U.S. patent application number 09/954016 was filed with the patent office on 2002-05-16 for substituted cinnamic, acid guanidides, process for their preparation, their use as a medicament, and medicament comprising them.
This patent application is currently assigned to Aventis Pharma Deutschland GmbH.. Invention is credited to Bleich, Markus, Heinelt, Uwe, Hofmeister, Armin,, Hropot, Max, Lang, Hans-Jochen.
Application Number | 20020058710 09/954016 |
Document ID | / |
Family ID | 7657232 |
Filed Date | 2002-05-16 |
United States Patent
Application |
20020058710 |
Kind Code |
A1 |
Hofmeister, Armin, ; et
al. |
May 16, 2002 |
SUBSTITUTED CINNAMIC, ACID GUANIDIDES, PROCESS FOR THEIR
PREPARATION, THEIR USE AS A MEDICAMENT, AND MEDICAMENT COMPRISING
THEM
Abstract
Substituted cinnamic acid guanidides, process for their
preparation, their use as a medicament or diagnostic, and
medicament comprising them. Compounds of the 1 , which may be
obtained by reaction of a compound II 2 with guanidine.
Inventors: |
Hofmeister, Armin,;
(Nierstein, DE) ; Hropot, Max; (Florsheim, DE)
; Heinelt, Uwe; (Wiesbaden, DE) ; Bleich,
Markus; (Hunfelden-Dauborn, DE) ; Lang,
Hans-Jochen; (Hofheim, DE) |
Correspondence
Address: |
Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
1300 I Street, N.W.
Washington
DC
20005-3315
US
|
Assignee: |
Aventis Pharma Deutschland
GmbH.
|
Family ID: |
7657232 |
Appl. No.: |
09/954016 |
Filed: |
September 18, 2001 |
Current U.S.
Class: |
514/617 ;
514/618; 514/619; 564/161; 564/162; 564/163 |
Current CPC
Class: |
A61P 41/00 20180101;
C07C 311/58 20130101; C07C 311/29 20130101; C07D 295/13 20130101;
A61P 9/06 20180101; C07C 311/39 20130101; A61P 43/00 20180101; C07C
311/41 20130101; C07D 207/14 20130101; C07D 295/26 20130101; A61P
9/10 20180101 |
Class at
Publication: |
514/617 ;
514/618; 514/619; 564/161; 564/162; 564/163 |
International
Class: |
A61K 031/165; C07C
233/34 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 22, 2000 |
DE |
10046993.0 |
Claims
We claim:
1. A compound of the formula I, 69in which: at least one of R(1),
R(2), R(3), R(4) and R(5) is --X.sub.a--Y.sub.b--L.sub.n--U; X is
CR(16)R(17), O, S or NR(18); where R(16), R(17) and R(18)
independently of one another are H or an alkyl having 1, 2, 3 or 4
carbon atoms, where the alkyl is chosen from unsubstituted alkyls,
partially fluorinated alkyls and completely fluorinated alkyls; a
is zero or; Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, alkylene-T having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in
the alkylene group, T, or T-alkylene having 1, 2, 3, 4, 5, 6, 7 or
8 carbon atoms in the alkylene group; where T is NR(20), phenylene,
O or S, where the phenylene is not substituted or is substituted by
1-3 substituents chosen from F, Cl, CF.sub.3, methyl, methoxy and
NR(21)R(22); where R(20), R(21) and R(22) independently of one
another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where
the alkyl is chosen from unsubstituted alkyls, partially
fluorinated alkyls and completely fluorinated alkyls; b is zero or
1; L is O, S, NR(23) or C.sub.kH.sub.2k; where kis1, 2, 3, 4, 5, 6,
7 or 8; where R(23) is H or an alkyl group having 1, 2, 3 or 4
carbon atoms, where the alkyl is chosen from unsubstituted alkyls,
partially fluorinated alkyls and completely fluorinated alkyls; n
is zero or 1; U is 70 or a nitrogen-containing heterocycle having
1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is substituted by
an --SO.sub.2NR(30)R(31)-- group; where R(30) and R(31)
independently of one another are H or an alkyl group having 1, 2,
3, 4, 5, 6, 7 or 8 carbon atoms, where in the alkyl group,
independently of one another, one or more CH.sub.2 groups can be
replaced by O, NR(35), C.dbd.O, S or C.dbd.S; where R(35) is H or
alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen
from unsubstituted alkyls, partially fluorinated alkyls and
completely fluorinated alkyls; or R(30) and R(31) independently of
one another are H, an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, where the alkyl is chosen from partially fluorinated alkyls
and completely fluorinated alkyls, (C.sub.3-C.sub.8)-cycloalkyl,
phenyl-(C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl, where in the
alkyl or in the cycloalkyl ring, independently of one another, one
or more CH.sub.2 groups can be replaced by O, NR(35), C.dbd.O, S or
C.dbd.S; or R(30) and R(31) together are 4 or 5 methylene groups,
where, independently of one another, one or more CH.sub.2 groups
can be replaced by O, NR(35), C.dbd.O, S or C.dbd.S; or R(31) and
R(35) together are 4 or 5 methylene groups; R(32), R(33) and R(34)
independently of one another are H, F, Cl, Br, I,
(C.sub.1-C.sub.4)-alkyl, partially fluorinated
(C.sub.1-C.sub.4)-alkyl, completely fluorinated
(C.sub.1-C.sub.4)-alkyl, O--(C.sub.1-C.sub.4)-alkyl, partially
fluorinated O--(C.sub.1-C.sub.4)-al- kyl, completely fluorinated
O--(C.sub.1-C.sub.4)-alkyl, NO.sub.2, or NR(28)R(29); where R(28)
and R(29) independently of one another are H or an alkyl having 1,
2, 3 or 4 carbon atoms, where the alkyl is chosen from
unsubstituted alkyls, partially fluorinated alkyls and completely
fluorinated alkyls; where the N-containing heterocycles are N- or
C-bridged and are unsubstituted or are substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(36)R(37); R(36) and R(37) independently of
one another are H, an alkyl having 1, 2, 3 or 4 carbon atoms, where
the alkyl is chosen from unsubstituted alkyls, partially
fluorinateds, and completely fluorinated alkyls, or benzyl; and the
remaining substituents of R(1), R(2), R(3), R(4) and R(5)
independently of one another are H, F, Cl, Br, I, SO.sub.2NH.sub.2,
SO.sub.2CH.sub.3, NO.sub.2, NR(24)R(25), CN, unsubstituted
(C.sub.1-C.sub.8)-alkyl, partially fluorinated
(C.sub.1-C.sub.8)-alkyl, completely fluorinated
(C.sub.1-C.sub.8)-alkyl, unsubstituted O--(C.sub.1-C.sub.8)-alkyl,
partially fluorinated O--(C.sub.1-C.sub.8)-alkyl, completely
fluorinated O--(C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl,
(C.sub.3-C.sub.8)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl or
phenyl-(C.sub.1-C.sub.4)-alkyl, where the phenyl is not substituted
or is substituted by 1-3 substituents selected from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(11)R(12);
R(11), R(12), R(24) and R(25) independently of one another are H or
an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is
chosen from unsubstituted alkyls, partially fluorinated alkyls and
completely fluorinated alkyls; R(6) and R(7) independently of one
another are H, F, Cl, Br, I, CN, an alkyl having 1, 2, 3, 4, 5, 6,
7 or 8 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls, and completely fluorinated
alkyls, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or
phenyl, where the phenyl is not substituted or is substituted by
1-3 substituents selected from the group consisting of F, Cl,
CF.sub.3, methyl, methoxy and NR(14)R(15); R(14) and R(15)
independently of one another are H or an alkyl having 1, 2, 3 or 4
carbon atoms, where the alkyl is chosen from unsubstituted alkyls,
partially fluorinated alkyls and completely fluorinated alkyls; or
a pharmaceutically tolerable salt thereof, in any stereoisomeric
form, or a mixture of any such compounds in any ratio.
2. The compound of the formula I as claimed in claim 1, in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is
--X--U; X is CR(16)R(17), O, S or NR(18); R(16), R(17) and R(18)
independently of one another are H or an alkyl having 1, 2, 3 or 4
carbon atoms, where the alkyl is chosen from unsubstituted alkyls,
partially fluorinated alkyls and completely fluorinated alkyls; U
is 71or a nitrogen-containing heterocycle having 1, 2, 3, 4, 5, 6,
7, 8 or 9 carbon atoms, which is substituted by an
--SO.sub.2NR(30)R(31)-- group; R(30) and R(31) independently of one
another are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms, where in the alkyl chain, independently of one
another, one or more CH.sub.2 groups can be replaced by O, NR(35),
C.dbd.O, S or C.dbd.S; R(35) is H or an alkyl having 1, 2, 3, 4 or
5 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls; or R(30) and R(31) independently of one another are H, an
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where the alkyl
is chosen from partially fluorinated alkyl and completely
fluorinated alkyl, (C.sub.3-C.sub.8)-cycloalkyl,
phenyl-(C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl, where in the
alkyl or in the cycloalkyl ring, independently of one another, one
or more CH.sub.2 groups can be replaced by O, NR(35), C.dbd.O, S or
C.dbd.S; or R(30) and R(31) together are 4 or 5 methylene groups,
where, independently of one another, one or more CH2 groups can be
replaced by O, NR(35), C.dbd.O, S or C.dbd.S; or R(31) and R(35)
together are 4 or 5 methylene groups; R(32), R(33) and R(34)
independently of one another are H, F, Cl, Br, I,
(C.sub.1-C.sub.4)-alkyl, O--(C.sub.1-C.sub.4)-alkyl, CF.sub.3 or
NR(28)R(29); R(28) and R(29) independently of one another are H or
alkyl having 1, 2, 3 or 4 carbon atoms; where the N-containing
heterocycles are N-- or C-bridged and are not substituted or are
substituted by 1-3 substituents selected from the group consisting
of F, Cl, CF.sub.3, methyl, methoxy and NR(36)R(37); R(36) and
R(37) independently of one another are H, an alkyl having 1, 2, 3
or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinateds, and completely fluorinated alkyls,
or benzyl; and the remaining substituents of R(1), R(2), R(3), R(4)
and R(5) independently of one another are H, F, Cl, Br, I,
SO.sub.2NH.sub.2, SO.sub.2CH.sub.3, NO.sub.2, NR(24)R(25), CN,
unsubstituted (C.sub.1-C.sub.4)-alkyl, partially fluorinated
(C.sub.1-C.sub.4)-alkyl, completely fluorinated
(C.sub.1-C.sub.4)-alkyl, unsubstituted O--(C.sub.1-C.sub.4)-alkyl,
partially fluorinated O--(C.sub.1-C.sub.4)-alkyl, completely
fluorinated O--(C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl or
phenyl-(C.sub.1-C.sub.4)-alkyl, where the phenyl is not substituted
or is substituted by 1-3 substituents selected from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(11)R(12);
R(11), R(12), R(24) and R(25) independently of one another are H or
an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is
chosen from unsubstituted alkyls, partially fluorinated alkyls, and
completely fluorinated alkyls; R(6) and R(7) independently of one
another are hydrogen, F, Cl, Br, I, CN, an alkyl having 1, 2, 3, 4,
5, 6, 7 or 8 carbon atoms, where the alkyl is chosen from
unsubstituted alkyls, partially fluorinated alkyls, and completely
fluorinated alkyls, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon
atoms or phenyl, which is not substituted or is substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(1 4)R(1 5); R(14) and R(15) independently of
one another are H, alkyl having 1, 2, 3 or 4 carbon atoms, where
the alkyls are chosen from unsubstituted alkyls, partially
fluorinated alkyls and completely fluorinated alkyls; or a
pharmaceutically tolerable salt thereof, in any stereoisomeric
form, or a mixture of any such compounds in any ratio.
