IE83625B1 - Imidazopyridine - Google Patents

Description

PATENTS ACT, 1992 920968 IMTDAZOPYRIDTNE MERCK PATENT GMBH The invention relates to novel derivatives of formula I imidazopyridine R2 in which 6 R R‘—<'N I R is NR4 N .

/ Y R1 is A having up to 6 C atoms, R2 is COOH, COOA, CN or tetrazol-5—yl, R3 is H, R4 is H, tetrazol—5-ylalkyl having 1-6 C atoms with the "alkyl" moiety, aralkyl having 7-11 C atoms which is unsubstituted or monosubstituted by Hal, COOH, COOA, CN, N02 or tetrazol—5-yl, or \ CHr©X'Q 3 2 R ' R R6 is H, X is absent, _ Y is O, A is alkyl having 1-6 C atoms and Hal is F, Cl, Br or I, A and their salts. azabenzimidazole EP 0 415 886 discloses compounds having angiotensin II—antagonizing properties. Other imidazo—linked 6—membered ring heterocycles are disclosed in EP 0 400 974. Angiotensin II receptor-blocking benzimidazoles described in US 4,880,804. Other the treatment of high blood pressure and heart diseases in EP 0 434 038. EP 0 399 731 mentions imidazole—linked heterocycles for are disclosed azaindenes, EP 0 407 342 and EP 0 424 317 mention pyrimidine derivatives and EP 0 411 766 mentions quinazolinones as angiotensin II antagonists. J. Med.

Chem 34, 2919 (1991) describes other heterocyclic angiotensin II antogonists.

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 angioten— sin II—dependent hypertension, aldosteronism and cardiac insufficiency. These effects can be determined by conventional in vitro or in vivo methods such as e.g.

The compounds of formula I can be used as phar- maceutical active ingredients in human and veterinary medicine, especially for the prophylaxis and/or therapy of cardiac, circulatory and vascular diseases, in par- ticular 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) a compound of formula II in which E is Cl, Br, I, a free OH group or an OH group which has been functionally modified to acquire reactivity, and R2, R3 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, (b) to prepare a compound of formula I in which R4 is H and Y is 0, R3 R7-CH2—@-X av a compound of formula IV in which E1 is Cl, Br, I or an OH group which has been functionally modified to acquire reactivity, and R1, R2, R3, R6 and X are as defined in Claim 1, is treated with a solvolysing agent, (c) a compound of formula V R2 in which RQNH R6 R8 is R1oN ‘ ,NR4 1 Y R9 is R1-CO’or H, R10 is H (if R9 is R1—CO) or R1-CO (if R9 is ‘H) and R1, R2, R3, R4, R6, X and Y are as defined in Claim 1, is treated with a cyclising agent, (d) a compound of formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, and/or in that one or more radicals R and/or R2 in a compound of formula I are converted to one or more -, 2- or 3—methylbutyl, In the above formulae, preferably 1, , 3 or 4 C atoms. or else ethyl, propyl, tert—butyl, l,l—, 1,2- l—, 2-, 3- 2,3— or 3,3-dimethylbutyl, 1- l—methylpropyl, l—ethyl—2—methylpropyl or Alkenyl is prop—l-enyl or propenyl or but-l-enyl, isopropyl, isobutyl, or else pentyl, or 2,2—dimethylpropyl, 1-ethylpropyl, hexyl, l,l—, l,2—, 1,3—, 2,2—, or 2—ethylbutyl, l—ethyl— l,l,2— or preferably vinyl, or 4—methylpentyl, l,2,2—trimethylpropyl. or else pent- 1—enyl or hex—l—enyl. Alkynyl is preferably ethynyl or prop—l—ynyl or prop—2-ynyl, or else but—l—ynyl, pent-l- ynyl or hex—l-ynyl.

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

R is a radical derived from 3H—imidazo[4,5—c]— pyridine or, more precisely: —Rl—4—oxo—5—R4—6 (or 7) —R6—4, 5—dihydro—3H-imidazo— [4,5—c]pyridin-3—yl.

Preferably, the radical R1 is linear and is A or alkenyl having 3-6 C atoms in each especially butyl, case, or else propyl, pentyl, hexyl, allyl or prop—l- enyl, or else but-l-enyl, pent—1—enyl, hexenyl, prop- -ynyl, but-l-ynyl, pentynyl or hex—l-ynyl.

The preferably tetrazol—5—yl, COOH, COOCH3 or COOC2Hy radical R2 is preferably CN, or else The radical R3 is preferably H.

