CA2033121A1

CA2033121A1 - Diaza compounds

Info

Publication number: CA2033121A1
Application number: CA002033121A
Authority: CA
Inventors: Peter Herold; Peter Buhlmayer
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1989-12-28
Filing date: 1990-12-24
Publication date: 1991-06-29
Also published as: KR910011802A; HU207513B; PT96371A; IE904686A1; NZ236625A; JPH06199811A; IL96753A0; EP0435827A2; NO905602D0; AU646006B2; FI906387A7; HUT56091A; EP0435827A3; ZA9010395B; NO905602L; MX23949A; AU6853390A; FI906387A0

Abstract

4-17893/+

Diaza compounds Abstract Diaza compounds of the formula (1), in which one of the radicals R1 and R2 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or a cycloaliphadc or araliphadc hydrocarbon radical and the other of the radicals R1 and R2 is the group of the formula

Description

~3~21 4- 17893/+

Diaza compounds The invention relates to diaza compounds of the forrnula N ~N--R4 R2~0 (I), R, in which one of the radicals R1 and R2 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 Rl and R2 is the group of the formula (Ia), s :: :
in which Z1 is alkylene, O, S()m or N(R), Rs is carboxyl, haloalkanesulfonylamino, SO3H, PO2H2, PO3H2 or S-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 S-tetrazolyl, and either R3 is halogen, acyl, an aromatic hydrocarbon radical, c~rboxyl :which, if desired, is est~erified or amidated, cyano, SO3H, PO2H2,: PO3~I2, S-tetrazolyl, substituted or unsubstituted sulfamoyl or acylamino or is -Z2-R', wherein Z2 is a bond or~is 0, S(~m or N(Rj and R' is hydrogen or an aliphatic hydrocarbon radical which, if desired,~is interrupted by O or S()m and is unsubstituted or substituted by halogen, hydroxyl, substituted or unsubstituted amino or carboxyl which, if desired, is esterified or amidated, and:R4 is an aliphatic hydrocarbon radical which, if desired, is inte~rupted by O or S()m and is unsubstituted or substituted by carboxyl ~ . ,, ~ ' 2~3~2 ~

which, if desired, is esteri~1ed or amidated, hydroxyl which, if desired, is etheri~led by an aromatic alcohol, substituted or unsubstituted amino, S(O)m-R or an aromatic hydrocarbon radical, or R3 and R4 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 phannaceutically acceptable salt.

The compounds I can be present as salts, in particular pharrnaceutically acceptable salts. If the compounds I have, for example, at least one basic centre, they can form acid addition salts. These are forrned, 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 Cl-C4alkanecarboxylic acids which are unsubstituted orsubstituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxy1ic 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 C1-C4alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic centre. The 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 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-, diisopropy1-, 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 purihcation 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.

' . ~ .

: . . -.
.

2~33~2~

Esteri~led carboxyl is, for example, carboxyl which is esterified by an aliphatic alcohol which is delived 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.

Substituted amino is, for example, amino which is mono- or disubstituted by, independently of one another, an aliphatic or araliphatic hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl or phenyl-Iower 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. 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.

An aliphatic hydrocarbon radical which is interrupted by O is, in particular, lower 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 hydroca~rbon radical which is interrupted by S()m is, in particular, lower alkyl-thio-lower alkyl, -lower alkenyl or -lower alkynyl, lower a1kane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenyi-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl.

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

., ~ .

:

An aliphatic hydrocarbon radical which is substituted by halogen or hydroxyl and is interrupted by O or S()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, S(O)m-R, 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 O or S()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 abo~e or carboxyl which is arnidated as defined above.

A cycloaliphatic hydrocarbon radica1 is, for example, cycloalkyl or, secondarily, cycloalkenyl.

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 or lower alkenyloxy.
:.
Alkylene is methylene or lower aLIcylene.

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

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

Hydroxyl etherified by an aromatic alcohol is in particular phenoxy, also naphthyloxy.
:
Unsaturated aliphatic, cycloaliphatic and araliphatic substituents above and below are, in panicular, not linked to ao aromatic radical via a C atom from which a multiple bond .... , . ~
.' ' . ' ~:

~ .

2~33 ~ 21 starts.

Unless defined differently, aromatic radicals are in each case unsubstituted or mono- or polysubstituted, for example di- or trisubstituted, for example by (a) 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:

The term "lower" means that corresponding groups and compounds in each case contain, in particular, not more than 7, preferably not more than 4, carbon atoms.

Lower alkanesulfonyl is, in particular, Cl-C7alkanesulfonyl and is, for example, methane-, ethane-, n-propane- or isopropane-sulfonyl. Cl-C4Alkanesulfonyl is preferred.
Halogeno-lower alkanesulfonyl is halogeno-Cl-C7-alkanesulfonyl, such as trifluoromethanesulfonyl .

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

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

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

Lower aLkanoyl is, in particular, Cl-C7alkanoyl and is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or p*aloyl. C2-CsAlkanoyl is preferred.

.

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

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

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

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

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

Lower alkoxy-lower alkenyl or -lower alkynyl is, in particular, Cl-C4aLkoxy-C3-Csalkenyl or -alkynyl.

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

Halogeno-lower alkyl is, in particular, halogeno-Cl-C4alkyl, such as trifluoromethyl, 1,1,2-trifluoro-2-chloro-ethyl, chloromethyl or n-heptafluoropropyl.
:
Halogeno-lower alkenyl i9, in particular, halogeno-C3-Csalkenyl, such as 2-chloroallyl.

Halogeno-lower alkynyl is, in particular, halogeno-C3-Csalkynyl, such as 3-chloropropargyl.

Hydroxy-lower alkyl is, in particular, hydroxy-Cl-C4alkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.
:: :
Hydroxy-lower alkenyl is, in particular, hydroxy-C3-Csalkenyl, such as 3-hydroxyallyl.

2 ~ 2 1 Hydroxy-lower alkynyl is, in particular, hydroxy-C3-Csalkynyl, such as 3-hydroxypropargyl.

Phenyl-lower alkyl is, in particular, phenyl-C1-C4alkyl, and is preferably benzyl or 1- or 2-phenethyl, whilst phenyl-lower alkenyl or phenyl-lower alkynyl is, in particular, phenyl-C3-Csalkenyl or -alkynyl, in particular 3-phenylallyl or 3-phenylpropargyl.

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

Lower alkylenoxy-lower alkylene is, in particular, C2-C4alkylenoxy-C2-C4alkylene, preferably ethylenoxyethylene.

Lower alkylamino is, in particular, C1-C7alkylamino and is, for example, methyl-, ethyl-, n-propyl- or isopropyl-amino. Cl-C4Alkylamino is preferred.

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

Lower alkynylamino is, preferably, C3-Csalkynylamino,~such as propargylamino.

Phenyl-lower alkylamino is, preferably, phenyl-C1-C4alkylamino, in particular benzyl- or 1- or 2-phenylethyl-amino.

