PIPERIDINEACETIC ACID DERIVATIVES AS INHIBITORS OF FIBRINOGEN-DEPENDENT BLOOD PLATELET AGGREGATION

Abstract: The invention relates to acetic acid derivatives of formula (I) and pharmaceutically acceptable derivatives thereof and salts and solvates thereof, where: X<1> and Y<1>, which may be the same or different, represent CH or N; X<2> represents CH or, when X<1> represents CH, may also represent N; Y<2> represents N or, when Y<1> represents N, may also represent CH; Z represents N or N<+>R<5>; 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 N, may also represent a C1-4alkyl or hydroxymethyl group; R<4> represents a hydrogen atom or, when Z represents N, R<4> may also represent a C1-4alkyl group; R<5> represents a C1-4alkyl or phenylC1-4alkyl group; R<6> represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C1-4alkyl, C1-4alkoxy, phenylC1-3alkoxy, OH, halogen, where halogen is fluorine, chlorine, bromine or iodine, CF3, unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NR<7>R<8>, NHSO2R<7>, CONR<7>R<8> or CO2R<7>; a C1-4alkyl group substituted by one or more naphthyl, phenyl, OH or CO2R<7>; a C2-4alkenyl group substituted by one or more naphthyl, phenyl, OH or CO2R<7>; or a saturated or unsaturated C5-7cycloalkyl group; and R<7> and R<8>, 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. The compounds inhibit fibrinogen dependent blood platelet aggregation.

Description: Piperidineacetic acid derivatives as inhibitors of fibrinogen-dependent blood platelet aggregation 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 Ilb/IIIa 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 Ilb/IIIa complex. The invention thus provides the compounds of formula (I) and salts and solvates thereof, in which X 1 and Y 1 , which may be the same or different, represent CH or N; X 2 represents CH or, when X 1 represents CH, may also represent N; Y 2 represents N or, when Y 1 represents N, may also represent CH; Z represents N or N + R 5 ; R 1 represents a hydrogen atom or a hydroxyl, C M alkyl 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 M alkyl group; R 3 represents a hydrogen atom or, when both Y 1 and Y 2 represent N, may also represent a C M alkyl or hydroxymethyl group; R 4 represents a hydrogen atom or , when Z represents N, R 4 may also represent a C M alkyl group; R 5 represents a C M alkyl or phenylC M alkyl group; R 6 represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C M alkyl, C alkoxy, phenylC, -alkoxy, OH, halogen, where halogen is fluorine, chlorine, bromine or iodine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NR 7 R 8 , NHSO 2 R 7 , CONR 7 R 8 orCO-R. 7 ; a C M alkyl group substituted by one or more naphthyl, phenyl, OH or CO-Jt 7 ; a C-^alkenyl group substituted by one or more naphthyl, phenyl, OH or CO j R 7 ; or a saturated or unsaturated C j -cycloalkyl group; and R 7 and R 8 , which may be the same or different represent H or C M aIkyl 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): It will be 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. It will be further appreciated by those skilled in the art that the compounds of formula (I) contain at least one chiral centre (shown as * in formula (I)) and thus exist in the form of a pair of optical isomers (i.e. enantiomers). The invention includes all such isomers and mixtures thereof including racemic mixtures. Suitable physiologically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromϊdes, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p- toluenesulphonates, 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). It is to be further understood that the present invention includes pharmacuetically acceptable derivatives of the compounds of formula (I). 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 compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound 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. Thus compounds of interest include carboxylic acid esters of the compounds of formula (I). Examples of such esters include C,. 6 alkyl esters, more preferably C M 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 (I), 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 (I), the following meanings are preferred: X 1 and X 2 both represent CH; Y 1 represents N; Z preferably represents N; R 1 represents a hydrogen atom or a hydroxyl group; R l most preferably represents a hydrogen atom; R 2 represents a hydrogen atom; R 3 represents a hydrogen atom; R 4 represents a hydrogen atom; R 6 represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C M alkoxy, phenylC^alkoxy, OH, fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NH-., N(C M alkyl) 2 , NHSO 2 C M alkyl, CONR 7 R 8 (where R 7 and R 8 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring) or CO^H; a C M alkyl group substituted by one or more naphthyl, phenyl, OH, CO-C M alkyl or CO-H; a C-^alkenyl group substituted by one or more naphthyl, phenyl, OH, CO-C^alkyl or CO- > H; or an unsaturated C„cycloalkyl group; R 6 most preferably represents an unsubstituted phenyl or a phenyl substituted in the 4- position by fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, H 2 , N(C w alkyl) 2 , NHSO 2 C M alkyl, CONR 7 R 8 (where R 7 and R 8 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring) or CO,H. When R 2 represents a chlorine or bromine atom or a C M alkyl group, R 2 is preferably in the position meta to the amidine function. It is to be understood that the present invention covers all combinations of preferred and specific groupings referred to above. Particularly preferred compound of the invention are: 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-phenyl- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 1 '-[4-(Aminoiminomethyl)phenyl]-α-phenyI[4,4'-bipiperidine]-l -acetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-methoxyphenyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-fluorophenyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α- [4-[(methylsulphonyl)amino]phenyl]-l -piperidineacetic acid and physiologically acceptable salts and solvates thereof. Other preferred compounds of the invention include: 4-[4-[4-( Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-( 1 -naphthalenylmethyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-(phenylmethyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-(4-bromophenyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-phenyl- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 1 , -[4-[amino(hydroxyimino)methyl]phenyl]-α-phenyl[4,4'-bipiperidine]- 1 -acetate and physiologically acceptable salts and solvates thereof; Methyl 1 , -[4-(aminoiminomethyl)phenyl]-α-phenyl[4,4'-bipiperidine]- 1 -acetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α- (4-methoxyphenyl)-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]-l -piperazinyl]-α-(4-methoxyphenyl)-l - piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]- -(4-bromophenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyI]- 1 -piperazinyl]-α- (4-fluorophenyl)-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]-l -piperazinyl]-α- (4-fluorophenyl)-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]-l-piperazinyl]-α-(2-naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-(2-naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(AiT-_ioin_nomethyl)phenyl]-l-piperazinyl]-a-(2-naphthalenyl)-l-piperidineacetic acid and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α-(l -naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-(aminoiminomethyI)phenyl]- 1 -piperazinyl]-α-(l -naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(l -naphthalenyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyll-l-piperazinyl]-α-(2- methoxyphenyl)-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiπ_nomethyl)phenyl]- 1 -piperazinyl]-α-(2-methoxyphenyl)-l - piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aπ_noiminomethyI)phenyl]-l-piperazinyl]-α-(2-methoxyphenyl)-l- pϊperidineacetϊc acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α- [4-(phenylmethoxy)phenyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4- (phenylmethoxy)phenyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-hydroxyphenyl)- 1 - piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-hydroxyphenyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(hydroxymethyl)- 1 - piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-(hydroxymethyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α-([ 1 , 1 '-biphenyl]- 4-yl)-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-([ 1 , 1 -biphenyl]-4-yl)- 1 - piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-([ 1 , 1 -biphenylJ-4-yl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α-[4- (trifluoromethyl)phenylj-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]- -[4- (trifluoromethyl)phenyl]-l -piperidineacetate and physiologically acceptable salts _nd solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(trifluoromethyl)phenyl]- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 1 -( 1 , 1 -Dimethylethyl) 4-ethyl 2-[4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]- l-piperidinyI]-3-methylbutanedioate and physiologically acceptable salts and solvates thereof; 1 -Hydrogen 4-ethyI 2-[4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyl]-l- piperidinyl]-3-methylbutanedioate and physiologically acceptable salts and solvates thereof; 2-[4-[4-(Aminoiminomethyl)phenyl]-l -piperazinyl- l-piperidinyl]-3- methylbutanedioic acid and physiologically acceptable salts and solvates thereof; 1 , 1 -Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyl]-l -pϊpera_inyl]-α-( 1 -hydroxy- l-phenylethyl)-l -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Ammoin_nomethyl)phenyl]- 1 -pipera_inyl]-α-(l -hydroxy- 1-phenylethyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 1 , 1 -Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyI]-l -piperazinyl]-α-( 1 - phenylethyl)-l -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(phenylethyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; 1 , 1 -Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyl] - 1 τpiperazinyl]-α-( 1 - cyclohexen-l-y.)-l-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-(l -cyclohexen- 1 -yl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyI]-l -piperazinyl] -α- (4'-hydroxy[l, -biphenyl]-4-yl)-l-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4'-hydroxy[ 1 , 1 -biphenyl]-4-yl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(an_noiminomethyl)phenyl]- 1 -piperazinyI]-α-[4-(4-pyridinyl)phenyl]-l - piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(4-pyridinyl)phenyl]- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(2-thienyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(3-thienyl)- 1 - piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(3-thienyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-[amino(hydroxyamino)methyl]phenyl]-l-piperazinyl]-α-[4- (dimethylamino)phenyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-[4- (dimethylamino)phenyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(dimethylamino)phenyl]- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α-[4- [(methylsulphonyl)amino]phenyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Ethyl-α-[4-(acetylamino)phenyl]-4-[4-[4-[amino(hydroxyimino)methyl]phenyl]-l- piperazinyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-aminophenyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl] -α-[4-( 1 - pyrrolidinylcarbonyl)phenyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(l- pyrrolidinylcarbonyl)phenyl]-l -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)ρhenyl]-l-piperazinyl]-α-[4-(carboxyphenyl)-l- piperidineacetic acid and physiologically acceptable salts and solvates 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.N., 1962, Nature, 194, 927-929). 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 myocardial 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 Ilb/IIIa 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 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 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 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. A proposed 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 lOmg/kg may be suitable for systemic administration. 