The radical R4 is preferably H, or else preferably tetrazol—5—ylalkyl [especially tetrazol—5— ylmethyl, 2- yl)prOpyl], contain a total of up to 6 C atoms in each case. the (tetrazol—5—yl)ethyl, 3—(tetrazol—5— it being possible for all these radicals to Also, 7-11 C monosubstituted radical R4 is preferably aralkyl having unsubstituted or the o atoms which is (preferably in position) or disubstituted (preferably in the 2,6 position), especially benzyl, l- or 2-phenylethyl, l—, 2- or 3- phenylpropyl, 1-, 2-, 3- or 4-phenylbutyl, o—, m- or p- fluorobenzyl, (preferably) o—, m- or p-chlorobenzyl, o, m— or p- bromobenzyl, o—, m— or p—methylbenzyl, o—, m— or p- trifluoromethylbenzyl, o—, m— or p-methoxycarbonylben— zyl, o—, m— or p-ethoxycarbonylbenzyl, (preferably) o-, m— or p—cyanobenzyl, o—, m— or p—carboxybenzyl or o—, m- or p—nitrobenzyl. Also, the radical R4 can preferably be The radical R6 is preferably H.

Preferably, the radical X is absent.

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.

Accordingly, the invention relates especially to those compounds of formula I in which at least one of said radicals has one of the preferred meanings indicated above.

Very particularly preferred compounds are those of formulae I in which in addition R3, R4 and/or R6 are H and/or Y is O.

Among these, which R? is preferred compounds are those in CN, COOH, COOCH3, COOCfih or tetrazol—5—yl.

A very particularly preferred group of compounds has formula I in which -A-4,5—dihydro—4—oxo—5—R3—3H—imidazo[4,5—c]— pyridin—3—yl radical, R is a R2 is COOH, COOCH3, CN or tetrazol-5—yl, R3 is H, R4 is H or -CH2 and R2 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, R2 is COOH, COOCH3, CN or tetrazol—5—yl, R3 is H, Y is O and X is absent.

Another selected group of preferred compounds has formula I in which R4 is tetrazol—5— ylalkyl having -6 C atoms in the alkyl moiety in each case, or aralkyl having 7-11 C atoms which is unsubstituted or monosubstituted by Hal, COOH, COOA, CN, N02 or tetrazol— -yl.

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 (e.g. in the standard works like Houben—Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg—Thieme-Verlag, Stuttgart, but espe— cially 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 obtained by reacting compounds of formula II with com- pounds of formula III. Particularly the biphenyl deriva- tives of formula I (in which X is absent) are readily obtainable in this way.

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

The with III is atoms reaction of II conveniently carried out by first converting III to a salt by treat- e.g. in an alcohol such as CH3OH, ment with a base, with an alkali metal alcoholate such as CH3ONa or with an alkali metal hydride such as NaH in dimethylformamide (DMF), and then reacting said salt with II in an inert e.g. sulphoxide an amide such as DMF or dimethylacetamide, dimethyl sulphoxide (DMSO), -20 and 100°, Other suitable bases solvent, or a such as conveniently at temperatures of between preferably of between 10 and 305 are alkali metal carbonates such as Na2CO3 or K2COy or alkali metal hydrogen carbonates such as NaHCO3 or KHCOb In the reaction of II with III, it is possible to obtain two or, in the case of III, R4 = H, three regioisomeric monosubstitution products, namely the corresponding lH— and 3H-imidazo[4,5—c]pyridines in which the newly introduced substituent is in the l, 3 or It is also possible to obtain disubstitution products with substitution in the 1 and 3, 1 and 5 or 3 and 5 The type the products of formula I are extensively dependent on the of the and III and on the in the reaction of equimolar position. positions. and proportions of reactants II Thus, proportions reaction conditions. amounts of methyl 4’—bromomethylbiphenyl—2— ("IIa") imidazo[4,5-clpyridine CH3ONa ix} methanol, carboxylate 2—butyl—4—oxo—4,5-dihydro—1(or 3)H— ("IIIa") in the presence of the products disubstituted in the 1 ands 5 positions and 111 the Z3 and 5 positions can be in the reaction of 4'- ("IIb") with IIIa in the the product monosubstituted in isolated; on the other hand, bromomethylcyanobiphenyl presence of KZCO3 in DMF, the 3 position is obtained in very predominant propor- tions.

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 E1 is preferably C1. 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 This by the of formula V. cyclisation is conveniently carried out by heating with cyclisation of compounds acetic acid or diglyme to tempera- 80 and 180% polyphosphoric acid, tures of between about preferably of between 120 and 160°.

A compound of the formula I can furthermore be its liberated from one of functional derivatives by treating with a solvolyzing (e.g.hydrolyzing) or hydrogenolyzing agent. according to one of the which It is thus possible, indicated methods, to prepare a compound corresponds to formula I, but instead of a tetrazol (protected by in the 1 or 2 yl group contains a functionally modified a protective group) tetrazol—5~yl group _lO_ position. Suitable protective groups are, for example: triphenylmethyl, removable using HCl or formic acid in an inert solvent or solvent mixture, e.g. ether/dichloromethane/methanol; 2—cyanoethyl, removable using NaOH in water/THF; p—nitrobenzyl, removable using H2/Raney nickel in ethanol.