Phenyl-lower alkenylamino is preferably phenyl-C3-Csalkenylamino, in particular phenyla11ylamino or 3-phenylmethallylamino.

Phenyl-lower alkynylamino is preferably phenyl-C3-Csalkynylamino, in particular phenylpropargylamino. -Di-lower alkylamino is, in particular, di-C1-C4alky1amino, such as dimethyl-, diethyl-, di(n-propylj-, methyl-propyl-~ methyl-ethy1-, methyl-butyl or dibutyl-amino.

N-Lower alkyl-N-phenyl-lower alkyl-amino is, in particular, N-C1-C4alkyl-N-phenyl-Cl-C,,~lkyl-amino, preferably methyl-benzyl-amino or ethyl-benzyl-amino.

, - . : ,.
.

-2 ~

Di(phenyl-lower alkyl)-amino is, in particular, di(phenyl-CI-C4alkyl)amino, preferably dibenzylamino.

Lower alkenyloxy-lower alkyl is, in particular, C3-Csalkenyloxy-Cl-C4alkyl, such as 2-allyloxyethyl, and lower alkenyloxy-lower alkenyl or -lower alkynyl is, in particular, C3-C5aLkenyloxy-C3-CsaLcenyl or -alkynyl.

Lower alkylthio-lower alkenyl or -lower alkynyl is, in particular, Cl-C4alkylthio-C3-Csalkenyl or-alkynyl.

Lower alkylthio-lower alkyl is, in particular, Cl-C4alkylthio-Cl-C4alkyl, such as ethylthiomethyl, 2-ethylthioethyl, 2-methylthioethyl or 2-isopropylthioethyl, whilst particularly suitable lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl are corresponding Cl-C4alkane-sulfinyl-Cl-C4alkyl radicals or -sulfonyl-Cl-C4alkyl radicals.

Lower alkenylthio-lower alkyl is, in particular, C3-Cs-alkenylthio-Cl-C4alkyl, such as l-allylthioethyl or 3-allylthiopropyl, whilst lower alkenyl-sulfinyl-lower aL~cyl or -sulfonyl-lower alkyl is, in particular, C3-Csalkenyl-sulfinyl-Cl-C4alkyl or -sulfonyl-Cl-C4alkyl.

Lower alkynylthio-lower alkyl is, in particu1ar, C3-Csalkynylthio-Cl-C4alkyl, such as 2-propargylthioethyl or 3-propargylthiopropyl, whilst lower aLkynyl-sulfinyl-lower alkyl or -sulfonyl-lower alkyl in particular is C3-Csalkynyl-sulfinyl-Cl-C4alkyl or -sulfonyl-CI -C4alkyl.

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

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

Lower aLl~oxy-lower alkoxy-lower alkyl is, in particular, Cl-C4-aIkoxy-Cl-C4-alkoxy-Cl-C4-alkyl, such as 2-(2-methoxyothoxy)ethyl.

Extensive pharmacological investigations have shown that the compounds I and their pharmaceutically acceptable salts, for example, have pronounced angiotensin II antagonist 2~333^~21 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 n by competitiveinhibition of the binding of angiotensin II to the receptors.

The angiotensin II antagonist properties of the compounds of the formula I and their pharmaceutically acceptable salts can be detected in the angiotensin II binding test. Rat smooth muscle cells from homogenized rat aorta are used here. The solid centrifugate is suspended in 50 mM tris buffer (pH 7.4) using peptidase inhibitors. The samples are incubated for 60 minutes at 25C with 125I-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 IC50 values aredetermined from the dose-effect curve. ICso values from about 10 nM are determined for the compounds of the formula I and their pharmaceutically acceptable salts .

For the determination of angiotensin II-induced vasoconstriction, investigations on the isoIated 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 37C and aerated with a mixture Of 95 % 2 and 5 %
CO2. The isometric reactions are~ measured. At 20-minute intervals, the rings are a1 ernately stimulated with 10 nM angiotensin II (Hypertensin-CIBA) and 5 nM
noradrenaline chloride. The rings are then incubated with selected concentrations of the test substances before treatment with the agonists. The data are analysed using a Buxco digital computer. The concentrations which cause a 50 % inhibition of the inidal control values are given as ICso values. ICsO values from about 5 nM are detennined for the compounds of the formula I and their pharmaceudcally 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 %
NaCl (I ml/kg i.v.3, noradrenaline (I ~g~cg i.v.) or angiotensin II (0.3 ~g~cg i.v.) in each .

:~ . . .
, .. ~ .
~, , , ~3~

case, increasing doses (3-6) of the test substance are intravenously injected by bolus injection, after which angiotensin II or noradrenaline is administered after each dose at 5 minute intervals. The blood pressure is measured directly in the carotid artery and recorded using an on-line data recording system (Buxco). The specificity of the angiotensin II antagonism is shown by the selective inhibition of the pressure effect produced by angiotensin II, but not that produced by noradrenaline. In this test model, the compounds of the formula I and the* pharmaceutically acceptable salts show an inhibiting effect from a dose of about 0.3 mg/lcg i.v.

The antihypertensive activity of the compounds of the formula I and their pharmaceutically acceptable salts may also be manifested in the renally hypertensive rat test model. High blood pressure is produced in male rats by constricting a renal artery according to the Goldblatt method. Doses of the test substance are administered to the rats by means of a stomach tube. Control animals receive an equivalent volume of solvent.
Blood pressure and heart beat are measured indirectly at intervals in conscious animals by the tail clamp method of Gerold et al. IHelv. Phvsiol. Acta 24, (1966), 581 before administration of the test substances or of the solvent and during the course of the experiments. It was possible to detect the pronounced antihypertensive effect from a dose of about 30 mg/kg p.o.

The compounds of the formula I and their pharmaceutically acceptable salts can therefore be used, for example, as pharmaceutical active ingredients in antihypertensives which are employed, for example, for the treatment of high blood pressure and cardiac insufficiency.
The invention thus relates to the use of the compounds according to the invention and their 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 Rl and R2 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 Rl and R2 is the group Ia, in which Zl is methylene, lower alkylene, O, S()m or N(R), Rs is carboxyl, halo-lower aLkanesulfonylamino, SO3H, PO2H2, PO3H2 or 5-tetrazolyl and the rings A and B are independently of one another ., ~ .

, 2 ~

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 a~cyl, 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 esteri~led 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 a~nino group is unsubstituted orindependently 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 5-tetrazolyl, and either R3 is halogen, lower alkanoyl, subsdtuted 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, SO3H, PO2H2, PO3H2, 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 subsdtuted or unsubstituted benzenesulfonylamino or is -Z2-R', wherein Z2 is a bond or is ~ S()m or N~R) and R' is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, lower a1koxy-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 allcyl, -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, -sul~lnyl-lower alkyl or -sulfonyl-lower ~kyl, in each case unsubsdtuted 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 .
. . .

