CA2027839A1 - Pyrimidines - Google Patents

Abstract

4-17791/+

Pyrimidines Abstract Pyrimidine compounds of the formula (I), in which one of the radicals R1, R2 and R3 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl, or a cycloaliphatic or araliphatic hydrocarbon radical, the second of the radicals R1, R2 and R3 and the radical R4 in each case independently of one another are halogen, acyl, an aromatic hydrocarbon radical, free, esterified or amidated carboxyl, cyano, SO3H, PO2H2, PO3H2, 5-tetrazolyl, unsubstituted or substituted sulfamoyl, acylamino or -Z1-R', in which Z1 is a bond or is 0, S(O)m or N(R), R' is hydrogen or an aliphatic hydrocarbon radical, which is uninterrupted or interrupted by O or (SO)m and unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or free, esterified or amidated carboxyl, R is hydrogen or an aliphatic hydrocarbon radical and m in each case is 0, 1 or 2, and the third of the radicals R1, R2 and R3 is the group of the formula

Description

'k~ X7 ~ ~ 9 4-17791/+

Pvrimidines The invention relates to pyrimidine compounds of the forrnula N~N
R3J~RI
R2 :

in which one of the radicals Rl, R2 and R3 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl, or a cycloaliphatic or araliphatic hydrocarbon radical, the second of the radicals Rl, R2 and R3 and the radical R4 in each case independently of one another are halogen, acyl, an aromatic hydrocarbon radical, free, esterifled or amidated carboxyl, cyano, SO3H, PO2H2, PO3H2, S-tetrazolyl, unsubstituted or substituted sulfamoyl, acylamino or -Zl-R', in which Zl is a bond or is 0, S()m or N(R), R' is hydrogen or an aliphatic hydrocarbon radical, which is uninterrupted or interrupted by O or (S)m and unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or free, esterified or amidated carboxyl, R is hydrogen or an aliphatic hydrocarbon radical and m in each case is 0, 1 or 2, and the third of the radicals Rl, R2 and R3 is the group of the forrnula .
~ . :
Z2~ R5 (Ia) in which Z2 iS alkylene, O, S()m or N(R), Rs is carboxyl, halogenoallcanesulfonylamino, SO3H, PO2H2, PO3H2 or 5-tetrazolyl, R is hydrogen or an aliphatic hydrocarbon radical, m is 0, 1 or 2 and the rings A and B independendy of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical, which is uninterrupted or ;, . -~

.

intcrrupted by O and unsubstituted or substituted by hydroxyl or halogen, hydroxyl which is free or e therified by an aliphatic alcohol, carboxyl which is free, esterified or amidated or 5-tetrazolyl, and where appropriate tautomers thereof, in each case in the free form or in salt form, a process for the preparation of these compounds and tautomers, the use of these compounds and eautomers and pharmaceutical preparations containing such a compound I
or such a tautomer, in each case in the free form or in the form of a pharmaceutically acceptable salt.

Some of the compounds I can be present as proton tautomers. For example, if one of the radicals Rl, R2 or R3 is hydroxyl, corresponding compounds can be in equilibrium with the tautomeric oxo derivatives, tha~ is to say the corresponding pyrimid-4-ones, -5-ones or -6-ones. The compounds I above and below, where appropriate, are accordingly also to be understood as meaning corresponding tautomers.

The compounds of the formula I and where appropriate their tautomers can be in the form of salts, in particular pharmaceutically acceptable salts. If the compounds I contain, for example, 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 hydrogen halide acid, with strong organic carboxylic acids, such as Cl-C4alkanecarboxylic acids which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as dicarboxylic acids which are unsaturated or saturated, 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 Cl-C4alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed with a basic centre which may additionally be present. The compounds I having at least one acid group (for example COOH or 5-tetrazolyl) can furthermore form salts with bases. Examples of suitable salts with bases are metal salts, such as alkali metal salts or alkaline earth metal salts, for example sodium salts, potassium salts or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example, ethyl-, tert-butyl-, diethyl-, diisopropyl-, tlietllyl-, tributyl- or dimethyl-propyl-amine, or a mono-, di- or trihydroxy-lower alkylamine, for example mono-, di- or triethanolamine. Corresponding inner salts can moreover be formed. Salts which are not suitable for pharmaceutical uses and which are . ~ , employed, for example, for isolation or purification of free compounds I or pharrnaceutically aceptable salts thereof are also included.

An aromatic hydrocarbon radical is, in particular, phenyl.

Acyl is, in particular, lower alkanoyl.

Esteri~led carboxyl is, for exaTnple, 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 is uninterrupted or interrupted by 0, such as from lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl.

Amidated carboxyl is, for exarnple, carbarnoyl in which the arnino group is unsubstituted or mono- or disubstituted by, independently of one another, an aliphatic or araliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, -lower alkenyl or -lower alkynyl, or disubstituted by a divalent aliphatic hydrocarbon radical which is uninterrupted or interrupted by 0, such as lower alkylene or lower alkylenoxy-lower alkylene.

Substituted amino is, for example, amino which is mono- or disubstituted by, independently of one another, an aliphatic or araliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, -lower alkenyl or -lower alkynyl, or disubstituted by a divalent aliphatic hydrocarbon radical which is uninterrupted or interrupted by 0, such as lower alkylene or lower alkylenoxy-lower alkylene. Exa~nples are lower alkyl-, lower alkeny1-, 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 exarnple, 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, whilst an aliphatic hydrocarbon radical which is interrupted by S()m is, in particular, lower alkyl-thio-lower alkyl, -lower alkenyl or -lower aIkynyl, lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower .

, 3 ~

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, halogeno-lower alkyl, -lower alkenyl or -lower alkynyl or hydroxy-lower alkyl, -lower alkenyl or -lower alkynyl.

An aliphatic hydrocarbon radical which is substituted by halogen or hydroxyl and is interrupted by O or S(O)m is a corresponding radical as defined above which is substituted by halogen or hydroxyl.

An aliphatic hydrocarbon radical which is substituted by unsubstituted or substituted amino or free, esterified or amidated carboxyl and which is uninterrupted or interrupted by O or S()m is a corresponding radical as defined above which is substituted by amino, amino which is substituted as defined above, carboxyl, carboxyl which is esterified as defined above or carboxyl which is amidated as defined above.

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

Suitable araliphatic hydrocarbon radicals are, in particular, phenyl-lower alkyl, and furtherrnore phenyl-lower alkenyl and -lower alkynyl.

Hydroxyl etherified by an aliphatic alcohol is, in particular, lower alkoxy or lower aIkenyloxy.

ALkylene is methylene or lower alkylene.

Substituted sulfamoyl is lower aL~cyl- or di-lower aLkyl-sulfamoyl.

Acyl in acylamino is derived from an organic carboxylic acid or an organic sulfonic acid.
Examples of corresponding acyl are lower aL~canoyl, unsubstituted or substituted benzoyl, lower alkanesulfonyl, halogeno-lower alkanesulfonyl or unsubstituted or substituted benzenesulfonyl.

Unsaturated aliphatic, cycloaliphatic and araliphatic substituents above and below are, in , ., : ~ ' .

.

particular, not linked to an aromatic radical via a C atom from which a multiple bond starts.

Phenyl is in each case phenyl which is unsubstituted or substituted by one or more, for example two or three substituents, for example by (a) substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxyl This applies to phenyl radicals per se as well as to phenyl in phenyl-containing groups, such as benzoyl or benzenesulfonyl, The rings A and B form a biphenylyl radical, corresponding 4-biphenylyl being preferred.

The general terms used above and below, unless defined otherwise, have the following meanings:

The term "lower" means that corresponding groups and compounds in each case contain, in particular, not more than 7, preferably not more than 4, carbon atoms Lower alkanesulfonyl is, in particular, Cl-C7alkanesulfonyl and is, for example, methane-, ?
ethane-, n-propane- or isopropane-sulfonyl. Cl-C4Alkanesulfonyl is preferred.
Halogeno-lower alkanesulfonyl is halogeno-CI-C7-alkanesulfonyl, such as trifluoromethanesulfonyl.

Lower alkanesulfamoyl is Cl-C7alkanesulfamoyl, such as methane-, ethane-, n-propane-, isopropane-, n-butane-, sec-butane- or tert-butanesulfamoyl. Cl-C4-Alkanesulfamoyl is preferred, Di-lower alkanesulfamoyl is di-Cl-C7alkanesulfamoyl, such as dimethane-, methane-ethane- or di-tn-propane)-sulfamoyl Di-CI-C4alkanesulfamoyl is preferred.

Halogen is, in particular, halogen having an atomic number of not more than 35, i.e.
fluorine, chlonne or bromine, and furthermore includes iodine.

Halogenoalkanesulfonylamino is, in particular, halogeno-Cl-C7alkanesulfonylamino and is, for example, difluoromethane-, trifluoromethane-, 2-chloroethane-, 1,1,2-trifluoroethane-, 1,1,2-trichloroethane-, pentafluoroethane- or heptafluoropropane-sulfonylamino. Halogeno-Cl-C4-alkanesulfonylamino is preferred.

Lower alkanoyl is, in particular, Cl-C7alkanoyl and is, for example, formyl, acetyl, . ,' , ,'. ~

propionyl, butyryl, isobutyryl or pivaloyl. C2-CsAlkanoyl is preferred.

Lower alkyl is, in particular, Cl-C7alkyl, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s,ec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl radical.
Cl-C4Alkyl is prefer.ed.

Lower alkenyl is, in particular, C3-C7alkenyl and is, for example, propen-2-yl, allyl or but-l-en-3-yl, -1-en-4-yl, -2-en-1-yl or -2-en-2-yl. C3-CsAlkenyl is preferred.

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

Lower alkoxy is, in particular, Cl-C7alkoxy, i.e. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or corresponding pentyloxy, hexyloxy or heptyloxy. Cl-C4Alkoxy is preferred.

Lower alkoxy-lower alkyl is, in particular, Cl-C4alkoxy-Cl-C4alkyl, such as

2-methoxyethyl, 2-ethoxyethyl, 2-(n-propoxy)ethyl or ethoxymethyl.

Lower alkoxy-lower alkenyl or -lower alkynyl is, in particular, Cl-C4alkoxy-C3-Csalkenyl or -alkynyl.

Lower alkenyloxy is, in particular, C3-C7alkenyloxy and is, for example, allyloxy, but-2-en-1-yloxy or but-3-en-1-yloxy. C3-CsAlkenyloxy is preferred.

Halogeno-lower alkyl is, in particular, halogeno-CI-C4alkyl, such as trifluoromethyl, 1,1,2-trifluoro-2-chloro-ethyl, chloromethyl or n-heptafluoropropyl.

Halogeno-lower aLIcenyl is, in particular, halogeno-C3-Csalkenyl, such as 2-chloroallyl.

Halogeno-lower alkynyl is, in particular, halogeno-C3-CsaLIcynyl, such as

3-chloropropargyl.

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

Hydroxy-lower alkenyl isj in particular, hydroxy-C3-Csalkenyl, such as 3-hydroxyallyl.

.

.
; ' ' ' h~7 Hydroxy-lower alkynyl is, in particular, hydroxy-C3-Csalkynyl, such as 3-hyclroxypropargyl .

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

Lower alkylene is, in particula~, C2-C7alkylene, is straight-chain or branched and is, in particular, ethylene, 1,3-propylene, 1,4-butylene, 1,2-propylene, 2-methyl-1,3-propylene or 2,2-dimethyl-1,3-propylene. C2-C5Alkylene is preferred.

Lower alkylenoxy-lower alkylene is, in particular, C2-C4aLkylenoxy-C2-C4alkylene, preferably ethylenoxyethy]ene.