3. The compound of the formula I as claimed in claim 1, in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is
--X--U; X is CR(16)R(17), O, S or NR(18); R(16), R(17) and R(18)
independently of one another are H, alkyl having 1, 2, 3 or 4
carbon atoms or CF.sub.3; U is 72 or a nitrogen-containing
heterocycle having 1, 2, 3, 4, 5 or 6 carbon atoms, which is
substituted by an --SO.sub.2NR(30)R(31) group; R(30) and R(31)
independently of one another are H, alkyl having 1, 2, 3, 4, 5, 6,
7 or 8 carbon atoms, CF.sub.3, (C.sub.3-C.sub.8)-cycloalkyl, where
in the alkyl, independently of one another, one or more CH.sub.2
groups can be replaced by 0, NR(35), C.dbd.O, S or C.dbd.S; where
R(35) is H or alkyl having 1, 2, 3, 4 or 5 carbon atoms; or R(30)
and R(31) together are 4 or 5 methylene groups, where,
independently of one another, one or more CH.sub.2 groups can be
replaced by O, NR(35), C.dbd.O, S or C.dbd.S; or R(31) and R(35)
together are 4 or 5 methylene groups; R(32), R(33) and R(34)
independently of one another are H, F, Cl, methyl, ethyl, Omethyl,
Oethyl, CF.sub.3, NH.sub.2, NHmethyl or Nmethyl.sub.2; where the
N-containing heterocycles are N- or C-bridged and are not
substituted or are substituted by 1-3 substituents selected from
the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(36)R(37); R(36) and R(37) independently of one another are H,
alkyl having 1, 2, 3 or 4 carbon atoms, CF.sub.3 or benzyl; and the
remaining substituents of R(1), R(2), R(3), R(4) and R(5)
independently of one another are H, F, Cl, Br, I, SO.sub.2NH.sub.2,
SO.sub.2CH.sub.3, NR(24)R(25), CN, (C.sub.1-C.sub.4)-alkyl,
CF.sub.3, C.sub.2F.sub.5, O--(C.sub.1-C.sub.4)-alkyl, OCF.sub.3,
OC.sub.2F.sub.5, (C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub- .4)-alkyl or
phenyl-(C.sub.1-C.sub.4)-alkyl, where the phenyl is not substituted
or is substituted by 1-3 substituents selected from the group
consisting of F, Cl, CF.sub.3, methyl, methoxy and NR(11)R(12);
R(11), R(12), R(24) and R(25) independently of one another are H or
alkyl having 1, 2, 3 or 4 carbon atoms; R(6) and R(7) independently
of one another are hydrogen, F, Cl, Br, I, CN, alkyl having 1, 2,
3, 4, 5, 6, 7 or 8 carbon atoms, CF.sub.3, cycloalkyl having 3, 4,
5 or 6 carbon atoms; or a pharmaceutically tolerable salt thereof,
in any stereoisomeric form, or a mixture of any such compounds in
any ratio.
4. The compound of the formula I as claimed in claim 1, in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is
--X--U; X is CR(16)R(17), O, S or NR(18); R(16), R(17) and R(18)
independently of one another are H, CH.sub.3, C.sub.2H.sub.5 or
CF.sub.3; U is 73or an N-containing heterocycle having 3, 4 or 5
carbon atoms, which is substituted by an --SO.sub.2NR(30)R(31)-
group; R(30) and R(31) independently of one another are hydrogen or
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CF.sub.3,
(C.sub.3-C.sub.8)-cycloalkyl; where in the alkyl, independently of
one another, one or more CH.sub.2 groups can be replaced by O,
NR(35), C.dbd.O, S or C.dbd.S; R(35) is H or alkyl having 1, 2, 3,
4 or 5 carbon atoms; or R(30) and R(31) together are 4 or 5
methylene groups, where, independently of one another, one or more
CH.sub.2 groups can be replaced by O, NR(35), C.dbd.O, S or
C.dbd.S; or R(31)and R(35) together are 4 or 5 methylene groups;
R(32), R(33) and R(34) independently of one another are H, F, Cl,
methyl, CF.sub.3; where the N-containing heterocycles are N- or
C-bridged and are not substituted or are substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(36)R(37); R(36) and R(37) independently of
one another are H, CH.sub.3, C.sub.2H.sub.5 or CF.sub.3; and the
remaining substituents of R(1), R(2), R(3), R(4) and R(5)
independently of one another are H, F, Cl, SO.sub.2NH.sub.2,
SO.sub.2CH.sub.3, NR(24)R(25), CN, (C.sub.1-C.sub.4)-alkyl,
CF.sub.3, C.sub.2F.sub.5, O--(C.sub.1-C.sub.4)-alkyl, OCF.sub.3,
OC.sub.2F.sub.5, (C.sub.3-C.sub.6)-cycloalkyl or
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.s- ub.4)-alkyl; R(24) and
R(25) independently of one another are H, alkyl having 1, 2, 3 or 4
carbon atoms; R(6) and R(7) independently of one another are H, F,
Cl, Br, I, CN, CH.sub.3, C.sub.2H.sub.5, CF.sub.3 or cycloalkyl
having 3, 4, 5 or 6 carbon atoms; or a pharmaceutically tolerable
salt thereof, in any stereoisomeric form, or a mixture of any such
compounds in any ratio.
5. A process for the preparation of a compound I as claimed in
claim 1 comprising reacting a compound of formula II 74in which
R(1) to R(7) are as defined in claim 1, and L is an easily
substitutable leaving group, with guanidine.
6. A method of treating arrhythmias comprising administering to a
patient in need thereof an effective amount of at least one
compound chosen from the compounds as claimed in claim 1.
7. A method of treating or preventing cardiac infarct comprising
administering to a patient in need thereof an effective amount of
at least one compound chosen from the compounds as claimed in claim
1.
8. A method of treating or preventing angina pectoris comprising
administering to a patient in need thereof an effective amount of
at least one compound chosen from the compounds as claimed in claim
1.
9. A method of treating or preventing ischemic conditions of the
heart comprising administering to a patient in need thereof an
effective amount of at least one compound chosen from the compounds
as claimed in claim 1.
10. A method of treating or preventing ischemic conditions of the
peripheral or central nervous system or stroke of the heart
comprising administering to a patient in need thereof an effective
amount of at least one compound chosen from the compounds as
claimed in claim 1.
11. A method of treating or preventing ischemic conditions of
peripheral organs and limbs comprising administering to a patient
in need thereof an effective amount of at least one compound chosen
from the compounds as claimed in claim 1.
12. A method of treating a state of shock comprising administering
to a patient in need thereof an effective amount of at least one
compound chosen from the compounds as claimed in claim 1.
13. A method of preserving and storing a transplant for surgical
measure, comprising contacting the transplant with an effective
amount of at least one compound chosen from the compounds as
claimed in claim 1.
14. A method of treating cell proliferation comprising
administering to a patient in need thereof an effective amount of
at least one compound chosen from the compounds as claimed in claim
1.
15. A pharmaceutical comprising an efficacious amount of at least
one compound chosen from the compounds as claimed in claim 1.
Description
[0001] This application claims the benefit of foreign priority
under 35 U.S.C. .sctn.119 of German patent application no.
10046993.0, filed on Sep. 22, 2000, the contents of which are
incorporated by reference herein.
