GB2276164A

GB2276164A - Aniline and benzanilide derivatives

Info

Publication number: GB2276164A
Application number: GB9305510A
Authority: GB
Inventors: David Ian Carter Scopes; John Watson Clitherow; William Leonard Mitchell; Malcolm Carter
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1993-03-17
Filing date: 1993-03-17
Publication date: 1994-09-21
Also published as: GB9305510D0

Abstract

Compounds of the general formula (I): <IMAGE> or a physiologically acceptable salt or solvate thereof, in which R<1> represents a hydrogen or halogen atom or a C1-6alkyl or C1-6alkoxy group; R<2> represents an optionally substituted aromatic heterocyclic group R<3> represents a group selected from <IMAGE> R<4> and R<5>, each independently represent a hydrogen or halogen atom, or a hydroxy, C1-6alkoxy or C1-6alkyl group; R<13>, R<14> and R<15>, each independently represent a hydrogen atom or a C1-6alkyl group; X represents -CONH-, -NHCO-, -CH2NH- or -NHCH2-; n represents an integer from 2 to 4; p represents an integer from 1 to 3; and q represents an integer from 1 to 3; with the proviso that R<2> does not represent a pyridinyl group; are 5-HT1D antagonists useful in the treatment of CNS disorders, endocrine disorders and sexual dysfunction.

Description

CHEMICAL COMPOUNDS This invention relates to novel aniline and benzanilide derivatives, to processes for their preparation, and to pharmaceutical compositions containing them.

According to the present invention there is provided compounds of the general formula (I) :

or a physiologically acceptable salt or solvate thereof, in which R' represents a hydrogen atom or a halogen atom or a C1-6alkyl or C1-6alkoxy group; R2 represents an aromatic heterocyclic group which contains one, two or three heteroatoms selected from nitrogen, oxygen and sulphur, or a group -NH- or -NR9-, said heteroaryl group being optionally substituted by a substituent selected from Cí 6alkyl, hydroxyC1-6alkyl, C1-4alkylC1-6alkoxy, -COR6 or - NR7R8; R3 represents a group selected from (a) ~(%?n NR R14

R4 and R5, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a hydroxy, Cl4alkoxy or C ,alkyl group;; R6 represents a hydrogen atom or a hydroxy or C, 6alkyl group; R7, R8 and R9 , which may be the same or different, each independently represent a hydrogen atom or a Cm 6alkyl group; R13, R14 and Rl5, which may be the same or different, each independently represent a hydrogen atom or a C, 6alkyl group; X represents -CONH-, -NHCO-, -CH2NH- or -NHCEt-; n represents an integer from 2 to 4; p represents an integer from 1 to 3; and q represents an integer from 1 to 3; with the proviso that R2 does not represent a pyridinyl group.

It is to be understood that the present invention encompasses all geometric and optical isomers of the compounds of general formula (I) and their mixtures including the racemic mixtures thereof.

Physiologically acceptable salts-ofthe compounds of formula (I) include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, 12- toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballylates) and, where appropriate, inorganic base salts such as alkali metal salts (for example sodium salts).

In the compounds of formula (I), the term "C,,alkyl" or "C1 6alkoxy" as a group or part of a group means that the group is straight or branched and consists of 1 to 6 carbon atoms. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. The term "halogen" means fluorine, chlorine, bromine or iodine.

Suitable groups wherein R2 is a 5-membered aromatic heterocyclic group include a pyrrolyl, turanyl, thienyl, imidazolyl, thiazolyl, triazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl or 1,2,5-oxadiazol-3-yl group.

Suitable groups wherein R2 is 6-membered aromatic heterocyclic group include a pyrimidinyl, pyrazinyl or triazinyl group.

A preferred group of compounds of general formula (I) is that wherein R2 represents a group selected from a furanyl, 1,2,4-oxadiazol-3-yl, thiazolyl, pyrimidinyl or imidazolyl group.

Where R2 represents a furanyl group, the turban ring is preferably attached in the 2-position and is substituted by a hydroxyC,4alkyl, especially hydroxymethyl, group or the group -COR6, where R6 is a hydrogen atom or a Cl4alkyl, especially methyl, group.

Where R2 represents an oxadiazolyl group, the oxadiazole ring is preferably substituted by a Cl4alkyl, especially methyl, group.

The group R2 may preferably be attached in the meta or more particularly the para position of the phenyl ring A relative to the group X.

Also preferred is the group of compounds of general formula (I) wherein Rl is a hydrogen atom or a Cl4alkyl, especially methyl, group.

Another preferred group of compounds of general formula (I) is that wherein R' is attached at a position ortho to the group R2 in general formula (I).

A further preferred group of compounds of general formula (I) is that wherein R3 represents -(CH2)3N(CH3)2, -(CH2)3NHCH3,

Another preferred group of compounds of general formula (I) is that wherein R4 is attached in the para-position relative to the group X.

A further preferred group of compounds of general formula (I) is that wherein R4 is a halogen atom, especially a fluorine or chlorine atom, or a hydroxy or Cl4alkoxy, especially methoxy, group.

Also preferred is the group of compounds of general formula (I) wherein R5 is a hydrogen atom or a fluorine atom.

A yet further preferred group of compounds of general formula (I) is that wherein Rl3, Rl4 and R'5 each represent a C,4alkyl, especially methyl, group.

Also preferred is the group of compounds of general formula (I) wherein X is -NHCO- or -CONH-.

Another preferred group of compounds of general formula (I) is that wherein n is 3.

A further preferred group of compounds of general formula (I) is that wherein p is 2.

Preferred compounds of general formula (I) include: 3 - [3 - -[3 amino)propyl]-4-methoxy-N-[4-[5(hydroxymethyl)-2-furanyl]phenyl] benzamide; and its physiologically acceptable salts and solvates.

Particularly preferred compounds of general formula (I) include: 3-[3-(dimethylamino)propyl]-4-methoxy-N-[4-(4-formyl-2-furanyl)phenyl]benzamide; 3-[3 (dimethylamino)propyl]A-methoxy-N-[4-[4-(hydroxymethyl)-2-furanyl]phenyl] benzamide; N-[4-methoxy-3 -(4-methyl-l -piperazinyl)phenyl]-4-(5 -methyl-l ,2,4-oxadiazol-3 -yl) benzamide; N-[4-methoxy-3-(4-methyl- 1 -piperazinyl)phenyl]-4-(5-acetyl-2-furanyl)benzamide; and their physiologically acceptable salts and solvates.

5-Hydroxytryptamine (serotonin) is a neurotransmitter which is widely distributed within the central nervous system (CNS), platelets and the gastrointestinal tract. Changes in transmission in serotonergic pathways in the CNS are known to modify, for example, mood, psychomotor activity, appetite, memory and blood pressure. Release of 5-hydroxytryptamine from platelets can mediate vasospasm while changes in free 5-hydroxytryptamine levels in the gastrointestinal tract can modify secretion and motility.

