Heterocyclic compounds useful as pharmaceutical agents

Compounds of formula (I) ##STR1## in which all variables are defined in the description and their salts inhibit the enzyme oxido squalene cyclase and are useful in treating hypercholesterolemia and also as anti-fungal agents. Processes for their preparation are also described together with their use in medicine.

This invention concerns heterocyclic compounds which are useful in
 inhibiting oxido-squalene cyclase, processes for their preparation and
 pharmaceutical compositions containing them. The present invention is also
 concerned with heterocyclic compounds capable of inhibiting cholesterol
 biosynthesis and hence in lowering cholesterol levels in blood plasma. The
 present invention also relates to methods of using such heterocyclic
 compounds in diseases and medical conditions such as hypercholesterolemia
 and atherosclerosis.
 There is clinical evidence that raised serum cholesterol levels increase
 the risk of coronary heart disease and associated diseases such as
 atherosclerosis and ischaemic heart disease. As a result there has been a
 great deal of interest in finding ways of lowering cholesterol levels in
 blood plasma. Although it has been possible to obtain some reduction by
 means of diet, only modest reductions have been obtained by controlling
 the dietry intake of cholesterol. Consequently, there is a need for
 therapeutic approaches to reducing cholesterol levels.
 Several different classes of compounds have been reported to possess the
 capability of being able to lower cholesterol levels in blood plasma. For
 example agents which inhibit the enzyme HMGCoA reductase, which is
 essential for the production of cholesterol, have been reported to reduce
 levels of serum cholesterol. Illustrative of this class of compounds is
 the HMGCoA reductase inhibitor known as lovastatin which is disclosed in
 U.S. Pat. No. 4,231,938. Other agents which are reported to lower serum
 cholesterol include those which act by complexing with bile acids in the
 intestinal system and which are hence termed "bile acid sequestrants". It
 is believed that many of such agents act by sequestering bile acids within
 the intestinal tract. This results in a lowering of the levels of bile
 acid circulating in the enteroheptatic system and promotes replacement of
 bile acids by synthesis in the liver from cholesterol, which results in an
 upregulation of the hepatic LDL cholesterol receptor and in a lowering of
 circulating blood cholesterol levels.
 The biosynthesis of cholesterol is a complex process which will be
 considered here as three principal stages, namely 1) the conversion of
 acetic acid to mevalonic acid 2) the conversion of mevalonic acid to
 squalene and 3) the conversion of squalene to cholesterol. In the last
 stage, squalene is first converted into 2,3-oxido-squalene and then to
 lanosterol. Lanosterol is then converted to cholesterol through a number
 of enzymatic steps.
 The conversion of 2,3-oxido-squalene to lanosterol is a key step in the
 biosynthesis of cholesterol. This conversion is catalysed by the enzyme
 oxido-squalene cyclase. It follows that inhibition of this enzyme
 decreases the amount of lanosterol available for conversion to
 cholesterol. Consequently, inhibition of oxido-squalene cyclase should
 interupt cholesterol biosynthesis and give rise to a lowering of
 cholesterol levels in blood plasma via LDL receptor upregulation.
 The present invention is based on the discovery that certain heterocyclic
 compounds are inhibitors of oxido-squalene cyclase and are hence useful in
 treating diseases and medical conditions in which inhibition of
 oxido-squalene cyclase is desirable.
 According to the present invention there is provided a compound of formula
 I, or a pharmaceutically acceptable salt thereof, wherein
 According to the present invention there is provided a compound of formula
 I,
 ##STR2##
 wherein
 G.sup.1 is CH or N;
 G.sup.2 is CH or N;
 n is 1 or 2;
 R is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino,
 hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,
 di(1-4C)alkylarnino or phenyl(1-4C)alkyl;
 A is methylene or ethylene; B is ethylene; and wherein A and B may
 independently optionally bear a substituent selected from (1-6C)alkyl,
 (1-6C)alkoxy, phenyl(1-4C)alkyl, halogeno and (1-6C)alkoxycarbonyl;
 T is CH or N;
 when T is CH, X.sup.1 is selected from CR.sup.1 R.sup.2, SO.sub.2, SO, CO,
 CR.sup.3 R.sup.4 O, a bond, O, S and NR.sup.5 ; and when T is N, X.sup.1
 is selected from CR.sup.1 R.sup.2, SO.sub.2, SO, CO, CR.sup.3 R.sup.4 O
 and a bond; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
 independently selected from hydrogen and (1-4C)alkyl;
 Y.sup.1 represents CR.sup.6 R.sup.7 or a bond, wherein R.sup.6 and R.sup.7
 are independently selected from hydrogen and (1-4C)alkyl;
 Ar.sup.1 is a phenylene, naphthylene, a 5- or 6-membered monocyclic
 heteroaryl ring containing 1, 2 or 3 heteroatoms selected from nitrogen,
 oxygen and sulphur, or a 9- or 10-membered bicyclic heteroaryl ring
 containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and
 sulphur;
 Q is selected from hydrogen and a group of formula L.sup.1 X.sup.2 L.sup.2
 Z in which L.sup.1 is a bond, (1-4C)alkylene or (2-4C)alkenylene, L.sup.2
 is a bond or (1-4C)alkylene, X.sup.2 is a bond, O, S, SO, SO.sub.2,
 CR.sup.8 R.sup.9, CO, OSO.sub.2, OCR.sup.8 R.sup.9, OCO, SO.sub.2 O,
 CR.sup.8 (R.sup.9)O, COO, NR.sup.10 SO.sub.2, SO.sub.2 NR.sup.11,
 NR.sup.12 CO, CONR.sup.12, NR.sup.13 CONR.sup.14 and NR.sup.14 in which
 R.sup.8 and R.sup.9 are independently selected from hydrogen, hydroxy and
 (1-4C)alkyl; and R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are
 independently selected from hydrogen and (1-4C)alkyl;
 Z is hydrogen, (1-4C)alkyl, phenyl, naphthyl, phenyl(2-4C)alkenyl,
 phenyl(2-4C)alkynyl or a heterocyclic moiety containing 1, 2, 3 or 4
 heteroatoms selected from nitrogen, oxygen and sulphur;
 and wherein the phenyl, naphthyl or heteroaryl moiety in Ar.sup.1 and the
 alkyl, phenyl, naphthyl, or heterocyclic moiety in Z may optionally bear
 one or more substituents selected from halogeno, hydroxy, oxy, amino,
 nitro, cyano, carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl,
 (2-6C)alkynyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl,
 (3-6C)cycloalkyl(1-4C)alkyl, (1-4C)alkylenedioxy, (1-6C)alkylamino,
 di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, di-N[(1-6C)alkyl]carbamoyl,
 (1-6C)alkanoylamino, (1-6C)alkoxycarbonyl, (1-6C)alkylthio,
 (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl,
 halogeno(1-6C) alkylthio, halogeno(1-6C)alkoxy, (1-6C)alkanoyl, tetrazoyl,
 phenyl, phenoxy, phenylsulphonyl, piperidinocarbonyl, morpholinocarbonyl,
 hydroxy(1-6C)alkyl and amino(1-6C)alkyl; wherein any phenyl containing
 substituents may optionally bear one or more substituents selected from
 halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino, hydroxy, nitro,
 (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di(1-4C)alkylamino;
 provided that the compound is not
 N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]-(E)-4-chlorostyrenesulph
 onamide or
 N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]4'-bromio-4-biplhenylesul
 phonamide;
 and pharmaceutically acceptable salts thereof.
 The chemical formulae referred to herein by Roman numerals are, for
 convenience, set out on a separate sheet following the Examples.
 It will be understood that when formula I compounds contain a chiral
 centre, the compounds of the invention may exist in, and be isolated in,
 optically active or racemic form. The invention includes any optically
 active or racemic form of a compound of formula I which possesses the
 beneficial pharmacological effect of inhibiting oxido-squalene cyclase.
 The synthesis of optically active forms may be carried out by standard
 techniques of organic chemistry well known in the art, for example by,
 resolution of a racemic form, by synthesis from optically active starting
 materials or by asymmetric synthesis. It will also be appreciated that
 certain compounds of formula I may exist as geometrical isomers. The
 invention includes any geometrical isomer of a compound of formula I which
 possesses the beneficial pharmacological effect of inhibiting
 oxido-squalene cyclase.
 It will also be understood that certain compounds of the present invention
 may exist in solvated, for example hydrated, as well as unsolvated forms.
 It is to be understood that the present invention encompasses all such
 solvated forms which possess the property of inhibiting oxido-squalene
 cyclase.
 It is also to be understood that generic terms such as "alkyl" include both
 the straight chain and branched chain groups such as butyl and tert-butyl.
 However, when a specific term such as "butyl" is used, it is specific for
 the straight chain or "normal" butyl group, branched chain isomers such as
 "t-butyl" being referred to specifically when intended.
 In one embodiment of the present invention there is provided a compound of
 formula I, or a pharmaceutically acceptable salt thereof, as herein before
 defined, provided that when X.sup.1 is CO, Ar.sup.1 is phenylene which
 optionally bears 1 or 2 substituents selected from halogeno,
 trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, and L.sup.2 is a bond to Q,
 then X.sup.2 is a bond.