Some of the starting materials, especially those they can be prepared by known methods analogously to known of formula II, are known. If they are not known, of formula III are novel. Com- pounds of formula III (R4 = H, Y = O) substances. Compounds can be obtained e.g. by reacting carboxylic acids of the formula R9—COOH with compounds of formula X HZN R in the presence of polyphosphoric acid, the group E1 (preferably Cl) being hydrolysed in the process.

Compounds of formula IV can be obtained for example by reacting compounds of the formula H—R7 with compounds of formula II under the conditions indicated above for the reaction of II with III.

It is also possible to convert a compound of formula I to another compound of formula I by converting of the radicals R and/or R2 to e.g. one or more other radicals R and/or Ra by replacing halogen atoms with CN groups (e.g. 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.

Thus, for example, free amino groups can be acylated in conventional manner with an acid chloride or anhydride, or alkylated with a substituted or . _l:1__ unsubstituted alkyl, alkenyl, alkynyl or aralkyl halide, conveniently in an inert solvent such as chloride or THF, as triethylamine or pyridine, methylene and/or in the presence of a base such at temperatures of between -60 and +30°. Of particular importance is the corresponding conversion of a radical R in which R4 = H to another radical R in which R4 is other than H. This reaction is preferably carried out with an acid amide such as DMF, 1,3- hexahydropyrimidine or hexamethylphosphorotriamide, an N—methylpyrrolidone, dimethyl—2—oxo— alcohol such as methanol or tert- butanol, an ether such as THE, or a halogenated hydrocarbon such as methylene or mixtures thereof, and/or in alkali sodium nethylate or potassium tert—butylate, an alkali chloride, as the solvent, the presence of an metal alcoholate such as metal hydride such as sodium or potassium hydride, an alkali carbonate, metal carbonate such as sodium or potassium an alkali metal bicarbonate such as sodium or potassium bicarbonate, or a tertiary amine such as triethylamine or ethyldiisopropylamine, -30 and 200, at temperatures of between about and 60°.

The reaction of nitriles of formula I preferably of between 20 (R2 = CN) with hydrazoic acid derivatives leads to tetrazoles of formula I (R2 = 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 N- methylpyrrolidone 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 salts. physiologically acceptable Thus it is possible to use inorganic acids, e.g. sulphuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, as well as organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or . -12.. heterocyclic monobasic or polybasic e.g. acid, propionic acid, pivalic acid, diethylacetic acid, carboxylic, sul- phonic or sulphuric acids, formic acid, acetic 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 unac- ceptable 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 con- taining COOH or tetrazolyl groups can be converted with bases (e.g. 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 incorpora- tion 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 (e.g. or parenteral administration or for administra- and which do for example water, substances which are suitable for enteral oral or rectal) tion in the form of an inhalation spray, not react with the novel compounds, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, carbohydrates such as lactose or Tablets, juices or drops, in gelatin, soya lecithin, starch, magnesium stearate, talc and cellulose. coated tablets, capsules, syrups, particular, are used for oral administration; lacquered tablets and capsules with coatings or shells resistant . _l3_ 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 (e.g. 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 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, commercially available preparations, but in particular analogously to the compounds described in US patent 804, especially of between 50 and 500 mg per dosage preferably in dosages of between about 1 mg and l g, unit. The daily dosage is preferably between about 0.1 and 50 mg/kg, However, especially between 1 and 100 mg/kg of body weight. 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, body weight, general state of health, diet, age, sex, time and Inethod. of administration, rate of excretion, drug combination and severity of the particular disease to which the therapy is applied. Oral administration is preferred. _l4_ Above and below, all temperatures are given in °C. In the following Examples, "conventional working—up" means: to between 2 and lO constitution of the end product, Water is added if necessary, the pH is adjusted if necessary, depending on the extraction is carried out with ethyl acetate or methylene chloride and the organic phase is separated off, dried over sodium sul- phate, evaporated and purified by chromatography on silica gel and/or by crystallisation.

Rf = Rf value determined by thin layer chromatography on silica gel; eluent: ethyl acetate unless stated otherwise.

