U.S. patent application number 09/809008 was filed with the patent office on 2001-08-30 for 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical preparations comprising them.
This patent application is currently assigned to Aventis Pharma Deutschland GmbH. Invention is credited to Heitsch, Holger, Wiemer, Gabriele.
Application Number | 20010018449 09/809008 |
Document ID | / |
Family ID | 26053245 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018449 |
Kind Code |
A1 |
Heitsch, Holger ; et
al. |
August 30, 2001 |
1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7)
receptors, processes for their preparation, their use, and
pharmaceutical preparations comprising them
Abstract
The invention relates to novel 1-(p-thienylbenzyl)imidazoles of
formula (I) 1 where the radicals R(1) to R(6), X, and Y have the
meaning indicated in the description, which are potent agonists of
angiotensin (1-7) receptors and owing to the production and release
of the vasorelaxant, antithrombotic, and cardioprotective
messengers cyclic 3',5'-guanosine monophosphate (cGMP) and nitrogen
monoxide (NO) associated with the stimulation of these receptors on
endothelial cells are valuable pharmaceuticals for the treatment
and prophylaxis of high blood pressure, cardiac hypertrophy,
cardiac insufficiency, coronary heart diseases such as angina
pectoris, cardiac infarct, vascular restenosis after angioplasty,
cardiomyopathies, endothelial dysfunction or endothelial damage,
e.g., as a result of arteriosclerotic processes or diabetes
mellitus, and also of arterial and venous thromboses.
Inventors: |
Heitsch, Holger;
(Mainz-Kastel, DE) ; Wiemer, Gabriele; (Kronberg,
DE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT &
DUNNER LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Assignee: |
Aventis Pharma Deutschland
GmbH
|
Family ID: |
26053245 |
Appl. No.: |
09/809008 |
Filed: |
March 16, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09809008 |
Mar 16, 2001 |
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09564544 |
May 4, 2000 |
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6235766 |
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Current U.S.
Class: |
514/397 ;
548/315.1 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
43/00 20180101; A61P 9/00 20180101; A61P 9/08 20180101; A61P 17/02
20180101; C07D 409/10 20130101; A61P 9/04 20180101; A61P 9/12
20180101; A61P 7/02 20180101 |
Class at
Publication: |
514/397 ;
548/315.1 |
International
Class: |
A61K 031/4184; C07D
233/54 |
Foreign Application Data
Date |
Code |
Application Number |
May 5, 1999 |
DE |
19920815.8 |
Dec 21, 1999 |
DE |
19961686.8 |
Claims
What is claimed is:
1. A compound of formula (I) 34in which: R(1) is (1) halogen; (2)
hydroxyl; (3) (C.sub.1-C.sub.4)-alkoxy; (4)
(C.sub.1-C.sub.8)-alkoxy, wherein 1 to 6 carbon atoms are replaced
by the heteroatoms O, S, or NH, (5) (C.sub.1-C.sub.4)-alkoxy,
substituted by a saturated cyclic ether; (6)
O-(C.sub.1-C.sub.4)-alkenyl; (7) O-(C.sub.1-C.sub.4)-alkylaryl; or
(8) phenoxy, unsubstituted or substituted by a substituent selected
from halogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-alkoxy,
and trifluoromethyl; R(2) is (1) CHO; (2) COOH; or (3)
CO--O-(C.sub.1-C.sub.4)-alkyl; R(3) is (1) (C.sub.1-C.sub.4)-alkyl;
or (2) aryl; R(4) is (1) hydrogen; (2) halogen; or (3)
(C.sub.1-C.sub.4)-alkyl; X is (1) oxygen; or (2) sulfur; Y is (1)
oxygen; or (2) --NH--; R(5) is (1) hydrogen; (2)
(C.sub.1-C.sub.6)-alkyl; or (3) (C.sub.1-C.sub.4)-alkylaryl; where
R(5) can only be hydrogen if Y has the meaning mentioned under (2);
and R(6) is (1) (C.sub.1-C.sub.5)-alkyl; in any stereoisomeric form
or mixture thereof in any ratio, or a physiologically tolerable
salt thereof; wherein R(1) may not be halogen when R(2) is COOH or
CO-O--(C.sub.1-C.sub.4)-alkyl.
2. A compound of claim 1, in which: R(1) is (1) chlorine; (2)
hydroxyl; (3) methoxy, ethoxy, or propyloxy; (4) methoxyethoxy or
methoxypropoxy; (5) allyloxy; or (6) phenoxy; R(4) is (1) hydrogen;
or (2) chlorine; R(5) is (1) hydrogen; or (2)
(C.sub.1-C.sub.4)-alkyl; R(6) is (1) n-propyl or 2-isobutyl; and
the other radicals are as defined in claim 1, in any stereoisomeric
form or mixture thereof in any ratio, or a physiologically
tolerable salt thereof.
3. A compound of claim 1, in which: R(1) is halogen,
(C.sub.1-C.sub.4)-alkoxy, or (C.sub.1-C.sub.8)-alkoxy, where 1 to 6
carbon atoms are replaced by the heteroatoms O, S, or NH; R(2) is
CHO; R(3) is aryl; R(4) is halogen or hydrogen; R(5) is
(C.sub.1-C.sub.6)-alkyl; R(6) is (C.sub.1-C.sub.5)-alkyl; X is
oxygen; and Y is oxygen or --NH--; in any stereoisomeric form or
mixture thereof in any ratio, or a physiologically tolerable salt
thereof.
4. A compound of claim 1, in which the compound is a compound of
formula (II) 35in which the radicals R(1), R(4), R(5), R(6), and Y
have the meaning mentioned in claim 1, in any stereoisomeric form
or mixture thereof in any ratio, or a physiologically tolerable
salt thereof.
5. A compound of claim 1, in which R(1) is (C.sub.1-C.sub.4)-alkoxy
or (C.sub.1-C.sub.8)-alkoxy, where 1 to 6 carbon atoms are replaced
by the heteroatoms O, S, or NH, and the other radicals are as
defined in claim 1, in any stereoisomeric form or mixture thereof
in any ratio, or a physiologically tolerable salt thereof.
6. A compound of claim 1, in which R(2) is CHO and the other
radicals are as defined in claim 1, in any stereoisomeric form or
mixture thereof in any ratio, or a physiologically tolerable salt
thereof.
7. A compound of claim 1, in which X is 0 and the other radicals
are as defined in claim 1, in any stereoisomeric form or mixture
thereof in any ratio, or a physiologically tolerable salt
thereof.
8. A compound of claim 1, wherein the compound is:
4-chloro-5-formyl-2-phe-
nyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]m-
ethyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-is-
obutyl-3thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsu-
lfonamido)-5-isobutyl-3thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-
-[2-(ethoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazo-
le, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phen-
yl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methy-
l]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5--
isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsul-
fonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-
-[2-(methylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]im-
idazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxyc-
arbonylsulfonamido)-5-isobutyl-3thienyl]-2-chlorophenyl]methyl]imidazole,
or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl--
1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]-2chlorophen-
yl]methyl]imidazole, or a physiologically tolerable salt thereof;
4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-p-
ropyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsul-
fonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-
-[2-(methoxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidaz-
ole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phe-
nyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl-
]methyl]imidazole, or a physiologically tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5-n-
-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsul-
fonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole sodium salt;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-is-
obutyl-3-thienyl]phenyl]methyl]imidazole L-lysine salt; or
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-is-
obutyl-3-thienyl]phenyl]methyl]imidazole
tris(hydroxymethyl)aminomethane salt.
9. A compound of formula (X) 36in which R is hydrogen or
(C.sub.1-C.sub.6)-alkyl and the radicals R(1), R(2), R(3), R(4),
and R(6) are as defined in claim 1, in any stereoisomeric form or
mixture thereof in any ratio, or a physiologically tolerable salt
thereof.
10. A pharmaceutical composition, comprising at least one compound
of claim 1, and at least one pharmaceutically tolerable carrier or
excipient.
11. A pharmaceutical composition of claim 10, further comprising at
least one other pharmaceutically active compound.
12. A pharmaceutical composition, comprising at least one compound
of claim 9, and at least one pharmaceutically tolerable carrier or
excipient.
13. A pharmaceutical composition of claim 12, further comprising at
least one other pharmaceutically active compound.
14. A method for treating or preventing illnesses which are
primarily or secondarily caused or at least partly caused by
reduced production and/or release of the vasorelaxant,
antithrombotic, and cardioprotective messengers cyclic
3',5'-guanosine monophosphate and nitrogen monoxide, comprising
administering to a patient in need thereof an effective amount of
at least one compound of formula (I) of claim 1 37in which: R(1) is
(1) halogen; (2) hydroxyl; (3) (C.sub.1-C.sub.4)-alkoxy; (4)
(C.sub.1-C.sub.8)-alkoxy, wherein 1 to 6 carbon atoms are replaced
by the heteroatoms O, S, or NH; (5) (C.sub.1-C.sub.4)-alkoxy,
substituted by a saturated cyclic ether; (6)
O-(C.sub.1-C.sub.4)-alkenyl; (7) O-(C.sub.1-C.sub.4)-alkylaryl; or
(8) phenoxy, unsubstituted or substituted by a substituent selected
from halogen, (C.sub.1-C.sub.3)-alkyl, (C.sub.1-C.sub.3)-alkoxy,
and trifluoromethyl; R(2) is (1) CHO; (2) COOH; or (3)
CO-O-(C.sub.1-C.sub.4)-alkyl; R(3) is (1) (C.sub.1-C.sub.4)-alkyl;
or (2) aryl; R(4) is (1) hydrogen; (2) halogen; or (3)
(C.sub.1-C.sub.4)-alkyl; X is (1) oxygen; or (2) sulfur; Y is (1)
oxygen; or (2) --NH--; R(5) is (1) hydrogen; (2)
(C.sub.1-C.sub.6)-alkyl; or (3) (C.sub.1-C.sub.4)-alkylaryl; where
R(5) can only be hydrogen if Y has the meaning mentioned under (2);
and R(6) is (1) (C.sub.1-C.sub.5)-alkyl; in any stereoisomeric form
or mixture thereof in any ratio, or a physiologically tolerable
salt thereof.
