AU646006B2

AU646006B2 - Diaza compounds

Info

Publication number: AU646006B2
Application number: AU68533/90A
Authority: AU
Inventors: Peter Buhlmayer; Peter Herold
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1989-12-28
Filing date: 1990-12-27
Publication date: 1994-02-03
Anticipated expiration: 2010-12-27
Also published as: NO905602L; FI906387A0; CA2033121A1; IL96753A0; HU207513B; KR910011802A; FI906387A7; IE904686A1; AU6853390A; NZ236625A; NO905602D0; MX23949A; PT96371A; EP0435827A2; JPH06199811A; ZA9010395B; EP0435827A3; HUT56091A

Description

Our Ref: 349068

AUSTRALIA

Patents Act FORM COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: 0*

S

*o 5* 0 *55 S 55 5 *5 50 5*55 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: 5 5055 555 S

S

0

S

05 Complete specification for the invention entitled "Diaza compounds".

The following statement is a full descripcion best method of performing it known to me:of this invention, including the 6 0 j I 6 212 9o 1 5020 la Diaza compounds The invention relates to diaza compounds of the formula

R

2 0

R

I

o in which one of the radicals R 1 and R 2 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or a cycloaliphatic or araliphatic hydrocarbon radical and the other of the radicals R 1 and R 2 is the group of the formula A (Ia), *l R

R

in which Z 1 is alkylene, 0, S(O)n or R 5 is carboxyl, haloalkanesulfonylamino,

SO

3 H, P0 2

H

2 P0 3

H

2 or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by an aliphatic hydrocarbon radical which, if desired, is interrupted by O and is unsubstituted or substituted by hydroxyl or halogen, hydroxyl which, if desired, is etherified by an aliphatic alcohol, halogen, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, and either R 3 is halogen, acyl, an aromatic hydrocarbon radical, carboxyl which, if desired, is esterified or amidated, cyano, SO 3

H,

PO

2

H

2 P0 3

H

2 5-tetrazolyl, substituted or unsubstituted sulfamoyl or acylamino or is

-Z

2 wherein Z 2 is a bond or is O, or N(R) and R' is hydrogen or an aliphatic hydrocarbon radical which, if desired, is interrupted by O or S(O)m and is unsubstituted or substituted by halogen, hydroxyl, substituted or unsubstituted amino or carboxyl which, if desired, is esterified or amidated, and R 4 is an aliphatic hydrocarbon radical which, if desired, is interrupted by O or S(O)m and is unsubstituted or substituted by carboxyl which, if desired, is esterified or amidated, hydroxyl which, if desired, is etherified by an aromatic alcohol, substituted or unsubstituted amino, S(O)m-R or an aromatic hydrocarbon radical, or R 3 and R 4 together represent alkylene, R in each case being hydrogen or an aliphatic hydrocarbon radical and m in each case being 0, 1 or 2, in free form or in salt form, to a process for the preparation of these compounds, to the use of these compounds and to pharmaceutical preparations containing such a compound I in free form or in the form of a pharmaceutically acceptable salt.

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

-C

4 alkanecarboxylic acids which are unsubstituted or S substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, 0* phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as

C

1

-C

4 alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic centre. The S compounds I having at least one acid group (for example COOH or 5-tetrazolyl) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali S metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.

An aromatic hydrocarbon radical is, in particular, phenyl.

Acyl is, in particular, lower alkanoyl.

-3- Esterified carboxyl is, for example, carboxyl which is esterified by an aliphatic alcohol which is derived from an aliphatic hydrocarbon radical, such as from lower alkyl, lower alkenyl or, secondarily, lower alkynyl, which is uninterrupted or interrupted by 0, such as from lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl.

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

a° S Substituted amino is, for example, amino which is mono- or disubstituted by, S independently of one another, an aliphatic or araliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, -lower alkenyl or -lower alkynyl, or disubstituted by a divalent aliphatic hydrocarbon radical which is uninterrupted or interrupted by O, such as lower alkylene or lower alkylenoxy-lower alkylene. Examples are lower alkyl-, lower alkenyl-, lower alkynyl-, phenyl-lower alkyl-, phenyl-lower alkenyl-, phenyl-lower alkynyl-, di-lower alkyl-, N-lower alkyl-N-phenyl-lower alkyl- and di(phenyl-lower alkyl)-amino.

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

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

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

An aliphatic hydrocarbon radical which is substituted by halogen or hydroxyl and is interrupted by 0 or S(O)m is a corresponding radical as defined above which is substituted by halogen or hydroxyl.

An aliphatic hydrocarbon radical which is substituted by unsubstituted or substituted amino, an aromatic hydrocarbon radical, hydroxy which is etherified with an aromatic alcohol or free, esterified or amidated carboxyl and which is uninterrupted or interrupted by 0 or S(O)m is a corresponding radical as defined above which is substituted by amino, amino which is substituted as defined above, S(O)m-R, an aromatic hydrocarbon radical as defined above, hydroxy which is etherified with an aromatic alcohol as defined below, carboxyl, carboxyl which is esterified as defined above or carboxyl which is amidated as defined above.

*o 0. A cycloaliphatic hydrocarbon radical is, for example, cycloalkyl or, secondarily, cycloalkenyl.

9.

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

Hydroxyl etherified by an aliphatic alcohol is, in particular, lower alkoxy -r lower alkenyloxy.

Alkylene is methylene or lower a'"ylene.

Substituted sulfamoyl is lower alkyl- or di-lower alkyl-sulfamoyl.

O

Acyl in acylamino is derived from an organic carboxylic acid or an organic sulfonic acid.

Examples of corresponding acyl are lower alkanoyl, unsubstituted or substituted benzoyl, lower alkanesulfonyl, halogeno-lower alkanesulfonyl or unsubstituted or substituted benzenesulfonyl.

Hydroxyl etherified by an aromatic alcohol is in particular phenoxy, also naphthyloxy.

Unsaturated aliphatic, cycloaliphatic and araliphatic substituents above and below are, in particular, not linked to an aromatic radical via a C atom from which a multiple bond starts.

Unless defined differently, aromatic radicals are in each case unsubstituted or mono- or polysubstituted, for example di- or trisubstituted, for example by substituent selected from the group consisting of lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxyl.

The rings A and B form a biphenylyl radical, the corresponding 4-biphenylyl being preferred.

The general terms used above and below, unless defined otherwise, have the following meanings: *0 The term "lower" means that corresponding groups and compounds in each case contain, Sin particular, not more than 7, preferably not more than 4, carbon atoms.

S Lower alkanesulfonyl is, in particular, C 1

-C

7 alkanesulfonyl and is, for example, methane-, ethane-, n-propane- or isopropane-sulfonyl. C 1

-C

4 Akanesulfonyl is preferred.

Halogeno-lower alkanesulfonyl is halogeno-C 1

-C

7 -alkanesulfonyl, such as trifluoromethanesulfonyl.

*000 Lower alkanesulfamoyl is C 1

-C

7 alkanesulfamoyl, such as methane-, ethane-, n-propane-, S isopropane-, n-butane-, sec-butane- or tert-butanesulfamoyl. C 1

-C

4 -Alkanesulfamoyl is S preferred. Di-lower alkanesulfamoyl is di-C 1

-C

7 alkanesulfamoyl, such as dimethane-, Smethane-ethane- or di-(n-propane)-sulfamoyl. Di-C 1

-C

4 alkanesulfamoyl is preferred.

*0 S Halogen is, in particular, halogen having an atomic number of not more than 35, i.e.

Sfluorine, chlorine or bromine, and furthermore includes iodine.

Halogenoalkanesulfonylamino is, in particular, halogeno-C 1

-C

7 alkanesulfonylamino and is, for example, difluoromethane-, trifluoromethane-, 2-chloroethane-, 1,1 ,2-trifluoroethane-, 1,1 ,2-trichloroethane-, pentafluoroethane- or heptafluoropropane-sulfonylamino. Halogeno-C 1

-C

4 -alkanesulfonylamino is preferred.

Lower alkanoyl is, in particular, C 1

-C

7 alkanoyl and is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or pivaloyl. C 2

-C

5 Alkanoyl is preferred.

Lower alkyl is, in particular, Cl-C 7 alkyl, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl radical.

CI-C

4 Alkyl is pref-rred.

Lower alkenyl is, in particular, C 3

-C

7 alkenyl and is, for example, propen-2-yl, allyl or but-1-en-3-yl, -1-en-4-yI, -2-en-l-yl or -2-en-2-yl. C 3

-C

5 Alkenyl is preferred.

Lower alkynyl is, in particular, C 3

-C

7 alkynyl and is, preferably, propargyl.

Lower alkoxy is, in particular, Cl-C 7 alkoxy, i.e. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or corresponding pentyloxy, hexyloxy or heptyloxy. CI-C 4 Alkoxy is preferred.

:..Lower alkoxy-lower alkyl is, in particular, CI-C~alkoxy-CI-C~alkyl, such as a 2-methoxyethyl, 2-ethoxyethyl, 2-(n-propoxy)ethyl or ethoxymethyl.

Lower alkoxy-lower alkenyl or -lower alkynyl is, in particular, C 1

-C

4 alkoxy-C 3

-C

5 alkenyl or -alkynyl.

*Lower alkenyloxy is, in particular, C 3

-C

7 alkenyloxy and is, for example, allyloxy, but-2-en-1-yloxy or but-3-en-l-yloxy. C 3

-C

5 Alkenyloxy is preferred.

*.:Halogeno-lower alkyl is, in particular, halogeno-Cl-C 4 alkyl, such as trifluorom ethyl, 4: 1,1,2-trifluoro-2-chloro-ethyl, chioromethyl or n-heptafluoropropyl.

Halogeno-lower alkenyl is, in particular, halogeno-C 3

-C

5 alkenyl, such as 2-chloroallyl.

Halogeno-lower alkynyl is, in particular, halogeno-C 3

-C

5 alkynyl, such as 3-chioropropargyl.

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

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

-C

5 alkenyl, such as 3-hydroxyallyl.

-7- Hydroxy-lower alkynyl is, in particular, hydroxY-C 3

-C

5 alkynyl, such as 3-hydroxypropargyl.

