AP161A - Novel Quinoline derivatives. - Google Patents

Abstract

The invention concerns pharmaceutically useful novel compounds of the formula i, in which r1,r2,r3,r4,r5, ra,a,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 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

INVENTORS

2. SIMON THOMAS RUSSELL

3. ROBERT JAMES PEACE

ADDRESS

ALDERLEY PARK MACCLESFIELD UNITEO KINGDOM

NITROGEN COMPOUNDS

This invention concerns novel nitrogen compounds and, more particularly, novel quinoline 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 (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 renln-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-angiotensinaldosterone 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) from angiotensin I, itself produced by the action of the enzyme renin from the blood plasma protein anglotenslnogen. 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 substituted imidazoles and benzimidazoles described in European Patent Application, publication no. 253310 A2 and U.S.

bad ORIGINAL

APOnn16 1

Patent no. 4880804 respectively are known to inhibit the action of angiotensin II, as too are certain substituted pyrroles, pyrazoles and triazoles described in European Patent Application, publication no. 323841 A2. Also certain structurally related quinoline derivatives described in European Patent Application, publication no. 348155 Al are known to be antagonists of leukotriene D4. In addition, a structurally related compound, methyl 2-[(3-methoxycarbonylquinolin4-yloxy)methyljbenzoate, is described in J. Chem. Soc., Perkin Trans. 1, 1972, 1803-8 but without indication of any useful pharmacological properties.

Ve have nov 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 quinoline derivative of the formula I (set out hereinafter, together with the other chemical formulae identified by Roman numerals) wherein R^ is hydrogen, (l-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (l-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (l-4C)alkoxy or phenyl 2 substituent? R is hydrogen, (l-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-4C)alkyl, carboxy, (l-4C)alkoxycarbonyl, cyano,

4 nitro, phenyl or phenyl(l-4C)alkyl; R and R are independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, fluoro(l-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino, (l-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (l-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (l-4C)alkoxycarbonyl, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsu¹phonyl, and substituted (l-4C)alkyl, the latter bearing an amino, hydroxy or (l-4C)alkoxy substituent; or R and R together form (l-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R^ are independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, halj?geno, trifluoromethyl, cyano and nitro; A is methylene; X is phenylene optionally bearing a substituent selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, or X is a direct bond betveen the adjacent phenyl group and moiety A; Z is lH-tetrazol-5-yl, -CO.NH.(lH-tetrazol-5-yl) or a group of the formula ~ 6 7 ~ 6

-CO.OR or -CO.NH.SO2.R in which R is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or phenol, and R? 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 non-toxic salt thereof; but excluding methyl 2-[(3-methoxycarbonylquinolin-4-yloxy)methyl]benzoate.

It will 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 vhich 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 hov 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.

2

A particular value for R or R when it is alkyl is, for example, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl or hexyl; and when it is cycloalkyl is, for example, cyclopropyl, cyclo^entyl or cyclohexyl.

A particular value for R^ when it is alkyl bearing one or *

more fluoro substitutents is, for example, fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl; and when it is alkyl bearing a hydroxy, cycloalkyl, (l-4C)alkoxy or phenyl substituent is, for example, hydroxymethyl, 1-hydroxyethyl,

AP 0 0 0 1 6 1

2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl or 2-phenylethyl.

A particular value for R vhen it is cycloalkyl-alkyl is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or

2- cyclopentyl-ethyl; vhen it is phenylalkyl is, for example, benzyl,

1-phenylethyl or 2-phenylethyl; and vhen it is alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.

4 5

Appropriate values for R , R , R or Ra, or for an optional ,. substituent vhich may be present vhen X is phenylene, as defined above, include by vay of example:for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for halogeno: fluoro, chloro, bromo and iodo; for alkanoylamino: formamido, acetamido and propanamido; for alkylamino: methylaaino, ethylamino and butylaaino; for dialkylamino: dimethylamino, diethylamino and dipropylamino; for dialkylamino-alkyl: dimethylaminomethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl and

3- (diethylamino)propyl; for alkanoyl: formyl, acetyl and butyryl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; for di(N-alkyl)carbamoyl: Ν,Ν-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; for alkylthio: methylthio, ethylthio and butylthio; for alkylsulphinyl: methylsulphinyl, ethylsulphinyl and butylsulphinyl; and for alkylsulphonyl: methylsulphonyl, ethylsulphonyl and butylsulphonyl; for alkyl bearing an amino, hydroxy or alkoxy substituent: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, arainomethyl, 2-aminoethyl, 2-methoxyethyl and 2-ethoxyethyl; and alkylenedioxy: methylenedioxy and ethylenedioxy.

A particular value for vhen it is a non-toxic, biodegradable residue of a physiologically acceptable alcohol or 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 R? vhen it is alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or pentyl; and vhen it is cycloalkyl is, for example, cyclobutyl, cyclopentyl or cyclohexyl.

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

A specific value for X vhich is of particular interest is, for example, £-phenylene.

A preferred value for R$ or R⁵ is, for example, hydrogen and for R¹ is, for example, methyl, ethyl or propyl.

A preferred value for A is, for example, vhen it is methylene.

A preferred group of compounds of the invention comprises those compounds of the formula Ia (set out hereinafter) wherein r\

3 A 5 1

R , R , R and R^J have any of their meanings as defined above and Z^A is carboxy, lH-tetrazol-5-yl or benzenesulphonamido, the latter optionally containing one or tvo substituents independently selected from halogeno (such as fluoro, chloro or bromo), (1-4C)alkyl (such as methyl or ethyl), (l-4C)alkoxy (such as methoxy or ethoxy), cyano, nitro and trifluoromethyl; together vith the non-toxic salts thereof.

A preferred value for Z or Z^ is, for example, carboxy or lH-tetrazol-5-yl, vhich latter is especially preferred and, in particular, vhen it is attached ortho to the group X.

A particularly preferred combination of values in any of the above definitions is vherein the quinoline moiety together vith the attached substituents R¹, R^z, R^J and R*, and Ra vhen present, has any of the following values:- 2-methylquinoline, 2-ethylquinoline,

2-ethyl-6-methoxyquinoline, 6,7-dimethoxy-2-ethylquinoline, 2-ethyl5,6,7-trimethoxyquinoline, 2-ethyl-6-hydroxyquinoline, 2-ethyl-6methylthioquinoline, 2-ethyl-7-hydroxyraethylquinoline, 2-ethyl-6(2-fluoroethoxy)quinoline, 2-ethyl-6-(2,2,2-trifluoroethoxy)quinoline, 2-ethyl-6-carboxamidoquinoline, 2-ethyl-6-fluoroquinoline,

2-ethyl-6-isopropoxyquinoline or 6-aminomethyl-2-ethylquinoline; and in vhich the substituent 0.A.X- is attached at the 4-position of the quinoline ring.

Compounds of the invention vhich are of particular interest include, for example, the specific embodiments set out hereinafter in the accompanying Examples. Of these compounds, those described in

Examples 7, 25, 33, 36, 38 and 47 are particularly preferred and are provided, together vith their non-toxic salts, as a further feature of

AP 0 0 0 1 6 1 the invention.

Although all of the formula I compounds can form salts vith suitable acids, it vill be appreciated that those compounds of formula 3 4

I vherein Z is other than an ester group or in vhich R or R is a carboxy group can form salts vith bases as veil as vith acids. Particularly suitable non-toxic salts for such compounds therefore also include, for example, salts vith 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 veil as salts vith suitable organic bases, such as vith ethanolamine, methylamine, diethylamine or triethylamine, as veil as salts vith acids forming physiologically acceptable anions, such as salts vith mineral acids, for example vith hydrogen halides (such as hydrogen chloride and hydrogen bromide), sulphuric and phosphoric acid, and vith strong organic acids, for example vith p-toluenesulphonic and methanesulphonic acids.

The compounds of formula I may be obtained by standard procedures of organic chemistry veil knovn in the art for the production of structurally analogous compounds. Such procedures are provided as a further feature of the invention and include, by vay of example, the folloving procedures in vhich the generic radicals have any of the values given above, unless stated otherwise:

a) For those compounds in vhich Z is carboxy (that is in vhich

Z is a group of the formula -CO.OR^ in vhich R^ is hydrogen), a carboxylic acid derivative of the formula II, in vhich Q is a protected carboxy group selected from (l-6C)alkoxycarbonyl (especially methoxy-, ethoxy-, propoxy- or £-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. Hovever, it may also be performed in a mixture of an aqueous and non-aqueous solvent such as vater 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 - 40*C.

Further, when Q is £-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 vherein Z is tetrazolyl, a compound of the formula III in vhich L is a suitable protecting group*, such as trityl or benzhydryl, 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, vhen it is trityl or benzhydryl, 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.

c) A quinolone of the formula IV vherein is other than hydrogen is alkylated vith a compound of the formula V vherein Hal. stands for a suitable leaving group such as chloro, brodto, iodo, methanesulphonyloxy or £-toluenesulphonyloxy.

The reaction is generally carried out in the presence of a

AP 0 0 0 1 6 1 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 organic base such as di isopropyle thy Iamine and in a suitable solvent or diluent, for example, a (l-4C)alkanol such as methanol or ethanol vhen an alkali metal alkoxide is used, or in a polar solvent such as Ν,Ν-dimethylformamide and at a temperature in the range, for example, 10 - lOO’C. Alternatively, a quaternary ammonium hydroxide may be used in a mixture of an aqueous and non-aqueous solvent such as vater and dichloromethane. In carrying ¹ out process (c), vhen in the starting material Z is an acidic group, about tvo molecular equivalents of a suitable base is generally required, whereas vhen 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 vhich Z is a group of the formula -C0.0r6 in vhich is other than hydrogen, for example vhmrmln R® is (l-6C)alkyl, benzyl or phenyl, vhich compounds are also starting materials of formula II for the reaction described in (a) above. Similarly, using an analogous procedure, but starting vith the appropriate halomethyl tetrazolyl derivative of the formula VI, the starting materials of the formula III may be obtained for procedure (b).

The majority of the qulnolones of formula IV are already known and the remainder can be made by analogy therevith using standard procedures of organic chemistry veil knovn in the art, for example as described in standard vorks 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 vhich are illustrated in Scheme 1 for compounds in vhich X is phenylene.

d) A halogenoquinoline of the formula VII vherein Y^ is a halogeno group (such as chloro, bromo or iodo) is reacted vith an alcohol of the formula VIII.

The reaction is generally carried out in the presence of a suitable base, for example an alkali metal alkoxide such as sodium methoxide or ethoxide or an alkali metal hydride such as sodium hydride and in a suitable solvent or diluent, for example a (l-AC)alkanol such as methanol or ethanol when an alkali metal alkoxide is used, or a polar solvent such as Ν,Ν-dimethylformamide. Alternatively, an alcohol of the formula VIZI may be used in the form of its preformed alkali metal salt (vhen Z is a non-acidic group) or di-alkali metal salt (vhen Z is an acidic group). The reaction is usually performed at a temperature in the range of 40 to 120*C. Alternatively, the reaction may in preference be carried out vith a formula VIII compound in the presence of an acid catalyst such as £-toluenesulphonic acid, instead of under basic conditions, and in the presence of an inert solvent or diluent such as toluene.

The haloquinolines of the formula VII may be obtained, for example, by halogenation of the corresponding quinolones of formula IV, for example, by reaction vith phosphorus oxychloride in the absence of a solvent, or in the presence of an inert solvent or diluent such as toluene or dioxane, and at a temperature in the range 60 to 110’C. The alcohols of the formula VIII are in general knovn or can be prepared by standard procedures veil knovn in the art.

Vhereafter, those compounds of formula I vherein Z is lH-tetrazol-5-yl may be obtained by stepvlse conversion of a compound of the formula I vherein Z is a group of the formula -CO.OR^ into the corresponding nitrile under standard conditions, followed by reaction of the nitrile vith 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 Ν,Ν-dimethylformamide and at a temperature in the range, for example, 50 to 160*C.

Vhereafter, those compounds of the formula I vherein Z is

-CO.NH.(lH-tetrazol-5-yl), a group of the formula -CO.NH.SO-R? or a 6 6 group of the formula -CO.OR in vhich R is other than hydrogen, may be obtained, for example, by reacting a carboxylic acid of the formula I in vhich Z is carboxy (or a reactive derivative of said acid) vith

5-aminotetrazole, a sulphonamide of the formula NHj-SOjR? or a salt thereof (for example, an alkali metal salt), or a hydroxy compound of the formula HO.R^ or vith a salt thereof (for example, an alkali metal thereof). Suitable reactive derivatives include, for example the chloride, bromide, azide, anhydride and mixed anhydride vith formic or

AP 0 0 0 1 6 1

- 10 acetic acid of the carboxylic acid of formula I as defined above.

Vhen 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.

Vhen 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 vherein Z is a group of the formula -CO.NH.SOjR^ or a group of the formula -CO.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, ^-butyl methyl ether or tetrahydrofuran and at a temperature in the range, for example, 0 - 60°C.

Whereafter, vhen a non-toxic salt of a compound of formula I is required, it may be obtained, for example, by reaction vith the appropriate base affording a physiologically acceptable cation, or vith the appropriate acid affording a physiologically acceptable anion, or by any other conventional salt formation procedure.

Further, vhen 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 vhich Z is an acidic group may be resolved, for example by reaction vith an optically active form of a suitable organic base, for example, ephedrine, Ν,Ν,Ν-trimethyl(l-phenylethyl)ammonium hydroxide or 1-phenylethylamine, folloved by conventional separation of the diastereoisomeric 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 vith 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 and IV, and are provided as a further feature of the invention.

As stated above, the compounds of formula I vill have

- 11 beneficial pharmacological effects in varm-blooded animals (including man) in diseases and medical conditions vhere amelioration of the vasoconstrictor and fluid retaining properties of the reninangiotensin-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 vill thus be useful in the treatment of diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in varm-blooded animals (including man), as veil as in other diseases or medical conditions in vhich 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 vith the receptors vhich mediate its effects on a target tissue, may be assessed using one or more of the folloving, 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 vhich is veil knovn to respond to All. Interaction of the radiolabelled All vith its receptors (assessed as radiolabel bound to the particulate membrane fraction folloving removal of unbound radiolabel by a rapid filtration procedure such as is standard in such studies) is antagonized by compounds vhich 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 vith a control value determined in the absence of the test compound. Using this procedure compounds shoving at least 50X displacement of radiolabelled All binding at a -4 concentration of 10 M are retested at lover concentrations to determine their potency. For determination of the ΙΟ^θ (concentration for 50X displacement of radiolabelled All binding), concentrations of the test compound are ordinarily chosen to allov testing over at least

APO0016 1

- 12 four orders of magnitude centred about the predicted approximate ΙΟ^θ, which latter is subsequently determined from a plot of percentage displacement against concentration of the test compound.