15. A method for treating or preventing high blood pressure,
cardiac hypertrophy, cardiac insufficiency, coronary heart diseases
such as angina pectoris, cardiac infarct, vascular restenosis after
angioplasty, cardiomyopathies, endothelial dysfunction or
endothelial damage, and also of arterial and venous thromboses,
comprising administering to a patient in need thereof an effective
amount of at least one compound of claim 1.
16. A method for treating or preventing illnesses which are
primarily or secondarily caused or at least partly caused by
reduced production and/or release of the vasorelaxant,
antithrombotic, and cardioprotective messengers cyclic
3',5'-guanosinemonophoshate and nitrogen monoxide, comprising
administering to a patient in need thereof an effective amount of
at least one angiotensin (1-7) receptor agonist.
17. A method for treating or preventing high blood pressure,
cardiac hypertrophy, cardiac insufficiency, coronary heart diseases
such as angina pectoris, cardiac infarct, vascular restenosis after
angioplasty, cardiomyopathies, endothelial dysfunction or
endothelial damage, and also of arterial and venous thromboses,
comprising administering to a patient in need thereof an effective
amount of at least one ii angiotensin (1-7) receptor agonist.
18. A method for treating or preventing illnesses which are
primarily or secondarily caused or at least partly caused by
reduced production and/or release of the vasorelaxant,
antithrombotic, and cardioprotective messengers cyclic
3',5'-guanosine monophosphate and nitrogen monoxide, comprising
administering to a patient in need thereof an effective amount of
at least one compound of claim 1.
19. A method for treating or preventing illnesses which are
primarily or secondarily caused or at least partly caused by
reduced production and/or release of the vasorelaxant,
antithrombotic, and cardioprotective messengers cyclic
3',5'-guanosine monophosphate and nitrogen monoxide, comprising
administering to a patient in need thereof an effective amount of
at least one compound of claim 9.
20. A method for treating or preventing high blood pressure,
cardiac hypertrophy, cardiac insufficiency, coronary heart diseases
such as angina pectoris, cardiac infarct, vascular restenosis after
angioplasty, cardiomyopathies, endothelial dysfunction or
endothelial damage, and also of arterial and venous thromboses,
comprising administering to a patient in need thereof an effective
amount of at least one compound of claim 9.
Description
[0001] The invention relates to novel 1-(p-thienylbenzyl)imidazoles
of formula (I), 2
[0002] which are potent agonists of angiotensin (1-7) receptors
and, because of the production and release of the vasorelaxant,
antithrombotic, and cardio-protective messengers cyclic
3',5'-guanosine monophosphate (cGMP) and nitrogen monoxide (NO)
associated with the stimulation of these receptors on endothelial
cells, are valuable pharmaceuticals for the treatment and
prophylaxis of high blood pressure, cardiac hypertrophy, cardiac
insufficiency, coronary heart diseases such as angina pectoris,
cardiac infarct, vascular restenosis after angioplasty,
cardiomyopathies, an endothelial dysfunction or endothelial damage,
e.g., as a result of arteriosclerotic processes or in diabetes
mellitus, and of arterial and venous thrombosis.
[0003] EP-A 512675 and WO 94/27597 describe
thienylbenzyl-substituted imidazoles as angiotensin 11
receptor-antagonists and their use for the treatment of
hypertension, cardiac insufficiency, migraine, Alzheimer's disease,
and as antidepressants. Moreover, thienylbenzyl-substituted
imidazopyridines are disclosed in EP-A 513979 as antagonists of
angiotensin 11 receptors and their use for the treatment of
hypertension, cardiac insufficiency, migraine, and Alzheimer's
disease, and in U.S. Pat. No. 5,444,067 as angiotensin 11 agonists
and their use for the treatment of hypotension and of
hypoaldosteronism. In addition, in EP-A 534706
thienylbenzyl-substituted quinazolinones and pyridopyrimidones and
in EP-A 510812 thienylbenzyl-substituted triazoles are disclosed as
antagonists of angiotensin II receptors.
[0004] The 1-(p-thienylbenzyl)imidazoles of formula (I) described
here and their use as agonists of angiotensin (1-7) receptors are
in this case neither described, anticipated, nor suggested in the
applications mentioned.
[0005] Surprisingly, it has been found that
1-(p-thienylbenzyl)imidazoles of formula (I) have a marked action
on angiotensin (1-7) receptors and mimic the biological action of
the effector hormone angiotensin (1-7).
[0006] The invention thus relates to compounds of formula (I) 3
[0007] in which:
[0008] R(1) is (1) halogen;
[0009] (2) hydroxyl;
[0010] (3) (C.sub.1-C.sub.4)-alkoxy;
[0011] (4) (C.sub.1-C.sub.8)-alkoxy, wherein 1 to 6 carbon atoms
are replaced by the heteroatoms O, S, or NH, preferably by O;
[0012] (5) (C.sub.1-C.sub.4)-alkoxy, substituted by a saturated
cyclic ether such as tetrahydropyran or tetrahydrofuran;
[0013] (6) O-(C.sub.1-C.sub.4)-alkenyl;
[0014] (7) O-(C.sub.1-C.sub.4)-alkylaryl; or
[0015] (8) aryloxy, unsubstituted or substituted by a substituent
selected from halogen, (C.sub.1-C.sub.3)-alkyl,
(C.sub.1-C.sub.3)-alkoxy, and trifluoromethyl;
[0016] R(2) is (1) CHO;
[0017] (2) COOH; or
[0018] (3) CO--O-(C.sub.1-C.sub.4)-alkyl;
[0019] R(3) is (1) (C.sub.1-C.sub.4)-alkyl; or
[0020] (2) aryl;
[0021] R(4) is (1) hydrogen;
[0022] (2) halogen; or
[0023] (3) (C.sub.1-C.sub.4)-alkyl;
[0024] X is (1) oxygen; or
[0025] (2) sulfur;
[0026] Y is (1) oxygen; or
[0027] (2) --NH--;
[0028] R(5) is (1) hydrogen;
[0029] (2) (C.sub.1-C.sub.6)-alkyl; or
[0030] (3) (C.sub.1-C.sub.4)-alkylaryl;
[0031] where R(5) can only be hydrogen if Y has the meaning
mentioned under (2); and
[0032] R(6) (1) (C.sub.1-C.sub.5)-alkyl;
[0033] in any stereoisomeric form or mixture thereof in any ratio,
or a physiologically tolerable salt thereof;
[0034] wherein R(1) may not be halogen when R(2) is COOH or
CO--O-(C.sub.1-C.sub.4)-alkyl.
[0035] The term alkyl means, if not stated otherwise,
straight-chain or branched saturated hydrocarbon radicals. This
also applies to substituents derived therefrom such as alkoxy or
the radical S(O).sub.m-alkyl. Examples of alkyl radicals are
methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, and n-hexyl. Examples of alkoxy are methoxy,
ethoxy, n-propoxy, and isopropoxy. Examples of aryloxy are phenoxy
or naphthoxy. Phenoxy is preferred.
[0036] Alkenyl represents mono- or polyunsaturated hydrocarbon
radicals in which the double bonds can be situated in any desired
positions. Examples of alkenyl are vinyl, propenyl, and
butenyl.
[0037] Halogen represents fluorine, chlorine, bromine, or iodine,
preferably chlorine or fluorine.
[0038] Aryl represents phenyl or naphthyl, preferably phenyl.
[0039] In substituted aryl radicals, the substituents can be
situated in any desired position relative to one another.
[0040] Examples of arylalkyl radicals are phenylmethyl (benzyl),
phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl,
naphthylethyl, naphthylpropyl, and naphthylbutyl.
[0041] If compounds of formula (I) contain one or more acidic or
basic groups, the invention also encompasses the corresponding
physiologically tolerable salts, in particular the pharmaceutically
utilizable salts. Thus, compounds of formula (I) which carry acidic
groups, such as one or more COOH groups, can be present, for
example, as their alkali metal salts, preferably sodium or
potassium salts, or as their alkaline earth metal salts, e.g.,
calcium or magnesium salts, or as ammonium salts, e.g., as salts
with ammonia or organic amines or amino acids. Compounds of formula
(I) which carry one or more basic, i.e., protonatable, groups, can
also be used in the form of their physiologically tolerable acid
addition salts with inorganic or organic acids, for example as
hydrochlorides, phosphates, sulfates, methanesulfonates, acetates,
lactates, maleates, fumarates, malates, or gluconates. If compounds
of formula (I) simultaneously contain acidic and basic groups in
the molecule, the invention also includes, in addition to the salt
forms outlined, internal salts, so-called betaines. Salts can be
obtained from compounds of formula (I) by customary processes, for
example by combination with an acid or base in a solvent or
dispersant or otherwise from other salts by anion exchange.
[0042] Physiologically tolerable salts of compounds of formula (I)
are to be understood, for example, as also meaning organic and
inorganic salts, such as are described in Remington's
Pharmaceutical Sciences (17.sup.th Edition (1985) 1418). On account
of the physical and chemical stability and the solubility,
preferred acidic groups are, inter alia, sodium, potassium,
calcium, and ammonium salts; preferred basic groups are, inter
alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid,
or of carboxylic acids or sulfonic acids, such as, for example,
acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid,
tartaric acid, and p-toluenesulfonic acid.