[0002] The invention relates to substituted cinnamic acid
guanidides of the formula I 3
[0003] in which:
[0004] at least one of R(1), R(2), R(3), R(4) and R(5)
[0005] is --X.sub.a--Y.sub.b--L.sub.n--U;
[0006] X is CR(16)R(17), O, S or NR(18);
[0007] where R(16), R(17) and R(18)
[0008] independently of one another are H or an alkyl having 1, 2,
3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls;
[0009] a is zero or 1;
[0010] Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
alkylene-T having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the
alkylene group, T, or T-alkylene having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms in the alkylene group;
[0011] where T is NR(20), phenylene, O or S,
[0012] where the phenylene is not substituted or is substituted by
1-3 substituents chosen from F, Cl, CF.sub.3, methyl, methoxy and
NR(21)R(22);
[0013] where R(20), R(21) and R(22)
[0014] independently of one another are H or an alkyl having 1, 2,
3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls;
[0015] b is zero or 1;
[0016] L is O, S, NR(23) or C.sub.kH.sub.2k;
[0017] where k is 1, 2, 3, 4, 5, 6, 7 or 8;
[0018] where R(23)
[0019] is H or an alkyl group having 1, 2, 3 or 4 carbon atoms,
where the alkyl is chosen from unsubstituted alkyls, partially
fluorinated alkyls and completely fluorinated alkyls;
[0020] n is zero or 1;
[0021] U is 4
[0022] or a nitrogen-containing heterocycle having 1, 2, 3, 4, 5,
6, 7, 8 or 9 carbon atoms, which is substituted by an
--SO.sub.2NR(30)R(31)-- group;
[0023] where R(30) and R(31)
[0024] independently of one another are H or an alkyl group having
1,2,3,4,5,6,7 or 8 carbon atoms,
[0025] where in the alkyl group, independently of one another, one
or more CH.sub.2 groups can be replaced by O, NR(35), C.dbd.O, S or
C.dbd.S;
[0026] where R(35)
[0027] is H or alkyl having 1, 2, 3 or 4 carbon atoms, where the
alkyl is chosen from unsubstituted alkyls, partially fluorinated
alkyls and completely fluorinated alkyls;
[0028] or
[0029] R(30) and R(31)
[0030] independently of one another are H, an alkyl having 1, 2, 3,
4, 5, 6, 7 or 8 carbon atoms, where the alkyl is chosen from
partially fluorinated alkyls and completely fluorinated alkyls,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl-(C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl,
[0031] where in the alkyl or in the cycloalkyl ring, independently
of one another, one or more CH.sub.2 groups can be replaced by O,
NR(35), C.dbd.O, S or C.dbd.S;
[0032] or
[0033] R(30) and R(31)
[0034] together are 4 or 5 methylene groups,
[0035] where, independently of one another, one or more CH.sub.2
groups can be replaced by O, NR(35), C.dbd.O, S or C.dbd.S;
[0036] or
[0037] R(31) and R(35)
[0038] together are 4 or 5 methylene groups;
[0039] R(32), R(33) and R(34)
[0040] independently of one another are H, F, Cl, Br, I,
(C.sub.1-C.sub.4)-alkyl, partially fluorinated
(C.sub.1-C.sub.4)-alkyl, completely fluorinated
(C.sub.1-C.sub.4)-alkyl, O--(C.sub.1-C.sub.4)-alky- l, partially
fluorinated O--(C.sub.1-C.sub.4)-alkyl, completely fluorinated
O--(C.sub.1-C.sub.4)-alkyl, NO.sub.2, or NR(28)R(29);
[0041] where R(28) and R(29)
[0042] independently of one another are H or an alkyl having 1, 2,
3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls;
[0043] where the N-containing heterocycles are N- or C-bridged and
are unsubstituted or are substituted by 1-3 substituents selected
from the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(36)R(37); R(36) and R(37)
[0044] independently of one another are H, an alkyl having 1, 2, 3
or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated, and completely fluorinated alkyls,
or benzyl;
[0045] and the remaining substituents of R(1), R(2), R(3), R(4) and
R(5)
[0046] independently of one another are H, F, Cl, Br, I,
SO.sub.2NH.sub.2, SO.sub.2CH.sub.3, NO.sub.2, NR(24)R(25), CN,
unsubstituted (C.sub.1-C.sub.8)-alkyl, partially fluorinated
(C.sub.1-C.sub.8)-alkyl, completely fluorinated
(C.sub.1-C.sub.8)-alkyl, unsubstituted O--(C.sub.1-C.sub.8)-alkyl,
partially fluorinated O--(C.sub.1-C.sub.8)-al- kyl, completely
fluorinated O--(C.sub.1-C.sub.8)-alkyl,
(C.sub.3-C.sub.8)-cycloalkyl,
(C.sub.3-C.sub.8)-cycloalkyl-(C.sub.1-C.sub- .4)-alkyl or
phenyl-(C.sub.1-C.sub.4)-alkyl,
[0047] where the phenyl is not substituted or is substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(11)R(12);
[0048] R(11), R(12), R(24) and R(25)
[0049] independently of one another are H or an alkyl having 1, 2,
3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls;
[0050] R(6) and R(7)
[0051] independently of one another are H, F, Cl, Br, I, CN, an
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where the alkyl
is chosen from unsubstituted alkyls, partially fluorinated alkyls,
and completely fluorinated alkyls, cycloalkyl having 3, 4, 5, 6, 7
or 8 carbon atoms or phenyl,
[0052] where the phenyl is not substituted or is substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(14)R(15);
[0053] R(14) and R(15)
[0054] independently of one another are H or an alkyl having 1, 2,
3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls;
[0055] and their pharmaceutically tolerable salts.
[0056] In one embodiment, the compounds of the formula I are those
in which:
[0057] at least one of the substituents R(1), R(2), R(3), R(4) and
R(5)
[0058] is --X--U;
[0059] X is CR(16)R(17), O, S or NR(18);
[0060] R(16), R(17) and R(18)
[0061] independently of one another are H or an alkyl having 1, 2,
3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls;
[0062] U is 5
[0063] or a nitrogen-containing heterocycle having 1, 2, 3, 4, 5,
6, 7, 8 or 9 carbon atoms, which is substituted by an
--SO.sub.2NR(30)R(31)-- group; R(30) and R(31)
[0064] independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms,
[0065] where in the alkyl chain, independently of one another, one
or more CH.sub.2 groups can be replaced by O, NR(35), C.dbd.O, S or
C.dbd.S;
[0066] R(35)
[0067] is H or an alkyl having 1, 2, 3, 4 or 5 carbon atoms, where
the alkyl is chosen from unsubstituted alkyls, partially
fluorinated alkyls and completely fluorinated alkyls;
[0068] or
[0069] R(30) and R(31)
[0070] independently of one another are H, an alkyl having 1, 2, 3,
4, 5, 6, 7 or 8 carbon atoms, where the alkyl is chosen from
partially fluorinated alkyl and completely fluorinated alkyl,
(C.sub.3-C.sub.8)-cycloalkyl, phenyl-(C.sub.1-C.sub.4)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl,
[0071] where in the alkyl or in the cycloalkyl ring, independently
of one another, one or more CH.sub.2 groups can be replaced by O,
NR(35), C.dbd.O, S or C.dbd.S;
[0072] or
[0073] R(30) and R(31)
[0074] together are 4 or 5 methylene groups,
[0075] where, independently of one another, one or more CH2 groups
can be replaced by O, NR(35), C.dbd.O, S or C.dbd.S;
[0076] or
[0077] R(31) and R(35)
[0078] together are 4 or 5 methylene groups;
[0079] R(32), R(33) and R(34)
[0080] independently of one another are H, F, Cl, Br, I,
(C.sub.1-C.sub.4)-alkyl, O--(C.sub.1-C.sub.4)-alkyl, CF.sub.3 or
NR(28)R(29);
[0081] R(28) and R(29)
[0082] independently of one another are H or alkyl having 1, 2, 3
or 4 carbon atoms;
[0083] where the N-containing heterocycles are N- or C-bridged and
are not substituted or are substituted by 1-3 substituents selected
from the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(36)R(37); R(36) and R(37)
[0084] independently of one another are H, an alkyl having 1, 2, 3
or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated, and completely fluorinated alkyls,
or benzyl;
[0085] and the remaining substituents of R(1), R(2), R(3), R(4) and
R(5)
[0086] independently of one another are H, F, Cl, Br, I,
SO.sub.2NH.sub.2, SO.sub.2CH.sub.3, NO.sub.2, NR(24)R(25), CN,
unsubstituted (C.sub.1-C.sub.4)-alkyl, partially fluorinated
(C.sub.1-C.sub.4)-alkyl, completely fluorinated
(C.sub.1-C.sub.4)-alkyl, unsubstituted O--(C.sub.1-C.sub.4)-alkyl,
partially fluorinated O--(C.sub.1-C.sub.4)-al- kyl, completely
fluorinated O--(C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub- .4)-alkyl or
phenyl-(C.sub.1-C.sub.4)-alkyl,
[0087] where the phenyl is not substituted or is substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(11)R(12);
[0088] R(11), R(12), R(24) and R(25)
[0089] independently of one another are H or an alkyl having 1, 2,
3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted
alkyls, partially fluorinated alkyls, and completely fluorinated
alkyls;
[0090] R(6) and R(7)
[0091] independently of one another are hydrogen, F, Cl, Br, I, CN,
an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where the
alkyl is chosen from unsubstituted alkyls, partially fluorinated
alkyls, and completely fluorinated alkyls, cycloalkyl having 3, 4,
5, 6, 7 or 8 carbon atoms or phenyl,
[0092] which is not substituted or is substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and
[0093] NR(14)R(15);
[0094] R(14) and R(15)
[0095] independently of one another are H, alkyl having 1, 2, 3 or
4 carbon atoms, where the alkyls are chosen from unsubstituted
alkyls, partially fluorinated alkyls and completely fluorinated
alkyls;
[0096] and their pharmaceutically tolerable salts.
[0097] In another embodiment, the compounds of the formula I are
those in which: at least one of the substituents R(1), R(2), R(3),
R(4) and R(5)
[0098] is --X--U;
[0099] X is CR(16)R(17), O, S or NR(18);
[0100] R(16), R(17) and R(18)
[0101] independently of one another are H, alkyl having 1, 2, 3 or
4 carbon atoms or CF.sub.3;
[0102] U is 6
[0103] or a nitrogen-containing heterocycle having 1, 2, 3, 4, 5 or
6 carbon atoms, which is substituted by an --SO.sub.2NR(30)R(31)
group;
[0104] R(30) and R(31)
[0105] independently of one another are H, alkyl having 1, 2, 3, 4,
5, 6, 7 or 8 carbon atoms, CF.sub.3, (C.sub.3-C.sub.8)-cycloalkyl,
where in the alkyl, independently of one another, one or more
CH.sub.2 groups can be replaced by O, NR(35), C.dbd.O, S or
C.dbd.S;
[0106] where R(35)
[0107] is H or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
[0108] or
[0109] R(30) and R(31)
[0110] together are 4 or 5 methylene groups,
[0111] where, independently of one another, one or more CH.sub.2
groups can be replaced by O, NR(35), C.dbd.O, S or C.dbd.S;
[0112] or
[0113] R(31) and R(35)
[0114] together are 4 or 5 methylene groups;
[0115] R(32), R(33) and R(34)
[0116] independently of one another are H, F, Cl, methyl, ethyl,
Omethyl, Oethyl, CF.sub.3, NH.sub.2, NHmethyl or Nmethyl.sub.2;
[0117] where the N-containing heterocycles are N- or C-bridged and
are not substituted or are substituted by 1-3 substituents selected
from the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(36)R(37); R(36) and R(37)
[0118] independently of one another are H, alkyl having 1, 2, 3 or
4 carbon atoms, CF.sub.3 or benzyl;
[0119] and the remaining substituents of R(1), R(2), R(3), R(4) and
R(5)
[0120] independently of one another are H, F, Cl, Br, I,
SO.sub.2NH.sub.2, SO.sub.2CH.sub.3, NR(24)R(25), CN,
(C.sub.1-C.sub.4)-alkyl, CF.sub.3, C.sub.2F.sub.5,
O--(C.sub.1-C.sub.4)-alkyl, OCF.sub.3, OC.sub.2F.sub.5,
(C.sub.3-C.sub.6)-cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub- .4)-alkyl or
phenyl-(C.sub.1-C.sub.4)-alkyl,
[0121] where the phenyl is not substituted or is substituted by 1-3
substituents selected from the group consisting of F, Cl, CF.sub.3,
methyl, methoxy and NR(11)R(12);
[0122] R(11), R(12), R(24) and R(25)
[0123] independently of one another are H or alkyl having 1, 2, 3
or 4 carbon atoms;
[0124] R(6) and R(7)
[0125] independently of one another are hydrogen, F, Cl, Br, I, CN,
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CF.sub.3,
cycloalkyl having 3, 4, 5 or 6 carbon atoms;
[0126] and their pharmaceutically tolerable salts.
