CA2024137A1 - Aza compounds - Google Patents

Abstract

Aza compounds Abstract Azabenzimidazole compounds of the formula (I), in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, acyl, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, or R is -Z-R', wherein Z is a bond or is O, S(O)m or NH, R' is hydrogen or an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radical, if desired, is interrupted by O or S(O)m and the index m is in each case 0, 1 or 2, R1 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or is a cycloaliphatic or araliphatic hydrocarbon radical and R2 is the group of the formula (Ia), in which alk is a divalent aliphatic hydrocarbon radical, R3 is COOH, SO3H, haloalkanesulfonylamino, PO2H2, PO3H2 or 5-tetrazolyl and either the rings A and B
independently of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl or halogen and which, if desired, is interrupted by O, hydroxyl which, if desired, is etherified by an a ?natic alcohol, or carboxyl which, if desired, is esterified or amidated or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt, can be manufactured in a manner known per se and can be used, for example, as active ingredients in medicaments.

Description

- 1 - " ;' 4-17714/+ -' ''' ' '~' ~' Aza comDounds . ~ ~ ~

The invendon relates to azabenzimidazole compounds of the formula . : :

Z3~Z"

R2 . ' "., ~ '~

in which ono or two of thc variables Z~. Z2- Z3 and Z4 are N and the others are C(R), . ;
where R is halogen, acyl, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, or R is -Z-R', wherein Z is a bond or is O, S()m or NH, R' is hydrogen or an - .
aliphadc hydrocarbon radical which is unsubsdtuted or subsdtuted by halogen, hydroxyl, . .
unsubsdtuted or subsdtuted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radica1, if desired, is interrupted by O or S()m and the index m is in each case 0, 1 or 2, Rl is an aliphadc hydrocarbon radical which is unsubstituted or subsdtuted by halogen or hydroxyl or is a cycloaliphadc or araliphatic hydrocarbon radical ~ ~ ;
and R2 is tho group of the formula . . .

in which alk is a divalent aliphadc hydrocarbon radical, R3 is COOH, SO3H, . ~ :
haloalkanesulfonylamino, PO2H2, PO3H2 or 5-tetrazolyl and either the rings A and B : .
indcpondently of ono another are unsubstituted or substituted by halogen, an aliphadc ~ :
hydrccarbon radlcal whlch is unsubsdtuted or subsdtuted by hydroxyl or halogen and which, if desired, ls interrupted by O, hydroxyl whlch, if desited, is etherified by an allphadc alcohol, o~ carboxyl whlch, if desired, is esterified or amidated or the ring A is substituted by 5-tetrazolyl and the ring B is unsubsdtuted or subsdtuted as indicated : ; .

immediately hereinbefore, in free form or in fonn of a salt, to a process for the preparation of these compounds, to the use of these compounds and to pharmaceutical preparadons containing such a compound I in free form or in form of a pharmaceutically acceptable salt.
, The compounds of the formula I can be present as salts, in particular pharmaceudcally acceptable salts. If the compounds I have at least one basic centre, they can form acid addidon salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric acid or a halohydric acid, with strong organic carboxylic acids, such as Cl-C4alkanecarboxylic acids which are unsubsdtuted or substituted, for example, by halogen, for example acedc acid, such as dicarboxylic acids which, if desired, are unsaturated, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lacdc, malic, tartaric or citric acid, such as amino acids, for example aspardc or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as Cl-C4alkane- or aryl-sulfonic acids which are unsubsdtuted or subsdtuted, for example, by halogen, for example methane- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed with an addidonal basic centre which may opdonally be present.
Tho compounds I containing at least ono acidic group (for example COOH or 5-tetrazolyl) can addidonally form salts with bases. Suitable salts with bases are, for example, metal ~alts, such as alkali metal salts or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or with an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylarnine, for oxample ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- ordimethyl-propyl-amine, or a mono-, di- or trihydroxy-lower aLkylamine, for example mono-, di- or triethanolamine. Corresponding inner salts can furthermore be formed. Salts which are unsuitable for pharmaceudcal uses are addidonally included, which can be ~ ;~
employed, for example, for the isoladon or purification of free compounds of the formula T
or thoir pharmaceudcally acceptable salts. ~ ;
. ,-:
Acyl is, in particular, lower alkanoyl, Esterified carboxyl is, for example, carboxyl which is esterifiod by an aliphadc alcohol which is derived from an aliphadc hydrocarbon radical, such as from lower alkyl, lower ~ ;
alkenyl or 9econdarily lower alkynyl, which, if desircd, is interrupted by 0, such as from lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl. Examples which may be - ~;

:~.. ' '.' '." ~-. ...

2 ~ 3 ~

-3- ;
mentioned are lower alkoxy-, lower alkenyloxy- and 10wer alkoxy-lower alkoxy-carbonyl.

Amidated carboxyl is, for example, carbamoyl in which the amino group, if desired, is independently of one another mono- or disubsdtuted by an aliphatic or araliphadchydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl, or phenyl-lower alkyl, -lower alkenyl or -lower alkynyl, or is disubstituted by a divalent aliphadc hydrocarbon radical which, if desired, is interrupted by 0, such as lower alkylene or lower alkyleneoxy-lower alkylene.
.
Substituted amino is, for example, amino which is independently of one another mono- or di-substituted by an aliphatic or araliphadc hydrocarbon radical, such as lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl, -lower alkenyl or -lower alkynyl, or amino which is disubsdtuted by a divalent aliphadc hydrocarbon radical which, if desired, i8 interlupted by 0, such as lower alkylene or lower alkyleneoxy-lower alkylene.Exarnples which may be mendoned are lower alkyl-, lower alkenyl-, lower alkynyl-, ~ ~
phenyl-lower alkyl-, phenyl-lower alkenyl-, phenyl-lower aL~ynyl-, di(lower alkyl)-, ;;
N-lower a1kyl-N-phenyl-lower alkyl- and di(phenyl-lower a1kyl)amino.

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

An aliphatic hydrocarbon radical which is interrupted by 0 is, in particular, lower alkoxy-lower alkyl, -lower alkenyl or -lower alkynyl or lower alkenyloxy-lower alkyl, -lower alkenyl or -lower allynyl, while an aliphadc hydrocarbon radical which isinte~upted by S()m is, in pardcular, lower alkylthio-lower aLkyl, -lower aL~enyl or -lower alkynyl, lower alkane-sulfinyl-lower aL~yl or -sulfonyl-lower alkyl, lower alkenyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl or lower ~ -alkynyl-thio-lower alkyl, -sulfinyl-lower alkyl or -sulfonyl-lower alkyl. -; -An aliphadc hydrocarbon radical subsdtuted by halogen or hydroxyl is, for example, halo-lower alkyl, -lower alkenyl or -lower alkynyl or hydroxy-lower alkyl, -lower alkenyl or lower alkynyl.

An aliphatic hydrocarbon radical subsdtuted by halogen or hydroxyl which is interrupted by 0 or S()m is a corresponding radical indicated hereinbefore which is subsdtuted by halogen or hydroxy.

, - ' .

An aliphatic hydrocarbon radical which is substituted by unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radica1, if desired, is interrupted by O or S()m is a corresponding radical indicated hereinbefore which is substituted by amino, substituted amino as indicated hereinbefore, carboxy or carboxy which is esterified or amidated as indicated hereinbefore.

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

Possible araliphatic hydrocarbon radicals are, in particular, phenyl-lower alkyl, and additionally phenyl-lower alkenyl and -lower a1kynyl.
.. . .
A divalent aliphatic hydrocarbon radica1 is, in particular, lower alkylene or lower alkonyleno, whore in tho case of alk the C atom from which the double bond starts is in particular not linked to the N atom of the azabenzimidazole ring; alk is primarily mothylene. ~ I
., , ", ~,.
A divalent aliphadc hydrocarbon radical which is interrupted by O is, in pardcular, lower alkyleneoxy-lower alkylene.
. .
Hydroxyl etherified with an aliphadc alcohol is, in particular, lower alkoxy or lower alkenyloxy.

Abovo and bolow, unsaturated aliphadc, cycloaliphadc and araliphadc subsdtuents aro ~ ~ `
primarily not linked to an aromatic radical via a C atom from which a muldple bond starts. ~- -: :' ..~ :~' Phenyl is in oach case unsubsdtuted, monosubsdtuted or polysubstituted phenyl, for ~ -example disubsdtuted or trisubsdtuted phenyl, for example by (a) subsdtuent(s) selected fi~m the group comprising lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxyl~ ;

The rin~s A and B form a biphonyl radical, in which case the cor esponding 4-biphenylyl is preferred.
, ,,.; . .
If not dofined difforently, the general terms used above and below have the following ~",,~. . :.: ,;,.' ;:

'' ~
' 5 - ' ` " '.. ', meanings:

The expression "lower" means that appropriate groups and compounds in each case contain in particular not more than 7, preferably not more than 4, carbon atoms.
Halogen is in particular halogen with an atomic number of not more than 35, that is to say fluorine, chlorine or bromine, and addidonally includes iodine. ; ~

Haloalkanesulfonylarnino is, in particular, halo-C1-C7aLlcanesulfonylatnino and is, for ~;
example, trifluoromethane-, difluoromethane-, 1,1,2-trifluoroethane- or heptafluoropropane-sulfonylamino. Halo-C1-C4alkanesulfonylamino is preferred.

Lower alkanoyl is, in particular, Cl-C7alkanoyl and is, for example, formyl, acetyl, ~ :
propionyl, butyryl, isobutyryl pivaloyl. C2-CsAlkanoyl is preferred.

Lower alkyl is, in particular, Cl-C7alkyl, that is to say methy1, ethyl, n-propy1, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl radical. ;;
Cl-C4Alkyl is prefer ed.

Lower alkenyl i9, in particular, C3-C7alkenyl and is, for example, propen-2-yl, allyl or but l en-3-yl, -1-en-4-yl, -2-on-1-yl or -2-cn-2-yl. C3-CsAlkenyl is preferred. .:

Lower alkynyl is, in particular, C3-C7alkynyl and is preferably propargyl. i Lower alkoxy is, in palticular, Cl-C7alkoxy, that is to say methoxy, ethoxy, n-propyloxy,;
isopropyloxy, n-butyloxy, isobuqyloxy, sec-butyloxy, tert-butyloxy or corresponding - -pontyloxy, hexyloxy or hepqloxy. Cl-C4Alkoxy is preferred.