[0043] The present invention furthermore comprises solvates of
compounds of formula (I), for example hydrates or adducts with
alcohols, and also derivatives of compounds of formula (I) such as,
for example, esters, and prodrugs and active metabolites.
[0044] Preferred compounds of formula (I) are those in which
[0045] R(1) is (1) chlorine;
[0046] (2) hydroxyl;
[0047] (3) methoxy, ethoxy, or propyloxy;
[0048] (4) methoxyethoxy or methoxypropoxy;
[0049] (5) allyloxy; or
[0050] (6) phenoxy;
[0051] R(4) is (1) hydrogen; or
[0052] (2) chlorine;
[0053] R(5) is (1) hydrogen; or
[0054] (2) (C.sub.1-C.sub.4)-alkyl;
[0055] R(6) is (1) n-propyl or 2-isobutyl;
[0056] and the other radicals are as defined above, in any
stereoisomeric form or mixture thereof in any ratio, or a
physiologically tolerable salt thereof.
[0057] Compounds of formula (I) are furthermore preferred in
which
[0058] R(1) is halogen, preferably chlorine,
(C.sub.1-C.sub.4)-alkoxy, preferably methoxy, ethoxy, or propyloxy,
particularly preferably methoxy, or (C.sub.1-C.sub.8)-alkoxy, where
1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH,
preferably O, preferably methoxyethoxy or methoxypropoxy;
[0059] R(2) is CHO;
[0060] R(3) is aryl, preferably phenyl;
[0061] R(4) is halogen, preferably chlorine, or hydrogen;
[0062] R(5) is (C.sub.1-C.sub.6)-alkyl, preferably methyl, ethyl,
propyl, or butyl;
[0063] R(6) is (C.sub.1-C.sub.5)-alkyl, preferably ethyl, propyl,
or butyl;
[0064] X is oxygen;
[0065] Y is oxygen or --NH--;
[0066] in any stereoisomeric form or mixture thereof in any ratio,
or a physiologically tolerable salt thereof.
[0067] Compounds of formula (I) are very particularly preferred
when these are compounds of formula (II) 4
[0068] in which the radicals R(1), R(4), R(5), R(6), and Y have the
abovementioned meaning, in any stereoisomeric form or mixture
thereof in any ratio, or a physiologically tolerable salt
thereof.
[0069] Preferred compounds of formula (I) are also those in which
R(1) is (C.sub.1-C.sub.4)-alkoxy or (C.sub.1-C.sub.8)-alkoxy, where
1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH,
preferably O, and the other radicals are as defined above, in any
stereoisomeric form or mixture thereof in any ratio, or a
physiologically tolerable salt thereof.
[0070] Particularly preferred compounds of formula (I) are also
those in which R(2) is CHO, and the other radicals are as defined
above, in any stereoisomeric form or mixture thereof in any ratio,
or a physiologically tolerable salt thereof.
[0071] Preferred compounds of formula (I) are furthermore those in
which X is O, and the other radicals are as defined above, in any
stereoisomeric form or mixture thereof in any ratio, or a
physiologically tolerable salt thereof.
[0072] Particularly preferred compounds of formula (I) are:
[0073]
4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-
-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
[0074]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]rmethyl]imidazole, or a
physiologically tolerable salt thereof;
[0075]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamid-
o)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0076]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5--
isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
[0077]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-
-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
[0078]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonami-
do)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0079]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0080]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamid-
o)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0081]
5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfo-
namido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0082]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0083]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0084]
4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-
-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
[0085]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0086]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-
-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically
tolerable salt thereof;
[0087]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonami-
do)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0088]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamid-
o)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a
physiologically tolerable salt thereof;
[0089]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole sodium salt;
[0090]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole L-lysine salt;
or
[0091]
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
tris(hydroxymethyl)aminomet- hane salt.
[0092] The invention furthermore relates to processes for the
preparation of compounds of formula (I), comprising the following
reaction:
[0093] a) Providing 4-chloro-5-formylimidazole derivatives of
formula (III), 5
[0094] in which R(3) has the abovementioned meaning and whose
preparation is described, for example, in Chem. Pharm. Bull. 24
(1976) 960-969, and reacting with p-bromobenzyl bromides of formula
(IV), 6
[0095] in which R(4) is as defined above, resulting in the
formation of compounds of formula (V) 7
[0096] in which R(3) and R(4) have the abovementioned meanings,
where the alkylation can be carried out in the presence of an
organic or inorganic base such as, for example, triethylamine,
K.sub.2CO.sub.3, or Cs.sub.2CO.sub.3 in an inert solvent such as,
for example, DMF. Compounds of formula (IV) are commercially
obtainable or can be prepared by methods known per se.
[0097] b) Compounds of formula (V) can be reacted with
thiophene-3-boronic acids of formula (VI) 8
[0098] in which R(6) is as defined above and whose preparation is
disclosed in EP-A 512 675, to give 1-(p-thienyl)imidazoles of
formula (VII) 9
[0099] in which R(3), R(4), and R(6) are as defined above. This
Suzuki-type cross-coupling reaction is preferably carried out using
palladium(II) acetate and triphenylphosphine or
tetrakistriphenylphosphin- epalladium as catalysts in the presence
of a base such as, for example, cesium or potassium carbonate, for
example, in solvent mixtures of ethanol and toluene at temperatures
up to the boiling point of the solvents; corresponding reactions
are described, for example, in Synthetic Commun. 11 (1981) 513, J.
Med. Chem. 38 (1995) 2357-2377, and Liebigs Ann. (1995)
1253-1257.
[0100] c) Compounds of formula (VII) can be converted by removal of
the tert-butyl protective group into sulfonamides of formula (VII)
10
[0101] in which R(3), R(4), and R(6) are as defined above. This
removal is preferably carried out by treatment of compounds of
formula (VII) with organic acids such as, for example, concentrated
trifluoroacetic acid in the presence of anisole.
[0102] d) Compounds of formula (VIII) can be converted by
substitution of the chlorine atom in position 4 of the imidazole
ring into compounds of formula (IX) 11
[0103] in which R(3), R(4), and R(6) are as defined above, and
R(1)' represents the radicals mentioned under (2) to (8) for R(1).
This substitution of the chlorine atom can be carried out in this
case, for example, by treatment of compounds of formula (VIII) with
alkoxides formed in situ by the action of bases such as NaOH or NaH
on the alcohols generally used as solvents, such as, for example,
methanol, ethanol, or ethylene glycol monomethyl ether, at
temperatures of from 50.degree. C. up to the boiling point of the
alcohols.
[0104] Alternatively, compounds of formula (IX) in which R(1)' is
(C.sub.1-C.sub.4)-alkoxy can be converted via an ether cleavage, by
treatment preferably of the methoxy ethers of formula (IX) with
concentrated acids such as HI and HBr, or with Lewis acids such as
BF.sub.3, BCl.sub.3, BBr.sub.3, AlCl.sub.3, or their etherates,
preferably with BBr.sub.3, in an inert solvent such as, for
example, CH.sub.2Cl.sub.2, into the corresponding phenols, which
can then be reacted by processes known per se with the suitably
substituted halides such as, for example, 2-bromoethyl methyl ether
or benzyl bromide in the presence of a base in an inert solvent at
temperatures up to the boiling point of the solvent.
[0105] The corresponding diphenyl ether compounds can be obtained
from the reaction of the phenols of formula (IX) with boronic acids
such as, for example, phenylboronic acid or 4-methoxyphenylboronic
acid in the presence of copper catalysts such as, for example,
Cu(OAc).sub.2. Appropriate reactions are described, for example, in
Tetrahedron Lett. 39 (1998) 2937-2940.
[0106] e) From sulfonamides of formula (IX), it is possible by
reaction with R(5)-substituted chloroformic acid esters to prepare
sulfonylurethanes of formula (Ia) 12
[0107] in which R(1), R(2), R(3), R(4), and R(6) are as defined
above, and R(5) only has the meaning mentioned under (2) and (3).
This reaction can be carried out in the presence of a base such as,
for example, pyridine, and of an acylation accelerator, such as
4-pyrrolidinopyridine, at temperatures from room temperature (RT)
to 150.degree. C., but preferably at RT.
[0108] f) From sulfonamides of formula (IX), it is possible by
treatment with R(5)-substituted isocyanates or isothiocyanates to
obtain sulfonylureas of formula (Ib) 13
[0109] in which R(1), R(2), R(3), R(4), R(6), and X are as defined
above, and R(5) only has the meaning mentioned under (2) and (3).
The reaction with R(5)-substituted isocyanates and isothiocyanates
can be carried out in the presence of a base in an inert solvent at
temperatures from RT to 150.degree. C.
[0110] Suitable bases are, for example, alkali metal or alkaline
earth metal hydroxides, hydrides, amides, or alkoxides, such as
sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium
hydride, potassium hydride, calcium hydride, sodium amide,
potassium amide, sodium methoxide, sodium ethoxide, or potassium
tert-butoxide. Suitable inert solvents are ethers such as THF,
dioxane, ethylene glycol dimethyl ether, or diglyme, ketones such
as acetone or butanone, nitriles such as acetonitrile, nitro
compounds such as nitromethane, esters such as ethyl acetate,
amides such as DMF or N-methylpyrrolidone, hexamethylphosphoramide,
sulfoxides such as DMSO, and hydrocarbons such as benzene, toluene,
or xylenes. Furthermore, mixtures of these solvents with one
another are also suitable.
[0111] Sulfonylureas of formula (Ib) may also be prepared by
reaction of amines R(5)--NH.sub.2 with sulfonyl isocyanate
derivatives that result from sulfonamides of formula (IX), for
example, by treatment with phosgene or a phosgene substitute such
as triphosgene.
