IL106628A - Polysubstituted imidazopyridines and imidazodiazines their preparation and pharmaceutical compositions containing them - Google Patents

Description

ηηΐΝ α·»½Όηη nmpn "»- v!om POLYSUBSTITUTED IMIDAZOPYRIDINES AND IMIDAZODIAZINES ; THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM This invention concerns novel azaindenes and* more particularly* novel imidazopyridine and imidazodiazine derivatives which possess pharmacologically useful properties in antagonising at least in part one or more of the actions of the substances known as angiotensins* and in particular of that known as angiotensin II (hereafter referred to as All). The invention also concerns pharmaceutical compositions of the novel compounds for use in treating diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in vhich the renin-angiotensin-aldosterone system plays a significant causative role. The invention also includes processes for the manufacture of the novel compounds , The angiotensins are key mediators of the renin-angiotensin-aldosterone system, vhich is involved in the control of homeostasis and fluid/electrolyte balance in many varm-blooded animals, including man. The angiotensin knovn as All is produced by the action of angiotensin converting enzyme (ACE) from angiotensin I, itself produced by the action of the enzyme renin from the blood plasma protein angiotensinogen. All is a potent spasmogen especially in the vasculature and is knovn to increase vascular resistance and blood pressure. In addition* the angiotensins are knovn to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms. Hitherto there have been a number of different approaches to pharmacological intervention in the renin-angiotensin-aldosterone system for therapeutic control rf blood pressure and/or fluid/electroly e balance, including, for example, inhibiting the actions of renin or ACE. Hovever, there remains a continuing need for an alternative approach because of the side-effects and/or idiosyncratic reactions associated vith any particular therapeutic approach* GB 1186504 generiically dlscleses certain substituted Imldazopyrldlnes possessing blocldal activity, but does not specifically teach the compounds of the present Invention. Certain substituted imidazoles described In European Patent Application, publication no. 253310 A2 are known to Inhibit the action 0f angiotensin II.

Israeli Patent Application No. 94282 discloses novel azaindene compounds, possessing angiotensin antagonist activity^ We have now discovered that the compounds of the invention (set out below) surprisingly antagonise one or more of the actions of the substances known as angiotensins (and in particular of All) and thus minimise the physiological effects associated with their presence in warm-blooded animals (including man) and this is the basis of the invention.

According to the invention there is provided an azaindene derivative of the formula I (set out hereinafter, together with the other chemical formulae identified by Roman numerals) wherein A, together with the adjacent vinylene group of the imidazole moiety completes an azene ring selected from pyridine* pyrimidine* pyridazine or pyrazine ring; R1 is (l-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-4C)alkyl, phenyl or phenyl( l-4C)alkyl; R2 is hydrogen, (l-4C)alkyl* ( l-4C)alkoxy, halogeno* trifluoromethyl, cyano or nitro; R~* and R4 are substituents on the said azene ring wherein 3 one of R and R is selected from (3-8C)cycloalkyl* hydroxy, hydroxymethyl and formyl, and the other of R 3 and R is selected from hydrogen, (l-4C)alkyl, (3-8C)cycloalkyl, ( l-4C)alkoxy» halogeno, trifluoromethyl, cyano, nitro, hydroxy, hydroxymethyl and formyl; or when A together with the imidazole moiety to which it is attached is an imidazo( 4, 5-b] pyridine or imidazo[ 4, 5-c] pyridine group* R and R when they are on adjacent carbon atoms of A form a trimethylene or tetramethylene group* or together with the adjacent vinylene group of A complete a benzene ring, the latter optionally bearing a halogeno, (l-4C)alkyl or (l-4C)alkoxy substituent; or when A together with the imidazole moiety to which it is attached is other than a 3 lH-imidazo[4, 5-c1pyridine ring, one of R or R is a carboxy or (l-6C)alkoxycarbonyl group and the other is as. defined above; X is phenylene optionally bearing a substituent selected from (l-4C)alkylj (l-4C)alkoxy and halogeno* or X is a direct bond between the adjacent phenyl and methylene moieties; and Z is lH-tetrazol-5-yl or a group of the formula -CO.OR5 or -CO.NII.S02.R6 in which R5 is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol* and R6 is (l-6C)alkyl, (3-8C)cycloalkyl or phenyl? and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (l-4C)alkyl* (l-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a physiologically acceptable salt thereof except when R is other than en and R3 or R4 is other than carboxy.

It will appreciated that ten different groups of imidazo-pyridines (formulae la - Id) and iraidazodiazines (formulae Ie - Ij) are encompassed within the above formula I definition and are included as separate parts of the invention. Of these groups, the compounds of formula la are of particular interest. Also* depending on the nature of the substi tuents , certain of the formula I compounds may possess one or more chiral centres and may be isolated in one or more racemic or optically active forms. It is to be understood that this invention concerns any form of such a compound of formula I which possesses the afore-mentioned useful pharmacological properties, it being well known how to make optically active forms, for example by synthesis from suitable chiral intermediates, and how to determine their pharmacological properties, for example by use of the standard tests described hereinafter.

It is to be understood that generic terms such as "alkyl" include both straight and branched chain variants when the carbon numbers permit. However, when a particular radical such as "propyl" is given, it is specific to the straight chain variant, branched chain variants such as "isopropyl" being specifically named where intended. The same convention applies to other radicals.

A particular value for R when it is alkyl is* for example, methyl, ethyl, propyl, butyl, isobutyl* sec-butyl » pentyl or hexylj when it is cycloalkyl is, for example* cyclopropyl, cyclopentyl or cyclohexyl; when it is cycloalkyl-alkyl is, for example » cyclopropylmethyl, cyclopentylmethyl, cyclohexylmeth l or 2-cyclopentyl-ethyl; and when it is phenylalkyl is* for example, benzyl, 1-phenylethyl or 2-phenylethyl; Particular values for R^, R"^ R or an optional substituent which may be present when X is phenylene or when R and R together with the adjacent vinylene group of A complete a benzene ring, include, by way of example:-when it is alkyl, methyl and ethyl} when it is alkoxy, methoxy and ethoxyi and when it is halogeno, fluoro, chloro, bromo and iodo. 3 4 A particular value for R or R when it is cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.

A particular value for R or R when it is (l-6C)alkoxycarbonyl is, for example methoxycarbonyl* ethoxycarbonyl or propoxycarbonyl. 5 A particular value for R when it is a non-toxic , biodegradable residue of a physiologically acceptable alcohol oir phenol is, for example, a residue derived from a ( l-6C)alkanol such as methanol or ethanol, or phenol, glycerol or the like.

A particular value for ^ when it is alkyl is, for example, methyl, ethyl, propyl* isopropyl, butyl or pentyl; and when it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.

Particular values for optional substituents which may be present on phenyl moieties include, by way of example, for halogeno, fluoro, chloro and bromo; for alkyl, methyl or ethyl; and for alkoxy, methoxy and ethoxy.

Specific values for X which are of particular interest include, for example, when it is a direct bond or p_-phenylene.

A preferred value for R"* is, for example, hydrogen, for R is, for example, butyl, and for Z is, for example* lH-tetrazoi-5-yl.