In general, compounds of formula I as defined above wherein Z is an acidic group show significant inhibition in Test A at J 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, compounds of formula I as defined above wherein Z is an acidic group 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.011^ 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 Il-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 test involves the stimulation of endogenous All biosynthesis in a variety of species including rat, marmoset and dog by introducing a diet q.f 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

- 13 measurement of changes in blood pressure.

In general compounds of formula I will shov All-antagonist properties in Test D as demonstrated by a significant reduction in blood pressure at a dose of 50 mg/kg body veight 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 formula I, the compound of example 7 gave the following results in tests A, B and C described above:-8

In test A: an average ΙΟ^θ of 1.7x10 M;

In test B an average pA^ of 8.95;

In test C: of 0.5 mg/kg (i.v. administration).

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 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 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 veight (and preferably of up to 10 mg/kg) or a daily parenteral dose of up to 5 mg/kg body veight (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

APO 0016 1

- 14 treated according to principles veil knovn 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 varm-blooded animals, such as dogs, cats, horses and cattle. In general for such treatment, the compounds of the formula I vill 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 nev and improved therapeutic agents.

The invention vill nov be illustrated by the folloving nonlimiting Examples in vhich, unless othervise statedt(i) concentrations and evaporations vara carried out by rotary evaporation in vacuo;

(ii) operations vere carried out at room temperature, that is in the range 18-26^eC;

(iii) flash column chromatography vas performed on Merck Kieselgel 60 (Art. no. 9385) obtained from E Merck, Darmstadt, Germany;

(iv) yields, vhere given, are intended for the assistance of the reader only and are not necessarily the maximum attainable by diligent process development;

(v) NMR spectra vere normally determined at 200 MBz 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;

(vi) nmr spectra vere normally determined at 100 MHz in CDCl^ or dg-dimethylsulphoxide (dg-DMSO) using the solvent signal as internal standard, and are expressed as chemical shifts (delta values) in parts per million relative to TMS;

(vii) all end-products had satisfactory microanalyses; and (viii) the term lH-tetrazol-5-yl stands for

1H-1,2,3,4-te trazol-5-yl.

- 15 Example 1

1.25M sodium hydroxide solution (2.4 ml) vas added to a solution of methyl 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2- carboxylate (A) (380 mg) in ethanol (5 ml). The solution vas heated under reflux for 2 hours and then volatile material vas removed by evaporation. The residue vas dissolved in vater (30 ml) and the solution acidified to pH 4 vith 2M hydrochloric acid. The precipitated solid vas a collected, dried under high vacuum and recrystallised from ethanol to give 4'-((2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carboxylic acid (254 mg), as white crystals, m.p. 204-205’C;

NMR (d^-dimethylsulphoxide (d^-DMSO)): 1.34(t,3H), 2.9(q,2H), 5.42(s,2H), 7.1(s,lH), 7.38-7.78(complex m,10H), 7.88(d,lH), 8.15(dd,lH), 12.74(br,1H); mass spectrum (negative fast atom bombardment l-ve FAB], DMSO/glycerol (GLY): 382 (M-H)“, 172; microanalysis found: C,78.0; H,5.4; N,4.05; ^₂5θ21^Νθ3 ^re9^u^^res!

C,78.3; H,5.5j N,3.7X.

AP 0 0 0 1 6 1

The starting material (A) vas obtained as follovs:(i) A 1.6M solution of butyllithium in hexane (24.0 ml) vas added dropvise to a stirred solution of 4-bromotoluene (6.0 g) in dry tetrahydrofuran (THF) (50 ml) at -78*C under an atmosphere of argon. The temperature vas maintained at -78°C for 20 minutes and then a 1M solution of anhydrous zinc chloride in ether (38.6 ml) vas added. The solution vas kept at -78^eC for 15 minutes, and then tetrakis (triphenylphosphine)palladium (60 mg) in THF (5 ml) vas added, followed by methyl-2-iodobenzoate (6.1 g) in THF (10 ml). The solution vas alloved to reach ambient temperature over 1 hour, then heated under reflux for 5 hours. The solvent vas removed by evaporation and the residue vas dissolved in chloroform (150 ml). The solution vas vashed vith a solution of ethylene diaminetetracetic acid (10 g) in vater (100 ml) and the aqueous layer vas re-extracted vith chloroform (100 ml). The combined organic extracts vere dried (MgSO^) and the solvent removed by evaporation. The residue vas purified by flash chromatography, eluting vith ethyl acetate/hexane (1:9 v/v) to give methyl 4'-methylbiphenyl-2-carboxylate (B) as a colourless oil (4.4 g); NMR: 2.4(s,3H), 3.65(s,3H), 7.2(s,4H), 7.35(m,3H), 7.5(m,lH),

- 16 7.8(d,lH), (ii) N-Bromosuccinimide (8.1 g) and azo(bisisobutyronitrile) (130 mg) were added to a solution of compound (B) (9.3 g) in carbontetrachloride (300 ml). The mixture vas heated under reflux for 4 hours and then cooled to ambient temperature. Insoluble material vas removed by filtration and the filtrate concentrated. The residue vas purified by flash chromatography, eluting vith ethyl acetate/hexane (1:9 v/v) to give methyl 4'-(bromomethyl)biphenyl-2carboxylate (C) as a solid (10.9 g), m.p. 48-50’C; NMR: 3.65(s,3H), 4.55(s,2H), 7.25-7.60 complex (m,7H), 7.85(d,lH).

(iii) Sodium hydride (60X dispersion in mineral oil; 60 mg) vas added to a stirred solution of 2-ethyl-4-quinolone (260 mg) prepared by the method described in Org. Syn., 1955, Coll. Vol. Ill, p.374 and p593), in Ν,Ν-dimethylforaamide (DMF)(2.5 ml). The mixture vas stirred until evolution of hydrogen had ceased and then a solution of the bromomethyl compound (C) (460 mg) in DMF (1 ml) vas added. The reaction mixture vas stirred for 16 hours. The solvent vas removed by evaporation and the residue vas partitioned betveen vater (10 ml) and ethyl acetate (2x5 ml). The organic phase vas vashed vith vater, followed by saturated sodium chloride solution and dried (MgSO^). The solvent vas evaporated and the residue purified by flash chromatography, eluting vith ethyl acetate/dichloromethane (1:4 v/v) to give methyl 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2carboxylate (A) as a solid (385 mg), m.p. 132-134’C; NMR: 1.41(t,3H), ... 2.97(q,2H), 3.68(s,3H), 5.34(s,2H), 6.77(s,lH), 7.44-7.7(complex m,9H), 7.87(dd,lH), 8.0(d,lH), 8.26(dd,lH)j mass spectrum (positive chemical ionisation [+ve CI J: 398 (M+H) ⁺ , 225, 174; ^C NMR: (benzylic CH₂) 69.73.

Examples 2-4

Using a similar procedure to that described in Example 1, but starting from the appropriate ester of the formula IT in vhich Q is a methoxycarbonyl group the following compounds vere obtained:(Example 2): 4'-[(2-Methylquinolin-4-yloxy)methyl]biphenyl-2carboxylic acid hydrochloride, m.p. 184-186^eC; NMR (dg-DMSO):

- 17 2.93(s,3H), 5.67(s,2H), 7.38-7.72(m,8H), 7.77(dd,lH), 7.84(dd,lB), 8.08(dt,1H), 8.29(d,lH), 8.33(d,lH); mass spectrum (-ve FAB,

DMSO/m-nitrobenzyl alcohol)(NBA): 368 (M-H)^-; microanalysis found: C,71.2; H,5.0; N,3.6; Cl, 8.6Z, ^C24^H19^NO3'^HCl requires:C,71.0; H,5.0; N,3.5; Cl,8.7X; starting from methyl 4'-[(2-methylquino..tn-4-yloxy)methyl]biphenyl-2-carboxylate, obtained as a solid, m.p. 146 *C; NMR: 2.71(s,3H), 3.67(s,3H), 5.33(s,2H), 6.74(s,lH), 7.3-7.6(complex m,8B), 7.68(dt,lH), 7.87(dd,lfl), 7.98(d,lH), 8.23(dd,lH); itself obtained from 2-methyl-4-quinolone, using analogous procedures to those described in Example 1;

(Example 3): 4' - ((2-Propylquinolin-4-yloxy)methylJbiphenyl-2carboxylie acid*, m.p. 198-200°C; NMR (dg-DMSO): O.97(t,3H),

l. 8(m,2H), 2.85(t,2H), 5.43(s,2H), 7.08(s,lH), 7.35-7.65(complex m, 8H), 7.73(dt,2H),7.87(d,lH), 8.15(dd,lB), 12.7(br s,lB); mass spectrum (-ve FAB, DMSO/GLY): 396 (M-H)“, 186; microanalysis, found: C,77.5; H,6.0; N,3.5Z; ^26^Η23^Ν03·θ·requires: C,77.8; H,6.1; N,3,4Z; starting from methyl 4'-[(2-propylquinolin-4-yloxy)methyl]biphenyl-2-carboxylate, obtained as a viscous oil; NMR: l.O3(t,3H), 1.87(m,2B), 2.94(t,2H), 3.68(s,3H), 5.36(s,2H), 6.75(s,lH), 7.347.6(complex m,8H), 7.68(dt,lH), 7.85(dd,21B), 8.03(d,lH), 8.25(dd,lB);

NMR (CDCip: (benzylic CB2) 69.8; itself obtained from 2-propyl-4quinolone using analogous procedures to those described in Example 1;

[ Note: 1M aqueous citric acid solution vas used in placi of 2M hydrochloric acid in the vork-up procedure].

(Example 4): 4'-((2-Butylquinolin-4-yloxy)methyl]biphenyl-2-carboxylic acid, m.p. 148^eC; NMR (dg-DMSO): O.93(t,3B), l,38(m,2B), 1.8(m,2B), 2.95(t,2H), 5.5(s,2H), 7.25(s,lH), 7.33-7.68(complex m,8B), 7.77.85(m,2H), 7.98(d,lH), 8.2(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 410 (M-H)^-, 200; microanalysis found: C,77.1; 3,6.1; N,3.1Z; ^27^25^Νθ3*θ·^⁰2θ ^re9^ui^res: C,77.1; H,6.2; N,3.3Z; starting from methyl 4' -((2-butylquinolin-4-yloxy)methyl]biphenyl-2-carboxylate obtained as viscous oil; NMR: 0.97(t,3H), 1.45(m,2H), 1.78(m,2H), 2.94(t,2H), 3.68(s,3H), 5.35(s,2H), 6.76(s,lB), 7.35-7.6(complex m,8B), 7.69(dt,lH), 7.88(dd,lH), 8.0(d,lH)? 8.25(dd,lH); mass spectrum (+ve CI): 426 (M-H)*, 225, 202; itself obtained from 2-butyl-4-quinolone using analogous procedures to those described in Example 1.

AP 0 0 0 1 6 1

- 18 The starting materials, 2-methyl-4-quinolone and

2-propyl-4-quinolone, vere obtained as described in Org. Syn., 1955 Coll. Vol. Ill, page 374 and page 593. 2-Butyl-4-quinolone was obtained using an analogous procedure, starting from ethyl 3-oxoheptanoate and had the following NMR spectrum: O.88(t,3H), 1.34(m,2H), 1.7(m,2H), 2.7(t,2H), 6.27(s,lH), 7.34(t,lH), 7.6<dt,lH)), 7.78(d,lH), 8.36(d,lH), 11.8(br s, IH).

Example 5

5M Aqueous sodium hydroxide solution (2 ml) vas added to a solution of methyl 4-[ (2-propylquinolin-4-yloxy)methyl J benzoate (A) (500 mg) in methanol (5 ml), the solution vas allowed to stand for 16 hours. Vater (50 ml) vas added and the mixture heated to dissolve the solid precipitate. The solution vas filtered and the filtrate acidified to pB4 vith 1M aqueous citric acid solution. The precipitated solid vas collected by filtration and dried under high vacuum to give 4-[(2-propylquinolin~4-yloxy)methyl]benzoic acid (347 mg), as a white powder, m.p. 225-227’C; NMR (dg-DMSO): 0.95(t,3H),

1.7-1.9(m,2H), 2.84(t,2H), 5.5(s,2H), 7.05(s,lH), 7.5(dt,lH), 7.7<m,3H), 7.88(d,lH), 8.0(d,lH), 8.15(dd,lH), 12.9(br,lH); mass spectrum (-ve FAB, DMSO/Gly); 32) (M-H)~, 186; microanalysis found: C,73.9; H,5.9; N.4.2X; ^20^Η19^Νθ3'°'^25Η2° requires; C,73.7; H,6.0; N,4.3X.

The starting ester (A) vas obtained from 2-propyl4-quinolone (561 mg) and methyl 4-(bromomethyl)benzoate (700 mg) together vith appropriate amount to the other necessary agents and solvents, using a similar procedure to that described in Example 1, part (iii) and purification by flash chromatography eluting vith a mixture of methanol and dichloromethane (1:9 v/v), as a solid (540 mg), m.p. 62-65’C; NMR: 1.0(t,3H), 1.83(m,2H), 2.9(t,2H), 3.95(s,3H), 5.37(s,2B), 6.69(s,lH), 7.46(dt,lH), 7.58(d,2H), 7.67(dt,lH), 8.0(d,lH), 8.1(d,2H), 8.2(dd,13).

