Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-04
2001-05-22
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S315700
Reexamination Certificate
active
06235766
ABSTRACT:
The invention relates to novel 1-(p-thienylbenzyl)imidazoles of formula (I),
which are potent agonists of angiotensin (1-7) receptors and, because of the production hand 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.
EP-A 512675 and WO 94/27597 describe thienylbenzyl-substituted imidazoles as angiotensin II 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 II 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 II 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.
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.
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).
The invention thus relates to compounds of formula (I)
in which:
R(1) is
(1) halogen;
(2) hydroxyl;
(3) (C
1
-C
4
)-alkoxy;
(4) (C
1
-C
8
)-alkoxy, wherein 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably by O;
(5) (C
1
-C
4
)-alkoxy, substituted by a saturated cyclic ether such as tetrahydropyran or tetrahydrofuran;
(6) O-(C
1
-C
4
)-alkenyl;
(7) O-(C
1
-C
4
)-alkylaryl; or
(8) aryloxy, unsubstituted or substituted by a substituent selected from halogen, (C
1
-C
3
)-alkyl, (C
1
-C
3
)-alkoxy, and trifluoromethyl;
R(2) is
(1) CHO;
(2) COOH; or
(3) CO—O—(C
1
-C
4
)-alkyl;
R(3) is
(1) (C
1
-C
4
)-alkyl; or
(2) aryl;
R(4) is
(1) hydrogen;
(2) halogen; or
(3) (C
1
-C
4
)-alkyl;
X is
(1) oxygen; or
(2) sulfur;
Y is
(1) oxygen; or
(2) —NH—;
R(5) is
(1) hydrogen;
(2) (C
1
-C
6
)-alkyl; or
(3) (C
1
-C
4
)-alkylaryl;
where R(5) can only be hydrogen if Y has the meaning mentioned under (2); and
R(6)
(1) (C
1
-C
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
1
-C
4
)-alkyl.
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)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.
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.
Halogen represents fluorine, chlorine, bromine, or iodine, preferably chlorine or fluorine.
Aryl represents phenyl or naphthyl, preferably phenyl.
In substituted aryl radicals, the substituents can be situated in any desired position relative to one another.
Examples of arylalkyl radicals are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, and naphthylbutyl.
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.
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
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.
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.
Preferred compounds of formula (I) are those 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
1
-C
4
)-alkyl;
R(6) is
(1) n-propyl or 2-isobutyl;
and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Compounds of formula (I) are furthermore preferred in which
R(1) is halogen, preferably chlorine, (C
1
-C
4
)-alkoxy, preferably methoxy, ethoxy, or propyloxy, particularly preferably methoxy, or (C
1
-C
8
)-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably O, preferably methoxyethoxy or methoxypropoxy;
R(2) is CHO;
R(3) is aryl, preferably phenyl;
R(4) is halogen, preferably chlorine, or hydrogen;
R(5) is (C
1
-C
6
)-alkyl, preferably methyl, ethyl, propyl, or butyl;
R(6) is (C
1
-C
5
)-alkyl, preferably ethyl, propyl, or butyl;
X is oxygen;
Y is oxygen or —NH—;
in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
Compounds of formula (I) are very particularly preferred when these are compounds of formula (II)
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.
Preferred compounds of formula (I) are also those in which R(1) is (C
1
-C
4
)-alkoxy or (C
1
-C
8
)-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably
Heitsch Holger
Wiemer Gabriele
Aventis Pharma Deutschland GmbH
D'Souza Andrea M
Finnegan, Henderson Farabow, Garrett and Dunner L.L.P.
Ramsuer Robert W.
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