1-PIPERAZINEACETIC DERIVATIVES AS FIBRINOGEN RECEPTOR ANTAGONISTS

Abstract: The invention thus provides the compounds of general formula (I) and salts, solvates and pharmaceutically acceptable derivatives thereof, in which X<1> and X<2> represent CH or are different and represent CH or N; Y<1>, Y<2>, Y<3> and Y<4> represent CH, or Y<1> and Y<4> represent CH and Y<2> and Y<3> represent N, or Y<2> and Y<3> represent CH and Y<1> and Y<4> represent N, or three of Y<1> to Y<4> represent CH and the other represents N; Z<1> represents CH or N; Z<2> represents N or N<+>R<6>; R<1> represents a hydrogen atom or a hydroxyl, C1-4alkyl or 2,2,2-trifluoroethyl group; R<2> represents a hydrogen atom or, when both X<1> and X<2> represent CH, may also represent a fluorine, chlorine or bromine atom or a C1-4alkyl group; R<3> represents a hydrogen atom or, when both Y<1> and Y<2> represent CH, may also represent a fluorine, chlorine or bromine atom or a C1-4alkyl group; R<4> and R<5> each represent a hydrogen atom; or, when Z<1> represents CH and Z<2> represents N, R<4> may also represent C1-4alkyl; or, when both Z<1> and Z<2> both represent N, R<4> and R<5> may be the same or different, and represent hydrogen or C1-4alkyl; R<6> represents a C1-4alkyl group or phenylC1-3alkyl group; R<7> represents a hydrogen atom; a C1-4alkyl group; a naphthyl group; a thiophene group; an unsubstituted phenyl group; a phenyl group substituted by C1-4alkyl group, C1-4alkoxy, phenylC1-3alkoxy, OH, halogen (where halogen is fluorine, chlorine, bromine or iodine), CF3, unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NR<8>R<9>, NHSO2R<8>, CONR<8>R<9> or CO2R<8>; a C1-4alkyl group substituted by one or more naphthyl, phenyl, OH or CO2R<8>; a C2-4alkenyl group substituted by one or more naphthyl, phenyl, OH or CO2R<8>; or a saturated or unsaturated C5-7cycloalkyl group; and R<8> and R<9>, which may be the same or different represent H or C1-4alkyl or, together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring.

Description: 1-PIPERAZINEACETIC DERIVATIVES AS FIBRINOGEN RECEPTOR ANTAGONISTS This invention relates to acetic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing such compounds and to their use in medicine. It is widely accepted that the glycoprotein complex Gp llb/llla is the fibrinogen binding site on platelets that mediates the adhesive function required for platelet aggregation and thrombus formation. We have now found a group of non-peptidic compounds which inhibit fibrinogen-dependent platelet aggregation by blocking the binding of fibrinogen to the putative fibrinogen receptor Gp llb/llla complex. The invention thus provides the compounds of general formula (I) and salts, solvates and pharmaceutically acceptable derivatives thereof, in which X 1 and X 2 represent CH or are different and represent CH or N; Y\ Y 2 , Y 3 and Y 4 represent CH, or Y 1 and Y 4 represent CH and Y 2 and Y 3 represent N, or Y 2 and Y 3 represent CH and Y 1 and Y 4 represent N, or three of Y 1 to Y 4 represent CH and the other represents N; Z 1 represents CH or N; Z 2 represents N or N + R 6 ; R 1 represents a hydrogen atom or a hydroxyl, C-).4alkyl or 2,2,2- trifluoroethyl group; R 2 represents a hydrogen atom or, when both X 1 and X 2 represent CH, may also represent a fluorine, chlorine or bromine atom or a C 1 _ 4 alkyi group; SUBSTITUTE SHEET R 3 represents a hydrogen atom or, when both Y 1 and Y 2 represent CH, may also represent a fluorine, chlorine or bromine atom or a C^alkyl group; R 4 and R 5 each represent a hydrogen atom; or, when Z 1 represents CH and Z 2 represents N, R 4 may also represent C^alkyl; or, when both Z 1 and Z 2 both represent N, R 4 and R 5 may be the same or different, and represent hydrogen or C . 4 alkyl; R 6 represents a C^alkyl group or phenylC^alkyl group; R 7 represents a hydrogen atom; a C 1 . alkyl group; a naphthyl group; a thiophene group; an unsubstituted phenyl group; a phenyl group substituted by Pι_ 4 alkyl group, C 1 . 4 alkoxy, phenylC^alkoxy, OH, halogen (where halogen is fluorine, chlorine, bromine or iodine), CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NR 8 R 9 , NHS0 2 R 8 , CONR 8 R 9 or C0 2 R 8 ; a C^alkyl group substituted by one or more naphthyl, phenyl, OH or C0 2 R 8 ; a C 2 . 4 alkenyl group substituted by one or more naphthyl, phenyf, OH or C0 2 R 8 ; or a saturated or unsaturated C 5 . 7 cycloalkyl group; and R 8 and R 9 , which may be the same or different represent H or C-,. alkyl or, together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring. In the formulae that follow, the terms "ring-A-", "ring-B-" and "ring-C-" will hereinafter be used to describe certain rings of formula (I): ring -A- ring -B- ring -C- It will be appreciated by those skilled in the art that the compounds of formula (I) in which R 7 is other than hydrogen contain at least one chiral centre (shown as * in formula (I)) and that such compounds exist in the form of a pair of SUBSTITUTE SHEET optical isomers (i.e. enantiomers). The invention includes all such isomers and mixtures thereof including racemic mixtures. It will be further appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof. Suitable physiologically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates,- naphthoates, hydroxynaphthoates, p-toluenesuiphonates, methanesulphonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarballylates, citrates, fumarates and maleates) and inorganic base salts such as alkali metal salts (for example sodium salts). Other salts of the compounds of formula (I) include salts formed with trifluoroacetic acid. It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their salts and solvates, including all tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable ester or salt or solvate of such ester of the compounds of formula (I) or any other compund which upon administration to the recipient is capable of providing (directly or indirectly) a compund of formula (I) or an active metabolite or residue thereof. It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds. Of particular interest as such derivatives are compounds modified at the carboxyl or amidine functions. SUBSTITUTE SHEET Thus compounds of interest include carboxylic acid esters of the compounds of formula (I). Examples of such esters include C,_ 6 alkyi esters, more preferably C j _ 3 alkyl esters, such as ethyl esters. Other compounds of interest as pharmaceutically acceptable derivatives include benzoylamidine, alkyloxycarbonyl amidine and dialkyloxyphosphinyl amidine derivatives of the compounds of formula (1), which may be prepared by transformation of the amidine group. It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position. It will be further appreciated by those skilled in the art that carboxylic acid ester derivatives of formula (I) may be useful as intermediates in the preparation of compounds of formula (I), or as pharmaceutically acceptable derivatives of formula (I), or both. The term " alkyl * as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group. in compounds of formula (1), the following meanings are individually preferred X 1 and X 2 both represent CH; Y 1 , Y 3 and Y 4 each represent CH; Z 1 represents N; Z 2 represents N, N + methyl or N + benzyl; most preferably Z 2 represents N; R 1 represents a hydrogen atom or a hydroxyl group, most preferably a hydrogen atom; R 2 represents a hydrogen atom; R 3 represents a hydrogen atom; SHEET R 4 and R 5 are the same and each represents either a hydrogen atom or, when both Z 1 and Z 2 represent N, may also represent a methyl group; most preferably R 4 and R 5 each represent a hydrogen atom; R 6 represents a methyl or benzyl group; R 7 represents a hydrogen atom, a methyl group, a phenyl group or a phenyl group substituted by fluorine; most preferably R 7 represents a hydrogen atom, a phenyl group or a phenyl group substituted in the 4-position by fluorine. Preferred pharmaceutically acceptable derivatives are methyl ester, ethyl ester and butyl ester derivatives. A preferred subclass of compounds of formula (I) are compounds of formula (la) and salts, and pharmaceutically acceptable derivatives thereof, in which Y 23 represents CH or N; Z 2a represents N or N + R 6 ; R 1a represents hydrogen atom or a hydroxy group; R 4a and R 5a are the same, and each represents a hydrogen atom or, when Z 2a represents N, may also represent a methyl group; R 6a represents a methyl or benzyl group; and R 7a represents a hydrogen atom, a methyl group, a phenyl group or a phenyl group substituted by fluorine in the 4-position. A preferred class of compounds of formula (la) is that in which Y 2a represents N. Particularly preferred compounds of the invention are: SUBSTITUTE SHEET 4-[5-[4-(Aminoiminomethyl)phenyl]-2-pyridinyi]-1-piperazineacetic acid; 4-[5-[4-(Aminoiminomethyl)phenyl]-2-pyridϊnyl]-α-phenyl]-1-piperazineacetic acid, in the form of a racemic mixture or single enantiomer; 4-[5-[4-(Aminoiminomethyl)phenyl]-2-pyridinyl]-α-(4-fluorophenyl)-1- piperazineacetic acid, in the form of a racemic mixture or single enantiomer; and salts, solvates and pharmaceutically acceptable derivatives thereof. Other preferred compounds of the invention include: 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -piperazineacetic acid; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyi]-4-yl]-1 -(2-hydroxy-2-oxoethyl)-1 - methyl-1-piperazinium salt; Ethyl 4-[4'-(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1-piperazineacetate; Butyl 4-[4 * -(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -piperazineacetate; cis-4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-2,6-dimethyl-1 - piperazineacetic acid; 4-[4'-[(Hydroxyamino)iminomethyl][1 ,1 '-biphenyl]-4-yl]-1 -piperazineacetic acid ; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-α-methyl-1 -piperazineacetic acid, in the form of a racemic mixture or a single enantiomer; 1 ,1 Dimethylethyl-4-[5-[4-(aminoiminomethyl)phenyl]-2-pyridinyl]-α-(4- fluorophenyl)-1 -piperazineacetate, in the form of a racemic mixture or a single enantiomer; 1,1-Dimethylethyl-α-(4-fIuorophenyl)-4-[5-[4- [imino[[(phenylmethoxy)carbonyl]amino]-methyl]phenyl]-2-pyridinyl]-1- piperazineacephate, in the form of a racemic mixture or a single enantiomer; SUBSTITUTE SHEET 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -(2-hydroxy-2-oxoethyl)-1 - (phenylmethyl)-l -piperazinium salt; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -(2-methoxy-2-oxoethyl)-1 - methyl-1 -piperazinium salt; 1 ,1-Dimethylethyl 4-[4'-(aminoiminomethyl)[1 ,1'-biphenyl]-4-yl]-1- piperazineacetate; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -[2-(1 ,1 -dimethylethoxy)-2- oxoethyl]-1 -methyl-1 -piperazinium salt; 1 ,1 -Dimethylethyl 4-[5-[4-(aminoiminomethyl)phenyl]-2-pyridinyl]-1 - piperazineacetate; cis-1 ,1-Dimethylethyl 4-[4'-(aminoiminomethyl)[1 ,1'-biphenyl]-4-yl]-2,6- dimethyl-1 -piperazineacetate; [4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -(2-methoxy-2-oxoethyl)-1 - methyl-1 -piperazinium salt; 1 ,1 -Dimethylethyl 4-[4'-(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 - piperazineacetate; 4-[4'-(Aminoiminomethyl)[1 ,1'-biphenyl]-4-yl]-1-[2-(1 ,1-dimethylethoxy)-2- oxoethyl]-1 -methyl-1 -piperazinium salt; 1 ,1-Dimethylethyl 4-[5-[4-(aminoiminomethyl)phenyl]-2-pyridinyl]-1 - piperazineacetate; cis-1 ,1-Dimethylethyl 4-[4'-(aminoiminomethyl)[1 ,1'-biphenyl]-4-yl]-2,6- dimethyl-1 -piperazineacetate; 1 ,1 -Dimethylethyl 4-[4'-[(hydroxyamino)iminomethyl][1 ,1 '-biphenyl]-4-yl]-1 - piperazineacetate; Ethyl 4-[4'-(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-α-methyl-1- piperazineacetate, in the form of a racemic mixture or a single enantiomer; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1-[2-(1 ,1-dimethylethoxy)-2- oxoethyl]-1-(phenylmethyl)-1 -piperazinium acetate salt; and salts, solvates and pharmaceutically acceptable derivatives thereof. Compounds of formula (I) inhibit blood platelet aggregation as demonstrated by studies performed on human gel filtered platelets (GFP) using a Born-type optical aggregometer (Born, G.V., 1962, Nature, 194. 