proliferative diseases.
17. A medicine containing an effective quantity of a compound I as
claimed in claim 1.
Description
[0001] Diacyl-substituted guanidines, a process for their
preparation, their use as medicament or diagnostic aid, and
medicament containing them.
[0002] The invention relates to diacyl-substituted guanidines of
the formula I 5
[0003] in which:
[0004] X(1) and X(2) are 6
[0005] T1 is zero, 1, 2, 3 or 4,
[0006] R(A) and R(B) are, independently,
[0007] hydrogen, F, Cl, Br, I, CN, OR(106),
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8) -cycloalkyl,
O.sub.zk(CH.sub.2).sub.zlC.sub.zmF.sub.2zm- +1, NR(107)R(108),
phenyl or benzyl,
[0008] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(109)R(110),
[0009] R(109) and R(110) being
[0010] hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalk- yl,
[0011] z1 is zero, 1, 2, 3 or 4,
[0012] zk is zero or 1,
[0013] zm is 1, 2, 3, 4, 5, 6, 7 or 8,
[0014] R(106) is
[0015] hydrogen, (C.sub.1-C.sub.8)-alkyl,
(C.sub.1-C.sub.8)-perfluoroalkyl- , (C.sub.3-C.sub.8)-alkenyl,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl or benzyl,
[0016] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and
[0017] NR(111)R(112),
[0018] R(111) and R(112) being
[0019] hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalk- yl,
[0020] R(107) and R(108) are, independently of each other, defined
as R(106),
[0021] or
[0022] R(107) and R(108) are together 4 or 5 methylene groups of
which one CH.sub.2 group can be replaced by oxygen, S, NH,
N--CH.sub.3 or N-benzyl,
[0023] or
[0024] X(1) and X(2) are 7
[0025] T2a and T2b are, independently of each other, zero, 1 or
2,
[0026] where the double bond can have the E or Z configuration;
[0027] or
[0028] X(1) and X(2) are 8
[0029] T3 is zero, 1 or 2,
[0030] U, YY and Z are, independently of each other, C or N,
[0031] where U, YY and Z can carry the following number of
substituents:
1 Bonded to a double Number of permitted U, YY or Z bond in the
ring substituents C yes 1 C no 2 N yes 0 N no 1
[0032] R(D) is hydrogen, (C.sub.1-C.sub.8)-alkyl or
(C.sub.1-C.sub.8)-perfluoroalkyl, R(U1), R(U2), R(Y1), R(Y2), R(Z1)
and R(Z2) are, independently of each other,
[0033] hydrogen, F, Cl, Br, I, CN, OR(114),
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl, O.sub.zka
(CH.sub.2).sub.zlaC.sub.zmaF.sub.- 2zma+1,
[0034] NR(115)R(116), phenyl or benzyl,
[0035] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(117)R(118),
[0036] R(117) and R(118) being hydrogen,
(C.sub.1-C.sub.4)-alkyl
[0037] or (C.sub.1-C.sub.4) perfluoroalkyl,
[0038] zka is zero or 1,
[0039] zla is zero, 1, 2, 3 or 4,
[0040] zma is 1, 2, 3, 4, 5, 6, 7 or 8,
[0041] R(114) is hydrogen, (C.sub.1-C.sub.8)-alkyl,
(C.sub.1-C.sub.8)-perfluoroalkyl, (C.sub.3-C.sub.8)-alkenyl,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl or benzyl,
[0042] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(119)R(120),
[0043] R(119) and R(120) being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl,
[0044] R(115) and R(116) are, independently of each other, defined
as R(114),
[0045] or
[0046] R(115) and R(116)
[0047] are together 4 or 5 methylene groups of which one CH.sub.2
group can be replaced by oxygen, S, NH, N--CH.sub.3 or
N-benzyl,
[0048] where, however, the constitution U is nitrogen (N), YY is
nitrogen (N) and Z is carbon (C) is excepted,
[0049] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0050] hydrogen, F, Cl, Br, I, --C.ident.N,
X.sub.zoa--(CH.sub.2).sub.zpa-- -(C.sub.zqaF.sub.2zqa+1),
R(110a)-SO.sub.zbm, R(110b)R(110c)N--CO, R(111a)-CO-- or
R(112a)R(113a)N--SO.sub.2--,
[0051] where the perfluoroalkyl group is straight-chain or
branched,
[0052] X is hydrogen, S or NR(114a),
[0053] zoa is zero or 1,
[0054] R(114a) being H or (C.sub.1-C.sub.3)-alkyl,
[0055] zbm is zero, 1 or 2,
[0056] zpa is zero, 1, 2, 3 or 4,
[0057] zqa is 1, 2, 3, 4, 5, 6, 7 or 8,
[0058] R(110a), R(110b), R(111a) and R(112a) are,
independently,
[0059] (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-alkenyl,
--C.sub.znH.sub.2zn--R(115a) or
(C.sub.1-C.sub.8)-perfluoroalkyl,
[0060] zn is zero, 1, 2, 3 or 4,
[0061] R(115a) is
[0062] (C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
[0063] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(116a)R(117a),
[0064] R(116a) and R(117a) being
[0065] hydrogen, (C.sub.1-C.sub.4)-perfluoroalkyl or
(C.sub.1-C.sub.4)-alkyl,
[0066] or
[0067] R(110b), R(111a) and R(112a) are also hydrogen,
[0068] R(110c) and R(113a) are, independently,
[0069] hydrogen, (C.sub.1-C.sub.4)-perfluoroalkyl or
(C.sub.1-C.sub.4)-alkyl,
[0070] or
[0071] R(110b) and R(110c) and also R(112a) and R(113a) are
together 4 or 5 methylene groups, of which one CH.sub.2 group can
be replaced by oxygen, sulfur, NH, N--CH.sub.3 or N-benzyl,
[0072] or
[0073] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0074] (C.sub.1-C.sub.8)-alkyl, --C.sub.zaH.sub.2zalR(118a) or
(C.sub.3-C.sub.8)-alkenyl,
[0075] zal is zero, 1, 2, 3 or 4,
[0076] R(118a) is
[0077] (C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
[0078] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy or NR(119a)R(119b),
[0079] R(119a) and R(119b) being
[0080] hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalk- yl,
[0081] or
[0082] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0083] (C.sub.1-C.sub.9)-heteroaryl which is linked via C or N and
which is unsubstituted or is substituted by 1-3 substituents from
the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino and dimethylamino,
[0084] or
[0085] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0086] --C.ident.C--R(193),
[0087] R(193) is
[0088] phenyl which is not substituted or is substituted by 1-3
substituents from the group consisting of F, Cl, CF.sub.3, methyl,
methoxy or NR(194)R(195),
[0089] R(194) and R(195) being
[0090] hydrogen or CH.sub.3,
[0091] or
[0092] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0093]
--Y-para-C.sub.6H.sub.4--(CO).sub.zh--(CHOH).sub.zi--(CH.sub.2).sub-
.zj--(CHOH).sub.zk--R(123),
[0094]
--Y-meta-C.sub.6H.sub.4--(CO).sub.zad--(CHOH).sub.zae--(CH.sub.2).s-
ub.zaf--(CHOH).sub.zag--R(124)
[0095] or
[0096]
--Y-ortho-C.sub.6H.sub.4--(CO).sub.zah--(CHOH).sub.zao--(CH.sub.2).-
sub.zap--(CHOH).sub.zak--R(125):
[0097] Y is oxygen, --S-- or --NR(122d)-,
[0098] zh, zad and zah are, independently,
[0099] zero or 1,
[0100] zi, zj, zk, zae, zaf, zag, zao, zap and zak are,
independently,
[0101] zero, 1, 2, 3 or 4,
[0102] where, however, in each case,
[0103] zh, zi and zk are not simultaneously zero,
[0104] zad, zae and zag are not simultaneously zero and
[0105] zah, zao and zak are not simultaneously zero,
[0106] R(123), R(124) R(125) and R(122d) are, independently,
hydrogen or (C.sub.1-C.sub.3)-alkyl,
[0107] or
[0108] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0109] SR(129), --OR(130), --NR(131)R(132) or
--CR(133)--R(134)R(135),
[0110] R(129), R(130), R(131) and R(133), are, independently,
[0111] --C.sub.zabH.sub.2zab--(C.sub.1-C.sub.9)-heteroaryl which is
unsubstituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino,
methylamino and dimethylamino,
[0112] zab is zero, 1 or 2,
[0113] R(132), R(134) and R(135) are, independently of each
other,
[0114] defined as R(129), or hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl,
[0115] or
[0116] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0117] --W-para-(C.sub.6H.sub.4)--R(196),
--W-meta-(C.sub.6H.sub.4)--R(197- ) or
--W-ortho-(C.sub.6H.sub.4)--R(198),
[0118] R(196), R(197) and R(198) are, independently,
[0119] (C.sub.1-C.sub.9)-heteroaryl which is linked via C or N and
which is unsubstituted or is substituted by 1 to 3 substituents
from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino, dimethylamino and benzyl,
[0120] W is oxygen, S or NR(136)-,
[0121] R(136) being hydrogen or (C.sub.1-C.sub.4)-alkyl,
[0122] or
[0123] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0124] R(146)X(1a)-,
[0125] X(1a) is oxygen, S, NR(147), (D=O)A- or
[0126] NR(148)C=MN.sup.(+)R(149)-,
[0127] M is oxygen or sulfur,
[0128] A is oxygen or NR(150), and
[0129] D is C or SO,
[0130] R(146) is (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-alkenyl,