Phenyl-lower alkyl is, in particular, phenyl-Cl-C 4 alkyl, and is preferably benzyl or I or 2-phenethyl, whilst phenyl-lower alkenyl or phenyl-lower alkynyl is, in particular, phenyl-C 3

-C

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

Lower alkylene is, in particular, C 2

-C

7 alkylene, is straight-chain or branched and is, in particular, ethylene, 1,3-propylene, 1 ,4-butylene, 1,2-propylene, 2-methyl- 1,3-propylene or 2,2-dimethyl- 1,3-propylene. C 2

-C

5 Alkylene is preferred.

Lower alkylenoxy-lower alkylene is, in particular, C 2

-C

4 alkyleiioxy-C 2

-C

4 alkylene, preferably ethylenoxyethylene.

Lower alkylamino is, in particular, CI-C 7 alkylamino and is, for example, methyl-, ethyl-, n-propyl- or isopropyl -amino. C 1

-C

4 Alkvlamino is preferred.

Lower alkenylamino is, preferably, C 3

C

5 alkenylamino, such as allyl- or methallyl-amino.

Lower alkynylarnino is, preferably, C 3

-C

5 alkynylamino, such as propargylamino.

Phenyl-lower alkylarnino is, preferably, phenyl-Cl-C 4 alkylamino, in particular benzyl- or I or 2-phenylethyl-amino.

:Phenyl-lower alkenylamino is preferably phenyl-C 3

-C

5 alkenylamino, in particular phenylallylamino or 3-phenylmethallylamino.

**Phenyl-lower alkynylamino is preferably phenyl-C 3

-C

5 alkyniylamino, in particular Di-lower alkylamino is, in particular, di-Cl-C 4 alkylamino, such as dimethyl-, diethyl-, di(n-propyl)-, methyl-propyl-, methyl-ethyl-, methyl-butyl or dibutyl-amino.

N-Lower alkyl-N-phenyl-lower alkyl-amino is, in particular, N-C 1

-C

4 alkyl-N-phenyl- Cl-C 4 alkyl-amino, preferably methyl-benzyl-amino or ethyl-benzyl-amino.

Di(phenyl-lower alkyl)-amino is, in particular, di(phenyl-C 1

-C

4 alkyl)amino, preferably dibenzylamino.

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

-C

5 alkenyloxy-CI-C 4 alkyl, such as 2-allyloxyethyl, and lower alcenyloxy- lower alkenyl or -lower alkynyl is, in particular,

C

3

-C

5 alkenyloxy-C 3

-C

5 alkenyl or -alkynyl.

Lower alkylthio-lower alkenyl or -lower alkynyl is, in particular, Cl-C 4 alkYlthio-

C

3

-C

5 alkenyl or -alkynyl.

Lower alkylthio-lower alkyl is, in particular, CI-C 4 alkylthio-CI-C 4 alkyl, such as ethylthiom ethyl, 2-ethylthioethyl, 2-methylthioethyl or 2-isopropylthioethyl, whilst .particularly suitable lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl are *-Lcorresponding CI-C 4 alkane-sulfinyl-C 1

-C

4 alkyl radicals or -sulfonyl-Cl-C 4 alkyl radicals.

**Lower alkenylthio- lower alkyl is, in particular, C 3

-C

5 -alkenylthio-CI-C 4 alkyl, such as 1-allylthioethyl or 3-allylthiopropyl, whilst lower alkenyl-sulfinyl-lower alkyl or -ulfony-lower alkyl is, in particular, C 3

-C

5 alkenyl-sulfinyl-C 1

-C

4 aylo -sulfonyl-C 1

-C

4 alkyl.

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

-C

5 alkynylthio-CI-C~alkyl, such as eae2-propargylthioethyl or 3-propargylthiopropyl, whilst lower alkcynyl-s ulIfinyl -lower alkyl or -sulfonyl-lower alkyl in particular is C 3

-C

5 alkynyl-sulfinyl-Cl-C 4 alkyl or -sulfonyl-Cl-C 4 alkyl.

Cycloalkyl is, in particular, C 3

-C

7 cycloalkyl, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is, in particular, C 3

-C

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

Lower alkoxy-lower alkoxy-lower alkyl is, in particular, C 1

-C

4 -alkoxy-C*- C4-alkoxy-

CI-C

4 -alkyl, such as 2-(2-methoxyethoxy)ethyl.

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

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, inter alia, 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 H by competitive inhibition of the binding of angiotensin II to the receptors.

0 o The angiotensin II antagonist properties of the compounds of the formula I and their o* pharmaceutically acceptable salts can be detected in the angiotensin II binding test. Rat o smooth muscle cells from homogenized rat aorta are used here. The solid centrifugate is S suspended in 50 mM tris buffer (pH 7.4) using peptidase inhibitors. The samples are incubated for 60 minutes at 25 0 C with 125 I-angiotensin II (0.175 nM) and a varying concentration of angiotensin II or test substance. The incubation is then ended by addition of saline buffered with ice-cold phosphate, and the mixture is filtered through Whatman GF/F filters. The filters are counted using a gamma counter. The IC 50 values are determined from the dose-effect curve. IC 50 values from about 10 nM are determined for the compounds of the formula I and their pharmaceutically acceptable salts e* S" For the determination of angiotensin II-induced vasoconstriction, investigations on the isolated rabbit aorta ring can be used. For this purpose, aorta rings are dissected from each chest and fixed between two parallel clamps at an initial tension of 2 g. The rings are then immersed in 20 ml of a tissue bath at 37 0 C and aerated with a mixture of 95 02 and 5

CO

2 The isometric reactions are measured. At 20-minute intervals, the rings are alternately stimulatd with 10 nM angiotensin II (Hypertensin-CIBA) and 5 nM noradrenaline chloride. The rings are then incubated with selected concentrations of the test substances before treatment with the agonists. The data are analysed using a Buxco digital computer. The concentrations which cause a 50 inhibition of the initial control values are given as IC 50 values. IC 50 values from about 5 nM are determined for the compounds of the formula I and their pharmaceutically acceptable salts.

The fact that the compounds of the formula I and their pharmaceutically acceptable salts can reduce high blood pressure induced by angiotensin II can be verified in the normotensive anaesthetized rat test model. After calibration of the preparations with 0.9 NaCI (1 ml/kg noradrenaline (1 [g/kg or angiotensin II (0.3 .g/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 minute intervals. The blood pressure is measured directly in the carotid artery and recorded using an on-line data recording system (Buxco). The specificity of the angiotensin II antagonism is shown by the selective inhibition of the pressure effect produced by angiotensin II, but not that produced by noradrenaline. In this test model, the compounds of the formula I and their pharmaceutically acceptable salts show an inhibiting effect from a dose of about 0.3 mg/kg i.v.

0 The antihypertensive activity of the compounds of the formula I and their i:°o pharmaceutically acceptable salts may also be manifested in the renally hypertensive rat test model. High blood pressure is produced in male rats by constricting a renal artery S according to the Goldblatt method. Doses of the test substance are administered to the rats by means of a stomach tube. Control animals receive an equivalent volume of solvent.

Blood pressure and heart beat are measured indirectly at intervals in conscious animals by the tail clamp method of Gerold et al. [Helv. Physiol. Acta 24, (1966), 58] before administration of the test substances or of the solvent and during the course of the experir.,l-kt. It was possible to detect the pronounced antihypertensive effect from a dose S of about 30 mg/kg p.o.

S The compounds of the formula I and their pharmaceutically acceptable salts can therefore S be used, for example, as pharmaceutical active ingredients in antihypertensives which are S employed, for example, for the treatment of high blood pressure and cardiac insufficiency.

S. The invention thus relates to the use of the compounds according to the invention and their o" pharmaceutically acceptable salts for the production of appropriate medicaments and to the therapeutic treatment of high blood pressure and cardiac insufficiency. The industrial production of the active substances is also included in the production of the pharmaceuticals.

The invention relates in particular to compounds of the formula I in which one of the radicals R 1 and R 2 is lower alkyl, lower alkenyl o- '3wer alkynyl, in each case unsubstituted or substituted by halogen or hydroxyl, in each case 3- to 7-membered cycloalkyl or cycloalkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, the other of the radicals R 1 and R 2 is the group Ia, in which Z 1 is methylene, lower alkylene, 0, S(O)m or R 5 is carboxyl, halo-lower alkanesulfonylamino, SO 3

H,

PO

2

H

2 P0 3

H

2 or 5-tetrazolyl and the rings A and B are independently of one another -11unsubstituted or substituted by halogen, or by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lowe alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, low r alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl or lower alkoxy-lower alkoxy-lower alkyl, in each case unsubstituted or substituted by hydroxyl or halogen, by hydroxy, by ower alkoxy, by lower alkenyloxy, by carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, by carbamoyl in which the amino group is unsubstituted or independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-low r alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or S disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or by S and either R 3 is halogen, lower alkanoyl, substituted or unsubstituted phenyl, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyi, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, carbamoyl in which the amino group is unsubstituted or independently of one another mono- cr disubstituted by lower alkyl, lower alkc.l. lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or .0.0 S disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, cyano, SO 3

H,

PO

2

H

2 P0 3

H

2 5-Letrazolyl, sulfamoyl in which the amino group is unsubstituted or S mono- or disubstituted by lower alkyl, lower alkanesulfonylamino, halo-lower alkanesulfonylamino, lower alkanoylamino, substituted or unsubstituted benzoylamino or 000*0* substituted or unsubstituted benzenesulfonylamino or is -Z 2 wherein Z 2 is a bond or is 0O, S(0)m or N(R) and R' is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-low-r a.ynyl, lower alktnyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkoxy-lower alkoxy-lower alkyl, lower alkyl-thio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case Liunsubstituted or substituted by hydroxyl, halogen, amino, lower alkyleneamino, lower alkylenoxy-lower alkyleneamino, lower alkylamino, lower alkenylamino, lower alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or carbamoyl in which the amino -12group is unsubstituted or mono- or disibstituted by, independently of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disuhstituted by lower alkylene or lower alkylenoxy-lower alkylene, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkoxy-lower alkoxy-lower alkyl, lower alkyl-thio-lower alkyl, -lower alkenyl or -lower alkynyl, lower aikane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case unsubstituted or substituted by hydroxyl, S(O)m-R, substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy, substituted or unsubstituted naphthyloxy, amino, lower alkyleneamino, lower alkylenoxy-lower alkyleneamino, lower alkylamino, lower alkenylamino, lower 9999 alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower 9999 alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independently of one another, lower S: alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, or R 3 and R 4 together represent methylen or lower alkylene, R in each case V. being hydrogen, lower alkyl, lower alkenyl or lower alkynyl, m in each case being 0, 1 or S 2 and aromatic radicals being in each case unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl, in free form or in salt form.