Lowor alkoxy lower alkyl is, in particular, Cl-C4alkoxy-CI-C4alkyl, such as I I `
2-mothoxyethyl, 2-ethoxyethyl, 2-(n-propyloxy)ethyl or ethoxymethyl.

l.owor aL~oxy-lower alkenyl or -lower alkynyl is, in particular, Cl-C4alkoxy-C3-Csalkenyl or-alkynyl.

Lowor alkoxycarbonyl is, in particular, Cl-C7alkoxycarbonyl and is, for examplo,methoxy-, ethoxy-, propyloxy- or neopentyloxy-car~onyl. Cl-C4Alkoxycarbonyl is . ~, 2 0 2 ~ ~ 3 7 preferred.

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

Lower alkenyloxycarbonyl is, in particular, C3-Csalkenyloxycarbonyl, preferably allyloxycarbonyl, while lower alkynyloxycarbonyl is, in particular, C3-Csalkynyloxycarbonyl, such as propargyloxycarbonyl.
- ': ' Lower alkoxy-lower alkoxycarbonyl is, in particular, C~-C4alkoxy-Cl-C4alkoxycarbonyl, -preferably ethoxyethoxycarbonyl, methoxyethoxycarbonyl or isopropyloxyethoxycarbonyl. ~;

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

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

Hah-lower alkynyl is, in palticular, halo-C3-Csalkynyl, such as 3-chloropropargyl.

Hydroxy-lower alkyl is, in particular, hydroxy-C1-C4alkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.
,.: .. ...
Hydroxy-lower alkenyl is, in particular, hydroxy-C3-C5alkenyl, such as 3-hydroxyallyl. ;;

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

Phenyl-lower alkyl is, in pardcular, phenyl-CI-C4alkyl and is, preferably, benzyl or i- or ; ~ ~ ;
2-phenethyl, while phenyl-lower alkenyl or phenyl-lower alkynyl are, in particular, phenyl-C3-Csalkonyl or -alkynyl, in particular 3-phenylallyl or 3-phenylpropargyl.

Lowc-r alkylono is, in particular, C2-C7alkyleno, is straight~chain or branched and is, in ' - -particular, ethylene, 1,3-propylono, 1,4-butyleno, 1,2-propyleno, 2-methyl-i,3-propyiene or 2,2-dimethyl-1,3-propylono. C2-CsAlkylono is preforred. - ~
-'."',',',', :"", ~ . ~ , ~ ,. . .;

, -," - ,,~

Lower alkyleneamino is, in particular, C2-C7alkyleneamino, is straight-chain or branched and is, in particular, ethyleneamino, 1,3-propyleneamino, 1,4-butyleneamino, ;
1 ,2-propyleneamino, 2-methyl- 1 ,3-propyleneamino or 2,2-dimethyl- 1 ,3-propyleneamino.
C2-CsAlkyleneamino is preferred.

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

Lower alkyleneoxy-lower alkyleneamino is, in particular, CrC4alkyleneoxy-C2-C4alkyleneamino, preferably ethyleneoxyethyleneamino. -Lower alkylamino is, in particular, Cl-C7alkylamino and is, for example, methyl-, ethyl-, n-propyl- or isopropyl-amino. Cl-C4Alkylamino is preferred.

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

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

Phonyl-lower alkylamino is, prefcrably, phenyl-C~-C4alkylamino, in par~icular benzyl- or 1- or 2-phonylethyl-amino.

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

Phenyl-lower alkynylamino is, preferably, phenyl-C3-Csalkynylamino, in particular phonylpropargylamino~

Di(lower alkyl)amino is, in particular, di(Cl-C4alkyl)amino, such as dimethyl-, diethyl~
di(n-propyl)-, methyl-propyl-, methyl-ethyl-, methyl-butyl- or dibutyl-a nino.
' ~'' N-Lower alkyl-N-phenyl-lower alkyl-amino is, in par~icular, N-CI-C4alkyl-N-phenyl-Cl-C4alkyl-amino, preferably methyl-benzyl-amino or ethyl-benzyl-amino.

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

13 ~ !

Lower alkenyloxy-lower alkyl is, in particular, C3-Csalkenyloxy-CI-C4alkyl, such as 2-allyloxyethyl, and lower alkenyloxy-lower alkenyl or -lower alkynyl is, in particular, C3-Csalkenyloxy-C3-Cs-alkeny1 or-alkynyl.

Lower alkylthio-lower alkenyl or -lower alkinyl is, in particular, C1-C4alkylthio-C3-Cs-alkenyl or -alkinyl. .~ ' Lower alkylthio-lower alkyl is, in particular, Cl-C4alkylthio-CI-C4alkyl, such as ethylthiomethyl, 2-ethylthioethyl, 2-methylthioethyl or 2-isopropylthioethyl, while suitable lower alkane-sulfinyl-lower alkyl or -sulfonyl-lower alkjl are, in particular, corresponding Cl-C4alkane-sulfinyl-Cl-C4alkyl or -sulfonyl-CI-C4alkyl radicals. ;
,....... .. .... : ':
Lower alkenylthio-lower alkyl is, in particular, C3-Csalkenylthio-Cl-C4alkyl, such as I-allylthioethyl or 3-allylthiopropyl, while lower alkenyl-sulfinyl-lower alkyl or -sulfonyl-lower alkyl is, in particular, C3-Csallcenyl-sulfinyl-CI-C4alkyl or -sulfonyl-CI-C4alkyl.
, .. "
L r a ynylthio-lower a kyl is, in par cular, 3-Csalkynylthio Cl-C4alkyl, such as ; `
p~pargy1thioethyl or 3-propargylthiopropyl, whilo lower a11cynyl-sulfinyl-lower aLkyl or ;i`
-sulfonyl-lower alkyl is, h particular, C3-C5alkynyl-sulfinyl-CI-4alkyl or ;
-9u1fony1-Ct-C~alkyl~ ,'"',,; !'.,'~'.. ,'`.,'' ~balkyl is, in parlicular, C3-~ye~yl, that is to say cyclopropyl, cyclobuty~
~nlyl, eyelohexyl or cyel~l. Cyelopentyl and cyclohexyl are prefer~ ~ v~ ;

~yl is, in particular, C3-Cpycloalkenyl and is preferably cyclopent-2-enyl or 3 onyl or eyelohex-2-enyl or -3-enyl.

Lower ~L~enybne is, in pardcùlar, C3-Csalkenylene and is, for example, but-2-en-1,4-ylene~

Lower a1koxy-lower alkenyloxyearbonyl or -lower alkinyloxyearbonyl is, in parhcular~
CI~C,~alkoxy C3-Cs-alkonyloxycarbonyl or -alkinyloxycarbonyl.

I;xtonsivo pharmacologica1 invesdgadons havo shown that the compounds I and their pha~maceudcally acceptablo salts han, for examplo, pronounced angiotensin II antagonist ~ i ~ '~ 2~

2~2~37 g properties.
., As is known, angiotensin II has strong vasoconstrictor properties and additionally stimulates the aldosterone secretion and thus causes distinct sodium/water retention. The ~ -consequence of angiotensin II acdvity is manifested, among other things, in an increase in ;
blood pressure. ~ -The importance of angiotensin II antagonists is in suppressing the vasoconstrictor and the -aldosterone secretion-sdmuladng effects caused by angiotensin II by compeddve inhibition of the binding of angiotensin II to the receptors.

The angiotensin II antagonist properties of the compounds of the formula I and their pharmaceudcally acceptablo salts can be detected in the angiotensin II binding test. Rat ~ -smooth muscle cells from homogenized rat aorta ate used here. The solid centrifugate is susponded in S0 mM tris buffer (pH 7.4) using pepddase inhibitors. The samples are incubated for 60 minutes at 25C with l25I-angiotensin II (0.175 nM) and a varying concenttadon of angiotensin II or of the test substance. The incubadon is then ended by addidon of saline buffered with ice-cold phosphate, and the mixture is filtered through Whatman C~F/F filters. The filters ate counted using a gamma counter. The ICSo values are determined from the dose-effect curve. ICSo values from about 10 nM are determined for the compounds of the formula I and their phatmaceudcally acceptable salts.

For the detetminadon of angiotensin Il-induced vasoconstricdon, invesdgadons on the isolated rabbit aorta ring can be used. For this purpose, aorta rings ate dissected from each chost and fixed between two parallel clamps at an inidal tension of 2 g. The rings are then immersed in 20 ml of a dssue bath at 37C and aerated with a mixture of 95 % 2 and 5 %
CO2. The isometric reacdons are measured. At 20-minute intervals, the rings are alternately sdmulated with 10 nM angiotensin II (Hypertensin-ClBA) and 5 nM
noradrèhaline chloride. The rings arei then incubated with selected concentradons of the test substances before treatrnent with the agonists. The data are analysed using a Buxco di~ltal computer. The concentradons which cause a S0 9b inhibidon of the inidal control ~aluos are givon as ICSo valuos. ICSo values from about S nM are determined for the compounds of the formula I and their pharmaceudcally acceptable salts.

The fact that the compounds of the formula I and their pharmaceudcally acceptable salts can reduce high blood pressure induced by angiotensin II can be verified in the 2Q2~ 37 ~::

normotensive anaesthetized rat test model. After calibration of the preparations vith 0.9 %
NaCI (1 mVkg i.v.), noradrenaline (1 ,~-g/kg i.v.) or angiotensin II (0.3 ~.g/lcg i.v.) in each case, increasing doses (3-6) of the test substance are intravenously injected by bolus injection, after which angiotensin II or noradrenaline is administered after each dose at S
mlnute intervals. Tho blood pressure is measured directly in the carotid artery and recorded using an on-line data recording system (Buxco). The specificity of the ~ ~
angiotensin Il antagonism is shown by the seiective inhibition of the pressure effect ~ ~;
produced by angiotensin II, but not that produced by noradrenaline. In this test model, the compounds of the formula I and their pharmaceutically acceptabb salts show an inhibidng effect from a dose of about 0.3 mgrlg i.v..
: .. ..
. ... .
Tho antihypertensive acdvity of the compounds of the formula I and their pharmaceutically acceptable salts may also be manifested in the renally hypertensive rat ~ i :
tost model. High blood pressure is produced in male rats by constricdng a renal anery accotding to the Goldblau method. Doses of the test substance are administered to the rats ~ i :
by means of a stomach tube. Control animals receive an equivalent volume of solvent. ~;
Blood pressure and heart beat are measured indirecdy at interva1s in conscious animals by ~;
tho tail clamp method of Gerold et al. IHelv. Phvsiol. Acta 24 (1966), 58] before administradon of the test substanco or of tho solvent and during the course of the ` ~; `
oxporimonts. It is possibb to detect the pronounced antihypertensive effect from a dose of ; ;
about 30 mg/kg p.o..

