AU655458B2 - Imidazopyridine - Google Patents

Abstract

Novel imidazopyridine derivatives of the formula I <IMAGE> in which R denotes <IMAGE> and R<1> to R<6>, X and Y have the meanings given in Patent Claim 1, and their salts display angiotensin II-antagonistic properties and can be used for the treatment of hypertension, aldosteronism and cardiac insufficiency.

Description

J.r i i: Our Ref: Our Ref: 420830 655458 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

I

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT r I

I'

Applicant(s): Address for Service: Invention Title: Merck Patent Gesellschaft Mit Beschrankter Haftung Frankfurter Strasse 250 D-6100 DARMSTADT 1

GERMANY

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Imidazopyridine The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 q i 7 4- 1- Imidazopyridines The invention relates to novel imidazopyridine derivatives of formula I: R-CH 2 -O-X-q R2 000000 0 0 0*p0 0 0000 0 000000 00 00 0 0 0 0 0 000004 in which R is (a) N R 4 A' N R R 6 0 .0004 000 0 0 04 00 00 a 0f or (d) RI is A, alkenyl or alkynyl. having each case,

R

2 is COOH, COOA, CN, NOV, N2

R

3 is H, Hal, A, OA or N402, up to 6 C atoms in

NHCOR

5

NHSOR

5 or

I.

i 2

R

4 is H, R 5 cyanoalkyl, AOOC-alkyl, carboxyalkyl or having 1-6 C atoms in the "alkyl" moiety in each case, alkenyl or alkynyl having up to 6 C atoms in each case, aralkyl having 7-11 C atoms which is unsubstituted or mrno- or disubstituted by Hal,

R

5 COOH, COOA, CN, NO 2

NH

2 NHA, N(A)2 ,NHCOR 5

NHCOOA,

NHSO2R 5 OH, OA or tetrazol-5-yl, or -CH,-O -X-

R

2 t ((c4ct t I r 15 IE I

R

5 is alkyl having 1-4 C atoms, in which one or more H atoms can also be replaced with F,

R

6 is H or Hal, X is absent or is -NH-CO-, -CO-NH-, CHO- or Y is O or S, A is alkyl having 1-6 C atoms and Hal is F, Cl, Br or I, and their salts.

Similar compounds are known from European patent document A2-0 400 974.

The object of the invention was to find novel compounds with valuable properties, especially those which can be used for the preparation of drugs.

It was found that the compounds of formula I and their salts possess very valuable pharmacological properties coupled with a good tolerance. In particular, they have antagonistic properties towards angiotensin II and can therefore be used for the treatment of angiotensin II-dependent hypertension, aldosteronism and cardiac insufficiency. These effects can be determined by conventional in vitro or in vivo methods such as e.g. those described in US patent 4 880 804 and also by A.T. Chiu et al., J. Pharmacol. Exp. Therap. 250, 867-874 (1989), and by P.C. Wong et al., ibid. 252, 719-725 (1990; in vivo, on rats).

The compounds of formula I can be used as phar- I I I I II I I i -3maceutical active ingredients in human and veterinary medicine, especially for the prophylaxis and/or therapy of cardiac, circulatory and vascular diseases, in particular of hypertonia, cardiac insufficiency and hyperaldosteronism.

The invention relates to the compounds of formula I and their salts and to a process for the preparation of these compounds and their salts, characterised in that a compound of formula II:

R

3

E-CH

2

&X

R

2 in which E is Cl, Br, I, a free OH group or an OH group which has S° been functionally modified to acquire reactivity, and 200 .44 R 2

R

3 and X are as defined in Claim 1, 15 is treated with a compound of formula III: 0 0 0 a 0 o 0 H-R III 0 I in which R is as defined in Claim 1, ,o or 1 20 to prepare a compound of formula I in which R is H and Y is O, a compound of formula IV: R3 R 7-c X- Iv in which El

R

7 is or R 1 r El is C1, Br, I or an OH group which has been functionally I4 -4 modified to acquire reactivity, and

R

2 R 3 R5 and X are as def ined in Claim 1, is treated with a solvolysing agent, or a compound of formula V: RO-CHz.-QX-Q( in which R, is R 9N ff 10 R N R 1

I

I

.4.

£4 4I .1(1

IS

I I 4 1 4 tItt4~ 4 1 4444 4 44 It

R

9 is R'-CO or H, R1 0 is H (if R 9 is R 1 -CO) or R 1 -CO (if R" is H) and R 1, R 2 R 3 R 4

R

6 X and Y are as def ined in Claim 1, is treated with a cyclising agent, or to prepare a compound of formula I in which X is -NH- Ca- or -CO-NH-, a compound of formula VI: ]R-c 2 O -xl 44 II I C 120 in which X1 is NH 2 or COOH and R is as defined in Claim 1, or a reactive derivative of this compound is reacted with a compound of formula VII:

R

2

VII

in which C ii 5

X

2 is COOH (if X' is NH 2 or NH 2 (if X 1 is COOH) and

R

2 and R 3 are as defined in Claim 1, or with a reactive derivative of this compound, or to prepare a compound of formula I in which X is CHz- O- or a compound of formula VIII:

R-CH

2 x3

VIII

in which

X

3 is CH 2 E or OH and R is as defined in Claim 1, or a reactive derivative of this compound is reacted with a compound of formula IX:

X

4 4 4 4. 4 4 44 41 in which

X

4 is OH (if X 3 is CH 2 E) or CH 2 E (if X 3 is OH) and

R

2 and R 3 are as defined in Claim 1, or with a reactive derivative of this compound, 20 4 1 4.

I a 4. 1 or to liberate a compound of formula I by treatment of one of its functional derivatives with a solvolysing or hydrogenolysing agent, and/or in that one or more radicals R, R 2 and/or R 3 in a compound of formula I are converted to one or more other radicals R, R 2 and/or R 3 and/or a base or acid of formula I is converted to one of its salts.

Above and below, unless expressly stated otherwise, the radicals or parameters R, R 1 to R 0 X, Y, A, Hal, E, X 1

X

2

X

3 and X 4 are as defined in formulae I to IX.

In the above formulae, A has 1-6, preferably 1, 2, 3 or 4 C atoms. A is preferably methyl, or else ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, or else pentyl, 2- or 3-methylbutyl, 1,2- or 2,2-dimethylpropyl, l-ethylpropyl, hexyl, 4-.

-6 t4 4 t 4 44 2 I 3- or 4-methylpentyl, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl- 1-methyipropyl, 1-ethyl-2-methylpropyl or 1,1,2- or 1,2,2-trimethyipropyl. Alkenyl is preferably vinyl, prop-l-enyl or prop-2-enyl or but-l-enyl, or else pent- 1-enyl or hex-1-enyl. Alkynyl is preferably ethynyl or prop-1-ynyl or prop-2-ynyl, or else but-l-ynyl, pent-iynyl or hex-1-ynyl.

Hal is preferably F, Cl or Br, or else I.

0 R is a radical derived from 3H-imidazo[4,5-c]pyridine (cases and or a radical derived from 1H-imidazo[4,5-c]pyridine [cases and or, more precisely: 2-R'-4-(thi)oxo-5-R 4 -6(or 7)-R 6 -4,5-dihydro-3Himidazo[4,5-c]pyridin-3-yl, 2-R'-4-(thi)oxo-5-R 4 -6(or 7)-R 6 imidazo [4,5-c ]pyridin-1-yl, 2-R'-4-(thi)oxo-6(or 7)-R 6 -4,5-dihydro-1-imidazo o 2-R'-4-(thi)oxo-6(or 7)-R 6 -4,5-dihydro-1H-imidazo Accordingly, the compounds of formula I include those of formula Ia, in which R is as def ined under those of formula Ib, in which R is as defined under those of formula Ic, in which R is as defined under and those of formula Id, in which R is as defined under The compounds pf formula la are preferred. The compounds of formulae Ic and Id are tautomeric and normally exist as a mixture.

0 Preferably, the radical R' is linear and is A, alkenyl or alkynyl having 3-6 C atoms in each case, especially butyl, or else propyl, pentyl, hexyl, allyl or prop-l-enyl, or else but-l-enyl, pent-l-enyl, hex-ienyl, prop-l-ynyl, but-l-ynyl, pent-l-ynyl or hex-iynyl.

The radical R 2 is preferably CN, or else preferably tetrazol-5-yl, COOH, COOCH 3 0 COOC 2

H

5 or NHSO 2 C.%.3 The radical R is preferably H.

