WO1994011379A1

WO1994011379A1 - Heterocyclic compounds as angiotensin ii antagonists

Info

Publication number: WO1994011379A1
Application number: PCT/GB1993/002282
Authority: WO
Inventors: Arnold Harry Ratcliffe; Keith Hopkinson Gibson
Original assignee: Zeneca Limited
Priority date: 1992-11-06
Filing date: 1993-11-04
Publication date: 1994-05-26
Also published as: GB9223371D0; AU5376194A

Abstract

The invention concerns pharmaceutically useful compounds of formula (I), in which R?1, R2, R3, R4¿, Ra, Rb, X and Z have the various meanings defined herein, and their non-toxic salts, and pharmaceutical compositions containing them. The novel compounds are of value in treating such conditions such as hypertension and congestive heart failure. The invention further concerns processes for the manufacture of the novel compounds and the use of the compounds in medical treatment.

Description

HETEROCYCLIC COMPOUNDS AS ANGIOTENSIN II ANTAGONISTS

This invention concerns novel heterocyclic compounds and, more particularly, novel heterocyclic compounds 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 (hereinafter 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 which the

renin-angiotensin-aldosterone system plays a significant causative role. The invention also includes processes for the manufacture of the novel compounds and their use in treating one of the

afore-mentioned diseases or medical conditions and for the production of novel pharmaceuticals for use in such medical treatments.

The angiotensins are key mediators of the renin-angiotensin- aldosterone system, which is involved in the control of homeostasis and fluid/electrolyte balance in many warm-blooded animals, including man. The angiotensin known as All is produced by the action of angiotensin converting enzyme (ACE) on angiotensin I, itself produced by the action of the enzyme renin on the blood plasma protein angiotensinogen. All is a potent spasmogen especially in the vasculature and is known to increase vascular resistance and blood pressure. In addition, the angiotensins are known 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 of blood pressure and/or fluid/electrolyte balance, including, for example, inhibiting the actions of renin or ACE. However, there remains a continuing need for an alternative approach because of the side-effects and/or idiosyncratic reactions associated with any particular therapeutic approach. Certain 1,6-naphthyridin-2-ones having All antagonist activity are described in European Patent Application, Publication No. 516392.

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 a heterocyclic compound of the formula I (set out hereinafter, together with the other chemical formulae identified by Roman numerals) wherein R¹ is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted

(1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent; R² is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, carbamoyl, (1-4C)alkanoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6 carbon atoms, 3-(1-4C)alkylureido or (1-4C)alkanoylamino; R³ is selected from halogeno, (1-4C)alkoxy, hydroxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and any of the values defined for R¹; Ra is selected from hydrogen, (1-4C)alkyl, substituted

(1-4C)alkyl containing one or more fluoro substituents or bearing a

(3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent,

(3-8C)cycloalkyl, phenyl, pyridyl, (1-4C)alkoxycarbonyl and

(3-6C)alkenyloxycarbonyl; Rb is hydrogen or (1-4C)alkyl; R⁴ is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno,

trifluoromethyl, cyano and nitro; X is phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno,

(1-4C)alkanoyl, trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl and methylene groups; Z is

1H-tetrazol-5-yl, -CO.NH. (1H-tetrazol-5-yl), -NHSO₂CF₃ or a group of the formula -CO.OR⁵, -CO.NH.SO₂-R⁶ or -SO₂.NHR⁷ in which R⁵ is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, R⁶ is (1-6C)alkyl, (3-8C)cycloalkyl or phenyl, and R⁷ is hydrogen, (1-4C)alkyl, (1-4C)alkanoyl or

-CO.NH. (1-4C)alkyl; or when X is a direct bond between the adjacent phenyl and methylene groups, Z is a 2-carboxybenzamido,

2-sulfobenzamido or 2-carboxybenzyloxy group, the benzene ring of which last three groups may optionally bear 1 or 2 additional substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy and halogeno; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from

(1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or an N-oxide thereof; or a non-toxic salt thereof.

It will be appreciated that, depending on the nature of the substituents, 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 R¹ or R³ when it is alkyl includes, for example, (1-6C)alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl and hexyl; and when it is

cycloalkyl includes, for example, cyclopropyl, cyclopentyl and cyclohexyl. A particular value for R¹ or R³ when it is alkyl containing one or more fluoro substitutents includes, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; and when it is alkyl bearing a cycloalkyl, (1-4C)alkoxy or phenyl substituent includes, for example, cyclopropylmethyl, cyclopentylmethyl,

cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl and 2-phenylethyl. A particular value for R² when it is alkyl includes, for example, methyl, ethyl, propyl, isopropyl and butyl; when it is alkoxycarbonyl includes, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; when it is alkenyloxycarbonyl includes, for example, allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl and

3-methyl-3-butenyloxycarbonyl; and when it is alkanoyl includes, for example, formyl, acetyl and propionyl. Particular values for R² or R³ include, by way of example, for alkylamino: methylamino, ethylamino and butylamino; for

dialkylamino: dimethylamino, diethylamino and dipropylamino; for halogeno: fluoro, chloro, bromo and iodo; and for alkoxy: methoxy and ethoxy. Particular values for R² include, by way of example, for