Particular groups of compounds of the invention comprise: - (1) imidazopyridines of the formula la, lb, Ic or Id; (2) imidazopyrazines of the formula Ie; (3) imidazopyrimldines (that is purines) of the formula If or Ig; and (4) imidazopyridazines of the formula Ih, Ii or Ij j in any of which R , R , R , R , X and Z have any of the meanings defined above; together with the pharmaceutically acceptable salts thereof.

A particularly preferred group of compounds of the formula I comprises :- (a) imidazopyridines of the formula la, lb or Id; (b) imidazopyrazines of the formula Ie; (c) imidazopyrimldines of the formula If or Ig; and (d) imidazopyridazines of the formula Ij ; 1 2 wherein in any of the above groups R is (l-6C)alkyl; R is hydrogen 3 4 or halogeno; one of R and R is selected from hydroxymethyl and — . * —* - - - . _ hydroxy, and the other of R and R is selected from hydrogen, halogeno, (l-4C)alkyl, ( l-4C)alkoxy, hydroxymethyl and hydroxy; X is a direct bond or p_-phenylenej and Z is selected from lH-tetrazol-5-yl, carboxy and a group of the formula -C0.NH. S02.R6 in which R6 has any of the meanings defined above, and wherein Z is attached at the 2- or 4-position relative to X.

Compounds of the invention which ace of particular interest include, for example* the specific embodiments set out hereinafter in the accompanying Examples, and in particular those in Examples 1* 3, 4, 5, 11, 12, 15 and 17.

Particularly suitable salts of compounds of formula I include, for example, salts with bases affording physiologically acceptable cations, for example* alkali metal (such as sodium and potassium), alkaline earth metal (such as magnesium and calcium), aluminium and ammonium salts* as well as salts with suitable organic bases* such as with ethanolamine, methylamine* diethylamine or triethylamine. In addition* for those compounds in which the ring containing A is sufficiently basic (for example, where it is pyrazine or pyridine), particularly suitable salts of formula I compounds also include, salts with acids affording physiologically acceptable anions, for example salts with hydrohalides (such as hydrochloride or hydrobromide salts), sulphuric and phosphoric acid.

The compounds of formula I may be obtained by standard procedures of organic chemistry well known in the art for the production of structurally analogous heterocyclic compounds. Such procedures are provided as a further feature of the invention and include, by way of example, the following illustrative procedures in which the generic radicals have any of the values given above* unless stated otherwise. a) For those compounds in which Z is carboxy (that is in which Z is a group of the formula -CO.OR^ in which R5 is hydrogen), a carboxylic acid derivative of the formula II* in which Q is a protected carboxy group selected from (l-6C)alkoxycarbonyl (especially methoxy-, ethoxy-, propoxy- or t^-butoxy-carbonyl) * phenoxycarbonyl, benzyloxycarbonyl and carbamoyl, is converted to carboxy.

The conversion may be carried out* for example by hydrolysis, conveniently in the presence of a suitable base such as an alkali metal hydroxide, for example, lithium, sodium or potassium hydroxide. The hydrolysis is generally carried out in the presence of a suitable aqueous solvent or diluent, for example in an aqueous (l-4C)alkanol, such as aqueous methanol or ethanol. However, it may also be performed in a mixture of an aqueous and non-aqueous solvent such as water and toluene using a conventional quaternary ammonium phase tranfer catalyst. The hydrolysis is generally performed at a temperature in the range, for example, 0 - 120°C, depending on the reactivity of the group Q. In general, when Q is carbamoyl, temperatures in the range, for example, 40 - 120°C are required to effect the hydrolysis.

Alternatively, when Q is benzyloxycarbonyl, the conversion may also be performed by hydrogenolysis, for example using hydrogen at 1-3 bar in the presence of a suitable catalyst, such as palladium on charcoal or on calcium sulphate, in a suitable solvent or diluent such as a (l-4C)alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 - 40eC.

Further, when Q is t:-butoxycarbonyl, the conversion may also be carried out by hydrolysis at a temperature in the range, for example, 0 - 100°C, in the presence of a strong acid catalyst, such as trifluoroacetic acid. The hydrolysis may either be performed in an excess of the acid or in the presence of a suitable diluent such as tetrahydrofuran, jt-butyl methyl ether or 1,2-dimethoxyethane. b) For those compounds of formula I wherein Z is tetrazolyl, a compound of the formula III in which L is a suitable protecting group, such as trityl, benzhydryl, trialkyltin (for example trimethyltin) or triphenyltin, affixed to a nitrogen of the tetrazolyl moiety, is deprotected.

The reaction conditions used to carry out the deprotection necessarily depend on the nature of the group L. As an illustration, when it is trityl, benzhydryl, trialkyltin or triphenyltin, the decomposition conditions include, for example, acid catalysed hydrolysis in a mineral acid (such as aqueous hydrochloric or hydrobromic acid), conveniently in an aqueous solvent (such as aqueous dioxan or 2-propanol). The compound of formula I may then be conveniently isolated as the corresponding acid addition salt.

Alternatively, a trityl or benzhydryl group may be removed by hydrogenolysis, for example as described in (a) above for conversion of benzyloxycarbonyl to carboxy.

Compounds of the formula III wherein L is trialkyltin or triphenyltin may be obtained, for example, by reaction of a nitrile of the formula IX with a trialkyltin, such as trimethyltin, or triphenyltin respectively. The reaction is conveniently carried out in a suitable solvent or diluent, such as toluene or xylene, and at a temperature in the range 50-150°C. It will be appreciated that the use of suitable work-up conditions, for example acidic work-up conditions, may enable compounds of the formula I wherein Z is tetrazolyl to be obtained directly without prior isolation of the protected tetrazole. The nitriles of formula IX may be obtained, for example, by alkylation of an imidazole derivative of the formula IV with a nitrile of the formula X wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or £-toluenesulphonyloxy, using similar conditions to those used in process (c) described hereinafter. The necessary compounds of formula IX may be made by standard procedures such as that illustrated in Scheme 1 for compounds in which X is phenylene. c) Reacting an imidazole derivative of the formula IV with a compound of the formula V wherein Hal, stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p_-toluenesulphonyloxy.

The reaction is generally carried out in the presence of a suitable base, for example, an alkali metal carbonate such as potassium carbonate or an organic base such as diisopropylethylamine and in a suitable solvent or diluent, for example in a polar solvent such as dimethylformamide and at a temperature in the range, for example, 10 - 80°C.

Procedure (c) is particularly suitable for the production of those compounds of the formula I in which Z is a group of the formula -CO. OR"* in which R^ is other than hydrogen, for example wherein R^ is (l-6C)alkyl, benzyl or phenyl, which compounds are also starting materials of formula II for the reaction described in (a) above.

Similarly, using an analogous procedure, but starting with the appropriate compound of the formula VI, the starting materials of the formula III may be obtained for procedure (b). In this context, it will be appreciated that when the ring containing A contains the nitrogen atoms asymmetrically disposed (that is when it is [c] pyridazine, [djpyrimidine or pyridine), various positional isomeric forms of formula II or III will generally be obtained during alkylation of the imidazole derivative of formula IV with the compound of formula V and VI, respectively. Such positional isomeric forms may be separated by conventional procedures such as fractional crystallisation or chromatography.