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 , Y 2 , Z, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in formula (I) above unless otherwise stated; R p 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. triethyloxonium 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 M alkyl or phenylC M alkyl halide alkylation to provide compounds in which Z represents N * R 5 may also result. According to a further process (B), compounds of formula (I) in which R' represents a hydroxyl group may be prepared from compounds of formula (III) or protected derivatives thereof by treating said compounds of formula (III) 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 or tert-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, C M alkyl or 2,2,2-trifluoroethyl 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'NH., (where R 1 represents hydroxyl, C M alkyl or 2,2,2-trifluoroethyl), with subsequent removal of the carboxylic acid protecting group. The reaction with the amine R'NH, may 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 (IN) 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'ΝEL. (where R l is a hydroxyl, C M alkyl or 2,2,2- trifluoroethyl group), respectively under the conditions described in processes (A) or (C) above, or 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 1 is hydrogen, C M alkyl or 2,2,2-trifluoroethyl and ring -C- represents may conveniently be prepared by hydrogenating compounds of formula (XII) (where R 1 is hydrogen, C M alkyl or 2,2,2-trifluoroethyl) at an elevated pressure and in the presence of a platinum catalyst (e.g. PtO~), 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 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 or trifluoroacetic acid at room temperature or using hydrochloric acid in acetic acid. Benzyl, diphenylmethyl and nitrobenzyl ester groups may be removed by hydrogenolysis 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 (LI) may be prepared from compounds of formula (IN) by treating said compounds of formula (IN) with hydrogen sulphide. The reaction may conveniently be carried out in a solvent such as dimethylforrnamide 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 (IN) by removing the carboxylic acid protecting group R p according to the method described in process (E) hereinabove. Compounds of formula (IN) in which ring -C- represents may conveniently be prepared from corresponding compounds of formula (IN) in which ring -C- represents by alkylation according to the method described in process (A) above. Compounds of formula (IN) in which ring -B- represents and ring -C- represents may be prepared by reacting compounds of formula (N) with compounds of formula (NI) (wherein R 6 is as defined above or a protected derivative thereof but is not a. benzyl or napthylmethyl group) under reducing conditions. Thus, for example, a mixture of compounds of formulae (N) and (VI) may be treated with a reducing agent such as a metal borohydride in the presence of a suitable acid and in a suitable solvent at about room temperature. The reduction may conveniently be carried out using sodium cyanoborohydride in a solvent such as an alcohol (e.g. methanol) in the presence of an acid (e.g. hydrochloric acid) and preferably also with molecular sieves. Alternatively, the reduction may be effected using sodium triacetoxyborohydride in a solvent such as tetrahydrofuran or dichloromethane in the presence of an acid (e.g. acetic acid). Compounds of formula (NI) may be prepared from an Ν-protected (e.g. Ν-benzyl protected) piperidin-4-one, optionally substituted by C alkyl, by removal of the protecting group followed by treatment with a reagent LCHR 6 CO 2 R p (where R 6 is as defined in formula (NI) above and L is a leaving group, such as a halogen atom (e.g. bromine) or a sulphonate ester group (e.g. mesylate)). When the protecting group is an aralkyl group such as benzyl the removal of the protecting group may be effected by hydrogenolysis in the presence of a suitable transition metal catalyst such as a palladium catalyst (e.g pd(OH) . Thus, for example, compounds of formula (VI) in which R 6 represents a naphthyl, phenyl, naphthylC^alkyl or phenyl C M alkyl group may be prepared by use of a reagent _3_dCΗR 6 CO 2 R. p (wherein R 6 represents a naphthyl, phenyl, naphthylC-^alkyl or phenylC^alkyl 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 nitrile (e.g. acetonitrile), conveniently at an elevated temperature (e.g. reflux). The reagents of formula HalCHR 6 CO 2 R p (wherein R 6 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-halogenation of the corresponding carboxylic acid ester, by standard methods. The α-halo carboyxlic acids and the carboxylic acid esters above are known compounds or are readily prepared using conventional chemistry. Compounds of formula (VI) in which R 6 represents a C j -cycloalkyl group or a substituted phenyl group wherein the substituent is selected from a C M alkoxy, phenylC. .3 alkoxy or protected hydroxy group or a halogen atom, may be prepared by use of a reagent RO^OCHRtO^ (wherein R 6 represents a C 5 -cycloalkyl group or a substituted phenyl group wherein the substituent is selected from a C M alkoxy, phenylC,. 3 alkoxy or protected hydroxy group or a halogen atom and RO 2 SO 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 m a polar, aprotic solvent, such as dimethylsulphoxide and preferably at elevated temperature (e.g. 80-100°C). The reagents of formula RO 2 SOCHR 6 CO-R p (wherein R 6 and RO 2 SO are as defined just above) may be prepared from the corresponding α-hdyroxy 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 (IN) in which R 6 is as defined in formula (NI) above, ring -B- represents and ring -C- represents may be prepared by reacting compounds of formula (Nil) with compounds of formula (NIII) (wherein R 6 is as defined in formula (NI) above) in the presence of a base such as an alkali or alkaline earth metal carbonate or bicarbonate (e.g. sodium bicarbonate) and in a suitable solvent such as an aprotic polar solvent (e.g. dimethylformamide, acetonitrile or dimethylsulphoxide), conveniently at an elevated temperature. Compounds of formula (VIII) may be prepared from compounds of formula (NI) by reacting said compounds of formula (VI) with a suitable piperazine derivative, optionally protected (e.g. Ν-benzyl protected), under reducing conditions, for example as described above for the reaction between compounds of formulae (V) and (VI), followed, where appropriate, by the removal of any Ν-protecting group present using conventional conditions, for example as described above. Compounds of formula (IV) in which R 6 is as defined in formula (VI) above, ring -B-represents may be prepared from compounds of formula (IX) by treating said compounds of formula (IX) with a reagent LCHR 6 CO 2 R p under the conditions described above for preparing compounds of formula (VI). Compounds of formula (LX) may be prepared by reacting a compound of formula (Vπ) with a compound of formula (X) under the conditions described above for preparing compounds of formula (IV) from compounds of formula (VH). The compound of formula (X) in which R 4 is hydrogen is a known compound. Compounds of formula (X) where R 4 is alkyl may be prepared by hydrogenation of compounds of formula (XI) Compounds of formula (XI) may be prepared by reacting a 4- halopyridine derivative with 4-pyridylboronic acid, 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-ethanediol dimethyl ether). Compounds of formula (XII) above in which R 1 is hydrogen may be prepared from compounds of formula (XIII) under the conditions described above for preparing compounds of formula (I) from compounds of formula (IV) via compounds of formula (II). Compounds of formula (XII) in which R 1 is C M alkyl or 2,2,2- trifluoroethyl may also be prepared from compounds of formula (XIII) under the conditions described in processes (C) or (D) above. Compounds of formula (XIII) in which R 6 is as defined in formfula (VI) above may be prepared from compounds of formula (XIV) by treatment with a reagent LCHR 6 CO 2 R p under the conditions described above for preparing compounds of formula (VI), except that the reaction is conveniently effected in the absence of a base. Compounds of formula (XIV) in which ring -B- represents may be prepared by reacting compounds of formula (V) with a suitable 4-halopyridine in a solvent such as an alcohol (e.g. butanol). Compounds of formula (XIV) in which ring -B- represents may be prepared by reacting compounds of formula (VII) with compounds of formula (XV) under the conditions described above for the reaction between compounds of formulae (Vπ) and (Vm). Compounds of formula (XV) may be prepared by reacting a suitable 4-halopyridine with a suitable piperazine under the conditions described above for preparing compounds of formula (IV) from compounds of formula (VII). Compounds of formula (V) in which ring -B- represents 3 R may be prepared by reacting a piperazine with a compound of formula (VII) under basic conditions. Suitable bases include alkali or alkaline earth metal carbonates or bicarbonates such as sodium bicarbonate or potassium carbonate. The reaction may conveniently be effected in a solvent such as dimethylformamide or dimethylsulphoxide at an elevated temperature (e.g. 100°-200°C). Compounds of formula (V) in which ring -B- represents may be prepared from compounds of formula (XVI) under suitable reducing conditions. Conveniently, compounds of formula (XVI) are treated with benzyl bromide in an alcoholic solvent (e.g. ethanol) or a halogenated hydrocarbon (e.g. dichloromethane) at an elevated temperature to provide a salt of formula (XVII) which is reduced, for example using a borohydride reducing agent such as sodium borohydride in a suitable solvent such as an alcohol (e.g. ethanol) or dimethylformamide or a mixture of such solvents to a compound of formula (XVIII) (XVIII ) Removal of the benzyl group and reduction of the double bond from a compound of formula (XVIII) provides the desired compounds of formula (V). The removal of the benzyl group may conveniently be effected by hydrogenolysis in the presence of a palladium catalyst such as Pd(OH) 2 -on-carbon, or by reaction with 1-chloroethyl chloroformate in the presence of a base such as 'proton sponge, followed by treatment with methanol. The reduction of the double bond may conveniently be effected by hydrogenation in the presence of a platinum catalyst such as platinum-on-carbon or platinum oxide or a palladium catalyst such as palladium hydroxide-on-carbon and optionally in the presence of an acid (e.g. hydrochloric acid). Compounds of formula (IV) in which ring -C- represents may be prepared from compounds of formula (XHI) by reduction and hydrogenation under the conditions described just above for the reduction and hydrogenation of compounds of formulae (XVII) and (XVIII). Compounds of formula (XNI) may be prepared by converting compounds of formula (VTI) to the corresponding boronic acids of formula (XIX) under conventional conditions, and thereafter reacting said compounds of formula (XLX) with a 4-halopyridine such as 4- bromopyridine under the conditions described above for preparing compounds of formula (XI). Compounds of formula (XVI) may also be prepared by reacting an appropriate compound of formula (VII) in which Hal is a bromine atom with a compound of formula (XX) under the boronic acid coupling conditions described previously. The compound of formula (XX) is a known compound described by W. J. Thompson et al. in J. Org. Chem., 1988, 53, 2052. Compounds of formula (VII) are either known compounds or may be prepared from the known compounds of formula (VII) using conventional chemistry. Compounds of formula (I) or intermediates thereto in which ring -A- represents a C M alkyl substituted phenyl group may conveniently be prepared by modification of the corresponding compound in which ring -A- represents a bromo substituted phenyl group. Thus, for example, the bromo substituted intermediate may be treated with a zinc reagent RZnBr (where R is C M alkyl) in the presence of a palladium catalyst such as 1 chloro[ 1 , 1 '-bis(diρhenylphosphino)feπocene]palladium (II). Alkylation may also be effected using a tin reagent R 4 Sn (where R is C M alkyl) in the presence of a palladium catalyst such as bis (triphenylphosphine)benzylpalladium chloride. Compounds of formula (I) or intermediates thereto in which R 6 represents a phenyl group substituted by a C M alkyl group, may be prepared under the conditions described just above for the preparation of compounds of formula (I) or intermediates thereto in which ring -A- represents a C M alkyl substituted 1,4-phenylene group. Compounds of formula (IV) in which R 6 is as defined in formula (VI) above, ring -B- represents -N r N- or and ring -C- represents may also be prepared by treating a compound of formula (XXI) with a reagent LC D-C'COTR 1 ' under the conditions described above for preparing compounds of formula (VI). Compounds of formula (XXI) may be prepared by reacting compounds of formula (V) with an N-protected piperidin-4-one, optionally substituted by C M alkyl, under reducing conditions (for example as described above for the reaction between compounds of formulae (V) and (VI)), followed by removing the N-protecting group. Suitable protecting groups include -CO,Alk (where Alk is an alkyl group such as t-butyl), or aralkyl, for example benzyl. The former protecting group may be removed by acid hydrolysis (e.g. using trifluoroacetic acid at about room temperature), the latter under the conditions described above for the removal of the benzyl group from compounds of formula (XVIIΪ). Compounds of formula (IV) in which R 6 is as defined in formula (VI) above, ring -A- represents , π .ng - „B- represents or N A R and ring -C- represents ( N- may be prepared by treating a corresponding halo compound of formula (XXII) (wherein R 6 is as defined in formula (VI) above) with a suitable inorganic nitrile such as sodium cyanide in the presence of a palladium catalyst [e.g. tetrakis(triphenylphosphine)palladium(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 (XXII) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a compound of formula (VDI) or a compound of formula (XXIII), (XXIII) (wherein R 6 is as defined in formula (VI) above) as appropriate. The reaction may conveniently be effected under the conditions described above for the reaction between compounds of formulae (VII) and (VIII). Compounds of formula (IX) in which ring -A- represents may conveniently be prepared from compounds of formula (XXIV) using the procedure described above for preparing compounds of formula (IV) from compounds of formula (XXII). Compounds of formula (XXIV) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a compound of formula (X) under the conditions described above for the reaction between compounds of formulae (VII) and (VIII). Compounds of formula (XIV) in which ring -A- represents and ring -B- represents may be prepared from compounds of formula (XXV) using the procedure described above for preparing compounds of formula (IN) from compounds of formula (XXII). Compounds of formula (XXV) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a compound of formula (XV) under the conditions described above for the reaction between compounds of formulae (VII) and (VHI). Compounds of formula (V) in which ring -A- represents and ring -B- represents may be prepared from compounds of formula (XXVI) using the procedure described above for preparing compounds of formula (IV) from compounds of formula (XXII). Compounds of formula (XXNI) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a suitable piperazine derivative under the conditions described above for the reaction between compounds of formulae (VII) and (VTTT) Compounds of formula (XXffl) may be prepared by treating a compound of formula (X) with a reagent LCHR 6 CO-Jt p under the conditions described above for preparing compounds of formula (VI). Compounds of formula (XVI) in which ring -A- represents may conveniently be prepared from compounds of formula (XXVII) (xxvii) by reacting said compounds with a suitable inorganic nitrile according to the method described above utilising compounds of formula (XXII). Compounds of formula (XXVII) may be prepared by reacting a 2,5- dihalopyridine (e.g. 2,5-dibromopyridine) with a compound of formula (XX) under the boronic acid coupling conditions described previously. Halopyridines and dihalopyridines described above are known in the art. Alkyl substituted halopyridines are either known compounds described in Chem. Pharm. Bull., 1988, 36, 2244 and J. Het. Chem., 1988, 25, 81 or may be prepared according to the methods described therein. Compounds of formula (IV) in which R 6 represents a benzyl or naphthylmethyl group may be prepared by treating compounds of formula (XXVIII) 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 ceπain 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 v 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 (IN) are key intermediates and represent a particular aspect of the present invention. Conveniently, compounds of formula (I) are isolated following work-up as acid addition salts, 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 neutralisation of the trifluoroacetate salt using a base such as aqueous sodium hydroxide, followed 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. All temperatures are in °C. Thin layer chromatography (T.l.c-) was carried out on silica plates. System A is dichloromethane-ethanol- 0.880 ammonia. System B is dichloromethane-methanol - 0.880 ammonia. Preparative high performance liquid chromatography (h.p.lx.) was carried out using a Dynamax 60 A 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. Analytical h.p.l.c. was carried out using a Dynamax 60A Cl 8 8μM 25cm x 4.6mm i.d. column using eluants as for preparative h.p.l.c. The following further abbreviations appear in the tables of exemplification: Me = methyl; Et = ethyl; t-bu = tert-butyl: Ph = phenyl; Cy = cyclohexene, Py = pyridine; Th = thiophene; Prr = pyrrolidine; MS = mass spectrum; h.p.l.c. = Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min); Ex = example; Int = intermediate. Intermediate 1 4-( 1 -PiperazinyPbenzonitrile 4-Chlorobenzonitrile (16.5g) was heated at 180°C with piperazine (3 lg) and sodium carbonate (26. lg) in dimethylsulphoxide (300ml) with stirring under nitrogen for 20h. The mixture was poured into water (1.21) and extracted with chloroform (3x500ml). The organic layers were washed with water, dried (MgS0 4 ) and evaporated to give the title compound as a yellow oil (23.6g) . T.l.c. Si0 2 (System A 83.5:15:1.5) Rf 0.55. Intermediate 2 1.1 -Dimethylethyl 4-oxo- 1 -piperidinecarboxylate A mixture of 4-piperidone monohydrate hydrochloride (25g) and dimethylaminopyridine (2g) in acetonitrile (500ml) and triethylamine (100ml) was cooled in an ice-bath and treated with di-tertiary butyl dicarbonate (35.5g). The mixture was stirred at room temperature under nitrogen overnight. The acetonitrile was removed in vacuo and the residue partitioned between ethyl acetate (400ml) and IN hydrochloric acid (400ml). The aqueous layer was extracted with ethyl acetate (2x200ml). The combined ethyl acetate extracts were washed with brine (400ml), dried (MgSO 4 ) and evaporated in vacuo to afford the title compound as a white crystalline solid (15.9g). T.l.c. SiO 2 (hexane:ethyl acetate 1 :1) Rf 0.4. Intermediate 3 1.1 -Dimethyl ethyl 4-[4-( ~ 4-cvanopheny0-l -piperazinyll-1 -piperidinecarboxylate A solution of Intermediate 2 (15.9g) and Intermediate 1 (14.95g) in dry tetrahydrofuran (500ml) was treated with glacial acetic acid (4.6ml) and sodium triacetoxyborohydride (22g). The reaction was stirred at room temperature under nitrogen for 4.5h. The mixture was concentrated in vacuo and the residue partitioned between 2N sodium carbonate (500ml) and ethyl acetate (500ml). The aqueous layer was extracted with ethyl acetate (2x500ml). The combined organic extracts were washed with brine (750ml) and the solvent removed in vacuo to afford an off-white solid. Purification by flash chromatography on silica gel (Merck 9385) eluting with dichloromethane-methanol (100:1) containing 2% triethylamine gave the title compound as a white solid (19.2g). Tic. SiO 2 (System B 90:10:1) Rf 0.67. Intermediate 4 4-[4-f4-PiperidinylVl-piperazinyl]benzoιι.trile trifluoroacetate salt Intermediate 3 (17.3g) was stirred in trifluoroacetic acid (100ml) and distilled water (10ml) at room temperature under nitrogen for 4.25h. The reaction was concentrated in vacuo and the residue purified by trituration with ether. The resulting white solid was filtered off and dried to afford the title compound (_4.0g). Analysis Found: C,44.6; H,4.62; N,9.69; C,44.9; H,4.37; N,9.88%. Intermediate 5 Methyl 4- r 4-( ' 4-cyanophenv0-l -piperazinyl]-α-phenyl- 1 -piperidineacetate A mixture of intermediate 4, methyl α-bromophenyl acetate (2.49g) and potassium carbonate (2.66g) in dimethylformamide (100ml) was heated at ca. 100°C under nitrogen overnight. The dimethylformamide 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 1:1, brine: water (2x200ml) and brine (1x200ml), dried (MgSO 4 ) and evaporated to afford an orange oil (3.66g). Purification by flash chromatography on silica gel (Merck 9385), eluting with dichloromethane: methanol 10: 1, gave the title compound (0.658g) as a tan solid. T.l.c SiO 2 (9:1, dichloromethane:methanol) Rf 0.33 Intermediate 6 Methyl 4- 4-[4-(aminothioxomethyl phenvn- 1 -piperazinyl]-α-phenyl- 1 - piperidineacetate Hydrogen sulphide gas was bubbled through a solution of intermediate 5 (0.650g) in dry pyridine (50ml) and triethylamine (6.5ml) for 0.5h. The flask was stoppered and the reaction stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue purified by trituration with hexane: ether, 3: 1 (100ml). A dark yellow solid was filtered off and dried to afford the title compound (0.527g). T.l.c. SiO 2 (10:l dichloromethane:methanol) Rf 0.07 Intermediate 7 4-( " 4.4'-Bipiperidine]- 1 -yPbenzonitrile 4,4'-Bipiperidine dihydrochloride (3.2g) was dissolved in dimethylsulphoxide (80ml), potassium carbonate (5.0g) added and the mixture heated at 130°C for 20min. 4-Fluorobenzonitrile (0.93g) was added and the mixture stirred at 130°C under nitrogen for 16h. The mixture was cooled, ethyl acetate (250ml) added and the mixture filtered through hyflo. Water (200ml) was added and the organic phase separated. The aqueous phase was re-extracted with ethyl acetate (100ml) and the combined extracts washed with water (2x100ml) and brine (50ml), dried (Na-,SO 4 ) and evaporated in vacuo to afford the title compound as a colourless solid (1.17g). T.l.c. SiO 2 (System A 29:10: 1) Rf 0.20. Intermediate 8 Methyl l'-(4-cyanophenyπ-α-phenylf4.4'-bipiperidine]-l -acetate Intermediate 7 (1.20g) and sodium bicarbonate (750mg) in dimethylsulphoxide (60ml) were treated with methyl α- bromophenylacetate (1.25g), and heated at 100-110°C for 18h under nitrogen. The cooled mixture was poured into water (250ml) and extracted with ethyl acetate (2x150ml); the extracts were washed with water (2xl00ml) and brine (100ml), dried (Na-,SO 4 ) and evaporated in vacuo to give a solid. Trituration with hexane afforded the title compound (1.62g) as a cream solid. T.l.c. SiO 2 doped with triethylamine (diethylether) Rf 0.53. Intermediate 9 4-Piperidinone hvdrochloride N-Benzyl-4-piperidone (10g) was dissolved in absolute ethanol (100ml), treated with dilute hydrochloric acid (2N; 29ml) and hydrogenated at room temperature and pressure over Pearlmann's catalyst (lg) for 18h. The catalyst was removed by filtering through "hyflo" and the solvent was removed in vacuo to leave the title compound (8.59g). T-l.c. SϊO 2 (System B 95:5:0.5) Rf 0.33. Intermediate 10 1.1 -Dimethylethyl 4-oxo-l -piperidineacetate Intermediate 9 (8.5g) was suspended in acetonitrile (100ml) and treated with t-butyl 2-bromoacetate (1 lml) and potassium carbonate (17.3g). The mixture was heated under reflux for 24h. The solvent was removed in vacuo and the residue partitioned between water (250ml) and ethyl acetate (3x250ml). The organic layers were washed with brine (100ml), dried (MgSO 4 ), and evaporated in vacuo to leave the title compound (12. lg) as a yellow oil. Tic. SiO 2 (System B 95:5:0.5) Rf 0.65. Intermediate 11 1.1 -Dimethylethyl 4-r4-f4-cyanophenylV 1 -piperazinyl]-! -piperidineacetate A solution of Intermediate 1 (3g) in methanol (100ml) was treated with Intermediate ]0 (6.84g), 1M hydrogen chloride in ethanol (5ml) and 3 molecular sieves (~2.5g). Sodium cyanoboro hydride (1.06g) was added and the mixture was stirred at room temperature for 48h. The solvent was removed in vacuo and the residual solid was partitioned between water (25ml) and dichloromethane (150ml) and filtered. The layers of the filtrate were separated and the aqueous layer extracted with dichloromethane (3x100ml). The combined organic layers were washed with brine (100ml), dried (MgSO 4 ), filtered and evaporated in vacuo to leave a yellow oil. Purification by "flash" column chromatography using Merck 9385 silica gel and eluting with System B (96:4:0.4) gave the title compound (5.46g) as a white solid. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R_ 11.2min. Intermediate 12 1.1 -Dimethylethyl 4- r 4-(4-cvanophenv0- 1 -piperazinyll-α-f 1 - naphthalenylmethylV 1 -piperidineacetate Lithium bis(trimethylsilyl)amide (lM solution in tetrahydrofuran, 11ml) was added to a solution of intermediate 11 (3.0g) in dry tetrahydrofuran (75ml) at -72°C under nitrogen. The solution was stirred at -70°C for 15 min. l-(Bromomethyl)naphthalene (1.72g) in tetrahydrofuran (10ml) was added dropwise over lOmin, and the solution was allowed to reach room temperature over 18h. The solvent was removed in vacuo and saturated aqueous ammonium chloride (50ml) added. The resultant solution was extracted with ethyl acetate (3 x 75ml), and the combined, dried (MgSO 4 ) extracts were evaporated in vacuo to give a yellow foam. Trituration with ether gave the title compound as a yellow solid (0.875g). T.l.c. (System A, 95:5:0.5) Rf 0.75. Intermediate 13 1.1 -Dimethylethyl 4-[4-[4-f an_no(hydroxyimino methyl]phenyl]- 1 - piperaziny^-α-C 1 -naphthalenylmethyO- 1 -piperidineacetate A suspension of intermediate 12 (0.825g), in methanol (20ml) was treated with four equal portions of potassium t-butoxide (0.061g) and hydroxylamine hydrochloride (0.038g) at 2h intervals while the mixture was heated under reflux under nitrogen. After the final portion had been added, the mixture was heated under reflux for a further 18h. To the cooled solution, water (30ml) was added and the precipitate was collected to give the title compound as a cream solid (0.7g). Tic. (System A, 90:10:1) Rf 0.65. Intermediate 14 1.1 -Dimethylethyl 4-l4- 4-faminoiminomethvDphenyl]-l-piperazinyl1- α-π-naphthalenylmethylVl -piperidineacetate trifluoroacetate salt Acetic acid (7ml) containing acetic anhydride (0.177ml) was added to intermediate 13 (0.698g) and 10% palladium on carbon (0.140g). The suspension was stirred under an atmosphere of hydrogen until uptake had ceased (2h). The catalyst was filtered off and the filtrate evaporated in vacuo. Purification by preparative h.p.l.c. gave the title compound as a pink solid (0.4 lOg). Analytical h.plc. (gradient profile 10-90% (ii) in 25min) R. 13.7min. Intermediate 15 1.1-Dimethylethyl 4-[4-( ' 4-cvanophenylVl-piperazinyl]-α-( ' phenylmethyl -l-piperidineacetate Lithium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran, 3.4ml) was added to a solution of intermediate 11 (lg) in dry tetrahydrofuran (25ml) at -72°C under nitrogen. The solution was stirred at -70°C for 15min. Benzyl bromide (0.309ml) in tetrahydrofuran (70ml) was added dropwise over lOmin, and the solution was allowed to reach room temperature (18h). The solvent was removed in vacuo and saturated aqueous ammonium chloride (50ml) added. The resultant solution was extracted with ethyl acetate (3x 75ml), and the combined, dried (MgSO 4 ) extracts were evaporated in vacuo to give a yellow solid. Trituration with ether (20ml) gave the title compound (0.541g). Tic. (System A 95:5:0.5) Rf 0.55 Intermediate 16 1.1 -Dimethylethyl 4-[4-[4- amino(hvdroxyimino)methyl]phenyl]-l - piperazinyl]-α-( " phenylmethyl)- 1 -piperidineacetate A suspension of intermediate 15 (0.513g) in methanol (15ml) was treated with four equal portions of potassium t-butoxide (0.042g) and hydroxylamine hydrochloride (0.026g) at 2h intervals while the mixture was heated at reflux under nitrogen. After the final portion had been added, the mixture was heated at reflux for a further 18h. To the cooled solution, water (30ml) was added and the white solid which precipitated was collected to give the title compound (0.425g). T.l.c. (System A, 90: 10: 1) Rf 0.55. Intermediate 17 1.1 -Dimethylethyl 4-[4-[4-f aminoiminomethyl)phenyl]- 1 -piperazinyl]- α-fphenylmethyO-1 -piperidineacetate trifluoroacetate salt Acetic acid (6ml) containing acetic anhydride (0.110ml), was added to intermediate 16 (0.397g) and 10% palladium on carbon (0.08g). The suspension was stirred under an atmosphere of hydrogen until uptake ceased (2h). The suspension was filtered through acid washed hyflo and the filtrate evaporated in vacuo. Purification by preparative h.p.l.c. (gradient profile 10-70% (ii) in 18 min) gave after R τ 12.5min the title compound as a cream solid (0.381g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) Rt 