Abundant pharmacological studies have led to the discovery of multiple types of receptors for 5-hydroxytryptamine, thus providing a molecular basis to the diversity of its actions. These receptors are classed as 5-HT1, 5-HT2 and 5-HT3, with 5-HTl receptors being sub-classified as 5-HTlA, 5-HTlB, 5-HTaCv 5-HTlD and 5-HTlD(like) receptors. The identification of these classes and sub-classes of receptor is based mainly on radioligand binding studies.

Compounds having a selective antagonist action at 5-HT,D receptors such as those described herein may exhibit a beneficial effect on subjects suffering from CNS disorders.

In the present specification, a 5-HTaD antagonist is a non-naturally occurring (synthetic) compound that specifically and selectively antagonises 5-HT,D receptors, i.e.

blocks the specific actions of 5-hydroxytryptamine mediated by S-HT,D receptors. Such compounds may be identified by a high level of affinity (pKi > 8) in the in vitro human cortex and guinea-pig striatum radioligand binding assays described by Hoyer et al, Neuroscience Letters, 1988, 85. p357-362. Activity at 5HTi, receptors may be confirmed in wvo using the guinea pig rotation model described by G A Higgins et al, Br.

J. Pharmacol., 1991, 102, p305-310.

The affinity of a compound for 5-HT,A, 5-HT and/or 5-HT2 receptors is measured using the in vitro tests described in the following publications: S-HT,A Gozlan et al, Nature, 1983 305. p140-142 5-HTlc Pazos et al, Eur. J.Pharmacol., 1984, 106, p53 1-538 5-HT2 Humphrey et al, Br. J. Pharmacol, 1988, 94, pl 123-1132 (rabbit aorta model).

Thus, for example, compounds of the present invention have been shown to inhibit 5-hydroxytryptamine induced contraction of the dog isolated saphenous vein and to antagonise the 5-hydroxytryptamine induced inhibition of neurotransmission in central and peripheral neurones.

5-HT,D antagonists, and in particular the compounds of the present invention, may therefore be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviour, including anorexia nervosa and bulimia nervosa. Other CNS disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.

.5HTID antagonists, and in particular compounds of the -present invention, may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction.

Therefore, according to a second aspect of the invention, we provide a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy.

According to a further aspect of the present invention, we therefore provide a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment ofthe aforementioned disorders.

According to another aspect of the invention, we provide the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a therapeutic agent for the treatment of the aforementioned disorders.

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

In particular, according to another aspect of the present invention, we provide a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.

It will be appreciated that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g.

amitriptyline, dothiepin, doxepin, trimipramine, butriptyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g. isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT reuptake inhibitors (e.g. fluvoxamine, sertraline, fluoxetine or paroxetine), and/or antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g. levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g. benserazide or carbidopa), or a dopamine agonist (e.g. bromocriptine, lysuride or pergolide). It is to be understood that the present invention covers the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic agents.

Thus there is provided in a further or alternative aspect of the present invention a compound of general formula (I) or a physiologically acceptable salt or solvate thereof and an antidepressant agent in the presence of each other in the human or non-human animal body for use in the treatment of the aforementioned disorders.

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 general formula (I) and their physiologically acceptable salts and solvates may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof. Such compositions may be presented for use in a 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 compositions 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, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch 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, methylcellulose, glucose/sugar syrup, gelatin, hydroxypropyl methylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The compositions 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.

The composition according to the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection 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 either orally or nasally the compositions according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. 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 the compositions 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.

The compositions according to the invention may be prepared by mixing the various ingredients using conventional means.

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, a proposed dose of the compounds of the invention for administration in man is 0.5 to 1000mg, preferably I to 200mg ofthe active ingredient per unit dose which could be administered, for example, l to 4 times per day.

The compounds of the invention may be prepared by a number of processes as described in the following. In describing the processes which may be used for preparing the compounds of general formula (I) or intermediates useful in the preparation thereof, any of R'-R'5, n, p and q in the various formulae are as defined in general formula (I) unless otherwise stated.

It will be appreciated that in the following methods for the preparation of compounds of general formula (I), for certain reaction steps it may be necessary to protect various reactive substituents in the starting materials for a particular reaction and subsequently to remove the protecting group. Such protection and subsequent deprotection may be particularly pertinent where R7 Rg, Rl3, Rl4 and/or R15 in intermediates used to prepare compounds of general formula (I) are hydrogen atoms. Standard protection and deprotection procedures can be employed, for example formation of a phthalimide (in the case of a primary amine), benzyl, trityl, benzyloxycarbonyl or trichloroethoxycarbonyl derivatives. Subsequent removal of the protecting group is achieved by conventional procedures.Thus a phthalimide group may be removed by treatment with hydrazine or a primary amine, for example methylamine. Benzyl or benzyloxycarbonyl groups may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium, and trichloroethoxycarbonyl derivatives may be removed by treatment with zinc dust. Trityl groups may be removed under acidic conditions using standard procedures.

It may also be necessary in some cases to protect carboxylic acid groups (e.g. as esters) or aldehyde or ketone groups (e.g. as acyclic or cyclic acetals or ketals or as thioacetals or thioketals). Subsequent removal of these protecting groups is achieved by conventional procedures. Thus for example alkyl esters may be removed under conditions of acidic or basic hydrolysis, benzyl esters may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium. Acyclic or cyclic acetals or ketals may be removed under conditions of acidic hydrolysis and thioacetals and thioketals may be removed using a mercuric salt.

Hydroxyl groups may also need protection and these may be adequately protected under amenable conditions as their esters or trialkylsilyl, tetrahydropyran and benzyl ethers. Such derivatives may be deprotected by standard procedures.

According to one general process (1A), the compounds of general formula (I) in which X represents the group -CONH-, may be prepared by a carbonylation reaction involving an aniline (II)

(where R3, R4 and R5, are as defined in general formula (I)) and a halophenyl compound (III)

(where Rl and R2 are as defined in general formula (I) and Y is a bromine or iodine atom or the group -OSO2CF3).

Alternatively, according to the general process (1B), the compounds of general formula (I), in which X represents the group -NHCO-, may be prepared by a carbonylation reaction involving a halophenyl compound (IV)

(where R3, R4, and R5 are as defined in general formula (I) and Y represents a bromine or iodine atom or the group -OSO2CF3) and an aniline of formula (V)

(where R1 and R2 are as defined in general formula (I)).

Both reactions take place, for example, in the presence of carbon monoxide using a palladium salt as a catalyst. The reaction is effected in the presence of a suitable base e.g.

a trialkylamine such as triethylamine or tri-n-butylamine and may be conducted in a suitable solvent such as an amide e.g. dimethylformamide or a nitrile e.g. acetonitrile at a temperature within the range of-100C to +1500C.

Suitable palladium salts for the reaction include triarylphosphine palladium (11) salts such as bis(triphenylphosphine)palladium (11) chloride.

According to another general process (2A), the compounds of general formula (I), in which X represents the group -CONFI-, may be prepared by reacting an aniline of formula (II) with an activated carboxylic acid derivative of formula (VI)

(where Z is a leaving group).