 Particular values for optional substituents which may be present on a
 phenyl, napthyl, heteroaryl or heterocyclic moiety include, for example,
 for alkyl; (1-4C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl,
 isobutyl, sec-butyl or tert-butyl;
 for cycloalkyl cyclopropyl, cyclobutyl or cyclopentyl;
 for cycloalklalkyl (3-6C)cycloalkyl(1-2C)alkyl such as cyclopropylmethyl,
 cyclopropylethyl, cyclobutylmethyl or cyclopentylmethyl;
 for alkenyl; (2-4C)alkenyl, such as allyl, prop-1-enyl, 2-methyl-2-propenyl
 or 2-butenyl;
 for alkynyl; (2-4C)alkynyl, such as prop-2-ynyl or but-2-ynyl;
 for alkoxy; (1-6C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy,
 butoxy, pentoxy or 3-methylbutoxy;
 for alkylarnino; (1-4C)alkylamino, such as methylamino, ethylamino,
 propylamino or butylamino;
 for di-alkylamino; di-[(1-4C)alkyl]amino such as dimethylamino,
 diethylamino, methylpropylamino or dipropylamino;
 for alkylcarbamoyl; (1-4C)alkylcarbamoyl such as N-methylcarbamoyl,
 N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl or
 N-tert-butylcarbamoyl or (N-(2-methylpropyl)carbamoyl;
 for di-alkylcarbamoyl; di-[(1-4C)alkyl]carbamoyl, such as
 N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl;
 for alkoxycarbonyl; (1-4C)alkoxycarbamoyl such as methoxycarbonyl,
 ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl or
 tert-butoxycarbonyl;
 for alkylthio; (1-4C)alkylthio such as methylthio, ethylthio, propylthio,
 isopropylthio or butylthio;
 for alkylsulphinyl; (1-4C)alkylsulphinyl such as methylsulphinyl,
 ethylsulphinyl, propylsulphinyl, isopropylsulphinyl or butylsulphinyl;
 for alkylsulphonyl; (1-4C)alkylsulphonyl such as methylsulphonyl,
 ethylsulphonyl, propylsulphonyl, isoproylsulphonyl or butylsulphonyl;
 for halogeno; fluoro, chloro, bromo or iodo;
 for halogenoalkyl; halogeno(1-4C)alkyl such as halogenoalkyl containing
 one, two or three halo groups selected from fluoro, chloro, bromo and iodo
 and an alkyl group selected from methyl, ethyl, propyl, iso-propyl, butyl,
 iso-butyl and sec-butyl, thus particular values will include
 trifluoromethyl, difluoromethyl and fluoromethyl;
 for alkanoylamino; (1-4C)alkanoylamino such as formamido, acetamido,
 propionamido, iso-propionamido, butyramido or iso-butyramido;
 for alkylenedixoy; methylenedioxy or ethylenedioxy;
 for alkanoyl; (1-4C)alkanoyl such as formyl, acetyl, propionyl or butyryl;
 for hydroxyalkyl 1-hydroxy-1-methylethyl, hydroxymethyl, 2-hydroxyethyl, or
 2-hydroxypropyl;
 for aminoalkyl; aminomethyl, 2-aminoethyl, 1-aminoethyl or aminopropyl.
 Particular values for optional substituents on A and B include, for
 example:
 for alkyl; (1-4C)alkyl such as methyl, ethyl, propyl, isopropyl, butyl,
 isobutyl, sec-butyl or tert-butyl;
 for alkoxy; (1-4C)alkoxy such as methoxy, ethoxy, propoxy, isopropoxy or
 butoxy;
 for phenylalkyl; phenyl (1-2C)alkyl such as benzyl, 2-phenylethyl or
 1-phenylethyl
 for halogeno; fluoro, chloro, bromo or iodo
 for alkoxycarbonyl; methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or
 butoxycarbonyl;
 Particular values for R include, for example,
 for alkyl; methyl, ethyl, propyl, iso-propyl or tert-butyl;
 for alkoxy methoxy, ethoxy, propoxy, isopropoxy or butoxy;
 for alkylamino methylamino, ethylamino or propylamino;
 for di-alkylamino dimethylamino, N-ethyl-N-methylamino or diethylamino;
 for halogeno fluoro, chloro, bromo or iodo.
 A particular value for R when trifluoromethyl is 3-trifluoromethyl and/or
 5-trifluoromethyl. A further particular value for R is hydrogen, also
 (1-2C) alkyl, for example 2-methyl.
 A particular value for Ar.sup.1 when it is a 5- or 6-membered heteroaryl
 ring is, for example, furandiyl, thiopheniediyl, pyridinediyl,
 pyrazinediyl, pyrimidinediyl, pyridazinediyl, pyrrolediyl, pyrazolediyl,
 imidazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl, isotliazolediyl,
 1,2,3-trizolediyl, 1,2,4-triazolediyl, oxadiazolediyl, furazandiyl,
 thiadiazolediyl and 1,3,5-triazinediyl which may be attached through any
 available position including any available nitrogen atom. It will be
 appreciated that when Q=H the above group will only have one position of
 attachment and so group such as furandiyl will be furanyl etc.
 A particular value for Z when it is a heterocyclic moiety is, for example,
 a monocyclic 5- or 6-membered heterocyclic ring or a 5- or 6-membered
 heterocyclic ring which is fused to a benzene moiety. Thus, particular
 values will include, furyl, benzofuranyl, thienyl, benzothienyl, pyridyl,
 quinolyl, isoquinolyl, 1,2,3,4-tetrahydroquinolyl,
 1,2,3,4-tetrahydroisoquinolyl, pyrimidinyl, pyrazinyl, pyrrolyl, indolyl,
 indolinyl, benzimidazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl,
 benzthiazolyl and oxadiazolyl.
 A particular value for R.sup.1 to R.sup.14 when alkyl, is, for example
 methyl, ethyl, propyl, isopropyl and tert-butyl.
 A particular value for L.sup.1 or L.sup.2 when alkylene is, for example,
 methylene, ethylene or trimethylene.
 A particular value for Ar.sup.1 when naphthyl is, for example, 1-naphthyl
 or 2-naphthyl.
 A particular value for Ar.sup.1 when phenylalkenyl is, for example, styryl,
 cinnamyl or 3-phenylprop-2-enyl.
 A particular value for Ar.sup.1 when phenylalkynyl is, for example,
 2-phenylethynyl, 3-phenylprop-2-ynyl or 2-phenylprop-1-ylnyl.
 A particular value for A is methylene.
 A particular value for T is CH.
 More particularly, G.sup.2 is CH or N; G.sup.1 is CH.
 More particular values are G.sup.1 is CH or N; G.sup.2 is CH.
 More particularly when T is N, X.sup.1 is selected from a bond, CO,
 SO.sub.2, and CR.sup.1 R.sup.2.
 More particularly when T is CN, X.sup.1 is selected from a bond, CO,
 SO.sub.2, CR.sup.1 R.sup.2 and O.
 More particularly Y.sup.1 is a bond.
 More particularly, Ar.sup.1 is selected from a phenylene ring and a
 6-membered heteroaryl moiety selected from these mentioned above.
 More particularly, Q is selected from hydrogen and a group of formula
 L.sup.1 X.sup.2 L.sup.2 Z in which L.sup.1 is (1-4C)alkylene or a bond,
 X.sup.2 is selected from NR.sup.12 CO, NR.sup.10 SO.sub.2, NR.sup.13
 COR.sup.14 and SO.sub.2, and L.sup.2 is a bond or (1-4C)alkylene; and Z is
 as defined above.
 More particularly X.sup.1 --Y.sup.1 taken together are O or S.
 In general, it is preferred that G.sup.1 and G.sup.2 are both CH.
 In general, it is preferred that when Q is hydrogen, X.sup.1 is selected
 from CR.sup.1 R.sup.2, SO.sub.2 and CO.
 In general, it is preferred that L.sup.1 and L.sup.2 are selected from
 CH.sub.2 and a bond.
 In general, it is preferred that when Q is a group of formula L.sup.1
 X.sup.2 L.sup.2 Z, X.sup.1 is a bond.
 In general, it is preferred that T is N.
 In general, it is preferred that Ar.sup.1 is a phenylene ring or a pyridyl
 ring.
 In general, it is preferred that Z is a phenyl, phenyl(2-4C)alkenyl, or
 naphthyl moiety.
 In general it is preferred that Ar.sup.1 and Ar.sup.2, if substituted are
 independently mono- or di-substituted.
 More preferably, Ar.sup.1 is a phenylene ring optionally substituted as
 hereinbefore defined.
 More preferably, Z is a phenyl ring, optionally substituted as hereinbefore
 defined.
 More preferably A and B are both ethylene.
 A specific value for G.sup.1 is CH or N.
 A specific value for G.sup.2 is CH or N (especially CH).
 A specific value for T is CH or N.
 A specific value for X.sup.1 is a bond, CO, SO.sub.2, CH.sub.2 and O. A
 further specific value is O or S.
 A specific value for Ar.sup.1 is a phenylene ring or a pyridyl ring. In
 particular the pyridyl ring is 2-pyridyl. More particular values include
 furanyl, pyrimidinyl, thiazolyl and oxazolyl.
 A specific value for the group L.sup.1 X.sup.2 L.sup.2 is CH.sub.2
 NHSO.sub.2, NHSO.sub.2, CH.sub.2 SO.sub.2, CH.sub.2 NHCONH, CH.sub.2 NHCO,
 CH.sub.2 N(Me)SO.sub.2, SO.sub.2, CO, O, CH.sub.2, OCH.sub.2, CH.sub.2
 CH.sub.2 O, COCH.sub.2 CH.sub.2 and a bond.
 Further specific values for the group L.sup.1 X.sup.2 L.sup.2 include
 CH.sub.2 NHCO, NHSO.sub.2, CH.sub.2 NHSO.sub.2, CH.sub.2 NH, CONH and
 SO.sub.2.
 A specific value for Z is phenyl, styryl and naphthyl.
 A specific value for A is unsubstituted ethylene or unsubstituted
 methylene.
 A specific value for B is unsubstituted ethylene.
 A suitable pharmaceutically-acceptable salt of an aminoheterocyclic
 derivative of the invention is, for example, an acid-addition salt of an
 aminoheterocyclic derivative of the invention which is sufficiently basic,
 for example, an acid-addition salt with, for example, an inorganic or
 organic acid, for example hydrochloric, hydrobromic, sulphuric,
 phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable
 pharmaceutically-acceptable salt of an aminoheterocyclic derivative of the
 invention which is sufficiently acidic is an alkali metal salt, for
 example a sodium or potassium salt, an alkaline earth metal salt, for
 example a calcium or magnesium salt, an ammonium salt or a salt with an
 organic base which affords a physiologically-acceptable cation, for
 example a salt with methylamine, dimethylamine, trimethylamine,
 piperidine, morpholine or tris-(2-hydroxyethyl)amine.