The majority of the imidazole derivatives of formula IV are already known and the remainder can be made by analogy therewith using standard procedures of organic chemistry well known in the art, for example as described in standard works of heterocyclic chemistry such as that edited by Elderfield. The necessary compounds of the formula V (and also of formula VI) may be made by standard procedures such as those which are illustrated in Scheme 1 for compounds in which X is phenylene. (d) Reacting a diamino derivative of the formula VII with a carboxylic acid of the formula R .CO^ or a (l-AC)alkyl orthoester (for example the methyl or ethyl orthoester) thereof.

When the acid is used, the reaction is generally performed in the presence of a dehydrating agent. Particularly suitable dehydrating agents include, for example, polyphosphoric acid and lower alkyl esters thereof, for example, the ethyl ester thereof.

The reaction may be performed in the absence of solvent or conveniently in the presence of an excess of the carboxylic acid of formula or of an orthoester thereof. The reaction is usually performed at an elevated temperature, for example in the range A0-150°C.

It will be appreciated that an intermediate frequently obtained in the reaction is an alkanoylamino compound of the formula VIII, formed by initial acylation of the primary amino group. This compound of formula VIII may be separately formed, for example, by reaction of the compound of formula VII with the acid chloride, bromide or anhydride of those alkanoic acids of formula R^".CO„H in 1 which R is other than hydrogen, generally in the presence of a suitable base such as triethylamine or pyridine at a temperature in the range, for example, 0 - 50°C. Those compounds of formula VIII wherein R^" is hydrogen may be obtained, for example, by heating the diamino compound of formula VII with formic acid or triethylortho-formate at a temperature in the range, for example, 40 - 100°C. The alkanoylamino compound of formula VIII may then be cyclised by heating with a suitable dehydrating agent as described for process (d) above.

The diamine derivatives of formula VII may be obtained by standard procedures of heterocyclic chemistry, for example as are described in the standard textbooks such as those edited by Elderfield eJC alia.

Whereafter, those compounds of the formula I wherein Z is a group of the formula -CO.NH. SO-R^ or a group of the formula -CO.OR^ in 5 which R is other than hydrogen, may be obtained, for example, by reacting a carboxylic acid of the formula I in which Z is carboxy (or a reactive derivative of said acid) with a sulphonamide of the formula NE^.SC^R** or a hydroxy compound of the formula HO.R^, or with a salt thereof (for example, an alkali metal thereof). Suitable reactive derivatives include, for example the chloride, bromide, azide, anhydride and mixed anhydride with formic or acetic acid of the carboxylic acid of formula I as defined above. When the free acid form is used, the reaction is generally carried out in the presence of a suitable dehydrating agent such as dicyclohexycarbodiimide or 3-(3-dimethylaminopropyl)-l-ethylcarbodiimide in the presence of a base such as triethylamine or pyridine. When a reactive derivative is used, either the reaction is carried out in the presence of a base such as mentioned above, or the sulphonamide or hydroxy compound is used in the form of a salt, such as its alkali metal salt (in particular the lithium, sodium or potassium salt thereof). The reaction is generally performed in the presence of a suitable diluent or solvent such as dioxan, t-butyl methyl ether or tetrahydrofuran and at a temperature in the range, for example, 0 - 60°C.

Whereafter, when a salt of a compound of formula I is required, it may be obtained, for example, by reaction with the appropriate base or acid affording a physiologically acceptable ion, or by any other conventional salt formation procedure.

Further, when an optically active form of a compound of formula I is required, one of the aforesaid processes may be carried out using an optically active starting material. Alternatively, the racemic form of a compound of formula I may be resolved, for example when Z is an acidic group by reaction with an optically active form of a suitable organic base, for example, ephedrine, Ν,Ν,Ν-trimethyl-(l-phenylethyl)ammonium hydroxide or 1-phenyletnylamine j followed by conventional separation of the diastereolsomeric mixture of salts thus obtained, for example by fractional crystallisation from a suitable solvent, for example a (l-4C)alkanol, whereafter the optically active form of said compound of formula I may be liberated by treatment with acid using a conventional procedure, for example using an aqueous mineral acid such as dilute hydrochloric acid. In an analogous manner, when the compound of formula I is sufficiently basic, the resolution may also be performed, for example by reacting the racemic form with the optically active form of a suitable organic acid such as camphorsulphonic acid.

As stated above, the compounds of formula I will have beneficial pharmacological effects in warm-blooded animals (including man) in diseases and medical conditions where amelioration of the vasoconstrictor and fluid retaining properties of the renin-angiotensin-aldosterone system is desirable, at least in part by antagonism of one or more of the physiological actions of All. The compounds of the invention will thus be useful in the treatment of diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.

The antagonism of one or more of the physiological actions of All and, in particular, the antagonism of the interaction of All with the receptors which mediate its effects on a target tissue, may be assessed using one or more of the following, routine laboratory procedures:- Test A; This in vi tro procedure involves the incubation of the test compound initially at a concentration of 100 micromolar (or less) in a buffered mixture containing fixed concentrations of radiolabelled All and a cell surface membrane fraction prepared from a suitable angiotensin target tissue. In this test, the source of cell surface membranes is the guinea pig adrenal gland vhich is well known to respond to All. Interaction of the radiolabelled All with its receptors (assessed as radiolabel bound to the particulate membrane fraction following removal of unbound radiolabel by a rapid filtration procedure such as is standard in such studies) is antagonized by compounds which also bind to the membrane receptor sites and the degree of antagonism (observed in the test as displacement of - membrane-bound radioactivity) is determined readily by comparing the receptor-bound radioactivity in the presence of the test compound at the specified test concentration with a control value determined in the absence of the test compound. Using this procedure compounds showing at least 50% displacement of radiolabelled All binding at a -4 concentration of 10 M are retested at lower concentrations to determine their potency. For determination of the (concentration for 502 displacement of radiolabelled All binding), concentrations of the test compound are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.

In general, acidic compounds of formula I as defined above show significant inhibition in Test A at a concentration of 50 micromolar or much less.

Test B; This in vitro test involves the measurement of the antagonistic effects of the test compound against All-induced contractions of isolated rabbit aorta, maintained in a physiological salt solution at 37°C. In order to ensure that the effect of the compound is specific to antagonism of All, the effect of the test compound on noradrenaline-induced contractions may also be determined in the same preparation.

In general, acidic compounds of formula I as defined above show significant inhibition in Test B at a final concentration of 50 micromolar or much less.

[Note: Compounds of formula I wherein Z is a group of the formula -CO.OR in which R is other than hydrogen in general show only weak activity in the in vitro Tests A or B. ] Test C; This in vivo test involves using terminally-anaesthetised or conscious rats in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure. The All antagonistic effects of the test compound following oral or parenteral administration, are assessed against angiotensin II-induced pressor responses. To ensure that the effect is specific the effect of the test compound on vasopressin-induced pressor responses may also be determined in the same preparation.

The compounds of formula I generally show specific All-antagonist properties in Test C at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.

Test D: This in vivo involves the stimulation of endogenous All biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet of low sodium content and giving appropriate daily doses of a saluretic known as frusemide. The test compound is then administered orally or parenterally to the animal in which an arterial catheter has been implanted under anaesthesia for the measurement of changes in blood pressure.