12.65min. Intermediate 18 Methyl α-hvdroxy-4-methoxybenzeneacetate A solution of 4-methoxymandelic acid (1.7g) in 1M methanolic hydrogen chloride (50ml) was stirred at room temperature under nitrogen overnight. The mixture was concentrated in vacuo to afford a pale yellow oil (1.83g). T.l.c. SiO 2 (1 : 1, hexane:ethyl acetate) Rf 0.4 Intermediate 19 Methyl 4-methoxy-α-[fmethylsulphonvDoxy]benzeneacetate A solution of intermediate 18 (L833g) and triethylamine (1.95ml) in dry dichloromethane (50ml) was treated dropwise at 0°C with methanesulphonyl chloride (0.904ml). The mixture was stirred at room temperature under nitrogen for lh. The mixture was poured into water (100ml) and the aqueous layer extracted with dichloromethane (2x75ml). The combined organic extracts were washed with ice-cold 8% sodium bicarbonate solution (150ml), dried (MgSO 4 ) and the solvent removed in vacuo to afford the title compound as a yellow oil (2.05g). Tic. SiO 2 (1 : 1 hexane:ether) Rf 0.4 Intermediate 20 Methyl 4-r4-f4-cvanophenyl> 1 -pipera_inyl]-α-f4-methoxyphenyD- 1 - piperidineacetate A mixture of intermediate 4 (1.56g), intermediate 19 (2.05g) and potassium carbonate (1.03g) in dry dimethylsulphoxide (30ml) was stirred at 80°C under nitrogen overnight. The mixture was partitioned between ethyl acetate (200ml) and water (200ml). The aqueous layer was extracted with ethyl acetate (2x150ml). The combined ethyl acetate extracts were washed with brine (300ml), dried (MgSO 4 ) and the solvent removed in vacuo to afford a yellow oil (4.5 lg). Purification by short path chromatography on silica gel (Merck 7729, eluting with dichloromethane:methanol 20: 1) gave a yellow oil (2.8 lg). The yellow oil was dissolved in acetonitrile (15ml) and further purified by preparative h.p.l.c. (gradient profile 10-40% (ii) in lOmin and 40% (ii) ϊsochratic for 8min) to give after R_ 13.5min a white solid. The white solid was partitioned between 8% sodium bicarbonate solution (150ml) and ethyl acetate (150ml). The aqueous layer was extracted with ethyl acetate (2x100ml) and the combined organic layers dried (MgSO 4 ) and evaporated in vacuo to afford the title compound as a colourless oil (1.02g). Tic. SiO 2 (System B, 89:10:1) Rf 0.61. Intermediate 21 Methyl 4-bromo-α-hydroxybenzeneacetate Hydrogen chloride gas was bubbled through an ice cooled solution of 4-bromomandelic acid (4.9g) in methanol (100ml) for 60min. The mixture was stirred at room temperature for 3 days and the solvent was removed in vacuo to leave a colourless oil. The oil was dissolved in ethyl acetate (100ml), washed with 8% aqueous sodium bicarbonate (2x100ml), water (100ml) and brine (100ml), dried (MgSO 4 ), and evaporated in vacuo to give the title compound as a colourless oil (2.95g). T.l.c. SiO 2 (Ethylacetate:Hexane 40:60) Rf 0.36 Intermediate 22 Methyl 4-bromo-α-[(methylsulphonyl oxy]benzeneacetate A stirred solution of intermediate 21 (2.95g) in dry dichloromethane (50ml) and triethylamine (2.52ml) was treated dropwise at 0°C under nitrogen with methanesulphonyl chloride (1.16ml). Stirring was continued at room temperature under nitrogen for lh, methanesulphonyl chloride (1.16ml) was added, and stirring was continued for lh. The mixture was poured into water (100ml) and extracted with dichloromethane (2x100ml). The combined organic layers were washed with 8% aqueous sodium bicarbonate (150ml), dried (MgSO^, filtered and evaporated in vacuo to give the title compound as a dark yellow oil (4.0g). T.l.c. SiO 2 (Etheπhexane, 1 :1) Rf 0.23 Intermediate 23 Methyl α-(4-bromophenyl -4-[4-( ' 4-cvanophenyπ- 1 -piperazinyl]- 1 -piperidineacetate A mixture of intermediate 4 (3.86g), intermediate 22 (3.3g) and sodium bicarbonate (2.57g) was dissolved in dimethylsulphoxide (70ml) and heated at 80°C under nitrogen for 4h. The mixture was partitioned between water (200ml) and ethyl acetate (200ml), and the aqueous layer was extracted with ethyl acetate (100ml). The combined organic layers were washed with a mixture of brine and water (1:1; 3x200ml), and finally with brine (200ml), dried (MgSO , and evaporated in vacuo to give a yellow gum. Purification by flash column chromatography on silica gel (Merck 9385, eluting with system B 97.5:2.5:0.2) gave the title compound as a yellow solid (3.19g). T.l.c. SiO 2 (System B 95:5:0.5) Rf 0.27 Intermediate 24 Methyl 4-[4- 4-( " aminothioxomethvπphenyl]-l -piperazinyl]-α-f4- bromophenyl - 1 -piperidineacetate Intermediate 23 (lg) was suspended in dry dimethylformamide (10ml) and treated with triethylamine (0.56ml). Whilst cooling in ice, hydrogen sulphide gas was bubbled through the solution for 20min. After stirring at room temperature for 24h, aqueous sodium carbonate (2N, 100ml) was added, and the precipitate was filtered off, washed with water and ether, and dried to give the title compound as a yellow solid (I.40g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R- 13.1min Intermediate 25 Methyl 4-fluoro-α-hvdroxybenzeneacetate A solution of 4-fluoromandelic acid (lOg) in 1M methanolic hydrogen chloride (150ml) was stirred at room temperature under nitrogen overnight. The mixture was concentrated in vacuo to afford the title compound as a pale yellow oil (10.8g). T.l.c. SiO 2 (1:1, hexane:ethyl acetate) Rf 0.46 Intermediate 26 Methyl 4-fluoro-α-f(methylsulphonvDoxy]benzeneacetate A solution of intermediate 25 (10.83g) and triethylamine (12.3ml) in dichloromethane (150ml) was cooled to 0°C and treated dropwise with methanesulphonyl chloride (5.7ml). The mixture was stirred at room temperature under nitrogen for 1 hour. The mixture was poured into distilled water (150ml), and the aqueous layer was extracted with dichloromethane (100ml). The combined organic extracts were washed with ice-cold 5% sodium bicarbonate (150 ml) and brine (150ml), dried (MgSO 4 ) and the solvent removed in vacuo to afford the title compound as a yellow solid (14. lg). T.l.c. SiO 2 (1 :1 hexane:ethyl acetate) Rf 0.48 Intermediate 27 Methyl 4-[4-(4-cyanopheny0- 1 -piperazinyl]-α-(4-fluorophenyP- 1 - piperidineacetate A mixture of intermediate 4 (6g), sodium hydrogen carbonate (2.4g) and intermediate 26 (7.56g) in dry dimethylsulphoxide (100ml) was heated at 80° under nitrogen for 10 hours. The mixture was partitioned between ethyl acetate (400ml) and water (400ml), and aqueous layer extracted with ethyl acetate (2x200ml). The combined ethyl acetate extracts were washed with water (2x400ml) and brine (400ml), dried (MgSO 4 ), and the solvent removed in vacuo to afford a brown oil (9.5g). Purification by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate containing 2% triethylamine, gave the title compound as a yellow foam (4.89g). T.l.c. SiO 2 doped with triethylamine (Ethylacetate) Rf 0.2 Intermediate 28 Methyl 2-naphthaleneacetae 2-Naphthylacetic acid (lOg) was dissolved in 1M methanolic hydrochloric acid (100ml) and the mixture stirred at room temperature for 48h, under nitrogen. The solution was evaporated in vacuo to yield the title compound as a cream solid (10.8g). T.l.c SiO 2 (ethyl acetate:hexane, 1 :9) Rf 0.4 Intermediate 29 Methyl α-bromo-2-naphthaleneacetate N-bromosuccinimide (2.85g) and benzoyl peroxide (0.36g) were added to intermediate 28 (3g) in carbon tetrachloride (35ml), and the solution was heated under reflux under nitrogen, with irradiation (200 W. fungsten lamp) for 18h. The cooled solution was filtered and the filtrate was evaporated to give the title compound as a light brown oil, which crystallised on standing (3.53g). Tic. SiO 2 (ethyl acetate±exane, 5.95) Rf 0.3. Intermediate 30 Methyl 4-[4-f4-cyanophenvD- 1 -piperazinv.]-α-(_-naphthalenyD- 1 - piperidineacetate A mixture of Intermediate 4 (2.0g), Intermediate 29 (2.06g) and potassium carbonate (2.24g) in dimethylsulphoxide (50ml) was heated at 70° under nitrogen for 3h. To the cooled solution water (300ml) was added and the mixture extracted with ethyl acetate (2x 250ml). The combined, organic extracts were washed with water (2x 250ml) and brine (500ml), dried (MgSO and evaporated in vacuo to give a light brown oil. Purification by flash chromatography on silica gel (Merck 9385) eluting with system A (98:2:0.2) gave the title compound as a cream foam (1.95g) T.l.c SiO 2 (System A, 95:5:0.5) Rf 0.8 Intermediate 31 Ethyl α-bromo- 1 -naphthaleneacetate Lithium diisopropylamide mono (tetrahydrofuran) complex (1.5M in cyclohexane, - 29.6ml) was added to a stirred solution of ethyl 1- naphthaleneacetate (8g) in dry tetrahydrofuran (60 ml) at -70°, under nitrogen, and stirring was continued at -70° for 30 min. Carbon tetrabromide (14.6ml) was added, the vessel removed from the cold bath and the mixture was stirred at room temperature for 2h. Ammonium chloride (100 ml) was added and the solution extracted with ethyl acetate (3x150 ml). The combined, dried (MgSO 4 ) extracts were evaporated in vacuo and the residue partially purified by flash column chromatography on silica gel (Merck 9385), diluting with hexane: ethyl acetate 95:5 to give an impure sample of the title compound (5.3g). T.l.c SiO 2 (ethyl acetate±exane, 95.5) Rf 0.25. Intermediate 32 Methyl 4-[4-(4-cyanophenyP- 1 -piperazinyl]-α-( 1 -naphthalenyl)- 1 - piperidineacetate A mixture of intermediate 4 (3g), intermediate 31 (4.83g) and potassium carbonate (3.04g) in dimethylsulphoxide (50 ml) was heated at ca 70°C, under nitrogen for 2h. To the cooled solution, water (300ml) was added and the solution extracted with ethyl acetate (2 x 250ml). The combined, organic extracts were washed with water (2 x 400ml) and brine (400ml), dried (MgSO 4 ) and evaporated in vacuo to give a brown oil. Purification by flash chromatography on silica gel (Merck 9385), eluting with hexane:ethyl acetate:triethylamine 70:30:2, gave the title compound as a beige foam (l-59g). T.l.c SiO 2 (System A, 95:5:0.15) Rf 0.75. Intermediate 33 Methyl α-hydroxy-2-methoxybenzenacetate A solution of 2-methoxymandelic acid (dicyclohexyl ammonium salt) (5g), in 1M methanolic hydrogen chloride (100ml), was stirred at room temperature under nitrogen overnight. The mixture was filtered, the filtrate concentrated in vacuo. and the residue treated Λvith ether. A white solid was filtered off, and the filtrate concentrated in vacuo to afford the title compound as a yellow oil which crystallised on standing (2.35g). T.l.c. SiO 2 (1:1, hexane:ethylacetate) Rf 0.44. Intermediate 34 Methyl 2-methoxy-α-[(methylsulphonyPoxy]benzeneacetate A solution of intermediate 33 (2.3 g) in dry pyridine (40ml) was treated dropwise at o°C with methanesulphonyl chloride (1.13ml). The mixture was stirred at room temperature under nitrogen for 3 hours. The pyridine was removed in vacuo and the residue partitioned between dichloromethane (100ml) and ice cold 8% sodium bicarbonate solution (100ml). The aqueous layer was extracted with dichloromethane (2 x 100ml), and the combined organic extracts were dried (MgSO and evaporated in vacuo to afford the title compound as a light brown oil (2.39g). T.Lc. SiO 2 (1:1 hexane.ethyl acetate) Rf 0.56. Intermediate 35 Methyl 4-[ " 4-f4-cyanophenvP-l -piperazinyl]-α-(_-methoxyphenyP-l- piperidineacetate A mixture of intermediate 4 (1.81g), intermediate 34 (2.39g) and sodium bicarbonate (0.73 lg) in dry dimethylsulphoxide (30ml) was heated at 80°C under nitrogen for 8 hours. The mixture was partitioned between ethyl acetate (200ml) and water (200ml), and the aqueous layer was extracted with ethyl acetate (2x150ml). The combined organic extracts were washed with water (2x300 ml) and brine (300ml), dried (MgSO^ and.the solvent removed in vacuo to afford a yellow oil (5.2g). Purification by flash chromatography on silica gel (Merck 9385) eluting with ethyl acetate containing 2% triethylamine, gave the title compound as a white foam (1.59g). T.l.c Si0 2 doped with triethylamine (ethyl acetate) Rf 0.36. Intermediate 36 α-Hydroxy-4-(phenyImethoxy)benzeneacetate A mixture of 4-hydroxymandelic acid (20g), benzyl chloride (14.4ml) and potassium carbonate (36.5g) was heated under reflux in methanol (500ml) for 18h. The mixture was cooled to room temperature and the solvent removed in vacuo. The residual solid was dissolved in water (600ml) and washed with ethyl acetate (200ml). The aqueous layer was reacidified with 5N HC1 and the precipitated solid was filtered off and dissolved in ethyl acetate. The solution was washed with brine, dried (Na-SO 4 ) and evaporated to give an orange solid. Trituration with 50:50 etheπhexane gave the title compound as a white crystalline solid (16.8g). T.Lc. SiO 2 (etheπacetic acid 99:1) Rf 0.47 Intermediate 37 Methyl α-hvdroxy-4-(phenylmethoxy)benzeneacetate A solution of intermediate 36 (11.7g) in methanolic hydrogen chloride was stirred at room temperature under nitrogen for lόhrs. The solvent was removed in vacuo to leave the title compound as a white solid 12.2g. T.l.c. SiO 2 (Ethyl acetate :hexane 70:30) Rf 0.23 Intermediate 38 Methyl α-[(methylsulphonyPoxy]-4-(phenylmethoxy)benzeneacetate A solution of intermediate 37 (4g) and triethylamine (3 ml) in dry dichloromethane (l 50ml) was treated dropwise, at 0°C under nitrogen, with a solution of methanesulphonyl chloride (1.4ml) in dry dichloromethane (50ml). The solution was allowed to warm to room temperature and stirred for 2hrs. More methansulphonyl chloride (0.3ml) was added and the solution stirred for another hour, then poured into water (200ml). The aqueous layer was further extracted with dichloromethane (2x150ml), and the organic extracts were washed with 8% sodium bicarbonate and brine, dried (Na j SO and evaporated to give the title compound as a yellow solid (5g). T.l.c. SiO 2 (Etheπhexane 50:50) Rf 0.42 Intermediate 39 Methyl 4-[4-f4-cyanophenyP- 1 -piperazinyl]-α-[4-(phenylmethoxy)phenyl - 1 -piperidineacetate A mixture of intermediate 4 (3g), intermediate 38 (5g) and potassium carbonate (2g) in dry dimethylsulphoxide (120ml) was heated at 80°C for 2hrs. The mixture was partitioned between water (600ml) and ethyl acetate (2x500ml). The