 In one embodiment of the present invention there is provided a compound of
 formula I, or a pharmaceutically acceptable salt thereof, wherein
 G.sup.1 is CH or N;
 G.sup.2 is CH or N;
 n is 1 or 2;
 R is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano, amino,
 hydroxy, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino or
 di(1-4C)alkylamino;
 A is methylene or ethylene; B is ethylene; and wherein A and B may
 independently optionally bear a substituent selected from (1-6C)alkyl,
 (1-6C)alkoxy, phenyl (1-4C)alkyl, halogeno and (1-6C)alkoxycarbonyl;
 T is CH or N;
 when T is CH, X.sup.1 is selected from CR.sup.1 R, SO.sub.2 SO, CO, a bond,
 CR.sup.3 R.sup.4 O, O, S and NR.sup.5, and when T is N, X.sup.1 is
 selected from CR.sup.1 R.sup.2, SO.sub.2, SO, CO, CR.sup.3 R.sup.4 O and a
 bond, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
 independently selected from hydrogen and (1-4C)alkyl;
 Y.sup.1 represents CR.sup.6 R.sup.7 or a bond, wherein R.sup.6 and R.sup.7
 are independently selected from hydrogen and (1-4C)alkyl;
 Ar.sup.1 is a phenylene ring or a 5- or 6-membered monocyclic heteroaryl
 ring containing 1,2 or 3 heteroatoms selected from nitrogen, oxygen and
 sulphur;
 Q is selected from hydrogen and a group of formula L.sup.1 X.sup.2 L.sup.2
 Z in which L.sup.1 is a bond or (1-4C)alkylene, L.sup.2 is a bond or
 (1-4C)alkylene, X.sup.2 is a bond, S, SO, SO.sub.2, CR.sup.8 R.sup.9, CO,
 NR.sup.10 SO.sub.2, SO.sub.2 NR.sup.11, NR.sup.12 CO, CONR.sup.12 and
 NR.sup.13 CONR.sup.14 in which R.sup.8,R.sup.9,R.sup.10,R.sup.11,R.sup.12,
 R.sup.13 and R.sup.14 are independently selected from hydrogen and
 (1-4C)alkyl;
 Z is selected from phenyl, naphthyl, phenyl(2-4C)alkenyl,
 phenyl(2-4C)alkvnyl and a heterocyclic moiety containing 1, 2, 3 or 4
 heteroatoms selected from nitrogen, oxygen and sulphur:
 and wherein the phenyl or heteroaryl moiety in Ar.sup.1 and the phenyl,
 naphthyl, or heterocyclic moiety in Z may optionally bear one or more
 substituents selected from halogeno, hydroxy, amino, nitro, cyano,
 carboxy, carbamoyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,
 (1-6C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-4C)alkyl,
 (1-4C)alkylenedioxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
 N-(1-6C)alkylcarbamoyl, di-N[(1-6C)alkyl]carbamoyl, (1-6C)alkanoylamino,
 (1-6C)alkoxycarbonyl, (1-6C)alkylthio. (1-6C)alkylsulphinyl,
 (1-6C)alkylsulphonyl, halogeno(1-6C)alkyl, halogeno(1-6C)alkoxy,
 (1-6C)alkanoyl and tetrazoyl;
 provided that the compound is not
 N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl]-(E)-4-chlorostyrenesulph
 onamide,
 and pharmaceutically acceptable salts thereof.
 Particular, prepared and specific values include the appropriate values
 mentioned above. In a particular aspect of this embodiment when X.sup.1 is
 CO, Ar.sup.1 is phenylene which optionally bears 1 or 2 substituents
 selected from halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, and
 L.sup.2 is a bond to Q, then X.sup.2 is not a bond.
 In a further embodiment of the present invention Q is hydrogen and G.sup.1,
 G.sup.2, R, n, A, B, T, X.sup.1, Ar.sup.1 and the optional substituents
 for the phenyl or heteroaryl moities in Ar.sup.1 may have any of the
 values hereinbefore defined.
 Particular compounds of this embodiment include compounds of formula I and
 their pharmaceutically acceptable salts in which R, n, Z, the optional
 substituents for a phenyl or heteroaryl moiety on Ar.sup.1 and the
 optional substituents for A and B may take the values hereinbefore
 defined, (unless stated otherwise) and:
 (a) G.sup.1 is CH or N; G.sup.2 is CH; T is N or CH; when T is N, X.sup.1
 is CR.sup.1 R.sup.2,SO.sub.2, CO; when T is CH, X.sup.1 is CR.sup.1
 R.sup.2,SO.sub.2,CO,O,S,NR.sup.3 or a bond, in which R.sup.1,R.sup.2 and
 R.sup.3 are independently selected from hydrogen and (1-4C)alkyl; Y.sup.1
 is a bond, A and B are both ethylene; Ar.sup.1 is a phenyl ring;
 (b) G.sup.1 is CH or N; G.sup.2 is CH, T is N, X.sup.1 is CH.sub.2,
 SO.sub.2 or CO, A and B are ethylene Y.sup.1 is a bond, Ar.sup.1 is a
 phenyl ring;
 (c) G.sup.1 is CH, G.sup.2 is CH, T is N, X.sup.1 is CH.sub.2, SO.sub.2 or
 CO, A and B are ethylene. Y.sup.1 is a bond, Ar.sup.1 is a phenyl ring;
 (d) G.sup.1 is CH or N, G.sup.2 is CH, T is CH, A is methylene, B is
 ethylene, X.sup.1 is O or a bond, Y.sup.1 is a bond, Ar.sup.1 is a phenyl
 or pyridyl ring;
 (e) G.sup.1 is CH or N, G.sup.2 is CH, T is N, X.sup.1 is CH.sub.2,
 SO.sub.2, CO, A and B are ethylene, Y.sup.1 is a bond, Ar.sup.1 is a
 pyridyl ring; or additionally (f) which is as (d) above but wherein
 X.sup.1 is O or S. It will be appreciated that Q is H in each of the
 above.
 Further particular compounds of this embodiment (Q=H), include compounds of
 formula I and their pharmaceutically acceptable salts in which R, n, the
 optional substituents for a phenyl or heteroaryl moiety on Ar.sup.1 and
 the optional substituents for A and B may take the values hereinbefore
 defined, (unless stated otherwise) and:
 (a) G.sup.2 is CH or N; G.sup.1 is CH; T is N or CH; when T is N, X.sup.1
 is CR.sup.1 R.sup.2,SO.sub.2, CO; when T is CH, X.sup.1 is CR.sup.1
 R.sup.2,SO.sub.2,CO,O,S,NR.sup.3 or a bond, in which R.sup.1,R.sup.2 and
 R.sup.3 are independently selected from hydrogen and (1-4C)alkyl; Y.sup.1
 is a bond, A and B are both ethylene; Ar.sup.1 is a phenyl ring;
 (b) G.sup.2 is CH or N; G.sup.1 is CH, T is N, X.sup.1 is CH.sub.2,SO.sub.2
 or CO, A and B are ethylene, Y.sup.1 is a bond, Ar.sup.1 is a phenyl ring;
 (c) G.sup.2 is CH or N, G.sup.1 is CH, T is CH, A is methylene, B is
 ethylene, X.sup.1 is O or a bond, Y.sup.1 is a bond, Ar.sup.1 is a phenyl
 or pyridyl ring;
 (d) G.sup.2 is CH or N, G.sup.1 is CH, T is N, X.sup.1 is CH.sub.2,
 SO.sub.2, CO, A and B are ethylene, Y.sup.1 is a bond, Ar.sup.1 is a
 pyridyl ring; or additionally (e) which is as (c) above but wherein
 X.sup.1 is O or S.
 In a further embodiment of the present invention, Q is a group of formula
 L.sup.1 X.sup.2 L.sup.2 Z and G.sup.1, G.sup.2, R, n, A, B, T, X.sup.1,
 Ar.sup.1, Z and the optional substituents for the phenyl, naphthyl,
 heteroaryl and heterocyclic moieties in Ar.sup.1 and Z are as defined
 above.
 Particular compounds of this embodiment include compounds of formula I and
 their pharmaceutically acceptable salts in which R, n, Ar.sup.1, Z the
 optional substituents for A and B and the optional substituents for a
 phenyl, heteroaryl, naphthyl or benzene moieties in Ar.sup.1 or Z may take
 the values hereinbefore defined (unless stated otherwise) and:
 (a) G.sup.1 is CH or N, G.sup.2 is CH, T is N or CH, A is ethylene, or
 methylene, B is ethylene, X.sup.1 and Y.sup.1 are bonds, Q is a group of
 formula L.sup.1 X.sup.2 L.sup.2 Z in which L.sup.1 is (1-4C)alkylene or a
 bond, X.sup.2 is selected from CONR.sup.12,NR.sup.12 CO, NR.sup.10
 SO.sub.2, NR.sup.13 CONR.sup.14 and SO.sub.2, L is a (1-4C)alkylene or a
 bond, R.sup.10, R.sup.12,R.sup.13 and R.sup.14 are independently selected
 from hvdrogen and (1-4C)alkyl;
 (b) G.sup.1 is CH or N, G.sup.2 is CH, T is N or CH, A and B are ethylene.
 X.sup.1 and Y.sup.1 are bonds; Q is a group of formula L.sup.1 X.sup.2
 L.sup.2 Z in which L.sup.1 is (1-4C)alkylene or a bond, X.sup.2 is NHCO,
 NHSO.sub.2, NHCONH or SO.sub.2, L.sup.2 is (1-4C)alkylene or a bond, and R
 and n are as hereinbefore defined;
 (c) G.sup.1 is CH, G.sup.2 is CH, T is N or CH, A and B are ethylene.
