IE903131A1 - Aza compounds - Google Patents

Abstract

Azabenzimidazole compounds of the formula in which one or two of the variables Z1, Z2, Z3 and Z4 represent N and the others represent C(R), where R denotes halogen, acyl, optionally esterified or amidated carboxyl or 5-tetrazolyl or R represents -Z-R', in which Z represents a bond or O, S(O)m or NH, R' denotes hydrogen or an aliphatic hydrocarbon radical which is optionally substituted by halogen, hydroxyl, optionally substituted amino or optionally esterified or amidated carboxyl and which is optionally interrupted by O or S(O)m, and the index m in each case represents 0, 1 or 2, R1 denotes an aliphatic hydrocarbon radical optionally substituted by halogen or hydroxyl or a cycloaliphatic or araliphatic hydrocarbon radical and R2 represents the group of the formula in which alk denotes a divalent aliphatic hydrocarbon radical, R3 denotes COOH, SO3H, haloalkanesulphonylamino, PO2H2, PO3H2 or 5-tetrazolyl and the rings A and B, independently of one another, are either optionally substituted by halogen, an aliphatic hydrocarbon radical which is optionally substituted by hydroxyl or halogen and optionally interrupted by O, hydroxyl optionally etherified by an aliphatic alcohol or optionally esterified or amidated carboxyl, or ring A is substituted by 5-tetrazolyl and ring B is optionally substituted as indicated immediately above, in free from or in salt form, can be prepared in a manner known per se and can be used, for example, as pharmaceutical active substances.

Description

The invention relates to azabenzimidazole compounds of the formula in which one or two of the variables Zb Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, acyl, carboxyl which, if desired, is esterified or amidated, or -tetrazolyl, or R is -Z-R’, wherein Z is a bond or is O, S(O)m or NH, R’ is hydrogen or an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radical, if desired, is interrupted by O or S(O)m and the index m is in each case 0, 1 or 2, R! is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or is a cycloaliphatic or araliphatic hydrocarbon radical and R2 is the group of the formula in which alk is a divalent aliphatic hydrocarbon radical, R3 is COOH, SO3H, haloalkanesulfonylamino, ΡΟ2Η2, PO3H2 or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl or halogen and which, if desired, is interrupted by O, hydroxyl which, if desired, is etherified by an aliphatic alcohol, or carboxyl which, if desired, is esterified or amidated or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated -2immediately hereinbefore, in free form or in form of a salt, to a process for the preparation of these compounds, to the use of these compounds and to pharmaceutical preparations containing such a compound I in free form or in form of a pharmaceutically acceptable salt.

The compounds of the formula I can be present as salts, in particular pharmaceutically acceptable salts. If the compounds I have at least one basic centre, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric acid or a halohydric acid, with strong organic carboxylic acids, such as C1-C4alkanecarboxylic acids which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as dicarboxylic acids which, if desired, are unsaturated, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as Cj-C^alkane- or aryl-sulfonic acids which are unsubstituted or substituted, for example, by halogen, for example methane- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed with an additional basic centre which may optionally be present. The compounds I containing at least one acidic group (for example COOH or 5-tetrazolyl) can additionally form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal salts or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or with an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propyl-amine, or a mono-, di- or trihydroxy-lower alkylamine, for example mono-, di- or triethanolamine. Corresponding inner salts can furthermore be formed. Salts which are unsuitable for pharmaceutical uses are additionally included, which can be employed, for example, for the isolation or purification of free compounds of the formula I or their pharmaceutically acceptable salts.

Acyl is, in particular, lower alkanoyl.

Esterified carboxyl is, for example, carboxyl which is esterified by an aliphatic alcohol which is derived from an aliphatic hydrocarbon radical, such as from lower alkyl, lower alkenyl or secondarily lower alkynyl, which, if desired, is interrupted by O, such as from lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl. Examples which may be -3mentioned are lower alkoxy-, lower alkenyloxy- and lower alkoxy-lower alkoxy-carbonyl.

Amidated carboxyl is, for example, carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by an aliphatic or araliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl, or phenyl-lower alkyl, -lower alkenyl or -lower alkynyl, or is disubstituted by a divalent aliphatic hydrocarbon radical which, if desired, is interrupted by O, such as lower alkylene or lower alkyleneoxy-lower alkylene.

Substituted amino is, for example, amino which is independently of one another mono- or di-substituted by an aliphatic or araliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, -lower alkenyl or -lower alkynyl, or amino which is disubstituted by a divalent aliphatic hydrocarbon radical which, if desired, is interrupted by O, such as lower alkylene or lower alkyleneoxy-lower alkylene.

Examples which may be mentioned are lower alkyl-, lower alkenyl-, lower alkynyl-, phenyl-lower alkyl-, phenyl-lower alkenyl-, phenyl-lower alkynyl-, di(lower alkyl)-, N-lower alkyl-N-phenyl-lower alkyl- and di(phenyl-lower alkyl)amino.

An aliphatic hydrocarbon radical is, for example, lower alkyl, lower alkenyl or secondarily lower alkynyl.

An aliphatic hydrocarbon radical which is interrupted by O is, in particular, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl or lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, while an aliphatic hydrocarbon radical which is interrupted by S(O)m is, in particular, lower alkylthio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl.

An aliphatic hydrocarbon radical substituted by halogen or hydroxyl is, for example, halo-lower alkyl, -lower alkenyl or -lower alkynyl or hydroxy-lower alkyl, -lower alkenyl or -lower alkynyl.

An aliphatic hydrocarbon radical substituted by halogen or hydroxyl which is interrupted by O or S(O)m is a corresponding radical indicated hereinbefore which is substituted by halogen or hydroxy. -4An aliphatic hydrocarbon radical which is substituted by unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radical, if desired, is interrupted by O or S(O)m is a corresponding radical indicated hereinbefore which is substituted by amino, substituted amino as indicated hereinbefore, carboxy or carboxy which is esterified or amidated as indicated hereinbefore.

A cycloaliphatic hydrocarbon radical is, for example, cycloalkyl or secondarily cycloalkenyl.

Possible araliphatic hydrocarbon radicals are, in particular, phenyl-lower alkyl, and additionally phenyl-lower alkenyl and -lower alkynyl.

A divalent aliphatic hydrocarbon radical is, in particular, lower alkylene or lower alkenylene, where in the case of alk the C atom from which the double bond starts is in particular not linked to the N atom of the azabenzimidazole ring; alk is primarily methylene.

A divalent aliphatic hydrocarbon radical which is interrupted by O is, in particular, lower alkyleneoxy-lower alkylene.

Hydroxyl etherified with an aliphatic alcohol is, in particular, lower alkoxy or lower alkenyloxy.

Above and below, unsaturated aliphatic, cycloaliphatic and araliphatic substituents are primarily not linked to an aromatic radical via a C atom from which a multiple bond starts.

Phenyl is in each case unsubstituted, monosubstituted or polysubstituted phenyl, for example disubstituted or trisubstituted phenyl, for example by (a) substituent(s) selected from the group comprising lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxyl.

The rings A and B form a biphenyl radical, in which case the corresponding 4-biphenylyl is preferred.

If not defined differently, the general terms used above and below have the following -5meanings: The expression lower means that appropriate groups and compounds in each case contain in particular not more than 7, preferably not more than 4, carbon atoms.

Halogen is in particular halogen with an atomic number of not more than 35, that is to say fluorine, chlorine or bromine, and additionally includes iodine.

Haloalkanesulfonylamino is, in particular, halo-Cj-Cjalkanesulfonylamino and is, for example, trifluoromethane-, difluoromethane-, 1,1,2-trifluoroethane- or heptafluoropropane-sulfonylamino. Halo-Ci-C4alkanesulfonylamino is preferred.

Lower alkanoyl is, in particular, Q^alkanoyl and is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or pivaloyl. C2-C5Alkanoyl is preferred.

Lower alkyl is, in particular, Cj-C7alkyl, that is to say methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl radical. CrC4Alkyl is preferred.

Lower alkenyl is, in particular, C3-C7alkenyl and is, for example, propen-2-yl, allyl or but-l-en-3-yl, -l-en-4-yl, -2-en-l-yl or -2-en-2-yl. C3-C5Alkenyl is preferred.

Lower alkynyl is, in particular, C3-C7alkynyl and is preferably propargyl.

Lower alkoxy is, in particular, Cj^alkoxy, that is to say methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy or corresponding pentyloxy, hexyloxy or heptyloxy. Cj-C4Alkoxy is preferred.

Lower alkoxy-lower alkyl is, in particular, C1-C4alkoxy-C1-C4alkyl, such as 2-methoxyethyl, 2-ethoxyethyl, 2-(n-propyloxy)ethyl or ethoxymethyl.

Lower alkoxy-lower alkenyl or -lower alkynyl is, in particular, C1-C4alkoxy-C3-C5alkenyl or -alkynyl.

Lower alkoxycarbonyl is, in particular, C1-C7alkoxycarbonyl and is, for example, methoxy-, ethoxy-, propyloxy- or neopentyloxy-carbonyl. Cj-C4Alkoxycarbonyl is -6preferred.

Lower alkenyloxy is, in particular, C3-C7alkenyloxy and is, for example, allyloxy, but-2-en-l-yloxy or but-3-en-l-yloxy. C3-C5Alkenyloxy is preferred.