Alternatively, according to the general process (2B), the compounds of general formula (I), in which X represents the group -NHCO-, may be prepared by reacting an aniline of formula (V) with an activated carboxylic acid derivative of formula (VII)

(where Z is a leaving group).

Suitable activated carboxylic acid derivatives represented in formulae (VI) and (VII) include acyl halides (e.g. acid chlorides) and acid anhydrides including mixed anhydrides.

These activated derivatives may be formed from the corresponding acids of formulae (VIII) or (IX)

respectively, by well known procedures. For example, acid chlorides may be prepared by reaction with phosphorus pentachloride, thionyl chloride or oxalyl chloride and acid anhydrides may be prepared by reaction with an appropriate acid anhydride (e.g.

trifluoroacetic anhydride), an acid chloride (e.g. acetyl chloride), an alkyl or aralkyl haloformate (e.g. ethyl or benzyl chloroformate) or methanesulphonyl chloride.

Activated carboxylic acid derivatives of formulae (VI) and (VII) may also be prepared in situ by the reaction of the corresponding acids of formulae (VIII) and (IX), respectively, with a coupling reagent such as 1,1 '-carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide.

The conditions under which the activated carboxylic acid derivatives of formulae (VI) and (VII) are formed and subsequently reacted with the anilines of formulae (II) and (V), respectively, will depend upon the nature of the activated derivative. However, in general the reaction between the compounds (II) and (VI), or (V) and (VII), may be carried out in a non-aqueous medium such as, for example, dimethylformamide, tetrahydrofuran, acetonitrile or a halohydrocarbon such as dichloromethane at a temperature within the range -250C to +1200C. The reaction may optionally be carried out in the presence of a base such as triethylamine or pyridine and the base may also be used as the solvent for reaction.

Where acid chlorides are used, the reaction may be carried out using the Schotten-Baumann technique in the presence of a suitable base, for example, aqueous sodium hydroxide, conveniently at a temperature between 0 C and 100"C, for example, room temperature.

According to another general process (3), the compounds of general formula (I) in which R3 represents the group (a), may be prepared by reducing a compound of formula (x)

(where W represents a group convertible to the group -(CH2)nNRl3Rl4 under reducing conditions).

Examples of the type of group W which may be converted into the group -(CH2)nNR13R14 are: -(CE9I, lCN, -(CH2)n lCHO, and when n is 3, -C=CCN, -CH=CHCN, -CH=CHCHO, -CH=CHCH2NRI3Rl4 or -C~CCH2NRI3Rl4. When W contains an aldehyde as defined above, the conversion is carried out in the presence of an appropriate amine of formula NHRI3Rl4. When W contains a nitrile as defined above, the conversion may be carried out in the presence of an amine of formula NHR'3R'4, with the proviso that Rl3 and Rl4 do not both represent a hydrogen atom, in order to obtain a secondary or tertiary amine of general formula (I).

The reaction may be effected using an alkali or alkaline earth metal borohydride, e.g.

sodium borohydride, or hydrogen and a metal catalyst such as palladium or platinum or oxides thereof. The reaction may be carried out at a temperature between 0 C and 100 C, conveniently at room temperature, and preferably in a solvent.

Suitable solvents for chemical reduction include ethers e.g. tetrahydrofuran, or alcohols e.g. ethanol. Suitable solvents for catalytic reduction include alcohols e.g.

ethanol, ethers e.g. dioxan, amides e.g. dimethylformamide or a mixture of solvents e.g.

ethanoUdimethylformamide.

According to another general process (4), the compounds of general formula (I) in which R3 represents the group (c), may be prepared by treating a compound of formula (xI)

with an amine dihalide of formula (Xfl) R'5N(CH2CH2Hal)2 (XII) (where Hal is a chlorine, bromine or iodine atom).

The reaction may conveniently take place in the presence of a polar solvent such as an alcohol (e.g. n-butanol) or a nitrile (e.g. acetonitrile), optionally in the presence of a base, for example, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or alternatively in a non-polar solvent (e.g. chlorobenzene) in the absence of a base. The reactions may conveniently be carried out at an elevated temperature, for example, reflux.

According to another general process (5), the compounds of general formula (I) in which X represents either of the groups -NHCH2- or -CH2NH- may be prepared by reduction of the corresponding compounds of general formula (I) in which X represents the groups -NHCO- or -CONH-, respectively, except that the reaction cannot be used to prepare compounds in which R2 represents another group reducible under the reaction conditions, for example, CONR9R10 , SO2NRl'R'2, CO2H, or (CH2)kCOR7.

The reduction may be effected using a suitable metal hydride such as lithium aluminium hydride in a solvent e.g. an ether (such as tetrahydrofuran) at a temperature in the range of-10 C to +100 C.

According to another general process (6A), the compounds of general formula (I) in which X represents the group -NHCH may be prepared by reacting an aniline of formula (V) with an aldehyde of formula (XIII)

under reducing conditions.

Alternatively, according to general process (6B), the compounds of general formula (I) in which X represents the group -CH2NH- may be prepared by reacting an aniline of formula (11) with an aldehyde of formula (XrV)

under reducing conditions.

Both reactions may conveniently take place in the presence of a solvent such as an alcohol e.g. methanol or ethanol using for example a hydride reducing agent such as an alkali or alkaline earth metal borohydride (e.g. sodium borohydride or sodium cyanoborohydride). The reactions may be carried out at a temperature in the range from 0 to 600C, conveniently at room temperature.

According to another general process (7A), the compounds of general formula (I) may be prepared by treating a compound of formula (XXXVa)

(where Y represents a bromine or iodine atom or the group -OSO2CF3) with a compound of formula (XXXVIa) R2B(OH)2 (XXXVIa) or an ester, an anhydride or a salt (e.g. lithium) thereof.

Alternatively, according to thegeneral process (6B), the compounds of general formula (I) may be prepared by treating a compound of formula (XEVb)

or an ester, an anhydride or a salt (e.g. lithium) thereof, with a compound of formula (XXXVIb) R2-Y (XXXVIb) where Y represents a bromine or iodine atom or the group -OSO2CF3.

Both reactions may be effected in the presence of a transition metal catalyst such as (Ph3P)4Pd (where Ph represents phenyl) in a suitable solvent such as an ether (e.g.

1,2-dimethoxyethane or tetrahydrofuran) in the presence or absence of water, or an aromatic hydrocarbon (e.g. benzene). The reaction is preferably carried out in the presence of a base such as an alkali or alkaline earth metal carbonate (e.g. sodium carbonate) at a suitable temperature up to reflux.

Compounds of general formula (I) in which R2, R4 and R5 have a particular meaning may be converted into another compound of the invention by standard methods of interconversion.

For instance, when R2 contains a hydroxy or alkoxy group and/or when R4 and/or R5 represents hydroxy or alkoxy these groups may be interchanged by standard methods of O-alkylation or O-dealkylation. Thus, for example, a compound in which R4 represents hydroxy may be prepared by treating a corresponding compound in which R4 represents methoxy with a reagent system capable of removing the methyl group e.g. a mercaptide such as sodium ethylmercaptide in a solvent such as dimethyiformamide, lithium iodide in collidine, boron tribromide in a halohydrocarbon solvent e.g. methylene chloride or molten pyridine hydrochloride.