[0131] (CH.sub.2).sub.zbzC.sub.zdzF.sub.2zdz+1 or
--C.sub.zxaH.sub.2zxa--R- (151),
[0132] zbz is zero or 1,
[0133] zdz is 1, 2, 3, 4, 5, 6 or 7,
[0134] zxa is zero, 1, 2, 3 or 4,
[0135] R(151) is
[0136] (C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
[0137] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy and NR(152)R(153),
[0138] R(152) and R(153) being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl,
[0139] R(147), R(148) and R(150) are, independently, hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-perfluoroalkyl,
[0140] R(149) is defined as R(146),
[0141] or
[0142] R(146) and R(147), or R(146) and R(148), respectively, are
together 4 or 5 methylene groups of which one CH.sub.2 group can be
replaced by oxygen, sulfur, NH, N--CH.sub.3 or N-benzyl, where A
and N.sup.(+) are bonded to the phenyl nucleus of the alkanoyl
parent substance,
[0143] or
[0144] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0145] --SR(164), --OR(165), --NHR(166), --NR(167)R(168), --CH
R(169)R(170),
[0146] --CR(154)R(155)OH, --C.ident.CR(156), --CR(158).dbd.CR(157)
or
--[(CR(159)R(160).sub.zu-(C.dbd.O)--[CR(161)R(162)].sub.zv-R(163),
[0147] R(164), R(165), R(166), R(167) and R(169) are identical or
different and are
[0148]
--(CH.sub.2).sub.zy--(CHOH).sub.zz--(CH.sub.2).sub.zaa--(CHOH).sub.-
zt--R(171) or
--(CH.sub.2).sub.zab--O--(CH.sub.2--CH.sub.2O).sub.zac--R(17-
2),
[0149] R(171) and R(172) being hydrogen or methyl,
[0150] zu is 1, 2, 3 or 4,
[0151] zv is zero, 1, 2, 3 or 4,
[0152] zy, zz, zaa, zab and zac are identical or different and
are
[0153] zero, 1, 2, 3 or 4,
[0154] zt is 1, 2, 3 or 4,
[0155] R(168), R(170), R(154) and R(155) are identical or different
and are
[0156] hydrogen or (C.sub.1-C.sub.6)-alkyl,
[0157] or
[0158] R(169) and R(170), or R(154) and R(155), respectively, are,
together with the carbon atom carrying them, a
(C.sub.3-C.sub.8)-cycloalk- yl,
[0159] R(163)
[0160] is hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl or --C.sub.zebH.sub.2zeb--R(173),
[0161] zeb is zero, 1, 2, 3 or 4,
[0162] R(156), R(157) and R(173) are, independently, phenyl which
is unsubstituted or is substituted by 1-3 substituents from the
group consisting of F, Cl, CF.sub.3, methyl, methoxy and
[0163] NR(174)R(175),
[0164] R(174) and R(175) being hydrogen or
(C.sub.1-C.sub.4)-alkyl,
[0165] or
[0166] R(156), R(157) and R(173) are, independently,
[0167] (C.sub.1-C.sub.9)-heteroaryl which is unsubstituted or is
substituted as phenyl,
[0168] R(158), R(159), R(160), R(161) and R(162) are hydrogen or
methyl,
[0169] or
[0170] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0171] R(176)-NH--SO.sub.2--,
[0172] R(176) is R(177)R(178)N--(C.dbd.Y')--,
[0173] Y' is oxygen, S or N--R(179),
[0174] R(177) and R(178) are identical or different and are
[0175] hydrogen, (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.6)-alkenyl
or --C.sub.zfaH.sub.2zfa--R(180)
[0176] zfa is zero, 1, 2, 3 or 4,
[0177] R(180) is (C.sub.5-C.sub.7)-cycloalkyl or phenyl which is
unsubstituted or substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methoxy or
(C.sub.1-C.sub.4)-alkyl,
[0178] or
[0179] R(177) and R(178)
[0180] are together 4 or 5 methylene groups of which one CH.sub.2
group can be replaced by oxygen, sulfur, NH, N--CH.sub.3 or
N-benzyl,
[0181] R(179) is defined as R(177) or is amidine,
[0182] or
[0183] R(101), R(102), R(103), R(104) and R(105) are, independently
of each other,
[0184] NR(184a)R(185), OR(184b), SR(184c) or
--C.sub.znxH.sub.2znx--R(184d- )
[0185] znx is zero, 1, 2, 3 or 4,
[0186] R(184d)
[0187] is (C.sub.3-C.sub.7)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(116k)R(117k),
[0188] R(116k) and R(117k) being hydrogen or
(C.sub.1-C.sub.4)-alkyl,
[0189] R(184a), R(184b), R(184c) and R(185) are, independently of
each other,
[0190] hydrogen, (C.sub.1-C.sub.8)-alkyl,
(C.sub.1-C.sub.8)-perfluoroalkyl or
(CH.sub.2).sub.zao--R(184g),
[0191] zao is zero, 1, 2, 3 or 4,
[0192] 184g is (C.sub.3-C.sub.7)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(184u)R(184v),
[0193] R(184u) and R(184v) being hydrogen or
(C.sub.1-C.sub.4)-alkyl,
[0194] or
[0195] R(184a) and R(185) are together 4 or 5 methylene groups of
which one CH.sub.2 group can be replaced by oxygen, sulfur, NH,
N--CH.sub.3 or N-benzyl,
[0196] and also pharmaceutically tolerated salts thereof,
[0197] where, however, the following compounds are excepted: 9
[0198] and
[0199] where, additionally, the compounds are excepted in which the
radicals R(1) to R(5) are combined as follows:
2 R(101) R(102) R(103) R(104) R(105) R(105) R(104) R(103) R(102)
R(101) [X(1)] [X(1)] [X(1)] [X(1)] [X(1)] [X(2)] [X(2)] [X(2)]
[X(2)] [X(2)] H Cl Cl H H H H Cl Cl H H H NH.sub.2 H H H H NH.sub.2
H H H H H H H H H H H H Cl H H H H H H H H Cl H H Cl H H H H Cl H H
H H CH.sub.3 H H H H CH.sub.3 H H H H NH.sub.2 H H H H H H H H H Cl
H H H H H H H H H CH.sub.3 H H H H H H H
[0200] Compounds of the formula I are preferred in which X(1) is
the same as X(2) and in which the other substituents are as defined
above.
[0201] Compounds of the formula I are particularly preferred in
which:
[0202] X(1) and X(2) are 10
[0203] T1 is zero or 2,
[0204] R(A) and R(B) are, independently,
[0205] hydrogen, F, Cl, CN, OR(106), (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.6)-cycloalkyl, CF.sub.3 or NR(107)R(108),
[0206] R(106)
[0207] is hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3, phenyl or
benzyl,
[0208] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(111)R(112),
[0209] R(111) and R(112) being hydrogen, CH.sub.3 or CF.sub.3,
[0210] R(107) and R(108) are, independently of each other, defined
as R(106),
[0211] or
[0212] R(107) and R(108) are together 4 or 5 methylene groups of
which one CH.sub.2 group can be replaced by oxygen, S, NH,
N--CH.sub.3 or N-benzyl,
[0213] or
[0214] X(1) is 11
[0215] where the double bond can be in the E or Z
configuration,
[0216] or
[0217] X(1) is 12
[0218] U, YY and Z are, independently of each other, C or N;
[0219] with, however, the restriction that only one of the
positions U, YY and Z can be nitrogen;
[0220] where
[0221] U, YY and Z can carry the following number of
substituents:
3 U, YY Bonded to a double Number of permit- or Z bond in the ring
ted substituents C yes 1 C no 2 N yes 0 N no 1
[0222] R(D) is hydrogen,
[0223] R(U1), R(U2), R(Y1), R(Y2), R(Z1) and R(Z2) are,
independently of each other,
[0224] hydrogen, F, Cl, CN, OR(114), CH.sub.3, CF.sub.3 or
NR(115)R(116)
[0225] R(114)
[0226] is hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3, phenyl or
benzyl,
[0227] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(119)R(120),
[0228] R(119) and R(120) being hydrogen, CH.sub.3 or CF.sub.3,
[0229] R(115) and R(116) are, independently of each other, defined
as R(114),
[0230] or
[0231] R(115) and R(116)
[0232] are together 4 or 5 methylene groups of which one CH.sub.2
group can be replaced by oxygen, S, NH, N--CH.sub.3 or
N-benzyl,
[0233] R(101)
[0234] is hydrogen, F, Cl, CH.sub.3, OH, NH.sub.2 or CF.sub.3,
[0235] R(102)
[0236] is hydrogen, F, Cl, Br, --C.ident.N,
--C.sub.zqaF.sub.2zqaCF.sub.3, R(110a)-SO.sub.2,
R(110b)R(110c)N--CO--, R(111a)-CO-- or
R(112a)R(113a)N--SO.sub.2--,
[0237] R(110a), R(110b), R(111a) and R(112a) are,
independently,
[0238] (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-alkenyl,
--C.sub.znH.sub.2zn--R(115a)
[0239] or CF.sub.3,
[0240] zn is zero or 1,
[0241] zqa is zero, 1, 2, 3, 4 or 5,
[0242] R(115a)
[0243] is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(116a)R(117a),
[0244] R(116a) and R(117a) being hydrogen or methyl,
[0245] or
[0246] R(110b), R(111a) and R(112a) are also hydrogen,
[0247] R(110c) and R(113a) are, independently, hydrogen or
methyl,
[0248] R(103)
[0249] is
--Y-para-C.sub.6H.sub.4--(CO).sub.zh--(CHOH).sub.zi--(CH.sub.2).-
sub.zj--(CHOH).sub.zk--R(123),
[0250]
--Y-meta-C.sub.6H.sub.4--(CO).sub.zad--(CHOH).sub.zae--(CH.sub.2).s-
ub.zaf--(CHOH).sub.zag--R(124) or
[0251]
--Y-ortho-C.sub.6H.sub.4--(CO).sub.zah--(CHOH).sub.zao--(CH.sub.2).-
sub.zap--(CHOH).sub.zak--R(125),
[0252] Y is oxygen, S or --NR(83),
