ZA200108801B - 1-(p-thienylbenzyl)-imidazoles as angiotensin-(1-7) receptor agonists, method for the production and the utilization thereof and pharmaceutical preparations containing said compounds. - Google Patents

1-(p-thienylbenzyl)-imidazoles as angiotensin-(1-7) receptor agonists, method for the production and the utilization thereof and pharmaceutical preparations containing said compounds. Download PDF

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ZA200108801B
ZA200108801B ZA200108801A ZA200108801A ZA200108801B ZA 200108801 B ZA200108801 B ZA 200108801B ZA 200108801 A ZA200108801 A ZA 200108801A ZA 200108801 A ZA200108801 A ZA 200108801A ZA 200108801 B ZA200108801 B ZA 200108801B
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phenyl
formula
formyl
methoxy
isobutyl
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ZA200108801A
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Holger Heitsch
Gabriele Wiemer
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Aventis Pharma Gmbh
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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  • Organic Chemistry (AREA)
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Description

1-(p-Thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use and pharmaceutical preparations comprising them
The invention relates to novel 1-(p-thienylbenzyl)imidazoles of the formula (0),
R(1) a8 —— R(2) oH ~s— Yo (1) 2s I ee
R(4) —
R(6) which are potent agonists of angiotensin (1-7) receptors and, owing to 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.
The applications EP-A 512675 and WO 94/27597 describe thienylbenzyl- substituted imidazoles as angiotensin Il receptor antagonists and their use for the treatment of hypertension, cardiac Insufficiency, migraine, oT
Alzheimer's disease and as antidepressants. Moreover, thienylbenzyl- substituted imidazopyridines are disclosed in EP-A 513979 as antagonists of angiotensin Il receptors and their use for the treatment of hypertension, cardiac insufficiency, migraine and Alzheimer's disease and in US-5444067 as angiotensin Il 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 |i receptors.
The 1-(p-thienylbenzyl)imidazoles of the 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 the formula (lI) 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 the formula (1)
R(1) 38 ——e R(2) 5 oN Yo (1)
Ag J R(5)
R(4) —
R(6) in which the radicals mentioned have the following meaning:
R(1) 1. halogen; 2. hydroxyl; 3. (C1-C4)-alkoxy; 4. (C1-Cg)-alkoxy, 1 to 6 carbon atoms being replaced by the heteroatoms O, S or NH, preferably by O; 5. (C1-Cy)-alkoxy, substituted by a saturated cyclic ether such as tetrahydropyran or tetrahydrofuran; N 6. O-(C1-Cy)-alkenyl; 7. O-(C1-Cg4)-alkylaryl; and 8. aryloxy, unsubstituted or substituted by a substituent from the group consisting of halogen, (C1-C3)-alkyl, (C1-Cg)-alkoxy or trifluoromethyl;
R(2) 1. CHO; 2. COOH; and 3. CO-0-(C1-Cy)-alkyl;
R(3) 1. (C1-Cy)-alkyl; and 2. aryl
R(4) 1. hydrogen; 2. halogen, and 3. (C1-Cy)-alkyl,
X 1. oxygen; 2. sulfur;
Y 1. oxygen; and 2. -NH-;
R(5) 1. hydrogen; 2. (C1-Cg)-alkyl; and 3. (C1-Cg4)-alkylaryl; where R(5) can only also be hydrogen if Y has the meaning mentioned under 2.;
R(B) 1. (C1-Cs)-alkyl; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts; excluding compounds of the formula (I) in which, simultaneously, R(1) is halogen and R(2) has the meaning mentioned under 2. and 3.
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, n-hexyl. Examples of alkoxy are methoxy, ethoxy, n-propoxy, 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 ary! radicals, the substituents can be situated in any desired positions relative to one another.
Examples of arylalkyl radicals are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthyibutyl.
If the compounds of the formula (I) contain one or more acidic or basic groups, the invention also relates to the corresponding physiologically tolerable salts, in particular the pharmaceutically utilizable salts. Thus the compounds of the formula (I) which carry acidic groups, e.g. one or more
COOH groups, can be used, for example, as alkali metal salts, preferably sodium or potassium salts, or as 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 the 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, methane- sulfonates, acetates, lactates, maleates, fumarates, malates, gluconates etc. If the compounds of the formula (lI) 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 the compounds of the 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 the 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
Edition, page 1418 (1985)). 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 the formula (I), for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formula (I) such as, for example, esters, and prodrugs and active metabolites.
