WO1992009600A1 - Benzofuran and benzthiophene derivatives - Google Patents

Abstract

The invention provides compounds of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof wherein Q represents an oxygen or sulphur atom; R1 represents a hydrogen atom or a halogen atom or a group selected from C¿1-6?alkyl, C2-6alkenyl, fluoroC1-6alkyl, -CHO, -CO2H, C1-6alkoxy, or -COR?2¿; Ar represents the group (a); R2 represents a group selected from C¿1-6?alkyl, C2-6alkenyl, C1-6alkoxy or the group -NR?12R13; R3¿ represents a group selected from -CO¿2?H, -NHSO2CF3 or a C-linked tetrazolyl group; R?4 and R5¿, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a C¿1-6?alkyl group; Het represents the group (b); X represents N or CH; Y represents N or CR?7¿; Z represents N or CR7; R6 represents a hydrogen atom or a C¿1-6?alkyl, C2-6alkenyl or a C1-6alkylthio group; R?7¿ represents a halogen atom or a group selected from cyano, nitro, C¿1-6?alkyl, C2-6alkenyl, fluoroC1-6alkyl, -(CH2)mR?8¿, -(CH¿2)nCOR?9, or -(CH¿2?)pNR?10COR11; R8¿ represents a hydroxy or C¿1-6?alkoxy group; R?9¿ represents a hydrogen atom or a group selected from hydroxy, C¿1-6?alkyl, C1-6alkoxy, phenyl, phenoxy or the group -NR?12R13; R10¿ represents a hydrogen atom or a C¿1-6?alkyl group; R?11¿ represents a hydrogen atom or a group selected from C¿1-6?alkyl, C1-6alkoxy, phenyl, phenoxy or the group -NR?12R13; R12 and R13¿, which may be the same or different, each independently represent a hydrogen atom or a C¿1-4?alkyl group or -NR?12R13¿ forms a saturated heterocyclic ring which has 5 or 6 ring members and may optionally contain in the ring one oxygen atom; m represents an integer from 1 to 4; n represents zero or an integer from 1 to 4; and p represents an integer from 1 to 4; with the proviso that at least one of X, Y and Z is a nitrogen atom, and with the further proviso that when X is N at least one of Y and Z is N and when Y is N at least one of X and Z is N. The compounds may be used in the treatment or prophylaxis of hypertension and diseases associated with cognitive disorders.

Description

BENZOFURAN AND BENZTHIOPHENE DERIVATIVES

This invention relates to benzofuran or benzthiophen derivatives, processes for their preparation and pharmaceutical compositions containing them. According to a first aspect of the invention we provide a compound of general formula (I):

or a physiologically acceptable salt, solvate (e.g. hydrate) or metabolically labile ester thereof in which

Q represents an oxygen or sulphur atom;

R¹ represents a hydrogen atom or a halogen atom or a group selected from

C_{1 -6}alkyl, C_2-6alkenyl, fluoroC_1-6alkyl, -CHO, -CO₂H, C_1-6alkoxy, or -CO^R2;

Ar represents the group

R² represents a group selected from C_1-6alkyl, C_2-6alkenyl, C_{1 -6} alkoxy or the group -NR¹²R¹³;

R³ represents a group selected from -CO₂H, -NHSO₂CF₃ or a C-linked tetrazolyl group;

R⁴ and R⁵ which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a C_1-6alky! group;

Het represents the group ;

X represents N or CH:

Y represents N or CR⁷;

Z represents N or CR⁷;

R⁶ represents a hydrogen atom or a C_1-6alkyl, C_2-6alkenyl or a C_1-6alkylthio group;

R⁷ represents a halogen atom or a group selected from cyano, nitro, C_1-6alkyl,

C_{2- 6}alkenyl, fluoro C _{1 - 6}alkyl, - (CH₂)_mR⁸ , - (CH₂ )_n COR⁹ , or

-(CH₂)_pNR¹⁰COR¹¹;

R⁸ represents a hydroxy or C_1-6alkoxy group;

R⁹ represents a hydrogen atom or a group selected from hydroxy, C_{1 -6}alkyl,

C_1-6alkoxy, phenyl, phenoxy or the group -NR ¹² R¹³;

R¹⁰ represents a hydrogen atom or a C_1-6alkyl group;

R¹¹ represents a hydrogen atom or a group selected from C_1-6alkyl, C_1-6alkoxy, phenyl, phenoxy or the group -NR¹²R¹³;

R¹² and R¹³, which may be the same or different, each independently represent a hydrogen atom or a C_1-4 alkyl group or -NR¹²R¹³ forms a saturated heterocyclic ring which has 5 or 6 ring members and may optionally contain in the ring one oxygen atom;

m represents an integer from 1 to 4;

n represents zero or an integer from 1 to 4; and

p represents an integer from 1 to 4;

with the proviso that at least one of X, Y and Z is a nitrogen atom, and with the further proviso that when X is N at least one of Y and Z is N and when Y is N at least one of X and Z is N.

Where optical isomers may exist formula (I) is intended to cover all enantiomers, diastereoisomers and mixtures thereof including racemates. Compounds containing one or two double bonds may exist in the cis or trans configuration and mixtures thereof. The invention also includes within its scope the solvates, especially the hydrates of compounds of general formula (I).

Within the above definition the term 'alkyl' or 'alkoxy' as a group or part of a group means that the group is straight or branched. The term 'alkenyl' as a group or pan of a group means that the group is straight or branched and contains at least one carbon-carbon double bond.

The term 'halogen' means a fluorine, chlorine, bromine or iodine atom.

The term 'fluoroC_{1 -6}alkyl' means a C_{1 -6}alkyl group in which one or more hydrogen atoms have been replaced by a fluorine atom, for example, -CH₂CF₃, or in particular a perfluoroC_{1 -3}alkyl group which means a fully fluorinated alkyl group, i.e. trifluoromethyl, pentafluoroethyl, heptafluoropropyl or heptafluoroisopropyl.

Within the above definition when -NR ¹² R ₁ ³ represents a saturated heterocyclic ring, this contains 5 or 6 ring members, one of which may be an oxygen atom. Suitable heterocyclic groups are a pyrrolidino, piperidino or morpholino group.

A preferred class of compounds of general formula (I) is that wherein the group R⁶ is a hydrogen atom or a C_1-5alkyl or C_3-5alkenyl group. Particularly preferred are those compounds wherein R⁶ is a C_{2- 4}alkyl group, for example, an ethyl, n-propyl or n-butyl group.

Another preferred class of compounds of general formula (I) is that wherein the group R⁷ is selected from a halogen atom or a group selected from C _{1 -6}alkyl, -(CH₂)_mR⁸ or -(CH₂)_nCOR⁹ especially wherein R⁸ represents a hydroxy group or methoxy group and R⁹ represents a hydrogen atom, or a hydroxy, methoxy or ethoxy group, and m is 1 or 2 and n is 0, 1 or 2. In particular, R⁷ substituents may represent a chlorine atom or a group selected from -CH²OH, -CHO, -CH₃, -CH₂OCH₃, -CO₂H, -CO₂CH₂CH₃, -CO₂CH₃, -CONH₂ or -CONHCH₃.

A further preferred class of compounds of general formula (I) is that wherein Het represents a group selected from:

A yet further preferred class of compounds of general formula (1) is that wherein R¹ is attached at the 3-position on the benzofuran or benzthiophen ring. Also preferred are those compounds wherein R¹ represents a hydrogen atom or in particular a halogen (especially bromine) atom.

Conveniently, in the compounds of general formula (I), the group Het-CH₂- is attached at the 5- or 6-position on the benzofuran or benzthiophen ring, and preferably at the 5-position.

Also conveniently, in the compounds of general formula (I), R³ may be the group -CO₂H, or in particular, a C-linked tetrazolyl group.

Still conveniently, in the compounds of general formula (I), R⁴ and R⁵ may each independently represent a hydrogen atom.

The physiologically acceptable acid addition salts of the compounds of formula (I) may be derived from inorganic or organic acids. Examples of such salts include hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, methanesulphonates or trifluoroacetates.