 X.sup.1 and Y.sup.1 are bonds, Q is L.sup.1 X.sup.2 L.sup.2 Z in which
 L.sup.1 is (1-4C)alkylene, L.sup.2 is a bond, X.sup.2 is NHCO, NHSO.sub.2,
 NHCONH and SO.sub.2 ; or
 (d) G.sup.1 is CH or N (preferably CH), G.sup.2 is CH; T is N or CH
 (preferably N), X.sup.1 and Y.sup.1 are bonds, A and B are ethylene,
 Ar.sup.1 is phenyl, Q is a group of formula L.sup.1 X.sup.2 L.sup.2 Z in
 which L.sup.1 is (1-4C)alkylene or a bond (preferably alkylene such as
 CH.sub.2), X.sup.2 is NHCO, NHSO.sub.2, NHCONH or SO.sub.2, L.sup.2 is
 (1-4C)alkylene or a bond (preferably a bond);
 Further particular compounds of this embodiment include compounds of
 formula I and their pharmaceutically acceptable salts in which R, n,
 Ar.sup.1 , Z the optional substituents for A and B and the optional
 substituents for a phenyl, heteroaryl, naphthyl or benzene moieties in
 Ar.sup.1 or Z may take the values hereinbefore defined (unless stated
 otherwise) and:
 (a) G.sup.2 is CH or N, G.sup.1 is CH, T is N or CH, A is ethylene, or
 methylene, B is ethylene, X.sup.1 and Y.sup.1 are bonds, Q is a group of
 formula L.sup.1 X.sup.2 L.sup.2 Z in which L.sup.1 is (1-4C)alkylene or a
 bond, X.sup.2 is selected from CONR.sup.12, NR.sup.12 CO, NR.sup.10
 SO.sub.2, NR.sup.13 CONR.sup.14 and SO.sub.2, L is a (1-4C)alkylene or a
 bond, R.sup.10, R.sup.12 ,R.sup.13 and R.sup.14 are independently selected
 from hydrogen and (1-4C)alkyl;
 (b) G.sup.2 is CH or N, G.sup.1 is CH, T is N or CH, A and B are ethylene,
 X.sup.1 and Y.sup.1 are bonds; Q is a group of formula L.sup.1 X.sup.2
 L.sup.2 Z in which L.sup.1 is (1-4C)alkylene or a bond. X.sup.2 is NHCO,
 NHSO.sub.2, NHCONH or SO.sub.2, L.sup.2 is (1-4C)alkylene or a bond, and R
 and n are as hereinbefore defined;
 (c) G.sup.2 is CH or N (preferably CH), G.sup.1 is CH; T is N or CH
 (preferably N), X.sup.1 and Y.sup.1 are bonds, A and B are ethylene,
 Ar.sup.1 is phenyl, Q is a group of formula L.sup.1 X.sup.2 L.sup.2 Z in
 which L.sup.1 is (1-4C)alkylene or a bond (preferably alkylene such as
 CH.sub.2), X.sup.2 is NHCO, NHSO.sub.2, NHCONH or SO.sub.2, L.sup.2 is
 (1-4C)alkylene or a bond (preferably a bond);
 In a preferred embodiment there is provided a compound of formula I or a
 pharmaceutically acceptable salt thereof, wherein:
 G.sup.1 is CH, G.sup.2 is CH, T is N, X.sup.1 is CO, SO.sub.2, or CH.sub.2,
 A and B are ethylene, Ar.sup.1 is phenyl, Q is hydrogen, and R, m and the
 optional substituent for the phenyl moiety of Ar.sup.1 are as hereinbefore
 defined.
 Particular, preferred and specific values include the appropriate values
 mentioned above.
 In a further preferred embodiment there is provided a compound of formula I
 or a pharmaceutically acceptable salt thereof wherein: G.sup.1 is CH,
 G.sup.2 is CH, T is N, X.sup.1 is a bond, Y.sup.1 is a bond, A and B are
 ethylene, Ar.sup.1 is phenyl, Q is of formula L.sup.1 X.sup.2 L.sup.2 Z in
 which L.sup.1 is (1-4C)alkylene (preferably CH.sub.2), X.sup.2 is NR.sup.6
 SO.sub.2 in which R.sup.6 is (1-4C)alkyl or hydrogen (preferably
 hydrogen), and Z is phenyl, wherein the phenyl moiety of Ar.sup.1 and Z
 may optionally be substituted as hereinbefore defined and R and m are as
 hereinbefore defined.
 Particular, preferred and specific values include the appropriate values
 mentioned above.
 In a further embodiment of the present invention, Z is (1-4C)alkyl or
 hydrogen, more particularly (1-4C)alkyl, and the other groups are as
 hereinbefore defined.
 Compounds of particular interest include the compounds described in the
 accompanying examples and as such they and their pharmaceutically
 acceptable salts are provided as a further feature of the present
 invention.
 The compounds of formula I and their pharmaceutically acceptable salts may
 be prepared by processes known to be applicable to the preparation of
 structurally related compounds. These procedures are illustrated by the
 following representative processes in which the various groups and
 radicals such as G.sup.1, G.sup.2, A, B, X.sup.1, Ar.sup.1 and Q are as
 hereinbefore defined (unless stated otherwise), and are provided as a
 further feature of the present invention. In cases where the compounds
 contain a group such as an amino, hydroxy, or carboxy group, this group
 may be protected using a conventional protecting group which may be
 removed when desired by conventional means.
 (a) For the production of those compounds of the formula I wherein T is N
 and X.sup.1 is CO, the reaction, conveniently in the presence of a
 suitable base, of an amine of the formula II,
 ##STR3##
 with an acid of the formula III,
EQU HO.sub.2 C--Y.sup.1 --Ar.sup.1 --Q III
 or a reactive derivative thereof.
 A suitable reactive derivative of an acid of the formula III is, for
 example, an acyl halide, for example an acyl chloride formed by the
 reaction of the acid and an inorganic acid chloride, for example thionyl
 chloride; a mixed anhydride, for example an anhydride formed by the
 reaction of the acid with a chloroformate such as isobutyl chloroformate
 or with an activated ketone such as 1,1'-carbonyldiimidazole: an active
 ester, for example an ester formed by the reaction of the acid and a
 phenol such as pentafluorophenol, an ester such as pentafluorophenyl
 trifluoroacetate or an alcohol such as N-hydroxybenzotriazole or
 N-hydroxysuccinimide; an acyl azide, for example an azide formed by the
 reaction of the acid and an azide such as diphenylphosphoryl azide; an
 acyl cyanide, for example a cyanide formed by the reaction of an acid and
 a cyanide such as diethylphosphoryl cyanide; or the product of the
 reaction of the acid and a carbodiimide such as
 N,N'-dicyclohexylcarbodiimide or
 N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.
 The reaction is conveniently carried out in the presence of a suitable base
 such as, for example, an alkali or alkaline earth metal carbonate,
 alkoxide, hydroxide or hydride, for example sodium carbonate, potassium
 carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide,
 potassium hydroxide, sodium hydride or potassium hydride, or an
 organometallic base such as an alkyl-lithium, for example n-butyl-lithium,
 or a dialkylamino-lithium, for example lithium di-isopropylamide, or, for
 example, an organic amine base such as, for example, pyridine,
 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
 morpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is also
 preferably carried out in a suitable inert solvent or diluent, for example
 methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran,
 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide,
 N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a
 temperature in the range, for example, -78.degree. to 150.degree. C.
 conveniently at or near ambient temperature.
 A suitable protecting group for an amino or alkylamino group is, for
 example, an acyl group, for example an alkanoyl group such as acetyl, an
 alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or
 tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example
 benzyloxycarbonyl, or an aroyl group, for example benzoyl. The
 deprotection conditions for the above protecting groups necessarily vary
 with the choice of protecting group. Thus, for example, an acyl group such
 as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed
 for example, by hydrolysis with a suitable base such as an alkali metal
 hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl
 group such as a tert-butoxycarbonyl group may be removed, for example, by
 treatment with a suitable acid such as hydrochloric, sulphuric or
 phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group
 such as a benzyloxycarbonyl group may be removed, for example, by
 hydrogenation over a catalyst such as palladium-on-carbon, or by treatment
 with a Lewis acid for example boron tris(trifluoroacetate). A suitable
 alternative protecting group for a primary amino group is, for example, a
 phthaloyl group which may be removed by treatment with an alkylamine, for
 example dimethylaminopropylamine, or with hydrazine.
 A suitable protecting group for a hydroxy group is, for example, an acyl
 group, for example an alkanoyl group such as acetyl, an aroyl group, for
 example benzoyl, or an arylmethyl group, for example benzyl. The
 deprotection conditions for the above protecting groups will necessarily
 vary with the choice of protecting group. Thus, for example, an acyl group
 such as an alkanoyl or an aroyl group may be removed, for example, by
 hydrolysis with a suitable base such as an alkali metal hydroxide, for
 example lithium or sodium hydroxide. Alternatively an arylmethyl group
 such as a benzyl group may be removed, for example, by hydrogenation over
 a catalyst such as palladium-on-carbon.
 A suitable protecting group for a carboxy group is, for example, an
 esterifying group, for example a methyl or an ethyl group which may be
 removed, for example, by hydrolysis with a base such as sodium hydroxide,
 or for example a tert-butyl group which may be removed, for example, by
 treatment with an acid, for example an organic acid such as
 trifluoroacetic acid, or for example a benzyl group which may be removed,
 for example, by hydrogenation over a catalyst such as palladium-on-carbon.
 An analogous procedure may be used for those compounds of formula I wherein
 X.sup.1 is a group of the formula SO or SO.sub.2.
 (b) For the production of those compounds of the formula I wherein T is CH
 and X.sup.1 is O the reaction, conveniently in the presence of a suitable
 coupling agent, of a compound of the formula IV.
 ##STR4##
 wherein Z' is a displaceable group, with a compound of the formula V.
EQU HO--Y.sup.1 --Ar.sup.1 --Q V
 A suitable value for the displaceable group Z' is, for example, a halogeno
 or sulphonyloxy group, for example a fluoro, chloro, bromo, mesyloxy or
 4-tolylsulphonyloxy group.
 A suitable reagent for the coupling reaction when Z' is a halogeno or
 suiphonyloxy group is, for example, a suitable base, for example, an
 alkali or alkaline earth metal carbonate, hydroxide or hydride, for
 example sodium carbonate, hydroxide or hydride, for example sodium
 carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,
 sodium hydride or potassium hydride. The alkylation reaction is preferably
 performed in a suitable inert solvent or diluent, for example
 N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone,
 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range,
 for example, -10.degree. to 150.degree. C., conveniently at or near
 ambient temperature.