Preferred compounds of the formula (1) are those in which
R(1)is 1. chlorine; 2. hydroxyl; 3. methoxy, ethoxy, propyloxy; 4. methoxyethoxy, methoxypropoxy; 5. allyloxy; and 6. phenoxy;
R(4) is 1. hydrogen; and 2. chlorine;
R(5)is 1. hydrogen; and 2. (C1-Cy)-alkyt;
R(6) is n-propyl and 2-isobutyl; and the other radicals are as defined above, in all their stereoisomeric forms and mixtures thereof, and their physiologically tolerable salts.
Compounds of the formula (I) are furthermore preferred in which B
R(1) is halogen, preferably chlorine; (C1-Cg4)-alkoxy, preferably methoxy, ethoxy, propyloxy, particularly preferably methoxy; or (C1-Cg)- alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms
O, S or NH, preferably O, preferably methoxyethoxy or methoxy- propoxy;
R(2) is CHO;
R(3) is aryl, preferably phenyl;
R(4) is halogen, preferably chlorine, or hydrogen;
R(5) is (C1-Cg)-alkyl, preferably methyl, ethyl, propyl, butyl;
R(B) is (C1-Cs)-alkyl, preferably ethyl, propyl or butyl;
X is oxygen;
Y is oxygen or —NH-; in all their stereocisomeric forms and mixtures thereof, and their physio- logically tolerable salts.
Compounds of the formula (I) are very particularly preferred when these are compounds of the formula (ll)
R(1)
N s@ \ Oo 0]
J ev an
R(4) = Ss 0) R(5)
R(6) in which the radicals R(1), R(4), R(5), R(6) and Y have the abovementioned meaning, in all their stereoisomeric forms and mixtures thereof, and their physiologically tolerable salts. —
Preferred compounds of the formula (I) are also those in which R(1) is (C1-C4)-alkoxy or (C1-Cg)-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 all their stereoisomeric forms and mixtures thereof, and their physiologically tolerable salts.
Particularly preferred compounds of the formula (I) are also those in which
R(2) is CHO and the other radicals are as defined above, in all their stereoisomeric forms and mixtures thereof, and their physiologically tolerable salts.
Preferred compounds of the formula (I) are furthermore those in which X is
O and the other radicals are as defined above, in all their stereocisomeric forms and mixtures thereof, and their physiologically tolerable salts.
Particularly preferred compounds of the formula (I) which may be mentioned are: 4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonyisulfonamido)-5- isobutyl-3-thienyl]phenyl]methyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyllphenyllmethyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5-iso- butyl-3-thienyl]phenyljmethyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-iso- butyl-3-thienyl]phenyljmethyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5- N isobutyl-3-thienyl]phenyl]methyllimidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyllimidazole sodium salt;
S-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyllmethyl]imidazole L-lysine salt 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyllimidazole tris(hydroxymethyl)amino- methane salt 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl)phenyl]methyllimidazole; 5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfon- amido)-5-isobutyl-3-thienyllphenyljmethyl]imidazole; 5-formyi-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]-2-chlorophenyi]methyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]-2-chlorophenyllmethyllimidazole; 4-chloro-5-formyi-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n- propyl-3-thienyl]phenylimethyl]limidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n- propyl-3-thienyl]phenyljmethyljimidazole; 5-formyl-4-methoxy-2-phenyi-1-[[4-[2-(methoxycarbonylsulfonamido)-5-n- propyl-3-thienyllphenyllmethyljimidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5- n-propyl-3-thienyllphenyl]methyllimidazole; or 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5- n-propyl-3-thienyl]phenyl]methyllimidazole; and their physiologically tolerable salts.
The invention furthermore relates to processes for the preparation of the compounds of the formula (I), which comprise the reaction steps shown below:
a) 4-chloro-5-formylimidazole derivatives of the formula (lll),
Cl
N
ANH (1
R(3) N
H © in which R(3) has the abovementioned meaning and whose preparation is described, for example, in Chem. Pharm. Bull. 24, 1976, 960-969, are reacted with p-bromobenzyl bromides of the formula (IV),
Br (IV)
Br
R(4) in which R(4) is as defined above, to give compounds of the formula (V)
Cl
N
R(3 (3) N Y V) : Br
R(4) in which R(3) and (R4) have the abovementioned meaning, where the alkylation can be carried out in the presence of an organic or inorganic base such as, for example, triethylamine, K2CO3 or CspCOg3 in an inert solvent such as, for example, DMF. Compounds of the formula (IV) are commercially obtainable or can be prepared by methods known per se. b) The compounds of the formula (V) can be reacted with thiophene-3- - boronic acids of the formula (VI)
B(OH),
H
Fat N (VI)
R(6) s” A
O00 in which R(6) is as defined above and whose preparation is disclosed in
EP-A 512 675, to give the 1-(p-thienyl)imidazoles of the formula (VII)
Cl
N
Py
R@)™ “N S °
H
BES (VIN) =
R(4) ~/°
R(6) 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(ll) acetate and triphenylphosphine or tetrakistriphenylphosphinepalladium 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. ¢) The compounds of the formula (VII) can be converted by removal of the tert-butyl protective group into the sulfonamides of the formula (VIII)
Cl
N paw
R(3) N 0 2 _
Ox NH, (VIII) =
R(4) -/°
R(6)
in which R(3), R(4) and R(6) are as defined above. This removal is preferably carried out by treatment of the compounds of the formula (VI) with organic acids such as, for example, concentrated trifluoroacetic acid in the presence of anisole. d) The compounds of the formula (Vill) can be converted by substitution of the chlorine atom in position 4 of the imidazole ring into the compounds of the formula (IX)
RQ)
Ba
R(3) N 0 0)
OY NH, (1X) =
R(4) -/
R(6) in which R(3), R(4) and R(6) are as defined above and R(1)‘ represents the radicals mentioned under 2. to 8. This substitution of the chlorine atom can be carried out in this case, for example, by treatment of the compounds of the formula (VIII) with alkoxides which are formed in situ by the action of bases such as NaOH or NaH on the alcohols in general also used as solvents, such as, for example, methanol, ethanol or ethylene glycol monomethyl ether, at temperatures of 50°C up to the boiling point of the alcohols.