[0127] In a further embodiment, compounds of the formula I are
those in which: at least one of the substituents R(1), R(2), R(3),
R(4) and R(5)
[0128] is --X--U;
[0129] X is CR(16)R(17), O, S or NR(18);
[0130] R(16), R(17) and R(18)
[0131] independently of one another are H, CH.sub.3, C.sub.2H.sub.5
or CF.sub.3;
[0132] U is 7
[0133] or an N-containing heterocycle having 3, 4 or 5 carbon
atoms, which is substituted by an --SO.sub.2NR(30)R(31)- group;
[0134] R(30) and R(31)
[0135] independently of one another are hydrogen or alkyl having 1,
2, 3, 4, 5, 6, 7 or 8 carbon atoms, CF.sub.3,
(C.sub.3-C.sub.8)-cycloalkyl;
[0136] where in the alkyl, independently of one another, one or
more CH.sub.2 groups can be replaced by O, NR(35), C.dbd.O, S or
C.dbd.S;
[0137] R(35)
[0138] is H or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
[0139] or
[0140] R(30) and R(31)
[0141] together are 4 or 5 methylene groups,
[0142] where, independently of one another, one or more CH.sub.2
groups can be replaced by O, NR(35), C.dbd.O, S or C.dbd.S;
[0143] or
[0144] R(31) and R(35)
[0145] together are 4 or 5 methylene groups;
[0146] R(32), R(33) and R(34)
[0147] independently of one another are H, F, Cl, methyl, CF.sub.3;
where the N-containing heterocycles are N- or C-bridged and are not
substituted or are substituted by 1-3 substituents selected from
the group consisting of F, Cl, CF.sub.3, methyl, methoxy and
NR(36)R(37); R(36) and R(37)
[0148] independently of one another are H, CH.sub.3, C.sub.2H.sub.5
or CF.sub.3; and the remaining substituents of R(1), R(2), R(3),
R(4) and R(5)
[0149] independently of one another are H, F, Cl, SO.sub.2NH.sub.2,
SO.sub.2CH.sub.3, NR(24)R(25), CN, (C.sub.1-C.sub.4)-alkyl,
CF.sub.3, C.sub.2F.sub.5, O--(C.sub.1-C.sub.4)-alkyl, OCF.sub.3,
OC.sub.2F.sub.5, (C.sub.3-C.sub.6)-cycloalkyl or
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.s- ub.4)-alkyl;
[0150] R(24) and R(25)
[0151] independently of one another are H, alkyl having 1, 2, 3 or
4 carbon atoms;
[0152] R(6) and R(7)
[0153] independently of one another are H, F, Cl, Br, I, CN,
CH.sub.3, C.sub.2H.sub.5, CF.sub.3 or cycloalkyl having 3, 4, 5 or
6 carbon atoms;
[0154] and their pharmaceutically tolerable salts.
[0155] If the compounds of the formula I contain one or more
centers of asymmetry, these can have either the S or R
configuration . The compounds may be present as optical isomers, as
diastereomers, as racemates or as mixtures thereof, including
mixtures of at least one stereoisomeric form and at least one
pharmaceutically tolerable salt.
[0156] The double bond geometry of the compounds of the formula I
may be either E or Z. The compounds may be present in a mixture of
double bond isomers.
[0157] The designated alkyls, including substituted alkyls
partially fluorinated alkyls and completely fluorinated alkyls may
be chosen from straight-chain alkyls or branched alkyls.
[0158] N-containing heterocycles having 1, 2, 3, 4, 5, 6, 7, 8 or 9
carbon atoms include, but at not limited to, pyrrolyl, imidazolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl,
isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl,
cinnolinyl.
[0159] In one embodiment, the N-containing heterocycles are chosen
from pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,
pyrimidinyl and pyridazinyl.
[0160] In a further embodiment, the N-containing heterocycles is
chosen from Pyridyl.
[0161] The invention furthermore relates to a process for the
preparation of the compounds I, which comprises reacting a compound
of the formula II 8
[0162] in which R(1) to R(7) have the meanings indicated and L is
an easily nucleophilically substitutable leaving group, with
guanidine.
[0163] Examples of leaving groups include, but are not limited to,:
--OMe, --OEt, --OPh, --SPh, --SMe, and 1-imidazolyl.
[0164] The activated acid derivatives of the formula II, in which L
is an alkoxy group, for example a methoxy group, a phenoxy group,
phenylthio group, methylthio group or 2-pyridylthio group, a
nitrogen heterocycle, for example 1-imidazolyl, may be obtained,
for example, in a manner known per se from the carboxylic acid
chlorides on which they are based (formula II, L=Cl), which for
their part may in turn be prepared in a manner known per se from
the carboxylic acids on which they are based (formula II, L=OH),
for example using thionyl chloride.
[0165] Beside the carboxylic acid chlorides of the formula II
(L=Cl), other activated acid derivatives of the formula II may also
be prepared directly from the benzoic acid derivatives on which
they are based (formula II, L=OH) in a manner known per se, such as
the methyl esters of the formula II with L=OCH.sub.3 by treating
with gaseous HCl in methanol, the imidazolides of the formula II by
treating with carbonyldiimidazole [L=1-imidazolyl, Staab, Angew.
Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II
with C.sub.1--COOC.sub.2H.sub.5 or tosyl chloride in the presence
of triethylamine in an inert solvent, and the activation of benzoic
acids with dicyclohexylcarbodiimide (DCC) or with
O-[(cyano(ethoxycarbonyl)methylene)-amino]-1,1,3,3-tetramethyluroniumtetr-
afluoroborate ("TOTU") [Proceedings of the 21st European Peptide
Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom,
Leiden, 1991]. A number of suitable methods for the preparation of
activated carboxylic acid derivatives of the formula II are given
with details of the source literature in J. March, Advanced Organic
Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.
[0166] The reaction of an activated carboxylic acid derivative of
the formula II with guanidine may be carried out in a manner known
per se in a protic or aprotic polar but inert organic solvent. In
the reaction with guanidine of the methyl or ethyl benzoates (II,
L=Ome, OEt), methanol, isopropanol, DMF or THF from 20.degree. C.
up to the boiling temperature of these solvents may be suitable.
Most reactions of compounds II with salt-free guanidine may be
carried out in aprotic inert solvents such as THF, DMF,
dimethoxyethane or dioxane. IN one embodiment, when using a base
such as, for example, NaOH, water may also be used as solvent in
the reaction of II with guanidine.
[0167] When L=Cl, the reaction may be carried out, for example,
with addition of an acid scavenger, e.g. in the form of excess
guanidine, for the binding of the hydrohalic acid.
[0168] Some of the underlying benzoic acid derivatives of the
formula II are known and described in the literature. The unknown
compounds of the formula II may be prepared by methods known from
the literature. The alkenylcarboxylic acids obtained may be reacted
by one of the process variants described above to give compounds I
according to the invention.
[0169] The introduction of some substituents may be achieved by
methods known from the literature of palladium-mediated
cross-coupling of aryl halides or aryl triflates with, for example,
organostannanes, organoboronic acids or organoboranes or
organocopper or -zinc compounds.
[0170] In general, carboxylguanidines I are weak bases and may bind
acid with formation of salts. Possible acid addition salts include,
but are not limited to, salts of all pharmacologically tolerable
acids, for example halides, such as hydrochlorides, lactates,
sulfates, citrates, tartrates, acetates, phosphates,
methylsulfonates and p-toluenesulfonates.
[0171] The compounds I may be substituted acylguanidines.
[0172] Similar cinnamic acid guanidides are disclosed in European
laid-open publication 755 919 (HOE 94/F 168), but these known
compounds do not meet all desired requirements. Using the compounds
of the formula I, it was possible to achieve improved water
solubility, which may result in increased excretion via the
kidneys. Moreover, in one embodiment, the compounds of the formula
I show a very good inhibitory action on NHE.sub.3 (Na.sup.+/H.sup.+
exchanger subtype 3). This may be achieved by the compounds
according to the invention, which, in one embodiment, have no
undesired and disadvantageous salidiuretic properties, but very
good antiarrhythmic properties, such as are useful, for example,
for the treatment of illnesses which are caused by oxygen
deficiency. As a result of their pharmacological properties, the
compounds may be suitable, as antiarrhythmic pharmaceuticals having
a cardioprotective component, for infarct prophylaxis and infarct
treatment and also for the treatment of angina pectoris, where they
also preventively inhibit or greatly decrease the
pathophysiological processes in the formation of ischemically
induced damage, in particular in the induction of ischemically
induced cardiac arrhythmias.
[0173] In one embodiment, because of their protective actions
against pathological hypoxic and ischemic situations, the compounds
of the formula I according to the invention may be used, as a
result of inhibition of the cellular Na.sup.+/H.sup.+ exchange
mechanism, as pharmaceuticals for the treatment of all acute or
chronic damage induced by ischemia or illnesses primarily or
secondarily induced thereby. This relates to their use as
pharmaceuticals for surgical interventions, e.g. in organ
transplantation, where the compounds may be used both for the
protection of the organs in the donor before and during removal,
for the protection of removed organs, for example during treatment
with or storage thereof in physiological bath fluids, and during
transfer to the recipient's body. The compounds may also be
valuable pharmaceuticals which have a protective action when
carrying out angioplastic surgical interventions, for example on
the heart and on peripheral vessels. Corresponding to their
protective action against ischemically induced damage, the
compounds may also be suitable as pharmaceuticals for the treatment
of ischemias of the nervous system, in particular of the CNS, where
they may be suitable, for example, for the treatment of stroke or
of cerebral edema. Moreover, the compounds of the formula I
according to the invention may likewise be suitable for the
treatment of forms of shock, such as, for example, of allergic,
cardiogenic, hypovolemic and of bacterial shock.