Lower alkylamino is, in particular, Cl-C7aLIcylamino and is, for example, methyl-, ethyl-, n-propyl- or isopropyl-amino. Cl-C4Alkylamino is preferred.

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

Lower alkynylamino is, préferably, C3-Csalkynylamino, such as propargylamino.

Phenyl-lower alkylamino is, preferably, phenyl-Cl-C4alkylarnino, in particular benzyl- or 1- or 2-phenylethyl-amino.

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

Phenyl-lower aL~cynylamino is preferably phenyl-C3-CsaLlcynylamino, in particular phenylpropargylamino.

Di-lower alkylamino is, in particular, di-CI-C4alkylamino, 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-Cl-C4alkyl-N-phenyl-Cl-C4alkyl-amino, preferably methyl-benzyl-arnino or ethyl-benzyl-amino.

. ' :' ', ' ' ~ ~ :

Di(phenyl-lower alkyl)-amino is, in particular, di(phenyl-CI-C4alkyl)amino, preferably dibenzylamino Lower alkenyloxy-lower alkyl is, in particular, C3-Csalkenyloxy-Cl-C4alkyl, such as 2-allyloxyethyl, and lower alkenyloxy-lower alkenyl or -lower alkynyl is, in particular, C3-C5alkenyloxy-C3-CsaLkenyl or -alkynyl Lower alkylthio-lower alkenyl or -lower alkynyl is, in particular, Cl-C4aL~ylthio-C3-C5alkenyl or -alkynyl Lower alkylthio-lower alkyl is, in particular, Cl-C4alkylthio-Cl-C4alkyl, such as ethylthiomethyl, 2-ethylthioethyl, 2-methylthioethyl or 2-isopropylthioethyl, whilst particularly suitable lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl are corresponding Cl-C4alkane-sulfinyl-Cl-C4alkyl radicals or -sulfonyl-Cl-C4alkyl radicals Lower alkenylthio-lower alkyl is, in particular, C3-C5-alkenylthio-Cl-C4alkyl, such as l-allylthioethyl or 3-allylthiopropyl, whilst lower alkenyl-sulfinyl-lower alkyl or -sulfonyl-lower alkyl is, in particular, C3-Csalkenyl-sulfinyl-Cl-C4alkyl or -sulfonyl-CI-C4alkyl.

Lower alkynylthio-lower alkyl is, in particular, C3-C5alkynylthio-CI-C4alkyl, such as 2-propargylthioethyl or 3-propargylthiopropyl, whilst lower alkynyl-sulfinyl-lower alkyl or -sulfonyl-lower alkyl in particular is C3-Csalkynyl-sulfinyl-Cl-C4alkyl or -sulfonyl-CI-C4alkyl.

Cycloalkyl is, in particular, C3-C7cycloalkyl, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, Cyclopentyl and cyclohexyl are preferred.

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

Extensive pharmacological investigations have shown that the compounds I and their tautomers and/or their pharmaceudcally acceptable salts have, for exarnple, pronounced angiotensin II-antagonizing properties.

.

3 ~

As is known, angiotensin II has strong vasoconstricting properties and moreover stimulates aldosterone secretion and thus causes a significant sodium/water retention. The conscquence of the angiotensin II activity manifests itself, inter alia, in an increase in blood pressure. The importance of angiotensin II antagonists is that they suppress the vasoconstricting and aldosterone secretion-stimulating effects caused by angiotensin II by competitive inhibition of the bonding of angiotensin II to the receptors.

The angiotensin II-antagonizing properties of the compounds of the formula I and their tautomers and/or their pharmaceutically acceptable salts can be detected in the angiotensin II bonding test. In this, smooth muscle cells from the homogeniæd rat aorta are used. The solid centrifugate is suspended in 50 mM Tris-buffer (pH 7.4) using peptidase inhibitors.
The samples are incubated with 125I-angiotensin II (0.175 nM) and a varying concentration of angiotensin II or test substance at 25C for 60 minutes. The incuba~ion is then ended by addition of sodium chloride buffered with ice-cold phosphate and the mixture is filtered through a Whatman GF/F filter. The filters are counted with a gamma counter. The ICso values are determined from the dose-effect curve. ICso values from about 10 nM are determined for the compounds of the formula I and their pharmaceutically acceptable salts.

Studies on the isolated rabbit aorta ring can be used to determine the vasoconstriction induced by angiotensin II. Por this, aorta rings are prepared from each chest and are 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 37C and gassed with a mixture of 95 % of 2 and 5 % of CO2. The isometric reactions are measured. The rings are stimulated alternately with 10 nM of angiotensin II (Hypertensin-CIBA) and 5 nM of noradrenaline chloride at intervals of 20 minutes. The rings are then incubated with selected concentrations of the test substances before the treatment with the agonists. The data are analysed with a Buxco digital computer. The concentrations which cause a 50 % inhibition of the initial control values are quoted as the ICso values. ICso values from about S nM are determined for the compounds of the formula I and their tautomers and/or their pharmaceutically acceptable salts.

The fact that the compounds of the formula I and their tautomers andlor their pharmaceutically acceptable salts can reduce high blood pressure induced by angiotensin II can be verified in the test model of the normotensive anaesthetized rat. After calibration of the preparations with in each case 0.9 % of NaCI (1 ml/kg i.v.), noradrenaline (1 ~, g/kg .. . . . .
, .

.

~ ~' h ~

i.v.) or angiotensin II (0.3 ~lg/kg i.v.), increasing doses (3-6) of the test substance are injected intravenously by bolus injection, angiotensin II or noradrenaline beingadministered after each dose at 5 minute intervals. The blood pressure is measured directly in the carotid artery and recorded with an on-line data acquisition system (Buxco). The specificity of the angiotensin II antagonism is indicated by the selected inhibition of the pressure effect caused by angiotensin II but not of that by noradrenaline. In this test model, the compounds of the formula I and their tautomers and/or their pharmaceutically usable salts show an inhibiting effect from a dose of about 0.3 mg/kg i.v.

T he antihypertensive activity of the compounds of the formula I and their tautomers and/or their pharmaceutically acceptable salts can also be manifested in the test model of the renal hypertensive rat. High blood pressure is generated in male rats by constnction of a renal artery in accordance with the Goldblatt method. Doses of the test substance are administered to the rats by means of a stomach tube. Control animals are given an equivalent volume of solvent. The blood pressure and heart rate are measured indirectly on conscious animals by the tail clamp method of Gerol et al. lHelv. Physiol. Acta 24 (1966), 58] before administration of the test substance or solvent and at intervals during the course of the experiments. The pronounced antihypertensive effect can be demonstrated from a dose of about 30 mg/kg p.o.

The compounds of the formula I and their tautomers and/or their pharmaceuticallyacceptable salts can accordingly be used, for example, as active ingredients in antihypertensives which are used, for example, for the treatment of high blood pressure and of cardiac insufficiency. The invention thus relates to the use of the compounds of the formula I and their tautomers and/or their pharmaceutically acceptable salts for the preparation of corresponding medicaments and for the therapeutic treatment of high blood pressure and of cardiac insufficiency. The preparation of the medicaments also includes the commercial preparation of the active substances.

The invention particularly relates to compounds of the formula I in which one of the radicals Rl, R2 and R3 is lower alkyl, lower alkenyl or lower alkynyl, in each case unsubstituted or substituted by halogen or hydroxyl, in each case 3- to 7-membered cycloalkyl or cycloaLkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower aLkynyl, the second of the radicals Rl, R2 and R3 and the radical R4 in each case independently of one another is halogen, lower alkanoyl, unsubstituted or substituted phenyl, carboxyl, which is free or esterified by an alcohol which is derived from lower b 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 unsubstituted, mono- or disubstituted by, independently of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or is disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, cyano, SO3H, PO2H2, PO3H2, 5-tetrazolyl, sulfamoyl, lower alkanesulfamoyl, di-lower alkanesulfamoyl, lower alkanoylamino, unsubstituted or substituted benzoylamino, lower alkanesulf~nylamino, halogeno-lower alkanesulfonylamino, unsubstituted or substituted benænesulfonylamino or -Zl-R', in which Zl is a bond or 0, S()m or N(R), 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 alkyl-thio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenyl-thio-lower alkyl, -sulfinyl-lower aIkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case unsubstituted or substituted by hydroxyl, halogen, amino, lower alkyleneamino, lower alkylenoxy-lower alkyleneamino, lower alkylamino, lower alkenylamino, lower alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or 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 carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independently of one another, lower -:
alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl orphenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl and m is 0, 1 or 2, and the third of the radicals Rl, R2 and R3 is the group of the formula Ia, in which Z2 iS
methylene, lower aIkylene, O, S()m or N(R), RS is carboxyl, halogenoalkanesulfonylamino, SO3H, PO~H2, PO3H2 or 5-tetrazolyl, R is hydrogen, lower aIkyl, lower aLkenyl or lower alkynyl, m is 0, 1 or 2 and 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 is unsubstituted or substituted by hydroxyl or halogen, by hydroxyl, by lower alkoxy, by lower alkenyloxy, by carboxyl which is free or esterif~ed by an alcohol which is derived from lower alkyl, lower alkenyl, lower aIkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, bycarbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independently of on another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, or by S-tetrazolyl, the aromatic substituents in each case being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl, and where appropriate tautomers thereof, in each case in the free form or in salt form.

The invention particularly relates to compounds of the formula I in which Rl is halogen, carboxyl, which is free or esterified by an alcohol which is derived from lower alkyl or lower alkoxy-lower alkyl, carbamoyl, cyano, PO3H2, 5-tetrazolyl, lower-alkanesulfamoyl, lower-alkanoylamino, lower-alkanesulfonylamino or -Zl-R', in which Zl is a bond or is 0, S()m or N(R), R' is hydrogen or lower alkyl or lower alkoxy-lower alkyl, in each case unsubstituted or substituted by carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl or hydroxyl, R is hydrogen or lower alkyl and m is 0, 1 or 2, R2 is the group of the formula Ia, in which Z2 is methylene, lower alkylene, O, S()m or N(R), R is hydrogen or lower alkyl, m is 0, 1 or 2, R5 is carboxyl or S-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, low~r alkoxy, carboxyl, lower alkoxycarbonyl or 5-tetrazolyl, R3 is lower alkyl or lower alkenyl, unsubstituted or substituted by hydroxyl or halogen, and R4 is lower alkyl, and where appropriate tautomers thereof, in each case in the free form or in salt form.

The invention particularly relates to compounds of the formula I in which Rl is halogen, in particular having an atomic number of not more than 35, such as chlorine, carboxyl, lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, PO3H2, S-tetrazolyl, lower alkanoylamino, such as acetylamino, lower alkanesulfonylamino, such as methanesulfonylamino, hydrogen, lower alkyl, such as methyl, lower alkoxy-lower alkyl, such as 2-methoxyethyl, carboxy-lower alkyl, such as carboxymethyl, lower alkoxycarbonyl-lower alkyl, such as ethoxycarbonylmethyl, hydroxy-lower alkyl, such as hydroxymethyl, hydroxy-lower alkoxy-lower alkyl, such as hydroxyethoxymethyl, hydroxyl, lower alkoxy, such as rnethoxy, lower alkoxy-lower alkoxy, such as 2-methoxyethoxy, carboxy-lower alkoxy, such as carboxymethoxy, lower alkoxycarbonyl-lower alkoxy, such as ethoxycarbonylmethoxy, hydroxy-lower alkoxy, such as 2-hydroxyethoxy, mercapto, lower alkylthio, such as methylthio, lower ~lkanesuïfinyl, such as methanesulfinyl, lower alkanesulfonyl, such as methanesulfonyl, amino, lower alkylamino, such as methylamino, or di-lower alkylarnino, such as dimethylamino, R2 is the group of the formula Ia, in which Z2 iS methylene or lower alkylene, such as ethylene, O or S(O)m, m is 0, 1 or 2, R5 is carboxyl or 5-tetrazolyl and the rings ~ and B independently of one another are unsubstituted or substituted by lower alkyl, sucll as methyl, halogen, in particular having an atomic number of not more than 35, such as chlorine, or lower aLt~oxy, such as methoxy, R3 is Cl-C~alkyl, such as n-propyl or n-butyl, and R4 is lower alkyl, such as methyl or n-butyl, paIt structures designated "lower" in each case in particular containing not more than 7, preferably not more than 4, C atoms, and where appropriate tautomers thereof, in each case in the free forrn or in salt form.