The invention relates in particular to compounds of the formula I, in which R 1 is the group la, in which Z 1 is methylene, lower alkylene, 0, S(O)m or R 5 is carboxyl or and the rings A and B independently of one another are insubstituted or substicuted by halogen, lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl of

R

2 is lower alkyl or lower alkenyl, in each case unsubstituted or substituted by hydroxyl or halogen, and either R 3 is halogen, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl or lower alkoxy-lower alkyl, carbamoyl, cyano, P0 3

H

2 5-tetrazolyl, lower alkanesulfamoyl, lower alkanoylamino or lower alkanesulfonylamino or is -Z 2 wherein Z 2 is a bond or is O, S(0)m or N(R) and R' is hydrogen or lower alkyl or lower alkoxy-lower alkyl, in each case unsubstituted or 13substituted by carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl or hydroxyl, and R 4 is lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy-lower alkoxycarbonyl-lower alkyl, carbamoyl-, lower alkyicarbamoyl- or di-lower alkylcarbamoyl-lower alkyl, hydroxy-lower alkyl, substituted or unsubstituted phenoxy-lower alkyl, amino-, lower alkylamino- or di-lower alkylamino-lower alkyl or substituted or unsubstituted phenyl-lower alkyl, or R 3 and R 4 together represent methylen or lower alkylene, R in each case being hydrogen or lower alkyl, m in each case being 0, 1 or 2 and aromatic radicals Sbeing in each case unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl, in free form or in salt form.

The invention relates in particular to compounds of the formula I, in which R 1 is the group la, in which Z 1 is methylene, lower alkylene, such as ethylene, O or S(O)m, R 5 is carboxyl or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by lower alkyl, such as methyl, halogen, in particular with an atomic number of not more than 35, such as chlorine, or lower alkoxy, such as methoxy, R 2 is lower alkyl or lower alkenyl, such as n-propyl, n-butyl or allyl, in each case unsubstituted or substituted by hydroxyl or halogen, in particular with an atomic number not more than such as chlorine, and either R 3 is halogen, in particular with an atomic number not more than 35, such as chlorine, carboxyl, lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, PO 3

H

2 5-tetrazolyl, lower alkanoylamino, such as acetylamino, lower alkanesulfonylamino, such as methanesulfonylamino, hydrogen, lower alkyl, such as methyl, lower alkoxy-lower alkyl, such as 2-methoxyethyl, carboxy-lower alkyl, such as carboxymethyl, lower alkoxycarbonyl-lower alkyl, such as ethoxycarbonylmethyl, hydroxy-lower alkyl, such as hydroxymethyl, hydroxy-lower alkoxy-lower alkyl, such as hydroxyethoxymethyl, hydroxyl, lower alkoxy, such as methoxy, lower alkoxy-lower alkoxy, such as 2-methoxyethoxy, caiboxy-lower alkoxy, such as carboxymethoxy, lower alkoxycarbonyl-lower alkoxy, such as ethoxycarbonylmethoxy, hydroxy-lower alkoxy, such as 2-hydroxyethoxy, mercapto, lower alkylthio, such as methylthio, lower alkanesulfinyl, such as methanesulfinyl, lower alkanesulfonyl, such as methanesulfonyl, amino, lower alkylamino, such as methylamino, or di-lower alkylamino, such as dimetnylamino, and R 4 is lower alkyl, such as methyl, ethyl or n-butyl, hydroxylower alkyl, such as hydroxymethyl, carboxy-lower alkyl, such as carboxymethyl, or lower alkoxycarbonyl-lower alkyl, such as etho ycarbonylmethyl, or R 3 and R 4 together represent methylen or lower alkylene, m being 0, 1 or 2 and part structures being designated by "lower" in each case in particular including not more than 7, preferably not -14more than 4, C atoms, in free form or in salt form.

The invention relates in particular to compounds of the foimula I, in which R 1 is the group la, in which Z 1 is methylene or lower alkylene, such as ethylene, R 5 is carboxyl or and the rings A and B independently of one another are unsubstituted or substituted by lower alkyl, such as methyl, halogen, in particular with an atomic number not more than 35, such as chlorine, or lower alkoxy, such as methoxy, R 2 is lower alkyl, S such as n-propyl or n-butyl, R 3 is halogen, in particular with an atomic number not more than 35, such as chlorine, hydrogen, lower alkyl, such as methyl, lower alkoxy-lower

S

alkyl, such as 2-methoxyethyl, carboxy-lower alkyl, such as carboxymethyl, lower alkoxycarbonyl-lower alkyl, such as ethoxycarbonylmethyl, hydroxy-lower alkyl, such as hydroxymethyl, hydroxy-lower alkoxy-lower alkyl, such as hydroxyethoxymethyl, hydroxyl, lower alkoxy, such as methoxy, lower alkoxy-lower alkoxy, such as 2-methoxyethoxy, carboxy-lower alkoxy, such as carboxymethoxy, lower alkoxycarbonyl-lower alkoxy, such as ethoxycarbonylmethoxy, hydroxy-lower alkoxy, such as 2-hydroxyethoxy, or lower alkoxy-lower alkoxy, such as 2-methoxy-lower alkoxy, and R 4 is lower alkyl, such as methyl, ethyl or n-butyl, hydroxy-lower alkyl, such as hydroxymethyl, carboxy-lower alkyl, such as carboxymethyl, or lower alkoxycarbonyl-lower alkyl, such as ethoxycarbonylmethyl, part structures being designated by "lower" in each case in particular including not more than 7, preferably not more than 4, C atoms, in free form or in salt form.

The invention relates nrimarily to compounds of the formula I, in which R 1 is the group of S the formula AB (Ib), in free form or in salt form.

The invention relates primarily to compounds of the formula I, in which R 1 is the group Ib, in which Z 1 is methylene, R 5 is carboxyl or in particular 5-tetrazolyl and the rings A and B are unsubstituted, R 2 is C 3

-C

7 alkyl, in particular C 3

-C

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

-C

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

-C

4 alkyl, such as methyl, ethyl or propyl, carboxy-C 1

-C

4 alkyl, such as carboxymethyl,

C

1

-C

4 alkoxycarbonyl-CI-C 4 alkyl, such as ethoxycarbonylmethyl, or hydroxy-C 1

-C

4 alkyl, such as hydroxymethyl, in free form or in salt form.

The invention relates primarily to compounds of the formula I, in which R 1 is the group Ib, in which Z 1 is methylene, R 5 is carboxyl or tetrazolyl and the rings A and B are unsubstituted, R 2 is C 3

-C

5 alkyl, such as n-propyl or n-butyl, R 3 is hydrogen or Ci-C 4 alkyl, such as methyl or n-butyl, and R 4 is C 1

-C

4 alkyl, such as methyl, in free form or in salt form.

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

The invention furthermore relates to a process for the preparation of the compounds of the formula I in free form or in salt form, which process comprises, for example, converting

X

1 into R 5 in a compound of the formula N N-R, (Ra), S 2 R 2 0

SR'

1 in which one of the radicals R' 1 and R' 2 is the group of the formula

B

ZI

A

(Ib) Xl and X 1 is a radical which can be converted into R 5 or in a salt thereof and, if desired, converting a compound I obtainable according to the process or in another manner, in free form or in salt form, into another compound I, separating a mixture of isomers obtainable according to the process and isolating the desired isomer and/or converting a free compound I obtainable according to the process into a salt or converting a salt of a -16compound I obtainable according to the process into the free compound I or into another salt.

What has been stated hereinbefore with respect to salts of compounds I applies analogously also to salts of the starting materials.

The reactions described above and below are carried out in a manner which is known per se, for example in the absence or usually in the presence of a suitable solvent or diluent or S* of a mixture thereof, the reaction being carried out, as required, with cooling, at room temperature or with heating. for example in a temperature range from about -80 0 C up to the boiling point of the reaction medium, preferably from about -100 to about +200 0

C,

and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

Radicals X 1 which can be converted into the variable R 5 are, for example, cyano, mercapto, halogen, the group -N 2 in which A- is an anion derived from an acid, amino, functional derivatives of COOH, S03H, PO 3

H

2 and P0 2

H

2 and N-protected o 0o Functionally modified carbcxyl is, for example, cyano or esterified or amidated carboxyl.

oo Radicals X 1 which can be converted into 5-tetrazolyl R 5 are, for example, cyano and S N-protected 0 ooo To prepare compounds of the formula I, in which R 5 is 5-tetrazolyl, the process starts, for example, from starting materal of the formula Ia, in which X 1 is cyano, and this is reacted with an azide, for example with HN 3 or, in particular, a salt, such as an alkali metal salt, thereof or with an organotin zide, such as tri-lower alkyl- or tri-aryl-tin azide.

Preferred azides are, for example, sodium azide and potassium azide and tri-C 1

-C

4 alkyl-, for example triethyl- or tributyl-tin azide, and triphenyltin azide.

Suitable protecting groups for N-protected 5-tetrazolyl are the protecting groups customarily used in tetrazole chemistry, in particular triphenylmethyl, benzyl which is unsubstituted or substituted, for example by nitro, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- or ethoxy-methyl, lower alkylthiomethyl, such as methylthiomethyl, as well as 2-cyanoethyl, and additionally lower alkoxy-lower alkoxy methyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. The protecting 17groups are removed following known methods. Thus, for example, triphenylmethyl is customarily removed by hydrolysis, in particular in the presence of an acid, or hydrogenolysis in the presence of a hydrogenation catalyst, 4-nitrobenzyl is removed, for example, by hydrogenolysis in the presence of a hydrogenation catalyst, methoxy- or ethoxy-methyl is removed, for example, by treating with a tri-lower alkyltin bromide, such as triethyl- or tributyl-tin bromide, methylthiomethyl is removed, for example, by treating with trifluoroacetic acid, 2-cyanoethyl is removed, for example, by hydrolysis, for example with sodium hydroxide solution, 2-methoxyethoxymethyl is removed, for example, by hydrolysis, for example with hydrochloric acid, and benzyloxymethyl and Sphenacyl are removed, for example, by hydrogenolysis in the presence of a hydrogenation catalyst.