Example l 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-butyl—4—oxo-4,5-dihydro—l(or 3)H—imidazo[4,5—c]pyridi— ne ("llla") at 20° for a further 30 min and evaporated, is dissolved in 20 ml of DMF, in 75 ml of methanol. The mixture is stirred the residue and a solution of 5.2 g of methyl 4'—bromomethylbiphenylcarboxylate (Ila) in 10 ml of DMF is added dropwise at 0°, with stirring. The mixture is stirred at 20° for l6 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:O.5 to 9:l): 2—butyl—3,5—bis(2'—methoxycarbonylbiphenyl—4-ylmethyl)— 4,5—dihydrooxo—3H—imidazo[4,5—c]pyridine, oil; 2—butyl—l—(2'—methoxycarbonylbiphenyl—4—ylmethyl)—4,5— dihydro—4—oxo—lH—imidazo[4,5—c]pyridine, m.p. 224% 2—butyl—5—(2'—methoxycarbonylbiphenyl-4—ylmethyl)—4,5- dihydro—4—oxo—l(or 3)H—imidazo[4,5—c]pyridine, m.p. l5l°; - 2—butyl(2'-methoxycarbonylbiphenylylmethyl)—4,5— dihydro-4—oxo—3H-imidazo[4,5-c]pyridine, m.p. 186°; 2—butyl—l,5—bis(2'—methoxycarbonylbiphenyl-4—ylmethyl)— ,5—dihydro—4-oxo-lH-imidazo[4,5—c]pyridine, m.p. 6 . _l5_ Preparation of the starting material Illa: A mixture of 16.2 g of 3,4-diamino—2—chloro— pyridine, 14 m1 of valeric acid and 300 g of poly- phosphoric acid is heated at lOO—l40° for 8 hours and then at 170—l80° with cooled and poured on to ice, tion is added to pH 9. for 5 hours, stirring. It is and sodium hydroxide solu- After concentration and conven- Illa is obtained: m.p. 285-290? The following are obtained analogously from Ila 2-butyl—6—chloro—4—oxo—4,5—dihydro-1(or 3)H— (m.p. 235-2405 ,4—diamino—2,6—dichloropyridine and Valerie acid): tional working-up, imidazo[4,5-c]pyridine obtainable from —butyl—6—chloro—3,5—bis(2'—methoxycarbonylbiphenyl-4—yl— methyl)-4,5-dihydro—4—oxo—3H—imidazo[4,5—c]pyridine7 —butyl—6—chloro—l—(2'—methoxycarbonylbiphenyl-4—yl— methyl)—4,5-dihydro—4-oxo-1(or 3)H—imidazo[4,5—c]pyrid— ine; 2—butyl—6—chloro—5—(2'—methoxycarbonylbiphenyl—4—yl— methyl)—4,5—dihydrooxo-1(or 3)H-imidazo[4,5~ clpyridine; 2—butyl—6—chloro(2'—methoxycarbonylbiphenyl-4—yl— methyl)-4,5—dihydrooxo—3H—imidazo[4,5—c]pyridine; —butyl—6—chloro—1,5-bis(2'—methoxycarbonylbiphenyl~4— ylmethyl)-4,5—dihydrooxo—1H—imidazo[4,5—c]pyridine.

Example 2 A mixture of 0.7 g of IIIa, ml of DMF is stirred at 20° g of 4'-bromomethyl—2—cyanobiphenyl in 5 rml of DMF is with and the hours, .5 g of K2CO3 and 40 for 10 min. A solution of 1 added dropwise over 45 min, stirring, at 20° further 5 evaporated and worked up in conventional manner to give the (methylene chloride/methanol 98:2 to 9:1): -butyl(2'-cyanobiphenyl-4—y1methyl)—4,5—dihydro—4- mixture is stirred for a following after chromatography on silica gel oxo—1H—imidazo[4,5-c]pyridine; . _16_. —butyl(2‘-cyanobiphenyl—4—ylmethyl)—4,5—dihydro—4— 179° (main product); 2—butyl—5—(2'—cyanobiphenyl—4—ylmethyl)—4,5—dihydro—4— oxo—3H—imidazo[4,5—c]pyridine, m.p. oxo—l(or 3)H-imidazo[4,5—c]pyridine; 2—butyl—l,5-bis(2'—cyanobiphenyl—4-ylmethyl)—4,5—di— hydro—4—oxo-lH—imidazo[4,5—c]pyridine; 2—butyl-3,5-bis(2'—cyanobiphenyl—4—ylmethyl)—4,5~di— hydro—4—oxo—3H—imidazo[4,5—c]pyridine, m.p. 83°.

The following are obtained analogously with 2'- nitrobiphenyl—4—ylmethyl bromide: 2—butyl—1—(2'—nitrobiphenyl-4—ylmethyl)—4,5—dihydro—4— oxo—lH-imidazo[4,5-c]pyridine; 2-butyl—3-(2'-nitrobiphenyl—4—ylmethyl)—4,5—dihydro—4— oxo—3H—imidazo[4,5-c]pyridine; 2—butyl—5-(2'—nitrobiphenyl—4—ylmethyl)—4,5—dihydro oxo—l(or 3)H—imidazo[4,5—c]pyridine; 2—butyl—l,5—bis(2'-nitrobiphenyl—4—ylmethyl)—4,5—di— hydro—4—oxo—lH—imidazo[4,5-c]pyridine; 2—butyl-3,5-bis(2'-nitrobiphenyl—4—ylmethyl)-4,5—di— hydro—4-oxo—3H—imidazo[4,5—c]pyridine.