The compounds may also form salts with suitable bases. Examples of such salts are alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium and substituted ammonium (e.g. dimethylammonium, triethylammonium, 2-hydroxyethyldimethylammonium, piperazinium, N,N-dimethylpiperazinium, tetralkylammonium, piperidinium. ethylenediammonium and choline).

It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable, but other salts may find use, for example, in the preparation of the compounds of formula (I) and the physiologically acceptable salts thereof. It will be further appreciated that the compounds of general formula (I) may be chemically modified in the form of compounds which in vivo (for example, by enzymic attack) will provide the parent compounds of general formula (I). Such prodrugs may be, for example, physiologically acceptable metabolically labile ester derivatives. These may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I), with prior protection of any other reactive groups present in the molecule. Examples of such esters include lower alkyl esters (e.g. methyl or ethyl esters), alkenyl esters (e.g. vinyl or alkyl esters), alkynyl esters(e.g. ethynyl or propynyl esters), alkoxyaikyl esters, (e.g. methoxymethyl or 2-methoxyethyl esters), alkylthioalkyl esters (e.g. methylthiomethyl esters) haloalkyl esters (e.g. 2-iodoethyl or 2,2,2,-trichloromethyl esters), alkanoyloxyalkyl esters (e.g. acetoxymethyl, 1 -acetoxyethyl or pivaloyloxymethyl esters) , alkoxycarbon yloxyalkyl esters (e.g. 1 -ethoxycarbonyloxyethyl or 1-methoxycarbonyloxyethyl esters), aroyloxyalkyl esters (e.g. benzoyloxymethyl or 1-benzoyloxyethyl esters), substituted or unsubstituted aralkyl esters (e.g. benzyl or 4-amidobenzyl esters), substituted or unsubstituted aminoalkyl esters (e.g aminoethyl or 2-N,N-dimethylaminoethyl esters) or hydroxyalkyl esters (e.g. 2-hydroxyethyl or 2,3-dihydroxypropyl esters).

In addition to the above ester derivatives the present invention includes within its scope compounds of general formula (I) in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo into the parent compounds of general formula (I).

According to a second aspect of the present invention we provide a compound of formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof for use in therapy.

In particular, the compounds of the invention may be used in the treatment or prophylaxis of hypertension. They are also potentially useful for the treatment of cognitive disorders such as dementia (e.g. Alzheimer's disease) and other diseases such as renal failure, hyperaldosteronism, cardiac insufficiency, congestive heart failure, post-myocardial infarction, cerebrovascular disorders, glaucoma and disorders of intracellular homeostasis.

According to a further aspect of the present invention we provide a compound of formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof for use in the treatment of the aforementioned diseases, especially hypertension.

According to another aspect of the present invention we provide a compound of formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester solvate thereof for the manufacture of a therapeutic agent for the treatment of the aforementioned diseases, especially hypertension.

According to a further aspect of the present invention we provide a method of treating the aforementioned diseases, especially hypertension, which method comprises administering an effective amount to a patient in need of such treatment of a compound of formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof.

It will be appreciated that the compounds of formula (I) or a physiologically acceptable salt, solvate, or metabolically labile ester thereof may advantageously be used in conjunction with one or more other therapeutic agents, such as for example diuretics and/or different antihypertensive agents such as ß-blockers, calcium channel blockers or ACE inhibitors. It is to be understood that such combination therapy constitutes a further aspect of the present invention.

It will be further appreciated that reference herein to treatment extends to prophylaxis as well as to the treatment and relief of established symptoms.

While it is possible that a compound of general formula (I) may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.

The compounds of formula (I) and their physiologically acceptable salts, solvates and metabolically labile esters may be formulated for administration in any convenient way, and the invention also includes within its scope pharmaceutical compositions comprising at least one compound of formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof adapted for use in human or veterinary medicine. Such compositions may be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Thus, the compounds according to the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The compounds or their salts or esters may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

It will be appreciated that both tablets and capsules may be manufactured in the form of sustained release formulations, such that they provide a controlled continuous release of the compounds according to the invention over a period of hours. The compounds of formula (I) and their physiologically acceptable salts, solvates and metabolically labile esters may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a neb uliser, with the use of a suitable propellant, e.g. dichlorodifiuoromethane, trichlorofluoro methane, dichlorotetrafluoroethane or other suitable gas. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

The pharmaceutical formulations according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.

It will be appreciated that the amount of a compound of general formula (I) required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian. In general, however, when the compositions comprise dosage units, each unit will preferably contain 5mg to 500mg, advantageously where the compounds are to be administered orally 25mg to 400mg of the active compound. The daily dosage as employed for adult human treatment will preferably range from 5mg to 3g, most preferably from 25mg to 1g which may be administered in 1 to 4 daily doses.

The compounds of the invention may be prepared by a number of processes as described below wherein the various groups are as defined for general formula (I) unless otherwise specified.

Thus, according to a further aspect of the present invention we provide a process (Al) for preparing the compounds of general formula (I) when X, Y and Z each represent N; or when X represents CH, Y represents CR⁷ and Z represents N; or when X and Z represent N and Y represents, CR , which comprises treating a compound of general formula (II)

(wherein L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy, or p-toluenesulphonyloxy and R¹, Ar and Q are as defined in general formula (I)) with an heterocycle of formula (III)

(wherein R ⁶ represents a group selected from C _{1- 6}alkyl, C_2-6alkenyl or C_1-6alkylthio and X, Y and Z are as defined for this process) followed by the removal of any protecting groups where present, as described hereinafter.

The reaction is preferably effected under basic conditions, for example, in the presence of sodium hydride, potassium carbonate or sodium methoxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, or a substituted amide e.g. dimethylformamide, at a temperature between 0ºC and the reflux temperature of the solvent. The intermediate compounds of general formula (II) and their salts are novel compounds and form a further aspect of the present invention.

In another general process (A2) a compound of general formula (I) when X and Y represent N and Z represents CR⁷ may be obtained by treating a compound of general formula (IV)

(wherein R¹, Ar and Q are as defined in general formula (I)) with an oxadiazole of formula (V)

(wherein R⁶ and R⁷ are as defined in general formula (I)) followed by the removal of any protecting groups where present, as described hereinafter.

The reaction is conveniently effected in a high boiling solvent such as an alcohol, for example, n-propanol, or an aromatic hydrocarbon e.g xylene or toluene, at elevated temperature such as the reflux temperature of the solvent for between 1 and 10 days.

The intermediate compounds of general formula (IV) and their salts are novel compounds and form a further aspect of the present invention.

In another general process (A3) a compound of general formula (I) when X represents CH and Y and Z each represent N may be obtained by treating a compound of general formula (VI)

(wherein R¹, Ar and Q are as defined in general formula (I)) with a compound of formula (VII) R⁶C≡CH (VII)

(wherein R⁶ is as defined in general formula (I)) followed by the removal of any protecting groups where present, as described hereinafter.

The reaction is conveniently effected in an excess of the alkyne at a temperature between room temperature and the reflux temperature of the alkyne.

The intermediate compounds of general formula (VI) and their salts are novel compounds and form a further aspect of the present invention.

In another general process (B) a compound of general formula (I) may be obtained by deprotection of a protected intermediate of general formula (VIII):

(wherein Q, R¹, Ar and Het are as defined in general formula (I) except that at least one reactive group is blocked by a protecting group).

The protecting groups may be any conventional protecting groups, for example as described in "Protective Groups in Organic Synthesis" by Theodora Greene (John Wiley and Sons Inc., 1981). Examples of carboxyl protecting groups include C_1-6alkyl such as methyl or t-butyl, or C_{7- 10}aralkyl such as benzyl.

When R³ is a tetrazole group, this may be protected with, for example, the trityl group -C(phenyl)₃, or a p-nitrobenzyl or 1-ethoxyethyl group.