The invention relates in particular to compounds of the formual I in which R2 is the group of the formula -Z2~ (Ib) and where appropriate tautomers thereof, in each case in the free form or in salt form.

The invention relates in particular to compounds of the formula I in which Rl is halogen having an atomic number of not more than 35, such as chlorine, hydroxyl, lower alkoxy having not more than 4 C atoms, such as methoxy, lower alkoxy-lower alkoxy having not more than 4 C atoms in each lower alkoxy moiety, such as 2-methoxyethoxy, hydroxy-lower alkoxy having not more than 4 C atoms, such as 2-hydroxyethoxy, lower alkylarnino having not more than 4 C atoms, such as methylamino, or di-lower alkylamino having not more than 4 C atoms in each lower alkyl moiety, such as dimethylamino, R2 is the group of the formula Ib, in which Z2 iS methylene, Rs is carboxyl or, in particular, 5-tetrazolyl and the rings A and B are unsubstituted, R3 is Cl-C7alkyl, in particular Cl-Csalkyl, such as n-propyl or n-butyl, and R4 is lower alkyl having not more than 4 C
atoms, such as methyl or n-butyl, and where appropriate tautomers thereof, in each case in the fre~ form or in salt form.

The invention relates in particular to compounds of the formula I in which Rl is hydroxyl, R2 is the group of the formula Ib, in which Z2 is methylene, Rs is 5-tetrazolyl and the rings J ~ ~ ~

A and B are unsubstituted, R3 is Cl-C5alkyl, such as n-propyl or n-butyl, and R4 iS lower alkyl having not more than 4 C atoms, such as methyl or n-butyl, and where appropriate tautomers thereof, in each case in the free form or in salt form.

The invention in fact relates to the novel compounds of the formula I mentioned in the examples and where appropriate tautomers thereof, in each case in the free form or in salt form.

The invention furthermore relates to a process for the preparation of the compounds of the formula I and where appropriate their tautomers, in each case in the free form or in salt form, for example which comprises a) in a compound of the formula NJ~N
la) R 3~R' R'2 or a tautomer and/or salt thereof, in which one of the radicals R'l, R'2 and R'3 is the group of the formula ~ (llh) in which Xl is a radical which can be converted into Rs, and the other two radicals have meanings of Rl, R2 or R3 other than the group of the formula Ia, converting Xl into R5, or b) reacting a compound of the formula .

~7~3~

Rq--C--CH--X2 ~IIIa), in which X2 is non-modified or functionally modified carboxyl, with a compound of the formula NH
R4--C--NH2 (IIIb) or a salt thereof, and in each case, if desired, converting a compound of the formula I
obtainable according to the process or in another manner or a tautomer thereof, in each case in the free form or in salt form, into another compound of the formula I, or a tautomer thereof, separating a mixture of isomers obtainable according to the process and-isolating the desired isomer and/or converting a free compound of the formula I obtainableaccording to the process or a tautomer thereof into a salt, or converting a salt of a compound of the formula I obtainable according to the process or a tautomer thereof into the free compound of the formula I or a tautomer thereof or into another salt.

What has been stated hereinbefore with respect to tautomers and salts, respective1y, of compounds I applies analogously also to tautomers and salts, respectively, of the starting materials.

Radicals Xl which can be converted into the variable Rs are, for example, cyano,mercapto, halogen, the group -N2+A-, in which A- is an anion derived from an acid, amino, functional derivatives of CO(~H, SO3H, P03H2 and PO2H2 and N-protected 5-tetrazolyl.

Functionally modified carboxyl is, for example, cyano or esterified or amidated carboxyl.

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

.

. .
, - -.

i 3 ~

Variant a~
~adicals Xl which can be converted into 5-tetrazolyl R5 are, for example, cyano and N-protected S-tetrazolyl.

To prepare compounds of the formula I, in which Rs is 5-tetrazolyl, the process starts, for example, from starting material of the formula IIa, in which Xl is cyano, and this is reacted with an azide, for example with HN3 or, in par~icular, 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-CI-C4aL~cyl-, 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, loweralkoxymethyl, 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 ~roups 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 ethoxy-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 Xl which can be converted into SO3H Rs is, for example, the mercapto group.
Starting compounds of the formula IIa 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 Rs 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 psrcarboxylic or persulfonic acids, for example performic, peracetic, - .

.
' ~

- ~ ~

~7~

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 +100C.

A group Xl which can be converted into PO3H2 Rs 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 P(III) halide, such as PCI3 or PBr3, and worked up by hydrolysis, those compounds of the formula I being obtainable in which Rs is PO3H2.

Compounds I, wherein R5 is P02H2, are obtained, for example, by the conversion, ca Tied out in customary manner, of Xl in a compound IIa, wherein Xl is a functional derivative of PO2H2, into PO2H2.

A suitable Xl radical which can be converted into haloalkanesulfonylamino R5 is, for example, amino. In order to prepare compounds of the formula I in which Rs is haloalkanesulfonylamino, corresponding anilines, for example, are reacted with acustomarily reactively esterified haloalkanesulfonic acid, the reaction being carried out, if desired"n the presence of a base. The suitable preferred reactively esterified haloalkanesulfonic acid is the corrosponding halide, such as the chloride or bromide.

A radical Xl which can be converted into COOH R5 is, for example, a functionallymodified 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 ~-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.

~\midated 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. Exarnples which may be mentioned are carbamoyl, N-mono- or N,N-di-(lower aL~cyl)carbamoyl, such as N-methyl-, N-ethyl-, N,N-dimethyl-, N,N-diethyl- and N,N-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 modifled carboxyl is, for example, lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, and cyano.

Compounds of the formula I in which R5 is carboxyl can be prepared, for example,starting from compounds of the formula IIa in which Xl is cyano or esterified or amidated carboxyl, by hydrolysis, in particular in the presence of a base, or, starting from compounds of the formula lIa in which Xl 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 examp}e tetrahydrofuran, in a heterocyclic aromatic, for example pyridine, or in water, or in a mixture thereof, if necessary with cooling or warming, for example in a temperature range of from about 0 to about +150C. 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 a) 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 IIa is accessible, for example, by using as the starting substance, analogously to variant b), a compound of the formula o R'3--C--CH--X2 (IIc), R'2 the preparation of which again is carried out in a manner which is known per se, and reacting this with a compound of the formula IIIb. It is possible to carry out in the starting materials IIa so obtained before converting Xl into Rs further transformations, for example transforrnations of a halogen atom Rl, especially a chlorine atom Rl, as described hereinafter.

Variant b):
If required, the reaction is carried out in the presence of a base.

Suitable bases are, for example, alkali hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di-lower alkylamides, aminoalkylamides or loweralkylsilylamides, naphthaleneamines, lower alkylamines, basic heterocyclic compounds, ammonium hydroxides and carbocyclic amines. Examples are sodium hydroxide, hydride and amide, potassium tert-butylate and carbonate, lithium triphenylmethylide anddiisopropylamide, potassium 3-(aminopropyl)-amide and bis-(trimethylsilyl)amide,dimethylaminonaphthalene, di- or triethylamine or ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyltrimethyl-ammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (I:)BN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Compounds of the formula IIIa can be prepared, for example, by a procedure analogous to that described above for compounds of the forrnula IIc. Compounds of the formula mb are known or can be prepared using methods which are known per se.

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

A compound of the formula I containing hydroxyl can be etherified, for example, by methods which are known per se. The etheriacation can be camed out, for exarnple, with an alcohol, such as an optionally substituted lower alkanol, or a reactive ester thereof.
Suitable reactive esters of the d.esired alcohols are, for example, those with strong inorganic or organic acids, such as corresponding halides, sulfates, lower alkanesulfonates or unsubstitllted or substituted benænesulfonates, 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 an alkali metal hydride, hydroxide or carbonate, or a basic amine Conversely, corresponding ethers, such as lower alkoxy compounds, can be split, for example, by means of strong acids, such as mineral acids, for example hydrobromic or hydriodic acid, which can advantageously be in the forrn of pyridinium halides, or by means of Lewis acids, for example halides of elements of main group III or of the corresponding sub-groups. If necessary, these reactions can be carried out while cooling or heating, for example in a temperature range from about -20 to about +100C, in the presence or absence of a solvent or diluent, under an inert gas and/or under pressure and if appropriate in a closed vessel.

If an aromatic structural constituent is substituted by lower allcylthio, this can be oxidized to the corresponding lower alkane-sulfinyl or -sulfonyl in the customary manner. Suitable oxidizing agents for oxidation to the sulfoxide level 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 often carried out in the presence of suitable catalysts, catalysts being suitable acids, such as unsubstituted or substituted 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 +100C. Furtheroxidation to the sulfone level can be carried out correspondingly with dinitrogen tetroxide as the catalyst in the presence of oxygen at low temperatures, as can direct oxidation of lower alkylthio to lower alkanesulfonyl However, the oxidizing agent is usually employed in excess here.

If one of the variables contains amino, corresponding compounds I can be N-(ar)alkylated in a manner which is known per se; carbamoyl or radicals containing carbamoyl can likewise be N-(ar)alkylated. The (ar)alkylation is carried out, for example, with an (aryl)Cl- C7alkyl halide, for example bromide or iodide, (aryl)Cl-C7alkanesulfonate, for ~ f~ `` 3 ~

example methanesulfonate or p-toluenesulfonate, or a di-CI-C7alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of so~ium hydroxide solution or potassium hydroxide solution, and advantageously in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethyl-ammonium chloride, in which case more strongly basic condensing agents, such as alkali metal amides, hydrides or alcoholates, for example sodium amide, sodium hydride or sodium ethanolate, may be necessary.

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

Furthermore, in compounds of the formula I which contain a carboxyl group as a substituent (especially if Rs is other than carboxyl), this can be converted into an esterified carboxyl group, for example by treatment 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 water-binding condensing agent, for example a carbodiimide, sueh as N,N'-dieyelohexylearbodiimide, or by treatment with a diazo reagent, sueh as with a diazo-lower alkane, for example diazomethane. This esterified carboxyl group can also be obtained if compounds of the formula I in which the carboxyl group is present in the free form or in salt form, such as ammonium or metal, for example alkali metal, such as sodium or potassium, salt form, are treated with a Cl-C7alkyl halide, for example methyl or ethyl bromide or iodide, or an organic sulfonic acid ester, such as a corresponding Cl-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 treatment with an alcohol, usually with an alcohol which is higher than that corresponding to the esterified carboxyl group in the starting material, in the presence of a suitable transesterification agent, such as a basic agent, for exarnple an alkali metal Cl-C7alkanoate, Cl-C7alkanolate or cyanide, such as sodium acetate, methanolate,ethanolate, tert-butanolate or cyanide, or a suitable acid medium, the alcohol formed being removed if appropriate, for example by distillation. Corresponding so-called activated esters of the formula I which contain an activated esterified carboxyl group as a ~7~

substituent (see below) can also be used as starting substances, and these can be converted into another ester by treatment with a Cl-C7alkanol.