The radical R 4 is preferably H, or else preferably 4 44 4$ p 344 4, 14 F 4 -7 R 5 (especially CH 3

CF

3 1 C 2

F

5

CH

2

CF

3 1 CH 2

CH

2

CF

3 cyanoalkyl (especially cyanomethyl, 2-cyanoethyl, 3- cyanopropyl), AOOC-alkyl (especially methoxycarbonylniethyl, ethoxycarbonylmethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl), carboxyalkyl (especially carboxynethyl, 2"carboxyethyl, 3-carboxypropyl) or [especially tetrazol-5--ylmethyl, 2- (tetra zo1- 5-yl) ethyl, it being possible for all these radicals to contain a total of up to 6 C atoms in each case. Also, the radical R 4 is preferably unsubst ituted or mnono~ubstituted (preferably in 0 -position) or disubstituted (preferably in 2,6-position) aralkyl having 7-1l C atoms, especially benzyl, 1- or 2-phenylethyl, 2- or 3- phenylpropyl, 3- or 4-phenylbutyl, m- or p- fluorobenzyl, (preferably) mn- or pchlorobenzyl, o, m- or p-bromobenzyl, m- or p-methylbenzyl, mn- or p-trifluoromethylbenzyl, mn- or piethoxycarbonylbenzyl, mn- or p-ethoxycarbonylbenzyl, (preferably) m- or p-cyanobenzyl, mn- or p-carboxybenzyl, o- m- or p-nitrobenzyl, mn- or p-aminobenzyl, o-,m-,or p-methylaminobenzyl, or p-ethylamiinobenzyl, or p-isopropylaminobenzyl, or p-dimnethylIarninobenzyl, o-,rn- or p-acetamidobenzyl, or p-pentanamnidobenzyl, or p-trIfluoracetamnidobenzyl,o-,mn- or p-methoxycarbonylaminobenzyl, or p-tert.-butoxycarbonylaminobenzyl, or p-trifluormethylsulfonamidobenzyl, or p-hydroxybenzyl, o or p-mnethoxybenzyl, (preferably) or p-(tetrazol-5-yl)benzyl, 2,4-, (preferably) 3,4- or 3,5-difluorbenzyl, 2,4-.

(preferably) 3,4- or 3,5-dlchlorobenzyl, 2-chioro- 6-fluoro-benzyl, 2-chloro-6-methyl-benzyl, 2-fluoro-6-trifluoromethyl-benzyl, 2-chloro-6-trifluoromethyl-bonzyi, 2-f luoro-6-carboxy-benzyl 2-f luoro-6-methioxycarbonyl-benzvlI 2-fluoro-6-nitro-benzyl, 2-fluoro-6-amno-belzyl, 2-chioro- V 35 6-nitro-benzyl, 2-chloro-6-amlno-bentyl, (preferably) or 4

_I

-7a- Also,the radical R 4 can preferably be ,R3

R

2 Preferably, the radical R 5 contains 1, 2 or 3 C atoms and is methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl or 3,3,3-trifluoropropyl.

The radical R 6 is preferably H or Cl.

Preferably, the radical X is absent or is -NHCOor -CO-NH-.

The radical Y is preferably 0.

The compounds of formula I can possess one or more chiral centres and can therefore exist in different forms (optically active or optically inactive). Formula I includes all these forms.

SfAccordingly, the invention relates especially to I I 'Il 4 i St I€ i 8those compounds of formula I in which at least one of said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following partial formulae Ie to Ik, Iae to lak, Ibe to Ibk, Ice to Ick and Ide to Idk, which correspond to formulae I and Ia to Id and in which the radicals not described more precisely are as defined in formulae I and Ia to Id: compounds of formulae le and Iae, Ibe, Ice and Ide, which correspond to formulae I and Ia to Id except that in addition X is absent; compounds of formulae If and laf, Ibf, Icf and Idf, which correspond to formulae I and la to Id except that in addition X is -CO-; compounds of formulae Ig and lag, Ibg, Icg and Idg, which correspond to formulae I and Ia to Id except that in addition X is compounds of formulae Ih and lah, Ibh, Ich and Idh, which correspond to formulae I and Ia to Id except that in 20 addition X is -NH-CO-; compounds of formulae li and Iai, Ibi, Ici and Idi, which 44 4o0 i correspond to formulae I and Ia to Id except that in addition X is -CO-NH-; compounds of formulae Ij and Iaj, Ibj, Icj and Idj, which 25 correspond to formulae I and Ia to Id except that in addition X is -CH 2 and

S

t compounds of formulae Ik and lak, Ibk, Ick and Idk, which correspond to formulae I and Ia to Id except that in addition X is -O-CH 2 Of the above compounds, those of formula Ie and 0. o0 especially those of formulae Iae and Ibe are particularly preferred.

4 Very particularly preferred compounds are those of formulae I and Ia to Ik, Iae to Ide, laf to Idf, lag to Idg, lah to Idh, Iai to Idi, Iaj to Idj and lak to Idk in which in addition R 3

R

4 and/or R 6 are H and/or Y is 0.

Among these, preferred compounds are those in which R 2 is CN, COOH, COOCHa, COOC 2

H

5

NHSO

2

CF

3 or

I

*1 -9- A very particularly preferred group of compounds has formula I in which R is 2-A-4,5-dihydro-4-oxo-5-R'-lH-imidazo[4,5-c] pyridin---yl, 2-A-4 ,5-dihydro-4-oxo-5-R 4-3H-imidazo[4,5-cjpyridin- 3-yl, 2-A-4,5-dihydro-4-oxo-5-R 4 -_lH-imidazo[4, 5-c Ipyridinor 2-A-4, 5-dihydro-4-oxo-5-R 4 -3H-imidazo [4,5-c ]pyridin- 5 -yl, R' is COOH, COOCH,, CN or R 3 is H, R 4 is H or -CH 2 0 -0 and Ij 0 0 9 X is absent.

A small selected group of preferred compounds has formula I in which R is a 2-butyl-4,5-dihydro-4-oxo-3H-imidazo(4,5-c]pyridin-3-yl radical, RZ is COOH, COOCH 3 CN or R 3 is H, y is 0and X is absent.

Another selected group of preferred compounds has formula I in which R 2 is CN.

Another selected group of preferred compounds has formula I in which R 4 is 00 00 0 0 0 0 9 00 00 00 0 0 0 00 0 0 0 0 0 00 -CH2-O-xR 3 R2 Another selected group of preferred compounds has formula I in which R' is cyanoalkyl or tetrazol-5- ylalkyl having 1-6 C atoms in the alkyl moiety in each case, or aralkyl having 7-11 C atoms which is unsubstituted or DAVIES COLLISON CAVE for and on behalf of the applicant(s).

p:\wpdocs\mmb\420830\mkr L i 1 I tllllll~ 4 10

I

monosubstituted by Hal, R 5 COOH, COOA, CN, NOz, NH 2

NH-

CO-R

5

NH-SO

2

-R

5 or The compounds of formula I and also the starting materials for their preparation are moreover prepared by methods known per se, such as those described in the literature in the standard works like Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart, but especially US patent 4 880 804), under conditions which are known and suitable for said reactions, it also being possible to make use of variants known per se, which are not mentioned in greater detail here.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of formula I.

.The compounds of formula I can preferably be os'" obtained by reacting compounds of formula II with compounds of formula III. Particularly the biphenyl deriva- 20 tives of formula I (in which X is absent) are readily obtainable in this way.

•t In the compounds of formula II, E is preferably Cl, Br, I or an OH group which has been functionally modified to acquire reactivity, such as alkylsulphonyloxy having 1-6 C atoms (preferably methylsulphonyloxy) or 1t. arylsulphonyloxy having 6-10 C atoms (preferably phenylor p-tolyl-sulphonyloxy).

The reaction of II with III is conveniently carried out by first converting III to a salt by treatment with a base, e.g. with an alkali metal alcoholate such as CH 3 ONa in an alcohol such as CH 3 OH, or with an S. alkali metal hydride such as NaH in dimethylformamide I' (DMF), and then reacting said salt with II in an inert solvent, e.g. an amide such as DMF or dimethylacetamide, or a sulphoxide such as dimethyl sulphoxide (DMSO), conveniently at temperatures of between -20 and 100°, preferably of between 10 and 30'. Other suitable bases are alkali metal carbonates such as Na 2

CO

3 or K 2 C0 3 or alkali metal hydrogen carbonates such as NaHCO 3 or KHCO 3 .1

P

-1 1: K 11

C

In the reaction of II with III, it is possible to obtain two or, in the case of III, R 4 H, three regioisomeric monosubstitution products, namely the corresponding 1H- and 3H-imidazo[4,5-c]pyridines in which the newly introduced substituent is in the 1, 3 or position. It is also possible to obtain disubstitution products with substitution in the 1 and 3, 1 and 5 or 3 and 5 positions. The type and proportions of the products of formula I are extensively dependent on the proportions of the reactants II and III and on the reaction conditions. Thus, in the reaction of equimolar 'amounts of methyl 4'-bromomethylbiphenyl-2- carboxylate and 2-butyl-4-oxo-4,5-dihydro-l(or 3)H-imidazo[4,5-c]pyridine ("IIIa") in the presence of CH30Na in methanol, the products disubstituted in the 1 and 5 positions and in the 3 and 5 positions can be isolated; on the other hand, in the reaction of bromomethyl-2-cyanobiphenyl with IIIa in the presence of K 2

CO

3 in DMF, the product monosubstituted in the 3 position is obtained in 20 very predominant proportions.

The compounds of formula I can also be obtained by the solvolysis, especially acid or alkaline hydrolysis, of compounds of formula IV. In IV, the radical E' is preferably Cl. The solvolysis of IV is also carried out particularly advantageously with silver acetate in acetic acid at temperatures of between 20" and the boiling point.

The compounds of formula I can also be obtained S by the cyclisation of compounds of formula V. This cyclisation is conveniently carried out by heating with polyphosphoric acid, acetic acid or diglyme to tempera- S. tures of between about 80 and 180, preferably of between ,120 and 160°.