927-929). SUBSTITUTE SHEET In view of their fibrinogen antagonist activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment or prophylaxis of thrombotic disorders. Particular examples of thrombotic disorders are known in the art and include occlusive vascular diseases such as myocardiai infarction, cardiac fatalities, angina, transient ischaemic attacks and thrombotic stroke, arteriosclerosis, vessel wall disease, peripheral vascular disease, nephropathy, retinopathy, postoperative thrombosis, pulmonary embolism, deep vein thrombosis and retinal vein thrombosis. The compounds of the invention are also of interest for use in the prophylaxis of peri- and postoperative complications following organ transplantation (particularly cardiac and renal), coronary artery bypass, peripheral artery bypass, angioplasty, thrombolysis and endarterectomy. The compounds of the invention may also be useful for the treatment or prophylaxis of other conditions in which the glycoprotein complex Gp llb/llla or other integrin receptors are implicated. Thus, for example, the compounds of the invention may potentiate wound healing and be useful in the treatment of osteoporosis. The compounds of the invention may also be useful for the treatment of certain cancerous diseases. For example, compounds of the invention may be of use to prevent or delay metastasis in cancer. According to a further aspect of the invention, we provide a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine, particularly for use in the treatment or prophylaxis of thrombotic disorders. According to another aspect of the invention, we provide the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prophylaxis of thrombotic disorders. According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from or susceptible to a thrombotic disorder, which method comprises administering to said subject an effective SUBSTITUTE SHEET amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof. It will be appreciated that the compounds of formula (I) may advantageously be used in conjunction with one or more other therapeutic agents. Examples of suitable agents for adjunctive therapy include thrombolytic agents or any other compound stimulating thrombolysis or fibrinolysis and cytotoxic drugs. It is to be understood that the present invention covers the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic agents. The compounds of formula (I) and their physiologically acceptable salts and . solvates are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients. The compounds according to the invention may v be formulated for administration in any suitable manner. The compounds may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral or parenteral administration. For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously). 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. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative. SUBSTITUTE SHEET Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle. The compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. As stated above, the compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutic agent, in particular a thrombolytic agent. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of formula (I) or a physiologically acceptable salt or solvate thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. Aproposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 30 mg/kg, which may be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.1 mg/kg to 10mg/kg may be suitable for systemic administration. SUBSTITUTE SHEET Suitable methods for the preparation of compounds of formula (I) and salts and solvates thereof are described below. In the formulae that follow, X 1 , X 2 , Y 1 , γ2 t γ3 f γ4 j z 1 1 z 2 R 1 1 R 2 j R3, R4_ R 5 f R6, R7 > R 8 and R 9 arΘ as defined in formula (I) above unless otherwise stated; RP represents a protecting group; and Hal represents a halogen, e.g. bromine. Thus, according to a first process (A), compounds of formula (I) in which R 1 represents a hydrogen atom may be prepared from compounds of formula (II) by treating said compounds of formula (II) with a suitable alkylating agent, followed by reaction with a source of ammonia (e.g. ammonium acetate) in a suitable solvent, such as an alcoholic solvent (e.g. methanol) at an elevated temperature (e.g. reflux), and thereafter removing the carboxylic acid protecting group. The alkylation (e.g. ethylation) may conveniently be effected by employing an appropriate trialkyloxonium salt (e.g. triethylσxonium tetrafluoroborate) in a suitable solvent (e.g. dichloromethane) at room temperature. Alternatively the alkylation (e.g. methylation or benzylation) may conveniently be effected using an alkyl or benzyl halide (e.g. iodomethane) in a suitable solvent such as a ketone (e.g. acetone) at an elevated temperature (e.g. reflux). It will be appreciated that when the alkylation is effected with a C-| _4alkyl or phenylC-i^alkyl halide alkylation to provide compounds in which Z 2 represents N+R 6 may also result. According to a further process (B), compounds of formula (I) in which R 1 represents a hydroxyl group may be prepared from compounds of formula (III) SUBSTITUTE SHEET or protected derivatives thereof by treating said compounds of formula (111) with hydroxylamine or an acid addition salt thereof (e.g. hydroxylamine hydrochloride) in the presence of a suitable base such as an alkali or alkaline earth metal carbonate or bicarbonate (e.g. potassium carbonate) or an alkoxide such as potassium tert-butoxide and in a solvent such as an alcohol (e.g. methanol ortert-butanol), followed, where necessary, by removing any protecting groups present. The reaction with hydroxylamine or an acid addition salt thereof may conveniently be effected at an elevated temperature (e.g. reflux) when a carbonate or bicarbonate is used. When an alkoxide is used the reaction may conveniently be effected at a temperature in the range of about 20° to 80°C. According to a yet further process (C), compounds of formula (I) in which R 1 represents a hydroxyl, or 2,2,2-trifiuoroethyl group may be prepared by treating compounds of formula (II) with a suitable alkylating agent as described in process (A) above followed by reaction of the in situ formed thioimidate with an amine R 1 NH2 (where R1 represents hydroxyl, C-|_4alkyl or 2,2,2-trifiuoroethyl), with subsequent removal of the carboxylic acid protecting group. The reaction with the amine RINH2 mav conveniently be carried out in a suitable solvent such as an alcohol (e.g. methanol) or an ether (e.g. tetrahydrofuran) at an elevated temperature. According to a still further process (D), compounds of formula (I) may also be prepared by reacting a compound of formula (IV) hereinafter with an alcohol (e.g. ethanol) under acid conditions, followed by treatment of the resulting imidate with a source of ammonia (e.g. ammonium acetate), or an amine R 1 NH2 (where R 1 is a hydroxyl, C-^al yl or 2,2,2- trifluoroethyl group), respectively under the conditions described in processes (A) or (C) above, or SUBSTITUTE SHEET at ambient temperature, with subsequent removal of the carboxylic acid protecting group. According to another process (E), compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors. Thus, for example, compounds of formula (I) in which R 1 represents a hydrogen atom may be prepared from corresponding compounds of formula (I) in which R 1 represents a hydroxyl group by catalytic hydrogenation in a solvent such as an alcohol (e.g. ethanol), or acetic acid preferably in the presence of acetic anhydride. Suitable catalysts include Raney Nickel or conventional palladium, platinum or rhodium catalysts. According to yet another process (F), compounds of formula (I) in which R " ! is hydrogen, Cι_4alkyl or 2,2,2-trifluoroethyl and ring -C- represents may conveniently be prepared by hydrogenating compounds of formula (XXI) (where R 1 is hydrogen, Ci^alkyl or 2,2,2-trifluoroethyl) at an elevated pressure and in the presence of a catalys, such as a platinum catalystt (e.g. Ptθ2), and thereafter removing the carboxyl protecting group. The reaction may conveniently be effected in a solvent such as an alcohol (e.g. ethanol), and optionally in the presence of an acid, such as hydrochloric acid. Another process (G) for preparing compounds of formula (I) comprises deprotecting protected derivatives of compounds of formula (I). In a particular SUBSTITUTE SHEET embodiment of this process compounds of formula (I) may be prepared from protected carboxyl derivatives of compounds of formula (I). Suitable carboxyl protection groups include, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991) which also describes methods for the removal of such groups. Particular carboxyl protecting groups include, for example, carboxylic acid ester groups such as carboxylic acid alkyl or aralkyl esters, for example where the alkyl or aralkyl portion of the ester function is methyl, ethyl, tert-butyl, methoxymethyl, benzyl, diphenylmethyl, triphenylmethyl or p-nitrobenzyl. When the ester is an unbranched alkyl (e.g. methyl) ester deprotection may be effected under conditions of acid hydrolysis, for example using hydrochloric acid. Tert-butyl and triphenylmethyl ester groups may be removed under conditions of moderate acid hydrolysis, for example using formic ortrifluoroacetic acid at room temperature or using hydrochloric acid in acetic acid. Benzyl, diphenylmethyl and nitrobenzyl ester groups may be removed by hydrogenolysϊs in the presence of a metal catalyst (e.g. palladium). When a particular isomeric form of a compound of formula (I) is desired, for example where the compound is a quaternary ammonium salt, the required isomer may conveniently be separated using preparative high performance liquid chromatography (h.p.l.c.) applied to the final products of processes (A)-(G) above or applied prior to any final deprotection step in said processes. Compounds of formula (II) may be prepared from compounds of formula (IV) by treating said compounds of formula (IV) with hydrogen sulphide. The reaction may conveniently be carried out in a solvent such as SUBSTITUTE SHEET dimethylformamide or pyridine and in the presence of an organic base such as an amine (e.g. triethylamine). Unprotected compounds of formula (III) may also be prepared from compounds of formula (IV) by removing the carboxylic acid protecting group R p according to the method described in process (G) hereinabove. Compounds of formula (IV) in which Z 2 represents N + R 6 may conveniently be prepared from corresponding compounds of formula (IV) in which Z 2 represents N by alkylation according to the method described in process (A) above. Compounds of formula (IV) in which ring -A- represents and ring -C- represents may be prepared by treating compounds of formula (V) with a boronic acid of formula (VI) preferably in the presence of a suitable transition metal catalyst such as a palladium catalyst [e.g. tetrakis-(triphenylphosphine)palladium(0)] and a suitable base such as an alkali metal carbonate (e.g. sodium carbonate). The reaction may conveniently be effected in a solvent such as an aqueous ether (e.g. aqueous 1 ,2-dimethoxyethane) and at ambient or elevated temperature. SUBSTITUTE SHEET The boronic acids of formula (VI) may be prepared from halides of formula (VII) under conventional conditions. Compounds of formula (VII) are either known compounds or may be prepared by methods well known in the art. Compounds of formula (IV) in which ring -A- represents may be prepared by reacting compounds of formula (VIII) with an inorganic nitrile such as sodium cyanide, preferably in the presence of a suitable transition metal catalyst such as a palladium catalyst [e.g. tetrakis(triphenylphosphine)palIadium(0)]. The reaction may conveniently be effected in a solvent such as an aromatic hydrocarbon (e.g. toluene) and preferably in the presence of alumina at an elevated temperature. Compounds of formula (VIII) may be prepared by coupling compounds of formula (IX) SUBSTITUTE SHEET with compounds of formula (X) (wherein R represents a Cι_4alkyl, e.g. butyl) preferably in the presence of a transition metal catalyst such as a palladium catalyst [e.g. bis(acetonitrile)palladium(ll) chloride]. The reaction may conveniently be effected in an aprotic solvent (e.g. dimethylformamide) at elevated temperature (e.g. 60-120°C). Compounds of formula (IX) are either known compounds or may be prepared by methods well known in the art. Compounds of formula (X) may be prepared by treating compounds of formula (V) with a bis(trialkyltin) reagent, (e.g.bis(tributyltin)), preferably in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0). The reaction is conveniently effected at elevated temperature (e.g. reflux) and in a suitable solvent, such as an aromatic hydrocarbon (e.g. toluene). Compounds of formula (IV) in which ring -A- represents a fluoro, chloro or bromo substituted 1 ,4-phenylene and ring -C- represents SUBSTITUTE SHEET may conveniently be prepared by reacting a compound of formula (X) with a compound of formula (XI) (wherein R 2 represents a fluorine, chlorine or bromine atom) under the coupling conditions described above for preparing compounds of formula (Vlll). Compounds of formula (XI) are either known compounds or may be prepared by methods well known in the art. Compounds of formula (V) in which ring -B- represents (wherein R 3 represents a hydrogen, fluorine, chlorine or bromine atom) and ring -C- represents -N N — J may be prepared by treating compounds of formula (XII) (wherein R 3 is a fluorine, chlorine or bromine atom) with a reagent t-butyl nitrite in bromoform, conveniently at elevated temperature. SUBSTITUTE SHEET Compounds of formula (XII) may be prepared from compounds of formula (XIII) ' (wherein R 3 is as defined in formula (XII) above) under reducing conditions. The reduction may, for example, be carried out by hydrogenation in the presence of a suitable transition metal catalyst such as palladium on activated carbon, and in a suitable solvent, such as an alcohol (e.g. ethanol). Alternatively the reduction may be effected by employing a suitable hydride reagent (e.g. sodium borohydride) in the presence of a Lewis Acid (e.g. tin(il) chloride), and in a suitable solvent such as an alcohol (e.g. ethanol), conveniently at elevated temperature (e.g. 60°C). Compounds of formula (XIII) in which ring -C- represents — may be prepared by reacting compounds of formula (XIV) (wherein R 3 is as defined in formula (XII) above) with a reagent LCHR 7 C02R (where L is a leaving group, such as a halogen atom (e.g. bromine) or a sulphonate ester group (e.g. mesyiate)). SUBSTITUTE SHEET Thus, for example, compounds of formula (XIII) In which R 7 represents a naphthyl, phenyl, naphthylC2-4alkyl or phenyiC2-4alkyl group may be prepared by use of a reagent HalCHR 7 C02RP (wherein R 7 represents a naphthyl, phenyl, naphthylC2-4alkyl or phenylC2-4alkyl group) as described above and preferably in the presence of a suitable base such as an alkali metal carbonate or bicarbonate (e.g. potassium carbonate) and in a solvent such as a nitrite (e.g. acetonitrile), conveniently at an elevated temperature (e.g. reflux). The reagents of formula HalCHR 7 Cθ2RP (wherein R 7 is as defined just above) are known compounds or may be prepared by either esterification of the corresponding α-halo carboxylic acid or by α-haiogenation of the corresponding carboxylic acid ester, by standard methods. The α-halo carboxylic acids and the carboxylic acid esters above are known compounds or are readily prepared using conventional chemistry. Compounds of formula (XIII) in which R 7 represents a C5_7cycloalkyl group or a substituted phenyl group wherein the substituent is selected from a C-μ 4alkoxy, phenylC-|_3alkoxy or protected hydroxy group or a halogen atom, may be prepared by use of a reagent Rθ2SOCHR 7 Cθ2RP (wherein R 7 represents a C-5-7cycloalkyl group or a substituted phenyl group whereir the substituent is selected from a C-|_4alkoxy, phenylCι_3alkoxy or protected hydroxy group or a halogen atom and RO2SO is a sulphonate ester group, such as a mesylate) as described above and preferably in the presence of a base such as an alkali metal hydrogen carbonate (e.g. sodium hydrogen carbonate) or carbonate (e.g. potassium carbonate). The reaction is conveniently effected in a polar, aprotic solvent, such as dimethylsulphoxide and preferably at elevated temperature (e.g. 80-100°C). The reagents of formula Rθ2SOCHR 7 Cθ2RP (wherein R 7 and RO2SO are as defined just above) may be prepared from the corresponding α-hydroxy carboxylic acids, under standard conditions. α-Hydroxy carboxylic acids are known compounds or may be prepared by methods well known in the art. Compounds of formula (XIV) may be prepared by treating a suitable piperazine derivative with a compound of formula (XV) SUBSTITUTE SHEET (wherein R 3 is as defined above in formula (XII) above) preferably in the presence of a base (e.g. potassium carbonate) and a solvent (e.g. dimethylformamide), and conveniently at elevated temperature (e.g. 100- 12θOC). Compounds of formula (XV) are either known compounds or may be prepared by methods well known in the art. The compounds of formula (Xlll) containing the moiety may be prepared by reacting compounds of formula (XVI) with a compound of formula (XV) under the conditions used to prepare compounds of formula (XIV). Compounds of formula (XVI) may be prepared from a suitable piperazine derivative by treatment with a reagent LCHR 7 Cθ2R p employing the conditions used for the preparation of compounds of formula (Xlll) above containing the moiety SUBSTITUTE SHEET Compounds of formula (V) in which ring -B- represents may be prepared by reacting compounds of formula (XVII) with a reagent LCHR 7 C02R P under the conditions used for the preparation of compounds of formula (Xlll) above. Compounds of formula (XVII) may be prepared by treating a suitable piperazine derivative with a compound of formula (XVIII) (XVIII) preferably in the presence of a base such as an alkali metal carbonate or bicarbonate (e.g. potassium carbonate) and in a solvent such as an aprotic solvent (e.g. dimethylformamide, or dimethylsulphoide), conveniently at elevated temperature (e.g. 60-120°C). The compounds of formula (XVIII) are either known compounds or may be prepared by methods well known in the art. SUBSTITUTE SHEET It will be appreciated by a person skilled in the art that compounds of formula (V) in which ring -B- represents and ring -C- represents — N — R may be prepared by reacting compounds of formula (XVI) with a compound of formula (XVIII) under the basic coupling conditions described above for preparing compounds of formula (XVII). Compounds of formula (V) containing either the moiety (wherein R 4 and R 5 are both C-j_4alkyl) may be prepared from a suitable disubstituted piperazine derivative using a method selected from those described above for the preparation of compounds of formula (V) from piperazine derivatives. It will be appreciated by a person skilled in the art that compounds of formula (V) prepared from such disubstituted piperazine derivatives may be in the form of a mixture; compounds with the desired regiochemistry in which ring -C- is either wholly may be obtained by separating this mixture by conventional methods. Compounds of formula (V) in which ring -C- represents SUBSTITUTE SHEET / \ — N N \ I ■ may also be prepared by treating compounds of formula (XIX) with a reagent LCHR 7 C02R P under the conditions described for the preparation of compounds of formula (Xlll) above. Compounds of formula (XIX) may be prepared by treating compounds of formula (XX) with a reagent bis(2-chloroethyl)amine hydrochloride in a suitable solvent such as chlorobenzene and conveniently at elevated temperature (e.g. 100- 13θOC). Compounds of formula (XX) are either known compounds or may be prepared by methods known in the art. Compounds of formula (I) or intermediates thereto in which ring -A- or ring -B- represents a C-j_4alkyl substituted 1 ,4-phenylene group may conveniently be prepared by modification of the corresponding compound in which ring -A- or ring -B- represents a bromo substituted 1 ,4-phenylene group. Thus, for example, the bromo substituted intermediate may be treated with a zinc reagent RZnBr (where R is Ci^alkyl) in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0). Alkylation may also be effected using a tin reagent (R)4Sn (where R is a Cι_4alkyl) in the presence of a palladium catalyst such as bis(triphenylphosphine)benzylpalladium chloride. TITUTE SHEET Compounds of formula (IV) in which -C- represents may be prepared from compounds of formula (XXII) under reducing conditions. Thus said compounds of formula (XXII) are treated with a reducing agent such as a metal hydride (e.g. sodium borohydride) in a solvent such as an alcohol (e.g. ethanol) at ambient temperature to give compounds of formula (XXIII) (XXIII) The removal of the double bond gives the desired compounds of formula (IV) and may conveniently be achieved by hydrogenolysis in the presence of a suitable transition metal catalyst (e.g. platinum on activated carbon, or platinum oxide). The reaction may conveniently be effected in a solvent such as an alcohol (e.g. ethanol), optionally in the presence of an acid (e.g. hydrochloric acid) and at ambient temperature. Compounds of formula (XXII) may be prepared by reacting compounds of formula (XXIV) SUBSTITUTE SHEET with a reagent LCHR 7 C02R P in a solvent such as a nitrile (e.g. acetonitrile) and at elevated temperature (e.g. reflux). Compounds of formula (XXIV) may be prepared by reacting compounds of formula (XXV) (wherein ring -A- and ring -B- are as defined above with the proviso that when ring -A- is ring -B- may not be with a boronic acid of formula (XXVI) under the boronic acid coupling conditions described previously in the reaction between compounds of formulae (V) and (VI). Compounds of formula (XXIV) in which ring -A- represents and ring -B- represents SUBSTITUTE SHEET may be prepared by coupling compounds of formula (XVIII) firstly with a boronic acid of formula (XXVI) and then with a boronic acid of formula (VI), both reactions under the boronic acid coupling conditions described previously. The boronic acids of formula (XXVI) may be prepared from the corresponding halides under conventional conditions. Compounds of formula (XXV) in which ring -A- represents and thus ring -B -represents may be prepared by reacting a boronic acid of formula (VI) with a compound of formula (XXVII) (XXVII) under the boronic acid coupling conditions described previously. Compounds of formula (XXVII) are either known compounds or may be prepared by methods well known in the art. Compounds of formula (XXV) in which ring -A- represents may be prepared by reacting compounds of formula (XXVIII) SUBSTITUTE SHEET (XXVIII) with a reagent such as t-butyl nitrite in bromoform, conveniently at ambient temperature. Compounds of formula (XXVIII) in which -ring -A- represents a fluoro, chloro, or bromo substituted 1 ,4-phenylene may be obtained by reacting compounds of formula (XI) with compounds of formula (XXIX) (wherein R is a Chalky! group, e.g. butyl) under the conditions described in the preparation of compounds of formula (VIII) above. Compounds