When R2 contains a hydroxymethyl group this may be converted by oxidation into a corresponding compound of general formula (I) in which R2 contains a group CHO or CO2H. Thus, for example, oxidation may be effected using a suitable oxidising agent such as a manganese oxidising agent (e.g. manganese dioxide) in a solvent such as an ether (e.g. 1,4-dioxan) at a suitable temperature up to reflux, a chromium oxidising agent (e.g.

Jones reagent) or pyridinium dichromate in a suitable solvent such as a halohydrocarbon (e.g. methylene chloride).

When R2 contains an aldehyde group this may be converted by oxidation into a corresponding compound of general formula (I) in which R2 contains a group CO2H.

Thus, for example, oxidation may be effected using a suitable oxidising agent such as a source of silver (I) (e.g. silver nitrate) in aqueous alkali optionally in the presence of a cosolvent such as an alcohol (e.g. methanol).

Intermediates of formula (II), in which R3 represents the group -(CH.)nNR'3Ri4, may be prepared by reduction of a compound of formula (XV)

(where W is as defined in formula (X)) under the reducing conditions described for process (3).

Compounds of formula (XV) may be prepared by reduction of the corresponding nitro compounds of formula (XVI)

Suitable reducing conditions include, for example, catalytic hydrogenation using a metal catalyst such as palladium oxide on a support such as charcoal, optionally in a solvent such as an alcohol (e.g. ethanol) or an ether (e.g. tetrahydrofuran). Under such conditions, the group W may also be reduced and hence the intermediates of formula (II) may be prepared directly from the compounds of formula (XVI) without prior isolation of the compounds of formula (XV).

The nitro compounds of formula (XVI) may be prepared from the corresponding halo compounds of formula (XVII)

(where Hal is bromine or iodine) using standard methodology.

Intermediates of formula (II) in which R3 represents the group (c) may be prepared from the corresponding compound of formula (XVIII)

by reaction with a compound of formula (XIX)

in the presence of acetic anhydride, followed by reduction of the diketopiperazine intermediate thus formed using, for example, borane. The reaction may be carried out at a temperature between 50"C and reflux, and optionally in a solvent such as an ether, e.g.

tetrahydrofuran. The nitro group may be subsequently converted into an amine using standard methodology.

Intermediates of formula (XI) may be prepared by reduction of the corresponding nitro compound of general formula (XE)

The reduction may be effected by catalytic hydrogenation using a metal catalyst such as palladium or platinum or oxides thereof; preferably, in a solvent such as an alcohol e.g.

ethanol, or alternatively by using Raney nickel and hydrazine in a solvent such as an alcohol e.g. ethanol.

Intermediates of of formula (XXL) in which X is, for example, -CONH-, may be prepared by condensing a compound of formula (V') or (VII) (in which R3 represents a nitro group) with a compound of formula (XVIII) or (V), respectively, under the conditions of general process (2A).

Intermediates of formula (IV) in which R3 is the group (a), may be prepared by the following reaction sequence:

Step (a) is carried out using suitable halogenating conditions, for example, when Hal represents iodine the iodine atom may be introduced using iodine monochloride in a solvent such as methylene chloride; step (b) is carried out under standard brominating conditions such as using phosphorous tribromide in a halohydrocarbon solvent or using carbon tetrabromide in the presence of triphenylphosphine; and step (c) is carried out using an amine Rl3R'4NH in a suitable solvent such as ethanol, preferably in the presence of a base; with the proviso that either R4 or R5 is a directing group (i.e. fluorine, chlorine, hydroxy, Cl4alkoxy or Cl4alkyl) in a position either ortho or para to the group -(CH2)nOH.

Intermediates of formula (X), in which Xis -CONH-, may be prepared by reaction of a compound of formula (XV) with a compound of either formula (III) or (VI) according to the method of general process (1) or (2), respectively.

Alternatively, intermediates of formula (X), in which W is -CH=CHCHO, -CH=CHCN, -CH=CHCH2NRl3Rl4 or -C=CCH2NRl3Rl4, may be prepared from a compound of formula (XXII)

(wherein Hal is the only bromine or iodine atom in the molecule) by reaction with an alkene: H2C=CHCHO, H2C=CHCH2NRl3R'4 or H2C=CHCN; or an alkyne: HC=CCH,NR13R14.

The reaction may be effected in the presence of a palladium reagent and preferably in the presence of a base. The palladium reagent may be, for example, a palladium salt derived from an organic acid (e.g. an acetate) or derived from an inorganic acid (e.g. a chloride or bromide), a palladium complex such as a triarylphosphine palladium complex (e.g. triphenylphosphine or tri(2-methylphenyl)phosphine palladium complex), or a finely divided palladium metal such as palladium on charcoal. The triarylphosphine palladium complex may be generated in situ by reacting a palladium salt (e.g. palladium acetate) with the appropriate triarylphosphine.

Suitable bases include tertiary amines (e.g. triethylamine or tri-n-butylamine) or alkali metal (e.g. sodium or potassium) carbonates, bicarbonates and acetates.

The reaction may be effected in the presence or absence of a solvent. Suitable solvents include nitriles (e.g. acetonitrile), amides (e.g. dimethylformamide, N-methylpyrrolidinone) and water. The reaction may conveniently be carried out at a temperature between room temperature and 200"C, preferably between 50"C and 1600C.

Compounds of formula (XXII) may be prepared by the reaction of a compound of formula (V) or (VI) with a compound of formula (XXIII) or (XXIV), respectively,

according to the method of general process (2).

Alternatively, intermediates of formula (X) in which W is -(CH2)n 1CN or -(CH2)D ,CHO may be prepared by the reaction of a compound of formula (III) or (V) with a compound of formula (XXV) or (XXVI), respectively,

(wherein W' represents -(CH2)n,CN or -(CH2)nlCHO), according to the method of general process (1).

Intermediates of formulae (XXV) and (XXVI) in which Wl contains a nitrile group may be prepared from the corresponding halo (e.g. bromo) compound using standard methodology.

Intermediates of formula (IX) wherein R3 represents the group (b) and in which q is 1 may be prepared by reducing a compound of formula (XXVII)

Similarly, intermediates of formula (IX) wherein R3 represents the group (b) and in which q is 2, may be prepared by reducing a salt of formula (XXVIII)

(wherein Hal is a halide ion e.g. an iodide ion).

These reductions may be effected under standard conditions of hydrogenation e.g.

using hydrogen in the presence of a catalyst such as palladium or platinum or oxides thereof. The reaction may be carried out at any suitable temperature, for example, from Oo to 1000C, conveniently at room temperature, and preferably in a solvent. Suitable solvents include alcohols (e.g. ethanol), ethers (e.g. dioxan or dimethoxyethane), amides (e.g. dimethylformamide) or esters (e.g ethyl acetate) or a mixture of solvents (e.g.

ethanoUdimethylformamide) .