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 chloride (for example by treatment with a thionyl halide, for example chloride), an anhydride with a formic acid ester, for example Cl-C7alkyl ester (for example by treatment of a salt, such as an ammonium or alkali metal salt, with a halogeno-, such as chloro-formic acid ester, such as Cl-C7alkyl ester), or an activated ester, such as a cyanomethyl, nitrophenyl, for example 4-nitro-phenyl, or polyhalogenophenyl, for example pentachlorophenyl, ester (for example by treatment with a corresponding hydroxyl compound in the presence of a suitable condensing agent, such as N,N'-dicyclohexylcarbodiimide), and such a reactive derivative can then be reacted with an amine to give in this way amide compounds of the formula I which contain an amidated carboxyl group as a substituent. In this case, these compounds 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 having a carboxyl group can first be reacted with a l-unsubstituted imidazole and the l-imidazolylcarbonyl compound thus forrned can be reàcted with an amine. However, it is also possible for other non-activated esters, such as Cl-C7alkyl esters, of compounds of the formula I to be reacted with amines.

If an aromatic ring contains a hydrogen atom as a substituent, this can be replaced by a halogen atom with the aid of a halogenating agent in the customary manner, for example by bromine using bromine, hypobromic acid, an acyl hypobromite or another organic bromine compound, for example N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridinium perbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin or 2,4l4,~tetrabromo-2,5-cyclohexanedien-1-one, or by chlorine using elemental chlorine, for e ample in a halogenated hydrocarbon, such as chloroform, and while cooling, for example down to about -10C.

If an aromatic ring contains an amino group, this can be diazotized in the customary manner, for example by treatment with a nitrite, for example sodium nitrite, in the presence of a suitable proton acid, for example a mineral acid, the reaction temperature advantageously being kept below about 5C. The diazonium group thus obtainable, which is present in salt form, can be substituted by customary processes, for example as follows:
by the hydroxyl group analogously to phenol boiling in the presence of water, by an -' .. ,,., ". .
. . .:, ,~ ..

::

alkoxy group by treatment with a corresponding alcohol, in which case energy must be supplied; by the fluorine atom analogously to the Schiemann reaction in the case of thermolysis of corresponding diazonium tetrafluoborate; or by chlorine, bromine, iodine or the cyano group analogously to the Sandmeyer reaction by reaction with corresponding Cu(I) salts, initially by cooling, for example to below about 5C, with subsequent heating, for example to about 60 to about 150C

If the compounds of the formula I contain unsaturated radicals, such as lower alkenyl or lower alkynyl groupings, these can be converted into saturated radicals in a manner which is known per se Thus, for example, the hydrogenation of multiple bonds is carried out by catalytic hydrogenation in the presence of hydrogenation catalysts, for which, for example, nickel, such as Raney nickel, and noble metals or derivatives thereof, for example oxides, such as palladium or platinum oxide, which can be absorbed on support materials if appropriate, for example on charcoal or calcium carbonate, are suitable. The hydrogenation can preferably be carried out under pressures between about 1 and about 100 atmospheres at temperatures between about -80 and about +200C, in particular between room temperature and about 100C. 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.

In compounds I in which, for example, one of the radicals Rl, R2, R3 and R4 is halogen, such as chlorine, halogen can furthermore be replaced by reaction with an unsubstituted or substituted amine or an alcohol or mercaptan. It is also possible, to replace a halogen atom Rl, especially a chlorine atom Rl, by reaction with a reagent of the formula Alk3SnR6 (Alk = lower alkyl; R6 = optionally substituted lower alk-1-en-1-yl or optionally substituted lower alk-1-yn-1-yl), for example in the presence of a metal catalyst, such as in the presence of (P(C6Hs)3)2PdCI2, by corresponding lower alk-1-en-1-yl or lower alk-1-yn-1-yl radicals, which can then be further transformed, for example be subjected to ozonolysis or reduction, which lead to the formation of an aldehyde function, which in turn can be transforrned for example into carboxy, or to the formation of the lower alkyl group. Furthermore, it is possible to replace a corresponding chlorine atom R1, for example by reaction with CsF, by a fluorAne atom, which in turn can easily be subjected to a further nucleophilic substitution, for example by cyano.

The invention particularly relates to the processes descAbed in the examples.

: - . ,. .. .-. ~

~ f`~ J

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

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

The compounds I with salt-forming properties, in particulzr basic properties, can be obtained in the free form or in the form of salts, depending on the procedure and reaction conditions.

As a result of the close relationship be~ween the compound I in the free form and in the form of its salts, the free compound I or its salts above and below is also to be understood as meaning in the general sense and appropriately, where relevant, the corresponding salts and the free compound I.

The compounds I, including their salts of salt~forming compounds, can also be obtained in the form of their hydrates and/or include other solvents, for example those used for crystallization The compounds I and their salts can be in the form of one of the possible isomers or as a mixture thereof, depending on the choice of starting substances and procedures, for example 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, depending on the number and the absolute and relative configuration of the asymmetric carbon atoms.

Diastereomer mixtures and racemate mixtures obtained can be resolved into the pure diastereomers or racemates on the basis of the physico-chemical differences of the constituents in a known manner, for example by fractional crystallization. Enantiomer mixtures obtained, such as racemates, can be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent or chromatography on chiral adsorbents, with the aid of suitable microorganisms, by . . ~ : - . .
,:
..' -:

' :

J ~ ~ ~

cleavage with specific immobilized enzymes, via 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 end 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 resoludon of the diastereomer mixture obtained in this manner into the diastereomers, for example on the basis of its different solubilities, from which the desired enantiomers can be liberated by the acdon of suitable agents. The more active enantiomer is advantageously isolated.

The invention also relates to those embodiments of the process in which a compound obtainable as an intermediate at any stage of the process is used as the starting substance and the missing steps are carried out, or a starting substance is used, or in particular formed under the reaction conditions, in the form of its derivative or salt and/or its racemates or antipodes.

Those starting substances and intermediates which lead to the compounds I described above as particularly useful are preferably used in the process according to the present invention. The invention likewise relates to novel starting substances and intermediates for the preparation of the compounds 1, their use and a process for their preparation, the variables Rl, R2, R3 and R4 being as defined for the compounds I.

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

The invendon thus likewise relates to pharmaceutical preparadons containing a compound of the formula I as the active ingredient in the free form or in the form of a pharmaceutically acceptable salt, and to a process for their preparation. These pharmaceudcal preparations are those for enteral, such as oral, and furthermore rectal or parenteral administration to warm-blooded animals, the preparation containing the pharmacological active ingredient by itself or together with customary pharmaceutical auxiliaries. The pharmaceudcal preparations contain, for example, about 0.1 % to 100 %, preferably about 1 % to about 60 %, of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration are, for example, those in dose unit forrns, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These , 7~

are prepared in a manner which is known per se, for example by means of conventional mixing, granulating, sugar-coa~ing, dissolving or Iyophilizing processes. Pharmaceuticai preparations which are suitable for oral administration ean thus be obtained by combining the aetive ingredient with solid earriers, if appropriate granulating the resulting mixture, and processing the mixture or granules, if desired or necessary after addition of suitable adjunets, to tablets or sugar-coated tablet cores.

Suitable carriers are in particular fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, ~or example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, using, for example, maize starch, wheat starch, rice starch or potato stareh, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the abovementioned starches, and also carboxymethyl-starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
Adjuncts are chiefly glidants and lubricants, for example silicie acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glyeol.
Sugar-eoated tablet eores are provided with suitable eoatings whieh ean be resistant to gastrie juiees, using, inter alia, eoneentrated sugar solutions whieh may eontain gum arabie, tale, polyvinylpyrrolidone, polyethylene glyeol and/or titanium dioxide, shellae solutions in suitable organie solvents or solvent mixtures or, for the preparation of eoatings resistant to gastrie juiees, solutions of suitable eellulose preparations, sueh as aeetyleellulose phthalate or hydroxypropylmethyleellulose phthalate. Dyes or pigments ean be added to the tablets or sugar eoatings, for example to identify or indieate different doses of aetive ingredient.

Further pharmaeeutieal preparations for oral administration are dry-filled eapsules of gelatin and also soft, sealed capsules made from gelatin and a plasticizer, such as glycerol or sorbitol. The dry-filled capsules can eontain the aetive ingredient in the form of granules, for example in admixture with fillers, such as laetose, binders, sueh as starehes, and/or lubrieants, sueh as talc or magnesium stearate, and if appropriate stabilizers. In soft eapsules, the aetive ingredient is preferably dissolved or suspended in suitable liquids, such as i atty oils, paraffin oil or liquid polyethylene glyeols, to whieh stabilizers ean also be added.

Suitable pharmaeeutieal preparations for reetal administradon are, for example, suppositories, whieh eonsist of a eombination of the aetive ingredient with a suppository -' ' , , , : :
.: . .: .
.
. .. . ~ . - , . ~

base. Examples of suitable suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. Gelatin rectal capsules, which contain a combination of the active ingredient with a base material, can furtherrnore also be used. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols and paraff~m hydrocarbons.

Suitable forms for parenteral administration are, in parti~ular, 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 corresponding oily injection suspensions, in which case suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, are used, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate also stabilizers.

The dosage of the active ingredient can depend on various factors, such as the mode of administration, the warm-blooded species, age and/or the state of the individual. In the normal case, an approximate daily dose of about 10 mg to about 250 mg is to be estimated for oral administration to a patient weighing about 75 kg.

The following examples illustrate the invention described above; however, they are not intended to limit this in its scope in any way. Temperatures are stated in degrees Celsius.
"THF" means "tetrahydrofuMn".

Example 1: 6-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methyl-pyrimidine (910 mg, 2.54 mmol) and tributyltin azide (1.68 g,5.08 mmol) in o-xylene (30 ml) are stirred under reflux for 24 hours. The reaction mixture is evaporated in vacuo, the residue is treated with CH2CI2/CH30H/NH3 (5:3:1, 50 ml) and the miture is stirred for 30minutes. After renewed evaporation in vacuo, the residue is separated by means of flash chromatography (silica gel 60,40-63 ,~-m, CH2CI2/CH30H/NH3 = 160:10:1). ~(n-Butyl)-4-hydroxy-2-methyl-5-l2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained as an amorphous solid, which crystallizes from ethyl acetate. Melting point: 236C
(decomposition).

The starting material can be prepared, for example, as follows:
a) NaH (~0 % in white oil, 2.4 g,55.1 mmol) is added in portions to a solution of ethyl x ~

3-oxoheptanoate (9.5 g, 55.1 mmol) in absolute THF (100 ml) at room temperature. When the addition has ended, the mixture is stirred for 30 minutes and a solution of 4-bromomethyl-2'-cyano-biphenyl (15.0 g, 55.1 mmol) in absolute tetrahydrofuran (150 ml) is then added dropwise. The reaction mixture is stirred at room temperature for 12 hours and then evaporated in vacuo. The residue is partitioned between ethyl acetate and H2O and the organic phase is washed with H2O and saturated NaCI solution, dried (Na2S04) and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 ~Im, hexane/ethyl acetate = g:l) gives ethyl 2-(2'-cyanobiphenyl-4ylmethyl)-3-oxo-heptanoate as an oil, which is further processed directly.

b) Acetamidine-HCI (3.64 g, 38.5 mmol) is added to a solution of sodium methanolate (3.22 g,57.8 mmol) in absolute methano; (45 ml) at room temperature. After 10 minutes, a solution of ethyl 2-(2'-cyanobiphenyl-4ylmethyl)-3-oxo-heptanoate (7.0 g, 19.26 mmol) in absolute methanol (30 ml) is added dropwise. The yellow suspension is stirred at 50C for 24 hours and then evaporated in vacuo. The residue is suspended in H2O and dle suspension is acidifled to pH S with lN hydrochlric acid and then extracted with ethyl acetate. The organic phase is washed with saturated NaCI solution, dried (Na2SO4) and evaporatcd. Flash chromatography (silica gel 60,40-63 ,um, CH2CI21CH30H = 98:2) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methyl-pyrimidine, which is crystallized from diethyl ether and further processed direcdy.