2~

group is unsubstituted or mono- or disubstituted by, independently of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl orphenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, and R4 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 alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case unsubstituted or substituted by hydroxyl, 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 alkenylarnino, lower alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independendy of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl orphenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, or R3 and R4 together represent methylen or lower alkylene, R in 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.

The invention relates in particular to compounds of the formula I, in which Rl is the group Ia, in which Zl is rnethylene, lower alkylene, O, S()m or N(R), Rs is carboxyl or S-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 S-tetrazolyl, R2 is lower alkyl or lower alkenyl, in each case unsubstituted or substituted by hydroxyl or halogen, and either R3 is halogen, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl or lower alkoxy-lower alkyl, carbamoyl, cyano, PO3H2, S-tetrazolyl, lower alkanesulfamoyl, lower alkanoylamino or lower alkanesulfonylamino or is -Z2-R', wherein Z2 iS a bond or is 0, S()m or N(R) and R' is hydrogen or lower alkyl or lower alkoxy-lower alkyl, in each case unsubstituted or ' ~

.
-,...
' 2~3~2~

substituted by carboxyl, lower alkoxycarbonyl, lower alkoxy-lower aLkoxycarbonyl or hydroxyl, and R4 is lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, carboxy-iower alkyl, lower alkoxycarbonyl-lower alkyl, lower alkoxy-lower alkoxycarbonyl-lower aL~yl, carbamoyl-, lower alkylcarbamoyl- 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 R3 and R4 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.

The invention relates in particular to compounds of the formula I, in which R1 is the group Ia, in which Zl is methylene, lower alkylene, such as ethylene, O or S(O)m, R5 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, R2 is lower alkyl or lower alkenyl, such as n-propy1, n-butyl or allyl, in each case unsubstituted or substituted by hydroxyl or halogen, in particular with an atomic number not more than 35, such as chlorine, and either R3 is halogen, in particular with an atomic number not more than 35, such as chlorine, carboxyl, lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, PO3H2, S-tetrazolyl, lower alkanoylamino, such as acetylamino, lower alkanesuIfonylamino, such as methanesulfonylamino, hydrogen, lower alkyl, such as methyl, lower alkoxy-lower alkyl, such as 2-methoxyethyl, carboxy-lower aLIcyl, 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-loweralkoxy, such as 2-methoxyethoxy, carboxy-lower alkoxy, such as carboxymethoxy, lower aLkoxycarbonyl-lower alkoxy, such as ethoxycarbonylmethoxy, hydroxy-lower alkoxy, such as 2-hydroxyethoxy, mercapto, lower alkylthio, such as methylthio, lower alkanesulfinyl, such as methanesulfinyl, lower alkanesulfonyl, such as methanesulfonyl, amino, lower aLkylamino, such as methylamino, or di-lower alkylamino, such as dimethylamino, and R4 is lower`alkyl, such as methyl, ethyl or n-butyl, hydroxylower alkyl, such as hydroxymethyl, carboxy-lower alkyl, such as carboxymethyl, or lower aLkoxycar~ony}-lower alkyl, such as ethoxycarbonylmethyl, or R3 and R4 together represent methylen or lower alkylene, m being 0, 1 or 2 and part structures being deslgn:ated by i'lower" in: each case in particular including not more than 7, preferably not .

~ ^ :. . . - : ., 2~33~ 21 more than 4, C atoms, in free forrn or in salt form.

The invention relates in particular to compounds of the formula I, in which Rl is the group Ia, in which Zl is methylene or lower alkylene, such as ethylene, Rs 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 not more than 35, such as chlorine, or lower alkoxy, such as methoxy, R2 is lower alkyl, such as n-propyl or n-butyl, R3 is halogen, in particular with an atomic number not more than 35, such as chlorine, hydrogen, lower alkyl, such as methyl, lower alkoxy-lower alkyl, such as 2-methoxyethyl, carboxy-lower alkyl, such as carboxymethyl, loweralkoxycarbonyl-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 R4 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 primarily to compounds of the formula I, in which Rl is the group of the formula - Zl ~ (Ib), in free form or in salt form.

The invention relates primarily to compounds of the formula I, in which Rl is the group Ib, in which Zl is methylene, Rs is carboxyl or in particular 5-tetrazoly} and the Iings A
and B are unsubstituted, R2 is C3-C7alkyl, in particular C3-Csalkyl, such as n-propyl or n-butyl, R3 is hydrogen or Cl-C4aLkyl, such as methyl or n-butyl, and R4 is Cl-C4aLkyl, '' ' . ~ , :' ' -... . . .
.
~, . ' .

2~3~
,5 such as methyl, ethyl or propyl, carboxy-CI-C4alkyl, such as carboxymethyl, Cl-C4aL~coxycarbonyl-CI-C4alkyl, such as ethoxycarbonylmethyl, or hydroxy-Cl-C4alkyl, such as hydroxymethyl, in free form or in salt form.

The invention relates primarily to compounds of the formula I, in which Rl is the group Ib, in which Zl is methylene, Rs is carboxyl or tetrazolyl and the rings A and B are unsubstituted, R2 is C3-C5aL~cyl, such as n-propyl or n-butyl, R3 is hydrogen or Cl-C4aL~cyl, such as methyl or n-butyl, and R4 is Cl-C4alkyl, such as methyl, in free form or in salt forrn.

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 X1 into Rs in a compound of the formula N~N--R4 (IIa), R2~0 R', in which one of the radicals R'l and R'2 is the group of the forrnula ~: :
; ~ 'Zl~
(IIb) .

and X1 is a radical which can be converted into Rs, 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 fIee compound I obtainable according to the process into a salt or converting a salt of a . .

: ' ' , 2~3~121 compound 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 of a mixture thereof, the reaction being caIried out, as required, with cooling, at room temperature or with heating, for example in a temperature range from about -80C up to the boiling point of the reaction medium, preferably from about -10 to about +200C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere andlor under anhydrous conditions.

Radicals Xl which can be converted into the variable Rs are, for example, cyano,mercapto, halogen, the group -N2+A-, in which A- is an anion derived from an acid, amino, functional derivatives of COOH, SO3H, PO3H2 and P02H2 and N-protected 5-tetrazolyl.

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

Radicals Xl which can be converted into 5-tetrazolyl R5 are, for example, cyano and N-protected 5-tetrazolyl.

To prepare compounds of the formula I, in which Rs is 5-tetrazolyl, the process starts, for example, from starting material of the formula IIa, in which Xl is cyano, and this is reacted with an azide, for example with HN3 or, in particular, a salt, such as an alkali metal salt, thereof or with an organotin azide, such as tri-lower alkyl- or tri-aryl-dn azide.
Preferred azides are, for example, sodium azide and potassium azide and tri-CI-C4alkyl-, for example triethyl- or tributyl-tin azide, and triphenyltin azide.