[0174] In another embodiment, the compounds may furthermore induce
an improvement in the respiratory drive and may therefore be used
for the treatment of respiratory conditions in the following
clinical conditions and illnesses: impaired central respiratory
drive (e.g. central sleep apneas, sudden infant death,
postoperative hypoxia), muscle-related respiratory disorders,
respiratory disorders after long-term respiration, respiratory
disorders during adaptation in a high mountain region, obstructive
and mixed forms of sleep apneas, acute and chronic lung diseases
with hypoxia and hypercapnia.
[0175] The compounds may additionally increase the muscle tone of
the upper airways, so that snoring is suppressed.
[0176] In one embodiment, a combination of an NHE inhibitor with a
carboanhydrase inhibitor (e.g. acetazolamide), the latter producing
a metabolic acidosis and thereby even increasing the respiratory
activity, proves to be a favorable combination with increased
action and decreased use of active compound.
[0177] It has been shown that the compounds according to the
invention may have a mild laxative effect and accordingly may be
used as laxatives or if there is a threat of intestinal blockage,
the prevention of the ischemic damage which accompanies blockages
in the intestinal area being particularly advantageous.
[0178] There is furthermore the possibility of preventing gallstone
formation.
[0179] In another embodiment, the compounds of the formula I
according to the invention may moreover be distinguished by strong
inhibitory action of the proliferation of cells, for example,
fibroblast cell proliferation and the proliferation of vascular
smooth muscle cells. The compounds of the formula I may therefore,
in one embodiment, be suitable as valuable therapeutics for
illnesses in which cell proliferation is a primary or secondary
cause, and may therefore be used as antiatherosclerotics, agents
against diabetic late complications, carcinomatous disorders,
fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or
renal fibrosis, organ hypertrophies and hyperplasias, in particular
in prostate hyperplasia or prostate hypertrophy.
[0180] In a further embodiment, the compounds according to the
invention may be effective inhibitors of the cellular sodium-proton
antiporter (Na.sup.+/H.sup.+ exchanger), which is raised in
numerous disorders (essential hypertension, atherosclerosis,
diabetes etc.) even in those cells which are easily accessible to
measurements, such as, for example, in erythrocytes, platelets or
leukocytes. The compounds according to the invention may therefore,
in one embodiment, be suitable as outstanding and simple scientific
tools, for example in their use as diagnostics for the
determination and differentiation of certain forms of hypertension,
but also of atherosclerosis, of diabetes, proliferative disorders,
etc. Moreover, the compounds of the formula I may be suitable for
preventive therapy for averting the genesis of high blood pressure,
for example of essential hypertension.
[0181] It has additionally been found that NHE inhibitors may have
a favorable influence on the serum lipoproteins. It is generally
recognized that for the formation of arteriosclerotic vascular
changes, in particular of coronary heart disease, excessively high
blood lipid values, so-called hyperlipoproteinemias, are a
significant risk factor. The lowering of raised serum lipoproteins
is therefore of extreme importance for the prophylaxis and the
regression of atherosclerotic changes. In one embodiment, the
compounds according to the invention may therefore be used for the
prophylaxis and for the regression of atherosclerotic changes, in
that they exclude a causal risk factor. With this protection of the
vessels against the endothelial dysfunction syndrome, compounds of
the formula I may be valuable pharmaceuticals for the prevention
and for the treatment of coronary vasospasms, atherogenesis and
atherosclerosis, left-ventricular hypertrophy and dilated
cardiomyopathy, and thrombotic disorders.
[0182] The compounds mentioned may therefore be used advantageously
for the production of a medicament for the prevention and treatment
of sleep apneas and muscle-related respiratory disorders; for the
production of a medicament for the prevention and treatment of
snoring; for the production of a medicament for lowering blood
pressure; for the production of a medicament having a laxative
effect for the prevention and treatment of intestinal blockages;
for the production of a medicament for the prevention and treatment
of disorders induced by ischemia and reperfusion of central and
peripheral organs, such as acute kidney failure, stroke, endogenous
states of shock, intestinal disease etc.; for the production of a
medicament for the treatment of hypercholesterolemia; for the
production of a medicament for the prevention of atherogenesis and
atherosclerosis; for the production of a medicament for the
prevention and treatment of diseases which are caused by increased
cholesterol levels; for the production of a medicament for the
prevention and treatment of diseases which are caused by
endothelial dysfunction; for the production of a medicament for the
treatment of attack by ectoparasites; for the production of a
medicament for the treatment of the illnesses mentioned in
combinations with hypotensive substances, preferably with
angiotensin-converting enzyme (ACE) inhibitors and angiotensin
receptor antagonists. A combination of an NHE inhibitor of the
formula I with a blood lipid level-lowering active compound,
preferably with an HMG-CoA-reductase inhibitor (e.g. lovastatin or
pravastatin), where the latter produces a hypolipidemic action and
thereby increases the hypolipidemic properties of the NHE inhibitor
of the formula 1, proves to be a favorable combination with
increased action and decreased use of active compound.
[0183] In a further embodiment, the administration of sodium/proton
exchange inhibitors of the formula I may be used as novel
pharmaceuticals for lowering increased blood lipid levels, and also
the combination of sodium/proton exchange inhibitors with
hypotensive and/or hypolipidemic pharmaceuticals.
[0184] Pharmaceuticals which contain a compound I may in this case
be administered, for example, orally, parenterally, intravenously,
rectally or by inhalation. In one embodiment, administration is
dependent on the particular clinical picture of the disorder. The
compounds I may in this case be used on their own or together with
pharmaceutical auxiliaries, to be specific both in veterinary and
in human medicine. The person skilled in the art is familiar on the
basis of his expert knowledge with auxiliaries which are suitable
for the desired pharmaceutical formulation. Beside solvents,
gel-forming agents, suppository bases, tablet auxiliaries and other
active compound excipients, it is possible to use, for example,
antioxidants, dispersants, emulsifiers, antifoams, flavor
corrigents, preservatives, solubilizers or colorants.
[0185] For an oral administration form, the active compounds may,
for example, be mixed with the additives suitable for this, such as
excipients, stabilizers or inert diluents, and are brought by means
of the customary methods into the suitable administration forms,
such as tablets, coated tablets, hard gelatin capsules, or aqueous,
alcoholic or oily solutions. Inert excipients which can be used
are, for example, gum arabic, magnesia, magnesium carbonate,
potassium phosphate, lactose, glucose or starch, in particular corn
starch. In this case preparation can take place either as dry or as
moist granules. Suitable oily excipients or solvents are, for
example, vegetable or animal oils, such as sunflower oil or cod
liver oil.
[0186] For subcutaneous or intravenous administration, the active
compounds may be brought into solution, suspension or emulsion, if
desired using the substances customary for this, such as
solubilizers, emulsifiers or other auxiliaries. Possible solvents
are, for example: water, physiological saline solution or alcohols,
e.g. ethanol, propanol, glycerol, in addition also sugar solutions
such as glucose or mannitol solutions, or alternatively a mixture
of the various solvents mentioned.
[0187] Suitable pharmaceutical formulations for administration in
the form of aerosols or sprays may be, for example, solutions,
suspensions or emulsions of the active compound of the formula I in
a pharmaceutically acceptable solvent, such as, in particular,
ethanol or water, or a mixture of such solvents.
[0188] If desired, the formulation may also contain other
pharmaceutical auxiliaries such as surfactants, emulsifiers and
stabilizers, as well as a propellant. Such a preparation contains
the active compound customarily in a concentration of approximately
0.1 to 10, in particular from approximately 0.3 to 3,% by
weight.
[0189] The dose of the active compound of the formula I to be
administered and the frequency of administrationdepend on the
potency and duration of action of the compounds used; additionally
also on the nature and severity of the illness to be treated and on
the sex, age, weight and individual responsiveness of the mammal to
be treated.
[0190] On average, the daily dose of a compound of the formula I in
the case of a patient approximately 75 kg in weight is at least
0.001 mg/kg, preferably 0.01 mg/kg, to at most 10 mg/kg, preferably
1 mg/kg, of body weight. In acute episodes of the illness, for
example, directly after suffering a cardiac infarct, even higher
and especially more frequent doses may also be necessary, e.g. up
to 4 individual doses per day. In particular on i.v.
administration, for example in the case of an infarct patient in
the intensive care unit, up to 200 mg per day may be necessary.
[0191] List of abbreviations:
[0192] MeOH Methanol
[0193] DMF N,N-Dimethylformamide
[0194] EI Electron impact
[0195] DCI Desorption-chemical ionisation
[0196] RT Room temperature
[0197] EA Ethyl acetate (EtOAc)
[0198] mp Melting point
[0199] HEP n-Heptane
[0200] DME Dimethoxyethane
[0201] ES Electron spray
[0202] FAB Fast atom bombardment
[0203] C.sub.1-Chemical ionization
[0204] CH.sub.2Cl.sub.2 Dichloromethane
[0205] THF Tetrahydrofuran
[0206] eq. Equivalent
[0207] TFA Trifluoroacetate
[0208] LCMS Liquid chromatography mass spectroscopy
[0209] Experimental Section
[0210] General Procedure for the Preparation of Alkenylcarboxylic
Acid Guanidides (I)
[0211] Variant 1 A: from alkyl alkenylcarboxylates (II,
L=O-alkyl)
[0212] 5.0 eq. of potassium tertiary-butoxide are introduced into
DMF, treated with 6.0 eq. of guanidine hydrochloride and the
mixture is stirred at room temperature for 30 min. 1.0 eq. of the
alkyl cinnamate is added to this solution and it is stirred at room
temperature until an increase in conversion can no longer be
determined by means of a thin-layer chromatogram or CMS. For
work-up, the solvent is distilled off under reduced pressure. The
residue is taken up in H.sub.2O and treated dropwise with 1 N HCl
until a precipitate deposits. This is filtered off with suction and
washed with EA. The HCl salt of the alkenylcarboxylic acid
guanidide thus obtained can be converted into the free
cinnamoylguanidine by treatment with bases. In turn, it is possible
to prepare other pharmacologically tolerable salts from these by
treating with aqueous, methanolic or ethereal solutions of organic
or inorganic acids.
[0213] Variant 1 B: from alkenylcarboxylic acids (II, L=OH)
[0214] 1.0 eq. of the cinnamic acid derivative is introduced into
DMF, 1.1 eq. of carbonyidiimidazole are added and the mixture is
stirred at room temperature for 3 h. A solution of the guanidine
base, freshly prepared as described under 1 A, is added to this
solution and it is additionally stirred at room temperature until
complete conversion is achieved, or an increase in conversion can
no longer be determined. The work-up is carried out analogously to
the procedure described in 1 A.