Example 2 Starting from 5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methyl-6-(n-propyl)-pyrimidine and tributyltin azide, 4-hydroxy-2-methyl-6-(n-propyl)-

5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. White crystals from ethyl acetate. Melting point: 206C
(decomposition) .

The starting material can be prepared, for example, as follows.
a) Alkylation of ethyl 3-oxohexanoate with 4-bromomethyl-2'-cyano-biphenyl in the manner described in Example la) gives ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo-hexanoate, which is purified by flash chromatography (silica gel 60, 40-63 ~,-m, hexane/ethyl acetate = 4:1), as an oil. This is further processed directly.

b) Reaction of ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo-hexanoate with acetamidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives 5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methyl-6-(n-propyl)-- .
.
.

.: , ~ ù ~

pyrimidine. This is further processed directly.

Exam~le 3: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-(n-propyl)-pyrimidine and tributyltin azide, 6-(n-butyl)-4-hydroxy-2-(n-propyl)-5-[2'-(lHI-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. White crystals from isopropanol/diethyl ether. Melting point:
208C-210C.

The starting material can be prepared for example, as follows.
a) Reaction of ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo-heptanoate with butyramidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-(n-propyl)-pyrimidine, which is purified by flash chromatography (silica gel 60,40-63 ~lm, CH2C12/CH30H = 98.2). This is further processed directly.

Example 4: Starting from 5-(2'-cyanobiphenyl-4-ylmethyl)-2,6-di-(n-buty2)-4-hydroxy-pyrimidine and tributyltin azide, 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-S-yl)-biphenyl-4- ylmethyl]-pyrimidine is obtainedin the manner described in Example 1. White crystals from ethyl acetate. Melting point: 212C-213C, The starting material can be prepared, for example, as follows:
a) Reaction of ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo-heptanoate with valeramidine HCI and sodium methanolate in methanol in the manner described in Example lb) gives 5-(2'-cyanobiphenyl-4-ylmethyl)-2,6-di-(n-butyl)-4-hydroxy-pyrimidine, which is purified by flash chromatography (silica gel 60, 40-63 ~Im,CH2CI2/CH30H = 98:2) This is further processed directly.

Example S Starting from ~(n-butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine and tributyltin azide, 6-(n-butyl)-4-chlor-2-methyl-5-[2'-(lH-tetrazol-S-yl)-biphenyl-4-ylmethyl]-pyrimidine is obtained as an amorphous solidin the manner described in Example 1. Melting point: 120C-122C.

The starting material can be prepared, for example, as follows:
a) N,N-Dimethylaniline (1.67 ml, 13.15 mmol) and then 6-(n-butyl)-4-hydroxy-2-methyl-5-(2'-cyanobiphenyl-4-ylmethyl)-pyrimidine (4 7 g, 13 15 mmol) are metered into 11 ml of POCI3at 0C, while stirring The reaction mixture is heated up slowly and is stirred .

3 ~

under retlux for 1.5 hours. The reaction mixture is then poured onto water having a temperature of 20-25C and left to stand for 30 minutes. It is then extracted with diethyl ether. The organic phase is dried (Na2SO4) and evaporated and the residue is purified by means of flash chromatography (silica gel 60,40-63 ~,~m, CH2CI2). 6-(n-Butyl)-4-chlor-5 (2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine, which is further processed directly, is thus obtained.

Example 6: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxy-2-methyl-pyrimidine and tributyltin azide, 6-(n-butyl)-4-methoxy-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. White crystals from ethyl acetate/diethyl ether. Melting point: 113C-115C.

The starting material can be prepared, for example, as follows:
a) 6-(n-Butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl~-2-methyl-pyrimidine (~.0 g, 2.66 mmol) in absolute methanol (10 ml) is added dropwise to a solution of sodium methanolate (355 mg, 6.38 mmol) in absolute methanol (5 ml). The reaction mixture is stirred at room temperature for 24 hours and then evaporated in vacuo. The residue is partitioned between ethyl acetate and H2O and the organic phase is washed with H2O and saturated NaCl solution, dried (Na2SO4) and evapora~ed in vacuo. The crude product is purifled by means of flash chroma~ography (silica gel 60,40-63 ~m, CH2CI2/CH30H =
98:2). 6-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxy-2-methyl-pyrimidine, which is further processed directly, is thus obtained.

Example 7: Starting from ~tn-butyl)-5-(2'-cyanobiphenyl-4-ylmethy1)-4-(2-methoxy-ethoxy)-2-methyl-pyrimidine and tributyltin azide, ~(n-butyl)-4-(2-methoxyethoxy)-2-methyl--5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. White crystals from ethyl acetate/hexane. Melting point:
133C-135C.

The starting material can be prepared for example, as follows:
a) Sodium (122 mg, 5.32 mmol) is dissolved in 10 ml of 2-methoxyethanol at room temperature, and a solution of 6-(n-butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine (1.0 g, 2.66 mmol) in 2-methoxyethanol (5 ml) is then added dropwise. The reaction mixture is stirred at room temperature for 24 hours and then evaporated in vacuo. The residue is partitioned between ethyl acetate and H2O and the organic phase is washed with H2O and saturated NaCI solution, dried (Na2SO4) and ' evaporated in vacuo. The crude product is purified by means of flash chromatography (silica gel 60, 40-63 ~.m, CH2CIJCH30H = 98:2). 6-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-(2-methoxyethoxy)-2-methyl-pyrimidine, which is further processed directly, is thus obtained.

ExamPle 8: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-dimethylamino-2-methyl-pyrimidine and tributyltin azide, 6-(n-butyl)-4-dimethylamino-2-methyl--5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. White crystals from acetone. Melting point: 195C-197C.
The starting material can be prepared for example, as follows:
a) Dimethylamine (33 % in ethanol, 1.9 ml) is added to a solution of 6-(n-butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl)-2-me~hyl-pyrimidine (1.0 g, 2.66 mmol) in ethanol (10 ml). The reaction mixture is stirred under reflux for 24 hours and then evaporated in vacuo. The residue is partitioned between ethy1 acetate and H2O and the organic phase is washed with H2O and saturated NaCl solution, dried (Na2SO4) andevaporated in vacuo. The crude product is purified by means of flash chromatography (silica gel 60, 40-63 ,um, CH2CI2/CH30H = 98:2). 6-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-dimethylamino-2-methyl-pyrimidine, which is further processed directly, is thus obtained.

Example 9: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-isopropyl-pyrimidine and tributyltin azide, 6-(n-butyl)-4-hydroxy-2-isopropyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. Melting point: 234-236C (from isopropanoUdiethyl ether,decomposition).

The starting material can be prepared, for example, as follows:
a) Reaction of ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3-ox~heptanoate with isobutyramidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-isopropyl-pyrimidine, which is purifled by flash chromatography (silica gel 60, 40-63 llm,CH2CI2/CH3OH = 98:2) and further processed directly.

Example 10: 2.7 ml of a IN solution of KOH in ethanol are added to a suspension of 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine (1.2 g, 2.7 mmol) in 60 ml of ethanol and the solution formed is evaporated in vacuo.
After addition of isopropanol, crystallization starts. The crystals are filtered off and dried at 100C i,n vacuo. The potassium salt of 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(lH-teerazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine is thus obtained. Melting point: 276-278C
(decomposition) .

Example 11: Starting from 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine and lN NaOH in ethanol, the sodium salt of 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, which is crystallized from acetonitrile, is obtained in the manner described in Example 10.
Melting point: 333-335C (decomposition).

Example 12: Starting from 6-(but-1-en-4-yl)-2-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-pyrimidine and tributyltin azide, 6-(but-1-en-4-yl)-2-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. Melting point: 203-205C (from acetic acid/H20;
decomposition).

The starting material can be prepared, for example, as follows:
a) Alkylation of ethyl 3-oxohept-6-enoate with 4-bromomethyl-2'-cyano-biphenyl in the manner described in Example Ia) gives ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo-hept-6-enoate which is purified by flash chromatography (silica gel 60,40-63 ~m, hexane/ethyl acetate = 9:1) and further processed direcdy.

b) Reaction of ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3Oxo-hept-6-enoate with valeramidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives ~(but-l-en-4-yl)-2-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-pyrimidine, which is purified by flash chromatography (silica gel 60j 40-63 ~Im, ethyl acetate/hexane = 1:1) and further processed direcdy.

Example 13: Starting from 4-amino-6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl~
2-methyl-pyrimidine and tributyltin azide, 4-amino-6-(n-butyl)-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the rnanner described in Example 1. Melting point: 177-179C (from methanol; decomposition).

The starting material can be prepared, for example, as follows:

~ ~ ~7 ~

a) 6-~n-Butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine (0.2 g, 0.53 mmol) and 2 ml of NH3 ir. 10 ml of ethanol are kept in a bomb tube at 120C for 4 days. After evaporation in vacuo, the residue is purified by means of flash chromatography (silica gel 60, 40-63 ~m, CH2CI2/CH30H = 95:5). 4-Amino-6-(n-butyl)-5-(2'-cyano-biphenyl-4-ylmethyl)-2-methyl-pyrimidine, which is further processed directly, is thus obtained.

Example 14: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-4-methylthio-pyrimidine and tributyltin azide, 6-(n-butyl)-2-methyl-4-methylthi~-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. Melting point: 176-178C (from ethyl acetate; decomposition).

The starting material can be prepared, for example, as follows:
a) 6-(n-Butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine (1.0 g, 2.66 mmol) and sodium methanethiolate (0.21 g, 2.92 mmol) are stirred in 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone at room temperature for 6 hours. The reaction mixture is poured onto H2O and extracted with ethyl acetate. The organic phase is washed thoroughly with H2O, dried (Na2SO4) and evaporated in vacuo. Flash chromato~raphy (silica gel 60,40-63 ~, m, hexane/ethyl acetate = 4: 1) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-4-methylthio-pyrimidine, which is further processed directly.

Example 15: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-ethyl-4-hydroxy-pyrimidine and tributyltin azide, 6-(n-butyl)-2-ethyl-4-hydroxy-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. Melting point: 235-237C (from isopropanol; decomposition).

The starting material can be prepared, for example, as follows:
a) Reaction of ethyl 2-(2'-cyanobiphenyl-4-ylmethyl~3-oxo-heptanoate with propionarnidine-HCI and sodium methanolate in methanol in the manner described in Exarnple lb) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-ethyl-4-hydroxy-pyrimidine, which is purified by flash chromatography (silica gel 60,40-63 ~m, CH2Cl2/CH3OH = 98.2) and further processed directly.

Example 16: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-(2-hydroxy-ethoxy)-2-methyl-pyrimidine and tributyltin azide, 6-(n-butyl)-4-(2-hydroxyethoxy)-3 ~

2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. Melting point: 16~-170C (from ethyl acetate;
decomposition).