[0112] Alternatively, sulfonylureas of formula (lb) can be prepared
by reaction of sulfonamides of formula (IX) with
2,2,2-trichloroacetamide derivatives of a suitable amine
R(5)--NH.sub.2 in the presence of a base in an inert, high-boiling
solvent such as, for example, DMSO or from the corresponding
sulfonylurethane of formula (la) accessible by reaction with ethyl
chloroformate by action of the corresponding amine R(5)--NH.sub.2
in an inert, high-boiling solvent such as, for example, toluene, at
temperatures up to the boiling point of the respective solvent,
which is described, for example, in J. Med. Chem. 38 (1995)
2357-2377, and in Bioorg. Med. Chem. 5 (1997) 673-678.
[0113] N-Unsubstituted sulfonylureas of formula (lb), in which R(5)
is hydrogen, can be prepared by hydrolysis of sulfonamidonitriles
resulting after reaction of sulfonamides of formula (IX) with
cyanogen bromide in the presence of K.sub.2CO.sub.3 in acetonitrile
with sulfuric acid at temperatures of from -10.degree. C. to
0.degree. C.
[0114] By methods known per se, such as are described in the
literature (e.g., in the standard works such as Houben-Weyl,
Methoden der Organischen Chemie (Methods of Organic Chemistry),
Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley &
Sons, Inc., New York; or Larock, Comprehensive Organic
Transformations, VCH, Weinheim), it is possible by oxidation of the
aldehyde group in compounds of formula (I) to prepare the
corresponding carboxylic acids or carboxylic acid esters of formula
(I). The invention also relates to compounds of formula (X) 14
[0115] in which R is hydrogen or a suitable protective group such
as, for example, (C.sub.1-C.sub.6)-alkyl, preferably tert-butyl,
and the radicals R(1), R(2), R(3), R(4), and R(6) are as defined
above, in any stereoisomeric form or mixture thereof in any ratio,
or a physiologically tolerable salt thereof.
[0116] Compounds of formula (X) are valuable intermediates for the
preparation of compounds of formula (I) according to the invention.
In addition, compounds of formula (X) have a high affinity for the
angiotensin (1-7) receptor and can be used as angiotensin (1-7)
receptor agonists and thus as pharmaceuticals for the treatment
and/or prophylaxis of illnesses which are primarily or secondarily
caused or at least partly caused by a reduced production and/or
release of the vasorelaxant, anti-thrombotic, and cardioprotective
messengers cyclic 3',5'-guanosine monophosphate (cGMP) and nitrogen
monoxide (NO). For example, these compounds are used for the
treatment and/or prophylaxis of high blood pressure, cardiac
hypertrophy, cardiac insufficiency, coronary heart diseases such as
angina pectoris, cardiac infarct, vascular restenosis after
angioplasty, cardiomyopathies, an endothelial dysfunction or
endothelial damage, e.g., as a result of arteriosclerotic processes
or in diabetes mellitus, and also of arterial and venous
thrombosis.
[0117] The vascular endothelium is a metabolically active organ
with a large number of regulatory functions, that is capable of the
synthesis and release of vasoactive substances. A dysfunction of
the endothelial layer lining the vessel is correlated with the
pathogenesis of various cardiovascular disorders such as
arteriosclerosis and hypertension (Eur. J. Clin. Invest. 23 (1993)
670-685). An endothelial dysfunction is characterized by a reduced
synthesis and/or release of the vasorelaxant, vasoprotective,
antithrombotically, and antiproliferatively active messengers NO
and cGMP, which play an important role in the prevention and
regression of vascular remodeling and arterial hypertension.
Substances that are able to stimulate the synthesis and release of
these messengers are therefore valuable pharmaceuticals for the
treatment of all diseases that are characterized by endothelial
dysfunction.
[0118] A large number of published experiments confirm that a
degradation product of the renin-angiotensin system, the
heptapeptide angiotensin (1-7), is a potent, endogenous effector
hormone of the renin-angiotensin system (Hypertension 12 (Suppl.
III) (1991) III-126-III-133), whose biological action is caused by
the stimulation of specific receptors, which preferably bind
angiotensin (1-7) (Peptides 14 (1993) 679-684; Hypertension 29
(part 2) (1997) 388-393). This action is in many cases directed
against that of the vasoconstrictory hormone angiotensin II or
opposes this in a counter regulatory manner (Hypertension 30 (part
2) (1997) 535-541; Regulatory Peptides 78 (1998) 13-18).
[0119] Hypertension 19 (Suppl. II) (1992)11-49-11-55, and Am. J.
Cardiol. 82 (1998) 17S-19S, showed that angiotensin (1-7)
stimulated the production and/or the release of NO/cGMP and the
prostaglandins E.sub.2 and I.sub.2, which is not blocked by
pretreatment with AT.sub.1 and AT.sub.2 receptor antagonists.
[0120] An endothelium-dependent relaxation of intact coronary
arteries of dogs and pigs was described in Hypertension 27 (part 2)
(1996) 523-528, and an endothelium-dependent relaxation of intact,
KCl-precontracted rat aortas by angiotensin (1-7), which is not
affected by AT.sub.1 receptor antagonists, was described in J.
Cardiovasc. Pharmacol. 30 (1997) 676-682.
[0121] The hypotensive action of angiotensin (1-7) in spontaneously
hypertensive rats on continuous infusion by means of an osmotic
minipump was shown in Peptides 14 (1993) 679-684, and in Am. J.
Physiol. 269 (1995) H313-H319, angiotensin (1-7) in normotensive
rats having no action on the blood pressure in the same dose.
Complementary to these investigations, it was demonstrated in
Hypertension 31 (1998) 699-705, that the infusion of an angiotensin
(1-7) antibody increases the mean arterial blood pressure in
conscious, spontaneously hypertensive rats which had been
pretreated with lisinopril and losartan.
[0122] Am. J. Hypertension 11 (1998) 137-146, showed that in
persons having essential hypertension, markedly lower plasma levels
of angiotensin (1-7) are detectable than in normotensive
persons.
[0123] The anti-proliferative action of angiotensin (1-7) on
vascular smooth muscle cells was confirmed in Hypertension 28
(1996) 104-108, and the inhibition of the proliferation of smooth
muscle cells after vascular tissue damage was confirmed in
Hypertension 33 (part II) (1999) 207-211.
[0124] Moreover, angiotensin (1-7) in sodium chloride-loaded,
anesthetized normo-tensive Wistar rats also showed renal effects
such as increased natriuresis and diuresis (Am. J. Physiol. 270
(1996) F141-F147).
[0125] Compounds of formula (I) described here are potent,
nonpeptide agonists of the postulated angiotensin (1-7) receptors,
which are preferably located in the vessels (including
endothelium), in the kidney, in the CNS, and in the heart. They
therefore mimic the biological action of the peptide hormone
angiotensin (1-7) directed against angiotensin II, described above,
which is to be attributed to the production and/or release of cGMP
and NO from the endothelium, without in this case being subject to
the rapid metabolic degradation of this hormone. Because of the
stimulation of the production and/or release of these vasorelaxant,
antithrombotic, and cardioprotective messengers, angiotensin (1-7)
receptor agonists of formula (I) described are valuable
pharmaceuticals for the treatment and/or prophylaxis of illnesses
which are primarily or secondarily caused, or at least partly
caused, by a reduced production and/or release of the vasorelaxant,
antithrombotic, and cardioprotective messengers cGMP and NO. These
compounds can thus be employed, for example, in the treatment
and/or prophylaxis of high blood pressure, cardiac hypertrophy,
cardiac insufficiency, coronary heart diseases such as angina
pectoris, cardiac infarct, vascular restenosis after angioplasty,
cardiomyopathies, an endothelial dysfunction or endothelial damage,
e.g., as a result of arteriosclerotic processes or in diabetes
mellitus, and also of arterial and venous thrombosis.
[0126] The stimulation of endothelial angiotensin (1-7) receptors
by agonists of formula (I) causes the release of vasodilatory and
organ-protective autacoids. This mechanism differs here from that
of ACE inhibition and AT.sub.1 receptor blockade by the avoidance
either of lowered tissue angiotensin II (in the case of ACE
inhibitors) or of effects which still cannot be estimated at
present, which are associated with increased ANG II plasma values
(in the case of AT.sub.1 receptor antagonists).
[0127] Compounds of formula (I) or their physiologically tolerable
salts can thus be used in animals, preferably in mammals, and in
particular in humans, as pharmaceuticals, either on their own, as
mixtures with one another or together with other active compounds,
in particular in the form of pharmaceutical preparations. The
present invention therefore relates to the use of compounds of
formula (I) and/or their physiologically tolerable salts for the
production of a medicament for the therapy or prophylaxis of the
abovementioned syndromes, and to pharmaceutical preparations which
contain an efficacious dose of at least one compound of formula (I)
and/or of a physiologically tolerable salt thereof as active
constituent in addition to at least one customary, pharmaceutically
innocuous vehicle and/or excipient. The pharmaceutical preparations
can be intended for enteral or parenteral use, and normally contain
0.5 to 90% by weight of at least one compound of formula (I) and/or
a physiologically tolerable salt thereof. The amount of active
compound of formula (I) and/or a physiologically tolerable salt
thereof in the pharmaceutical preparations is in general 0.2 to 500
mg, preferably 1 to 300 mg.
[0128] Pharmaceuticals employed according to the invention, which
contain at least one compound of formula (I), and/or a
physiologically tolerable salt thereof, can be administered
enterally, for example orally or rectally, in the form of pills,
tablets, film-coated tablets, sugar-coated tablets, granules, hard
and soft gelatin capsules, solutions such as aqueous, alcoholic, or
oily solutions, juices, drops, syrups, emulsions, or suspensions.