Lower alkenyloxycarbonyl is, in particular, C3-C5alkenyloxycarbonyl, preferably allyloxycarbonyl, while lower alkynyloxycarbonyl is, in particular, C3-C5alkynyloxycarbonyl, such as propargyloxycarbonyl.

Lower alkoxy-lower alkoxycarbonyl is, in particular, C1-C4alkoxy-C1-C4alkoxycarbonyl, preferably ethoxyethoxycarbonyl, methoxyethoxycarbonyl or isopropyloxyethoxycarbonyl.

Halo-lower alkyl is, in particular, halo-Cj-C4alkyl, such as trifluoromethyl, l,l,2-trifluoro-2-chloro-ethyl, chloromethyl or n-heptafluoropropyl.

Halo-lower alkenyl is, in particular, halo-C3-C5alkenyl, such as 3-chloroallyl.

Halo-lower alkynyl is, in particular, halo-C3-C5alkynyl, such as 3-chloropropargyl.

Hydroxy-lower alkyl is, in particular, hydroxy-C]-C4alkyl, such as hydroxymethyl, 2- hydroxyethyl or 3-hydroxypropyl.

Hydroxy-lower alkenyl is, in particular, hydroxy-C3-C5alkenyl, such as 3-hydroxyallyl.

Hydroxy-lower alkynyl is, in particular, hydroxy-C3-C5alkynyl, such as 3- hydroxypropargyl.

Phenyl-lower alkyl is, in particular, phenyl-Ci-C4alkyl and is, preferably, benzyl or 1- or 2-phenethyl, while phenyl-lower alkenyl or phenyl-lower alkynyl are, in particular, phenyl-C3-C5alkenyl or -alkynyl, in particular 3-phenylallyl or 3-phenylpropargyl.

Lower alkylene is, in particular, C2-C7alkylene, is straight-chain or branched and is, in particular, ethylene, 1,3-propylene, 1,4-butylene, 1,2-propylene, 2-methyl-l,3-propylene or 2,2-dimethyl- 1,3-propylene. C2-C5Alkylene is preferred. -7Lower alkyleneamino is, in particular, C2-C7alkyleneamino, is straight-chain or branched and is, in particular, ethyleneamino, 1,3-propyleneamino, 1,4-butyleneamino, 1,2-propyleneamino, 2-methyl-l,3-propyleneamino or 2,2-dimethyl-1,3-propyleneamino. C2-C5Alkyleneamino is preferred.

Lower alkyleneoxy-lower alkylene is, in particular, C2-C4alkyleneoxy-C2-C4alkylene, preferably ethyleneoxyethylene.

Lower alkyleneoxy-lower alkyleneamino is, in particular, C2-C4alkyleneoxy-C2-C4alkyleneamino, preferably ethyleneoxyethyleneamino.

Lower alkylamino is, in particular, C1-C7alkylamino and is, for example, methyl-, ethyl-, n-propyl- or isopropyl-amino. Cj-QAlkylamino is preferred.

Lower alkenylamino is, preferably, C3-C5alkenylamino, such as allyl- or methallyl-amino.

Lower alkynylamino is, preferably, C3-C5alkynylamino, such as propargylamino.

Phenyl-lower alkylamino is, preferably, phenyl-CrC4alkylamino, in particular benzyl- or 1- or 2-phenylethyl-amino.

Phenyl-lower alkenylamino is, preferably, phenyl-C3-C5alkenylamino, in particular phenylallylamino or 3-phenylmethallylamino.

Phenyl-lower alkynylamino is, preferably, phenyl-C3-C5alkynylamino, in particular phenylpropargylamino.

Di(lower alkyl)amino is, in particular, di(Ci-C4alkyl)amino, such as dimethyl-, diethyl-, di(n-propyl)-, methyl-propyl-, methyl-ethyl-, methyl-butyl- or dibutyl-amino.

N-Lower alkyl-N-phenyl-lower alkyl-amino is, in particular, N-Cj-C^alkyl-N-phenylC1-C4alkyl-amino, preferably methyl-benzyl-amino or ethyl-benzyl-amino.

Di(phenyl-lower alkyl)amino is, in particular, difphenyl-Cj-^alkylJamino, preferably dibenzylamino. - 8Lower alkenyloxy-lower alkyl is, in particular, C3-C5alkenyloxy-C1-C4alkyl, such as 2-allyloxyethyl, and lower alkenyloxy-lower alkenyl or -lower alkynyl is, in particular, C3-C5alkenyloxy-C3-C5-alkenyl or -alkynyl.

Lower alkyl thio-lower alkenyl or -lower alkinyl is, in particular, C1-C4alkylthio-C3-C5-alkenyl or -alkinyl.

Lower alkylthio-lower alkyl is, in particular, Ci-C4alkylthio-Ci-C4alkyl, such as ethylthiomethyl, 2-ethylthioethyl, 2-methylthioethyl or 2-isopropylthioethyl, while suitable lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl are, in particular, corresponding Ci-C4alkane-sulfinyl-CrC4alkyl or -sulfonyl-C]-C4alkyl radicals.

Lower alkenylthio-Iower alkyl is, in particular, C3-C5alkenylthio-Ci-C4alkyl, such as 1- allylthioethyl or 3-allylthiopropyl, while lower alkenyl-sulfinyl-lower alkyl or -sulfonyl-lower alkyl is, in particular, C3-C5alkenyl-sulfinyl-C1-C4alkyl or -sulfonyl-Ci*C4alkyl.

Lower alkynylthio-lower alkyl is, in particular, Cj-Csalkynylthio-Cj-Qalkyl, such as 2- propargylthioethyl or 3-propargylthiopropyl, while lower alkynyl-sulfinyl-lower alkyl or -sulfonyl-lower alkyl is, in particular, C3-C5alkynyl-sulfinyl-Ci-C4alkyl or -sulfonyl-Cj-Qalkyl.

Cycloalkyl is, in particular, C3-C7cycloalkyl, that is to say cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is, in particular, C3-C7cycloalkenyl and is preferably cyclopent-2-enyl or -3-enyl or cyclohex-2-enyl or -3-enyl.

Lower alkenylene is, in particular, C3-C5alkenylene and is, for example, but-2-en-1,4-ylene.

Lower alkoxy-lower alkenyloxycarbonyl or -lower alkinyloxycarbonyl is, in particular, C1-C4alkoxy-C3-C5-alkenyloxycarbonyl or -alkinyloxycarbonyl.

Extensive pharmacological investigations have shown that the compounds I and their pharmaceutically acceptable salts have, for example, pronounced angiotensin II antagonist -9properties.

As is known, angiotensin II has strong vasoconstrictor properties and additionally stimulates the aldosterone secretion and thus causes distinct sodium/water retention. The consequence of angiotensin II activity is manifested, among other things, in an increase in blood pressure.

The importance of angiotensin II antagonists is in suppressing the vasoconstrictor and the aldosterone secretion-stimulating effects caused by angiotensin Π by competitive inhibition of the binding of angiotensin II to the receptors.

The angiotensin II antagonist properties of the compounds of the formula I and their pharmaceutically acceptable salts can be detected in the angiotensin Π binding test. Rat smooth muscle cells from homogenized rat aorta are used here. The solid centrifugate is suspended in 50 mM tris buffer (pH 7.4) using peptidase inhibitors. The samples are incubated for 60 minutes at 25°C with 125I-angiotensin Π (0.175 nM) and a varying concentration of angiotensin II or of the test substance. The incubation is then ended by addition of saline buffered with ice-cold phosphate, and the mixture is filtered through Whatman GF/F filters. The filters are counted using a gamma counter. The IC50 values are determined from the dose-effect curve. IC50 values from about 10 nM are determined for the compounds of the formula I and their pharmaceutically acceptable salts.

For the determination of angiotensin Il-induced vasoconstriction, investigations on the isolated rabbit aorta ring can be used. For this purpose, aorta rings are dissected from each chest and fixed between two parallel clamps at an initial tension of 2 g. The rings are then immersed in 20 ml of a tissue bath at 37°C and aerated with a mixture of 95 % O2 and 5 % CO2. The isometric reactions are measured. At 20-minute intervals, the rings are alternately stimulated with 10 nM angiotensin II (Hypertensin-CIBA) and 5 nM noradrenaline chloride. The rings are then incubated with selected concentrations of the test substances before treatment with the agonists. The data are analysed using a Buxco digital computer. The concentrations which cause a 50 % inhibition of the initial control values are given as IC50 values. IC50 values from about 5 nM arc determined for the compounds of the formula I and their pharmaceutically acceptable salts.

The fact that the compounds of the formula I and their pharmaceutically acceptable salts can reduce high blood pressure induced by angiotensin II can be verified in the -10normotensive anaesthetized rat test model. After calibration of the preparations with 0.9 % NaCl (1 ml/kg i.v.), noradrenaline (1 gg/kg i.v.) or angiotensin II (0.3 gg/kg i.v.) in each case, increasing doses (3-6) of the test substance are intravenously injected by bolus injection, after which angiotensin II or noradrenaline is administered after each dose at 5 minute intervals. The blood pressure is measured directly in the carotid artery and recorded using an on-line data recording system (Buxco). The specificity of the angiotensin II antagonism is shown by the selective inhibition of the pressure effect produced by angiotensin II, but not that produced by noradrenaline. In this test model, the compounds of the formula I and their pharmaceutically acceptable salts show an inhibiting effect from a dose of about 0.3 mg/ig i.v..