In general compounds of formula I will show All-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.

The compounds of formula I will generally be administered for therapeutic or prophylactic purposes to warm-blooded animals (including man) requiring such treatment in the form of a pharmaceutical composition in conjunction with a pharmaceutically acceptable diluent or carrier, as is well known in the pharmaceutical art. Such a pharmaceutical composition is provided as a further faeture of the invention and will conveniently be in a form suitable for oral administration (e.g. as a tablet, capsule, solution, suspension or emulsion) or parenteral administration (e.g. as an injectable aqueous or oily solution, or injectable emulsion).

The compounds of formula I may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art. -to be of value in treating one or more of the diseases or medical conditions referred to hereinabove.

In general a compound of formula I (or a pharmaceutically acceptable salt thereof as appropriate) will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body weight (and preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or salt) administered and the route and form of administration depending on size, age and sex of the person being treated and on the particular disease or medical condition being treated according to principles well known in the medical arts.

By way of illustration of the angiotensin II inhibitory properties of compounds of formula I, the compound of Example 3 gave the following results in tests A, B and C described above: -In test A: IC5Q of 1.49xlO~8M; In test B: A2 of 9.2; In test C: of 1.07mg/kg (parenteral administration); 54% inhibition after one hour at a dose of 20mg/kg (oral administration).

In addition to their aforesaid use in therapeutic medicine in humans, the compounds of formula I are also useful in the veterinary treatment of similar conditions affecting commercially valuable warm-blooded animals, such as dogs, cats, horses and cattle. In general for such treatment, the compounds of the formula I will generally be administered in an analogous amount and manner to those described above for administration to humans. The compounds of formula I are also of value as pharmacological tools in the development and standardisation of test systems for the evaluation of the effects of All in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the continuing search for new and improved therapeutic agents.

The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:- (i) concentrations and evaporations were carried out by rotary evaporation in vacuo; (ii) operations were carried out at room temperature, that is in the range 18-26eC; (iii) flash column chromatography was performed on Merck ieselgel 60 (Art. no. 9385) obtained from E Merck, Darmstadt, Germany; (iv) yields, where given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development; (v) proton NMR spectra were normally determined at 200 MHz in CDCl^ using tetramethylsilane (TMS) as an internal standard, and are expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for designation of major peaks: s, singlet; m, multiplet; t, triplet; br, broad; d, doublet; and (vi) all end-products had satisfactory microanalyses.

Reference Examp l e 1 4M Aqueous sodium hydroxide solution (0;4 ml) was added to a solution of methyl 4'-[ (2-butyl-3H-irnidazo[4 >5-b]pyrid-3-yl)methyl]- biphenyl-2-carboxylate (A) (210 mg) in methanol (3 ml)i The solution was heated under reflux for 2 hours and then volatile material was removed by evaporation. The residue was dissolved in water (5 ml) and the solution acidified to pH 4 with 20% w/v aqueous citric acid. The precipitated solid was filtered off and triturated with ether to give 4 ' -[ (2-butyl-3H-imidazo [4 , 5-b] yrid-3-yl)raethyll-biphenyl-2-carboxylic acid (153 mg), as a cream powder, m.p. 185- 187eC; NMR (dg-DMSO): 0.9(t,3H), 1.35(m,2H), 1.7(m,2H), 2.85(t,2H), 5.6(sj2H)j 7.1-7.6 (complex mt8H), 7.7(dd,lH), 8.0(dd,lH), 8.3(dd,lH), 12.6(br, IB) ; mass spectrum (negative fast atom bombardment, hereinafter referred to as " -ve FAB"), 199, 174, 168? microanalysis found: Cj74.3; H>5.9} N,10.7 C24H23N3°2 reclulres! C,74.8j H,6.0; N,10.9¾.

The starting material (A) was obtained as follows:- (i) A 1.6H solution of butylli thium in hexane (24.0 ml) was added dropwise to a stirred solution of 4-bromotoluene (6.0 g) in dry tetrahydrofuran (THF) (50 ml) at -78"C under an atomosphere of argon. The temperature was maintained at -78°C for 20 minutes and then a 1M solution of anhydrous zinc chloride in ether (38.6 ml) was added. The solution was kept at -78eC for 15 minutes and then tetrakis(triphenyl-phosphine)palladium (60 mg) in THF (5 ml) was added, followed by methyl-2-idodobenzoate (6.1 g) in THF (10 ml). The solution was allowed to reach ambient temperature over 1 hour and then heated under reflux for 5 hours. The solvent was removed by evaporation and the residue was dissolved in chloroform (150 ml). The solution was washed with a solution of ethylenediaminetetraacetic acid (10 g) in water (100 ml) and the aqueous layer was re-extracted with chloroform (100 ml). The combined orgaric extracts were dried (MgSO^) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl/acetate hexane (1:9 v/v to give methyl 4' -methylbiphenyl-2-carboxylate (B) as a colourless oil (4.4 g); NHR (CDC13): 2.4(s,3H), 3.65(s,3H), 7.2(s,4H)j 7.35(n 2H), 7.5(m,lH), 7.8(d,lH). (ii) N-Bromosuccinimide (8.1 g) and azo(bisisobutyroni trile) (130 mg) were added to a solution of the compound (B) (9i3 g) iii carbon tetrachloride (300 ml). The mixture was heated under reflux for 4 hours and then cooled to ambient temperature. Insoluble material was removed by filtration and the filtrate concentrated in vacuo. T e residue was purified by flash chromatography* eluting with ethyl acetate/hexane (1:9 v/v) to give methyl 4' -(broraoraethyl)biphenyl-2-carboxylate (C) as a solid (10.9 g), in. . 48eCj NMRi 3.65(s,3B), 4.55(s,2H), 7.25-7.60 (complex m,7B), 7.85(d,lB). (iii) A mixture of 2-butylimidazo(4»5-b]pyridine (400 mg), [Indian J. Chem., Sec. B, 1978, 16B, 531), the bromomethyl compound (C) (700 mg) and potassium carbonate (630 mg) in Ν,Ν-dimethylformajnide (DHF) (7 ml) was stirred for 4 hours. The solvent was removed by evaporation and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The organic phase was separated, washed with water (20 ml) and then with saturated brine (20 ml), dried (MgSO^) and the solvent evaporated. The residue was purified by flash chromatography, eluting with methanol/dichlororaethane (3i97 v/v, gradually changing to 5i95 v/v), to give initially methyl 4'-i(2-butyl-3H-imidazo[4,5-blpyrid-3-yl)methyl]biphenyl-2-carboxylate (A) (260 mg), as an orange guraj NHR (CDCl3)i 0.9(t,3H)» 1.4(m,2H), 1.8(ra,2B), 2.85(t,2H), 3.6(s>3B), 5.55(si2H)i 7.1-7.6(complex m,8H), 7.8(dd,lfl), 8.0(dd,lH)r 8.35(djlH)| and then methyl 4'-[(2-butyl-lH-imidazo[4,5-b)pyrid-l-yl)methyllbiphenyl-2-carboxylate (80 mg), as a yellow gum; NMJR(CDCl3)t 0.9(t>3B)» l»45(m,2B), 1.85(m,2H), 2.9(t,2H), 3.6(s,3H), 5.4(sj2H)> 7;0-7.6(complex m,9H), 7.8(dd,lB)i 8.5(dd,lH)t and finally methyl 4' -( (2-butyl-4H-imidazo-(4,5-b]pyrid-4-yl)methyl]biphenyl-2-carboxylate (220 mg)* as a yellow gum; NHR (CDCl-j): 1.0(t,3H)> 1.5(m,2H), 1.9(m,2H)» 3.05(ti2H), 3.6(s,3B), 5.9(s,2H), 7.0(t,lB), 7.2-7.6(complex m,3H)> 7.85(d»lH), 8.1(d,lB).