Example 6

4-((2-Propylquinolin-4-yloxy)methyl]benzoic acid (240 mg) vas added to a mixture of benzene sulphonamide (120 mg),

- 19 4-dimethylaminopyridine (90 mg) and l-[3-(dimethylamino)propyll3-ethylcarbodiimide hydrochloride (150 mg) in dichloromethane (20 al) and the mixture stirred overnight. Chloroform (20 ml) vas added the mixture vas washed successively with 1M citric acid solution (10 ml), vater (2 x 10 ml), saturated sodium chloride solution (5 ml) and then dried (MgSOp. The solvent vas removed by evaporation and the residue triturated vith methanol to give 4-[(2-propylquinolin-4-yloxy)methyl]N-phenylsulphonylbenzaaide as a vhite povder (160 mg), m.p. 140 °C (dec.); NMR (dg-DMSO): 0.95(t,3B), 1.79(m,2B), 2.88(t,2H), 5.5(s,2H), 7.14(s,lH), 7.5-7.7(m,6H), 7.78(dt,lH), 7.87-8.02(ra,5H), 8.18(dd,lH); mass spectrum (-ve FAB, DMSO/Gly): 495 (M-H)“; microanalysis found: C,66.1; H,5.4; N,5.8X; ^C26^B24^N2°4^S,0'^5H2° requires: C.66.5; H,5.3; N,6.0X.

Example 7

A mixture of 2-methyl-4-((2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl)methoxyJquinoline (A) (890 mg) and a 7.5M solution of hydrogen chloride dioxane (10 ml) and vater (1 ml) vas alloved to stand for 72 hours. Volatile material vas removed by evaporation and the residue vas triturated vith ether (2 x 50 ml). The ether vas decanted off and the solid residue crystallised from Isopropanol to give 2-methy 1-4-[(2'-(lB-tetrazol-5-y 1)bipheny 1-4-y 1)methoxy]quinoline hydrochloride (370 mg), as a vhite solid, m.p, 188-190®C; NMR (d$DMSO): 2.92(s,3H), 5.63(s,2H), 7.21(d,2H), 7.56-7.87(m,8B), 8.07(dt,lH), 8.28(dd,lB), 8.32(dd,lH); mass spectrum [-ve FAB, DMSO/NBA]: 392 (M-H)~, 158; microanalysis found: C,66.0; H.4.6; N.15.5X; C₂₄B₁₉N₅O.HCl.0.5H₂O requires: C,65.7; H,4.8; N,16.0X.

The starting material (A) vas obtained as follovs:Sodium hydride (60X dispersion in mineral oil; 90 mg) vas added to a stirred solution of 2-methyl-4-quinolone (340 mg) in DMF (10 ml). The mixture vas stirred until evolution of hydrogen had *

ceased and a solution of 5-2-(4'-bromomethylbiphenylyl)]-2triphenylmethyl-2H tetrazole (1.2 g) (obtained as described in

European Patent 0291969) in DMF (5 ml) vas added. The mixture vas stirred for 16 hours. The solvent vas removed by evaporation and the

I 9 L 0 0 0 dV

- 20 residue partitioned between water (20 ml) and dichloromethane (2 x 10 ml). The organic layer was washed with saturated sodium chloride solution (5 ml) and dried (MgSO^). The solvent was removed by evaporation and the resultant oil vas purified by flash chromatography, eluting with methanol/dichloromethane (1:99 v/v) to give 2-methyl-4-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4ylmethoxyJquinoline (A) (890 mg) as a vhite solid m.p. 168-170 °C (dec.); NMR: 2.7(s,3H), 5.14(s,2H), 6.7(s,lH), 6.9(dd,6H), 7.157.55(complex m,17H), 7.65(dt,1H), 7.95(m,2H), 8.1(dd,lH).

Example 8

Using an analogous procedure to that described in Example 7 but starting from 2-propyl-4-((2'-(2-triphenylmethyl-2H-tetrazol-5yl)biphenyl-4-yl)methoxyJquinoline (A), there vas obtained

2-propy1-4- (( 2' - (1H- te t razol-5-y1) bi pheny 1-4-y 1) me thoxy J quinoline hydrochloride, m.p. 178-180‘C; NMR (d₆~DMSO): 0.98(t,3B), 1.88(m,2H), 3.08(t,2B), 5.6(s,2B), 7.2(d,2B), 7.5- 7.85(co«plex m,8fl),

8.02(dt,lH), 8.2(d,lB), 8.28(dd,lB); mass spectrum (-ve FAB,

DMSO/NBA): 420(M-H)~; microanalysis found: C,67.9; B,5.2; N.14.9X; ^C26®23ⁱ⁾5^’®^{C3 re}9^ui^res 0,68.2; H,5.3; N,15.3X.

The starting material (A) vas obtained as vhite solid, m.p. 150-152’C; NMR: 1.05(t,3H), 1.88(m,2B), 2.92(t,2H), 5.2(s,2H), 6.73(s,lH), 6.94(dd,6B), 7.15-7.58(complex m,17H), 7.68(dt,lH), 8.0(m,2H), 8.12(dd,lH), ¹³C NMR (CDClj): (benzylic CBj) 69.67; starting from 2-propyl-4~quinolone using a similar procedure to that described in Example 7.

Examples 9-29

Using an analogous procedure to that described in Example 7, but starting from the appropriate triphenylmethyl tetrazoles (III), the following compounds of formula I were obtained in yields of 70-90X:(Example 9): 5-Cyano-2-e thy1-4-[(2'-(1H-1e t razol-5-yl)bi pheny1-4-y1)methoxy Jquinoline hydrochloride, m.p. 240’C (dec); NMR (d^-DMSO):

1.40(t,3H), 3.16(q,2H), 5.57(s,2B), 7.17(d,2H), 7.50-7.75(m,7H),

- 21 8.10(t,1H), 8.32(d,lH), 8.62(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 431 (M—H)~; microanalysis, found: C,65.2; H,4.5; N,16.6; E^O, 2.OX; ^C26^H2O^N6°^,HCl,O'^5H2° ^reR^uires: C.64.9; H,4.8; N.16.8; HjO, 1.8X; (Example 10): 2-Ethyl-6-trifluoromethyl-4-[(2'-(lB-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloric*., m.p. 188-190’C; NMR (dg-DMSO): 1.43(t,3H), 3.20(q,2H), 5.67(s,2H), 7.20(d,2H), 7.55-7.73(m,7H), 8.30(d,lB), 8.48(d,2B); mass spectrum (-ve FAB, DMSO/GLY): 474 (M-B)”; microanalysis, found: C,60.6; B,3.9; N,13.3X;

^C26^B2O^N5^OP3^{,HCl re}9^uires: C,61.0; B.4.1; N,13.7X;

(Example 11): 2-Ethyl-8-trifluoromethyl-4-((2'-(lB-tetrazol-5-yl)biphenyl-4-yl)aethoxy]quinoline*, m.p. 110-113^eC; NMR (CDCl^): 1.42(t,3H), 3.05(q,2B), 5.37(s,2H), 6.85(s,lH), 7.28-7.62(m,8H), 8.03(d,lH), 8.14(dd,lB), 8.43(d,lB); mass spectrum (-ve FAB,

DMSO/GLY): 474 (M-B)“; microanalysis, found: C.64.6; H,4.4; N,13.3X; ^t'26^H20^N5^OP3* dioxane requires C,64.5; B,4.7; N,13.1X. «Isolated as free base;

(Example 12): 2-Ethyl-6-methoxy-4-{(2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxyJquinoline hydrochloride, m.p. 213-215^eC; NMR (dg-DMSO): 1.41(t,3H), 3.12(q,2B), 3.95(s,3H), 5.68(s,2B), 7.2O(d,2H),

7.50- 7.76(m,9H), 8.21(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 436 (M-H)“; microanalysis, found: C,66.1; H,5.0; N,14.6X; C^B^N^Oj.HCl. requires C,65.9; B,5.1; N,14.8X;

(Example 13): 2-Ethyl-8-methoxy-4-[(2'-(lH-tfctrazol-5-yl)biphenyl4-yl)methoxyJquinoline hydrochloride, m.p. 125-127’C; NMR (d^-DMSO): 1.40(t,3H), 3.24(q,2B), 4.14(s,3H), 5.66(s,2H), 7.21(d,2H),

7.50- 7.84(m,10H); mass spectrum (-ve FAB, DMSO/GLY): 436 (M-B)~; microanalysis, found: C,63.7; H,5.8; N,13.5X;

⁽'26^Β23^Ν5°2’^Ηί'^θ^^Β2θ’θ*^^^^{ΟΧ3ηβ re}9^u^^res C,63.8; H,5.3; N.13.3X. (Example 14): 2-Ethyl-5,7-dimethoxy-4-[(2'-(lB-tetrazol-5-yl)biphenyl4-yl)methoxy]quinoline hydrochloride, m.p. 2O3-2O5°C; NMR (d^-DMSO): 1.40(t,3H), 3.07(q,2H), 3.91(s,3B), 3.94(s,3B), 5.56(s,2H),

6.80(d,lH), 7.21(d,2B), 7.31(s,2H), 7.51(d,?H), 7.56-7.62(m,2H),

7.68-7.75(m,2H); mass spectrum (-ve FAB, DMSO/GLY): 466(M-H)“; microanalysis, found: C,63.6; H,5.3; N,12.9; H₂0, 1.0X;

C^Hz^N^OyHCl.0.25^0.0.25dioxane requires C,63.5; H,5.2; N,13.2;

H₂0, 0.9X;

(Example 15): 2-Ethyl-6,7-dimethoxy-4-((2'-(lH-tetrazol-5-yl)AP 0 0 0 1 6 1

- 22 biphenyl-4-yl)methoxyJquinoline hydrochloride, m.p. 272^eC (decomp);

NMR (d₆DMSO): 1.40(t,3B), 3.10(q,2fl), 3.95(s,3H), 3.98(s,3B), 5.65(s,2B), 7.20(d,2B), 7.43(d,2B), 7.53-7.74(m,7H); mass spectrum (-ve FAB, DMSO/GLY): 466(M-B)~; microanalysis, found: C,62.7; B,5.1; N,13.5; H₉0, 2.5X; C₉₇B_?sNeO,.HC1.0.75H-0 requires C,62.7; H,5.1; N,13.5; B₂0, 2.6X;

(Example 16): 2-Bthyl-5,8-dimethoxy-4-[(2'-(lH-tetraxol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride, m.p. 171°C (decomp.); NMR (dg-DMSO): 1.39(t,3B), 3.22(q,2B), 3.90(s,3B), 4.09(s,3B), 5.62(s,2B), 7.19-7.28(m,3B), 7.51-7.77(m,8H); mass spectrum (-ve FAB, DMSO/GLY): 466 (M-B); microanalysis, found: C,61.3; B,5.4; N,12.9; B₂0, 5.8X; CjyB^N^OyBCl.l.SB^ requires C,61.1; B,5.3; N,13.2; B₂0, 5.IX;

(Example 17): 2-Ethyl-5,6,7-trimethoxy-4-l(2'-(lfl-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride, m.p. 181-182*C| NMR (d₆-DHSO): 1.42(t,3B), 3.1O(q,2B), 3.68(s,3H), 3.87(s,3B), 4.00(s,3H), 5.55(s,2B), 7.2O(d,2H), 7.42(s,lB), 7.53-7.62(m,5B), 7.68-7.74(m,2B); mass spectrum (-ve FAB, DMSO/GLY): 496 (M-H)”; microanalysis, found: C,60.6.; B.5.1; N,12.6; B₂O, 2.9X; ^C28^H27^N5°4^,aC1’^H2° requires C.60.9; B,5.3; N,12.7; BjO, 3.3X;

(Example 18): 7-Cyano-2-ethyl-4-[(2'-(lfl-tetrazol-5-yl)biphenyl-4-yl)ethoxyJquinoline hydrochloride, m.p. 160-163’C; NMR (dg-DMSO): 1.43(t,3B), 3.17(q,2B), 5.64(s,2B), 7.20(d,2B), 7.55(d,2H), 7.58-7.72(m,5B), 8.08(d,lB), 8.40(d,lB), 8.76(s,lB); mass spectrum (-ve FAB, DMSO/GLY): 431 (M-B)”; microanalysis, found: C,64.3; B,4.9; N,16.6X; C₂₆H₂₀N^0.BCl.B₂0.0.1dioxane requires C,64.1; B,4.8; N,17.0X; (Example 19): 2-Ethyl-7-methoxy-4-((2'-(lB-tetrazol-5-yl)biphenyl4-yl)methoxyJquinoline hydrochloride, m.p. 172-174*C; NMR(d^-DMSO): 1.44(t,3H), 3.15(q,2H), 3.97(s,3B), 5.64(s,2B), 7.21(d,2B),

7.38-7.77(31,9H), 8.2O(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 436(M-H)”; microanalysis, found: C,63-8; H,5.5; N,13.8; B₂0, 3.5X; ^C26^H23^N5°2^recl^uires C,63-5; B.5.3; N,14.2; B₂0, 3.7X;

(Example 20): 6-Carbomethoxy-2-ethy1-4-((2'-(lB-tetrazol-5-yl)te ¹¹ _w biphenyl-4-yl)methoxyJquinoline hydrochloride, m.p. 202-204’C; NMR (dg-DMSO): 1.50(t,3B), 3.28(q,2B), 4.00(s,3B), 5.74(s,2B), 7.29(d,2B),

7.56-7.82(m,7B), 8.48-8.55(m,2B), 8.82(s,lH); mass spectrum (-ve FAB,

DMSO/GLY): 464 (M-B)”; microanalysis, found: C,64.6; B,4.7; N,13.8X;

- 23 ^C27^H23^N5°3'^{HC1 re}9^uires C.64.6; H,4.8; N,14.0X;

(Example 21): 2-Ethyl-5-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl4-yl)- methoxyjquinoline hydrochloride, m.p. 168-169^eC (dec.); NMR (d₆-DMSO): 1.42(t,3H), 2.75(s,3H), 3.17<q,2H), 5.61(s,2H), 7.20(d,2H),

7.54- 7.71(m,8H), 7.89(t,lH), 8.19(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 420 (M-B)'; microanalysis, found: C,65.8; H,5.4; N,14.0; H₂0, 3.OX; ^C25®23^N5®’BClO^iHjO.0.33 EtOAc requires C,65.6; H,5.6; N,14.0; H₂0, 2.7X;

(Example 22): 2-Ethyl-7-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy[quinoline hydrochloride, m.p. 213-215^eC (dec.); NMR (d₆-DMS0): 1.43(t,3H), 2.59(s,3H), 3.19(q,2H), 5.65(s,2H), 7.22(d,2B),

7.54- 7.75(m,8H), 8.09(s,lB), 8.19(d,lB); mass spectrum (-ve FAB, DMSO/GLY); 420 (M-B)‘; microanalysis, found: C,68.5; H,5.3; N.15.3X; ^26^23^5θ’^^ ^re9^u^^res C,68.2; H,5.3; N,15.3X;