Example 3 A mixture of 4 g of 2-butyl—3—(2'-cyanobiphenyl— 4-ylmethyl)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— 65°) and reacting the latter with IIIa Example 2], 2 g of CH3COOAg and 40 ml of boiled for l6 hours. It is filtered and the residue is worked up in conventional 2—butyl—3—(2'-cyanobiphenyl—4—ylmethyl)—4,5—dihydro—4— oxo—3H—imidazo[4,5—c}pyridine, m.p. l79°. , -chloro—1(or 3)H-imidazo[4,5—c]pyridine (m.p. analogously to acetic acid is evaporated and manner to give Example 4 A mixture of 1.02 g of valeric acid, 3.59 g of 4-amino—2-oxo—3—[2'-(tetrazol—5—yl)biphenyl—4—yl- methylamino]—l,2—dihydropyridine [obtainable by reacting - amino—4—benzylamino—1,2-dihydro—2—oxopyridine with 4- _l7_ bromomethyl—2'-cyanobiphenyl to give 4—benzylamino—3— (2'—cyanobiphenyl—4—ylmethylamino)—l,2—dihydro oxopyridine, reacting the latter with trimethyltin azide according to Example 13 to give 4-benzylamino—3-[2“— (tetrazol—5—yl)biphenylylmethylamino]—l,2—dihydro—2— oxopyridine, and removing" the benzyl group by hydro- genolysis] and 50 g of polyphosphoric acid is heated at l40° for 5 yl)biphenyl—4-ylmethyl—N—valerylaminoJ-l,2—dihydro— —oxo-3—[2‘—(tetrazol—5—yl)biphenyl—4- hours. 4-amino—2—oxo—3—[N—2'-(tetrazol—5— pyridine and ylmethylamino]—4—valerylamino—l,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 2-butyl—4, 5-dihydro—4—oxo—3— [2 ' — (tetrazol—5— yl)biphenyl—4—ylmethyl]—3H—imidazo[4,5—c]pyridine, m.p. l67°. to give Example 5 A mixture of 1 g of 2—butyl—l~(2'—methoxy— carbonylbiphenyl—4—ylmethyl)—4,5—dihydro—4—oxo—lH— imidazo[4,5-c]pyridine, 12 ml of 2 N aqueous NaOH solu- tion and 43 ml of ethanol is boiled for 2 hours and then evaporated. to pH 3 with HCl gives 2- butyl—l-(2'—carboxybiphenyl-4—ylmethyl)-4,5—dihydro~4— filtered off, Acidification oxo—lH—imidazo[4,5—c]pyridine, which is washed with water and dried: m.p. 286? The saponification of the corresponding methyl esters: 2-butyl(2’—carboxybiphenyl-4—ylmethyl)—4,5—dihydro oxo—3H-imidazo[4,5—c]pyridine, m.p. 275°; 2—butyl(2‘—carboxybiphenyl—4—ylmethyl)-4,5—dihydro—4~ oxo—l(or 3)H—imidazo[4,5—c]pyridine; _ 2—butyl—l,5-bis(2'—carboxybiphenyl—4-ylmethyl)—4,5-di- dihydrate, m.p. following are obtained analogously by hydro—4—oxo-lH-imidazo[4,5—c]pyridine, 137°; 2-butyl—3,5-bis(2'-carboxybiphenyl—4—ylmethyl)—4,5-di- hydro—4-oxo—3H—imidazo[4,5-c]pyridine, m.p. 165°. . _l8_ Example 6 A solution of 0.79 g of chloroacetonitrile in 5 ml of DMF is added dropwise at 20°, to a with stirring, solution of 3.82 g of 2-butyl—3—(2'—cyanobiphenyl- 4- ylmethyl)-4,5—dihydro—4—oxo—3H-imidazo[4,5—c]pyridine and 1.17 g of potassium tert-butylate in 20 ml of DMF.