The antihypertensive activity of the compounds of the formula I and their pharmaceutically acceptable salts may also be manifested in the renally hypertensive rat test model. High blood pressure is produced in male rats by constricting a renal artery according to the Goldblatt method. Doses of the test substance are administered to the rats by means of a stomach tube. Control animals receive an equivalent volume of solvent. Blood pressure and heart beat are measured indirectly at intervals in conscious animals by the tail clamp method of Gerold et al. iHelv. Physiol. Acta 24 (1966), 58] before administration of the test substance or of the solvent and during the course of the experiments. It is possible to detect the pronounced antihypertensive effect from a dose of about 30 mg/kg p.o..

The compounds of the formula I and their pharmaceutically acceptable salts can therefore be used, for example, as active ingredients in antihypertensives, which are used, for example, for the treatment of high blood pressure and cardiac insufficiency. The invention therefore relates to the use of the compounds I and their pharmaceutically acceptable salts for the production of corresponding medicaments and for the therapeutic treatment of high blood pressure and cardiac insufficiency. The industrial production of the active substances is also included in the production of the pharmaceuticals.

The invention relates in particular to compounds of the formula I, in which one or two of the variables 7X, 7^,7^ and Z4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, carbamoyl in which the amino group is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower - 11 alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or 5-tetrazolyl or R is -Z-R’, in which Z is a bond or is O, S(O)m or NH, R’ is hydrogen, or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkylthio-lower alkyl, lower alkylthio-lower alkenyl, lower alkylthio-lower alkynyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, lower alkenylthio-lower alkyl, lower alkenylsulfinyl-lower alkyl, lower alkenylsulfonyl-lower alkyl, lower alkynylthio-lower alkyl, lower alkynylsulfinyl-lower alkyl or lower alkynylsulfonyl-lower alkyl which radicals, in each case, are unsubstituted or substituted by halogen, by hydroxyl, by amino which, if desired, is substituted as indicated immediately hereinbefore in the definition of the amino group . of the carbamoyl radical R, by carboxyl which, if desired, is esterified as indicated immediately hereinbefore, or by carbamoyl in which the amino group, if desired, is substituted as indicated immediately hereinbefore, and the index m is 0,1 or 2, Rj is lower alkyl, lower alkenyl or lower alkynyl which radicals, in each case, are unsubstituted or substituted by halogen or by hydroxyl, cycloalkyl or cycloalkenyl which are in each case 3- to 7-membered, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, and R2 is the group of the formula la in which alk is lower alkylene or lower alkenylene, R3 is COOH, SO3H, halo-lower alkanesulfonylamino, PO2H2, PO3H2 or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl or lower alkenyloxy-lower alkynyl which radicals, in each case, are unsubstituted or substituted by halogen or hydroxyl, by hydroxyl, by lower alkoxy, by lower alkenyloxy, by carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or by carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt.

The invention relates in particular to compounds of the formula I, in which one or two of the variables Zl5 Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, lower - 12alkanoyl, carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene, or R is -Z-R’, in which Z is a bond or is O and R’ is hydrogen, or lower alkyl or lower alkoxy-lower alkyl which radicals, in each case, are unsubstituted or substituted by halogen, by hydroxyl, by amino which, if desired, is independently of one another monoor disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene, by carboxyl, by lower alkoxycarbonyl or by lower alkoxy-lower alkoxycarbonyl, Rj is lower alkyl or lower alkenyl which radicals, in each case, are unsubstituted or substituted by halogen or by hydroxyl, or 3- to 7-membered cycloalkyl or phenyl-lower alkyl, and R2 is the group of the formula la, in which alk is lower alkylene, R3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl which is unsubstituted or substituted by halogen or by hydroxyl, by lower alkoxy, by carboxyl or by lower alkoxycarbonyl, in free form or in form of a salt.

The invention relates in particular to compounds of the formula I, in which one or two of the variables Zb Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, carbamoyl which, if desired, is mono- or disubstituted by lower alkyl, or 5-tetrazolyl or R is -Z-R’, in which Z is a bond or is O, S(O)m or NH, m is 0, 1 or 2 and R’ is hydrogen or lower alkyl which is unsubstituted or substituted by halogen, by hydroxyl or by amino, Rj is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lower alkyl, 3- to 7-membered cycloalkyl or phenyl-lower alkyl and R2 is the group of the formula la in which alk is lower alkylene, R3 is COOH or -tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl which is unsubstituted or substituted by halogen or by hydroxyl, by lower alkoxy, by carboxyl or by lower alkoxycarbonyl, in free form or in form of a salt.

The invention relates in particular to compounds of the formula I, in which R2 is the group of the formula -13in free form or in form of a salt.

The invention relates in particular to compounds of the formula I, in which one or two of the variables Zb Z2, Z3 and Z4 are N and the others are C(R), where R is hydrogen, halogen, carboxyl, lower alkoxycarbonyl, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl or lower alkoxy, Rj is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lower alkyl, 3- to 7-membered cycloalkyl or phenyl-lower alkyl and R2 is the group of the formula lb, in which alk is lower alkylene, R3 is COOH or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, carboxyl or lower alkoxycarbonyl or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt.

The invention relates in particular to compounds of the formula I, in which R2 is the group of the formula la or lb and alk is methylene, in free form or in form of a salt.

The invention relates primarily to compounds of the formula I, in which one or two of the variables Zb Z2,Z3 and Z4 are N and the others are CH, in particular Zb Z^ and 7^ are CH and Z4 is N, Rj is lower alkyl, in particular having not more than 4 C atoms, such as propyl or n-butyl, lower alkenyl, in particular having from 3 up to and including 5 C atoms, such as propen-2-yl or but-2-en-l-yl, or halo-lower alkyl, in particular having not more than 4 C atoms and containing halogen with an atomic number of not more than 35, such as n-heptafluoropropyl, and R2 is the group of the formula lb in which alk is methylene, R3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or, secondarily, substituted by halogen, in particular with an atomic number of not more than 35, such as chlorine, lower alkyl, in particular having not more than 4 C atoms, such as methyl, or lower alkoxy, in particular having not more than 4 C atoms, such as methoxy, in free form or in form of a salt.

The invention relates in particular to compounds of the formula I, in which one or two of the variables Zb Z2,7^ and Z4 are N and the others are CH or in which in particular one of the variables Z2,7$ and Z4 is N and Zj and the other variables of Z2,7^ and Z4 are C(R), in particular CH, or in which Zj and Z3 are C(R), in particular CH, and Z2 and Z4 are N, in free form or in form of a salt. - 14The invention relates primarily to compounds of the formula I, in which Zb Z2 and Z3 are CH and Z4 is N or Zj and Z3 are CH and Z2 and Z4 are N, Rj is lower alkyl, in particular having not more than 4 C atoms, such as propyl or n-butyl, lower alkenyl, in particular having from 3 up to and including 5 C atoms, such as propen-2-yl or but-2-en-l-yl, or halo-lower alkyl, in particular having not more than 4 C atoms and containing halogen with an atomic number of not more than 35, such as n-heptafluoropropyl, and R2 is the group of the formula lb in which alk is methylene, R3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or, secondarily, substituted by halogen, in particular with an atomic number of not more than 35, such as chlorine, lower alkyl, in particular having not more than 4 C atoms, such as methyl, or lower alkoxy, in particular having not more than 4 C atoms, such as methoxy, in free form or in form of a salt.

The invention relates primarily to compounds of the formula I, in which Zb Z2 and are CH, Z4 is N, Rj is C3-C4alkyl, such as propyl or n-butyl, and R2 is the group of the formula lb in which alk is methylene, R3 is 5-tetrazolyl and the rings A and B are unsubstituted, in free form or in form of a salt.

The invention relates in particular to the novel compounds of the formula I mentioned in the examples, in free form or in form of a salt.

The invention further relates to a process for the preparation of the compounds of the formula I and their salts, which process comprises, for example, a) reacting a compound of the formula or a salt thereof with a compound of the formula XrR2 (lib) - 15or a salt thereof, in which Xj is reactive esterified hydroxyl, or b) converting X2 into the variable R3 in a compound of the formula or a salt thereof, in which X2 is a radical which can be converted into the variable R3, or c) cyclizing a compound of the formula (IV) or a salt thereof and, in each case, if desired, converting a compound of the formula I in free form or in form of a salt which can be obtained according to the process or in another manner into another compound of the formula I, separating a mixture of isomers which can be obtained according to the process and isolating the desired isomer and/or converting a free compound of the formula I which can be obtained according to the process into a salt or converting a salt of a compound of the formula I which can be obtained according to the process into the free compound of the formula I or into another salt.

Salts of starting materials which contain at least one basic centre are corresponding acid addition salts, while salts of starting materials which contain at least one acidic group are salts with bases, in each case as mentioned above in connection with corresponding salts of compounds of the formula I.

Reactive esterified hydroxyl Xj is, in particular, hydroxyl esterified with a strong - 16inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy, Cj-C7alkanesulfonyloxy which is unsubstituted or substituted, for example by halogen, for example methane- or trifluoromethanesulfonyloxy, C5-C7cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or benzenesulfonyloxy which is unsubstituted or substituted, for example by CrC7alkyl or halogen, for example p-bromophenyl- or p-toluene-sulfonyloxy.

Radicals X2 which can be converted into the variable R3 are, for example, cyano, mercapto, halogen, the group -N2+A‘, in which A' is an anion derived from an acid, amino, functional derivatives of COOH, SO3H, PO3H2 and PO2H2 and N-protected 5-tetrazolyl.