Acid amides of formula I (X -NH-CO- or -CONH-) can also be obtained by reacting compounds of formula VI (or reactive derivatives thereof) with compounds of formula VII (or reactive derivatives thereof).

Suitable reactive derivatives of the carboxylic acids of formulae VI and VII (x or x 2 COOH) are advantageous-

H-R

in which R is as defined in Claim 1.

I fl~ 7 ,.cl i~ 1 i- 12 ly the corresponding chlorides, bromides or anhydrides.

The reaction is conveniently carried out in the presence of an inert solvent, e.g. a halogenated hydrocarbon such as methylene chloride, chloroform, trichloroethene or 1,2-dichloroethane, or an ether such as tetrahydrofuran (THF) or dioxane, at temperatures of between 0 and 150°, preferably of between 20 and 800. If acid halides are reacted, it is recommended to add a base, e.g. a tertiary amine such as triethylamine, pyridine or 4-dimethylaminopyridine.

V1 Ethers of formula I (X -CH 2 or can be obtained by reacting compounds of formulae VIII and IX (or reactive derivatives thereof). Suitable reactive I derivatives of the phenols VIII and IX (X 3 or X 4 OH) are e.g. the corresponding alkali metal Na, K) phenates, which can also be formed in situ from the phenol and a base potassium carbonate). The reaction is conveniently carried out in the presence of an a inert solvent, e.g. an amide such as DMF or a sulphoxide 20 such as DMSO, at temperatures of between 0 and 150", S' preferably of between 20 and 100°.

a a at t a tr a ~25 *r 0 as 0 o .da a, a a C C Additionally, one can liberate a compound of formula I from one of its functional derivatives by solvolysis hydrolysis) or by hydrogenolysis.

Thus, it is possible by one of the methods described above to prepare a compound corresponding to formula I which, however, contains a tetrazol-5-yl group functionally modified (protected by a protective group) in 1 (or 2) position instead of containing a free tetrazol-5-yl group. Suitable protective groups are, f.e., triphenylmethyl (removable with HC1 or formic acid in an inert solvent or solvent mixture, f.e. ether/dichloromethane/methanol); 2-cyanoethyl (removable with NaOH in aqueous THF); p-nitrobenzyl (removable with hydrogen on Raney nickel in ethanol).

I

i ii 5020 -12a- Some of the starting materials, especially those of formula II, are known. If they are not known, they can be prepared by known methods analogously to known substances. Compounds of formula III are novel. Compounds of S formula III (R 4 H, Y 0) can be obtained e.g. by reacting carboxylic acids of the formula R 1 -COOH with compounds of formula X:

H

2

N

x

H

2

N

E1 in the presence of polyphosphoric acid, the group E 10 (preferably Cl) being hydrolysed in the process.

Compounds of formula IV can be obtained for example by reacting compounds of the formula H-R 7 with compounds of formula II under the conditions indicated o *o 6 S 0 0 4 'I

I,

L

13 above for the reaction of II with III.

Compounds of formula V can be obtained e.g. by reacting compounds of formula XI: 6 HrY-HN 4

XI

NR<

H

2

N

Y

in which, however, one of the amino groups is protected by an amino-protecting group benzyl, A-O-CO- or benzyloxycarbonyl), with compounds of formula II and subsequently cleaving the protecting group and reacting Sthe products with acids of the formula R1-COOH or functional derivatives thereof; they are not normally isolated, but are formed in situ in the last-mentioned reaction.

It is also possible to convert a compound of Sformula I to another compound of formula I by converting one or more of the radicals R, R 2 and/or R 3 to other radicals R, R 2 and/or R 3 e.g. by reducing nitro groups to amino groups by hydrogenation on Raney nickel in an inert solvent such as methanol or ethanol), and/or functionally modifying free amino and/or hydroxyl groups, and/or freeing functionally modified amino and/or hydroxyl groups by solvolysis or hydrogenolysis, and/or S replacing halogen atoms with CN groups by reaction with copper(I) cyanide), and/ or hydrolysing nitrile groups to COOH groups, or converting nitrile groups to tetrazolyl groups with hydrazoic acid derivatives, e.g.

sodium azide in N- methylpyrrolidone or trimethyltin azide in toluene.

4" Thus, for example, free hydroxyl and/or amino groups can be acylated in conventional manner with an acid chloride or anhydride, or alkylated with a substituted or unsubstituted alkyl, alkenyl, alkynyl or aralkyl halide, conveniently in an inert solvent such as methylene chloride or THF, and/or in the presence of a base such as triethylamine or pyridine, at temperatures li 14

.I

14 44@*o* 4 0 4r 4 1( 4 of between -60 and Of particular importance is the corresponding conversion of a radical R in which R 4 H to another radical R in which R 4 is other than H. This reaction is preferably carried out with an acid amide such as DMF, N-methylpyrrolidone, 1,3- dimethyl-2-oxohexahydropyrimidine or hexamethylphosphorotriamide, an alcohol such as methanol or tert- butanol, an ether such as THF, or a halogenated hydrocarbon such as methylene chloride, or mixtures thereof, as the solvent, and/or in the presence of an alkali metal alcoholate such as sodium methylate or potassium tert-butylate, an alkali metal hydride such as sodium or potassium hydride, an alkali metal carbonate such as sodium or potassium carbonate, an alkali metal bicarbonate such as sodium or potassium bicarbonate, or a tertiary amine such as triethylamine or ethyldiisopropylamine, at temperatures of between about 30 and 200, preferably of between 20 and If desired, a functionally modified amino and/ or hydroxyl group in a compound of formula I can be freed by solvolysis or hydrogenolysis using conventional methods.

Thus e.g. a compound of formula I containing an NHCOR 5 or AOOC group can be converted to the corresponding compound of formula I containing an NH 2 or HOOC group instead. AOOC groups can be saponified e.g. with NaOH or KOH in water, 25 water/THF or water/ dioxane, at temperatures of between 0 and 100".

The reaction of nitriles of formula I (R 2

CN)

with hydrazoic acid derivatives leads to tetrazoles of formula I (R 2 tetrazol-5-yl). It is preferable to use trialkyltin azides such as trimethyltin azide, in an inert solvent, e.g. an aromatic hydrocarbon such as toluene, at temperatures of between 20 and 150°, preferably of between 80 and 140", or sodium azide in Nmethylpyrrolidone at temperatures of between about 100 and 200".

A base of formula I can be converted with an acid to the corresponding acid addition salt. Suitable acids for this reaction are especially those which yield physiologically acceptable salts. Thus it is possible to AiI

R

R

1 6

R

E

1 is Cl, Br, I or an OH group which has been functionally i i! ir kj 1 l- t p 15 use inorganic acids, e.g. sulphuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, and sulphamic acid, as well as organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulphonic or sulphuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethane-sulphonic acid, ethanedisulphonic acid, 2- hydroxyethanesulphonic acid, benzenesulphonic acid, p- toluenesulphonic acid, naphthalene-monosulphonic and disulphonic acids and laurylsulphuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for isolating and/or purifying the compounds of formula I.

On the other hand, compounds of formula I containing COOH or tetrazolyl groups can be converted with Sbases sodium or potassium hydroxide or carbonate) to the corresponding metal salts, especially alkali metal or alkaline earth metal salts, or to the corresponding ammonium salts. The potassium salts of the tetrazolyl derivatives are particularly preferred.

The novel compounds of formula I and their physiologically acceptable salts can be used for the manufacture of pharmaceutical preparations by incorporation into a suitable dosage form together with at least one excipient or adjunct and, if desired, together with one or more other active ingredients. The resulting ,formulations can be used as drugs in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral oral or rectal) or parenteral administration or for administration in the form of an inhalation spray, and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, 4

'""CII

FJ:t *SW^ I 1 I-.C1 hi; ~~rii; 3I UuL gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose. Tablets, coated tablets, capsules, syrups, juices or drops, in particular, are used for oral administration; lacquered tablets and capsules with coatings or shells resistant to gastric juices are of special interest. Suppositories are used for rectal administration and solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, are used for parenteral administration. For administration as inhalation sprays, it is possible to use sprays containing the active ingredient either dissolved or suspended in a propellant mixture fluorochlorohydrocarbons). It is convenient here to use the active ingredient in micronised form, it being possible for one or more additional physiologically compatible solvents, e.g. ethanol, to be present. Inhalation solutions can be administered with the aid of ''conventional inhalers. The novel compounds can also be lyophilised and the resulting lyophilisates used e.g. for 20 the manufacture of injection preparations. The indicated formulations can be sterilised and/or can contain adjuncts such as preservatives, stabilisers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colours and/or flavourings.

If desired, they can also contain one or more other active ingredients, e.g. one or more vitamins, diuretics or antiphlogistics. The substances according to the invention are ;normally administered analogously to other known, commer- 30 cially available preparations, but in particular analogously to the compounds described in US patent 4 880 804, preferably in dosages of between about 1 mg and 1 g, especially of between 50 and 500 mg per dosage unit. The daily dosage is preferably between about 0.1 and 500mg/kg, especially between 1 and 100 mg/kg of body weight. However, the special dose for each particular patient depends on a very wide variety of factors, for example on the efficacy of the special compound used, age, body weight, general state of health, sex, diet, of iet 17 time and method of administration, rate of excretion, drug combination and severity of the particular disease to which the therapy is applied. Oral administration is preferred.

