AU637617B2

AU637617B2 - 1-((biphenyl-4-yl)alkyl)-6-oxopyrimidine derivatives

Info

Publication number: AU637617B2
Application number: AU58696/90A
Authority: AU
Inventors: Peter Buhlmayer; Peter Herold
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1989-07-06
Filing date: 1990-07-04
Publication date: 1993-06-03
Anticipated expiration: 2010-07-04
Also published as: JPH0344377A; CA2020370A1; EP0407342A2; AU5869690A; PT94586A; EP0407342A3; IE902440A1

Description

Our Ref: Our Ref: 329978 S637617

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: Applicant(s): Ciba-Geigy AG Klybeckstrasse 141 4002 BASLE

SWITZERLAND

ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Address for Service: SComplete specification for the invention entitled

"I-[(BIPHENYL

-4-YL)ALKYL]-6-OXOPYRIMIDINE DERIVATIVES'.

The following statement is a best method of performing it full description known to me:of this invention, including the 1 5020 la I "1-[(BIPHENYL -4-YL)ALKYL]-6-OXOPYRIMIDINE

DERIVATIVES'.

The invention relates to novel pyrimidine derivatives of the formula R2 N R 3 1 N Z ee 4 their tautomers and salts, in which Z is O, S or N(R) and R is hydrogen or an aliphatic S hydrocarbon radical; R 1 is an unsubstituted or substituted aliphatic hydrocarbon radical, a *o cycloaliphatic or araliphatic hydrocarbon radical or an aromatic radical; R 2 and R 3 independently of one another, are halogen, acyl, an aromatic radical, unsubstituted or substituted amino, or carboxyl which, if desired, may be esterified or amidated; or R 2 is

-Z

1

-R'

2 and R 3 is -Z 2

-R'

3

Z

1 and Z 2 independently of one another being a bond, O or S S(0)n and n being 0, 1 or 2, and R' 2 and R' 3 independently of one another being hydrogen, S an araliphatic or aliphatic hydrocarbon radical, the latter being unsubstituted or substituted and, if desired, interrupted by or n being 0, 1 or 2; or R 2 and R 3 together are t propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH-, in which, if desired, one or two of the methyne groups are replaced by R 4 is a group of the formula AkA (Ia) Alk- /A B--a in which Alk is a divalent aliphatic hydrocarbon; R 5 is COOH, S0 3 1H, -2haloalkanesulfamoyl, PO 2

H

2 PO3H 2 or 5-tetrazolyl; the rings A and B or the (hetero)aromatic ring jointly formed by R 2 and R 3 are, independently of one another, unsubstituted or substituted; and to processes for their preparation, pharmaceutical preparations and their use.

Compounds of the formula I may exist as proton tautomers. If, for example, R 2 is hydroxyl, appropriate compounds may be in equilibrium with the tautomeric 4-oxo derivatives.

The compounds of the formula I may be present as salts, in particular pharmaceutically acceptable salts. If the compounds according to the invention have at least one basic centre, they can thus form acid addition salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C 1

-C

4 )alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, 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, benzoic acid or with organic sulfonic acids, such as

(C

1

-C

4 )alkane- or arylsulfonic acids which are unsubstituted or substituted, for example, by halogen, for example methane- or toluenesulfonic acid. Corresponding acid addition S salts having, if desired, an additionally present basic centre can also be formed.

1 Furthermore, the compounds according to the invention having an acid group (R 5 for example, COOH or 5-tetrazolyl) can form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal salts or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or of substituted organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, such as mono-, di- or tri(lower alkyl)amines or mono-, di- or trihydroxy(lower alkyl)amines, for example mono-, di- or triethanolamine. Mono(lower alkyl)amines are, for example, ethylamine or tert-butylamine. Di(lower alkyl)amines are, for example, diethylamine or dipropylamine, and possible tri(lower alkyl)amines are, for example, triethylamine, tributylamine or dimethylpropylamine. In addition, corresponding internal salts can be formed. Furthermore included for pharmaceutical uses are non-suitable salts, as these can be employed, for example, for the isolation or purification of compounds according to the invention or their pharmaceutically acceptable salts.

ITI

-3- An aliphatic hydrocarbon radical is, for eyr nple, lower alkyl, lower alkenyl and secondarily lower alkynyl.

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

A suitable araliphatic radical is, in particular, phenyl-lower alkyl and furthermore phenyl-lower alkenyl and phenyl-lower alkynyl.

An aromatic radical is, for example, a carbocyclic or heterocyclic aromatic radical, in particular phenyl and furthermore naphthyl, or in particular an appropriate 5- or 6-membered and monocyclic radical which has up to 4 identical or different heteroatoms, such as nitrogen, oxygen or sulfur atoms, preferably one, two, three or four nitrogen atoms, an oxygen atom or a sulfur atom. Appropriate 5-membered heteroaryl radicals are, for example, monoaza-, diaza-, triaza-, tetraaza-, monooxa- or monothia-cyclic aryl radicals, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazoly, furyl and thienyl, while suitable appropriate 6-membered radicals are, in particular, pyridyl.

0 Acyl is, in particular, lower alkanoyl, phenyl-lower alkanoyl or unsubstituted or substituted benzoyl.

Substituted amino is, for example, independently of one another mono- or disubstituted by an aliphatic or araliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, or by a divalent aliphatic hydrocarbon radical, such as lower alkylene or lower alkyleneoxy-lower alkylene, disubstituted amino, for example lower alkyl-, lc ver alkenyl-, lower alkynyl-, phenyl-lower alkyl-, phenyl-lower alkenyl-, phenyl-lower alkynyl-, di(lower alkyl)-, N lower alkyl-N-phenyl-lower alkyl-, di-phenyl-lower alkyl-amino, lower alkyleneamino or lower alkyleneoxy-lower alkyleneamino.

Esterified carboxyl is, for example, carboxyl which is esterified by an aliphatic alcohol, this being derived from an aliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl and secondarily lower alkynyl and being interrupted, if desired, by such as lower alkoxy-lower alkyl, -lower alkenyl and -lower alkynyl, for example lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxy-carbonyl.

-4- Amidated carboxyl is, for example, carbamoyl in which the amino group, for example as stated above, is, if desired, independently of one another mono- or disubstituted by an aliphatic or araliphatic hydrocarbon radical or disubstituted by a divalent aliphatic hydrocarbon radical which, if desired, is interrupted by a suitable divalent aliphatic hydrocarbon radical which, if desired, can be interrupted by being, in particular, lower alkylene or lower alkyleneoxy-lower alkylene.

An aliphatic hydrocarbon radical which is interrupted by is, in particular, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, while the aliphatic hydrocarbon radical which is interrupted by is, in particular, lower alkylthio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkanesulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, and lower alkynylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl.

9 A partial structure of the formula -CH=CH-CH=CH- in which one or two of the methyne groups are replaced by is, for example, -N=CH-CH=CH-, -CH=N-CH=CH-, to -CH=CH-N=CH-, -CH=CH-CH=N-, -N=CH-N=CH- or -CH=N-CH=N-.

A divalent aliphatic hydrocarbon radical is, for example, lower alkylene or lower alkylidene.

too* Haloalkanesulfamoyl is, in particular, halo-lower alkanesulfamoyl.

Substituents of an aliphatic hydrocarbon which, if desired, is interrupted by 0 or S(O)n are, for example, selected from the group comprising halogen, unetherified or etherified hydroxyl, S(0)n-R, unsubstituted or substituted amino or carboxyl which, if desired, is o" esterified or amidated. Preferred substituents of an aliphatic hydrocarbon R 1 are, for example, halogen or hydroxyl. Appropriate substituted aliphatic hydrocarbon radicals preferably have a substituent which is primarily located in longer-chain radicals in a higher position than the a-position. Preferred aliphatic hydrocarbon radicals which may be mentioned are, for example, halo-lower alkyl, and furthermore -lower alkenyl or -lower alkynyl, hydroxy-lower alkyl, and furthermore -lower alkenyl or -lower alkynyl.

Etherified hydroxyl is, for example, hydroxyl etherified by an aliphatic alcohol, in particular lower alkoxy or lower alkenyloxy and is also a phenyl-lower alkoxy or phenoxy

I

radical. i (Hetero)aromatic radicals, including the rings A and B and, if R 2 and R 3 are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, one or two of the methyne groups are replaced by the (hetero)aromatic ring formed by this partial structure, are, in particular, if not differently defined, in each case unsubstituted, monosubstituted or polysubstituted, for example disubstituted or trisubstituted, in particular, for example, by a substituent selected from the group comprising halogen, unetherified or etherified hydroxyl, S(O)m-R and a hydrocarbon radical which is uninterrupted and/or interrupted by and unsubstituted or substituted, for example, by halogen or hydroxyl. Phenyl which is unsubstituted or monosubstituted or polysubstituted, for example disubstituted or trisubstituted, for example by a substituent selected from the group comprising lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxyl, is preferred.

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

The general definitions used above and below have, if not defined differently, the following meanings: The expression "lower" means that corresponding groups and compounds in each case contain in particular not more than 7, preferably not more than 4, carbon atoms.

Halogen is, in particular, halogen of atomic number not more than 35, such as fluorine, chlorine or bromine, and furthermore includes iodine.

Lower alkyl is, in particular, C 1

-C

7 alkyl and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and furthermore includes corresponding pentyl, hexyl and heptyl radicals. C 1

-C

4 Alkyl is preferred.

Lower alkenyl is, in particular, C 3

-C

7 alkenyl and is, for example, 2-propenyl or 2- or 3-butenyl. C 3

-C

5 Alkenyl is preferred.

Lower alkynyl is, in particular, C 3

-C

7 alkynyl and is preferably propargyl.

-6- Cycloalkyl is, in particular, C 3

-C

7 Cycloalkyl and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is, in particular, C 3

-C

7 cycloalkenyl and is preferably cyclopent-2- or -3-enyl, or cyclohex-2- and -3-en-yl.

Phenyl-lower alkyl is, in particular, phenyl-Cl-C 4 alkyl and is preferably benzyl, 1- and 2-phenethyl, while phenyl-lower alkenyl and phenyl-.lower alkynyl are, in particular, phenyl-C 3

-C

5 alkenyl and -alkynyl, in particular 3-phenylallyl and 3-phenylpropargyl.

Pyrrolyl is, for example, 2- or 3-pyrrolyl. Pyrazolyl is 3- or 4-pyrazolyl. Imidazolyl is 2- or 4-imidazolyl. Triazolyl is, for example, 1,3,5-1H-triazol-2-yl or 1,3,4-triazol-2-yl.

Tetrazolyl is, for example, 1,2,3,4-tetrazol-5-yl. Furyl is 2- or 3-furyl and thienyl is 2- or 3-thienyl, while suitable pyridyl is 3- and 4-pyridyl.

Lower alkanoyl is, in particular, Cl-C 7 alkanoyl and is, for example, formnyl, acetyl, propionyl, butyryl, isobutyryl or pivavolyl. C 2

-C

5 Alkanoyl is preferred.

Phenyl-lower alkanoyl is, in particular, phenyl-C 2

-C

7 alkanoyl and is, for example, phenylacetyl or 2- or 3-phenylpropionyl. PhenYl-C 2

-C

4 alkanoyl is preferred.

Lower alkylene is, in particular, Ci-C 7 alkylene, is straight-chain or branched and is, in :::particular, methylene, ethylene, propylene or butylene and also 1,2-propylene, 2-methyl- 1,3-propylene and 2,2-dimethyl-1 ,3-propylene. C 2

-C

5 Alkylene is preferred.

Lower alkyleneoxy-lower alkylene is, in particular, Cj-C 4 alkyleneoxy-C 2

-C

4 alkylene, preferably ethyleneoxyethylene.

Lower alkylamino is, in particular, Cl-C 7 alkylamino and is, for example, methyl-, ethyl-, n-propyl- and isopropyl-amino. Cl-C 4 Alkylamino is preferred.

Lower alkenylamino is preferably C 3

-C

5 alkenylamino, such as allyl- xnd methallylamino.

Lower alkynylamino is preferably C 3

-C

5 alkynylamnino, such as propargylamino.

Phenyl-lower alkylamino is preferably phenyl-C 1

-C

4 alkylamino, in particular benzyl-, 1- 4 and 2-phenylethylamino.

Phenyl-lower alkenylamino is preferably phenYl-C 3

-C

5 alkenylrmino, in particular phenylallylamino and 3-phenylmethallylamino.

Phenyl-lower alkynylamino is preferably phenyl-C 3

-C

5 alkynylamino, in particular 3-phenyipropargylamino.

Di (lower alkylamino) is, in particular, di-C 1

-C

4 alkylamino, such as dimethyl-, diethyl-, di-n-propyl-, methylpropyl-, methylethyl-, methylbutyl- amino and dibutylamino.

N-Lower alkyl-N-phenyl-lower alkylamino is, in particular, N-Cl-C 4 alkyl-Nphenyl-Cl-C 4 alkylamino, preferably methylbenzylamino and ethylbenzylamino.

:ihnl-oe alyamn is, in particular, di-pheny]-Cl-C 4 alkylamino, preferably Lower alkyleneamino is, in particular, C 2

-C

6 alkyleneamino, such as 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepidinyl, while suitable lower alkyleneoxy-lower alkyleneamino is, in particular, 4-morpholinyl.

Lower alkoxy is, in particular, C 1

-C

7 alkoxy and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and furthermore includes corresponding pentyloxy, hexyloxy and heptyloxy radicals.

Cj-C 4 Alkoxy is preferred.

Lower alkenyloxy is, in particular, C 3

-C

7 alkenyloxy and is, for example, allyloxy or but-2-en- or but-3-enyloxy. C 3

-C

5 Alkenyloxy is preferred.

Lower alkoxy-lower alkyl is, in particular, Cj-C 4 a1koxy-Cj-C 4 alkyl, such as 2-methoxyethyl, 2-ethoxyethyl, 2-n-propyloxyethyl or ethoxymethyl.

Lower alkoxy-lower alkenyl is, in particular, Cj-C 4 alkoxy-C 3

-C

4 alkenyl, such as 3-methoxyallyl, 3-ethoxyallyl or 2-n-propyloxyallyl, while suitable lower alkoxy-lower alkynyl is, in particular, Cj-C 4 alkoxy-C 3

-C

4 alkynyl, such as 3-methoxypropargyl.

-8- Lower alkoxycarbonyl is, in particular, C 2

-C

8 alkoxycarbonyl and is, for example, methoxy-, ethoxx"-, propyloxy- or pivaloy~oxy-carbony1. C 2

-C

5 Alkoxycarbonyl is preferred.

Lower alkoxy-lower alkoxycarbonyl is, in particular, C l-C 4 alkoxy-Cl-C 4 alkoxycarbonyl, preferably ethoxyethoxycarbonyl, methoxyethoxycarbonyl and isopropyloxyethoxycarbonyl.

Lower alkenyloxycarbonyl is, in particular, C 3

-C

5 alkenyloxycarbonyl, preferably allyloxycarbon) while lower alkynyloxycarbonyl is, in particular,

C

3

-C

5 alkynyloxycarbonyl, such as propargyloxycarbonyl.

Lower alkenyloxy-lower alkyl is, in particular, C 3

-C

5 alkenyloxy-Cl-Q41ower alkyl, such as 2-allylethyl, or 2- or 3-allylpropyl.

*..Lower alkenyloxy-lower alkenyl is, in particular, C 3

-C

5 alkenyloxy-C 3

-C

5 alkenyl, such as -ailyloxyallyl, while lower alkenyloxy-lower alkynyl is, in particular,

C

3

-C

5 alkenyloxy-C 3

-C

5 alkynyl, such as 3-allyipropargyl.

Lower alkylthio is, in particular, C. -C 7 alkylthio and is, for example, methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl- or tert-butylthio. Cj-C 4 Alkylthio is preferred.

Lower alkanesulfinyl or -sulfonyl is, in particular, Cl-C 7 alkanesulfinyl or -sulfonyl and is, for example, methane-, ethane-, n-propane- or isopropane-sulfinyl or -sulfonyl.

C

1

-C

4 Alkanesulfinyl or -sulfonyl is preferred.

Lower alkenylthio is, in particular, C 3

-C

5 alkenylthio, such as allylthio, while lower alkynylthio is, in particular, C 3

-C

5 alkynylthio, such as propargylthio.

Lower alkylthio-lower alkyl is, in particular, CI-C~alkylthio-CI-G 4 alkyl, such as ethyithiomethyl, 2-ethylthioethyl, 2-rrethylthioethyl, 2-isopropylthioethyl, while suitable lower alkanesulfinyl- or lower alkanesulfonyl-lower alkyl are, in particular, appropriate Cl-C 4 alkanesulfinyl- or CI-C~alkanesulfonyl-C 1 -C~lkyl radicals.

Lower alkylthio-lower alkenyl oi -lower alkynyl is, in particular -9-

C

1

C

4 alkyithio-C 3

-C

5 alkenyl or -alkynyl. 11 Lower alkenylthio-lower alkyl is, in particular, C 3

-C

5 alkenylthio-C 1

-C

4 alkyl, such as l-allylthioethyl or 3-allyipropyl, while suitable lower alkenylsulfinyl- or -sulfonyl-lower alkyl are, in particular, C 3

-C

5 alkenylsulfinyl- or -sulfonyl-C 1

-C

4 alkyl.