The compounds of the fonnula I and their pharmaceudcaUy acceptable salts can therefore ;
bo u~ed, forexample, as acdve ingredients in andhypertensives, which are used, for oxamplo, for d~e treatment of high blood pressure and cardiac insufficiency. The invendon the~ relates to the use of the compounds I and their pha maceudcally acceptable salts for the producdon of corresponding medicaments and for the therapeudc treat nent of high blood pressure and cardiac insufficiency. The industrial producdon of the acdve substances is also included in the producdon of the pharmaceudca1s. . - -Tho invention relates in pardcutar to compounds of the fotmula I, in which one or t vo of tho varlablos Zl. Z2 Z3 and Z4 are N and the othors are C(R), where R is halogen, lower alkanoyl, carboxyl which, if desired, is esterified by an alcohol which is dedved from lower alkyl, Iower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, carbamoyl in which the amino group is indopondently of one another mono- or disubsdtuted by lower aLcyl, lower aLcenyl, lower ~ :,,. -,,' .:

- 11 - .

alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or 5-tetrazolyl or R
is -Z-R', in which Z is a bond or is 0, S()m or NH, R' is hydrogen, or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkylthio-lower alkyl, lower alkylthio-lower alkenyl, lower alkylthio-lower alkynyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, lower alkenylthio-10wer alkyl, lower alkenylsulfinyl-lower alkyl, lower alkenylsulfonyl-lower alkyl, lower alkynylthio-lower alkyl, lower alkynylsulfinyl-lower alkyl or lower alkynylsulfonyl-lower alkyl which radicals, in each :
case, are unsubsdtuted or subsdtuted by halogen, by hydroxyl, by amino which, if desired, is subsdtuted as indicated immediately hereinbefore in the definition of the amino group of the carbamoyl radical R, by carboxyl which, if desired, is esterified as indicated immediately hereinbefore, or by carbamoyl in which the arnino group, if desired, is subsdtutcd as indicated immediately hereinbefore, and the index m is 0, 1 or 2, Rl is lower alkyl, lower alkenyl or lower alkynyl which radicals, in each case, are unsubsdtuted or subsdtuted by halogen or by hydroxyl, cycloalkyl or cycloalkenyl which are in each case 3~ to 7-membered, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, and R2 is the group of the for~nula Ia in which alk is lower alkylene or lower alkenylene, R3 is COOH, S03H, halo-lower alkanesulfonylamino, PO2H2, PO3H2 or 5-tetrazolyl and either tho rings A and B independently of one another are unsubsdtuted or subsdtuted byhalogon, by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lowcr alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl or lower alkenyloxy-lower alkynyl which radicals, in oach case, are unsubsdtuted or subsdtuted by halogen or hydroxyl, by hydroxyl, by lower alkoxy, by lower alkenyloxy, by carboxyl which, if desired, is ester;f1ed by an alcohol which is derivcd from lower alkyl, lower alkeny1, lower alkynyl, lower a1koxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or by carbamoyl in which the amino group, if desired, is independendy of one another mono- or disubsdtuted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubsdtuted by lower alkylenc or lower alkyleneoxy-lower alkylene, or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or subsdtuted as indicated immediately hereinbefore, in free form or in for n of a salt.

The invendon relates in particular to compounds of the formula I, in which one or two of the variables Zl, Z2~ Z3 and Z4 are N and the others are C(R), where R is halogen, lower 2~%~7 1 : ~
- 12- ~ -. ~ .
alkanoyl, carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, carbamoyl in which the amino group, if desired, is independently of one another mon~ or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkybne, or R
is -Z~R', in which Z is a bond or is O and R' is hydtogen, or lower alkyl or lower alkoxy-lower alkyl which radicals, in each case, are unsubsdtuted or subsdtuted by halogen, by hydroxyl, by amino which, if desired, is independendy of one another mono-or disubstituted by lower alkyl or phenyl-lower alkyl or disubstdtuted by lower alkylene, ; - ~ -by carboxyl, by lower alkoxycarbonyl or by lower alkoxy-lower alkoxycarbonyl, R1 is lower alkyl or lower alkenyl which radicals, in each case, are unsubsdtuted or subsdtuted by halogen or by hydroxyl, or 3- to 7-membered cycloalkyl or phenyl-lower alkyl, and R2 is the group of the formula la, in which alk is lower alkylene, R3 is COOH or S-tetrazolyl and the rings A and B indepcndently of one another are unsubstituted or subsdtuted by halogen, by lower alkyl which is unsubsdtuted or subsdtuted by halogen or by hydroxyl, ~ :
by lower alkoxy, by carboxyl or by lower alkoxycarbonyl, in free form or in form of a salt. ~;

The invendon relates in pardcular to compounds of the formula 1, in which one or two of the variables Zl, Z2~ Z3 and Z4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl, lower alkoxycarbony!, carbamoyl which, if desired, is mono- or `- --~ .
disubsdtuted by lower alkyl, or S-tetrazolyl or R is ~ZR', in which Z is a bond or is O, S()m NH, m is 0, 1 or 2 and R' is hydtogen or lower alkyl which is unsubsdtuted or substituted by halogen, by hyd~xyl or by amino, Rl is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lowor alkyl, 3- to 7-membered cycloalkyl or phenyl-lower alkyl and`~R2 is the group of the formula la in which alk is lower alkylene, R3 is C~OOH or s~ottazolyl and tho rings A and B independently of ono another are unsubsdtuted or substituted by halogen, by lower alkyl which is unsubsdtuted or subsdtuted by halogen or by hydroxyl, by lower alkoxy, by carboxy! or by lower alkoxyca~bonyl, in free form or in farln of a salt.

Tho invèndon relates in pardcular to compounds of the formula 1, in which R2 is thelgroup~
of tho formula ~ ~-., ~

. ~ ~

..,,~, ' ~ .' -", f2~ 3~ ' ~

in free form or in form of a salt. ;

The inventdon relates in particular to compounds of the formula I, in which one or two of the variables Zl, Z2~ Z3 and Z4 are N and the others are C(R), where R is hydrogen, halogen, carboxyl, lower alkoxycarbonyl, 10wer alkyl, halo-lower alkyl, hydroxy-lower alkyl or lower alkoxy, Rl is lower alkyl, lower alkenyl, hydroxy-lower alky!, halo-lower alkyl, 3- to 7-membered cycloalkyl or phenyl-lowa alkyl and R2 is the group of the formula Ib, in which alk is lower alkylene, R3 is COOH or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, carboxyl or lower aL~oxycarbonyl or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt.
" , ~ ,, Tho invendon relates in particular to compounds of the formula I, in which R2 is the group of the forrnula Ia or Ib and alk is methylene, in free forrn or in form of a salt.

Tho invendon relates primalily to compounds of the formula I, in which one or tWO of the variables Zl, Z2, Z3 and Z4 are N and the others are CH, in particular Zl, Z2 and Z3 are CH
and Z" is N, Rl is lower alkyl, in particular having not more than 4 C atoms, such as propyl or n-bu~yl, lower alkenyl, in particular having from 3 up-to and including 5 C ~ ~
atoms, such as propen-2-yl or but-2-en-1-yl, or halo-lower alkyl, in particular having not ~ ~ ;
more than 4 C atoms and containing halogen with an atomic number of not more than 35, such as n-heptafluoropropyl, and R2 is the group of the formula Ib in which alk is methylene, R3 is COOH or 5-tetrazolyl and the rings A and B independently of oneanother are unsubstituted or, secondarily, substituted by halogen, in particular with an atomic number of not more than 35, such as chlorine, lower aL~cyl, in pa~ticular having not more than 4 C atoms, such as methyl, or lower alkoxy, in particular having not more than 4 C atoms, such as methoxy, in free fonn or in form of a salt.

The invendon relates in parlicular to compounds of the formula I, in which one or two of tho variables Zl. Z2. Z3 and Z4 are N and the others are CH or in which in particular one of the variables Z2, Z3 and Z4 is N and Zl and the other variables of Z2, Z3 and Z4 are C(R), in particular CH, or in which Zl and Z3 are C(R), in particular CH, and Z2 and Z4 are N, in free form or in form of a salt.

', ~., - 14 ~

The invention relates primari1y to compounds of the formula I, in which Zl, Z2 and Z3 are CH and Z4 iS N or Zl and Z3 are CH and Z2 and Z4 are N, R1 is 10wer alky1, in particu1ar ;
having not more than 4 C atoms, such as propy1 or n-buty1, lower alkeny1, in particu1ar having from 3 up to and inc1uding 5 C atoms, such as propen-2-y1 or but-2-en- 1-y1, or halo-lower alkyl, in particular having not more than 4 C atoms and containing halogen with an atomic number of not more than 35, such as n-heptafluoropropyl, and R2 is the group of the formula Ib in which alk is methylene, R3 is COOH or S-tetrazolyl and the - .
rings A and B independently of one another are unsubsdtuted or, secondarily, subsdtuted by halogen, in particular with an atomic number of not more than 3S, such as chlorine, lower alkyl, in pardcular having not more than 4 C atoms, such as methyl, or lower ~ ~ -alkoxy, in particular having not more than 4 C atoms, such as methoxy, in free form or in form of a salt.
.. .~ . .
The invention relates primarily to compounds of the formula I, in which Zl, Z2 and Z3 are CH, Z4 is N, Rl is C3-C4alkyl, such as propyl or n-butyl, and R2 is the group of the formula Ib in which atk is methyleno, R3 is S-tetrazolyl and thc rings A and B are ~ ~ , unsubsdtuted, in free form or in form of a salt.

The invondon relates in particular to the novel compounds of the formula I mendoned in the examples, in free form in form of a salt.