The reactions described in the variants above and below are carried out in a manner known per se, for example in the absence or, customarily, in the presence of a suitable solvent or diluent or of a mixture thereof, the reaction being carried out, according to need, with cooling, at room temperature or with warming, for example in a temperature range from about -80°C up to the boiling point of the reaction medium, preferably from about -10° to about +200°C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

Variant a): The reaction of compounds of the formula Ha with compounds of the formula Rb is carried out advantageously in the presence of a base. Suitable bases are, in particular, alkali metal hydroxides, hydrides, amides, alkoxides, carbonates, triphenylmethylides, di(lower alkyl)amides, -aminoalkylamides or -lower alkylsilylamides, naphthylamines, diand tri-lower alkylamines, basic heterocycles, ammonium hydroxides, and carbocyclic amines. Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium (m)ethoxide, potassium tert-butoxide, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, dimethylaminonaphthalene, di- and triethylamine, diisopropyl-ethyl-amine, N-methylpiperidine, pyridine, benzyltrimethylammonium hydroxide, l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diaza-bicyclo[5.4.0] undec-7-ene (DBU).

Xj is preferably halogen, such as chlorine or bromine, or sulfonyloxy, such as Q-Cgalkane-, for example methane-sulfonyloxy, or benzenesulfonyloxy which is unsubstituted or substituted, for example by Ci-C7alkyl, for example - 17p-toluenesulfonyloxy.

To prepare the starting compounds of the formula Ila, the process starts in a manner known per se, for example from compounds of the formula and these are reacted while warming with compounds of the formula Rj-COOH (lid).

The starting material of the formula lib is known or can be prepared in a manner known per se.

Variant b): Radicals X2 which can be converted into 5-tetrazolyl R3 are, for example, cyano and N-protected 5-tetrazolyl.

To prepare compounds of the formula I, in which R3 is 5-tetrazolyl, the process starts, for example, from starting material of the formula ΠΙ, in which X2 is cyano, and this is reacted with an azide, for example with HN3 or, in particular, a salt, such as an alkali metal salt, thereof or with an organotin azide, such as tri-lower alkyl- or tri-aryl-tin azide. Preferred azides are, for example, sodium azide and potassium azide and tri-CrC4alkyl-, for example triethyl- or tributyl-tin azide, and triphenyltin azide.

Suitable protecting groups for N-protected 5-tetrazolyl are the protecting groups customarily used in tetrazole chemistry, in particular triphenylmethyl, benzyl which is unsubstituted or substituted, for example by nitro, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- or ethoxy-methyl, lower alkylthiomethyl, such as methylthiomethyl, as well as 2-cyanoethyl, and additionally lower alkoxy-lower alkoxy methyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. The protecting groups are removed following known methods. Thus, for example, triphenylmethyl is customarily removed by hydrolysis, in particular in the presence of an acid, or hydrogenolysis in the presence of a hydrogenation catalyst, 4-nitrobenzyl is removed, for example, by hydrogenolysis in the presence of a hydrogenation catalyst, methoxy- or - 18ethoxy-methyl is removed, for example, by treating with a tri-lower alkyltin bromide, such as triethyl- or tributyl-tin bromide, methylthiomethyl is removed, for example, by treating with trifluoroacetic acid, 2-cyanoethyl is removed, for example, by hydrolysis, for example with sodium hydroxide solution, 2-methoxyethoxymethyl is removed, for example, by hydrolysis, for example with hydrochloric acid, and benzyloxymethyl and phenacyl are removed, for example, by hydrogenolysis in the presence of a hydrogenation catalyst.

A radical X2 which can be converted into SO3H R3 is, for example, the mercapto group. Starting compounds of the formula III containing a group of this type are, for example, oxidized by oxidation processes known per se to those compounds of the formula I in which R3 is SO3H. Suitable oxidizing agents are, for example, inorganic peracids, such as . peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid. The oxidation is commonly carried out in the presence of suitable catalysts, suitable acids, such as substituted or unsubstituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VI, for example molybdenum oxide or tungsten oxide, being mentioned as catalysts. The oxidation is carried out under mild conditions, for example at temperatures from about -50° to about +100°C.

A group X2 which can be converted into PO3H2 R3 is to be understood as meaning, for example, a group -N2+A, in which A' is an anion of an acid, such as a mineral acid. Corresponding diazonium compounds of this type are, for example, reacted in a manner known per se with a Ρ(ΠΙ) halide, such as PC13 or PBr3, and worked up by hydrolysis, those compounds of the formula I being obtainable in which R3 is PO3H2.

Compounds I, wherein R3 is PO2H2, are obtained, for example, by the conversion, carried out in customary manner, of X2 in a compound III, wherein X2 is a functional derivative of PO2H2, into PO2H2.

A suitable X2 radical which can be converted into haloalkanesulfonylamino R3 is, for example, amino. In order to prepare compounds of the formula I in which R3 is haloalkanesulfonylamino, corresponding anilines, for example, are reacted with a - 19customarily reactively esterified haloalkanesulfonic acid, the reaction being carried out, if desired, in the presence of a base. The suitable preferred reactively esterified haloalkanesulfonic acid is the corresponding halide, such as the chloride or bromide.

A radical X2 which can be converted into COOH R3 is, for example, a functionally modified carboxyl, such as cyano, esterified or amidated carboxyl, hydroxymethyl or formyl.

Esterified carboxyl is, for example, carboxyl esterified with a substituted or unsubstituted aliphatic, cycloaliphatic or aromatic alcohol. An aliphatic alcohol is, for example, a lower alkanol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol or tert-butanol, while a suitable cycloaliphatic alcohol is, for example, a 3- to 8-membered cycloalkanol, such as cyclo-pentanol, -hexanol or -heptanol. An aromatic alcohol is, for example, a phenol or a heterocyclic alcohol, which may in each case be substituted or unsubstituted, in particular hydroxypyridine, for example 2-, 3- or 4-hydroxypyridine.

Amidated carboxyl is, for example, carbamoyl, carbamoyl which is monosubstituted by hydroxyl, amino or substituted or unsubstituted phenyl, carbamoyl which is mono- or disubstituted by lower alkyl or carbamoyl which is disubstituted by 4- to 7-membered alkylene or 3-aza-, 3-lower alkylaza-, 3-oxa- or 3-thiaalkylene. Examples which may be mentioned are carbamoyl, N-mono- or N,N-di-(lower alkyl)carbamoyl, such as N-methylN-ethyl-, Ν,Ν-dimethyl-, Ν,Ν-diethyl- and Ν,Ν-dipropyl-carbamoyl, pyrrolidino- and piperidino-carbonyl, morpholino-, piperazino-, 4-methylpiperazino- and thiomorpholino-carbonyl, anilinocarbonyl and anilinocarbonyl substituted by lower alkyl, lower alkoxy and/or halogen.

Preferred functionally modified carboxyl is, for example, lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, and cyano.

Compounds of the formula I in which R3 is carboxyl can be prepared, for example, starting from compounds of the formula ΙΠ in which X2 is cyano or esterified or amidated carboxyl, by hydrolysis, in particular in the presence of a base, or, starting from compounds of the formula ΠΙ in which X2 is hydroxymethyl or formyl, by oxidation. The oxidation is carried out, for example, in an inert solvent, such as in a lower alkanecarboxylic acid, for example acetic acid, in a ketone, for example acetone, in an ether, for example tetrahydrofuran, in a heterocyclic aromatic, for example pyridine, or in -20water, or in a mixture thereof, if necessary with cooling or warming, for example in a temperature range of from about 0° to about +150°C. Suitable oxidizing agents are, for example, oxidizing transition metal compounds, in particular those with elements of sub-groups I, VI or VII. Examples which may be mentioned are: silver compounds, such as silver nitrate, silver oxide and silver picolinate, chromium compounds, such as chromium trioxide and potassium dichromate, and manganese compounds, such as potassium permanganate, tetrabutylammonium permanganate and benzyltri(ethyl)ammonium permanganate. Other oxidizing agents are, for example, suitable compounds with elements of main group IV, such as lead dioxide, or halogen-oxygen compounds, such as sodium iodate or potassium periodate.

The variant b) is preferably suitable for the preparation of those compounds of the formula I in which the variables have meanings which are different from unsaturated radicals.

The starting material of the formula III is, for example, accessible by starting from compounds of the formula Ila and reacting these in analogy to variant a) with a compound in which X! and X2 have the abovementioned meanings.

Compounds Ilia are known or can be prepared according to methods known per se.

Variant c): This variant is suitable, in particular, for the preparation of those compounds of the formula I in which R3 is 5-tetrazolyl.

The cyclization is carried out in a manner known per se, for example while warming, for example in a temperature range from about 70° to about 200°C, preferably at the reflux temperature of the solvent system, if desired in the presence of an acid, such as a mineral acid or carboxylic acid, for example acetic acid. -21 The starting material of the formula IV is accessible using customary methods, for example by reaction of a compound of the formula no2 (IVa), x3 in which X3 is halogen, such as chlorine, with a compound of the formula H2N-R2 (IVb), which is followed in the next reaction step by an N-acylation, which, if desired, is catalysed by bases, with a compound of the formula HOOC-Rj (lid) or a reactive acid derivative, in particular an acid halide, thereof. The compounds of the formula R2 (IVc) obtainable in this way can then be reduced, for example by hydrogenation, to the corresponding compounds of the formula IV.