Alternatively, the compounds of the formula (IX) in which R(1) is (C1-C4)- alkoxy can be converted via an ether cleavage, by treatment preferably of the methoxy ethers of the formula (IX) with concentrated acids such as Hl and HBr or with Lewis acids such as BF3, BCl3, BBr3, AlCl3 or their ether- ates, preferably with BBr3, in an inert solvent such as, for example, -
CH2Clp, 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.
The corresponding diphenyl ether compounds can be obtained from the reaction of the phenols of the 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)2: appropriate reactions are described, for example, in Tetrahedron Lett. 39 (1998), 2937- 2940. e) From the sulfonamides of the formula (IX), it is possible by reaction with
R(5)-substituted chloroformic acid esters to prepare the sulfonylurethanes of the formula (la)
R(1) al ——_ R(2) 0 ql!
R(5) = S Oo
R(4) —
R(6) in which R(1), R(2), R(3), R(4), 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-pyrrolidinopyridines at temperatures from
RT to 150°C, but preferably at RT. f) From the sulfonamides of the formula (IX), it is possible by treatment with
R(5)-substituted isocyanates or isothiocyanates to obtain the sulfonylureas of the formula (Ib)
al ra, R(2) 1A
Oxg- N_ (Ib)
Ag I R(5)
R(4) —
R(6) 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 the
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°C.
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.
The sulfonylureas of the formula (Ib) are also preparable by reaction of amines R(5)-NH2 with sulfonyl isocyanate derivatives which result from the sulfonamides of the formula (IX), for example, by treatment with phosgene or a phosgene substitute such as triphosgene.
The sulfonylureas of the formula (Ib) can alternatively also be prepared by reaction of the sulfonamides of the formula (IX) with 2,2,2-trichloro- acetamide derivatives of a suitable amine R(5)-NHz in the presence of a base in an inert, high-boiling solvent such as, for exampie, DMSO or from the corresponding sulfonylurethane of the formula (la) accessible by reaction with ethyl chloroformate by action of the corresponding amine
R(5)-NHz 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.
The N-unsubstituted sulfonylureas of the formula (Ib), in which R(5) is hydrogen, can be prepared by hydrolysis of the sulfonamidonitriles B resulting after reaction of the sulfonamides of the formula (IX) with cyanogen bromide in the presence of KoCOg in acetonitrile with sulfuric acid at temperatures of -10 — 0°C.
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 the compounds of the formula (I) to prepare the corresponding carboxylic acids or carboxylic acid esters of the formula (I).
The invention also relates to compounds of the formula (X)
R(1)
N
Pal
R(3) N R(2) o oN
NT (X) =
R(4) — S
R(6) in which R is hydrogen or a suitable protective group such as, for example, (C1-Cg)-alkyl, preferably tert-butyl and the radicals R(1), R(2), R(3), R(4),
R(6) are as defined above, in all their stereoisomeric forms and mixtures thereof, and their physiologically tolerable salts.
The compounds of the formula (X) are valuable intermediates for the preparation of the compounds of the formula (I) according to the invention.
In addition, the compounds of the 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 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 aneriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
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 disorder such as arteriosclerosis and hypertension (Eur. J. Clin. Invest. 1993, 23, 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 which are able to stimulate the synthesis and release of these messengers are therefore valuable pharmaceuticals for the treatment of all diseases which are characterized by an endothelial dysfunction.