The compounds of formulae (XXVII) and (XXVIII) may be prepared from compounds of formula (XXIX)

(where R'7 represents

respectively Thus, compounds of formula (XXVII) may be prepared from compounds of formula (XXIX) where R17 represents

by treating the compound of formula (XXIX) with, for example, an alkali metal amide such as potassium amide or sodium amide in liquid ammonia, an alkali metal hydride such as sodium hydride or potassium hydride in a suitable solvent such as an ether (e.g.

tetrahydrofuran) or an amide (e.g. dimethylformamide) or with n-butyllithium in hexane, followed by an alkylation step using a halide Rl5 Hal (where Hal is a halogen atom e.g.

chlorine, bromine or iodine) in a suitable solvent such as an ether (e.g. dimethoxyethane) or an amide (e.g. dimethylformamide).

Compounds of formula (XXVIII) may be prepared from compounds of formula (XXIX) where R'7 is

by reaction with a halide R15 Hal (where Hal is chlorine, bromine or iodine), in a suitable solvent such as a ketone (e.g. acetone), a nitrile (e.g. acetonitrile) or an alcohol (e.g.

ethanol).

Intermediates of formula (XXIX) in which p is 2 may be prepared by reducing a compound of formula (XXX)

(where R17 is as defined in formula (Xw above).

Additionally, intermediates of formula (In wherein R3 represents the group (b)and where p is 2 and q is 3 may be prepared by reducing a compound of formula (XXX) where R'7 represents

The reduction of compounds of formula (XXX) may be effected using hydrogen and a metal catalyst such as palladium or platinum or oxides thereof in a suitable solvent.

Compounds of formula (XXX) may be prepared from a compound of formula (XXXI)

(where Hal is bromine or iodine) by reaction with an appropriate alkene of formula CH2=CH-R'7 (where Rl7 represents

The reaction may be effected in the presence of a palladium reagent such as palladium acetate and preferably in the presence of a base such as a tertiary amine e.g. triethylamine.

The reaction may be effected in the presence or absence of a solvent. Suitable solvents include nitriles (e.g. acetonitrile), amides (e.g. dimethylformamide) and water.

Intermediates of formula (XXIX) in which R17 represents

and p is 1 may be prepared by reducing a compound of formula (XXXII)

(where R'7 is as defined in formula (XXIX) above).

Intermediates of formula (IX) wherein R3 represents the group (b) and where p is 1 and q is 3 may be prepared by reducing a compound of formula (XXXII) where R'7 is

The reduction of compounds of formula (XXXII) may be effected using hydrogen and a metal catalyst such as palladium or platinum or oxides thereof or using hydrazine hydrate and a base (e.g. an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide).

Compounds of formula (XXXII) may be prepared from a compound of formula (XXXIII)

by a Friedel Craft reaction involving an acyl halide of the formula Hal-CO-R17 (where R'7 represents

and Hal represents chlorine or bromine) with the proviso that at least one of the positions on the phenyl ring meta in relation to the carboxyl group is unoccupied.

Alternatively, intermediates of formula (XXX) may be prepared by the reaction of a phosphonium salt of a halide of formula (XXXIV)

(where Hal represents a halide (e.g. chloride) ion and Rl8 represents, for example, an aryl or alkoxy group) with an aldehyde of the formula R17CHO (where R'7 represents

in the presence of a suitable strong base such as an alkoxide (e.g. potassium t-butoxide) and in the presence of a suitable solvent such as an ether (e.g. tetrahydrofuran) at ambient temperature.

Suitable phosphonium salts include aryl phosphonium salts such as triphenylphosphonium salts (where RíS represents an aryl group) which may be prepared according to established procedures.

Biaryl intermediates of formulae (III), (V), (Vm) and (XIV) may be prepared from appropriate starting materials by a boronic acid coupling reaction under the conditions described above as general process (7).

It will be appreciated that, where necessary, a halogen substituent may be converted into a carboxyl group using standard methodology thus, for example, compounds of formula (VIII) or (IX) may be prepared from an intermediate of formula (III) or (IV), respectively, by lithiation using, for example, n-butyl lithium followed by quenching with carbon dioxide.

The aldehydes of formula (XIII) or (MV) may be prepared from an intermediate of formula (IV) or (III), respectively, by lithiation using, for example, n-butyl lithium followed by formylation using, for example, dimethylformamide.

Intermediates of formulae (III), (XII), (XVII) (XVIII), (XIX), (XXIII), (XXIV), (XXXI) and (XXXIII) are either known compounds or may be prepared by standard methodology or methods analogous to those described herein.

Physiologically acceptable acid addition salts of the compounds of general formula (I) may be prepared by treating the corresponding free base with a suitable acid using conventional methods. Thus, for example, a generally convenient method of forming the acid addition salts is to mix appropriate quantities of the free base and the acid in an appropriate solvent e.g. an alcohol such as ethanol or an ester such as ethyl acetate.

Inorganic basic salts of compounds of general formula (I) may be prepared by treating the corresponding acid of general formula (I) (i.e. a compound of general formula (I) in which R2 represents the group CO2H) with a suitable base using conventional methods.

Salts of compounds of general formula (I) may also be converted into different physiologically acceptable salts of compounds of general formula (I) using conventional methods.

The invention is illustrated but not limited by the following examples in which temperatures are in OC. Thin layer chromatography (T.l.c.) was carried out on silica plates. Dried' refers to drying using sodium sulphate or magnesium sulphate unless otherwise stated. Flash column chromatography (FCC) was carried out on silica gel (Merck 9385) unless otherwise stated. Short path column chromatography (SPC) was carried out on silica gel (Merck 7747) unless otherwise stated.

The following solvent systems were used: System A - dichloromethane:ethanol:0.88 ammonia; System B - dichloromethane:ethanol; System C - hexane:diethyl ether; System D - dichloromethane:hexane; System E - ethyl acetate:ethanol:triethylamine; System F dichloromethane:methanol:0.88 ammonia.

The following abbreviations are used: ether - diethyl ether; THF - tetrahydrofuran; DME - 1,2-dimethoxyethane; DMF - dimethylformamide.

Intermediate 1 Methyl Smethoxv-3-(methvl-1-piperazinsl)benzoate hydrochloride A suspension of 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.92g) and methyl 3-amino4-methoxybenzoate (1.81g) in n-butanol was refluxed with stirring for 19h. Anhydric sodium carbonate (0.54g) was added and refluxing continued for 8.5h.

The solvent was then removed to give an oil which was taken up in water (SOml) and 2N hydrochloric acid (50ml) and extracted with ethyl acetate (2x50ml). The acid solution was then basified with sodium bicarbonate and re-extracted with ethyl acetate (3x50ml).

The extracts were dried and concentrated to a semi-solid (2.47g) which was absorbed from System A (200:8:1) (5ml) onto Kieselgel G (100g). Elution with the same solvent gave starting material and minor basic impurities. Further elution with System A (100:8:1) (450ml) gave first minor impurities and later fractions afforded the free base of the desired product as a gum (0.48g). This was taken up in methanol (5 ml), filtered and treated with ethereal hydrogen chloride and diluted to 25ml with ethyl acetate. A cream coloured solid separated, was filtered and the solid (0.586g) recrystalised from methanol:ethyl acetate to give the title compound m.p. 202-204"C.