Deprotection to yield the compound of general formula (I) may be effected using conventional techniques. Thus, for example, aralkyl groups may be cleaved by hydrogenolysis in a suitable organic solvent such as an alcohol, e.g. ethanol, in the presence of a noble metal catalyst such as palladium or platinum or an oxide thereof on a support such as charcoal, and conveniently at room temperature and pressure. It should be noted however that where susceptible halogen atoms exist in the molecule deprotection by catalytic hydrogenation should preferably be avoided since such conditions may remove the halogen atom as well as the protecting group. Carboxyl protecting groups such as alkyl groups may be cleaved by hydrolysis using a base such as an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) in a suitable solvent (e.g. an aqueous alcohol such as methanol or ethanol) at any suitable temperature up to reflux , or alternatively, using an acid such as trifluoroacetic acid in a suitable solvent such as dichloromethane at any suitable temperature up to reflux. Deprotection of the tetrazole group when protected with a trityl group may be effected by acid hydrolysis using trifluoroacetic acid or a mineral acid such as hydrochloric acid in a suitable solvent such as acetone conveniently at room temperature. Alternatively, when possible, deprotection of the tetrazolyl group can be effected by catalytic hydrogenation as previously described.

In another general process (C) a compound of general formula (I) in which the substituent R³ in the group Ar represents a C-linked tetrazolyl group, may also be prepared from a compound of general formula (la)

(wherein Q, R¹, Ar and Het are as defined in general formula (I) except that in the group Ar, R³ represents a nitrile group) by reaction with a suitable azide such as sodium azide, ammonium azide (preferably prepared in situ from sodium azide and ammonium chloride), trialkyl-(e.g.triethyl) ammonium azide (preferably prepared in situ from sodium azide and a trialkylamine (e.g. triethylamine)) or tributyl tin azide. The reaction is conveniently effected in a solvent such as xylene at an elevated temperature, such as the reflux temperature of the solvent, for between 1 and 10 days. Where the azide is tributyl tin azide the reaction may conveniently be effected in the absence of a solvent at a temperature between room temperature and 180ºC. Such a reaction leaves the tetrazolyl group protected with a tributyl tin group, which can readily be removed using aqueous base or acid. Where aqueous base is used to effect this deprotection, the compound may be treated with an aqueous acid to liberate the free acid. Compounds of general formula (la) may be prepared by processes analogous to those described herein commencing from a compound of formula (XIII) and a corresponding benzofuran or benzthiophen intermediate.

The intermediate compounds of general formula (la) and their salts are novel compounds and form a further aspect of the present invention.

In another general process (D) a compound of general formula (I) in which the substituent R³ in the group Ar represents -NHSO₂CF₃, may also be prepared from a compound of general formula (Ib)

(wherein R ¹, Ar and Het are as defined in general formula (I) except that in the gro u p A r, R ³ rep re s e n t s an ami n o gro u p ) b y re ac t i o n w i t h trifluoromethanesulphonic anhydride, in a suitable solvent such as dichloromethane.

Compounds of general formula (lb) may be prepared by processes analogous to those described herein commencing from a compound of formula (XV) and a corresponding benzofuran or benzthiophen intermediate.

Alternatively, compounds of general formula (lb) may be prepared by a Curtius rearrangement of a compound of formula (I) wherein R³ in the group Ar is -CO₂H (provided that this is the only carboxyl group in the molecule) using, for example, diphenylphosphorylazide in the presence of a base such as triethylamine and in a solvent such as an alcohol (e.g. tert-butanol) to form a carbamate followed by deprotection of the amine in a conventional manner, for example by acid hydrolysis using hydrochloric acid in a solvent such as ethanol.

The intermediate compounds of general formula (lb) and their salts are novel compounds and form a further aspect of the present invention.

In the processes (A), (B) and (C) described above, the compounds of general formula (I) may be obtained in the form of a salt, conveniently in the form of a physiologically acceptable salt. Where desired, such salts may be converted into the corresponding free acids or free bases using conventional methods. Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) with an appropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or isopropanol.

Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compounds of general formula (I), using conventional methods.

The intermediate compounds of formula (IV) may be prepared from a compound of general formula (II) wherein L represents a bromine or iodine atom by a two-step reaction with potassium phthalimide, followed by treatment with hydrazine or methylamine or by acid or base hydrolysis. The reaction is conveniently effected under basic conditions, for example, in the presence of potassium carbonate or sodium hydride, and in a solvent such as a substituted amide e.g. dimethylformamide, at a temperature between 0ºC and the reflux temperature of the solvent.

The intermediate compounds of formula (VI) may be prepared from a compound of general formula (II) wherein L represents a bromine or iodine atom by reaction with an azide such as sodium azide. The reaction is conveniently effected in a solvent such as a substituted amide e.g. dimethylformamide, at a temperature between room temperature and 80ºC.

The intermediate compounds of general formula (II) may be prepared from a compound of formula (IX):

using any suitable reagent well known in the art for converting the methyl on the 6-membered ring into the group -CH₂L (wherein L is as defined above). Thus, for example, when L is a halogen atom, a compound of formula (IX) can be converted into a compound of general formula (II) using N-chloro amides, tert-butyl hypochlorite or N-bromosuccinimide. Halogenation of the side chain may be catalysed by light, thus the reaction can be illuminated with a suitable artificial light source, and preferably in the presence of a free radical initiator such as azobisisobutyronitrile (AIBN) or benzoyl peroxide.

Compounds of formula (IX) wherein R¹ is a halogen atom, for example, a bromine atom, may be prepared by halogenation of a compound of formula (IX) wherein R represents a hydrogen atom, using for example, bromine, in a suitable solvent such as a halogenated hydrocarbon, e.g. carbon tetrachloride.

Compounds of formula (IX) wherein Ar is attached at the 2-position on the benzofuran or benzthiophen ring may be prepared by reaction of a compound of formula (X)

(wherein R^1a represents a hydrogen atom or a group selected from C_1-6alkyl or C_2-6alkenyl) with a compound of formula (XI)

(wherein W represents a bromine or iodine atom or the group -OSO₂CF₃, R⁴ and R⁵ are as defined in general formula (I) and R^3a is as defined for R³ in general formula (I) or is a protected derivative thereof).

The compound of formula (X) is first treated with an alkyl lithium compound such as n-butyl lithium at a reduced temperature, for example, between -100º and 0ºC in a solvent such as an ether (e.g. tetrahydrofuran). The mixture is then treated with a tri-substituted alkylborate compound such as triisopropylborate and the temperature conveniently brought up to room temperature. Subsequently, water may be added and the mixture treated with a mineral acid such as sulphuric acid thus producing a compound of formula (Xa)

The intermediate compound of formula (Xa) is then reacted with a compound of formula (XI) in the presence of a palladium (O) compound such as tetrakis(triphenylphosphine) palladium (O) in a solvent such as an ether (e.g. dimethoxy ethane), and in the presence of an aqueous base such as sodium bicarbonate sodium carbonate or thallium hydroxide. The reaction is conveniently effected at an elevated temperature, such as the reflux temperature of the solvent.

Compounds of formula (IX) wherein Ar is attached at the 3-position on the benzofuran or benzthiophen ring may be prepared by reaction of a compound of formula (XII)

with a compound of formula (XI) as described above for arylation at the 2-position, except that the reaction proceeds via intermediate (Xlla)

Compounds of formula (IX) in which the substituent R³ in the group Ar represents a C-linked tetrazolyl group may be prepared from a precursor of a compound of formula (IX) wherein the substituent R³ represents a nitrile group using the reagents and conditions described in process (C).

Similarly, intermediates of formula (XI) wherein R^3a represents a C-linked tetrazolyl group may be prepared from a compound of formula (XIII)

followed where necessary by protection of any reactive groups, using methods well-known in the art such as those described in process (C).

Intermediates of formula (XII) in which Q represents an oxygen atom may be prepared by reaction of a compound of formula (XIV)

with a base such as potassium hydroxide, sodium ethoxide or potassium t-butoxide, in an alcoholic solvent such as ethanol or t-butanol at a temperature between 0ºC and the reflux temperature of the solvent.

Compounds of formula (IX) in which the substituent R³ in the group Ar is

-NHSO₂CF₃ may be prepared from a precursor of a compound of formula (IX) wherein the substituent R³ is an amine group using the reagents and conditions described in process (D).

Similarly, intermediates of formula (XI) wherein R^3a represents -NHSO₉CF₃ may be prepared from a compound of formula (XV)

(followed where necessary by the protection of any reactive group) using methods well known in the art such as those described in process (D).