The starting material can be prepared, for example, as follows:
a) 6-(n-Butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidin (1.0 g, 2.6 mmol) is added to a solution of sodium (0.12 g, 5.3 mmol) in 20 ml of ethylene glycol and the reaction mixture is stirred at 100C for 3 hours. After evaporation in vacuo, the residue is partitioned between ethyl acetate and H2O and the organic phase is dried with Na2SO4 and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 ~1m, CH2CI2/CH30H
= 95:5) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-(2-hydroxyethoxy)-2-methyl-pyrimidine, which is further processed directly.

Exam~le 17: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-ethoxycarbonylmethoxy-2-methyl-pyrimidine and tributyltin azide, 6-(n-butyl)-4-ethoxycarbonylmethoxy-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained as an amorphous solid in the manner described in Example 1.

The starting material can be prepared, for example, as follows:
a) NaH (0.17 g,5.6 mmol, 80 % in white oil) is added to a solution of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-yln1ethyl)-4-hydroxy-2-methyl-pyrimidine (2.0 g,5.6 mmol) in S0 ml of dimethylformamide and the reaction mixture is stirred at room temperature for 30 minutes. Ethyl bromoacetate (0.81 ml,7.3 mmol) is then added. After 3 hours, the mixture is evaporated in vacuo and the residue is partitioned between ethyl acetate and H2O. The organic phase is dried with Na2SO4 and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 ~,lm, hexane/ethyl acetate = 4:1) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-ethoxycarbonylmethoxy-2-methyl-pyrimidine, which is further processed directly.

ExamPle 18: Starting from 5-[3-bromo-2'-cyano-biphenyl-4-ylmethyl]-2,~di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, 5-~3-bromo-2'-(lH-tetrazol-S-yl)-biphenyl-4-ylmethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine is obtained in the manner described in Example 1. Melting point: 222-224C (from isopropanoVdiethyl ether,decomposition).

The starting material can be prepared, for example, as follows:

s 3 a) 4-Methyl-2'-cyano-biphenyl is added to a suspension of AICI3 (21.0 g, 0.157 mol) in tetrachloroethane. The mixture is heated to 60C, while stirring. A solution of bromine (20.7 g, 0.13 mol) in 100 ml of tetrachloroethane is added dropwise to the resulting ~olution at 60C and the reaction mixture is stirred for 24 hours. After addition of a further

6.2 g of AICI3 and heating to 70C, no further educt can be detected in the thin layer chromatogram (toluene). The reaction mixture is then broken down with 200 ml of concentrated HCI, while cooling with ice, and the organic phase is separated off and evaporated in vacuo. The residue is dissolved in ethyl acetate and ~,he solution is washed with HCI and sodium carbonate solution, dried (MgSO4) and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 ~lm, hexane/ethyl acetate = 4:1) gives 3-bromo-2'-cyano-4-methyl-biphenyl which is recrystalliæd from cyclohexane. Melting point:
104-106C.

b) A solution of bromine (5.6 g, 0.035 mol) in 20 ml of tetrachloroethane is added dropwise to a solution of 3-bromo-2'-cyano-4-methyl-biphenyl (8.9 g, 0.033 mol) in 900 ml of tetrachloroethane, after addition of benzoyl peroxide (0.1 g) and under UVirradiation at 100-110C. After 30 minutes, the reaction mixture is cooled and evaporated in vacuo. Recrystallization of the residue from ethyl acetate gives 3-bromo-4-bromo-methyl-2'-cyano-biphenyl. Melting point: 152-153C.

c) Alkylation of ethyl 3-oxoheptanoate with 3-bromo-4-bromomethyl-2'-cyano-biphenyl in the manner describe in Example la) gives ethyl 2-(3-bromo-2'-cyano-biphenyl-4-yl-methyl)-3-oxo-heptanoate, which is purified by means of flash chromatography (silica gel 60, 40-63 ~m, hexane/ethyl acetate = 9:1) and further processed directly.

d) Reaction of ethyl 2-(3-bromo-2'-cyano-biphenyl4-ylmethyl)-3-oxo-heptanoate with valeramidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives 5-[3-bromo-2'-cyano-biphenyl-4-ylmethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine, which is purified by means of flash chromatography (silica gel 60, 40-63 ~lm, CH2CI2/CH30H = 98:2) and further processed directly.

Example 19: Starting from 5-(3'-cyanobiphenyl-4-ylmethyl)-2,6-di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, 2,6-di-(n-butyl)-4-hydroxy-5-[3'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-pyrimidine is obtained as an amorphous solid in the manner described in Example 1.

r ~

The starting material can be prepared, for example, as follows:
a) 4-Methylphenyl-trimethyl-ti n (5.9 g, 20 mmol), 3-iodobenzonitrile (S.0 g, 22 mmol) and tetrakis(triphenylphosphane)palladium (1.16 g, 1 mmol) in 60 ml of o-xylene are stirred under reflux for 12 hours. After cooling to room temperature, the black suspension is filtered and the filtrate is evaporated in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with a solution of potassium fluoride in H2O (10 %), dried with Na2SO4 and evaporated in vacuo. Flash chromatography (silica gel 60,40-63 ,~n, hexane/ethyl acetate = 9:1) gives 3'-cyano-4-methyl-biphenyl, which is furtherprocessed directly.

b) 3'-cyano-4-methyl-biphenyl (1.8 g, 9.3 mmol), N-bromosuccinimide (1.66 g, 9.3 mmol) and a,c~'-azoisobutyronitrile (20 mg) in 30 ml of tetrachloromethane are stirred under reflux for 6 hours. After evaporating the reaction mixture in vacuo, the residue is dissolved in ethyl acetate and the solution is washed with H2O, dried (Na2SO4) and evaporated in vacuo. Crystallization from ethyl acetatelhexane gives 4-bromomethyl-3'-cyano-biphenyl.
Meltingpoint: 106-108C.

c) Alkylation of ethyl 3-oxoheptanoate with 4-bromomethyl-3t-cyano-biphenyl in the manner described in Example la) gives ethyl 2-(3'-cyanobiphenyl-4-ylmethyl)-3-oxo-heptanoate, which is purified by means of flash chromatography (silica gel 60,40-63 -m, hex~ne/ethyl acetate = 9:1) and further processed directly.

d) Reaction of ethyl 2-(3'-cyanobiphenyl-4-ylmethyl)-3-oxo-heptanoate with valeramidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives 5-(3'-cyanobiphenyl-4-ylmethyl)-2,6-di-(n-butyl)-4-hydroxy-pyrimidine, which is purifled by means of flash chromatography (silica gel 60,40-63 ~Im, CH2CI2/CH3OH = 98:2) and further processed direcdy.

Example 20: Starting from 5-(2'-cyanobiphenyl-3-ylmethyl)-2,6-di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, 2,6-di-(n-butyl)-4-hydroxy-5-12'-(lH-tetrazol-S-yl)-biphenyl-3-ylmethyl]-pyrimidine is obtained in the manner described in Example 1.
Melting point: 185-187C (from isopropanol/diethyl ether, decomposition).

The starting material can ~e prepared, for example, as follows:
a) Reaction of 3-methylphenyl-trimethyl-tin with 2-iodobenzonitrile in the manner described in Example l9a) gives 2'-cyano-3-methyl-biphenyl, which is purified by means - ' : ' . .

J .''! ~ ,~

of flash chromatography (silica gel 60, 40-63 ~m, hexane/ethyl aceiate = 9:1) and further processed directly.

b) Reactivn of 2'-cyano-3-methyl-biphenyl with N-bromosuccinimide in the manner described in Example l9b) gives 3-bromomethyl-2'-cyano-biphenyl, which is purified by means of column chromatography (silica gel 60, 40-63 ~m, hexane/ethyl acetate = 8:1) and further processed directly.

c) Alkylation of ethyl 3-oxoheptanoate with 3-bromomethyl-2'-cyano-biphenyl in the manner described in Example la) gives ethyl 2-(2'-cyanobiphenyl-3-ylmethyl)-3-oxo-heptanoate, which is purified by means of flash chromatography (silica gel 60, 40-63 ~m, hexane/ethyl acetate = 9:1) and further processed directly.

d) Reaction of ethyl 2-(2'-cyanobiphenyl-3-ylmethyl)-3-oxo-heptanoate with valeramidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives 5-(2'-cyanobiphenyl-3-ylmethyl)-2,6-di-(n-butyl)-4-hydroxy-pyrimidine, which is purified by means of column chromatography (silica gel 60,40-63 llm, CH2C12/CH30H = 98:2) and further processed directly.

ExamDle 21: Starting from 5-[2-(2'-cyanobiphenyl-4-yl)ethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, 2,6-di-(n-butyl)-4-hydroxy-5-[2-(2'-(lH-tetrazol-S-yl)biphenyl-4-yl)ethyl]-pyrimidine is obtained in the manner described in Example 1. Melting point: 217-218C (from isopropanoVethyl acetate, decomposition).

The starting material can be prepared, for example, as follows:
a) A solution of lithium bis(trimethylsilyl)-amide in tetrahydrofuran (1 M, 7.5 ml, 7.5 mmol) is added dropwise to a solution of methoxymethyl-triphenyl-phosphonium chloride (2.57 g,7.5 mmol) in 25 ml of anhydrous tetrahydrofuran at room temperature. After 30 minutes, a solution of 2'-cyano-4-formyl-biphenyl (1.04 g, 5 mmol) in 30 ml of tetrahydrofuran is added dropwise, while cooling with ice, and the reaction mixture is then stirred at room temperature for 30 minutes. The reaction mixture is poured into 150 ml of ice-cold saturated ammonium chloride solution and extracted with diethyl ether. The organic phase is washed with H2O, dried (Na2SO4) and evaporated in vacuo. The residue is purified by means of flash chromatography (silica gel 60, 40-63 ~m, hexane/ethyl acetate = 4: 1). 2'-Cyano-4-(2-methoxyethenyl)-biphenyl, which is further processed directly, îs thus obtained.

. , ~ ,.... .

c~ r~

b) 2'-Cya~o-4-(2-methoxyethenyl)-biphenyl (8.2 g, 34.9 mmol) is suspended in 120 ml of formic acxd (95 %) and the suspension is stirred at room temperature for 30 minutes. The solution formed is diluted with 1.5 1 of H2O and the mixture is extracted with diethyl ether. The organic phase is washed with saturated NaHCO3 solution, dried (MgSO4) and evaporated in vacuo. The residue is purified by means of flash chromatography (silica gel 60, 40-63 ~1m, hexane/ethyl acetate = 2:1). 2'-Cyano-4-(2-oxoethyl)-biphenyl, which is further processed directly, is thus obtained.

c) NaBH4 (0.86 g, 22.62 mmol) is added in portions to a solution of 2'-Cyano-4-(2-oxoethyl)-biphenyl (2.5 g, 11.3 mmol) in 50 ml of methanol, while cooling with ice and stirring. After stirring at 0C for 30 minutes, the reaction mixture is evaporated in vacuo and the residue is partitioned between diethyl ether and H2O. The organic phase is washed with H20, dried (Na2SO4) and evaporated in vacuo. Elash chromatography (silica gel 60,40-63 ,um, hexane/ethyl acetate = 1:1) gives 2'-Cyano-4-(2-hydroxyethyl)-biphenyl, which is funher processed directly.

d) N-Bromosuccinimide (1.96 g, 11 mmol) is added to a solution of 2'-Cyano-4-(2-hydroxyethyl)-biphenyl (2.23 g, 10 mmol) and triphenylphosphane (2.9 g, 11 mmol) in 50 ml of CH2C12 at 0C, while stirring. The reaction mixture is stirred at room temperature for 12 hours ahd then evaporated in vacuo. Flash chromatography (silica gel 60, 40-63,um, hexane/ethyl acetate = 4:1) gives 4-(2-bromoethyl)-2'-cyano-biphenyl, which is further processed directly.

e) ALkylation of ethyl 3-oxoheptanoate with 4-(2-bromoethyl)-2'-cyano-biphenyl in the manner described in Example la) gives ethyl 2-[2-(2'-cyanobiphenyl-4-yl)ethyl]-3-oxo-heptanoate, which is purified by means of flash chromatography (silica gel 60, 40-631 m, hexane/ethyl acetate = 6: l) and further processed directly.

f) Reaction of ethyl 2-[2-(2'-cyanobiphenyl-4-yl)ethyl]-3-oxo-heptanoate with valeramidine-HCI and sodium methanolate in methanol in the manner described in Example lb) gives 5-[2-(2'-cyanobiphenyl-4-yl)ethyl]-2,~di-(n-butyl)-4-hydroxy-pyrimidine, which is purified by means of flash chromatography (silica gel 60, 40-63 ~Im, CH2Cl2/CH30H = 95:5). Melting point: 166-167C.
Example 22: Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-' ... ~

: ~ .