of formula (XXVlll) in which ring -A- represents may be obtained by treatment of compounds of formula (IX) with those of formula (XXIX) under the conditions described just above for the trialkylstannane coupling reaction, followed by reaction with an inorganic nitrile such as sodium cyanide employing the conditions described previously for the preparation of compounds of formula (IV) from those of formula (Vlll). Compounds of formula (XXIX) may be prepared from compounds of formfula (XX) under the conditions described in the preparation of compounds of formula (X) above. Compounds of formula (XXI) in which R 1 is hydrogen may be prepared from compounds of formula (XXll) under the conditions described above for preparing SUBSTITUTE SHEET compounds of formula (I) from compounds of formula (IV) via compounds of formula (II). Compounds of formula (XXI) in which R "1 is a Ci^alkyl or 2,2,2-trifluoroethyl group may also be prepared from compounds of formula (XXll) under the conditions described in process (C) above. Compounds of formula (IV) in which R 7 represents a benzyl or naphthylmethyl group may be prepared from the corresponding compounds of formula (IV) in which R 7 represents a hydrogen atom by treating said compounds of formula (IV) with a strong base such as a lithium amide (e.g. lithium bis(trimethylsilyl)amide or lithium diisopropylamide) at reduced temperature (e.g. -70°C) in a suitable solvent (e.g. tetrahydrofuran), followed by alkylation, between -70°C and room temperature. The alkylation may be effected by using, for example, a benzyl or naphthylmethyl halide (e.g. benzyl or naphthylmethyl bromide). It will be appreciated by those skilled in the art that certain of the procedures described hereinabove for the preparation of compounds of formula (I) or intermediates thereto may not be applicable to some of the possible combinations of rings and substituents. It will also be appreciated by those skilled in the art that for certain of the methods described hereinabove the desired stereochemistry of the product may be obtained either by commencing with an optically pure starting material or by resolving the racemic mixture at any convenient stage in the synthesis. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art: see for example 'Stereochemistry of Carbon Compounds' by E L Eliel (McGraw Hill, 1962) and 'Tables of Resolving Agents' by S H Wilen. Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formula (IV) are key intermediates and represent a particular aspect of the present invention. SUBSTITUTE SHEET Conveniently, compounds of formula (I) are isolated following work-up as acid addition saits, e.g. trifluoroacetate salts. Physiologically acceptable acid addition salts of the compounds of formula (I) may be prepared from the corresponding trifluoroacetate salts by exchange of ion using conventional means, for example by addition of a suitable organic or inorganic acid. Inorganic base salts of the compounds of formula (I) may also be prepared from the corresponding trifluoroacetate salts by addition of a suitable strong base such as sodium hydride. Solvates (e.g. hydrates) of a compound of formula (I) may be formed during the work-up procedure of one of the aforementioned process steps. The following Preparations and Examples illustrate the invention but do not limit the invention in any way. AH temperatures are in °C. System A is dichloromethane-ethanol-0.880 ammonia. System B is ethyl acetate-hexane. System C is dichloromethane-methanol-0.880 ammonia. Preparative high performance liquid chromatography (h.p.l.c.) was carried out using a Dynamax 60A C18 8μM 25cm x 41.4mm i.d. column eluted with a mixture of solvents (i) 0.1% trifluoroacetic acid in water and (ii) 0.05% trifluoroacetic acid in acetonitrile, at a flow rate of 45ml minute. Analytical h.p.l.c. was carried out using a Dynamax 60A C18 8μ 25cm x 4.6mm i.d. column using eluants as for preparative h.p.l.c, at a flow rate of 1 ml/minute. Intermediate 1 1-(4-Bromophenvnpiperazine monohvdrobromide To a solution of phenylpiperazine (32.4g) in chloroform (300ml) tetrabutyl ammonium tribromide (96.4g) was added portionwise, and the mixture left to stir under nitrogen for 24h. The mixture was filtered, and the solid washed with chloroform (500ml) and dried in vacuo to give the title compound as an off-white solid (35.5g). T.l.c. Siθ2 System A (89:10:1) Rf 0.25 SUBSTITUTE SHEET Intermediate 2 1.1 -Dimethylethyl 4-'4-bromophenvlV1 -piperazineacetate Intermediate 1 (5g) was heated under reflux with t-butyl bromoacetate (2.84ml) and potassium carbonate (6.62g) in acetonitrile (80ml) with stirring, under nitrogen for 17h. The solvent was evaporated and the residue partitioned between water (100ml) and ethyl acetate (3x100ml); the organic layers were combined and evaporated in vacuo to dryness to give a cream coloured solid. Trituration with hexane provided a sample of the title compound (1.72g). T.i.c. Si0 2 (System B, 1 :1) Rf 0.85. Intermediate 3 4-CyanophenylbQrpnic acid A solution of n-butyllithium in hexane (1.58M; 383ml) was added dropwise, at ca. -100° under nitrogen to a stirred solution of 4-bromobenzonitrile (100g) in freshly distilled tetrahydrofuran (1.9L). Addition was complete in 50min and the temperature was maintained at ca. -100° for 15min before triisopropylborate (140ml) was added dropwise between -97° and -96°. Addition was complete in 1 h and stirring was continued at £a. -97 u for 2.5h. The mixture was allowed to warm to -10° and hydrochloric acid (2M; 352ml) was added dropwise over 10min., The reaction mixture was poured into water (11) and the layers were separated. The organic layer was washed with water (11) and saturated brine (11), dried (MgS04), filtered and concentrated in vacuo to give the title compound (60.0g) as a white solid. N.m.r. (δ, D 6 -DMSO) : 7.82, 7.96 (4H,AA'BB', aromatics), 8.45 (2H,br.s, OH). Intermediate 4 1.1 -Dimethvlethvl 4-[4'-cvano-[1.1 '-biphenvl]-4-vl1-1 -piperazineacetate A stirred mixture of Intermediate 3(0.83g), Intermediate 2 (1.71g), tetrakis(triphenylphosphine)palladium (0) (0.29g) and anhydrous sodium SUBSTITUTE SHEET carbonate (1.64g) in water (12ml) and 1 ,2-dimethoxyethane (25ml) was heated under reflux, under nitrogen for 17h. Water (100ml) was added to the cooled solution, and the solution was extracted with ethyl acetate (3x120ml). The combined organic extracts were evaporated in vacuo to give a residue. Trituration of the residue with ether/hexane (1 :1, 40ml) provided the Jills compound (1.12g) as a yellow solid. T.I.C. Siθ2 (System B 1 :1), Rf 0.3. Intermediate 5 1.1 -Dimethvlethvl 4-f4'-faminothioxomethvrιf1.1 '-biphenvn-4-vη-1 - piperazineacetate Intermediate 4 (0.6g) was dissolved in dry dimethylformamide (30ml); triethylamine (3ml) was added and hydrogen sulphide was bubbled through the mixture for 20min, giving a dark green solution. The mixture was stirred at room temperature for 16h and then poured into aqueous sodium carbonate (2N; 120ml) and extracted with ethyl acetate (3x120ml). The combined organic layers were washed with brine/water (1 :1 , 2x140ml) and brine (100ml), dried (MgSθ4) and evaporated in vacuo to give the title compound as a pale yellow solid (0.631 g). T.l.c. Si0 2 (System B 1 :1), Rf 0.15. Intermediate 6 1.1 -Dimethvlethvl 4- heπvlmethvlV1 -piperazineacetate A mixture of 1-benzylpiperazine (20g), t-butyl bromoacetate (20.1ml) and potassium carbonate (47.0g) in dry acetonitrile (700ml) was heated under reflux for 17h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (500ml) and distilled water (800ml). The aqueous layer was extracted with ethyl acetate (2x300ml). The combined ethyl acetate SUBSTITUTE SHEET extracts were washed with brine (2x500ml), dried (MgSθ4), and the solvent removed in vacuo to afford the title compound as a red oil (35.8g). T.l.c. Siθ2 (ethyl acetate) Rf 0.37 Intermediate 7 1.1 -Dimethylethyl-1 -piperazineacetate Intermediate 6 (10g) and 1 M ethanolic hydrogen chloride (35ml) in absolute ethanol (150ml) were added to pre-hydrogenated palladium hydroxide (5g) in ethanol (150ml) and hydrogenated at room temperature and pressure overnight. More palladium hydroxide (5g) was added and hydrogenation continued for a further 3.5h. The mixture was filtered through hyflo and evaporated in vacuo to dryness. The residue was taken up in water (100ml), the pH adjusted to 12 with 2N sodium carbonate, and the water removed in vacuo. The residue was pulversied with dichloromethane:ethyl acetate [1 :1], and the filtrate evaporated in vacuo to afford a brown oil (6.5g). Purification by flash chromatography on silica gel (Merck 9385, 500ml) eluting with system A (40:9:1) gave the title compound as a yellow oil (3.77g). T.l.c. Siθ2 (System A, 3:1 :0.1), Rf 0.11 intermediate g 1 ,1 -Pimethylethyl-4-[5-brpmo-2-pyridinyi]-1 -piperazineacetate A mixture of 2,5-dibromopyridine (6.9g), Intermediate 7 (7g) and potassium carbonate (4g) in dry dimethylformamide (200ml) was heated under reflux under nitrogen for 72h. The dimethylformamide was removed in vacuo and the residue partitioned between ethyl acetate (400ml) and water (400ml). The aqueous layer was extracted with ethyl acetate (2x250ml). The combined extracts were washed with water (2x500ml) and brine (1x500ml), dried (MgS0 4 )and the solvent removed in vacuo to afford a tan solid (8.99g). Purification by flash SUBSTITUTE SHEET chromatography on silica gel (Merck 9385) eluting with hexane:ethyl acetate (3:1 ) gave the title com p ound as a white crystalline solid (5.62g). T. c. Siθ2 (System B, 1 :3), Rf 0.27 intermediate 9 1.1 -Dimethvlethvl 4-f5-r4-cvanophenvη-2-pvridinvl]-1 -piperazineacetate A mixture of intermediate 3 (1.39g), intermediate 8 (2.8g), sodium carbonate (2.5g) andtetrakis(triphenylphosphine)palladium(0) (0.45g) in 1 ,2- dimethoxyethane (80ml) and water (40ml) was heated under reflux under nitrogen for 22h. The mixture was concentrated in vacuo and the residue pre- adsorbed onto silica gel (Merck 7734). Purification by flash chromatograpghy on silica gel (Merck 9385) eluting with system C (97:3:0.3) followed by trituration with etheπhexane (2:1) gave the title compound as a white crystalline solid (0.493g). T.Lc. Siθ2 (System C, 96:4:0:4) Rf 0.3. Intermediate 10 1.1 -Dimethvlethvl 4-r5-f4-feminothioxomethvnphenvlj-2-pvridinvl1-1 - piperazineacetate Hydrogen sulphide was bubbled through a solution of intermediate 9 (0.475g) in dry dimethylformamide (25ml) and triethylamine (5ml) for about 20min giving a dark green solution. The reaction flask was stoppered and the mixture stirred at room temperature overnight. The mixture was partitioned between water (100ml) and ethyl acetate (2x50ml). The combined organic extracts were washed with 2N sodium carbonate (2x150ml), water (2x150ml) and brine (2x150ml), dried (MgS0 4 ), and the solvent removed in vacuo to afford a yellow residue which was triturated with ether. The title compound, a yellow crystalline solid, was filtered off and dried in vacuo (0.324g). SUBSTITUTE SHEET T.l.c. Siθ2 (System C, 90:9:1), Rf 0.6 Intermediate 11 cis-4-f4-Nitrophenyl -2.6-dimethyl-1 -piperazine A mixture of 1 -fluoro-4-nitrobenzene (12.3g), cis 2,6-dimethylpiperazine (10g), and potassium carbonate (24.2g) in dry dimethylformamide was heated at 110° under nitrogen for 24h. The solvent was removed in vacuo. and water (200ml) added to the residue. The resultant solution was extracted with ethyl acetate (3x300ml). The combined, organic extracts were dried (MgSθ4) and evaporated in vacuo to give the title compo nd as a yellow solid (19.7g). T.l.c. Siθ2 (System A, 96:4:0.4) Rf 0.4 Intermediate d cis-1.1 -Pimethylethyl 4-[4-nitrophenyl]-_, . -dimethyl-1 -piperazineacetate Intermediate 11 (8g) was heated under reflux with t-butyl bromoacetate (6.04ml) and potassium carbonate (5.16g) in acetonitrile (80ml) with