Administration can also be carried out parenterally, for example
subcutaneously, intramuscularly, or intravenously in the form of
injection solutions or infusion solutions. Further possible
administration forms are, for example, percutaneous or topical
administration, in the form of ointments, creams, pastes, lotions,
gels, sprays, powders, foams, aerosols, or solutions, or use in the
form of implants.
[0129] The pharmaceutical preparations employed according to the
invention can be prepared by the known standard processes for the
production of pharmaceutical preparations. For this, at least one
compound of formula (I) and/or a physiologically tolerable salt
thereof are brought together with at least one solid or liquid
pharmaceutical vehicle and/or additive or excipient, and, if
desired, in combination with at least one other pharmaceutical
active compound having therapeutic or prophylactic action, for
example cardiovascular-active pharmaceuticals such as, for example,
calcium antagonists, ACE inhibitors, AT.sub.1 receptor antagonists,
NO donors, endothelin receptor antagonists, K.sup.+ channel
openers, phosphodiesterase inhibitors, diuretics, or .alpha.- and
.beta.-blockers, into a suitable administration form or dose form,
which can then be used as a pharmaceutical in human medicine or
veterinary medicine.
[0130] Possible vehicles are organic or inorganic substances which
are suitable for enteral (for example oral) or parenteral (for
example intravenous) administration or topical application and do
not react with active compounds of formula (I), for example water,
vegetable oils, alcohols such as ethanol, isopropanol, or benzyl
alcohol, 1,2-propanediol, polyethylene glycols, glycerol
triacetate, gelatin, carbohydrates such as lactose or starch,
magnesium stearate, talc, lanolin, petroleum jelly, acetonitrile,
dimethylformamide, and dimethylacetamide. In particular,
pharmaceutical forms such as tablets, sugar-coated tablets,
capsules, solutions, preferably oily or aqueous solutions, syrups,
juices, or drops. Furthermore, suspensions or emulsions are used
for oral and rectal administration. Mixtures of two or more
vehicles can also be employed, for example, mixtures of two or more
solvents, in particular also mixtures of at least one organic
solvent with water. As additives or excipients, the pharmaceutical
preparations can contain, for example, stabilizing and/or wetting
agents, emulsifiers, salts, for example for affecting the osmotic
pressure, lubricants, preservatives, colorants and flavorings,
and/or aromatizers and buffer substances. If desired, they can also
contain at least one further active compound, for example at least
one vitamin. Compounds of formula (I) and/or their physiologically
tolerable salts can also be lyophilized and the lyophilizates
obtained can be used, for example, for the production of injection
preparations. Liposomal preparations are also particularly suitable
for topical application.
[0131] The dose of at least one active compound of formula (I) to
be administered and/or of a physiologically tolerable salt thereof
in the case of use according to the invention depends on the
individual case and is to be tailored to the individual conditions
as customary for an optimal action. Thus it depends on the nature
and severity of the illness to be treated, and on the sex, age,
weight, and individual responsiveness of the human or animal to be
treated, on the potency and duration of action of the compounds
employed, on whether the therapy is acute or chronic or prophylaxis
is carried out, or on whether further active compounds are
administered in addition to compounds of formula (I). In general, a
dose range for the treatment of the abovementioned syndromes in
humans of approximately 0.1 mg to approximately 100 mg per kg per
day on administration to an adult weighing about 75 kg is adequate
to achieve the desired action. A dose range of 1 to 20 mg per kg
per day (in each case mg per kg of body weight) is preferred. The
daily dose can be administered here as an individual dose or can be
divided into a number, for example, 1, 2, 3, or 4, of individual
doses. It can also be administered continuously. If appropriate,
depending upon individual behavior, it may be necessary to deviate
upwards or downwards from the daily dose indicated. Pharmaceutical
preparations normally contain 0.2 to 500 mg, preferably 1 to 300
mg, of at least one active compound of formula (I) and/or a
physiologically tolerable salt thereof.
[0132] The invention also very generally comprises the use of
preferably nonpeptide compounds which bring about a stimulation of
angiotensin (1-7) receptors which are located, for example, in the
vessels (including endothelium), in the kidney, in the CNS, and in
the heart, as pharmaceuticals, preferably for oral administration,
or for use as substances which stimulate the production and/or
release of the vasorelaxant, antithrombotic, and cardioprotective
messengers cGMP and NO, and as pharmaceuticals for the treatment
and/or prophylaxis of illnesses which are primarily or secondarily
caused or at least partly caused by a reduced production and/or
release of the vasorelaxant, antithrombotic, and cardioprotective
messengers cGMP and NO, in particular for the treatment and
prophylaxis of high blood pressure, cardiac hypertrophy, cardiac
insufficiency, coronary heart diseases such as angina pectoris,
cardiac infarct, vascular restenosis after angioplasty,
cardiomyopathies, an endothelial dysfunction or endothelial damage,
e.g., as a result of arteriosclerotic processes or in diabetes
mellitus, and also of arterial and venous thrombosis.
[0133] List of abbreviations:
1 abs. absolute cGMP cyclic 3',5'-guanosine monophosphate
CH.sub.2Cl.sub.2 dichloromethane DCI desorption chemical ionization
DMF N,N-dimethylformamide EA ethyl acetate ESI electron spray
ionization FAB fast atom bombardment M.p. melting point satd
saturated h hour(s) min minute(s) NO nitrogen monoxide RT room
temperature THF tetrahydrofuran
[0134] The invention is illustrated by the examples below, without
being restricted to these.
EXAMPLES
Example 1
[0135]
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-
-5-isobutyl-3-thienyl]phenyl]methyl]imidazole 15
[0136] a)
4-Chloro-1-[(4-bromophenyl)methyl]-5-formyl-2-phenylimidazole
[0137] A solution of 8.0 g (32.0 mmol) of
4-chloro-5-formyl-2-phenylimidaz- ole (prepared according to Chem.
Pharm. Bull. 24 (1976) 960-969) and 5.3 g (32.0 mmol) of
K.sub.2CO.sub.3 in 200 ml of abs. DMF was stirred at RT for 20 min.
A solution of 9.6 g (32.0 mmol) of 4-bromobenzyl bromide in 200 ml
of abs. DMF was then added dropwise and the reaction solution was
stirred at RT for 6 h. It was concentrated in vacuo, and the
residue obtained was taken up in EA, washed with water, 10%
strength KHSO.sub.4, 10% strength NaHCO.sub.3, and satd sodium
chloride solution, and dried over Na.sub.2SO.sub.4. Chromatographic
purification on SiO.sub.2 using EA/heptane (1:4) as eluent of the
residue which remained after stripping off the EA yielded 11.5 g of
the title compound in the form of a beige solid.
[0138] M.p.: 92-95.degree. C.
[0139] R.sub.f (SiO.sub.2, EA/heptane 1:4)=0.24
[0140] MS (ESI): m/e=375/377 [M+H].sup.+
[0141] b)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonamido)-5--
isobutyl-3-thienyl]phenyl]methyl]imidazole
[0142] A solution of 7.2 g (22.6 mmol) of
5-isobutyl-2-[(N-tert-butyl)sulf- onamido]-thiophene-3-boronic acid
(disclosed in EP-A 512 675) in 125 ml of ethanol was added dropwise
at RT to a solution of 8.5 g (22.6 mmol) of the compound from
Example 1a) and 800 mg of tetrakistriphenylphosphinepal- ladium(0)
in 100 ml of toluene. 26 ml of a 2 M Cs.sub.2CO.sub.3 solution were
added and the resultant reaction solution was stirred at reflux for
5 h. It was concentrated to dryness and the residue that remained
was taken up in EA/water (1:1). The organic phase was separated
off, washed with water, dried over Na.sub.2SO.sub.4, and
concentrated. Chromatographic purification of the residue on
SiO.sub.2 using EA/heptane (1:4) as eluent afforded 6.7 g of the
title compound as a white solid.
[0143] M.p.: 104-105.degree. C.
[0144] R.sub.f (SiO.sub.2, EA/heptane 1:2)=0.26
[0145] MS (ESI): m/e=570 [M+H].sup.+
[0146] c)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thi-
enyl]phenyl]-methyl]imidazole
[0147] A solution of 3.3 g (5.96 mmol) of the compound from Example
lb) and 3.5 ml (5.96 mmol) of anisole in 33 ml of trifluoroacetic
acid was stirred at RT for 48 h. It was concentrated to dryness in
vacuo and the residue was taken up in EA. The EA solution was
washed with water, dried over Na.sub.2SO.sub.4, and concentrated.
After chromatographic purification of the residue on SiO.sub.2
using EA/heptane (1:1) as eluent, 1.52 g of the desired compound
was obtained, in the form of a slowly crystallizing solid.
[0148] M.p.: 118-120.degree. C.
[0149] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.32
[0150] MS (ESI): m/e=515 [M+H].sup.+
[0151] d)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonami-
do)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
[0152] A solution of 100 mg (0.19 mmol) of the compound from
Example 1c) in 1.7 ml of abs. pyridine was treated successively
with 3 mg (0.02 mmol) of 4-pyrrolidinopyridine and 252 .mu.l (0.19
mmol) of butyl chloroformate in an argon atmosphere. The reaction
solution was stirred at RT for 24 h. 0.7 ml of methanol were then
added, the solution was concentrated to dryness, and the residue
was taken up in EA. The EA solution was then washed with a 10%
strength citric acid solution, water, and a satd sodium chloride
solution, dried over Na.sub.2SO.sub.4, and concentrated.
Chromatographic purification on SiO.sub.2 using EA/heptane (1:1) of
the residue obtained after stripping off the solvent finally
yielded 85 mg of the title compound in the form of an amorphous
solid.