 Alternatively, the displaceable group Z' is provided in place of the
 HO-group in the compound of formula V and the HO-group is provided in
 place of the displaceable group Z' in the compound of formula IV.
 A suitable reagent for the coupling reaction of the alcohol of the formula
 IV wherein Z is a hydroxy group is, for example, the reagent obtained when
 said alcohol is reacted with a di-(1-4C)alkyl azodicarboxylate in the
 presence of a triarylphosphine or tri-(1-4C)alkylphosphine, for example
 with diethyl azodicarboxylate in the presence of triphenylphosphine or
 tributylphosphine. The reaction is preferably performed in a suitable
 inert solvent or diluent, for example acetone, 1,2-dimethoxyethane or
 tetrahydrofuran, and at a temperature in the range, for example,
 10.degree. to 80.degree. C., conveniently at or near ambient temperature.
 An analogous procedure may be employed for the preparation of those
 compounds of the formula I wherein T is CH and X.sup.1 is a group of the
 formula S.
 (c) For the production of those compounds of the formula I wherein T.sup.1
 is N and X.sup.1 is CH(R.sup.2), the reductive amination of a keto
 compound of the formula VI,
EQU R.sup.2 --CO--Y.sup.1 Ar.sup.1 --Q VI
 with an amine of the formula II.
 Any reducing agent known in the art for promoting a reductive amination
 reaction may be employed. A suitable reducing agent is, for example, a
 hydride reducing agent, for example an alkali metal aluminium hydride such
 as lithium aluminium hydride or, preferably, an alkali metal borohydride
 such as sodium borohydride, sodium cyanoborohydride, sodium
 triethylborohydride, sodium trimethoxyborohydride and sodium
 triacetoxyborohydride. The reaction is conveniently performed in a
 suitable inert solvent or diluent, for example tetrahydrofuran and diethyl
 ether for the more powerful reducing agents such as lithium aluminium
 hydride, and, for example, methylene chloride or a protic solvent such as
 methanol and ethanol for the less powerful reducing agents such as sodium
 triacetoxyborohydride. The reaction is performed at a temperature in the
 range, for example, 10.degree. to 80.degree. C., conveniently at or near
 ambient temperature.
 (d) The reaction of an amine of formula II with a compound of formula VII,
EQU Z'--X.sup.1 --Y.sup.1 --Ar.sup.1 --Q XI
 wherein Z' is a displaceable group as defined hereinbefore. The reaction
 may be performed, for example, in the presence of a catalytic amonut of
 sodium hydride. The reaction is conveniently performed in a suitable inert
 solvent or diluent as defined hereinbefore and at a temperature in the
 range, for example, 0.degree. to 150.degree. C., conveniently at or near
 ambient temperature.
 (e) The reaction of a compound of formula VIII
 ##STR5##
 wherein Z' is a displaceable group as defined herein before with a compound
 of formula IX
 ##STR6##
 The reaction is conveniently performed in a suitable inert solvent or
 diluent as defined hereinbefore and at a temperature in the range, for
 example, 0.degree. to 150.degree. C., conveniently at or near ambient
 temperature.
 (f) For the production of those compounds of the formula I wherein X.sup.2
 is a group of the formula NR.sup.10 SO.sub.2, the reaction, conveniently
 in the presence of a suitable base as defined hereinbefore, of an amine of
 the formula X, with a compound of the formula XI,
EQU Z'--SO.sub.2 --L.sup.1 Z XI
 wherein Z' is a displaceable group as defined hereinbefore.
 The reaction is conveniently performed in a suitable inert solvent or
 diluent as defined hereinbefore and at a temperature in the range, for
 example, 0.degree. to 150.degree. C., conveniently at or near ambient
 temperature.
 An analogous procedure may be employed for those compounds of the formula I
 wherein X.sup.2 is a group of the formula NR.sup.12 CO.
 (g) For the production of those compounds of the formula I wherein X.sup.2
 is a group of the formula NR.sup.13 CONR.sup.14, the reaction,
 conveniently in the presence of a suitable base as defined hereinbefore,
 of an amine of the formula X,
 ##STR7##
 with a compound of the formula XII,
EQU O.dbd.C.dbd.N--L.sup.1 --Z XII
 The reaction is conveniently performed in a suitable inert solvent or
 diluent as defined hereinbefore and at a temperature in the range, for
 example, 0.degree. to 150.degree. C., conveniently at or near ambient
 temperature.
 (h) For the production of those compounds of the formula I wherein X.sup.2
 is a group of the formula NR.sup.10 S0.sub.2 and R.sup.10 represents
 (1-4C)alkyl, the reaction, conveniently in the presence of a suitable base
 as defined hereinbefore, of a corresponding sulphonamide of the formula
 XIII,
 ##STR8##
 with a compound of the formula XIV,
EQU R.sup.10 --Z' XIV
 wherein Z' is a displaceable group as defined hereinbefore.
 The reaction is conveniently performed in a suitable inert solvent or
 diluent as defined hereinbefore and at a temperature in the range, for
 example, 0 to 150.degree. C. conveniently at or near ambient temperature.
 An analogous procedure may be employed for those compounds of the formula I
 wherein X.sup.2 is a group of the formula SO.sub.2 NR.sup.11 or NR.sup.12
 CO.
 (i) For the production of those compounds of the formula I wherein L.sup.1
 represents (1-4C)alkylene and X.sup.2 is S, the reaction, conveniently in
 the presence of a suitable base as defined hereinbefore, of a compound of
 the formula XV,
 ##STR9##
 wherein m is 1,2,3 or 4, and Z' is a displaceable group as defined
 hereinbefore with a thiol of the formula XVI,
EQU HS--L.sup.2 --Z XVI
 The reaction is conveniently performed in a suitable inert solvent or
 diluent as defined hereinbefore and at a temperature in the range, for
 example, 0.degree. to 150.degree. C. conveniently at or near ambient
 temperature.
 (j) For the production of those compounds of the formula I wherein Ar.sup.1
 or Z bears a carboxy or carboxy-containing group, the hydrolysis of a
 compound of the formula I wherein Ar.sup.1 or Z bears a
 (1-6C)alkoxycarbonyl group.
 The hydrolysis reaction may conveniently be carried out in a conventional
 manner using, for example, acidic or basic catalysis. A suitable acid for
 the acidic hydrolysis of an ester group is, for example, an inorganic acid
 such as hydrochloric or sulphuric acid. A suitable base for the basic
 hydrolysis of an ester group is, for example, an alkali or alkaline earth
 metal hydroxide such as sodium hydroxide or potassium hydroxide.
 The reaction is conveniently performed in a suitable solvent or diluent
 such as an alcohol, for example methanol or ethanol, and at a temperature
 in the range, for example 0.degree. to 120.degree. C. conveniently in the
 range of 15.degree. to 60.degree. C.
 (k) For the production of those compounds of the formula I wherein Ar.sup.1
 or Z bears a carbamoyl, N-(1-6C)alkylcarbamoyl or
 alkyldi-N[(1-6C)carbamoyl group, the reaction of a compound of the formula
 I wherein A.sup.1 or Z bears a carboxy group, or a reactive derivative
 thereof as defined hereinbefore, with ammonia or an appropriate alkylamine
 or dialkylamine.
 The reaction is conveniently performed in a suitable inert solvent or
 diluent as defined hereinbefore and at a temperature in the range, for
 example, 0.degree. to 120.degree. C. conveniently in the range 15.degree.
 to 60.degree..
 (l) For the production of those compounds of the formula I wherein X.sup.1
 is a group of the formula SO or SO.sub.2 wherein Ar.sup.1 or Z bears a
 (1-6C)alkylsulphinyl or (1-6C)alkylsulphonyl, substituent or wherein
 X.sup.2 is a group of the formula SO or SO.sub.2 the oxidation of the
 corresponding compound of the formula I which contains a thio group.
 A suitable oxidising agent is, for example, any agent known in the art for
 the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen
 peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid),
 an alkali metal peroxysulphate (such as potassium peroxymonosulphate),
 chromium trioxide or gaseous oxygen in the presence of platinum. The
 oxidation is generally carried out under as mild conditions as possible
 and with the required stoichiometric amount of oxidising a gent in order
 to reduce the risk of over oxidation and damage to other functional
 groups. In general the reaction is carried out in a suitable solvent or
 diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran
 or tert-butyl methyl ether and at a temperature, for example, at or near
 ambient temperature, that is in the range 15 to 35.degree. C. When a
 compound carrying a sulphinyl group is required a milder oxidising agent
 may also be used, for example sodium or potassium metaperiodate,
 conveniently in a polar solvent such as acetic acid or ethanol. It will be
 appreciated that when a compound of the formula I containing a sulphonyl
 group is required, it may be obtained by oxidation of the corresponding
 sulphinyl compound as well as of the corresponding thio compound.
 As mentioned above, it will be appreciated that in some of the reactions
 mentioned herein it may be necessary/desirable to protect any sensitive
 groups in the compounds. The instances where protection is necessary or
 desirable and suitable methods for protection are known to those skilled
 in the art. Thus, if reactants include groups such as amino, carboxy or
 hydroxy it may be desirable to protect the group in some of the reactions
 mentioned herein. Suitable protecting groups are mentioned under (a)
 above. The protecting groups may be removed at any convenient stage in the
 synthesis, using conventional techniques well known in the chemical art.
 It will also be appreciated that certain of the various optional
 substituents in the compounds of the present invention may be introduced
 by standard aromatic substitution reactions or generated by conventional
 functional group modifications either prior to or immediately following
 the processes mentioned above, and as such are included in the process
 aspect of the invention. Such reactions and modifications include, for
 example, introduction of a substituent by means of an aromatic
 substitution reaction, reduction of substituents, alkylation of
 substituents and oxidation of substituents. The reagents and reaction
 conditions for such procedures are well known in the chemical art.