N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for

di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkanoylamino: formamido, acetamido and propanamido; and for

3-alkylureido: 3-methylureido, 3-ethylureido and 3-propylureido

Particular values for Ra include, by way of example, for alkyl: methyl, ethyl and propyl; for alkyl containing one or more fluoro substitutents or bearing a cycloalkyl, alkoxy or phenyl substituent: fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl, cyclopropylmethyl, cyclopentylmethyl,

cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl and 2-phenylethyl; for cycloalkyl: cyclopropyl, cyclopentyl and cyclohexyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; and for alkenyloxycarbonyl: allyloxycarbonyl,

2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl. A particular value for Rb when it is alkyl includes, by way of example, methyl and ethyl. A particular value for R⁴ when it is alkyl includes, for example, methyl and ethyl; when it is halogeno includes, for example, fluoro, chloro, bromo and iodo; and when it is alkoxy includes, for example, methoxy and ethoxy.

A particular value for R⁵ when it is a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol includes, for example, a residue derived from a (1-6C)alkanol (such as methanol and ethanol), phenol, glycerol and the like.

A particular value for R⁶ when it is alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl and pentyl; and when it is cycloalkyl includes, for example, cyclobutyl, cyclopentyl and cyclohexyl.

A particular value for R⁷ when it is alkyl includes, for example, methyl and ethyl; when it is alkanoyl includes, for example, formyl, acetyl and propionyl; and when it is -CO.NH. (1-4C)alkyl includes, for example, -CONHCH₃ and -CONHC₂H₅.

Particular values for optional substituents which may be present on phenyl moieties, or for an optional substituent which may be present when X is phenylene, or for an optional additional substituent on Z when it is a 2-carboxybenzamido, 2-sulfobenzamido or 2-carboxybenzyloxy group include, by way of example, for halogeno: fluoro, chloro and bromo; for alkyl: methyl and ethyl; and for alkoxy: methoxy and ethoxy.

A particular value for an optional alkanoyl substituent on X which may be present when X is phenylene includes, for example, formyl, acetyl and propionyl.

A particular combination of values for Ra and Rb of interest includes, for example, for when one or both are hydrogen. A specific value for X which is of particular interest includes, for example, p-phenylene.

A preferred value for R¹ includes, for example, (1-4C)alkyl such as methyl, ethyl and propyl. A preferred value for R² includes, for example, hydrogen. A preferred value for R³ includes, for example, (1-4C)alkyl such as methyl and ethyl. A preferred value for R⁴ or R⁵ includes, for example, hydrogen.

A preferred value for Ra or Rb includes, for example, hydrogen. A preferred combination of values for R¹ and R³ includes, for example, when they are both alkyl; and for Ra and Rb includes, for example, when they are both hydrogen.

A preferred value for Z includes, for example,

1H-tetrazol-5-yl, which is especially preferred when attached ortho to the group X.

A particular group of compounds of the formula I which are of interest comprises compounds of the formula I wherein R¹, R², R³, R⁴ , Ra, Rb and X have any of the meanings defined above and Z is

1H-tetrazol-5-yl, -CO.NH.(1H-tetrazol-5-yl) or a group of the formula

-CO.OR⁵ or -CO.NH.SO₂-R in which R⁵ is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, and R⁶ is (1-6C)alkyl, (3-8C)cycloalkyl or phenyl; or an

N-oxide thereof; or a non-toxic salt thereof.

A preferred group of compounds of the formula I comprises compounds of the formula la wherein R¹, R², R³, R⁴, Ra and Rb have any of the meanings defined above; and Z is carboxy or 1H-tetrazol-5-yl; and the non-toxic salts thereof. Within this group, compounds wherein R¹ and R³ are both (1-4C)alkyl and Z¹ is 1H-tetrazol-5-yl are particularly preferred.

A compound of the invention which is of particular interest includes, for example, the specific embodiment set out hereinafter in the accompanying Example, and this compound, or a non-toxic salt thereof, is provided as a further feature of the invention.

Although all of the formula I compounds can form salts with suitable acids, it will be appreciated that those compounds of formula I wherein Z is other than an ester group or in which R² is a carboxy group can form salts with bases as well as with acids. Particularly suitable non-toxic salts for such compounds therefore also 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, as well as salts with acids forming physiologically acceptable anions, such as salts with mineral acids, for example with hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and with strong organic acids, for example with

p-toluenesulphonic and methanesulphonic acids.

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 compounds. Such procedures are provided as a further feature of the invention and include, by way of example, the following 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.OR⁵ in which R⁵ is hydrogen), a carboxylic acid derivative of the formula II, in which Q is a protected carboxy group selected from (1-6C)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 (1-4C)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 transfer catalyst. Alternatively, the hydrolysis may be carried out under acidic conditions, for example, using a suitable mineral acid, such as hydrochloric acid, and conveniently in the presence of a suitable solvent or diluent, such as dioxan. 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 (1-4C)alkanol (typically ethanol or 2-propanol) and at a temperature in the range, for example, 0 - 40°C.