Lower alkynylthio-lower alkyl is, in particular, C 3

-C

5 aLkynylthio-Cj-C 4 alkyl, such asI 2-propargylthioethyl or 3-propargyipropyl, while suitable lower alkynylsulfinyl- or -sulfonyl-lower alkyl are, in p.rticular, C 3

-C

5 alkynylsulfinyl- or -sulfonyl-Cl-C 4 atkyl.

Lower alkylidene is, in particular, c 2 -C 7 -alkylidene, such as ethylidene, 1,1- or 2,2-propylidene, and furthermore 1,1- or 2,2-butylidene. C 2

-C

3 Alkylidene is preferred.

S Haloalkylsulfamoyl is, in particular, halo-C 1

-C

7 alkanesulfamoyl, in particular halo-Cl-C 4 alkylsulfamoyl, and is, for example, trifluoromethane-, difluoromethane- or 1, 1,2-trifluoroethanesulfamoyl.

*SHalo-lower alkyl is, in particular, halo-Cl-C 4 alkyl, such as trifluoromethyl, 1, 1,2-trifluoro-2-chloroethyl or chloromethyl.

Halo-lowier ailkenyl is, in particular, halo-C 3

-C

5 alkenyl, such as 3-chioroallyl.

:s Halo-lower alkynyl is, in particular, halo-C 3

-C

5 alkcynyl, such as 3-chloropropargyl.

Hydroxy-lower alkyl is, in particular, hydroxy-Cl-C 4 alkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.

Hydroxy-lower alkenyl is, in particular, hydroxy-C 3

-C

5 alkenyl, such as 3-hydroxyallyl.

Hydroxy-lower alkynyl is, in particular, hydroxy-C 3

-C

5 alkynyl, such as 3-hydroxypropargyl.

Phenyl-lower alkoxy is, in particular, phL._Yl-C 1

-C

4 alkoxy, such as benzyloxy, 1- or 2-phenylethoxy, or 2- or 3-phenylpropyloxy.

Extensive pharmacological investigations have shown that the compounds according to the invention have pronounced angiotensin II antagonist prope As is known, angiotensin II has strong vasoconstrictor properties, additionally stimulates aldosterone secretion and thus causes distinct sodium/water retention. The consequence of angiotensin II activity is manifested in an increase in blood pressure.

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

The angiotensin II antagonist properties of the compounds according to the invention can be detected in the angiotensin II binding test. Rat smooth muscle cells from homogenized rat aorta are used here. The solid centrifugate is suspended in 50 mM tris buffer, pH 7.4, using peptidase inhibitors. Samples are incubated for 60 minutes at 25 0 C with 5I-angiotensin 1II (0.175 nM) and a varying concentration of angiotensin II or the test S substance. The incubation is then ended by addition of saline buffered with ice-cold phosphate, and the mixture is filtered through a Whatman GF/F filter. The filters are counted using a gamma counter. The IC 50 values are determined from the dose-effect curve. IC 50 values from about 10 nM were determined for the compounds according to the invention.

For the determination of angiotensin II-induced vasoconstriction, investigations on the isolated guinea-pig aorta ring can be used. For this purpose, aorta rings are dissected from each chest and fixed between two parallel clamps at an initial tension of 2 g. The rings are then immersed in 20 ml of a tissue bath at 37 0 C and aerated with 95 02 and 5 CO 2 The isometric reactions are measured. At 20-minute intervals, the rings are alternately stimulated with 10 nM angiotensin II (Hypertensin-CIBA) and 5 nM noradrenaline chloride. The rings are then incubated with selected concentrations of the test substances before treatment with the agonists. The data are analysed using a Buxco digital computer.

The concentrations which cause a 50 inhibition of the initial control value are given as

IC

50 values. IC 50 values from about 5 nM were determined for the compounds according to the invention.

The fact that the compounds according to the invention can reduce high blood pressure induced by angiotensin II can be verified in the normotensive anaesthetized rat test model.

After calibration of the preparations with 0.9 NaCl (1 ml/kg noradrenaline (1 Vg/kg -11or angiotensin II (0.3 tg/kg in each case, increasing doses of the test substance are intravenously injected by bolus injection, after which angiotensin II or noradrenaline is administered after each dose at 5 minute intervals. The blood pressure is measured directly in the carotid artery and recorded using an on-line data recognition system (Buxco). The specificity of the angiotensin II antagonism is shown by the selective inhibition of the pressure effect produced by angiotensin II, but not that peoduced by noradrenaline. In these investigations, the compounds according to the invention showed an inhibiting effect from a dose of about 0.3 mg/ig i.v.

The antihypertensive activity of the compounds according to the invention may also be manifested in the renally hyperten ive rat. High blood pressure is 'roduced in male rats by constricting a renal artery according to the Goldblatt method. Doses of the substance are adminstered to the rats by means of a stomach tube. Control animals receive an equivalent volume of solvent. Blood pressure and heart beat are measured indirectly at intervals in S conscious animals by the tail clamp method of Gerold et al. (Helv. Physiol. Acta 24, 58, 1966) before administration of the substances or of the placebo and during the course of the experiment. It was possible to detect the pronounced antihypertensive effect below a dose of about 30 mg/kg p.o.

The compounds of the formula I can therefore be used, for example, as pharmaceutical active ingredients, such as antihypertensives, for example for the treatment of high blood pressure and cardiac insufficiency. The invention further relates to the use of the compounds according to the invention for the production of medicaments, in particular angiotensin II antagonists and antihypertensives, and the use of these compounds for the S therapeutic treatment of high blood pressure and cardiac insufficiency. The industrial production of the active substances is also included in the production of the pharmaceuticals.

The invention relates in particular to compounds of the formula I, their tautomers and salts, in which Z is O, S or N(R) and R is hydrogen or an aliphatic hydrocarbon radical, R 1 is an aliphatic radical which is unsubstituted or substituted by halogen or hydroxyl, a cycloaliphatic or araliphatic hydrocarbon radical or an aromatic radical, R 2 and R 3 independently of one another, are halogen, acyl, an aromatic radical, carboxyl which, if desired, is esterified or amidated, or R 2 is -Z 1

-R'

2 and R 3 is -Z 2 -R3, Z 1 and Z 2 independently of one another being a bond or O, S(0)n or NH, n being 0, 1 or 2 and R' 2 and R' 3 independently of one another being hydrogen or an aliphatic hydrocarbon radical -12-

I

which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino, or carboxyl which, if desired, is esterified or amidated, and which, if desired, is interrupted by or n being 0, 1 or 2, R 4 being a group of the formula

R

H

2 (Ib) in which R 5 is COOH, SO 3 H, haloalkanesulfamoyl, P0 2

H

2 P0 3

H

2 or The invention relates in particular to compounds of the formula I, their tautomers and salts in which Z is O, S or N(R) and R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R, is lower alkyl, lower alkenyl or lower alkynyl which in each case are unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonyl, lower alkenylthio, lower alkenylsulfinyl or -sulfonyi, lower alkynylthio, lower alkynylsulfinyl or -sulfonyl, amino which, if desired, is 0, independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower-alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxyor lower alkenyloxy-carbonyl and carbamoyl in which, if desired, the amino group is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl lower alkyl or phenyl-lower alkynyl or disubstituted by lowe: alkylene or lower alkyleneoxy-lower alkylene, or in each case 3- to 7- membered cycloalkyl or cycloalkenyl, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl. phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, biazolyl, tetrazolyl, furyl, thienyl or pyridyl; R 2 and R 3 independently of one another are halogen, lower alkanoyl, phenyl-lower alkanoyl, benzoyl phenyl, naphthyl, pyrrolyl, pyrazolyl, imnidazolyl, triazolyl, tetrazolyl, furyl, thienyl, pyridyl, amino which, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxycarbonyl or carbamoyl in which the amino group,if desired,is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower 13alkyleneoxy- lower alkylene; or R 2 is -Z 1

-R

2 and R 3 is -Z2-R 3 Zland Z 2 independently of one another being a bond, 0 or and n being 0, 1 or 2, and and R 3 independently of one another being hydrogen, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or being lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkylthio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkanesulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, which are in each case independently of one another unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy.. lower alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or S-sulfonyl, lower alkenylthio, lower alkenylsulfinyl or -sulfonyl, lower alkynylthio, lower alkynylsulfinyl or -sulfonyl, amino which is, if desired, inndependently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower K alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkeniloxy-carbonyl and carbamoyl in which,if desired, the amino group is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, one or two of the methyne groups is replaced by R 4 is a group of the formula in particular in which alk is lower alkylene or lower alkylidene, in particular methylene; R 5 is COOH, S03H, halo-lower alkanesulfamoyl, P0 2 z, P0 3 H1 or 5-tetrazolyl; the rings A and B and the (hetero)aromatic radicals or the (hetero)aromatic ring jointly formed by R 2 and R 3 are in each case independently of one another unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonyl, lower alkenylthio, lower alkenylsulfinyl or -sulfonyl, lower alkynylthio, lower alkynylsulfinyl or -sulfonyl, or selected from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, or lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, which are in each case unsubstituted or substituted by substituents sciected from the group comprising halogen, hydroxyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonyl, lower alkenylthio, lower alkenylsulfinyl Li I I I P64 -14or -sulfonyl, lower alkynylthio, lower alkynylsulfinyl or -sulfonyl, anmino which, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxy-carbonyl and carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl,lower alkenyl,lower alkynyl,phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkleneoxy-lower alkylene.

The invention relates in particular to compounds of the formula I, their tautomers and salts in which Z is O, S or N(R) and R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl,

R

1 is lower alkyl, lower alkenyl or lower alkynyl, in each case 3- to 7-membered cycloalkyl or cycloalkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or phenyl, which is unsubstituted or substituted by halogen or hydroxyl, R 2 and R.3 independently of one another are halogen, lower alkanoyl, phenyl or carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower «alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, or lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, -lower alkenyl or -lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or R 2 is -Z 1

-R'

2 and

R

3 is -Z 2

-R'

3

Z

1 and Z 2 independently of one another being a bond or O, S(0)n c. NH, n being 0, 1 or 2, and R'2 and R' 3 independently of one another being hydrogen, or lower alkyl, lower alkenyl or lower alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkylthio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkanesulfinyl-lowe r alkyl or -sulfonyl-lower alkyl, lower alkenylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkynylthio-lower alkyl, -sulfinyl-lower alkyl or is -sulfonyl-lower alkyl, which is unsubstituted or substituted by halogen, hydroxyl, amino which, if desired, is substituted as indicated above, carboxyl which, if desired, is esterified as indicated above, or carbamoyl which, if desired, is substituted as indicated above, R 4 is the group of the formula Ib in which R 5 is COOH, S0 3 H, halo-lower alkanesulfamoyl,

PO

2

H

2

,PO

3

H

2 or 5-tetrazolyl; and wherein phenyl rings and radicals containing phenyl rings in each case being unsubstituted or substituted by substituents selected from the group comprising lower alkyl,lower alkoxy,halogen, trifluoromethyl and hydroxyl.

Ilt~ [1T The invention relates in particular to compounds of the formula I, their tautomers and I salts, in which Z is O, S or N(R) and R is hydrogen or lower alkyl, R 1 in each case is lower alkyl or lower alkenyl which is unsubstituted or substituted by halogen or hydroxyl, or C 3

-C

7 cycloalkyl, C 3

-C

7 cycloalkenyl, phenyl-lower alkyl, phenyl or pyridyl; R 2 and R 3 independently of one another, are halogen, lower alkanoyl, phenyl-lower alkanoyl, benzoyl, phenyl, tetrazolyl, pyridyl, amino which, if desired, is mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxy-carbonyl or carbamoyl in which,if desired,the amino group is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene; R 2 is -Z 1

-R

2 and

R

3 is -Z 2

-R

3

Z

1 and Z 2 independently of one another being a bond, O or S(0)n and n being 0, 1 or 2; and R 2 and R3' independently of one another being hydrogen or S phenyl-lower alkyl or are lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower S alkylthio-lower alkyl, or lower alkanesulfinyl-lower alkyl or -sulfonyl-lower alkyl, which S in each case are independently of one another unsubstituted or substituted by substituents 1* selected from the group comprising halogen, hydroxyl, lower alkoxy, phenyl-lower al oxy, phenoxy, amino wl ich, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, s carboxyl,lower alkoxy- or lower alkoxy-lower alkoxy-carbonyl and carbamoyl in S. which, if desired the amino group is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH-, in which, if desired, one or two methyne group(s) are replaced by R 4 is a group of the formula Ia, primarily Ib, in which Alk is lower alkylene or lower alkylidene, primarily methylene; R 5 is carboxyl, halo-lower alkanesu'' moyl or 5-tetrazolyl; the rings A and B and the (hetero)aromatic radicals or the (hetero)aromatic ring formed jointly by R 2 and R 3 are in each case independently of one another unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, phenyl-lower alkoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonyl, or lower alkyl or lower alkoxy-lower alkoxy-lower alkyl which is unsubstituted or substituted by halogen, hydroxyl, lower alkoxy, phenyl-lower alkoxy or phenoxy.

The invention relates in particular to compounds of the formula I, their tautomers and Ua -16salts, in which Z is O, S or N(R) and R is hydrogen or lower alkyl, R, is lower alkyl,

C

3

-C

7 cycloalkyl, phenyl-lower alkyl or phenyl, R 2 and R 3 independently of one another, are halogen, phenyl, lower alkanoyl, carboxyl, lower alkoxy- or lower alkoxy-lower alkoxy-carbonyl, carbamoyl, lower alkyl- or di(lower alkyl)-carbamoyl, lower alkylene-carbamoyl or lower alkyleneoxy-lower alkylene-carbamoyl, or R 2 is -Z 1

-R'

2 and

R

3 is -Z-R' 3

Z

1 and Z 2 independently of one another being a bond or O, S or NH and R' 2 and R' 3 independently of one another being hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di(lower alkylamino)-lower alkyl, lower alkyleneamino-lower alkyl, lower alkyleneoxy-lower alkyleneamino-lower alkyl, carboxy-lower alkyl, or lower alkoxy- or lower alkoxy-lower alkoxy-carbonyl-lower alkyl, R 4 is the group of the formula S Ib in which R 5 is COOH or 5-tetrazolyl; and wherein phenyl rings and radicals containing phenyl rings in each case being unsubstituted or substituted by e •lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl.

The invention relates primarily to compounds of the formula I, their tautomers and salts, S in which Z is O, R 1 is lower alkyl, in particular having 3 and not more than 5 C atoms, such as n-propyl or n-butyl, or lower alkenyl, in particular having 3 and not mor than 5 C atoms, such as 2-propenyl, R 2 and R 3 independently of one another are halogen, in particular of atomic number not more than 35, such as chlorine, tetrazolyl, such as 5-tetrazolyl, amino, which, if desired, is mono- or disubstituted by lower alkyl or phenyl-lower alkyl, in particular having not more than 4 C atoms per alkyl moiety, or disubstituted by lower alkyleneoxy-lower alkylene, in particular having not more than 4 C atoms per lower alkylene moiety, such as 4-morpholinyl, carboxyl, lower alkoxycarbonyl, in particular having 2 and not more than 5 C atoms, such as methoxy- or ethoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, in particular having not more than 4 C atoms in the alkoxy moiety, such as 2-methoxyethoxycarbonyl; or R 2 is -Z 1

-R

2 and R 3 is -Z-R 3

Z

1 and Z 2 independently of one another being a bond, O or S(0)n and n being 0, 1 or 2, and

R

2 and R 3 independently of one another being hydrogen or phenyl-lower alkyl, in particular having not more than 4 C atoms in ihe alkyl moiety, such as benzyl, or lower alkyl or lower alkoxy-lower alkyl, in particular in each case having not more than 4 C atoms in the alkyl moiety, which in each case, if desired, is mono- or disubstituted by halogen, in particular of atomic number not more than 35, such as chlorine, hydroxyl, amino which, if desired, is mono- or disubstituted by lower alkyl or phenyl-lower alkyl, in particular having not more than 4 C atoms per alkyl moiety, or disubstituted by lower alkenyloxy-lower alkylene, in particular having not more than 4 C atoms per lower alkyl TIf -17moiety, such as methyl-, dimethyl-, benzyl- or dibenzylamino or 4-morpholinyl, carboxyl, lower alkoxycarbonyl, in particular having 2 and not more than 5 C atoms, such as methoxy- or ethoxycarbonyl; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH-, in which, if desired, one or two methyne group(s) are replaced by R 4 is a group of the formula Ia, in particular Ib, in which Alk is lower alkylene or lower alkylidene, in particular in each case having not more than 4 C atoms, such as methylene, ethylene or ethylidene, primarily methylene; R is carboxyl, halo-lower alkanesulfamoyl, in particular of atomic number not more than and having not more than 4 C atoms, in particular trifluoromethanesulfamoyl, or the rings A and B and the aromatic radicals or the (hetero)aromatic ring jointly formed by R 2 and R 3 are in each case independently of one another unsubstituted or substituted by hydroxyl, halogen, in particular of atomic number not more than 35, such as chlorine, trifluoromethyl, lower alkyl, in particular having not more than 4 C atoms, such as methyl, and/or lower alkoxy, in particular having not more than 4 C atoms, such as methoxy.