Intermediate 1 (free base) was also made by the alternative two-step reaction as follows: (a) Methvl 3-(2.6-dioxo-4-methv!-1-piperazinyl!4-methoxvbenzoate N-(Carboxymethyl)-N-methylglycine (812mg) was suspended in acetic anhydride (4ml) and heated to reflux for 30 min. The excess acetic anhydride was then evaporated off and the dark residue treated with a solution of methyl 3-amino-4-methoxybenzoate (lug) in toluene (20ml). The mixture was stirred at 20 for 5 min, then at 100" for lOmin.The toluene was evaporated off giving a fawn crystalline solid which was suspended in acetic anhydride (5ml) and heated to reflux for 10min. The excess acetic anhydride was evaporated off giving a brown solid which was crystallised from methanol (2ml) giving the title compound as colourless microneedles (665mg) m.p. 157-158 .

(b) Methvl 4-methoxy-3 -C4-methvl- 1 -piperazinvflbenzoate To stirred solution ofthe product of step (a) (400mg) in dry THF (15ml) at reflux, under nitrogen, was added dropwise borane:THF complex (1M solution, 5.5ml). Heating was maintained for 1 8h whereupon the mixture was allowed to cool, and hydrochloric acid (2N,2ml) was added, dropwise at first. The mixture was then heated to reflux for 1 .5h and the solvents evaporated. The residue was partitioned between 8% sodium bicarbonate solution (30ml) and ethyl acetate (2x35ml). Evaporation of the dried extracts gave a yellow oil which was purified by FCC eluting with System A (200:8:1) to give the title compound (Intermediate 1) as a pale yellow oil (176mg).

T.l.c. System A (100:8:1) Rf0.58.

Intermediate 2 4-Methoxv-3-(4-methvl-1-piperazinvl?benzoicacid hydrazide A solution of the free base of Intermediate 1 (2g) in methanol (20ml) was treated with hydrazine hydrate (4ml) and refluxed under nitrogen for 16h. The solution was evaporated and then adsorbed from ethanol onto silica gel [Merck Art 7734, 5g]. The product was purified from a plug of this silica gel by SPC eluting with System A (91:9:0.9) to give the title compound as an off white solid (0.764g).

T.l.c. System A (90:10:0.1), Rf 0.2 Intermediate 3 SMethoxv-3-(4-methv!-1 -piperazinvl)benzenamine A solution of Intermediate 2 (0.73g) in water (30ml) was mixed with concentrated hydrochloric acid (0.6ml), the solution cooled to 0-5"C and a solution of sodium nitrite (0.219g) in water (10ml) added during Smin.The solution was stirred at 0-5" for 20min, then Ih at 23"C, and treated with concentrated hydrochloric acid (40ml) and acetic acid (40ml). The mixture was heated at reflux for 2h, cooled and poured into aqueous sodium hydroxide (sun; 260ml). The mixture was extracted with ethyl acetate (3x500ml), and the combined, dried organic extracts were evaporated to give the title compound (0.190g), as gum.

T.l.c. System A (95:5:0.5), Rf 0.2.

Intermediate 4 (E)-3-(2-Cyanoethenvl)A-methoxybenzoic acid. mixture with (Z) isomer (2:1) A stirred mixture of 3-iodo4-methoxybenzoic acid (18.06g), 2-propenenitrile (5.4ml), triethylamine (22.5ml), palladium (II) acetate (300mg), and acetonitrile (30ml) were heated at 1000 in an autoclave. After 36h, the reaction was incomplete. Half of the reaction mixture was removed, treated with palladium (II) acetate (300mg) and this mixture heated at 1000 for 18h in an autoclave. The cooled reaction mixture was filtered, evaporated, and the residue treated with water (1 00ml), aqueous saturated sodium bicarbonate (150my), and aqueous 2M-sodium hydroxide (50ml).The mixture was extracted with ethyl acetate (1 00ml) and the organic extract discarded. The aqueous extract was acidified to pH 1 by the addition of aqueous 2M-hydrochloric acid, extracted with ethyl acetate and the combined, dried extracts were evaporated. The residue was crystallised from ethanol to give the title compound (3.37g) as cream-coloured microcrystals, T.l.c. (ether:acetic acid 100:1) Rf 0.58.The mother liquors from the above crystallisation were concentrated and crystallised to give a second crop of the title compound (1.15g). Evaporation of the mother liquors afforded a further quantity of the title compound (1.15g).

Intermediate 5 3- r3 -(Dimethvlamino)propvliA-methoxybenzoic acid A solution of Intermediate 4 (2.00g) in a mixture of 33% ethanolic dimethylamine (60ml) and DMF (10ml) was hydrogenated at room temperature and pressure over 10% pre-reduced palladium oxide on carbon (2.00g) in ethanol (10ml) for 2.25h. The catalyst was filtered off, replaced with fresh catalyst (2.0g) and hydrogenation continued for a further 19.25h. The catalyst was filtered off, the filtrate concentrated in vacuo. and the residual white oil was triturated with hexane (3x200mi). The resultant white solid was filtered off and dried. A portion of this material (1.20g) was crystallised from acetonitrile (65ml) to give the title compound (0.84g) as white crystals m.p. 140-141 50 Intermediate 6 3-[3-lDimethvlamino!propvl]-4-methoxvbenzovl chloride hvdrochloride Thionyl chloride (3.5ml, 5.7g) and dry DMF (2 drops) was added to Intermediate 5 (1.5g) and the mixture heated on a steam bath for 5 min. The excess thionyl chloride was evaporated under reduced pressure whilst heating and the solid residue which formed re-evaporated with dry toluene (15ml x 2) then dried in vacuo to give the title compound as a buff powder (1.88g).

Intermediate 7 N-(4-Bromophenvl!-3-[3-(dimethvlamino!propYI]-4-methoXvbenzamide Intermediate 6 (5.84g) was treated with 4-bromobenzeneamine (3.4g) and dry pyridine (20ml) and heated at reflux under nitrogen for 1.5h. When cool, water (20ml) was added, followed by solid sodium carbonate (lg) and the solution evaporated in vacuo affording a grey-white residue which was washed with water, filtered, air-dried, and recrystallised from ethyl acetate to give the title compound as a cream-coloured solid (3.93g) m.p.

145.5-146"C. Evaporation of the filtrate yielded further solid, which was re-crystallised from ethyl acetate to give a second crop of crystals (1.79g) m.p. 145.5-146"C.

Intermediate 8 [4-[[3-[3-(Dimethylamino)propyl]-4-methoxybenzoyl]amino]phenyl]boronic acid A stirred solution of Intermediate 7 (3g) in dry mF (125ml), under nitrogen at -780C was treated dropwise with n-butyllithium (10.lml of a 1.52M solution in hexane). After lh, triisopropylborate (4.4ml) was added dropwise at -780C, and the reaction was allowed to stir for 30min. The cooling bath was then removed, and the reaction was stirred under nitrogen at 23 C for 17h. Hydrochloric acid (2N,4ml) and water (50ml) were added and the reaction mixture evaporated to dryness. Purification by FCC eluting with System A (75:23:2) gave the title compound as a cream-coloured foam (1.14g).