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, t-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 tributyltin) 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 acid), conveniently in an aqueous solvent (such as aqueous dioxan or

2-propanol). Alternatively, a trityl or benzhydryl group may be removed by hydrogenolysis, for example as described in (a) above for conversion of a benzyloxycarbonyl to a 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 VII with a trialkyltin azide, such as tributyltin azide, or triphenyltin azide 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, for example, 50-150°C. In a modified procedure, a formula I compound wherein Z is tetrazolyl may be obtained directly by in situ removal of the trialkyltin or triphenyltin group without prior isolation of the formula III compound, for example by the addition of aqueous mineral acid or gaseous hydrogen chloride to the reaction mixture. The nitriles of the formula VII may be obtained, for example, by alkylation of a compound of the formula IV with a nitrile of the formula VIII wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p-toluenesulphonyloxy, using similar conditions to those used in process (c) described hereinafter. The necessary compounds of formula VIII may be made by standard procedures such as that illustrated in Scheme 1, using methods of organic chemistry well known in the art. Alternatively, the nitriles of the formula VII may be obtained from stepwise conversion of a compound of formula I wherein Z is a group of the formula -CO. O R⁵ under standard conditions. Trialkyltin azides and triphenyltin azides are either commercially available or may be prepared by standard procedures well known in the art, such as by reaction of a trialkyltin halide with an alkali metal azide. c) A compound of the formula IV is alkylated 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 alkoxide such as sodium methoxide or sodium ethoxide or an alkali metal hydride such as sodium hydride or an alkali metal carbonate such as sodium or potassium carbonate, or an organic base such as diisopropylethylamine and in a suitable solvent or diluent, for example, a (1-4C)alkanol such as methanol or ethanol when an alkali metal alkoxide is used, or in a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in the range, for example, 10 - 100°C.

Alternatively, a quaternary ammonium hydroxide may be used in a mixture of an aqueous and non-aqueous solvent such as water and dichloromethane. In carrying out process (c), when in the starting material Z is an acidic group, about two molecular equivalents of a suitable base is generally required, whereas when Z is a non-acidic group the presence of one molecular equivalent of a suitable base is generally sufficient.

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.OR⁵ in which R⁵ is other than hydrogen, for example wherein R⁵ is

(1-6C)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 halomethyl tetrazolyl derivative of the formula VI, the starting materials of the formula III may be obtained for procedure

(b).

Compounds of the formula IV can be made using standard procedures of organic cheeistry well known in the art, for example as described in standard works of heterocyclic chemistry such as those edited by Elderfield or Wiessberger, or as illustrated in Scheme 2 by ring closure of an appropriately substituted 4-amino-3-hydroxymethyl- pyridine or protected derivative thereof. It will be appreciated that a compound of the formula IV can be converted into another compound of the formula IV by functional group interconversion using procedures well known in the art. For example, carboxylic acids or their esters may be converted to amides or nitriles under standard conditions. 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.

Compounds of the formula VI wherein X is phenylene may also be conveniently obtained by. reaction of a Grignard reagent, formed from a suitably substituted 4-bromotoluene, with a trialkyltin halide, such as tributyltin chloride, followed by reaction of the resulting (substituted)phenyltrialkyltin compound with a bromobenzonitrile in the presence of a palladium(O) catalyst, such as

tetrakis(triphenylphosphine)palladium, and azo(bisisobutyronitrile) . The resultant substituted 4'-methyl-biphenylcarbonitrile may then be converted to a compound of the formula VI by carrying out steps (b),

(c) and (d) in a similar manner to that shown in Scheme 1.

Alternatively, suitably substituted 4'-methylbiphenylcarbonitriles may be obtained by reaction of 4-methylphenylboronic acid with an appropriately substituted bromobenzonitrile in the presence of a suitable palladium catalyst, such as palladium (II)chloride or tetrakis(triphenylphosphine)palladium, and azo(bisisobutyronitrile).

(d) For those compounds of the formula I wherein X is a direct bond between the adjacent phenyl and methylene groups and Z is a 2-carboxybenzamido or 2-sulfobenzamido group, the benzene ring of which last two groups may optionally bear 1 or 2 additional

substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy and halogeno, a compound of the formula XII in which X is a direct bond is reacted with an anhydride of the formula XIII wherein Xa is carbonyl or sulphonyl and Rc and Rd are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy or halogeno. The reaction is generally carried out in a suitable solvent or diluent, for example, an ether such as tetrahydrofuran, and at a temperature in the range, for example, 0-50°C. The compounds of formula XII wherein X is a direct bond may be obtained, for example, by alkylation of a compound of the formula IV with an unsubstituted or appropriately substituted nitrobenzyl halide, using analogous conditions to those described in process (c) above, followed by reduction of the nitro group under standard conditions, for example by catalytic hydrogenation over platinum oxide in a suitable solvent, such as a (1-4C)alcohol (typically ethanol or 2-propanol) or ether (for example, dioxan or tetrahydrofuran), and at a temperature in the range, for example, 0-40°C. The anhydrides of formula XIII are commercially available or can be made by standard procedures.