[0215] The retention times (Rt) indicated below relate to LCMS
measurements using the following parameters:
1 Stationary phase: Merck Purospher 3.mu., 2 .times. 55 mm Mobile
phase: 95% H.sub.2O (0.05% TFA) .fwdarw. 95% acetonitrile; 4 min;
95% acetonitrile; 1.5 min .fwdarw. 5% acetonitrile; 1 min; 0.5
ml/min.
EXAMPLE 1
[0216]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]benze-
nesulfonamide; HCl salt 9
[0217] Intermediate 1:
[0218] Ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate 10
[0219] 1.0 eq. of 3,4,5-trifluorobenzaldehyde is dissovied in DMF
and stirred at room temperature with 1.1 eq. of ethyl
2-(triphenylphosphanyli- dene)propionate until complete conversion
can be determined by means of thin-layer chromatography. The
mixture is freed from the solvent and the residue is stirred in
diisopropyl ether. The insoluble residue is filtered off, the
filtrate is concentrated in vacuo and the residue is
chromatographed on silica gel (EA/heptane 1:1), the title compound
being obtained in the form of a colorless solid. (M.p.:
66-68.degree. C.).
[0220] Intermediate 2:
[0221] Ethyl 3-[3,5-difluoro-4-(4-sulfamoyl
phenoxy)phenyl]-2-methylacryla- te 11
[0222] 1.5 eq. of 4-hydroxybenzenesulfonamide are treated with the
equimolar amount of NaH in dimethylacetamide and deprotonated at
room temperature for 1 h. A solution of 1.0 eq. of the intermediate
1 in dimethylacetamide is added dropwise and the reaction mixture
is stirred at 150.degree. C. until starting material can no longer
be detected by means of TLC or LCMS. For work-up, the solvent is
removed in vacuo, the residue is taken up in H.sub.2O and the
mixture is extracted 2.times. with EA. The organic phases are dried
using MgSO.sub.4 and concentrated.
[0223] Chromatography on silica gel gives the desired bisphenyl
ether as a colorless solid in 40 to 50% of the theoretical yield.
(MS-ES+: 398.2; M.p.: 113-115.degree. C.).
[0224]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]benze-
nesulfonamide; HCl salt
[0225] The reaction of the intermediate 2 according to the method
described under 1 A yields the title compound as a colorless solid.
(MS-ES+: 411.0; LCMS-R.sub.t=3.710 min).
Example 2
[0226]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]benze-
nesulfonamide; methanesulfonate 12
[0227] The compound described in Example 1 is converted into the
corresponding methanesulfonate using acetonitrile/H2O mixtures, 1%
strength in methanesulfonic acid. (MS-ES+: 411.2;
LCMS-R.sub.t=3.995 min).
Example 3
[0228]
4-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenoxy]benzenesulfonamide-
; HCl salt 13
[0229] Intermediate 1
[0230] Ethyl 2-methyl-3-(4-fluorophenyl)acrylate 14
[0231] Analogous procedure to that in the case of intermediate 1,
starting from 4-fluorobenzaldehyde Example 1 gives the desired
cinnamic acid ester in almost quantitative yield as a colorless
oil. (MS-Cl+: 209.2).
[0232] Intermediate 2
[0233] Ethyl 2-methyl-3-[4-(4-sulfamoylphenoxy)phenyl]acrylate
15
[0234] can be prepared according to the procedure described in
intermediate 2, Example 1, where on account of the lower reactivity
of the monofluoro compound (intermediate 1), lower yields have to
be expected. The title compound can be isolated as a colorless
oil.
[0235]
4-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenoxy]benzenesulfonamide-
; HCl salt Intermediate 2 is reacted according to the manner
described in 1 A, 75% of the desired cinnamic acid guanidide being
obtained as a crystalline solid. (MS-ES+: 375.2; LCMS-R.sub.t=3.933
min).
Example 4
[0236]
4-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenylamino]benzenesulfona-
mide; trifluoroacetate 16
[0237] Intermediate 1
[0238] Ethyl 2-methyl-3-(4-bromophenyl)acrylate 17
[0239] Analogous procedure to that in the case of intermediate 1,
starting from 4-bromobenzaldehyde, Example 1 yields the desired
cinnamic acid ester in almost quantitative yield as a colorless
oil. (MS-Cl+: 269.1/ 271.1).
[0240] Intermediate 2:
[0241] 4-Amino-N-dimethylaminomethylenebenzenesulfonamide 18
[0242] is synthesized in a manner known to the person skilled in
the art, starting from 4-aminobenzenesulfonam ide and DMF dimethyl
acetal (see, for ex ample: J. Med. Chem., 1983, 26, 1174-1187).
(MS-ES+: 228.0).
[0243] Intermediate 3:
[0244] Ethyl 3-{4-[4-(dimethylaminomethylene
sulfamoyl)phenylamino]phenyl}- -2-methylacrylate 19
[0245] 1.4 eq. of Cs.sub.2CO.sub.3, 0.03 eq. or Pd(OAc).sub.2, as
well as 0.045 eq. of 2,2-bis(diphenyl-phosphino)-1
,1'-binaphthalene are introduced in anhydrous toluene under argon.
1.0 eq. of intermediate 1, as well as 1.2 eq. of intermediates 2,
are added to this solution and it is stirred at 100.degree. C.
under a protective gas atmosphere until complete conversion can be
determined (TLC or LCMS). For work-up, it is treated with ether and
the resulting precipitate is filtered off. The filtrate is
concentrated and purified on silica gel, it being possible to
isolate the desired product as a colorless oil. (MS-ES+:
416.3).
[0246] Intermediate 4:
[0247] 2-Methyl-3-[4-(4-sulfamoylphenylamino)phenyl]acrylic acid
20
[0248] The intermediate 3 is heated at 40 to 60.degree. C. for 4 to
5 h in 2 N NaOH. The mixture is then concentrated in vacuo, the
residue is taken up in H.sub.2O and a pH of 6 to 7 is set using 2N
HCl, the product depositing in the form of a slightly yellow solid.
Filtering off with suction and drying over P.sub.2O.sub.5 gives the
desired cinnamic acid derivative in a yield of 90%. (MS-ES+:
333.2).
[0249] 4-[4-(3-Guanidino-2-methyl-3-oxopropenyl
)phenylamino]benzenesulfon- amide; trifluoroacetate Starting from
intermediate 4, the title compound is prepared by the procedure
described in 1 B. After HPLC, the product is isolated as a
yellowish crystalline solid in a yield of 40 to 50%. (MS-ES+:
374.2; LCMS R.sub.t=3.761 min).
Example 5
[0250]
3-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenylamino]benzenesulfona-
mide, trifluoroacetate 21
[0251] Intermediate 1:
[0252] Ethyl 2-methyl-3-(4-bromophenyl)acrylate 22
[0253] see Example 4
[0254] Intermediate 2:
[0255] 3-Amino-N-dimethylaminomethylenebenzenesulfonamide 23
[0256] is synthesized in the manner known to the person skilled in
the art, starting from 3-aminobenzenesulfonamide and DMF dimethyl
acetal (see, for example: J. Med. Chem., 1983, 26, 1174-1187).
(MS-ES+: 228.0).
[0257] Intermediate 3:
[0258] Ethyl
3-{4-[3-(dimethylaminomethylenesulfamoyl)phenylamino]phenyl}--
2-methylacrylate 24
[0259] The synthesis of the title compound is carried out to a
procedure analogous to intermediate 3, Example 4, it being possible
to isolate 77% of the desired product. (MS-ES+: 416.3).
[0260] Intermediate 4:
[0261] 2-Methyl-3-[4-(3-sulfamoylphenylamino)phenyl]acrylic acid
25
[0262] The protective group removal and ester cleavage of
intermediate 3 is carried out according to the procedure specified
in Example 4, intermediate 4, it being possible to isolate
intermediate 4 in the form of a colorless solid in 87% yield.
(MS-ES+: 333.1).
[0263]
3-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenylamino]benzenesulfona-
mide, trifluoroacetate
[0264] Starting from intermediate 4, the title compound is prepared
by the procedure described in 1 B. After HPLC, the product is
isolated as a yellowish crystalline solid in a yield of 40 to 50%.
(MS-ES+: 374.2; LCMS R.sub.t=3.851 min).
Example 6
[0265]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]-N-(2-
-dimethylaminoethyl)benzenesulfonamide, HCl salt 26
[0266] Intermediate 1:
[0267] 4-Hydroxybenzenesulfonyl chloride 27
[0268] is synthesized by processes known from the literature (R. W.
Campbell, H. W. Hill, jr.; J. Org. Chem., 38, 1973, 1047.)
[0269] Intermediate 2:
[0270] N-(2-Dimethylaminoethyl)-4-hydroxybenzenesulfonamide 28
[0271] 1.0 eq. of the intermediate 1 is introduced in
dichloromethane and 2.2 eq. of N,N-dimethylaminoethanediamine,
dissolved in dichloromethane, are added dropwise at room
temperature and the mixture is stirred at room temperature. After
complete conversion has been detected, the mixture is freed from
the solvent and the residue is taken up in H2O. It is extracted
2.times. with EA and the aqueous phase is concentrated in vacuo.
The residue is washed once with acetone and recrystallized from hot
isopropanol, the sulfonamide being isolated as a colorless solid.
(M.P.: 165-168.degree. C.).
[0272] Intermediate 3:
[0273] Ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate 29
[0274] see Example 1.
[0275] Intermediate 4:
[0276] Ethyl
3-[4-[4-(2-dimethylaminoethylsulfamoyl)phenoxy]-3,5-difluorop-
henyl}-2methylacrylate 30
[0277] 1.5 eq. of intermediate 2 are treated with 1.75 eq. of NaH
in dimethylacetamide and the mixture is stirred at 75.degree. C.
for 30 min with exclusion of moisture. A solution of 1.0 eq. of
intermediate 3 in dimethylacetamide is added thereto and the
mixture is stirred at 150.degree. C. until an increase in
conversion can no longer be detected (DC, LCMS). For work-up, the
mixture is freed from the solvent and the residue is taken in
H.sub.2O . The aqueous phase is extracted 2.times. with EA, dried
using MgSO.sub.4 and concentrated. The crude product thus obtained
is purified by chromatography on silica gel.
[0278]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]-N-(2-
-dimethyl-aminoethyl)benzenesulfonamide, HCl salt
[0279] Intermediate 4 is converted according to the method
described in 1 A into the corresponding cinnamic acid guanidide,
which can be isolated in the form of a yellowish solid. (MS-ES+:
482.2; LCMS R.sub.t=3.750 min).