combined organic extracts were washed (water, brine), dried (Na ^ SO^ and evaporated to give a yellow foam (5.64g). Purification by flash column chromatography on silica gel (Merck 9385) eluting with 96:4:0.4 (System A) gave a yellow foam (4.2g). Trituration with ether gave the title compound as an orange- white powder (1.83g). T.l.c. SiO 2 (System A, 95:5:0.5) Rf 0.2 Intermediate 40 Methyl 4-r4-C4-cvanophenvP-l-piperazinyl]-α-( ' hvdroxymethyP-l-piperidineacetate The title compound, a light brown solid, was prepared from intermediate 4 and methyl α-bromo-3-hydroxypropanoate by a method analogous to that used for intermediate 5. Tic. SiO 2 (System B, 89:10:1) Rf 0.47 Intermediate 41 Methyl 4- 4-[4-rarnmotnioxomethyPphenyl]-l-piperazinyl]-α- hvdroxymethyl)-l- piperidineacetate The title compound was prepared from intermediate 40 by a method analogous to that used for intermediate 6. Tic. SiO 2 (System B, 89:10:1) Rf 0.33. Intermediate 42 Methyl 4-[4-C4-cvanophenvP-l-piperazinvn-α- [l.r-bipheπyl]-4-vP-l-piperidineacetate The title compound was prepared from intermediate.23 by a method analogous to that used for intermediate 55 hereinafter. T.l.c. SiO 2 (System B, 97.5:2.5:0.25) Rf 0.32. Intermediate 43 Methyl α-hvdroχy-4-ftrifluoromethyPbenzeneacetate The title compound was prepared from 4-(trifluoromethyl)mandelic acid by a method analogous to that used for intermediate 18. Tic. SiO 2 (hexane:ethyl acetate, 1:1) Rf 0.53. Intermediate 44 Methyl α-[fmet-hvsulphonvPoxy]-4-ftrifluoromethvPbenzeneacetate The title compound was prepared from intermediate 43 by a method analogous to that used for intermediate 19. T.l.c. SiO 2 (hexane:ethyl acetate, 1:1) Rf 0.52. Intermediate 45 Methyl 4- r 4-(4-cyanophenyD- 1 -piperazinyl]-α-[4-(trifluoromethyl)phenyl]- 1 - piperidineacetate The title compound was prepared from intermediate 44 by a method analogous to that used for intermediate 20. T.l.c. SiO 2 (ethyl acetate:triethylamine, 98:2) Rf 0.2. Intermediate 46 1 — ( 1,1 -DimethylethyP-4-ethyl 2-[4-[4-(4-cyanophenyP- 1 -piperazinyl]- 1 -piperidinyl]-3- methylbutanedioate A solution of intermediate 11 (6.0g) in dry tetrahydrofuran (120ml) was treated with lithium diisopropylamide mono tetrahydrofuran complex (1.5 M sol. in cyclohexane; 13.5ml) at -75°C while stirring under nitrogen. After 1.5h, ethyl-2-bromopropionate (2.23ml) was added at -72°C; the mixture was stirred for 2h at - 72°C and allowed to warm up to room temperature overnight. The solvent was evaporated to leave a solid which was partitioned between dichloromethane (2x250ml) and saturated ammonium chloride (250ml). The combined organic layers were dried (MgSO 4 ), and evaporated in vacuo to leave a brown oil. Purification by column chromatography on silica gel (Merck 9385), eluting with system B, 98:2:0.2 gave the title compound as a yellow oil (1.57g). T.l.c. SiO 2 (System B, 95 : 5 : 0.5) Rf = 0.66 Intermediate 47 1 -Cl .1 -DimethylethyP-4-ethyl 2- 4-[4-[4-f aminothioxomethyPphenyl]- 1 -piperazinyl]- 1 - piperdiinyl]-3-methylbutanedioate The title compound was prepared from intermediate 46 by a method analogous to that used for intermediate 6. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) Rt 15.9min. Intermediate 48 1.1 -Dimethylethyl 4-[4-f4-cvanophenvP- 1 -piperaziriyl]-α-( 1 -hydroxy- 1 -phenylethyP-1 - piperidineacetate Lithium diisopropylamide mono tetrahydrofuran complex (1.5 M in cyelohexane, 9.02ml) was added to a stirred solution of intermediate 11 (4.0g) in dry tetrahydrofuran (75ml) at -75°C under nitrogen and stirring was continued for lh. Chlorotitanium triisopropoxide (3.23ml) was added at -72°C and stirring was continued at -72°C for 30 mins. Acetophenone (1.37ml) was added and the mixture stirred at -70°C for 30 mins and allowed to warm up to room temperature overnight (16h). The solvent was removed in vacuo to leave an orange solid, which was partitioned between dichloromethane (2x300ml) and saturated ammonium chloride (250ml). The combined organic layers were dried (MgSO^, and evaporated to leave a brown oil, which was purified by column chromatography on silica gel (Merck 9385) eluting with system B, 97.5:2.5:0.25, to give the title compound as a cream coloured solid (2.76g). Tic. SiO 2 (System B, 95 : 5 : 0.5) Rf =0.59. Intermediate 49 1.1 -Dimethylethyl 4-[4-f4-aminothioxomethvPphenyI]-l-p.perazinyl]- α-fl -hydroxy-l-phenylethvP-1 -piperidineacetate The title compound was prepared from intermediate 48 by a method analogous to that used for intermediate 6. Analytical h.p.l.c (gradient profile 10-90% (ii) in 25min) Rt 14.2min. Intermediate 50 l.l-Dimethylethyl 4-[ " 4- " 4-cvanophenyP-l-piperazinyl]-α-ri-phenylethenvP-l- piperidineactate Intermediate 48 (4.2g) was heated under reflux with phosphorus oxychloride (1.94ml) in dry pyridine (30ml) with stirring under nitrogen for 2 hrs. The solvent was removed in vacuo and the residue partitioned between 8% sodium bicarbonate (300ml) and dichloromethane (2x300ml). The combined organic layers were washed with brine (250ml), dried (MgSO 4 ) and evaporated to give a brown oil. Purification by column chromatography on silica gel (Merck 9385) eluting with system B, 98:2:0.2, gave the title compound as a white solid (2.29g). T.l.c. SiO 2 ( System B, 97.5 : 2.5 : 0.25), Rf = 0.28. Intermediate 51 1.1 -Dimethylethyl 4-[4-[4-(aminothioxomethvPphenyl]- 1 -piperazinyl]- α-O-phenylethyP-1 -piperidineacetate The title compound was prepared from intermediate 50 by a method analogous to that used for intermediate 6. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 mins) Rt 14.2min. Intermediate 52 1.1 -Dimethylethyl 4-[4-(4-cvanophenvP- 1 -piperazinyl]-α-( 1 -hvdroxycvclohexyP- 1 - piperidineacetate Lithium diisopropylamide mono tetrahydrofuran complex (1.5M in cyclohexane; 8.3ml) was added to a stirred solution of intermediate 11 (4.0g) in dry tetrahydrofuran (100ml) at -75° under nitrogen, and stirring was continued at -75° to -72° for 1.5h. Chlorotitanium triisopropoxide (2.98ml) was added at -72°, and stirring was continued at -72° for 30 min. Cyclohexane (1.39ml) was added and the mixture was stirred at -70° for 30 min and allowed to warm to room temperature overnight (16h). The mixture was poured into saturated aqueous ammonium chloride (200ml) and extracted with ethyl acetate (3x100ml). The organic layers were washed with brine, dried (MgSO 4 ) and evaporated to give a pale yellow solid (4.42g). Purification by column chromatography on silica gel (Merck 7736), eluting with system A, 99: 1:0.1 - 96:4: 0.4 gave the title compound as a pale yellow solid (3.52g) Tic. SϊO 2 (System A, 95:5:0.5) Rf 0.6 Intermediate 53 1.1 -Dimethylethyl 4- r 4-f4-cyanophenvP-α-f 1 -cvclohexen-1 -vP- 1 -piperazinyll-1 - piperidineacetate Intermediate 52 (1.68g) was heated under reflux with phosphorous oxychloride (0.8ml) in dry pyridine (10ml) with stirring under nitrogen for 1.25h. The solvent was evaporated and the residue partitioned between 8% aqueous sodium bicarbonate (100ml) and ethyl acetate (3x70ml). The organic layers were ashed with brine, dried (MgSO and evaporated to give a brown oil (1.57g). Purification by column chromatography on silica gel (Merck 7736), eluting with system A, 99:1:0.1 - 96:4:0.4, gave the title compound as a yellow oil (0.536g) Tic. SiO 2 (System A, 95: 5: 0.5) Rf 0.45 Intermediate 54 1.1 -Dimethylethyl 4-[4-[4- aminothioxomethyPphenyl]-l -piperazinyl]-α- ( 1-cyclohexen-l -vP- 1 -piperidineacetate The title compound was prepared from intermediate 53 by a method analogous to that used for intermediate 6. Tic. Sio 2 (System A, 95:5:0.5) Rf 0.25 Intermediate 55 Methyl-α-f4'-hvdroxy[ " 1.1 l -biphenyl]-4-vP4- 4-( ' 4-cvanophenvP- 1 -piperazinyl]- 1 - piperidineacetate Intermediate 23 (lg), [4-[[(l,l-dimethylethyl)dϊmethylsilyI]oxy]phenyl]boronic acid ' (0.66g), sodium bicarbonate (0.5g) and tetrakis (triphenyIphosphine)palladium (0) (0.2g) were heated under reflux in water (4ml) and 1,2- dimethoxyethane (8ml), with stirrring under nitrogen for 20h. The mixture was evaporated onto silica gel. Purification by column chromatography on silica gel (Merck 9385), eluting with system A, 97:3:0.3 gave the title compound as a beige foam (0.7g). T.l.c. SiO 2 (System A, 95:5:0.5), Rf: 0.36. Intermediate 56 Methyl 4-[4-[4-(aminothioxomethyPphenyl]- 1 -piperazinyl]-α- (4'-hydroxy[ 1.1 '-biphenyl]-4-yP- 1 -piperidineacetate The title compound was prepared from intermediate 54 by a method analogous to that used for intermediate 6. Mass spectrum [MFT] 545. Intermediate 57 Methyl 4-r4-(4-cvanophenvP- 1 -piperazinyl]-α-f 4-(4-pyridinvPphenyl]- 1 - piperidineacetate The title compound was prepared from intermediate 23 by a method analogous to . that used for intermediate 55. T.l.c. SiO 2 (System A, 95:5:0.5) Rf 0.5. Intermediate 58 Methyl 4-[4-[4-faminothioxomethvPphenyl]- 1 -piperazinyll-α-[4-( ' 4-pyridinyPphenyl]- 1 -piperidineacetate The title compound was prepared from intermediate 57 by a method analogous to that used for intermediate 56. Intermediate 59 Methyl α-bromo-2-thiopheneacetate Methyl 2-thienylacetate (2.40g) in dry THF (40ml) was cooled to -70° under nitrogen and a 1M solution of lithium hexamethyldisilazide in THF (16ml) added dropwise over 5 min. After a further 5 min the cold solution was added to a solution of N- bromosuccinimide (2.72g) in THF (80ml) at -70° under nitrogen. The mixture was stirred at -70° for 20 min, then quenched with 30% ammonium chloride (35ml). After warming to room temperature the mixture was extracted with ethyl acetate (100ml) and the extract dried (Na-.SO and evaporated in vacuo. The residue was purified by flash chromatography over silica gel (type 60, 120g) eluting with hexane - ether (4:1-1:1) and ether to afford the title compound as an oil (1.28g). Tic. SiO 2 (hexane:ether 1:1) Rf = 0.5 Intermediate 60 Methyl 4-[4-f4-cvanophenvP- 1 -piperazinvπ-α-f2-thienvP- 1 -piperidineacetate The title compound was prepared from intermediates 4 and 59 by a method analogous to that used for intermediate 5. T.Lc. SiO 2 (System B, 89:10:1) Rf 0.37. Intermediate 61 Methyl 4-[4-[4-AminothioxomethvPphenyll- 1 -piperazinyl]-α-C2-thienyP- 1 - piperidineacetate The title compound was prepared from intermediate 60 by a method analogous to that used for intermediate 6. T.l.c. SϊO, doped with triethylamine (ethyl acetate:methanol, 9:1) Rf 0.25. Intermediate 62 Methyl α-bromo-3-thiopheneacetate The title compound was prepared from intermediate 61 by a method analogous to that used for intermediate 59. T.l.c. SiO 2 (hexane:ethyl acetate) Rf 0.4. Intermediate 63 Methyl 4-[4-( ' 4-cvanophenvP- 1 -piperazinyl]-α-(3 -thienyP- 1 -piperidineacetate The title compound was prepared from intermediates 4 and 62 by a method analogous to that used for intermediate 5. T.l.c. SiO 2 (dichloromethane:methanol:triethylamine 96:2:2) Rf 0.39. Intermediate 64 Methyl 4-r4-[4-(aminothioxomethyPphenyl]- 1 -piperazinyl]-α-(3-thienyP- 1 - piperidineacetate The title compound was prepared from intermediate 63 by a method analogous to that used for intermediate 6. T.l.c. SiO 2 (System B, 89: 10:1) Rf 0.64 Intermediate 65 Ethyl 4-nitrobenzeneacetate 4-Nitrophenylacetic acid (25g) in ethanolic hydrogen chloride (~lM,200ml) was stirred at room temperature under nitrogen for 16h. The solvent was removed in vacuo to give the title compound as a pale yellow crystalline solid (29g). T.l.c. (SiO 2 , 30:70 Ethyl acetate :Hexane) Rf = 0.24 Intermediate 66 Ethyl α-bromo-4 nitrobenzeneacetate A solution of intermediate 65 (15g) in carbon tetrachloride (180ml) was treated with N-bromosuccinimide (25.5g) and benzoyl peroxide (0.175g) and heated under reflux with stirring, and irradiation (200W tungsten lamp) under nitrogen, for 24h. The solid succinimide was removed by filtration and the filtrate evaporated to leave yellow oil. Purification by column chromatography on silica gel (Merck 9385), eluting with ethyl acetate: hexane, 5:95 gave the title compound as a colourless oil, (10.4g). T.l.c. (SiO 2 , 30:70 ethyl acetate :Hexane) Rf = 0.48 Intermediate 67 Ethyl α-f4-nitrophenyP-4-oxopiperidineacetate A mixture of intermediate 66 (6g), piperidone (3.2g) and potassium carbonate (6.3g) in acetonitrile (50ml) was heated under reflux under nitrogen for 16h. The mixture was carefully concentrated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2x100ml) and the combined extracts were washed (water, brine), dried (Na-SO and evaporated to give a black gum. Purification by column chromatography on silica gel (Merck 9385), eluting with 10-30% ethylacetate in hexane, gave a dark yellow oil (2.0g). Tic. SiO 2 (30:70 Ethyl acetate.Hexane) Rf = 0.2 Intermediate 68 Ethyl α-[4-f dimethylamino ' )phenyl]-4-oxo- 1 -piperidineacetate A mixture of intermediate 67 (1.9g) and aqueous formaldehyde (1.8ml) in ethanol (80ml) was hydrogenated at 50psi over 10% palladium on carbon (0.2g) for 24h. The catalyst was filtered off and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel (Merck 9385) eluting with hexane:ethyl acetate, 7:3, to give the title compound as a yellow oil (0.74g). Mass spectrum (MET " ] 305 Intermediate 69 Ethyl 4-r4-r4-cvanophenvP-l-piperazinyl]-α- 4-dimethylamino phenyl]-l- piperidineacetate The title compound was prepared from intermediates 1 and 64 by a method analogous to that used for intermediate 3. T.l.c. SiO 2 (ethyl acetate:hexane:triethylamine, 65:35:2) Rf 0.15. Intermediate 70 Ethyl α-(4-aminophenvP-4 oxo-1-piperdineacetate A solution of intermediate 67 (2.0g) in ethanol 100ml and dimethylformamide (20ml) was hydrogenated at room temperature and atmospheric pressure over pre-reduced 10% palladium on carbon (400mg) for 30 minutes. The catalyst was filtered off and the filtrate was evaporated to give the title compound as a brown oil (1.89g). T.l.c. SiO 2 (Ethyl acetate:Hexane 2:1) Rf = 0.5 Intermediate 71 Ethyl α-[4- (methylsulphonyPamino]phenyl]-4-oxo- 1 -piperidineacetate Methane sulphonyl chloride (0.26ml) was added at 0° under nitrogen to a stirred solution of the aniline (940mg) in pyridine (10ml). After 1.5h the orange solution was cooled to ca 15°C and more methane sulphonyl chloride (0.13ml) was added. After 30 min. saturated sodium bicarbonate (50ml) was added and the mixture evaporated to dryness. Water (50ml) and ethyl acetate (50ml) were added to the residue and the aqueous layer was extracted again with ethyl acetate (50ml). The combined organic extracts were washed with brine, dried (Na-SO and evaporated to give an orange foam. Purification by column chromatography on silica gel (Merck 9385), eluting with 50-100% ethyl acetate in hexane gave the title compound as a yellow oil, (0.615mg). T.l.c. SiO 2 (System A, 90:10:1) Rf = 0.66 Intermediate 72 Ethyl 4- 4-(4-cyanophenyP- 1 -piperazinyl]-α-[4-[(methylsulphonvPamino]phenyl]- 1 - piperidineacetate The title compound was prepared from intermediates 1 and 71 by a method analogous to that used for intermediate 3. T.l.c. SiO 2 (System A, 90:10:1) Rf 0.55 Intermediate 73 Ethyl α-[4-(_cetylamino)phenyl]-4-oxo- 1 -piperidineacetate Acetyl chloride (0.24ml) was added under nitrogen to a stirred solution of intermediate 69 (940mg) in pyridine (10ml) .at 0°C. After 1.5h sodium bicarbonate solution (~50ml) was added to the green-brown suspension and the mixture was evaporated to dryness. Water (50ml) was added and the mixture extracted with ethyl acetate (2x50ml). The extracts were washed with brine, dried (NaSO 4 ) and evaporated to give a yellow foam. Purification by column chromatography on silica (Merck 9385), eluting with hexane:ethyl acetate, 1 :2 gave the title compound as a yellow foam, (520mg). T.Lc. SiO, (30:70 Ethyl acetate:Hexane), Rf = 0.15 Intermediate 74 Ethyl α-[4-(acetylamino ' )phenyl]-4- 4-r4-cvanophenvP-l-pipera_inyl]-l-piperidineacetate The title compound as prepared from intermediates 1 and 73 by a method analogous to that used for intermediate 3. Tic. SiO 2 (System A, 95:5:0.5) Rf = 0.55 Intermediate 75 Methyl 4-[ " 4-f4-cyanophenvD-l -piper.