[0253] R(123), R(124), R(125) and R(83) are, independently,
hydrogen or methyl,
[0254] zh, zad and zah are, independently,
[0255] zero or 1,
[0256] zi, zk, zae, zag, zao and zak are, independently,
[0257] zero, 1, 2 or 3,
[0258] zj, zaf and zap are, independently,
[0259] zero or 1,
[0260] where, however, in each case, zh, zi and zk are not
simultaneously zero,
[0261] zad, zae and zag are not simultaneously zero and
[0262] zah, zao and zak are not simultaneously zero,
[0263] or
[0264] R(103) is hydrogen, F, Cl, Br, CN, (C.sub.1-C.sub.8)-alkyl,
CF.sub.3, (C.sub.3-C.sub.8)-alkenyl or
--C.sub.zalH.sub.2zalR(118a),
[0265] zal is zero, 1 or 2,
[0266] R(118a) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is
not substituted or is substituted by 1-2 substituents selected from
the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
[0267] NR(119a)R(119b),
[0268] R(119a) and R(119b) being hydrogen or CH.sub.3,
[0269] or
[0270] R(103)
[0271] is (C.sub.1-C.sub.9)-heteroaryl which is linked via C or N
and which is unsubstituted or is substituted by 1-2 substituents
from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino and dimethylamino,
[0272] or
[0273] R(103)
[0274] is --W-para-(C.sub.6H.sub.4)--R(196),
--W-meta-(C.sub.6H.sub.4)--R(- 197) or
--W-ortho-(C.sub.6H.sub.4)--R(198),
[0275] R(197) and R(198) are, independently, pyrrolyl, imidazolyl,
pyrazolyl or pyridyl which in each case is unsubstituted or
substituted by 1 to 2 radicals selected from the group consisting
of F, Cl, CF.sub.3, CH.sub.3, methoxy, dimethylamino and
benzyl,
[0276] W is oxygen, --S-- or NR(136)-,
[0277] R(136) being hydrogen or methyl,
[0278] or
[0279] R(103) is
[0280] --SR(129), --OR(130), --NR(131)R(132) or
--CR(133)R(134)R(135),
[0281] R(129), R(130), R(131) and R(133) are, independently of each
other,
[0282] --C.sub.zabH.sub.2zab--(C.sub.1-C.sub.9)-heteroaryl which is
unsubstituted or substituted by 1-2 substituents selected from the
group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl,
amino, methylamino and dimethylamino,
[0283] zab is zero or 1,
[0284] R(132), R(134) and R(135) are, independently of each
other,
[0285] hydrogen or CH.sub.3,
[0286] or
[0287] R(103) is
[0288] R(110a)-SO.sub.2 or R(112a)R(113a)N--SO.sub.2--,
[0289] R(110a) is
[0290] (C.sub.1-C.sub.4)-alkyl, CF.sub.3, (C.sub.3-C.sub.4)-alkenyl
or --C.sub.znH.sub.2zn--R(115a),
[0291] zn is zero or 1,
[0292] R(115a) is
[0293] (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents selected from the
group consisting of F, Cl, CF.sub.3, methyl, methoxy and
[0294] NR(116a)R(117a),
[0295] R(116a) and R(117a) being hydrogen or CH.sub.3,
[0296] R(112a) is
[0297] hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3,
(C.sub.3-C.sub.4)-alkenyl or --C.sub.zaH.sub.2za--R(115a),
[0298] za is zero or 1,
[0299] R(115a) is
[0300] (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents selected from the
group consisting of F, Cl, CF.sub.3, methyl, methoxy and
[0301] NR(116a)R(117a),
[0302] R(116a) and R(117a) being hydrogen or CH.sub.3,
[0303] R(113a) is
[0304] hydrogen or CH.sub.3,
[0305] or
[0306] R(112a) and R(113a) are together 4 or 5 methylene groups of
which one CH.sub.2 group can be replaced by oxygen, S, NH,
N--CH.sub.3 or N-benzyl,
[0307] or
[0308] R(103) is
[0309] R(146)X(1a)-,
[0310] X(1a) is oxygen, S, NR(147), (C.dbd.O)A- or
[0311] NR(148)C=MN(*)R(149)-,
[0312] M is oxygen, and
[0313] A is oxygen or NR(150),
[0314] R(146) and R(147) are, independently,
[0315] hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.4)-alkenyl,
[0316] (CH.sub.2).sub.zbzC.sub.zdzF.sub.2zdz+1 or
C.sub.zxaH.sub.2zxa--R(1- 51)
[0317] zbz is zero or 1,
[0318] zdz is 1, 2, 3, 4, 5, 6 or 7,
[0319] zxa is zero or 1,
[0320] R(151)
[0321] is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents selected from the
group consisting of F, Cl, CF.sub.3, methyl, methoxy or
NR(152)R(153),
[0322] R(152) and R(153) being hydrogen or CH.sub.3,
[0323] R(148)
[0324] is hydrogen or (C.sub.1-C.sub.4)-alkyl,
[0325] R(149) is defined as R(146),
[0326] or
[0327] R(146) and R(147), or R(146) and R(148), respectively, are
together 4 or 5 methylene groups of which one CH.sub.2 group can be
replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl,
[0328] where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent substance,
[0329] or
[0330] R(103)
[0331] is --SR(164), --OR(165), --NHR(166), --NR(167)R(168),
--CHR(169)R(170), --[CR(154)R(155)OH], --C.ident.CR(156),
--CR(158)=CR(157) or
[0332]
--[CR(159)R(160a)].sub.zu-(CO)--[CR(161)R(162)].sub.zv-R(163),
[0333] R(164), R(165), R(166), R(167) and R(169) are identical or
different and are
[0334]
--(CH.sub.2).sub.zy--(CHOH).sub.zz--(CH.sub.2).sub.zaa--(CHOH).sub.-
zt--R(171) or
[0335]
--(CH.sub.2).sub.zab--O--(CH.sub.2--CH.sub.2O).sub.zac--R(172),
[0336] R(171) and R(172) are hydrogen or methyl,
[0337] zu is 1 or 2,
[0338] zv is zero, 1 or 2,
[0339] zy, zz, zaa, zab and zac are identical or different and
are
[0340] zero, 1 or 2,
[0341] zt is 1, 2 or 3,
[0342] R(168), R(170), R(154) and R(155) are identical or different
and are
[0343] hydrogen or methyl,
[0344] or
[0345] R(169) and R(170), or R(154) and R(155), respectively,
together with the carbon atom carrying them, are a
(C.sub.3-C.sub.6)-cycloalkyl,
[0346] R(163) is
[0347] hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl or
[0348] C.sub.zebH.sub.2zeb--R(173)
[0349] zeb is zero, 1 or 2,
[0350] R(156), R(157) and R(173) are, independently of each
other,
[0351] phenyl which is unsubstituted or is substituted by 1-2
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and
[0352] NR(174)R(175),
[0353] R(174) and R(175) being hydrogen or CH.sub.3,
[0354] or
[0355] R(156), R(157) and R(173) are, independently of each
other,
[0356] (C.sub.1-C.sub.9)-heteroaryl which is unsubstituted or is
substituted as phenyl,
[0357] R(15B), R(159), R(160), R(161) and R(162) are hydrogen or
methyl,
[0358] or
[0359] R(103)
[0360] is R(176)-NH--SO.sub.2--,
[0361] R(176)
[0362] is R(177)R(178)N--(C.dbd.Y')--,
[0363] Y, is oxygen, S or N--R(179),
[0364] R(177) and R(178) are identical or different and are
hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-alkenyl or
--C.sub.zfaH.sub.2zfa--R(180),
[0365] zfa is zero or 1,
[0366] R(180)
[0367] is (C.sub.1-C.sub.7)-cycloalkyl or phenyl which is
unsubstituted or substituted by 1-2 substituents selected from the
group consisting of F, Cl, CF.sub.3, methoxy or methyl,
[0368] or
[0369] R(177) and R(178) are together 4 or 5 methylene groups of
which one CH.sub.2 group can be replaced by oxygen, S, NH,
N--CH.sub.3 or N-benzyl,
[0370] R(179) is defined as R(177),
[0371] R(104)
[0372] is hydrogen, CF.sub.3 (C.sub.1-C.sub.8)-alkyl or
--C.sub.zalH.sub.2zalR(118a)
[0373] zal is zero or 1,
[0374] R(118a)
[0375] is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents selected from the
group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(119a)R(119b),
[0376] R(119a) and R(119b) being hydrogen or CH.sub.3,
[0377] or
[0378] R(104)
[0379] is quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl
which are linked via C or N and which are unsubstituted or
substituted by 1-2 substituents selected from the group consisting
of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino, methylamino
and dimethylamino,
[0380] or
[0381] R(104)
[0382] is R(110a)-SO.sub.2 or R(112a)R(113a)N--SO.sub.2--,
[0383] R(110a)
[0384] is (C.sub.1-C.sub.4)-alkyl or CF.sub.3,
[0385] R(112a)
[0386] is hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3 or
C.sub.zaH.sub.2za--R(115a),
[0387] za is zero or 1,
[0388] R(115a)
[0389] is phenyl which is not substituted or is substituted by 1-2
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(116a)R(117a),
[0390] R(116a) and R(117a) being hydrogen or CH.sub.3,
[0391] R(113a)
[0392] is hydrogen or CH.sub.3,
[0393] or
[0394] R(104)
[0395] is --C.ident.CR(193),
[0396] R(193)
[0397] is phenyl which is unsubstituted or substituted by 1-2
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(194)R(195),
[0398] R(194) and R(195) being hydrogen or CH.sub.3,
[0399] R(105)
[0400] is hydrogen,
[0401] and also the pharmaceutically tolerated salts thereof.