 Particular examples of aromatic substitution reactions include the
 introduction of a nitro group using concentrated nitric acid, the
 introduction of an acyl group using, for example, an acylhalide and Lewis
 acid (such as aluminium trichloride) under Friedel Crafts conditions; the
 introduction of an alkyl group using an alkyl halide and Lewis acid (such
 as aluminium trichloride) under Friedel Crafts conditions; and the
 introduction of a halogeno group. Particular examples of modifications
 include the reduction of a nitro group to an amino group by for example,
 catalytic hydrogenation with a nickel catalyst or treatment with iron in
 the presence of hydrochloric acid with heating; oxidation of alkylthio to
 alkylsulphinyl or alkylsulphonyl.
 When a pharmaceutically-acceptable salt of a compound of the formula I is
 required, it may be obtained, for example, by reaction of said compound
 with the appropriate acid (which affords a physiologically acceptable
 anion), or with the appropriate base (which affords a physiologically
 acceptable cation), or by any other conventional salt formation procedure.
 When an optically active form of a compound of the formula I is required,
 it may be obtained, for example, by carrying out one of the aforesaid
 procedures using an optically active starting material or by resolution of
 a racemic form of said compound using a conventional procedure. As
 mentioned previously, the compounds of the formula I (and their
 pharmaceutically-acceptable salts) are inhibitors of the enzyme
 oxido-squalene cyclase. Thus, the compounds of the present invention are
 capable or inhibiting cholesterol biosynthesis and hence in lowering
 cholesterol levels in blood plasma.
 The beneficial pharmacological properties of the compounds of the present
 invention may be demonstrated using one or more of the following
 techniques.
 (a) In vitro Test to Measure Inhibition of Oxido-squalene Cyclase
 This test measures the inhibition of microsomal oxido-squalene cyclase in
 vitro by compounds at set concentrations in the incubation medium.
 Microsomes are prepared from rat liver according to methods known in the
 art, for example, the method described in published European Patent
 Application No 324,421 and stored in liquid nitrogen prior to assay. Assay
 vials are kept at 37.degree. C. throughout the incubation. The microsomes
 typically contain 15-20 mg of protein per ml of microsomes. For assay, 1
 ml of microsomes are diluted by the addition of 722 .mu.l of 50 mM
 phosphate buffer pH 7.4.
 Phosphate buffered Tween 80 (polyoxyethylene sorbitan monolaurate) is
 prepared by adding 0.1 g Tween 80 to 100 ml of 50 mM phosphate buffer.
 A stock solution of oxido-squalene is made up as a solution in ethanol
 (0.65 mg.ml.sup.-1). 18 .mu.l of radio-labelled oxido-squalene (1
 .mu.Ci.ml.sup.-1) is evaporated to dryness under a stream of nitrogen and
 redissolved in 1 ml of ethanol and 1 ml of the stock solution of
 oxido-squalene is added.
 The test compound is dissolved in dimethyl sulphoxide to give a 10.sup.-4 M
 stock solution. Dilutions are made from the stock to give 10.sup.-5 M,
 10.sup.-6 M etc.
 Phosphate buffered Tween 80 (28 .mu.l) is placed in 5 ml disposable plastic
 vials and 4 .mu.l of the solution of the test compound is added and mixed
 well. An aliquot of the oxido-squalene mix (15 .mu.l) is added and the
 vials pre-incubated for 10 minutes at 37.degree. C. A portion of the
 microsomes (14.6 .mu.l) are then added and incubated for a further 1 hour.
 The reaction is stopped by the addition of 315 .mu.l of a mixture of 16%
 KOH in 20% ethanol.
 The samples are then placed in a water bath at 80.degree. C. for 2 hours to
 saponify. At the end of this process water (630 .mu.l) is added followed
 by hexane (5 ml). The samples are tumble mixed for 5 minutes and then
 centrifuged. The hexane phase is removed and evaporated under nitrogen.
 The samples are then reconstituted in 300 .mu.l of a 80:20 mixture of
 acetonitrile:isopropyl alcohol. The samples are then chromatographed using
 a Hichrom 30DS1 column with an isocratic elution using a 95:5 mixture of
 acetonitrile:isopropyl alcohol and a flow rate of 1 ml.min.sup.-1. The
 output from the UV detector is connected to a radio-chemical detector to
 visualise radiolabelled sterols. Reaction rate is measured as the
 conversion of oxido-squalene to lanosterol, and the effects of test
 compounds are expressed as an inhibition of this process.
 By way of example, the compound described in Example 25 cave 100%
 inhibition at 1 .mu.M.
 (b) In vivo Test to Measure Inhibition of Oxido-Squalene Cyclase
 The ability of a compound to inhibit oxido-squalene cyclase and/or inhibit
 cholesterol biosynthesis may be assessed by a routine laboratory procedure
 carried out in the rat. The test involves administration of the compound
 to rats on a reversed lighting regimen. Female rats (35-55 g) are housed
 in reverse lighting conditions (red light from 0200 h-1400 h) for a period
 of about 2 weeks prior to test. Animals are allowed free access to chow
 and drinking water throughout this period. At test, animals should weigh
 100-140 g. The rats are dosed orally, with the compound (typically 10-50
 mg/kg) formulated in a polyethylene glycol/hydroxypropylmethyl cellulose
 mix. After 1 hour the rats are given triturated sodium mevalonate (15
 .mu.Ci/kg) intraperitoneally. Two hours after administration of the
 compound the rats are terminated and a piece of liver removed and weighed.
 The tissue is saponified at 80.degree. C. for 2 hours in an
 ethaniolic/potassium hydroxide solution (80% w/v aqueous KOH diluted 1:10
 with ethanol). Water (2 ml) is added and the mixture extracted with
 iso-hexane (2.times.5 ml). The organic extracts are combined, evaporated
 to dryness under a stream of nitrogen and the residue is dissolved in a
 mixture of acetonitrile/iso-propanol (300 .mu.l). An aliquot (200 .mu.l)
 of this solution is loaded onto a HPLC column to separate the sterols. The
 radio-label content of each fraction is assessed using a radio chemical
 flow detector. Inhibitors of oxido-squalene cyclase are classed as those
 compounds which caused a build up of substrate and a concomitant
 disappearance of cholesterol and its precursors. ED50 values are generated
 in the usual manner.
 By way of example, the compound described in Example 18 below gave 59%
 inhibition of cholesterol biosynthesis when dosed at 2 mg/kg; and the
 compound described in Example 27 70% inhibition when dosed at 2 mg/kg.
 The compounds of the present invention are oxido-squalene cyclase
 inhibitors and hence possess the property of inhibiting cholesterol
 biosynthesis. Accordingly, there is also provided the use of a compound of
 formula I, or a pharmaceutically acceptable salt thereof. (as hereinbefore
 defined) for the manufacture of a medicament for inhibiting cholesterol
 biosynthesis. The compound
 N-[4-[4-(4-pyridyl)piperazin-1-ylcarbonyl]phenyl](E)-4-chlorostyrenesulpho
 namide and its salts are included in this aspect of the present invention
 and the aspect which follow relating to uses of the compounds of the
 present invention. Thus the compounds of the present invention will be
 useful in treating diseases or medical conditions in which an inhibition
 of oxido-squalene cyclase is desirable, for example those in which a
 lowering of the level of cholesterol in blood plasma is desirable.
 In particular, the compounds of the present invention will be useful in
 treating hypercholesterolemia and hypertriglyceridaemia, and in the
 treatment of atherosclerotic vascular diseases such as atherosclerosis,
 coronary heart disease including myocardial infarction, angina, stroke and
 peripheral vascular disease. Such uses may lead to a reduction of
 morbidity in patients with ischaemic heart disease, whether or not they
 have a medical history of coronary heart disease. Compounds of the
 invention may also have benefit in the treatment of dermatological
 conditions such as xanthomas and xanthelasmas and in the treatment of
 gallstones.
 Thus according to a further feature of the present invention there is
 provided a method of inhibiting oxido-squalene cyclase in a warm-blooded
 animal (such as man) requiring such treatment, which method comprises
 administering to said animal an effective amount of a compound of formula
 I (as herein defined), or a pharmaceutically-acceptable salt thereof. In
 particular, the present invention provides a method of inhibiting
 cholesterol biosynthesis, and more particularly to a method of treating
 hypercholesterolemia and atheromatous vascular degeneration (such as
 atherosclerosis).
 Thus the present invention also provides the use of a compound of formula I
 (as herein defined), or a pharmaceutically-acceptable salt thereof, for
 the manufacture of a medicament for treating diseases or medical
 conditions in which a lowering of the level of cholesterol in blood plasma
 is desirable (such as hypercholesterolemia and atherosclerosis).
 In particular, the compounds of the present invention are potentially
 useful in inhibiting cholesterol biosynthesis in man and hence in treating
 the above-mentioned medical conditions in man.
 When used in the treatment of diseases and medical conditions such as those
 mentioned above it is envisaged that a compound of formula I (or a
 pharmaceutically acceptable salt thereof) will be administered orally,
 intravenously, or by some other medically acceptable route so that a dose
 in the general range of, for example, 0.01 to 10 mg per kg body weight is
 received. However it will be understood that the precise dose administered
 will necessarily vary according to the nature and severity of the disease,
 the age and sex of the patient being treated and the route of
 administration.
 In general, the compounds of formula I (or a pharmaceutically-acceptable
 salt thereof) will usually be administered in the form of a pharmaceutical
 composition, that is together with a pharmaceutically acceptable diluent
 or carrier, and such a composition is provided as a further feature of the
 present invention.
 A pharmaceutical composition of the present invention may be in a variety
 of dosage forms. For example, it may be in the form of tablets, capsules,
 solutions or suspensions for oral administration, in the form of a
 suppository for rectal administration; in the form of a sterile solution
 or suspension for parenteral administration such as by intravenous or
 intramuscular injection.
 A composition may be obtained by conventional procedures using
 pharmaceutically acceptable diluents and carriers well known in the art.
 Tablets and capsules for oral administration may conveniently be formed
 with a coating, such as an enteric coating (for example, one based on
 cellulose acetate phthalate), to minimise dissolution of the active
 ingredient of formula I (or a pharmaceutically-acceptable salt thereof) in
 the stomach or to mask unpleasant taste.