ιzinyl]-α-r4-fpyrrolidinylcarbonyPphenyl]-l - piperidineacetate Intermediate 23 (1.0g) was heated under reflux with pyrrolidine (0.5ml) and dichlorobis(triphenylphosphine)palladium II chloride (67mg) in dry acetonitrile (5ml) with stirring under carbonmonoxide (latm) for 21h. More catahyst (67mg) and pyrrolidine (0.25ml) were added, and heating under reflux under carbon monoxide was continued for 24h. The solvent was evaporated and the residue purified by column chromatography on silica gel (Merck 7736), eluting with system A (99:1:0.1 to 89:10:1) to give the title compound as a yellow oil (0.255g). Tic. SiO 2 (System A, 95:5:0.5) Rf 0.3 Example 1 4-[4-[4-( AminoiminomethyPphenyl]- 1 -piperazinyl]-α-phenyl- 1 -piperidineacetic acid trifluoroacetate salt A solution of Example 7 (0.500g) in 2N hydrochloric acid was stirred at 60°C for 21 h and at 80°C for 3 days. The acid was removed in vacuo and the residue dissolved in a minimum volume of distilled water. Purification by gradient preparative h.p.l.c. (gradient profile 5-20% (ii) in lOmin and 20% (ii) isochratic for 8 min) gave after R τ 13.0min the title compound as a white solid (0.266g). Mass spectrum [MFT] 422 Assay Found : C.44.15, H,4.5, N,8.4; C 24 H 31 N 5 O 2 .3.75C 2 HF 3 O 2 .0.44H 2 0 Requires C,44.15; H,4.2; N,8.2%. Example 2 1 '-[4-(AminoiminomethyPphenyl]-α-phenyl[4.4'-bipiperidine]- 1 -acetic acid trifluoroacetate salt Example 9 (164mg) was dissolved in 2M hydrochloric acid (25ml) and the mixture heated at 80°C for 65 h. The solvent was removed in vacuo and the residue purified by preparative h.p.l.c (gradient profile 10-40% (ii) in 10 min and .40% (ii) isochratic for 8min) to give after R_ 1 1 to 12min the title compound as a pale yellow solid (97mg). Mass spectrum [MIT] 421 Assay Found: C,51.9, H,5.2, N,8.3; C 25 H 32 N 4 O 2 .2.3C,HF 3 O 2 Requires C,52.1, H,5.1, N,8.2%. Example 3 4-[4-[4-(AminoiminomethyPphenyl]- 1 -piperazinyl]-α-C 1 -naphthalenylmethvP-1 - piperidineacetic acid trifluoroacetate salt Intermediate 14 (0.405g) was stirred in trifluoroacetic acid (27ml) and water (2ml) at room temperature under nitrogen for 14h. The solvent was removed in vacuo and the remaining oily residue solidified on adding ether. The solid was collected to give the title compound (0.301g). Analysis Found C,49.2; H.4.2; N,8.0; C 29 H 3S N s O 2 .3 ΛC,HF 3 0 2 Requires C,49.2; H,4.4; N,8.0%. Mass Spectrum [MH + ]486 Example 4 4-[4-[4-rA-fninoin_nomethyPphenyll-l-piperazinyl]-α-( " phenylmethvP-l-piperidineacetic acid trifluoroacetate salt Intermediate 17 (0.36g) was stirred in-trifluoroacetic acid (18ml) and water (2ml) at room temperature under nitrogen for 4h. The solvent was removed in vacuo and the oily residue solidifed on adding ether. The solid was collected to provide the title compound (0.325g). Assay Found: C,41.95; H,3.9; N,7.0; C 25 H 33 N 5 0 2 .5.0C 2 HF 3 O 2 requires C,41.80; H,3.8; N,7.0%. Mass Spectrum pVfflT] 436 Example 5 4-[4-[4-rAminoiminomethyPphenyl]-l-piperazinyl]-α-( ' 4-methoxyphenvP-l- piperidineacetic acid trifluoroacetate salt A solution of Example 11 (0.140g) in 2N hydrochloric acid (30ml) was heated at 80°C under nitrogen for 3 days and at 90°C for 24h. The m ture was concentrated in vacuo and the residue dissolved in a minimum volume of water. Purification by preparative h.p.l.c. (gradient profile 5-20% (ii) in lOmin and 20% (ii) isochratic for 8min) gave after R_ 14 min the title compound as a white solid (0.0975g). Assay Found: C,45.79; H,4.79; N,8.35; C^-N -JJC-HF-O, requires: C.45.85; H.4.42; N,8.46%. Mass Spectrum [MFT] 452 Example 6 4-[4-[4-(AminoiminomethvPphenvn-l-piperazinvn-α-C4-bromophenyP- 1 -piperidineacetic acid trifluoroacetate salt Example 12 (1.5g, crude) was treated with hydrochloric acid (5N, 150ml) and heated to 90°C for 18h. The mixture was concentrated in vacuo to leave a pale yellow solid which was purified by preparative h.p.l.c. (gradient profile 10-45% (ii) in 1 Imin) to give after R. 10.5min the title compound as a white solid (497mg). Assay Found: C,41.3; H,4.0; N.7.9; C 24 H 30 BrN 5 O 2 .3.5C 2 HF 3 O 2 requires C,41.4; H,3.8; N,7.8%. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R, 8.02min Example 7 Methyl 4-f 4-[4-(_minoiminomethyPphenyl]- 1 -piperazinyl]-α-phenyl- 1 -piperidineacetate trifluoroacetate salt Intermediate 6 (0.500g) was dissolved in acetone (60ml) and methyl iodide (0.090ml) added. The mixture was heated under reflux under nitrogen for 2.75h. More methyl iodide (0.048ml) was added and heating under reflux continued for a further 2.5h. The mixture was concentrated in vacuo and the residue dissolved in methanol (60ml). Ammonium acetate (0.25g) was added, and the mixture was stirred at 60°C under nitrogen for 7h. The solvent was evaporated in vacuo and the residue dissolved in acetonitrile/water and purified by preparative h.p.l.c. (gradient profile 10-35% (ii) in lOmin and 35% isochratic for 8 min) to give after R_ 1 Imin the title compound as a white solid (10.5g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R-9.38min. Example 8 Methyl 1 '-[4-[amino(hvdroxyimino)methyl]phenyl]-α-phenyl[4.4'-bipiperidine]- 1 -acetate Intermediate 8 (1.41g) was taken up in methanol (120ml) and portions of hydroxylamine hydrochloride (82mg) and potassium t- butoxide (126mg) were added after 0, 2 and 4h while heating under reflux, under nitrogen. Heating under reflux was continued for 17h, the mixture was concentrated to 20ml and further hydroxylamine hydrochloride (85mg) and potassium t-butoxide (128mg) were added. Heating under reflux was continued for 8h before further reagents, as above, were added. After heating under reflux overnight the mixture was concentrated to ca. 5ml and poured into water (100ml). The precipitate was filtered off, dried in vacuo and triturated with hot toluene (20ml). After cooling to ca. 40°C, the mixture was filtered to afford the title compound (1.17g) as a white solid. Mass spectrum [MH + ] 451. Example 9 Methyl 1 '-[4-f aιm " noiπ-nomethvPphenvπ-α-phenyir4.4'-bipiperidine]- 1 -acetate Example 8 (1.02g) was suspended in acetic acid (20ml) and acetic anhydride (0.8ml) added. The suspension was added to dry 10% palladium on carbon (800mg) in acetic acid (25ml) and hydrogenated at room temperature and pressure for 5h. The mixture was filtered through hyflo and the solvent evaporated in vacuo. Purification by flash chromatography on silica gel (Merck 9385, eluent system B 89:10:1-19:10:1) gave the title compound (169mg) as a pale yellow solid. Mass spectrum [Mir] 435. Example 10 Methyl 4-[4-[4-ramino( ' hydroxyimino ' )methyl]phenyl]-l-pipera_inyl]-α- ( " 4-methoxyphenvP- 1 -piperidineacetate A mixture of intermediate 20 (0.848g), hydroxylamine hydrochloride (4Img) and potassium t-butoxide (0.066g) in methanol (13ml) was heated to 75°C under nitrogen for 2h. Three further portions of hydroxylamine hydrochloride (41mg) and potassium t-butoxide (66mg) were added at 2 hourly intervals. The mixture was heated at 75°C under nitrogen overnight. The mixture was concentrated slightly in vacuo and water (15ml) added. The white precipitate formed was filtered off and dried to give the title compound (0.472g) as a white solid. T.l.c. SiO 2 (System B, 89: 10: 1) Rf 0.37 Example 1 1 Methyl 4-[4-[4-(aminoiminomethyPphenyl]- 1 -piperazinyl]-α-(4- methoxyphenvP- 1 -piperidineacetate A mixture of Example 10 (0.450g), acetic anhydride (0.352ml) and 10% palladium on carbon (50mg) in glacial acetic acid (10ml) was hydrogenated at room temperature and pressure for lh. The catalyst was filtered off and the filtrate concentrated in vacuo: the residue was partitioned between dichloromethane (100ml) and 2N sodium carbonate (100ml). The aqueous layer was extracted with dichloromethane (2x100ml), and the combined organic extracts were dried (anhydrous potassium carbonate) and evaporated in vacuo to afford a dark brown solid (0.808g). Purification by flash chromatography on silica gel (Merck 9385, eluting with system B 89:10:1, 70:30:3, and finally 50:50:1) gave the title compound as a light brown solid (0.143g). T.l.c. SiO 2 (System B 70:30:3) Rf 0.41 Example 12 Methyl 4-[4-[4-(aminoiminomethvPphenyl]-l -piperazinyl]-α-(4- bromophenvP- 1 -piperidineacetate Intermediate 24 (1.33g) was suspended in dry chloroform (100ml) and treated with triethyloxonium tetrafluoroborate (1.0M solution, 2.51ml) at room temperature under nitrogen. Stirring was continued at room temperature, with further additions of triethyloxonium tetrafluoroborate solution (2x5.02ml, 1x2.5 lml) at 30min intervals. The mixture was stirred for 30min after the last addition, ammonium acetate (968mg) and methanol (50ml) were added, and the mixture was heated at 70°C for 8h. The solvent was removed in vacuo to give the title compound as a yellow oil (1.5g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R_ 11.4min Example 13 Methyl 4-[4-[4-f aminof hydroxyin_no methyl]phenyl]- 1 -piperazinyl]-α- f4-fluorophenyP- 1 -piperidineacetate A suspension of intermediate 27 (0.812g) in methanol (25ml) was treated with four portions each of potassium t-butoxide (78mg), and hydroxylamine hydrochloride (48mg) at 2h intervalSi while the mixture was heated under reflux, under nitrogen. After the final portion had been added, the mixture was heated under reflux for 16h. To the cooled solution, water (50ml) was added and the cream precipitate was filtered off to give the title compound as a cream solid (0.53g). Tic. (System A 95:5:0.5) Rf 0.2 Example 14 Methyl 4-[4-[4-f aminoin_nomethvPphenyl]- 1 -pipera_inyl]-α- f 4-fluorophenvD- 1 -piperidineacetate Acetic acid (8ml) containing acetic anhydride (0.57ml) was added to Example 13 (0.52g) and 10% palladium on carbon (75mg). The suspension was stirred under an atmosphere of hydrogen until uptake had ceased (lh). The suspension was filtered through hyflo and the filtrate evaporated in vacuo to give the title compound (0.5g . Analytical h.plc. (gradient profile 10-90% (ii) in 25 min) R.9.7min. Example 15 4-[4-f4-f AniinoiπiinomethyPphenyl]- 1 -pipera_inyl]-α-f4-fluorophenvP- 1 -piperidineacetic acid trifluoroacetate salt Example 14 (ca 0.5g) was stirred in 5N hydrochloric acid (25ml) at 75° for 18h. The solvent was evaporated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-60% (ii) in 17min) to give after R_ 12. Imin the title compound as a beige solid (0-35g). Analysis Found: C,45.9; H.4.6; N,9.5; C 24 H 30 FN 5 O 2 .3 CF 3 CO 2 H requires C,46.1 ; H,4.3 ; N,9.0%. Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R.7.09min. Example 16 Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α- (2-naphthalenvP- 1 -piperidineacetate A suspension of Intermediate 30 (lg) in methanol (25ml) was treated with four portions of potassium t-butoxide (0.090g) and hydroxylamine hydrochloride (0.055g) at 2h intervals while the mixture was heated under reflux, under nitrogen. After the final portion had been added, the mixture was heated under reflux for 16h. To the cooled solution, water (50ml) was added, and the cream precipitate was collected to give the title compound (1.05 g . T.l.c SiO 2 (System A, 95:5:0.5) Rf 0.15. Example 17 Methyl 4-[4-[4-f aminoiminomethyPphenyl]- 1 -piperazinyl]-α-(2- naphthalenyl)- 1 -piperidineacetate Acetic acid (10ml) containing acetic anhydride (0.324ml) was added to Example 16 (1.15g) and 10% palladium on carbon (150mg). The suspension was stirred under an atmosphere of hydrogen until uptake ceased (2h). The suspension was filtered through acid washed hyflo and the filtrate evaporated in vacuo to give the title compound as a red oil (0.8g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) R_ 1 l.