, 3 ~

pyrimidine and tributyltin azide, 6-(n-butyl)-4-hydroxy-5-L2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained in the manner described in Example 1. Melting point:
215-219C (from ethanol; decomposition).

The starting material can be prepared, for example, as follows:
Reaction of ethyl 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo-heptanoate with forrnamidine-HCl and sodium methanolate in methanol in the manner described in Example lb) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-pyrimidine.
Melting point: 169-171C (from ethyl acetate).

Example 23: 6-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxycarbonyl-2-methyl-pyrimidine (3.0 g, 7.5 mmol) and tributyltin azide (12.46 g,37.5 mmol) in o-xylene (75 ml) are stirred at 120C for 48 hours. After evaporation of the reaction mixture in vacuo, the residue is dissolved in diethyl ether, and hydrogen chloride is passed into the solution.
The precipitate formed is filtered off and then dissolved in lN potassium hydroxide solution. The solution is extracted with diethyl ether, acidified with 2N hydrochloric acid and then extracted with ethyl acetate. The organic phase is washed with saturated NaCI
solution, dried (Na2SO4) and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 ,~.m, CH2CI2/CH30~1/NH3 = 40:10:1) gives 6-(n-butyl)-4-carboxy-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine [melting point: 120- 122 (from isopropanol/water)] .

The starting material can be prepared, for example, as follows:
a) 6-(n-Butyl)-4-chlor-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine (16.0 g, 42.6 mmol), tributyl-vinyl-tin (14.9 ml,51.1 mmol) and bis(triphenylphosphane)palladium(II)-dichloride (0.57 g, 0.82 mmol) in dimethylformamide (160 ml) are sdrred at 90C for 2 hours. After cooling to room temperature, the reacdon mixture is diluted with H2O and extracted with diethyl ether. The organic phase is washed 3 times with potassium fluoride solution (10 %), dried (Na2SO4) and evaporated in vacuo. The residue is purified by means of flash chromatography (silica gel 60,40-63 ~,m, hexane/ethyl acetate = 3:1) and the product is then recrystallized from diisopropyl ether/hexane. 6-(n-Butyl)-5-(2'-cyano-biphenyl-4-ylmethyl)-2-methyl-4-vinyl-pyrimidine is thus obtained (melting point:
115-117).

b) Ozone is passed into a solution of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-4-vinyl-pyrimidine (14.6 g,39.7 mmol) in CH2CI2 (275 ml) and methanol (275 .

, ml) at -70'DC until a blue coloration persists. The reaction mixture is stirred at -70C for a further 30 minutes and argon is then passed through until the mixture becomes colourless.
Dimethyl sulfide (29 ml, 0.4 mol) and NaHCO3 (0.5 g) are then added. The cooling bath is removed and the reaction mixture is stirred at room temperature for 12 hours. Evaporation of the reaction mixture in vacuo and flash chromatography of the residue (silica gel 60, 40-631lm, hexane/ethyl acetate = 4:1) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-formyl-2-methyl-pyrimidine ~melting point: 114- 115 (from diisopropyl ether)].

c) Sodium cyanide (5.81 g,0.12 mol), activated manganese dioxide (0.474 mol) and acetic acid (2.4 ml) are added to a solution of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-formyl-2-methyl-pyrimidine (8.8 g, 0.024 mol) in methanol (135 ml) and the suspension being formed is stirred at room temperature for 12 hours. After filtration of the reaction mixture, the filtrate is evaporated in vacuo and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase is washed with saturated NaCI
solution, dried (Na2SO4) and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 ~m, hexane/ethyl acetate = 2:1) gives 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxycarbonyl-2-methyl-pyrimidin, which is further processed directly.

Example 24: The following can be prepared in an analogous manner as described in one of the above examples:
6-(n-Butyl)-4-ethyl-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-4-ethoxycarbonyl-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-2-(tert.-butyl)-4-hydroxy-5-[2' -( lH-tetrazol-5-yl)biphenyl-4-ylmethyll-pyrimidine, 6-(n-Butyl~-4-mercapto-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-4-methansulfonyl-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, ~(n-Butyl)-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine-4-sulfonic acid, 6-(n-Butyl)-2-methyl-4-sulfamoyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-2-methyl-4-methylamino-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrlmidine?6-(n-Butyl)-4-methansulfonylamino-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, 4-Acetylamino-6-(n-butyl)-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-4-ethoxycarbonylmethyl-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-4-carboxymethyl-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-4-hydroxymethyl-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-4-methoxymethyl-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, ~(n-Butyl)-2,4-dimethyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine,6-~n-Butyl)-2-methyl-5-~2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine-4-phosphonic acid, 6-(n-Butyl)-2-methyl-4-(lH-tetrazol-S-yl)-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, 4-Hydroxy-2-methyl-5-[2'-( lH-tetrazol-S-yl)biphenyl-4-yloxy]-pyrimidine, 4-Hydroxy-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylthio]-pyrimidine, 6-(n-Butyl)-4-carboxymethoxy-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, 6-(n-Butyl)-4-ethoxycarbonylmethylamino-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine, and 6-(n-Butyl)-4-carboxymethylamino-2-methyl-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-pyrimidine.

Example 25: Tablets each containing S0 mg of active ingredient, for example 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, are prepared as follows:

Composition (for 10,000 tablets) Active ingredient S00.0 g Lactose 500-0 g Potato starch 352.0 g Gelatin 8.0 g Talc 60.0 g Magnesium stearate 10.0 g J ;'s' Silicon dioxide (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 remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silicon dioxide are added and the mixture is compressed to tablets which weigh 145.0 mg and contain 50.0 mg of active ingredient and if desired can be provided with dividing grooves for finer adjustment of the dosage.

Example 26: Shellac-coated tablets each containing 100 mg of active ingredient, for example 2,6-di-(n-butyl)-4-hydroxy-~-~2'-(lH-tetrazol-5-yl)biphenyl-4-yl-methyl]-pyrimidine, can be prepared as follows:

Com~osition for (1000 tablets):
Active ingredient 100.00 g Lactose 100.00 g Maize starch 70.00 g Talc 8.50 g Calcium stearate 1.50 g Hydroxypropylmethylcellulose 2.36 g Shellac 0.64 g Water q.s.
Methylene chloride q.s.

The active ingredient, the lactose and 40 g of the maize starch are mixed and the mixture is moistened with a paste prepared from 15 g of maize starch and water (while heating) and granulated. The granules are dried and the remainder of the maize starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to tablets (weight: 280 mg) and these are coated with a solution of the hydroxypropylmethyl-cellulose and the shellac methylene chloride (final weight of the shellac-coated tablet:
283 mg).

Example 27: Other tablets and shellac-coated tablets containing a different compound of the formula I or a tautomer andJor a pharmaceutically acceptable salt of a compound of the formula I, for example according to one of Examples 1 to 24, can be prepared in a manner 3 ~ :

analogous to that described in Examples 25 and 26.

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. . .
., " ,

Claims (71)

WHAT IS CLAIMED IS:

1. A compound of the formula (I), in which one of the radicals R1, R2 and R3 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl, or a cycloaliphatic or araliphatic hydrocarbon radical, the second of the radicals R1, R2 and R3 and the radical R4 in each case independently of one another are halogen, acyl, an aromatic hydrocarbon radical, free, esterified or amidated carboxyl, cyano, SO3H, PO2H2, PO3H2, 5-tetrazolyl, unsubstituted or substituted sulfamoyl, acylamino or -Z1-R', in which Z1 is a bond or is O, S(O)m or N(R),R' is hydrogen or an aliphatic hydrocarbon radical, which is uninterrupted or interrupted by O or (SO)m and unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or free, esterified or amidated carboxyl, R is hydrogen or an aliphatic hydrocarbon radical and m in each case is 0, 1 or 2, and the third of the radicals R1, R2 and R3 is the group of the formula (Ia) in which Z2 is alkylene, O, S(O)m or N(R), R5 is carboxyl, halogenoalkanesulfonylamino, SO3H,PO2H2,PO3H2 or 5-tetrazolyl, R is hydrogen or an aliphatic hydrocarbon radical, m is 0, 1 or 2 and the rings A and B independently of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical, which is uninterrupted or interrupted by O and unsubstituted or substituted by hydroxyl or halogen, hydroxyl which is free or etherified by an aliphatic alcohol, carboxyl which is free, esterified or amidated or 5-tetrazolyl, and where appropriate a tautomer thereof, in each case in free form or in salt form.

2. A compound according to claim 1 of the formula I, in which one of the radicals R1, R2 and R3 is lower alkyl, lower alkenyl or lower alkynyl, in each case unsubstituted or substituted by halogen or hydroxyl, in each case 3- to 7-membered cycloalkyl or cycloalkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, the second of the radicals R1, R2 and R3 and the radical R4 in each case independently of one another is halogen, lower alkanol, unsubstituted or substituted phenyl, carboxyl, which is free or 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 unsubstituted, mono- or disubstituted by, independently of one another, lower alkyl, lower alkenyl, lower alkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or is disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, cyano, SO3H, PO7H2, PO3H2, 5-tetrazolyl, sulfamoyl, lower alkanesulfamoyl, di-lower alkanesulfamoyl, lower alkanoylamino,unsubstituted or substituted benzoylamino, lower alkanesulfonylamino, halogeno-lower alkanesulfonylamino, unsubstituted or substituted benzenesulfonylamino or -Zl-R', in which Zl is a bond or O, S(O)m or N(R), 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 alkyl-thio-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, in each case unsubstituted or substituted by hydroxyl, halogen, amino, lower alkyleneamino, lower alkylenoxy-lower alkyleneamino, lower alkylamino, lower alkenylamino, lower alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower aIkynyl, lower alkoxy-lower aIkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower aLkynyl, or carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independendy of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl and m is 0, 1 or 2, and the third of the radicals R1, R2 and R3 is the group of the formula Ia, in which Z2 is methylene, lower alkylene, O, S(O)m or N(R), R5 is carboxyl, halogenoalkanesulfonylamino, S03H, P02H2, P03H2 or 5-tetrazolyl, R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl, m is 0, 1 or 2 and 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 is unsubstituted or substituted by hydroxyl or halogen, by hydroxyl, by lower alkoxy, by lower alkenyloxy, by carboxyl which is free or 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, bycarbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independently of on another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, or by 5-tetrazolyl, the aromatic substituents in each case being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl, and where appropriate a tautomer thereof, in each case in free form or in salt form.