Suitable protecting groups for N-protected 5-tetrazolyl are the protecting groups customarily used in tetrazole chemistry, in particular triphenylmethyl, benzyl which is unsubstituted or substituted, for example by nitro, such as 4-nitrobenzyl, loweralkoxymethyl, such as methoxy- or ethoxy-methyl, lower aL~cylthiomethyl, such asmethylthiomethyl, as well as 2-cyanoethyl, and additionally lower alkoxy-lower alkoxy methyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. The protecdng . . . , ~ .- , - .

.
.
.
- ~ .

, 2~3~1 groups are removed following known methods. Thus, for example, triphenylmethyl is customarily removed by hydrolysis, in particular in the presence of an acid, or hydrogenolysis in the presence of a hydrogenation catalyst, 4-nitrobenzyl is removed, for example, by hydrogenolysis in the presence of a hydrogenation catalyst, methoxy- or ethoxy-methyl is removed, for example, by treating with a tri-lower alkyltin bromide, such as triethyl- or tributyl-tin bromide, methy}thiomethyl is removed, for example, by treating with trifluoroacetic acid, 2-cyanoethyl is removed, for example, by hydrolysis, for example with sodium hydroxide solution, 2-methoxyethoxymethyl is removed, for example, by hydrolysis, for example with hydrochloric acid, and benzyloxymethyl and phenacyl are removed, for example, by hydrogenolysis in the presence of a hydrogenation catalyst.

A radical Xl which can be converted into S03H R5 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 R5 is S03H. Suitable oxidizing agents are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid. The oxidation is commonly carried out in the presence of suitable catalysts, suitable acids~
such as substituted or unsubstituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VI, for example molybdenum oxide or tungsten oxide, being mentioned as catalysts. The oxidation is carried out under mild conditions, for example at temperatures from about -50 to about +100C.

A group Xl which can be converted into P03H2 R5 is to be understood as meaning, for example, a group -N2~A-, in which A- is an anion of an acid, such as a mineral acid.
Corresponding diazonium compounds of this type are, for example, reacted in a manner known per se with a P(III) halide, such as PCI3 or PBr3, and worked up by hydrolysis, those compounds of the forrnula I being obtainable in which R5 is P03H2.

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

.
.

2~33~ ~

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

A radical Xl which can be converted into COOH Rs is, for example, a functionallymodified carboxyl, such as cyano, esterified or amidated carboxyl, hydroxymethyl or formyl.

Esteri~led carboxyl is, for example, carboxyl esterified with a substituted or unsubstituted aliphatic, cycloaliphatic or aromatic alcohol. An aliphatic alcohol is, for example, a lower alkanol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol or tert-butanol, while a suitable cycloaliphatic alcohol is, for example, a 3- to ~ membered cycloalkanol, such as cyclo-pentanol, -hexanol or -heptanol. An aromatic alcohol is, for example, a phenol or a heterocyclic alcoho1, which may in each case be substituted or unsubstituted, in particular hydroxypyridine, for example 2-, 3- or 4-hydroxypyridine.

Amidated carboxyl is, for example, carbamoyl, carbamoyl which is monosubsdtuted 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-membeTed alkylene or 3-aza-, 3-lower alkylaza-, 3-oxa- or 3-thiaalkylene. Examples which may be mendoned 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 subsdtuted by lower alkyl, lower alkoxy and/or halo~en~

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

Compounds of the forrnula I in which Rs is carboxyl can be prepared, for example, - `
starting from compounds of the formula IIa in which Xl is cyano or esterified or amidated carboxyl, by hydrolysis, in particular in the presence of a base, or, starting from ~ ~ .

.

~ G ~ 2 ~

compounds of the formula IIa in which Xl is hydroxymethyl or formyl, by oxidation. The oxidation is carried out, for example, in an inert solvent, such as in a lower alkanecarboxylic acid, for example acetic acid, in a ketone, for example acetone, in an ether, for 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 0 to about +150C. Suitable oxidizing agents are, for example, oxidizing transition metal compounds, in particular those with elements of sub-groups I, VI or VII. Examples which may be mentioned are: silver compounds, such as silver nitrate, silver oxide and silver picolinate, chromium compounds, such as chromium trioxide and potassium dichromate, and manganese compounds, such as potassium permanganate, tetrabutylammonium permanganate and benzyltri(ethyl)ammonium permanganate. Other oxidizing agents are, for example, suitable compounds with elements of main group IV, such as lead dioxide, or halogen-oxygen compounds, such as sodium iodate or potassium periodate.

The starting material IIa is, for example, accessible by starting from a compound of the formula o R'2--C--C, H--X2 (IIc)~
R', in which X2 is carboxyl which, if desired, is functionally modified, the preparation of the compounds IIc being carried out in a manner known per se, and reacting this with a compound of the formula NH
R3--C--NH2 (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 allcylamides, aminoalkylamides or lower alkylsilylamides, naphthaleneamines, lower alkylarnines, basic heterocyclic compounds, 28~ 2 ~

ammonium hydroxides and carbocyclic amines. Examples are sodium hydroxide, hydride and amide, potassium tert-butylate and carbonate, lithium triphenylmethylide anddiisopropylamide, potassium 3-(aminopropyl)-amide and bis-(trimethylsilyl)amide,dimethylaminonaphthalene, di- or triethylamine or ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyltrimethyl-ammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

In compounds IIa, in which R4 is hydrogen, the radical R4 can be introduced in a manner known per se by customary alkylation with appropriate alkylating reagents.

Compounds IIa can also be prepared by starting from compounds IIc and reacting these with a compound of the formula R3-C(--NH)-NH-R4 (IIe) or a salt, in particular an acid addition salt, thereof in the presence of a base. Compounds IIe are in turn accessible, for example, by reaction of compounds IId or a salt, in particular an acid addition salt, thereof with an amine of the forrnula R4-NH2 (IIf) 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.

A compound I containing hydroxyl can be etherified, for example, by methods which are 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 reacdve esters of the desired alcohols are, for example, those with strong inorganic or organic acids, such as corresponding halides, sulfates, lower a kanesulfonates or unsubsdtuted or subsdtuted 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 m or of the corresponding sub-groups. If necessary, these reactions can be carried out while cooling or heating, for example in a temperature range from about -20 to about +100C, in the presence or absence of a solvent or diluent, under an inert gas and/or under pressure and if appropriate in a closed vessel.

~3~2~L

Compounds I containing hydroxymethyl groups can be prepared, for example, starting from compounds containing corresponding carboxyl or esterifled 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 1 st and 3rd main group of the periodic table of the elements, for example a borohydride or an aluminohydride, for example sodium borohydride, lithium aluminium hydride or diisobutylaluminium hydride, and also diborane.

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 for oxidation to the sulfoxide level are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtures of hydrogen peroxide and acetic acid. The oxidation is often carried out in the presence of suitable catalysts, catalysts being suitable acids, such as unsubstituted or substituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VI, for example molybdenum oxide or tungsten oxide. The oxidation is carried out under mild conditions, for example at temperatures from about -50 to about +100C. Furtheroxidati to the sulfone level can be carried out correspondingly with dinitrogen tetroxide as the catalyst in the presence of oxygen at low temperatures, as can direct oxidation of lower alkylthio to lower alkanesulfonyl. However, the oxidizing agent is usually employed in excess here.