The mixture is stirred at 20° 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 -butyl—3—(2'-cyanobiphenyl—4—y1methyl)-5—cyanomethyl— ,5—dihydro-4—oxo—3H-imidazo[4,5—c]pyridine, m.p. 64°. methyl)-4,5—dihydrooxo—3H—imidazo[4,5—c]pyridines obtained analogously: following 2—butyl—3—(2'—cyanobiphenyl—4—yl— with methyl iodide: 5—methyl—, m.p. 107° with ethyl iodide: 5—ethyl— with isopropyl iodide: 5—isopropyl- with butyl bromide: 5—butyl— with tert—butyl bromide: 5—tert-butyl- with 2,2,2—trifluoroethyl iodide: 5—(2,2,2—trifluoro— ethyl)—, oil, Rf 0.3 (ethyl acetate/hexane 9:1) with pentafluoroethyl iodide: 5—pentafluoroethyl— with 3,3,3-trifluoropropyl iodide: 5—(3,3,3—trifluoro- propyl>- with 3—bromopropionitrile: 5—(2—cyanoethyl)— with 4—bromobutyronitrile: 5-(3—cyanopropyl)— with methyl bromoacetate: 5—methoxycarbonyl— methyl—, monohydrate, m.p. 82° with ethyl 3—bromopropionate: 5—(2—ethpxycarbonyl— ethyl)—, with allyl bromide: 5—allyl— with propargyl bromide: 5—propargyl— with benzyl bromide: 5—benzyl—, m.p. 119° _]_9_ with o—fluorobenzyl bromide: with m—f1uorobenzyl bromide: with p—f1uorobenzy1 bromide: with o—ch1orobenzy1 bromide: with m-chlorobenzyl bromide: with p-chlorobenzyl bromide: with o—bromobenzy1 bromide: with m—bromobenzyl bromide: with p—bromobenzy1 bromide: with p—methy1benzy1 bromide: with o—trif1uoromethy1benzy1 bromide: with m—trifluoromethylbenzy1 bromide: with p—trif1uoromethy1benzy1 bromide: with o—methoxycarbonylbenzyl bromide: with m-methoxycarbonylbenzyl bromide: with p—methoxycarbony1benzy1 bromide: with o-ethoxycarbonylbenzyl -(o—f1uorobenzyl)—, oily, Rf 0.56 (ethyl acetate/hexane 1:1) —(m-fluorobenzyl)—, oily, Rf 0.54 (ethyl acetate/hexane 1:1) -(fluorobenzy1)—, m.p. 156° —(o—f1uorobenzy1)—, m.p. 130° —(m-ch1orobenzy1)—, m.p. 127° —(p—ch1orobenzy1)—, m.p. 124° —(o—bromobenzy1)—, m.p. 142° —(m—bromobenzyl)— —(p—bromobenzy1)-, m.p. 98° —(p—methy1benzyl)— —(o—trifluoromethy1— benzyl)—, m.p. 105° —(m-trif1uoromethy1— benzyl)- -(p—trif1uoromethy1— benzyl)- —(o—methoxycarbony1— benzyl)—, m.p. 59° —(m-methoxycarbony1- benzyl)- -(p-methoxycarbonyl— benzyl)—, m.p. 120° — 20 bromide: with m—ethoxycarbony1benzyl bromide: with p—ethoxycarbony1benzyl bromide: with o-cyanobenzyl bromide: with m—cyanobenzy1 bromide: with p-cyanobenzyl bromide: with o—nitrobenzy1 chloride: with m—nitrobenzyl chloride: with p—nitrobenzy1 chloride: with o—trif1uoroacetamido— benzyl bromide: with m—trif1uoroacetamido— benzyl bromide: with p—trif1uoroacetamido— benzyl bromide: with 2,6-dichlorobenzyl bromide: with 2—fluoro—6—nitrobenzyl bromide: with 2—chloro—6-nitrobenzyl bromide: -(o—ethoxycarbony1— benzy1)— —(m—ethoxycarbonyl— benzy1)— —(p—ethoxycarbonyl— benzyl)— -(o~cyanobenzy1)—, m.p. 65° —(m—cyanobenzy1)—, m.p. 140° —(p-cyanobenzyl)— —(o—nitrobenzyl)—, m.p. 149° —(m—nitrobenzyl)— —(p—nitrobenzyl)—, m.p. 142° —(o-trif1uoroacet— amidobenzy1)— -(m-trifluoroacet— amidobenzy1)— ~(p—trif1uoroacet— amidobenzy1)— —(2,6—dich1oro— benzy1)—, m.p. 178° -(2-fluoro—6—nitro— benzyl):, m.p. 193° —(2—ch1oro-6—nitro- benzyl)—, m.p. 206°. _21_..

Example 7 A mixture of 800 mg of 2—butyl—3-(2'-cyano- biphenyl—4—ylmethyl)-4,5—dihydro—4-oxo—3H—imidazo[4,5- cjpyridine, 515 mg of trimethyltin azide and 20 ml of toluene is boiled for 96 hours and evaporated. Chroma- tography of the residue (silica gel; methylene chloride/methanol 9:1, then 85:15 and 80:20) yields 2- butyl—4,5—dihydro—4-oxo—3—[2'-(tetrazol—5-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'-(tetrazol—5—yl)biphenyl— 4—ylmethyl]—lH—imidazo[4,5—c]pyridine; 2—butyl—4,5—dihydro—4—oxo—5—[2'—(tetrazol—5—yl)biphenyl— 4-ylmethyl]—l(or 3)H—imidazo[4,5—c]pyridine; 2—butyl—4,5—dihydro—4—oxo—l,5—bis[2'-(tetrazol~5—yl)bi- phenyl—4—ylmethyl]—lH—imidazo[4,5—c]pyridine; 2—butyl—4,5—dihydro—4—oxo—3,5—bis[2'—(tetrazol—5—yl)bi— phenyl—4—ylmethyl]-3H-imidazo[4,5—c]pyridine, tetradecahydrate; m.p. > 300°; 2—butyl—4,5-dihydrooxo—3-[4—o—(tetrazol-5—yl)phenoxy— methylbenzyl]-3H-imidazo[4,5-c]pyridine; 2—butyl—4,5—dihydro—4—oxo[4—o-(tetrazol—5—yl)— benzyloxybenzyl]-3H-imidazo[4,5-cjpyridine.