 The compounds of the present invention may, if desired, be administered
 together with (or sequentially to) one or more other pharmacological
 agents known to be useful in the treatment of cardiovascular disease, for
 example, together with agents such as HMG-CoA reductase inhibitors, bile
 acid sequestrants, other hypocholesterolaemic agents such as fibrates, for
 example gemfibrozil, and drugs for the treatment of coronary heart
 disease.
 As inhibitors of oxido-squalene cyclase, the compounds of the present
 invention may also find utility as antifungal agents, and so the present
 invention also provides a method of inhibiting cholesterol biosynthesis in
 fungi. In particular the present invention provides a method of treating
 fungal infections which comprises administration to a warm blooded animal,
 such as man, in need of such treatment an effective amount of a compound
 of formula I, or a pharmaceutically acceptable salt thereof. When used in
 this way the compounds of the present invention may, in addition to the
 formulations mentioned above, be adapted for topical administration and
 such a composition is provided as a further feature of the present
 invention. Such compositions may be in a variety of forms, for example
 creams or lotions.
 Selected compounds of the, invention having utility as antifungal agents
 are compounds of the formula I wherein
 G.sup.1 is CH,
 G.sup.2 is CH or N
 R is as defined hereinbefore
 n is 1 or 2
 T is CH or N, when T is CH then X.sup.1 Y.sup.1 together are O or S, when T
 is N then X.sup.1 Y.sup.1 together are a bond,
 Ar.sup.1 is a phenylene ring, a pyridyl ring, or a 9- or 10-membered
 bicyclic heteroaryl ring containing 1, 2, or 3 hetereoatoms selected from
 nitrogen, oxygen and sulphur, and may optionally bear one or more
 substituents selected from halogeno, nitro, cyano, (1-6C) alkyl,
 (1-6C)alkylthio, halogeno(1-6C)alkyl, halogeno(1-6C)alkylthio,
 halogeno(1-6C)alkoxy, (1-6C)alkoxycarbonyl,
 Q is selected from hydrogen and a group of formula L.sup.1 X.sup.2 L.sup.2
 Z in which L.sup.1 is a bond or (1-4C)alkylene, L.sup.2 is a bond or
 (1-4C)alkylene, X.sup.2 is a bond, NR.sup.8, O or S, in which R.sup.8 is
 hydrogen or (1-4)C alkyl; and
 Z is selected from phenyl, and a monocyclic heterocyclic moiety containing
 1,2,3 or 4 heteroatoms selected from nitrogen, oxygen and sulphur, and may
 optionally bear one or more substituents selected from halogeno, nitro,
 cyano, (1-6C) alkyl, (1-6C)alkylthio, halogeno(1-6C)alkyl,
 halogeno(1-6C)alkylthio, halogeno(1-6C)alkoxy, (1-6C)alkoxycarbonyl;
 Further selected antifungal compounds are as above and wherein Ar.sup.1 is
 a phenylene ring, a 2-pyridyl ring, a benzthiazol-2yl ring, a 2-quinoyloxy
 ring, a benzoxazolyl ring, a thiazolopyridin-2yl ring, or a
 quinoxalinyloxy ring. Further selected antifungal compounds are as above
 and wherein R is hydrogen, halogeno or (1-4C)alkyl. Further selected
 antifungal compounds are as above and wherein the substituent Q on
 Ar.sup.1 is in the 4-position. Further selected antifungal compounds are
 as above and wherein the substituent(s) on Ar.sup.1 and/or Z are
 independently selected from methyl, methylthio, cyano, nitro,
 trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorine, bromine,
 fluorine and methoxycarbonyl.
 In a further aspect of the invention we claim the use of a compound as
 defined above as an antifungal agent. We also claim a method for
 inhibiting cholesterol biosynthesis in fungi which comprises the use of a
 compound as defined above.
 In a further aspect of the invention we claim a pharmaceutical composition
 comprising one or more compounds as defined above for use in the treatment
 of fungal infections of the human or animal body.
 The antifungal activity of the compounds of the invention may be determined
 in vitro in standard agar dilution tests and disc-diffusion tests and
 minimum inhibitory concentrations are obtained. Standard in vivo tests in
 mice are used to determine the effective dose of the test compounds in
 controlling systemic fungal infections.
 By way of example the following test protocols may be used:
 Primary in-vitro Screen
 Compounds are formulated in DMSO at 2560 .mu.g/ml and diluted to four-times
 the top test concentration in a synthetic medium RPMI-1640. Serial 2-fold
 dilutions are prepared in microtitre plates and an equal volume of the
 inoculum added. Compounds are tested against 11 fungal species strains
 including Candida spp. Cryptococcus neoformans, Saccharomyces cerevisiae,
 Aspergillus fumigatus and Trichophyton quinckeanum. The plates are
 incubated at 30.degree. C., read by eye at 24 h and then at 48 h. MICs and
 IC.sub.50 s are determined from visual and multiscan (540 nm) readings
 respectively.
 Primary in-vivo Screen
 Mice are inoculated intravenously with a lethal challenge of Candida
 albicans. Groups of 4 mice are dosed with test compound at 0.5 and 24 h
 after infection. The health of the mice is monitored for 72 h at which
 point the test is terminated. Untreated mice would be expected to die or
 be culled within 24 h of infection. Activity is determined by increased
 survival of the treated group over that of control animals.
 The invention will now be illustrated in the following Examples in which,
 unless otherwise stated:
 (i) evaporations were carried out by rotary evaporation in vacuo and
 work-up procedures were carried out after removal of residual solids by
 filtration;
 (ii) operations were carried out at room temperature, that is in the range
 18-25.degree. C. and under an atmosphere of an inert gas such as argon;
 (iii) column chromatography (by the flash procedure) and medium pressure
 liquid chromatography (MPLC) were generally performed on Merck Kieselgel
 silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase
 silica obtained from E. Merck, Darmstadt, Germany; alternatively high
 pressure liquid chromatography (HPLC) was performed on a Dynamax C-18 60A
 preparative reversed-phase column;
 (iv) yields are given for illustration only and are not necessarily the
 maximum attainable;
 (v) the structures of the end-products of the formula I were confirmed by
 nuclear magnetic resonance (NMR) and mass spectral techniques; unless
 otherwise stated, CD.sub.3 SOCD.sub.3 solutions of the end-products of the
 formula I were used for the determination of NMR spectral data, chemical
 shift values were measured on the delta scale: the following abbreviations
 have been used; s, singlet; d, doublet; t, triplet; q, quartet; m,
 multiplet;
 (vi) intermediates were not generally fully characterised and purity was
 assessed by thin layer chromatographic, infra-red (IR) or NMR analysis;
 (vii) melting points were determined using a Mettler SP62 automatic melting
 point apparatus or an oil-bath apparatus: melting points for the
 end-products of the formula I were generally determined after
 crystallisation from a conventional organic solvent such as ethanol,
 methanol, acetone, ether or hexane, alone or in admixure; and
 (viii) the following abbreviations have been used:
 DMF N,N-dimethylformamide; THF tetrahydrofuran;
 DMSO dimethylsulphoxide; Et.sub.3 N triethylamine;
 CH.sub.2 Cl.sub.2 dichloromethane; Na.sub.2 SO.sub.4 sodium sulphate
 (anhydrous);
 K.sub.2 CO.sub.3 potassium carbonate; NaOH sodium hydroxide;
 MeOH methanol; NH.sub.4 OH ammonium hydroxide;
 EtOAc ethyl acetate; .sup.1 PrNH.sub.2 isopropylamine;
 Et.sub.2 O diethyl ether; MTBE methyl t-butyl ether;
 `Column chromatography` refers to separation of components of a mixture by
 passage of a solution through a sinter filled with silica gel (230-400
 mesh, E Merck, Darmstadt, Germany), with suction applied from beneath.
 The starting materials are described below or are known materials. Many of
 the starting materials are commercially available. The following lists
 some of the commercially available starting materials:

EXAMPLE 1
 A solution of 4-toluenesulphonyl chloride (0.38 g) in dichloromethane (25
 ml) was added dropwise to a stirred solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (536 mg) in
 dichloromethane (50 ml) containing triethylamine (0.5 ml). The reaction
 mixture was stirred at ambient temperature overnight. The mixture was
 washed with aqueous sodium carbonate solution, water, brine, dried
 (MgSO.sub.4) and evaporated. The residue was recrystallised from methanol
 to give 1-(4-pyridyl)-4-(4-toluenesulphonamidomethylphenyl)piperazine
 (0.36 g) as a solid, m.p. 196-198.degree. C.; microanalysis, found: C,
 65.2; H,6.2; N,13.2%; C.sub.23 H.sub.26 N.sub.4 O.sub.2 S requires:
 C,65.4; H,6.2; N,13.3%; NMR: 2.37(s, 3H), 3.15-3.3(m, 4H), 3.4-3.55(m,
 4H), 3.81-3.88(d, 2H), 6.8-6.93(dd, 4H), 7.03-7.15 (d, 2H), 7.32-7.4(d,
 2H), 7.6-7.7(d, 2H), 7.8-7.95(t, 1H), 8.1-8.2(d, 2H); MS: m/z 423
 (MH).sup.+.
 The 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine used as starting
 material was prepared as follows:
 A solution of N-(4-pyridyl)piperazine (9.78 g), 4-fluorobenzonitrile (7.26
 g) and powdered potassium carbonate(10 g) was stirred at 100.degree. C. in
 DMSO (100 ml) overnight. The solution was poured into water (500 ml) to
 give a precipitate which was filtered and washed with water. The crude
 solid was dried in a vacuum oven overnight then dissolved in
 dichloromethane and purified by flash chromatography on alumina (ICN
 Alumina N 32-63) using an increasing concentration of ethyl acetate in
 dichloromethane (up to 100% ethyl acetate) as eluant. This gave a solid
 which was recrystallised from a mixture of ethyl acetate/isohexane to give
 1-(4-cyanophenyl)-4-(4-pyridyl)piperazine (7.5 g) as a solid,
 m.p.157-158.degree. C.; microanalysis. found: C,72.7; H,6.1; N,21.0%;
 C.sub.16 H.sub.16 N.sub.4 requires: C,72.7; H,6.1; N,21.2%; NMR:
 3.45-3.55(bs, 8H), 6.8-6.9(d, 2H), 7.0-7.1(d, 2H), 7.55-7.65(d, 2H),
 8.1-8.2(d, 2H); MS: m/z 265 (MH).sup.+.