Compounds of formula (IX) wherein Ar is attached at the 2-position on the benzofuran or benzthiophen ring may also be prepared by an intramolecular cyclisation reaction of a compound of formula (XVI)

(wherein R¹ is as previously defined) with a suitably substituted benzene of formula (XVII)

(wherein L is as previously defined and R^3b is as defined for R^3a in formula (XI) or is a nitrile group suitable for subsequent conversion into a tetrazolyl group or is an amino group suitable for conversion into -NHSO₂CF₃), in the presence of a base such as sodium hydride or potassium carbonate. The cyclisation is a two step reaction which requires one equivalent of base per step. It will be appreciated however that the reaction can be effected in the presence of two equivalents of base to avoid the need to isolate the intermediate. The reaction is conveniently effected in a solvent such as an ether e.g tetrahydrofuran, an alcohol e.g ethanol or a substituted amide e.g dimethylformamide, at a temperature between room temperature and the reflux temperature of the solvent.

It will be appreciated that compounds of formula (IX) in which R¹ represents a hydrogen or halogen atom may be converted into compounds of formula (IX) in which R¹ represents the group methyl (via hydrogenolysis of the Mannich base),

-CHO or -COR² (wherein R² is as defined in general formula (I)) using techniques well known in the an, such as those described in "Heterocyclic Chemistry" by J.A.

Joule and G.F. Smith, Van Nostrand Reinhold Company, London (1972),

"Heterocyclic Chemistry" by A. Albert, 2nd Edition, The Athlone Press, London

(1968), "Heterocyclic Compounds", Vol. 29 by A. Mustafa, John Wiley and Sons

Inc., New York (1974), "Heterocyclic Compounds", Vol. 2 by R.C. Elderfield, John

Wiley and Sons Inc., New York (1951) and "Advances in Heterocyclic Chemistry",

Vol. 29 by A.R. Katritsky and A.J. Boulton, Academic Press, New York (1981). The heterocycles of formula (III) may be prepared as described in European Specification No. 0323841 or by methods analogous to those described therein. The content of these references is hereby incorporated by reference.

Intermediates of formulae (X), (XI), (XII), (XIII), (XIV), (XV), (XVI) and (XVII) are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds.

The following examples illustrate the invention. Temperatures are in ºC. "Dried" refers to drying using magnesium sulphate. Thin layer chromatography (t.l.c.) was carried out over silica and column chromatography was carried out on silica (Merck 9385), using one of the following solvent systems : A - ether:hexane, B - ether:dichloromethane or C - dichloromethane:ethanol:conc. aqueous ammonia. The following abbreviations are used : THF - tetrahydrofuran; DME -dimethoxyethane; AIBN - azobisisobutyronitrile; DMF - dimethylformamide; TMEDA - tetramethylethylenediamine; NBS - N-bromosuccinimide.

Intermediate 1

5-Methylbenzofuran-2-boronic acid

n-Butyl lithium (1.6M in hexane; (35.16ml) was added dropwise to a stirred solution of TMEDA (9.58ml) and 5-methylbenzofuran (8.22g) in ether (250ml) maintaining the temperature below - 60ºC throughout. The solution so formed was warmed to about -10°C over 45 minutes and stirred at this temperature for about 30 minutes. A precipitate formed on warming. The suspension so formed was cooled and triisopropylborate (43ml) was added, maintaining the temperature below -60ºC. The solution was warmed gradually to room temperature before quenching with 2N HCl (70ml). The mixture was extracted with ether (3×50ml) and the combined organic extracts washed with 2N HCl (4×30ml), water (2×30ml) and dried before evaporation to give the title compound as an orange solid (12.75g).

t.l.c. System A (1:1), Rf 0.3.

Intermediate 2

Methyl 2-(5-methyl-2-benzofuranyl)benzoate A solution of methyl 2-bromobenzoate (11.70g), Intermediate 1 (12.75g) and tetrakis(triphenylphosphine) palladium (0) (0.5g) in DME (300ml) and 2N Na₂CO₃ (60ml) was heated to reflux with vigorous stirring under nitrogen. After 1.5h a further 500mg of catalyst was added and stirring at reflux under nitrogen continued. After about 5h the reaction mixture was cooled to room temperature and diluted with ether (300ml). The organic layer was separated and washed with water (3× 100ml) and dried. Filtration and evaporation gave a yellow oily suspension (19.27g) which was purified by chromatography eluting with System A (1:9) to give a yellow oil (11.06g). This was further purified by Kugelrohr distillation to give the title compound (4.31g).

t.l.c. System A (1:9), Rf 0.5.

Intermediate 3

Methyl 2-(3-bromo-5-methyl-2-benzofuranyl)benzoate

A solution of Intermediate 2 (0.25g) in carbon tetrachloride (5ml) was cooled to

-20ºC and treated dropwise with 1M bromine in carbon tetrachloride (0.7ml).

Stirring at -20ºC was then continued for 1h before gradual warming to room temperature. Stirring at room temperature was continued overnight. Cyclohexene

(0.1ml) was added dropwise and the solvents were evaporated to give the title compound as an orange oil (0.26g).

Ll.c. System A (1:9), Rf 0.45.

Intermediate 4

Methyl 2-[3-bromo-5-(bromomethyl)-2-benzofuranyl]benzoate

A solution of Intermediate 3 (0.26g) in carbon tetrachloride (8ml) was treated with

NBS (0.134g) and AIBN (10mg) before heating to reflux and irradiating with a

200W bulb. After about lh the solvent was evaporated to give an orange gum/solid which was purified by chromatography eluting with System A (1:9) to give the title compound as a pale yellow oil (0.19g).

LLc. System A (1:9), Rf 0.4. Intermediate 5

Methyl 2-[3-bromo-5-[[5-butyl-3-(methoxymethyl)-1H-pyrazol-1-yl] methyl]-2-benzofuranyllbenzoate

Sodium hydride (80% dispersion in oil; 72mg) was added to a stirred solution of 5-butyl-3-(methoxymethyl)-1H-pyrazole (270mg) in dry DMF (15ml) and the reaction. allowed to stir at room temperature for 15minutes. Intermediate 4 (700mg) was added and the reaction allowed to stir for 16h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated to give a yellow oil which was chromatographed to give the title compound as a pale yellow oil (230mg).

t.l.c. System A (3:2) Rf 0.2.

Intermediate 6

Methyl 2-[3-bromo-5-[(5-butyl-1H-tetrazol-1-yl)methyl]-2-benzofuranyl]benzoate A mixture of 5-butyl-1H-tetrazole (281mg), Intermediate 4 (1g) and anhydrous potassium carbonate (281mg) in acetonitrile (20ml) was heated at reflux overnight. The reaction mixture was cooled and the solvent removed in vacuo. The residue was purified by chromatography, eluting with petroleum ether/ether (1:1) followed by ether, to give the title compound as a yellow oil (434mg).

T.l.c. ether Rf 0.55.

Intermediate 7

2-(5-Methyl-2-benzofuranyl)benzonitrile

Intermediate 1 (20g) was added to a stirred solution of 2-bromobenzonitrile (10.34g) and tetrakistriphenyiphosphine palladium (0) (1.5g) in DME (200ml) and 8% NaHCO₃ (50ml) at reflux under nitrogen. Further catalyst (1.5g) was added and the reaction continued overnight. The reaction was cooled to room temperature and diluted with ether (200ml). The organic layer was separated, washed with water (3×100ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with system A (1:9) to give the title compound (10.58g) as a white solid. T.l.C System A (1:9), Rf 0.45.

Intermediate 7 was also prepared by the alternative two-step reaction:

a) 2-Hydroxy-5-methylbenzaldehyde

p-Cresol (100g) in dry THF(100ml) was added dropwise to a mechanically stirred, freshly prepared solution of ethyl magnesium bromide [magnesium (25.0g) and bromoethane (75ml)] in THF (500ml) under nitrogen at a rate which maintained a slow reflux (about 30mins). After a further 30mins toluene (1.21) was added, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (125ml), and paraformaldehyde (70g). The mixture was then heated at reflux for 16h. The mixture was concentrated by distillation and aqueous hydrochloric acid (2M, 600ml) then added. Water (600ml) was added and the mixture filtered through "hyflo". The organic phase was separated, dried, filtered and concentrated in vacuo to give a brown oil. The oil was steam distilled and the product extracted from the distillate with ether (1 litre). The organic extract was dried, filtered and concentrated in vacuo to give a pale yellow slurry which was cooled to -10ºC, triturated with ether (precooled to -78°C, 100ml), filtered off rapidly and washed with ether (precooled to -78ºC) to give the title compound as colourless needles, (131.4g).