[0402] Dibenzoylguanidines of the formula Ia
[0403] are likewise preferred
[0404] in which:
[0405] R(1), R(5), R(6) and R(10) are, independently of each other,
13
[0406] hydrogen, F, Cl, (C.sub.1-C.sub.3)-alkyl, --OR(11),
C.sub.rF.sub.2r+1 or
[0407] --NR(11)R(12),
[0408] R(11) and R(12) are, independently, hydrogen or
(C.sub.1-C.sub.3)-alkyl,
[0409] r is from 1 to 4,
[0410] R(2), R(4), R(7) and R(9) are, independently of each
other,
[0411] hydrogen, F, Cl, Br, I, --C.ident.N,
X.sub.o--(CH.sub.2).sub.p--(CF- .sub.2).sub.q--CF.sub.3,
R(13)-SO.sub.m, R(14)R(15)N--CO--, R(16)-CO-- or
[0412] R(17)R(18)N--SO.sub.2--,
[0413] X is oxygen, S or NR(19),
[0414] m is zero, 1 or 2,
[0415] o is zero or 1,
[0416] p is zero, 1 or 2,
[0417] q is zero, 1, 2, 3, 4, 5 or 6,
[0418] R(13), R(14), R(16) and R(17) are, independently,
[0419] (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.6)-alkenyl,
--C.sub.nH.sub.2n--R(20) or CF.sub.3,
[0420] n is zero, 1, 2, 3 or 4,
[0421] R(19) is hydrogen or (C.sub.1-C.sub.3)-alkyl,
[0422] R(20) is (C.sub.3-C.sub.7)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(21)R(22) with
R(21) and R(22) being H or (C.sub.1-C.sub.4)-alkyl,
[0423] where R(14), R(16) and R(17) also have the meaning of H,
[0424] R(15) and R(18) are, independently, hydrogen or
(C.sub.1-C.sub.4)-alkyl,
[0425] where R(14) and R(15) and also R(17) and R(18) can together
be 4 or 5 methylene groups of which one CH.sub.2 group can be
replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl,
[0426] or
[0427] R(2), R(4), R(7) and R(9) are, independently of each
other,
[0428] (C.sub.1-C.sub.8)-alkyl or --C.sub.alH.sub.2alR(84),
[0429] al is zero, 1 or 2,
[0430] R(84) is (C.sub.3-C.sub.8)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(85)R(86), with
R(85) and R(86) being hydrogen or CH.sub.3; or
[0431] R(2), R(4), R(7) and R(9) are, independently of each
other,
[0432] (C.sub.1-C.sub.9)-heteroaryl which is linked via C or N and
which is unsubstituted or is substituted by 1-3 substituents from
the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino or dimethylamino; or
[0433] R(2), R(4), R(7) and R(9) are, independently of each
other,
[0434] --C.ident.CR(93),
[0435] R(93) is phenyl which is unsubstituted or is substituted by
1-3 substituents from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy or NR(94)R(95), with R(94) and R(95) being hydrogen
or CH.sub.3;
[0436] R(3) and R(8) are, independently of each other, defined as
R(2), or are 14
[0437] Y is oxygen, --S-- or --NR(83)-,
[0438] h, ad and ah are, independently, zero or 1,
[0439] i, j, k, ae, af, ag, ao, ap and ak are, independently,
[0440] zero, 1, 2, 3 or 4,
[0441] where, however, in each case, h, i and k are not
simultaneously zero,
[0442] ad, ae and ag are not simultaneously zero and
[0443] ah, ao and ak are not simultaneously zero,
[0444] R(23), R(24), R(25) and R(83) are, independently, hydrogen
or (C.sub.1-C.sub.3)-alkyl,
[0445] or
[0446] R(3) and R(8) are, independently of each other, hydrogen, F,
Cl, Br, I, CN, (C.sub.1-C.sub.8)-alkyl,
(C.sub.1-C.sub.8)-perfluoroalkyl, (C.sub.3-C.sub.8)-alkenyl or
--C.sub.gH.sub.2gR(26),
[0447] g is zero, 1, 2, 3 or 4,
[0448] R(26) is (C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
[0449] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy or
[0450] NR(27)R(28), with R(27) and R(28) being hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-perfluoroalkyl; or
[0451] R(3) and R(8) are, independently of each other,
[0452] SR(29), --OR(30), --NR(31)R(32) or --CR(33)R(34)R(35);
[0453] R(29), R(30), R(31) and R(33) are, independently,
[0454] --C.sub.aH.sub.2a--(C.sub.1-C.sub.9)-heteroaryl which is
unsubstituted or substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino,
methylamino or dimethylamino,
[0455] a is zero, 1 or 2,
[0456] R(32), R(34) and R(35) are, independently of each other,
[0457] defined as R(29), or hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl; or
[0458] R(3) and R(8) are, independently of each other, 15
[0459] R(96), R(97) and R(98) are, independently,
[0460] (C.sub.1-C.sub.9)-heteroaryl which is linked via C or N and
which is unsubstituted or is substituted by 1 to 3 substituents
from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino, dimethylamino or benzyl,
[0461] W is oxygen, S or NR(99)-,
[0462] R(99) is hydrogen or (C.sub.1-C.sub.4)-alkyl,
[0463] or
[0464] R(3) and R(8) are, independently of each other,
[0465] R(72)-SO.sub.m or R(73)R(74)N--SO.sub.2--,
[0466] m is 1 or 2,
[0467] R(72) is (C.sub.1-C.sub.9)-alkyl,
(C.sub.1-C.sub.8)-perfluoroalkyl,
[0468] (C.sub.3-C.sub.8)-alkenyl or --C.sub.sH.sub.2s--R(75),
[0469] s is zero, 1, 2, 3 or 4,
[0470] R(75) is (C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
[0471] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy or NR(76)R(77), with R(76) and R(77)
being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl;
[0472] R(73) is hydrogen, (C.sub.1-C.sub.8)-alkyl,
(C.sub.1-C.sub.8)-perfl- uoroalkyl, (C.sub.3-C.sub.8)-alkenyl
or
[0473] --C.sub.wH.sub.2w--R(78),
[0474] w is zero, 1, 2, 3 or 4,
[0475] R(78) is (C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
[0476] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy or NR(79)R(80), with R(79) and R(80)
being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl,
[0477] R(74) is hydrogen, (C.sub.3-C.sub.4)-alkyl or
(C.sub.3-C.sub.4)-perfluoroalkyl,
[0478] where R(73) and R(74) can together be 4 or 5 methylene
groups of which one CH.sub.2 group can be replaced by oxygen, S,
NH, N--CH.sub.3 or N-benzyl; or
[0479] R(3) and R(8) are, independently of each other,
[0480] R(39)X--,
[0481] X is oxygen, SI NR(40), (D=O)A- or
[0482] NR(41)C=MN(*)R(42)-, with
[0483] M is oxygen or S,
[0484] A is oxygen or NR(43), and
[0485] D is C or SO,
[0486] R(39) is (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-alkenyl,
[0487] (CH.sub.2).sub.bC.sub.dF.sub.2d+1 or
--C.sub.xH.sub.2x--R(44),
[0488] b is zero or 1,
[0489] d is 1, 2, 3, 4, 5, 6 or 7,
[0490] x is zero, 1, 2, 3 or 4,
[0491] R(44) is (C.sub.3-C.sub.8)-cycloalkyl, phenyl, biphenylyl or
naphthyl,
[0492] where the aromatic radicals are not substituted or are
substituted by 1-3 substituents from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy or NR(45)R(46); with R(45) and R(46)
being hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalkyl;
[0493] R(40), R(41) and R(43) are, independently,
[0494] hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-perfluoroalk- yl,
[0495] R(42) is defined as R(39), where
[0496] R(39) and R(40), or R(39) and R(41), respectively, can
together be 4 or 5 methylene groups of which one CH.sub.2 group can
be replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl, where
[0497] A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent substance; or
[0498] R(3) and R(8) are, independently of each other,
[0499] --SR(47), --OR(48), --NHR(49), --NR(50)R(51),
--CHR(52)R(53), 16
[0500] R(47), R(48), R(49), R(50) and R(52) are identical or
different and are
[0501]
--(CH.sub.2).sub.y--(CHOH).sub.z--(CH.sub.2).sub.aa--(CH.sub.2OH).s-
ub.t--R(64) or
(CH.sub.2).sub.ab--O--(CH.sub.2--CH.sub.2O).sub.ac--R(65),
[0502] R(64) and R(65) are hydrogen or methyl,
[0503] u=1, 2, 3 or 4,
[0504] v=zero, 1, 2, 3 or 4,
[0505] y, z and aa are identical or different and are zero, 1, 2, 3
or 4,
[0506] t=1, 2, 3 or 4,
[0507] R(51), R(53), R(54) and R(55) are identical or different
and
[0508] are hydrogen or (C.sub.1-C.sub.6)-alkyl, or
[0509] R(52) and R(53), or R(54) and R(55), respectively, are,
together with the carbon atom carrying them, a
(C.sub.3-C.sub.8)-cycloalkyl;
[0510] R(63) is hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-cyclo- alkyl or --C.sub.eH.sub.2e--R(81),
[0511] e is zero, 1, 2, 3 or 4,
[0512] R(56), R(57) and R(81) are, independently, phenyl which is
unsubstituted or is substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(82)R(66) with
R(82) and R(66) being H or (C.sub.1-C.sub.4)-alkyl, or
[0513] R(56), R(57) and R(81) are, independently,
[0514] (C.sub.1-C.sub.9)-heteroaryl which is unsubstituted or is
substituted as phenyl;
[0515] R(58), R(59), R(60), R(61) and R(62) are hydrogen or methyl,
or
[0516] R(3) and R(8) are, independently of each other,
[0517] R(67)-NH--SO.sub.2--,
[0518] R(67) is R(68)R(69)N--(C.ident.Y')--,
[0519] Y' is oxygen, S or N--R(70),
[0520] R(68) and R(69) are identical or different and
[0521] are hydrogen, (C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.6)-alkenyl or --C.sub.fH.sub.2f--R(71),
[0522] f is zero, 1, 2, 3 or 4,
[0523] R(71) is (C.sub.5-C.sub.7)-cycloalkyl or phenyl which is
unsubstituted or substituted by 1-3 substituents from the group
consisting of F, Cl, CF.sub.3, methoxy or (C.sub.1-C.sub.4)-alkyl,
or
[0524] R(68) and R(69) together form 4 or 5 methylene groups of
which one CH.sub.2 group can be replaced by oxygen, S, NH,
N--CH.sub.3 or N-benzyl, where R(70) is defined as R(68) or is
amidine;
[0525] and also the pharmaceutically tolerated salts thereof,
[0526] where, however, compounds are excepted in which the radicals
R(1) to R(10) are combined as follows:
4 R(1) R(2) R(3) R(4) R(5) R(6) R(7) R(8) R(9) R(10) H Cl Cl H H H
H Cl Cl H H H NH.sub.2 H H H H NH.sub.2 H H H H H H H H H H H H Cl
H H H H H H H H Cl H H Cl H H H H Cl H H H H CH.sub.3 H H H H
CH.sub.3 H H H H NH.sub.2 H H H H H H H H H Cl H H H H H H H H H
CH.sub.3 H H H H H H H
[0527] Compounds of the formula Ia are likewise particularly
preferred in which:
[0528] R(5)=R(6)=hydrogen,
[0529] the remaining residues are defined as above, and
[0530] R(1)=R(10)
[0531] R(2)=R(9)
[0532] R(3)=R(8)
[0533] R(4)=R(7).