0 A radical X 1 which can be converted into SO 3 H R 5 is, for example, the mercapto group.

Starting compounds of the formula IIa containing a group of this type are, for example, oxidized by oxidation processes known per se to those compounds of the formula I in which R 5 is SO 3 H. Suitable oxidizing agents are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid. The oxidation is commonly carried out in the presence of suitable catalysts, suitable acids, such as substituted or unsubstituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VI, for example molybdenum oxide or tungsten oxide, being mentioned as catalysts. The oxidation is carried out under mild conditions, for example at temperatures from about -500 to about +100 0

C.

A group X 1 which can be converted into PO 3

H

2

R

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

Corresponding diazonium compounds of this type are, for example, reacted in a manner known per se with a P(III) halide, such as PCI 3 or PBr 3 and worked up by hydrolysis, those compounds of the formula I being obtainable in which R 5 is P0 3

H

2 Compounds I, wherein R 5 is PO 2

H

2 are obtained, for example, by the conversion, carried out in customary manner, of X 1 in a compound IIa, wherein X 1 is a functional derivative of PO 2

H

2 into PO 2 Hz.

18- A suitable X 1 radical whicn can be converted into haloalkanesulfonylamino R 5 is, for example, amino. In order to prepare compounds of the formula I in which R 5 is haloalkanesulfonylamino, corresponding anilines, for example, are reacted with a customarily reactively esterified haloalkanesulfonic acid, the reaction being carried out, if desired, in the presence of a base. The suitable preferred reactively esterified haloalkanesulfonic acid is the corresponding halide, such as the chloride or bromide.

A radical X 1 which can be converted into COOH R 5 is, for example, a functionally i modified carboxyl, such as cyano, esterified or amidated carboxyl, hydroxymethyl or *y S* formyl.

0 0 00 Esterified carboxyl is, for example, carboxyl esterified with a substituted or unsubstituted aliphatic, cycloaliphatic or aromatic alcohol. An aliphatic alcohol is, for example, a lower alkanol, such as methanol, ethanol, n-propanoi, isopropanol, n-butanol, sec-butanol or tert-butanol, while a suitable cycloaliphatic alcohol is, for example, a 3- to 8-membered cycloalkanol, such as cyclo-pentanol, -hexanol or -heptanol. An aromatic alcohol is, for example, a phenol or a beterocyclic alcohol, which may in each case be substituted or S" unsubstituted, in particular hydroxypyridine, for example 3- or 4-hydroxypyridine.

0* 0 S Amidated carboxyl is, for example, carbamoyl, carbamoyl which is monosubstituted by hydroxyl, amino or substituted or unsubstituted phenyl, carbamoyl which is mono- or disubstituted by lower alkyl or carbamoyl which is disubstituted by 4- to 7-membered alkylene or 3-aza-, 3-lower alkylaza-, 3-oxa- or 3-thiaalkylene. Examples which may be mentioned are carbamoyl, N-mono- or N,N-di-(lower alkyl)carbamoyl, such as N-methyl-, N-ethyl-, N,N-dimethyl-, N,N-diethyl- and N,N-dipropyl-carbamoyl, pyrrolidino- and piperidino-carbonyl, morpholino-, piperazino-, 4-methylpiperazino- and thiomorpholino-carbonyl, anilinocarbonyl and anilinocarbonyl substituted by lower alkyl, lower alkoxy and/or halogen.

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

Compounds of the formula I in which R 5 is carboxyl can be prepared, for example, starting from compounds of the formula IIa in which X 1 is cyano or esterified or amidated carboxyl, by hydrolysis, in particular in the presence of a base, or, starting from 19compounds of the formula IIa in which X 1 is hydroxymethyl or formyl, by oxidation. The oxidation is carried out, for example, in an inert solvent, such as in a lower alkanecarboxylic acid, for example acetic acid, in a ketone, for example acetone, in an ether, for example tetrahydrofuran, in a heterocyclic aromatic, for example pyridine, or in water, or in a mixture thereof, if necessary with cooling or warming, for example in a temperature range of from about 00 to about +150 0 C. Suitable oxidizing agents are, for example, oxidizing transition metal compounds, in particular those with elements of sub-groups I, VI or VII. Examples which may be mentioned are: silver compounds, such S as silver nitrate, silver oxide and silver picolinate, chromium compounds, such as chromium trioxide and potassium dichromate, and manganese compounds, such as potassium permanganate, tetrabutylammonium permanganate and benzyltri(ethyl)ammonium permanganate. Other oxidizing agents are, for example, S suitable compounds with elements of main group IV, such as lead dioxide, or halogen-oxygen compounds, such as sodium iodate or potassium periodate.

The starting material IIa is, for example, accessible by starting from a compound of the formula **S o** *e o

II

R C CH- X 2 (Hc), o

R'

0 in which X 2 is carboxyl which, if desired, is functionally modified, the preparation of the compounds IIc being carrier' out in a manner known per se, and reacting this with a compound of the formula

NH

R C NH, (IId) or a salt thereof.

If required, the reaction is carried out in the presence of a base.

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

In compounds IIa, in which R 4 is hydrogen, the radical R 4 can be introduced in a manner S* known per se by customary alkylation with appropriate alkylating reagents.

0 0 Compounds IIa can also be prepared by starting from compounds IIc and reacting these with a compound of the foimula R 3

-C(=NH)-NH-R

4 (lie) or a salL, in particular an acid S addition salt, thereof in the presence of a base. Compounds IIe are in turn accessible, for example, by reaction of compounds lid or a salt, in particular an acid addition salt, thereof with an amine of the formula R 4

-NH

2 (If) or a salt thereof, in particular an acid addition salt.

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

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

Conversely, corresponding ethers, such as lower alkoxy compounds, can be split, for example, by means of strong acids, such as mineral acids, for example hydrobromic or hydriodic acid, which can advantageously be in the form of pyridinium halides, or by means of Lewis acids, for example halides of elements of main group III or of the corresponding sub-groups. If necessary, these reactions can be carried out while cooling or heating, for example in a temperature range from about -200 to about +100 0 C, in the presence or absence of a solvent or diluent, under an inert gas and/or under pressure and if appropriate in a closed vessel.

-21 Compounds I containing hydroxymethyl groups can be prepared, for example, starting from compounds containing corresponding carboxyl or esterified carboxyl, corresponding compounds being reduced in a manner known per se, for example by hydrogenation with hydrogen in the presence of one of the hydrogenation catalysts mentioned below or in particular by reduction with a hydride which, if desired, may be complex, such as a hydride formed from an element of the 1st and 3rd main group of the periodic table of the elements, for example a bo:ohydride or an aluminohydride, for example sodium borohydride, lithium aluminium hydride or diisobutylaluminium hydride, and also Sdiborane.

*0 0 If an aromatic structural constituent is substituted by lower alkylthio, this can be oxidized to the corresponding lower alkane-sulfinyl or -sulfonyl in the customary manner. Suitable oxidizing agents fo' oxidation to the sulfoxide level are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen pei .xide and acids, for example mixtures of hydrogen peroxide and acetic acid. The oxidation is often carried out in the presence of suitable catalysts, catalysts being suitable acids, such as unsubstituted or substituted carboxylic acids, for example acetic acid or

SO

trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VI, for example molybdenum oxide or tungsten oxide. The oxidation is carried out under mild conditions, for example at temperatures from about -50° to about +100 0 C. Further oxidation to the sulfone level can be carried out correspondingly with dinitrogen tetroxide as the catalyst in the presence of oxygen at low temperatures, as can direct oxidation of lower alkylthio to lower alkanesulfonyl. However, the oxidizing agent is usually employed in excess here.

If one of the variables contains amino, corresponding compounds I can be N-(ar)alkylated in a manner which is known per se; carbamoyl or radicals containing carbamoyl can likewise be N-(ar)alkylated. The (ar)alkylation is carried out, for example, with an (aryl)C 1

-C

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

-C

7 alkanesulfonate, for example 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 benzyltrimethyl- -22ammonium chloride, in which case more strong: isic condensing agents, such as alkali metal amides, hydrides or alcoholates, for example sodium amide, sodium hydride or sodium ethanolate, may be necessary.

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

Furthermore, in compounds of the formula I which contain a carboxyl group as a S. substituent (especially if R 5 is other than carboxyl), this can be converted into an esterified S carboxyl group, for example by treatment with an alcohol, such as a lower alkanol, in the S presence of a suitable esterifying agent, such as an acid reagent, for example an inorganic or organic acid or a Lewis acid, for example zinc chloride, or a water-binding condensing agent, for example a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by treatment with a diazo reagent, such as with a diazc-lower alkane, for example diazomethane. This esterified carboxyl group can also be obtained if compounds of the formula I in which the carboxyl group is present in the free form or in salt form, such as ammonium or metal, for example alkali metal, such as sodium or potassium, salt form, are treated with a C 1

-C

7 alkyl halide, for example methyl or ethyl bromide or iodide, or an S organic sulfonic acid ester, such as a corresponding C 1

-C

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

S Compounds of the formula I which contain an esterified carboxyl group as a substituent can be converted into other ester compounds of the formula I by transesterification, for example by treatment with an alcohol, usually with an alcohol which is higher than that corresponding to the esterified carboxyl group in the starting material, in the presence of a suitable transesterification agent, such as a basic agent, for example an alkali metal

C

1

-C

7 alkanoate, C 1

-C

7 alkanolate or cyanide, such as sodium acetate, methanolate, ethanolate, tert-butanolate or cyanide, or a suitable acid medium, the alcohol formed being removed if appropriate, for example by distillation. Corresponding so-called activated esters of the formula I which contain an activated esterified carboxyl group as a substituent (see below) can also be used as starting substances, and these can be converted into another ester by treatment with a Ci-C 7 alkanol.