The invention relates primarily to compounds of the formula I, their tautomers and salts, in which Z is O, R 1 is lower alkyl, in particular having 3 and not more than 5 C atoms, such as n-butyl, one of the radicals R 2 and R 3 is halogen, in particular of atomic number not more than 35, such as chlorine, phenyl, carboxyl, lower alkoxycarbonyl, in particular having 2 and not more than 5 C atoms, such as ethoxycarbonyl, hydrogen, hydroxyl, lower alkylthio, in particular having not more than 4 C atoms, such as methylthio, lower alkanesulfonyl, in particular having not more than 4 C atoms, such as methanesulfonyl, amino, di(lower alkyl)amino, in particular having not more than 4 C atoms per lower alkyl moiety, such as dimethylamino, morpholino, lower alkyl, in particular having not more than 4 C atoms, such as methyl, hydroxy-lower alkyl, in particular having not more than 4 C atoms, such as hydroxymethyl, halo-lower alkyl, in particular of atomic number not more than 35 and having not more than 4 C atoms, such as trifluoromethyl, di(lower alkyl)amino-lower alkyl, in particular having not more 4 C atoms per lower alkyl moiety, such as 2-dimethylaminoethyl, carboxy-lower alkyi, in particular having not more than C atoms, such as carboxymethyl, lower alkoxycarbonyl-lower alkyl, in particular having not more than 4 C atoms per lower alkoxy or lower alkyl moiety, such as ethoxycarbonylmethyl, lower alkoxy, in particular having not more than 4 C atoms, such as methoxy, hydroxy-lower alkoxy, in particular having not more than 4 C atoms, such as 2-hydroxyethoxy, lower alkoxy-lower alkoxy, in particular having not more than 4 C atoms per lower alkoxy moiety, such as 2-methoxyethoxy, di(lower alkyl)amino-lower -18alkoxy, in particular having not more than 4 C atoms per lower alkyl or lower alkoxy moiety, such as 2-dimethylaminoethyl, carboxy-lower alkoxy, in particular having not more than 5 C atoms, such as 2-carboxyethoxy, or lower alkoxycarbonyl-lower alkoxy, in particular having not more than 4 C atoms per lower alkoxy moiety, such as 2-ethoxycarbonylethoxy, and the other hydrogen or lower alkyl, in particular having not more 4 C atoms, such as methyl, and R 4 is the group of the formula Ib in which R 5 is The invention relates primarily to compounds of the formula I and their salts in which Z is O, R 1 is C 3

-C

5 alkyl, such as n-propyl or n-butyl, R 2 and R 3 independently of one another, are halogen of atomic number not more than 35, such as chlorine, di-C 1

-C

4 alkylamino, such as dimethylamino, 4-morpholinyl, carboxyl or Cz-C 5 alkoxycarbonyl, such as methoxy- or ethoxycarbonyl; or R 2 is -Z 1

-R

2 and R 3 is -Z 2

-R

3

Z

1 ard 2 independently of one another being a bond, O or S(O)n and n being 0, 1 or 2, and R 2 and R 3 independently of one another being hydrogen, phenyl-C 2

-C

5 alkyl, such as benzyl, or

C-C

4 alkyl, such as methyl which is unsubstituted or substituted by hydroxyl or S di-C 1

-C

4 alkylamino, such as dimethylamino, or C 1

-C

4 alkoxy-C 1

-C

4 alkoxy, such as 2-methoxyethoxy; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, one or two methyne groups are replaced by R 4 is a group of the formula Ib in which R 5 is carboxyl or S primarily 5-tetrazolyl; and the rings A and B or the (hetero)aromatic ring jointly formed by R 2 and R 3 are primarily unsubstituted, or furthermore substituted by hydroxyl, halogen, in particular of atomic number not more than 35, such as chlorine, trifluoromethyl, lower alkyl, in particular having not more than 4 C atoms, such as methyl, and/or lower alkoxy, in particular having not more than 4 C atoms, such as methoxy.

The invention relates primarily to compounds of the formula I and their salts in which Z is 0, R 1 is C 3

-C

5 alkyl, such as n-propyl or n-butyl, R 2 is halogen of atomic number not more than 35, svch as chlorine, trifluoromethyl, carboxyl, C 2

-C

5 alkoxycarbonyl, such as ethoxycarbonyl, hydrogen, hydroxyl, C 1

-C

4 alkyl, such as methyl or n-butyl, C 1

-C

4 alkoxy, such as methoxy, phenyl-C 1

-C

4 alkoxy, such as benzyloxy, hydroxy-C 1

-C

4 alkoxy, such as 2-hydroxyethoxy, C 1

-C

4 alkoxy-C 1

-C

4 alkoxy, such as 2-methoxyethoxy, or di-C 1

-C

4 alkylamino-C 1

-C

4 alkoxy, such as 2-dimethylaminoethoxy; R 3 is hydrogen,

C

1

-C

4 alkyl, such as methyl or n-butyl, carboxyl, C 2

-C

5 alkoxycarbonyl, such as ethoxycarbonyl, or hydroxy-C 1

-C

4 alkyl, such as hydroxymethyl; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in

II

-19which, if desired, a methyne group is replaced by R 4 is a group of the formula Ib in i F i which R 5 is carboxyl or primarily 5-tetrazolyl; and the rings A and B are primarily unsubstituted, or furthermore substituted by hydroxyl, halogen of atomic number not more than 35, such as chlorine, trifluoromethyl, C 1

-C

4 alkyl, such as methyl, or C 1

-C

4 alkoxy, such as methoxy.

The invention relates primarily to compounds of the formula I and their salts in which Z is 0, RI is C 3

-C

5 alkyl, such as n-propyl or n-butyl, R 2 is C 1

-C

5 alkyl, such as methyl, n-propyl or n-butyl, or hydroxyl, R 3 is hydrogen or C 1

-C

5 alkyl, such as n-propyl or n-butyl; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, a methyne group is replaced by R 4 is a group of the formula Ib in which R 5 is carboxyl or primarily 5-tetrazolyl; and the rings A and B are primarily unsubstituted or furthermore substituted by hydroxyl, halogen of atomic number not more than 35, such as chlorine, trifluoromethyl, C 1

-C

4 alkyl, such as methyl, or C 1

-C

4 alkoxy, such as methoxy.

The invention relates primarily to compounds of the formula I and their salts in which Z is O, R 1 is C 3

-C

5 alkyl, such as n-propyl or n-butyl, R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, a methyne group is replaced by R 4 is a group of the formula Ib in which R 5 is 5-tetrazolyl; and the rings A and B are unsubstituted.

-C

5 alkyl, such as n-butyl, R 2 is hydrogen, halogen of atomic number not more than 35, such as chlorine, C 1

-C

4 alkyl, such as methyl, C 1

-C

4 alkoxy, such as methoxy, and

R

3 is hydrogen, and R 4 is the group of the formula Ib in which R 5 is The invention relates primarily to compounds of the formula I and their salts in which Z is O, R 1 is C 3

-C

5 alkyl, such as n-butyl, R 2 is hydrogen, halogen of atomic number not more than 35, such as chlorine or C 1

C

4 alkyl, such as methyl, R 3 is hydrogen, and R 4 is the group of the formula Ib in which R 5 is The invention relates primarily to compounds of the formula I and their salts in which Z is O, R 1 is C 3

-C

5 alkyl, such as n-butyl, R 2 is C 1

-C

4 alkyl, such as methyl or n-butyl, and R 3 is

C

1

-C

4 alkyl, such as n butyl, or R 2 is hydroxy and R 3 is hydrogen or methyl, and R 4 is the group of the formula Ib in which R 5 is The invention relates in particular to the novel compounds mentioned in the examples and to the manners of preparation described therein.

The invention further relates to processes for the preparation of the compounds according to the invention. The preparation of compounds of the formula I takes place in a manner known per se and is, for example, characterized in that a) a compound of the formula

NH

R

1 C (Ha)

NH-R

4 or a salt thereof is reacted with a compound of the formula *0 7 O R 3

Z

II n

X

1 C- CH- C X 2 (IIb) a salt, a tautomer or a functionally modified derivative of the tautomer thereof, in which X is the variable R 2 or is etherified hydroxyl and X 2 is etherified hydroxyl, or b) in a compound of the formula

R

2 N R 3 R1 N Z

CH

2 or a salt thereof in which X 3 is a radical which can be converted into the variable R 5

X

3 is converted into the variable R 5 or c) a compound of the formula -21-

R

2 N R3 (IVa),

R

1

N

I

H

a tautomer or salt thereof is reacted with a compound of the formula X4-R4 (IVb) or a salt thereof in which X 4 is reactive esterified hydroxyl and, if desired, a compound of the formula I or a salt thereof obtainable according to the process or in another manner is converted into another compound or a salt thereof according to the invention, a free compound of the formula I obtainable according to the process is converted into a salt, a S salt obtainable according to the process is converted into the free compound of the formula I or into another salt, or a mixture of isomers obtainable according to the process is resolved and the desired compound is isolated.

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

A suitable tautomer of a compound of the formula IIb is, in particular, a compound of the formula R, Z I

II

X- X 2 (Hlb')

R

3 in which X is hydroxyl. The enolic hydroxyl group is advantageously functionally modified; X is accordingly, for example, reactive esterified hydroxyl, such as halogen, etherified hydroxyl, such as lower alkoxy, unetherified or etherified mercapto, such as lower alkylthio, or unsubstituted or substituted amino, such as lower alkyl- or di(lower alkyl)-amino.

-22- Etherified hydroxyl (X 1 or X 2 is, in particular, alkoxy, such as lowe; :lkoxy, for example methoxy or ethoxy.

X

3 radicals which can be converted into the variable R 5 are, for example, cyano, mercapto, halogen, the group -N 2 A in which A- is an anion derived from an acid, amino and different functionally modified forms of COOH, SO 3 H, P0 3

H

2 or PO 2

H

2 and also N-protected Reactive esterified hydroxyl, for example X 4 is, in particular, hydroxyl esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for S example fluorosulfonyloxy, (C 1

-C

7 )alkanesulfonyloxy which, if desired, is substituted, lor example by halogen, for example methane- or trifluoromethanesulfonyloxy,

(C

5

-C

7 )cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or benzenesulfonyloxy which, if desired, is substituted, for example by (C3-C 7 )alkyl or halogen, for example p-bromobenzene- or p-toluenesulfonyloxy.

The reactions described in the variants above and below are carried out in a manner known per se, for example in the absence or in the customary manner in the presence of a suitable solvent or diluent or a mixture thereof, the reaction being carried out, according to need, with cooling, at room temperature or with warming, for example in a temperature range from about -80 0 C up to the boiling point of the reaction medium, preferably from S about -10C to about +180 0 C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

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

Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di(lower alkyl)amides, aminoalkylamides or lower alkyl silylamides, or naphthaleneamines, lower alkylamines, basic heterocycles, ammonium hydroxides, and also carbocyclic amines. Examples which may be mentioned are sodium iydroxide, sodium hydride, sodium amide, sodium (m)ethoxide, potassium tert-butoxide, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-(aminopropyl)amide, potassiumbis(trimethylsilyl)amide, dimethylaminonaphthalene, di- Y CI I -23or triethylamine, or ethyldiisopropylamine, N-methylpiperidine, pyridine, benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

If compounds of the formula IIb of this type are employed, in which both X 1 and X 2 are etherified hydroxyl, compounds of the formula I are obtained in which R 2 is hydroxyl.

Preferably, those compounds of the formula IIb employed in which Z is O.

In order to prepare compounds of the formula I in which Z is NH, nitriles of the formula

X

1

-CO-CH(R

3 )-CN (IIc) are advantageously used.

•E

In order to prepare the starting material of the formula Ia, a compc .nd of the formula 4

NH

S. R 1 (d) *Ik (HId) Ce 060 C or a salt thereof is used in which X 2 is etherified hydroxyl, such as lower alkoxy, for example methoxy or ethoxy, and this is reacted with a compound of the formula R 4

-NH

2 (He) or a salt thereof. Compounds of the formula lid can be prepared, for example, from the corresponding nitriles, while compounds of the formula IIb and IIe are known in some cases or can be prepared in a manner known per se. Thus, compounds of the formula IIe are described, for example, in EP 253,310 or can be prepared in an analogous manner.

Functionally modified derivatives of tautomers of the formula IIb in which X is halogen S are, for example, accessible by using compounds of the formula b in which X 1 is R 2 and reacting these in a manner known per se, for example with an oxalyl halide, such as oxalyl chloride. The resulting derivative of the formula Ib' (X halogen) can be further converted into other corresponding derivatives of the formula IIb', for example by reaction with a lower alkoxide, such as sodium methoxide, with a lower alkyl thiolate, such as sodium methylthiolate, or with ammonia or a corresponding amine, such as lower alkyl- or di(lower alkyl)amine, for example ethylamine or diethylamine.

Variant b):

X

3 radicals which can be converted into 5-tetrazolyl R 5 are, for example, cyano or I i I I -24protected In order to prepare compounds of the formula I in which R 5 is 5-tetrazolyl, starting materials of the formula III, for example, are used in which X 3 is cyano, and these are reacted with an azide, such as HN 3 or, in particular, a salt, such as an alkali metal salt thereof, or with an organotin azide, such as tri(lower)alkyl- or triaryltin azide. Preferred azides are, for example, sodium azide and potassium azide and tri-C 1

-C

4 alkyl-, for example triethyl- or tributyltin azide, and triphenyl azide.

Suitable protecting groups for protected 5-tetrazolyl are the protecting groups customarily used in tetrazole chemistry, in particular triphenylmethyl, benzyl which is unsubstituted or substituted, for example by nitro, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- and ethoxyethyl, lower alkylthiomethyl, such as methylthiomethyl, and 2-cyanoethyl, and furthermore lower alkoxy-lower alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and also phenacyl.

The protecting groups are removed following known methods, for example as described in J. Green, Protective Groups in Organic Synthesis, Wiley-Interscience (1980). Thus, for example, the triphenylmethyl group 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 ethoxyethoxy is removed, for example, by treating with a lower alkyltin bromide, such as triethyl- or tributyltin bromide, methylthiomethyl is S 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 which can be converted into S0 3 H R 5 is, for example, the mercapto group.

Starting compounds of the formula III containing a group of this type are, for example, oxidized by oxidation processes known per se to those compounds of the formula I in which R 5 is S03H. Possible oxidizing agents are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as appropriate percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example a mixture of hydrogen peroxide with 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 VII, for example vandium oy molybdenum oxide or tungsten oxide, being mentioned as catalysts. The oxidation is carried out under mild conditions, for example at temperatures of about -500 to about +100 0

C.

A group which can be converted into P0 3

H

2

R

5 is to be understood as meaning, for example, a group N 2 +A in which A- is an anion of an acid, such as a mineral acid.

Diazonium compounds of this type are, for example, reacted in a manner known per se with a P(III) halide, such as PC1 3 or PBr 3 and worked up by hydrolysis, those compounds S of the formula I being obtainable in which R 5 is P03H 2 A suitable X 3 radical which can be converted into haloalkylsulfamoyl R 5 is, for example, primary amino.

In order to prepare compounds of the formula I in which R 5 is haloalkylsulfamoyl, corresponding anilines, for example, are reacted with a customarily reactive esterified 0 haloalkylsulfonic acid, the reaction being carried out, if desired, in the presence of a base.

A suitable preferred reactive esterified halosulfonic acid is the corresponding halide, such as the chloride or bromide.

4 rdical X 3 which can be converted into COOH R 5 is, for example, a functionally modified carboxyl, such as cyano, esterified or amidated carboxyl, hydroxymethyl or S 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, propanol, isopropanol, n-butanol, sec- or tert-butanol, while a suitable cycloaliphatic alcohol is, for example, a 3- to 8-membered cycloalkanol, such as cyclopentanol, -hexanol or -heptanol. An aromatic alcohol is, for example, a phenol or heterocyclic alcohol, which may in each case be substituted or unsubstituted, in particular hydroxypyridine, for example 3- or 4-hydroxypyridine.

-26- Amidated carboxyl is, for example, carbamoyl, carbamoyl which is monosubstituted by hydroxyl, amino or substituted or unsubstituted phenyl, carbamoyl which is mono- or disubstituted by lower alkyl or carbamoyl which is disubstituted by 4- to 7-membered alkylene or 3-aza-, 3-lower alkylaza-, 3-oxo- or 3-thiaalkylene. Examples which may be mentioned are carbamoyl, N-mono- or N,N-di(lower alkyl)carbamoyl, such as N-methyl-, N-ethyl-, N,N-dimethyl-, N,N-diethyl- or N,N-dipropylcarbamoyl, pyrrolidino- or piperidinocarbonyl, morpholino-, piperazino- or 4-methylpiperazino- and also thiomorpholinocarbonyl, anilinocarbonyl or anilinocarbonyl substituted by lower alkyl, lower alkoxy and, or halogen.