[0534] Compounds of the formula Ia are likewise very particularly
preferred in which:
[0535] R(1)=R(10)
[0536] =hydrogen, F, Cl, CH.sub.3, OH, NH.sub.2 and CF.sub.3,
[0537] R(2)=R(9)
[0538] =hydrogen, F, Cl, Br, --C.ident.N,
--C.sub.qF.sub.2qCF.sub.3, R(13)-SO.sub.2,
[0539] R(14)R(15)N--CO--, R(16)-CO-- or
R(17)R(18)N--SO.sub.2--,
[0540] R(13), R(14), R(16) and R(17) are, independently,
[0541] (C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.4)-alkenyl,
--C.sub.nH.sub.2n--R(20) or CF.sub.3,
[0542] n is zero or 1,
[0543] q is zero, 1, 2, 3, 4 or 5,
[0544] R(20) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(21)R(22),
[0545] R(21) and R(22) being hydrogen or methyl,
[0546] where R(14), R(16) and R(17) also have the meaning of
hydrogen,
[0547] R(15) and R(18) are, independently, hydrogen or methyl,
[0548] R(3) and R(8) are, independently of each other, 17
[0549] Y is oxygen, S or --NR(83),
[0550] R(23), R(24), R(25) and R(83) are, independently,
[0551] hydrogen or methyl,
[0552] h, ad and ah are, independently,
[0553] zero or 1,
[0554] i, k, ae, ag, ao and ak are, independently,
[0555] zero, 1, 2 or 3,
[0556] j, af and ap are, independently,
[0557] zero or 1,
[0558] where, however, in each case, h, i and k are not
simultaneously zero,
[0559] ad, ae and ag are not simultaneously zero and
[0560] ah, ao and ak are not simultaneously zero,
[0561] or
[0562] R(3)=R(8)
[0563] =hydrogen, F, Cl, Br, CN, (C.sub.1-C.sub.8)-alkyl, CF.sub.3,
(C.sub.3-C.sub.8)-alkenyl or --C.sub.gH.sub.2gR(26)
[0564] g is zero, 1 or 2,
[0565] R(26) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(27)R(28), with
R(27) and R(28) being H or CH.sub.3;
[0566] or
[0567] R(3)=R(8)
[0568] =(C.sub.1-C.sub.9)-heteroaryl, which is linked via C or N
and which is unsubstituted or is substituted by 1-2 substituents
from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino or dimethylamino;
[0569] or
[0570] R(3) and R(8) are, independently of each other, 18
[0571] R(96), R(97) and R(98) are, independently, pyrrolyl,
imidazolyl, pyrazolyl or pyridyl which in each case is
unsubstituted or substituted by 1 to 2 radicals from the group
consisting of
[0572] F, Cl, CF.sub.3, CH.sub.3, methoxy, dimethylamino or
benzyl,
[0573] W is oxygen, --S-- or NR(99)-,
[0574] R(99) being hydrogen or methyl,
[0575] or
[0576] R(3)=R(8)
[0577] =--SR(29), --OR(30), --NR(31) R(32) or
[0578] --CR(33)R(34)R(35),
[0579] R(29), R(30), R(31) and R(33) are, independently of each
other,
[0580] --C.sub.aH.sub.2a--(C.sub.1-C.sub.9)-heteroaryl which is
unsubstituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino,
methylamino or dimethylamino,
[0581] a is zero or 1,
[0582] R(32), R(34) and R(35) are, independently of each other,
[0583] hydrogen or CH.sub.3;
[0584] or
[0585] R(3)=R(8)
[0586] =R(72)-SO.sub.2 or R(73)R(74)N--SO.sub.2--,
[0587] R(72) is (C.sub.1-C.sub.4)-alkyl, CF.sub.3,
(C.sub.3-C.sub.4)-alken- yl or --C.sub.sH.sub.2s--R(75),
[0588] s is zero or 1,
[0589] R(75) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(76)R(77);
with
[0590] R(76) and R(77) being hydrogen or CH.sub.3,
[0591] R(73) is hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3,
(C.sub.3-C.sub.4)-alkenyl or
[0592] --C.sub.wH.sub.2w--R(78),
[0593] w is zero or 1,
[0594] R(78) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or
[0595] NR(79)R(80), with R(79) and
[0596] R(80) being hydrogen or CH.sub.3,
[0597] R(74) is hydrogen or CH.sub.3,
[0598] where R(73) and R(74) can together be 4 or 5 methylene
groups of which one CH.sub.2 group can be replaced by oxygen, S,
NH, N--CH.sub.3 or N-benzyl;
[0599] or
[0600] R(3)=R(8)
[0601] =R(39)X--,
[0602] X is oxygen, S, NR(40), (C.dbd.O)A-,
NR(41)C=MN(*)R--(42)-,
[0603] M is oxygen, and
[0604] A is oxygen or NR(43),
[0605] R(39) is (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.4)-alkenyl,
[0606] (CH.sub.2).sub.bC.sub.dF.sub.2d+1 or
--C.sub.xH.sub.2x--R(44),
[0607] b is zero or 1,
[0608] d is 1-7,
[0609] x is zero or 1,
[0610] R(44) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or
[0611] NR(45)R(46), with R(45) and
[0612] R(46) being hydrogen or CH.sub.3,
[0613] R(41) is hydrogen or (C.sub.1-C.sub.4)-alkyl,
[0614] R(42) is defined as R(39), where
[0615] R(39) and R(40), or R(39) and R(41), respectively, can
together be 4 or 5 methylene groups of which one CH.sub.2 group can
be replaced by oxygen, S, NH, N--CH.sub.3 or N-benzyl,
[0616] where A and N(*) are bonded to the phenyl nucleus of the
benzoylguanidine parent substance;
[0617] or
[0618] R(3) and R(8) are
[0619] --SR(47), --OR(48), --NHR(49), --NR(50)R(51),
--CHR(52)R(53), 19
[0620] R(47), R(48), R(49), R(50) and R(52) are identical or
different and are
[0621]
--(CH.sub.2).sub.y--(CHOH).sub.x--(CH.sub.2).sub.aa--(CH.sub.2OH).s-
ub.t--R(64) or
[0622]
--(CH.sub.2).sub.ab--O--(CH.sub.2--CH.sub.2O).sub.ac--R(65),
[0623] with R(64) and R(65) being hydrogen or methyl,
[0624] u is 1 or 2,
[0625] v is zero, 1 or 2,
[0626] y, z, aa, ab and ac are identical or different and are zero,
1 or 2,
[0627] t is 1, 2 or 3,
[0628] R(51), R(53), R(54) and R(55) are identical or different and
are
[0629] hydrogen or methyl, or
[0630] R(52) and R(53), or R(54) and R(55), respectively, are,
together with the carbon atom carrying them, a
(C.sub.3-C.sub.6)-cycloalkyl,
[0631] R(63) is hydrogen, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.6)-cyclo- alkyl or --C.sub.eH.sub.2e--R(81),
[0632] e is zero, 1 or 2,
[0633] is R(56), R(57) and R(81) are, independently of each
other,
[0634] phenyl which is unsubstituted or is substituted by 1-2
substituents from the group consisting of F, Cl, CF.sub.3, methyl,
methoxy or NR(65)R(66) with R(65) and R(66) being hydrogen or
CH.sub.3; or
[0635] R(56), R(57) and R(81) are, independently of each other,
[0636] (C.sub.1-C.sub.9)-heteroaryl which is unsubstituted or is
substituted as phenyl;
[0637] R(58), R(59), R(60), R(61) and R(62) are hydrogen or
methyl,
[0638] or
[0639] R(3) and R(8) are
[0640] R(67)-NH--SO.sub.2--,
[0641] R(67) is R(68)R(69)N--(C.ident.Y')--,
[0642] Y' is oxygen, S or N--R(70),
[0643] R(68) and R(69) are identical or different and are
[0644] hydrogen, (C.sub.1-C.sub.4)-alkyl, (C.sub.3-C.sub.4)-alkenyl
or --C.sub.fH.sub.2f--R(71),
[0645] f is zero or 1,
[0646] R(71) is (C.sub.5-C.sub.7)-cycloalkyl or phenyl which is
unsubstituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methoxy or methyl, or
[0647] R(68) and R(69) together form 4 or 5 methylene groups of
which one CH.sub.2 group can be replaced by oxygen, S, NH,
N--CH.sub.3 or N-benzyl,
[0648] R(70) is defined as R(68);
[0649] R(4)=R(7)
[0650] =(C.sub.1-C.sub.8)-alkyl, --C.sub.alH.sub.2alR(84) or
CF.sub.3,
[0651] al is zero or 1,
[0652] R(84) is (C.sub.3-C.sub.6)-cycloalkyl or phenyl which is not
substituted or is substituted by 1-2 substituents from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy or NR(85)R(86), with
R(85) and R(86) being hydrogen or CH.sub.3,
[0653] or
[0654] R(4)=R(7)
[0655] =quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl
which are linked via C or N and which are unsubstituted or are
substituted by 1-2 substituents from the group consisting of F, Cl,
CF.sub.3, CH.sub.3, methoxy, hydroxyl, amino, methylamino or
dimethylamino,
[0656] or
[0657] R(4)=R(7)
[0658] =R(87)-SO.sub.am or R(88)R(89)N--SO.sub.2--,
[0659] am is 2,
[0660] R(87) is (C.sub.1-C.sub.4)-alkyl or CF.sub.3.
[0661] R(88) is hydrogen, (C.sub.1-C.sub.4)-alkyl, CF.sub.3 or
--C.sub.anH.sub.2an--
[0662] R(90),
[0663] an is zero or 1,
[0664] R(90) is phenyl which is not substituted or is substituted
by 1-2 substituents from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy or NR(90)R(91), with
[0665] R(90) and R(91) being hydrogen or CH.sub.3,
[0666] R(89) is hydrogen or CH.sub.3,
[0667] or
[0668] R(4)=R(7)
[0669] =--C.ident.CR(93),
[0670] R(93) is phenyl which is unsubstituted or is substituted by
1-2 substituents from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy or NR(94)R(95) with
[0671] R(94) and R(95) being hydrogen or CH.sub.3;
[0672] R(5)=R(6)
[0673] =hydrogen,
[0674] and also the pharmaceutically acceptable salts thereof.
[0675] (C.sub.1-C.sub.9)-Heteroaryl is, in particular, understood
to mean radicals which are derived from phenyl or naphthyl and in
which one or more CH groups are replaced by N, and/or in which at
least two adjacent CH groups are replaced by S, NH or O (with the
formation of a five-membered aromatic ring). In addition, one or
both atoms of the condensation site of bicyclic radicals can also
be N atoms (as in indolizinyl).
[0676] Heteroaryl is considered, in particular, to be furanyl,
thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl,
isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and
cinnolinyl.
[0677] Should one of the substituents R(1) to R(198) contain one or
more centers of asymmetry, these centers can then be in either the
S or the R configuration. The compounds can be present as optical
isomers, as diastereomers, as racemates, or as mixtures
thereof.
[0678] The designated alkyl and perfluoroalkyl radicals can be
present either in the straight-chain or the branched form.
[0679] The invention relates furthermore to a process for preparing
the compounds I, wherein either two equivalents of the compounds of
the formula II are reacted with one equivalent of guanidine 20
[0680] where X(1) and X(2) have the given meaning and L is a
leaving group which can readily be substituted nucleophilically, or
a compound of the formula IIa 21
[0681] is reacted with a compound of the formula III 22
[0682] with the participation of a base, for example
K.sub.2CO.sub.3, NaOH or triethylamine, where X(1) and X(2) have
the given meaning and L is a leaving group which can readily be
substituted nucleophilically.
[0683] The activated acid derivatives of the formula II, in which L
is an alkoxy, preferably a methoxy, group, a phenoxy group, a
phenylthio, methylthio or 2-pyridylthio group, or a nitrogen
heterocycle, preferably 1-imidazolyl, are advantageously obtained,
in a manner known per se, from the underlying carbonyl chlorides
(formula II, L=Cl), which, for their part, can be prepared, once
again in a manner known per se, from the underlying carboxylic
acids (formula II, L=OH), for example using thionyl chloride.
[0684] In addition to the carbonyl chlorides of the formula II
(L=Cl), other activated acid derivatives of the formula II can also
be prepared, in a manner known per se, directly from the underlying
benzoic acid derivatives (formula II, L=OH) as can, for example,
the methyl esters of the formula II with L=OCH.sub.3 by treatment
with gaseous HCl in methanol, the imidazolides of the formula II by
treatment with carbonyldiimidazole (L=1-imidazolyl, Staab, Angew.
Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II
with Cl--COOC.sub.2H.sub.5 or tosyl chloride in the presence of
triethylamine in an inert solvent, in addition to which there is
also the activation of benzoic acids with dicyclohexylcarbodiimide
(DCC) or with O-[(cyano(ethoxycarbonyl)methylene-
)amino]--1,1,3,3-tetramethyluronium tetrafluoroborate ("TOTU")
[Proceedings of the 21st European Peptide Symposium, Peptides 1990,
Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A series of
suitable methods for preparing activated carboxylic acid
derivatives of the formula II is given, with citation of the source
literature, on p. 350 in J. March, Advanced Organic Chemistry,
Third Edition (John Wiley & Sons, 1985).