(Example 23): 2,6-Dimethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxyjquinoline hydrochloride, m.p. 2OO-2O2°C (dec.); NMR (d^-DMSO): 2.56(s,3H), 2.89(s,3H), 5.62(s,2H), 7.22(d,2H), 7.54-7.72(m,7H), 7.91(dd,lH), 8.06(s,lH), 8.18(d,lH); mass spectrum (-ve FAB,

DMSO/GLY): 406 (M-H)~; microanalysis, found: C,67.1; H,4.8; N,15.4X;

^C25^H21^N5^O,HC1,O’^25H2° ^re9^uires C,67.O; H,5.0; N.15.6X;

(Example 24): 2,8-Dimethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride, m.p. 193-195°C (dec.); NMR (dg-DMSO): 2.82(s,3H), 2.99(s,3H), 5.63(s,2H), 7.21(d,2H), 7.53-7.72(m,8H), 7.89(d,lH), 8.16(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 406 (M-B)'; microanalysis, found: 0,67.5; H,5.0; N,15.6X; requires

C,67.6; H,5.0; N,15.8X;

(Example 25): 2-Ethyl-4-((2'-(lB-tetra2ol-5-yl)biphenyl-4-yl)methoxy[quinoline hydrochloride, m.p. 178-181’C (dec.); NMR (d^-DHSO): 1.48(t,3H), 3.22(q,2H), 5.68(s,2H), 7.23(d,2H), 7.5-7.8(m,7H), 7.83(t,lB), 8.08(t,IH), 8.32(t,2H); ¹³C NMR: (benzylic CH2) 71.9; mass spectrum (-ve FAB, DMSO/GLY): 406 (M-H)~; microanalysis, found: C,68.0; B,5.1; N.15.8X; ^C25^H21^N5°‘^HCl requires C,67.6; H,5.0; N,15.8X. (Example 26): 6,8-Dimethyl-2-ethyl-4-((2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy]quinoline hydrochloride, m.p. 195-197^eC (dec.); NMR (dg-DMSO): 1.4(t,3H), 2.5(s,3H), 2.81(s,3H), 3.34(q,2H), 5.65(s,2B), 7.22(d,2H), 7.54-7.72(m,8H), 7.89(s,lH); mass spectrum (-ve FAB, DMSO/GLY): 434 (M-H)~; microanalysis, found: C.68.7; H,5.6; N.14.8X;

AP 0 0 0 1 6 1

- 24 ^C27^H25^N5°‘^{HC1 requires c}’⁶⁸·⁷’ ^H»⁵·⁵? N.14.9X;

(Example 27): 6-Chloro-2-aethyl-4-((2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy]quinoline hydrochloride m.p. 197-198^eC (dec.); NMR (d^-DMSO): 2.9(s,3H), 5.61(s,2H), 7.22(d,2H), 7.53-7.77(m,7B), 8.08(dd,lH), 8.21-8.28(m,2H); ¹³C NMR: (benzylic CHj) 72; mass spectrum (-ve FAB, DMSO/GLY): 426 (M-H)~; microanalysis, found:

C,62.2; H,4.1; N,15.1; Cl,15.OX; Cj^gNjClO.BCl requires C,62.1; H,4.1; N,15.1; Cl,15.3X;

(Example 28): 7-Chloro-2-ethyl-4-((2'-(lH-tetra2ol-5-yl)biphenyl4-yl)methoxy]quinoline hydrochloride m.p. 170-172^eC (dec.); NMR (d₆-DMSO): 1.43(t,3H), 3.18(q,2B), 5.64(s,2H), 7.21(d,2H),

7.5-7.75(m,7H), 7.81(dd,lB), 8.29(d,lH), 8.40(d,lB); mass spectrum (-ve FAB, DMSO/GLY): 440 (M-H)“; microanalysis, found: C,61.8; H,4.3; N,14.2; Cl, 14.3; H₂0, 2.IX; ^C25^H20^N5^Cl0,BCl,0,5H2° requires C,61.6; 8,4.5; N,14.4; Cl,14.6; BjO, 1.8X; and (Example 29): 8-Chloro-2-ethyl-4-l (2' -(lH-tetrazol-5-yl)biphenyl4-yl)methoxy]quinoline hydrochloride m.p. 146-148“C (dec.); NMR (d^-DMSO): 1.38(t,3B), 3.08(q,2H), 5.52(s,2B), 7.19(d,2B), 7.38(t,lB),

7.51-7.75(m,7B), 8.Q2(d,lB), 8.18(dd,lB); mass spectrum (-ve FAB, DMSO/GLY): 440(M-H)‘; microanalysis, found: C.60.8; B,4.6; N,14.1X; ^C25^H2O^N5^ClO,HC1,02° ^{requires C}’⁶⁰-^5; N,14.1X.

The necessary starting materials of formula III vere obtained in yields of 2O-7OX using an analogous procedure to that described in Example 7 but starting from the appropriate quinolines of formula IV. The compounds of formula III had the following properties:

(9) : 5-Cyano-2-ethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, isolated as a foam; NMR (d^-DHSO): 1.34(t,3H), 2.96(q,2B), 5.55(s,2H), 6.82-6.93(m,6B), 7.14(d,2H),

7.25-7.36(m,9H), 7.40-7.65(m,6H), 7.80(dd,lH), 7.93(t,lH), 8.16(d,lH), 8.30(d,1H);

(10) : 2-Ethyl-6-trifluoromethyl-4-([2'-(2-triphenylmethyl-2Btetrazol-5-yl)biphenyl-4-yl]niethoxy)quinoline, isolated as a foam;

NMR: 1.55(t,3H), 3.12(q,2B), 5.35(s,2B), 6.91(s,lH), 7.05-7.10(m,6H),

7.33-7.45(m,13B), 7.52-7.69(m,3B), 7.99(dd,lH), 8.10(dd,lH),

8.24(d,lH), 8.64(s,lH);

- 25 (11) : 2-Ethyl-8-trifluoromethyl-4-([2'-(2-triphenylmethyl-2Htetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, isolated as a foam;

NMR: 1.45(t,3H), 3.01(q,2H), 5.19(s,2H), 6.80(s,18), 6.88-7.0(m,6B),

7.18-7.55(m,17H), 8.05(dd,2B), 8 32(d,lB); ¹³C NMR: (benzylic CBp 69.96;

(12) : 2-Ethyl-6-me thoxy-4-([2'-(2-tri phenylme thyl-2B-te trazol-5yl)biphenyl-4-yl]methoxy)qulnoline, isolated as a foam; NMR: 1.37(t,3B), 2.9O(q,2B), 3.80(s,3B), 5.19(s,2B), 6.7O(s,lH),

6.91- 6.97(m,6B), 7.19-7.35(m,14B), 7.42-7.52(m,4H), 7.89-7.95(a,2B); ¹³C NMR: (benzylic CHp 69.72;

(13) : 2-Ethyl-8-methoxy-4-([2'-(2-triphenylmethyl-2H-tetrazol-5yl)biphenyl-4-yl]methoxy)quinoline, isolated as a foam; NMR (dg-DMSO): 1.33(t,3H), 2.88(q,2H); 3.93(s,3B), 5.31(s,2H), 6.81-6.92(m,6B);

7.10-7.12(m,4H), 7.25-7.7O(m,15H), 7.85(d,2B);

(14) -: 2-Ethyl-5,7-dimethoxy-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, isolated as a foam; NMR: 1.39(t,3H), 2.89(q,2H), 3.87(s,3H), 3.93(s,3H), 5.14(s,2H),

6.46(d,lH), 6.58(s,1H),6.86-6.95(a,6B), 7.01(d,lB), 7.16-7.29(m,llB),

7.35-7.52(m,5H), 7.91-7.95(m,lH); ¹³C NMR: (benzylic CHp 69.63;

(15) : 2-Ethyl-6,7-dimethoxy-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 211®C (decomp.); NMR (dg-DMSO): 1.39(t,3B), 2.9O(q,2B), 3.87(s,3B), 4.03(s,3B), 5.20(s,2H), 6.65(s,lH), 6.94-7.00(m,6H), 7.19-7.33(m,13H), 7.39-7.55(m,5H), 7.94(dd,lH); ¹³C NMR: (benzylic CBj) 69.72;

(16) : 2-Ethyl-5,8-dimethoxy-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 94-97’C; NMR (CDCl^): 1.41(t,3H), 3.04(q,2H), 3.85(s,3H), 4.04(s,3H), 5.18(s,2H),

6.75(d,2H), 6.88-6.98(m,7H), 7.18-7.29(m,11H), 7.37-7.56(m,5H),

7.91- 7.96(m,18); ¹³C NMR: (benzylic CH₂) 69.85;

(17) : 2-Ethyl-5,6,7-trimethoxy-4-([2'-(2-triphenylmethyl-2Htetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 90-95’C; NMR: 1.39(t,3H), 2.90(q,2H), 3.78(s,3ri), 3.96(s,3H), 4.00(s,38),

5.19(s,2H), 6.63(s,lH), 6.92-6.98(m,6H), 7.18-7.56(m,17H),

7.91- 7.95(m,lB); ¹³C NMR: (benzylic CHp 70.26;

(18) : 7-Cyano-2-ethy1-4-([2'-(2-triphenylmethyl-2H-tetrazol-5yl)biphenyl-4-yl]methoxy)quinoline , m.p. 172-175’C; NMR (dg-DMSO): 1.33(t,3H), 2.94(q,2H), 5.36(s,2H), 6.81-6.9O(m,6H), 7.18(d,2B),

I 9 I 0 0 0 dV

- 26 7.25-7.36(m,108), 7.43(d,2H), 7.47-7.70(m,4H), 7.85(dd,lH),

8.13(d,lH), 8.39(d,lH);

I*Note: Prepared by alkylation of a 70:30 mixture of 7-cyano2-ethyl-4-quinolone and 5-cyano-2-ethyl-4-quinolone and purified by flash chromatography using ethyl acetate/dichloromethane ¢2:98 v/v) as eluant.] (19) : 2-Ethyl-7-methoxy-4-({2'-(2-triphenylmethyl-2H-tetrazol-5yl)biphenyl-4-yl]methoxy)quinoline*, m.p. 159-161’C; NMR: 1.39(t,3H), · 2.92(q,2H), 3.93(s,3H), 5.12(s,2H), 6.62(s,lB), 6.90-6.95(m,7B),

7.21-7.55(m,17H), 7.95-7.8O(m,2H); ¹³C NMR: (benzylic CHj) 69.69;

[ Note: Prepared by alkylation of a 80:20 mixture of 2-ethyl7-methoxy-4-qulnolone and 2-ethyl-5-methoxy-4-quinolone and purified by flash chromatography using ethyl acetate/hexane (50:50 v/v) as eluant.] (20) : 6-Carboaethoxy-2-ethyl-4-([2'-(2-triphenylaethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 179-181’C; NMR (d^-DMSO): 1.33(t,3H), 2.89(q,2H), 3.85(s,3H), 5.39(s,2H), 6.81-6.95(m,6H), 7.12-7.23(m,3H), 7.24-7.38(m,9H), 7.43(d,2B), 7.50-7.69(m,3B), 7.82(dd,lH), 7.95(d,lH), 8.17(dd,lH), 8.76(d,lH);

(21) : 2-Ethyl-5-methyl-4-((2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy)quinoline; m.p. 179-181’C (dec.); NMR: 1.38(t,3H), 2.78(s,3H), 2.9O(m,2H), 5.15(s,2H), 6.69(s,lH), 6.9-6.98(m,6H), 7.13-7.34(m,13B), 7.4-7.57(m,5H), 7.85(d,lB), 7.94(dd,lH); ¹³C NMR: (benzylic CH₂) 70.27; microanalysis, found: C,79.3; H,5.9; N,10.5Z; ^C45^H37^N5°-^H2° requires C,79.3; H,5.7; N.10.3Z;

(22) : 2-Ethyl-7-methyl-4-([2' -(2-triphenylmethyl-2H-tetrazol-5- *· yl)biphenyl-4-yl]methoxy)quinoline; m.p. 205-206^eC (dec.); NMR: 1.39(t,3H), 2.52(s,3H), 2.94(q,2H), 5.14(s,2H), 6.66(s,lH), 6.90-6.95(m,6H), 7.17-7.32(m,14H), 7.39-7.43(m,38), 7.79(s,lB),

7.96-8.02(m,2H); ¹³C NMR: (benzylic CH₂) 69.69; microanalysis, found C,81.6; H,5.9; N,10.6X; C^H^^O requires C,81.4; H,5.6; N,10.6Z;

(23) : 2,6-Dimethyl-4-( [2' -(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy)quinoline, isolated as a foam; NMR: 2.41(s,3H), 2.69(s,3H), 5.15(s,2HO, 6.67(s,lB), 6.91-6.95(m,6H0, 7.22-7.25(m, 13H), 7.44-7.51(m,4H), 7.89-7.99(m,3H);

(24) : 2,8-Dimethyl-4-( [2' -(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline; m.p. 175-177’C (dec.); NMR:

- 27 2.7<s,3H), 2.78(s,3H), 5.14(s,2H), 6.69(s,lB), 6.87-6.95(m,6B),

7.15- 7.3(m,14H), 7.38-7.54(m,4H), 7.94-8.02(m,2B); microanalysis, found: C,81.6; B,5.2; N,10.9Z; requires C,81.3; B,5.4;

N,10.8Z;

(25) : 2-Ethyl-4-((2'-(2-triphenylmethyl-2B-tetrazol-5-yl)biphenyl4-yl]methoxy)quinoline; m.p. 173-174^eC (dec.); NMR: 1.4(t,3H), 2.96(q,2H), 5.16(s,2B), 6.73(s,lB), 6.9-6.94(m,6B), 7.18-7.32(m,13B), 7.33-7.55(m,4H), 7.67(dt,lH), 7.99(m,2B), 8.11(d,lH); microanalysis, found; C,81.1; B,5.4; N,10.9Z; requires C,81.4; H,5.4;

N.10.8X;

(26) : 6,8-Dimethyl-2-ethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-5yl)biphenyl-4-yl]methoxy)quinoline; m.p. 183-185’C (dec.); NMR: 1.4(t,3B), 2.37(s,3B), 2.76(s,3B), 2.95(q,2B), 5.13(s,2B), 6.68(s,lB), 6.90-6.95(m,6H), 7.17-7.35(m,13B), 7.43-7.50(m,4H), 7.76(s,lH), 7.95(m,lH);

(27) : 6-Chloro-2-methyl-4-({2'(2-triphenylmethyl-2B-tetrazol-5yl]methoxy)quinoline; m.p. 182-184’C (dec.); NMR: 2.68(s,3H), 5.15(s,2B), 6,75(s,lB), 6.87-6.97(m,6B), 7.15-7.35(m,13B),

7.4-7.62(m,4B), 7.9(d,lB), 7.98(m,lB), 8.08(d,lB);

(28) : 7-Chloro-2-ethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-ylJmethoxy)quinoline; m.p. 176-178’C (dec.); NMR: 1.53(t,3H), 3.08(q,2B), 5.29(s,2H), 6.86(s,lB), 7.02-7.10(m,6B), 7.32-7.48(m,14B), 7.52-7.70(m,3B), 8.08-8.18(m,3B); ¹³C NMR (benzylic CB₂) 70.01;

(29) : 8-Chloro-2-ethy1-4-([2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline; m.p. 156-158’C (dec.); NMR: 1.42(t,3H), 3.05(q,2B), 5.16(s,2B), 6.8(s,lB), 6.87-6.98(m,6H),

7.15- 7.33(m,14H), 7.38-7.55(m,3B), 7.78(dd,lH), 7.95-8.06(m,2B).