[0153] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.15
[0154] MS (FAB): m/e=614 [M+H].sup.+
Example 2
[0155]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole 16
[0156] a)
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-th-
ienyl]-phenyl]methyl]imidazole
[0157] A solution of 850 mg (1.65 mmol) of the compound from
Example Ic) in 25 ml of methanol was treated with 665 mg (16.53
mmol) of NaOH and stirred under reflux for 20 h. The reaction
solution was concentrated, the residue was taken up in 60 ml
EA/water (1:1), the pH of the solution was adjusted to 6 by
addition of 1 N hydrochloric acid, and the organic phase was
separated off. The aqueous phase was extracted twice with EA and
the combined organic phases were dried over Na.sub.2SO.sub.4.
Chromatographic purification on SiO.sub.2 using EA/heptane (1:1) as
eluent of the residue obtained after stripping off the EA afforded
690 mg of the title compound in the form of a yellow, amorphous
foam.
[0158] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.23
[0159] MS (FAB): m/e=510 [M+H].sup.+
[0160] b)
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonam-
ido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
[0161] The title compound was prepared by reaction of the compound
from Example 2a) with butyl chloroformate according to the process
mentioned in Example 1d). In this case, starting from 106 mg (0.21
mmol) of the compound from Example 2a) after chromatographic
purification on SiO.sub.2 using EA/heptane (1:1) as eluent, 75 mg
of the desired compound was obtained as an amorphous foam.
[0162] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.18
[0163] MS (ESI): m/e=610 [M+H].sup.+
Example 3
[0164]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamid-
o)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole 17
[0165] The title compound was prepared by reaction of the compound
from Example 2a) with propyl chloroformate according to the process
mentioned in Example 1d). In this case, starting from 60 mg (0.12
mmol) of the compound from Example 2a) after chromatographic
purification on SiO.sub.2 using EA/heptane (1:1) as eluent, 61 mg
of the title compound were obtained as an amorphous foam.
[0166] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.13
[0167] MS (ESI): m/e=596 [M+H].sup.+
Example 4
[0168]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5--
isobutyl-3-thienyl]phenyl]methyl]imidazole 18
[0169] The title compound was prepared by reaction of the compound
from Example 2a) with ethyl chloroformate according to the process
mentioned in Example 1d). In this case, starting from 60 mg (0.12
mmol) of the compound from Example 2a) after chromatographic
purification on SiO.sub.2 using EA/heptane (1:1) as eluent, 55 mg
of the title compound were obtained as an amorphous foam.
[0170] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.10
[0171] MS (ESI): m/e=582 [M+H].sup.+
Example 5
[0172]
5-Formyl4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5--
isobutyl-3-thienyl]phenyl]methyl]imidazole 19
[0173] A solution of 80 mg (0.16 mmol) of the compound from Example
2a), 43.3 mg (0.32 mmol) of K.sub.2CO.sub.3, and 8.3 mg of
dimethylaminopyridine in 6 ml of diethylene glycol dimethyl ether
was treated with 16.8 11 (0.16 mmol) of dimethyl dicarbonate and
then stirred under reflux for 1.5 h. The reaction solution was
concentrated to dryness and the residue was taken up in a solution
of EA and a 10% strength KH.sub.2PO.sub.4 solution (1:1). The
organic phase was separated off, washed twice with a 10% strength
KH.sub.2PO.sub.4 solution, dried over Na.sub.2SO.sub.4, and
concentrated. Chromatographic purification of the residue on
SiO.sub.2 using EA/heptane (2:1) as eluent, yielded 55 mg of the
title compound in the form of an amorphous foam.
[0174] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.23
[0175] MS (ESI): m/e=568 [M+H].sup.+
Example 6
[0176]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonami-
do)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole 20
[0177] A solution of 60 mg (0.12 mmol) of the compound from Example
2a) in 2 ml of abs. DMF was treated successively with 48 mg (0.35
mmol) of K.sub.2CO.sub.3 and 13.2 .mu.l (0.12 mmol) of n-butyl
isocyanate and then stirred under reflux for 3 h. After cooling, 15
ml of a 10% strength KH.sub.2PO.sub.4 solution were added to the
reaction solution and the solution obtained was extracted a number
of times with EA. The combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated. The residue obtained was treated
with EA/diisopropyl ether and the precipitate deposited was
filtered off with suction. Drying of the precipitate in vacuo
afforded 55 mg of the title compound.
[0178] M.p.: 131-133.degree. C.
[0179] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.30
[0180] MS (FAB): m/e=609 [M+H].sup.+
Example 7-
[0181]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole 21
[0182] The title compound was prepared by reaction of the compound
from Example 2a) with ethyl isocyanate according to the process
mentioned in Example 6). In this case, starting from 60 mg (0.12
mmol) of the compound from Example 2a), 46 mg of the title compound
were obtained.
[0183] M.p.: 105-106.degree. C.
[0184] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.30
[0185] MS (ESI): m/e=581 [M+H].sup.+
Example 8
[0186]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamid-
o)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole 22
[0187] A solution of 80 mg (0.16 mmol) of the compound from Example
2a) in 1.5 ml of DMSO was treated with 30.4 mg (0.17 mmol) of
N-methyl-2,2,2-trichloroacetamide and-19.1 mg (0.47 mmol) of
powdered NaOH and stirred at 80.degree. C. for 1 h. The reaction
solution was cooled, treated with ice, and the pH was adjusted to 4
by addition of 2 N hydrochloric acid. The precipitate that
deposited in the course of this was filtered off with suction,
washed with water, dried, and purified by chromatography on
SiO.sub.2 using EA/heptane (2:1) as eluent. 62 mg of the title
compound were obtained in the form of a white solid.
[0188] M.p.: 102-103.degree. C.
[0189] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.14
[0190] MS (ESI): m/e=567 [M+H].sup.+
Example 9
[0191]
5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfo-
namido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole 23
[0192] a)
5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobuty-
l-3-thienyl]phenyl]methyl]imidazole
[0193] A solution of 200 mg (0.38 mmol) of the compound from
Example 1 c) in 7.8 ml of ethylene glycol monomethyl ether was
treated with 155 mg (3.89 mmol) of powdered NaOH in an argon
atmosphere and then stirred at 80.degree. C. for 5 h. It was
concentrated to dryness and the residue obtained was taken up in a
saturated NaHCO.sub.3 solution and EA. The EA phase was separated
off and the aqueous solution was extracted several times with EA.
The organic phases were combined, dried over Na.sub.2SO.sub.4, and
concentrated. Chromatographic purification on SiO.sub.2 using
EA/heptane (1:1) of the remaining residue yielded 140 mg of the
title compound as a pale yellow-colored solid.
[0194] M.p.: 91-92.degree. C.
[0195] R.sub.f (SiO.sub.2, EA/heptane 1: 1)=0.12
[0196] MS (FAB): m/e=554 [M+H].sup.+
[0197] b)
5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsu-
lfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
[0198] The title compound was prepared by reaction of the compound
from Example 9a) with butyl chloroformate according to the process
mentioned in Example 1d). In this case, starting from 70 mg (0.13
mmol) of the compound from Example 9a) after chromatographic
purification on SiO.sub.2 using EA/heptane (1:1) as eluent, 78 mg
of the title compound was obtained as an amorphous foam.
[0199] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.07
[0200] MS (ESI): m/e=654 [M+H].sup.+
Example 10
[0201]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole 24
[0202] a)
4-Chloro-1-[(4-bromo-2-chlorophenyl)methyl]-5-formyl-2-phenyl-im-
idazole
[0203] The title compound was prepared by reaction of
4-chloro-5-formyl-2-phenylimidazole with 4-bromo-2-chlorobenzyl
bromide according to the process mentioned in Example la). In this
case, starting from 2.0 g (9.68 mmol) of
4-chloro-5-formyl-2-phenylimidazole, 2.6 g of the title compound
was obtained.
[0204] R.sub.f (SiO.sub.2, EA/heptane 1:2)=0.56
[0205] MS (DCI): m/e=409/411 [M+H].sup.+
[0206] b)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonamido)-5--
isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole
[0207] The title compound was prepared by reaction of the compound
from Example 10a) and
5-isobutyl-2-[(N-tert-butyl)sulfonamido]thiophene-3-boro- nic acid
according to the process mentioned in Example 1b). In this case,
starting from 2.0 g (4.88 mmol) of the compound from Example 10a),
1.2 g of the title compound were obtained in the form of a pale
brown oil.
[0208] R.sub.f (SiO.sub.2, EA/heptane 1:2)=0.47
[0209] MS (FAB): m/e=604 [M+H].sup.+
[0210] c)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thi-
enyl]-2-chlorophenyl]methyl]imidazole
[0211] The title compound was prepared from the compound from
Example 10b) according to the process mentioned in Example 1c).
Starting from 1.2 g (1.99 mmol) of the compound from Example 10b),
606 mg of the title compound was obtained as an amorphous, yellow
foam.
[0212] R.sub.f (SiO.sub.2, EA/heptane 1:2)=0.32
[0213] MS (FAB): m/e=548 [M+H].sup.+
[0214] d)
5-Formyl-2-methoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-th-
ienyl]-2-chlorophenyl]methyl]imidazole
[0215] The title compound was prepared from the compound from
Example 10c) according to the process mentioned in Example 2a). In
this case, starting from 400 mg (0.73 mmol) of the compound from
Example 10c), 280 mg of the title compound was obtained in the form
of a yellow, amorphous foam.