Above and below, all temperatures are given in In the following Examples, "conventional working- up" means: Water is added if necessary, the pH is adjusted to between 2 and 10 if necessary, depending on the constitution of the end product, extraction is carried out with ethyl acetate or methylene chloride and the organic phase is separated off, dried over sodium sulphate, evaporated and purified by chromatography on silica gel and/or by crystallisation. Rf values are determined by thin layer chranatography on silica gel using ethyl acetate as eluent unless specified otherwise.

Example 1 A solution of 0.4 g of Na in 20 ml of methanol is added dropwise over 15 min to a solution of 3.2 g of 2- 0 butyl-4-oxo-4,5-dihydro-l(or 3)H-imidazo[4,5-c]pyridine ("IIIa") in 75 ml of methanol. The mixture is stirred at 6 *1 20 200 for a further 30 min and evaporated, the residue is dissolved in 20 ml of DMF, and a solution of 5.2 g of methyl 4' -bromomethylbiphenyl-2-carboxylate (IIa) in ml of DMF is added dropwise at 00, with stirring. The mixture is stirred at 20' for 16 hours, evaporated, worked up in conventional manner and chromatographed on *silica gel to give the following in succession using methyl tert-butyl ether/methanol (9.5:0.5 to 2-butyl-3,5-bis(2'-methoxycarbonylbiphenyl-4-ylmethyl)- *Q So Si 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine, oil; 2-butyl-l-(2'-methoxycarbonylbiphenyl-4-ylmethyl)-4,5dihydro-4-oxo-lH-imidazo[4,5-c]pyridine, m.p. 224'; 2-butyl-5-(2'-methoxycarbonylbiphenyl-4-ylmethyl)-4,5dihydro-4-oxo-1(or 3)H-imidazo[4,5-c]pyridine, m.p.

151"; 2-butyl-3-(2'-methoxycarbonylbiphenyl-4-ylmethyl)-4,5dihydro-4-oxo-3H-imidazo[4,5-c]pyridine, m.p. 186*; 2-butyl-1,5-bis(2 '-methoxycarbonylbiphenyl-4-ylmethyl)- 4,5-dihydro-4-oxo-1H-imidazo[4,5-c]pyridine, m.p. 68'.

A

ynyl.

The radical R 2 is preferably CN, or else preferably tetrazol-5-yl, COOH, COOCH 3 1 COOC 2

H

5 or NHSO 2

CF

3 The radical R 3 is preferably H.

The radical R 4 is preferably H, or else preferably 4 p

I

y.

I,

18 (t 004044 O 1114 O 004 4 ~4t 4 I 1 0* 44

I

4 4 4411.

4 01 4

I'

0 #4 .4 04 0 0 0 00 00 4 0 4.

4.1 4. 4 Preparation of the starting material Ila: A mixture of 16.2 g of 3,4-diamino-2-rhIoropyridine, 14 ml of valeric acid and 300 g of polyphosphoric acid is heated at 100-140* for 8 hours and then at 170-1800 for 5 hours, with stirring. It is cooled and poured on to ice, and sodium hydroxide solution is added to pH 9. After concentration and conventional working-up, Il~a is obtained: m.p. 285-~290*.

The following are obtained analogously from Iha and 2-butyl-6-chloro-4-oxo-4,5-dihydro-l(or 3)H- 235-24O@; obtainable from 3, 4-diamino-2,6-dichloropyridine and valeric acid): 2-butyl-6-chloro-3, 5-bis (2 '-methoxycarbonylbiphenyl-4ylmethyl) 5-dihydro-4-oxo-3H-imidazo( 4,5-c ]pyridine; 2-butyl-6-chloro-1-(2'-methoxycarbonylbiphenyl-4-ylmethyl) -4 ,5-dihydro-4-oxo-lH-imidazo(4,5-c ]pyridine; 2-butyl-6-chloro-5-(2 '-methoxycarbonylbiphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-1(or 3)H-iniidazo(4,5c]pyridine; 20 2-butyl-6-chloro-3-(2 '-methoxycarbonylbiphenyl-4-ylmethyl) 5-dihydro-4-oxo-3H-imidazo [4,5-c Jpyridine; 2-butyl-6-chloro-1, 5-bis (2 '-methoxycarbonylbiphenyl-4ylmethyl) 5-dihydro-4-oxo-lH-imidazo [4,5-c Jpyridine.

The following are obtained analogously from 25 Iha and 2-butyl-4,5-dihydro-4-thioxo-1(or 3)H-imidazo- (4,5c~pyridine (obtainable from II~a and Lawesson's reagent in toluene): 2-butyl-3, 5-bis (2 '-methoxycarbonylbiphenyl-4-ylmethyl) 4, 5-dihydro-4-thioxo-3H-imidazo (4,5-c Ipyridine; 2-butyl-l-( 2'-methoxycarbonylbiphenyl-4-ylnethyl) dihydro-4-thioxo-lH-imidazo( 4,5-c ]pyridine; 2-butyl-5- (2 '-methoxycarbonylbiphenyl-4-ylmethyl) dihydro-4-thioxo-1(or 3)H-imidazo(4,5-c~pyridine; 2-butyl-3- -methoxycarbonylbiphenyl-4-ylmethyl) dihydro-4-thioxo-3H-imidazo(4 2-butyl- 1,5-bis (2 '-methoxycarbonylbiphenyl-4-ylmethyl) 4, 5-dihydro-4-thioxo-1H-imidazo (4,5-c Ipyridine.

The following are obtained analogously from ha and 2-butyl-6-chloro-4,5-dihydro-4-thioxro-l(or 3)H- I r:7 -19 imidazo [4,5-c ]pyridine: 2-butyl-6-chloro-3, 5-bis (2 '-methoxycarboflylbiphenyl-4ylmethyl) -4 ,5-dihydro-4-thioxo-3H-inidazo[4,5-cJpyridile; 2-butyl-6-chloro-1-( 2'-methoxycarbonylbiphenyl-4-ylmethyl) 5-dihydro-4-thioxo-lH-imidazo[4, 5-c 3pyridine; 2-butyl-6-chloro-5- (2 '-methoxycarbonylbiphenyl-4-ylmethyl)-4,5-dihydro-4-thioxo-l(or 3)H-imidazo[4,5-c]pyridine; 2-butyl-6-chloro-3-(2'-methoxycarbonylbiphelyl-4-ylmethyl) -4 ,5-dihydro-4-thioxo-3H-imidazo[ 4, 5-c Ipyridine; 2-butyl-6-chloro-1, 5-bis -methoxycarbonylbiphenyl-4ylmethyl) 5-dihydro-4-thioxo-lH-imidazo 4,5-c ]pyridine; Example 2 A mixture of 0.7 g of Il~a, 0.5 g of K 2 C0 3 and ml of DM.F is stirred at 20" for 10 min. A solution of 1 g of 4'-bromomiethyl-2-cyanobiphenyl in 5 ml of DMF is st'.added dropwise over 45 min, with stirring, and the 68si mixture is stirre( at 20' for a further 5 hours, evaporated and workid up in conventional manner to give the following after chromatography on silica gel fit, (methylene chloride/methanol 98:2 to 9:1): 2-butyl-1- -cyanobiphenyl-4-ylmethyl) 5-dihydro-4oxo- 1H-imidazo [4,5-c )pyridine; 2-butyl-3- (2 '-cyanobiphenyl-4-ylmethyl) 5-dihydro-4oxo-3H-imidazo[415-c~pyridine, m.p. 179 (main product); 2-butyl-5-(2 '-cyano)iphenyl-4-ylmethyl)-4,5-dihydro-4oxo-1(or 3)H-imidazo(415-cjpyridine; 2-butyl-1 ,5-bis -cyanobiphenyl-4-ylmethyl) 4-oxo-1H-ixnidazo pyridine; 2-butyl-3, 5-bis (2 '-cyanobiphenyl-4-ylmethyl) 4-oxo-3H-imidazo[4,5-c~pyridine,. m.p.830 The following are obtained analogously with 2'nitrobiphenyl-4-ylmethyl bromide: 2-butyl-1- -nitrobiphenyl-4-ylmethyl) 5-dihydro-4oxo-1H-imidazo(4 2-butyl-3- (2 '-nitrobiphenyl-4-ylmethyl) 5-dihydro-4oxo-3H-imidazo pyridine; (2 '-nitrobiphenyl-4-ylmethyl) 5-dihydro-4- I- p 20 oxo-1(or 3)H-ixnidazo[4,5-c]pyridine; 2-butyl-1,5-bis (2 '-nitrobiphenyl-4-ylmethyl)-4,5-dihydro- 4-oxo-1H-inidazo[4, 5-c Ipyridine; 2-butyl-3, 5-bis (2 '-nitrobiphenyl-4-ylmethyl) 4-oxo-3H-imidazo [4,5-c ]pyridine.