T.l.c. System A (1:5) Rf 0.5. b) 2-(5-Methyl-2-benzofuranyl)benzonitrile

A solution of the product of step (a) (130g) in dry DMF (400ml) was added dropwise to a solution of sodium methoxide (56.2g) in ethanol (400ml) mechanically stirred under nitrogen. After a further 20mins, a solution of 2-(bromomethyl)benzonitrile (182.2g) in dry DMF (400ml) was added dropwise. The mixture was then heated to 75ºC for 30min. The solution was allowed to cool for 1h. A slurry of sodium methoxide (56.2g) in dry DMF (100ml) was added and the mixture heated at reflux for 1.5h. The mixture was concentrated in vacuo and then poured into iced water. The solid was collected, and then triturated with methanol to give the title compound (Intermediate 7) as a beige solid (149.4g).

T.Lc. System A (1:9) Rf 0.4. Intermediate 8

5-[2-(5-Methyl-2-benzofuranyl)phenyl]-1H-tetrazole

A suspension of Intermediate 7 (94g) in tri-n-butyl tin azide (268g) was heated at

100-125°C for 1.25h under nitrogen. The resulting solution was then heated at 155- 160ºC for 2h under nitrogen, then poured into a solution of aqueous sodium hydroxide (0.8N, 3070ml). This solution was extracted with ether. The aqueous phase was acidified to pH1 with 5N hydrochloric acid and the resulting precipitate filtered, washed with water and dried under vacuum. The solid was dissolved in ethyl acetate, washed with brine and dried. The solvent was evaporated to give the title compound as a buff-coloured solid (100.3g).

T.lc. System A (1:1), Rf 0.2.

Intermediate 9

5-[2-(3-Bromo-5-methyl-2-benzofuranyl)phenyl]-1H-tetrazole

A solution of bromine (58g), in carbon tetrachloride (140ml) was added dropwise over 35min to a mechanically stirred solution of Intermediate 8 (50g) in dry dioxan

(2090ml) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 3h, then cyclohexene (63ml) was added. Another preparation of the product was carried out simultaneously on the same scale as described above, and at this stage they were combined. The solvent was evaporated and the residual brown oil (260g) partitioned between ether and aqueous sodium hydroxide. The alkaline solution was acidified to pH1 with hydrochloric acid, then extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried and evaporated to give a buff solid (125g) which was triturated under hot toluene, cooled and filtered off to give the title compound as a cream coloured solid

(101.8g).

T.l.c. Ether/petroleum ether/acetic acid (50:50:1), Rf 0.27.

Intermediate 10

5-[2-(3-Bromo-5-methyl-2-benzofuranyl)phenyl]-2-(triphenylmethyl)-2H-tetrazole Triethylamine (57.4g) was added to a mechanically stirred suspension of Intermediate 9 (101g) in dry dichloromethane (2.9 litres) at room temperature under nitrogen. Triphenylmethyl chloride (79.3g) followed by DMAP (1.0g) were added at room temperature and the mixture stirred for 3h under nitrogen. The reaction mixture was washed with water, then brine and dried. The solvent was filtered and concentrated to a volume of about 1.2 litres then filtered through silica (Merck 9385, 14cm diam. column). Elution with dichloromethane gave a colourless solid (158.4g) which was triturated with ether and filtered to give the title compound as a colourless solid (147.9g).

T.l.c. (Dichloromethane/hexane 1:1), Rf 0.28

Intermediate 11

5-[2-[3-Bromo-5-(bromomethyl)-2-benzofuranyl]phenyl]-2- (triphenylmethyl)-2H- tetrazole

Intermediate 10 (74g) was dissolved in carbon tetrachloride (2050ml) by heating the suspension to reflux. The resulting colourless solution was allowed to cool to 50ºC then NBS (22.1g) was added, followed by benzoyl peroxide (1.1g). The reaction mixture was heated at reflux for 3.25h, under nitrogen, then allowed to cool to room temperature. The reaction mixture was washed with water then brine. Another preparation of the product was carried out simultaneously on the same scale as described above, and at this stage they were combined and dried. The solvent was evaporated to give a colourless solid (168g) which was triturated with ether/methanol (1:1) and filtered to give the title compound as a colourless solid

(160.8g).

T.l.c. (Dichloromethane/hexane 1:1), Rf 0.15.

Intermediate 12

1-[[3-Bromo-2-[2-[2-(triphenvimethy l )-2H-tetrazol-5-yl] phenyn-5-benzofuranyl]methyl]-5-butyl-1H-tetrazole

A mixture of Intermediate 11 (1.93g), 5-butyI-1H-tetrazole (360mg) and anhydrous potassium carbonate (395mg) in acetonitrile (25ml) was heated at reflux overnight, cooled and concentrated in vacuo. the residue was purified by chromatography, eluting with petroleum ether/ether (2: 1) followed by ether, to give the title compound as a yellow foam (611mg).T.l.c. petroleum ether/ether (1:1) Rf 0.11

Intermediate 13

5-[2-[5-(Azidomethyl)-3-brdmo-2-benzofuranyl ]phenyl]-2-(triphenylmethyl)-2H-tetrazole

A suspension of Intermediate 11 (4g) and sodium azide (712mg) in dry DMF (40ml) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate and the extracts were combined, backwashed with water and brine, dried and evaporated in vacuo to give the title compound as a white solid

(3-92g).

T.l.c.. petroleum ether/ether (3:1) Rf 0.41

Intermediate 14

5-[2-[3-Bromo-5-[(5-butyl-1H-1,2,3-triazol-1-yl)methyl]-2-benzofuranyl]phenyl]-2- (triphenylmethyl)-2H-tetrazole

A suspension of Intermediate 13 (500mg) in 1-hexyne (7ml) was heated at 80°C in a sealed tube for 3 days. This was combined with another reaction on the same scale, and the solvent evaporated in vacuo. The orange solid residue was purified by chromatography, eluting with petroleum/ether (1 :2) to give the title compound as a white foam (216mg).

T.l.c. ether, Rf 0.49.

Intermediate 15

5-[2-Bromo-5-[[5-butyl-3-(methoxymethyl)- 1 H-pyrazol- 1 -yl ]meth yl]-2-benzofuranyl]phenyl]-2-(triphenylmethyl)-2H-tetrazole

Sodium hydride (60% in oil; 214mg) was added to a stiired solution of 5-butyl-3- (methoxymethyl)-1H-pyrazole (500mg) in dry DMF and the mixture stirred for

30min. Intermediate 1 1 (2.01g) was added and the mixture stirred for 18h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine and concentrated to give a yellow solid. This solid was chromatographed eluting with System A (1:1) to give the 3-butyl-5-(methoxymethyl)-1H-pyrazol-1-yl isomer as the higher running component (240mg), followed by the title compound (190mg).

T.l.c. System A (1:1), Rf 0.3

Intermediate 16

(Methoxymethoxy)acetic acid hydrazide

A solution of methyl methoxymethoxy acetate (10.05g) and hydrazine hydrate (85%,

5.63ml) in ethanol (50ml) was heated at reflux for 7h. The reaction mixture was concentrated in vacuo and the residue purified by chromatography eluting with

System C (100:8:1) to give the title compound as a colourless oil (9.1g).

T.l.c. System C (100:8:1) Rf 0.35

Intermediate 17

2-(3-Bromo-5-methyl-2-benzofuranyI)benzonitrile

A solution of Intermediate 7 (5.0g) in dichloromethane (80ml) was cooled to -20ºC and treated dropwise with 1M bromine in carbon tetrachloride (32ml). The mixture was stirred at -20ºC for 1h before being warmed to room temperature. After 1h at room temperature the reaction mixture was filtered and evaporated. The residue was triturated with ether and the resultant solid collected to give the title compound as an orange solid (3.54g).