Preferred functionally modified carboxyl is, for example, lower alkoxycarbonyl, such as a l, methoxy- or ethoxycarbonyl, or cyano. Compounds of the formula I in which R 5 is 2: carboxyl can be prepared by oxidation, for example starting from compounds of the Sformula III in which X 3 is functionally modified carboxyl, by hydrolysis, in particular in the presence of a base, or starting from those compounds of the formula II in which X 3 is hydroxymethyl or formyl, using customary oxidizing agents.

As oxidizing agents, for example in an inert solvent, such as a lower alkanecarboxylic acid, for example acetic acid, a ketone, for example acetone, an ether, for example tetrahydrofuran, a heterocyclic aromatic, for example pyridine, or water or a mixture thereof, if necessary with cooling or warming, for example from about 0° to about 150°.

Suitable oxidizing agents are, for example, oxidizing transition metal compounds, in particular those with elements of sub-groups I, VI or VIII. Examples which may be mentioned are: silver compounds, such as silver nitrate, silver oxide or silver picolinate, chromium compounds, such as chromium trioxide or potassium dichromate, manganese compounds, such as potassium ferrate, tetrabutylammonium permanganate or benzyl(triethyl)ammonium permanganate. Other oxidizing agents are, for example, suitable compounds with elements of main group IV, such as lead dioxide, or halogen-oxy, compounds, such as sodium iodate or potassium periodate.

Thus, for example, hydroxymethyl and formyl are oxidized to carboxyl R 5 This variant is preferably suitable for the preparation of those compounds of the formula I in which the variables have meanings which are different from unsaturated radicals.

The starting material of the formula III is, for example, accessible by starting from -27compounds of the formula IVa and reacting these in analogy to variant c) with a compound of the formula

X

3

X

4

-CH

2

(I

in which X 3 and X 4 have the abovementioned meanings.

Compounds of the formula III are known in some cases or can be prepared by known S methods, for example as shown in EP 253,310 (page 52 et seq.).

Variant c: The reaction of compounds of the formula IVa with compounds of the formula IVb is advantageously carried out in a manner known per se in the presence of one of the abovementioned bases.

X

4 is preferably halogen, such as chlorine or bromine, or sulfonyloxy, such as methane- or p-toluenesulfonyloxy.

The starting compounds of the formula IVa and IVb are known in some cases or can be prepared in a manner known per se. Thus, for example, compounds of the formula IVa are S• obtained by starting from compounds of the formula IIa in which R 4 is hydrogen, in analogy to variant and reacting these with a compound of the formu'a IIb. Compounds of the formula IVa in which R 2 and R 3 are jointly the partial structure of the formula -CH=CH-CH=CH-, in which, if desired, one or two of the methyne groups are replaced by can be prepared, for example, by starting from a corresponding compound of the formula RO (IVc) R2 NH 0 -28 and reacting this, if appropriate in the presence of a base, with an amidine of the formula IIa.

The starting material of the formula IVb is known from EP 253,310 in some cases or can be prepared using customary methods.

[TI

A compound according to the invention which is obtainable by the process can be Ui converted into another compound according to the invention in a manner known per se.

A compound according to the invention containing hydroxyl can be etherified by methods known per se. The ethzrification can be carried out, for example, using an alcohol, such as a substituted or unsubstituted lower alkanol, or a reactive ester thereof. Possible reactive esters of the desired alcohols are, for example, those with strong inorganic or organic S acids, such as corresponding halides, sulfates, lower alkanesulfonates or substituted or unsubstituted benzenesulfonates, for example chlorides, bromides, iodides, methane-, S benzene- or p-toluenesulfonates. The etherification can be carried out, for example, in the presence of a base, an alkali metal hydride, hydroxide or carbonate, or a basic amine.

Inversely, corresponding ethers, such as lower alkoxy compounds, can be cleaved, for example, by means of strong acids, such as mineral acids, for example the hydrohalic acids, hydrobromic or hydriodic acid, which may advantageously be present in the form of pyridinium halides, or by means of Lewis acids, for example halides of elements of main group III or the corresponding sub-groups. These reactions can be carried out, if necessary, with cooling or warming, for example in a temperature range of about -200 to about 100 0 C, in the presence or absence of a solvent or diluent, under inert gas and/or under pressure and, if appropriate, in a closed vessel.

Compounds according to the invention containing hydroxymethyl groups can be prepared, for example, starting from corresponding compounds containing carboxyl or esterified carboxyl, the corresponding compounds being reduced in a manner known per se, for example by reduction with a hydride which may be complex, such as a hydride formed from an element of main groups I and III of the periodic table of the elements, for example a borohydride or aluminohydride, for example lithium borohydride, or lithium- or diisobutylaluminium hydride (a subsequent reduction step using an alkali metal cyanoborohyride, such as sodium cyanoborohydride, may be necessary), and further diborane.

-29- If an aromatic structural component is substituted by (lower)aikylthio, this can be oxidized in the customary manner to the corresponding (lower)alkanesulfinyl or -sulfonyl. Suitable oxidizing agents for the oxidation to the sulfoxide step are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as appropriate percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example a mixture of hydrogen peroxide with acetic acid.

The oxidation is commonly carried out in the presence of suitable catalysts, catalysts which can be mentioned being suitable acids, such as substituted or unsubstituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, S such as oxides of elements of sub-group VII, for example vanadium oxide, molybdenum S oxide or tungsten oxide. The oxidation is carried out under mild conditions, for example at temperatures of about -500 to about +100 0

C.

The oxidation to the sulfone step may also be carried out appropriately at low temperatures using dinitrogen tetroxide as the catalyst in the presence of oxygen, just like the direct oxidation of (lower)alkylthio to (lower)alkanesulfonyl. However, in this case the oxidizing agent is customarily employed in excess.

If one of the variables (for example R 2 and contains amino, corresponding compounds of the formula I, their tautomers or salts can be N-alkylated in a manner known per se; likewise, carbamoyl or radicals (for example R 2 containing carbamoyl can be N-alkylated. The (aryl)alkylation is carried out, for example, using a reactive ester of an (aryl)C 1

-C

7 alkyl halide, for example a bromide or iodide, an (aryl)C 1

-C

7 alkylsulfonate, for example a methanesulfonate or p-toluenesulfonate, or a di-C 1

-C

7 alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide solution, and advantageously in the presence of a phase-transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammonium chloride, where, however, stronger basic condensing agents, such as alkali metal amides, hydrides or alkoxides, for example sodium amide, sodium hydride or sodium ethoxide, may be necessary.

In compounds of the formula which contain an esterified or amidated carboxyl group (for example R 2 or R 3 as a substituent, a group of this type can be converted into a free r i carboxyl group, for example by means of hydrolysis, for example in the presence of a basic agent, or an acidic agent, such as a mineral acid. Tert-butyloxycarbonyl, for example, may furthermore be converted into carboxyl, for example in a manner known per se, such as by treating with trihaloacetic acid, such as trifluoroacetic acid, and benzyloxycarbonyl may be converted into carboxyl, for example by catalytic hydrogenation in the presence of a hydrogenation catalyst, for example in the manner described below.

Furthermore, in compounds of the formula which contain a carboxyl group (for example R 3 as a substituent, in particular if R, is different from carboxyl, this can be converted into an esterified carboxyl group (for example R 3 for example, by treating with an alcohol, such as a lower alkanol, in the presence of a suitable esterifying agent, such as •an acid reagent, for example an inorganic or organic acid or a Lewis acid, for example zinc chloride, or a condensing agent which combines with water, for example a carbodiimide, such as N,N'-dicycloh,. ylcarbodiimide, or by treating with a diazo reagent, such as with a diazo-lower alkane, for example diazomethane. This can also be obtained if compounds of the formula I in which the carboxyl group (for example R 2 is present in free form or in salt form, such as ammonium salt or metal salt, for example alkali metal salt, such as sodium salt or potassium salt form, are treated with a reactive ester of a

(C

1

-C

7 )alkyl halide, for example methyl or ethyl bromide or iodide, or an organic sulfonic acid ester, such as an appropriate (C 1

-C

7 )alkyl ester, for example methyl or ethyl mrnethanesulfonate or p-toluenesulfonate.

Compounds of the formula which contain an esterified carboxyl group (for example

R

3 as a substituent can be transesterified into other ester compounds of the formula by transesterification, for example by treating with an alcohol, customarily a higher appropriate alcohol than that of the esterified carboxyl group in the starting material, in the presence of a suitable transesterifying agent, such as a basic agent, for example an alkali metal (C 1

-C

7 )alkanoate, (C 1

-C

7 )alkanolate or cyanide, such as sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide or sodium cyanide, or a suitable acid agent, if appropriate with removal of the resulting alcohol, for example by distillation.

Appropriate, so-called activated esters of the formula may also be used which contain an activated esterified carboxyl group as a substituent (see below), and these may be converted into another ester by treating with a (C1-C 7 )alkanol.

In compounds of the formula which contain the carboxyl group (for example R 2 as a -31 substituent, this can also first be converted into a reactive derivative, such as an anhydride, including a mixed anhydride, such as an acid halide, for example an acid chloride (for example by treating with a thionyl. 'de, for example thionyl chloride), or an anhydride using a formic acid ester, for example a (C 1

-C

7 )alkyl ester (for example by treating a salt, such as an ammonium or alkali metal salt, with a haloformic acid ester, such as a chloroformic acid ester, such as a (C 1

-C

7 )alkyl ester), or into an activated ester, such as a cyanomethyl ester, a nitrophenyl ester, for example a 4-nitrophenyl ester, or a polyhalophenyl ester, for example a pentachlorophenyl ester (for example by treating with an appropriate hydroxyl compound in the presence of a suitable condensing agent, such as N,N'-dicyclohexycarbodiimide), and then a reactive derivative of this type can be reacted with an amine and in this way amide compounds of the formula which contain an amidated carboxyl group as a substituent can be obtained. In this case, these can be obtained directly or via intermediate compounds; thus, for example, an activated ester, S such as a 4-nitrophenyl ester or a compound of the formula I containing a carboxyl group S can first be reacted with a 1-unsubstituted imidazole and the 1-imidazolylcarbonyl compound obtained in this way brought to reaction with an amine. However, other non-activated esters, such as (C 1

-C

7 )alkyl esters of compounds of the formula r' which contain, for example, (C 2

-C

8 )alkoxycarbonyl (for example R 2 as a substituent, can also be brought to reaction with amines.

S If an aromatic ring contains a hydrogen atom as a substituent, the latter can be replaced by a halogen atom with the aid of a halogenating agent in a customary manner, for example brominated with bromine, hypobromic acid, acyl hypobromite or other organic bromine compounds, for example N-bromosuccinimide, N-bromoacetamidc, N-bromophthalimide, pyridinium perbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin or 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one, or chlorinated with elemental chlorine, for example in a halogenated hydrocarbon, such as chloroform, and with cooling, for example from down to about -100 to about +100 0

C.

If an aromatic ring in the compounds according to the invention contains an amino group, this can be diazotized in a customary manner, for example by treating with a Pitrite, for example sodium nitrite, in the presence of a suitable protonic acid, for example a mineral acid, the reaction temperature advantageously being kept below about 5 0 C. The diazonium group present in the salt form v nich can be obtained in this way can be substituted by analogous processes, for example as follows: through the hydroxyl group analogously to the boiling-out of phenol in the presence of water; by an alkoxy group by treating with an -32appropriate alcohol, energy having to be added; by the fluorine atom analogous to the Schiemann reaction in the thermolysis of corresponding diazonium tetrafluoroborates; by the halogen atoms chlorine, bromine or iodine and also the cyano group analogously to the Sandmeyer reaction in the reaction with corresponding Cu(I) salts, initially with cooling, for example to below about 5 0 C, and then heating, for example, to about 600 to about 150 0

C.

If the compounds of the formula contain unsaturated radicals, such as (lower)alkenyl or (lower)alkynyl groups, these can be converted into saturated radicals in a manner known per so. Thus, for example, multiple bonds are hydrogenated by catalytic hydrogenation in the presence of hydrogenation catalysts, suitable for this purpose being, for example, .nickel, such as Raney nickel, and noble metals or their derivatives, for example oxides, such as palladium or platinum oxide, which may be applied, if desired, to support materials, for example to carbon or calcium carbonate. The hydrogenation may preferably carried out at pressures between 1 and about 100 at and at room temperature between about -800 to about 200 0 C, in particular between room temperature and about 100 0 C. The reaction is advantageously carried out in a solvent, such as water, a lower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkanecarboxylic acid, for example acetic acid.

Furthermore, in compounds of the formula I in which, for example, one of the radicals Ri and/or Alk is halogen, such as chlorine, halogen can be replaced by reaction with an appropriate substituted or unsubstituted amine, an alcohol, in particular a salt thereof, or a mercaptan, in particular a salt thereof.

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

Salts of compounds of the formula or their tautomers can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of the formula or a tautomer thereof are obtained by treating with an acid or a suitable ion exchange reagent.

Salts can be converted into the free compounds in a customary manner, and acid addition salts can be converted, for example, by treating with a suitable basic agent.

Depending on the procedure or reaction conditions, the compounds according to the invention having salt-forming, in particular basic properties, can be obtained in free form or preferably in the form of salts.

I r- -33- In view of the close relationship between the novel compound in the free form and in the form of its salts, in the preceding parts and below the free compound or its salts may analogously and expediently also be understood as meaning the corresponding salts or the free compound.

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

The novel compounds may exist, depending on the choice of the starting materials and procedures, in the form of one of the possible isomers or as mixtures thereof, for example, S• depending on the number of asymmetrical carbon atoms, as pure optical isomers, as antipodes, or as isomer mixtures, such as racemates, diastereomer mixtures or racemate mixtures.

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

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

In the process of the present invention, those starting materials are preferably used which -34lead to the compounds described as particularly useful at the beginning. The invention likewise relates to novel starting materials which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation, the variables Z, R 1

R

2

R

3

R

4 and R 5 having the meanings indicated in each case for the preferred compound groups of the formula I or tautomers thereof. In particular, compounds of the formula III, their tautomers and salts in which X 3 is cyano are preferred as a starting material.

The invep don likewise relates to the use of the compounds of the formula or tautomers thereof or of pharmaceutically acceptable salts of compounds of this type with salt-forming properties, in particular as pharmacological, primarily angiotensin II antagonist, active substances. In this connection, they can be used, preferably in the form of pharmaceutically acceptable preparations, in a method for the prophylactic and/or therapeutic treatment of the animal or human body, in particular as angiotensin II antagonists.

The invention likewise relates to pharmaceutical preparations which contain the compounds according to the invention or pharmaceutically acceptable salts thereof as active ingredients, and to processes for their preparation.

S The pharmaceutical preparations according to the invention which contain the compound according to the invention or pharmaceutically acceptable salts thereof are those for enteral, such as oral, furthermore rectal, and parenteral administration to (a) i warm-blooded animal(s), the pharmacological active ingredient being contained alone or together with a pharmaceutically acceptable carrier material. The daily dose of the active ingredient depends on the age and ti. individual condition and also on the manner of administration.

The novel pharmaceutical preparations contain, for example, from about 10 to about preferably from about 20 to about 60 of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in dose unit forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture

I

35 obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable adjuncts to give tablets or sugar-coated tablet cores.

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

Colorants or pigments, for example to identify or to indicate different doses of active ingredient, may additionally be added to the tablets or sugar-coated tablet coatings.

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

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

-36 Suitable preparations for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.

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

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

Example 1: 2-n-Butyl-1,6-dihydro- -[(2'-cyanobiphenyl-4-yl)methyl]-6-oxo pyrimidine g, 5.82 mmol) and tributyltin azide [Synthesis 1976, 329] (3.86 g, 11.64 mmol) in o-xylene (50 ml) are stirred under reflux for 24 hours. The reaction mixture is evaporated oo* in vacuo and stirred into a mixture of CH 2 C1 2 /CH30H/NH3 100 ml) during the course of 30 minutes. After evaporating again in vacuo, the residue is separated by means of flash chromatography (silica gel 60, 40-63 Rm, CH 2

C

2

/CH

3

OH/NH

3 80:10:1) and the product is recrystallize 1 from ethanol-H 2 0. White crystals of 2-n-butyl-l,6-dihydro-1- [(2'-(1H-tetrazolyl-5-yl)biphenyl-4-y 1)methyl]-6-oxopyrimidine are obtained in this way.

180-182 0

C.

N=N

NJ N NH

CH

3

-(CH

2 3 N O

CH

2 The starting material can be prepared as follows: a) NaH (80 in white oil, 0.92 g, 30.5 mmol) is added in portions at room temperature to a solution of 5.7 g (3.05 mmol) of 2-n-butyl-4-chloro-6-hydroxypyrimidine Chem. Soc.