(e) For those compounds wherein Z is -NHSO₂CF₃, a compound of the formula XII is reacted with trifluoromethanesulphonic anhydride.

The reaction is generally carried out in a suitable solvent or diluent, for example a chlorinated hydrocarbon such as

dichloromethane or chloroform, and at a temperature in the range, for example, -78°C to ambient temperature. The compounds of formula XII wherein X is a direct bond may be obtained as described above and and the compounds of formula XII wherein X is biphenylene may be obtained, for example, using the procedures described in European Patent

Application, Publication No. (EPA) 400974, or by analogy therewith.

(f) For those compounds of formula I wherein Z is a group of the formula -SO₂NHR⁷, a compound of the formula IV is alkylated with a compound of the formula XV wherein Hal. stands for a suitable leaving group such as chloro, bromo, iodo, methanesulphonyloxy or p-toluenesulphonyloxy.

The reaction is generally carried out using similar conditions to those described for procedure (c). The compounds of formula XV may be obtained by standard procedures such as those described in EPA 400974 for compounds in which X is phenylene, or by analogy therewith. (g) For those compounds of the formula I wherein X is phenylene and Z is a group of the formula -SO₂NHR⁷ , a compound of the formula X is reacted with a compound of the formula XIV wherein W¹ is a bromo, iodo or trifluoromethanesulphonyloxy group.

The reaction may be carried out using similar conditions to those described hereinafter for the reaction of a compound of formula X with a compound of formula XI. The compounds of formula XIV may be obtained by standard procedures well known in the art. A compound of the formula I wherein Z is -SO₂NH₂ may also be obtained by acid hydrolysis of a compound of the formula I wherein Z is a group of the formula -SO₂NHR⁷ in which R⁷ is a tert-butyl group. The hydrolysis is generally carried out in the presence of a strong acid, such as trifluoroacetic acid. The acid may be used in excess or in the presence of a suitable diluent such as tetrahydrofuran, t-butyl methyl ether or 1,2-dimethoxyethane, and at a temperature in the range, for example, 0-100°C. Alternatively, compounds of the formula I wherein Z is -SO₂NHR⁷ may be obtained from the corresponding compound in which Z is -SO₂NH₂, for example, by alkylation, acylation (such as with an appropriate acid chloride, acid anhydride or other acylating agent) or reaction with an alkyl isocyanate, using standard conditions.

(h) For those compounds of the formula I wherein Z is

tetrazolyl and X is p-phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano and nitro, a compound of the formula IX, wherein P¹ is an electron-deficient phenyl group or a pyridyl or pyrimidyl group and Ry is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano or nitro, is reacted with a base selected from an alkali metal hydroxide,

(1-12C)alkanolatej (1-12C)alkanethiolate, phenolate, thiophenolate and diphenylphosphide, wherein any phenyl ring of the latter three groups may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or halogeno group.

The reaction is conveniently carried out in a suitable inert organic solvent or diluent, for example, a polar solvent such as N,N-dimethylformamide or N-methylpyrrolidone. Alternatively, an alkanol such as methanol or ethanol may be used, for example, when an alkali metal hydroxide or alkoxide such as sodium or potassium hydroxide, methoxide or ethoxide is employed. The reaction is generally carried out at a temperature in the range, for example, -30°C to 50°C. It will be appreciated that the choice of temperature will depend on the nature of the base employed. Particular bases which may be used in the reaction are, for example, sodium or potassium hydroxide, an alkali metal (1-4C)alkoxide (such as sodium or potassium methoxide, ethoxide, propoxide or butoxide or an alkali metal (1-4C)alkanethiolate (such as sodium or potassium

methanethiolate, ethanethiolate, propanethiolate or butanethiolate). For example, when an alkali, metal alkanethiolate or alkanolate is used, a temperature in the range of 0°C to ambient temperature is preferred. A particular value for P¹ includes, for example, a phenyl group bearing 1, 2 or 3 electron-withdrawing groups independently selected from nitro, cyano and trifluoromethyl, p-nitrophenyl being particularly preferred.

Compounds of the formula IX may be obtained by reaction of a boronic acid of the formula X with a compound of the formula XI wherein P¹ is an electron-deficient phenyl group or a pyridyl or pyrimidyl group and W is a bromo, iodo or trifluoromethanesulphonyloxy group, in the presence of a palladium(O) catalyst, such as

tetrakis(triphenylphosphine)palladium, and azo(bisisobutyronitrile). The reaction is preferably carried out in the presence of a base, such as sodium or potassium carbonate, in an inert solvent or diluent, for example, a hydrocarbon such as toluene or xylene, an ether, such as dioxan or tetrahydrofuran, an (1-4C)alkanol such as methanol or ethanol, water, or mixture thereof, for example a mixture of water, methanol and toluene, and at a temperature in the range of, for example, 50°C to 150°C, and conveniently at or about the reflux temperature of the solvent or mixture of solvents used.