The invendon further relates to a procoss for the preparation of the compounds of the ~ - ~ x formula I and their salts, which procoss comprises, for example, a) reacdng a compound of the formula ~Z~ ~N -.
Zl2 ~ Rl :~
Z3~z4~ ~N (IIa) H
': . '.:
or a salt thereof with a compound of the formula .~
X,-R2 (IIb) ~
'`'' ~ ""'~'''''' :;, . . .. .
.. . ..
, .. . ... ..
... .. . ...
. ~ . ., , -. ,, ~,' , , ; , . .. . .. . , . . , ~ : ' , , .; .,. ;, i . A ~ .

. ~ :
3 7 : :
- 1.5-or a salt thereof, in which Xl is reactive esterified hydroxy1, or b) converting X2 into the variable R3 in a compound of the formu1a Z3~z4XN~ ~m) ':'' X2 . ' ' .:

or a sa1t thereof, in which X2 is a radical which can be converted into the variab1e R3, or ., ~' "- :.'..
c) cyc1izing a compound of the formula .

s~Z1~NH2 ~
¦¦ C--Rl 3~Z4~N/ (IV) R2 : .
' ""
or a salt thereof and, in each caso, if desired, converting a compound of the formula I in fteo form or in form of a salt which can be obtained according to the process or in another manner into another compound of the formula I, separating a mixture of isomers which can bo obtained according to tho process and isoladng the desired isomer and/or ~:
converdng a free compound of the formula I which can be obtained according to the process into a salt or converdng a salt of a compound of the foqmula I which can be obtained according to the process into the free compound of the formula I or into another : ~ .
salt.

Salts of staTting materials which contain at least one basic centre are corresponding acid addidon salts, while sa1ts of starting mate~rials whicb contain at least one acidic group are .
sDlts with bases, in oach caso as mentioncd above in connccdon with corresponding salts of compounds of the formula I. . . ~ . ;

Reacdve esterified hydroxyl Xl is, in pardcular, hydroxyl esterified with a strong , 2~ 37 ~

inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for examplefluorosulfonyloxy, Cl-C7aL~canesulfonyloxy which is unsubstituted or substituted, for example by halogen, for example methane- or trifluoromethanesulfonyloxy, Cs-C7cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or benzenesulfonyloxy which is unsubstituted or substituted, for example by Cl-C7alkyl or halogen, for example p-bromophenyt or p-toluene-sulfonyloxy.

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

~he reactions described in the variants above and below are carried out in a manner known per se, for example in the absence or, customarily, in the presence of a suitab1e - ~ ~;
solvent or diluent or of a mixture thereof, the reaction being carried out, according to need, with cooling, at room temperature or with warming, for example in a temperature range from about -80C up to the boiling point of the reacdon medium, preferably from about ` ~ :
-10 to about +200C, and, if necessary, in a closed vessel, undbr pressure, in an inert gas ~ -atmosphere and/or under anhydrous conditions. :

Variant a~:
Tho reaction of compounds of the formula na with compounds of the forrnula IIb is carried out advantageously in the presence of a base. Suitable bases are, in pardcu!ar, alkali metal hydroxides, hydrides, amidbs, alkoxides, carbonates, triphenylmethylides, di(lower alkyl)amides, -aminoalkylamides or -!ower alkylsilylamides, naphthylamines, di- ~-and tri-lower alkylamines, basic heterocycbs, ammonium hydroxides, and carbocyclic aminos. Examples which may be mendoned are sodium hydroxide, sodium hydride, ~ - ;
sodium amide, sodium (m)ethoxide, potassium tert-butoxide, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, dimethylaminonaphthalene, di- and triethylamine,diisopropyl-ethyl-amine,N-methylpiperidine,pyridine, ; ;~
benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diaza-bicyclo~5.4.0]undec-7-ene (DB~J).

Xl is preferably halogen, such as chlorine or bromine, or sulfonyloxy, such as Cl-C7alkane-, for example methane-sulfonyloxy, or benzenesulfonyloxy which is unsubsdtuted or substituted, for example by Cl-C7alkyl, for example ' ~: ' . .
~': ~; .' - " ,".:
.

17 2~2~37 , .
p-toluenesulfony10xy.

To prepare the starting compounds of the formula Ila, the process stans in a manner known per se, for example from compounds of the forrnula ~Z1 NH2 Z2 ~ ~
Z3 ~ ~ (lIc) ~z4 NH2 and these are reacted while warming with compounds of the forrnula Rl-COOH (Ild).
. .
The staning material of the formula lIb is known or can be prepared in a manner known per so.

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

To preparo compounds of the formula I, in which R3 is 5-tetrazolyl, the process stans, for oxamp1e, from staning material of the formu1a III, in which X2 iS cyano, and this is reactod with an azide, for oxamplo with HN3 or, in panicular, a salt, such as an alkali meta1 salt, thereof or with an organotin azidc, such as tri-lowcr alkyl- or tri-aryl-dn azide.
Prefer ed azides are, for example, sodium azide and potassium azide and tri-CI-C4a1ky1-, for example triethyl- or tributyl-dn azide, and triphenyldn azide.

$ultablo protecdng groups for N-protected 5-tetrazolyl are the protecting groupscustomarily used in tetrazole chemistry, in particular triphenylmethyl, benzyl which is -unsubsdtuted or subsdtuted, for example by nitro, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- or ethoxy-methyl, lower alkylthiomethyl, such as methylthiomethyl, as well as 2-cyanoethyl, and addidona11y lower alkoxy-lower alkoxy methyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. The protecdng groups aro removod following known methods. Thus, for example, triphenylmethyl is customarily removod by hydrolysis, in particular ir the presence of an acid, or hydrogonolysis in the presence of a hydrogenadon catalyst, 4-nitrobenzyl is removed, for example, by hydrogenolysis in the presence of a hydrogenadon cata1yst, methoxy- or ~ ~ 2 ~ ~ 3 7 ethoxy-methyl is removed, for example, by treating with a tri-lower alkyltin bromide, such as triethyl- or tributyl-tin bromide, methylthiomethyl is removed, for example, by treating with trifluoroacetic acid, 2-cyanoethyl is removed, for example, by hydrolysis, for example with sodium hydroxide solution, 2-methoxyethoxymethyl is removed, for example, by hydrolysis, for example with hydrochtoric acid, and benzyloxymethyl and phenacyl are removed, for example, by hydrogenolysis in the presence of a hydrogenation catalyst. ` -A radical X2 which can be converted into SO3H R3 is, for example, the mercapto group.
Starting compounds of the formula III containing a group of this type are, for example, ~ -oxidized by oxidation processes known per se to those compounds of the formula I in which R3 is SO3H. Suitable oxidizing agents are, for example, inorganic peracids, such as poracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, ~uch as percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacedc, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example mixtu~es of hydrogen peroxide and acetic acid. The oxidadon is commonly carried out in the presencc of suitabb catalysts, suitable acids, -such as subsdtuted or unsubstituted carboxylic acids, for example acetic acid ortrifluo~oacetic acid, or transition metal oxides, such as oxides of elements of sub-group VI, ~ , ;
for examplo molybdenum oxide or tungsten oxide, being mendoned as catalysts. The ;
oxidadon is carriod out under mild condidons, for examplo at temperatures from about ~ ;;
-SO to about +100C.

A group X2 which can be converted into PO3H2 R3 is to be understood as meaning, for ~ ~ -oxamplo, a group -N2+A, in which A- is an anion of an acid, such as a mineral acid. i ::
Corrosponding diazonium compounds of this type are, for example, reacted in a manner known per so with a P(IIn halide, such as PCI3 or PBr3, and worked up by hydrolysis, ~ ~ ;
thoso compounds of the formula I being obtainable in which R3 is PO3H2.
:: ".: .;
Compounds I, wherein R3 is PO2H2, are obtained, for example, by the conversion, carried out in customary manner, of X2 in a compound I~, wherein X2 is a functional derivadve of PO2H2, }nto Po2H2 A suitable X2 radical which can be converted into haloalkanesulfonylamino R3 is, for example, amino. In order to prepare compounds of the formula I in which R3 is ~;
haloalkanesulfonylamino, corresponding anilines, for example, are reacted vith a ; -~2~ 37 .
customarily 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 X2 which can be converted into COOH R3 is, for example, a funcdonally modifled carboxyl, such as cyano, esterified or amidated carboxyl, hydroxymethyl or formyl.

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

Amidated carboxyl is, for example, carbamoyl, carba noyl which is monosubsdtuted by hydroxyl, arnino or substituted or unsubstituted phenyl, carbamoyl which is mono- or ~ -disubsdtutod by lower alkyl or carbamoyl which is disubsdtuted by 4- to 7-membered alkylone or 3-aza-, 3-lower alkylaza-, 3-oxa- or 3-thiaalkylene. Examples which may be menthnod are carbamoyl, N-mono- or N,N-di-(lower alkyl)carbamoyl, such as N-methyl-, N-othyl-, N,N-dimethyl-, N,N-diethyl- and N,N-dipropyl-carbamoyl, pynolidino- and piperidino-carbonyl, morpholino-, piperazino-, 4-methylpiperazino- and thiomorpholino-carbonyl, anilinocarbonyl and anilinocarbonyl substituted by lower alkyl, lowcr alkoxy and/or halogen.

Preferred funcdonally modified carboxyl is, for example, lower alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, and cyano.
,; . . I , Compounds of the formula I in which R3 is carboxyl can be prepared, for example,starting from compounds of the formula III in which X2 is cyano or esterified or amidated carboxyl, by hydrolysis, in particular in tho presence of a base, or, starting from compounds of the formula nI in which X2 is hydroxymethyl or forrnyl, by oxidation~ The oxidadon 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 aromadc, for example pyridine, or in - -~ .