Examn1e 3 A mixture of 4 g of 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-4-chloro-3H-imidazo[4,5-c]pyridine [obtainable by condensing 3,4-diamino-2-chloropyridine with valeric acid analogously to Example 4 to give 2-butyl- 4-chloro-1(or 3)H-imidazo[4,5-c]pyridine 650) and reacting the latter with Il~a analogously to Examnple 2 g of~

CH

3 COOAg and 40 ml of acetic acid is boiled for 16 hours.

It is filtered and evaporated and the residue is worked up in conventional manner to give 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-4,5-dihydro-4- oxo-3H-ixuidazo[4,5-c]pyridine, m.p. J79O.

Example 4 Nt ANN

I

I t~

N.

4

I

Y

I t A mixture of 1.02 g of valeric acid, 3.59 g of 4-amino-2-oxo-3-[2 '-(tetrazol-5-yl)biphenyl-4-ylmethylamino] -1,2 -dihydropyridine [obtainable by reacting 3- amino-4-benzylamino-1,2-dihydro-2-oxopyridine with 4bromomethyl-2 '-cyanobiphenyl to give 4-benzylamino-3- (2 1-cyanobiphenyl -4 -ylmethyl amino) -Ij2 -dihydro-2oxopyidine, reacting the latter with trimethyltin azide according to Example 13 to give 4-benzylaniino-3-(2'oxopyridine, and removing the benzyl group by hydrogenolysis] and 50 g of polyphosphoric acid is heated at 140' for 5 hours. 4-amino-2-oxo-3-(N-2'-(tetrazol- yl)biphenyl-4-ylmethyl-N-valerylamino]-1,2-dihydropyridine and 2-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4ylmethylamino] -4-valerylamino-1, 2-dihydropyridine are formed in situ as intermediates. The mixture is cooled, poured on to ice, rendered alkaline with sodium hydroxide solution and worked up in conventional manner to give 2butyl-4-oxo-3-(2 '-(tetrazol-5-yl)biphenyl-4- ylmethyl]- 21 4,5-dihydro-3H-imidazo[4,5-c~pyridine, m.p. 1670 Example A mixture of 1 g of 3-p-aminobenzyl-2-butyl- dihydro-4-oxo-3H-imidazo[4,5-c]pyridine, 0.6 g of phthalic anhydride and 40 ml of CHCl 3 is stirred at 208 for 16 hours. The precipitate of 2-butyl-3-[4-(2- carboxybenzamido )benzyl]-4, 5-dihydro-4-oxo-3H-imidazo c]pyridine is filtered off.

The following are obtained analogously from the corresponding aminobenzyl compounds: 2-butyl-1- (2-carboxybenzamido)benzyl 5-dihydro-4oxo-1H-imidazo[4, 5-c ]pyridine; 2-butyl-5-(4-(2-carboxybenzamido)benzyl]-4,5-dihydro-4oxo--l(or 3)H-imidazo[4,5-c]pyridine; 2-butyl-3,5-bis[4-(2-carboxybenzamido)benzyl]-4,5-dihydro-4-oxo-3H-imidazo [4,5-c Jpyridine.

t t% Preparation of the starting material: 3 g of IIla are dissolved in 75 ml of methanol, and a solution of 0.4 g of Na in 10 ml of methanol is added dropwise at 200, with stirring. The mixture is stirred f or a further 45 min and evaporated, the residue is dissolved in 30 ml of DNF, the solution is cooled to 00, a solution of 3.7 g of p-nitrobenzyl bromide is added at this temperature and the mixture is stirred at 20* for 16 S hours. It is evaporated and worked up in conventional manner to give 2-butyl-3, 5-bis(p-nitrobenzyl) ro-4-oxo-3H-imidazo[4,5-c]pyridine 142-1430), 2butyl-l-p-nitrobenzyl-4 ,5-dihydro-4- oxo-lH-imidazo[4 Ic]pyridine, 2-butyl-3-p-nitrobenzyl- 4, 5-dihydro-4-oxo- 3H-imidazo[4,5-c]pyridine 193- 1940) and 2-butyl-- 5-p-nitrobenzyl-4 ,5-dihydro-4-oxo- 1(or 3)H-imidazo[4,5c]pyridine (Mt 310) after chromatographic separation~ (silica gel; CH 2 Cl 2

/CH

3 OH 95:5).

A solution of 1.7 g of 2-butyl-3-p-nitrobenzyl-4,5dihydro-4-oxo-3H-imidazo[4,5-c]pyridine in 50 ml of methanol is hydrogenated at 20* on 1.7 g of Raney Ni until the absorption of H 2 has ceased. The mixture is

V

formula I in which R 4 is cyanoalkyl or tetrazol-5- ylalkyl having 1-6 C atoms in the alkyl moiety in each case, or aralkyl having 7-11 C atoms which is unsubstituted or p

U

"7'

'S

22 1~ 9)1 +0~0 4 0 0 0 *400 9 400*40 0 4 4 4 4 t 4

C

4444, .4 4 41 4 4 4 4 44 4144 4 44 (4 4 Ci (4 4 4 4 I SI 41 4. 0 4 0 44 4 4 I 0 4 04 filtered and evaporated to give 3-p-aminobenzyl-2- butyl- 4, 5-dihydro-4-oxo-3H-imidazo pyridine.

The following are obtained analogously by hydrogenation of the corresponding nitro compounds: 1-p-aminobenzyl-2-butyl-4,5-dihydro-4-oxo-1H-imidazo[4,5c ]pyridine; 5-p-aminobenzyl-2-butyl-4,5-dihydro-4-oxo-1(or 3)Himidazo[ 4,5-c ]pyridine; 3, 5-bis (p-aminobenzyl) -2-butyl-4, 5-dihydro-4-oxo-3Himidazo[ 4,5-c Jpyridine.

Example 6 A mixture of 2.96 g of 1-p-aminobenzyl-2-butyl- 4,5-dihydro-4-oxo-1H-imidazo[4,5-c]pyridine, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 15 ml of CH 2 Cl 2 is cooled to 50 and a solution of 2.88 g of o-trifluoromethanesulphonanidobenzoyl chloride in 20 ml of CH 2 C1 2 is added dropwise. The mixture is stirred at 20* for a further 16 hours, evaporated and worked up in conventional manner to give 2-butyl-4-oxo-l-[4-(2- 20 trifluoromethanesulphonamidobenzamido )benzyl]-4, hydro- lH- imidazo pyridine.

The following are obtained analogously from the corresponding p-aminobenzyl derivatives: 2-butyl-4-oxo-3- (2-trifluoromethanesulphonamidobenz- 25 amido)benzyl]-4,5-dihydro-3H-iiidazo[4,5-c]pyridine; 2-butyl-4-oxo-5-[ 2-trifluoromethanesulphonamidobenzamido)benzyl 5-dihydro-l(or 3 )H-imidazo[4 pyridine; 2-butyl-4-oxo-3,5-bis[4-(2-trifluoromethanesulphonamidobenzamido)benzyl]-4,5-dihydro-3H-imidazo[4 c ]pyridine.

Example 7 A mixture of 3.25 g of 2-butyl-3-p-carboxybenzyl- 4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine, 12 g of thionyl chloride and 35 ml of CHC1 3 is bailed for 6 hours and evaporated. The crude acid chloride obtained is freed by multiple dissolution in toluene and evaporation of 1 AU =4 &L.LL. A AJ L .Vl==AL J V .4 UV I preferably of between 10 and 300. Other suitable bases are alkali metal carbonates such as Na 2

CO

3 or K 2 C0 3 or alkali metal hydrogen carbonates such as NaHCO 3 or KHCO 3 23 thionyl chloride residues and dissolved in 50 ml of THF.

This solution is added dropwise to a solution of 1.7 g of anthranilic acid and 0. 8 g of NaOH in 100 ml of water and the mixture is stirred for 24 hours and acidified to pH 5 with hydrochloric acid. After conventional working-up, 2-butyl- 2-carboxyanilinocarbonyl)benzyl]-4 dihydro-4- oxo-3H-imidazo[4,5-c]pyridine is obtained.

The following are obtained analogously: 2-butyl-l-[4-(2-carboxyanilinocarbortyl)benzyl]-4,5-dihydro-4-oxo-1H-imidazo[4,5-c]pyridine; (2-carboxyanilinocarbonyl )benzyl hydro-A-oxo-l(or 3)H-imidazo[4,5-c]pyridine; 2-butyl-i,5-bis[4-(2-carboxyanilinocarbonyl)benzyl]- dihydro-4-oxo-lH-imidazo[4, 15 2-butyl-3,5-bis[4-(2-carboxyanilinocarbonyl)benzyl]- dihydro-4-oxo-3H-imidazo [4,5-c ]pyridine.

0000 0 000 0 00044 04 10 4 1

C

*tg( 0 1 44 1 4 11 I 11 4040 I 4 4 41 4 14 11 1 0 4 4 00 01 0 O 4 40 0 4.