[0685] An activated carboxylic acid derivative of the formula II is
reacted with guanidine, in a manner known per se, in a protic or
aprotic polar, but nevertheless inert, organic solvent. In this
context, methanol, isopropanol or THF, at a temperature of from
20.degree. C. up to the boiling temperature of these solvents, have
proved of value when reacting the methylbenzoates (II, L=OMe) with
guanidine. Most of the reactions of compounds II with salt-free
guanidine were advantageously carried out in aprotic inert solvents
such as THF, dimethoxyethane or dioxane. However, water can also be
used, while employing a base such as, for example, NaOH, as the
solvent, when reacting II with guanidine.
[0686] When L denotes Cl, the reaction is advantageously carried
out with the addition of an acid-capturing agent, for example in
the form of excess guanidine, for binding and thus removing the
hydrohalic acid.
[0687] Some of the underlying benzoic acid derivatives of the
formula II are known and are described in the literature. The
unknown compounds of the formula II may be prepared by methods
which are known from the literature. The introduction of some of
the substituents is achieved by the methods, which are known from
the literature, of palladium-mediated cross-coupling of aryl
halides or aryl triflates with, for example, organostannanes,
organoboronic acids, organoboranes, or organocopper or organozinc
compounds, or terminal alkynes. The resulting benzoic acids are
converted into activated benzoic acid derivatives of the formula II
by one of the above-described process variants. The compounds of
the formula II are either converted directly into the compounds of
the formula I according to the invention or transformed initially
with guanidine into compounds of the formula III which, following
isolation, are converted into the compounds of the formula I
according to the invention by reaction with a further compound of
the formula II.
[0688] In general, dialkanoyl-substituted guanidines of the formula
I are weak bases and can bind acid with the formation of salts.
Suitable acid addition salts are the salts of all pharmacologically
tolerated acids, for example halides, in particular hydrochlorides,
lactates, sulfates, citrates, tartrates, acetates, phosphates,
methylsulfonates and p-toluenesulfonates.
[0689] The compounds I are dialkanoyl-substituted guanidines which
both directly inhibit the cellular sodium/proton exchanger
(Na.sup.+/H.sup.+ exchanger or Na.sup.+/H.sup.+ antiporter) and
also lose one of their acyl radicals in vivo, with a half life of
between 1 minute and 10 hours, and thus, in turn, liberate
monoacylguanidines, which are efficient inhibitors of the cellular
sodium/proton exchanger. Compounds of the formula I are therefore
potent inhibitors of the cellular sodium/proton exchanger and lead
to an improvement in the kinetics of the underlying
monoacylguanidines. Over and above this, they give rise, owing to
their lipophilic nature, to higher concentrations in the CNS of
active compounds in the form of dialkanoylguanidines and
monoacylguanidines than are achieved using the
monoacylguanidines.
[0690] As a consequence of their pharmacological properties, the
compounds are outstandingly suitable for use as anti-arrhythmic
pharmaceuticals possessing a cardioprotective component for the
prophylaxis and treatment of infarction and for the treatment of
angina pectoris, in connection with which they also inhibit or
strongly reduce, in a preventive manner, the pathophysiological
processes associated with the genesis of ischemically induced
damage; in particular associated with the elicitation of
ischemically induced cardiac arrhythmias. On account of their
protective effects against pathological hypoxic and ischemic
situations, the compounds of the formula I according to the
invention can, as a consequence of inhibiting the cellular
Na.sup.+/H.sup.+ exchange mechanism, be used as pharmaceuticals for
treating all acute or chronic damage elicited by ischemia, or
diseases induced primarily or secondarily thereby. This is the case
with regard to their use as pharmaceuticals for surgical
interventions, for example in organ transplantations, where the
compounds can be used both for protecting the organs in the donor
prior to and during removal, for protecting organs which have been
removed, for example when they are being treated with or stored in
physiological bathing fluids, and when transferring the organs into
the recipient. The compounds are likewise valuable protective
pharmaceuticals to be used when carrying out angioplastic surgical
interventions, for example on the heart or on peripheral vessels.
In conformity with their ability to protect against ischemically
induced damage, the compounds are also suitable for use as
pharmaceuticals for treating ischemias of the nervous system, in
particular of the CNS, in connection with which they are suitable,
for example, for treating stroke or cerebral edema. Over and above
this, the compounds of the formula I according to the invention are
also suitable for use in the treatment of forms of shock, such as,
for example, allergic, cardiogenic, hypovolemic and bacterial
shock.
[0691] In addition to this, the compounds of the formula I
according to the invention are notable for their strong inhibitory
effect on the proliferation of cells, for example the proliferation
of fibroblast cells and the proliferation of the smooth muscle
cells of the blood vessels. For this reason, the compounds of the
formula I are valuable therapeutic agents for use in diseases in
which cell proliferation represents a primary or secondary cause
and may, therefore, be used as anti-atherosclerotic agents, and as
agents against diabetic late complications, cancerous diseases,
fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or
renal fibrosis, and against organ hypertrophies or hyperplasias, in
particular hyperplasia or hypertrophy of the prostate.
[0692] The compounds according to the invention are efficient
inhibitors of the cellular sodium/proton antiporter
(Na.sup.+/H.sup.+ exchanger), which, in numerous diseases
(essential hypertension, atherosclerosis, diabetes, etc.), is also
elevated in those cells which are readily accessible to
measurement, such as, for example, erythrocytes, thrombocytes or
leucocytes. The compounds according to the invention therefore
represent outstanding and simple scientific tools, for example in
their use as diagnostic aids for defining and differentiating
particular forms of hypertension and also of atherosclerosis,
diabetes, proliferative diseases, etc. In addition to this, the
compounds of the formula I can suitably be used in preventive
therapy for preventing the genesis of high blood pressure, for
example of essential hypertension.
[0693] In this context, pharmaceuticals which contain a compound I
may be administered orally, parenterally, intravenously or
rectally, or by inhalation, the preferred route of administration
depending on the given features of the disease. In this context,
the compounds I may be used either alone or together with
pharmaceutical auxiliary substances, both in veterinary and in
human medicine.
[0694] Owing to his specialist knowledge, the person skilled in the
art is familiar with those auxiliary substances which are suitable
for the desired pharmaceutical formulation. Antioxidants,
dispersants, emulsifiers, defoamers, taste corrigents,
preservatives, solubilizers or dyes, for example, can be used in
addition to solvents, gel formers, suppository bases, tablet
auxiliaries and other active compound excipients.
[0695] For a form for oral use, the active compounds are mixed with
the additives, such as carrier substances, stabilizers or inert
diluents, which are suitable for the purpose, and brought by the
customary methods into the forms, such as tablets, coated tablets,
hard gelatin capsules, or aqueous, alcoholic or oily solutions,
which are suitable for administration. Gum arabic, magnesium
hydroxide, magnesium carbonate, potassium phosphate, lactose,
glucose or starch, in particular corn starch, can, for example, be
used as inert excipients. In this context, the preparation can be
effected either as a dry granulate or as a wet granulate. Vegetable
or animal oils, for example, such as sunflower oil or cod-liver
oil, are suitable for use as oily excipients or as solvents.
[0696] For subcutaneous or intravenous administration, the active
compounds are brought into solution, suspension or emulsion, if
desired using the substances, such as solubilizers, emulsifiers or
other auxiliary substances, which are customary for the purpose.
Examples of suitable solvents are: water, physiological sodium
chloride solution or alcohols, for example ethanol, propanol or
glycerol, as well as sugar solutions, such as glucose or mannitol
solutions, or else a mixture of the different solvents
mentioned.
[0697] Solutions, suspensions or emulsions of the active compound
of the formula I in a pharmaceutically harmless solvent, such as,
in particular, ethanol or water, or in a mixture of such solvents,
represent examples of suitable pharmaceutical formulations for
administration in the form of aerosols or sprays.
[0698] As required, the formulation can also contain additional
pharmaceutical auxiliary substances such as surfactants,
emulsifiers and stabilizers, as well as a propellent gas. Such a
preparation customarily contains the active compound in a
concentration of from about 0.1 to 10, in particular of from about
0.3 to 3, % by weight.
[0699] The dosage of the active compound of the formula I to be
administered, and the frequency of administration, depend on the
strength and duration of the effect of the compounds used;
additionally also on the nature and severity of the disease to be
treated and on the sex, age, weight and individual responsiveness
of the mammalian subject to be treated.
[0700] On average, the daily dose of a compound of the formula I
is, for a patient of approximately 75 kg in weight, at least 0.001
mg/kg, preferably 0.01 mg/kg, up to at most 10 mg/kg, preferably 1
mg/kg, of body weight. In acute manifestations of the disease, for
example immediately after suffering a cardiac infarction, even
greater and, in particular, more frequent dosages may also be
necessary, for example up to 4 individual doses per day. In the
case of i.v. use in particular, for example in an infarction
patient in intensive care, up to 200 mg per day may be
necessary.
[0701] List of abbreviations:
5 Bn benzyl CH.sub.2Cl.sub.2 dichloromethane DCI desorption
chemical ionization DIP diisopropyl ether DME dimethoxyethane DMF
N,N-dimethylformamide EA ethyl acetate (EtOAc) EI electron impact
eq. equivalent ES electrospray ionization Et ethyl FAB fast atom
bombardment HEP n-heptane Me methyl MeOH methanol mp melting point
MTB methyl tert-butyl ether Pd/C palladium on carbon Pt/C platinum
on carbon RT room temperature THF tetrahydrofuran CNS central
nervous system
[0702] Experimental Section
[0703] General Instructions for Preparing Monoacylguanidines
(III)
[0704] Variant A: from Carboxylic Acids (II, L=OH)
[0705] 1.0 eq. of the carboxylic acid derivative of the formula II
is dissolved or suspended in anhydrous THF (5 ml/mmol), and 1.1 eq.
of carbonyldiimidazole are then added. After the mixture has been
stirred at RT for 2 hours, 5.0 eq. of guanidine are introduced into
the reaction solution. After the mixture has been stirred
overnight, the THF is distilled off under reduced pressure in a
rotary evaporator and water is added to the residue, which is
adjusted to from pH 6 to 7 with 2N HCl; the corresponding
monoacylguanidine (formula III) is then filtered off. The
monoacylguanidines obtained in this way can be converted into the
corresponding salts by treatment with aqueous, methanolic or
ethereal hydrochloric acid or other pharmacologically tolerated
acids.
[0706] General Instructions for Preparing Monoacylguanidines
(III)
[0707] Variant B: from Alkyl Carboxylates (II, L=O-alkyl)
[0708] 1.0 eq. of the alkyl carboxylate of the formula II and also
5.0 eq. of guanidine (free base) are dissolved in isopropanol or
suspended in THF and boiled under reflux until the reaction is
complete (monitoring by thin layer chromatography) (typical
reaction time, from 2 to 5 h). The solvent is distilled off under
reduced pressure in a rotary evaporator and the residue is taken up
in EA and washed 3.times. with a solution of NaHCO.sub.3. Drying
takes place over Na.sub.2SO.sub.4, after which the solvent is
distilled off in vacuo and the residue is chromatographed on silica
gel using a suitable eluent, for example EA/MeOH 5:1.