It was confirmed by a large number of published experiments that a degradation product of the renin-angiotensin system, the heptapeptide angiotensin(1-7), is a potent, endogenous effector hormone of the renin- B angiotensin system (Hypertension 1991, 18 [Suppl Il]: 1I-126-111133), whose biological action is caused by the stimulation of specific receptors, which preferably bind angiotensin(1-7) (Peptides 1993, 14, 679-684,
Hypertension 1997, 29 [part 2]: 388-393)). This action is in many cases directed against that of the vasoconstrictory hormone angiotensin Il or opposes this in a counter regulatory manner (Hypertension 1997, 30 [part 2]: 535-541, Regulatory Peptides 1998, 78, 13-18).
It was shown in Hypertension 1992, 19 [Suppl. li]: 11-49-11-55 and in Am. J.
Cardiol. 1998, 82, 17S-19S that angiotensin(1-7) stimulates the production and/or the release of NO/cGMP and the prostaglandins E2 and lp, which is not blocked by pretreatment with AT1 and AT2 receptor antagonists.
An endotheilium-dependent relaxation of intact coronary arteries of dogs and pigs was described in Hypertension 1996, 27 [part 2]: 523-528, and an endothelium-dependent relaxation of intact, KCl-precontracted rat aortas by angiotensin(1-7), which is not affected by AT receptor antagonists, was described in J. Cardiovasc. Pharmacol. 1997, 30, 676-682.
The hypotensive action of angiotensin(1-7) in spontaneously hypertensive rats on continuous infusion by means of an osmotic minipump was shown in Peptides 1993, 14, 679-684 and in Am. J. Physiol. 1995, 269: 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 1998, 31: 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.
It was demonstrated in Am. J. Hypertension 1998, 11: 137-146 that in persons having essential hypertension markedly lower plasma levels of angiotensin(1-7) are detectable than in normotensive persons.
The anti-proliferative action of angiotensin(1-7) on vascular smooth muscle cells was confirmed in Hypertension 1996, 28, 104-108 and the inhibition of the proliferation of smooth muscle cells after vascular tissue damage was confirmed in Hypertension 1999, 33 [part Il}: 207-211.
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. 1996, 270, F141-F147).
The compounds of the 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 BN and in the heart. They therefore mimic the biological action of the peptide hormone angiotensin(1-7) directed against angiotensin Il, 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. Owing to the stimulation of the production and/or release of these vasorelaxant, antithrombotic and cardioprotective messengers, the angiotensin(1-7) receptor agonists of the formula (I) described are therefore valuable pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily
S caused or at least partly caused by a reduced production and/or release of the vasorelaxant, antithrombotic and cardioprotective messengers cyclic 3',5'-guanosine monophosphate (cGMP) and nitrogen monoxide (NO) and ) 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 endo- thelial damage, e.g. as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
The stimulation of endothelial angiotensin(1-7) receptors by the agonists of the formula (I) causes the release of vasodilatory and organ-protective autacoids. This mechanism differs here from that of ACE inhibition and AT receptor blockade by the avoidance either of lowered tissue angiotensin I (in the case of ACE inhibitors) or of effects which still cannot be estimated at present, which are associated with increased ANG Il plasma values (in the case of ATq receptor antagonists).
The compounds of the formula (I) and their physiologically tolerable salts can thus be used in animals, preferably in mammals, and in particular in humans as pharmaceuticals on their own, as mixtures with one another or together with other active compounds, in particular in the form of pharma- ceutical preparations. The present invention therefore relates to the use of compounds of the 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 the formula (I) and/or of a physiologically tolerable salt thereof as active constituent in addition to customary, pharmaceutically innocuous vehicles and/or excipients. The pharmaceutical preparations can be intended for enteral or parenteral use and normally contain 0.5 to 90% by weight of the compound of the formula (I) and/or its physiologically tolerable salts. The amount of active compound of the formula (I) and/or its physiologically tolerable salts in the pharmaceutical preparations is in general 0.2 to 500 mg, preferably 1 to 300 mg.
Pharmaceuticals which can be employed according to the invention which contain the compounds of the formula (I) and/or their physiologically tolerable salts can be administered enterally, for example orally or rectally, for example 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 i 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, for example in the form of ointments, creams, pastes, lotions, gels, sprays, powders, foams, aerosols or solutions, or use in the form of implants.