00 Preparation of the starting materials: Analogously to Example 1, Il~a is reacted with pbromomethylbenzonitrile to give the following after chromatography on silica gel (methyl tert-butyl ether! methanol): 2-butyl-l-p-cyanobenzyl-lH-imidazo[4 2-butyl-3-p-cyanobenzyl-3H-imidazo pyridine; 2-butyl-5-p-cyanobenzyl-1(or 3)H-imidazo[4, 25 2-butyl-1,5-bis(p-cyanobenzyl)-4,5-dihydro-4-oxo-1Himidazo[4, 5-c Ipyridine; 2-butyl-3,5-bis(p-cyanobenzyl)-4,5-dihydro.-4-oxo-3Himidazo[4, A mixture of 1 g of 2-butyl-3-p-cyanobenzyl-4,5dihydro-4-oxo-3H-imidazo[4,5-c]pyridine, 0.7 g of KOH, ml of ethanol and 5 ml of water is boiled for 24 hours, with stirring, and evaporated, the residue is dissolved in water and the solution is acidified with hydrochloric acid. The precipitate of 2-butyl-3-p- dihydro-4-oxo-3H-imidazo[4,5-c]pyridine is filtered off and washed with water.

The following are obtained analogously by hydrolysis of the nitriles described under 1~

I,

-24 2-butyl-l-p-carboxybenzyl-4 ,5-dihydro-4-oxo-1H-imidazo- 2-butyl-5-p-carboxybenzyl-4 ,5-dihydro-4-oxo-1(or 3)Himidazo pyridine; 2-butyl-1,5-bis(p-carboxybenzyl)-4,5-dihydro-4-oxo-lHimidazo [4,5-c ]pyridine; 2-butyl-3, 5-bis (p-carboxybenzyl) -4 ,5-dihydro-4-oxo-3Himidazo [4,5-c ]pyridine.

Example 8 A mixture of 1.19 g of o-cyanophenol, 0.75 g of

K

2 C0 3 and 10 ml of DMF is stirred for 0.5 hour. A solution of 3.76 g of 3-p-bromomethylbenzyl-2-butyl- 4-oxo-3H-imidazo[4,5-c]pyridine (obtainable by reacting s. IIb with p-benzyloxymethylbenzyl bromide to give 3-pbenzyloxymethylbenzyl-2-butyl-4, 5-dihydro- 4-oxo-3Hsubjecting the latter to hydro- 8 genolysis to give the 3-p-hydroxymethylbenzyl compound and reacting the latter with PBr) in 20 ml of DMF is added dropwise and the mixture is heated at 900 for 8 hours and evaporated to give 2-butyl-3-(4-o- cyanophenoxymethylbenzyl) 5-dihydro-4-oxo-3H-imidazo c]pyridine after conventional working-up.

Example 9 A mixture of 2.97 g of 2-butyl-3-p-hydroxybenzyl- -4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine (obtainable from Il~a and p-hydroxybenzyl bromide), 0.5 g of CH 3 ONa and 40 ml of DMSO is stirred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of DMSO is added dropwise and the mixture is stirred at 20* for 16 hours and evaporated to give 2-butyl-3-(4-o- cyanobenzyloxybenzyl) -4,5-dihydro-4-oxo-3H-imidazo[4 c]pyridine after conventional working-up.

Examynle A mixture of 1 g of 2-butyl-1-(2'-methoxycarbonylbiphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-1H-- 12 ml of 2 N aqueous NaOH solu-

"I

I.

25 99 9 9 0 *9* 9 9999*9 0 .9 4* 0 8 0 *090*0 4 9 99 I 9 9* 9 9.

9, 90 9 9 9 0

C

@9 0 9.

4 99 tion and 43 ml of ethanol is boiled for 2 hours and then evaporated. Acidification to pH 3 with HCl gives 2-butyll-(2 '-carboxybiphenyl-4-ylmethyl) 5-dihydro-4-oxo-1Hwhich is filtered off, washed with water and dried: m.p. 2860.

The following are obtained analogously by saponification of the corresponding methyl esters: 2-butyl-3- (2 1 -car-boxybiphenyl-4-ylmethyl) 4-oxo-3H-imidazo[4,5-cpyridile, m.p. 2750; 2-butyl-5-(2 '-carboxybiphenyl-4-ylmethyl)-4,5-dihydro- 4-oxo-l(or 3)H-imidazo[4,5-c]pyridine; 2-butyl-1, 5-bis (2 '-carboxybiphenyl-4-ylmethyl) hydro-4-oxo-1H-imidazo[4,5-c~pyridine, m.p. 1370; 2-butyl-3, 5-bis (2 '-carboxybiphenyl-4-ylmethyl) -4 15 hydro-4-oxo-3H-imidazo[4,5-c]pyridine, m.p. 1650.

Example 11 A solution of 0.79 g of chloroacetonitrile in ml of DMF is added dropwise at 20%, with stirring, to a solution of 3.82 g of 2-butyl-3-(2'-cyanobiphenyl- 4ylmethyl) 5-dihydro-4-oxo-3H-imidazo[ 4,5-c Jpyridine and 1.17 g of potassium tert-butylate in 20 ml of DMF. The mixture is stirred at 200 for a further 30 min and poured on to ice, hydrochloric acid is added to pH 6 and the mixture is worked up in conventional manner to give 2- 25 butyl-3- -cyanobiphenyl-4-ylmethyl) -5-cyanomethyl-4, dihydro-4-oxo-3H-imidazo[4,5-c~pyridinep m. p. 640.

The following 2-butyl-3- (2 '-cyanobiphenyl-4-ylmethyl) -4 ,5-dihydro-4-oxo-3H-imidazo(4 ,5-c ipyridines are obtained analogously: 30 with methyl iodide: 5-methyl-, m.p.107 0 with ethyl iodide: with isopropyl iodide: with butyl bromide: with tert-butyl bromide: with pentafluoroethyl iodide: with 3,3, 3-trifluoropropyl iodide: 5-(3,3,3-trifluoro-propy with 2,2,2-trifluoroethyl 5-(2,2,2-trifluoroethyl) iodide: oil 'Rf n0 (ethvlar 1)hexane 9:1) 0',

I

to' 26 with 3-bromopropionitrile: with 4-bromobutyronitrile: with methyl bromoacetate: with ethyl 3-bromopropionate:

I

with with with allyl bromide: propargyl bromide: benzyl bromide: with o-fluorobenzyl bromide: with n-fluorobenzyl bromide: tlta

S

II

S S 4 I a

SI

with p-f iuorobenzyl bromide: with o-chlorobenzyl bromide: with m-chlorobenzyl bromide: with p-chlorobenzyl bromide: with o-bromobenzyl bromide: 20 with m-bromobenzyl bromide: with p-bromobenzyl bromide: with p-methylbenzyl bromide: with o-trif luoromethylbenz~l bromide: with m-trifluoromethylbenzyrl bromide: with p-trifluoromethylbenzyl bromide: with o-methoxycarbonylbenzyl bromide: with m-methoxycarbonylbenzyl bromide: 2-cyanoethyl) 5- (3-cyanopropyl) methyl-, m.p.82 0 5- (2-ethoxycarbonyl ethyl)- 5 -propargyl 5-benzyl-, m.p.119 0 5-(o-fluorobelz oil, Rf 0.56 (ethyl acetate/hexale 1:1) 5-(rn-fluorobelzyl)-, oil, Rf 0.54 (ethyl acetate/hexale 1:1) 5-(P-fluorobenzyl)-, m.p. 1560 5-(o-chlorobenzyl)-, m.p.130 0 5-(M-chlorobenzyi)-, m-p. 1270 5-(P-chlorobenzyl)-, m-p. 1240 5-(o-bromobenzyl)- m.p.142 0 5- (M-bromobenzyl) 5-(p-bromobenzyl)-, M.P. 980 5-(p-methylbenzy.) 5- (0-trifluoromethyl benzyl)-, m-p.105 0 5- (m-trifluoromethyl benzyl)- 5- (p-trifluoromethyl benzyl)benzyl)-, m-p.59' 5- (m-methoxycarbonyl banzyl)- 1.

Ii -26a with p-methoxycarbonylbenzyl bromide: with o-cyanobenzyl bromide: with m-cyanobenzyl bromide: with o-ethoxycarbonylbenzyl bromide: with m-ethoxycarbonylbenzyl bromide: with p-ethoxycarbonylbenzyl bromide: 5- (p-methoxycarbolyl benzyl) m 120 0 5-(o-cyanobenzyl)-, m.p. 6.50 5-(m-cyanobenzyl)-, m.p. 1400 5-(o-ethoxycarbonyl-benzy1 9 .9,49, 9 4 0* 44 9,

I

06 4 4. 4 4 4 44 4.

4. 1 44 44.4' 44 .4 4 94 4,4.

4 4.

4.

9, 94 9

S

9. 9 9 99

I

27 with P-cyanobenzyl bromide: with o-nitrobenzyl chloride: with m-nitrobenzyl chloride: with p-nitrobenzyl chloride: with o-trifluoroacetamidobenzyl bromide: with m-trifluoroacetamidobenzyl bromide: with p-trifluoroacetamidobenzyl bromide: with o-trifluoromethylsulphonamidobenzyl bromide: with m-trifluor omethylsulphonamidobenzyl bromide: with p-trifluoromethylsulphonamidobenzyl bromide: with 2,6-dichlorobenzyl brarnide: with 2-fluoro-6-nitrobenzyl bromide: with 2-chloro- 0-nitrobenzyl bromide: 5-(o-nitrobenzyl)-, 5-(p-nitrobe-nzyl)-, m.p. 149 0 m. p. 142 0 amidobenzyl)amidobenzyl.)amidobenzyl)sulphonamidobenzyl)- 0 4 4 1 0 A 4 sulphonamidobenzyl)sulphonamidobenzyl)- 0 5-(2,6-dichIorobenzvI)-, m.p.178 5-(2-fluoro-6-nitrobenzyl)-, m. p. 1930 5- (2-chloro- 6-nitrobenzyl)--, m. p. 2060, JR4,1'.