:

water, or in a mixture thereof, if necessary with cooling or warming, for example in a temperature range of from about 0 to about +150C. Suitable oxidizing agents are, for example, oxidizing transition metal compounds, in particular those with elements of sub-groups I, VI or VII. Examples which may be mentioned are: silver compounds, such as silver nitrate, silver oxide and silver picolinate, chromium compounds, such as chromium trioxide and potassium dichromate, and manganese compounds, such as potassium permanganate, tetrabutylammonium permanganate and benzyltri(ethyl)ammonium permanganate. Other oxidizing agents are, for example, suitable compounds with elements of main group IV, such as lead dioxide, or -halogen-oxygen compounds, such as sodium iodate or potassium periodate. , .
The variant b) is preferably suitable for the preparation of those compounds of the formula I in which the variables havo meanings which are different from unsaturated radicals.
... .
The starting material of the formula III is, for example, accessible by starting from compounds of the formula na and reacting these in analogy to variant a) with a compound , of the forrnula ' '" "; '' Xl ~Ik ~ (IIIa), . '' -,:
in which Xl and X2 have the abovementioned meanings. ;
Compounds IIIa are known or can be prepared according to methods known per se.
Variant c): ~ a .
This variant is suitable, in particular, for the preparation of those compounds of the -formula I in which R3 is 5-tetrazolyl.
. :..., ' .
Tho cycllzadon is carried out in a manner known per se, for example while warming, for example in a temperature range from about 70 to about 200C, preferably at the reflux temperature of the solvent system, if desiled in the presence of an acid, such as a mineral -acid or carboxylic acid, for example acetic acid. ~

:, :, 2 ~ 3 ~

The starting material of the formula IV is accessible using customary methods, for example by reaction of a compound of the formula ~Zl~"N2 ~x in which X3 iS halogen, such as chlorine, with a compound of the formula H2N-R2 (IVb), ~ ;
which is followed in the next reaction step by an N-acylation, which, if desired, is catalysed by bases, with a compound of the formula HOOC-R1 ~Id) or a reactive acid derivadve, in particular an acid halide, thereof. The compounds of the formula Z~ N02 ' ': ' ~2 y o :~ .
Z4 ~--C--Rl (IVc) :
obtainable in this way can then be reduced, for exampk by hydrogenation, to the corresponding compounds of tho formula IV.

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

For example, a compound of the formula I containing hydroxyl can be etherified by ;
methods known per se. The etherificadon can be canied out, for example, using an ~
dcohol, such as a substituted or unsubsdtuted lower dkanol, or a reactive ester thereof.
Suitablo eacdvo osters of tho desired alcohols are, for oxample, those with strong inorganic or organic acids, such as corresponding halides, sulfates, lower alkanesulfonates subsdtuted or unsubstituted benzenesulfonates, for oxampb chlorides, bromides, iodides or methano-, benzeno- or p-toluene sulfonates. The etherificadon can be carried ~
out, for examplo, in the presence of a base, for examplo in the presence of an alkali metat -hydrido, hydroxide or carbonate, or of a basic amine. Invasely, corresponding ethers, such ~; ~

' .,' ::.~.

2Q2~37 :; ~

::
as lower alkoxy compounds, can be cleaved, for example, by means of strong acids, such ~ .
as mineral acids, for examp1e hydrobromic or hydriodic acid, which may advantageously , be present in the form of pyridinium halides, or by means of Lewis acids, for example halides of elemènts of main group III or the corresponding sub-groups. These reacdons can be carried out, if necessary, with cooling or warming, for example in a temperature range from about -20 to about +100C, in the presence or absence of a solvent or diluent, under inert gas and/or under pressure and, if appropriate, in a closed vessel.

If an aromatic structural component is subsdtuted by lower alkylthio, this can be oxidized in a customary manner to the corresponding lower alkane-sulfinyl or -sulfonyl. Suitable oxidizing agents for the oxidation to the sulfoxide step are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as percarboxylic or persulfonic acids, for example performic, peracedc, trifluoroperacetic, perbenzoic or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for exampb mixtures of hydrogen peroxide and acetic acid. ;
The oxidadon is commonly carried out in the presence of suitable catalysts, catalysts which can be mendoned being suitable acids, such as subsdtuted or unsubsdtuted ca~boxylic acids, for example acedc acid or trifluoroacedc acid, or transidon metal oxides, such as oxides of elements of sub-group VI, for example molybdenum oxide or tungsten oxido. Tho oxidadon is carried out under mild condidons, for example at temperatures from about -S0 to about +100C. The further oxidadon to the sulfone step may be carried out appropriately at low temperatures using dinitrogen tetroxide as the catalyst in the ~ ~
presence of oxygen, just like the direct oxidadon of lower alkylthio to lower ;;
alkanesulfonyl. However, in this case the oxidizing agent is customarity employed in -excess.

If one of the variables contains amino, corresponding compounds I can be N-(ar)alkylated -in a manner known per se; likewise, carbamoyl or radicals containing carbamoyl can be N-(ar)alkylated. The (ar)alkyladon is car ied out, for example, using an (aryl)CI-C7alkyl halidb, for oxample a bromide or iodide, an (aryl)CI-C7alkanesulfonate, for exampb a methanesulfonats or p-toluenesulfonato, or a di-CI-C7alkyl sulfate, for example dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide solution or potassium hydroxide soludon, and advantageously in the presence of aphas~transfer catalyst, such as tetrabutylammonium bromide or bsnzyltrimethylammonium chloride, where, however, stronger basic condensing agents, ;;
such as alkali metal amides, hydrides or alkoxides, for example sodium amide, sodium ;. ,.
"
. . .

2 ~ 7 . . - . .
hydride or sodium ethoxide, may be necessary.

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

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

Compounds of tho formula I which contain an esterifled carboxyl group as a subsdtuent can bo converted into other ester compounds of the formula I by transosterification, for oxamplo by treadng with an alcohol, customarily with a higher appropriate alcohol than ~ Y
that of the osterified carboxyl group in the starting material, in the presence of a suitable -~
transesterifying agent, such as a basic agent, for example an alkali metal Cl-C7alkanoate, Cl-C7alkanolate or cyanido, such as sodium acetate, sodium methoxide, sodium ethoxide, ~ -sodium tert-butoxide or sodium cyanide, or a suitable acid agent, if appropriate with removal of the resuldng alcohol, for example by disdlladon. Appropriate, so-called acdvated esters of the formula I may also bo used as stardng materials which contain an acdvated esterif`ied carboxyl group as a subsdtuent (see bolow), and these may bo convoned into another ester by treadng with a C1-C7alkanol. ;

In compounds of the formula I which contain the carboxyl group as a subsdtuent, this can also ~Irst be convorted into a reacdve derivadve, such as an anhydride (including a mixed anhydride), an acid halide, for exampb an acid chloride (for example by treadng with a , ~:

~2kl37 - - ~
- 24 - ~ ;

thionyl halide, for example thionyl chloride), an anhydride using a formic acid ester, for example a Cl-C7aL~cyl ester (for example by treating a salt, such as an ammonium or aL~cali metal salt, with a haloformic acid ester, such as a chloroformic acid ester, such as a Cl-C7alkyl ester), or an activated ester, such as a cyanomethyl ester, a nitrophenyl ester, for example a 4-nitrophenyl ester, or a polyhalophenyl ester, for example a ;
pentachlorophenyl ester (for example by treating with an appropriate hydroxyl compound in the presence of a suitable condensing agent, such as N,N'-dicyclohexylcarbodiimide), and then a reactive derivative of this type can be reacted with an amine and in this way arnide compounds of the formula I which contain an amidated carboxyl group as a substituent can be obtained. In this case, these can be obtained directly or via intermediate compounds; thus, for example, an activated ester, such as a 4-nitrophenyl ester, of a compound of the formula I containing a carboxyl group can first be reacted with a ~ ~ `
l-unsubstituted imidazole and the 1-imidazolylcarbonyl compound obtained in this way -~
brought to reacdon with an amine. However, other non-activated esters, such as Ct-C7alkyl esters, of compounds of the formula I can also be brought to reaction with aminos.

If an aromatic ring contains a hydrogen atom as a subsdtuent, the latter can be replaced by a halogen atom with tho aid of a halogenating agent in a customary manner, for example brominated with bromine, hypobromic acid, an acyl hypobromite or a different organic bromino compound, for exampb N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, pyridinium perbromide, dioxano dibromide, 1,3-dibromo-S,S-dimethylhydantoin or 2,4,4,~tetrabromo-2,5-cyclohexadien-1-one, or chlorinated with olemental chlorine, for example in a halogenated hydrocarbon, such as chloroform, and with cooling, for example down to about -10C.

If an aromatic ring contains an amino group, this can be diazodzed in a customa~y manner, ; - :
for example by treadng with a nitrite, for example sodium nitrite, in the presence of a ~ -suitablo protonic acid, for example a mineral acid, the reacdon temperature advantageously being kept below about 5C. The diazonium group present in the salt fo~m which can bo obtained in this way can be subsdtuted by customary processes, for example as follows: by the hydroxyl group analogously to the boiling-out of phenol in the presence of water, by an alkoxy group by treating with an appropriate alcohol, energy having to be added; by the fluorine atom anatogous to the Schiemann reaction in the thermolysis of corresponding diazonium tetraftuoroborates; or by chlorine, bromine, iodine or the cyano group analogously to the Sandmeyer reacdon by reacdon with corresponding Cu(I) satts, initially with cooling, for example to below about 5C, and then 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 groups, these can be converted into saturated radicals in a manner known per se. Thus, for example, multiple bonds are hydrogenated by catalydc hydrogenadon in the presence of hydrogenation catalysts, suitable for this purpose being, for example, nickd, such as Raney nickel, and noble metals or their derivadves, for example oxides, such as palladium or platinum oxide, which may be applied, if desired, to supponmaterials, for example to carbon or calcium carbonate. The hydrogenation may preferably be carried out at pressures between about 1 and about 100 at and at a temperature between about -80 and about l 200C, in particular between room temperature and about 100C
The reaction is advantageously carried out in a solvent, such as water, a lower aLlcanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a lower alkanecatboxylic acid, for example acedc acid.
;, , ~
Purthetmore, in compounds of the formula I in which R is halogen, such as chlorine, ha1ogen can be replaced by cotresponding -Z-R' by reaction with a substituted orunsubsdtuted amine, an alcohol or a mercaptan.
lbo invondon relates in pa~icu1ar to tho processes described in the examples. ;
. ,. .;
Sdt of compounds of the formula I can bo prepared in a manner known per se. Thus, for . ' ~
examplo, acid addidon salts of compounds of the formula I are obtained by treadng with a ; ~ ;
sùitibb acid a suitable ion exchange reagent. Sdts of compounds I can be converted ~ ;
into tho free compounds I in customa~y manner, acid addition salts, for exa nple, by treating with a suitable basic agent or a suitable ion exchange reagent.
Salts of compounds I can be convened in a manner known per se into different sdts of co npoundsI. i ;

Doponding on the procedure and the reaction condidons, the compounds of the fonnula I
having ~alt fonning, in pardcular basic properdes, can be obtained in free fo~n orin the ; ;
fonn of salts. ~;
.,; .. :, In vicw of the close reladonship between tho compound of the fonnula I in the free form : .. ~;.,. ~, ,,,.; . . . .. .
,,; ~ ., - - . .