The pharmaceutical preparations which can be employed according to the invention can be prepared by the known standard processes for the production of pharmaceutical preparations. For this, one or more compounds of the formula (I) and/or their physiologically tolerable salts are brought together with one or more solid or liquid pharmaceutical vehicles and/or additives or excipients and, if desired, in combination with other pharmaceutical active compounds having therapeutic or prophylactic action, for example cardiovascular-active pharmaceuticals such as, for example, calcium antagonists, ACE inhibitors, AT1 receptor antagonists,
NO donors, endothelin receptor antagonists, K channel openers, phosphodiesterase inhibitors, diuretics or o- and B-blockers, into a suitable administration form or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
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 the active compounds of the formula (lI), for example water, vegetable oils, alcohols such as ethanol, isopropanol or benzyl alcohols, 1,2-propanediol, poly- ethylene 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 one or more organic solvents 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 one or more further active compounds, for i example one or more vitamins. The compounds of the formula (I) and/or their physiologically tolerable salts can also be lyophilized and the lIyophilizates obtained can be used, for example, for the production of injection preparations. Liposomal preparations are also particularly suitable for topical application.
The dose of the active compound of the 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 iliness 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 the formula (1). 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 adminis- tration 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 active compound of the formula (I) and/or its physiologically tolerable salts.
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 pharma- ceuticals, 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 cyclic 3',5'-guanosine monophosphate (cGMP) and nitrogen monoxide (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.
List of abbreviations: abs. absolute cGMP cyclic 3',5'-guanosine monophosphate
CH2Clo 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
The invention is illustrated by the examples below, without being restricted - to these.
Examples:
Example 1
4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyllmethyljimidazole
Ct
N
/ NH
N ; lo) 0]
WH
O==g— fo) og Ne
ZN © a) 4-Chioro-1-[(4-bromophenyl)methyl]-5-formyl-2-phenylimidazole
A solution of 8.0g (32.0 mmol) of 4-chloro-5-formyl-2-phenylimidazole (prepared according to Chem. Pharm. Bull. 24, 1976, 960-969) and 5.3 g (32.0 mmol) of KoCO3 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 KHSO4, 10% strength NaHCO3 and satd sodium chloride solution and dried over Na2SOs.
Chromatographic purification on SiOz 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.
M.p.:92-95°C
Rt (SiOz, EA/heptane 1:4) = 0.24
MS (ESI): m/e = 375/377 [M+H]" b) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonamido)-5-isobutyl- 3-thienyllphenyllmethyllimidazole
A solution of 7.2 g (22.6 mmol) of 5-isobutyl-2-[(N-tert-butyl)sulfonamido}- - thiophene-3-boronic acid (disclosed in EP-A 512 675) in 125 ml of ethanol was added dropwise at RT to a solution of 8.5g (22.6 mmol) of the compound from Example 1a) and 800mg of tetrakistriphenyl- phosphinepalladium(0) in 100 ml of toluene. 26 ml of a 2 M CspCO3 solution were added and the resultant reaction solution was stirred at reflux for 5 h. It was concentrated to dryness and the residue which remained was taken up in EA/water (1:1). The organic phase was separated off, washed with water, dried over Na>SO4 and concentrated. Chromato- graphic purification of the residue on SiOz using EA/heptane (1:4) as eluent afforded 6.7 g of the title compound as a white solid.
M.p.: 104 - 105 °C
Rt (SiO2, EA/heptane 1:2) = 0.26
MS (ESI): m/e = 570 [M+H]" c) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thienyl]- phenyljmethyl]imidazole
A solution of 3.3 g (5.96 mmol) of the compound from Example 1b) 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
Na2SO4 and concentrated. After chromatographic purification of the residue on SiO2 using EA/heptane (1:1) as eluent, 1.52 g of the desired compound resulted in the form of a slowly crystallizing solid.
M.p.:118-120°C
Rs (SiO2, EA/heptane 1:1) = 0.32
MS (ESI): m/e = 515 [M+H]" d) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyllmethyl]limidazole
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 pl (0.19 mmol) of butyl chloroformate in an argon atmosphere. The reaction solution was stirred at RT for 24 h. 0.7 mi 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 NapSO4 and concentrated. Chromatographic purifica- BN tion on SiOz 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.
Rt (SiOz, EA/heptane 1:1) = 0.15
MS (FAB): m/e = 614 [M+H]"
Example 2 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyllphenyllmethyl]imidazole
O— i
N
/ NH
N lo) 0
NH
O==g— lo} = oT = S Oo a) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thienyl]- phenyljmethyljimidazole
A solution of 850 mg (1.65 mmol) of the compound from Example 1c) in 25 mi 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 separ- ated off. The aqueous phase was extracted 2 x with EA and the combined organic phases were dried over NapSO4. Chromatographic purification on
SiO2 using EA/heptane (1:1) as eluent of the residue obtained after stripping off the EA afforded 630 mg of the title compound in the form of a yellow, amorphous foam.
Rs (SiO2, EA/heptane 1:1) = 0.23
MS (FAB): m/e = 510 [M+H]" b) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)- 5-isobutyl-3-thienyl]phenyllmethyl]imidazole
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» using EA/heptane (1:1) as eluent, 75 mg of the desired compound resulted as an amorphous foam.