4N., -27a-

I

Example 12 A mixture of 800 mg of 2-butyl-3-(2'--cyanobiphenyl-4-ylmethyl) -4 ,5-dihydro-4-oxo-3H-imidazo( 4,5-c] pyridine, 515 mg of trimethyltin azide and 20 ml of toluene is boiled for 96 hours and evaporated. Chromatography of the residue (silica gel; methylene chloride/methanol 9:1, then 85:15 and 80:20) yields 2- dihydzro-4-oxo-3-[2 '-(tetrazol-S--yl)biphenyl- 4-ylmethyl]- 3H-imidazo[4,5-c]pyridine., m.p. 167? The corresponding K salt is prepared therefrom in conventional manner.

The following are obtained analogously from the corresponding cyano compounds: 2-butyl-4,5-dihydro-4-oxo-l-[2 4-ylmethyl lH-imridazo 4,5-c] pyridine; 15 2-butyl-4,5-dihydro-4-oxo-5-[2 4-ylmethyl)-l(or 3)H-ixidazo[4,5-c]pyridine;

"S.

4 44414 4 ST It I S S~4~I4:~ S 4: It II 14 4 4 5 5* 4 L 54 I SC -2 A t.

-28 2-butyl-4 ,5-dihydro-4-oxo-1, 5-bis[2'- tetrazol-5-yl )biphenyl- 4-ylmethyl])-1IH- imidazo 5 -c )pyridine, m. 300 0 2-butyl-4,5-dihydro-4-oxo-3,5-bis[2'-(tetrazol-5-yl)biphenyl -4 -ylmethyl 3H- imidazo 4, 5-c pyridine; 2-butyl-4,5-dihydro-4-oxo-3-[4-o-(tetrazol-5-yl)phenoxymethylbenzyl] -3H-imidazo 5-c] pyridine; 2-butyl-4 ,5-dihydro-4-oxo-3- (tetrazol-5-yl) ben~yloxybenzyl ]-3H-imidazo [4,5-c )pyridine.

The following 2-butyl-4,5-dihydro-4-oxo-3-[2 (tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridines are obtained analogously from the compounds described in Example 11: 5-(tetrazol-5-yl)methyl-,m.p.>300 0 Rf 0.07 (ethyl acetate/n-ethanol 1:1) -tert -butyl o 5 -pentafluoroethyl- 5-(3,3,3-trifluoropropyl)- (tetrazol-5-yl )ethyl] (tetrazol-5-yl )propyl] -methoxycarbonylmethyl- 5- (2-ethoxycarbonylethyl) to 4 m.p.130 0 potasst~r salt, m.p.2500 m. p. 118 0 m. p. 1820 (Aec) 0 5-(p-fluorobenzyl)- ,m-p.135 m~p 120 p. 1260 m. p. 1450 ,mp. 1730 5- (m-bromobenzyl) (p-bromobenzyl) (p-methylbenzyl) (o-trif luoromethylbenzyl) (m-trif luoromethylbenzyl) 5- (p-trif luoromethylbenzyl) m.p. 1240 -29- (m-methoxycarbonylbenzyl) 1880 5-(p-ethoxycarbonylbenzyl 243 0 p> 3000 m.p. 1890 300 0 (o-trifluoroacetamidobenzyl) (m-trifluoroacetamidobenzyl) (p-trif luoroacetamidobenzyl) (m-trif luoromethylsulphonamidobenzyl) (p-trif luoromethylsulphonamidobenzyl (2-f Iuoro-6-nitro-benzyl)-, m.p. 198~0 (2-chIoro-6-nItro-benzyl)-, m.p. 1440 Example 13 A solution of 1 g of 2-butyl-3-(2'-nitrobiphenyl- 4-ylmethyl)-4 ,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine in 30 ml of ethanol is hydrogenated at 20" on 1 g of Raney Ni until the absorption of has ceased. The mixture is filtered and evaporated to give aminobiphenyl-4-ylmethyl) -2-butyl-4, 5-dihydro-4-oxo-3Hixnidazo pyridine.

0*The following are obtained analogously by hydrogenation of the corresponding nitro compounds: 1-(2 '-aminobipheny4ylmy1).. 2butyl4,5-.dihydro-4.

0 oxo-lH-imidazo pyridine; 5-(2 '-aminobiphenyl4ylmethy)2bul..4,.dihydro4- I oxo-l(or 3)H-imidazo(4,5-c]pyridine; 1, 5-bis (2'-aminobiphenyl-4-ylmethyi) -2-butyl-4, 4 -oxo-1H-imidazo[4,5-c]pyridine; (2 -mnbpey--lehy)2btl45dhdo 4-oxo-3H-imidazo( 4,5-c ]pyridine; 5-(o-aminobenzyl)2..buty3(21-cyanobiphenyl4.y..

methyl)- 4 5dihyo4oxo-.3H..imidazo(4,s..c]pyridine; -,S4 5(m-aminobenzyl)2butyl3(2..cyanobipheny4y..

methyl) 4 5dihydro4..oxo.3H-.imidazo t415..-c ]pyridine; p-aminobenzyl) -2-butyl-3- (2 '-cyaknobipheny4-y..

methyl- 4 ,5dihydro4oxo..3H-imidazo45c]pyidine 5-(Q-aminobenzyl)-2-butyl--4,5-dihydro-4-oxo-3-[2'-(tetrazol-5-Yl)biplheniyl-4-ylmethyl]-3H-inidazo[4,5-clpyridin, m.p.223 0 5-(un-aminobenzyl)-2-butyl-4,5-dhydro-4-oxo-3-[i2'-(tetrazol-5:-y)biphenyl-4-ylmethyl]-3H-imidazo[4,5-clpyr-idin 5-(p-aminiobenzyl)-2-buty--4,5-dihydro--4-oxo-3-(2'-(tetrazol-5-y1)bipheny1-4-ylmethy1]-3'H-imida, Example 14 A solution of 2.82 g of trifluoromethanesuiphonic anhydride in 10 ml of CH- 2 Cl 2 is added dropwise to a solution of 3.72 g of 3-(2'-aminobiphenyl-4-ylmethyl)-2butyl-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine and 1.01 g of triethylamine in 30 ml of CH 2 Cl 2 at -50 to -600.

*1 The mixture is left to warm up to 200 and poured into dilute acetic acid to give 2-butyl-4.;5-dihydro-4-oxo-3- (2 '-trifluoromethanesulphonamidobiphenyl-4-ylmethyl) -3imidazo 4 ,5-c]pyridine after conventional working-up.

The following are obtained analogously from the corresponding amino compounds: 20 2-butyl-4,5-dihydro-4-oxo-l-(2'-trifluoromethane- .4 sulphonamidobiphenyl-4-ylmethiyl) -lil-imidazo pyridine; 2-butyl-4, 5-dihydro-4-oxo-5- (2 '-trifluoromethanesulphonamidobiphenyl-4-ylmethyl)-1(or 3)H-imidaio(4,5-c]pyridine; 2-butyl-4 ,5-dihydro-4-oxo-l ,5-bis -trifluoromethanesulphonamidobiphenyl-4-ylmethyl)-lH-imidazo(4,5-c)pyridine; 2-butyl-4 ,5-dihydro-4-oxo-3, 5-bis (2 '-trifluoromethanesulphonamidobipheny1-4-ylmethyl)-3nt-imidazo(415-c]pyridine.

-31- Example a) In analogy to Example 2, 2-butyl--3-[2'-(1(or 2)triphenylmethyl-tetrazol-5-yl)-biphenyl-4-ylmethyl--4,5dihydro-4-oxo--3H-imidazo [4,5-cjpyridine, m.p.127 0 is obtained from Il~a and 4-bromomethyl-2'-(1(or 2)-triphenylmethyl- )-biphenyl.

b) In analogy to Example 11, 5-benzyl--2-butyl-3-[2'--(1(or 2)triphenylmethyl-tetrazol-5-yl)'-biphenyl-4-ylmethyl]-4,5dihydro-4-oxo-3H-imidazo[4,5-cjpyridine is obtained therefrom with benzyl bromide.

c) A solution of HNl in diethyl ether (4m1) is added to a solution of 1 g of the product1 obtained according to b) in 4m1 of dichloromethane and 4 ml of au The mixture is stirred for 3 hour's at 20G, evb.porated and worked up in conventional 1, 5manner. After chromatographical separation of the triphenylcarbinol formed, 5-benzyl--2-butyl-4,5-dihydro-4-oxo-3- [2'-(tetrazol-5-Ifi)-biphenyl-4-ylmethyl]-3H-imidazo[4,5c~pyridine is obtoined; m.p..130 0 Potassium salt, m.p. 2500.