In compounds of the formula I which contain the carboxyl group as a substituent, this can -23also first be converted into a reactive derivative, such as an anhydride (including a mixed anhydride), an acid halide, for example chloride (for example by treatment with a thionyl halide, for example chloride), an anhydride with a formic acid ester, for example

C

1

-C

7 alkyl ester (for example by treatment of a salt, such as an ammonium or alkali metal salt, with a halogeno-, such as chloro-formic acid ester, such as C 1

-C

7 alkyl ester), or an activated ester, such as a cyanomethyl, nitrophenyl, for example 4-nitro-phenyl, or polyhalogenophenyl, for example pentachlorophenyl, ester (for example by treatment with a corresponding hydroxyl compound in the presence of a suitable condensing agent, such Sas N,N'-dicyclohexylcarbodiimide), and such a reactive derivative can then be reacted S with an amine to give in this way amide compounds of the formula I which contain an o* amidated carboxyl group as a substituent. In this case, these compounds can be obtained directly or via intermediate compounds; thus, for example, an activated ester, such as a 4-nitrophenyl ester, of a compound of the formula I having a carboxyl group can first be reacted with a 1-unsubstituted imidazole and the 1-imidazolylcarbonyl compound thus formed can be reacted with an amine. However, it is also possible for other non-activated esters, such as Ci-C 7 alkyl esters, of compounds of the formula I to be reacted with amines.

O*

If an aromatic ring contains a hydrogen atom as a substituent, this can be replaced by a C halogen atom with the aid of a halogenating agent in the customary manner, for example *o by bromine using bromine, hypobromic acid, an acyl hypobromite or another organic bromine compound, for example N-bromosuccinimide, N-bromoacetamide, S N-bromophthalimide, pyridinium perbromide, dioxane dibromide, 1,3-dibromo-5,5dimethylhydantoin or 2,4,4,6-tetrabromo-2,5-cyclohexanedien- 1-one, or by chlorine using elemental chlorine, for example in a halogenated hydrocarbon, such as chloroform, and while cooling, for example down to about -10 0

C.

If an aromatic ring contains an amino group, this can be diazotized in the customary manner, for example by treatment with a nitrite, for example sodium nitrite, in the presence of a suitable proton acid, for example a mineral acid, the reaction temperature advantageously being kept below about 5 0 C. The diazonium group thus obtainable, which is present in salt form, can be substituted by customary processes, for example as follows: by the hydroxyl group analogously to phenol boiling in the presence of water, by an alkoxy group by treatment with a corresponding alcohol, in which case energy must be supplied; by the fluorine atom analogously to the Schiemann reaction in the case of thermolysis of corresponding diazoni im tetrafluoborate; or by chlorine, bromine, iodine or the cyano group analogously to the Sandmeyer reaction by reaction with corresponding -24- Cu(I) salts, initially by cooling, for example to beiow about 5°C, with subsequent heating, for example to about 600 to about 150°C.

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

In compounds I in which, for example, one of the radicals R 1

R

2

R

3 and R 4 is halogen, e such as chlorine, halogen can furthermore be replaced by reaction with an unsubstituted or substituted amine or an alcohol or mercaptan.

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

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

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

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

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

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

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

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

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

-26- Those starting substances and intermediates which lead to the compounds I described above as particularly useful are preferably used in the process according to the present invention. The invention likewise relates to novel starting substances and intermediates for the preparation of the compounds I, their use and a process for their preparation, the variables R 1

R

2

R

3 and R 4 being as defined for the compounds I.

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

0 0 S The invention thus likewise relates to pharmaceutical preparations containing a compound SI as the active ingredient in the free form or in the form of a pharmaceutically acceptable S salt, and to a process for their preparation. These pharmaceutical preparations are those for enteral, such as oral, and furthermore rectal or parent -ral administration to warm-blooded animals, the preparation containing the pharmacological active ingredient by itself or together with customary pharmaceutical auxiliaries. The pharmaceutical preparations contain, for example, about 0.1 to 100 preferably about 1 to about 60 of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration are, for example, those in dose unit forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner which is known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Pharmaceutical preparations which are suitable for oral administration can thus be obtained by combining the active ingredient with solid carriers, if appropriate granulating the resulting mixture, and processing the mixture or granules, if desired or necessary after addition of suitable adjuncts, to tablets or sugar-coated tablet cores.

Suitable carriers are in particular fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, using, for example, maize starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the abovementioned starches, and also carboxymethyl-starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.

Adjuncts are chiefly glidants and lubricants, for example silicic acid, talc, stearic acid or -27salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.

Sugar-coated tablet cores are provided with suitable coatings which can be resistant to gastric juices, using, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, shellac solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets or sugar coatings, for example to identify or indicate different doses of active ingredient.

Further pharmaceutical preparations for oral administration are dry-filled capsules of gelatin and also soft, sealed capsules made from gelatin and a plasticizer, such as glycerol or sorbitol. The dry-filled capsules can contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and if appropriate stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilizers can also be added.

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

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

-28- The dosage of the active ingredient can depend on various factors, such as the mode of ministration, the warm-blooded species, age and/or the state of the individual. In the n approximate daily dose of about 10 mg to about 250 mg is to be estimated i administration to a patient weighing about 75 kg.

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

Example 1: A mixture of 870 mg (2.34 mmol) of 4-(n-butyl)-5-(2'-cyanobiphenyl- 4-ylmethyl)-l,2-dimethyl-6-oxo-l,6-dihydro-pyrimidine, 1.55 g (4.68 mmol) of tributyltin azide and 30 ml of o-xylene is heated under reflux and stirred for 24 hours. The reaction S mixture is subsequently evaporated in vacuo, the residue is taken up in 50 ml of a dichloromethane/methanol/ammonia mixture and this mixture is stirred for S minutes. After evaporating in vacuo again, the residue is separated by means of flash se chromatography [silica gel 60 (40-63 utm), dichloromethane/methanol/ammonia 4-(n-Butyl)-1,2-dimethyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine is obtained in this way in the form of an amorphous solid which crystallises from acetonitrile 165-1690 (decomposition)].

The starting material can be prepared, for example, as follows: a) 84 mg (2.8 mmol) of sodium hydride (80 in white oil) are added at room temperature S to a solution of 1.0 g (2.8 mmol) of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)- 9 4-hydroxy-2-methyl-pyrimidine in 20 ml of N,N-dimethylformamide. After addition is complete, the reaction mixture is stirred for a further 30 minutes. Subsequently, 0.23 ml (3.7 mmol) of methyl iodide are added dropwise. The reaction mixture is then stirred at room temperature for 3 hours and subsequently concentrated in vacuo. The residue is partitioned between ethyl acetate and water and the organic phase is washed with water and raturated sodium chloride solution, dried using Na 2

SO

4 and concentrated in vacuo.

Flash chromatography [silica gel 60 (40-63 dichloromethane/methanol gives 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)- 1,2-dimethyl-6-oxo- 1,6-dihydro-pyrimidine, which is further processed withcut further purification.

Example 2: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-1-ethyl-2-methyl- 6-oxo- ,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)- -ethyl-2-methyl-6-oxo- 5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, which crystallises from acetonitrile in the form of white crystals 180-1820 (decomposition)], is 29 obtained in a manner analogous to that described in Example 1.

The starting material can be prepared, for example, as follows: a) By alkylation of 6- butyl)- 5 -(2'-cyanobiphenyl-4-yIm ethyl)- I- hydroxy-2-meth ylpyrimidine with ethyl iodide in the manner described in Example Ila) and flash chromatography [silica gel 60 (40-63 jimn), hexane/ethyl acetate 4-(n-butyl)- -(2'-cyanobiphenyl-4-ylmethyl)- 1-ethyl- 2-methyl-6-oxo- 1,6-dihydro-pyrim idine is obtained and is directly further processed.

Example 3: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-6-oxo- 1-(n-propyl)-1,6-dihydro-pyrirnidine and tributyltin azide, 4-(n-butyl)-2-methyl-6-oxo- 1H-terrazol-5-yl)biphenyl-4-ylmethylj- 1,6-dihydro-pyrimidine, which crystallises from acetic acid/wat~r in the form of white crystals 168-170' (decomposition)], is obtained in a manner analogous to that described in Example 1.

The starting material can be prepared, for example, as follows: a) By alkylation of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-niethylpyrimidine with n-propyl iodide in the manner described in Example la) and flash chromatogaphy [silica gel 60 (40-63 jim), hexane/ethyl acetate 4-(n-butyl)- -(2'-cyanobiphenyl-4-ylm ethyl)-2-m ethyl -6-oxo- 1-(n-propyl)- 1,6-dihydro-pyrimidine is obtained and is directly fur-ther proessed.

Example 4: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-1-ethoxycarbonylmethyl-2-methyl-6-oxo-l,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)- *1 -ethoxycarbonylmethyl-2-m ethyl- 6-oxo-5 1H-tetrazol-5 -yl)biphenyl-4-ylmethyl] 91,6-dihydro-pyrimidire, which crystallises from diisopropyl ether in the formn of white crystals 150-155' (decomposition)], is obtained in a manner analogous to that described in Example 1.

The starting material can be prepared, for example, as follows: a) By alkylation of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methylpyrimidine with ethyl bromoacetate in the manner described in Example 1la) and flash chromatography [silica gel 60 (40-63 jim), hexane/ethyl acetate 4-(n-butyl).

5-(2'-cyanobiphenyl-4-ylmethyl)-, -ethoxyc arbonylm ethyl- 2-m ethyl- 6-oxo- I ,6-dihydropyrimidint is obtained and is directly further processed.

30 Example 5: 973 mg (2 mmol) of 4-(n-butyl)-l1-ethoxycarbonylmethyl-2-methyl-6-oxo- H-tetrazol-5 -yl) biphenyl-4-ylnmiethyl]I 1, 6-dihydro-pyri midi ne are stirred at room temperature in 4 ml (4 mmol) of 1 N-sodium hydroxide solution for 12 hours. The mixture is acidified to pH 2 with ice-cooling using 1 N-hydrochloric acid and the precipitate is filtered off. Recrystallisation from acetonitrile/water gives the pure 4- butyl)- 1 -carboxymethyl-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-'-.ylmethyl]- 1 ,6-dihydropyrimidine, which melts at 137 to 1400.

Example 6: 870 mg (2.34 mmol) of 4-(n-u~utyl)-5-(2'-cyanobiphenyl-4-ylmethyl)- *1 ,2-dimethyl-6-oxo- 1,6-dihydro-pyrimidine are stirred under reflux in 3 ml of 4 N-potassium hydroxide solution and 3 ml of n-propanol for 48 hours. After concentrating the reaction mixture in vacuo, the residue is dissolved in water and the solution is extracted using dichloromethane. The aqueous phase is acidified using 4 N-hydrochloric acid, and the precipitate is filtered off and dried over phosphorus pentoxide in vacuo.