Compounds of the formula X may be obtained, for example, by heating at reflux a 4-methylphenylboronic acid in a solvent such as methyl chloroform with azeotropic removal of water, followed by radical bromination of the product which may be carried out in situ, for example with bromine or N-bromosuccinimide in the presence of azo(bisisobutyronitrile). The resultant 4-bromomethylphenylboronic acid anhydride may then be used to alkylate a compound of the formula IV (using similar alkylation conditions to those used in process (c) described above), followed by subsequent acidic hydrolysis, to give a formula X compound. Alternatively the product from the alkylation step prior to hydrolysis may be isolated and reacted directly with a compound of the formula XI under similar conditions to those described above to obtain a formula IX compound directly. In a yet further alternative procedure, a 4-methylphenylboronic acid and an appropriate alkanediol, for example 2,2-dimethylpropan-1,3-diol, may be heated at reflux in a solvent (such as cyclohexane) with azeotropic removal of water followed by free radical bromination of the product, which may be carried out in situ. The resultant bromomethyl compound may then be reacted using analogous procedures to those described above for the 4-bromomethylphenylboronic acid anhydride to obtain a formula X compound or a compound of the formula IX directly. Compounds of the formula XI may be obtained, for example, as shown in EPA 495626.

Alternatively compounds of the formula IX may be obtained, for example, by alkylation of a compound of the formula IV with a compound of formula XVI in which P¹, Ry and Hal. have any of the meanings defined above. The reaction is conveniently carried out using similar conditions to those described for procedure (c). The compounds of formula XVI may be obtained, for example, as described in EPA 495626.

It will be appreciated that where necessary in any of the above processes, reactive or labile groups may be protected in a conventional manner and subsequently deprotected, using conventional protecting groups and deprotection procedures, for example, as described in "Protective Groups in Organic Synthesis" by Theodora Green (John Wiley and Sons Inc, 1981).

Whereafter, those compounds of formula I wherein Z is

1H-tetrazol-5-yl may be obtained by stepwise conversion of a compound of the formula I wherein Z is a group of the formula -CO.OR⁵ into the corresponding nitrile under standard conditions, followed by reaction of the nitrile with an azide such as an alkali metal azide, preferably in the presence of an ammonium halide, and preferably in the presence of a suitable polar solvent such as N,N-dimethylformamide and at a temperature in the range, for example, 50 to 160°C.

Whereafter, those compounds of the formula I wherein Z is

-CO.NH. (1H-tetrazol-5-yl), a group of the formula -CO.NH.SO₂R⁶ or a group of the formula -CO.OR⁵ in which R⁵ 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

5-aminotetrazole, a sulphonamide of the formula NH₂.SO₂R⁶ or a salt thereof (for example, an alkali metal salt), or a hydroxy compound of the formula HO.R⁵ 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)-1-ethylcarbodi- imide in the presence of a base such as triethylamine, pyridine or

4-dimethylaminopyridine. When a reactive derivative is used, either the reaction is carried out in the presence of a base such as mentioned above, or, for the preparation of a compound of the formula

I wherein Z is a group of the formula -CO.NH.SO₂R⁶ or a group of the formula -CO.OR⁵, 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 an N-oxide derivative of a compound of the formula I is required, a compound of the formula I is oxidised.

Suitable oxidising agents include those well known in the art for the conversion of nitrogen heterocycles to their corresponding N-oxide derivatives, for example, hydrogen peroxide or an organic peracid such as m-chloroperbenzoic acid or peracetic acid. The oxidation is preferrably carried out in a suitable conventional solvent or diluent for such oxidations, for example dichloromethane, chloroform or acetic acid, and at a temperature in the general range, for example 0 to 80°C.

Whereafter, when a non-toxic salt of a compound of formula I is required, it may be obtained, for example, by reaction with the appropriate base affording a physiologically acceptable cation, or with the appropriate acid affording a physiologically acceptable anion, 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 in which Z is an acidic group may be resolved, for example by reaction with an optically active form of a suitable organic base, for example, ephedrine, N,N,N-trimethyl- (1-phenylethyl)ammonium hydroxide or 1-phenylethylamine, followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, for example by fractional crystallisation from a suitable solvent, for example a (1-4C)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.

Certain of the intermediates defined herein are novel, for example the compounds of the formula II, III, IV, VII and IX and are provided as a further feature of the invention.

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 compounds of the invention may also be useful for the treatment of ocular hypertension, glaucoma, cognitive disorders (such as Alzheimer's disease, amnesia, senile dementia and learning disorders), as well as other diseases such as renal failure, cardiac insufficiency, post-myocardial infarction, cerebrovascular disorders, anxiety, depression and certain mental illnesses such as

schizophrenia.

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 vitro 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 which 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 concentration of 10^-4 M are retested at lower concentrations to determine their potency. For determination of the IC₅₀ (concentration for 50% 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 IC₅₀ , 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 about 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 about 50 micromolar or much less. [Note: Compounds of formula I wherein Z is a group of the formula -CO.OR⁵ in which R⁵ 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 cinaesthesia 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 about 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.

Test D: This in vivo test 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 about 50 mg/kg body weight or much less, without any overt toxicological or other untoward pharmacological effect.

By way of illustration of the angiotensin II inhibitory properties of compounds of the formula I, the compound of Example 1 gave a IC50 of 6 x 10^-9 M. in test A.