T.l.c. System A (1:9) Rf=0.40.

Intermediate 18

2-[3-Bromo-5-(bromomethyl)-2-benzofuranyl]benzonitrile

A suspension of Intermediate 17 (6.38g) in carbon tetrachloride (130ml) was heated at reflux for 10min. The resultant solution was cooled then NBS (3.81g) and dibenzoyl peroxide (130ml) were added and the mixture heated at reflux for 3h.

Further dibenzoyl peroxide (130ml) was added and stirring at reflux was continued for 16h. The reaction mixture was cooled and washed with water (3×30ml), dried and concentrated in vacuo to yield the title compound as a brown solid (10.83g). T.l.c. ether:petroleum ether (1:1) Rf 0.43

Intermediate 19

2- [3-Bromo-5-[( 1 ,3-dihydro- 1 ,3-dioxo-2H-isoindol-2-yl)methyl]-2-benzofuranyl]benzonitrile

Potassium phthalimide (6.34g) was added to a stirred solution of Intermediate 18 (10.30g) in dry DMF (120ml) at 20° C. The resultant suspension was stirred at 20 ° C for 18h, further potassium phthalimide (6.34g) was added and stirring was continued for 5h. The reaction mixture was partitioned between water (250ml) and ethyl acetate (3×50ml). The combined organic layers were dried and concentrated in vacuo to yield a brown oil (8.36g). Purification by chromatography eluting with ether:petroleum ether (2:1) yielded the title compound as a yellow solid (6.4g) T.l.c. ether:petroleum ether (3:1) Rf 0.62

Intermediate 20

2-[5-(Aminomethyl)-3-bromo-2-benzofuranyl]benzonitrile

Hydrazine hydrate (85%, 8.02ml) was added to a stirred suspension of Intermediate

19 (6.30g) in ethanol (300ml) at 20° . The suspension was stirred at reflux for 7h then concentrated in vacuo to yield a yellow solid. The residue was partitioned between sodium hydroxide (2N, 100ml) and ether (3×50ml). The combined extracts were dried and concentrated in vacuo to yield a yellow solid (5.02g). Purification by chromatography eluting with System C (200:8:1) yielded the title compound as a pale yellow solid (3.15g).

T.l.c. System C (100:8:1) Rf 0.27

Intermediate 21

2-[3-Bromo-5-[[3-butyl-5-[(methoxymethoxy)methyl]-4H-1,2,4-trizol-4-yl]methyl]- 2-benzofuranyl]benzonitrile A solution of Intermediate 16 (855mg), 1.8-dizazbicyclo[5.4.0]undec-7-ene (0.68ml) and trimethyl orthovalerate (1.10ml) in dry xylene (20ml) was heated at reflux for 3h. The reaction mixture was cooled, Intermediate 20 (1.27g) was added and stirring at reflux was continued for 3 days. The reaction mixture was cooled and purified directly by chromatography eluting with System C (150:8:1) to give the title compound as a brown gum (455mg).

Tic. System C (100:8: 1) Rf 0.59

Intermediate 22

2-[3-Bromo-5-[[3-butyl-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]methyl]-2- benzofuranyl]benzonitrile

Dilute hydrochloric acid (5N, 4ml) was added to a stirred solution of Intermediate 21 (450mg) in THF:water (1: 1.6ml). The resultant solution was stirred at 50° C for 6h, cooled and poured into sodium carbonate solution (2N, 30ml). The aqueous mixture was extracted with ethyl acetate (3×30ml) and the combined extracts were dried and concentrated in vacuo to yield a brown oil (41 1 mg). Purification by chromatography eluting with dichloromethane:methanol (10: 1) yielded the title compound as a pale yellow gum (309mg).

T.l.c. dichloromethane:methanol (10:1) Rf 0.47

Example 1

2-[3-Bromo-5-[[5-butyl-3-(methoxymethyl)-1H-pyrazol- 1 -yl]methyl]-2-benzofuranyl]benzoic acid

Sodium hydroxide solution (2N; 1ml) was added to a solution of Intermediate 5

(220mg) in methanol (5ml) and the mixture stirred at room temperature for 80h.

The methanol was evaporated off in vacuo and the residue was acidified with dilute hydrochloric acid solution. The resulting white precipitate was filtered off, washed with water and dried to give the title compound as a white powder (121mg) m.p 60- 65°C,

Assay Found: C,59.2; H,4.85; N,5.6.

C₂₅H₂₅BrN₂O₄0.5 H₂O requires C,59.3; H,5.1 : N,5.6% Example 2

2-[3-Bromo-5-[(5-butyl-1H-tetrazol-1-yl)methyl]-2-benzofuranyl]benzoic acid

A solution of Intermediate 6 (430mg) in sodium hydroxide solution (2N,4ml) and methanol (20ml) was stirred at room temperature for 4 days. The reaction mixture was diluted with water and acidified with dilute HCl to pH 4. The white solid was collected by filtration and dried to give the title compound (363mg) m.p. 82-84°C. T.l.c ether/acetic acid (100:1) Rf 0.58

Example 3

1-[[3-Bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl]-5-butyl-1H-tetrazole

A mixture of Intermediate 12 (400mg), camphor sulphonic acid (64mg) and methanol (20ml) was stirred overnight at room temperature. A further quantity of camphor sulphonic acid (64mg) was added and stirring continued for 18h. The solvent was evaporated in vacuo and the residue partitioned between water containing sodium hydroxide solution (2N) to pH 12 and ether. The aqueous layer was further extracted with ether, acidified with dilute HCl to pH 3 and extracted with ethyl acetate. The organic extracts were combined, dried and evaporated in vacuo to a cream-coloured foam (240mg). This was combined with a smaller scale reaction (on 50mg of Intermediate 12) which had been worked up similarly, and purified by preparative HPLC to give the title compound as a white solid (77mg) m.p. 102-104°C.

T.l.c ether/acetic acid (100:1) Rf 0.74

Example 4

5-[2-[3-Bromo-5-[(5-butyl-1H-1,2,3-triazol-1-yl)methyl]-2-benzofuranyl]phenyl]- 1H-tetrazole

Intermediate 14 (190mg) was added to methanol (10ml) and concentrated HCl

(0.1ml) and the mixture was stirred for 10 mins. Sodium hydroxide solution (2N) was added to pH 12 and most of the solvent was evaporated in vacuo. The residue was partitioned between water and ether. The aqueous layer was further extracted with ether, acidified with dilute HCl to pH 3 and then extracted with ethyl acetate.

The organic extracts were combined, backwashed with water and brine, and concentrated in vacuo to give the title compound as a white foam (128mg). m.p. 93- 95°C.

T.l.c. ether/acetate acid (100:1.) Rf 0.18

Example 5

5-[2-[3-Bromo-5-[[5-butyl-3-(methoxymethyl)-1H-pyrazol-1-yl]methyl]-2-benzofuranyl]phenyl]-1H-tetrazole

A suspension of Intermediate 15 (160mg) in methanol (15ml) was treated with concentrated HCl (0.15ml) and the mixture stirred for 16h. The pH of the reaction mixture was adjusted to 10 with dilute sodium hydroxide solution and then the methanol removed in vacuo. The aqueous phase was acidified to pH 1 with 2N HCl and then extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried and concentrated to give the title compound as a white foam (73mg).

T.l.c. System A (1:1), Rf 0.05

Found C57.4; H.4.8; N.15.8.

C₂₅H₂₅BrN₆O₂ requires C,57.6; H,4.8; N.16.1%

Example 6

Ethyl 1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl]-5-butyl- 1H-pyrazole-3-carboxylate

A solution of ethyl 3-butyl-1H-pyrazole-5-carboxylate (0.58g) in dry DMF (5ml) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in oil, 0.15g) in dry DMF (50ml) at 0-5°C under an atmosphere of nitrogen. After stirring for 10 minutes a solution of Intermediate 11 (2.77g) in dry DMF (40ml) was added dropwise at 0-5° C. The mixture was allowed to warm to room temperature and stirred for a further 4 hours. After standing overnight the mixture was partitioned between water (200ml) and ethyl acetate (4×50ml). The organic phases were combined, washed with brine (100ml), dried and the solvent removed in vacuo.