Rs (SiO2, EA/heptane 1:1) = 0.18
MS (ESI): m/e = 610 [M+H]"
Example 3 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenylmethyl]imidazole
O—
N
J NH
N lo) Oo
NH
O=—g— fo) og MN = s [0]
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» using EA/heptane (1:1) 61 mg of the title compound were obtained as an amorphous foam.
Rt (SiOz, EA/heptane 1:1) = 0.13
MS (ESI): m/e = 596 [M+H]"
Example 4 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyl]imidazole
O—
N
J \_ H
N le) 0]
NS, —
O==g—
S ON
= s [0]
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 SiOz using EA/heptane (1:1), 55 mg of the title compound were obtained as an amorphous foam.
Rt (SiO2, EA/heptane 1:1) = 0.10
MS (ESI): m/e = 582 [M+H]"
Example 5 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyl]limidazole
O—
N oA o
TN
= s Oo
A solution of 80 mg (0.16 mmol) of the compound from Example 2a), 43.3 mg (0.32 mmol) of K2CO3 and 8.3 mg of dimethylaminopyridine in 6 ml of diethylene glycol dimethyl ether was treated with 16.8 ul (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 KHoPO4 solution (1:1). The organic phase was separated off, washed 2x with a 10% strength KH2PQ4 solution, dried over NapxSO4 and concentrated. Chromatographic purification of the residue on SiOz using EA/heptane (2:1) yielded 55 mg of the title compound in the form of an amorphous foam.
Rt (SiO2, EA/heptane 4:1) = 0.23 —
MS (ESI): m/e = 568 [M+H]"
Example 6 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)- 5-isobutyl-3-thienyl]phenyl)methyllimidazole
O~— - 3 :
N
Noi
A, rr Ne
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 KoCO3 and 13.2 ul (0.12 mmol) of n-butyl isocyanate and then stirred under reflux for 3 h. After cooling, 15 ml of a 10% strength KH2PO4 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 NasSO4 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.
M.p.: 131-133 °C
Rs (SiO2, EA/heptane 4:1) = 0.30
MS (FAB): m/e = 609 [M+H]"
Example 7 5-Formyl-4-methoxy-2-phenyl-1-{[4-[2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyllmethyl]imidazole
QO
N
I \.
N lo) 0, \ WR
O==g— ag = 0}
S
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.
M.p.: 105 - 106 °C
Rt (SiO2, EA/heptane 4:1) = 0.30
MS (ESI): m/e = 581 [M+H]"
Example 8 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)- 5-isobutyl-3-thienyl]phenyijmethyl]limidazole
O—
N
/ NH
N lo} 0] ™ = 0]
S
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°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 which deposited in the course of this was filtered off which suction, washed with water, dried and purified by chromatography on SiO»
using EA/heptane (2:1) as eluent. 62 mg of the title compound were obtained in the form of a white solid.
M.p.: 102 - 103 °C
Rs (SiO2, EA/heptane 4:1) = 0.14
MS (ESI): m/e = 567 [M+H]"
Example 9 5-Formyl-4-methoxyethoxy-2-phenyl-1-[{4-[2-(n-butyloxycarbonylsulfon- amido)-5-isobutyl-3-thienyl]phenyl]methyllimidazole
J or" 3 or 0 QA H oy 0 wd N- a) 5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3- thienyllphenyl)methyljimidazole
A solution of 200 mg (0.38 mmol) of the compound from Example 1c) 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°C for 5 h. It was concentrated to dryness and the residue obtained was taken up in a satd NaHCO3 solution and EA. The EA phase was separated off and the aqueous phase was extracted several times with EA. The organic phases were combined, dried over Na,SO, and concentrated.
Chromatographic purification of the residue which remained on SiO, using
EA/heptane (1:1) yielded 140 mg of the title compound as a slightly yellow- N colored solid.
M.p.: 91-92 °C
Rt (SiO2, EA/heptane 1:1) = 0.12
MS (FAB): m/e = 554 [M+H]"
b) 5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyl- sulfonamido)-5-isobutyl-3-thienyljphenyljmethyljimidazole
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 SiO2 ] using EA/heptane (1:1) as eluent, 78 mg of the title compound resulted as an amorphous foam. R(SiO2, EA/heptane 1:1) = 0.07
MS (ESI): m/e = 654 [M+H]"
Example 10 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]-2-chlorophenyllmethyl]limidazole
O— eR
N
NP
TAAL TH a) 4-Chloro-1-[(4-bromo-2-chiorophenyl)methyl]-5-formyl-2-phenyl- imidazole
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 1a). 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 resulted.