AP 0 0 0 1 6 1

Using an analogous procedure to that described in Org. Syn., 1955, Coll. Vol. III, pages 374 and 593, the following quinolones of formula IV were obtained in yields of 20-60X:2-Ethyl-6-trifluoromethyl-4-quinolone, m.p. 288-289 °C;

2-Ethyl-8-trifluoromethyl-4-quinolone, m.p. 162-163 *C;

5-Cyano-2-ethyl-4-quinolone, m.p.250 °C (dec.);

7-Cyano-2-ethyl-4-quinolone, (isolated as a 70:30 mixture of 7-CN and

- 28 5- CN isomers);

2-Ethyl-6-methoxy-4-quinolone, m.p. 210-212 °C;

2-Ethyl-7-methoxy-4-quinolone, (isolated as an 80:20 mixture of 7-0Me and 5-0Me isomers);

2-Ethyl-8-methoxy-4-quinolone, m.p. 196-198 ’C;

2-Ethyl-5,7-dimethoxy-4-quinolone, m.p. 242-244 ’C;

2-Ethyl-5,8-dimethoxy-4-quinolone, m.p. 196-198 ’C;

2-Ethyl-6,7-dimethoxy-4-quinolone, m.p. 284-287 ’C;

2-Ethyl-5,6,7-trimethoxy-4-quinolone, m.p. 226-228 ’C;

Methyl 2-ethyl-4-hydroxyquinol-6-ylcarboxylate, 245 ’C (dec.);

2-Ethyl-5-methyl-4-quinolone, m.p. 264-266’C ;

2-Ethyl-7-methyl-4-quinolone, m.p. 242-244*0*;

2-Ethyl-6,8-dimethyl-4-quinolone, m.p. 264-266’C; and 8-Chloro-2-ethyl-4-quinolone, m.p. 183-184’C.

7-chloro-2-ethyl-4-quinolone (isolated as a 43.5:56.5) mixture of 7-C1 and 5-Cl isomers).

[*Note: these compounds were separated by flash chromatography on silica, eluting with methanol/dichloromethane (1:9 v/v) as eluant.].

2,6-Dimethyl-4-quinolone and 2,8-dimethyl-4-quinolone vere obtained as described in Ann. Chem., 1982, 1656-1676.

6- Chloro-2-methyl-4-quinolone was obtained as described in Synthesis, 1987, 482-3.

Example 30

2M Aqueous sodium hydroxide solution (3.8 ml) vas added to a solution of 6-carbomethoxy-2-ethyl-4-[(2'-(2-triphenylmethyl-2Htetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline in methanol (10 ml) and dioxane (15 ml). The solution vas heated to reflux for 1 hour, cooled, and the solvent removed by evaporation. Vater (40 ml) vas added and the solution extracted vith ethyl acetate (40 ml). The aqueous phase vas acidified vith concentrated hydrochloric acid (2 ml) and the resulting suspension dissolved in dioxane (20 ml). The solution vas stirred for 1 hour then evaporated to a yellow gum. Crystallisation from methanol gave 6-carboxy-2-ethyl-4-((2’-(lBtetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline hydrochloride (0.24 g)

- 29 as a white powder, m.p. 161-164*C; NMR (d^-DMSO): 1.45(t,3H), 3.24(q,2H), 5.68(s,2H), 7.24(d,2H), 7.53-7.76(m,7H), 8.47(d,2H), 8.77(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 450 (M—H)~; microanalysis, found: C,61.3; H,4.9; N,13.3; ^0, 1.7Z; ^C26^H21^N5°3'^HC1,Me0H-^0,5B2^{0 re}9^uires C.61.3; H,5.1; N,13.2; H₂0, 1.7Z.

Example 31

Using an analogous procedure to that described in Example 7, but starting from 2-ethyl-6-(tert-butyldimethylsilyloxy)-4-([2'(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, itself isolated as a foam [NMR: 0.25(s,6H), 1.02(3,98), 1.38(t,3H), 2.94(q,2B), 5.20(s,2H), 6.68(s,lH), 6.88-6.98(m,6H), 7.17-7.34(m,14H),

7.40-7.60(m,4H), 7.89-8.00(m,2H); ¹³C NMR: (benzylic CHp 69.52J starting from 2-ethyl-6-(jtert-butyldimethylsilyloxy)-4-quinolone, there was obtained 2-ethyl-6-hydroxy-4-[(2'-(lH-tetrazol-5yl)biphenyl-4-yl)methoxy]quinoline hydrochloride, m.p. 189-191*C; NMR (d6-DMSO): 1.42(t,3H), 3.14(q,2H), 5.61(s,2H), 7.22(d,2H), 7.49-7.72(m,9H), 8.20(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 422 (M-H)'; microanalysis, found: C,62.7; H,4.8; N,14.4; HjO, 4.4Z; ^C25^H21^N5°2’^HCl'^B2° ^re9^uires C,62.8; H,4.8; N,14.6; H20, 3.8Z.

Examples 32-54

Using an analogous procedure to that described in Example 7, but starting from the appropriate triphenylmethyl tetrazole (III), the following compounds of formula I were obtained in yields of 7O-9OZ:(Example 32): 2-Ethyl-6-methylthio-4-[(2'-(lfl-tetrazol-5-yl)biphenyl4-yl)methoxyJquinoline hydrochloride, m.p. 156-158^eC; NMR (d^-DMSO): 1.40(t,3H), 2.62(s,3H), 3.17(q,2H), 5.66(s,2H), 7.2O(d,2H),

7.51-7.70(m,7H), 7.90-7.95(m,2H), 8.25(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 452 (M-H)^-; microanalysis, found: C,63.2; H,4.8; N,13.7%;

^C26^H23^N5^OS’^HC1’^O‘^25,h2^{O re}9^uires C,63.2; H,4.8; N.14.2X;

(Example 33): 2-Ethyl-7-hydroxymethyl-4-[(2'-(lH-tetrazol-5yl)biphenyl-4-yl)methoxyJquinoline hydrochloride, m.p. 228-230’C; NMR (dg-DMSQ): 1.41(t,3H), 3.15(q,2H), 5.06(s,2H), 5.62(s,2H), 7.20(d,2H),

7.55(d,2H), 7.56-7.62(m,3H), 7.65-7.72(m,2H), 7.99(d,2H),

8.12-8.20(m,1H); mass spectrum (-ve FAB, DMSO/GLY): 436 (M-H)';

ΑΡ0 0 0 1 6 1

- 30 microanalysis, found: C,65.7; H,5.1; N.14.8X; C₂gH₂₃N5O₂·HCl ^re9^u^^res C,65.9; H,5.1; N.14.8X;

(Example 34): 2-Ethy1-6-methylsulphony1-4-((2'-(lH-tetrazol-5yl)biphenyl-4-yl)methoxy(quinoline hydrochloride, m.p. 149-151^eC; NMR (d^-DMSO): 1.40(t,3H), 3.11(q,2H), 3.3O(s,3H), 5.59(s,2H), 7.2O(d,2H), 7.53-7.70(m,7H), 8.2O(d,lH), 8.33(dd,lH), 8.67(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 484 (M-H); microanalysis, found: C,58.3; 8,5.0; N,12.2X; C2gH23N5O3S.BCl.H2O requires C,57.8; H,4.9; N,13.0X;

(Example 35): 2-Ethy1-6,7-methylenedioxy-4-((2'-(1H-tetrazol5-yl)biphenyl-4-yl)methoxy(quinoline hydrochloride, m.p. 174-175®C;

NMR (dg-DMSO): 1.40(t,3H), 3.11(q,2H), 5.62(s,2H), 6.35(s,2H), 7.19(d,2H), 7.45-7.76(m,9H); mass spectrum (-ve FAB, DMSO/GLY): 450 (M-H)~; microanalysis, found: C,61,6; H,4.8; N.13.2; HjO, 4.3X; ^26^21^5θ3’^^*^’^®2θ ^re9^u^^res C.61.3; H,4.8; N.13.7; HjO, 4.2X; (Example 36): 2-Ethyl-6-(2-fluoroethoxy)-4-((2'-(lH-tetrazol5-yl)biphenyl—4-yl)methoxyJquinoline hydrochloride, m.p. 161-163’C;

NMR (dg-DMSO): 1.40(t,3H), 3.12(q,2H), 4.32-4.55(m,2H),

4.66-4.98(m,2H), 5.64(s,2H), 7.2O(d,2H), 7.5O-7.81(m,9H), 8.24(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 468 (M-H); microanalysis, found: C,63.1; H,4.9; N,12.9; H₂0, 1.7X; ^C27^B24^N5^O2^F,HCl'^O,5H2^O requires C.63.0; H.4.8; N.13.6; H₂0, 1.8X;

(Example 37): 7-Carboethoxy-2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy(quinoline hydrochloride, m.p. 226-228°C; NMR (CD3CN/CF3CO2H): 1.55(t,3H), 1.62(t,3H), 3.31(q,2H), 4.60(q,2H), 5.75(s,2H), 7.42(d,2H), 7.52(s,lH), 7.7O(d,2H), 7.73-7.78(m,2H),

7.85-7.91(m,2H), 8.44(dd,lH), 8.60(d,lH), 8.78(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 479 (M-H)~; microanalysis, found: C,64.7; H,5.0; , N.13.4; H₂0, 0.4X; ^C28^H25^N5°3'^HCl‘θ'^1H2° requires C,64.9; H,5.1; N.13.5; H₂0, 0.3X;

(Example 38): 2-Ethyl-6-(2,2,2-trifluoroethoxy)-4-((2'-(lH-tetrazol5-yl)biphenyl-4-yl)methoxyJquinoline hydrochloride, m.p. 140-141’C;

NMR (dg-DMSO): 1.41(t,3H), 3.14(q,2H), 5.03(q,2H), 5.68(s,2H),

7.20(^,2H), 7.52-7.75(m,8H), 7.85(dd,lH), 8.28(d,lH), mass spectrum (-ve FAB, DMSO/GLY): 504 (M-H); microanalysis, found: C,58.0; H,4.7;

N,12.4; H₂0, 2.6X; ^c27^H22^N5°2^F3^,HCl,S2⁰ requires C.57.9; H,4.3;

N.12.5; H₂0, 3.2X;

(Example 39): 6-Carboxamido-2-ethyl-4-((2'-(lH-tetrazol-5-yl)- 31 biphenyl-4-yl)methoxyJquinoline hydrochloride, m.p. 178-180^eC; NMR (d^-DMSO): 1.44(t,3H), 3.21(q,2H), 5.69(s,2H), 7.22(d,2H), 7.57-7.75(m,6H), 8.36(d,lH), 8.46(dd,2H), 8.76(d,lH); mass spectrum (+ve FAB, DMSO/GLY): 451 (M+H)+; microanalysis, found: C,62.4; H,5.1; N,16.1; H₂0, 1.7X; C₂6^a22^N6^O2^,HCl‘^O,25H2^O'^O,4CH3^O0 requires C,62.3;

H, 5.0; N,16.5; 8₂0, 1.8X;

(Example 40): 2-Ethyl-6-trifluoroaethoxy-4-[(2*-(lH-tetrazol5-yl)biphenyl-4-yl)Bethoxy]quinoline hydrochloride, m.p. 180-182^eCj NMR (dg-DMSO): 1.43(t,3H), 3.18(q,2H), 5.65(s,2H), 7.20(d,2H),

7.52-7.73(m,7H), 8.03-8.15(m,2H), 8.41(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 490 (M-H); microanalysis, found: C,59.0; H,3.6; N,13.2X; ^C26^H2O^N5°2^F3‘Hd ^re9^ui^res C,59.1; H,4.0; N,13.3X;

(Example 41): 6-Cyano-2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy]quinoline hydrochloride, m.p. 153-155’C; NMR (d^-DMSO):

I. 41(t,3H), 3.15(q,2H), 5.62(s,2fl), 7.20(d,2H), 7.53-7.75(m,7H),

8.22-8.39(m,2H), 8.79(s,lH); mass spectrum (+ve FAB, DMSO/GLY): 433 (M+H)*; microanalysis, found: C,66.9; H,4.3; N.17.6X; C^H^NgO.HCl requires C,66.6; H,4.5; N,17.9X;

(Example 42): 2-Ethyl-6-formyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4yl)methoxy]quinoline hydrochloride, m.p. 142-144’C; NMR (d^-DMSO): 1.45(t,3H), 3.20(q,2H), 5.70(s,2H), 7.22(d,2H), 7.52-7.75(a,7H), 8.34-8.49(m,2H), 8.85(s,lH), 10.22(s,lH); mass spectrum (+ve FAB, DMSO/NBA): 436 (M+H)*; microanalysis, found: C,65.0; H,4.6; N.14.4X; C₂gH₂iN₃0₂.HCl.0.5B₂0 requires C,64.9; H,4.8; N,14.6X;

(Example 43): 6-Dimethylamino-2-ethyl-4-((2'-(lH-tetrazol-5yl)biphenyl-4-yl)methoxy]quinoline dihydrochloride, m.p. 206-209^eC; NMR (d₆-DHS0): 1.40(t,3H), 3.07(s,6H), 3.12(q,2H), 5.63(s,2H), 7.05(d,lH), 7.21(d,2H), 7.45(s,lH), 7.51(s,lH), 7.55-7.65(m,3H),