[0709] (Salt Formation, Compare Variant A)
[0710] General Instructions for Preparing Dialkanoylguanidines
(I)
[0711] Variant F: from Carboxylic Acids (II, L=OH)
[0712] 2.0 eq. of the carboxylic acid derivative of the formula II
are dissolved or suspended in anhydrous THF (5 ml/mmol), and 2.2
eq. of carbonyldiimidazole are then added. After the mixture has
been stirred at RT for 2 hours, 1.0 eq. of guanidine is introduced
into the reaction solution. After the mixture has been stirred
overnight, the THF is distilled off under reduced pressure in a
rotary evaporator, and water is added to the residue, which is
adjusted to from pH 6 to 7 with 2M HCl; the corresponding
dialkanoylguanidine (formula I) is then filtered off. The
monoacylguanidines obtained in this way can be converted into the
corresponding salts by treatment with aqueous, methanolic or
ethereal hydrochloric acid or other pharmacologically tolerated
acids.
[0713] General Instructions for Preparing Dialkanoylguanidines
(I)
[0714] Variant G: from Carboxylic Acid Esters (II, L=O-alkyl)
[0715] 2.0 eq. of the alkyl carboxylate of the formula II and also
1.0 eq. of guanidine (free base) are dissolved in isopropanol or
suspended in THF and boiled under reflux until the reaction is
complete (monitoring by thin layer chromatography) (typical
reaction time, from 2 to 5 h). The solvent is distilled off under
reduced pressure in a rotary evaporator and the residue is taken up
in EA and washed 3.times. with a solution of NaHCO.sub.3. Drying
takes place over Na.sub.2SO.sub.4, after which the solvent is
distilled off in vacuo and the residue is chromatographed on silica
gel using a suitable eluent, e.g. EA/MeOH 5:1.
[0716] (Salt Formation, Compare Variant A)
[0717] General Instructions for Preparing Dialkanoylguanidines
(I)
[0718] Variant K: from Monoacylguanidines (III) and a Carboxylic
Acid Derivative of the Formula II (for Example, a Carboxylic Acid
Ester or Activated Carboxylic Acid)
[0719] 1.0 eq. of the monoacylguanidine of the formula III (free
base) and also 1.0 eq. of the carboxylic acid derivative of the
formula II (for the preparation of an activated carboxylic acid,
compare variant A) are dissolved or suspended, respectively, in
isopropanol or in THF and the mixture is stirred at an appropriate
temperature (RT to reflux) until the reaction is complete
(monitoring by thin layer chromatography). The solvent is distilled
off under reduced pressure in a rotary evaporator and the residue
is taken up in EA and washed 3.times. with a solution of
NaHCO.sub.3. Drying over takes place Na.sub.2SO.sub.4, after which
the solvent is distilled off in vacuo and the residue is
chromatographed on silica gel using a suitable eluent, e.g. EA/MeOH
10:1.
[0720] (Salt Formation, Compare Variant A)
EXAMPLE 1
[0721] Bis(3-methylsulfonyl-4-i-propylbenzoyl)guanidine
[0722] a) 3-Methylsulfonyl-4-i-propylbenzoyl chloride 4.0 g of
3-methylsulfonyl-4-i-propylbenzoic acid, 1.5 ml of thionyl chloride
and 3 drops of DMF are heated under reflux for 10 h in 30 ml of
toluene. The solvent is subsequently removed in vacuo and the
product is taken for further use without purification.
[0723] b) Bis(3-methylsulfonyl-4-i-propylbenzoyl)guanidine The acid
chloride 1 a) and 3.9 g of
3-methylsulfonyl-4-i-propylbenzoylguanidine are dissolved in 50 ml
of DMF, and 3.4.g of K.sub.2CO.sub.3 are then added. The mixture is
stirred at RT for 4 h and then left to stand overnight. The
solution is subsequently concentrated and the residue stirred up in
200 ml of water. The solid is filtered off and washed with 100 ml
of water. This solid is then dissolved in 100 ml of EA and washed
1.times. with 10 ml of 1N HCl and then 1.times. with 50 ml of NaCl
solution. Drying takes place over Na.sub.2SO.sub.4 and the solvent
is removed in vacuo. A yellow solid is obtained which is purified
by being triturated twice with 20 ml of diethyl ether and
subsequently being filtered off. The product is dried in vacuo and
1.9 g are obtained of a white solid, mp 218-221.degree. C.
[0724] R.sub.f (CH.sub.2Cl.sub.2/MeOH 20:1)=0.57 MS (ES): 508
(M+1)
[0725] Precursors
[0726]
4-Isopropyl-3-methylsulfonylbenzoylguanidine-methanesulfonate:
[0727] Colorless crystals, mp 226-28.degree. C.
[0728] Synthesis route:
[0729] a) 4-Isopropylbenzoic acid, by the oxidation of
4-isopropylbenzaldehyde with sodium perborate in acetic acid at
50.degree. C., mp 118.degree. C.,
[0730] b) 4-isopropyl-3-chlorosulfonylbenzoic acid, from a) by
heating in chlorosulfuric acid at 95.degree. C. for 3 h, mp
203-4.degree. C.,
[0731] c) 2-isopropyl-5-carboxybenzenesulfinic acid, from b) by
reduction with sodium sulfite at 60.degree. C. in aqueous sodium
hydroxide solution (pH.apprxeq.9-10), mp 205-7.degree. C.,
[0732] d) 4-isopropyl-3-methylsulfonylbenzoic acid, from c) by
alkylation with methyl bromide in the presence of NaOH in DMF at
60.degree. C. for 3 h, mp 209-11.degree. C.,
[0733] e)
4-isopropyl-3-methylsulfonylbenzoylguanidine-methane-sulfonate,
from d) by reaction with thionyl chloride in toluene (reflux) for 1
h. After the toluene has been stripped off, the residue is taken up
in THF and the resulting acid chloride is added to a mixture of
guanidine hydrochloride, 2N NaOH and THF. After the mixture has
been stirred at 30-40.degree. C. for 4 h, the THF is distilled off,
whereupon the product accrues in crystal-line form as a free base.
Subsequent treatment with methanesulfonic acid yields the salt.
EXAMPLE 2
[0734] Bis(4-fluoro-3-trifluoromethylbenzoyl)guanidine
[0735] a) 4-Fluoro-3-trifluoromethylbenzoyl chloride
[0736] 1.5 g of 4-fluoro-3-trifluoromethylbenzoic acid, 0.65 ml of
thionyl chloride and two drops of DMF are heated under reflux for
12 h in 17 ml of toluene and the mixture is subsequently
concentrated and used without further purification.
[0737] b) Bis (4-fluoro-3-trifluoromethylbenzoyl)guanidine
[0738] The acid chloride 2a) and 0.87 g of
4-fluoro-3-trifluoromethylbenzo- ylguanidine are dissolved in 15 ml
of DMF, and 1.3 g of potassium carbonate are then added. The
mixture is stirred at RT for 20 h and then worked up as described
under 1b). The resulting, clear oil is purified by column
chromatography (silica gel, heptane/EA 8:2), and a colorless solid,
mp 143-45.degree. C., is obtained.
[0739] R.sub.f (heptane/EA 7:3)=0.7; MS (ES): 440 (M+1)
[0740] Precursor
[0741] 4-Fluoro-3-trifluoromethylbenzoylguanidine:
[0742] Colorless crystals, mp 159-60.degree. C.
[0743] Synthesis Route:
[0744] 4-Fluoro-3-trifluoromethylbenzoylguanidine, from
4-fluoro-3-trifluoromethylbenzoic acid by reaction with
N,N'-carbonyldiimidazole in THF at RT and subsequent addition of
guanidine.
EXAMPLE 3
[0745] Bis[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]guanidine
[0746] and
EXAMPLE 4
[0747]
N-(4-(1-Imidazolyl)-3-trifluoromethylbenzoyl]-N'-(4-fluoro-3-triflu-
oromethylbenzoyl)guanidine hydrochloride
[0748] 0.25 g of bis(4-fluoro-3-trifluoromethylbenzoyl)guanidine,
0.16 g of imidazole and 0.16 g of potassium carbonate are heated
for 16 h in 5 ml of DMF, and after that the solvent is evaporated.
Separation of the crude product by column chromatography yielded
0.12 g of bis[4-(1-imidazolyl)-3-trifluoromethylbenzoyl]guanidine
as a colorless solid, mp 130.degree. C., decomp., R.sub.f
(CH.sub.2Cl.sub.2/MeOH 9:1)=0.4 MS (ES): 536 (M+1) and 0.07 g of
N-[4-(1-imidazolyl)-3-trifluoro-
methylbenzoyl]-N'-(4-fluoro-3-trifluoromethyl-benzoyl)guanidine as
an oil. Treatment with HCl/ether yielded 0.06 g of
N-[4-(1-imidazolyl)-3-trifluor-
omethylbenzoyl]-N'-(4-fluoro-3-trifluoromethyl-benzoyl)guanidine
hydrochloride as a colorless solid, mp 217-218, decomp., R.sub.f
(CH.sub.2Cl.sub.2/MeOH 9:1)=0.53; MS (ES): 488 (M+1)
EXAMPLE 5
[0749] N,N'-Bis(1,2,3,4-tetrahydronaphthalene-2-carbonyl)guanidide
was prepared according to variant F from
1,2,3,4-tetrahydronaphthalene-2-carb- oxylic acid and isolated as a
free base.
[0750] MS (ES): 376 (M+1)
[0751] mp 99.degree. C.
[0752] Was also prepared in accordance with variant K via
1,2,3,4-tetrahydronaphthalene-2-carbonylguanidide [prepared in
accordance with variant A from
1,2,3,4-tetra-hydronaphthalene-2-carboxylic acid: MS (ES): 218
(M+1)]and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid.
EXAMPLE 6
[0753] N,N'-Bis[(E)-2-methylcinnamoyl]guanidide was prepared from
(E)-2-methylcinnamic acid in accordance with variant F and isolated
as the hydrochloride.
[0754] MS (ES): 348 (M+1)
[0755] mp 193.degree. C.
EXAMPLE 7
[0756] N,N'-Bis[3-(2-trifluoromethylphenyl)propionyl]guanidide was
prepared from 3-(2-trifluoromethylphenyl)propionic acid in
accordance with variant F and isolated as the hydrochloride.
[0757] MS (ES): 460 (M+1)
[0758] mp 75.degree. C.