3. A compound according to claim 1 of the formula I, in which R1 is halogen, carboxyl, which is free or esterified by an alcohol which is derived from lower alkyl or lower alkoxy-lower alkyl, carbamoyl, cyano, PO3H2, 5-tetrazolyl, lower-alkanesulfamoyl, lower-alkanoylamino, lower-alkanesulfonylamino or -Zl-R', in which Zl is a bond or is 0, S(O)m or N(R), R' is hydrogen or lower alkyl or lower alkoxy-lower alkyl, in each case unsubstituted or substituted by carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl or hydroxyl, R is hydrogen or lower alkyl and m is 0, 1 or 2, R2 is the group of the formula Ia, in which Z2 is methylene, lower alkylene, O, S(O)m or N(R), R is hydrogen or lower alkyl, m is 0, 1 or 2, R5 is carboxyl or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl or 5-tetrazolyl, R3 is lower alkyl or lower alkenyl, unsubstituted or substituted by hydroxyl or halogen, and R4 is lower alkyl, and where appropriate a tautomer thereof, in each case in free form or in salt form.

4. A compound according to claim 1 of the formula I, in which R1 is halogen, in particular having an atomic number of not more than 35, carboxyl, lower alkoxycarbonyl, PO3H2, 5-tetrazolyl, lower alkanoylamino, lower alkanesulfonylamino, hydrogen, lower alkyl, lower alkoxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl,hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, hydroxyl, lower alkoxy, lower alkoxy-lower alkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, hydroxy-lower alkoxy, mercapto, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, lower alkylamino or di-lower alkylamino R2 is the group of the formula Ia, in which Z2 is methylene or lower alkylene, O or S(O)m, m is 0, 1 or 2, R5 is carboxyl or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by lower alkyl, halogen, in particular having an atomic number of not more than 35, or lower alkoxy, R3 is C1-C7alkyl and R4 is lower alkyl, part structures designated "lower" in each case in particular containing not more than 7, preferably not more than 4, C atoms, and where appropriate a tautomer thereof, in each case in free form or in salt form.

5. A compound according to any one of claims 1 to 4 of the formula I, in which R2 is the group of the formula (Ib) and where appropriate a tautomer thereof, in each case in free form or in salt form.

6. A compound according to claim 1 of the formula I, in which R1 is halogen having an atomic number of not more than 35, hydroxyl, lower alkoxy having not more than 4 C
atoms, lower alkoxy-lower alkoxy having not more than 4 C atoms in each lower alkoxy moiety, hydroxy-lower alkoxy having not more than 4 C atoms, lower alkylamino having not more than 4 C atoms or di-lower alkylamino having not more than 4 C atoms in each lower alkyl moiety, R2 is the group of the formula Ib, in which Z2 is methylene, R5 is carboxyl or, in particular, 5-tetrazolyl and the rings A and B are unsubstituted, R3 is C1-C7alkyl, in particular C1-C5alkyl and R4 is lower alkyl having not more than 4 C
atoms, and where appropriate a tautomer thereof, in each case in free form or in salt form.

7. A compound according to claim 1 of the formula I, in which R1 is hydroxyl, R2 is the group of the formula Ib, in which Z2 is methylene, R5 is 5-tetrazolyl and the rings A and B
are unsubstituted, R3 is C1-C5alkyl and R4 is lower alkyl having not more than 4 C atoms, and where appropriate a tautomer thereof, in each case in free form or in salt form.

8. 6-(n-Butyl)-4-hydroxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

9. 4-Hydroxy-2-methyl-6-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

10. 6-(n-Butyl)-4-hydroxy-2-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

11. 2,6-Di-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-5-yl)biphenyl-4- ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

12. 6-(n-Butyl)-4-chlor-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

13. 6-(n-Butyl)-4-methoxy-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

14. 6-(n-Butyl)-4-(2-methoxyethoxy)-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

l5. 6-(n-Butyl)-4-dimethylamino-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

16. 6-(n-Butyl)-4hydroxy-2-isopropyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimicline or a tautomer and/or salt thereof.

17. 4-Amino-6-(n-butyl)-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

18. 6-(n-Butyl)-2-methyl-4-methylthio-5-[2'-(lH-tetrazol-5-yl)biphenyl-4ylmethyl]-pyrimidine or salt thereof.

19. 6-(n-Butyl)-2-ethyl-4-hydroxy-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer andJor salt thereof.

20. 6-(n-Butyl)-4-(2-hydroxyethoxy)-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a thereof.

21. 6-(n-Butyl)-4-ethoxycarbonylmethoxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

22. 6-(n-Butyl)-4-carboxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

23. 6-(n-Butyl)-4-ethoxycarbonyl-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

24. 6-(n-Butyl)-2-(tert.-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

25. 6-(n-Butyl)-4-mercapto-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

26. 6-(n-Butyl)-4-methansulfonyl-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

27. 6-(n-Butyl)-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine-4-sulfonic acid or a salt thereof.

28. 6-(n-Butyl)-2-methyl-4-sulfamoyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

29. 6-(n-Butyl)-2-methyl-4-methylamino-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

30. 6-(n-Butyl)-4-methansulfonylamino-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

31. 4-Acetylamino-6-(n-butyl)-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

32. 6-(n-Butyl)-4-ethoxycarbonylmethyl-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

33. 6-(n-Butyl)-4-carboxymethyl-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

34. 6-(n-Butyl)-4-hydroxymethyl-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

35. 6-(n-Butyl)-4-methoxymethyl-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

36. 6-(n-Butyl)-2,4-dimethyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

37. 6-(n-Butyl)-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrirnidine-4-phosphonic acid or a salt thereof.

38. 6-(n-Butyl)-2-methyl-4-(1H-tetrazol-5-yl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

39. 4-Hydroxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-pyrimidine or atautomer and/or salt thereof.

40. 4-Hydroxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylthio]-pyrimidine or a tautomer and/or salt thereof.

41. 6-(n-Butyl)-4-carboxymethoxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

42. 6-(n-Butyl)-4-ethoxycarbonylmethylarnino-2-methyl-5-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

43. 6-(n-Butyl)-4-carboxymethylamino-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

44. 6-(n-Butyl)-4-ethyl-2-methyl-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a salt thereof.

45. 6-(But-l-en-4-yl)-2-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

46. 5-[3-Bromo-2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine or a tautomer and/or salt thereof.

47. 2,6-Di-(n-butyl)-4-hydroxy-5-[3'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

48. 2,6-Di-(n-butyl)-4-hydroxy-5-[2'-(lH-tetrazol-5-yl)biphenyl-3-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

49. 2,6-Di-(n-butyl)-4-hydroxy-5-[2-(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)ethyl]-pyrimidine or a tautomer and/or salt thereof.

50. 6-(n-Butyl)-4-hydroxy-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or salt thereof.

51. A compound according to any one of claims 1 to 50 or where appropriate a tautomer thereof, in each case in free form or in the form of a pharmaceutically acceptable salt, for use in a method for the therapeutic treatment of the human or animal body.

52. A compound according to any one of claims 4, 5 and 8 to 43 or where appropriate a tautomer thereof, in each case in free form or in the form of a pharmaceutically acceptable salt, for use in a method for the therapeutic treatment of the human or animal body.

53. A compound according to any one of claims 1 to 52 or where appropriate a tautomer thereof, in each case in free form or in the form of a pharmaceutically acceptable salt, for use as an antihypertensive.

54. A compound according to any one of claims 4, 5, 8 to 43 and 52 or where appropriate a tautomer thereof, in each case in free form or in the form of a pharmaceutically acceptable salt, for use as an antihypertensive.

55. A pharmaceutical preparation containing, as the active compound, a compound according to any one of claims 1 to 54 or where appropriate a tautomer thereof, in each case in free form or in the form of a pharmaceutically acceptable salt, if appropriate in addition to customary pharmaceutical adjuncts.

56. A pharmaceutical preparation containing, as the active compound, a compound according to any one of claims 4, 5, 8 to 43, 52 and 54 or where appropriate a tautomer thereof, in each case in free form or in the form of a pharmaceutically acceptable salt, if appropriate in addition to customary pharmaceutical adjuncts.

57. An antihypertensive pharmaceutical preparation according to claim 55 or 56, in which an antihypertensive active ingredient is chosen.

58. An antihypertensive pharmaceutical preparation according to claim 56, in which an antihypertensive active ingredient is chosen.

59. A process for the preparation of a compound according to any one of claims 1 to 50 of the formula I or where appropriate a tautomer thereof, in each case in free form or in salt form, which process comprises a) in a compound of the formula (IIa) or a tautomer and/or salt thereof, in which one of the radicals R'1, R'2 and R'3 is the group of the formula (IIb) in which X1 is a radical which can be converted into R5, and the other two radicals have meanings of R1, R2 or R3 other than the group of the formula Ia, converting X1 into R5, or b) reacting a compound of the formula (IIIa), in which X2 is non-modified or functionally modified carboxyl, with a compound of the formula (IIIb) or a salt thereof, and in each case, if desired, converting a compound of the formula I
obtainable according to the process or in another manner or a tautomer thereof, in each case in the free form or in salt form, into another compound of the formula I, or a tautomer thereof, separating a mixture of isomers obtainable according to the process and isolating the desired isomer and/or converting a free compound of the formula I obtainableaccording to the process or a tautomer thereof into a salt, or converting a salt of a compound of the formula I obtainable according to the process or a tautomer thereof into the free compound of the formula I or a tautomer thereof or into another salt.

60. A process for the preparation of a pharmaceutical preparation according to any one of claims 55 to 58, which process comprises processing the active ingredient to a pharmaceutical preparation, customary pharmaceutical adjuncts being mixed in if appropriate.

61. A process for the preparation of a pharmaceutical preparation according to claim 56 or 58, which process comprises processing the active ingredient to a pharmaceuticalpreparation, customary pharmaceutical adjuncts being mixed in if appropriate.

62. The process according to claim 60 or 61 for the preparation of an antihypertensive pharmaceutical preparation according to claim 57 or 58, wherein an antihypertensive active ingredient is chosen.

63. The process according to claim 61 for the preparation of an antihypertensivepharmaceutical preparation according to claim 58, wherein an antihypertensive active ingredient is chosen.

64. A method of treating high blood pressure and/or cardiac insufficiency, whichcomprises administering a compound according to any one of claims 1 to 54 or if appropriate a tautomer thereof, in each case in the free form or in the form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to any one of claims 55 to 58.

65. A method of treating high blood pressure and/or cardiac insufficiency, whichcomprises administering a compound according to any one of claims 4, 5, 8 to 43, 52 and 54 or if appropriate a tautomer thereof, in each case in the free form or in the form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to claim 56 or 58.

66. The use of a compound according to one of claims 1 to 54 or if appropriate a tautomer thereof, in each case in the free form or in the form of a pharmaceutically acceptable salt, for the preparation of a pharmaceutical preparation.

67. The use of a compound according to one of claims 1 to 54 or if appropriate a tautomer thereof, in each case in the free form or in the form of a pharmaceutically acceptable salt, for the preparation of a pharmaceutical preparation by a non-chemical route.

68. The use of a compound according to claim 66 or 67 for the preparation of an antihypertensive.

69. The use of a compound according to one of claims 1 to 54 or if appropriate a tautomer thereof, in each case in the free form or in the form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to any one of claims 55 to 58 for the treatment of high blood pressure and/or cardiac insufficiency.

70. The process of the Examples 1 to 24.

71. The novel starting substances used according to the process in the process according to either of claims 59 and 70, the novel intermediates formed and the novel end products obtainable.

FO 7.4 GR