A compound of the formula I which is obtainable according to the process or in another manner can be converted into another compound of the formula I in a manner known per se.

For example, a compound of the formula I containing hydroxyl can be etherified by methods known per se. The etherification can be carried out, for example, using an alcohol, such as a substituted or unsubstituted lower alkanol, or a reactive ester thereof. Suitable reactive esters of the desired alcohols are, for example, those with strong inorganic or organic acids, such as corresponding halides, sulfates, lower alkanesulfonates or substituted or unsubstituted benzenesulfonates, for example chlorides, bromides, iodides or methane-, benzene- or p-toluene-sulfonates. The etherification can be carried out, for example, in the presence of a base, for example in the presence of an alkali metal hydride, hydroxide or carbonate, or of a basic amine. Inversely, corresponding ethers, such -22as lower alkoxy compounds, can be cleaved, for example, by means of strong acids, such as mineral acids, for example hydrobromic or hydriodic acid, which may advantageously be present in the form of pyridinium halides, or by means of Lewis acids, for example halides of elements of main group III or the corresponding sub-groups. These reactions can be carried out, if necessary, with cooling or warming, for example in a temperature range from about -20° to about +100°C, in the presence or absence of a solvent or diluent, under inert gas and/or under pressure and, if appropriate, in a closed vessel.

If an aromatic structural component is substituted by lower alkylthio, this can be oxidized in a customary manner to the corresponding lower alkane-sulfinyl or -sulfonyl. Suitable oxidizing agents for the oxidation to the sulfoxide step are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid. The oxidation is commonly carried out in the presence of suitable catalysts, catalysts which can be mentioned being suitable acids, such as substituted or unsubstituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VI, for example molybdenum oxide or tungsten oxide. The oxidation is carried out under mild conditions, for example at temperatures from about -50° to about +100°C. The further oxidation to the sulfone step may be carried out appropriately at low temperatures using dinitrogen tetroxide as the catalyst in the presence of oxygen, just like the direct oxidation of lower alkylthio to lower alkanesulfonyl. However, in this case the oxidizing agent is customarily employed in excess.

If one of the variables contains amino, corresponding compounds I can be N-(ar)alkylated in a manner known per se; likewise, carbamoyl or radicals containing carbamoyl can be N-(ar)alkylated. The (ar)alkylation is carried out, for example, using an (aryljCj^alkyl halide, for example a bromide or iodide, an (aryl)C1-C7alkanesulfonate, for example a methanesulfonate or p-toluenesulfonate, or a di-Ci-C7alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide solution, and advantageously in the presence of a phase-transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammonium chloride, where, however, stronger basic condensing agents, such as alkali metal amides, hydrides or alkoxides, for example sodium amide, sodium -23hydride or sodium ethoxide, may be necessary.

In compounds of the formula I which contain an esterified or amidated carboxyl group as a substituent, a group of this type can be converted into a free carboxyl group, for example by means of hydrolysis, for example in the presence of a basic agent or of an acidic agent, such as a mineral acid.

Furthermore, in compounds of the formula I which contain a carboxyl group as a substituent (in particular if R3 is different from carboxyl), this can be converted into an esterified carboxyl group, for example, by treating with an alcohol, such as a lower alkanol, in the presence of a suitable esterifying agent, such as an acid reagent, for example an inorganic or organic acid or a Lewis acid, for example zinc chloride, or a condensing agent which combines with water, for example a carbodiimide, such as Ν,Ν’-dicyclohexylcarbodiimide, or by treating with a diazo reagent, such as with a diazo-lower alkane, for example diazomethane. This can also be obtained if compounds of the formula I in which the carboxyl group is present in free form or in salt form, such as ammonium salt or metal salt, for example alkali metal salt, such as sodium salt or potassium salt form, are treated with a CrC7alkyl halide, for example methyl or ethyl bromide or iodide, or an organic sulfonic acid ester, such as an appropriate Ci-C7alkyl ester, for example methyl or ethyl methanesulfonate or p-toluenesulfonate.

Compounds of the formula I which contain an esterified carboxyl group as a substituent can be converted into other ester compounds of the formula I by transesterification, for example by treating with an alcohol, customarily with a higher appropriate alcohol than that of the esterified carboxyl group in the starting material, in the presence of a suitable transesterifying agent, such as a basic agent, for example an alkali metal CrC7alkanoate, Cj-C7alkanolate or cyanide, such as sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide or sodium cyanide, or a suitable acid agent, if appropriate with removal of the resulting alcohol, for example by distillation. Appropriate, so-called activated esters of the formula I may also be used as starting materials which contain an activated esterified carboxyl group as a substituent (see below), and these may be converted into another ester by treating with a CrC7alkanol.

In compounds of the formula I which contain the carboxyl group as a substituent, this can also first be converted into a reactive derivative, such as an anhydride (including a mixed anhydride), an acid halide, for example an acid chloride (for example by treating with a -24thionyl halide, for example thionyl chloride), an anhydride using a formic acid ester, for example a Cj-Cgalkyl ester (for example by treating a salt, such as an ammonium or alkali metal salt, with a haloformic acid ester, such as a chloroformic acid ester, such as a Cj-C7alkyl ester), or an activated ester, such as a cyanomethyl ester, a nitrophenyl ester, for example a 4-nitrophenyl ester, or a polyhalophenyl ester, for example a pentachlorophenyl ester (for example by treating with an appropriate hydroxyl compound in the presence of a suitable condensing agent, such as N,N’-dicyclohexylcarbodiimide), and then a reactive derivative of this type can be reacted with an amine and in this way amide compounds of the formula I which contain an amidated carboxyl group as a substituent can be obtained. In this case, these can be obtained directly or via intermediate compounds; thus, for example, an activated ester, such as a 4-nitrophenyl ester, of a compound of the formula I containing a carboxyl group can first be reacted with a 1-unsubstituted imidazole and the 1-imidazolylcarbonyl compound obtained in this way brought to reaction with an amine. However, other non-activated esters, such as C1-C7alkyl esters, of compounds of the formula I can also be brought to reaction with amines.

If an aromatic ring contains a hydrogen atom as a substituent, the latter can be replaced by a halogen atom with the aid of a halogenating agent in a customary manner, for example brominated with bromine, hypobromic acid, an acyl hypobromite or a different organic bromine compound, for example N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridinium perbromide, dioxane dibromide, l,3-dibromo-5,5-dimethylhydantoin or 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one, or chlorinated with elemental chlorine, for example in a halogenated hydrocarbon, such as chloroform, and with cooling, for example down to about -10°C.

If an aromatic ring contains an amino group, this can be diazotized in a customary manner for example by treating with a nitrite, for example sodium nitrite, in the presence of a suitable protonic acid, for example a mineral acid, the reaction temperature advantageously being kept below about 5°C. The diazonium group present in the salt form which can be obtained in this way can be substituted by customary processes, for example as follows: by the hydroxyl group analogously to the boiling-out of phenol in the presence of water, by an alkoxy group by treating with an appropriate alcohol, energy having to be added; by the fluorine atom analogous to the Schiemann reaction in the thermolysis of corresponding diazonium tetrafluoroborates; or by chlorine, bromine, iodine or the cyano group analogously to the Sandmeyer reaction by reaction with corresponding Cu(I) salts, -25initially with cooling, for example to below about 5°C, and then heating, for example, to about 60° to about 150°C.

If the compounds of the formula I contain unsaturated radicals, such as lower alkenyl or lower alkynyl groups, these can be converted into saturated radicals in a manner known per se. Thus, for example, multiple bonds are hydrogenated by catalytic hydrogenation in the presence of hydrogenation catalysts, suitable for this purpose being, for example, nickel, such as Raney nickel, and noble metals or their derivatives, for example oxides, such as palladium or platinum oxide, which may be applied, if desired, to support materials, for example to carbon or calcium carbonate. The hydrogenation may preferably be carried out at pressures between about 1 and about 100 at and at a temperature between about -80° and about +200°C, in particular between room temperature and about 100°C. The reaction is advantageously carried out in a solvent, such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkanecarboxylic acid, for example acetic acid.

Furthermore, in compounds of the formula I in which R is halogen, such as chlorine, halogen can be replaced by corresponding -Z-R’ by reaction with a substituted or unsubstituted amine, an alcohol or a mercaptan.

The invention relates in particular to the processes described in the examples.

Salts of compounds of the formula I can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of the formula I are obtained by treating with a suitable acid or a suitable ion exchange reagent. Salts of compounds I can be converted into the free compounds I in customary manner, acid addition salts, for example, by treating with a suitable basic agent or a suitable ion exchange reagent.

Salts of compounds I can be converted in a manner known per se into different salts of compounds I.

Depending on the procedure and the reaction conditions, the compounds of the formula I having salt-forming, in particular basic properties, can be obtained in free form or in the form of salts.

In view of the close relationship between the compound of the formula I in the free form -26and in the form of its salts, in the preceding parts and below the free compound of the formula I or its salts, respectively, may analogously and expediently also be understood as meaning the corresponding salts or the free compound of the formula I, respectively.

The compounds I including their salts of salt-forming compounds can also be obtained in the form of their hydrates and/or can include other solvents, for example solvents used for crystallization.

The compounds I and their salts may exist, depending on the choice of the starting materials and procedures, in the form of one of the possible isomers or as a mixture thereof, for example, depending on the number and the absolute and relative configuration of asymmetrical carbon atoms, as pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, diastereomer mixtures or racemate mixtures.