.

'. ' and in the form of its salts, in the preceding parts and below the free compound of the formula I or its salts, respectively, may analogously and expediently also be understood as meaning the corresponding sa1ts or the free compound of the formula I, respectively.

The compounds I including the* salts of salt-forming compounds can also be obtained in the form of their hydrates and/or can include other solvents, for example solvents used for crystallization.
.,.;, ,., ,,~..
The compounds I and their salts may exist, depending on the choice of the starting materials and procedures, in the form of one of the possible isomers or as a mixture thereof, for example, depending on the number and the absolute and relative configuradon of asymmetrical carbon atoms, as pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, diastereomer mixtures or racemate mixtures. , Diastereomer mixtures and racemate mixtures obtained can be separated into the pure ; :
dlastereomers or racemates in a known manner on the basis of the physicochemicaldifferences of the components, for example by fracdonal crystallizadon. Enandomer mixtures, forexample racemates, obtained may be resolved into the opdcal antipodes by ~; ~
known methods, for exampb by recrystallizadon from an opdcally acdve solvent, ~ ; -chromatography on chiral adsorbents, with the aid of suitable microorganisms, bycleavage with specific immobilized enzymes, via the formadon of inclusion compounds, ~ ;
for oxamplo using chiral crown ethers, only one enandomer being complexed, or byconvorsion into diastereomeric salts, for example by reacdon of a basic anal substance racemate with an opdcally acdve acid, such as a carboxylic acid, for example tar~aric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separadon of the diastoreomer mixture obtained in this manner, for example on the basis of its differing ~ ~ -solubilides, into the diastereomers from which the desired enandomer can be liberated by `
the acdon of suitable agents. The more acdve enandomer is advantageously isolated.

The invendon also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a sta~ting matorial and tho missing stops are carried out or a starting material in the form of a derivadvo or salt and/or its racemates or antipodes is used or, in particular, formed under tho roacdon conditions~

., In the process of the present invention, those starting materials and intermediates are preferably used which lead to the compounds I described as particularly useful at the beginning. The invendon 1ikewise relates to novel starting materials and intermediates for the preparadon of the compounds I, to their use and to a process for their preparation, the variables Zl, Z2~ Z3. Z4, Rl and R2 having the meanings indicated for the compounds I. In particular, compounds of the formula III, in free form or in form of a salt, in which X2 is cyano are preferred as starting materials.
., The compounds of the formula I and their pharmaceutically acceptable salts can be used, preferably in the form of pharmaceudcally acceptable preparationS in a method for the prophylacdc and/or therapeudc treatment of the animal or human body, in pardcular as andhypertensives.

The invendon therefore likewiso relates to pharmaceudcal preparadons which contain a oompound I in free fonn in fm of a phannaceudcally aa:epl bb salt as acdve u hl~redient, and toa process fortheirp~bon. T~ese preparadons are -~o fon~al, such # oaal, f~Annc ~tal orparente~al administ~on to ~ ~ ;
wann-bloo~d animals, the ph~ acdve _ being con_ alone Qr to~èr with cus~na~y dcal~juncta The pb~c l~p~ s , folumpb, frn aboutO.1:%~10~100 96,~pnl bb~from ~about I % to about 60 '"'. . ., ' ,~
*, ~f lho ctive ing~edient. Ph~nnào~l piepu~ons for enteral p~ y ~ninii~ion~,;foxamplo,~in ie~unit~i suchai su~leti, ~,`~ suppod~, and f~ore un_. Tho# aro p epa~ed h a ~ ~ ~
., ~ mù~ per so~ fe~mpk`~r moans of ~ 1 mixing, g~nulaling, .,.~ .", s~ dissolvin~ ~ing ~. ~us,~pharmaceudcal p~s for ui ~n~o t ined~byc~g~ he~in~th solid~;if~
~ng~a ~ o i~ a ~s g t mi ~
necessary after addidon of suitabb adjuncts, to give tablels sugar coaled lablet cores. ;~i -Suilabb earriers are, in panieular, fiUers,~sueh asi suga~, f~ ~pk ~ s~, mànnitol sorbilol, cellulo~ p~- a~~_ p~, f~e~pb Y ~ iealeium phosphato ealeium hydrogen phosphto, fiird~ bin~, sueh as stareh pasto, using, hr oxamplo, eorn, whoat, ~co potato starch,~ge1adn, i~and~
mO~llCellU10# and/ polyvinylpy~olidone, snd, if tesir~d, didntegranls, such~as the ~ :
abo~mend~ed starches, fur~ermore e~lhyl starch, erosslinked -polyvinylpynolidone, agar or alginie acid a s~lt d~of~ such as sodium algina ' . i '~

Auxiliaries are primarily flow-regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are provided with suitable coatings which are, if desired, resistant to gastric juice, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, for example to identify or to indicate different doses of active ingredient, may additionally be added to the tablets or sugar-coated tablet coatings.

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

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

Suitable preparations for parenteral administration are primarily aqueous soludons of an acdve ingredient in water-soluble form, for example a water-soluble salt, and furthermore suspensions of the acdve ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthedc fatty acid esters, for example etbyl oleate or triglycerides, or aqueous injecdon suspensions which contain viscosity-incn~asing substances, for example sodium c~rboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.

The dose of the active ingredient can depend on different factors, such as the manner of , ~B~3~ ~

administration, the warm-blooded animal species, the age and/or the individual condition.
In the norrnal case, an approximate daily dose of about 10 mg to about 250 mg is to be estimated in the case of oral administration for an approximately 75 kg patient.
The following examples illustrate the invention described above, however, they are not intended to limit its extent in any manner. Temperatures are given in degrees Celsius.

Tho nomenclature of the azabenzimidazole base structures on which the compounds I are based is derived from the appropriate name according to "Ring Systems Handbook", Ring Systems File I, of tho American Chemical Society, 1988 edition; the RF Nos. 828Q 8284, 8285, 8293, 8334 and 8335 being referred to in particular.

Example 1: 2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine (700 mg, 1.91 mmol) and tributyltin azide (1.27 g, 3.82 mmol) in o-xylene (20 ml) are stuTed under reflux for 24 hours. The reacdon mixture is evaporated in vacuo and the residue is stirred in a mixture of CH2CI2/CH30H/NH3 (5/3/1; 30 ml) for 30 minutes. After ~ ;
ovaporadng again h vacuo, tho residue is separated by means of flash chromatography `
(sUica gel 60, ~63 I m, CH2Cl2/CH3/NH3 - 160/10/1) and the product is recrystallized f~om ethyl acetate. In this way, white crystals of 2-(n-butyl)-3-[2'-(lH-tetrazol-5-yl)bi- ;
phenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine are obtained [m.p.: 139 (dec.)]. ; - ~ .

N NH
N_N

lbe starthg material can be prepared, for example, as follows:
, ", ., ;.. ;,,:
a~ 2,3-Diaminopyridine (7.7 g, 7Q56 mmol) and valeric acid (16.6 ml, 141.1 mmol) are - u sd~ed at 160 for 20 hours. Aftor cooling, the reacdon mixture is dissolved in ethyl -acotate, and tho soludon is washed with saturatcd NaHa~3 soludon and saturated NaCI
solution, dried (Na2SO4) and evaporated in vacuo. The residue is suspended in diethyl ` ' ~;
,,,:'' ,~ ' '.
" .

ether and filtered off. S1ightly brownish crystals of 2-(n-butyl)-3H-imidazo[4,5-b]pyridine remain (m.p.: 87-89).

b) NaH (80 % in white oil, 300 mg, 10 mmol) is added in ponions at room temperature to a solution of 2-(n-butyl)-3H^imidazo[4,5-b]pyridine (1.75 g, 10 mmol) in dimethylformamide (10 ml). After completion of the addition, the mixture is stirred at -room temperature for a funher 30 minutes and a solution of 4-bromomethyl-2'-cyano-biphenyl (2.72 g, 10 mmol) in dimethylformamide (25 ml) is then added dropwise. The reaction mixture is sdrred at room temperature for 12 hours and then evaporated in vacuo.
Ethyl acetate is added to the residue and the mixture is washed twice with water, dried (Na2SO4) and evaporated in vacuo. Flash chromatography (silica gel 60, 40-63 ~Im, CH2C12/CH3OH = 95/5) yields 2-(n-butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-3H-imidazo-[4,5-b]pyridine, which is directly funher processed.

Example 2: Starting from 2-(n-propyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-3H-imidazo-14,5-b]pyridine and tributyldn azide, 2-(n-propyl)-3-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine is obtained in the manner described in Example 1 [white crystals of m.p. 161 (dec.) from isopropanoVethyl acetate].
.:
,O N

CH2 ~CH3 CH2{~ . ' ~,~d ' N~NH
N N

The statting material can be prepared, for example, as fol1Ows:
'~
a) 2-(n-Propyl)-3H-imidaw[4,5-b]pyridinc is prepared by reacdon of 2,3-diaminopyridine with butyric acid in the manner described in Example la). The crude product is rccrystallized from ethyl acetate/hexane (m.p.: 97-99).

b) 2 (n-Propyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-3H-imidaw[4,5-b]pyridine is obtained as an oil which is purifled by flash chromatography (silica gel 60, 40-63 llm, ethyl ., : ~
.

-~2~137 acetate/hexane = 1/1) by alkylation of 2-(n-propyl)-3H-imidazo[4,5-b]pyridine with 4-bromomethyl-2'-cyano-biphenyl in the manner described in Example lb). This oil is directly further processed. ]

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

I~N :
NJ \>--CH2-cH2-cH2-cH3 N 'NH .
N: N
,,.:. .~.,:.,: :~:
Tho starting material can be prepared, for example, as follows: ~ -,,,:
a) 2-(n-Butyl)-3H-imidazo[4,5-c]pyridine is preparcd by reaction of 3,4~iaminopyridine ;
with valoric acid in the manner dbscribcd in Exampb la) and is directly fur~her processed.
~: ,:,,; ,~, b) A mixtu~e of 2-(n-butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-3H-imidazo[4,5-c]pyridine and 2-(n-butyl)-1-(2'-cyanobiphenyl~4-ylmethyl)-lH-imidazol4,5-c]pyridine is fonned by :
allcyladon of 2-(n-butyl~3H-imidazol4,5-c]pyridino with 4bromomethyl-2'-cyano-biphonyl in tho manner dbscribed in Example lb), and is separated into the individual components by means of flash chromatography (silica gel 60, 40-63 ,~m, CH2CI2/CH3OH ~ -- 98/2).' The desired component is directly furdler processed.