The 2—butyl—4,5—dihydro-4—oxo—3-[2‘- (tetrazol—5—yl)biphenyl—4—ylmethyl]—3H-imidazo[4,5—c]— following pyridines are obtained analogously from the compounds described in Example 6: -(tetrazol—5—yl)methyl—, acetate/methanol 1:1) —methyl- _ —ethyl— —isopropyl— -butyl— -tert-butyl— m.p. > 300°; Rf 0.07 (ethyl —pentafluoroethyl— -(3,3,3-trifluoropropyl)- _22_ —[2—(tetrazol—5—y1)ethy1]— {3—(tetrazo1—5—y1)propyl]— —methoxycarbonylmethy1— -(2~ethoxycarbony1ethy1)— —a11y1— —propargyl- —benzyl—, heptahydrate, m.p. 130°; K salt, dihydrate, m.p. 250° —(o—f1uorobenzy1)—, m.p. 118°; K salt, tetrahydrate, m.p. > 300° —(m—f1uorobenzyl)—, m.p. 182° (decomp.) —(p—f1uorobenzy1)—, dihydrate, m.p. 135° -(o—chlorobenzy1)-, m.p. 123°; K salt, dihydrate, m.p. 190° —(m—ch1orobenzyl)—, m.p. 126° —(p—chlorobenzy1)-, monohydrate, m.p. 145° —(o—bromobenzy1)—, m.p. 173° -(m—bromobenzyl)— —(p—bromoben2yl)— -(p—methy1benzyl)— -(0-trifluoromethylbenzyl)— -(m—trif1uoromethy1benzy1)— -(p—trif1uoromethylbenzy1)- -(o-methoxycarbonylbenzyl)—, m.p. 124°; K salt, semihydrate, m.p. 152° -(m-methoxycarbonylbenzyl)— -(p—methoxycarbony1benzy1)—, m.p. 188° -(o-ethoxycarbonylbenzyl)—, K salt, dihydrate, map. > 300° -(m—ethoxycarbony1benzy1)— -(p—ethoxycarbony1benzy1)— -[o-(tetrazol—5—yl)benzy1]—, m.p. 243° -[m—(tetrazol-5—y1)benzy1]—, m.p. > 300° -[p~(tetrazol—5—y1)benzy1]— -(o—nitrobenzyl)-, m.p. 189° —(m-nitrobenzyl)- —(p—nitrobenzy1)—, m.p. > 300° -(o—trifluoroacetamidobenzyl)— -(m—trifluoroacetamidobenzyl)— _23_ -(p—trifluoroacetamidobenzyl)- -(2-f1uoro—6-nitrobenzyl)—, m.p. 198° m.p. -(2—ch1oro-6—nitrobenzyl)—, 144°; K dihydrate, m.p. 249° salt, Example 8 a) Analogously to Example 2, starting from Illa —bromomethyl—2'~(l(or 2)—triphenylmethyltetrazol- 2—buty1-3—[2'-(l(or tetrazol—5—yDbiphenyl—4—ylmethyl]—4,5—dihydro—4—oxo—3H— m.p. 127°, b) Analogously to Example 6, and —yl)biphenyl, 2)—triphenylmethyl- imidazo [4,5—c ]pyridine, is obtained. starting from this —benzyl—2-butyl[2‘—(1(or 2)- triphenylmethyltetrazol4Fyl)biphenyl—4—ylmethyl]—4,5- m.p. 81°, is with benzyl bromide, dihydro—4—oxo—3H-imidazo[4,5—c]pyridine, obtained. c) A solution of 1. g of the product obtained in 4 ml of dichloromethane and 4 ml of for 3 hours with 4 ml of according to b) methanol is stirred at 20° ethereal HCl solution. It is evaporated, the residue is worked up in the customary manner and, after chromatographic separation of the triphenylcarbinol formed, 5-benzylbutyl-4,5—dihydro—4—oxo—3-[2'— (tetrazo1—5-yl)biphenyl—4—ylmethy1]—3H— imidazo[4,5—c]pyridine, heptahydrate, m.p. 130°. K salt, dihydrate, m.p. 250°, is obtained.