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, as is well known in the pharmaceutical art. According to a further feature of the invention there is provided a pharmaceutical composition comprising a compound of formula I, or a salt or N-oxide thereof as defined above, together with a pharmaceutically acceptable diluent or carrier. Such compositions 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, or a non-toxic salt thereof, 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, such as a beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting enzyme (ACE) inhibitor (for example lisinopril) or a diuretic (for example furosemide or

hydrochlorothiazide). It is to be understood that such combination therapy constitutes a further aspect of the invention.

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.

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 18-26°C;

(iii) flash column chromatography was performed on Merck Kieselgel

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) ¹H NHR spectra were determined at 200 MHz in CDCl₃ or d₆-dimethylsulphoxide (d₆-DMSO) 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) the term "1H-tetrazol-5-yl" stands for

"1H-1,2,3,4-tetrazol-5-yl".

EXAMPLE 1

Concentrated hydrochloric acid (1.0 ml) was added to a suspension of 5,7-diethyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)- biphenyl-4-yl)methyl]-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one (A) (0.25 g) in methanol (5 ml) and the mixture was stirred for 30 minutes. Volatile material was removed by evaporation and the residue was triturated with ether (6 x 5 ml). The insoluble material was collected by filtration and recrystallised from ethanol/ether to give 5,7-diethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)nethyl]-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one hydrochloride (0.16 g) as a solid, m.p. 218-221°C; NMR (d₆-DMSO): 1.18(t, 3H), 1.20(t, 3H), 2.90(double q, 4H), 5.22(s ,2H), 5.61(s, 2H), 7.08(d, 2H), 7.16(s, 1H), 7.29(d, 2H), 7.49-7.68(m, 4H) ; mass spectrum (positive fast atom bombardment (+ve FAB), methanol/nitrobenzyl alcohol): 441(M+H)⁺;

microanalysis, found: C,62.2; H,5.70; N,16.6%;

C₂₅H₂₄N₆O₂.1.OHC1.0.33H₂O requires: C,62.2; H,5.31; N,17.4%.

The starting material A was obtained as follows:- (i) Di-tert-butyl dicarbonate (0.24 g) was added to a solution of methyl 4-amino-2,6-diethylpyridine-3-carboxylate (0.21 g) (obtained as described in European patent application, publication number

499415) in pyridine (3 ml) and the mixture was stirred for 1 hour. Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give methyl 4-tert-butyloxycarbonylamino-2,6- diethylpyridine-3-carboxylate (B) (90 mg) as an oil; NMR (d₆-DMSO): 1.1(double t, 6H), 1.46(s, 9H), 2.67(q, 2H), 2.77(q, 2H), 3.80(s, 3H), 7.40(s, 1H), 9.34(s, 1H); mass spectrum (chemical ionisation, ammonia): 309(M+H)⁺.

(ii) Lithium borohydride (1.07 g) was added to a solution of compound B (1.0 g) in tetrahydrofuran (THF) (15 ml) and the mixture was stirred for 7 days and then heated at reflux for 60 hours. The mixture was cooled to ambient temperature, water (100 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried (MgSO₄) and solvent was

removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 5,7-diethyl-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one (C) (0.48 g) as a solid, m.p 125-128ºC; NMR (d₆-DMSO): 1.13(t, 3H), 1.17(t, 3H), 2.54-2.68(double q, 4H), 5.36(s, 2H), 6.53(s, 1H), 10.36(s 1H); mass spectrum (chemical ionisation, ammonia): 207(M+H)⁺.

(iii) Sodium hydride (60% dispersion in mineral oil; 44 mg) was added to a stirred solution of compound C (0.21 g) in

N,N-dimethylformamide (10 ml) and the mixture was stirred for 30 minutes. 5-[2-(4'-Bromomethylbiphenylyl)]-2-triphenylmethyl-2H- tetrazole (0.66 g) (obtained as described in European patent

application, publication no. 291969) was added and the mixture was stirred for 2 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (50 ml) and the organic phase separated and dried (MgSO₄). Solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 5,7-diethyl-1-[(2'-(2-triphenylmethyl-2H-tetrazol- 5-yl)biphenyl-4-yl)methyl]-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2- one (A) (0.25 g) as a foam; NMR (d₆-DMSO): 1.02(t, 3H), 1.14(t, 3H), 2.47(q, 2H), 2.67(q, 2H), 5.08(s, 2H), 5.54(s, 2H), 6.65(s, 1H), 6.8-7.8(complex m, 23H); mass spectrum (+ve FAB, methanol/nitrobenzyl alcohol): 683(M+H)⁺.

EXAMPLE 2 (Note: all parts by weight)

The compounds of the invention may be administered for therapeutic or prophylactic use to warm-blooded animals such as man in the form of conventional pharmaceutical compositions, typical examples of which include the following:- a) Capsule (for oral administration)

Active ingredient * 20

Lactose powder 578.5

Magnesium stearate 1.5 b) Tablet (for oral administration)

Active ingredient * 50

Microcrystalline 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)

Active ingredient * 0.05 - 1.0 Methylcellulose 0.5

Tween 80 0.05

Benzyl alcohol 0.9

Benzalkonium chloride 0.1

Purified water to 100%

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.