όmin. Example 18 4-f4-[4-(AminoiminomethyPphenyl]-l-piperazinyl]-α-f2-naphthalenyP-l -piperidineacetic acid trifluoroacetate salt Example 17 (0.8g) was stirred in 5N hydrochloric acid (25ml) at 90° for 24h. The solvent was evaporated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-60% (ii) in 17 min.) to give after R_ 12.3 min the title compound as a beige solid (0.061g) Analysis Found C,50.7; H,4.8; N,9.1 ; C 28 H 33 N 5 O 2 .2.9CF 3 CO 2 H requires C,50.6; H,4.5; N.8.7%. Example 19 Ethyl 4-F4-[4-[arrunof hydroxyirninolmethyllphenyl]- 1 -piperazinyl]-α- (1 -naphthalenvP- 1 -piperidineacetate A suspension of intermediate 32 (lg) in methanol (25ml) was treated with four portions of potassium t-butoxide (0.08 lg) and hydroxylamine hydrochloride (0.05g) at 2h intervals while the mixture was heated under reflux under nitrogen. After the final portion had been added, the mixture was heated under reflux for a further 15h. To the cooled solution, water (50ml) was added and the solid which precipitated was collected to give the title compound f0.890g). T.l.c SiO 2 (System A 95:25:05) Rf 0.5 Example 20 Ethyl 4-[4-[4-f aminoiminomethvPphenyl]- 1 -piperazinyl]-α-f 1 - naphthalenvP- 1 -piperidineacetate Acetic acid (8ml) containing acetic anhydride (0.229ml) was added to Example 19 (0.837g) and 10% palladium on carbon (0. lg). The suspension was stirred under an atmosphere of hydrogen for 1.5h. The catalyst was filtered off through acid washed hyflo, and the filtrate evaporated in vacuo to give the title compound as a dark brown oil (1-Og). T.I.c SϊO 2 (System A, 95:5:0.5) Rf 0.05 Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25min) R_ 12.1min. Example 21 4-[4-f4-f Aminoiιr_nomethvPphenyr]- 1 -piperazinyl] -α-f 1 -naphthalenvP- 1 -piperidineacetic acid trifluoroacetate salt Example 20 (lg) was stirred in 5N hydrochloric acid (20ml) at 90°C for 60h. The solvent was evaporated in vacuo and the residue purified by preparative h.p.l.c. (gradient profile 10-60% (ii) in 17 min) to give after R_ 1 1.9 min the title compound as a beige solid (0.4 lOg). Analysis Found: C.50.15; H,4.8; N,9.1; C 28 H-.N 5 O 2 .3CF 3 CO 2 H requires C,50.2; H.4.5; N,8.6%. Mass Spectrum [MH + ] 472 Example 22 Methyl 4-f 4-[4-[an_nof hvdroxyirnino)methyl]phenyl]- 1 -piperazinvP-α-CΣ- methoxyphenyP- 1 -piperidineacetate A mixture of Intermediate 35 (1.5g) in methanol (22ml) was treated with hydroxylamine hydrochloride (73 mg) and potassium t- butoxide (117mg) and heated to 75°C under nitrogen for 2 hours. Three further portions of hydroxylamine hydrochloride (73 mg) and potassium t-butoxide (117mg) were added at 2 hourly intervals. The mixture was heated at 75°C under nitrogen overnight, cooled to room temperature, and concentrated slightly in vacuo. Distilled water (25ml) was added and a white precipitate filtered off and dried to give the title compound (1.14g). T.l.c SiO 2 (System B, 89:10:1) Rf 0.36. Example 23 Methyl 4- r 4-[4-(_minoiminomethyDphenyl]-l -piperazinyl]-α-(_.- methoxyphenyl)-l -piperidineacetate trifluoroacetate salt A mixture of Example 22 (lg) acetic anhydride (0.786 ml) and 10% palladium on carbon (11 Omg) in acetic acid (25ml) was stirred under hydrogen for 1.75h. The catalyst was filtered off, the filtrate concentrated in vacuo and the residue partitioned between ethyl acetate (200ml) and 2N sodium carbonate (200ml). The aqueous layer was extracted with ethyl acetate (2x 100ml). The combined ethyl acetate extracts were washed with brine (250ml), dried (MgSO 4 ) and the solvent removed in vacuo to afford a brown solid. Purification by preparative h.p.l.c. (gradient profile 10-35% (ii) in 10 min and 35% (ii) isochratic for 8 min) gave after R_ 11.5 min the title compound as a white solid (0.28g). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) R_ 9.2 min. Example 24 4-[4-[4-f AminoiminomethvPphenyl]- 1 -piperazinyl]-α-(2- methoxyphenyP-1 -piperidineacetic acid trifluoroacetate salt A solution of Example 23 (0.250g) in 2N hydrochloric acid (100ml) was heated at 80-90°C under nitrogen for 3 days. The mixture was concentrated to ca 10ml in vacuo and purified by preparative h.p.l.c. (gradient profile 5-20% (ii) in 10 min and 20 (ii) isochratic for 8 min) to give after R. 13.8 min the title compound as an off white solid (0.120g). Mass Spectrum [MIT] 452 Assay Found: C,45.7; H,4.8; N,8.6; 0.15 H Requires: C,45.7; H,4.4; N,8.4% Example 25 Methyl 4-[4-f4-[amino( ' hvdroxyimino methyl]phenyl]-l-piperazinyl]-α- r4-Cphenylmethoxy)phenvI]- 1 -piperidineacetate A suspension of intermediate 39 (l.Og) in methanol (15ml) was treated with four portions of hydroxylamine hydrochloride (40mg) and potassium t-butoxide (65mg) at 2 hour intervals, while the mixture was heated under reflux, under nitrogen. After the final portion had been added, the mixture was heated under reflux overnight. Water (50ml) was added and the precipitate filtered off to give the title compound as a white solid (795mg). Tic. SiO 2 (System A, 90:9:1) Rf 0.3 Example 26 Methyl 4-[4-l4-(_minoiminomethyPphenyl]- 1 -piperazinyl]-α- 4- (phenylmethoxy)phenyl]- 1 -piperidineacetate Acetic acid (10ml) containing acetic anhydride (0.2ml) was added to Example 25 (795mg) and 10% palladium on carbon (lOOmg). The suspension was stirred in a hydrogen atmosphere until hydrogen uptake ceased, the catalyst filtered off through a small pad of acetic acid washed hyflo, and the filtrate was evaporated to give a red-brown gum. Purification by preparative h.p.l.c. (gradient profile 10-55% (ii) in 17min,) gave after R_ 14.9min the title compound as a beige solid (482mg). Mass spectrum [M-rT] 542 Example 27 Methyl 4-r4-[4-(aminoiminomethyPphenyl]-l -piperazinyl]-α-(4- hydroxyphenyP- 1 -piperidineacetate A solution of Example 26 (480mg) in ethanol (15ml) and dimethylformamide (3 ml) was added to pre-reduced 10% palladium on carbon (lOOmg) in ethanol (6ml). The mixture was stirred in a hydrogen atmosphere at room temperature and atmospheric pressure for 3hrs. The catalyst was removed by filtration through "hyflo 1 and the filtrate evaporated to give the title compound as a beige solid (320mg). Mass spectrum [MrT] 452 Example 28 4-[4-[4-(ΑminoiminomethyPphenyl]- 1 -piperazinyl]-α-f 4- hvdroxyphenyP-1 -piperidineacetic acid hydrochloride salt A solution of Example 27 (235mg) in hydrochloric acid (4N, 15ml) was stirred at 80°C for 30hrs, evaporated to dryness and the residue triturated with isopropanol to give the title compound as a pink solid (114mg). Mass spectrum [MET] 438 Assay found C,47.3; H,6.6; N,l 1.4; C 24 H 3I N 5 O 3 .3.5HC1.2.5H 2 O requires C,47.2; H,6.5; N,l 1.5%. TABLE 1 TABLE 2 TABLE 3 TABLE 4 # R 6 in Ex 61 is PhCONPrr 1 Analysis data, Table 5 TABLE 5 Ex No 33 Assay Found: C,55.6; H,6.3; N,11.1; C 30 H 35 N 5 O 2 . 4.1HC1 Requires C,55.7; H,6.1; N,10.8% 38 Assay Found: C,47.5; H,5.6; N,10.3; C^H- j N ,^.15C 2 HF 3 O 2 Requires C,47.5; H,5.4; N, 10.1 % 41 Assay Found: C,48.1; H,5.1; N,8.9; C 26 H 35 N 5 O 3 .2.9CJ_F 3 O 2 Requires C,48.0; H,4.8; N,8.8% 43 Assay Found: C,48.0; H,4.8; N,8.9; C 26 H B N 5 O 2 .3.15C 2 HF 3 O 2 Requires C,48.1; FL4.5; N,8.7% 45 Assay Found: C,45.6; H,5.2; N,9.0; C 24 H 35 N 5 O 2 .3.35C 2 HF 3 O 2 Requires C,45.7; H,4.8; N,8.7% 47 Assay Found: C,49.2; H,4.5; N,7.95; C 30 H 35 N 5 O 3 .3.35C 2 HF 3 O 2 Requires C,49.2; N,4.3; N,7.8% 52 C,43.4; H,4.8; N,9.2; Requires C,43.7; H,4.3; N,8.9% 62 Assay Found C,43.8; H,4.4; N,8.5; C^H j ^O^S C 2 HF 3 O 2 .2H 2 O Requires C,44.1; H,4.5; N,8.3% Table 6 - Example Names (29 to 38; 40 to 49: 51 to 56: 58 & 60 to 62) 29 Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl)]-α-(hydroxymethyl)- 1 5 piperidineacetate 30 4-[4-[4-(Aminoiminomethyl)phenyI]-l-piperazinyl]-α-(hydroxymethyl)-l- piperidineacetic acid 31 Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α-([ 1 , 1 -biphenyl]- 4-yl)- 1 -piperidineacetate 32 Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-([ 1 , 1 -biphenyl]-4-yl)- 1 - 10 piperidineacetate 33 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-([ 1 , 1 -biphenyl]-4-yl)- 1 - piperidineacetic acid hydrochloride salt 34 Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α-[4- (trifluoromethyl)phenyl]- 1 -piperidineacetate 35 Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-[4- (trifluoromethyl)phenyl]- 1 -piperidineacetate 36 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-[4-(trifluoromethyl)phenyl]- 1 -piperidineacetic acid trifluoroacetate salt 37 1 -(1,1 -Dimethylethyl) 4-ethyl 2-[4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyl]- l-piperidinyl]-3-methylbutanedioate 38 1 -Hydrogen 4-ethyl 2-[4-[4-[4-(aminoiminomethyl)phenyl]-l -piperazinyl]- 1- piperidinyl]-3-methylbutanedioate trifluoroacetate salt 20 40 1,1 -Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyl]-l-pipera_inyl]-α-(l-hydroxy- 1 -phenylethyl)- 1 -piperidineacetate 41 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-( 1 -hydroxy- 1 -phenylethyl)- 1 -piperidineacetic acid trifluoroacetate salt 42 1,1 -Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-( 1 - phenylethyl)- 1 -piperidineacetate 25 43 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(phenylethyl)- 1 - piperidineacetic acid trifluoroacetate salt 44 1,1 -Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-( 1 - cyclohexen- 1 -yl)- 1 -piperidineacetate 45 4-[4-[4-( AminoiminomethyPphenyl]- 1 -piperazinyl]-α-( 1 -cyclohexen- 1 -yl)- 1 - piperidineacetic acid trifluoroacetate salt 30 46 Methyl 4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyl]-α- (4'-hydroxy[l , l'-biphenyl]-4-yl)-l -piperidineacetate 47 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4'-hydroxy [ 1 , 1 -biphenyl]-4-yl)- 1 -piperidineacetic acid trifluoroacetate salt 48 Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-[4-(4-pyridinyl)phenyl]- 1 - 5 piperidineacetate 49 4-[4-[4-(Aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(4-pyridinyl)phenyl]- 1 -piperidineacetic acid 51 Methyl 4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyl]-α-(3-thienyI)-l- piperidineacetate 52 4-[4-[4-(Aminoiminomethyl)phenyl]-l-piperazinyl]-α-(3-thienyl)-l- piperidineacetic acid trifluoroacetate salt 10 53 Ethyl 4-[4-[4-[amino(hydroxyamιno)methyl]phenyl]-l-piperazinyI]-α-[4- (dimethylamino)phenyl]- 1 -piperidineacetate 54 Ethyl 4-[4-[4-(aminoin_nomethyl)phenyl]-l-piperazinyl]-α-[4- (dimethylamino)phenyl]-l-piperidineacetate 55 4-[4-[4-(Aπ_nom_nomethyl)phenyl]-l-piperazinyl]-α-[4-(dimethylamino)phenyl]- 1 -piperidineacetate trifluoroacetate salt 15 56 Ethyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]-l-piperazinyl]-α-[4- [(methylsulphonyl)amino]phenyl]-l-piperidineacetate 58 EthyI-α-[4-(acetylanιino)phenyl]-4-[4-[4-[amino(hydroxyimino)methyl]phenyl]-l- pϊperazinyl]-l-piperidineacetate 60 Methyl 4-[4-[4-[amino(hydroxyimino)methyl]phenyl]- l-piperazinyl]-α-[4-(l - pyrrolidinylcarbonyl)phenyl]- 1 -piperidineacetate 20 61 Methyl 4-[4[4-(aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(l- pvrrolidinylcarbonyPphenyl]- 1 -piperidineacetate 62 4-[4-[4-(Aminoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(carboxyphenyl)-l- piperidineacetic acid trifluoracetate salt 25 0 Example 39 2- 4-[4-(AminoiminomethyPphenyl]- 1 -piperazinyl- 1 -piperidinyl]-3-methylbutanedioic acid hydrochloride salt The ethyl ester (150mg) was treated with 5N hydrochloric acid (10ml) and the mixture stirred at 50°C for 48hrs. The mixture was concentrated in vacuo to give a solid which was triturated with ether to give the title compound as a cream coloured solid (124mg). Assay Found: C,40.7; H,6.2; N, 11.2; C^H^O,.5HC1.H-0 Requires C,40.8; H,6.2; N,l 1.3% Mass Spectrum [MIT] 418 Example 50 4-[4-[4-(AminoiminomethyPphenyl]- 1 -piperazinyl " l-α-(_-thienyl)- 1 -piperidineacetic acid The title compound was prepared from intermediate 61 by a method analogous to that used for the preparation of Example 1 from intermediate 6 (via Example 7). Mass Spectrum [MIT] 428 Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) Rt 4.3 Example 57 4- 4-f 4-(AminoiminomethyPphenyl]- 1 -piperazinyl]-α- [4-[(methylsulphonyPamino]phenvn- 1 -piperidineacetic acid The title compound was prepared from Example 56 by a method analogous to that used for the preparation of Example 2 from Example 8 (via Example 9). Mass Spectrum [MIT] 515 Assay Found C,42.4; H,4.6; N,9.6; C 25 H^ 6 O 4 S.3C 2 HF 3 O 2 .H 2 O Requires C,42.6; H,4.5; N,9.6% Example 59 4-[4-[4-(AminoiminomethyPphenyll- 1 -piperazinyl]-α-(4-aminophenvP- 1 - piperidineacetic acid .The title compound was prepared from Example 58 by a method analogous to that used for Example 57. Mass Spectrum [MH + ] 437 Analytical h.plc. (gradient profile 10-90% (ii) in 25 min) Rt2.99 Example 63 Biological Data 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 collection. The blood was incubated with 0.1 mM aspirin and 0.05μM prostacyclin and then centrifuged at lOOOg for 4 minutes (20°C). 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 (HEPES 5mM, NaHCO 3 12mM, NaCl 140mM, KH-PO, 0.74mM, D-Glucose 5.6mM, KC1 2.82mM and BSA 20g/l, pH 7.4) to remove residual plasma. After washing, the pellet was resuspended in physiological salt solution and then applied to a sepharose : CL-2B column, pre-equilibrated 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, 46(3), 593-596) was added to a final concentration of 0.5mg/ml together with Ca2+ and Mg2+ at ImM and 0.5mM 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: Com ound Exam le No. IC nM 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 through a 250 micron sieve and blended with the granule. The resultant blend is compressed using suitable tablet punches. Example 65 Pharmacy Example - Capsules 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. 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 250 micron sieve and blended with the granules. The resultant blend is filled into hard gelatine capsules of a suitable size. Example 66 Pharmacy Example - Syrup a) Compound of the invention 5.0mg Hydroxypropyl Methylcellulose 45.0mg Propyl Hydroxybenzoate 1.5mg Butyl Hydroxybenzoate 0.75mg Saccharin Sodium 5.0mg 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 67 Pharmacy Example - Injection Formulation % w/v Compound of the invention 1.00 Water for injections B .P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the 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.