T.l.c. System A (60:40:4) Rf 0.26 Intermediate 9 N-(4-Bromophenyl)A-methoxy-3 -(4-methyl-i -piperazinyl)benzamide A solution of the free base of Intermediate 1 (lg) and sodium hydroxide (0.4g) in aqueous.

methanol (1:1, 60ml) was heated at reflux for 3.5h. The clear colourless solution was concentrated, acidified with 2N hydrochloric acid and concentrated to dryness. The residual white solid was then suspended in dry pyridine (15ml) and the mixture chilled in an ice-salt bath and treated with thionyl chloride (2420t1) with stirring. The mixture was stirred in the ice-salt bath for Ih, then 4-bromobenzeneamine (573mg) was added and the mixture allowed to reach room temperature.Stirring was continued for 18h, then the solution was diluted with water (75ml), followed by sodium carbonate (2N; 75ml). The aqueous solution was extracted with ethyl acetate (3x1 50ml). The combined organic extracts were washed with brine (150ml) and water (15 0ml), dried, filtered and evaporated in vacuo to give an oily residue. Purification by SPC eluting with System A (98:2:0.2) gave the title compound as a cream-coloured foam (455mg), m.p. 72-73"C.

Intermediate 10 4-[[4-Methoxv-3-(4-methvl-1 -piperazinvl)benzovliaminoiphenvl]bornnic acid A stirred solution of Intermediate 9 (1.7g) in dry THF (100ml), under nitrogen, at -78 C was treated dropwise with n-butyllithium (7.9ml of a 1.59M solution in hexane). After lh, triisopropylborate (2.9ml) was added dropwise at -78 C and the reaction was stirred at this temperature for 2h. Hydrochloric acid (2N, 2.6ml) was added followed by water (25ml) and the resultant mixture was evaporated to yield a yellow residue, which was preadsorbed onto silica [Merck Art. 7734]. Purification by FCC eluting with System A (65:35:3.5) gave the title compound as a yellow-foam (r:403g) m.p. 104-106"C (decomp).

Intermediate 11 4-(4Nitrophenvl)- 1 H-imidazole A mixture of o-bromo-4-nitroacetaphenone (10.0g) in formamide (50ml) was heated at reflux for 3h. The residue was purified by FCC eluting with hexane and then ethyl acetate to give a solid. The mixture was treated with water (100ml), the solid was filtered off, washed with water, and dried under vacuum to give the title compound (3.61g) as a brown solid m.p. 210-215"C.

Intermediate 12 4-(( 1 H)-Imidazol-4-vl)benzeneamine A solution of Intermediate 11 (3.40g) in ethanol (l00ml) and methanol (SOml) was hydrogenated over 5% palladium on carbon (l.Og) for 5h. The catalyst was filtered off; washed with ethanol, and the filtrate evaporated to give a brown gum. The gum was purified by FCC eluting with System A (100:8:1) to give the title compound (1.797g) as a brown gum.

T.l.c. System A (100:8:1) Rf0.12 Intermediate 13 5-(4-Nitrophenvl)- 1 H-1.2,4-triazole-3 -methanol To a stirred solution of 4-nitrobenzenecarboximidic hydrazide (0.949g) in acetonitrile (70ml) at room temperature was added triethylamine (0.7g) and then acetoxyacetyl chloride (0.9g). The mixture was stirred for Ih at room temperature and then evaporated to dryness in vacuo and the residue mixed with water (100ml). The suspension was filtered and washed well with water then ethyl acetate and dried.The yellow solid, consisting of 4-nitrobenzenecarboximidic acid [2-(2-acetyloxy)- 1 -oxoethyl]hydrazide (1.288g) m.p. 180-181 , was heated at 190-200C for 2h and, on cooling, the residue was dissolved in methanol (50ml) and solid potassium hydroxide (lug) added. The mixture was mixed with water (70ml) and acidified with 2N hydrochloric acid (4ml). The solid which formed was filtered, washed with water and dried to give the title compound (0.943g).

T.l.c. System A (70:8:1) Rio.28.

Intermediate 14 5-($Aminophenvl!-lH-1 2.4-triazole-3-methanol dihvdrochloride A stirred suspension of Intermediate 13 (l.llg) and Raney Nickel (0.5g) in ethanol (70ml) and heated on a steam bath and hydrazine hydrate (2ml) was added dropwise.

The mixture was heated until the effervescence had ceased and the mixture was filtered through hyflo in a stream of nitrogen. The combined filtrate and washings were evaporated in vacuo to give an oil which was redissolved in ethanol (20ml) and excess ethereal hydrogen chloride added. The suspension was evaporated to remove the ether and the solid was filtered, washed with ethanol and dried to give the title compound (0.816g).

T.l.c. System A (50:8:1) Rf0.35.

Intermediate 15 4-(5-Acetyl-2-fiiranyl)benzoic acid A suspension of methyl 4-(5-acetyl-2-firanyl)benzoate in methanol (5ml) and sodium hydroxide (2N, 5ml) was stirred at room temperature for 24 hours before pouring into hydrochloric acid (2N,50ml). A thick yellow precipitate formed which was filtered, washed well with water and dried in vacuo at 80"C for 4 hours to give the title compound as a yellow powdery solid (403mg).

Analysis Found: C,67.6; H, 4.3 Cl3H,004 Requires C,67.8; X4.4% Example 1 N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4-(5-methyl-1,2,4-oxadiazol-3-yl) benzamide To a cold (0 ) stirred solution of 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (200mg) in dry pyridine (5ml) was added thionyl chloride (0.08ml). The mixture was stirred at 00 for 1h then at 200 for lh. Intermediate 3 (216mg) was then added and the mixture stirred at 20 for 4h. The solvent was evaporated and the dark residue purified by FCC eluting with System A (200:8:1) to give the title compound as a yellow foam (294mg).

T.l.c. System A (100:8:1) Rf0.29 Assay Found: C,62.6; H,6.2; N,16.3: C22H25N5O3.0.3H2O.0.1CH2Cl2.0.1C2H6O requires C,62.85; H,6.25; N,16.4S% Water Determination 1.36% w/w = 0.3mol% H20 Similarly prepared was: Example 2 3-[3-(Dimethylamino)propyl]-N-[4-(1 H-imidazol-4-yl)phenyl]-4-methoxybenzamide.

ethanedioic acid (1:2) as an off-white crystalline solid (2.135g) m.p. 199-202"C T.l.c. System A (50:8: 1) Rf 0.14 From a mixture of Intermediate 5 (2.00g) and thionyl chloride (20ml) followed by Intermediate 12 (1.28g) in dry pyridine (35ml), which gave a yellow gum (2.36g). A hot solution of the gum in ethanol (150ml) was treated with a hot solution of oxalic acid (1.09g) in ethanol (lOml) to give the title compound.