stirring, under nitrogen for 24h. The solvent was removed in vacuo and the residue dissolved partially in water (200ml). The suspension was extracted with ethyl acetate (3x200ml), and the combined organic extracts dried (MgS04) and evaporated in vacuo to give the title compound as a beige solid. T.l.c. (System A, 96:4:0.4) Rf 0.85 Intermediate 13 cis-1 ■ 1 -Dimethylethyl 4-[4-aminophenyl]-2.6-dimethyi-1 -piperazineacetate A solution of intermediate 12 (11.7g) in ethanol (200ml) and hydrochloric acid (2J4; 32ml) was hydrogenated at room temperature and pressure over palladium on carbon (2g) in ethanol (100ml) for 1 h. The catalyst was filtered off, the ethanol was removed in vacuo and sodium bicarbonate solution (8%, 200ml) SUBSTITUTE SHEET added to the residue. The resultant mixture was extracted with ethyl acetate (3x200ml) and the combined, dried (MgS04) extracts were evaporated in vacuo to give the title compound as a brown oil (10.4g). T.l.c. Siθ2 (System B, 1 :1) Rf 0.25 Intermediate 14 cis-1.1 -Dimethylethyl 4-f4-bromophenvη-2.6-dimethvl-1 -piperazineacetate i-Butyl nitrite (4.13ml) was added to a solution of intermediate 13 (5g) in bromoform (15ml) and the mixture heated at 60^ for 15min. The mixture was . evaporated onto silica gel (Merck 7734) and applied as a plug to a flash chromatography column (Merck 9385), eluting with ethyl acetate:hexane [1 :1] and ethyl acetate:methanoI [99:1] to give the title compound as a dark red oil (1.82Q). T.l.c. Siθ2 (System B, 1 :1) Rf 0.85 Intermediate 15 cis-1.1 -Dimethvlethvl 4-f4'-cvano-f1.1'-biphenvl]-4-vlV2.6-dimethvl-1- pjperazineacetate A stirred mixture of intermediate 3 (0.76g), intermediate 14(1.8g), tetrakis(triphenylphosphine)palIadium (0) (0.27g) and anhydrous sodium bicarbonate (1.18g) in water (25ml) and 1 ,2-dimethoxyethane (50ml) was heated under reflux for 24h under nitrogen. Water (150ml) was added to the cooled solution, and the solution was extracted with ethyl acetate (3x150ml). The combined organic extracts were dried (MgSθ4) and evaporated in vacuo to give a black residue, which was preadsorbed onto silica gel. Purification by flash chromatography (Merck 9385) eluting with dichloromethane:methanol [99:1] gave the title compound as a yellow solid (0.75g). T.l.c. Siθ2 (System B 1 :1 ) Rf 0.75 SUBSTITUTE SHEET Intermediate 16 cis-1.1 -Dimethvlethvl 4-[4'- aminothioxomethvh[1.1'-biphBnvη-4-vη-2.6-dimethvl- 1 -piperazineacetate Intermediate 15 (0.740g) was dissolved in pyridine (30ml), triethylamine (4ml) was added and hydrogen sulphide was bubbled through the mixture for 20min, giving a dark green solution. The mixture was stirred at room temperature for 25h, and evaporated in vacuo to give the title compound as a mustard coloured solid (0.75g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 16.9min. Intermediate 17 4-Bromo-N-hvdroxv-benzenecarboximidamide 4-Bromobenzonitrile (5g) was dissolved in methanol (250ml), potassium carbonate (11.4g) followed by hydroxylamine hydrochloride (5.73g) were added, and the mixture was heated under reflux under nitrogen overnight. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (300ml) and distilled water (300ml). The aqueous layer was extracted with ethyl acetate (2x200ml). The combined ethyl acetate extracts were washed with brine (1x500ml), dried (MgSθ4) and evaporated in vacuo to afford the title compound as a white solid (5.63g). T.l.c. Siθ2 (System B, 1 :1) Rf 0.32 Intermediate 18 N-Hvdroxv 4-ftributvlstannvl benzenecarboximidamide Intermediate 17 (11g) and hexabutylditin (47ml) in dry toluene (300ml) were treated with tetrakis (triphenylphosphine) palladium (0) (4.5g)and heated at 100° under nitrogen for 4 hours. The mixture was cooled to room temperature and SUBSTITUTE SHEET 5% aqueous potassium fluoride (400ml) added. After vigorous shaking for 10 minutes, the emulsion was filtered through hyflo. The organic layer was separated, dried (Na2S04) r and the solvent removed in vacuo. The residue was purified by dry flash chromatography (Merck 7736) eluting with hexane: ethyl acetate (1 :0)-(5:1 ), to afford the title compound as a yellow oil. (10.4g) T.l.c. Siθ2 (System B, 1 :1) Rf 0.84 Intermediate 19 1 -r4-lodophenvhpiperazine . 1-Phenylpiperazine (50.6g) and iodine (119g) in methanol (600ml) were treated with calcium carbonate (62.5g) and water (40ml), and the mixture stirred at room temperature for 24h under nitrogen and warmed to 45° for a further 24h. The mixture was filtered and evaporated in vacuo. 1 M aqueous sodium thiosulphate solution (1 L) was added to the residue, and the solution extracted with ethyl acetate (3x750ml), which gave rise to a cream coloured precipitate between the layers. The combined organic extracts were evaporated in vacuo. and combined with the precipitate to give the title compound as light brown solid (20g). T.I.C. Siθ2 (System B, 1 :1) Rf 0.5 Intermediate 20 .1 -Dimethvlethvl 4-f4-iodophenvn-1 -piperazineacetate Intermediate 19 (10g) was heated under reflux, under nitrogen with t-butyl bromoacetate (6.22ml) and potassium carbonate (5.8g) in acetonitrile (100ml). The solvent was removed in vacuo and the residue partiitoned between water (200ml) and ethyl acetate (3x250ml). The combined, dried (MgSθ4) extracts were evaporated in vacuo to give a cream coloured solid; trituration with System B (1 :1, 2x50mi) gave the title compound as a yellow solid (1.86g). T.l.c. Siθ2 (System B, 1 :1) Rf 0.4 SUBSTITUTE SHEET Intermediate 21 4'-M -Piperazinvn[1.1 '-biphenvll-4-carbonitrile Intermediate 1 (27.8g), intermediate 3 (15.5g), sodium carbonate (38.2g) and tetrakis(triphenylphosphine)palladium (0) (1.6g) were dissolved in water (90ml) and 1 ,2-dimethoxyethane (210mi), and the mixture was heated under reflux under nitrogen for 18 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (300ml), and concentrated onto silica gel (Merck 7734). Purification by flash chromatography on silica get (Merck 9385) eluting with System C (95:4.5:0.5) gave the title compound as a tan solid (6.4g) T.l.c. Siθ2 (System C, 95:5:0.5) Rf 0.3 Intermediate 22 Ethyl 4-[4'-cvano[1.1 '-biphenvlH-vl]-oι-methvl-1 -piperazineacetate A mixture of intermediate 21 (2g), ethyl 2-bromopropionate (1.09ml) and potassium carbonate (1.05g) in dry acetonitrile (100ml) was heated under reflux, under nitrogen overnight. The acetonitrile was removed in vacuo and the residue partitioned between ethyl acetate (150ml) and water (150ml). The aqueous layer was extracted with ethyl acetate (2x100ml); the combined ethyl acetate extracts were washed with water (1x200ml) and brine (1x200ml), dried (MgSθ4) and the solvent removed in vacuo to afford a light tan solid (2.57g). Purification by column chromatography on silica gel (Merck 9385; compound pre-adsorbed onto silica gel (Merck 7734)) eluting with ethyl acetate gave the title compound as a pale yellow solid (2.14g). T.l.c. Siθ2 (ethyl acetate) Rf 0.5 Intermediate 23 Ethvl 4-[4'-(aminothioxomethvnn .1 '-biphenvl1-4-vl]-tx-methvl-1 -piperazineacetate Hydrogen sulphide gas was bubbled through a solution of intermediate 22 (1.6g) in dry pyridine (75ml) and triethylamine (15ml) for 0.5h. The reaction SUBSTITUTE SHEET flask was stoppered and the mixture stirred at room temperature for 3 days. The mixture was concentrated in vacuo. and the residue purified by trituration with ether. A yellow solid was filtered off and dried to give the title compound (1.65g). T.l.c. S1O2 (ethyl acetate) Rf 0.48 Intermediate 24 4-r4'-Cvano-[1.1'-biphenvl]-4-vl]- -piperazineacetic acid Intermediate 4 (1.8g) was treated with a mixture of trifluoroacetic acid (18ml) and water (2ml), and the mixture stirrred at room temperature for 1 h. The solvent was removed in vacuo to leave the title compound as a cream solid (1.79). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R t 14.0 min. Intermediate 25 2-rEthvlf1 -methvlethvhamino]-2-oxoethvl 4-f4'-cvano-f1.1 '-biphenvl]-4-vπ-1 - piperazineacetate A solution of intermediate 24 (1g), potassium carbonate (1.25g) and 2- [ethyl(1-methylethyl)amino]-2-oxoethyl bromoacetate (0.76g) in dry dimethylformamide (30ml)" was stirred at 100°, under nitrogen, for 2h. The reaction mixture was partitioned between ethyl acetate (200ml) and water (200ml). The aqueous layer was extracted with ethyl acetate (3x200ml). The combined, dried (MgS04) extracts were evaporated in vacuo to give the title compound as a cream solid (0.79g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 16.9 min. SUBSTITUTE SHEET Intermediate 26 2-rEthyl(1-methylethvnamino]-2-oxoethyl 4-[4'-(aminothioxomethvn[1.1 '- biohenvl]-4-vl]-1 - piperazineacetate Hydrogen sulphide gas was bubbled through a solution of Intermediate 25 (0.8g) in dry dimethylformamide (30ml) and triethylamine (4ml) for 0.5h. The reaction flask was stoppered and the mixture stirred at room temperature for 6h. The mixture was concentrated in vacuo. and the residue purified by trituration with ether. A yellow solid was filtered off and dried to give the title compound (0.7g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R 15.7 min. Intermediate 27 1 -(5-Bromo-2-pvridinvnpiperazine A mixture of 2,5-dibromopyridine (11.7g), piperazine (8.5g) potassium carbonate (6.9g) and dimethyisulphoxide (100ml) was heated at 140° with stirring under nitrogen for 24h. Ethyl acetate (400ml) was added and the mixture washed with water (3x150ml) and brine (100ml), dried (Na 2 S0 4 ) and evaporated in vacuo. The residue was purified by flash chromatography over silica gel (Merck 9385, 90g) with system C (70:30:1 ) eluant to give the title com p ound as a colourless solid (7.64g). m.p. 72-74°. Intermediate 28 Methyl 4-f5-bromo-2-pyridinylVα-phenyl-1 -piperazineacetate A mixture of intermediate 27 (6.55g), potassium carbonate (7.5g), methyl α- bromophenylacetate (7.4g) and dimethyisulphoxide (150ml) was heated at 110° for 24h. Ethyl acetate (400ml) was added and the mixture washed with water (3x100ml) and brine (50ml), dried (Na 2 S0 4 ) and evaporated in vacuo. The SUBSTITUTE SHEET residue was purified by flash chromatography over silica gel (Merck 9385, 100g) with ethyl acetate - triethylamine (49:1 ) eluant to furnish the title compound as a pale yellow solid (11.43g). T.l.c. Si0 2 (Ethyl acetate:triethylamine 49:1) Rf = 0.5. Intermediate 29 Methvl 4-[5-r4-cvanophenvn-2-pvridinvl]- -phenvl-1-piperazineacetate A mixture of intermediate 28 (5.02g), intermediate 3 (1.90g), dimethoxyethane (110ml), 8% sodium bicarbonate (15ml) and tetrakis (triphenylphosphine) palladium (0) (0.25g) was heated under reflux under nitrogen for 16h. The mixture was concentrated in vacuo. the residue partitioned between ethyl acetate (400ml) and brine (200ml), and the organic phase dried (Na 2 S0 4 ) and evaporated in vacuo. The residue was purified by flash chromatography over silica gel (Merck 9385, 100g) with ether-ethyl acetate-triethylamine eluant (50:48:2) to give the title compound as a pale yellow solid (1.27g). T.l.c. Si0 2 (Ethyl acetate : triethylamine 49:1 ) Rf = 0.4. Intermediate 30 Methv|-4-[5-f4-ramiπothioxomethvnphenvl1-2-pvridinvl]- -phenvl-1- piperazineaoetate Intermediate 29 (1.13g) was dissolved in dimethylformamide (15ml)- trϊethylamine (3ml) and hydrogen sulphide gas passed through the solution for 20 mins. The dark mixture was stirred at ambient temperature for 16h then poured into 2M sodium carbonate solution (100ml). The solid precipitate was collected by filtration, washed with water (10ml) and dried in vacuo. The crude product was triturated with hexane-ether (1 :1, 25ml) to afford the title compound as a pale yellow solid (1.12g). Tic: Si0 2 (System B 89:10:1) Rf = 0.5 SUBSTITUTE SHEET Intermediate 31 1.1 -Dimethvlethvl 4-(5-bromo-2-pvridinvlV1 -piperazinecarboxvlate Di-t-butyl dicarbonate (38.8g) in dry 1 ,4-dioxan (100ml) was added dropwise to a stirred solution of intermediate 27 (43g) and dry triethylamine (65ml) in dry 1 ,4-dioxan (375ml) with ice cooling. The reaction was stirred at room temperature under nitrogen overnight. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (300ml) and water (300ml). The aqueous later was extracted with ethyl acetate (2x250ml). The combined ethyl acetate extracts were washed with brine (600ml), dried (MgS0 4 ) and the solvent removed in vacuo to afford an off white solid. The solid was triturated in hexane. A white solid was filtered off and dried to give the title compound (50.6g). T.l.c Si0 2 (1 :1 , hexane: ethyl acetate) Rf=0.71 Intermediate 32 1.1 -Dimethvlethvl 4-[5-(4-cvanophenvn-2-pvridinvl]-1 -piperazinecarboxvlate A stirred mixture of intermediate 3 (13g), intermediate 31 (30g) and anhydrous sodium carbonate (9.3g) in 2:1 , dimethoxyethane: water (1200ml) was treated with tetrakis (triphenylphosphine) palladium (0) (4.3g) and heated at reflux temperature and water (350ml) added. The resultant solution was extracted with ethyl acetate (3 x 600ml). The combined ethyl acetate extracts were washed with water (750ml), brine (750ml), dried (MgS0 4 ) and the solvent removed in vacuo to afford a pale yellow solid (46.4g) which was purified by flash chromatography on silica gel (Merck 9385) eluting with System A (98:2:0:2) to give the title compound as a pale yellow solid (15.3g). T.l.c. Si0 2 (1 :1 , hexane: ethyl acetate) Rf=0.56 SUBSTITUTE SHEET Intermediate 33 1.1 -Dimethylethvl 4-f5-r4-[aminofhvdroxvimino^methvl]]phenvn-2-pvridinvn-1 - piperazine carboxylate A mixture of intermediate 32 (15g), hydroxylamine hydrochloride (1.4g) and potassim t-butoxide (2.3g) in methanol (360ml) was heated at reflux under nitrogen for 2 hours. Three further portions of hydroxylamine hydrochloride and potassium t-butoxide, (1.4g) and (2.3g) respectively, were added after 2, 4 and 6 hours. The reaction was heated at reflux under nitrogen overnight. The reaction was cooled and water (75ml) added. A white solid was filtered off and dried to give the title compound (14.8g). T.l.c. Si0 2 (90:10:1 r System C) Rf = 0.5 Intermediate 34 1.1 -Dimethvlethvl 4-f5-[4-faminoiminomethvnphenvn-2-pvridinvn-1 -piperazine carboxylate acetate Acetic acid (200ml) containing acetic anhydride (5.3ml) was added to intermediate 33 (14.7g) and 10% palladium on carbon (1.1g). The suspension was stirred under an atmosphere of hydrogen for 3 hours. The catalyst was filtered off, and the filtrate evaporated in vacuo to yield a yellow solid which was triturated in ether to give the title compound as a pale yellow solid (14.2g). T.Lc. Si0 2 (System C, " 90:10:1) Rf = 0.1 Intermediate 35 1.1>Dimethvlethvl -r5-r4- nminoffrphenvlmethoxv^carbonvl]amino1methvl]phenvl1-2-pvridinvl -1- piperazinecarboxvlate Intermediate 34 (5.5g) in dry dichloromethane (550ml) was treated with benyl chloroformate (1.56ml) and the mixture stirred at room temperature for 30 SUBSTITUTE SHEET minutes. Sodium hydroxide solution (0.1 M, 548ml) was added dropwise and the resultant two-phase mixture stirred vigorously for 1 hour. The organic layer was separated, dried (MgS0 4 ) and evaporated in vacuo to yield a yellow solid which was purified by flash column chromatography on silica gel (Merck 9385) eluting with system A (98:2:0:2) to give the title compound as a yellow solid (4.29g). T.l.c. Si0 2 (System A, 98:2:0:2) Rf = 0.2 Intermediate 36 Phenvlmethvl [imino[4-[6-π-piperazinvn-3-pvridinvl]phenvl1methvncarbamate trifluoroacetate Intermediate 35 (8.5g) was treated with a mixture of trifluoroacetic acid (70ml) and water (7ml), and the mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo to leave the title compound as a pale yellow solid (12.6g). Analysis found C.44.7; H, 3.5; N, 8.0 C 24 H 25 N 5 0 2 .3.75CF 3 C0 2 H requires C,44.9; H, 3.4; N, 8.3% Intermediate 37 1.1 -Dimethvlethvl 4-fluorobenzeneacetate N.N-Dimethylformamide di-t-butyl acetal (50g) was added to a stirred mixture of 4-fluorobenzeneacetic acid (10g), in toluene (70ml). The reaction mixture was stirred at 90° for 4h. The solution was cooled and washed with respectively water (250ml), aqueous sodium carbonate (2N, 250ml), 10% aqueous lithium chloride (2 x 250ml), water (250mi) and brine (250ml). The organic layer was dried (MgS0 4 ), filtered and evaporated in vacuo to yield the title compound (5.9g) as a yellow oil. T.l.c. Si0 2 (System B, 9:1) Rf = 0.5 SUBSTITUTE SHEET Intermediate 38 1.1 -Dimethvlethvl re-bromo-4-fluorobenzeneacetate M-Bromosuccinimide (8.9g) and benzoyl peroxide (0.121 g) were added to a solution of intermediate 37 (10g) in carbon tetrachloride (100ml) and the suspension was heated to reflux under nitrogen with irradiation (200W tungsten lamp) for 1.5h. The solution was cooled and the succinimide filtered off. The resultant filtrate was washed with water (2 x 100ml), dried (MgS0 4 ) and evaporated in vacuo to give the title compound as a yellow oil (12.3g). T.l.c. Si0 2 (System B, 9:1) Rf = 0.65 Example 1 1.1 -Dimethvlethvl 4-[4'-faminoiminomethvn[1.1'-biphenvi]-4-vl]-1- piperazineacetate Intermediate 5 (0.62g) was dissolved in acetone (30ml) and methyl iodide (0.5ml) added. The mixture was heated under reflux under nitrogen for 1 h; after cooling, the mixture was concentrated in vacuo to a yellow semi-solid which was subsequently dissolved in methanol (30ml). Ammonium acetate (0.46g) was added and the solution heated under nitrogen at 60° for 2h. The mixture was concentrated in vacuo to a brown semi-solid which was purified by preparative h.p.l.c.(gradient profile 10-70% (ii) in 18 min) to give after Rt 11.5 min the title compound (0.037g). Mass spectrum [MH+] 395. Example 2 4-f4'-f Aminoiminomethvnfl .1 '-biphenvl]-4-vl]-1 -[2-f1.1 -dimethvlethoxvV2- oxoethvl]-1-methvl-1 -piperazinium trifluoroacetate salt Intermediate 5 (0.62g) was dissolved in acetone (30ml) and methyl iodide (0.5ml) added. The mixture was heated under reflux under nitrogen for 1 h; after SUBSTITUTE SHEET cooling, the mixture was concentrated in vacuo to a yellow semi-solid which was subsequently dissolved in methanol (30ml). Ammonium acetate (0.46g) was added and the solution heated under nitrogten to 60° for 2h. The mixture was concentrated to a brown semi-solid which was purified by preparative h.p.i.c.(gradient profile 10-70% (ii) in 18 min) to give after Rt 12.5 min the title compound (0.043g). Mass spectrum [MH+] 410. Example 3 1.1 -Dimethvlethvl 4-[5-f4-raminoiminomethvnphenvη-2-pvridinvn-1 - piperazineacetate Intermediate 10 (0.400g) was dissolved in acetone (50ml) and methyl iodide (0.181ml) was added. The mixture was heated under reflux under nitrogen for 1.75h. More methyl iodide (0.120ml) was added and heating under reflux was continued for a further 2.5h. The solvent was evaporated in vacuo and the residue dissolved in methanol (50ml). Ammonium acetate (0.224g) was added and the mixture warmed at 60°C under nitrogen for 7h. The methanol was removed in vacuo and the residue dissolved in the minimum volume of acetic acid and water. Purification by preparative h.p.l.c (gradient profile 10-90% (ii) in 25min) gave after Rγ 10.7min the title compound as a white solid (0.245g). Mass Spectrum [MH + ] 39.6 Example 4 cis-1.1 -Dimethvlethvl 4-f4'-faminoiminomethvn[1.1'-biphenvn-4-vr|-2.6-dimethvl- 1 -piperazineacetate Intermediate 16 (0.74g) was dissolved in acetone (30ml) and methyl iodide (0.21 ml) added. The solution was heated under reflux under nitrogen for 3h. After cooling, the mixture was concentrated in vacuo to an orange solid, which was dissolved in methanol (30ml). Ammonium acetate (0.52g) was added, and the solution heated under nitrogen at 60° for 2h. The solvent was removed in UTE SHEET vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-90% (ii) in 25min) to give after Rt 13.4 min the title compound as a yellow solid (0.26g). Analysis Found: C,46.9; H.4.8; N,7.0; C25H34N4O2.3.5 CF3CO2H requires C,46.8; H,4.6; N,6.8%. Example 5 1.1 -Dimethvlethvl 4-[4'-raminofhvdroxvimino^methvnri .1 '-biphenvl -vll-l - piperazineacetate Intermediate 20 (1.86g) and intermediate 18 (3.04g) were dissolved in dry dimethylformamide (30ml) and treated with bis(acetonitrile)palladium(ll) chloride (0.119g). The mixture was heated at 60° under nitrogen for 25h, cooled to room temperature and the solvent removed in vacuo. to leave a brown/black residue which was taken up in ethyl acetate (300ml). The solution was added to aqueous potassium fluoride (10%, 500ml) and filtered. After separation of the organic layer, the aqueous phase was further extracted with ethyl acetate (3x300ml). The combined organic extracts were washed with brine (1x500ml), dried (MgS04) and evaporated in vacuo to yield an orange brown oil, which was purified by preparative h.p.l.c. (gradient profile 10-90% (ii) in 25min) to give after Rt 8.3min an impure sample of the title compound (0.105g). Mass spectrum [MH + ] 411 Example 5 Ethvl 4-f4'-feminoiminomethvnri .1 '-biphenvl]-4-vl1-α-methvl-1 -piperazineacetate Intermediate 23 (0.80g) was dissolved in acetone (100ml) and methyl iodide (0.63ml) added. The mixture was heated under reflux, under nitrogen for 3.25h. Further methyl iodide (376μl) was added, and the mixture heated under reflux for a further 1.25h. The solvent was evaporated in vacuo. and the residue dissolved in methanol (100ml). Ammonium acetate (0.46g) was added and the mixture warmed at 60°C under nitrogen for 7h. The methanol was removed in SUBSTITUTE SHEET vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-90% (ii) in 25min) to afford after Rt 10.28min the title compound as a white solid (0.8g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 10.2min. Example 7 4-[4'- AminoiminomethvlU1.1 '-biDhenvη-4-vl1-1-f2- .1-dimethvlethoxvV2- oxoethvl]-1-fphenvlmethvlV1 -piperazinium acetate salt Intermediate 5 (450mg) was dissolved in acetone (130ml), treated with benzyl bromide (0.65ml) and the mixture heated under reflux for 18h. The solvent was removed in vacuo to leave an orange solid, which was dissolved in methanol (120ml), treated with ammonium acetate (252mg), and stirred at 60°C under nitrogen for 6h. The solvent was removed in vacuo to give the title compound (580mg) as an orange solid. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 15.0min. Example 8 4-[4'-f Aminoiminomethyl)[1.1 '-biphenyl]-4-yl]-1 -piperazineacetic acid trifluoroacetate salt Example 1 (0.118g) was dissolved in trifluoroacetic acid (9ml) and water (1 ml) and the mixture stirred at room temperature for 4h. Evaporation in vacuo gave the title compound as a cream solid (0.094g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R δ.Omin. Analysis Found: C.43.0; H,3.6; N,7.8; C-i 9H22N4O2.3.2CF3CO2H requires C.43.4; H.3.6; N,8.0%. SUBSTITUTE SHEET Example 9 4-[4'-f Aminoiminomethvfl| ' 1.1 '-biphenyl -4-yl]-1 -f2-hvdroxy-2-oxoethvπ-1 -methyl- -piperazinium trifluoroacetate salt Example 2 (0.046g) was dissolved in trifluoroacetic acid (4ml) and water (1 ml) and the mixture stirred at room temperature for 2h. Evaporation in vacuo gave the title compound as a light yellow solid (0.037g). Mass Spectrum [MH+] 353 Analysis Found: C,45.8; H,4.2; N.7.6; C20H25N4O2.2.9CF3CO2H requires C.45.3; .H,4.1 ; N.8.1 %. Example 10 Ethvl 4-[4'-faminoiminomethvnr ι 1.1 '-biDhenvl]-4-vl]-1 -piperazineacetate trifluoroacetate salt Hydrogen chloride gas was bubbled through a solution of Example 8 (0.09g) in ethanol (40ml) for 25min, and the mixture left to stir at room temperature for 12h. The solvent was removed in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-70% (ii) in 18 min) to give the title compound as a white solid (0.025g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R 9.7min. Example 11 Butvl 4-r4'-raminoiminomethvnf1 -1 '-biphenvl]-4-vl]-1 -piperazineacetate trifluoroacetate salt Hydrogen chloride gas was bubbled through a solution of Example 8 (0.12g) in n-butanol (40ml) for 20min and the mixture left to stir at room temperature for 24h. The solvent was removed in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-70% (ii) in 18 min) to give the title compound as a white solid (0.06g). SUBSTITUTE SHEET Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 12.2min. Analysis Found: C,50.2; H,5.3; N,7.9; C23H30N4O2.2.4CF3CO2H requires C,50.0; H,4.9; N,8.4%. Example 12 4-r5-r4-fAminoiminomethvnphenvπ-2-Pvridinvl1-1 -piperazineacetic acid trifluoroacetate salt A solution of Example 3 (0.160g) in trifluoroacetic acid (9ml) and water (1 ml) was stirred at room temperature under nitrogen for 2h. The mixture was concentrated in vacuo to afford an off-white solid (130mg), which was purified by trituration with ether. The title com p ound was filtered off and dried in vacuo (80mg). Mass spectrum [MH+] 340 Analysis Found: C,47.2; H.4.3; N.12.9; c 18 21 N5O2.1.85CF3CO2H requires: C.47.4; H,4.2; N,12.7%. Example 13 cis-4-r4'-rAminoiminomethvn[1.1 '-biphenvH-4-vl1-2.6-dimethvl-1 -piperazineacetic acid trifluoroacetate salt Example 4 (0.25g) was dissolved in trifluoroacetic acid (9ml) and water (1 ml) and the mixture stirred at room temperature for 18h. The solvent was removed in vacuo. and the residue triturated in ether (15m!) The solid was filtered off to give the title compound (0.18g). Analysis Found: C.47.7; H.4.4; N,8.55; c 21 H26N4O2.2.6CF3CO2H requires C,47.5; H.4.35; N,8.45%. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R 8.76min. SUBSTITUTE SHEET Example 14 4-[4'-[<Ηvdroxyamino^iminomethyl)π .1 '-biPhenyl -4-yl]-1 -piperazineacetic acid trifluoroacetate salt Example 5 (0.1 OOg) was stirred in trifluoroacetic acid (18ml) and water (2ml) for 23h. The solvent was removed in vacuo to give the crude product (0.088g). Purification by preparative h.p.l.c. (gradient profile 5-20% (ii) in 10min; 20% (ii) isochratic for 8min) provided after R 13.2min the title compound as a yellow solid, (0.029g). Analysis Found: C.41.6; H.3.6; N,7.8; C-i 9H22N4O3.3.5CF3CO2H requires C,41.45; H,3.4; N,7.4%. Mass Spectrum [MH+] 355 Example 15 4-[4'-f Aminoiminomethvπfl .1 '-biphenyl1-4-ylj-rc-methyl-1 -piperazineacetic acid trifluoroacetate salt Example 6 (0.70g) was dissolved in 2N hydrochloric acid (100ml), and the mixture stirred under nitrogen at 60°C for 56h. The solvent was removed in vacuo and the residue dissolved in a minimum volume of water. Purification by preparative h.p.l.c. (gradient profile 10-90% (ii) in 25min) gave after Rt 8.54min the title compound as a white solid (0.489g). Analysis Found: . C,46.4; H,4.2; N.8.6; C20H24N4O2.2.65CF3CO2H requires: C46.4; H,4.1 ; N,8.6%. Mass Spectrum [MH + ] 353 Example 16 4-f4'-( Aminoiminomethvhri .1 '-biDhenvl -4-vn-1 -f2-hvdroxv-2-oxoethvh-1 - φhenylmethvh-1 -piperazinium trifluoroacetate salt Example 7 (500mg) was treated with a mixture of trifluoroacetic acid (36ml) and water (4ml), and the mixture stirred at room temperature for 24h. The SUBSTITUTE SHEET solvent was removed in vacuo to leave a yellow solid, which was purified by preparative h.p.l.c. (gradient profile 10-45% (ii) in 9min; 45% (ii) isochratic for 4 min) to give after Rt 11.7min a cream coloured solid as the title compound (80mg). Analysis Found: C.53.2; H.4.5; N.8.0; C26H29N4O2.2.3 CF3CO2H requires: C.53.1 ; H,4.6; N,8.1% Mass spectrum [M + ] 429 Example 17 4-f4'-(Aminoiminomethvl)[1.1 '-biphenvl1-4-vl]-1 -(2-methoxv-2-oxoethvn-1 -methvl- 1 -piperazinium trifluoroacetate salt Intermediate 26 (0.4g) was dissolved in acetone (20ml) and methyl iodide (5ml) added. The mixture was heated under reflux, under nitrogen for 17h. The solvent was evaporated in vacuo and the residue dissolved in methanol (30ml). Ammonium acetate (0.25g) was added and the mixture warmed at 60°C, under nitrogen for 4h. The methanol was removed in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-90% (ii) in 25min) to afford after R 12.6 min the title compound as a cream solid (0.14g). Mass spectrum [MH + ] 368. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) Rt 11.6 min. Example 18 4-[5-f4ffAminoiminomBthvnphenvη-2-pvridinvη-α-phenvl-1-piperazinea-etic acid. trifluoroacetate salt Intermediate 30 (1.1 Og) was suspended in acetone (50ml), iodomethane (170μl) added and the mixture heated under reflux for 7h, with further additions of iodomethane (3x170μl) after 1 ,3 and 5h. The solution was cooled, and evaporated in vacuo. The residue was taken up in methanol (60ml), treated with ammonium acetate (1 g) and heated under reflux for 17h under nitrogen. The solvent was removed in vacuo and the residue dissolved in 5M hydrochloric acid SUBSTITUTE SHEET (50ml) and heated at 90-100° for 22h under nitrogen. The acid solvent was removed in vacuo and the residue purified by gradient preparative hpic (10-60% (ii) over 17 min, R t = 11 min) to afford the title compound as a cream solid (1.05g). Mass-Spec MH + (calc) = 415 MH + (found) = 415 Assay Found: C, 49.4; H, 4.4; N, 10.6 C 24 H 25 N 5 0 2 0.5 C 3 H 7 N0.2.6CF 3 C0 2 H requires: C, 49.3; H, 4.2; N, 0.3% Analytical hpic (gradient profile, 10-90% (ii) in 25 min) R t = 8.5min. Example 19 1.1 -Dimethvlethvl-o:-r4-fluorophenvlV4-f5-f4- rimino[f henvlmethoxv^carbonvl]amino -methvl]phenvl]-2-pvridiπvn-1- pjperazineacephate Intermediate 35 (2.62g), intermediate 38 (1g) and potassium carbonate (1.9g) in dry acetonitrile (60ml) were heated at reflux under nitrogen for 2.5 hours. The reaction was concentrated in vacuo and the residue partitioned between dichloromethane (100ml) and water (100ml). The aqueous layer was extracted with dichloromethane (2 x 75ml). The combined dichloromethane extracts were washed with water (100ml) and brine (100ml), dried (MgS0 4 ) and the solvent removed in vacuo to afford a dark yellow solid (2g) which was purified by flash column chromatography on silica gel (Merck 9385) eluting with (system A, 98:2:0.2) to give the title compound as a pale yellow solid (1.09g). T.Lc. Si0 2 (System A, 95:5:0.5) Example 20 1.1 Dimethvlethvl-4-f5-f4-raminoiminomethvnphenvl]-2-pvridinvl]-fx-f4- fluorophenvn-1-piperazineacetate A solution of Example 19 (1.0g) in dimethylformamide (30ml) was stirred over 10% palladium on carbon (125mg) at room temperature in an atmosphere SUBSTITUTE SHEET of hydrogen for 6 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo to give the title compound as a dark green foam (780mg). Analytical hpic (gradient profile 10-90% (ii) in 25 minutes) Rt = 14.1 min Example 21 4-r5-r4- Aminoiminomethvhphenvn-2-Pvridinvl1-«- 4-fluorophenvlV1- piperazineacetic acid trifluoroacetate salt A solution of Example 20 (0.8g) in trifluoroacetic acid (25ml) was stirred at room temperature for 2 hours. The trifluoroacetic acid was evaporated in vacuo . and the residue was triturated in ether: ethyl acetate (2:1) (15ml) to give the title compound as a beige powder (1.18g). Mass Spectrum [MH + ] = 434 Assay found: C 44.3; H 3.3; N 8.3% C 24 H 24 FN 5 0 2 .3.63 CF 3 C0 2 H requires C 44.3; H 3.3; N 8.3% Example 22 * Biological Pata Inhibition of blood platelet aggregation by compounds of the invention was determined according to the following procedure. Citrated whole blood (1 part 3.8% trisodium citrate : 9 parts blood) was obtained from human volunteers, free of medication for at least 10 days prior to colleciton. The blood was incubated with 0.1 mM aspirin and 0.5μM prostacyclin and then centrifuged at 1000g for 4 minutes (20°). The supernatant platelet rich plasma (PRP) was further centrifuged at 1300g for 10 minutes (20°C) to sediment the platelets. The supernatant was discarded and the pellet washed with a physiological salt solution 9HEPES 5Mm, NaHC0 3 12mM, NaCI 140mM, KH 2 P0 4 0.74mM, D- Glucose 5.6mM, KC1 2.83mM and BSA 20g/1 , pH 7.4) to remove residue plasma. After washing, the pellet was resuspended in physiological salt solution SUBSTITUTE SHEET and then applied to a sepharose CL-2B column, pre-equiiibrated with physiological salt solution at room temperature. The platelets (GFP) eluted within the void volume and were diluted to approximately 300,000 platelets/μl in buffer. Purified human fibrinogen (Knight L.C. et al, 1981 Thromb. Haemostasis, 4J_(3), 593-596) was added to a final concentration of 0.5mg/mi together with Ca2+ and Mg2+ at 1 mM and O.δmM respectively. Test compounds were incubated in GFP for 5 minutes at 37°C and the platelet aggregating agent adenosine diphosphate (ADP) was added to a final concentration of 1 x 10 "5 M. The potency of the compounds may be expressed as an IC 50 value defined as the concentration of compound required to produce 50% inhibition of platelet aggregation. the following IC 50 values were obtained for compounds of the invention: Compound Example No iΩ § o(ΩMl 8 23 9 47 10 2408 11 9539 12 14 13 219 14. 86 15 30 16 31 17 346 18 40 21 27 SUBSTITUTESHEET The compound of the invention, microcrystalline cellulose, lactose and cross-linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and blended with the active blend. The blend is compressed into tablets using suitable punches. The compound of the invention, lactose and pregelatinised starch are blended together and granulated with water. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened SUBSTITUTE SHEET through a 250 micron sieve and blended with the granule. The resultant blend is compressed using suitable tablet punches. The compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium stearate, (meshed through a 250 micron sieve). The blend is filled into hard gelatine capsules of a suitable size. b) Compound of the invention δ.Omg Lactose 177.0mg Polyvinylpyrrolidone δ.Omg Cross-linked polyvinylpyrrolidone δ.Omg Magnesium Stearate 2.0mg Fill weight 200.0mg The compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and milled. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 2δ0 micron sieve and blended with the granules. The resultant blend is filled into hard gelatine capsules of a suitable size. SUBSTITUTE SHEET δ9 Example 25 Pharmacy Example - Svrup a) Compound of the invention δ.Omg Hydroxypropyl Methylcellulose 4δ.0mg Propyi Hydroxybenzoate 1.δmg Butyl Hydroxybenzoate 0.7δmg Saccharin Sodium ' δ.Omg Sorbitol Solution 1.0ml Suitable Buffers qs Suitable flavours qs Purified Water to 10.ml The hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with the hydroxybenzoates and the solution is allowed to cool to room temperature. The saccharin sodium flavours and sorbitol solution are added to the bulk solution. The compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable buffers may be added to control the pH in the region of maximum stability. The solution is made up to volume, filtered and filled into suitable containers. Example 26 Pharmacy Example - Injection Formulation % w/v Compound of the invention 1.00 Water for injections B.P. to 100.00 SUBSTITUTE SHEET 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 compound of the invention 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. SUBSTITUTE SHEET Example 27 (1 RV1-(2-Naohthalenvnethvl -(4-fluorophenvn-4-rδ-r4- [imino r(phenvlmethoxv^carbonvl]amino1methvl1phenvll-2-pvridinvl]-1- piperazineacetate Hsomers 1 and 2, Intermediate 36 (1g), intermediate 40 (0.46g) and potassium carbonate (0.66g) in dry acetonitrile (20. ml) were heated at reflux under nitrogen for 4 hours. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (60.ml) and water (60.ml). The aqueous layer was extracted with ethyl acetate (βO.ml). The combined ethyl acetate extracts were washed with brine (δO.ml), dried (MgS04) and the solvent removed in vacuo to give a crude diastereomeric mixture of the title compound as a yellow oil (0.7g). The sample was initially purified using preparative hpic.(ABZ Supelco column, 2.δcm i.d., 2δcm long; gradient profile 30-70% acetonitrile/0.12%trifiuoroacetic acid, for 1δ mins, isochratic at 70% acetonitrile/0.12% trifluoroacetic acid for 10 minutes, flow rate 20ml/minute ) to give after R τ = 9 mins the diastereoisomers as a yellow gum. The diastereoisomers were separated by further preparative hpic, using the system as above, to give after R τ = δ.6 mins isomer 1 as a colourless gum, 30mg, and after R τ = 9.2 mins isomer 2 as a colourless gum, 60mg. Analytical hpic (ABZ Supelco column, 4.6 mm i.d., 1δ cm long; gradient profile 30 - 70% acetonitrile/0.12% trifluoroacetic acid for 1δ minutes, isochratic at 70% acetonitrile/0.12% trifluoroacetic acid for 10 minutes, flow rate 1 ml/minute) R τ (isomer 1) = 12.6 minutes; R τ (isomer 2) = 13.0 minutes SUBSTITUTE SHEET Example 28 4-f5-r4-rAminoiminomethvnphenvn-2-pvridinvl]- -r4-fluorophenvh-1- piperazineacetic acid trifluoroacetate salt ( Isomer 2^ 10% palladium on carbon (20mg) was added to a solution of isomer 2 (60mg) in ethanol (δml) and the mixture stirred In an atmosphere of hydrogen for 4 hours. The catalyst was filtered off and the filtrate evaporated in vacuo to give a white waxy solid which was purified by preparative hpic (gradient profile, 10-90% (ii) in 2δ minutes) to give after Rt = 11.0 min title compound as a white solid (3mg). Analytical hpic (gradient profile 10-90% (ii) in 2δ minutes) Rt = δ.δ minutes. Mass Spectrum. MH + = 434 SUBSTITUTE SHEET