If one of the variables contains amino, corresponding compounds I can be N-(ar)alkylated in a manner which is known per se; carbamoyl or radicals containing carbamoyl can likewise be N-(ar)alkylated. The (ar)alkylation is carried out, for example, with an (aryl)Cl-C7alkyl halide, for example bromide or iodide, (aryl)Cl-C7aLkanesulfonate, for example methanesulfonate or p-toluenesulfonate, or a di-Cl-C7alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide solution, and advantageously in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethyl-- ~

~.

2~33~

ammonium chloride, in which case more strongly basic condensing agents, such as alkali metal amides, hydrides or alcoholates, for example sodium amide, sodium hydride or sodium ethanolate, may be necessary.

In compounds of the formula I which contain an 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 substituent (especially if Rs is other than carboxyl), this can be converted into an esterified carboxyl group, for example by treatment with an alcohol, such as a lower alkanol, in the presence of a suitable esterifying agent, such as an acid reagent, for example an inorganic or organic acid or a Lewis acid, for example zinc chloride, or a water-binding condensing agent, for example a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by treatment with a diazo reagent, such as with a diazo-lower aLkane, for example diazomethane. This esterified carboxyl group can also be obtained if compounds of the formula I in which the carboxyl group is present in the free form or in salt form, such as ammonium or metal, for example alkali metal, such as sodium or potassium, salt form, are treated with a Cl-C7alkyl halide, for example methyl or ethyl bromide or iodide, or an organic sulfonic acid ester, such as a corresponding Cl-C7aLkyl ester, for example methyl or ethyl methanesulfonate or p-toluenesulfonate.

Compounds of the formula I which contain an esterified carboxyl group as a substituent can be converted into other ester compounds of the formula I by transesterification, for example by treatment with an alcohol, usually with an alcohol which is higher than that corresponding to the esterified carboxyl group in the starting material, in the presence of a suitable transesterification agent, such as a basic agent, for example an alkali metal Cl-C7alkanoate, Cl-C7alkanolate or cyanide, such as sodium acetate, methanolate,ethanolate, tert-butanolate or cyanide, or a suitable acid medium, the alcohol formed being removed if appropriate, for example by distillation. Corresponding so-called activated esters of the formula I which contain an activated esterified carboxyl group as a substituent (see below) can also be used as starting substances, and these can be converted into another ester by treatment with a Cl-C7alkanol.

In compounds of the formula I which contain the carboxyl group as a substituent, this can ~ ~ -, .

also first be converted into a reactive derivative, such as an anhydride (including a mixed anhydride), an acid halide, for example chloride (for example by treatment with a thionyl halide, for example chloride), an anhydride with a formic acid ester, for example Cl-C7alkyl ester (for example by treatment of a salt, such as an ammonium or alkali metal salt, with a halogeno-, such as chloro-formic acid ester, such as Cl-C7aL~cyl ester), or an activated ester, such as a cyanomethyl, nitrophenyl, for example 4-nitro-phenyl, or polyhalogenophenyl, for example pentachlorophenyl, ester (for example by treatment with a corresponding hydroxyl compound in the presence of a suitable condensing agent, such as N,N'-dicyclohexylcarbodiimide), and such a reactive derivative can then be reacted with an amine to give in this way amide compounds of the formula I which contain an amidated carboxyl group as a substituent. In this case, these compounds can be obtained directly or via intermediate compounds; thus, for example, an activated ester, such as a 4-nitrophenyl ester, of a compound of the formula I having a carboxyl group can first be reacted with a 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 Cl-C7alkyl esters, of compounds of the formula I to be reacted with amines.

If an aromatic ring contains a hydrogen atom as a substituent, this can be replaced by a halogen atom with the aid of a halogenating agent in the customary manner, for example by bromine using bromine, hypobromic acid, an acyl hypobromite or another organic bromine compound, for example N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridinium perbromide, dioxane dibromide, 1,3-dibromo-5,5-dimethylhydantoin or 2,4,4,~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 -lO~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 exampie a mineral acid, the reaction temperature advantageously being kept below about 5C. The diazonium group thus obtainable, which is present in salt form, can be substituted by customary processes, for example as follows:
by the hydroxyl group analogously to phenol boiling in the presence of water, by an alkoxy group by treatment with a corresponding alcohol, in which case energy must be supplied; by the fluorine atom analogously to the 5chiemann reaction in the case of thermolysis of corresponding diazonium tetrafluoborate; or by chlorine, bromine, iodine or the cyano group analogously to the Sandmeyer reaction by reaction with corresponding ., . -:
,.

2~13~2 lL

Cu(I) salts, initially by cooling, for example to below about SOC? with subsequent heating, for example to about 60 to about 150C.

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

In compounds I in which, for example, one of the radicals Rl, R2, R3 and R4 is halogen, such as chlorine, halogen can furthermore be replaced by reaction with an unsubstituted or substituted amine or an alcohol or mercaptan.

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

Salts of compounds I can be~ prepared in a manner which is known per se. Thus, for example, acid addition sa!ts 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 exarnple, 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 condidons. ~

As a result of the close relationship between the compound I in the free form and in the . . , : .
.
-, .

2 ~

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

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

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

~iastereomer 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 chira1 adsorbents, with the aid of suitable microorganisms, bycleavage with specific immobilized enzymes, via formation of inclusion compounds, for example using chiral crown ethers, only one enantiomer being complexed, or by conversion into diastereomeric salts, for examp1e by reaction of a basic end racemate with an optically active acid, such as a carboxylic acid, for example tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and resoludon of the diastereomer mixture obtained in this manner into the diastereomers, for example on the basis of its different solubilities, from which the desired enantiomers can be liberated by the 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 anhpodes.

'"' ~ ' .

2~33~ 21 Those starting substances and intermediates which lead to the compounds 1 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 Rl, R2, R3 and R4 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.

The invention thus likewise relates to pharmaceutical preparations containing a compound I as the active ingredient in the free form or in the form of a pharrnaceutically acceptable salt, and to a process for their preparation. These pharrnaceutical preparations are those for enteral, such as oral, and furthermore rectal or parenteral adrninistration 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 forrns, 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 Iyophilizing processes. Pharmaceutical preparations which are suitable for oral administration can thus be obtained by combining the acdve 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 hydt~gen phosphate, and also binders, such as starch pastes, using, for example, maize starch, wheat starch, rice starch or potato starch, geladn, 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 ~ :' 2~331211 salts 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.

.