ExamDlo 4: 2-(n-Butyl)-1-[2'-(lH-tetrazol-S-yl)biphenyl-4ylmethyl]-lH-imidazol4,5-c]- ~'. . : :,' .
pyridine lwhite crystals iDf m.p. 179 (dec.) from ethanoVethyl acetate] is obtained in the manner described in Example 1 starting from 2-(n-butyl)- 1 -(2'-cyanobiphenyl-4-yl-mothyl)~lH-imidazo[4,5-c]pyridine Example 3b)] and tributyltin azide. ~ ;

.' ~,, ,~. .: ',~

2~2~137 ' : -N~C~ CH2-CH2-CH2-CH3 CH~3 N NH
N- N

Example S: 2-(n-Heptafluoropropyl)-3-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine [m.p.: 120-121 (from ethy1 acetate/cyclohexane)] is obtained ~ :~
in the manner described in Example 1 starting from 2-(n-heptafluoropropyl)-3-(2'-cyano-biphenyl-4-ylmethyl)-3H-imidazo[4,5-b]pyridine and tributyldn azide.
Tho starting material can be prepared, for example, as follows:

a) 2-(n-Heptafluoropropyl)-3H-imidazo[4,5-b]pyridine [m.p.: 203-204 (from ethylacetate/hexane)] is prepared by reaction of 2,3-diaminopyridine with perfluorobutyric acid in tho manner described in Example la).

b) 2 ~n-HoptafluoropropyV-3-(2'-cyanobiphenyl~ylmethyl)-3H-imidazo[4,5-b]pyridine ~; ~ is obtained by alkylation of 2-(n-hoptafluoropropyl)-3H-imidazo[4,5-b]pyridine with 4-bromomothyl-2'-cyano-biphenyl in tho manner doscribed in Example lb) and flash~ chromatography (silica gel 60, 4~63 ~m, hexane/ethyl acetate - 4/1) and is direcdy ~; ~; funhorprocessed.

13xamDle 6: 8-(n-Butyl)-9-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-9H-purine [m.p.: ~ -lSS (dec.); from ethyl acetate)] is obtained in the manna described in Example 1 starting ;~
from 81(n-butyl)-9-(2'-cyanobiphenyl-4-ylmethyl)-9H-purine and tributyldn azide.
.
: .

~`~kN ~L CH2 ~ CH2 3 y N =~
N, N,NH - -"' ':
T~he starting material can be prepared, for example, as follows~
: ~
a) 8-(n-Butyl)-9H-purine is prepared by reaction of 4,5-diaminopyridimine with valeric acid in the manner described in Example la) and is directly further processed. ; ;

b) 8-(n-Buql)-9-(2'-cyanobtphenyl-4-ylmethyl)-9H-purine is obtained by alkylation of `
8-(n-butyl)-9H-purine with 4-bromomethyl-2'-cyano-biphenyl in the manner described in Example lb) and flash chromatography (silica gel 60, 4~63 ,um, CH2CI2/CH3OH = 9S/S) and is direcdy further processed.
.,. - .,,; .;
xamDlo 7: Tho following can bo prepared in an analogous manner as doscribed in one of tho abovo oxample~

2-(n-buty-1~[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyll-lH-imidazo[4,S-b]pyrazine, (n-butyl)-7-t2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyll-7H-imidazo[4,5-c]pyridazine, ` ~ -2-(n-butyl)-1-[2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyll-lH-imidazo[4,5-d]pyridazine, :,~,~ ,.".',', butyl)-S-[2'-(lH-tetrazol-S-yl)biphonyl-4ylmethyl]-SH-imidazo[4,5-c]pyridazine, ~ ~
8-(n~butyl)-7-[2'-(lH-tetrazol-S-yl)biphenyl-4ylmethyl]-7H-purine, ~ " " ' 2-(n butyl)-l-t2'-(lH-tetrazol-S-yl)biphenyl-4-ylmethyl]-lH-imidazo[4jS-b]pyridinp~
2-[(E;~but-l-en-l-yl]-3-[2'-(lH-tetrazol-S-yl)biphenyl4-ylmethyl]-3H-imidazo[4,5-b]- ;~
py idino, 2-C(~3)-propen-1-yl]-3-[2'-(lH-tetrazol-S-ybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]- .,~
pyridino, ! ~2 (n buql)-3-[2'-carboxybiphenyl-4-ylmethy1]-3H-imidaw[4,S-b]py idine, ~ ` ""' ~ ~.:'.
2 ~n-prow1)-3-[2' c~rboxybiphenyl-4-ylmethyll-3H-imidaw[4,5-b]pyridine, . .
2-(n~heptafluoropropyl)-3-~2'-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]py~idine, ! ~

202~1 37 2-(n-butyl)-3-[2'-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine, 2-(n-butyl)-1-[2'-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-c]pyridine, 8-(n-butyl)-9-[2'-carboxybiphenyl-4-ylmethyl]-9H-purine, 2-(n-butyl)-1-[2'-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-b]pyrazine, 6~(n-butyl)-7-[2'-carboxybiphenyl-4-ylmethyl]-7H-imidazo[4,5-c]pyridazine, 2-(n-butyl)-1-[2'-carboxybiphenyl-4-ylmethyl]-lH-imidazo[4,5-d]pyridazine, 6-(n-butyl)-5-[2'-carboxybiphenyl-4-ylmethyl]-SH-imidazo[4,5-c]pyridazine, 8-(n-butyl)-7-[2'-carboxybiphenyl-4-ylmethyl]-7H-purine, 2-(n-butyl)-1-[2'-carboxybiphenyl-4-ylmethyl]-lH-imidazot4,5-b]pyridine, '~-[(E)-but-1-en-1-yl]-3-[2'-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, and 2-[(E)-propen-l-yl]-3-12'-carboxybiphenyl-4ylmethyl]-3H-imidazo[4,5-b]pyridine.

Example 8: Tablets, each containing 50 mg of active ingredient, for example 2-(n-butyl)-3-12'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, can be prepared as follows:

Composition (for 10,000 tablets):
Aetive ingredient 500.0 g Laetose 500.0 g Potato stareh 352.0 g aelatin 8.0 g ;
Tale 6û.0 g Magnesium stearate lO.O g Siliea (highly disperse) 20.0 g Ethanol q.s.
,~
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an alcoholic soludon of the gelatin and granu1ated through a sieve. After drying,l the rest of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is compressed to give tablets of 145.0 mg weight each and 50.0 mg acdve ingredient content which, if desired, can be provided with dividing g~ooves for finer adjustment of the dosage.

BxamDlo 9: Lacquered tablets, each containing 100 mg of acdve ingredient, for example 2-(n-butyl)-3-[2'-(lH-tetrawl-5-yl)biphenyl-4-ylmethyl]-3H-imidaw[4,5-ypyridine, can be prepared as follows:

-352~2~I37 Composition (for 1,000 tablets): ' Active ingredient 100.00 g Lactose 100.00 g Corn flour 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 flour are mixed, moistened with a paste prepared from 15 g of corn flour and water (with warrning) and granulated. The granules are dried, and the rest of the corn flour, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to give tablets (weight:
280 mg) and these are lacquered with a soludon of the hydroxypropylmethylcellulose and shellnc in dicllloromethane (final weight of the 1acquered tablet: 283 mg).

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

:-: . . .

Claims (60)

1. A compound of the formula (I), in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, acyl, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, or R is -Z-R', wherein Z is a bond or is O, S(O)m or NH, R' is hydrogen or an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radical, if desired, is interrupted by O or S(O)m and the index m is in each case 0, 1 or 2, R1 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or is a cycloaliphatic or araliphatic hydrocarbon radical and R2 is the group of the formula (Ia), in which alk is a divalent aliphatic hydrocarbon radical, R3 is COOH, SO3H, haloalkanesulfonylamino, PO2H2, PO3H2 or 5-tetrazolyl and either the rings A and B
independently of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl or halogen and which, if desired, is interrupted by O, hydroxyl which, if desired, is etherified by an aliphatic alcohol, or carboxyl which, if desired, is esterified or amidated or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form of in form of a salt.

2. A compound according to claim 1 of the formula I, in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, carbamoyl in which the amino group is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or 5-tetrazolyl or R is -Z-R', in which Z is a bond or is O, S(O)m or NH, R' is hydrogen, or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl, lower alkenyloxy-lower alkynyl, lower alkylthio-lower alkyl, lower alkylthio-lower alkenyl, lower alkylthio-lower alkynyl, lower alkanesulfinyl-lower alkyl, lower alkanesulfonyl-lower alkyl, lower alkenylthio-lower alkyl, lower alkenylsulfinyl-lower alkyl, lower alkenylsulfonyl-lower alkyl, lower alkynylthio-lower alkyl, lower alkynylsulfinyl-lower alkyl or loweralkynylsulfonyl-lower alkyl which radicals, in each case, are unsubstituted or substituted by halogen, by hydroxyl, by amino which, if desired, is substituted as indicatedimmediately hereinbefore in the definition of the amino group of the carbamoyl radical R, by carboxyl which, if desired, is esterified as indicated immediately hereinbefore, or by carbamoyl in which the amino group, if desired, is substituted as indicated immediately hereinbefore, and the index m is 0, 1 or 2, R1 is lower alkyl, lower alkenyl or lower alkynyl which radicals, in each case, are unsubstituted or substituted by halogen or by hydroxyl, cycloalkyl or cycloalkenyl which are in each case 3- to 7-membered, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl, and R2 is the group of the formula Ia in which alk is lower alkylene or lower alkenylene, R3 is COOH, SO3H, halo-lower alkanesulfonylamino, PO2H2, PO3H2 or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl, lower alkoxy-lower alkynyl, lower alkenyloxy-lower alkyl, lower alkenyloxy-lower alkenyl or lower alkenyloxy-lower alkynyl which radicals, in each case, are unsubstituted or substituted by halogen or hydroxyl, by hydroxyl, by lower alkoxy, by lower alkenyloxy, by carboxyl which, if desired, is esterified by an alcohol which is derived from lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkenyl or lower alkoxy-lower alkynyl, or by carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl, lower alkenyl, lower alkynyl, phenyl-lower alkyl, phenyl-lower alkenyl or phenyl-lower alkynyl or disubstituted by lower alkylene or lower alkyleneoxy-lower alkylene, or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt.