-37- 1964, 3204] in 60 ml of DMF. After addition is complete, the mixture is stirred for a further 30 minutes at room temperature and a solution of 8.3 g (30.5 mmol) of 4-bromomethyl-2'-cyanobiphenyl [EP 253,310] in 50 ml of DMF is then added dropwise.

The reaction mixture is stirred at room temperature for 12 hours and then evaporated in vacuo. Ethyl acetate is added to the residue and the mixture is washed twice with H 2 0, dried (Na 2

SO

4 and evap-r.;ted in vacuo. Flash chromatography (silica gel 60, 40-63 Rm, hexane-ethyl acetate -,fes 2-n-butyl-4-chloro- 1,6-dihydro-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidiae which is recrystallized from diethyl ether. White crystals remain. M.p. 96-98 0

C.

b) A mixture of 5.5 g (14.5 mmol) of 2-n-butyl-4-chloro-1,6-dihydro-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine in 80 ml of methanol and 1.62 g (16 mmol) of triethylamine is hydrogenated at room temperature and 1 atm of H 2 in the course of 1 hour in the presence of 5 Pd-C (0.5 The catalyst is filtered off and the filtrate is

*S

evaporated in vacuo. Ethyl acetate is added to the residue and the mixture is washed twice with H 2 0, dried (Na 2

SO

4 and evaporated in vacuo. 2-n-Butyl-1,6-dihydro-1-[(2'- Scyan uiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained in this way, and is reacted without further purification.

Example 2: Starting from 2-n-butyl-4-c' 1 oro-1,6-dihydro-1-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine (Example la) and tributyltin azide, 2-n-butyl-4-chloro-1,6dihydro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained in the manner described, for example, in Example 1. 127 0 C (dec.).

Example 3: Starting from 2-n-butyl-1,6-dihydro-4-dimethylamino- cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6- S dihydro-4-dimethylamino- l-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained in the manner described, for example, in Example 1. 246 0

C

(decomposition).

The starting material can be prepared, for example, as follows: g (5.36 mmol) of 2-n-butyl-4-chloro-1,6-dihydro-1-[(2'-cyanobiphenyl-4 yl)methyl]-6oxopyrimidine and 33 dimethylamine in ethanol (3.8 ml, 21.4-mmol) in 10 ml of ethanol are stirred under reflux. for 12 hours. After evaporating in vacuo, ethyl acetate is added to the residue and the mixture is washed twice with H 2 0, dried (Na 2

SO

4 and -38evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 [Im, hexane/ethyl acetate 1:2) gives 2-n-butyl- 1,6-dihydro-4. dimethylaminio-1- [(2'-cyanobiphenyl-4-yl)methyl] -6oxopyrimidine as a white foam which is immediately further processed.

Example 4: Starting from 2-n-butyl- 1,6-dihydro-4-methyl-l1-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6-dihydro-4-methyl-l1-[(2'tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 213-216'C.

The starting material can be prepared, for example, as follows: 2-n-Butyl- 1,6-dihydro-4-methyl-l1 .(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained by alkylation of 2-n-butyl-4-hydroxy-6-methylpyrimidine Chem. Soc. 1963, ::5642] with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example la. The product obtained by flash chromatography (silica gel 60, 40-63 R±m, CH 2

CI

2

/CH

3

OH

9:)is immediately further processed.

Example Starting from 2-n-butyl- 1 ,6-dihydro-4-methoxy- 1-[(2'-cyanobiphenyl-4yl)methyl]..6-oxopyrimnidine and tributyltin azide, 2-n-butyl-1,6-dihydro-4-methoxy-1- -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 223-225 0

C.

The starting material can be prepared, for example, as follows: g (2.65 mmol) of 2-n-butyl-4-chloro- 1,6-dihydro-[(2'-cyanobiphe.nyl-4-yl)methyl]-6oxopyrimidine is added to a solution of 343 mg (6.35 mmol) of sodium methoxide in ml of methanol. The reaction mixture is stirred at room temperature for 12 hours and then evaporated in vacuo. Ethyl acetate is added to the residue and the mixture is washed twice with H-20, dried (Na 2 S0 4 and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 pin, hexane/ethyl acetate 1: 1) gives 2-n-butyl- 1,6-dihydro-4-methoxy-1 -cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine, which is immediately further processed.

Example 6: Starting.from 2-n-butyl- 1,6-dihydro-4-morpholino-l1-[(2'-cyanobiphenyl-4yl)rnethyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6-dihydro-4-morpholino- 1- 1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in -39- the manner described in Example 1. M.p. 2781C (from ethyl acetate).

The starting material can be prepared, for example, as follows: g (2.65 mmol) of 2-n-butyl-4-chloro-1 ,6-dihydro- 1-[(2'-cyanobiphenyl-4-yl)methyl]-6oxopyrimidine and 0.92 ml (10.6 mmol) of morpholine in 20 ml of n-butanol are stir-red under reflux for 12 hours. After evaporating in vacuo, ethyl acetate is added to the residue and the mixture is washed twice with H120, dried (Na 2

SO

4 and evaporated in vacuo. The residue is recrystallized from ethyl acetate/hexane. 2-n-Butyl-1,6-dihydro-4morpholino-1-[(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained in this way.

M.p. 124-126'C.

Example 7: Starting from 2-n-butyl-1,6-dihydro-4-methylthio-1-1I(2'-cyanobiphenyl-4- SWyl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6-dihydro-4-methylthio-1- [2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 205'C (from ethyl acetate).

The starting material can be prepared, for example, as follows: 870 mg (2.30 mmol) of 2-n-butyl-4-chloro- 1,6-dihydro-l1-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and 180 mg (2.53 mmol) of sodium methanethiolate in 10 Ml.

of 1 ,3-dimethyl-3,4,5 ,6-tetrahydro-2(1H)-pyrimidinone are stirred at room temperature for minutes. After addition of H 2 0, the mixture is extracted with ethyl acetate, and the organic phase is washed with H 2 0, dried (Na 2

SO

4 and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 gim, hexane/ethyl acetate 1: 1) gives 2-n-butyl- 1,6-dihydro-4-methylthio- -cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine as a resin which is immediately further processed.

Example 8: 240 mg (0.55 mmol) of 2-n-butyl-1,6-dihydro-4-methylthio-1-[2'-(1Htetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine and 500 mg (1.45 mmol) of 50 3-chloroperbenzoic acid in 10 ml of CH 2 C1 2 are stirred at room temperature for 12 hours.

After evaporating in vacuo, ethyl acetate is added to the residue and the mixture is washed twice with H120, dried (Na 2

SO

4 and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 gim, CH 2 Cl 2

/CH

3

OHINII

3 =80:10:1) gives 2-n-butyl-1,6-dihydro-4methanesulfonyl- -(111-tetrazol-5-yl)biphenyl-4-yl)methyl] 6-oxopyrimidine as an amorphous solid.

40 Example 9: Starting from 2-n-butyl- 1,6-dihydro-4-(2-hydroxyethoxy)-l1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6dihydro-4-(2-hydroxyethoxy)- 1 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p.

150'C (from isopropanollethyl acetate).

The starting material can be prepared, for example, as follows: 1 g of (2.65 mmol) 2-n-butyl-4-chloro- 1,6-dihydro-1- -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyridine is addoed to a solution of 122 mg (5.3 mmol) of sodium in 20 ml of ethan-1,2-diol and the reaction mixture is stirred at 700 for one hour. After evaporating in sequ vacuo, ethyl acetate is added to the residue and the mixture is washed with H 2 0, dried (Na 2

SO

4 and evaporated in vacuo. 2-n-Butyl- 1,6-dihydro-4-(2-hydroxyethoxy)- (1H-tetrazol-5-yl)biphenyl-4-yl)methyl ]-6oxopyrimidine is obtained. M.p. 1 19-121' (from ethyl acetate/hexane).

Example 10: Starting from 2-n-butyl- 1,6-dihydro-4-(2-methoxyethoxy)-l1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6dihydro-2-(2-methoxyethoxy)-l142' H-tetrazol-5-yl)biphenyl-4--yl)methyl] -6- .**.oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p.

195-197'C (from ethyl acetate).

Si,, The starting material can be prepared, for example, as follows: g (2.65 mmol) of 2-n-butyl-4-chloro- 1,6-dihydro-1- [(2'-cyanobiphenyl-4yl)methyll-6-oxopyrimidine is added to a solution of 122 mg (5.2 mmol) of sodium in ml of 2-methoxyethanol and the reaction mixture is stirred at room temperature for 12 hours. After evaporating in vacuo, ethyl acetate is added to the residue and the mixture is washed with 1120, dried (Na 2 S0 4 and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 g±m, ethyl acetate/hexane 1:1) gives 2-n-butyl-1,6-dihydro-4-(2methoxyethoxy)- 1-[(2'-cyanobiphenyl-4-yl)methylj-6-oxopyrimidine as a viscous oil which is immediately further processed.

Example 11: Starting from 2-n-butyl- 1,6-dihydro-4-(2-dimethylaminoethoxy)-1 [(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, W M -41- 2-n-butyl- 1,6-dihydro-4-(2-dime-thylaminoethoxy)-l1-[(2'-( 1H-tet biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1 as an amorphous solid.

The starting material can be prepared, for example, as follows: g (2.65 mmol) of 2-n-butyl-4-chloro- 1,6-dihydro- -cyanobiphenyl-4-yl)methyl]-6oxopyrimidine is added to a solution of 142 mg (5.92 mmol) of sodium in 20 ml of 2-dimethylaminoethanol and the reaction mixture is stirred at room temperature for 12 hours. After evaporating in vacuo, ethyl acetate is added to the residue and the mixture is washed with H20 dried (Na 2

SO

4 and evaporated in vacuo. Flash chromatography *..(silica gel 60, 40-63 g±m, CH 2 Cl 2

/CH

3 OH 95:5) gk*; -s 2-n-butyl- 1,6-dihydro-4-(2- ***:dimethylarini-octhoxy)-1-[(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine as an oil 0 .0 which is immediately further processed.

Example 12: Starting from 4-benzyloxy-2-n-butyl- 1,6-dihydro- 1- (2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and tributyltin azide, 4-benzyloxy-2-n-butyl- 1,6-dihydro- 1- -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 240'C (from N,N-dimethylformamide/H 2 0).

The starting material can be prepared, for example, as follows: 1.Og (2.65 mmoi) of 2-ii-butyl-4-chloro-1,6-dihydro-1-[(2'-cyanobiphenyl-4-yl)methyl]- 6-oopyimiineis added to a solution of 122 mg (5.3 mmol) of sodium in 10 ml of" benzyl alcohol and the reaction mixture is stirred at 60'C for 3 hours. After evaporating in Nlacuo, ethyl acetate is added to the residue and the mixture is washed with H120, dried (Na 2 S0 4 0to and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 xmr, hexane/ethyl acetate 3:1) gives 4-benzyloxy-2-n-butyl- 1,6-dihydro- 1-[(2'-cyanobiphenyl-4yl)methyll-6-oxopyrimidine as an oil which is immediately further processed.

Example 13: Starting from 2,4-di-n-butyl-1 ,6-dihydro-l1-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and tributyltin azide, 2,4-di-n-butyl- 1,6-dihydro-1- (1H-tetrazoli-5-yl)biphenyl-4-yl)methyl] -6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 167-169'C (from acetic acid/H 2 0).

A

The starting material can be prepared, for example, as -follows: -42a) 2.73 g (20 mmol) of n-valeroylamidine.HCI are added with ice-cooling to a solution of 920 ml (40 mmol) of sodium in 40 ml of absolute ethanol. After addition is complete, the mixture is stirred for 30 minutes and a solution of 3.44 g (20 mmol) of ethyl 3-oxohexanoate in 5 ml of absolute ethanol is then added dropwise. The reaction mixture is stirred at room temperature for 12 hours and then evaporated in vacuo. The residue is dissolved in H.

2 0 and acidified by addition of acetic acid. The mixture is extracted with ethyl acetate, washed with H 2 0, dried (Na 2 SO04) and evaporated in vacuo. Flash -I chromatography (silica gel 60, 40-63 gm, hexane/ethyl acetate 1:1) gives 2,4-di-n-butyl-6-hydroxypyrimidine which is immediately further processed.

By alkylation of 2,4-di-n-butyl-6-hydroxypyrimidine with 4-bromomethyl-2't cyanobiphenyl in the manner described in Example la) and flash chromatography (silica gel 60, 40-63 Rm, hexane/ethyl acetate 2,4-di-n-butyl-1,6-dihydro-1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained as an oil which is immediately further processed.

*6 Example 14: Starting from 2-n-propyl-1,6-dihydro-4-methyl-1-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-propyl-1,6-dihydro-4-methyl-1- [2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]l-6-oxopyrimidine is obtained, for example, in S the manner described in Example 1. M.p. 203-205 0 C (from ethyl acetate).

The starting material can be prepared, for example, as follows: *go a) By reaction of ethyl 3-oxopentanoate with acetamidine.HCI and sodium in absolute :0 ethanol in the manner described in Example 13a), 2-n-propyl-4-methyl-6- 6606 hydroxypyrimidine is obtained and is immediately further processed.

b) By alkylation of 2-n-propyl-4-minethyl-6-hydroxypyrimidine with 4-bromomethyl-2'cyanobiphenyl in the manner described in Example la) and flash chromatography (silica gel 60, 40-63 gm, hexane/ethyl acetate 2-n-propyl-1,6-dihydro-4-methyl-1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained. M.p. 101-103 0 C (from diethyl ether/hexane).

Example 15: Starting from 2-n-butyl-1,6-dihydro-4,5-dimethyl- 1-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6-dihydro-4,5-dimethyl- 1- 43 [2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 198-2001C (from acetic acidll- 2 0).

The starting material can be prepared, for example, as follows: a) By reaction of ethyl 2-methyl-acetylacetate with n-valeroylamnidine.HCl and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-4,5-dimethyl-6hydroxypyrimidine is obtained and is immediately further processed.

b) By alkylation of 2-n-butyl-4,5-dimethyl-6-hydroxypyrimidine with 4-bror -nethyl-2'cyanobiphenyl in the manner described in Example 1a) and flash chromatography (silica gel 60, 40-63 gm, hexane/ethyl acetate 2-n-butyl-1,6-dihydro-4,5-dimethyl-l- [(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained and is immediately further processed.

Example 16: Starting from 2-n-butyl-l,6-dihydro-4-trifluoromnethyl-1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-l,6dihydro-4-tifluoromethyl- 1.42 lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 138-140'C (from ge* diethyl ether).

*.:The starting material can be prepared, for example, as follows: a) By reaction of ethyl trifluoroacetate with n-valeroylamidine.HCl and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-4-trifluoromethyl-6hydroxypvrimidine, is obtLained and is immediately further processed.

too& b) By alkylation of 2-n-butyl-4-trifluoromethyl-6-hydroxypyrimidine with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example l a) and flash chromatography (silica gel 60, 40-63 Rm, hexane/ethyl acetate 2-n-butyl-l,6dihydro-4-trifluoromethyl-1-[(2' -cyanobiphenyl-4-yl)rnethyl]-6-oxopyrimidine is obtained and is immediately further processed.

Example 17: Starting from 2-n-butyl- 1,6-dihydro-5-ethyl-4-methyl-l1-[(2'cyanobiphenyl-4-yl)methyll-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6dihydro-5-ethyl-4-methyl-l1-[(2'-( 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimiddine -44 is obtained, for example, in the manner described in Example 1. M.p. 162-1631C (from acetonitrile).

The starting material can be prepared, for example, as follows: a) By reaction of ethyl 2-ethyl-acetylacetate with n-valeroylamidine.HCl and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-5-ethyl-4is obtained and is immediately further processed.

b) By alkylation of 2-n-butyl-5-ethyl-4-methyl-6-hydroxypyrimidine with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example 1 a) and flash chromatography (silica gel 60, 40-63 kim, hexane/ethyl acetate 2-n-butyl- 1,6dihydro-5-ethyl-4-methyl-lI-[(2'-cyanobiphenyl-4-yl)methyl] -6-oxopyrimidine is obtained and is immediately further processed.

Example 18: Starting from 2-n-butyl-1,6-dihydro-5-isopropyl-4-methyl-1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6dihydro-5-isopropyl-4-methyl- 1H-tetrazol-5-yl)biphenyl-4-yl)-methyl]-6oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p.

182'C (fr-om diethyl ether).

S:The starting material can be prepared, for example, as follows: a) By reaction of ethyl 2-isopropyl-acetylacetate with n-valeroylamidine.HCl and sodium in absolute ethanol in the manner d1escrib'A in Example 13a), 2-n-butyl-5-isopropyl-4- 0:6 methyl-6-hydroxypyrimidine is obtained and is immediately further processed.

b) By alkylation of 2-n-butyl-5-isopropyl-4-methyl-6-hydroxypyrimidine with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example 1la) and flash chromatography (silica gel 60, 40-63 tim, hexane/ethyl acetate 2-n-butyl- 1,6dihydro-5-isopropyl-4-methyl- 1-[(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained and is immediately further processed.