Diastereomer mixtures and racemate mixtures obtained can be separated into the pure diastereomers or racemates in a known manner on the basis of the physicochemical differences of the components, for example by fractional crystallization. Enantiomer mixtures, for example racemates, obtained may be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleavage with specific immobilized enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, only one enantiomer being complexed, or by conversion into diastereomeric salts, for example by reaction of a basic final substance racemate with an optically active acid, such as a carboxylic acid, for example tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separation of the diastereomer mixture obtained in this manner, for example on the basis of its differing solubilities, into the diastereomers from which the desired enantiomer can be liberated by the action of suitable agents. The more active enantiomer is advantageously isolated.

The invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material and the missing steps are carried out or a starting material in the form of a derivative or salt and/or its racemates or antipodes is used or, in particular, formed under the reaction conditions. -27In the process of the present invention, those starting materials and intermediates are preferably used which lead to the compounds I described as particularly useful at the beginning. The invention likewise relates to novel starting materials and intermediates for the preparation of the compounds I, to their use and to a process for their preparation, the variables Zb Z2, Z3, Z4, Rj and R2 having the meanings indicated for the compounds I. In particular, compounds of the formula III, in free form or in form of a salt, in which X2 is cyano are preferred as starting materials.

The compounds of the formula I and their pharmaceutically acceptable salts can be used, preferably in the form of pharmaceutically acceptable preparations, in a method for the prophylactic and/or therapeutic treatment of the animal or human body, in particular as antihypertensives.

The invention therefore likewise relates to pharmaceutical preparations which contain a compound I in free form or in form of a pharmaceutically acceptable salt as active ingredient, and to a process for their preparation. These pharmaceutical preparations are those for enteral, such as oral, furthermore rectal or parenteral administration to warm-blooded animals, the pharmacological active ingredient being contained alone or together with customary pharmaceutical adjuncts. The pharmaceutical preparations contain, for example, from about 0.1 % to 100 %, preferably from about 1 % to about 60 %, of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration are, for example, those in dose unit forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary after addition of suitable adjuncts, to give tablets or sugar-coated tablet cores.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch paste, using, for example, com, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. -28Auxiliaries are primarily flow-regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are provided with suitable coatings which are, if desired, resistant to gastric juice, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, for example to identify or to indicate different doses of active ingredient, may additionally be added to the tablets or sugar-coated tablet coatings.

Other orally utilizable pharmaceutical preparations are hard gelatin capsules and also soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible to add stabilizers.

Suitable rectally utilizable pharmaceutical preparations are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. Furthermore, gelatin rectal capsules which contain a combination of the active ingredient with a base substance may also be used. Suitable base substances are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.

Suitable preparations for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.

The dose of the active ingredient can depend on different factors, such as the manner of -29administration, the warm-blooded animal species, the age and/or the individual condition. In the normal case, an approximate daily dose of about 10 mg to about 250 mg is to be estimated in the case of oral administration for an approximately 75 kg patient.

The following examples illustrate the invention described above; however, they are not intended to limit its extent in any manner. Temperatures are given in degrees Celsius.

The nomenclature of the azabenzimidazole base structures on which the compounds I are based is derived from the appropriate name according to Ring Systems Handbook, Ring Systems File I, of the American Chemical Society, 1988 edition; the RF Nos. 8280, 8284, 8285, 8293, 8334 and 8335 being referred to in particular.

Example 1: 2-(n-Butyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine (700 mg, 1.91 mmol) and tributyltin azide (1.27 g, 3.82 mmol) in o-xylene (20 ml) are stirred under reflux for 24 hours. The reaction mixture is evaporated in vacuo and the residue is stirred in a mixture of CH2C12/CH3OH/NH3 (5/3/1; 30 ml) for 30 minutes. After evaporating again in vacuo, the residue is separated by means of flash chromatography (silica gel 60,40-63 μπι, CH2C12/CH3/NH3 = 160/10/1) and the product is recrystallized from ethyl acetate. In this way, white crystals of 2-(n-butyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine are obtained [m.p.: 139° (dec.)].

N The starting material can be prepared, for example, as follows: a) 2,3-Diaminopyridine (7.7 g, 70.56 mmol) and valeric acid (16.6 ml, 141.1 mmol) are stirred at 160° for 20 hours. After cooling, the reaction mixture is dissolved in ethyl acetate, and the solution is washed with saturated NaHCO3 solution and saturated NaCl solution, dried (Na2SO4) and evaporated in vacuo. The residue is suspended in diethyl -30ether and filtered off. Slightly brownish crystals of 2-(n-butyl)-3H-imidazo[4,5-b]pyridine remain (m.p.: 87-89°). b) NaH (80 % in white oil, 300 mg, 10 mmol) is added in portions at room temperature to a solution of 2-(n-butyl)-3H-imidazo[4,5-b]pyridine (1.75 g, 10 mmol) in dimethylformamide (10 ml). After completion of the addition, the mixture is stirred at room temperature for a further 30 minutes and a solution of 4-bromomethyl-2’-cyanobiphenyl (2.72 g, 10 mmol) in dimethylfoimamide (25 ml) is then added dropwise. The reaction mixture is stirred at room temperature for 12 hours and then evaporated in vacuo. Ethyl acetate is added to the residue and the mixture is washed twice with water, dried (Na2SO4) and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 μΐη, CH2C12/CH3OH = 95/5) yields 2-(n-butyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine, which is directly further processed.

Example 2: Starting from 2-(n-propyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine and tributyltin azide, 2-(n-propyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl4-ylmethyl]-3H-imidazo[4,5-b]pyridine is obtained in the manner described in Example 1 [white crystals of m.p. 161° (dec.) from isopropanol/ethyl acetate].

The starting material can be prepared, for example, as follows: a) 2-(n-Propyl)-3H-imidazo[4,5-b]pyridine is prepared by reaction of 2,3-diaminopyridine with butyric acid in the manner described in Example la). The crude product is recrystallized from ethyl acetate/hexane (m.p.: 97-99°). b) 2-(n-Propyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine is obtained as an oil which is purified by flash chromatography (silica gel 60,40-63 gm, ethyl -31 acetate/hexane = 1/1) by alkylation of 2-(n-propyl)-3H-imidazo[4,5-b]pyridine with 4-bromomethyl-2’-cyano-biphenyl in the manner described in Example lb). This oil is directly further processed.

Example 3: 2-(n-Butyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine [white crystals of m.p. 120° (dec.) from ethanol/diethyl ether] is obtained in the manner described in Example 1 starting from 2-(n-butyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-c]pyridine and tributyltin azide.

Nz NH The starting material can be prepared, for example, as follows: a) 2-(n-Butyl)-3H-imidazo[4,5-c]pyridine is prepared by reaction of 3,4-diaminopyridine with valeric acid in the manner described in Example la) and is directly further processed. b) A mixture of 2-(n-butyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-c]pyridine and 2-(n-butyl)-l-(2’-cyanobiphenyl-4-ylmethyl)-lH-imidazo[4,5-c]pyridine is formed by alkylation of 2-(n-butyl)-3H-imidazo[4,5-c]pyridine with 4-bromomethyl-2’-cyanobiphenyl in the manner described in Example lb), and is separated into the individual components by means of flash chromatography (silica gel 60,40-63 gm, CH2CI2/CH3OH = 98/2). The desired component is directly further processed.

Example 4: 2-(n-Butyl)-l-[2,-(lH-tetrazol-5-vl)biphenvl-4-vlmethvll-lH-imidazor4,5-c1pyridine [white crystals of m.p. 179° (dec.) from ethanol/ethyl acetate] is obtained in the manner described in Example 1 starting from 2-(n-butyl)-l-(2’-cyanobiphenyl-4-ylmethyl)-lH-imidazo[4,5-c]pyridine [Example 3b)] and tributyltin azide.

Example 5: 2-(n-Heptafluoropropyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]3H-imidazo[4,5-b]pyridine [m.p.: 120-121° (from ethyl acetate/cyclohexane)] is obtained in the manner described in Example 1 starting from 2-(n-heptafluoropropyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine and tributyltin azide.

The starting material can be prepared, for example, as follows: a) 2-(n-Heptafluoropropyl)-3H-imidazo[4,5-b]pyridine [m.p.: 203-204° (from ethyl acetate/hexane)] is prepared by reaction of 2,3-diaminopyridine with perfluorobutyric acid in the manner described in Example la). b) 2-(n-Heptafluoropropyl)-3-(2’-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine is obtained by alkylation of 2-(n-heptafluoropropyl)-3H-imidazo[4,5-b]pyridine with 4-bromomethyl-2’-cyano-biphenyl in the manner described in Example lb) and flash chromatography (silica gel 60,40-63 nm, hexane/ethyl acetate = 4/1) and is directly further processed.

Example 6: 8-(n-Butyl)-9-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-9H-purine [m.p.: 155° (dec.); from ethyl acetate)] is obtained in the manner described in Example 1 starting from 8-(n-butyl)-9-(2’-cyanobiphenyl-4-ylmethyl)-9H-purine and tributyltin azide.

The starting material can be prepared, for example, as follows: a) 8-(n-Butyl)-9H-purine is prepared by reaction of 4,5-diaminopyridimine with valeric acid in the manner described in Example la) and is directly further processed. b) 8-(n-Butyl)-9-(2’-cyanobiphenyl-4-ylmethyl)-9H-purine is obtained by alkylation of 8-(n-butyl)-9H-purine with 4-bromomethyl-2’-cyano-biphenyl in the manner described in Example lb) and flash chromatography (silica gel 60,40-63 gm, CH2CI2/CH3OH = 95/5) and is directly further processed.