The residue was purified by column chromatography, eluting with dichloromethane:hexane (2: 1) then methanol. Further purification by column chromatography, eluting with, ether:petroleum ether:acetic acid (80:20:1) gave the title compound (0.45g).

T.l.c. (ether:petroleum ether:acetic acid, 80:20:1) Rf = 0.22

nmr (CDCl₃,250MHz) δ 0.9 (>3H,t), 1.2-1.48 (>5H, t+m), 1.6 (2H,m), 2.56 (2H,t),

4.27 (2H,q), 5.28 (2H,s) 6.63 (1H,s), 6.95 (1H,dd), 7.1-7.2(2H,2xd), 7.63 (2H,m),

7.81(1H,m), 8.01 (1H,m).

Example 7

1-[[3-Bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl]-5-butyl-1H-pyrazole-3-carboxylic acid

A mixture of the product of Example 6 (0.38g), potassium hydroxide (0.16g) and ethanol (5.5. ml) was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue diluted with water (10ml) and acidified to pH 4 (2N HCl). The aqueous phase was extracted with ethyl acetate (3×15ml) and the combined organic phases were dried and concentrated in vacuo to afford the title compound (0.28g). m.p. = 125-130ºC

T.l.C (2% acetic acid in ether) Rf = 0.05

Example 8

4-[[3-Bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl ]methyl]-5-butyl-1H-1,2,4-triazole-3-methanol

A suspension of Intermediate 22 (300mg) in tri-n-butyl tin azide (3.10g) was heated at 160° C for 45min. The reaction mixture was cooled, dilute sodium hydroxide solution (5N) was added to pH=12 and the suspension extracted with ether (3×20ml). The aqueous phase was acidified to pH=1 with 5N hydrochloric acid and extracted with ethyl acetate (3×30ml). The combined extracts were dried and concentrated in vacuo to yield yellow gum ( 189mg). Purification by chromatography eluting with dichloromethane:methanol (10: 1) yielded the title compound as a white solid (4mg). m.p. 96-99 °

T.l.c. dichloromethane:methanol (10:1) Rf 0.36

The compounds of the invention are tested in vitro for angiotensin II antagonism. Aortic strips are obtained from male New Zealand white rabbits and prepared for recording isometric contractions in response to cumulative addition of angiotensin II. The potencies of test antagonists are assessed by measuring their abilities to displace the angiotensin II cumulative concentration response curve. The method used is that of Ackerly et al., Proc. Natl. Acad. Sci., 74(12), pp5725-28 (1977) with the exception that the final composition of the physiological salt solution is as given below in Table 1:

TABLE 1

Ingredient Amount (mM)

Na + 143.4

K⁺ 5.9

Mg²⁺ 0.6

Ca²⁺ 1.3

Cl- 124.5

HPO₄- 1.2

SO₄ ^2- 0.6

HCO₃- 25.0 glucose 11.1 indomethacin 0.005 ascorbic acid 0.1 The tissues are initially challenged with K+ (80mM) and then washed at 0, 5, 10 and 15 minutes after the response to K+ has plateaued. After a further 45 minutes an angiotensin II cumulative response curve is constructed (0.1 nM to 0.1μM in 10-fold increments) and the tissues are washed as before. A second, third and fourth angiotensin II cumulative response curve (0.1 nM to 0.1μ M in 3-fold increments) is then constructed at hourly intervals (15 minutes washing after each curve followed by 45 minutes equilibration). The compounds of the invention (30μM) are tested for angiotensin II antagonism by application 45 minutes before construction of the fourth angiotensin II curve. The third and fourth angiotensin II curves are expressed graphically and a concentration ratio (CR) is calculated by dividing the angiotensin II EC₅₀ value obtained in the presence of the test antagonist (i.e. fourth curve) by the angiotensin II EC₅₀ value obtained in the absence of the test antagonist (i.e. third curve).

The potency of the test antagonist is expressed as a pKb which is calculated from the equation :

which is a rearrangement of equation 4 described by Furchgott, in Handbook of Exp. Pharmacol.. 33, p290 (1972) (eds. Blaschko and Muscholl).

Compounds of the invention will desirably exhibit a pKb in the range between 5 and 12. Thus we have found that the compounds of the invention inhibit the action of the hormone angiotensin II and are therefore useful in the treatment of conditions in which it is desirable to inhibit angiotensin II activity. In particular, the compounds of the Examples have been tested in the above test and have been found to be active.

There is thus provided as a further aspect of the present invention on a compound of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof for use in the treatment of conditions associated with excessive or unregulated angiotensin II activity.

In a further or alternative aspect of the present invention there is provided a compound of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof for the manufacture of a therapeutic agent for the treatment of conditions associated with excessive or unregulated angiotensin II activity.

There is also provided in a further or alternative aspect of the present invention a method for the treatment of conditions associated with excessive or unregulated angiotensin II activity in a mammal including man comprising administration of an effective amount to a mammal in need of such treatment a compound of general formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof.

The following examples illustrate pharmaceutical formulations according to the invention. The term "active ingredient" is used herein to represent a compound of formula (I).

Pharmaceutical Example 1

Oral Tablet A

Active Ingredient 700mg

Sodium starch glycollate 10mg

Microcrystalline cellulose 50mg

Magnesium stearate 4mg

Sieve the active ingredient and microcrystalline cellulose through a 40 mesh screen and blend in a appropriate blender. Sieve the sodium starch glycollate and magnesium stearate through a 60 mesh screen, add to the powder blend and blend until homogeneous. Compress with appropriate punches in an automatic tablet press. The tablets may be coated with a thin polymer coat applied by the film coating techniques well known to those skilled in the art. Pigments may be incorporated in the film coat.

Pharmaceutical Example 2

Oral Tablet B

Active Ingredient 500mg

Lactose 100mg

Maize Starch 50mg

Polyvinyl pyrrolidone 3mg

Sodium starch glycollate 10mg

Magnesium stearate 4mg

Tablet Weight 667mg

Sieve the active ingredient, lactose and maize starch through a 40 mesh screen and blend the powders in a suitable blender. Make an aqueous solution of the polyvinyl pyrrolidone (5 - 10% w/v). Add this solution to the blended powders and mix until granulated; pass the granulate through a 12 mesh screen and dry the granules in a suitable oven or fluid bed dryer. Sieve the remaining components through a 60 mesh screen and blend them with the dried granules. Compress, using appropriate punches, on an automatic tablet press.

The tablets may be coated with a thin polymer coat applied by film coating techniques well known to those skilled in art. Pigments may be incorporated in the film coat.

Pharmaceutical Example 3

Inhalation Cartridge

Active Ingredient 1mg

Lactose 24mg Blend active ingredient, particle size reduced to a very fine particle size (weight mean diameter ca. 5μ m) with the lactose in a suitable powder blender and fill the powder blender into No. 3 hard gelatin capsules.

The contents of the cartridges may be administered using a powder inhaler.

Pharmaceutical Example 4

Injection Formulation

% w/v

Active ingredient 1.00

Water for injections B.P. to 100.00

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the active ingredient using dilute acid or alkali or by the addition of suitable buffer salts. Antioxidants and metal chelating salts may also be included.

The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen.