Reference Example 2 2-Butyl-3-{(2'-(2-triphenymethyl-2fl-tetrazol-5-yl)biphenyl- 4-yl)methyll-3U-imidazo[4,5-b]pyridine (D) (600 mg) was dissolved in dioxan (20 ml) and concentrated hydrochloric acid (20 ml) was added. The solution vas alloved to stand for 6 hours and then volatile material vas removed by evaporation* The residue was stirred vigorously vith dichlorome thane (5 ml) and ether (20 ml) vas added. The mixture vas stirred for 15 minutes* The solid material was collected by filtration and washed vith ether (10 ml) to give 2-butyl-3-l(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyll-3fl-imidazo- [4,5-b]pyridine hydrochloride (300 mg)» as a cream powder* m.p. 224eC (decomposition); NHR (dg-DMSO)! 0.9(t.3H), 1.4(m,2H), l.l(m,2H)* 3.05(t.2H)f 5.6(s,2U), 7.1(d,2U), 7.2(d,2H), . -7 * 7 (complex , 511), 8.2(dd,lU), 8.5(dd,lil)» mass spectrum (-ve FAB* DHSO/ni trobenzyl alcohol)! 408(M-H)~| microanalysis found! C,64.2| H*5;6» N,219} Cl,8.0? C2 U23 7,UC1 requires! C,64.6| H,5»4) N,22.0> Cl 8.5X.

The starting material (0) was obtained as follows i- Λ mixture of 2-butylimidazo[4,5-b]pyridine (1*0 g)* 5- l2-(4' - bromomethylbiphehylyl) ]-2-triphenylmethyl-2H-tetrazole (obtained as described in European patent application* publication no. 291969 j 3.17 g) and potassium carbonate (1*16 g) in DHF (20 ml) was heated at 95'C overnight. The reaction mixture vas then treated using the vork-up procedure described in Example 1, part (iii). The material obtained vas purified by flash chromatography, eluting vith ethyl acetate/ hexane (17.3 v/v), gradually changing to ethyl acetate/methanol (9s 1 v/v). There vas thus obtained initially 2-butyl-3-[(2'-(2-triphenylraethyl-2H-tetrazol-5-yl)biphenyl-4-yl)- me thy1 J -3H-imidazo[ Λ ( 5-b)pyridine (D) (0.72 g), as a yellow foam; NHR(CDCl3)s 1.0(t,3H), 1.45(m,2H), 1.9(m,2H)* 2.8(t,2H), 5.5(s,2H), 7.0(m,8H), 7.2(df 2H) , 7.3-7.5 (complex, 12U) 7.55(ra,2H), 8.0(m,lH), 8.1(dd,lll), 8.45(dd,lH)j and then 2-butyl-4-| (2'-(2-triphenylmethyl- 211-te trazol-5-yl)biphenyl-4-yl)-me thy1 J-4H-imidazo[ , 5-b] pyridine (1.10 g), as a reddish foam} NHR: l*0(t,3H), 1.5(m,2H), 1.9(m,2H), 3.1(t,2H), 5.7(s,2H), 6.7(dd,lH), 6.9(m,6H), 7.1-7.4 (complex m,16H), 7.5(m,lH), 8.0(m,lH), 8.1(d,lH).

Example 1 Using an analogous procedure to that described in Reference Exampl 1, but starting from the appropriate ester instead of compound A,, the following compound was prepared in yields of 54-74X J - 4'-( (2-butyl-4-hydroxy-3H-imidazo[4,5-d]pyridazin-3-yl)methylJbiphenyl-2-carboxylic acid was obtained as a solid, to. p. 232-233°Cj NHR (dg-DMSO): 0.8(t,3H)| 1.3(n»2H)f 1.6(ai2H)» 2.75(t,2H), 5.8(s,2H), 7.18-7.35(m,5H), 7.45(m,2H), 7.7(dd,lH), 8.35(d,lH), 12.75(srlH); mass spectrum (-ve FAB, DHSO/glycerol) ! 401(M-H)~j microanalysis, found: C,68.'3; H,5.4; N,13.7X; C23H22N2°4 requires C,68.7; H,5.5j Njl3.9X. ng an analogous procedure to that described in Referenced part (iii) by alkylation of the appropriate imidazole derivative of formula IV with 4' -(bromomethyl)biphenyl-2-carboxylate. The compound was obtained in yields of 12-74X as described In Example 1A.

Reference Example 3 2-butyl-5-bromoimidazo[4,5-b]pyrazine vas obtained by cyclisation of 5-bromo-2,3-diaminopyrimidine as follows. - A mixture of 5-bromo-2, 3-diaminopyriraidine (obtained as described in Gazz. Chira. Ital. , 1960, 90j 1809) (0.4 g)» valeric acid (0.6 ml) and polyphosphoric acid (10 g) was heated at 160eC for 1.5 hours. The mixture was cooled to ambient temperature* poured into water and the solution basified with sodium carbonate solution. The solution was extracted with ethyl acetate and the organic extract worked up using the procedure described in Example 1, part (ill). The resultant product was recrystallised from ethyl acetate to give 2-butyl-5-bromoimidazo[4,5-b]pyrazine (0.33 g) as a solid, m.p. 211-213'C| NHR (CDCl-j/dg-DMSO) ! 1.0(t,3H), 1.4(m,2H)» 1.9(m,2H), 3.0(t,2H), 8.3(s,lH)> mass spectrum (chemical ionisation, ammonia) 255(M+H)* - - Reference Example 4 8-butylpurine was obtained by cyclisation of 2 * 3-diaminopyrimidine as follows :- A mixture of 2 , 3-diaminopyrimidine (0.55 g) and valeric anhydride (4.9 ml) was heated at 210°C for 1.5 hours under an atmosphere of argon. The mixture was cooled to ambient temperature, added to methanol (100 ml) and the resultant solution heated at reflux for 1.5 hours. Solvent and volatile material was removed by evaporation (60°C/0.1 mm of mercury) and the residue purified by flash chromatography eluting with ethyl acetate/methanol (5:1 v/v). The product was triturated with ether to give 8-butylpurine* m.p.l64-165°C; NMR (CDCL-): 1.0(t,3H), 1.5(m,2H); 2;0(m,2H)i 3.1(t,2H), 8.95(s,lH), 9.1(s,lH); mass spectrum (chemical ionlsation, ammonia): 177(M+H)† (Example 1 A)t Alkylation of 2-butyl-4-hydroxyimidazot4j5-djpyridazine gave methyl 4'-[ (2-butyl-4-hydroxy-3H-imidazo[4,5-d]pyridazin-3-yl)-methyl]biphenyl-2-carboxylate as a solid, in. p. 166-1680Cj NMR (d6-DMS0): 0.8(t,3H), 1.3(m,2H), 1.6(m,2H)} 2.75(t,2H)i 3.55(s,3H), 5.78(s,2H), 7.2-7.3(m,4H), 7.4(d,lH), 7.5(dt,lH)j 7.6(dt,lH), 7.7(dd,lH), 8.4(s,lH), 12.8(s,lH); mass spectrum (chemical ionlsation, ammonia): 417(H+H)+; the starting material 2-butyl-4-hydroxyiraidazo-[4,5-d]pyridazine was obtained as follows:- 4 j5-diamino-3-hydroxypyridazine (obtained as described in Belgian patent No. 660637; Chem. Abs. , 1966, 64, 5108) (5 g) was cyclised in an analogous manner to that described in Reference Example 4 for the preparation of 8-butylpurine to give 2-butyl-4-hydroxy-imidazo[4,5-d]pyridazine (2.4 g) as a solid, m.p. 241-243eC; NMR (d6-DMS0): 0.9(t,3H), 1.3(m,2H), 1.7(m,2H), 2.8(t 2H)j 8.28(s,lH), 12.6(s,lH), 13.5(bs,lH)j mass spectrum (chemical ionlsation, ammonia): 193(M+H)+; microanalysis, found: C,55.9; H,6.2} N,29.0¾; C9H12 A0 requires C,56.3; H.6.3; N,29.2%.