Example 9 A solution of 573 mg of 2—butyl—4,5—dihydro p—methoxycarbonylbenzyl—4—oxo—3—[2'-(tetrazol—5- yl)biphenyl—4—ylmethyl]-3H—imidazo[4,5—c]pyridine in 17 ml of THF and 6 ml of methanol is treated with 3 ml for 5 in the of 1 n aqueous NaOH solution and stirred_at 20° acidified with HCl, manner hours. It is worked up customary and 2-butyl-5—p—carboxybenzy1-4,5- dihydrooxo[2'-(tetrazol—5—yl)biphenyl ylmethyl]-3H-imidazo[4,5-c]pyridine, 300°; Rf .26 (ethyl acetate/methanol 1:1), m.p. > is obtained. _24_ Analogously, by hydrolysis of the corresponding methyl the 2—butyl—4,5-dihydro—4—oxo—3-[2‘— (tetrazol—5-yl)biphenyl—4—ylmethyl]—3H— esters imidazo[4,5—c]pyridines below are obtained: m.p. 211°, mono—K salt, m.p. > 300°, di—K salt, monohydrate, m.p. 283° -o-carboxybenzyl—, ~m-carboxybenzyl—.

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 composition are produced by compression in conventional manner and, where required, are provided with a conventional sucrose— based coating: —Butyl—3—(2‘—cyanobiphenyl-4—ylmethyl)—4,5—dihydro—4— oxo—3H—imidazo[4,5-c]pyridine 100 mg Microcrystalline cellulose 278.8 mg Lactose 110 mg Maize starch 11 mg Magnesium stearate 5 mg Finely divided silicon dioxide 0.2 mg Example B: Hard gelatin capsules Conventional two-part hard gelatin each filled with capsules are Active ingredient of formula I 100 mg Lactose 150 mg Cellulose 50 _mg Magnesium stearate 6 mg Example C: Soft gelatin capsules filled with a mixture of 40 mg of active ingredient and 250 mg Conventional soft gelatin capsules are of olive oil in each case. -25..

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

Claims (9)

Claims Imidazopyridine derivatives of formula I tetrazol-5—y1a1ky1 having 1-6 C atoms with aralkyl having 7-11 C atoms which COOH, COOA, R2 in which 6 R

1 ,N R is ‘?'< 1 4 N NR / Y R1 is A having up to 6 C atoms, R2 is COOH, COOA, CN or tetrazo1—5—yl, R3 is H, R4 is H, the "alkyl" moiety, is unsubstituted or monosubstituted by Hal, CN, N02 or tetrazo1—5—y1, or \ CH2 x 3 2 R ' R R6 is H, X is absent, Y is O, A is alkyl having 1-6 C atoms and 1O _2'7_ Hal is F, Cl, Br or I, and their salts.

2. 5-Benzyl—2-butyl-4,5-dihydro-4—oxo—3—[2’— (tetrazol-5—ylbiphenyl—4—ylmethyl]—3H—imidazo[4,5— c]pyridine and its potassium salt.

3. Process for the preparation of imidazopyridine derivatives of formula I according to Claim 1, and their salts, characterised in that (a) a compound of formula II R E—CH2—©—X R? 3 in which E is Cl, Br, I, a free OH group or an OH group which has been functionally modified to acquire reactivity, and R2, R3 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, O3.’ (b) to prepare a compound of formula I in which R4 is H and Y is O, a compound of formula IV 1O 2 R in which R7 ls and 1 R E1 is Cl, Br, I or an OH group which has been functionally modified to acquire reactivity, and R1, R2, R3, R6 and X are as defined in Claim 1, is treated with a solvolysing agent, or (c) a compound of formula V R2 in which RQNH R6 ’ 8 I 4 R is ¥Q1ghl /PQFQ 1 Y R9 is R9—CO or H, 35 _29_ R10 is H (if R9 is Rl—CO) or Rl—CO (if R9 is H) and R1, R2, R3, R4, R6, X and Y are as defined in Claim 1, is treated with a cyclising agent, or (d) a compound of formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, and/or in that one or more radicals R and/or R2 in a compound of formula I are converted to one or more other radicals R and/or R2, and/or a base or acid of formula I is converted to one of its salts.

4. Process for the preparation of pharmaceutical characterised in that a formulations, 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. Pharmaceutical formulation, characterised in that it contains at least one compound of formula I according to Claim 1, and/or one of its physiologically acceptable acid addition salts.

6. Compounds of formula I according to Claim 1, their physiologically acid addition and acceptable salts, for combating diseases.

7. Use of Claim 1, addition salts, for the preparation of a drug.

8. Use of Claim 1, addition compounds of formula I according to and/or their physiologically acceptable acid compounds of formula I according to and/or their physiologically acceptable acid salts, for the preparation of a drug, in combating diseases.

9. Compounds of formula III in which R is as defined in Claim 1. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.