Claims: CLAIMS 1. Compounds of formula (I) in which X 1 and Y 1 , which may be the same or different, represent CH or N; X 2 represents CH or, when X 1 represents CH, may also represent N; Y 2 represents N or, when Y 1 represents N, may also represent CH; Z represents N or Nil 5 ; R 1 represents a hydrogen atom or a hydroxyl, C M alkyl 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 M alkyl group; R 3 represents a hydrogen atom or, when both Y 1 and Y 2 represent N, may also represent a C M alkyl or hydroxymethyl group; R 4 represents a hydrogen atom or , when Z represents N, R 4 may also represent a C M alkyl group; R 5 represents a C M aIkyl or phenylC M alkyl group; R 6 represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C M alkyl, C M alkoxy, phenylC jj alkoxy, OH, halogen, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NR 7 R 8 , NHSO j R 7 , CONR'R 8 or CO-R 7 ; a C M alkyl group substituted by one or more naphthyl, phenyl, OH or CO-R. 7 ; a C w alkenyl group substituted by one or more naphthyl, phenyl, OH or CO^ 7 ; or a saturated or unsaturated C 5 . 7 cycloalkyl group; and R 7 and R 8 , which may be the same or different represent H or C w alkyi or, together with, the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring; and pharmaceutically acceptable derivatives thereof and salts and solvates thereof. 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 Y 1 represents N. 4. Compounds as claimed in any one of Claims 1 to 3 in which Z represents N. 5. Compounds as claimed in any one of Claims 1 to 4 in which R 1 represents a hydrogen atom. 6. Compounds as claimed in any one of Claims 1 to 5 in which R 2 , R 3 and R 4 each represent a hydrogen atom. 7. Compounds as claimed in any one of Claims 1 to 6 in which R 6 represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C M alkoxy, phenylC j -alkoxy, OH, fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NH-, N(C M alkyl) 2 , NHSO 2 C M alkyl, CONR'R 8 (where R 7 and R 8 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring) or CO-H; a C M alkyl group substituted by one or more naphthyl, phenyl, OH, CO 2 C M alkyl or CO.H; a C M alkenyi group substituted by one or more naphthyl, phenyl, OH, CO-C M alkyI or CO j H; or an unsaturated C j -cycloalkyl group. 8. Compounds as claimed in any one of Claims 1 to 7 in which R 6 represents an unsubstituted phenyl or a phenyl substituted in the 4- position by fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NH.,, N(C M alkyl) 2 , NHSO 2 C M alkyl, CONR_l 8 (where R 7 and R 8 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring) or CO j H. 9. Compounds as claimed in Claim 1 in which X 1 and X 2 both represent CH; Y 1 and Z both represent N; R 1 , R 2 , R 3 and R 4 represent a hydrogen atom; and R 6 represents a naphthyl group; a thiophenyl group; an unsubstituted phenyl group; a phenyl group substituted by C M alkoxy, phenylCι. 3 alkoxy, OH, fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NH-, N(C M alkyl) 2 , NHSO 2 C M alkyl, CONR'R 8 (where R 7 and R 8 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring) or CO-H; a C M alkyl group substituted by one or more naphthyl, phenyl, OH, CO 2 C M alkyl or CO^; a C M alkenyl group substituted by one or more naphthyl, phenyl, OH, CO 2 C M alkyl or CO^; or an unsaturated C 5 -cycloalkyl group. 10. Compounds as claimed in Claim 1 in which X 1 and X 2 represent CH; Y 1 and Z both represent N; R 1 , R 2 , R 3 and R 4 represent a hydrogen atom; and R 6 represents an unsubstituted phenyl or a phenyl substituted in the 4- position by fluorine, bromine, CF 3 , unsubstituted phenyl, phenyl substituted by OH, pyridinyl, NH-, N(C M alkyl) 2 , NHSO 2 C M alkyl, CONR -l 8 (where R 7 and R 8 , together with the nitrogen atom to which they are attached, form a saturated 5 to 7 membered ring) or CO^. 11. A compound selected from: 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -pipera_inyl]-α-phenyl- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 1 '-[4-(Arr_noirninomethyl)phenyl]-α-phenyl[4,4'-bipiperidine]- 1 -acetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-methoxyphenyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Arninoiminomethyl)phenyl]- 1 -p_perazinyl]-α-(4-fluorophenyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(An_noiminomethyl)phenyl]-l-piperazinyl]-α- [4-[(methylsulphonyl)amino]phenyl]-l -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Ammo_ nomethyl)phenyl]-l-pipera__ yl]-α-(l-naphthalenylmethyl)-l- piperidineacetic acid and physiologically acceptable salts and solvates thereof, 4-[4-[4-(Ammo_ι_nomemyl)phenyl]-l-pipera_inyl]-α-(phenylmethyl)-l-piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Am oiπ_nomethyl)phenyl]- 1 -piperazinyl]-α-(4-bromophenyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(anιmoiminomethyl)phenyl]- 1 -piperazinyl]-α-phenyl- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl l'-[4-[ammo(hydroxy___no)methyl]phenyl]-α-phenyl[4,4 , -bipiperidine]-l-acetate and physiologically acceptable salts and solvates thereof; Methyl -[4-(aπ_noiminomethyl)phenyl]-α-phenyl[4,4 l -bipiperidine]-I-acetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[a__ho(hydroxvimino)methyl]phenyl]- l-pipera__ιy_]-α- (4-methoxyphenyl)- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(arnmoimmomethyl)phenyl]-l-piperaz_ yl]-α-(4-methoxyphenyl)-l- piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(am_ιoiminomethyl)phenyl]-l-piperazinyl]-α-(4-bromophenyl)- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[ammo(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α- (4-fluorophenyP- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(an__ιoiminomethyl)phenyl]- 1 -piperazinyl]-α- (4-fluorophenyl)-l-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[ammo(hydroxy_ _-Qθ)methyl]phenyl]- 1 -piperazinyl]-α-(2-naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(anιinoiminomethyl)phenyl]- 1 -piperazinyl]-α-(2-naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Am omιinomethyl)phenyl]- 1 -pipera_inyl]-α-(2-naphthalenyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-[an_no(hydroxyirnino)methyl]phenyl]-l-piperazinyl]-α-(l-naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-( 1 -naphthalenyl)- 1 -piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(An_noiminomethyl)phenyl]- 1 -piperaz__yl]-α-( 1 -naphthalenyl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[an__αo(hychoxy_-_no)methy_]phenyl]- 1 -piperazinyl]-α-(2- methoxyphenyl)- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(ammoiminomethyl)phenyl]-l-piperazinyl]-α-(2-methoxyphenyl)-l- piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(An_noiminomethyl)phenyl]- 1 -piperazinyl]-α-(2-methoxyphenyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[ammo(hydroxyimino)methyl]phenyl]- 1 -piperazinyl]-α- [4-(phenylmethoxy)phenyl]-l-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-[4- (phenylmethoxy)phenyl]- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(ar__noiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-hydroxyphenyl)- 1 - piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aιmιιoiminomethyl)phenyl]- 1 -piperazinyl]-α-(4-hydroxyphenyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof, Methyl 4-[4-[4-(an_ιιo_ ιinomethyl)phenyl]-l-piper__inyl]-α-(hydroxymethyl)-l- piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Arn oin_inomemyl)phenyl]-l-pipera_i_yl]-α-(hydroxymethyl)-l- pϊperidmeacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[ammo(hydroxyimino)methyi]phenyl]- l-piperazinyl]-α-([l, l'-biphenyl]- 4-yl)-l-piperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(ar_inoiminomethyl)phenyl]-l-piperazinyl]-a-([l,r-biphenyl]-4-yl)-l- piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Ammoiπ__.omethyl)phenyl]-l-pipera__nyl]-α-([l,l'-biphenyl]-4-yl)-l- piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-[aπ_no(hydroxyimino)me yl]phenyl]-l-pipera_inyl]-α-[4- (trifluoromethyl)phenyl]-l-ρiperidineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(an_noiminomethyl)phenyl]- 1 -piperazinyl]-α- [4- (trifluoromethyl)phenyl]-l-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aπ_no_r_nomethyl)phenyl]-l-piperazinyl]-α-[4-(trifluoromethyI)phenyl]- 1-ρiperidineacetic acid and physiologically acceptable salts and solvates thereof; 1-(1, 1 -Dimethylethyl) 4-ethyl 2-[4-[4-[4-(aπ_noiminomethyl)phenyl]-l-piperazinyl]- l-piperidinyl]-3-methylbutanedioate and physiologically acceptable salts and solvates thereof; 1-Hydrogen 4-ethyl 2-[4-[4-[4-(ammoiminomethyl)phenyl]-l-piperazinyl]-l- piperidinyl]-3-methylbutanedioate and physiologically acceptable salts and solvates thereof; 2-[4-[4-(Aιr_noiminomethyl)phenyl]-l-piperazinyl-l-piperidinyl]-3- methylbutanedioic acid and physiologically acceptable salts and solvates thereof; l,l-Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyi]-α-(l-hydroxy- 1 -phenylethyl)- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-( 1 -hydroxy- 1 -phenylethyi)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 1, 1 -Dimethylethyl 4-[4-[4-(aπ_noiminomethyl)phenyl]-l-pipera_inyl]-α-(l- phenylethyl)- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Ammoiminomethyl)phenyl]- 1 -pipera_inyl]-α-(phenylethyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; 1 , 1 -Dimethylethyl 4-[4-[4-(aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-( 1 - cyclohexen- 1-yl)- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Ammoiminomethyl)phenyl]- 1 -pipera_inyl]-α-( 1 -cyclohexen- 1 -yl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(ammoiminomethyl)phenyl]- 1 -pipera_inyl]-α- (4'-hydroxy[l,l'-biphenyl]-4-yl)- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Am oiminomethyl)phenyl]- 1 -piperazinyl]-α-(4'-hydroxy [ 1 , 1 -biphenyl]-4-yl)- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(ammoiminomethyl)phenyl]-l-piperazinyl]-α-[4-(4-pyridinyI)phenyl]-l- piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Armnoin_nomethyl)phenyl]-l-piperazinyl]-a-[4-(4-pyridinyl)phenyl]- 1 -piperidineacetic acid and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Arninoiminomethyl)phenyl]- 1 -piperazinyl]-α-(2-thienyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(aminoiminomethyl)phenyl]-l-piperazinyl]-α-(3-thienyl)-l- piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aminoiminomethyl)phenyl]- 1 -piperazinyl]-α-(3 -thienyl)- 1 - piperidineacetic acid and physiologically acceptable salts and solvates thereof; Emyl 4-[4-[4-[an_-Qo(hydroxyamino)methyl]phenyl]-l-piperazinyl]-α-[4- (dimethylamino)phenyl]-l-piperidineacetate and physiologically acceptable salts and solvates thereof, Ethyl 4-[4-[4-(an_noiminomethyl)phenyl]-l-piperazinyl]-α-[4- (dimethylamino)phenyl]-l-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(Aι-_moiminomethyl)phenyl]-l-piperazinyl]-α-[4-(dimethylamino)phenyl]- 1-piperidineacetate and physiologically acceptable salts and solvates thereof; Ethyl 4-[4-[4-[an_no(hydroxy__iino)methyl]phenyl]- 1 -piperazinyl]-α-[4- [(methyIsulphonyI)amino]phenyl]-l-piρeridineacetate and physiologically acceptable salts and solvates thereof; Ethyl-α-[4-(acetylamino)phenyl]-4-[4-[4-[amino(hydroxyimino)methyl]phenyl]-l- piperazinyl]-l-piperidineacetate and physiologically acceptable salts and solvates thereof, 4-[4-[4-(ArmΗθiminomethyl)phenyl]-l-piperazinyl]-α-(4-aminophenyl)-l- piperidineacetic acid and physiologically acceptable salts and solvates thereof; Metiιyl 4-[4-[4-[a_ιino(hydroxyiπ_no)methyl]phenyl]-l-piperazinyl]-α-[4-(l- pyrrolidinyIcarbonyl)phenyl]-l-piperϊdineacetate and physiologically acceptable salts and solvates thereof; Methyl 4-[4-[4-(arn oiι_momethyl)phenyl]-l-piperaz_ιyl]-α-[4-(l- pyrrolidinylcarbonyl)phenyl]-l-piperidineacetate and physiologically acceptable salts and solvates thereof; 4-[4-[4-(An_jιoiπιmomethyl)phenyl]-l-pipera_inyl]-α-[4-(carboxyphenyl)-l- piperidineacetic acid and physiologically acceptable salts and solvates thereof. 12. A compound as claimed in any of Claims 1 to 11 in the form of a racemic mixture or single enantiomer. 13. Compounds as claimed in any of Claims 1 to 12 wherein the compound 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. 14. A process for the preparation of compounds of formula (I) as defined in any of Claims 1 to 13 or a physiologically acceptable salt or solvate thereof, which comprises: (A) for the preparation of compounds of formula (I) in which R 1 represents a hydrogen atom; alkylating a compound of formula (H) (whef ein R p 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 a hydroxyl group; treating a compound of formula (HI) 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, C M alkyl or 2,2,2-trifluoroethyl group, forming a thioimidate from a compound of formula (H) followed by reaction with an amine R 1 ^}!!-, (where R 1 represents hydroxy, C M alkyl or 2,2,2-trifluoroethyl); or (D) foπning an imidate from a compound of formula (IV) (wherein R represents a protecting group) followed by treatment with a source of ammonia or an amine R'NI^ (where R 1 is hydroxy, C M alkyl 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 a hydrogen, C M alkyl or 2,2,2-trifluoroethyl and Z represents N; hydrogenating a compound of formula (XH) (where R 1 is hydrogen, C M 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). 15. A pharmaceutical composition comprising a compound of formula Q) as defined in any one of Claims 1 to 13 or a physiologically acceptable salt or solvate thereof together with at least one physiologically acceptable carrier or excipient. 16. A compound of formula (I) as defined in any of Claims 1 to 13 or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine. 17. The use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof as defined in any of Claims 1 to 13 for the rnanufacture of a medicament for the treatment or phrophylaxis of thrombotic disorders. 18. 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 amount of a compound of formula (I) as defined in any of claims 1 to 13 or a physiologically acceptable salt or solvate thereof.

Inventors: ELDRED COLIN DAVID, JUDKINS BRIAN DAVID, KELLY HENRY ANDERSON, PORTER BARRY, WHEATCROFT JAMES RUSSELL, ELDRED, COLIN, DAVID, JUDKINS, BRIAN, DAVID, KELLY, HENRY, ANDERSON, PORTER, BARRY, WHEATCROFT, JAMES, RUSSELL
Applicants: GLAXO GROUP LTD, GLAXO GROUP LIMITED
Application year: 1993
Main classification: C07D401
IPC codes: A61K31, A61P7, A61P9, A61P13, A61P15, A61P27, A61P35, A61P43, C07D211, C07D401, C07D409