Example 2 Using an analogous procedure to that described in Reference 2, but starting from the appropriate compound of formula III wherein L is triphenylmethyl, the following compound was prepared in yields of 36-95*:- 2-butyl-4-hydroxy-3-[(2'-(lU-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4,5-d)pyridazine was obtained as a solid* m.p. 227-230°C: NH (dg-DHSO): 0.8(t,3H), 1.25(m,2H), 1.6(m,2H), 2.75(t,2H), 5.75(s,2U), 6.4(bs,3H), 7.05-7.2(m,4H) , 7.45- .7(mr AH) , 8.35(s,lH): mass spectrum (-ve FAB, DHSO/glycerol) : 425(H-H)~: microanalysis, found: C,59.A; H,4.9; N.23.6; C1.7.3X; C23H22N8°* HCl requires C,59.7; H,5.0; N,24.2; Cl,7.7¾.. an analogous procedure to that described in ReferenceVpart (i) by alkylation of the appropriate imidazole derivative of formula IV. The compound was obtained in yields of 19-67X as follovs!- (Example 2 D)y Alkylation of 2-butyl-4-hydroxyimidazo[4f 5-d]pyridine (obtained as described in Example 1A) gave 2-butyl-4-hydroxy-3-[ (2'-(2-triphenylmethyl-2Il-tetrazol-5-yl)biphenyl-A-yl)methyl]-3U-imidazo(4,5-d Jpyridazine as a solid, m.p. 169-170°C; NHR (CDClj): 0.9(t,3H), 1.3(m,2H), 1.7(m,2H), 2.67(t,2U), 5.65(s,2H), 6.8-6.95(complex m,6H), 7.0(d,2H), 7.1(d,2H), 7.2-7.35(complex m,10H), 7.45(m,2H), 7.9(m,lH), 8.35(s,lH), 11.16(s,lH); mp.ss spectrum (-ve FAB, DHSO/glycerol): 667(H-1I)~.

Examples Ύ,-Α ExaiRQlPausi g an analogous procedure to that described in Reference , but starting from the appropriate compound of formula III wherein L is triphenylmethyl, the following compounds were prepared in yields of 50-92*:- (Example 3) ! 2-butyl-6-(methoxycarbonyl)-3-[ (2' -lH-tetrazol-5-yl)-biphenyl-4-yl)methyl-3U-imidazol4,5-b]pyridine was obtained as a solid; NHR (dg-DHSO): 0.9(t,3H), 1.3-1..5(m, 2H) , 1.6-1.8(m, 2H) , 2.9(t,2H), 3.9(s,3H), 5.6(s,2H)f 7.0-7.2(m, H) , 6.95-7.2(m,4H) , 8.5(d,lH), 8.95(d,lU)| mass spectrum (-ve FAB* DHSO/glycerol): A66(H-H)"; microanalysis, founds C,62.0{ 0,5.1 J N,19.AX} C26H25N7°2'DC1 re(1ulres! c^2.0> U,5.2f N,19.5Xj (Example A ) i 2-butyl-4-hydroxy-3-( (2'-(lU-tetrazol-5-yl)biphenyl- 4-yl)methyl-3B-imidazo(4,5-clpyridine was obtained as a solid* m.p. 234-237°C> NMR (d6-DHSO)s 0.85(t,3B), 1.2-1.4(m,2H) , 1.5-1.68(m,2H) , 2.9(t,2H), 5.95(s,2H), 4.0-6.0( bs , 2B ) , 6.65(d,lH), 7.05-7.25(dd , 411) , 7.35(t,lH), 7.45-7.75(m,4B), 11.8-11.95(bs , 1H) ; mass spectrum (-ve FAB, DHSO/glycerol) ί 424(H-B)~; microanalysis, found! C,62.4} B,5.2{ N,21.22; C24H23 70,HC1 requires: C,62.4; H,5.1; N,21.2X . ing alkylation of the appropriate imidazole derivative of formula IV. The compound was obtained as follovs:- (Example 3D ) ; Alkylation of 2-butyl-6-(methoxycarbonyl)iraidazo-I4, 5-b] pyridine gave 2-butyl-6-(methoxycarbonyl)-3- ( (2' -( triphenyl-methyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazol4,5-b]-pyridine as a solid; NHR (CDC13)I 0.9(t,3fl), 1.3-1.5(m, 2B) , 1.7-1.85(m,2H), 2.7(t,2H), 4.0(s,3B), 5.4(s,2H), 6.9(complex m, ΘΗ) , 7-.l(m,2H), 7.2-7.35(complex m,10B), 7.4-7.5(m, 2B) , 7.9(m,lH), 8.65(d,lB), 9.05(d,lfl)j mass spectrum (-ve FAB, DHSO/glycerol) i 466(H-tri tyl)~; the starting material 2-butyl-6-(rae hoxycarbonyl)-imidazo[4,5-b]pyridine vas obtained as follovsi- (i) methyl 2-chloro-3-nitropyridine-5-carboxylate (obtained as described in J.C.S. , 1951, 2590) was dissolved in a mixture of concentrated aqueous ammonia solution (5ml) and dioxan (30ml). The mixture was stirred for 2 hours and then volatile material vai" removed by evaporation. The residue was purified by flash chromatography eluting with dichloromethane/ethyl acetate(4:l v/v) to give methyl 2-amino-3-ni tropyridine-5-carboxylate as a solid, m.p. 195-196"C} NMR(d6-DMSO)j 3.9(s,3H), 8.7(d,lfl), 8.8(d,lH)j mass spectrum (chemical ionisation, ammonia): 198(M+H) . (ii) Hethyl 2-amino-3-ni tropyr idine-5-carboxylate was reduced vith tin (II) chloride, using an analogous procedure to that described in Examples 13D and 14D. The crude diamine thus obtained was cyclised directly vith polypliosphor ic acid and valeric acid using a similar procedure to that described in Reference Example 3 †o give 2-butyl-6-(methoxycarbonyl)imidazo[4,5-b]pyridine as a solid, m.p. 182-184°C| NHR (d6-DHS0): 0.9(t,3B), 1.3-1.5(m, 2H) , 1.7-1.9(m, 2B) , 2.9(t,2IJ), 3.9(s,3U), 8.3(bs,lH), 8.9(bs,lH)j mass spectrum (chemical ionisation, ammonia): 234(H+B)+.