~3 ~ 2~

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

The following examples illustrate the invention described above; however, they aTe 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)-1,2-dimethyl-6-oxo-1,6-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 mixture is subsequently evaporated in vacuo, the residue is taken up in 50 ml of a dichloromethane/methanol/ammonia mixture (5:3:1) and this mixture is stirred for 30 minutes. After evaporating in vacuo again, the residue is separated by means of flash chromatography [silica gel 60 (40-63 llm), dichloromethane/methanol/ammonia (80:10:1)~. 4-(n-Butyl)-1,2-dimethyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine is obtained in this way in the form of an amorphous solld which crystallises from acetonitrile [m.p.: 165-169 (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 to a solution of 1.0 g (2.8 mmol) of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-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 saturated sodium chloride solution, dried using Na2SO4 and concentrated in vacuo.
Flash chromatography [silica gel 60 (40-63 ~lm), dichloromethane/methanol (~9:1)~ gives 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)- 1,2-dimethyl-6-oxo- 1,6-dihydro-pyrhnidine, which is further processed without furdler purification.

Example 2: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-1-ethyl-2-methyl-6-oxo-1,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)-1-ethyl-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, which crystallises from acetonitrile in the form of white crystals [m.p.: 180-182 (decomposition)], is - . , , . - ~ :

:,." ~ ~, .

2 ~

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-methyl-pyrimidine with ethyl iodide in the manner described in Example la) and flash chromatography [silica gel 60 (40-63 ~,lm), hexane/ethyl acetate (1:1)], 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-1-ethyl-2-methyl-6-oxo-1,6-dihydro-pyrimidine isobtained and is directly further processed.

Example 3: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-6-oxo-l-(n-propyl)-1,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)-2-methyl-6-oxo-1-(n-propyl)-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethy1]-1,6-dihydro-pyrimidine, which crystallises from acetic acid/water in the form of white crystals [m.p.: 168-170 (decomposition)], is obtained in a manner analogous to that describçd 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-methyl-pyrimidine with n-propyl iodide in the manner described in Example la) and flashchromatography [silica ge1 60 (40-63 ~,lm), hexanetethyl acetate (1:1)], A-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-6-oxo- 1 -(n-propyl)- 1,6-dihydro-pyrimidine is obtained and is directly further processed.

Example 4: Starting *om 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-1-ethoxycarbonyl-methyl-2-methyl-6-oxo-1,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)-l-ethoxycarbonylmethyl-2-methyl-6-oxo-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, which crystallises from diisopropyl ether in the form of white crystals [m.p.: l S0- 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-methyl pyrimidine with ethyl bromoacetate in the manner described in Example la) and flash chromatography [silica gel 60 (40-63 ~m), hexane/ethyl acetate (1:1)], 4-(n-butyl)-$-(2'-cyanobiphenyl-4-ylmethyl)-1 -ethoxycarbonylmethyl-2-methyl-6-oxo-l ,~dihydro-pyrimidine is obtained and is direcdy further processed.

.

. ' ;

,.. , ~ ,. .. .

Example 5: 973 mg (2 mmol) of 4-(n-butyl)-1-ethoxycarbonylmethyl-2-methyl-6-oxo-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine are stirred àt 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-(n-butyl)-1-carboxy-methyl-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1 ,6-dihydro-pyrimidine, which melts at 137 to 140.

Example 6: 870 mg (2.34 mmol) of 4-(n-butyl)-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-dihydro-pyrimidine is obtained in this way.

Example 7: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-1-(2-ethoxyethyl)-2-methyl-6-oxo-1,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)-1-(2-ethoxyethyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine [m.p.: 167-179 (from ethyl acetate)] is obtained in the manner described in Example 1.

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

Example 8: Starting from 4-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-1-[N,N-(3-oxapent- 1 ,5-ylen)aminocarbonylmethyl]-6-oxo- 1 ,6-dihydro-pyrimidine and tributyltin azide, 4-(n-butyl)-2-methyl- 1 -[N,N-(3-oxapent- 1 ,5-ylen)aminocarbonylmethyl]-6-oxo-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine [m.p.: 218-221 (from isopropanol/diethyl ether)] is obtained in the manner described in Example 1.

. ~ ~ : . - .

2 ~

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 ~lltered off.
4-(n-Butyl)- l-carboxymethyl-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-6-oxo-1,6-dihydro-pyrimidine [m.p.: 146-148 (from ethyl acetate)] is obtained in this way.

b) 230 mg (1.2 mmol) of N-(3-dimethylaminopropyl~-N'-ethyl-carbodiimide hydrochloride, 203 mg (1.5 mmol) of hydroxybenzotriazole and 0.175 ml (2 mmol) of morpholine are added at 0 to a solution of 415 mg (1 mmol) of 4-(n-butyl)-1 -carboxymethyl-S- (2 ' -cyanobiphenyl-4-ylmethyl)-2-methyl-6-oxo- 1,6-dihydro-pyrimidine in 5 ml of N,N-dimethylformamide. 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 NaHCO3 solution and saturated NaCI solution, dried (Na2SO4) and concentrated in vacua.
4-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-1-[N,N-(3-oxapent-1,5-ylen)-aminocarbonylmethyll-6-oxo-1,6-dihydro-pyrimidine is obtained in this way and isdirectly 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-butyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-y})biphenyl-4-ylmethyl]-1,6-dihydro-pynmidine, m.p.: 140-142;
2. 1-Benzyl-4-(n-butyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, amorphous;
3. 4-(n-Butyl)-2-methyl-6-oxo-1-(2-phenylethyl)-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, amorphous;
4. 4-(n-Butyl)-1-(2-hydroxyethyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 188-191;
5. 4-(n-Butyl)-1-[2-(2-methoxyethoxy)ethyl]-2-methyl-6-oxo-5-[2'-(lH-tetrazol-S-yl)-biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine, m.p.: 132-134;

6. 4-(n-Butyl)-2-ethyl-1-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

7. 4-(n-Butyl)-1-methyl-6-oxo-2-(n propyl)-5-[2'-(lH-tetrazol-5-yl)biphenyl-.

. . .