Example 7
[0280]
N-(3-{3,5-Difluoro-4-[4-(4-methylpiperazin-1-sulfonyl)phenoxy]pheny-
l}-2-methylacryloyl)guanidine; trifluoroacetate 31
[0281] Intermediate 1:
[0282] 4-Hydroxybenzenesulfonyl chloride 32
[0283] is synthesized according to a process known from the
literature (R. W. Campbell, H. W. Hill, jr.; J. Org. Chem.,
38,1973,1047).
[0284] Intermediate 2:
[0285] 4-(4-Methylpiperazin-1-sulfonyl)phenol 33
[0286] 1.0 eq. of intermediate 1 is introduced in dichloromethane
and 2.0 eq. of N-methylpiperazine, dissolved in dichloromethane,
are added dropwise at room temperature and the mixture is stirred
at room temperature. After complete conversion has been determined,
the resulting precipitate is filtered off. The filtrate is dried
using MgSO.sub.4 and freed from the solvent. The crude product thus
obtained can be employed in the next step without further
purification. (M.p.: 225-227.degree. C.).
[0287] Intermediate 3:
[0288] Ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate 34
[0289] see Example 1.
[0290] Intermediate 4:
[0291] Ethyl
3-{3,5-difluoro-4-[4-(4-methylpiperazine-1-sulfonyl)phenoxy]
phenyl}-2-methylacrylate 35
[0292] 1.0 eq. of intermediate 2 is dissolved in dimethylacetamide
and treated with 1.2 eq. of NaH at room temperature. After 30 min
at 75.degree. C., a solution of 0.7 eq. of intermediate 3 in
dimethylacetamide is added dropwise and the mixture is stirred at
150.degree. . After conversion is complete, the mixture is freed
from the solvent. The residue is taken up in H.sub.2O , adjusted to
a pH of 7 to 8 and extracted 2.times. with EA. The organic phases
are dried using MgSO.sub.4 and concentrated. The residue is
purified on silica, the title compound being isolated in a yield of
50 to 60%.
[0293] N-(3-{3,
5-Difluoro-4-[4-(4-methylpiperazine-1-sulfonyl)phenoxy]phe-
nyl}-2-methylacryloyl)guanidine; trifluoroacetate
[0294] Intermediate 4 is converted according to the method
described in 1 A into the corresponding cinnamic acid guanidide,
which can be isolated in the form of a yellowish solid. Final
purification by means of HPLC gives the corresponding TFA salt.
(MS-ES+: 494.3; LCMS R.sub.t=3.809 min).
Example 8
[0295] 4-[2
,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]benz-
enesulfone N-(carboxy-N'-methylamid)amide; HCl salt 36
[0296] Intermediate 1:
[0297] Ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate 37
[0298] see Example 1.
[0299] Intermediate 2:
[0300] Ethyl 3-[3,5-d
ifluoro-4-(4-sulfamoylphenoxy)phenyl]-2-methylacryla- te 38
[0301] see Example 1.
[0302] Intermediate 3:
[0303]
4-[2,6-Difluoro-4-(3-ethoxycarbonyl-3-methylpropen-1-yl)phenoxy]ben-
zenesulfone-N-(carboxy-N'-methylamid)amide 39
[0304] 1.0 eq. of intermediate 2 is introduced into acetone and
stirred under reflux for 1.5 h w ith 2.5 eq. of K.sub.2CO.sub.3. A
solution of 2.5 eq. of methyl isocyanate in acetone is added
dropwise and the mixture is heated further under reflux. After an
increase in conversion is no longer detectable by means of LCMS,
insoluble constituents are filtered off and the filtrate is
concentrated in vacuo. The residue is taken up in H.sub.2O and
adjusted to pH 1 using 2 N HCl, the title compound precipitating.
Filtering off with suction and drying in vacuo yields the desired
sulfonylurea in good yield. (MS-ES+: 455.1).
[0305]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]benze-
nesulfone-N-(carboxy-N'-methylamid)amide; HCl salt
[0306] Intermediate 3 is reacted according to the variant described
in 1 A and gives the corresponding cinnamic acid guanidide as a
colorless solid. (MS-ES+: 468.; LCMS R.sub.t=3.991 min).
Example 9
[0307]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]benze-
nesulfone N-(carboxy-N'-ethylamid)amide; HCl salt 40
[0308] Intermediate 1:
[0309] Ethyl 2-methyl-3-(3,4,5-trifluorophenyl)acrylate 41
[0310] see Example 1.
[0311] Intermediate 2:
[0312] Ethyl
3-[3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl]-2-methylacrylat- e
42
[0313] see Example 1.
[0314] Intermediate 3:
[0315]
4-[2,6-Difluoro-4-(3-ethoxycarbonyl-3-methylpropen-1-yl)phenoxy]ben-
zenesulfone N-(carboxy-N'-ethylamid)amide 43
[0316] The analogous procedure as described in Example 8,
intermediate 3, gives the title compound, starting from
intermediate 2 and ethyl isocyanate, as a colorless solid. (MS-ES+:
469.1).
[0317]
4-[2,6-Difluoro-4-(3-guanidino-2-methyl-3-oxopropenyl)phenoxy]benze-
nesulfone N-(carboxy-N'-ethylamid)amide; HCl salt
[0318] Reaction of intermediate 3 according to the method described
in 1 A gives the desired product as a colorless solid. (MS-ES+:
482.1; LCMS R.sub.t=4.128 min).
Example 10
[0319]
N-(2-Dimethylaminoethyl)-4-[4-(3-guanidino-2-methyl-3-oxopropenyl)p-
henylamino]-benzenesulfonamide; HCl salt 44
[0320] Intermediate 1:
[0321] Ethyl 2-methyl-3-(4-bromophenyl)acrylate 45
[0322] see Example 4.
[0323] Intermediate 2:
[0324] N-[4-(2-Dimethylaminoethylsulfamoyl)phenyl]acetamide 46
[0325] 4-Acetylaminobenzenesulfonyl chloride is introduced into
dichloromethane and treated at room temperature with two
equivalents of N,N-dimethylethylenediamine and stirred at room
temperature until complete conversion can be determined (LCMS). For
work-up, the solvent is distilled off, the oily residue is taken up
in dichloromethane or ethyl acetate and the mixture is washed with
NaHCO.sub.3 solution. The phases are separated and the aqueous
phase is extracted once more with dichloromethane or ethyl acetate.
The organic phases are dried using Na.sub.2SO.sub.4 and
concentrated. The crude product thus obtained is reacted further
without further purification. (MS-CI+: 286.0; LCMS R.sub.t=2.542
min)
[0326] Intermediate 3:
[0327] 4-Amino-N-(2-dimethylaminoethyl)benzenesulfonamide 47
[0328] 2.3 g of intermediate 2 are dissolved in 20 ml of methanol.
After addition of 5.0 eq. of sodium methoxide, the mixture is
heated under reflux until the reaction check indicates complete
conversion. In order to accelerate the reaction, a further 10 to 15
eq. of sodium methoxide were added. After reaction is complete, the
mixture is freed from the solvent and the residue is taken up in
H.sub.2O and adjusted to pH 8 using conc. HCl. The aqueous phase is
extracted three times with ethyl acetate. The organic phases are
dried using Na.sub.2SO.sub.4 and concentrated, the title compound
being obtained in the form of a yellowish solid. (MS-ES+: 244.1;
LCMS R.sub.t=0.468 min)
[0329] Intermediate 4:
[0330] Ethyl
3-{4-[4-(2-dimethylaminoethylsulfamoyl)phenylamino]phenyl}-2--
methylacrylate 48
[0331] Starting from intermediate 1 and intermediate 3, the
synthesis of the title compound proceeds analogously to the
procedure for intermediate 3, Example 4, the solvent used being a
mixtufe of toluene/DMF (1:1). After reaction is complete, the
mixture is freed from the solvent and the residue is taken up in
dichloromethane. The insoluble constituents are filtered off, the
filtrate is concentrated and the residue is purified on silica gel.
(MS-ES+: 432.3; LCMS R.sub.t=4.407 min)
[0332]
N-(2-Dimethylaminoethyl)-4-[4-(3-guanidino-2-methyl-3-oxopropenyl)p-
henylamino]-benzenesulfonamide; HCl salt
[0333] Intermediate 4 is converted into the title compound
according to method 1 A, the desired acylguanidide being obtained
as a yellow solid. (MS-ES+: 445.3; 386.2; 193.6; LCMS R.sub.t=3.552
min).
Example 11
[0334]
4-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenylamino]-N-(2-pyrrolid
in-1-ylethyl)-benzenesulfonamide; HCl salt 49
[0335] Intermediate 1:
[0336] Ethyl 2-methyl-3-(4-bromophenyl)acrylate 50
[0337] see Example 4
[0338] Intermediate 2:
[0339] N-[4-(2-Pyrrolidin-1-ylethylsulfamoyl)phenyl]acetamide
51
[0340] Starting from 4-acetylaminobenzenesulfonyl chloride and
2-pyrrolidin-1-ylethylamine, the title compound is prepared
analogously to the method described in Example 10, intermediate 2.
The crude product thus obtained can be used for further reaction
without further purification. (MS-ES+: 312.1; LCMS R.sub.t=1.957
min)
[0341] Intermediate 3:
[0342] 4-Amino-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamide 52
[0343] The acetal protective group is removed analogously to the
method described in Example 10, intermediate 3. (MS-ES+: 270.2;
LCMS R.sub.t=0.511 min)
[0344] Intermediate 4:
[0345] Ethyl
2-methyl-3-{4-[4-(2-pyrrolidin-1-ylethylsulfamoyl)phenylamino-
]phenyl}acrylate 53
[0346] The coupling reaction is carried out according to the method
described in Example 10, intermediate 4. (MS-ES+: 458.3; LCMS
R.sub.t=4.498 min)
[0347]
4-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenylamino]-N-(2-pyrrolid-
in-1-ylethyl)benzenesulfonamide; HCl salt
[0348] Reaction of the ethyl ester described as intermediate 4
according to the general method described in variant 1 A gives the
desired cinnamic acid guanidide as a yellow solid. (MS-ES+: 471.4;
412.3; 206.7; LCMS R.sub.t=3.634 min)
Example 12
[0349]
N-(2-Methyl-3-{4-[4-(4-methylpiperazine-1-sulfonyl)phenylamino]phen-
yl}acryloyl)-guanidine; HCl salt 54
[0350] Intermediate 1:
[0351] Ethyl 2-methyl-3-(4-bromophenyl)acrylate 55
[0352] see Example 4.