Example 3 3-r3-(Dimethvlamino!propvl3-N-[4-(3-hydroxvmethyl-lH-l .2.4-triazol-5-vl!phenvl]-4- methoxvbenzamide A mixture of Intermediate 5 (0.783g) and thionyl chloride (4ml) was heated for 5 min and then evaporated to dryness. The solid residue was re-evaporated with toluene (8ml) and dried in vacuo. The residue was suspended in pyridine (10ml) and Intermediate 14 (0.645g) added. The mixture was heated for 20min and the solution evaporated to dryness with the aid of water. The residue was extracted with water (2x30ml) then the oily residue evaporated with acetone (3x30mi). The residue was extracted with hot acetone (4x 50ml) and the extract filtered. The filtrate was evaporated to give a solid residue (0.362g).The solid was washed with ethanol then acetone and finally ether and dried to give the title compound (0.34g).

T.l.c. System A (25:8:1) Ref0.28.

Analysis Found C,64.0; H, 6.6; N,17.15.

C22Et7N503.0.31 H;O requires C,63.7; H,6.7; N,16.9% Water assay: indicates 1.35% w/w H2,O = 0.3 1mol H2O Example 4 N-[4-Methoxv-3-(4-methyl-1 -piperazinyl)phenyl]-4-(5-acetyl-2-furanyl)benzamide A solution of Intermediate 3 (221mg) and Intermediate 15 (230mg) in dichloromethane (5ml) was treated dropwise under nitrogen with a solution of N,N-dicyclohexylcarbodiimide (DCC) (227mg) in dichloromethane (2ml). The mixture was stirred at room temperature under nitrogen for 4 hours. Further DCC (150mg) was added and stirring continued for a further 8 hours. The precipitate which formed was filtered off and washed well with dichloromethane. The combined filtrates were concentrated in vacuo and the residue purified by FCC eluting with System A (300:8:1) to give an oil.ARer standing the oil overnight, a crystalline precipitate had formed. Ether was added and the crystalline solid triturated with ether (3x2ml). The resulting solid was dried in vacuo to give the title compound as a bright yellow crystalline solid (132mug) m.p.

180-181"C.

Analysis Found: C,68.7; H, 6.3; N,9.5; C25H27N304 requires C,69.3; H,6.3; N, 9.7% Example 5 3-[3-(Dimethylamino)propyl]-N-[4-(4-formyl-2-furanyl]phenyl]-4-methoxybenzamide A solution of sodium carbonate (34.5mg) in water (30ml) was added to a mixture of Intermediate 7 (1.20g), 4-formyl-2-furanboronic acid (456mg), tetrakis (triphenylphosphine)palladium (O) (137mg) and DME (60ml) and the stirred mixture was heated at reflux under nitrogen for 2h. Further 4-formyl-2-furanboronic acid (125mg) was added and the heating continued for 2h. When cool, the mixture was evaporated and the residue purified by FCC eluting with System A (945:50:5 to 912:80:8) to give a white solid (878mg).This was treated with reflexing ethanol (35ml), filtered and, on cooling, the title compound crystallised as fine cream-coloured crystals (221mg).

T.l.c. System A (945:50:5) Rf 0.13 Analysis Found: C,70.7; H, 6.3; N,6.8.

C24H26N204.0.12H20 requires C,70.5; H,6.5; N,6.9% Water assay Found: 0.55% H2O=0.12 mol Similarly prepared were: Example 6 3-[3-(Dimethylamino)propyl]-4-methoxy-N-[4-(2-thiazolyl)phenyl]benzamide as a creamcoloured solid (21 lmg) m.p. 143.5-145"C.

T.l.c. System A (100:8:1) Rf0.38 From a stirred mixture of Intermediate 8 (500mg), 2-bromothiazole (0.13my), tetrakis(triphenylphosphine)palladium (0) (76mg) and anhydrous sodium carbonate (154mg) in water (23ml) and DME (23ml). Purificaiton by chromatography [Merck 7729] eluting with System A (200:8:1) afforded the title compound.

Example 7 4-Methoxv-3-(4-methvl-1-piperazinvl!-N-g(5-pvrimidinvl!phenvlubenzamide as a white solid (0.244g) m.p. 122-123"C.

T.l.c System A (94:6:0.6) Rf 0.25 From a catalytic quantity of tetrakis(triphenylphosphine)palladium (0) (0.046g) added to Intermediate 10 (0.298g), 5-bromopyrimidine (0.142g) and sodium carbonate (0.258g) in glyme (5ml) and water (Sml). Purificaiton by SPC eluting with System A (95:5:0.5) afforded the title compound.

Example 8 3 -[3-(Dimethylamino)propyl]-N-[4[4(hydroxymethyl)-2-furanyl]phenyl]-4- methoxvbenzamide Sodium borohydride (40mg) was added in portions during 3min to a stirred solution of the product of Example 5 (366mg) in dry THF (lOml) and ethanol (lOml) at -5 to -10" under nitrogen. After ih, further sodium borohydride (lSmg) was added and stirring continued for 30min. Acetic acid (0.5ml) was added, followed by aqueous saturated sodium bicarbonate (3ml), and the mixture evaporated. The residue was treated with aqueous saturated potassium carbonate (40ml), extracted with ethyl acetate (4x50ml), and the combined, dried organic extracts were evaporated. The residue was purified by FCC eluting with System A (923:70:7 to 89:10:1) to give a solid (310mg). This crystallised from ethanol to give the title compound as fine white crystals (63mg). m.p. 166.5-169".

Analysis Found C,70.5; H, 6.8; N,6.8.

C248N2O4.0. 1IO requires C,70.3; H,6.9; N,6.8% Water assay Found: 0.42% w/w H20 --O. lOmol.

Claims

1. Compounds of the general formula (I) :

or a physiologically acceptable salt or solvate thereof, in which R1 represents a hydrogen atom or a halogen atom or a C1 6alkyl or C1- 6alkoxy group; R2 represents an aromatic heterocyclic group which contains one, two or three heteroatoms selected from nitrogen, oxygen and sulphur, or a group -NH- or NR9-, said heteroaryl group being optionally substituted by a substituent selected from C1-6alkyl, hydroxyC1-6alkyl, C1-4alkylC1-6alkoxy,-COR6 or NR7R8; R3 represents a group selected from (a) -(C NRB R14

R4 and R5, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a hydroxy, C1 alkoxy or C1-6alkyl group; ; R6 represents a hydrogen atom or a hydroxy or C1-6alkyl group; R7, R8 and R9 , which may be the same or different, each independently represent a hydrogen atom or a C1 6alkyl group; R1 3, R14 and R1 5, which may be the same or different, each independently represent a hydrogen atom or a Cm 6alkyl group; X represents -CONH-, -NHCO-, -CH2NH- or -NHCH2-; n represents an integer from 2 to 4; p represents an integer from 1 to 3; and q represents an integer from 1 to 3; with the proviso that R2 does not represent a pyridinyl group.

2. Compounds as claimed in Claim 1 for use in therapy.