Note: R = lower alkyl, benzyl, phenyl; Tr = triphenylmethyl (trityl)

Reagents: a) BuLi/THF; ZnCl₂/Et₂O; Pd(Ph₃P)₄

b) Bu₃Sn.N₃/toluene; HCl/toluene

c) Tr.Cl/Et₃N/CH₂Cl₂

d) N-bromosuccinimide/azoisobutyronitrile/CCl₄

Note: For example: R' = lower alkyl; R = lower alkoxy, phenoxy, N-imidazolyl, N-triazolyl or halogeno

Reagents: a) LiBH₄ or LiAlH₄, THF

b) LiAlH₄, THF

c) (i) (tert-BuOCO)₂O, pyridine; (ii) as for step (a) d) (i) as for step (c), part (i); (ii) as for step (b) e) THF, heat

Claims

CLAIMS What we claim is : -

1. A heterocyclic compound of the formula I

wherein

R¹ is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted

(1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent; R² is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, carbamoyl, (1-4C)alkanoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6 carbon atoms, 3-(1-4C)alkylureido or (1-4C)alkanoylamino; R³ is selected from halogeno, (1-4C)alkoxy, hydroxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and any of the values defined for R¹; R⁴ is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; Ra is selected from hydrogen, (1-4C)alkyl, substituted (1-4C)alkyl containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent, (3-8C)cycloalkyl, phenyl, pyridyl,

(1-4C)alkoxycarbonyl and (3-6C)alkenyloxycarbonyl; Rb is hydrogen or (1-4C)alkyl; X is phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl,

trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl and methylene groups; Z is 1H-tetrazol-5-yl,

-CO.NH. (1H-tetrazol-5-yl), -NHSO₂CF₃ or a group of the formula

-CO.OR⁵, -CO.NH.SO₂.R⁶ or -SO₂.NHR⁷ in which R⁵ is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, R⁶ is (1-6C)alkyl, (3-8C)cycloalkyl or phenyl, and R⁷ is hydrogen, (1-4C)alkyl, (1-4C)alkanoyl or -CO.NH.(1-4C)alkyl; or when X is a direct bond between the adjacent phenyl and methylene groups, Z is a 2-carboxybenzamido, 2-sulfobenzamido or

2-carboxybenzyloxy group, the benzene ring of which last three groups may optionally bear 1 or 2 additional substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy and halogeno; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or an N-oxide thereof; or a non-toxic salt thereof.

2. A compound as claimed in claim 1 wherein

R¹ is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,

fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,

2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl and

2-phenylethyl;

R² is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,

2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, cyano, nitro, carbamoyl, formyl, acetyl, propionyl, N-methylcarbamoyl,

N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, amino, methylamino, ethylamino, butylamino, dimethylamino, diethylamino, dipropylamino, formamido, acetamido, propanamido, 3-methylureido,

3-ethylureido or 3-propylureido;

R³ is selected from hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,

pentafluoroethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl,

1-phenylethyl, 2-phenylethyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, hydroxy, amino, methylamino, ethylamino, butylamino, dimethylamino, diethylamino and dipropylamino;

R⁴ is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano and nitro;

Ra is selected from hydrogen, methyl, ethyl, propyl, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,

cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,

2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl, 2-phenylethyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,

methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,

2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl;

Rb is hydrogen, methyl or ethyl;

X is phenylene optionally bearing a substituent selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, formyl, acetyl, propionyl, trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl and methylene groups;

Z is 1H-tetrazol-5-yl, -CO.NH. (1H-tetrazol-5-yl), -NHSO₂CF₃ or a group of the formula -CO.OR⁵, -CO.NH.SO₂.R⁶ or -SO₂NHR⁷ in which R⁵ is hydrogen or a residue derived from a (1-6C)alkanol, phenol or glycerol, R⁶ is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl and R⁷ is hydrogen, methyl, ethyl, formyl, acetyl, propionyl, -CONHCH₃ or -CONHC₂H₅; or when X is a direct bond between the adjacent phenyl and methylene groups, Z is a 2-carboxybenzamido, 2-sulfobenzamido or

2-carboxybenzyloxy group, the benzene ring of which last three groups may optionally bear 1 or 2 additional substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, cyano and trifluoromethyl; and wherein any of said phenyl moieties may be unsubstituted or bear one or two substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, cyano and trifluoromethyl.

3. A compound of the formula la

wherein R¹ , R² , R³ , R⁴ , Ra and Rb have any of the meanings defined in claim 1 or 2; and Z is carboxy or 1H-tetrazol-5-yl; and the non-toxic salts thereof.

4. A compound as claimed in claim 3 wherein R¹ is (1-4C)alkyl; R³ is (1-4C)alkyl; and Z¹ is 1H-tetrazol-5-yl; and the non-toxic salts thereof.

5. The compound 5,7-diethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl- 4-yl)methyl]-1,4-dihydro-2H-pyrido[4,3-d][1,3]oxazin-2-one, or a non-toxic salt thereof.