[0216] M.p.: 60.degree. C. (softening)
[0217] R.sub.f (SiO.sub.2, EA/heptane 1:2)=0.20
[0218] MS (ESI): m/e=544 [M+H].sup.+
[0219] e)
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonam-
ido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole
[0220] The title compound was obtained from the reaction of the
compound from Example 10d) with butyl chloroformate according to
the process mentioned in Example 1d). Starting from 200 mg (0.37
mmol) of the compound from Example 10d), 167 mg of the desired
compound were obtained in the form of a beige solid.
[0221] M.p.: 58.degree. C. (softening)
[0222] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.45
[0223] MS (ESI): m/e=644 [M+H].sup.+
Example 11
[0224]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole 25
[0225] The title compound was obtained from the reaction of the
compound from Example 10d) with ethyl isocyanate according to the
process described in Example 7). In this case, starting from 74 mg
(0.14 mmol) of the compound from Example 10d) after chromatographic
purification on SiO.sub.2 using CH.sub.2Cl.sub.2/methanol (20:1) as
eluent, 35 mg of the title compound was obtained in the form of a
white solid.
[0226] M.p.: 83.degree. C. (softening)
[0227] R.sub.f(SiO.sub.2, EA/heptane 1:1)=0.30
[0228] MS (ESI): m/e=614 [M+H].sup.+
Example 12
[0229]
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-
-5-n-propyl-3-thienyl]phenyl]methyl]imidazole 26
[0230] a)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonamido)-5--
n-propyl-.sup.3-thienyl]phenyl]methyl]imidazole
[0231] The title compound was prepared by the reaction of the
compound from Example la) with
5-n-propyl-2-[(N-tert-butyl)sulfonamido]thiophene-3- -boronic acid
(disclosed in EP-A 512 675) according to the process mentioned in
Example lb). In this case, starting from 4.8 g (13.1 mmol) of the
compound from Example la) after chromatographic purification on
SiO.sub.2 using EA/heptane (1:3) as eluent, 2.9 g of the title
compound were obtained in the form of a white solid.
[0232] M.p.: 140.degree. C.
[0233] R.sub.f (SiO.sub.2, EA/heptane 1:2)=0.30
[0234] MS (FAB): m/e=556 [M+H].sup.+
[0235] b)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamido-5-n-propyl-3-thi-
enyl]-phenyl]methyl]imidazole
[0236] The title compound was prepared from the compound from
Example 12a) according to the process mentioned in Example 1c).
Starting from 1.9 g (3.56 mmol) of the compound from Example 12a),
after chromatographic purification on SiO.sub.2 using EA/heptane
(1:2) as eluent, 1.1 9 of the title compound was obtained as a
white solid.
[0237] M.p.: 93-95.degree. C.
[0238] R.sub.f (SiO.sub.2, EA/heptane 1:2)=0.18
[0239] MS (ESI): m/e=500 [M+H].sup.+
[0240] c)
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonami-
do)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole
[0241] The title compound was prepared by reaction of the compound
from Example 12b) with butyl chloroformate according to the process
mentioned in Example 1d). In this case, starting from 100 mg (0.20
mmol) of the compound from Example 12b), after chromatographic
purification on SiO.sub.2 using EA/heptane (1:1) as eluent, 90 mg
of the title compound were obtained.
[0242] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.14
[0243] MS (ESI): m/e=600 [M+H].sup.+
Example 13
[0244]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido-
)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole 27
[0245] a)
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-sulfonamido-5-n-propyl-3-th-
ienyl]-phenyl]methyl]imidazole
[0246] The title compound was prepared by reaction of the compound
from Example 12b) according to the process mentioned in Example
2a). In this case, starting from 850 mg (1.70 mmol) of the compound
from Example 12b), after chromatographic purification on SiO.sub.2
using EA/heptane (1:2) as eluent, 460 mg of the title compound was
obtained in the form of a white solid.
[0247] M.p.: 85-86.degree. C.
[0248] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.22
[0249] MS (ESI): m/e=496 [M+H].sup.+
[0250] b)
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonam-
ido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole
[0251] The title compound was prepared by reaction of the compound
from Example 13a) with butyl chloroformate according to the process
mentioned in Example 1d). In this case, starting from 60 mg (0.12
mmol) of the compound from Example 13a), after chromatographic
purification on SiO.sub.2 using EA/heptane (1:1) as eluent, 52 mg
of the title compound were obtained.
[0252] R.sub.f (SiO.sub.2, EA/heptane 1:1)=0.18
[0253] MS (ESI): m/e=596 [M+H].sup.+
Example 14
[0254]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-
-n-propyl-3-thienyl]phenyl]methyl]imidazole 28
[0255] The title compound was prepared by reaction of the compound
from Example 13b) with dimethyl dicarbonate according to the
process mentioned in Example 5). Starting from 75 mg (0.15 mmol) of
the compound from Example 13b), after chromatography on SiO.sub.2
using EA/heptane (2:1) as eluent, 66 mg of the title compound were
obtained as an amorphous solid.
[0256] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.18
[0257] MS (ESI): m/e=554 [M+H].sup.+
Example 15
[0258]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonami-
do)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole 29
[0259] The title compound was prepared by reaction of the compound
from Example 13b) with n-butyl isocyanate according to the process
mentioned in Example 6). Starting from 59 mg (0.12 mmol) of the
compound from Example 13b), after chromatography on SiO.sub.2 using
EA/heptane (1:1) as eluent, 54 mg of the title compound were
obtained as an amorphous solid.
[0260] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.25
[0261] MS (ESI): m/e=595 [M+H].sup.+
Example 16
[0262]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamid-
o)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole 30
[0263] The title compound was prepared by reaction of the compound
from Example 13b) with N-methyl-2,2,2-trichloroacetamide according
to the process mentioned in Example 8). Starting from 70 mg (0.14
mmol) of the compound from Example 13b), after chromatography on
SiO.sub.2 using EA/heptane (2:1) as eluent, 55 mg of the title
compound were obtained as an amorphous solid.
[0264] R.sub.f (SiO.sub.2, EA/heptane 4:1)=0.15
[0265] MS (ESI): m/e=553 [M+H].sup.+
Example 17
[0266]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole sodium salt 31
[0267] 220 mg (0.38 mmol) of the compound from Example 7 were
treated with 3.7 ml of a freshly prepared 0.1 molar sodium
methoxide solution and the resulting solution was stirred at RT for
1 h. The reaction solution was concentrated to dryness and the
residue obtained was dissolved in 4 ml of n-butyl acetate with
slight warming. The precipitate crystallizing out after storage in
a refrigerator for 3 days was filtered off with suction and washed
with a little cold n-butyl acetate. Drying under high vacuum
finally yielded 120 mg of the desired sodium salt.
[0268] M.p.: 170.degree. C.
[0269] MS (ESI): m/e=603 [M+H].sup.+
Example 18
[0270]
5-Formyl-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)--
5-isobutyl-3-thienyl]phenyl]methyl]imidazole L-lysine salt 32
[0271] A solution of 500 mg (0.86 mmol) of the compound from
Example 7 and 125.8 mg (0.86 mmol) of L-lysine in 100 ml of ethanol
and 25 ml of water was stirred at RT for 2 h. It was then
concentrated to dryness, the residue was taken up in 30 ml of
water, and the solution obtained was freeze-dried. 200 mg of the
amorphous residue obtained were dissolved in 10 ml of hot toluene.
After storage in a refrigerator for several days, the precipitate
that crystallized out was filtered off and dried under high vacuum.
68 mg of the title compound was obtained as pale yellow-colored
crystals.
[0272] M.p.: 180.degree. C.
[0273] MS (ESI): m/e=727 [M+H].sup.+
Example 19
[0274]
5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido-
)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
tris(hydroxymethyl)aminomet- hane salt 33
[0275] A solution of 300 mg (0.516 mmol) of the compound from
Example 7 and 62.6 mg (0.516 mmol) of
tris(hydroxymethyl)aminomethane in 75 ml of ethanol and 15 ml of
water was stirred at RT for 2 h. It was then concentrated to
dryness, the residue was taken up in water, and the solution
obtained was freeze-dried. The amorphous residue obtained was
dissolved with heating in 30 ml n-butyl acetate. After storage in a
refrigerator for several days, the precipitate that crystallized
out was filtered off and dried under high vacuum. 120 mg of the
title compound was obtained as pale yellow-colored crystals.
[0276] M.p.: 144-145.degree. C.
[0277] MS (ESI): m/e=702 [M+H].sup.+
[0278] The affinity of compounds of formula (I) for angiotensin
(1-7) binding sites, and their agonistic properties on endothelial
cells, were demonstrated in the following assays (tests 1 and
2):
[0279] Test 1: Binding Assay
[0280] The affinity of compounds of formula (I) for angiotensin
(1-7) receptors was measured by ligand displacement experiments on
membrane preparations of primary bovine aorta endothelial cells,
such as are also described, for example, in Hypertension 29 (part
2) (1997) 388-393.
[0281] a) Membrane Preparation:
[0282] Following obtainment of endothelial cells from bovine aortas
(test 1, a), the cells were cultured in 75 cm.sup.2 culture bottles
(Becton Dickinson, Heidelberg) until achieving confluence. The
cells were then taken up with ice-cold phosphate/NaCl/EDTA buffer
(50 mmol/l NaHPO.sub.4, 0.15 mol/l NaCl, 5 mmol/l EDTA, pH 7.2),
detached with a rubber scraper, and centrifuged (1500.times.g, 5
min). The resulting cell pellet was frozen (-80.degree. C.) for
later membrane preparation. The thawed cell pellet was homogenized
(glass/Teflon Potter, 1000 rpm, 10 strokes) in ice-cold
phosphate/NaCl/EDTA buffer. Membrane isolation was carried out by
subsequent centrifugation (30,000.times.g, 20 min) of the cell
homogenate. The cell pellet thus obtained was resuspended in
modified HEPES buffer (10 nmol/l HEPES, 0.1 mol/l NaCl, 5 mmol/l
MgCl.sub.2, pH 7.4) with addition of 0.2% bovine serum albumin and
a protease inhibitor cocktail (COMPLETE.RTM., Boehringer Mannheim).