Example 7: The following can be prepared in an analogous manner as described in one of the above examples: 2-(n-butyl)-l-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyrazine, 6-(n-butyl)-7-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-7H-imidazo[4,5-c]pyridazine, 2-(n-butyl)-l-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-lH-imidazo[4,5-d]pyridazine, 6-(n-butyl)-5-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-5H-imidazo[4,5-c]pyridazine, 8-(n-butyl)-7-[2’-(lH-tetrazol-5-yl)biphenyI-4-ylmethyl]-7H-purine, 2-(n-butyl)-l-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyridine, 2-[(E)-but-l-en-l-yl]-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, 2-[(E)-propen-l-yl]-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, 2-(n-butyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, 2-(n-propyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, 2-(n-heptafluoropropyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, -342-(n-butyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine, 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-c]pyridine, 8-(n-butyl)-9-[2’-carboxybiphenyl-4-ylmethyl]-9H-purine, 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyrazine, 6-(n-butyl)-7-[2’-carboxybiphenyl-4-ylmethyl]-7H-imidazo[4,5-c]pyridazine, 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-d]pyridazine, 6-(n-butyl)-5-[2’-carboxybiphenyl-4-ylmethyl]-5H-imidazo[4,5-c]pyridazine, 8-(n-butyl)-7-[2’-carboxybiphenyl-4-ylmethyl]-7H-purine, 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyridine, 2- [(E)-but-1 -en-1 -yl]-3- [2 ’ -carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, and 2- [(E)-propen-l-yl]-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine.

Example 8: Tablets, each containing 50 mg of active ingredient, for example 2-(n-butyl)3- [2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, can be prepared as follows: Composition (for 10,000 tablets): Active ingredient 500.0 g Lactose 500.0 g Potato starch 352.0 g Gelatin 8.0 g Talc 60.0 g Magnesium stearate 10.0 g Silica (highly disperse) 20.0 g Ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an alcoholic solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is compressed to give tablets of 145.0 mg weight each and 50.0 mg active ingredient content which, if desired, can be provided with dividing grooves for finer adjustment of the dosage.

Example 9: Lacquered tablets, each containing 100 mg of active ingredient, for example 2-(n-butyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, can be prepared as follows: -35Composition (for 1,000 tablets): Active ingredient 100.00 g Lactose 100.00 g Com flour 70.00 g Talc 8.50 g Calcium stearate l-50g Hydroxypropylmethylcellulose 2.36 g Shellac 0.64 g Water q.s.

Dichloromethane q.s.

The active ingredient, the lactose and 40 g of the com flour are mixed, moistened with a paste prepared from 15 g of com flour and water (with warming) and granulated. The granules are dried, and the rest of the com flour, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to give tablets (weight: 280 mg) and these are lacquered with a solution of the hydroxypropylmethylcellulose and shellac in dichloromethane (final weight of the lacquered tablet: 283 mg).

Example 10: Tablets and lacquered tablets containing a different compound of the formula I or a pharmaceutically acceptable salt of a compound of the formula I, for example according to any one of Examples 1 to 7, can also be prepared in an analogous manner to that described in Examples 8 and 9.

Claims (66)

What is claimed is:

1. A compound of the formula (I), in which one or two of the variables Z b Z2, Z 3 and Z 4 are N and the others are C(R), where R is halogen, acyl, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, or R is -Z-R’, wherein Z is a bond or is O, S(O) m or NH, R’ is hydrogen or an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radical, if desired, is interrupted by O or S(O) m and the index m is in each case 0, 1 or 2, Rj is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or is a cycloaliphatic or araliphatic hydrocarbon radical and R 2 is the group of the formula in which alk is a divalent aliphatic hydrocarbon radical, R 3 is COOH, SO 3 H, haloalkanesulfonylamino, PO 2 H 2 , PO 3 H 2 or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl or halogen and which, if desired, is interrupted by O, hydroxyl which, if desired, is etherified by an aliphatic alcohol, or carboxyl which, if desired, is esterified or amidated or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt.

2. A compound according to claim 1 of the formula I, in which one or two of the variables Z b Z 2 , Z 3 and Z 4 are N and the others are C(R), where R is halogen, lower alkanoyl, -37carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, carbamoyl in which the amino group is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or 5-tetrazolyl or R is -Z-R’, in which Z is a bond or is O, S(O) m or NH, R’ is hydrogen, or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkylthio-lower alkyl, lower alkylthio-lower alkenyl, lower alkylthio-lower alkynyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, lower alkenylthio-lower alkyl, lower alkenylsulfinyl-lower alkyl, lower alkenylsulfonyl-lower alkyl, lower alkynylthio-lower alkyl, lower alkynylsulfinyl-lower alkyl or lower alkynylsulfonyl-lower alkyl which radicals, in each case, are unsubstituted or substituted by halogen, by hydroxyl, by amino which, if desired, is substituted as indicated immediately hereinbefore in the definition of the amino group of the carbamoyl radical R, by carboxyl which, if desired, is esterified as indicated immediately hereinbefore, or by carbamoyl in which the amino group, if desired, is substituted as indicated immediately hereinbefore, and the index m is 0,1 or 2, R t is lower alkyl, lower alkenyl or lower alkynyl which radicals, in each case, are unsubstituted or substituted by halogen or by hydroxyl, cycloalkyl or cycloalkenyl which are in each case 3- to 7-membered, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, and R 2 is the group of the formula la in which alk is lower alkylene or lower alkenylene, R 3 is COOH, SO 3 H, halo-lower alkanesulfonylamino, PO 2 H 2 , PO 3 H 2 or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl or lower alkenyloxy-lower alkynyl which radicals, in each case, are unsubstituted or substituted by halogen or hydroxyl, by hydroxyl, by lower alkoxy, by lower alkenyloxy, by carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or by carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as -38indicated immediately hereinbefore, in free form or in form of a salt.

3. A compound according to claim 1 of the formula I, in which one or two of the variables Zj, Z2, Z-j and Z 4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene, or R is -Z-R’, in which Z is a bond or is O and R’ is hydrogen, or lower alkyl or lower alkoxy-lower alkyl which radicals, in each case, are unsubstituted or substituted by halogen, by hydroxyl, by amino which, if desired, is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene, by carboxyl, by lower alkoxycarbonyl or by lower alkoxy-lower alkoxycarbonyl, R 1 is lower alkyl or lower . alkenyl which radicals, in each case, are unsubstituted or substituted by halogen or by hydroxyl, or 3- to 7-membered cycloalkyl or phenyl-lower alkyl, and R 2 is the group of the formula la, in which alk is lower alkylene, R 3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl which is unsubstituted or substituted by halogen or by hydroxyl, by lower alkoxy, by carboxyl or by lower alkoxycarbonyl, in free form or in form of a salt.

4. A compound according to claim 1 of the formula I, in which one or two of the variables Z b Z 2 , Z 3 and Z 4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, carbamoyl which, if desired, is mono- or disubstituted by lower alkyl, or 5-tetrazolyl or R is -Z-R’, in which Z is a bond or is O, S(O) m or NH, m is 0, 1 or 2 and R’ is hydrogen or lower alkyl which is unsubstituted or substituted by halogen, by hydroxyl or by amino, Rj is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lower alkyl, 3- to 7-membered cycloalkyl or phenyl-lower alkyl and R 2 is the group of the formula la in which alk is lower alkylene, R 3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl which is unsubstituted or substituted by halogen or by hydroxyl, by lower alkoxy, by carboxyl or by lower alkoxycarbonyl, in free form or in form of a salt.

5. A compound according to any one of claims 1 to 4 of the formula I, in which R 2 is the group of the formula (Ib), in free form or in form of a salt.

6. A compound according to claim 1 of the formula I, in which one or two of the variables Z b Z2, Z3 and Z 4 are N and the others are C(R), where R is hydrogen, halogen, carboxyl, lower alkoxycarbonyl, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl or lower alkoxy, Rj is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lower alkyl, 3- to 7-membered cycloalkyl or phenyl-lower alkyl and R 2 is the group of the formula lb, in which alk is lower alkylene, R 3 is COOH or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, carboxyl or lower alkoxycarbonyl or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt.

7. A compound according to any one of claims 1 to 6 of the formula I, in which R 2 is the group of the formula la or lb and alk is methylene, in free form or in form of a salt.

8. A compound according to claim 1 of the formula I, in which one or two of the variables Z b Z 2 , Z3 and Z 4 are N and the others are CH, in particular Z b Z 2 and 7^ are CH and Z 4 is N, Rj is lower alkyl, in particular having not more than 4 C atoms, lower alkenyl, in particular having from 3 up to and including 5 C atoms, or halo-lower alkyl, in particular having not more than 4 C atoms and containing halogen with an atomic number of not more than 35, and R 2 is the group of the formula lb in which alk is methylene, R 3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or, secondarily, substituted by halogen, in particular with an atomic number of not more than 35, lower alkyl, in particular having not more than 4 C atoms, or lower alkoxy, in particular having not more than 4 C atoms, in free form or in form of a salt.

9. A compound according to any one of claims 1 to 8 of the formula I, in which one or two of the variables Z b Z 2 , 7^ and Z 4 are N and the others are CH or in which in particular one of the variables Z 3 and Z 4 is N and and the other variables of Z2, and Z 4 are -40C(R), in particular CH, or in which Zj and are C(R), in particular CH, and Z2 and Z 4 are N, in free form or in form of a salt.