Example 19: Starting from 2-n-butyl- 1,6-dihydro-4-ethyl- 1-[(2'-cyanobiphenyl-4vl~methyl]-6-oxopyrirnidine and tributyltin azide, 2-n-butyl- 1,6-dihydro-4-ethyl-l1-[(2'- (lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 178-180'C (from acetonitrile).

The starting material can be prepared, for example, as follows: a) By reaction of ethyl 3-oxovalerate with n-valeroylamidine.HCl and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-4-ethyl-6-hydroxypyrimidine is obtained and is immediately further processed.

b) By alkylation of 2-n-butyl-4-ethyl-6-hydroxypyrimidine with 4-bromomethyl-2' cyanobiphenyl in the manner described in Example la) and flash chromatography (silicaI gel 60, 40-63 R±m, hexane/ethyl acetate 2-n-butyl-1,6-dihydro-4-ethyl-1--[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained and is immediately further processed.

Example 20: Starting from 2-n-L yl-1,6-dihydro-4-n-propyl-1-[(2'-cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6-dihydro-4-n-propyl-1- (1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p. 177-178'C (from ethyl acetate/hexane).

The starting material can be prepared, for example, as follows: By reaction of ethyl butyrylacetate with n-valeroylamidine.HCl and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-4-n-propyl-6- *hydroxypyrimidine is obtained and is immediately further processed. 7 b) By alkylation of 2-n-butyl-4-n-propyl-6-hydroxypyrimidine with 4-bromomethyl-2'cyanobiphenyl in the manner described in Example l a) and flash chromatography (silica gel 60, 40-63 gm hexane/ethyl acetate 2-n-butyl-1,6-dihydro-4-isopropyl-l-[(2'cyan-obiphenyl-4-yl)methyll-6-oxopyrin-idine is obtained and is immediately further processed.

Example 21: Starting from 2-n-butyl- 1,6-dihydro-4-methyl-5-n-propyl-l1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine is obtained, for example, in the manner described in Example 1 as an amorphous solid.

46 The starting material can be prepared, for example, as follows: a) By reaction of ethyl 2-n-propyl-2-acetylacetate with n-valeroylamnidine.H0l and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-4-methyl-5n-propyl-6-hydroxypyrimidine is obtained and is immediately further processed.

b) By alkylation of 2-n-butyi-4-methyl-5-n-propyl-6-hydroxypyrimidine with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example 1a) and flash chromatography (silica gel 60, 40-63 [tm, hexane/ethyl acetate 2-n-butyl-1,6dihydro-4-methyl-5-n-propyl-l1-[(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is o btained and is immediately further processed.

0 99 ~*Example 22: Starting from 2-n-butyl-1,6-dihydro-5-ethoxycarbonyl-1-[(2'cyanobiphenyl-4-yi)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6dihydro-5-ethoxycarbonyi. 14(2'-(1H-tetrazolb5-ylbiphenyl-4y'lmethyl]-6= 1 175-177'C (from ethyl acetate).

0Po The starting material can be prepared, for example, as follows: a) By reaction of diethyl ethoxymethylenemalonate with n-valeroylamidine.HCI and sodium in absolute ethanol in the manner described in Example 13a), ethoxycarbonyl-6-hydroxypyrimidine is obtained and is immediately further processed.

b) By alkylation of 2-n-butyl-5-ethoxycarbonyl-6-hydroxypyrimidine with 999 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example la) and flash chromatography (silica gel 60, 40-63 gim, hexane/ethyl acetate 2-n-butyl-1,6dihydro-5-ethoxycarbonyl-l1-[(2'-cyanobiphenyl-4-yl)methyll-6-oxopyrimidine is obtained and is immediately further processed.

Example 23: 1.1 n-l of IN NaCH are added to a solution of 245 mg (0.534 mmol) of 2-n-butyl- 1,6-dihydro-5-ethoxycarbonyl- 1-[(2'-(11I-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine in 8 ml of ethanol. The reaction mixture is stirred at room temperature for 2 hours and then evaporated in vacuo. After addition of H 2 0, it is acidified with 1N HC1 (pH 3) and extracted with CH 2

CI

2 The organic phases are dried (Na 2 S 04) and -47evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 gm, CH 2

CI

2

/CH

3 0H/NH3 5:3:1) gives 2-n-butyl-5-carboxy-1,6-dihydro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]-6-oxopyrimidine as an amorphous solid.

Example 24: Starting from 2-n-butyl- 1,6-dihydro-4-methoxymethyl- cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6dihydro-4-methoxymethyl- 1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p.

193 0 C (from ethyl acetate) The starting material can be prepared, for example, as follows: *6* a) By reaction of methyl 2-methoxyacetylacetate with n-valeroylamidine.HCl and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-4methoxymethyl-6-hydroxypyrimidine is obtained and is immediately further processed.

*O

b) By alkylation of 2-n-butyl-4-methoxymethyl-6-hydroxypyrimidine with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example la) and flash chromatography (silica gel 60, 40-63-gm, hexane/ethyl acetate 2-n-butyl-1,6dihydro-4-methoxymethyl- 1-[(2'-cyanobiphenyl-4-yl)methyll-6-oxopyrimidine is obtained and is directly further processed.

Example 25: Starting from 2-n-butyl-1,6-dihydro-5-hydroxymethyl-1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6dihydro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine is obtained, for example, in the manner described in Example 1. M.p.

147 0 C (from ethyl acetate).

The starting material can be prepared, for example, as follows: a) A solution of 2.6 g (11.6 mmol) of 2-n-butyl-5-ethoxycarbonyl-6-hydroxypyrimidine in ml of absolute tetrahydrofuran is added dropwise at room temperature to a suspension of 440 mg (11.6 mmol) of lithium aluminium hydride in 20 ml of absolute tetrahydrofuran. After completion of the addition, the mixture is stirred at room temperature for 1 hour and then hydrolysed by metering in 50 ml of H 2 0. After acidifying with acetic acia (pH the mixture is extracted with ethyl acetate. The organic phases -48are dried (Na 2

SO

4 and evaporated in vacuo. After addition of diethyl ether, the crystals are filtered off and dried in vacuo. 2-n-Butyl-5-hydroxymethyl-6-hydroxypyrimidine is obtained in this way. M.p. 107-109 0

C.

b) 13.6 g (49.4 mmol) of potassium carbonate are added to a solution of 9.0 g (49.4 mmol) of 2-n-butyl-5-hydroxymethyl-6-hydroxypyrimidine in 200 ml of N,N-dimethylformamide. The mixture is stirred at room temperature for 20 minutes and 13.4 g (49.4 mmol) of 4-bromomethyl-2'-cyanobiphenyl is then added in portions. After completion of the addition, the mixtrre is stirred at room temperature for 12 hours and then evaporated in vacuo. Ethyl acetate is added to the residue, and the mixture is washed with H20, dried (Na 2

SO

4 and evaporated in vacuo. Flash chromatography (silica gel 40-63 gm, hexane/ethyl acetate 1:1) gives 2-n-butyl-5-hydroxymethyl-1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine. M.p. 96-980C.

Example 26: By reaction of 2-n-butyl-1,6-dihydro-4-ethoxycarbonyl-l-[(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6-dihydro-4ethoxycarbonll-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained, for example, in the manner described in Example 1 as an amorphous solid.

The starting material can be prepared, for example, as follows: 1 a) By reaction of the sodium salt of diethyl oxalylacetate with n-valeroylamidine.HCI and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-4-ethoxycarbonyl-6-hydroxypyrimidine is obtained. M.p. 127-128 0 C (from diethyl ether/hexane).

b) By alkylation of 2-n-butyl-4-ethoxycarbonyl-6-hydroxypyrimidine with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example la) and flash chromatography (silica gel 60, 40-63 Im, hexane/ethyl acetate 2-n-butyl-1,6dihydro-4-ethoxycarbonyl- 1 -[(2'-cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained and is immediately further processed.

Example 27: By hydrolysis of 2-n-butyl-l1,6-dihydro-4-ethoxycarbonyl-1-[(2'-(1Htetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine in the manner described in Example 23, 2-n-butyl-1,6-dihydro-4-carboxy- 1-[(2'-(H-tetrazol-5-yl)biphenyl-4yl)methyl]-6-oxopyrimidine is obtained. M.p. 160-162 0 C (from acetic acid/H 2 0).

-49- Example 29: A solution of 400 mg (0.81 mmol) of 2-n-butyl-4-benzyloxy-1,6-dihydro-1- [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine in 75 n-l of methanolICH 2 Cl 2 1) is shaken at room temperature and 1 atm of H 2 in the presence of 100 mg of 7% Pd-C. After the uptake of hydrogen is complete, the catalyst is filtered off and washei, with methanol and the filtrate is evaporated in vacuo. 2-n-Butyl-1,6dihydro-4-hydroxy-l1-[(2'-( 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine is obtained in this way. M.p. 153'C (frc.-m isopropanol/ethyl acetate).

Example 29: By reaction of 2-n-buiyl- 1,6-dihydro-4-hydroxy-5-methyl-1- cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl-1,6dihydro-4-hydroxy-5-methyl- 1 -[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine is obtained, for exanmple, in the manner described in Example 1. M.p.

221-223 0 C (from acetonitrile).

The starting material can be prepared, for example, as follows: a) A mixture of 28.1 g (0.2 mol) of n-valeroylamidine.HCl and 42.8 g (0.2 mol) of 4-aminomethyl-2'-cyanobiphenyl (EP 253,310) in 50 ml of EtOH is stirred under reflux for 12 hours. After evaporating in vacuo and flash chromatography (silica gel 60, 40-63 R±m, CH 2 Cl 2

/CH

3 OH 4: N- -cyanobiphenyl-4-yl)methyl]-n-valeroylamidine.HCI is S: obtained as an amorphous solid, which is immediately further processed.

b) A solution of 1.97 g (6 mmol) of N-[(2'-cyanobiphenyl-4-yl)methyl]-nvaleroylamidine.HCl in 5 ml of absolute ethanol is added dropwise at room temperature to a solution of 280 mg (12 mmol) of sodium in 5 ml of absolute ethanol. After 10 minutes, 1.05 ml (6 mmol) of diethyl methylmalonate are added and the suspension is stirred under reflux for 24 hours. The reaction mixture is evaporated in vacuo, H 2 0 is added and the mixture is acidified with 2N HCi (pH It is extracted with ethyl acetate, washed with

H

2 0, dried (Na 2

SO

4 and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 gin, CH 2 Gl 2

/CH

3 OH 95:5) gives 2-n-butyl-1,6-dihydro-4-hydroxy-5-methyl-1-I(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine. M.p. 204-206 0 C (from diethyl ether).

Example 30: Starting from 2-n-butyl- 1,6-dihydro-5-ethyl-4-hydroxy-l1-[(2'cyanobiphenyl-4-yl)methyl]-6-oxopyrimidine and tributyltin azide, 2-n-butyl- 1,6dihydro-5-ethyl-4-hydroxy- 1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6- 50 oxopyrimidine is obtained,'for example, in the manner described in Example 1. M.p.

248-250'C (from ethanollH 2

O).

The starting material can be prepared, for example, as follows: a) By reaction of diethyl ethylmalonate with N-[(2'-cyanobiphenyl-4-yl)methyl]-nvaleroylamidine.HCl and sodium in absolute EtOH in the manner described in Example 29b), 2-n-butyl- 1,6-dihydro-5-ethyl-4-hydroxy-1 -cyanobiphenyl-4-yl)methylj-6oxopyrimidine is obtained. M.p. 157-158'C (from isopropanol).

ExamPL 31: Starting from 2,5-di-n-butyl- 1,6-dihydro-4-hydroxy- 1-1(2' -cyanobiphenyl-4yl)methyl]-6-oxopyrimidine and tributyltina~zide. 2,5-di-n-butyl-1,6-dihydro-4-hydroxy-1- :[(2'-(1H-tetrazoJ-5-yl)biphenyl-4-yl)methyl" pyrimidine is obtained, for example, in the manner described iia Example 1. M.p. 2,15-247'C (from acetic acid-IH 2

O).

:600 The starting material can be prepared, for example, as follows: a) By reaction of diethy! n-butylmalonate with N-[(2'-cyanobiphenyl-4-yl)methyl]-nvaleroylamidine.HCl and sodium in absolute ethanol in the manner described in Example 29b), 2,5-di-n-butyl- 1,6-cihydro,--4-hydroxy- -cyanobiphenyl-4-yl)methyl] -6oxopyrimidine is obtained and is immediately further processed.

Example 32: A solution of 1.96 g (5.02 mmol) of 2-n-butyl-1,6-dihydro-4-methyl-1-II(2'methoxycarbonyibiphenyl-4-yl)methyl]-6-oxopyrimidine in 15 ml of methanol and 5 ml of 2N NaOH is stirred at 50C'C for 12 hours. After evaporating the methanol in vacuo, the Mixture is acidified with 2N HCI (pH 1) and extracted with CH 2 Cl 2 The organic phase is dried (Na 2 SO0 4 and evaporated. 2-n-Butyl- 1,6-dihydro-4-methyl- 1- carboxybiphenyl-4-yl)methyl]-6-oxopyrimidine is obtained in this way. M.p. 190'-192'C (from CH 2 Cl 2 /hexane).

The starting material can be prepared, for example, as follows: By alkylation of 2-n-butyl-4-hydroxy-6-methylpyrimidinebiphenyl with 4-bromo-2'-methoxycarbonyl-biphenyl (EP 2 i3,3 10) in the manner described in Example 1a) and flash chromatography (silica gel 60, 40-63 g±m, hexane/ethyl acetate 1: 1), 2-n-butyl- 1,6-dihydro-4-methyl-1-II(2'-methoxycarbonyl- -51- I I biphenyl-4-yl)methyl]-6-oxopyriimidine is obtained and is immediately further processed.

Example 33: Starting from 2-n-butyl-3-[(2' -cyanobiphen-vl-4-yl)methyl]-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one and tributyltin azide-, 2-n-butyl-3-II(2'-( lHtetrazol- 5-yl)biphenyl-4-yl)methyl]-3,5 ,6,7-tetrahydro-4H-cyclopentapyrimnidin-4-one is obtained, for example, as described in Example 1. M.p. 1i4-216TC (from acetonitrile)

N

WHCN 0 N=N0 N NH Th strigmtra anb0rprd*o eape sflos a) By recino tyCylpnaoe2croyaewt -aeolmdn. n soimi boueehao ntemne esrbdi xml 3a,2nbtl3567 *erhdo4-ylpnayiii--n isotie.n.simeitl ute Thebtatingd ansma ediata e pr,eprorexaseds olos Ea)mpyetionSofrthyl fyope2nbtnone-r2-caoat ihn-vayletylmidin8e.Hlad hdsodium in absole ethanolni te manner described in Example 13a), 2-n-butyl-35,6,iphnl4y~ehl-,,78tetrahydro-4H-cclopntaprimiin-4-oie is obtainedandosrimediatlyefrthe s~S 4brmmthl2-yaoihey nthe manner described in Example a) and. flashro ceontil -52- The starting material can be prepared, for example, as follows: a) By reaction of ethyl cyclohexanone-2-carboxylate with n-valeroylamidine.HCl and sodium in absolute ethanol in the manner described in Example 13a), 2-n-butyl-5,6,7,8tetrahydro-3H-quinazolin-4-one is obtained and is immediately further proc- sed.

b) By alkylation of 2-n-butyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one with 4-bromomethyl-2'-cyanobiphenyl in the manner described in Example l a) and flash chromatography (silica gel 60, 40-63 gm, hexane/ethyl acetate 2-n-butyl-3-Ij(2'cyanobiphenyl-4-yl)methyl] -5,6,7,8-tetrahydro-3H-quinazolin-4-one is obtained and is immediately further processed.

*00 6 Example 35: Starting from 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-3Hquinazolin-4-one and tributyltin azide, 2-n-butyl-3-Lj(2'-( 1H-tetrazol-5-yl)biphenyl-4yl)methyl]-3H-quinazolin-4-one is obtained, for example, in the manner described in Example 1. M.p. 179-1901C (from ethyl acetate).

The starting material can be prepared, for example, as follows: a) A solution of 5.0 g (36.6 mmol) of n-valeroylamidine.HCl and 5.97 g (36.6 mmol) of isatoic anhydride in 200 ml of pyridine is stirred at 100'C for 24 hours. After evaporating ae: in vacuo, the residue is suspended in H 2 0, filtered off and dried at 50'C in vacuo. In this manner, 2-n-butyl-311-quinazolin-4-one is obtained and is immediately further processed.

b) By alkylation of 2-n-butyl-3H-quinazolin-4-one with 4-bromometliyl-2'-cyanobiphenyl in the manner described in Example 1 a) and flash chromatography (silica gel 40-63 jim, hexane/ethyl acetate 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl-31quinazolin-4-one is obtained and is immediately further processed.__ Example 36: Starting from 2-n-butyl-3- -cyanobiphenyl-4-yl)methyl]-3H-pyrido[2,3- Olpyrimidin-4-one and tributyltin azide, 2-n-butyl-3-[(2'-(lH-tetrazol-5-yl)biphenyl-4yl)methyl]-3H-pyrido[2,3-dlpyrimidin-4-one is obtained, for example, in the manner described in Example 1. M.p. 135-137TC (from metha-nol/ethyl acetate).