4-(n-Butyl)-5-(2'-carboxybiphenyl-4-ylmethyl)- 1,2-dimethyl-6-oxo- 1,6-dihydropyrimidine is obtained in this way.

Example 7: Starting from 4-(n-butyl)-5-(2' -cyanobiphenyl-4-ylrmethyl)- 1 -(2-ethoxyethyl)-2-methyl-6-oxo- 1,6-dihydro-pyrimidine and tributyltin azide, 4-(n-b utyl)- 1-(2-ethioxyethyl)-2-methyl-6-oxo-5-[2'-(1--te,.razol-5-yl)biphenyl- 4-ylm ethyl] -1,6-d ihydro-pyrim idine 167-179' (from ethyl acetate)] is obtained in the manner descri d in Example 1.

The starting material can be prepared, for example, as follows: a) By alkylation of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methylpyrimidine with bromoethyl ethyl ether in the manner described in Example 1a) and flash chromatography [silica gel 60 (40-63 pm), hexane/ethyl acetate 4-(n-butyl)- 5-(2 '-cyanobiphenyl-4-ylmethyl)-l1-(2-ethoxyethyl)-2-methyl-6-oxo- 1,6-dihydropyrimidine is obtained and is directly further processed.

Example 8: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-l1-[N,N- (3-oxapent- 1,5-yl'-n)aminocarbonylm.,ethyl] -6-oxo- 1,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)-2-methyl- i-F ,;-(3-oxapent- 1,5-ylen)aminocarbonylmethyl]-6-oxo- 5-[2'-(1H-tetrazol-5-yl)biphe -4-ylmethyl]- 1,6-dihydro-pyrinmidine 218-221' (from isopropanol/diethyl ether)] is obtained in the manner described in Example 1.

31 The starting material can be prepared, for example, as follows: a) A solution of 7.3 g (16.46 mmol) of 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)- 1-ethoxycarbonylmethyl-2-methyl-6-oxo- 1,6-dihydro-pyrimidine in 150 ml of ethanol is treated with 33 ml of 1 N-sodium hydroxide solution. The reaction mixture is stirred at room temperature for 12 hours. After removing the ethanol in vacuo, the aqueous phase is acidified to pH 2 using 1 N-hydrochloric acid. The precipitated crystals are filtered off.

4-(n-Butyl)- 1-carboxymethyl-5-(2' -cyanobiphenyl-4-ylmethyl)-2-methyl-6-oxo- 1,6-dihydro-pyrimidine 146- 1480 (from ethyl acetate)' is obtained in this way.

230 mg (1.2 mmol) of N-(3-dimethylaminopropyl)-N'-ethyi-carbodiimide **hydrochloride, 203 mg (1.5 mmol) of hydroxybenzotriazole and 0. 175 ml (2 mmol) of morpholine are added at 00 to a solution of 415 mg,- (1 mmol) of 4-(n-butyl)- 1 -carboxymethyl-5-(2' -cyanobiphenyl-4-ylmethyl)-2-methyl-6-oxo- 1,6-dihvdropyrimidine in 5 ml of N,N-dimethiylformamide. The reaction mixture is stirred at room .~temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with 0. 1 N-hydrochloric acid, saturated NaHCO 3 solution and saturated NaCl solution, dried (Na 2

SO

4 and concentrated in vacuo.

4-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methiyl- 1 -[N,N-(3-oxapent- 1 aminocarbonylmethyl]-6-oxo-1,6-dihydro-pyrimidine is obtained in this way and is directly further processed.

Example 9: The following can also be prepared in an analogous manner to that described in one of the above examples: 1. 1 ,4-Di- (n-bu tyl)-2-m ethyl- 6-oxo-5 H- tetrazol-5 -yl)biphenyl-4-ylm ethyl]l-

V.

1,6-dihydro-pyrimidine, 140-142'; a. 2. 1-Benzyl-4-(n-butyl)-2-methyl-6-oxo-5-[2'-( IH-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine, amorphous; 3. 4- (n-B utyl)-2-m ethyl- 6-oxo- 1-(2-phenylethyl)-5-[2'-(l1H-tetrazol-5-yl)biphenyl- 4-ylmethyll-1 ,6-dihydro-pyrimidine, amorphous; 4. 4-(n-Butyl)- 1-(2-hydroxyethyl)-2-methyl-6-oxo-5-[2'-( 4-ylm ethyl] 1,6-dihydro-pyrimidi ne, 1 88-19 4-(n-Butyl)-l1-[2-(2-methoxyethoxy)ethylll-2-methyl-6-oxo-5-[2'-( biphenyl-4-ylm ethyl] I ,6-dihydro-pyrimidine, 132-134'; 6. 4- Butyl)-2-ethyl 1 -me thyl- 6-oxo-5 (1 H-tetrazol-5 -yl)biphenyl-4-ylminethyl] 1 ,6-dihydro-pyrimidine; 7. 4-(n-Butyl)-l1-methiyi-6-oxo-2-(n-propyl)-5-[2'-( 32 4-ylmethyl]- 1,6-dihydro-pyrimidine, 161-1630; 8. 2,4-Di-(n-butyl)-l1-methyl-6-oxo-5-[2' H-tetrazoi-5-yl)biphenyl-4-ylmethyll- 1,6-dihydro-pyrimidine, 157-159'; 9. 4-(n-Butyl)-2-isopropyl-l1-niethyl-6-oxo-5-[2'-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine; 4-(n-Butyl)- 1,2-diethyl-6-oxo-5-[2'-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyll- 1 ,6-dihydro-pyrimidine; 11. 4-(n-Butyl)-l1-ethyl-6-oxo-2-(n-propyl)-5-[2'-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine; 2,4-Di- (n-butyl)- 1 -ethyl- 6-oxo-5 (1 H-tetrazol-5 -yl)b iphe nyl-4-ylmethyl] 1,6-dihydro-pyrimidine, 113-116'; 13. 4-(ri-Butyl)-l1-ethyl-2-isopropyl-6-oxo-5-[2'-(l1H-tetrazol-5-yl)biphenyl-4-ylme-thyl]- 1,6-dihydro-pyrimidine; .14. 4- Butyl)- 2-eth yl- 6-oxo- 1 (n-propyl)- 5- (1 H- tetrazol-5 -yl) biphenyl-4- ylm ethyl] 1,6-dihydro-pyrimidine; 4-(n-Butyl)- 1,2-di-(n-propyl)-6-oxo-5-[2'.(1H-tetrazol-5-yl)biphenyl-4-ylmethyll- 1 ,6-dihydro-pyrimidine; 16. 2,4-Di-(n-butyl)-6-oxo-lI-(n-propyl)-5-[2'-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyll- 1 ,6-dihydro-pyrimidine; 17. 4-(n-Butyl)-2-isopropylh6-oxo-l1-(n-propyl)-5-12' H-tetrazol--'-yl)biphenyl- 4-ylmethyl]- 1 ,6-dihydro-pyrimidine; 18. 1 ,4-Di-(n-butyl)-2-ethyl-6-oxo-5-12'-(1 H-tetazo-5-y1)bipiny1-4-ylmethyl]- 1,6-di hydro-pyrimidine; 19. 1 ,4-Di-(n-butyl)-6-oxo-2-(n-propyl)-5-[2'-(l1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine; S 20. 6-Oxo-5-12 H-tetrazol-5-yl)biphenyl-4-ylmethyll- 1 ,2,4-tri-(n-butyl)- 1,6-dihydropyrimidine; 21. 1 ,4-Di-(n-butyl)-2-isopropyl-6-oxo-5-j2'-( 1H-tetrazol-5-yl)biphenyl-4-ylrnethyl]i ,6-dihydro-pyrimidine; 22. 1 ,2-Dim ethyl- 6-cxo-4- (n-propyl)-5 -(2'-carboxybiphenyl-4-ylm ethyl)- 1, 6-di hydropyrimidine; 23. 1 -Benzylaminocarbonylmethyl-4-(n-butyl)-2-methyl-6-oxo-5-[2'-( biphenyl-4-ylmethyll- 1,6-dihydro-pyrimidine, m 215-22 1'; 24. 4-(n-Butyl)-2-methiyl-6-oxo- 1 -2-phenylethylaminocarbonylmethyl)-5-[2'-( 1Htetrazol-5-yl)biphenyl-4-ylmethyl] -1 ,6-dihydro-pyrimidine, m 121-1260; 4-(n-Butyl)- 1 butylaminoc arbonylm ethyl) -2-m ethyl -6-oxo-5 (1 H-tetrazol-5-yl) 33 biphen yl-4-ylm ethyl]I 1,6-di hydro-pyrim idi ne, m 239-241'; 26. 4-(n-Butyl)-2-methyl- 1 -methylaminocarbonylmethyl-6-oxo-5-[2'-( biphenyl-4-ylm ethyl] 1 ,6-di hydro- pyrim idi ne, 245-247'; 27. 4- B utyl)- 1 -dim eth ylamninocarbonylm ethyl- 2-methyl-6-oxo- 5 (1 H- tetrazol- 5-yl) biphenyl-4-ylm ethyl] -1 ,6-dihydro-pyrimidine, 21 9-222'; 28. 4-(n-Butyl)-6-oxo-1I,2-tetramethylen-5-[2'-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine, 205-206'; and 29. 4-(n-Butyl)-6-oxo-5-[2' 1H-tetrazol-5-yl)biphenyl-4-ylmethy1I,2-tr-imethylen- 1 ,6-dihydro-pyrimidine, 222-224'.

Examples 10: Tablets, each containing 50 mg of active ingredient, for example 1,6-dihydro-pyrimidine, can be prepared as follows: Composition (for 10,000 tablets) Active ingredient 500.0 g Lactose 500.0 g Potato starch 352.0Og Gelatin 8.O g .*:Talc 60.0 g Magnesium stearate 10.0 g Silica (highly disperse) 20.0 g SEthanol q.s.

The active ingredient is mixed with the lactosf- and 292 g of potato starch, and the mixture is moistened using an alcoholic solution of the gelatin and granulated by means of a sieve.

After drying, the remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is compressed to give tablets of weight 145.0 mg each and active ingredient content 50.0 mg which, if desired, can be provided with breaking notches for finer adjustment of the dose.