3. A compound according to claim 1 of the formula I, in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, carbamoyl in which the amino group, if desired, is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene, or R is -Z-R', in which Z is a bond or is O and R' is hydrogen, or lower alkyl or lower alkoxy-lower alkyl which radicals, in each case, are unsubstituted or substituted by halogen, by hydroxyl, by amino which, if desired, is independently of one another mono- or disubstituted by lower alkyl or phenyl-lower alkyl or disubstituted by lower alkylene, by carboxyl, by lower alkoxycarbonyl or by lower alkoxy-lower alkoxycarbonyl, R1 is lower alkyl or lower alkenyl which radicals, in each case, are unsubstituted or substituted by halogen or by hydroxyl, or 3- to 7-membered cycloalkyl or phenyl-lower alkyl, and R2 is the group of the formula Ia, in which alk is lower alkylene, R3 is COOH or 5-tetrazolyl and the rings A
and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl which is unsubstituted or substituted by halogen or by hydroxyl, by lower alkoxy, by carboxyl or by lower alkoxycarbonyl, in free form or in for n of a salt.

4. A compound according to claim 1 of the formula I, in which one or two of the variables Z1, Z2. Z3 and Z4 are N and the others are C(R), where R is halogen, lower alkanoyl, carboxyl, lower alkoxycarbonyl, carbamoyl which, if desired, is mono- or disubstituted by lower alkyl, or 5-tetrazolyl or R is -Z-R', in which Z is a bond or is O, S(O)m or NH, m is 0, 1 or 2 and R' is hydrogen or lower alkyl which is unsubstituted or substituted by halogen, by hydroxyl or by amino, R1 is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lower alkyl, 3- to 7-membered cycloalkyl or phenyl-lower alkyl and R2 is the group of the formula Ia in which alk is lower alkylene, R3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or substituted by halogen, by lower alkyl which is unsubstituted or substituted by halogen or by hydroxyl, by lower alkoxy, by carboxyl or by lower alkoxycarbonyl, in free form or in form of a salt.

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

6. A compound according to claim 1 of the formula I, in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are C(R), where R is hydrogen, halogen, carboxyl, lower alkoxycarbonyl, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl or lower alkoxy, R1 is lower alkyl, lower alkenyl, hydroxy-lower alkyl, halo-lower alkyl, 3- to 7-membered cycloalkyl or phenyl-lower alkyl and R2 is the group of the formula Ib, in which alk is lower alkylene, R3 is COOH or 5-tetrazolyl and either the rings A and B independently of one another are unsubstituted or substituted by halogen, lower alkyl, halo-lower alkyl, lower alkoxy, carboxyl or lower alkoxycarbonyl or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt.

7. A compound according to any one of claims 1 to 6 of the formula I, in which R2 is the group of the formula Ia or Ib and alk is methylene, in free for n or in form of a salt.

8. A compound according to claim I of the formula I, in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are CH, in particular Z1, Z2 and Z3 are CH and Z4 is N, R1 is lower alkyl, in particular having not more than 4 C atoms, lower alkenyl, in particular having from 3 up to and including 5 C atoms, or halo-lower alkyl, in particular having not more than 4 C atoms and containing halogen with an atomic number of not more than 35, and R2 is the group of the formula Ib in which alk is methylene, R3 is COOH or 5-tetrazolyl and the rings A and B independently of one another are unsubstituted or, secondarily, substituted by halogen, in particular with an atomic number of not more than 35, lower alkyl, in particular having not more than 4 C atoms, or lower alkoxy, in particular having not more than 4 C atoms, in free form or in form of a salt.

9. A compound according to any one of claims 1 to 8 of the formula I, in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are CH or in which in particular one of the variables Z2, Z3 and Z4 is N and Z1 and the other variables of Z2, Z3 and Z4 are C(R), in particular CH, or in which Z1 and Z3 are C(R), in particular CH, and Z2 and Z4 are N, in free form or in form of a salt.

10. A compound according to claim 1 of the formula I, in which Z1, Z2 and Z3 are CH and Z4 is N or Z1 and Z3 are CH and Z2 and Z4 are N, R1 is lower alkyl, in particular having not more than 4 C atoms, lower alkenyl, in particular having from 3 up to and including S
C atoms, or halo-lower alkyl, in particular having not more than 4 C atoms and containing halogen with an atomic number of not more than 35, and R2 is the group of the formula Ib in which alk is methylene, R3 is COOH or 5-tetrazolyl and the rings A and B
independently of one another are unsubstituted or, secondarily, substituted by halogen, in particular with an atomic number of not more than 35, lower alkyl, in particular having not more than 4 C atoms, or lower alkoxy, in particular having not more than 4 C atoms, in free form or in form of a salt.

11. A compound according to claim 1 of the formula I, in which Z1, Z2 and Z3 are CH, Z4 is N, R1 is C3-C4alkyl, and R2 is the group of the formula Ib in which alk is methylene, R3 is 5-tetrazolyl and the rings A and B are unsubstituted, in free form or in form of a salt.

12. 2-(n-butyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in freo for n or in form of a salt.

13. 2-(n-propyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

14. 2-(n-Butyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine, in free form or in fonn of a salt.

15. 2-(n-Butyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazo[4,5-c]pyridine, in free form or in form of a salt.

16. 2-(n-Heptafluoropropyl)-3-[2'-(1H-telrazol-s-yl)biphenyl-4-ylmethyl]-3H-imida [4,5-b]pyridine, in free form or in form of a salt.

17. 8-(n-Butyl)-9-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-9H-purine, in free form or in form of a salt.

18. 2-(n-butyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazo[4,5-b]pyrazine, in free form or in form of a salt.

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

20. 2-(n-butyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazo[4,5-d]pyridazine, in free form or in form of a salt.

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

22. 8-(n-butyl)-7-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-7H-purine, in free form or in form of a salt.

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

24. 2-[(E)-but-1-en-1-yl]-3-[2'-(1H-tetriuol-5-yl)biphenyl4-ylmethy]-3H-imidazo-[4,5-b]pyridine, in free form or in form of a salt.

25. 2-[(E)-propen-1-yl]-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-y-pyridino, in free form or in form of a salt.

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

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

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

29. 2-(n-butyl)-3-[2'-carboxybiphenyl-4ylmethyl]-3H-imidazo[4,5-c]pyridino, in free form or in form of a salt.

30. 2-(n-butyl)-1-[2'-carboxybipheny1-4-ylmethyl]-1H-imidazo[4,5-c]pyridine, in free form or in form of a salt.

31. 8-(n-buty1)-9-[2'-carboxybiphenyl-4-y1methyl]-9H-purine, in free form or in form of a sa1t.

32. 2-(n-butyl)-1-[2'-carboxybiphenyl-4-ylmethyl]-1H-imidazo[4,5-b]pyrazine, in free form or in form of a salt.

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

34. 2-(n-butyl)-1-[2'-carboxybiphenyl-4-y1methyl]-1H-imidazo[4,5-d]pyridazine, in free form or in form of a sa1t.

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

36. 8-(n-butyl)-7-[2'-carboxybipheny1-4-ylmethy1]-7H-purine, in free form or in form of a salt.

37. 2-(n-butyl)-1-[2'-carboxybiphenyl-4-ylmethyl]-1H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

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

39. 2-[(E)-propen-1-y1]-3-[2'-carboxybiphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine, in free form or in form of a salt.

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

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

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

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

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

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

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

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

48. A process for the manufacture of a compound of the formula (I), in which one or two of the variables Z1, Z2, Z3 and Z4 are N and the others are C(R), where R is halogen, acyl, carboxyl which, if desired, is esterified or amidated, or 5-tetrazolyl, or R is -Z-R', wherein Z is a bond or is 0, S(O)m or NH, R' is hydrogen or an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen, hydroxyl, unsubstituted or substituted amino or carboxyl which, if desired, is esterified or amidated and which hydrocarbon radical, if desired, is interrupted by O or S(O)m and the index m is in each case 0, 1 or 2, R1 is an aliphatic hydrocarbon radical which is unsubstituted or substituted by halogen or hydroxyl or is a cycloaliphatic or araliphatic hydrocarbon radical and R2 is the group of the formula (Ia), in which alk is a divalent aliphatic hydrocarbon radical, R3 is COOH, SO3H, haloalkanesulfonylamino, PO2H2, PO3H2 or 5-tetrazolyl and either the rings A and B
independently of one another are unsubstituted or substituted by halogen, an aliphatic hydrocarbon radical which is unsubstituted or substituted by hydroxyl or halogen and which, if desired, is interrupted by O, hydroxyl which, if desired, is etherified by an aliphatic alcohol, or carboxyl which, if desired, is esterified or amidated or the ring A is substituted by 5-tetrazolyl and the ring B is unsubstituted or substituted as indicated immediately hereinbefore, in free form or in form of a salt, which process comprises a) reacting a compound of the formula (IIa) or a salt thereof with a compound of the formula X1-R2 (IIb) or a salt thereof, in which X1 is reactive esterified hydroxyl, or b) converting X2 into the variable R3 in a compound of the formula (III) or a salt thereof, in which X2 is a radical which can be converted into the variable R3, or c) cyclizing a compound of the formula (IV) or a salt thereof and, in each case, if desired, converting a compound of the formula I in free for n or in form of a salt which can be obtained according to the process or in another manner into another compound of the formula I, separating a mixture of isomers which can be obtained according to the process and isolating the desired isomer and/orconverting a free compound of the formula I which can be obtained according to the process into a salt or converting a salt of a compound of the formula I which can be obtained according to the process into the free compound of the formula I or into another salt.

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

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

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

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

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

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

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

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

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

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

59. The process of Examples 1 to 7.

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