After subsequent protein determination (according to Lowry) of the
membrane suspension, this was used immediately for the ligand
binding test.
[0283] b) Binding Experiments:
[0284] The tests were carried out on 96-well opaque plates that are
equipped with Durapore filters (0.65 .mu.m pore size; Millipore,
Eschborn). Before the beginning of the test, the filters were
pretreated with 1% bovine serum albumin for 30 min in order to
minimize the nonspecific binding of the radioactive ligand and of
the cold substances to the filter material. The incubation was
carried out in a total volume of 200 .mu.l: 50 .mu.l of
.sup.125I-ANG (1-7), 20 .mu.l of cold, nonradioactive ANG (1-7) or
test substances of formula (I), 30 .mu.l of buffer, and 100 .mu.l
of membranes (20 .mu.g of protein). The binding reaction was
started by addition of the radioactive ligand. The incubation of
the samples was carried out with continuous shaking at RT for 45
min. The binding reaction was ended by means of vacuum filtration
(-20 kPa vacuum; multiscreen filtration system, Millipore,
Eschborn). In order to completely remove the non-membrane-bound,
free radioactivity, the filters were washed in vacuo twice with 250
.mu.l of ice-cold phosphate/NaCl/EDTA buffer (50 mmol/l of
NaHPO.sub.4, 0.15 mol/l of NaCl, 5 mmol/l of EDTA, pH 7.2), and
then dried. The radioactive content on the dried filters was
determined by means of a gamma counter.
[0285] For the competition experiments (determination of
"individual values" or IC.sub.50 values), a concentration of 7.5 to
10 nmol/l of .sup.125I-ANG (1-7) (specific activity 1500-2100
mCi/mg) was employed, with and without increasing concentrations of
the test substances of formula (I). The nonspecific binding was in
each case measured in the presence of 10 .mu.mol/l of
nonradioactive ANG (1-7).
[0286] c) Results:
2 Example IC.sub.50 (nM) 2a 20 2b 30 4 5 7 20
[0287] The results confirm the high affinity of compounds of
formula (I) for the angiotensin (1-7) receptor on endothelial
cells.
[0288] With respect to ANGII receptors of the AT.sub.1 and AT.sub.2
type, compounds of formula (I) in this case have no or only
negligible (>10.sup.-6 M) affinity.
[0289] Test 2: Functional Assay
[0290] As a marker of the production and release of NO in
endothelial cells, the stimulating action of compounds of formula
(I) on the production of intracellular cGMP was measured on
primary-cultured endothelial cells of bovine aortas, such as is
described, for example, in J. Pharmacol. Exp. Ther. 262 (1992)
729-733.
[0291] a) Cell Cultures:
[0292] After enzymatic digestion (Dispase II; Boehringer, Mannheim)
of the endothelial cells from the bovine aorta, the endothelial
cells were taken up in culture medium (Dulbecco's modified Eagle's
Ham's F 12 Medium 1:1 with penicillin (10 U/l), streptomycin (10
.mu.g/l), L-glutamine (1 mmol/l), glutathione, and L-(+)-ascorbic
acid (in each case 5 mg/l) and heat-inactivated fetal calf serum
(20%)), washed once (centrifugation at 170.times.g, 10 min), and
resuspended in culture medium. The cell suspension thus obtained
was inoculated (.about.250 .mu.g of protein or 3.times.10.sup.-5
cells per well) into 6-well plates (Nunc Intermed, Wiesbaden), made
up with culture medium, and kept at 37.degree. C. in an incubator
which was humidified and aerated with 95% O.sub.2/5% CO.sub.2.
[0293] b) cGMP Determinations:
[0294] After reaching confluence (6-8 days after inoculation), the
culture medium was removed and the cell monolayer was washed twice
with warm HEPES/Tyrode's solution. The cells were then
pre-incubated for 15 min at 37.degree. C. in HEPES/Tyrode's
solution which contains IBMX (3-isobutyl-1-methylxanthine,
10.sup.-4 mol/l, Serva, Heidelberg). The incubation was started by
addition of SOD (superoxide dismutase from bovine erythrocytes,
3.times.10.sup.-7mol/l, Serva, Heidelberg) and the test substances
of formula (I) in the given concentrations. After the appropriate
incubation time, the incubation medium was aspirated, and the
remaining cells were immediately extracted into 1 N formic
acid-acetone (v/v, 15:85) and scraped off. The suspension obtained
was ultrasonicated (10 sec) and then centrifuged off (3000.times.g,
10 min). For the determination of cGMP by means of radioimmunoassay
(New England Nuclear, Boston, Mass.), the supernatant was
lyophilized and taken up in sodium acetate buffer (0.05 mol/l; pH
6.2). The content (pmol) of intracellular cGMP was related to mg of
cell protein.
[0295] c) Results:
3 Example EC.sub.50 (nM) 2a 0.5 2b 0.3 4 0.1 7 0.5
[0296] The results confirm the agonistic action of compounds of
formula (I) on angiotensin (1-7) receptors.
[0297] The action of the compound according to the invention on the
production of cGMP as a marker of the NO synthesis and release is
not affected here by preincubation with an angiotensin II receptor
antagonist either of the AT.sub.1 subtype such as EXP3174, or of
the AT.sub.2 subtype such as PD 123,319. In contrast to this, the
described stimulating effect of the compound according to the
invention on the cGMP is inhibited by preincubation with a
selective antagonist of angiotensin (1-7) receptors,
[D-Ala.sup.7]-angiotensin (1-7), which is described, for example,
in Brain Res. Bull. 35 (1994) 293-298, which confirms the
specificity of this functional effect.
[0298] The action of compounds of formula (I) on the heart was
demonstrated in the model of isolated, working rat hearts (test 3)
which is described, for example, in J. Cardiovasc. Pharrmacol. 8
(Suppl. 10) (1986) S91-S99.
[0299] Test 3: Isolated, Working Rat Hearts
[0300] a) Method:
[0301] Isolated hearts of Wistar-Kyoto rats (280-300 g body weight)
are perfused with a constant perfusion pressure of 60 mmHg
according to the method of Langendorff using an oxygen-saturated
(95% O.sub.2, 5% CO.sub.2), nonrecirculating, modified
Krebs-Henseleit buffer solution (118 mmol/l of NaCl, 4.7 mmol/l of
KCl, 2.5 mmol/l of CaCl.sub.2, 1.6 mmol/l of MgSO.sub.41 24.9
mmol/l of NaHCO.sub.3, 1.2 mmol/l of KH.sub.2PO.sub.4, 5.5 mmol/l
of glucose, and 2.0 mmol/l of sodium pyruvate). For the measurement
of the coronary flow, a catheter having an electromagnetic
measuring head placed in the pulmonary artery was used. After a
15-minute equilibration period, the heart is converted into the
working mode, in which a preload of 15 mmHg and an afterload of 60
mmHg is set. The working load of the heart remains constant during
the entire test time of 90 minutes. Flow and pressure signals for
the analysis are recorded by means of a PLUGSYS measuring system
(Hugo Sachs Elektronik). The analysis of the data is carried out at
a collection frequency of 500 Hz, averaged every 2 seconds, using
the software Aquire Plus VI.21f (PO-NE-MAH).
[0302] b) Results:
[0303] On perfusion of the hearts (n=4) at a concentration of
10.sup.-6 mol/l of the compound from Example 2, the following
values for the coronary flow were determined in comparison to
control hearts (n=4):
[0304] 1. Treated hearts:
4 Coronary flow (ml/min) Time (min) 8.92 .+-. 0.68 0 11.29 .+-.
0.90 5 12.17 .+-. 0.74 10 12.22 .+-. 0.10 15
[0305] 2. Control hearts:
5 Coronary flow (ml/min) Time (min) 8.98 .+-. 0.59 0 8.94 .+-. 0.52
5 9.04 .+-. 0.70 10 8.91 .+-. 0.44 15
[0306] The heart rate remained unchanged in both groups during the
entire experiment.
[0307] This significant increase in the coronary flow in isolated,
working rat hearts confirms the cardioprotective action of
compounds of formula (I).
[0308] The action of compounds of formula (I) on collagen-induced
platelet aggregation was investigated in human platelet-rich
plasma, which is described, for example, in G. V. Born et al.,
Nature (1962).
[0309] Test 4:
[0310] a) Method:
[0311] Human platelet-rich plasma (PRP) from 6 blood donors was
incubated with the test compound at 37.degree. C. for 20 min, then
activated with collagen, and the maximal aggregation of the
platelets was quantified in % via light transmission.
[0312] b) Result:
[0313] On incubation of the platelet-rich plasma with 30 .mu.M of
the compound from Example 2, the following values were determined
for platelet aggregation (n=6):
[0314] Collagen (=maximal aggregation): 92.+-.2.7% aggregation
[0315] Collagen+30 .mu.M of the compound from Example 2: 52.+-.5.7%
aggregation
[0316] This significant inhibition of the platelet aggregation of
human platelet-rich plasma confirms the antithrombotic action of
compounds of formula (I).
[0317] The present invention may be embodied in other specific
forms without departing from its spirit or essential
characteristics. The described embodiments are to be considered in
all respects as illustrative only and not restrictive. The scope of
the invention is, therefore, indicated by the appended claims
rather than by the foregoing description. All changes which come
within the meaning and range of equivalency of the claims are to be
embraced within their scope.
* * * * *