6. A salt as claimed in any one preceding claim which is selected from salts with acids forming physiologically acceptable anions and, for those compounds of the formula I which are acidic, alkali metal, alkaline earth metal, aluminium and ammonium salts, and salts with organic bases affording physiologically acceptable cations.

7. A process for the manufacture of a compound of the formula I or a non-toxic salt thereof, as claimed in claim 1, which is

characterised in that:-

(a) For those compounds in which Z is carboxy, a carboxylic acid derivative of the formula II

in which Q is a protected carboxy group selected from

(1-6C)alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and carbamoyl, is converted to carboxy;

(b) For those compounds of the formula I wherein Z is tetrazolyl, a compound of the formula III

in which L is a protecting group affixed to a nitrogen of the tetrazolyl moiety, is deprotected;

(c) A compound of the formula IV

is alkylated with a compound of the formula V

wherein Hal. stands for a suitable leaving group;

(d) For those compounds of the formula I wherein X is a direct bond between the adjacent phenyl and methylene groups and Z is a 2-carboxybenzamido or 2-sulphobenzamido group, the benzene ring of which last two groups may optionally bear 1 or 2 additional

substituents independently selected from (1-4C)alkyl, (1-4C)alkoxy and halogeno, a compound of the formula XII

in which X is a direct bond is reacted with an anhydride of the formula XIII

wherein Xa is carbonyl or sulphonyl and Rc and Rd are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy or halogeno;

(e) For those compounds of formula I wherein Z is -NHSO₂CF₃, a compound of the formula XII is reacted with trifluoromethanesulphonic anhydride;

(f) For those compounds of formula I wherein Z is a group of the formula -SO₂NHR⁷, a compound of the formula IV is alkylated with a compound of the formula XV

wherein Hal. stands for a suitable leaving group;

(g) For those compounds of formula I wherein X is phenylene and Z is a group of the formula -SO₂NHR⁷, a compound of the formula X

is reacted with a compound of the formula XIV

wherein W¹ is a bromo, iodo or trifluoromethanesulphonyloxy group;

(h) For those compounds of the formula I wherein Z is

tetrazolyl, X is p-phenylene optionally bearing a substituent selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano and nitro, a compound of the formula IX

wherein P¹ is an electron-deficient phenyl group or a pyridyl or pyrimidyl group and Ry is hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano or nitro, is reacted with a base selected from an alkali metal hydroxide,

(1-12C)alkanolate, (1-12C)alkanethiolate, phenolate, thiophenolate or diphenylphosphide, wherein any phenyl ring of the latter three groups may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or halogeno group; whereafter: when a compound of the formula I is required wherein Z is

-SO₂NH₂, a compound of the formula I wherein Z is -SO₂NHR in which R⁷ is tert-butyl is hydrolysed under acidic conditions;

when a compound of the formula I is required wherein Z is a group of the formula -SO₂NHR⁷ in which R⁷ is (1-4C)alkyl, (1-4C)alkanoyl or

-CO.NH. (1-4C)alkyl, a compound of the formula I wherein Z is the group

-SO₂NH₂ is reacted with an alkylating agent, an acylating agent or an alkyl isocyanate;

when a compound of the formula I is required wherein Z is

1H-tetrazol-5-yl, a compound of the formula I wherein Z is a group of the formula -CO.OR⁵ is converted into the corresponding nitrile under standard conditions, followed by reaction of the nitrile with an azide;

when a compound of the formula I is required wherein Z is a group of - the formula -CO.NH.SO₂R⁶ or a group of the formula -CO.OR⁵ in which R⁵ is other than hydrogen, a carboxylic acid of the formula I in which Z is carboxy (or a reactive derivative of said acid) is reacted with a sulphonamide of the formula NH₂.SO₂ R⁶or a hydroxy compound of the formula HO.R⁵, or with a salt thereof; when an N-oxide of a compound of the formula I is required, a compound of the formula I is oxidised;

when a non-toxic salt of a compound of formula I is required, it is obtained by reaction with the appropriate acid or base affording a physiologically acceptable ion, or by any other conventional salt formation procedure; and

when an optically active form of a compound of formula I is required, one of the aforesaid processes (a)-(h) is carried out using an optically active starting material, or the racemic form of a compound of formula I in which Z is an acidic group is resolved by reaction with an optically active form of a suitable organic base followed by conventional separation of the diastereoisomeric mixture of salts thus obtained, and liberation of the required optically active form of said compound of formula I by conventional treatment with acid; and wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Ra, Rb, X and Z have any of the meanings defined in any of claims 1 to 4 unless otherwise stated.

8. A pharmaceutical composition which comprises a compound of the formula I or la, or a non-toxic salt thereof, as claimed in any of claims 1 to 6, together with a pharmaceutically acceptable diluent or carrier.

9. A compound of the formula III wherein R¹ , R² , R³ , R⁴ , Ra,

Rb and X have any of the meanings defined in any of claims 1 to 4, and L is a protecting group.

10. A compound of the formula IV wherein R¹, R², R³, Ra and Rb have any of the meanings defined in any of claims 1 to 4.