Claims: Claims 1. Compounds of general formula (I) and salts, solvates and pharmaceutically acceptable derivatives thereof, in δ which: X 1 and X 2 represent CH or are different and represent CH or N; Y 1 , Y 2 , Y 3 and Y 4 represent CH, or Y 1 and Y 4 represent CH and Y 2 and Y 3 represent N, or Y 2 and Y 3 represent CH and Y 1 and Y 4 represent N, or three of Y 1 to Y 4 represent CH and the other represents N; 0 Z 1 represents CH or N; Z 2 represents N or N + R 6 ; R 1 represents a hydrogen atom or a hydroxyl, C-i^alkyl or 2,2,2- trifluoroethyl group; R 2 represents a hydrogen atom or, when both X 1 and X 2 represent CH, may δ also represent a fluorine, chlorine or bromine atom or a Cι_ 4 alkyl group; R 3 represents a hydrogen atom or, when each of Y 1 to Y 4 represent CH, may also represent a fluorine, chlorine or bromine atom or a C 1 _ al yl group; R 4 and R 5 each represent a hydrogen atom; or, when Z 1 represents CH and Z 2 represents N, R 4 may also represent C-,. alkyl; or, when both Z 1 and Z 2 0 represent N, R 4 and R 5 may be the same or different, and represent hydrogen or C 1 _ 4 alkyl; R 6 represents a C 1 . 4 alkyl group or phenylCι_ 3 alkyl group; R 7 represents a hydrogen atom; a C 1 _ alkyl group; a naphthyl group; a thiophene group; an unsubstituted phenyl group; a phenyl group substituted by δ C . 4 alkyl, OH, halogen (where halogen is fluorine, chlorine, bromine or iodine), CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NR 8 R 9 , NHS0 2 R 8 , CONR 8 R 9 or C0 2 R 8 ; a C^alkyl group substituted by one or more naphthyl, phenyl, OH or C0 2 R 8 ; a C 2 . 4 alkenyl SUBSTITUTE SHEET group substituted by one or more naphthyl, phenyl, OH or C0 2 R 8 ; or a saturated or unsaturated C 5 . 7 cycloalkyl group; and R 8 and R 9 , which may be the same or different represent H or C _ 4 alkyl or, together with the nitrogen atom to which they are attached, form a saturated δ to δ 7 membered ring. 2. Compounds as claimed in Claim 1 in which both X 1 and X 2 represent CH. 3. Compounds as claimed in Claim 1 or 2 in which each of Y 1 , Y 3 and Y 4 represent CH. 4. Compounds as claimed in any one of Claims 1 to 3 in which Y 2 represents 0 N. δ. Compounds as claimed in any one of Claims 1 to 4 in which both Z 1 and Z 2 represent N. 6. Compounds as claimed in any one of Claims 1 to δ in which R 1 represents a hydrogen atom. 5 7. Compounds as claimed in any one of Claims 1 to 6 in which R 2 , R 3 , R 4 and R 5 each represent a hydrogen atom. δ. Compounds as claimed in any one of Claims 1 to 7 in which R 7 represents a hydrogen atom, a C | _ alkyl group, a phenyl group, or a phenyl group substituted by halogen. 0 9. Compounds as claimed in any one of Claims 1 to 8 in which R 7 represents a hydrogen atom, a phenyl group or a phenyl group substituted in the 4-position by fluorine. 10. Compounds as claimed in Claim 1 in which both X 1 and X 2 represet CH; each of Y 1 , Y 3 and Y 4 represent CH; Y 2 represents N; both Z 1 and Z 2 represent 5 N; R 1 represents a hydrogen atom; each of R 2 , R 3 , R 4 and R 6 represent a hydrogen atom; and R 7 represents a hydrogen atom, a phenyl group or a phenyl group substituted in the 4-position by fluorine. 11. 4-[5-[4'-(Aminoiminomethyl)phenyl]-2-pyridinyl]-α-phenyl]-1 - piperazineacetic acid, in the from of a racemic mixture or a single enantiomer; ET 6δ 4-[δ-[4-(Aminoiminomethyl)phenyl]-2-pyridinyl]-α-(4-fluorophenyl)-1- piperazineacetic acid trifluoroacetate salt; in the form of a racemic mixture or a single enantiomer; 4-[δ-[4-(Aminoiminomethyl)phenyl]-2-pyridinyl]-1 -piperazineacetic acid; δ and salts, solvates and pharmaceutically acceptable derivatives thereof. 12. 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -piperazineacetic acid; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -(2-hydroxy-2-oxoethyl)-1 - methyl-1 -piperazinium; Ethyl 4-[4'-(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -piperazineacetate; 0 Butyl 4-[4'-(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -piperazineacetate; cis-4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-2,6-dimethyl-1 -piperazineacetic acid; 4-[4'-[(Hydroxyamino)iminomethyl][1 ,1 '-biphenyl]-4-yl]-1 -piperazineacetic acid ; δ 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-y!]-α-methyl-1 -piperazineacetic acid in the form of a racemic mixture or a single enantiomer; 1 ,1 Dimethylethyl-4-[δ-[4-(aminoiminomethyl)phenyl]-2- pyridinyl]-α-(4-fluorophenyl)-1 -piperazineacetate, in the form of a racemic mixture or a single enantiomer; 0 1 ,1 -Dimethylethyl-α-(4-fluorophenyl)-4-[δ-[4- [imino[[(phenylmethoxy)carbonyl]amino]-methyl]phenyl]-2-pyridinyl]-1- piperazineacephate, in the form of a racemic mixture or a single enantiomer; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -(2-hydroxy-2-oxoethyl)-1 - (phenylmethyl)-l -piperazinium; δ 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -(2-methoxy-2-oxoethyl)-1 - methyl-1 -piperazinium; 1 ,1-Dimethylethyl 4-[4'-(aminoiminomethyl)[1 ,1'-biphenyl]-4-yl]-1- piperazineacetate; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -[2-(1 ,1 -dimethylethoxy)-2- 0 oxoethyl]-1 -methyl-1 -piperazinium salt; 1 ,1 -Dimethylethyl -[δ-[4-(aminoiminomethyl)phenyl]-2-pyridinyl]-1 - piperazineacetate; cis-1 ,1 -Dimethylethyl 4-[4'-(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-2,6- dimethyl-1 -piperazineacetate; SUBSTITUTE SHEET 1 ,1-Dimethylethyl 4-[4'-[(hydroxyamino)iminomethyl][1 ,1 '-biphenyl]-4-yl]-1 - piperazineacetate; Ethyl 4-[4'-(aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-α-methyl-1 - piperazineacetate r in the form of a racemic mixture or a single enantiomer; 4-[4'-(Aminoiminomethyl)[1 ,1 '-biphenyl]-4-yl]-1 -[2-(1 ,1 -dimethylethoxy)-2- oxoethyl]-1-(phenylmethyl)-1 -piperazinium acetate salt; 13. A compound as claimed in any one of Claims 1 to 12, wherein R 7 is other than hydrogen, in the form of a racemic mixture or a single enantiomer. 14. Compounds as claimed in any one of Claims 1 to 13 wherein the compound 0 of formula (I) is in the form of a hydrochloride, hydrobromide, sulphate, phosphate, benzoate, naphthoate, hydroxynaphthoate, p-toluenesulphonate, methanesulphonate, sulphamate, .ascorbate, tartrate, salicylate, succinate, lactate, glutarate, glutaconate, acetate, tricarballylate, citrate, fumarate, maleate or sodium salt. δ 1δ. A process for the preparation of compounds of formula (I) as defined in any of Claims 1 to 14 or a salt, solvate or pharmaceutically acceptable derivative thereof thereof, which comprises: (A) for the preparation of compounds of formula (I) in which R 1 represents a hydrogen atom; 0 alkylating a compound of formula (II) (wherein RP represents a protecting group) followed by reaction with a source of ammonia; or (B) for the preparation of a compound of formula (I) in which R 1 represents δ a hydroxyl group; SUBSTITUTE SHEET treating a compound of formula (III) or a protected derivative thereof with hydroxylamine or an acid addition salt thereof; or (C) for the preparation of a compound of formula (I) in which R 1 represents a hydroxyl, Cι_4alkyl or 2,2,2-trifluoroethyl group, forming a thioimidate from a compound of formula (II) followed by reaction with an amine R 1 NH2 (where R 1 . represents hydroxy, Cι_4alkyl or 2,2,2-trifluoroethyl); or (D) forming an imidate from a compound of formula (IV) (wherein RP represents a protecting group) followed by treatment with a source of ammonia or an amine R 1 NH2 (where R 1 is hydroxy, Cι_4alkyl or 2,2,2- trifluoroethyl); or (E) interconversion of a compound of formula (I) into another compound of formula (I); or (F) for the preparation of a compound of formula (I) in which R 1 represents hydrogen, C^alkyl, or 2,2,2-trifluoroethyl, Z 1 represents CH and Z 2 represents N; hydrogenating a compound of formula (XXI) SUBSTITUTE SHEET (where R 1 is hydrogen, C-i^alkyl or 2,2,2-trifluoroethyl); or (G) optionally removing any protecting groups from a protected derivative of formula (I); with the formation of a pharmaceutically acceptable derivative, salt formation and resolution as optional steps subsequent to any of processes (A) to (G). 16. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of Claims 1 to 14 or a salt, solvate or pharmaceutically acceptable derivative thereof together with at least one physiologically 0 acceptable carrier or excipient. 17. A compound of formula (I) as defined in any of Claims 1 to 14 or a salt, solvate or pharmaceutically acceptable derivative thereof for use in human or veterinary medicine. 1 δ. The use of a compound of formula (I) or a salt, solvate or pharmaceutically δ acceptable derivative thereof as defined in any of Claims 1 to 14 for the manufacture of a medicament for the treatment or phrophylaxis of thrombotic disorders. 19. A method of treating a human or animal subject suffering from or susceptible to a thrombotic disorder, which method comprises administering to 0 said subject an effective amount of a compound of formula (I) as defined in any of claims 1 to 14 or a salt, solvate or pharmaceutically acceptable derivative thereof. δ SUBSTITUTE SHEET 20. Compounds of formula (XXX) R 1 HNC(=NH)-A-B-C-CHR 2 CO 2 H (XXX) and salts and solvates thereof, in which -A- represents a 2,5-pyridylene group, a 1,4-phenylene group or a 1,4-phenylene group substituted by a fluorine, chlorine or bromine atom or by a C-^alkyl group; -B- represents a 2,5-pyridylene group, a 2,5-pyrimidylene group, a 1,4-phenylene group or a 1,4-phenylene group substituted by a fluorine, chlorine or bromine atom or by a C^ lkyl group; -C- represents either R represents a hydrogen atom or a hydroxyl, C 1 _ 4 alkyl or 2,2,2-trifluoroethyl gr ιo_uup, R represents a hydrogen atom or a C j ^al yl group; R -N represents a hydrogen atom or a C j ^al yl group; R 4 represents a hydrogen atom or a C * 4 alkyl group; R represents a C-^alkyl (e.g. methyl) or phenylC j _ 4 alkyl (e.g. benzyl) group; and X represents CH or N with the proviso that R 3 is a hydrogen atom when X represents CH. SUBSTITUTE SHEET

Inventors: ELDRED COLIN DAVID, JUDKINS BRIAN DAVID, KELLY HENRY ANDERSON, MIDDLEMISS DAVID, PORTER BARRY, ELDRED, COLIN, DAVID, JUDKINS, BRIAN, DAVID, KELLY, HENRY, ANDERSON, MIDDLEMISS, DAVID, PORTER, BARRY
Applicants: ELDRED COLIN DAVID, GLAXO GROUP LTD, JUDKINS BRIAN DAVID, KELLY HENRY ANDERSON, MIDDLEMISS DAVID, PORTER BARRY, GLAXO GROUP LIMITED
Application year: 1993
Main classification: C07D295
IPC codes: A61K31, A61P7, C07D213, C07D237, C07D241, C07D295