(Example 4Q )i Alkylation of 2-bu tyl-4-hydroxyimldazo [ 4 , 5-c] pyridine gave 2-butyl-4-hydroxy-3-[(2'-(2-triphenylrnethyl-2H-tetrazol-5-yl)- biphenyl-4-yl)methyl j-3H-imidazol4,5-c]pyridine as a solid, m.p. 158-161°C; NHR (dg-DMSO): 0.75(t,3H), 1.1-1.25(m, 2H) , 1.45-1.6(m, 2H) , 2.55 Pharm. Bull. Japan, 1924, 12(8) , 866) vas cyclised vith valeric anhydride by an analogous procedure to that described in Reference Example 4 to give crude 2-butyl-4-chloroimidazot4,5-c]pyridine, vhich was heated at reflux in formic acid overnight. Volatile material was removed by evaporation and the residue recrystallised from ether/methanol to give 2-butyl-4-hydroxyimidazol4 j5-c]pyridine as a solid, ra.p. 275-280°C; NHR (dg-DHSO)! 0.9(t,3H), 1.2-1.4(m,2H) , 1.6-1.75(m,2H), 2.7(t,2H), 6.45(d,lH), 7.05(t,lB), 10.9-11. l(bs , 1H) , 12.3-13.2( bs , 1U) ; mass spectrum (chemical ionisation, ammonia): 192(H+H)+.

Example ' 1H Sodium hydroxide solution (0.9 ml) vas added to a solution of 2-butyl-6-methoxycarbonyl-3-[ (2'-(2-triphenylmethyl-2H- te trazol-5-yl)biphenyl-4-yl)me thyl]-3H-imidazo[4, 5-b] pyridine (0.6 g) in dioxan/methanol (2:5 v/v; 5 ml) and the mixture was heated at reflux for 4 hours. Volatile material vas removed by evaporation and the residue vas triturated vith dichloromethane and 1H citric acid solution. The residue vas purified by flash chromatography, eluting vitli acetic acid/d i chlorome thane/me thanol( 1 i 20 : 80 v/v) to give 2-butyl-6-carboxy-3-t(2'-(iH-tetrazol-5-yl)biphenyl-4-yl)methyl-3H-imidazo[4j5-b]pyridine (0.19 g) as a solid* m.p; 230-232°C} NMR (d6-DMS0): 0.9(t,3H), 1.2-1.45(m, 2H) , 1.6-i;8(m»2H)f 3.85(t*2H)* 5.55(s,2H), 7.0-7.15(mj4H), 7.45-7.7(m,4H)* 8.4(d,lH)* 8«9(d*lH) mass spectrum (-ve FAB, DMSO/glycerol) s 452(M-H)~j microanalysis, found: c,65.2; H,5.1; N,21. ;° C25H23N-,02>0.36H20 requires: C*65.2 Hj5.2; N,21.3¾.

Example 6 Lithium borohydride (0.2 g) was added to an ice-cooled solution of 2-butyl-6-(methoxycarbonyl)-3-i (2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazot4j5-b]pyridine (0.97 g) in THF (50 ml). The cooled mixture was stirred for three hours and then acidified by dropwise addition of 2H hydrochloric acid. Volatile material vas removed by evaporation and the residue vas partially purified by flash chromatography* eluting vith dichlorocoethane/ methanol (9 si v/v). Purification vas completed by flash chromatography eluting vith acetic acid/dichloromethane/methanol (0.5:5:95 v/v), folloved by recrystallisation from ethyl acetate/methanol to give 2-butyl-6-(hydroxymethyl)-3-t (2*-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazo[4»5-b]pyridine (0.1 g) as a solid, m.p; 93-105eCj NMR (dg-DHSO): 0.9(t»3H)( 1.25-1.45(m,2H) , 1.6-1.8(m,2H), 2.8(t.2H), 4.6(s',2H), 5.7(s,2H)> .7^0-7.2(m,4H), 7.5-7.7(m,4H), 7.9(d,lH), 8.3(d,lH): mass spectrum (-ve FAB, DMSO/glycerol): 438(M-H)~j microanalysis, found* C>68i2} H*5.5j N, 22.3¾; C25H25N7° requires} 0,68.3} H,5.7i N,22.3X.

Example 7 (Note: all parts by veight) The compounds of the invention may be administered for therapeutic or prophylactic use to varm-blooded animals such as man in the form of conventional pharmaceutical compositions* typical examples of which include the follovingJ- a) Capsule (for oral administration) Active ingredient * 20 Lactose powder 578.5 Hagnesium stearate 1.5 b) Tablet (for oral administration) Active ingredient * 50 Microcrys talline cellulose 400 Starch (pregelatinised 47.5 Magnesium stearate 2.5 c) Injectable Solution (for intravenous administration) Active ingredient * 0*05 - 1.0 Propylene glycol 5.0 Polyethylene glycol (300) 3*0 - 5.0 Purified water to 100* d) Injectable Suspension (for intramuscular administration) .05 - 1.0 0.5 0.05 0.9 0.1 to 100X Note.* the active ingredient * may typically be an Example described hereinbefore and will conveniently be present as a pharmaceutically acceptable acid-addition salt* such as the hydrochloride salt* Tablets and capsules formulations may be coated in conventional manner in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating.

HP35291 02-Apr-1990 JJH v Chemical Formulae (continued. ) Scheme 1 (b) 1 X= C Note: R = lover alkyl, benzyl, phenyl; Tr = triphenylmethyl (trityl) Reagents : a) BuLI/THF; ZnCI2/E†20; Pd(Ph P> b) B^Sn.N^/toluene; HCI/†oluene c) Tr.CI/E†3N/CH2CJ2 d) N-bromosuccln!mlde/azelsobu†yronl†rl le/CCI

Claims (1)