Rt (SiO2, EA/heptane 1:2) = 0.56
MS (DCI): m/e = 409/411 [M+H]"

Claims (1)

Patent claim:
1. A compound of the formula (I) R(1) i ao, R(2) - 0] ql! Ox LN AN mn I R(5) “s R(4) _— R(6) in which the radicals mentioned have the following meaning: R(1) 1. halogen;
2. hydroxyl;
3. (C1-Ca)-alkoxy; 4, (C1-Cg)-alkoxy, 1 to 6 carbon atoms being replaced by the heteroatoms O, S or NH,
5. (C1-C4)-alkoxy, substituted by a saturated cyclic ether;
6. O-(C1-Cg4)-alkenyl;
7. O-(C1-Cy)-alkylaryl; and
8. phenoxy, unsubstituted or substituted by a substituent from the group consisting of halogen, (C1-Cgz)-alkyl, (C1-Ca)-alkoxy or trifluoromethyl; R(2) 1. CHO;
2. COOH; and
3. CO-0O-(C1-Cy)-alkyl; R(3) 1. (C4-Cy)-alkyl; and
2. aryl; Bh R(4) 1. hydrogen;
2. halogen, and
3. (C1-Cq)-alkyl;
X 1. oxygen;
2. sulfur;
Y 1. oxygen; and
2. -NH-; R(5) 1. hydrogen;
2. (C1-Cg)-alkyl; and
3. (C1-Cy)-alkylaryl; where R(5) can only also be hydrogen if Y has the meaning mentioned under 2.; R(6) 1. (C1-Cs)-alkyl; in all its stereoisomeric forms and mixtures thereof in all ratios, or its physiologically tolerable salts; excluding compounds of the formula (1) in which, simultaneously, R(1) is halogen and R(2) has the meaning mentioned under 2. and 3.
2. A compound of the formula (I) as claimed in claim 1, in which: R(1)is 1. chlorine;
2. hydroxyl;
3. methoxy, ethoxy, propyloxy;
4. methoxyethoxy, methoxypropoxy;
5. allyloxy; and
6. phenoxy; R(4) is 1. hydrogen; and
2. chlorine; R(5)is 1. hydrogen; and N
2. (C1-Cy)-alkyl; R(6) is n-propyl and 2-isobutyl;
and the other radicals are as defined in claim 1, in all its stereoisomeric forms and mixtures thereof, or its physiologically tolerable salts.
3. A compound of the formula (1) as claimed in claim 1 or 2, in which: R(1) is halogen; (C1-C4)-alkoxy; or (C1-Cg)-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 (C1-Cg)-alkyl; R(6) is (C1-Cs)-alkyl; X is oxygen; and Y is oxygen or —NH-; in all its stereoisomeric forms and mixtures thereof, and its physiologically tolerable salts.
4. A compound of the formula (I) as claimed in one or more of claims 1to 3, in which this is a compound of the formula (lI) R(1) N a \ oO 0) N ov (n R(5) R(4) = Ng O R(6)
in which the radicals R(1), R(4), R(5), R(6) and Y have the meaning mentioned in one or more of claims 1 to 3, in all its stereoisomeric forms and mixtures thereof, or its physiologically 5S tolerable salts.
5. A compound of the formula (I) as claimed in one or more of claims 1 to 4, in which R(1) is (C1-C4)-alkoxy or (C1-Cg)-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 to 4, in all its stereoisomeric forms and mixtures thereof, or its physiologically tolerable salts.
6. A compound of the formula (I) as claimed in one or more of claims 1 to 5, in which R(2) is CHO and the other radicals are as defined in claim 1 to 5, in all its stereoisomeric forms and mixtures thereof, or its physiologically tolerable salts.
7. A compound of the formula (1) as claimed in one or more of claims 1 to 6, in which X is O and the other radicals are as defined in claim 1 to 6, in all its stereoisomeric forms and mixtures thereof, or its physiologically tolerable salts.