2~33~1 4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 161-163;

8. 2,4-Di-(n-butyl)- 1 -methyl-6-oxo-5-[2' -( lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 157-159;

9. 4-(n-Butyl)-2-isopropyl-1-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

10. 4-(n-Butyl)- 1,2-diethyl-6-oxo-5-[2'-(lH-tetrazol^S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

11. 4-(n-Butyl)-l-ethyl-6-oxo-2-(n-propyl)-s-[2~-(lH-tetrazol-s-yl)biphenyl-4-ylmet 1,6-dihydro-pyrimidine;

12. 2,4-Di-(n-butyl)-l-ethyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyll-1,6-dihydro-pyrimidine, m.p.: 113-116;

13. 4-(n-Butyl)-l-ethyl-2-isopropyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

14. 4-(n-Butyl)-2-ethyl-6-oxo-1-(n-propyl)-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

15. 4-(n-Butyl)- 1,2-di-(n-propyl)-6-oxo-5-[2'-( lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

16. 2,4-Di-(n-butyl)-6-oxo-1-(n-propyl)-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

17. 4-(n-Butyl)-2-isopropyl-6-oxo-1-(n-propyl)-5-l2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine;

18. 1,4-Di-(n-butyl)-2-ethyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

19. 1,4-Di-(n-butyl) 6-oxo-2-(n-propyl)-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine;

20. 6-Oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,2,4-tri-(n-butyl)-1,6-dihydro-pyrimidine;

21~ 1,4-Di-(n-butyl)-2-isopropyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl 1,6-dihydro-pyrimidine;

22. 1,2-Dimethyl-6-oxo-4-(n-propyl)-5-(2'-carboxybiphenyl-4-ylmethyl)- 1,6-dihydro-pyrimidine;

23. 1-Benzylaminocarbonylmethyl-4-(n-butyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyll-1,6-dihydro-pyrimidine, m.p.: 215-221;

24. 4-(n-Butyl)-2-methyl-6-oxo-1-(2-phenylethylaminocarbonylmethyl)-5-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 121-126;

25. 4-(n-Butyl)-l-(n-butylaminocarbonylmethyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)-. .
-~ ~

.

2033~21 biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 239-241;

26. 4-(n-Butyl)-2-methyl-1-methylaminocarbonylmethyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 245-247;

27. 4-(n-Butyl)-1-dimethylaminocarbonylmethyl-2-methyl-6-oxo-5-[2'-(lH-tetræol-5-yl)-biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 219-222;

28. 4-(n-Butyl)-6-oxo- 1,2-tetramethylen-5-[2'-( lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, m.p.: 205-206; and 29. 4-(n-Butyl)-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,2-trimethylen-1,6-dihydro-pyrimidine, m.p.: 222-224.

Examples 10: Tablets, each containing 50 mg of active ingredient, for example 4-(n-butyl)-1,2-dimethyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-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 352.0 g Gelatin 8.0 g Talc 60.0 g Magnesium stearate 10.0 g Silica (highly disperse) 20.0 g Ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened 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 higllly 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-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine, can be prepared as follows:

Composition (for 1000 tablets):

~--' ' . , , -.. " ' ' '' ' '' .

; .

2~3~21 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 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.

.

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. " - . . : .

Claims

1. A compound of the formula (I), in which one of the radicals R1 and R2 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 R1 and R2 is the group of the formula (Ia), in which Z1 is alkylene, O, S(O)m or N(R), R5 is carboxyl, haloalkanesulfonylamino, SO3H, PO2H2, PO3H2 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 a1cohol, halogen, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, and either R3 is halogen, acyl, an aromatic hydrocarbon radical, carboxyl which, if desired, is esterified or amidated, cyano, SO3H, PO2H2, PO3H2, 5-tetrazolyl, substituted or unsubsdtuted sulfamoyl or acylamino or is -Z2-R', wherein Z2 is a bond or is O, S(O)m or N(K) 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 R4 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 ethelified by an aromatic alcohol, substituted or unsubstituted amino, S(O)m-R or an aromatic hydrocarbon r adical, or R3 and R4 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.

2. A compound according to claim 1 of the formula I, in which one of the radicals R1 and R2 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 R1 and R2 is the group Ia, in which Z1 is methylene, lower alkylene, O, S(O)m or N(R), R5 is carboxyl, halo-lower alkanesulfonylamino, SO3H, PO2H2, PO3H2 or 5-tetrazolyl 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 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 5-tetrazolyl, and either R3 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, SO3H, PO2H2, PO3H2, 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 -Z2-R', wherein Z2 is a bond or is O, S(O)m or N(R) and R' is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyli 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 alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case unsubstituted or substituted by hydroxyl, halogen, amino, lower alkylenearnino, lower alkylenoxy-lower alkyleneamino, lower alkylamino, lower alkenylamino, lower alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independently of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl orphenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, and R4 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 alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkyl, lower alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, or lower alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl, in each case unsubstituted or substituted by hydroxyl, 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 alkynylamino, phenyl-lower alkylamino, phenyl-lower alkenylamino, phenyl-lower alkynylamino, di-lower alkylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, di(phenyl-lower alkyl)-amino, carboxyl which is free or esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or carbamoyl in which the amino group is unsubstituted or mono- or disubstituted by, independently of one another, lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl orphenyl-lower alkynyl or disubstituted by lower alkylene or lower alkylenoxy-lower alkylene, or R3 and R4 together represent methylen or lower alkylene, R in 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 R1 is the group Ia, in which Z1 is methylene, lower alkylene, O, S(O)m or N(R), R5 is carboxyl or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl or 5-tetrazolyl, R2 is lower alkyl or lower alkenyl, in each case unsubstituted or substituted by hydroxyl or halogen, and either R3 is halogen, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl or lower alkoxy-lower alkyl, carbamoyl, cyano, PO3H2, 5-tetrazolyl, lower alkanesulfamoyl, lower alkanoylamino or lower alkanesulfonylamino or is -Z2-R', wherein Z2 is a bond or is O, S(O)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 R4 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, substituted or unsubstituted phenoxy-lower alkyl, amino-, lower alkylarnino- or di-lower alkylamino-lower alkyl or substituted or unsubstituted phenyl-lower alkyl, or R3 and R4 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 R1 is the group Ia, in which Z1 is methylene, lower alkylene, O or S(O)m, R5 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, R2 is lower alkyl or lower alkenyl, in each case unsubstituted or substituted by hydroxyl or halogen, and either R3 is halogen, carboxyl, lower alkoxycarbonyl, PO3H2, 5-tetrazolyl, lower alkanoylamino, lower alkanesulfonylarnino, 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 R4 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl or R3 and R4 together represent methylen or lower alkylene, 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.

5. A compound according to claim 1 of the formula I, in which R1 is the group Ia, in which Z1 is methylene or lower alkylene, R5 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, R2 is lower alkyl, R3 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 orlower alkoxy-lower alkoxy and R4 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 R1 is the group of the formula (Ib), in free form or in salt form.

7. A compound according to claim 1 of the formula I, in which R1 is the group Ib, in which Z1 is methylene, R5 is carboxyl or 5-tetrazolyl and the rings A and B are unsubstituted, R2 is C3-C7alkyl, R3 is hydrogen or C1-C4alkyl and R4 is C1-C4alkyl, carboxy-C1-C4alkyl, C1-C4alkoxycarbonyl-C1-C4alkyl or hydroxy-C1-C4alkyl, in free form or in salt form.

8. A compound according to claim 1 of the formula I, in which R1 is the group Ib, in which Z1 is methylene, R5 is carboxyl or tetrazolyl and the rings A and B are unsubstituted, R2 is C3-C5alkyl, R3 is hydrogen or C1-C4alkyl and R4 is C1-C4alkyl, 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.

10. 4-(n-Butyl)-1-ethyl-2-methyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

11. 4-(n-Butyl)-2-methyl-6-oxo-1-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

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

13. 4-(n-Butyl)-1-carboxymethyl-2-methyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1,6-dihydro-pyrimidine or a salt thereof.