EXAMPLE 8
[0759] N,N'-Bis[3-(2,5-difluorophenyl)-2-methylpropionyl)guanidide
was prepared from 3-(2,5-difluorophenyl)-2-methylpropionic acid in
accordance with variant F and isolated as the hydrochloride.
[0760] MS (ES): 424 (M+1)
[0761] mp amorphous
[0762] Pharmacological Data:
[0763] Inhibition of the Na.sup.+/H.sup.+ exchanger of rabbit
erythrocytes:
[0764] New Zealand White rabbits (Ivanovas) were given a standard
diet containing 2% cholesterol for six weeks in order to activate
Na.sup.+/H.sup.+ exchange and thus to be able to use flame
photometry to determine the Na.sup.+ influx into the erythrocytes
via Na.sup.+/H.sup.+ exchange. The blood was removed from the aural
arteries and rendered incoagulable by the addition of 25 IU of
potassium heparin per ml. One part of each sample was used for the
duplicate determination of the hematocrit by centrifugation.
Aliquots of in each case 100 .mu.l were employed for measuring the
initial content of Na.sup.+ in the erythrocytes.
[0765] In order to determine the amiloride-sensitive sodium influx,
100 .mu.l of each blood sample were in each case incubated, at pH
7.4 and 37.degree. C., in 5 ml of a hyperosmolar salt/sucrose
medium (mmol/l: 140 NaCl, 3 KCl, 150 sucrose, 0.1 ouabain, 20
tris(hydroxymethyl)amino-methan- e). The erythrocytes were then
washed three times with ice cold MgCl.sub.2/ouabain solution
(mol/l: 112 MgCl.sub.2, 0.1 ouabain) and hemolyzed in 2.0 ml of
distilled water. The intracellular content of sodium was determined
by flame photometry.
[0766] The nett influx of Na.sup.+ was calculated from the
difference between the initial sodium values and the sodium content
of the erythrocytes following incubation. The amiloride-inhibitable
sodium influx was given by the difference in the sodium content of
the erythrocytes following incubation with and without
3.times.10.sup.-4 mol/l amiloride. The same procedure was also used
in the case of the compounds according to the invention.
[0767] Results relating to the inhibition of the Na.sup.+/H.sup.+
exchanger:
6 IC.sub.50 (.mu.mol) Example 10 1 10 2 5 3 3 4 0.3 5 1.1 6 2 7 0.3
8
[0768] The following were obtained in analogy with Example 1:
7 Example R(1) = R(10) R(2) = R(9) R(3) = R(8) R(4) = R(7) R(5) =
R(6) 9 H H Cl n-BuNH-- H 10 H H 23 H.sub.2NSO.sub.2-- H 11 H H 24
MeSO.sub.2 H 12 H 25 Me H H 13 H 26 27 H H 14 H 28 Me H H 15 H 29
Cl H H 16 H 30 MeSO.sub.2-- H H 17 H H NH.sub.2 MeSO.sub.2 H 18 H H
31 MeSO.sub.2-- H 19 H H 32 MeSO.sub.2-- H 20 H H 33 MeSO.sub.2-- H
21 H H 34 MeSO.sub.2-- H 22 H H 35 MeSO.sub.2-- H 23 H H 36
MeSO.sub.2-- H 24 H H 37 Cl.sub.2-- H 25 H H
(CH.sub.3).sub.2--CHCH.sub.2--O-- MeSO.sub.2-- H 26 H H 38
MeSO.sub.2-- H 27 H H 39 MeSO.sub.2-- H 28 H H 40 MeSO.sub.2-- H 29
H 41 42 H H 30 H 43 44 H H 31 H 45 46 H H 32 H 47 48 H H 33 H 49 50
H H 34 H 51 52 H H 35 H H 53 MeSO.sub.2-- H 36 H H 54 MeSO.sub.2--
H 37 Me H H Me H 38 H Me Me H.sub.2NSO.sub.2-- H 39 H H H CF.sub.3
H 40 H 55 Cl H H 41 H H MeNH-- MeSO.sub.2-- H 42 H H Et.sub.2N--
MeSO.sub.2-- H 43 H t-Bu OH t-Bu H 44 H H 56 MeSO.sub.2-- H 45 H H
57 MeSO.sub.2-- H 46 H H 58 MeSO.sub.2-- H 47 H H 59 MeSO.sub.2-- H
48 H H 60 MeSO.sub.2-- H 49 H H 2-naphthyl MeSO.sub.2-- H 50 H H 61
MeSO.sub.2-- H 51 H 62 Me H H 52 H 63 64 H H 53 H Cl Et.sub.2N--
MeSO.sub.2-- H 54 H Me.sub.2N-- H CF.sub.3 H 55 H H 65 MeSO.sub.2--
H 56 H Br NH.sub.2 Br H 57 H Cl H CF.sub.3 H 58 H H 66 MeSO.sub.2--
H 59 H H 67 MeSO.sub.2-- H 60 H CF.sub.3 H CF.sub.3 H 61 H H Me Me
H 62 H I H CF.sub.3 H 63 H Me H Me H 64 H H t-Bu H H 65 H H 68
MeSO.sub.2-- H 66 H H Cl Me H 67 H H Me Br H 68 H H MeO-- Cl H 69 H
Cl MeO-- Cl H 70 H Br H Br H 71 H H 69 MeSO.sub.2-- H 72 H H 70
MeSO.sub.2-- H 73 NH.sub.2 Br H Me H 74 H N.sub.3 H CF.sub.3 H 75 H
H t-Bu Me.sub.2N-- H 76 H H 71 MeSO.sub.2-- H 77 H 72 H H H 78 H 73
MeO-- H H 79 H H Br Me H 80 H H F Cl H 81 H t-Bu H t-Bu H 82
NH.sub.2 H H Cl H 83 H 74 H Me.sub.2N H 84 H Me.sub.2N H Cl H 85 H
H 7-iso-quinolinoxy MeSO.sub.2-- H 86 H H 6-quinolinoxy
MeSO.sub.2-- H 87 H H 75 MeSO.sub.2-- H 88 H H 76 MeSO.sub.2-- H 89
H H (CH.sub.3).sub.2CH--CH.sub.2-- MeSO.sub.2-- H 90 H H 77
MeSO.sub.2-- H 91 H H 78 Me.sub.2N-- H 92 H H 79 Me.sub.2N-- H 93 H
Me Me.sub.2N Me H 94 H H 80 81 H 95 H Me 82 Me H 96 H H
ClCH.dbd.C(CH.sub.3)-- MeSO.sub.2 H 97 H H i-Pr Cl H 98 H H i-Pr 83
H 99 H H 5-quinolinoxy MeSO.sub.2-- H 100 H 84 H CF.sub.3 H 101 H
i-Pr H MeSO.sub.2-- H 102 H i-Pr H CF.sub.3 H 103 H H i-Pr H H 104
NH.sub.2 H Br Br H 105 H H 85 MeSO.sub.2-- H 106 H 86 H
MeSO.sub.2-- H 107 H H 87 MeSO.sub.2-- H 108 H Cl 88 Cl H 109 H
Me.sub.2N i-Pr MeSO.sub.2-- H 110 H MeHN-- i-Pr MeSO.sub.2-- H 111
H Cl Cl Cl H 112 H Cl H.sub.2N-- Me H 113 H Cl H.sub.2N Cl H 114 H
H 89 MeSO.sub.2-- H 115 H H 90 MeSO.sub.2-- H 116 H H i-Pr
Me.sub.2N-- H 117 CF.sub.3 H H CF.sub.3 H 118 H Br H Me H 119 H Me
Cl Me H 120 H Me.sub.2N Me Br H 121 H CF.sub.3 H MeHN-- H 122 H H
(CH.sub.3).sub.2CH--CH.sub.2 CH.sub.3CO-- H 123 H H 91 MeSO.sub.2--
H 124 H H H CF.sub.3--O-- H 125 H H Me.sub.2N Me H 126 H Cl 92 Cl H
127 H Cl Me.sub.2N-- Cl H 128 H H 93 MeSO.sub.2-- H 129 H H i-Pr
CH.sub.3CO-- H 130 H Br BnO-- CH.sub.3CO-- H 131 H H Br CF.sub.3 H
132 H H MeO-- i-Pr H 133 H H 94 MeSO.sub.2-- H 134 H H 95
MeSO.sub.2-- H 135 H H t-Bu MeO-- H 136 H Br i-Pr MeSO.sub.2-- H
137 CF.sub.3 H H H H 138 H H F CF.sub.3 H 139 H Ph H CF.sub.3 H 140
H H i-imidazolyl CF.sub.3 H 141 H H cyclopentyl CH.sub.3CO-- H 142
H H t-butylmethyl CH.sub.3CO-- H 143 H H F Br H 144 H Br MeO-- Br H
145 NH.sub.2 Me H H H 146 H H PhO-- CF.sub.3 H 147 H H cyclopentyl
CF.sub.3 H 148 H H cyclobutyl MeSO.sub.2-- H 149 H Me H CF.sub.3 H
150 H H 4-CF.sub.3--PhO MeSO.sub.2-- H 151 H H OH t-butyl H 152 H
Me.sub.2N-- MeO-- Cl H 153 H H isopropyl CF.sub.3 H 154 H CF.sub.3
H H F 155 H H MeO-- t-butyl H 156 H H 96 MeSO.sub.2-- H 157 H Br 97
Br H 158 H H 98 MeSO.sub.2-- H 159 H H 99 CH.sub.3CO-- H 160 H H
100 CH.sub.3CO-- H 161 H H methylpropyl t-butyl H 162 H cyclopentyl
MeO-- CH.sub.3CO-- H 163 H H isopropyl CF.sub.3CF.sub.2 H 164 H H
101 CF.sub.3SO.sub.2 H 165 H CF.sub.3 H H Cl 166 H H 102 CF.sub.3 H
167 H H Ph--C.dbd.C CF.sub.3 H 168 H H 103 CF.sub.3 H 169 H F H
CF.sub.3 H 170 H H 104 MeSO.sub.2-- H 171 H H isopropyl t-butyl H
172 H H n-butyl t-butyl H 173 H H F isopr pyl H 174 H H F isobutyl
H 175 H I H CF.sub.3 F 176 H H CF.sub.3O-- Cl H 177 NH.sub.2 H Cl H
Cl 178 H H 105 MeSO.sub.2-- H 179 H I OH t-butyl H 180 H H
isopropyl CF.sub.3SO.sub.2 H 181 H H 106 CF.sub.3 H 182 H H 107
CF.sub.3 H 183 H H 108 CF.sub.3 H 184 H H 109 CF.sub.3 H 185 H H
110 CF.sub.3 H 186 H H MeO-- CF.sub.3 H 187 H H H isopropyl H 188 H
H isopropyl MeS-- H 189 111 190 112 191 113 192 114 193 115 194 116
195 117 196 118 197 119 198 120 199 121 200 122 201 123 202 124 203
125 204 126
* * * * *