1. CLAIMS What ve claim is:- 1. An azaindene derivative of the formula I vherein A, together vith the adjacent vinylene group of the imidazole moiety completes an azene ring selected from pyridine^ pyrimidine, pyridazine or pyrazine ring; R is (l-8C)alkyl( (3-8C)cycloalkyl , 2 (3-8C)cycloalkyl-(l-4C)alkyl, phenyl or phenyl(l-AC)alkyl; R is hydrogen, (l-4C)alkyl, (l-AC)alkoxy, halogeno, trifluoromethyl< cyano 3 A or nitro; R and R are substituents on the said, .azene ring vherein 3 A one of R and R is selected from (3-8C)cycloalkyl» hydroxy^ 3 A hydroxymethyl and formyl, and the other of R and R is selected from hydrogen, (l-AC)alkyl, (3-8C)cycloalkyl (l-AC)alkoxy, halogeno, trifluoromethyl, cyano, nitro, hydroxy* hydroxymethyl and formyl; or vhen A together vith the imidazole moiety to vhich it is attached is 3 4 an imidazo|A,5-b]pyridine or imidazo(A,5-c)pyridine group, R and R vhen they are on adjacent carbon atoms of A form a trimethylene or tetra ethylene group, or together vith the adjacent vinylene group of A complete a benzene ring, the latter optionally bearing a halogeno, (l-AC)alkyl or (l-AC)alkoxy substituent; or vhen A together vith the imidazole moiety to vhich it is attached is other than a 3 A lH-imidazo[A,5-c)pyridine ring, one of R or R is a carboxy or (l-6C)alkoxycarbonyl group and the other is as defined above; X is phenylene optionally bearing a substituent selected from (l-AC)alkyl, (l-AC)alkoxy and halogeno, or X is a direct bond betveen the adjacent r phenyl and methylene moieties; and Z is lH-tetrazol-5-yl or a group of 5 6 "* 5 ' the formula -CO. OR or -CO.NH.SO-.R in vhich R is hydrogen or a 106628/2 - 30 - non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, and R6 is (l-6C)alkyl, (3-8C)cycloalkyl or phenyl; and vherein any of said phenyl moieties may be unsubstituted or bear one or tvo substituents independently selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a physiologically acceptable salt thereof except vhen R"* is other than 3 4 hydrogen and R or R is other than carboxy* 2. A compound as claimed in claim 1 vherein R is methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl , cyclopentylmethyl, cyclohexylmethyl , 2-cyclopentylethyl , phenyl, benzyl, 1-phenylethyl or 2 2-phenylethyl ; R is hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, 3 4 chloro, bromo, iodo, trifluoromethyl, cyano or nitro; R and R are substituents on the said azene ring vherein one of ^ and ^ is selected from cyclopropyl, cyclopentyl, cyclohexyl, hydroxy, 3 4 hydroxymethyl and formyl, and the other of R and R is selected from hydrogen, methyl, ethyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, nitro, hydroxy, hydroxymethyl and formyl; or vhen A together vith the imidazole moiety to vhich it is attached .is an imidazo[4,5-b]pyridine or imidazo|4,5-c]pyridine group, R and R vhen they are on adjacent carbon atoms of A form a trimethylene or tetramethylene group, or together vith the adjacent vinylene group of A complete a benzene ring, the latter optionally bearing a fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy or ethoxy substituent; or vhen A together vith the imidazole moiety to vhich it is attached is other than a 3 4 lH-imidazo[4,5-c Jpyridine ring, one of R or R is a carboxy, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl group and the other is as defined above; X is phenylene optionally bearing a substituent selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo and iodo, or X is a direct bond betveen the adjacent phenyl and methylene moieties; R"* is hydrogen or a residue derived from a (l-6C)alkanol, phenol or glycerol; and R6 is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl; and vherein any of said phenyl moieties may be unsubstituted 1G6628/2 - 31 or bear one or tvo substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloroj bromoj cyano end trifluoromethyl. 3. A compound of the formula la 1 2 3 4 vherein R , R , R , R , X and Z have any of the values as defined in claim 1 or 2; or the physiologically acceptable salts thereof. 4. A compound as claimed in claim 1, 2 or 3 vherein R is 2 3 4 (l-6C)alkyl; R is hydrogen or halogeno; one of R and R is selected 3 4 from hydroxymethyl and hydroxy, and the other of R and R is selected from hydrogen, halogeno, (l-6C)alkylj ( i-6C)alkoxy, hydroxy and hydroxymethyl J X is a direct bond or p_-phenylenef and Z is selected from lH-tetrazol-5-yl, carboxy and a group of the formula -C0.NH.S02.R6 in vhich R6 is (l-6C)alkyl, (3-8C)cycloalkyl or phenyl, vherein Z is attached at the 2- or 4-position relative to X. 5. A compound as claimed in claims 1-4 vherein X is p_-phenylene; and Z is lH-tetrazol-5-yl attached at the 2-position relative to X. 6. A compound as claimed in any preceding claim vherein is butyl. 7. A compound of the formula I selected from A 2-butyl-4-hydroxy-3-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo(4,5-dJpyridazine{ 2-butyl-4-hydroxy-3-|(2'-(lH-tetrazol-5-«yl)biphenyl-4-yl)methyl]-3H-imidazo(4,5-c]pyridine; and 2-butyl-6- (hydroxymethyl) -3- I (2 '-(lH-tetrazol-5-yl)biphenyl-4-yl)- ethyl] imidazo [ 4 , 5-bJ pyridine } 106628/2 - 32 - and the physiologically acceptable salts thereof; 8. A salt as claimed in any one preceding claim vhich is selected from alkali metal, alkaline earth metal* aluminium and ammonium salts, and from salts with organic bases affording physiologically acceptable cations* and for those compounds of formula I vhich are basic, salts vith acids affording physiologically acceptable anions. 9. A process for the manufacture of a compound of formula I or a physiologically acceptable salt thereof, as defined in claim 1 vhich is characterised in that:-a) For those compounds in vhich Z is carboxy* a carboxylic acid derivative of the formula II in vhich Q is a protected carboxy group selected from (l-6C)alkoxycarbonyl, phenoxycarbonylj benzyloxycarbonyl and carbamoyl, is converted to carboxy; b) For those compounds of formula I vherein Z is tetrazolyl, a compound of the formula III in vhich L is a suitable protecting group affixed to a nitrogen of the tetrazolyl moiety, is deprotected; c) For those compounds of formula I vherein Z is a group of the formula an imidazole derivative of the formula IV 106628/2 - 33 - is reacted vith a compound of the formula V vherein Hal. stands for a suitable leaving group; or d) A diamino derivative of the formula VII is reacted vith or a (l-4C)alkyl orthoester thereof; whereafter, when a compound of the formula I is required vherein Z is a group of the formula -CO.NH.SO-R** or a group of the 5 5 formula -CO.OR in vhich R is other than hydrogen > a carboxylic acid of the formula I in vhich Z is carboxy (or a reactive derivative of said acid) is reacted vith a sulphonamide of the formula NH2.S02 ^ or a hydroxy compound of the formula HO.R"*, or vith a salt thereof; vhereafter, vhen a salt of a compound of formula I is required, it is obtained by reaction vith the appropriate base or acid affording a physiologically acceptable ion, or by any other conventional salt formation procedure; and vhen an optically active form of a compound of formula I is required, one of the processes (a)-(d) is carried out using an optically active starting material, or the racemic form of a compound of formula I is resolved by reaction vith an optically active form of a suitable organic base or acid, folloved by conventional separation of the diastereoisomeric mixture of salts thus obtained, and liberation of the required optically active form of said compound of formula ί by conventional treatment vith acid or base; and vherein A, R1, R2, R3* ^, X and Z have any of the meanings defined in any of claims 1-6 unless otherwise stated. 106628/2 - 34 - 11. A pharmaceutical composition uhich comprises a compound of the formula I or la* or a physiologically acceptable salt thereof* as claimed in any of claims 1 to 8j together vith a pharmaceutically acceptable diluent or carrier. AGENT FOR THE APPLICANTS