7.66-7.75(m,3H), 8.23(d,lH); mass spectrum (+ve FAB, DMSO/NBA): 451 (M+H)*; microanalysis, found: C,61.8; H,5.4; N,16.0; C1.13.2X; ^C27^H26^N6^{O,2aCl re}9^uires C,61.9; H,5.4; N.16.1; C1.13.6X;

(Example 44): 2-Ethyl-6-nitro-4-[(2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxyjquinoline hydrochloride, m.p. 149-15?°C; NMR (dg-DMSO): 1.45(t,3H), 3.18(q,2H), 5.66(s,2H), 7.22(d,2H), 7.54-7.75(m,7H), 8.45(d,lH), 8.68(dd,lH), 8.95(d,lH); mass spectrum (+ve FAB, DMSO/NBA): 453 (M+B)*; microanalysis, found: C,59.3; H,4.5; N,16.8; H₂0, 3.9X; ^C25^H2O^N6^O3'^HC1'^H2^O requires C,59.2; H.4.5; N,16.6; H₂0,

APO0 016 1

- 32 3.6X;

(Example 45): 6-Cyano-2-methy1-4-((2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy(quinoline hydrochloride, m.p. 280-282°C; NMR (dg-DMSO): 2.9O(s,3B), 5.63(s,2B), 7.21(d,2H), 7.57-7.79(m,8B), 8.25-8.41(m,2B), 8.79(s,lB); mass spectrum (-ve FAB, DMSO/GLY): 417 (M-H)'; microanalysis, found: C,66.0; B,4.5; N,17.8X; C₂₃H^gNgO.HCl requires C,66.0; H.4.2; N,18.5X;

(Example 46): 2-Bthyl-6-fluoro-4-((2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy(quinoline hydrochloride, m.p. 185-186’C; NMR (dg-DMSO): 1.44(t,3B), 3.2O(q,2H), 5.67(s,2H), 7.2O(d,2H), 7.50-7.78(m,7B), 7.93-8.08(m,2H), 8.36-8.49(m,lH); mass spectrum (-ve FAB, DMSO/GLY): 424 (M-H)~; microanalysis, found: C,64.7; B,4.4; N,14.8X; C25H2QN5FO.BCI requires: C,65.0; B,4.6; N,15.2X;

(Example 47): 2-Ethyl-6-isopropoxy-4-[(2'-(lB-tetrazol-5-yl)biphenyl-4-yl)methoxy(quinoline hydrochloride, m.p. 177-180’C (dec); NMR (d^-DMSO): 1.36(d,6B), 1.4(t,3B), 3.16(q,2H), 4.83(m,lB), 5.66(s,2B), 7.2O(d,2B), 7.48-7.65(m,6B), 7.65-7.75(m,3B), 8.28(d,lB); mass spectrum (-ve FAB, DMSO/GLY): 464 (M-B)“; microanalysis, found:

C,66.2; H,6.1; N,13.8; B₂O,O.2X; C28^H27^N5°2'^BCl*^0,1(CH3⁾2^CB0H,0,25B2° requires C,66.3; B,5.7; N,13.7; B₂O,O.9X;

(Example 48): 5-Chloro-2-ethyl-4-((2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy(quinoline hydrochloride, m.p. 189-190’C (dec); NMR (dg-DMSO): 1.41(t,3B), 3.14(q,2H), 5.63(s,2B), 7.19(d,2H), 7.5O-7.63(m,5B), 7.63-7.74(m,2B), 7.84(d,lB), 7.94(t,lB), 8.28(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 440 (M-B)’; microanalysis, found: C.62.8; H.4.2; N,14.7X; C₂₅H_2ON₅ClO.HCl requires C,62.8; B,4.4; *

N.14.6X; , (Example 49): 2-Trifluoromethyl-4-[(2'-(lB-tetrazol-5-yl)biphenyl-4yl)methoxy(quinoline, m.p. 187-190’C (dec); NMR (dg-DMSO): 5.53(s,2H), 7.2O(d,2H), 7.50-7.80(m,8H), 7.90(dt,lB), 8.12(d,lB), 8.28(dd,lB), 13.0(brs,1H); mass spectrum (-ve FAB, DMSO/GLY): 446 (M-H)~; microanalysis, found: C,64.3; B,3.3; N,15.5X; ^^H^N^F^O requires C.64.4; H,3.6; N,15.7X;

(Example 50): 2-Me thoxyme thy1-4-[(2'-(IB-1e trazol-5-y1)bi pheny14-yl)methoxy(quinoline hydrochloride, m.p. 169-171°C; NMR (d^-DHSO):

3.5O(s,3B), 4.98(s,2H), 5.67(s,2B), 7.22(d,2B), 7.54-7.74(m,7B),

7.84(t,lH), 8.08(t,lH), 8.32-8.38(m,2B); mass spectrum (-ve FAB,

- 33 DMSO/GLY): 422 (M-H); microanalysis, found; C,65.2; H,4.8; N,15.2X;

^C25^H21^N5°2^{,HCl re}9^uires C,65.3; H,4.8; N,15.2X;

(Example 51); 2-Ethoxymethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl4-yl)methnxy]quinoline hydrochloride, m.p. 164-166^eC; NMR (d^-DMSO): 1.25(t,3H), 3.68(q,2H), 4.99(s,2H), 5.68(s,2H), 7.21(d,2H),

7.54-7.72(m,7H), 7.84(t,lH), 8.08(t,lH), 8.34(d,2H); mass spectrum (-ve FAB, DMSO/GLY); 436(M-H); microanalysis, found; C,65.6; H,5.2; N,14.4X; C₂₆B₂₃N₅O₂.HC1 requires C,65.9; H,5.1; N,14.8X;

(Example 52): 2,3-Dimethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy[quinoline hydrochloride, m.p. 155-156’C (dec); NMR (dg-DMSO): 2.35(s,3H), 2.95(s,3H), 5.38(s,2H), 7.16(d,2H), 7.47(d,2H),

7.53-7.76(m,4H), 7.85(t,lH), 8.05(dt,lB), 8.19(d,lH), 8.38(d,lB); mass spectrum (+ve FAB, DMSO/NBA): 408 (M+H)⁺; microanalysis, found:

C,66.8; H,4.9; N,15.3X; C-eH-.N^O.HCl.O.25CH-0H requires C,67.1;

H,5.1; N,15.5X;

(Example 53): 2-(3,3,3-Tr ifluoropropyl)-4-[(2'-(1H-te trazol-5-yl)biphenyl-4-yl)methoxy[quinoline hydrochloride, m.p. 204-206’C (dec); NMR (dg-DMSO): 2.92-3.14(m,2H), 3.40-3.51(m,2H), 5.64(s,2H), 7.21(d,2H), 7.50-7.64(m,4H), 7.65-7.87(m,4H), 8.08(t,lH), 8.25-8.35(m,2H); mass spectrum (+ve FAB, DMSO/NBA): 476 (M+H)⁺; microanalysis, found: C,60.8; H,3.9; N,13.7X; C^H^N^F^O.HCl requires C,61.0; H,4.1; N.13.7X;

(Example 54): 2-Hydroxymethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl4-yl)methoxy]quinoline hydrochloride, m.p. 199-201^eC (dec); NMR (dg-DMSO): 5.07(s,2H), 5.66(s,2H), 7.22(d,2H), 7.53-7.63(m,4H),

7.65-7.75(m,3H), 7.83(t,lH), 8.09(t,lH), 8.32(d,lH), 8.39(d,lH); mass spectrum (-ve FAB, DMSO/GLY): 408 (M-H)^-; microanalysis, found:

C,64.2; H,4.7; N,15.5X; C₂₄H_igN₅O₂.HC1 requires C.64.6; H,4.5;

N.15.7X;

APO 0 01 6 1

The necessary starting materials of formula III used in Examples 32-53 vere obtained in yields of 20-70X using an analogous procedure to that described in Example 7 but starting from the appropriate quinolones of formula IV. The compounds of formula III had the following properties:(32): 2-Ethyl-6-methylthio-4-([2'-(2-triphenylmethyl-2H-tetrazol- 34 -5-yl)biphenyl-4-yjmethoxy)quinoline, m.p. 164-166’C; NMR: 1.37(t,3B), 2.50(s,3H), 2.92(q,2B), 5.19(s,2B), 6.7O(s,lB), 6.91-6.95(m,6B),

7.19-7.34(ra,14B), 7.44-7.60(m,4H), 7.89-7.99(m,2B); ¹³C NMR: (benzylic CH₂) 69.82;

(33) : 2-Ethyl-7-hydroxymethyl-4-([2'-(2-triphenylmethyl-2B-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 99-102’C; NMR(dg-DMSO): 1.29(t,3H), 2.82(q,2H), 5.10(s,2B), 5.31(s,2H), 6.84-6.93(m,6H), 7.02(s,lH), 7.15(d,2H), 7.27-7.38(a,9B), 7.44(d,2B), 7.48-7.83(a,7B);

(34) : 2-Ethyl-6-methylsulphonyl-4-((2'-(2-triphenylmethyl2B-tetrazol-5-yl)biphenyl-4-ylJmethoxy)quinoline, isolated as a foam; NMR: 1.19(t,3H), 2.76(q,2B), 2.89(s,3B), 5.03(s,2B), 6.61(s,lB), 6.72-6.77(m,6B), 7.00-7.12(m,13H), 7.22-7.35(m,3B), 7.74-7.78(m,lH),

7.85-7.98(m,2B), 8.67(s,lB); ¹³C NMR: (benzylic CBp 70.52;

(35) : 2-Ethyl-6,7-methylenedioxy-4-([2'-(2-triphenylmethyl2B-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, isolated aa a foaa; NMR 1.38(t,3B), 2.90(q,2H), 5.15(s,2H), 6.09(s,2H), 6.65(s,lB), 6.88-6.98(m,6B), 7.16-7.55(m,19B), 7.96-8.03(m,IB); ¹³C NMR (benzylic CH₂) 69.75;

(36) : 2-Ethyl-6-(2-fluoroethoxy)-4-((2'-(2-triphenylmethyl-2Btetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 173-175’C; NMR: 1.3O(t,3B), 2.84(q,2B), 4.03-4.19(m,2H), 4.51-4.74(m,2B), 5.11(s,2B), 6.64(s,lB), 6.85-6.90(m,6B), 7.12-7.46(m,18B), 7.85-7.89<a,2B); ¹³C NMR: (benzylic CBp 69.93;

(37) : 7-Carboethoxy-2-ethyl-4-([2'-(2-triphenylmethyl-2B-tetrazol5-yl)biphenyl-4-ylJmethoxy)quinoline, m.p. 160-163’C; NMR (d^-DMSO): 1.33(t,3B), 1.38(t,3H), 2.92(q,2H), 4.38(q,2B), 5.35(s,2B),

6.84-6.89(m,6H), 7.16(d,2H), 7.21(s,IB), 7.29-7.31(m,9B), 7.42(d,2fl),

7.52-7.65(m,3H), 7.83-7.89(m,2B), 8.10(d,lB), 8.46(d,lH);

(38) : 2-Ethyl-6-(2,2,2-tri fluoroethoxy)-4-([2'-(2-triphenylmethyl2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 147-149’C; NMR: 1.40(t,3H), 2.95(q,2H), 4.38(q,2H), 5.21(s,2H), 6.73(s,lH),

6.92-7.00(m,6H), 7.21-7.55(m,18H), 7.93-8.00(m,2B); 13 NMR: (benzylic CH₂) 70 ..00;

(39) : 6-Carboxamido-2-ethyl-4-((2'-(2-triphenylmethyl-2B-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, isolated as a foam; NMR: 1.31(t,3H), 2.87(q,2H), 5.38(s,2H), 6.82-6.89(m,6B), 7.13(d,2B),

7.31-7.34(tn,9H), 7.45<d,2H), 7.54-7.63(m,3H), 7.80-7.94(m,3B),

- 35 8.14(dd,lH), 8.70(d,lH);

(40) : 2-Ethyl-6-trifluoromethoxy-4-([2'-(2-triphenylmethyl2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 144-146^eC; NMR: 1.38(t,3H), 2.95(q,2H), 5.18(s,2H), 6.75(s,lH), 6.90-6.97(m,6H),

7.20-7.32(m,13B), 7.39-7.55(m,4H), 7.95-8.05(m,3B); ¹³C NMR: (benzylic CH₂) 70.22;

(41) : 6-Cyano-2-ethyl-4-(I2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 178-179’C; NMR (d^-DMSO): 1.33(t,3H), 2.92(q,2H), 5.36(s,2H), 6.80-6.90(m,6H), 7.16-8.02<m,20H), 8.42(s,lH);

(42) : 2-Ethyl-6-formyl-4-((2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-ylJmethoxyJquinoline, m.p. 164-166’C; NMR (d^-DMSO): 1.34(t,3B), 2.92(q,2H), 5.40(s,2B), 6.85-6.91(m,6B), 7.17-7.33(m,13H), 7.46-7.66(m,4B), 7.82(dd,lB), 8.05(dq,2H), 8.59(d,lH), 9.91(s,lH);

(43) : 6-Dlmethylamino-2-ethyl-4-([2*-2-trlphenylmethyl-2fl-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, isolated as a foam; NMR (dg-DMSO): 1.28(t,3H), 2.83(q,2B), 2.94(s,6B), 5.35(s,2H), 6.82-6.94(m,6H), 6.98(s,lB), 7.08(d,lH), 7.15(d,2H), 7.27-7.40(m,9H),

7.41-7.70(m,6H), 7.72-7.84(m,2B);

(44) : 2-Ethyl-6-nitro-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, isolated as a foam; NMR (d₆-DMS0): 1.34(t,3B), 2.94(q,2B), 5.42(s,2B), 6.84-6.89(m,6H), 7.18(d,2H), 7.30-7.36(m,9B), 7.42-7.65(m,6H), 7.84(d,lH), 8.07(d,lB), 8.41(dd,lB), 8.88(d,lB);

(45) : 6-Cyano-2-methyl-4-([2'-(2-triphenylmethyl-2B-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline, m.p. 188^eC (dec.); NMR (d₆-DMS0): 2.65(s,3H), 5.35(s,2H), 6.82-6.89(m,6H), 7.16-7.34(m,13B), 7.43-7.67(m,4H), 7.86(dd,lB), 7.98(s,2H), 8.42(s,lH);