Example 11: Coated tablets, each containing 100 mg of active ingredient, for example 4-(n-butyl)- 1,2-dimethyl-6-oxo-5- H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine, can be prepared as follows: Composition (for 1000 tablets): -34- Active ingredient 100.00 g Lactose 100.00 g Corn starch 70.00 g Talc 8.50 g Calcium stearate 1.50 g Hydroxypropylmethylcellulose 2.36 g Shellac 0.64 g Water q.s.

Dichloromethane q.s.

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste prepared from 15 g of corn starch and water (with warming). 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 dichloromethane (final weight of the coated tablet: 283 mg).

Example 12: Tablets and coated tablets containing another compound of the formula I or a S pharmaceutically acceptable salt of a compound of the formula I, for example as in one of Examples 1 to 9, can also be prepared in an analogous manner to that described in Examples 10 and 11.

Claims

1. A compound of the formula R 3 N-N R 4 Ri in which one of the radicals R 1 and R 2 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or a cycloaliphatic or araliphatic o hydrocarbon radical and the other of the radicals R 1 and R 2 is the group of the formula S OO er~ B A (Ia), in which Z 1 is alkylene, 0, S(O)m or R 5 is carboxyl, haloalkanesulfonylamino, S0 3 H, P02H 2 P0 3 H 2 or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or suostituted by an aliphatic hydrocarbon radical which, if desired, is interrupted by O and is unsubstituted or substituted by hydroxyl or halogen, hydroxyl which, if desired, is etherified by an aliphatic alcohol, halogen, carboxyl whi h, if desired, is esterified or amidated, or 5-tetrazolyl, and either R 3 is halogen, acyl, an aromatic S' hydrocarbon radical, carboxyl which, if desired, is esterified or amidated, cyano, SO 3 H, S PO 2 H 2 P0 3 H 2

5-tetrazolyl, substituted or unsubstituted sulfamoyl or acylamino or is -Z 2 wherein Z 2 is a bond or is O, S(0)m or N(R) and R' is hydrogen or an aliphatic hydrocarbon radical which, if desired, is interrupted by 0 or S(O)m and is unsubstituted or substituted by halogen, hydroxyl, substituted or unsubstituted amino or carboxyl which, if desired, is esterified or amidated, and R 4 is an aliphatic hydrocarbon radical which, if desired, is interrupted by O or S(O)m and is unsubstituted or substituted by carboxyl which, if desired, is esterified or amidated, hydroxyl which, if desired, is etherified by an aromatic alcohol, substituted or unsubstituted amino, S(0)m,-R or an aromatic hydrocarbon radical, or R 3 and R 4 together represent alkylene, R in each case being hydrogen or an aliphatic hydrocarbon radical and m in each case being 0, 1 or 2, in free form or in salt -36- form. 2. A compound according to claim 1 of the formula I, in which one of the radicals R 1 and R 2 is lower alkyl, lower alkenyl or lower alkynyl, in each case unsubstituted or substituted by halogen or hydroxyl, in each case 3- to 7-membered cycloalkyl or cycloalkenyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, the other of the radicals R 1 and R 2 is the group Ia, in which Z 1 is methylene, lower alkylene, 0, S(O)m or R 5 is carboxyl, halo-lower alkanesulfonylamino, SO 3 H, P0 2 2 P0 3 H 2 or and the rings A and B are independently of one another unsubstituted or substituted by halogen, or by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl or lower alkoxy-lower alkoxy-lower alkyl, in each case unsubstituted or substituted by hydroxyl or halogen, by hydroxy, by lower alkoxy, by lower alkenyloxy, by carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower S. alkoxy-lower alkynyl, by carbamoyl in which the amino group is unsubstituted or independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or by and either R 3 is halogen, lower alkanoyl, substituted or unsubstituted phenyl, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, carbamoyl in which the amino group is unsubstituted or independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, cyano, SO 3 H, S P0 2 11 2 P03H 2 5-tetrazolyl, sulfamoyl in which the amino group is unsubstituted or mono- or disubstituted by lower alkyl, lower alkanesulfonylamino, halo-lower alkanesulfonylamino, lower alkanoylamino, substituted or unsubstituted benzoylamino or substituted or unsubstituted benzenesulfonylamino or is wherein Z 2 is a bond or is O, S(0)m or N(R) and R' is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkoxy-lower alkoxy-lower alkyl, lower alkyl-thio-lower alkyl, -lower alkenyl or -lower alkynyl, lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower -37- alkenyl-thio-lower aikyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case unsubstituted or substituted by hydroxyl, halogen, amino, lower alkyleneamino, lower alkylenoxy-lower alkyleneamino, lower alkylamino, lower alkenylamino, lower alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynr.yl, lower alkoxy-lower alkyl, lower alkoxy-lower alkeny! or lower alkoxy-lower alkynyl, or carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independently of one another, lower alkyl, lower alkenyl, iowev alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, and R 4 is lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, o* lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkoxy-lower .0 alkoxy-lower alkyl, lower alkyl-thio-lower alkyl, -lower alkenyl or -lower alkynyl, lower .alkane-sulfinyl-lower alkyl or -sulfonyl-lower aikyl, lower ;alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case unsubstituted or substituted by hydroxyl, S(O)m-R, substituted or unsubstituted phenyl, substituted or unsubstituted *phenoxy, substituted or unsubstituted naphthyloxy, amino, lower alkyleneamino, lower alkylenoxy-lower alkyleneamino, lower alkylamino, lower alkenylamino, lower S alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, t i(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is .:00 derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower 0 alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independcntly of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, or R 3 and R 4 together represent methylen or lower alkylene, R ii) each case being hydrogen, lower alkyl, lower alkenyl or lower alkynyl, m in each case being 0, 1 or 2 and aromatic radicals being in each case unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl, in free form or in salt form. 3. A compound according to claim 1 of the formula I, in which R 1 is the group Ia, in which -38- Z 1 is methylene, lower alkylene, 0, S(O)m or R 5 is carboxyl or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, carboxyl. lower alkoxycarbonyl or 5-tetrazolyl, R 2 is lower alkyl or lower alkenyl, in each case unsubstituted or substituted by hydroxyl or halogen, and either R 3 is halogen, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl or lower alkoxy-lower alkyl, carbamoyl, cyano, P0 3 H 2 lower alkanesulfamoyl, lower alkanoylamino or lower alkanesulfonylamino or is -Z 2 wherein Z 2 is a bond or is O, S(0)m or N(R) and R' is hydrogen or lower alkyl or lower alkoxy-lower alkyl, in each case unsubstituted or substituted by carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl or hydroxyl, and R 4 is lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy-lower alkoxycarbonyl-lower alkyl, carbamoyl-, lower alkylcarbamoyl- or di-lower alkylcarbamoyl-lower alkyl, hydroxy-lower alkyl, S* substituted or unsubstituted phenoxy-lower alkyl, amino-, lower alkylamino- or di-lower alkylamino-lower alkyl or substituted or unsubstituted phenyl-lower alkyl, or R 3 and R 4 S together represent methylen or lower alkylene, R in each case being hydrogen or lower alkyl, m in each case being 0, 1 or 2 and aromatic radicals being in each case unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, trifluoromethyl and/or hydroxyl, in free form or in salt form. 4. A compound according to claim 1 of the formula I, in which R 1 is the group la, in which Z 1 is methylene, lower alkylene, O or S(0)m, R 5 is carboxyl or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by lower alkyl, halogen or lower alkoxy, R 2 is lower alkyl or lower alkenyl, in each case unsubstituted or Ssubstituted by hydroxyl or halogen, and either R 3 is halogen, carboxyl, lower alkoxycarbonyl, P0 3 H 2 5-tetrazolyl, lower alkanoylamino, lower alkanesulfonylamino, S hydrogen, lower alkyl, lower alkoxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, hydroxyl, lower alkoxy, lower alkoxy-lower alkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, hydroxy-lower alkoxy, mercapto, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, amino, lower alkylamino or di-lower alkylamino and R 4 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R 3 and R 4 together represent methylen or lower alkyiene, m being 0, 1 or 2 and part structures being designated by "lower" in each case including not more than 7 C atoms, in free form or in salt form. -39- A compound according to claim 1 of the formula I, in which Ri is the group Ia, in which Z 1 is methylene or lower alkylene, R 5 is carboxyl or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by lower alkyl, halogen with an atomic number not more than 35 or lower alkoxy, R 2 is lower alkyl, R 3 is halogen with an atomic number not more than 35, hydrogen, lower alkyl, lower alkoxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, hydroxyl, lower alkoxy, lower alkoxy-lower alkoxy, carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, hydroxy-lower alkoxy or lower alkoxy-lower alkoxy and R 4 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl lower alkyl, part structures being designated by "lower" in each case including not more than 7 C atoms, in free form or in salt form.

6. A compound according to any one of claims 1 to 5 of the formula I, in which R 1 is the group of the formula 0 0 (Ib), R in free form or in salt form. 7 A compound according to claim 1 of the formula I, in which R 1 is the group Ib, in which Z 1 is methylene, R 5 is carboxyl or 5-tetrazolyl and the rings A and B are unsubstituted, R 2 is C 3 -C 7 alkyl, R 3 is hydrogen or C 1 -C 4 alkyl and R 4 is C 1 -C 4 alkyl, carboxy-C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl-C 1 -C 4 alkyl or hydroxy-C 1 -C 4 alkyl, in free S form or in salt form. O 8. A compound according to claim 1 of the formula I, in which R 1 is the group Ib, in which Z 1 is methylene, R 5 is carboxyl or tetrazolyl and the rings A and B are unsubstituted, R 2 is C 3 -Csalkyl, R 3 is hydrogen or C 1 -C 4 alkyl and R 4 is C 1 -C 4 alkyl, in free form or in salt form.

9. 4-(n-Butyl)-1,2-dimethyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine or a salt thereof. 40 4- (n-B utyl)- 1 -ethyl- 2-me th yl- 6-oxo-5 (1 H-tetrazol -5 -yl)bi phen yl-4-ylmethyl] 1,6-dihydro-pyrimidine or a salt thereof.

11. 4-(n-Butyl)-2-niethyl-6-oxo-l1-(n-propyl)-5 -(1I1l-tetrazol-5-yl)biphenyl- 4-ylmethyli 1 ,6-dihydro-pyrimidine or a salt thereof.

12. 4-(n-Butyl)-l1-ethoxycarbonylmethyl-2-methyl-6-oxo-5- biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine or a salt thereof.