14. 4-(n-Butyl)-5-(2'-carboxybiphenyl-4-ylmethyl)-1,2-dimethyl-6-oxo-1,6-dihydro-pyrimidine or a salt thereof.

15. 4-(n-Butyl)-1-(2-ethoxyethyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl)-1,6-dihydro-pyrimidine or a salt thereof.

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

17. 1-Benzyl-4-(n-butyl)-2-methyl-6-oxo-5-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

18. 4-(n-Butyl)-2-methyl-6-oxo-1-(2-phenylethyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

19. 4-(n-Butyl)-1-(2-hydroxyethyl)-2-methyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

20. 4-(n-Butyl)-2-ethyl-1-methyl-6-oxo-5-12'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

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

22. 2,4-Di-(n-butyl)-1-methyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pylimidine or a salt thereof.

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

24. 4-(n-Butyl)- 1 ,2-diethyl-6-oxo-5-12' -( 1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

25. 4-(n-Butyl)-1-ethyl-6-oxo-2-(n-propyl)-5-[2'-(1H-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-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

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

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

29. 4-(n-Butyl)- 1 ,2-di-(n-propyl)-6-oxo-5-[2'-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

30. 2,4-Di-(n-butyl)-6-oxo- 1-(n-propyl)-5-[2'-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

31. 4-(n-Butyl)-2-isopropyl-6-oxo-1-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine or a salt thereof.

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

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

34. 6-Oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,2,A-tri-(n-butyl)-1,6-dihydro-pyrimidine or a salt thereof.

35. 1,4-Di-(n-butyl)-2-isopropyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-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- 1 -[N,N-(3-oxapent- 1 ,5-ylen)aminocarbonylmethyl]-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyll-1,6-dihydro-pyrimidine or a salt thereof.

38. 4-(n-Butyl)-1-[2-(2-methoxyethoxy)ethyl]-2-methyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyU-1,6-dihydro-pyrimidine or a salt thereof.

39. 1-Benzylaminocarbonylmethyl-4-(n-butyl)-2-methyl-6-oxo-5-[2'-(1H-tetrazol-4-yl)-biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine or a salt thereof.

40. 4-(n-Butyl)-2-methyl-6-oxo-1-(2-phenylethylaminocarbonylmethyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- 1 ,6-dihydro-pyrimidine or a salt thereof.

41. 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- 1-methylaminocarbonylmethyl-6-oxo-5-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,6-dihydro-pyrimidine or a salt thereof.

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

44. 4-(n-Butyl)-6-oxo-1,2-tetramethylen-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyU-1,6-dihydro-pydmidine or a salt thereof.

45. 4-(n-Butyl)-6-oxo-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1,2-trimethylen-1,6-dihydro-pyrimidine or a salt thereof.

46. A compound according to any one of claims 1 to 45, in free form or in form of a pharmaceutically acceptable salt, for use in a method for the therapeutic treatment of the human or animal body.

47. A compound according to any one of claims 5 and 9 to 36, in free form or in form of a pharmaceutically acceptable salt, for use in a method for the therapeutic treatment of the human or animal body.

48. A compound according to any one of claims 1 to 47, in free form or in form of a pharmaceutically acceptable salt, for use as an antihypertensive.

49. A compound according to any one of claims 5, 9 to 36 and 47, in free form or in form of a pharmaceutically acceptable salt, for use as an antihypertensive.

50. A pharmaceutical preparation containing, as the active ingredient, a compound according to any one of claims 1 to 49, in free form or in form of a pharmaceutically acceptable salt, if appropriate in addition to customary pharmaceutical adjuncts.

51. A pharmaceutical preparation containing, as the active ingredient, a compound according to any one of claims 5, 9 to 36, 47 and 49, in free form or in form of a pharmaceutically acceptable salt, if appropriate in addition to customary pharmaceutical adjuncts.

52. An antihypertensive pharmaceutical preparation according to claim 50 or 51, in which an antihypertensive active ingredient is chosen.

53. An antihypertensive pharmaceutical preparation according to claim 51, in which an antihypertensive active ingredient is chosen.

54. A process for the preparation of a compound of the formula (I).

in which one of the radicals R1 and R2 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 R1 and R2 is the group of the formula (Ia), in which Z1 is alkylene, O, S(O)m or N(R), R5 is carboxyl, haloalkanesulfonylamino, SO3H, PO2H2, PO3H2 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 R3 is halogen, acyl, an aromatic hydrocarbon radical, carboxyl which, if desired, is esterified or amidated, cyano, SO3H, PO2H2, PO3H2, 5-tetrazolyl, substituted or unsubstituted sulfamoyl or acylamino or is -Z2-R', wherein Z2 is a bond or is O, S(O)m 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 R4 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 R3 and R4 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, which process comprises converting X1 into R5 in a compound of the formula (IIa), in which one of the radicals R'1 and R'2 is the group of the formula (IIb) and X1 is a radical which can be converted into R5, 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 compound I obtainable according to the process into the free compound I or into another salt.

55. A process for the preparation of a pharmaceutical preparation according to any one of claims 50 to 53, which process comprises processing the active ingredient into apharmaceutical preparation, customary pharmaceutical adjuncts being mixed in if appropriate.

56. A process for the preparation of a pharmaceutical preparation according to claim 51 or 53, which process comprises processing the active ingredient into a pharmaceutical preparation, customary pharmaceutical adjuncts being mixed in if appropriate.

57. The process according to claim 55 or 56 for the preparation of an antihypertensive pharmaceutical preparation according to claim 52 or 53, wherein an antihypertensive active ingredient is chosen.

58. The process according to claim 56 for the preparation of an antihypertensivepharmaceutical preparation according to claim 53, wherein an antihypertensive active ingredient is chosen.

59. 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 49, in free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to any one of claims 50 to 53.

60. A method of treating high blood pressure and/or cardiac insufficiency, which method comprises administering a compound according to any one of claims 5, 9 to 36, 47 and 49, in free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to claim 51 or 53.

61. The use of a compound according to one of claims 1 to 49, in free form or in form of a pharmaceutically acceptable salt, for the preparation of a pharmaceutical preparation,

62. The use of a compound according to one of claims 1 to 49, in free form or in form of a pharmaceutically acceptable salt, for the preparation of a pharmaceutical preparation by a non-chemical route.

63. The use of a compound according to claim 61 or 62 for the preparation of an antiihypertensive.

64. The use of a compound according to one of claims 1 to 49, in free form or in form of a pharmaceutically acceptable salt, or a pharmaceutical preparation according to any one of claims 50 to 53 for the treatment of high blood pressure and/or cardiac insufficiency.

65. The process of the Examples 1 to 9.

66. The novel starting substances used according to the process in the process according to either of claims 54 and 65, the novel intermediates formed and the novel end products obtainable.

FO 7.4 GR