Claims

1. A compound of the general formula (I)

or a physiologically acceptable salt, solvate or metabolically labile ester thereof wherein

Q represents an oxygen or sulphur atom;

R¹ represents a hydrogen atom or a halogen atom or a group selected from

C _1-6alkyl, C_2-6alkenyl, fluoroC_1-6alkyl, -CHO, -CO₂H, C _1-6alkoxy, or -COR²;

Ar represents the group

*->

R² represents a group selected from C_{1 -6}alkyl, C_2-6alkenyl, C_{1 -6} alkoxy or the group -NR¹²R¹³;

R³ represents a group selected from -CO₂H, -NHSO₉CF₃ or a C-linked tetrazolyl group;

R⁴ and R⁵, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a C_1-6alkyl group;

Het represents the group

X represents N or CH;

Y represents N or CR⁷;

Z represents N or CR⁷ ;

R⁶ represents a hydrogen atom or a C_1-6alkyl, C_2-6alkenyl or a C_{1 -6}alkylthio group;

R⁷ represents a halogen atom or a group selected from cyano, nitro, C_{1- 6}alkyl,

C_2-6alkenyl, fluoroC _{1 -6}alkyl, - (CH₂) _mR⁸ , - (CH₂)_n COR⁹ , or

-(CH₂)_pNR¹⁰COR¹¹;

R⁸ represents a hydroxy or C_{1- 6}alkoxy group;

R⁹ represents a hydrogen atom or a group selected from hydroxy, C_{1- 6}alkyl, C_{1- 6}alkoxy, phenyl, phenoxy or the group -NR¹²R ¹³;

R¹⁰ represents a hydrogen atom or a C_{1- 6}alkyl group;

R¹¹ represents a hydrogen atom or a group selected from C_{1- 6}alkyl, C_{1- 6}alkoxy, phenyl, phenoxy or the group -NR¹²R¹³;

R¹² and R^{1 3}, which may be the same or different, each independently represent a hydrogen atom or a C_1-4 alkyl group or -NR¹²R¹³ forms a saturated heterocyclic ring which has 5 or 6 ring members and may optionally contain in the ring one oxygen atom;

m represents an integer from 1 to 4;

n represents zero or an integer from 1 to 4; and

p represents an integer from 1 to 4;

with the proviso that at least one of X, Y and Z is a nitrogen atom, and with the further proviso that when X is N at least one of Y and Z is N and when Y is N at least one of X and Z is N.

2. A compound as claimed in Claim 1 wherein R⁶ represents a hydrogen atom or a C_1-5alkyl or C_3-5alkenyl group, preferably a C_2-4alkyl group, for example, an ethyl, n-propyl or n-butyl group.

3. A compound as claimed in Claim 1 or Claim 2 wherein R⁷ represents a halogen atom or a group selected from C_{1- 6}alkyl, -(CH₂)_mR or -(CH₂)_nCOR⁹, especially wherein R⁸ represents a hydroxy or methoxy group and R⁹ represents a hydrogen atom or a hydroxy, methoxy or ethoxy group, and m is 1 or 2 and n is zero, 1 or 2.

4. A compound as claimed in any one of Claims 1 to 3 wherein Het represents a group selected from:

5. A compound as claimed in Claim 4 wherein R⁷ represents a chlorine atom or a group selected from -CH₂OH, -CH₃, -CH₂OCH₃,-CO₂H, -CO₂CH₂CH₃, -CO₂CH₃, -CONH₂ or -CONHCH₃.

6. A compound as claimed in any one of Claims 1 to 5 wherein the group Het-CH₂- is attached at the 5-position on the benzofuran or benzthiophen ring.

7. A compound as claimed in any one of Claims 1 to 6 wherein R¹ is attached at the 3-position on the benzofuran or benzthiophen ring.

8. A compound as claimed in any one of Claims 1 to 7 wherein R¹ represents a hydrogen atom or a halogen atom, preferably a bromine atom.

9. A compound a claimed in any one of Claims 1 to 8 wherein R³ represents a group selected from a -CO₂H group or, preferably, a C-linked tetrazolyl group.

10. A compound as claimed in any one of Claims 1 to 9 wherein R⁴ and R⁵ each independently represents a hydrogen atom.

11. A compound as claimed in any one of Claims 1 to 10 wherein Q is an oxygen atom.

12. A compound as claimed in Claim 1 or a physiologically acceptable salt, solvate or metabolically labile ester thereof

wherein

Q represents an oxygen atom;

R represents a bromine atom;

Ar represents the group

R³ represents the group -CO₂H or a C-linked tetrazolyl group;

R⁴ and R⁵ each independently represent a hydrogen atom;

Het represents the group

X represents N or CH;

Y represents N or CR⁷;

Z represents N or CR⁷;

R⁶ represents a C^alkyl group;

R⁷ represents a group selected from -(CH₂)_mR⁸ or -(CH₂)_nCOR⁹;

R⁸ represents a hydroxy or C_{1- 6}alkoxy group;

R⁷ represents a hydroxy group;

m represents an integer from 1 to 4; and

n represents zero or an integer from 1 to 4; with the proviso that at least one of X, Y and Z is a nitrogen atom, and with the further proviso that when X is N at least one of Y and Z is N and when Y is N at least one of X and Z is N.

13. A process for the preparation of a compound as claimed in any one of Claims 1 to 12 or a physiologically acceptable salt, solvate or metabolically labile ester thereof which comprises:

(Al) (where X, Y and Z each represent N; or where X represents CH, Y represents CR⁷ and Z represents N; or where X and Z represent N and Y represents CR⁷) treating a compound of general formula (II)

(wherein L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy, or p-toluenesulphonyloxy and R ¹, Ar and Q are as defined in general formula (I)) with a heterocycle of formula (III)

(wherein R⁶ represents a group selected from C_{1 -6}alkyl, C_2-5alkenyl or C_{1- 6}alkylthio and X, Y and Z are as defined for this process) followed by the removal of any protecting groups where present: or

(A2) (where X and Y represent N and Z represents CR⁷) treating a compound of general formula (IV)

(wnerein R¹, Ar and Q are as defined in general formula (I)) with a oxadiazoie of formula (V)

(wherein R⁶ and R⁷ are as defined in general formula (I)) followed by the removal of any protecting groups where present: or

(A3) (where X represents CH and Y and Z each represent N) treating a compound of general formula (VI)

(wherein R¹, Ar and Q are as defined in general formula (I)) with a compound of formula (VII)

R⁶COCH (VII)

(wherein R⁶ is as defined in general formula (I)) followed by the removal of any protecting groups where present: or

(B) deprotecting a protected intermediate of general formula (VIII)

(wherein Q, R¹, Ar and Het are as defined in general formula (I) except that at least one reactive group is blocked by a protecting group); or

(C) reacting a compound of general formula (Ia)

(wherein Q, R¹, Ar and Het are as defined in general formula (I) except that in the group Ar, R³ represents a nitrile group) with a suitable azide followed, if necessary, by the removal of any protecting groups where present; or

(D) reacting a compound of general formula (Ib)

(wherein R ¹, Ar and Het are as defined in general formula (I) except that in the group Ar, R³ represents an amino group) with trifluoromethanesulphonic anhydride, followed by the removal of any protecting groups, where present;

and when the compound of general formula (I) is obtained as a mixture of enantiomers optionally resolving the mixture to obtain the desired enantiomer, and/or, if desired, converting the resulting compound of general formula (I) or a salt thereof into a physiologically acceptable salt, solvate or metabolically labile ester thereof.

14. A pharmaceutical composition comprising at least one compound of general formula (I) as defined in any one of Claims 1 to 12 or a physiologically acceptable salt, solvate or metabolically labile ester thereof, together with at least one physiologically acceptable carrier or excipient.

15. A compound of general formula (I) as claimed in any one of Claims 1 to 12 or a physiologically acceptable salt, solvate or metabolically labile ester thereof for use in therapy, for example,

(i) for use in the treatment or prophylaxis of hypertension; or

(ii) for use in the treatment or prophylaxis of a disease associated with cognitive disorders, renal failure, hyperaldosteronism, cardiac insufficiency, congestive heart failure, post-myocardial infarction, cerebrovascular disorders, glaucoma and disorders of intracellular homeostasis; or (iii) for use in the treatment of conditions associated with excessive or unregulated angiotensin II activity.

16. A compound of general formula (IV)

or a salt thereof.

wherein

R¹, Ar and Q are as defined in Claim 1.

17. A compound of general formula (VI)

or a salt thereof

wherein

R¹, Ar and Q are as defined in Claim 1.

18. A compound of general formula (Ia)

or a salt thereof

wherein

R¹, Ar, Q and Het are as defined in Claim 1 except that in the group Ar, R³ represents a nitrile group.

19. A compound of general formula (Ib)

or a salt thereof

wherein

R¹, Ar, Q and Het are as defined in Claim 1 except that in the group Ar, R³ represents an amino group.