The starting material can be prepared, for example, as follows: -53a) A solution of 5.0 g (36.6 mmol) of n-valeroylamidine.HCl and 6.0 g (36.6 mmol) of 2H-pyrido[2,3-d][1,3]oxazine-2,4(IF)-dione in 200 ml of pyridine is stirred at 100"C for 24 hours. After evaporating in vacuo, ethyl acetate is added to the residue, and the mixture is washed with H20, dried (Na 2 S 04) and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 gim, CH 2 Cl 2

/CH

3 OH 98:2) gives 2-n-butyl-3H-pyrido[2,3dlpyrimidin-4-one which is immediately further processed.

b) By alkyation of 2-n-butyl-3H-pyrido[2,3-dlpyrimidin-4-one with 4-bromomethyl-2'cyanobiphenyl in the manner described in Example Ila and flash chromatography (silica gel 60, 40-63 jimn, CH 2 Cl 2

/CH

3 OH 98:2), 2-n-butyl-3-[(2'-cyanobiphenyl-4yl)methyl]-3H-pyrido[2,3-dlpyrimidin-4-one is obtained and is immediately further processed.

Example 37: Starting from 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyll-3H-pyrido[3,2dlpyrimidin-4-one and tributyltin azide, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4- .9 yl)methyl]-3H-pyrido[3,2-dlpyrimidin-4-one is obtained, for example, in the manner described in Example 1. M.p. 245'C (from etYyl acetate).A The starting material can be prepared, for example, as follows: a) A solution of 5.0 g (36.6 mmol) of n-valeroylamidine.HCI and 6.0 g (36.6 mmol) of 2H-pyrido[3,2-d][1,3]oxdzine-2,4(1H)-dione in 200 ml of pyridine is stirred at 100'C for 24 hours. After evaporating in vacuo, ethyl acetate is added to the residue, and the mixture is washed with H 2 0, dried (Na 2

SO

4 and evaporated in vacuo. Flash chromato,_aphy (silica gel 60, 40-63 jim, CH 2 Cl 2

/CH

3 OH 98:2) gives 2-n-butyl-3H-pyrido[3,2dlpyrimidin-4-one, which is immediately further processed.

b) By alkylation of 2-n-butyl-3H-pyrido[3,2-dlpyrimidin-4-one with 4-bromomethyl-2'cyanobiphenyl in the manner described in Example l a) and flash chromatography (silica gel 60, 40-63 gim, CH 2 Cl 2

/CH

3 OH 98:2), 2-n-butyl-3-[(2'-cyanobiphenyl-4yl)methyl]-3H-pyrido[3,2-d]pyrimidin-4-one is obtained and is immediately further processed.

Example 38: The following can be prepared in an analogous manner, for example as described in one of the preceding Examples 1 to 2-n-butyl- 1,6-dihydro-4-ethyl- lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxo- -54pyrimidine, 2-n-butyl- 1 ,6-dihydro-4-propyl- 1- 1H-:eftrazol-5-yl)biphenyl-4-yl)methyl] -6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-4-isopropyl- 1 [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine, 2,4-di-n-butyl- 1 ,6-dihydro- -(1H-tetrazol-5-yl)iiphenyl-4-yl)methyl]-6-oxopyrimidine, 2-n-butyl-4-t-butyl- 1 ,6-dihydro- 1H-tetrazol-5-yl)biphenyl-4-yl)methylj-6-oxopyrimidine, 2-n-butyl- 1 ,6-dihvdro-4-trifluorornethyl- 1 1H-tetrazoi-5-yl)biphenyl-4-yl)methyl] -6oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-phenyl- 1H-tetrazol-5-yI)biphenyl-4-yl)methyl]-6-oxopyrimidine, *.2-n-butyl- 1,6-dihydro-4-ethoxycarbonyl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl-6oxopyrimidine, 2-n-butyl-4-carboxy-I ,6-dihydro-l1-[(2' -(IH-tetrazol-5-y1)biphenyl-4-yl)methyll-6-oxotoa pyrimidine, 2-n-butyl- 1,6-dihydro-4-hydroxymethyl-l1-[(2' 1H-tetrazol-5-yl)biphenyl-4-yl)methyl] -6oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-methoxymethyl-l1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-dimethylaminomethyl-1- [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrirnidine, 2-n-butyl- 1,6-dihydro-3-ethoxycarbonylmethyl- 1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyll-6-oxopyrimidine, 2-n-butyl-4-carboxymet.yl- 1,6-dihydro- -(1H-tetrazol-5-yl)biphenyl-4-yl)methyi]-6oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-(2-hydroxyethyl)-l1-[(2' 1H-tetrazol-5-yl)biphenyl-4-yl)mnethyl]- 6-oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-(2-methoxyethyl)-l1-[(2' 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]- 6-oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-(2-dimethylaminoethyl)-l1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methylll-6-oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-hydroxy- 1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine, 2-n-butyl-1I,6-dihydro-4-methylthio- 1-[(2'-(IH-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-o-xo 55 pyrimidine, 2-n-butyl- 1,6-dihydro-4-methylsulfonyl-1 -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-4-morpholino- 1 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxo pyrimidine, 2-n-butyl- 1,6-dihydro-4-(2-mnethoxyethoxy)- 1 -[(2'-(1H-tetrazol-5-yl)biphenyl-4-y1)methyl] -6-oxopyrimidine, 2-n-butyl- 1,6-dihydro-4-(2-dimethylaminoethoxy)-l1-[(2' -(1H-tetrazol-5-yl)biphenyl-4-yl) methyll-6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-5-methoxy- 1 -[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-5-ethoxycarbonyl- 1 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine, 2-n-butyl-5-carboxy-1 ,6-dihydro-l1-[(2'-(IH-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine, 2-n-butyl- 1,6-dihydro-5-hydroxymethyi- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine, 2-n-butyl- 1,6-dihydro-5-methoxymethyl-1- -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine, 2-n-butyl-1 ,6-dihydro-5-dimethylaminomethyl- -(1H-tetrazol-5-yl)biphenyl-4-yl)ga. methyll-6-oxopyrin-idine, 0a -fl-utyl- 1 ,6-diyuro-5-metuiyl-i-[(2 ilH-tetrazol-5-yl)olpeny-+-yl)methlylJ-6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-4,5-dimethyl- 1- (l1T-tetrazol-5-yl)biphenyl-4-yl)methyl] -6-oxopyrimidine, 0*2-n-butyl-1 ,6-dihydro-5-ethyl-4-methyl-1 -[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-4-methyl-5-propyl- 1 -(H-tetrazol-5-y1)biphenyl-4-yl)methyl]- 6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-5-isopropyl-4-methyl- 1H-tetrazol-5-y1)biphenyl-4-yl)methyl]-6-oxopyrim-idine, 1,6-dihydro-4-methyl-l1-[(2' -(1H-tetrazol-5-yl)biphenyl-4-yl)methyll-6oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-5-methyl-4-phenyl- 1- 1H-tetrazol.-5-yl)biphenyl-4-yl)methyl] 6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-5-hydroxyethyl-4-methyl- 1 -[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-__ -56methyl]-6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-5-methoxyethyl-4-methyl- 1 1H-tetrazol-5-yl)biphenyl-4-yl)methyll-6-oxopyrimidine, 2-n-butyl- 1 ,6-dihydro-5-dimethylaminoethyl-4-methyl- 4-yl)methyll-6-oxopyrimidine, 2-n-butyl- 1,6-dihydro-5-ethoxycarbonylmethyl-4-methyl- 1 1H-tt yl)biphenyl-4-yl)methyl]-6-oxopyrimidine, I 1 ,6-dihydro-4-methyl- 1- H-tetrazol-5-yl)biphenyl-4-yl)- 1 methyl] -6-oxopyrirnidine, 2-n-propyl- 1,6-dihydro-4-methyl-1- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine, 2-n-pentyl- 1,6-dihydro-4-methyl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyll-6-oxopyrimidine.

0e Example 39: Tablets, each containing 50 mg of active ingredient, for example 2-n-butyl-4-chloro- 1,6-dihyclro-1 -(1}{-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyri midine, can be prepared as follows.

Composition (10,000 tablets) S Active ingredient 500.0 g Lactose 500.0 g S: Potato starch 352.0Og Gelatin 6 ev Talc 60.0Og Magnesium stearate 10.0Og J Silica (highly-disperse) 20.0 g Ethanol q.s.

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

Example 40: Coated tablets, each containing 100 mg of active ingredient, for example -57 iII 2-n-butyl-1,6-dihydro-1-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxopyrimidine, can be prepared as follows: Composition (10,000 tablets) Active ingredient 100.0 g Lactose 100.0 g Corn starch 70.0 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 corn starch are mixed and moistened with a paste, prepared from 15 g of corn starch and water (with warming), and granulated.

S The granules are dried, and the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to give tablets (weight: 280 mg) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of the coated tablet: 283 mg.

S Example 41: Tablets and coated tablets, containing a compound according to the invention, for example according to Examples 1-38, can be prepared in an analogous manner to that described in Examples 39 and

Claims

1. A compound of the formulaI R2 N \R 3 I I R4 its tautomers and salts, in which Z is O, S or N(R) and R is hydrogen or an aliphatic hydrocarbon radical; R 1 is an unsubstituted or substituted aliphatic hydrocarbon radical, a cycloaliphatic or araliphatic hydrocarbon radical or an aromatic radical selected from the group consisting of: phenyl, naphthyl, pyrrol, pyrazolyl, imidazoyl, triazolyl, furyl, thienyl and pyridyl; R 2 and R 3 independently of one another, are halogen, acyl, an aromatic radical (as defined above), unsubstituted or substituted amino, or carboxyl which, if desired, may be esterified or amidated; or R 2 is -Z 1 R'2 and R3 is -Z 2 -R' 3 Z 1 and Z 2 independently of one another being a bond, O or S(O)n and n being 0, 1 or 2, and R' 2 and R' 3 independently of one another being hydrogen, an araliphatic or aliphatic hydrocarbon radical, the latter being unsubstituted or substituted and, if desired, interrupted by or n being 0, 1 or 2; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH CH-CH CH-, in which, if desired, one or two of the methyne groups are replaced by -N R 4 is a group of the formula R (Ia) Ailk-< A in which Alk is a divalent aliphatic hydrocarbon; R 5 is COOH, SO 3 H, haloalkanesulfamoyl, P0 2 H2, P0 3 H 2 or 5-tetrazolyl; the rings A and B or the (hetero)aromatic ring jointly formed by R 2 and R 3 are, independently of one another, unsubstituted or substituted. 930216,p:\oper\hjc,58696-90.rsp,58 L i~ 59 fill

2. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is I O, S or N(R) and R is hydrogen or an aliphatic hydrocarbon radical, R 1 is an aliphatic radical which is unsubstituted or substituted by halogen or hydroxyl, a cycloaliphatic or araliphatic hydrocarbon radical or an aromatic radical, R 2 and R 3 independently of one another, are halogen, acyl, an aromatic radical, carboxyl which, if desired, is esterified or amidated, or R 2 is -Z 1 -R' 2 and R 3 is -Z 2 -R' 3 Z 1 and Z 2 independently of one another being a bond or O, S(0)n or NH, n being 0, 1 or 2 and R' 2 and R' 3 independently of one another being hydrogen or an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino, or carboxyl which, if desired, is esterified or amidated, and which, if desired, is interrupted by or n being 0, 1 or 2, R 4 is a group of the formula R .CH (Ib) S* in which R 5 is COOH, SO 3 H, haloalkanesulfamoyl, PO2H 2 P0 3 H 2 or

3. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is 0, S or N(R) and R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R 1 is lower alkyl, lower alkenyl or lower alkynyl which in each case are unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonyl, lower alkenylthio, lower alkenylsulfinyl or -sulfonyl, lower alkynylthio, lower alkynylsulfinyl or -sulfonyl, amino which, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxy-carbonyl and carbamoyl in which the amino group is,if desired, independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or in each case 3- to 7- membered cycloalkyl or cycloalkenyl, phenyl-lower alkyl, phenyl-lower alkenyl, phenyl-lower alkynyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, biazolyl, tetrazolyl, furyl, thienyl or pyridyl; R 2 and R 3 independently of one another are halogen, lower alkanoyl, phenyl-lower alkanoyl, benzovl phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl. terrazolyl, furl, thienyl. pyridyl, amino which, if desired, is independently of one another mono- or disubstituted by lower alcyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxy- carbonyl or carbamoyl in which the amino group, if desired,is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy- lower alkylene; or R 2 is -Z 1 -R 2 and R 3 is -Z 2 -R 3 Zland Z 2 independently of one another being a bond, O or and n being 0, 1 or 2, and R 2 and R 3 independently of one another being hydrogen, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or being lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkenvloxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkylthio-lower alkyl, -lower alkenyl or -lower S alkynyl, lower alkanesulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower S alkenylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, which are in each case independently of one another unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonvl, lower alkenvlthio, lower alkenylsulfinyl or -sulfonyl, lower alkynylthio, lower S alkynylsulfinyl or -sulfonyl, amino which, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or V. phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxy- carbonyl and carbamoyl in which,if desired, the amino group is independently @000 of one another mono- or disubstituted by lower alkyl,lower alkenyl,lower alkynyl phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, one or two of the methyne groups is replaced by R 4 is a group of the formula in particular in which alk is lower alkylene or lower alkylidene, in particular methylene; R 5 is COOH. SO 3 H, halo-lower alkanesulfamoyl, P0 2 2 P0 3 H 2 or 5-terrazolyl; the rings A and B and the (hetero)aromatic radicals or the (hetero)aromatic ring jointly formed by R 2 and R 3 are in each case independently of one another unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl. lower alkoxy, lower -61- alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonyl, lower alkenylthio, lower alkenylsulfinyl or -sulfonyl, lower alkynylthio, lower alkynylsulfinyl or -sulfonyl, or selected from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, or lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, which are in each case unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, mercapto, lower alkylthio, lower alkanesulfinyl or -sulfonyl, lower alkenylthio, lower alkenylsulfinyl or -sulfonyl, lower alkynylthio, lower alkynylsulfinyl or -sulfonyl, amino which, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy-, lower alkoxy- lower alkoxy- or lower alkenyloxy-carbonyl and carbamoyl in which the amino group, S if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or S disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene. C. C

4. A compound according to claim 2 of the formula I, its tautomers and salts, in which Z is O, S or N(R) and R is hydrogen, lower alkyl, lower alkenyl or lower alkynyl, R 1 is lower alkyl, lower alkenyl or lower alkynyl, in each case 3- to 7-membered cycloalkyl or cycloalkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or phenyl, which is unsubstituted or substituted by halogen or hydroxyl, R 2 and R 3 independently of one another are halogen, lower alkanoyl, phenyl or c5 7,Oxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, or lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, -lower alkenyl or -lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or R 2 is -Z 1 -R' 2 and R 3 is -Z 2 -R' 3 Z 1 and Z 2 independently of one another being a bond or O, S(0)n or NH, n being 0, 1 or 2, and R' 2 and R' 3 independently of one another being hydrogen, or lower alkyl, lower alkenyl or lower alkynyl, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkenyloxy-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkylthio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkanesulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenylthio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkynylthio-lower alkyl, -sulfinyl-lower alkyl or -62- -sulfonyl-lower alkyl, which is unsubstituted or substituted by halogen, hydroxyl, amino which, if desired, is substituted as indicated above, carboxyl which. if desired, is esterified as indicated above, or carbamoyl which, if desired, is substituted as indicated above, R 4 is the group of the formula Ib in which R 5 is COOH, SO 3 H, halo-lower alkanesulfamoyl, PO2H2,PO3H 2 or 5-tetrazolyl; and wherein phenyl rings and radicals containing phenyl rings in each case being unsubstituted or substituted by substituents selected from the group comprising lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxyl. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is O, S or N(R) and R is hydrogen or lower alkyl, R 1 in each case is lower alkyl or lower alkenyl which is unsubstituted or substituted by halogen or hydroxyl, or C3-C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, phenyl-lower alkyl, phenyl or pyridyl; R 2 and R 3 independently of one another, are halogen, lower alkanoyl, phenyl-lower alkanoyl, benzoyl, phenyl, Stetrazolyl, pyridyl, amino which, if desired, is mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene or lower alkyleneoxy-lower S alkylene, carboxyl, lower alkoxy-, lower alkoxy-lower alkoxy- or lower alkenyloxy- *carbonyl or carbamoyl in which,if desired, the amino group is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene; R 2 is -Z 1 -R 2 and R 3 is -Z 2 -R 3 Z 1 and Z 2 independently of one another being a bond, O or S(0)n and n being 0, 1 or 2; and R 2 and R 3 independently of one another being hydrogen or phenyl-lower alkyl or S being lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, or lower alkanesulfinyl-lower alkyl or -sulfonyl-lower alkyl, which in each case are independently of one another unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, phenyl-lower alkoxy, phenoxy, amino which, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl; lower alkynyl, phenyl-lower alkyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, carboxyl, lower alkoxy- or lower alkoxy-lower alkoxy-carbonyl and carbamoyl in which, if desired, the amino group is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH-, in which, if desired, one or two methyne group(s) are replaced by R 4 is a group of the formula Ia, primarily Ib, in which Alk is lower alkylene or lower alkylidene, primarily methylene; R 5 is carboxyl, halo-lower alkanesulfamoyl or the rings A and B and the (hetero)aromatic radicals or the (hetero)aromatic -63 1 ring formed jointly by R 2 and R 3 are in each case independently of one another unsubstituted or substituted by substituents selected from the group comprising halogen, hydroxyl, lower alkoxy, phenyl-lower alkoxy, mercapto, lower alkylth;o, lower alkanesulfinyl or -sulfonyl, or lower alkyl or lower alkoxy-lower alko. -lower alkyl which is unsubstituted or substituted by halogen, hydroxyl, lower alkoxy, phenyl-lower alkoxy or phenoxy.

6. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is O, S or N(R) and R is hydrogen or lower alkyl, R 1 is lower alkyl, C3-C 7 cycloalkyl, phenyl lower alkyl or phenyl, R 2 and R 3 independently of one another, are halogen, phenyl, lower alkanoyl, carboxyl, lower alkoxy- or lower alkoxy-lower alkoxy-carbonyl, •carbamoyl, lower alkyl- or di(lower alkyl)-carbamoyl, lower alkylene-carbamoyl or lower alkyleneoxy-lower alkylene-carbamoyl, or R 2 is -Z 1 and R 3 is -Z-R' 3 Z I and Z 2 independently of one another being a bond or 0, S or NH- and R' 2 and R' 3 independently of one another being hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di(lower o. alkyl)amino-lower alkyl, lower alkyleneamino-lower alkyl, lower alkyleneoxy lower alkyleneamino-lower alkyl, carboxy-lower alkyl, or lower alkoxy- or lower alkoxy-lower alkoxy-carbonyl-lower alkyl, R 4 is the group of the formula Ib in which R 5 is COOH or and wherein phenyl rings and radicals containing phenyl rings in each case being unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl.

7. A compound according to claim 2 of the formula I, its tautomers and salts, in which Z is O, R 1 is lower alkyl, in particular having 3 and not more than 5 C atoms, such as n-butyl, one of the radicals R 2 and R 3 is halogen, in particular of atomic number not more than such as chlorine, phenyl, carboxyl, lower alkoxycarbonyl, in particular having 2 and not more than 5 C atoms, such as ethoxycarbonyl, hydrogen, hydroxyl, lower alkylthio, in particular having not more than 4 C atoms, such as methylthio, lower alkanesulfonyl, in particular having not more than 4 C atoms, such as methanesulfonyl, amino, di(lower alkyl)amino, in particular having not more than 4 C atoms per lower alkyl moiety, such as dimethylamino, morpholino, lower alkyl, in particular havin'g not more than 4 C atoms, such as methyl, hydroxy-lower alkyl, in particular having not more than 4 C atoms such as hydroxymethyl, halo-lower alkyl, in particular of atomic number not more than 35 and having not more than 4 C atoms, such as trifluoromethyl, di(lower alkyl)amino-lower alkyl, in particular having not more 4 C atoms per lower alkyl moiety, such as

64- 2-dimethylaminoethyl, carboxy-lower alkyl, in particular having not more than 5 C atoms, such as carboxymethyl, lower alkoxycarbonyl-lower alkyl, in particular having not more than 4 C atoms per lower alkoxy or lower alkyl moiety, such as ethoxycarbonylmethyl, lower alkoxy, in particular having not more than 4 C atoms, such as methoxy, hydroxy-lower alkoxy, in particular having not more than 4 C atoms, such as 2-hydroxyethoxy, lower alkoxy-lower alkoxy, in particular having not more tha 4 C atoms per lower alkoxy moiety, such as 2-methoxyethoxy, dilower alkylamino-lower alkoxy, in particular having not more than 4 C atoms per lower alkyl or lower alkoxy moiety, such as 2-dimethylaminoethyl, carboxy-lower alkoxy, in particular having not more than 5 C atoms, such as 2-carboxyethoxy, or lower alkoxycarbonyl-lower alkoxy, in particular having not more than 4 C atoms per lower alkoxy moiety, such as 2-ethoxycarbonylethoxy, and the other hydrogen or lower alkyl, in particular having not more 4 C atoms, such as methyl, and R 4 is the group of the formula Ib in which R 5 is *eg* 8. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is O, R 1 is lower alkyl, in particular having 3 and not more than 5 C atoms, such as n-propyl or n-butyl, or lower alkenyl, in particular having 3 and not more than 5 C atoms, such as 2-propenyl, R 2 and R 3 independently of one another are halogen, in particular of atomic number not more than 35, such as chlorine, tetrazolyl, such as 5-tetrazolyl, amino, which, if desired, is mono- or disubstituted by lower alkyl or phenyl-lower alkyl, in particular having not more than 4 C atoms per alkyl moiety, or disubstituted by lower alkyleneoxy-lower alkylene, in particular having not more than 4 C atoms per lower alkylene moiety, such as 4-morpholinyl, carboxyl, lower alkoxycarbonyl, in particular having 2 and not more than 5 C atoms, such as methoxy- or ethoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, in particular having not more than 4 C atoms in the alkoxy moiety, such as 2-methoxyethoxycarbonyl; or R 2 is -Z 1 -R 2 and R 3 is -Z 2 -R 3 Z 1 and Z 2 independently of one another being a bond, O or S(O)n and n being 0, 1 or 2, and R 2 and R 3 independently of one another being hydrogen or phenyl-lower alkyl, in particular having not more than 4 C atoms in the alkyl moiety, such as benzyl, or lower alkyl or lower alkoxy-lower alkyl, in particular in each case having not more than 4 C atoms in the alkyl moiety, which, if desired, is in each case mono- or disubstituted by halogen, in particular of atomic number not more than 35, such as chlorine, hydroxyl, amino which, if desired, is mono- or disubstituted by lower alkyl or phenyl-lower alkyl, in particular having not more than 4 C atoms per alkyl moiety, or disubstituted by lower alkenyloxy-lower alkylene, in particular having not more 'ban 4 C atoms per lower alkyl L w moiety, such as methyl-, dimethyl-, benzyl- or dibenzylamino or 4-morpholinyl, carboxyl, lower alkoxycarbonyl, in particular having 2 and not more than 5 C atoms, such as methoxy- or ethoxycarbonyl; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH-, in which, if desired, one or two methyne group(s) are replaced by R 4 is a group of the formula Ia, in particular Ib, in which Alk is lower alkylene or lower alkylidene, in particular in each case having not more than 4 C atoms, such as methylene, ethylene or ethylidene, primarily methylene; R is carboxyl, halo-lower alkanesulfamoyl, in particular of atomic number not more than and having not more than 4 C atoms, in particular trifluoromethanesulfamoyl, or the rings A and B and the aromatic radicals or the (hetero)aromatic ring S jointly formed by R 2 and R 3 are in each case independently of one another unsubstituted or substituted by hydroxyl, halogen, in particular of atomic number not more than 35, such as chlorine, trifluoromethyl, lower alkyl, in particular having not more than 4 C atoms, such as methyl, and/or lower alkoxy, in particular having not more than 4 C atoms, such as methoxy. S S 9. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is O, R 1 is C 3 -C 5 alkyl, such as n-propyl or n-butyl, R 2 and R 3 independently of one another, are halogen of atomic number not more than 35, such as chlorine, di-C 1 -C 4 alkylamino, Ss such as dimethylamino, 4-morpholinyl, carboxyl or C 2 -C 5 alkoxycarbonyl, such as methoxy- or ethoxycarbonyl; or R 2 is -Z 1 -R 2 and R 3 is -Z 2 -R 3 Z 1 and Z 2 independently S of one another being a bond, O or S(O)n and n being 0, 1 or 2, and R 2 and R 3 S independently of one another being hydrogen, phenyl-C 2 -C 5 alkyl, such as benzyl, or C 1 -C 4 alkyl, such as methyl which is unsubstituted or substituted by hydroxyl or di-C 1 -C 4 alkylamino, such as dimethylamino, or C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, such as 2-methoxyethoxy; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula H=CH-CH=CH- in which, if desired, one or two methyne groups are replaced by R 4 is a group of the formula Ib in which R 5 is carboxyl or primarily 5-tetrazolyl; and the rings A and B or the (hetero)aromatic ring jointly formed by R 2 and R 3 are primarily unsubstituted, or furthermore substituted by hydroxyl, halogen, in particular of atomic number not more than 35, such as chlorine, trifluoromethyl, lower alkyl, in particular having not more than 4 C atoms, such as methyl, and/or lower alkoxy, in particular having not more than 4 C atoms, such as methoxy. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is O, R 1 is C 3 -C 5 alkyl, such as n-propyl or n-butyl, R 2 is halogen of atomic number not -66- more than 35, such as chlorine, trifluoromethyl, carboxyl, C 2 -C 5 alkoxycarbonyl, such as ethoxycarbonyl, hydrogen, hydroxyl, C 1 -C 4 alkyl, such as methyl or n-butyl, C 1 -C 4 alkoxy, such as methoxy, phenyl-C 1 -C 4 alkoxy, such as benzyloxy, hydroxy-C1-C 4 alkoxy, such as 2-hydroxyethoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkoxy, such as 2-methoxyethoxy, or di-C 1 -C 4 alkylamino-C 1 -C 4 alkoxy, such as 2-dimethylaminoethoxy; R 3 is hydrogen, C 1 -C 4 alkyl, such as methyl or n-butyl, carboxyl, C 2 -Csalkoxycarbonyl, such as ethoxycarbonyl, or hydroxy-C 1 -C 4 alkyl, such as hydroxyr ,thyl; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, a methyne group is replaced by R 4 is a group of the formula Ib in which R 5 is carboxyl or primarily 5-tetrazolyl; and the rings A and B are primarily unsubstituted, or furthermore substituted by hydroxyl, halogen of atomic number not more than 35, such as chlorine, trifluoromethyl, C 1 -C 4 alkyl, such as methyl, or C 1 -C 4 alkoxy, such as methoxy. 11. A compound according to claim 1 of the formula I, its tautomers and salts, in which Z is O, R 1 is C 3 -C 5 alkyl, such as n-propyl or n-butyl, R 2 is C1-C 5 alkyl, such as methyl, n-propyl or n-butyl, or hydroxyl, R 3 is hydrogen or C 1 -C 5 alkyl, such as n-propyl or n-butyl; or R 2 and R 3 together are propylene or butylene or are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, a methyne group is replaced by R 4 is a group of the formula Ib in which R 5 is carboxyl or primarily 5-tetrazolyl; and the rings A and B are primarily unsubstituted or furthermore substituted by hydroxyl, halogen of atomic number not more than 35, such as chlorine, trifluoromethyl, C 1 -C 4 alkyl, such as methyl, or C 1 -C 4 alkoxy, such as methoxy. 12. A compound according to claim 1 of the formula I and its salts, in which Z is O, R 1 is C 3 -C 5 alkyl, such as n-propyl or n-butyl, R 2 and R 3 together are propylene or butylene or S are the partial structure of the formula -CH=CH-CH=CH- in which, if desired, a methyne group is replaced by R 4 is a group of the formula Ib in which R 5 is 5-tetrazolyl; and the rings A and B are unsubstituted. 13. A compound according to claim 2 of the formula I and it salts, in which Z is O, R 1 is alkyl having 3 to 5 and not more than 5 C atoms, such as n-butyl, R 2 is hydrogen, halogen of atomic number not more than 35, such as chlorine, alkyl having not more than 4 C atoms, such as methyl, alkoxy having not more than 4 C atoms, such as methoxy, and R 3 is hydrogen, and R 4 is the group of the formula Ia in which R 5 is 67 14. A compound according to claim 2 of the formula I and its salts, in which Z is 0, R, is111 alkyl having 3 to 5 and not more than 5 C atoms, such as n-butyl, R 2 is hydrogen, halogen of atomic number not more than 35, such as chlorine, or alkyl having not more than 4 C atoms, such as methyl, R 3 is hydrogen, R 4 is the group of the formula Ia and R 5 is A compound according to claim 1 of the formula I and its salts, in which Z isO0, R, is C 3 -C 5 alkyl, such as n-butyl, R 2 is Cl-C 4 alkyl, such as methyl or n-butyl, R 3 is CI-C 4 alkyl, LI such as n-butyl, and R 4 is the group of the formula Ib in which R 5 is 16. 2-n-Butyl- 1,6-dihydro- 1H-tetrazolyl-5-yl)biphenyl-4-yl)methyl]-6- .~oxopyrimidine or a salt thereof. 17. 2-n-Butyl- 1,6-dihydro-4-methvl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6-oxo- pyrimidine or a salt thereof. 18. 2-n-Butyl- 1,6-dihydro-4-butyl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl] -6- oxopyrimidine or a salt thereof. 19. 2-n-Butyl- 1,6-dihydro-4,5-dimethyl-1- H-tetrazol-5-yl)biphenyl-4-yl)methyl]-6. oxopyrimidine or a salt thereof. 20. 2-n-Butyl- 1,6-dihydro-4-methyl-5-propyl-l1-[(2 1H-tetrazol-5-yl)biphenyl-4- ase yl)methyl]-6-oxopyrimidine or a salt thereof.M 21. 2-n-Butyl- 1,6-dihydro-4-hydroxy-l1-[2' -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] *6-oxopyrimidine or a salt thereof. 22. 2-n-Butyl- 1,6-dihydro-4-hydroxy-5-methyl-l1-[2'-( 1H-tetrazol-5-yl)biphenyl-4- yl)methyll-6-oxopyrimidine or a salt thereof. 23. 2-n-B utyl-3- -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] 3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one or a salt thereof. 24. 2-n-B utyl-3- (1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5 ,6,7,8-tetrahydro-3H- quirazolin-4-one or a salt thereof.

68- A compound according to any one of claims 1-24 in the form of a pharmaceutically acceptable salt. 26. Pharmaceutical preparations containing as active ingredient a compound according to any one of claims 1-24 in free form or in the form of a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or diluent. 27. Method for the treatment of high blood pressure and cardiac insufficiency comprising administering to a warm-blooded animal including human being in the need thereof a compound as claimed in any one of claims 1 to 26. 28. A process for the preparation of a compound according to any one of claims 1-25, wherein a) a compound of the formula o ~NH Ri (IIa) *NH-R4 or a salt thereof is reacted with a compound of the formula SR3 Z X 1 CH- C -X 2 (Ib) a salt, a tautomer or a functionally modified derivative of the tautomer thereof, in which X1 is the variable R 2 or is etherified hydroxyl and X 2 is etherified hydroxyl, or eoe or b) in a compound of the formula R 2 N R 3 x 3 3 R1 N Z 3 930216,p:\opcr\hjc58696--9.rsp,68 -68 II 'I A compound according to any one of claims 1-24 in the form of a pharmaceutically acceptable salt. 26. Pharmaceutical preparations containing as active ingredient a compound according to any one of claims 1-24 in free form or in the form of a pharmaceutically acceptable salt. 27. Method for the treatment of high blood pressure and cardiac insufficiency comprising administering to a warm-blooded animal including human being in the need thereof a compound as claimed in any one of claims 1 to 26. 28. A process for the preparation of a compound according to any one of claims 1-25, wherein *s a) a compound of the formula **NH M// R 1 -C (Ha) NH-R 4 or a salt thereof is reacted with a compound of the formula R 3 Z X -C-CH-C-X2 (IIb) a salt, a tautomer or a functionally modified derivative of the tautomer thereof, in which X 1 is the variable R 2 or is etherified hydroxyl and X 2 is etherified hydroxyl, or b) in a compound of the formula R2 N R 3 R1 N (III) CI 2 NCV 2 -69- or a salt thereof in which X 3 is a radical which can be converted into the variable R 5 X 3 is converted into the variable R 5 or c) a compound of the formula N R1 N' (IVa), 1, H 4 a tautomer or salt thereof is reacted with a compound of the formula X4-R4 (IVb) or a salt thereof in which X 4 is reactive esterified hydroxyl and, if desired, a compound of the formula I or a salt thereof obtainable according to the process or in another manner is converted into another compound or a salt thereof according to the invention, a free compound of the formula I obtainable according to the process is converted into a salt, a salt obtainable according to the process is converted into the free compound of the formula I or into another salt, or a mixture of isomers obtainable according to the process is resolved and the desired compound is isolated. 4.46 29. The compounds obtainable by the process according to claim 28. A compound of the formula its tautomers and salts, substantially as herein described, with reference to any one of Examples 1 to 38. V 70 31. Pharmaceutical prepara-ions, substantially as herein described, with reference to any one of Examples 39 to 41. DATED this 5th day of July, 1990. CIBA-GEIGY AG By Its Patent Attorneys ARTHUR S. CAVE CO. 6 S~ L .6 S a ~s *0 4*mg S. ~S 0 a. 6 6 a *vSS S 5555 606s 6O B. a 'I. a S *04