10. A compound according to claim 1 of the formula I, in which Z b Z2 and Z 3 are CH and Z 4 is N or Zj and Z 3 are CH and Z2 and Z 4 are N, Rj is lower alkyl, in particular having not more than 4 C atoms, lower alkenyl, in particular having from 3 up to and including 5 C atoms, or halo-lower alkyl, in particular having not more than 4 C atoms and containing halogen with an atomic number of not more than 35, and R 2 is the group of the formula lb in which alk is methylene, R 3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or, secondarily, substituted by halogen, in particular with an atomic number of not more than 35, lower alkyl, in particular having not more than 4 C atoms, or lower alkoxy, in particular having not more than 4 C atoms, in . free form or in form of a salt.

11. A compound according to claim 1 of the formula I, in which Z b Z 2 and are CH, Z 4 is N, Rj is C 3 -C 4 alkyl, and R 2 is the group of the formula lb in which alk is methylene, R 3 is 5-tetrazolyl and the rings A and B are unsubstituted, in free form or in form of a salt.

12. 2-(n-butyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

13. 2-(n-propyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

14. 2-(n-Butyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine, in free form or in form of a salt.

15. 2-(n-Butyl)-l-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-lH-imidazo[4,5-c]pyridine, in free form or in form of a salt.

16. 2-(n-Heptafluoropropyl)-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

17. 8-(n-Butyl)-9-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-9H-purine, in free form or in form of a salt. -41

18. 2-(n-butyl)-l-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyrazine, in free form or in form of a salt.

19. 6-(n-butyl)-7-[2’-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-7H-imidazo[4,5-c]pyridazine, in free form or in form of a salt.

20. 2-(n-butyl)-l-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-lH-imidazo[4,5-d]pyridazine, in free form or in form of a salt.

21. 6-(n-butyl)-5-[2’-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5H-imidazo[4,5-c]pyridazine, in free form or in form of a salt.

22. 8-(n-butyl)-7-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-7H-purine, in free form or in form of a salt.

23. 2-(n-butyl)-1 - [2 ’-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl] -1 H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

24. 2-[(E)-but-l-en-l-yl]-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

25. 2-[(E)-propen-l-yl]-3-[2’-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

26. 2-(n-butyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

27. 2-(n-propyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

28. 2-(n-heptafluoropropyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

29. 2-(n-butyl)-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine, in free form or in form of a salt. -4230. 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-c]pyridine, in free form or in form of a salt.

30. 31. 8-(n-butyl)-9-[2’-carboxybiphenyl-4-yImethyl]-9H-purine, in free form or in form of a salt.

31. 32. 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyrazine, in free form or in form of a salt.

32. 33. 6-(n-butyl)-7-[2’-carboxybiphenyl-4-ylmethyl]-7H-imidazo[4,5~c]pyridazine, in free form or in form of a salt.

33. 34. 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-d]pyridazine, in free form or in form of a salt.

34. 35. 6-(n-butyl)-5-[2’-carboxybiphenyl-4-ylmethyl]-5H-imidazo[4,5-c]pyridazine, in free form or in form of a salt.

35. 36. 8-(n-butyl)-7-[2’-carboxybiphenyl-4-ylmethyl]-7H-purine, in free form or in form of a salt.

36. 37. 2-(n-butyl)-l-[2’-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyridine, in free form or in form of a salt.

37. 38. 2-[(E)-but-l-en-l-yl]-3-[2’-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

38. 39. 2- [(E)-propen-1 -yl] -3- [2 ’-carboxybiphenyl-4-ylmethyl] -3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

39. 40. A compound according to any one of claims 1 to 39, in free form or in form of a pharmaceutically acceptable salt, for use in a method for the therapeutic and/or prophylactic treatment of the human or animal body.

40. 41. A compound according to any one of claims 4 to 6 and 12 to 39, in free form or in form of a pharmaceutically acceptable salt, for use in a method for the therapeutic and/or -43prophylactic treatment of the human or animal body.

41. 42. A compound according to any one of claims 1 to 41, in free form or in form of a pharmaceutically acceptable salt, for use as an antihypertensive.

42. 43. A compound according to any one of claims 4 to 6, 12 to 39 and 41, in free form or in form of a pharmaceutically acceptable salt, for use as an antihypertensive.

43. 44. A pharmaceutical preparation containing as active ingredient a compound according to any one of claims 1 to 43, in free form or in form of a pharmaceutically acceptable salt, optionally together with customary pharmaceutical adjuncts.

44. 45. A pharmaceutical preparation containing as active ingredient a compound according to any one of claims 4 to 6,12 to 39,41 and 43, in free form or in form of a pharmaceutically acceptable salt, optionally together with customary pharmaceutical adjuncts.

45. 46. An antihypertensively effective pharmaceutical preparation according to claim 44 or 45, wherein an antihypertensively effective active ingredient is chosen.

46. 47. An antihypertensively effective pharmaceutical preparation according to claim 45, wherein an antihypertensively effective active ingredient is chosen.

47. 48. A process for the manufacture of a compound of the formula in which one or two of the variables Z b Zj, Z 3 and Z 4 are N and the others are C(R), where R is halogen, acyl, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, or R is -Z-R’, wherein Z is a bond or is O, S(O) m or NH, R’ is hydrogen or an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated -44and which hydrocarbon radical, if desired, is interrupted by O or S(O) m and the index m is in each case 0, 1 or 2, is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or is a cycloaliphatic or araliphatic hydrocarbon radical and R 2 is the group of the formula da), in which alk is a divalent aliphatic hydrocarbon radical, R 3 is COOH, SO 3 H, haloalkanesulfonylamino, PO 2 H 2 , PO 3 H 2 or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl or halogen and which, if desired, is interrupted by O, hydroxyl which, if desired, is etherified by an aliphatic alcohol, or carboxyl which, if desired, is esterified or amidated or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt, which process comprises a) reacting a compound of the formula (Ila) or a salt thereof with a compound of the formula X r R 2 (Hb) or a salt thereof, in which X! is reactive esterified hydroxyl, or b) converting X 2 into the variable R 3 in a compound of the formula (III) or a salt thereof, in which X 2 is a radical which can be converted into the variable R 3 , or c) cyclizing a compound of the formula Z 4 Ν' (IV) or a salt thereof and, in each case, if desired, converting a compound of the formula I in free form or in form of a salt which can be obtained according to the process or in another manner into another compound of the formula I, separating a mixture of isomers which can be obtained according to the process and isolating the desired isomer and/or converting a free compound of the formula I which can be obtained according to the process into a salt or converting a salt of a compound of the formula I which can be obtained according to the process into the free compound of the formula I or into another salt.

48. 49. A process for the manufacture of a pharmaceutical preparation according to claim 44 or 45, which process comprises processing the active ingredient into a pharmaceutical preparation, optionally with the admixture of customary pharmaceutical adjuncts.

49. 50. A process for the manufacture of a pharmaceutical preparation according to claim 45, which process comprises processing the active ingredient into a pharmaceutical preparation, optionally with the admixture of customary pharmaceutical adjuncts.

50. 51. A process according to claim 49 for the manufacture of an antihypertensively effective pharmaceutical preparation according to claim 46 or 47, wherein an antihypertensively -46effective active ingredient is chosen.

51. 52. A process according to claim 50 for the manufacture of an antihypertensively effective pharmaceutical preparation according to claim 47, wherein an antihypertensively effective active ingredient is chosen.

52. 53. A method of treating high blood pressure and/or cardiac insufficiency, which comprises administering a compound according to any one of claims 1 to 43, in free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to any one of claims 44 to 47.

53. 54. A method of treating high blood pressure and/or cardiac insufficiency, which comprises administering a compound according to any one of claims 4 to 6,12 to 39,41 and 43, in free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to claim 45 or 47.

54. 55. Use of a compound according to any one of claims 1 to 43, in free form or in form of a pharmaceutically acceptable salt, for the manufacture of a pharmaceutical preparation.

55. 56. Use of a compound according to claim 55 for the manufacture of an antihypertensive.

56. 57. Use of a compound according to any one of claims 1 to 43, in free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to any one of claims 44 to 47 for the treatment of high blood pressure and/or cardiac insufficiency.

57. 58. Use of a compound according to any one of claims 1 to 43, in free form or in form of a pharmaceutically acceptable salt, for the manufacture of a pharmaceutical preparation by non-chemical methods.

58. 59. The process of Examples 1 to 7.

59. 60. The novel starting materials used, novel intermediates formed and novel end products obtainable in accordance with the process claimed in claim 48 or 59. FO 7.4 GR

60. 61. A compound of the formula (I) given and defined in claim 1, in free form or in form of a salt thereof, substantially as hereinbefore described and exemplified.

61. 62. A pharmaceutical composition according to claim 44, substantially as hereinbefore described and exemplified.

62. 63. A process for the manufacture of a compound of the formula (I) given and defined in claim 1, in free form or in form of a salt thereof, substantially as hereinbefore described and exemplified.

63. 64. A compound of the formula (I) given and defined in claim 1, in free form or in form of a salt thereof, whenever manufactured by a process claimed in claim 48 or 63 .

64. 65. Use according to claim 55, substantially as hereinbefore described.

65.

66. Use according to claim 57, substantially as hereinbefore described.