Example 16 One normal aqueous NaOH solutio' (3m1) is added to a solution of 573mg of 2-butyl-4,5-dihydro-5-p,-methoxycarbo)nylbernzyl-4-oxo-3- -(tetrazol-5-yl)-biphenyl-4-ylmethylJ-3H-imidazo[4,5-cjpyridine in 17 ml of THF and 6m1 of methanol. The mixture is stirred for hours at 200, acidified with HC1 and worked up in conventional manner. 2-Butyl-5-p-carboxybenzyl-4,5-dihydlo-4-oxo-3-[2'- )-blphenyl-4-ylmeth)yl3-311-imidazo[4,5-clpyrldine is S obtained; M.p.>300 0 Rf 0.26 (ethyl acetate/methanol 1:1).

Analogously, the following 2-butyl-.4,5-dihydro-4-oxo-8-t2'- (tetrazol-5-yl )-bipheanyl-4-ylrnethyl ]-3H-imidazot4,5-clpyridinos are obtained by saponification of the corresponding methyl asters: 4 4 B-o-carboxybonzyl-, m.p.211 0 6-m-carboxybonzyl-.

r

C

"1 i-i r -c -r l -32e The following Examples relate to pharmaceutical formulations containing active ingredients of formula I ,or their salts.

Example A: Tablets and coated tablets Tablets of the following comrsition are produced by compression in conventional manner and, where required, are provided with a conventional sucrose- based coating: 2-Butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-4,5-dihydro-4oxo-3H-imidazo[4,5-c]pyridine 100 mg Microcrystalline cellulose 278.8 mg at I t t Lactose Maize starch Magnesium stearate Finely divided silicon dioxide 110 mg 11 mg 5 mg 0.2 mg 11 i Example B: Hard gelatin capsules Conventional two-part hard gelatin capsules each filled with Active ingredient of formula I 100 mg Lactose 150 mg Cellulose 50 mg Magnesium stearate 6 mg are a, r Sal er '"2 Example C: Soft gelatin capsules Conventional soft gelatin capsules are filled with a mixture of 50 mg of active ingredient and 250 mg of olive oil in each case.

Example D: Ampoules A solution of 200 g of active ingredient in 2 kg of propane-l,2-diol is made up to 10 1 with water and filled into ampoules so that each ampoule contains 20 mg of active ingredient.

Claims (5)

1. An imidazopyridine derivative of formula I: R 3 R 2 in which R is (b) 6 Y R4 I R 4 R 1 6 Y R R a 04 4*~ R or (d) R I H R' is A, alkenyl or alkynyl having up to 6 C atoms in each case, R2 is COOHI COOA, CN, NO 2 NH 2 NHCORj NHSO 2 R5 or R 3 is H, Hal, A, OA or NO, R4 is H, R, cyanoalkyl, AOOC-alkyl, carboxyalkyl or a 0 tetrazol-5-ylalkyl having 1-6 C atoms in the "alkyl" moiety in each case, alkenyl or alkynyl having up to 6 C atoms in each case, aralkyl having 7-11 C atoms which is unsubstituted ,or rrono-or disubstitutedby Hal, R 5 COOH, COOA, CN, NO, NH 21 N(A) 2 NHCOR NHCOOA,NHSO 2 R 5 OH, W OA or tetrazol-5-yl, orR3 RZ -34- R 5 is alkyl having 1-4 C atoms, in which one or more H atoms can also be replaced with F,. R 6 is H or Hal, X is absent or is -NH-CO-j -CO-NH-, CH 2 O- or H Y is 0or S, A is alkyl having 1-6 C atoms and Hal is F, Cl, Br or I, and its salts.

2. 5-Benzyl-2-butyl-4,5-dihydro-4-ox-3-[2-(tetrazol-5-yl)-biphenyl4yv methylJ-3--imidazo[4,5-c]-pyridine and its potassium salt

3. A process for the preparation of imidazopyridine derivatives of formula I according to Claim 1, and. their o salts, characterised in that a compound of formula II: E-CH 2

9. Rz in which E is Cl, Br, I, a free OH group or an OH group which has ~~been functionally modified to acquire reactivity, and 35 R 2 R 3 and x are as defined in Claim 1, is treated with a compound of formula III: H-R III in which R is as defined in Claim 1, or to prepare a compound of formula I in which R' is H and Y is 0, a compound of formula IV: R 7 -CH 2 in which I. 4~ 4 r R' is '4 4. 44 SI 4. it El is Cl, Br, I or an OH group which has been functionally modiiled to acquire reactivity, and R 2 R 3 R 6 and X are as def ined in Claim 1, is is treated with a solvolysing agent, or a compound of formula Vs RO-~z-(9-X-Q' I V in which Re is k 36 RN R 6 R 9 N R R 10N R I Y 9 R 9NH 4 or A R10 N 6 I R 9 is R'-CO or H, is H (if R 9 is R -CO) or R1-CO (if R 9 is H) and R R 2 R R R 6 X and Y are as defined in Claim 1, is treated with a cyclising agent, or to prepare a compound of formula I in which X is -NH- CO- or -CO-NH-, a compound of formula VI: I L ti A R-CH2 -0-XI in which X' is NH 2 or COOH and R is as defined in Claim 1, or a reactive derivative of this compound is reacted with a compound of formula VII: f,~ R2 VII in which X 2 is COOH (if X is NH 2 or NH 2 (if X' is COOH) and R 2 and R 3 are as defined in Claim 1, or with a reactive derivative of this compound, or to prepare a compound of formula I in which X is CH,- 0- or -O-CH 2 a compound of formula VIII: R-C1 2 X3 VIII with 3,3,3-trifluoropropyl iodide: with 2,2,2-trifluoroethyl iodide: 5-(3,3,3-trifluoro-propyl)- 5-(2,2,2-trifluoroethyl)- oil, Rf 0.3 (ethyl acetate/ hexane 9:1) kr I; 37 in which X 3 is CH2E or OH and R is as defined in Claim 1, or a reactive derivative of this compound is reacted with a compound of formula IX: X4 RZ l t i. 1 ~l r r~ in which X' is OH (if X 3 is CHE) or CIHE (if X 3 is OH) and R 2 and R 3 are as defined in Claim 1, or with a reactive derivative of this compound, or to liberate a compound of formula I by treatment of one of its. functional derivatives with a solvolysing or hydro- genolysing agent, and/or in that one or more radicals R, R 2 and/or R 3 in a compound of formula I are converted to one or more other radicals R, R 2 and/or and/or a base or acid of formula I is converted to one of its salts. 4. A process for the preparation of pharmaceutical formulations, characterised in that a compound of formula I according to Claim 1, and/or one of its physiologically acceptable acid addition salts, is incorporated into a suitable dosage form together with at least,one solid, liquid or semiliquid excipient or adjunct. 5. A pharmaceutical formulation, characterised in that it 25 contains at least one compound of formula I according to Claim 1, and/or one of its physiologically acceptable acid addition salts,, in association with one or more pharma- ceutically acceptable excipients and/or adjuncts. .h L 1* i;

38- 6. A method for the prophylaxis and/or therapy of cardiac, circulatory and vascular diseases, and in particular hypertonia, cardiac insufficiency and hyperaldosteronism which comprises treating a patient suffering from or subject to such a disease with an effective dose of a compound of formula I, optionally in conjunction with a pharmaceutically acceptable carrier. 7. A compound of formula III: H-R in which R is as defined in Claim 1. ap I 4l 9* I 44 4 .44 8. A compound according to claim 1 substantially as herein described with reference to any one of Examples 1 to 12. 9. 2-Butyl-5-(o-ethoxycarbonylbenzyl)-4,5-dihydro-4-oxo-3-[2'-tetrazol-5-yl)- biphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine and its potassium salt. 10. An imidazopyridine derivative of formula I according to claim 1 in which Y is S and R, R' to R 6 X, A and Hal are as defined in claim 1 and its salts. 11. An imidazopyridine derivative of formula I according to claim 1 in which Y is O and R 4 is alkyl having 1-4 C atoms in which one or more H atoms are replaced with F; cyanoalkyl or tetrazol-5-yl-alkyl having 1-6 C atoms in the "alkyl" moiety in each case; alkynyl having up to 6 C atoms; aralkyl having 7-11 C atoms which is unsubstituted or mono- or disubstituted by Hal, R 5 COOH, COOA, CN, NO 2 NO 2 NH 2 NHA, N(A) 2 NHCOR 5 NHCOOA, IN NHSO 2 R 5 OH, OA and/or tetrazol-5-yl; or 4, I 39 andR,R1to R 3 R 5 R6,X, Aand Halare asdefiedi laim 1adits sats. DATED this 30th day of September, 1994. MIERCK PATENT GESELLSCHAFT MIT BESCIHRNKTER HAFIUNG By Its Patent Attorneys In DAVIES COLLISON CAVE 0 4~4*4* 0 0444 044044 0 I *4 44 4 4 4 4 4444*4 4 .44 41 I I I '2 Abstract of the Disclosure Novel imidazopyridine derivatives of formula I: R 3 R-CH 2 in which R is (a) t 0 7 4.. 4~ 44Y R R Y R R 6 6 Y or (d) Y R H R rt~ i ~C3 4 1 44 and R' to R 6 X and Y are as defined In Claim 1, and their salts have antagonistic properties towards angiotensin II and can be used for the treatment of hypertension, aldosteronism and cardiac insufficiency.