(46) : 2-Ethyl-6-fluoro-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline; m.p. 183-184°C; NMR: 1.40(t,3H), 2.95(q,2H), 5.18(s,2H), 6.75(s,lB), 6.87-6.98(m,6H), 7.17-7.35(m,13H), 7.36-7.58(m,4H), 7.7O(dd,lH), 7.93-8.05(m,2H); microanalysis, found: C.78.8; H,5.1; _N,10.5X; C₄₄H₃₄N₅F0 requires C,79.1; H,5.1; N.10.5X;

(47) : 2-Ethyl-6-isopropoxy-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yllmethoxy)quinoline, isolated as a foam; NMR: 1.35(d,6H), 1.38(t,3H), 2.90(q,2H), 4.64(m,lH), 5.19(s,2H),

6.69(s,lH), 6.90-6.98(m,6H), 7.15-7.35(m,14H), 7.38-7.55(m,4H),

AP 0 0 0 1 6 1

- 36 7.92(d,lH), 7.95(dd,lH);

(48) : 5-Chloro-2-ethyl-4-( [2'-(triphenylmethyl-2B-tetrazol5-yl)biphenyl-4-ylJmethoxy)quinoline; m.p. 180-181’C (dec.); NMR (dg-DMSO): 1.3(t,3H), 2.85(q.2H), 5.35(s,2H), 6.80-6.92(m,6H), 7.13(t,3H), 7.23-7.37(m,9H), 7.4O-7.67(m,7H), 7.74-7.88(m,2B);

(49) : 2-Trifluoromethyl-4-( [2'-(2-triphenylmethyl-2B-tetra2ol5-yl)biphenyl-4-yl]methoxyJquinoline, Isolated as an amorphous solid;

NMR (dx-DMSO): 5.48(s,2B), 6.8-6.94(m,6B), 7.19(d,2H), ⁶ 13

7.24-7.38(m,9H), 7.4-7.69(m,7H), 7.8-7.94(m,2H), 8.07-8.17(m,2B); ^AJC NMR: (benzylic CHp 70.45;

(50) : 2-Methoxymethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline; m.p. 174-176’C; NMR: 3.52(s,3H), 4.73(s,2H), 5.19(s,2H), 6.89-6.94(m,6B), 7.06(s,lB), 7.18-7.30<m,13B), 7.30-7.53(m,4H), 7.69(dt,lH), 7.98(m,2B), 8.14(dd,lH); microanalysis, found: C,78.7; B,5.2; N,10.4X; C^B^NjOj.O.25Η₂0 requires C,78.9; B,5.3; N.10.5X;

(51) : 2-Ethoxymethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol5-yl)biphenyl-4-ylJmethoxy)quinoline; m.p. 156-158’C; NMR: 1.29(t,3B), 3.66(q,2H), 4.77(s,2H), 5.20(s,2H), 6.90-6.94(m,6B), 7.09(s,lB),

7.18-7.29(m,13B), 7.30-7.53(m,4H), 7.68(dt,lH), 7.96-8.03(m,2B), 8.14(dd,lH); microanalysis, found: C,79.O; H,5.5; N,1O.3X; ^45^37^5θ₂ requires C,79.5; H,5.5; N.10.3X;

(52) : 2,3-Dimethyl-4-([2'-(2-triphenylmethyl-2B-tetrazol5-yl)biphenyl-4-yl]methoxy)quinoline; m.p. 170-172’C; NMR: 2.37(s,3H), 2.73(s,3H), 4.95(s,2H), 6.90-6.99(m,6H), 7.18-7.35(m,13B),

7.37-7.58(m,4H), 7.64(dt,lH), 7.95-8.07(m,3H);

(53) : 2-(3,3,3-Trifluoropropyl)-4-([2'-(2-triphenylmethyl-2Htetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, isolated as an amorphous solid, m.p. 182-184’C; NMR (d^-DMSO): 2.7-3.0(m,2H),

3.05-3.20(m,2H), 5.32(s,2H), 6.80-6.90(m,6H), 7.12-7.65(m,18H), 7.7O(dt,lH), 7.87(dt,2H), 8.03(d,lH);

The starting material used in Exampie 54 vas obtained as follovs:-_ (i) Using an analogous procedure to that described in Example 7 but starting from the appropriate quinolone of formula IV, there vas thus obtained 2-ethoxycarbonyl-4-( [2' -(2-triphenylmethyl-2H-tetrazol- 37 5-yl)biphenyl-4-yl]methoxy)quinoline; m.p. 146-147’C (dec.); NMR: 1.51(t,3H), 4.57(q,2H), 5.23(s,2H), 6.89-6.94(m,6B), 7.18-7.3O(m,13B), 7.40-7.53(m,4H), 7.68(s,lH), 7.75(dt,lH), 8.0(m,lB), 8.17(d,lH), 8.26(d,lH).

(ii) Lithium borohydride (11 mg) vas added to a solution of

2-ethoxycarbonyl-4-({2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl4-yl]methoxy)quinoline (346 mg) in tetrahydrofuran (4 ml) and the mixture stirred for 18 hours. Vater (20 ml) vas added to the mixture and a vhite solid precipitated. The solid vas collected by filtration, dissolved in ethyl acetate and the solution dried (MgSO^). The solvent vas removed by evaporation and the residue crystallised from ethyl acetate/hexane to give 2-hydroxymethy-4-([2'-(2triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy)quinoline (213 mg), as a vhite crystalline solid, m.p. 183-185’C (dec.); NMR: 4.85(s,2H), 5.18(s,2H), 6.70(s,lH), 6.85-6.98(a,6H), 7.15-7.35(m,13B), 7.35-7.58(m,4H), 7.7O(dt,lH), 7.95-8.08(m,2B), 8.15(d,lB);

microanalysis, found: C,78.7; H,4.7; N,10.7X; ¢43^33^5^2 requires C,79.2; B.5.1; N,10.7X.

I y l· U υ υ u v

Example 55

Using an analogous procedure to that described in Example 7, but starting from 6-(te£t-butyloxycarbonyl)aminomethyl-2-ethyl-4-([2'(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline, itself isolated as a foam [NMR: 1.40(t,3H), 1.45(s,9H), 2.96(q,2B), 4.37(d,2H), 4.83(brs,1H), 5.18(s,2B), 6.89-6.99(m,6H),

7.18-7.35(m,14H), 7.40-7.55(m,3H), 7.62(dd,lH), 7.92-8.O2(m,3H); ¹³C NMR: (benzylic CH₂) 70.02] starting from 6-(tert-butyloxycarbonyl)arainomethyl-2-ethyl-4-quinolone, there vas thus obtained

6-aminomethyl-2-ethyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline dihydrochloride, m.p. 150-153’C; NMR (d^-DMSO): 1.45(t,3B), 3.20(q,2H), 4.22-4.33(m,2H), 5.69(s,2H), 7.23(d,2H), 7.52-7.75(m,7H), 8.17(dd,lH), 8.34-8.46(m,2H), 8.62(brs,2H); mass spectrum (+ve FAB, DMSO/NBA): 437 (M+H)*; microanalysis, found: C,57.9; H,5.7; N.14.4;

Cl,14.5; H₂0, 3.7X; ^C26^H24^N6^{O,2,250C1-1,25H}2^O,O,25(C2^H5⁾2° requires C,57.9; H,5.5; N,15.0; Cl,14.3; HjO, 4.OX.

Using an analogous procedure to that described in Org. Syn.,

- 38 1955, Coll. Vol. Ill, pages 374 and 593, the following quinolones used in Examples 31, 32, 35-47 and 49-54 may be obtained in yields of 20-60X:2-Ethyl-6-(_tert-butyldimethylsilyloxy )-4-quinolone, m.p. 197-198’C; 2-Ethyl-6-methylthio-4-quinolone, m.p. 196-199’C;

2-Ethyl-6,7-aethylenedioxy-4-quinolone, a.p. 250’C (dec.); 2-Bthyl-6-(2-fluoroethoxy)-4-quinolone, a.p. 267-269’C;

7-Carboethoxy-2-ethyl-4-quinolone, a.p. 220-223’C; 2-Ethyl-6-(2,2,2-trifluoroethoxy)-4-quinolone, a.p. 260’C (dec.);

6-Carboxamido-2-ethyl-4-quinolone, a.p. >300’C;

2-Ethyl-6-trifluoroaethoxy-4-quinolone, m.p. 258-260^eC;

6-Cyano-2-ethyl-4-quinolone, a.p. 290^eC (dec.); 2-Ethyl-6-formyl-4-quinolone, m.p. 285’C (dec.);

6-Dimethylaaino-2-ethyl-4-quinolone, a.p. 237-239’C;

2-Ethyl-6-nitro-4-quinolone, a.p. >280’C;

6- Cyano-2-methyl-4-quinolone, a.p. 297-8’C;

2-Ethyl-6-fluoro-4-quinolone, a.p. 243-245’C;

2-Ethyl-6-isopropoxy«4-quinolone, a.p. 174-177’C;

2-Trifluoromethyl-4-quinolone, m.p. 210-212’C;

2-Methoxymethyl-4-quinolone, a.p. 186-188’C;

2-Ethoxymethyl-4-quinolone, m.p. 146’C;

2,3-Dimethyl-4-quinolone, a.p. >300*C;

2-Ethoxycarbonyl-4-quinolone, a.p. 214-215’C;

2-(3,3,3-Trifluoropropyl)-4-quinolone, a.p. 240-242’C.

2-Ethyl-7-hydroxymethyl-4-quinolone used in Example 33 vas obtained as follows:Lithium aluminium hydride (0.6 g) was added to a solution of

7- carboethoxy-2-ethyl-4-quinolone (2.65 g) in THF (200 ml) and the resulting suspension stirred for 2 hours at ambient temperature.

Water (100 ml) was slowly added, followed by ethyl acetate (100 ml). The suspension was filtered and washed with ethyl acetate (100 ml).

The phases of the filtrate were separated and the aqueous layer re-extracted with ethyl acetate (100 ml). The combined organic phases were dried (MgSO^) and evaporated to give a solid which on recrystallisation from ethyl acetate gave 2-ethyl-7-hydroxymethyl4-quinolone as a white powder, m.p. 254-257^eC.

- 39 2-Ethyl-6-methylsulphonyl-4-quinolone used in Example 34 vas obtained as follows:Oxone (920 mg) vas added to a solution of 2-ethyl6-methylthio-4-quinolone (220 mg) in methanol (10 ml) and vater (1 al). The suspension vas stirred at ambient temperature for 1 hour then evaporated to give a yellov solid. Saturated sodium bicarbonate solution (10 al) vas added and the resulting precipitate collected by filtration and dried to give 2-ethyl-6-methylsulphonyl-4-quinolone (150 mg) as a light yellov povder, m.p. 283*C.

5-Chloro-2-ethyl-4-quinolone used in Example 48 vas obtained as follovs:A mixture of 4-benzyloxy-5-chloro-2-ethyl quinoline (A) (1.8

g) and a solution of hydrogen bromide in acetic acid (45X v/v; 30 ml) vas heated at 100°C for 4 hours. The Mixture vas diluted vith ice/vater and basified to pH 9 vith 5M aqueous sodium hydroxide solution, vhen a solid precipitated. The mixture containing the solid precipitate vas extracted vith ethyl acetate (50 ml), and the solid vas then collected by filtration. The solid vas purified by flash chromatography, eluting vith methanol/dichloromethane (4:96 v/v) to give 5-chloro-2-ethyl-4-quinolone as a vhite solid, m.p. 236-239’C;

NMR (d₆-DMS0): 1.25(t,3H), 2.58(q,2H), 5.89(s,lH), 7.2(dd,lH),

7.42-7.53(m,2H), 11.4(brs,1H); microanalysis, found: C,63.2; H,4.8; N,6.6X; C_nH₁₀NCl0 requires C,63.6; H,4.8; N,6.8X.

The starting material (A) vas obtained as follovs:Sodium hydride (60X dispersion in mineral oil; 1.95 g) vas added to a stirred solution of a mixture of 7-chloro-2-ethyl-4-quinolone and 5-chloro-2-ethyl-4-quinolone (43.5:56.5, 10 g) in DMF (100 ml). The mixture vas stirred until evolution of hydrogen had ceased and benzylbromide (8.25 g) vas added. The mixture vas stirred for 18 hours. The solvent vas removed by evapoiation and the residue partitioned between vater (80 ml) and dichloromethane (2 x 100 ml).

The organic layer vas washed vith saturated sodium chloride solution (50 ml) and dried (MgSO^). The solvent vas removed by evaporation and the resultant yellov oil vas purified by flash chromatography, eluting vith increasing concentration of ethyl acetate in dichloromethane.

AP 0 0 0 1 6 1

- 40 The product vas eluted vith ethyl acetate/dichloromethane (10:90 v/v) to give 4-benzyloxy-5-chloro-2-ethylquinoline as a vhite solid (2.6 g), m.p. 78-80^eC; NMR: 1.39(t,3H), 2.94(q,2H), 5.38(s,2H), 6.72(s,lH),

7.30-7.55(m,6H), 8.0(d,lH), 8.13(d,lB).

6-(tert-butyloxycarbonyl)aminomethyl-2-ethyl-4-quinolone _L used in Example 55 vas obtained as follovs:Cobalt (II) chloride (2.87 g) vas added to a suspension of ₂ 2-ethyl-6-cyano-4-quinolone (1.2 g) in methanol (100 ml). Sodium borohydride (2.24 g) vas added in small portions to the resulting purple suspension and the mixture stirred for 2 hours during vhich time a colloidal precipitate appeared. Excess borohydride vas destroyed by careful acidification vith 2M hydrochloric acid and the mixture vas then made basic vith 1M sodium hydroxide solution. Dl-tert-butyl dicarbonate (1.32 g) vas added to the resulting slurry and stirring vas continued for 1 hour. The slurry vas filtered through diatomaceous earth and vashed vith methanol (100 ml). The filtrate vas evaporated and the residue vas extracted vith dlchloromethane, dried (MgSO^) and evaporated to give a cream foam. Trituration vith diethyl ether gave 6-(tert-butyloxycarbonyl)aminomethyl-2-ethyl-4-quinolone (1.2 g) as a cream povder, m.p. 228°C (dec.).