8. A compound of the formula (I) as claimed in one or more of claims 1 to 7, wherein this is 4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyljimidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonyisulfonamido)-5- isobutyl-3-thienyllphenyl]methyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl]methyl]limidazole N 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyi]methyllimidazole;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5- isobutyl-3-thienyl]phenylmethyllimidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsuifonamido)-5-
isobutyl-3-thienyllphenyl)methyl]imidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyllphenyl]methyllimidazole;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl)methyl]imidazole sodium salt; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyl]phenyl)methyl]imidazole L-lysine salt
5-tormyl-4-methoxy-2-phenyl-1-[[4-][2-(ethylaminocarbonylsulfonamido)-5- isobutyl-3-thienyllphenyllmethyllimidazole tris(hydroxymethyl)amino- methane salt
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5- isobutyl-3-thienyllphenyljmethyl]limidazole; 5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n- butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenylJmethyllimidazole;
5-formyi-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5- isobutyl-3-thienyl]-2-chlorophenyl)methyllimidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-
isobutyl-3-thienyl}-2-chlorophenyl]methyljimidazole; 4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n- propyl-3-thienyl)phenyllmethyl)imidazole;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n- propyl-3-thienyllphenyllmethyllimidazole; 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylisulfonamido)-5-n- propyi-3-thienyl]phenyi]methyllimidazole;
5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5- n-propyl-3-thienyl}phenyl]methyl]imidazole; or S 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5- n-propyl-3-thienyl]phenyllmethyl]imidazole; or its physiologically tolerable salts.
9. A compound of the formula (X) R(1) i fra ] NS (X) = S R(4) — R(6) in which R is hydrogen or (C1-Cg)-alkyl and the radicals R(1), R(2), R(3), R(4), R(6) are as defined in one or more of claims 1 to 8, in all its stereoisomeric forms and mixtures thereof, or its physiologically tolerable salts.
10. A compound of the formula (I) or (X) as claimed in one or more of claims 1 to 9 for use as a pharmaceutical.
11. A pharmaceutical preparation, which has an efficacious content of a compound of the formula (I) or (X) as claimed in one or more of claims 1 to 9 and/or of a physiologically tolerable salt thereof.
12. Use of compounds of the formula (I) _
R(1) ae, R(2) 0] ql! I R(5) “s R(4) — R(6) in which the radicals mentioned have the following meaning: R(1) 1. halogen;
2. hydroxyl;
3. (C1-Cg4)-alkoxy;
4. (C1-Cg)-alkoxy, 1 to 6 carbon atoms being replaced by the heteroatoms O, S or NH;
5. (C1-Cgq)-alkoxy, substituted by a saturated cyclic ether;
6. 0O-(C1-Cgy)-alkenyl;
7. O-(C1-Cg4)-alkylaryl; and
8. phenoxy, unsubstituted or substituted by a substituent from the group consisting of halogen, (C1-C3)-alkyl, (C1-Cg)-alkoxy or trifluoromethyl; R(2) 1. CHO;
2. COOH; and
3. CO-0-(C1-Cy)-alkyl; R(3) 1. (C1-Cy)-alkyl; and
2. aryl, R(4) 1. hydrogen;
2. halogen, and
3. (C1-C4)-alkyl; -
X 1. oxygen;
2. sulfur;
Y 1. oxygen; and
2. -NH-; R(5) 1. hydrogen;
2. (C1-Ceg)-alkyl; and
3. (C1-Cy)-alkylaryl; where R(5) can only also be hydrogen if Y has the meaning mentioned under 2.; R(6) is 1. (C1-Cs)-alkyl; in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically tolerable salts, for the production of a medicament for the treatment and/or prophylaxis of 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 (cGMP) and nitrogen monoxide (NO).
13. The use of compounds of the formula (I) as claimed in claim 12 for the production of a medicament 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, endothelial dysfunction or endothelial damage, e.g. as a result of arteriosclerotic processes or diabetes mellitus, and also of arterial and venous thromboses.
14. The use of angiotensin (1-7) receptor agonists for the production of a medicament for the therapy and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by reduced production and/or release of the vasorelaxant, antithrombotic and cardio- protective messengers cyclic 3',5’-guanosinemonophoshate (cGMP) and nitrogen monoxide (NO).
15. The use of angiotensin (1-7) receptor agonists for the production of a medicament for the therapy 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, endothelial dysfunction or endothelial damage, e.g. as a result of arteriosclerotic processes or diabetes mellitus, and also of arterial and venous thromboses.
16. A compound of the formula (I) or (X) as claimed in one or more of claims 1 to 9 for use as an agonist of angiotensin (1-7) receptors.
17. A compound of the formula (I) or (X) as claimed in one or more of claims 1 to 9 for use in the therapy and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by reduced production and/or release of the vasorelaxant, antithrombotic and cardio- protective messengers cyclic 3',5’-guanosine monophosphate (cGMP) and nitrogen monoxide (NO).
18. A compound of the formula (I) or (X) as claimed in one or more of claims 1 to 9 for use in the therapy 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, endothelial dysfunction or endothelial damage, e.g. as a result of arteriosclerotic processes or diabetes mellitus, and also of arterial and venous thromboses.
ZA200108801A 1999-05-05 2001-10-25 1-(p-thienylbenzyl)-imidazoles as angiotensin-(1-7) receptor agonists, method for the production and the utilization thereof and pharmaceutical preparations containing said compounds. ZA200108801B (en)

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