13. 4-(n-B utyl)-l1-carboxymethyl-2-methyl-6-oxo-5-[2'-(1I-tetrazol-5-yl)biphenyl- 4-y!Tnmethyl] -1,6-dihydro-pyimidine or a salt thereof.

14. 4-(n-Butyl)-5-(2'-carboxybiphenyl-4-ylmethyl)- 1,2-dimethyl-6-oxo- 1,6-dihydro- 0.*15. 4-(n-B utyl)-l1-(2-ethoxyethyl)-2-methyl-6-oxo-5-[2'-( 0% 4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

16. 1 ,4-Di- (n-butyl)-2-methyl-6-oxo-5-12' H-tetrazol-5 -yl)biphenyl-4-ylmethyll- 1 ,6-dihydro-pyrimidine or a salt thereof.

00017. 1 -B enzyl-4-(n-b utyl) -2-meth yl-6-oxo-5 H -tetrazol -5 -yl)b iph enyl-4-ylm ethyl] 1,6-dihydro-pyrimidine or a salt thereof. 4- (n-B utyl)-2-m ethyl- 6-oxo- 1 (2-phenylethyl)-5- (1 H-te trazol-5 -yl)biphenyl- 4-y1m ethylI- 1,6-dihydro-Dyrim idine or a salt thereof.

19. 4-(n-Butyl)- 1-(2-hydroxyethyl)-2-n-iethyl-6-oxo-5-[2' 4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof. -41-

22. 2,4-Di- (n-bu tyl) -I -methyl- 6-oxo- 5- [2 H- tetrazol -5 -yl)bip henyl-4- ylm ethyl- 1,6-dihydro-pyrimidine or a salt thereof.

23. 4-(n-Butyl)-2-isopropyl-l1-methyl-6-oxo-5-[2' 4-ylmethyl]- 1 ,6-dihydro-pyrimidine or a salt thereof.

24. 4-(n-Butyl)- 1,2-diethyl-6-oxo-5-L2' IH-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine or a salt thereof. 4-(n-Butyl)-l1-ethyl-6-oxo-2-(n-propyl)-5-[2' 1I--tetrazol-5-yl)biphenyl-4-ylmethyl] 1,6-dihydro-pyrimidine or a salt thereof.

26. 2,4-Di- (n-butyl)- 1 -ethyl- 6-oxo-5 (1 H- tetrazol-5 -yl) biphenyl-4-ylmeth yl] 1 ,6-dihydro-pyrimidine or a salt thereof.

27. 4-(n-Butyl)-l1-ethyl-2-isopropyl-6-oxo-5-[2' H-tetrazol-5-yl)biphenyl-4-ylmethyl] 1,6-dihydro-pyrimidine or a salt thereof.

28. 4-(n-Butyl)-2-ethyl-6-oxo-l1-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine or a salt thereof. *see

29. 4-(n-Butyl)- 1,2-di-(n-propyl)-6-oxo-5 -12' -(1H-tetrazol-5 -yl)biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine or a salt thereof. 2,4-Di- (n-butyl)-6-oxo- 1 -(n-propyl) I -L-e trazol-5 -yl)biphenyl1-4-ylm ethyl] 1,6-dihydro-pyrimidine or a salt thereof.

31. 4- (n-Butyl)-2-isopropyl-6-oxo-l1-(n-propyl)-5-12' 4-ylmethyl]- 1,6-dihydro-pyrimidine or a salt thereof.

32. 1 ,4-Di-(n-butyl)-2-ethyl-6-oxo-5-12'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyriinidine or a salt thereof.

33. 1 ,4-Di-(n-butyl)-6-oxo-2-(n-propyl)-5-[2'-( IH-tetrazol-5-yl)biphenyl-4-ylmethyl] 1,6-dihydro-pyrimidine or a salt thereof. 42

34. lH-tetrazol-5-yl)biphenyl-4-ylrnethyl]- 1,2,4-tri-(n-butyl)-1I,6-dihydro- pyrimidine or a salt thereof. 1 ,4Di(nbrt,.' -2-isopropv,1-6-oxo-5-[2'-( 1H-tetr-azol-5-yl)biphenyl-4-ylmethyll- 1,6-dihydro-pyrimidine or a salt thereof.

36. 1 2 -Dimethyl-6-oxo-4-(n-propyl)-5-(2'-carboxybiphenyl-4-ylmethyl)- 1,6-dihydro- pyrimidine or a salt thereof.

37. 4-(n-Butyl)-2-methyl-l1-IIN,N-(3-oxapent- 1,5-ylen)aminocarbonylmethyl]-6-oxo- (1H-tetrazol-5-yl)biphenyl-4-ylmethyl] -1 ,6-dihydro-pyrimidine or a salt thereof.

38.' 34-(n-Butyl>14-2-2-nethoxyethoxy)ethyl]2-nehyl-6-oxo-5-F2'-(I 9.39. 1 -Benzylaminocarbonylmethyl-4-(n-butyl)-2-methyl-6-oxo-5-[2'-(l1H-tetrazol-5-yl)- Sbiphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof. 4-(n-Butyl)-2-methyl-6-oxo-l1-(2-phenylethylaminocarbonylmethyl)-5-[2' H- -yl) biphenyl-4-ylrniethyl] 1, 6-dihydro-pyrimidi ne or a salt thereof. 4-(n-Butyl)- 1-(n-butylaminocarbonylmethyl)-2-methyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)- biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

42. 4-(n-Butyl)-2-methyl-l1-methylaminocarbonylmethyl-6-oxo-5-[2'-( 9biphenyl-4-ylmethyl] 1 ,6-dihydro-pyrimidine or a salt thereof.

43.: 4-(n-Butyl)-l1-dimethylaminocarbonylmethyl-2-methyl-6-oxo-5-[2' biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

44. 4-(n-Butyl)-6-oxo- 1,2-tetramethylen-5-[2 H-tetrazol-5-yl)biphenyl-4-ylmethyl] 1,6-dihyd'ro-pylimidine or a salt thereof. 4- (n-B utyl)- 6-oxo-5 (1 H-tetrazol-5 -yl)biphenyl-4-ylm ethyl] -1 ,2-trimethylen- 1 ,6-dihydro-pyrimidine or a salt thereof. 43

46. A pharmaceutical preparation containing, as the active ingredient, a compound according to any one of claims 1 to 45, in free form or in form of a pharmaceutically acceptable salt, in addition to a pharmaceutically acceptable auxiliary.

47. A pharmaceutical preparation containing, as the active ingredient, a compound according to any one of claims 5, 9 to 36 in free form or in form of a pharmaceutically acceptable salt, in addition to a pharmaceutically acceptable auxiliary.

48. A process for the preparation of a compound of the formula N 3N-R 4 N N R' R2_ R 0* o* B:UGS01\349068\AB -44- in which one of the radicals R 1 and R 2 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or a cycloaliphatic or araliphatic hydrocarbon radical and the other of the radicals R 1 and R 2 is the group of the formula -z 1 A (Ia), in which Z 1 is alkylene, 0, S(0)m or R 5 is caiboxyl, haloalkanesulfonylamino, SO 3 H, PO 2 H 2 P0 3 H 2 or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by an aliphatic hydrocarbon radical which, if desired, is interrupted by O and is unsubstituted or substituted by hydroxyl or halogen, hydroxyl .which, if desired, is etherified by an aliphatic alcohol, halogen, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, and either R 3 is halogen, acyl, an aromatic 4 hydrocarbon radical, carboxyl which, if desired, is esterified or amidated, cyano, S03H, PO 2 H 2 P0 3 H 2 5-tetrazolyl, substituted or unsubstituted sulfamoyl or acylamino or is -Z 2 wherein Z 2 is a bond or is O, or N(R) and R' is hydrogen or an aliphatic hydrocarbon radical which, if desired, is interrupted by O or S(O)m and is unsubstituted or substituted by halogen, hydroxyl, substituted or unsubstituted amino or carboxyl which, if o2: desired, is esterified or amidated, and R 4 is an aliphatic hydrocarbon radical which, if desired, is interrupted by O or S(O)m and is unsubstituted or substituted by carboxyl S which, if desired, is esterified or amidated, hydroxyl which, if desired, is etherified by an Saromatic alcohol, substituted or unsubstituted no, S(O)m-R or an aromatic hydrocarbon radical, or R 3 and R 4 together represent alkylene, R in each case being hydrogen or an S aliphatic hydrocarbon radical and m in each case being 0, 1 or 2, in free form or in salt o form, which process comprises converting X 1 into R 5 in a compound of the formula R 3 N N R 4 (Ha), 0 in which one of the radicals R' 1 and R' 2 is the group of the formula 45 .I t (11b) x 1 and X, is a radical which can be converted into R 5 or in a salt thereof and, if desired, converting a compound I obtainable according to the process or in another manner, in free form or in salt form, into another compund I, separating a mixture of isomers obtainable according to the process and isolating the desired isomer and/or converting a free compound I obtainable according to the process into a salt or converting a salt of a compound I obtainable according to the process into the free compound I or into another salt.

49. A process for the preparation of a pharmaceutical preparation according to claim 46 or 47, which process comprises processing the active ingredient into a pharmaceutical preparation, a pharmaceutically acceptable auxiliary being mixed in 20 50. A process for the preparation of a pharmaceutical preparation according to claim "47, which process comprises processing the active ingredient into a pharmaceutical preparation, a pharmaceutically acceptable auxiliary being mixed in. o

51. A method of treating high blood pressure and/or cardiac insufficiency, which method comprises administering a compound according to any one of claims 1 to 45, in o. free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to claim 46 or 47.

52. A method of treating high blood pressure and/or cardiac insufficiency, which 30 method comprises administering a compound according to any one of claims 5, 9 to 36, in free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to claim 47. B:\JGSO\349068AB 46

53. An aflgioteflsifl-II-aflagofliziflg pharmaceutical composition containing as active ingredient the complound 4-(nl-butyl)-1I,2-dimelthiyl-6-oxo-5-[2'-( I yllbiphlcnyl-4ylmcthyl]-1 ,6-dihlydro-pyrim-idinc, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

54. A process according to claim 48 substanf 'ally as herein described with reference to any one of the foregoing Examples thereof. A pharmaceutical preparation according to claim 46 substantially as herein described with reference to any one of the foregoing Examples thereof. DATED this 29th day of November, 1993. DAIE COLIS 20 CAVE B,\JGSOI\349068\A3