[0353] Intermediate 2:
[0354] N-[4-(4-Methylpiperazine-1-sulfonyl)phenyl]acetamide 56
[0355] The analogous procedure to that in Example 10, intermediate
2, gives the title compound in the form of a yellowish solid in a
yield of 84%. (MS-ES+: 298.1; LCMS R.sub.t=1.964 min)
[0356] Intermediate 3:
[0357] 4-(4-Methylpiperazine-1-sulfonyl)phenylamine 57
[0358] Starting from intermediate 2, the desired aniline is
prepared according to the method indicated in Example 10,
intermediate 3. (MS-ES+: 256.1; LCMS R.sub.t=1.275 min)
[0359] Intermediate 4:
[0360] Ethyl
2-methyl-3-{4-[4-(4-methylpiperazine-1-sulfonyl)phenylamino]p-
henyl}acrylate 58
[0361] The synthesis is carried out by reaction of intermediate 3
with intermediate 1 according to the method described in Example
10, intermediate 4, in pure toluene as solvent. For work-up, the
mixture is freed from the solvent and the residue is taken up in
dichloromethane. Insoluble constituents are filtered off and the
filtrate is purified on silica gel, the title compound being
obtained in almost quantitative yield. (MS-ES+: 444.3; LCMS
R.sub.t=4.539 min)
[0362]
N-(2-Methyl-3-{4-[4-(4-methylpiperazine-1-sulfonyl)phenylamino]phen-
yl}acryloyl)-guanidine; HCl salt
[0363] The ethyl ester described in intermediate 4 is reacted with
guanidine according to general variant 1 A and gives the desired
guanidide in the form of a yellow solid. (MS-ES+: 457.3; 398.2;
220.1; LCMS R.sub.t=3.651 min)
Example 13
[0364] 4-[4-(3-Guanid
ino-2-methyl-3-oxopropenyl)phenylamino]-N-methyl-N-(-
1-methyl-pyrrolidin-3-yl)benzenesulfonamide, HCl salt 59
[0365] Intermediate 1:
[0366] Ethyl 2-methyl-3-(4-bromophenyl)acrylate 60
[0367] see Example 4.
[0368] Intermediate 2:
[0369] N-{4-[Methyl-(1-methyl pyrrolid
in-3-yl)sulfamoyl]phenyl}lacetamide 61
[0370] 4-Acetylaminobenzenesulfonyl chloride and methyl-(1-methyl
pyrro lid in-3-yl)amine are reacted according to the method
described in Example 10, intermediate 2. The title compound
obtained in the form of a slightly yellowish solid can be reacted
further without further purification. (MS-ES+: 312.1; LCMS
R.sub.t=0.698 min)
[0371] Intermediate 3:
[0372] 4-Amino-N-methyl-N-(1-methyl
pyrrolidin-3-yl)benzenesulfonamide 62
[0373] Starting from intermediate 2, the desired aniline is
prepared according to the method indicated in Example 10,
intermediate 3. (MS-Cl+: 270.2; LCMS R.sub.t=1.922 min)
[0374] Intermediate 4
[0375] Ethyl 2-methyl-3-(4-{4-[methyl-(1-methylpyrrolid
in-3-yl)sulfamoyl]phenylamino}-phenyl)acrylate 63
[0376] The title compound is synthesized by palladium-catalyzed
reaction of intermediate 3 with intermediate 1 according to the
method described in Example 10, intermediate 4. After purification
on silica gel, the desired product can be isolated in 71% yield.
(MS-ES+: 458.4; LCMS R.sub.t=4.547 min)
[0377]
4-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenylamino]-N-methyl-N-(1-
-methyl-pyrrolidin-3-yl)benzenesulfonamide, HCl salt
[0378] Intermediate 4 is converted into the corresponding cinnamic
acid guanidide according to general variant 1 A, the isolated yield
being 78%. (MS-ES+: 471.4; 412.3; 206.7; LCMS R.sub.t=3.685
min)
Example 14
[0379]
4-[4-(3-Guanidino-2-methyl-3-oxopropenyl)phenylamino]-N-methylbenze-
nesulfonamide; HCl salt 64
[0380] Intermediate 1:
[0381] Ethyl 2-methyl-3-(4-bromophenyl)acrylate 65
[0382] see Example 4.
[0383] Intermediate 2:
[0384] N-(4-Methylsulfamoylphenyl)acetamide 66
[0385] 10.5 g (45 mmol) of 4-acetylaminobenzenesulfonyl chloride
are stirred at 50.degree. C. for 3 hours in 100 ml of 40% strength
methylamine solution. The solution is then extracted three times
with ethyl acetate. The organic phases are dried using
Na.sub.2SO.sub.4 and concentrated. The residue is stirred with
dichloromethane and the insoluble constituents are filtered off.
Concentration of the filtrate gives the desired sulfonamide in
adequate purity and almost quantitative yield. (MS-Cl+: 229.1; LCMS
R.sub.t=3.249 min)
[0386] Intermediate 3:
[0387] 4-Amino-N-methylbenzenesulfonamide 67
[0388] Starting from intermediate 2, the acetyl group is removed
according to the method described in Example 10, intermediate 3.
(MS-Cl+: 187. 1; LCMS R.sub.t=1.358 min)
[0389] Intermediate 4:
[0390] Ethyl
2-methyl-3-[4-(4-methylsulfamoylphenylamino)phenyl]acrylate 68
[0391] Intermediate 1 is reacted with intermediate 3 in the manner
described in Example 10, intermediate 4, the desired ethyl ester
being obtained in the form of a yellowish oil. (MS--CI+: 375.1;
LCMS R.sub.t=5.064 min)
[0392] 4-[4-(3-G
uanidino-2-methyl-3-oxopropenyl)phenylamino]-N-methylbenz-
enesulfonamide; HCl salt
[0393] Intermediate 4 is reacted with guanidine according to the
general method described in variant 1 A, the title compound being
obtained in the form of a yellow solid. The yield is 88%. (MS-ES+:
388.1; 329.1; LCMS R.sub.t=4.126 min).
[0394] Pharmacological Data:
[0395] Test Description
[0396] In this test, the recovery of the intracellular pH
(pH.sub.i) which commences with functional NHE after acidification
even under bicarbonate-free conditions. For this, the pH.sub.i was
determined using the pH-sensitive fluorescent dye BCECF
(Calbiochem, the precursor BCECF-AM is employed). The cells were
first loaded with BCECF. The BCECF fluorescence was determined in a
ratio fluorescence spectrometer (Photon Technology International,
South Brunswick, N.J., USA) at excitation wavelengths of 505 and
440 nm and an emission wavelength of 535 nm and converted into the
pH.sub.i by means of calibration curves. During BCECF loading, the
cells were already incubated in NH.sub.4Cl buffer (pH 7.4)
(NH.sub.4Cl buffer: 115 mM NaCl, 20 mM NH.sub.4Cl, 5 mM KCl, 1 mM
CaCl.sub.2, 1 mM MgSO.sub.4, 20 mM Hepes, 5 mM glucose, 1 mg/ml of
BSA; a pH of 7.4 is set using 1 M NaOH). The intracellular
acidification was induced by addition of 975 .mu.l of an
NH.sub.4Cl-free buffer (see below) to 25 .mu.l aliquots of the
cells incubated in NH.sub.4Cl buffer. The subsequent rate of the pH
recovery was recorded for 2 minutes in the case of NHE1, for 5
minutes in the case of NHE2 and 3 minutes in the case of NHE3. For
the calculation of the inhibitory potency of the tested substances,
the cells were first investigated in buffers in which a complete
recovery or no pH recovery at all took place. For complete pH
recovery (100%), the cells were incubated in Na.sup.+-containing
buffer (133.8 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl.sub.2, 1.25 mM
MgCl.sub.2, 0.97 mM Na.sub.2HPO.sub.4, 0.23 mM NaH.sub.2PO.sub.4, 5
mM Hepes, 5 mM glucose, a pH of 7.0 is set using 1 M NaOH). For the
determination of the 0% value, the cells were incubated in an
Na.sup.+-free buffer (133.8 mM choline chloride, 4.7 mM KCl, 1.25
mM CaCl.sub.2, 1.25 mM MgCl.sub.2, 0.97 mM K.sub.2HPO.sub.4, 0.23
mM KH.sub.2PO.sub.4, 5 mM Hepes, 5 mM glucose, a pH of 7.0 is set
using 1 M NaOH). The substances to be tested were applied in the
Na.sup.+-containing buffer. The recovery of the intracellular pH at
any tested concentration of a substance was expressed as a
percentage of the maximum recovery. By means of the program Sigma
Plot, the IC.sub.50 value of the respective substance for the
individual NHE subtypes was calculated from the percentage values
of the pH recovery.
Example 1
[0397] IC.sub.50(rNHE3)=0.07 .mu.M
Example 2
[0398] IC.sub.50(rNHE3)=0.02 .mu.M
Example 3
[0399] IC.sub.50(rNHE3)=0.13 .mu.M
Example 4
[0400] IC.sub.50(rNHE3)=0.62 .mu.M
Example 5
[0401] IC.sub.50(rNHE3)=1.20 .mu.M
Example 6
[0402] IC.sub.50(rNHE3)=0.06 .mu.M
Example 7
[0403] IC.sub.50(rNHE3)=2.60 .mu.M
Example 8
[0404] IC.sub.50(rNHE3)=0.09 .mu.M
Example 9
[0405] IC.sub.50(rNHE3)=0.07 .mu.M
Example 10
[0406] IC.sub.50(rNHE3)=1.10 .mu.M
Example 11
[0407] IC.sub.50(rNHE3)=0.85 .mu.M
Example 12
[0408] IC.sub.50(rNHE3)=2.60 .mu.M
Example 13
[0409] IC.sub.50(rNHE3)=0.59 .mu.M
Example 14
[0410] IC.sub.50(rNHE3)=0.85 .mu.M
[0411] Solubilities:
[0412] The solubilities indicated below are determined by UV
spectroscopy in a 0.9% strength NaCl solution.
Example 6
[0413] 1.86 mg/ml
Example 7
[0414] >2.19 mg/ml
Example 10
[0415] 1.28 mg/ml
Example 11
[0416] 1.52 mg/ml
Example 12
[0417] 1.76 mg/ml
Example 13
[0418] 3.08 mg/ml
* * * * *