Example 56

Using an analogous procedure to that described in Example 7, but starting from 4-((2'-(2-triphenylmethyl-2H-tetrazol-5-yl)- -biphenyl-4-yl)methoxyJquinoline (A), there vas obtained in 60Z yield _Λ 4-( (2' -(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline _t hydrochloride, as a vhite solid, m.p. 162-164^eC; NMR (dg-DMSO): 5.7(s,2H), 7.2(d,2H), 7.45-7.8(cotnplex ra,7H), 7.9(t,lH), 8.l(dt,lH), 8.3(dt,2H), 9.2(dd,lH); mass spectrum (-ve FAB, DMSO/GLY): 378 (M-H) ; microanalysis, found: C,66.6; H,4.2; N,16.4Z; C^H^N^O. HC1 requires: C,66.4; H.4.3; N.16.8Z.

The starting material (A) vas obtained as follovs:(i) Povdered potassium acetate (17.5 g) vas added to a solution of 5-(2-(4'-bromomethylbiphenylyl)]-2-triphenylmethyl-2H-tetrazole (50

- 41 g) (obtained as described in European Patent Application, Publication No. 0291969) and 1,4,7,10,13,16-hexaoxacyclooctadecane (100 mg) in

1.2- diraethoxyethane (DME) (600 ml), and the mixture vas heated under reflux for 20 hours. Insoluble material vas removed by filtration, and the residue triturated vith a mixture of ethyl acetate and hexane (1:4 v/v) to give 5-{2-(4'-acetoxymethylbiphenylyll-2-triphenylmethyl-2H-tetrazole (B) (41.8 g), as a cream povder, m.p. 119-121^eC; NMR (CDC1₃): 2.1(s,3B), 5.0(s,2B), 6.8-6.95(complex m,8H),

7.2- 7.55(complex m,14B), 7.9-8.0(m,lB).

(ii) A solution of compound (B) (41.8 g) in tetrahydrofuran (THF) (200 ml) vas added over a period of 40 minutes to a suspension of lithium borohydride (4.1 g) in TBF (400 ml) stirred at 0®C under an atmosphere of argon. The mixture vas stirred at ambient temperature for 20 hours and then cooled to 0°C. 20X Aqueous citric acid solution (40 ml) vas added and the mixture vas diluted vith saturated sodium chloride solution (600 ml). The mixture vas extracted vith ethyl acetate (2 x 500 ml) and the extracts vere vashed vith vater (500 ml) and saturated sodium chloride solution (500 ml). The extracts vere dried (MgSO^) and volatile material removed by evaporation. The residue vas purified by flash chromatography, eluting vith ethyl acetate/hexane (2:3 v/v), to give 5-(2-(4'-hydroxymethylbiphenylyl)J-2-triphenylmethyl-2B-tetrazole (C) (17.4 g), as a vhite solid, m.p. 168-169^OC (after recrystallisation from a mixture of ethyl acetate and hexane (1:9 v/v)); NMR (CDClj): 4.6(s,2H), 6.85-7.0(m,6H),

7.2- 7.5(complex m,16B), 7.9-8.0(m,IB).

(iii) Sodium hydride (60X dispersion in mineral oil; 80 mg) vas added to a stirred solution of compound (C) (0.99 g) in DMF (10 ml). The mixture vas stirred until evolution of hydrogen ceased and then 4-chloroquinoline (0.33 g) vas added. The mixture vas stirred for 24 hours, poured into vater (100 ml) and extracted vith ethyl acetate (2 x 50 ml). The extracts vere vashed vith vater (40 ml) and saturated sodium chloride solution (40 ml) and then dried (MgSO^). Volatile material vas removed by evaporation and the residue purified by flash chromatography, eluting vith ethyl acetate/hexane (1:1 v/v), to give 4-( (2' - (2-tripheny Imethy l-2H-tetrazol-5-yl) bi pheny 1-4-y l)me thoxy ]quinoline (A) (0.80 g), as a foam; NMR (CDCl^): 5.2(s,2B), 6.8(d,lH),

6.85-6.95(m,6B), 7.15-7.55(complex m,17B), 7.7(t,lB), 7.95-8.25(m,3B),

APO 0 0 16 1

- 42 8.7(d,lH).

Example 57 (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 -
Propylene glycol	5.0
Polyethylene glycol (300) 3.0 - 5.0 Purified water	to 100Z
d) Injectable Suspension (for intramuscular	administration)
Active ingredient *	0.05 -
Methylcellulose	0.5
Tween 80	0.05
Benzyl alcohol	0.9
Benzalkonium chloride	0.1
Purified water	to 100Z

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

- 43 in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated vith a conventional enterically digestible coating.

HE35934

JJH/KEB: 28JUN9O

AP 0 0 0 1 6 1

-44Scheae 1

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

Reagents: a) BuLi/TBF; ZnCl^/Et-O; Pd(Ph^P)^

b) Bu^Sn.N^/toluene; HCl/toluene

c) TrTCl/Et^N/CH^Cl»

d) N-bromosuccinimide/azoisobutyronitrile/CCl^

AP Ο Ο Ο 1 6 1

-+6,3

Chenical Formulae (continued)

Hal

ΥΪ

HO-^x

Claims (13)

1. What ve claim is :- vherein R* is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (l-4C)alkyl, the latter containing one or aora fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (l-4C)alkoxy or 2 phenyl substituent; R is hydrogen, (l-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, cyano, nitro, phenyl or phenyl(l-4C)alkyl; R and R are Independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, fluoro(l-4C)alkoxy, halogeno, hydroxy, tri fluoromethyl, cyano, nitro, amino, (l-4C)alkanoylaaino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (l-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (l-4C)alkoxycarbonyl, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, and substituted (l-4C)alkyl, the latter bearing an amino, hydroxy or (l-4C)alkoxy 3 4 substituent; or R and R together form (l-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R^ are independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; A is methylene; X is phenylene optionally bea.ing a substituent selected from (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro, or X is a *

   direct bond betveen the adjacent phenyl group and moiety A; Z is lH-tetrazol-5-yl, -CO.NH.(lH-tetrazol-5-yl) or a group of the formula

   -CO.OR^ or -CO.NH.SO^.R? in vhich R^ is hydrogen or a non-toxic, biodegradable residue of a physiologically acceptable alcohol or

   APO0016 1

   - 48 phenol, and R? 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 non-toxic salt thereof; but excluding methyl 2-[(3-methoxycarbonylquinolin-4-yloxy)methyl]benzoate.
2. 2. A compound as claimed in claim 1 wherein R³ Is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, fluoroaethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-ethoxyethyl, benzyl, 1-phenylethyl, or 2-phenylethyl; R is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopentyl-ethyl, carboxy, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, cyano, nitro, phenyl, benzyl,
3. 3 4

   1- phenylethyl or 2-phenylethyl; R and R are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethoxy,

   2- fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, fluoro, chloro, bromo, iodo, hydroxy, trifluoromethyl, cyano, nitro, amino, formamido, acetamido, propanamido, methylaaino, ethylaaino, butylamino, dimethylamino, diethylamino, dipropylaeino, dimethylaminomethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl,

   3- (diethylamino)propyl, formyl, acetyl, butyryl, carbamoyl, _

   N-methylcarbamoyl, N-ethylcarbamoyl, Ν,Ν-dimethylcarbamoyl, Ν,Ν-diethylcarbamoyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylthio, ethylthio, butylthio, methylsulphinyl, ethylsulphinyl, butylsulphinyl, methylsulphonyl, ethylsulphonyl, butylsulphonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, 2-methoxyethyl and 2-ethoxyethyl; or R and R⁴ together form methylenedioxy or ethylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; Ra and R³ are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano and nitro; X is phenylene optionally bearing a substituent selected from methyl,

   BAD ORIGINAL

   - 49 ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, trifluoromethyl, cyano and nitro, or X is a direct bond between the adjacent phenyl group and moiety A; is hydrogen or a residue derived from a (l-6C)alkanol, or phenol or glycerol; and R? is methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl; 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 as claimed in claim 1 wherein is hydrogen, (l-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(l-4C)alkyl, phenyl or 3 4 5 phenyl(l-4C)alkyl; R , R and R are independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; and Ra is hydrogen.

   3 4
4. 4. A compound as claimed in claim 1 wherein R and R are independently selected from hydrogen, (l-4C)alkyl, (l-4C)alkoxy, fluoro(l-4C)alkoxy, halogeno, trifluoromethyl, cyano, nitro, amino, (l-4C)alkanoylamino, alkyl ami no and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (1-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and dl-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (l-4C)alkoxycarbonyl, (l-6C)alkylthio, (l-6C)alkylsulphinyl, (l-6C)alkylsulphonyl, and substituted (l-4C)alkyl, the latter bearing an amino, hydroxy or (l-4C)alkoxy 3 4 substituent; or R and R together form (l-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I; and Ra is hydrogen.

   I 9 I 0 0 0 dV

   - 50 12 3 4 wherein R , R , R and R have any of their meanings as defined in any of claims 1-4, R^ is hydrogen and is carboxy or lB-tetrazol-
5. 5-yl; together with the non-toxic salts thereof.
6. 6. A compound as claimed in any of claims 1, 2 and 5 wherein

   1 2 the quinoline moiety together with the attached substituents R , R ,

   3 4

   R and R , and Ra when present, is selected from 2-methylquinoline, 2-ethylquinoline, 2-ethyl-6-methoxyquinoline, 6,7-dimethoxy-2-ethylquinoline, 2-ethyl-5,6,7-trimethoxyquinoline, 2-ethyl-6-hydroxyquinoline, 2-ethy1-6-methylthioquinoline, 2-ethyl-7-hydroxymethylquinoline, 2-ethyl-6-(2-fluoroethoxyJquinoline, 2-ethyl-6-(2,2,2trifluoroethoxyJquinoline, 2-ethyl-6-carboxamidoquinoline, 2-ethyl-6fluoroquinoline, 2-ethyl-6-isopropoxyquinoline and 6-aminomethyl-2ethylquinoline; and in which the substituent O.A.X- is attached at the 4-position of the quinoline ring.
7. 7. A compound of the formula I selected from :2-methyl-4-((2'-(lB-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline;

   2-ethyl-4-((2'-(IB-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline;

   6,8-dimethyl-2-ethyl-4-((2'-(lB-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline;

   2-ethyl-6-methylthio-4-J(2'-(lB-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline;

   2-ethyl-7-hydroxymethyl-4-[(2'-(lB-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline;

   2-ethyl-6-(2-fluoroethoxy)-4-((2'-(lB-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline;

   2-ethyl-6-(2,2,2-tri fluoroethoxy)-4-((2'-(lB-tetrazol-5-yl)biphenyl4-yl)methoxyJquinoline;

   6-carboxamido-2-ethyl-4-((2'-(lH-tetrazol-5-yl)-biphenyl-4-yl)methoxyJquinoline;

   6-cyano-2-ethyl-4-{(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline;

   2-ethyl-6-fluoro-4-[(2'-(IB-tetrazol-5-yl)bipKenyl-4-yl)methoxy ]quinoline;

   2-ethyl-6-isopropoxy-4-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline; and

   - 51 6-aminomethyl-2-ethyl-4-{(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline;

   and the non-toxic salts thereof.
8. 8. A compound of the formula I selected from:2-methyl-4-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxyJquinoline; 2-ethyl-4-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline; and 2-ethyl-6-isopropoxy-4-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline; and the non-toxic salts thereof.
9. 9. A salt as claimed in any one preceding claim vhich is selected from salts vith acids forming physiologically acceptable anions and, for those compounds of formula I vhich are acidic, alkali metal, alkaline earth metal, aluminium and ammonium salts, and salts vith organic bases affording physiologically acceptable anions.
10. 10. A process for the manufacture of a compound of formula I or a non-toxic salt thereof, as claimed in claim 1, 5, 7 or 8 vhich is characterised in that:(a) For those compounds in vhich Z is carboxy, a carboxylic acid derivative of the formula II

    AP 0 0 0 1 6 1 in vhich Q is a protected carboxy group selected from (l-6C)alkoxycrrbonyl, phenoxycarbonyl, benzyloxycarbonyl and carbamoyl, is converted to carboxy;

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

    BAD ORIGINAL 'hich L is a suitable protecting group affixed to a nitrogen of the azolyl moiety, is deprotected;

    A quinolone of the formula IV

    Ra ‘ein R is other than hydrogen is alkylated with a compound of the c ···’ iUla V

    Hal

    OO.OR rein Hal. stands for a suitable leaving group; or

    A halogenoquinoline of the formula VII

    R«.

    vn · rein Y^ is a halogeno group is reacted with an alcohol of the aula VIII

    BAD ORIGINAL <,

    4.- whereafter: vhen a compound of the foraula I is required wherein Z is lH-tetrazol-5-yl, a compound of the foraula I wherein Z is a group of the foraula -CO.OR⁶ is converted into the corresponding nitrile under standard conditions, followed by reaction of the nitrile with an azide;

    when a coapound of the foraula I is required wherein Z is a group of the foraula -CO.NH.SO.R⁷ or a group of the foraula -CO.OR^ in 6 which R is other than hydrogen, a carboxylic acid of the foraula I in which Z is carboxy (or a reactive derivative of said acid) is reacted vith a sulphonamide of the foraula NHg.SC^R? or a hydroxy coapound of the foraula HO.R^, or vith a salt thereof;

    vhen a non-toxic salt of a coapound of foraula 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 foraation procedure; and vhen an optically active fora of a coapound of foraula I is required, one of the aforesaid processes (a)-(d) is carried out using an optically active starting aaterial, or the raceaic fora of a compound of foraula I in which Z is an acidic group is resolved by reaction vith 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 vith acid;

    and wherein R¹, R , R , R , R , R , R , Ra, A, X and Z have an> of the meanings defined in any of claims 1-6 unless otherwise stated.

    *
11. 11. 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 9, together vith a pharmaceutically acceptable diluent or

    APO 0 0 16 1

    - 54 carrier.
12. 12 3 4 5

    12. A compound of the formula II vherein R¹, R\ R , R*, R , Ra,

    A and X have any of the meanings defined in any of claims 1-6, and Q is a protected carboxy group selected from (l-6C)alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and carbamoyl.

    12 3 4 5
13. 13. A compound of formula III vherein R , R , R , R , R , Ra, A and X have any of the meanings defined in any of claims 1-6, and L is a protecting group.