 A solution of 1-(4-cyanophenyl)-4-(4-pyridyl)piperazine (1.8 g) in ethanol
 saturated with ammonia gas (150 ml) was hydrogenated at 150 atmospheres
 and 100.degree. C. (using Raney Nickel as catalyst) in a high pressure
 hydrogenation apparatus for 18 hours. The solution was filtered through
 diatomaceous earth and the filtrate evaporated to give a solid which was
 purified by flash chromatography on alumina (ICN Alumina N 32-63) using a
 mixture of 95:5 dichloromethane:methanol as eluant. The residue was
 recrystallised from tetrahydrofuran/isohexane to give
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (1.3 g)
 m.p.168-170.degree. C.; microanalysis, found: C,71.5; H,7.6; N,20.5%;
 C.sub.16 H.sub.20 N.sub.4 requires: C,71.6; H,7.5; N,20.9%; NMR:
 3.2-3.4(m,4H), 3.4-3.6(m,4H), 3.65(s,2H), 6.8-6.9(d,2H), 6.9-7.0(d,2H),
 7.15-7.25(d,2H), 8.15-8.25(d,2H); MS: m/z 269 (MH).sup.+.
 EXAMPLE 2
 4-Toluenesulphonyl chloride (95 mg) was added to a solution of
 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (127 mg) in dichloromethane (25
 ml) and the mixture was stirred at ambient temperature for 16 hours. The
 resulting precipitate was collected by filtration and washed with
 dichloromethane. There was thus obtained
 1-(4-pyridyl)-4-[4-methylsulphonamido)phenyl]piperazine hydrochloride as a
 grey solid (160 mg). mp. 293-294.degree. C.; microanalysis, found: C,59.4;
 H,5.7; N,12.6; C.sub.22 H.sub.24 N.sub.4 O.sub.2 S.HCl requires: C,59.1;
 H,5.8; N,12.6; NMR: 2.35(s,3H), 3.24(t,4H), 3.81(t,4H), 6.84(d,2H),
 6.96(d,2H), 7.24(d,2H) 7.33(d,2H), 7.58(d,2H), 8.26(d,2H), 9.78(s,1H),
 13.45(broad,1H); MS: m/z 409 (MH).sup.+.
 EXAMPLE 3
 4-Chlorostyrylsulphonyl chloride (118 mg) in dichloromethane (5 ml) was
 added to a solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (127 mg)
 in dichloromethane (5 ml) and stirred at ambient temperature for 2 hours.
 The resulting precipitate was collected by filtration, washed with
 dichloromethane then triturated with 10% methanol in dichloromethane.
 There was thus obtained
 (E)-1-(4-pyridyl)-4-[4-chlorostyrylsulphonamido]piperazine hydrochloride
 as a yellow solid (77 mg). mp. 285-287.degree. C.; microanalysis, found:
 C,55.3; H,4.6; N,11.1; C.sub.23 H.sub.23 ClN.sub.4 O.sub.2 S. HCl.
 1/2H.sub.2 O requires: C,55.1; H,4.8; N,11.2; NMR: 3.24(m,4H), 3.81(m,4H),
 6.92(d,2H), 7.11(d,2H), 7.20(d,1H), 7.23(d,2H), 7.33(d,1H), 7.46(d,2H),
 7.71(d,2H), 8.24(d,2H), 9.65(s,1H), 13.25(broad,1H); MS: m/z 455
 (MH).sup.-.
 EXAMPLE 4
 4-Dimethylamino-pyridine (30 mg) and 4-bromophenylsulphonl chloride (260
 mg) was added to a solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (268 mg) in pyridine(5
 ml). The solution was heated on a steam bath for three hours. The solution
 was cooled to ambient temperature and evaporated. Water (100 ml) was added
 to the residue and the solution acidified to pH 1 by addition of
 concentrated hydrochloric acid. The aqueous solution was washed with ether
 (2.times.100 ml) and then basified by addition of aqueous ammonia.
 The mixture was extracted with methylene chloride and the methylene
 chloride extracts were washed with water, brine, dried (MgSO.sub.4) and
 evaporated. The residue was recrystallised from a mixture of ethyl
 acetate/tetrahydrofuran/isohexane to give
 1-(4-pyridyl)-4-(4-bromophenylsulphonamidomethyl-phenyl)piperazine (155
 mg.) as a solid m.p. 180-182.degree. C.; microanalysis, found: C,54.4;
 H,4.8; N,11.3%; C.sub.22 H.sub.23 BrN.sub.4 O.sub.2 S requires: C,54.2;
 H,4.7; N,11.5%; NMR: 3.15-3.3(m,4H), 3.4-3.55(m,4H), 3.85-3.95(d,2H),
 6.8-6.9(bm,4H), 7.0-7.1(d,2H), 7.6-7.8(q,4H), 8.05-8.15(t,2H),
 8.18-8.25(bd,1H); MS: m/z 487 (MH).sup.+.
 EXAMPLE 5
 4-Cyanophenylsulphonyl chloride (202 mg) was added to a solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (268 mg) in pyridine (20
 ml). The mixture was heated on a steam bath for three hours. The solvents
 were removed by evaporation and water (100 ml) added to give a precipitate
 which was extracted into ethyl acetate (2.times.100 ml). The ethyl acetate
 extracts were combined, washed with water, brine, dried (MgSO.sub.4)-10%
 methanol/methylene chloride as eluent to give a solid which was
 recrystallised from a mixture of tetrahydrofuran/methanol/isohexane to
 give 1-(4-pyridyl)-4-(4-cyanophenylsulphonamidomethyl-phenyl)piperazine
 (52 mg) as a solid m.p.229-230.degree. C.; microanalysis found: C,62.8;
 H,5.6; N,15.7%; C.sub.23 H.sub.23 N.sub.5 O.sub.2 S.0.25H.sub.2 O
 requires: C,62.4; H,5.4; N,15.8%; NMR: 3.15-3.3(m,4H), 3.4-3.55(m,4H),
 3.85-4.0(d,2H), 6.8-6.9(dd,4H), 7.0-77.1(d,2H), 7.8-7.9(d,2H),
 7.95-8.05(d,2H), 8.18-8.25(d,2H), 8.25-8.4(bt,1H); MS: m/z 434 (MH).sup.+
 EXAMPLE 6
 4-Methoxybenzenesulphonyl chloride (0.25 g) was dissolved in dry
 tetrahydrofuran (2.0 ml) and treated with a warm solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (0.27 g) in
 tetrahydrofuran (8.0 ml) and triethylamine (0.2 ml) in one portion. The
 reaction mixture was stirred overnight and then quenched by concentrating
 the reaction solution to a volume of 1 ml followed by the addition of 1 M
 solution of aq.NaHCO.sub.3 (8 ml). The mixture was stirred for 2 hours.
 The resulting precipitate was collected by filtration, washed with water
 and dried to give
 1-(4-pyridyl)-4-(4-methoxyphenylsulphonamidomethyl-phenyl)piperazine (0.29
 g) as a solid m.p. 212-213.degree. C.; microanalysis found: C,62.9; H,5.9;
 N,12.6%; C.sub.23 H.sub.26 N.sub.4 O.sub.3 S requires C,63.0; H,5.98;
 N,12.8%: NMR: 3.23(t,4H), 3.47(t,4H), 3.82(s,3H), 3.89(d,2H), 6.88(d,4H),
 7.07(m,4H),7.71(dd,2H), 7.79(t,1H), 8.18(bs,2H); MS: m/z 439 (MH).sup.+.
 EXAMPLE 7
 A solution of 4-bromophenyl isocyanate (198 mg) in tetrahydrofuran was
 added dropwise to a solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (268 mg) in
 tetrahydrofuran (50 ml). When the addition was complete, the solution was
 stirred at ambient temperature overnight. The precipitate was collected by
 filtration, filtered, washed with ether and recrystallised from methanol
 to give 1-(4-pyridyl)-4-(4-bromophenylureidomethyl-phenyl)piperazine (185
 mg) as a solid, m.p. 258-260.degree. C.; microanalysis found: C,59.1;
 H,5.3; N,14.8%; C.sub.23 H.sub.24 BrN.sub.5 O requires: C,59.2; H,5.2;
 N,15.0%; NMR: 3.15-3.3(m,4H), 3.4-3.55(m,4H), 4.15-4.25(d,2H),
 6.45-6.55(t,1H), 6.8-6.9(d,2H), 6.9-7.0 (d,2H), 7.15-7.25(d,2H),
 7.38(s,4H), 8.18-8.25(d,2H), 8.6(bs,1H); MS: m/z 466 (MH).sup.+.
 EXAMPLE 8
 A solution of 4-cyanophenyl isocyanate (144 mg) in tetrahydrofuran was
 added dropwise to a solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (268 mg) in
 tetrahydrofuran (50 ml). When the addition was complete, the solution was
 stirred at ambient temperature overnight. The precipitate was collected by
 filtration, washed with ether and recrystallised from a mixture of
 tetrahydrofuran/methanol/isohexane to give
 1-(4-pyridyl)-4-(4-cyanophenylureidomethyl-phenyl)piperazine (52 mg) as a
 solid, m.p. 254-255.degree. C.; microanalysis, found: C,69.5; H,6.0;
 N,20.1%; C.sub.24 H.sub.24 N.sub.6 O requires: C,69.9; H,5.9; N,20.4%;
 NMR: 3.15-3.3(m,4H), 3.4-3.55(m,4H), 4.15-4.25(d,2H), 6.65-6.75(t,1H),
 6.80-6.90(d,2H), 6.90-7.00(d,2H), 7.15-7.25(d,2H), 7.50-0.70(q,4H),
 8.18-8.25(d,2H), 9.0(bs,1H); MS: m/z 413 (MH).sup.+.
 EXAMPLE 9
 A solution of 4-bromobenzoyl chloride (240 mg) in dichloromethane (10 ml)
 was added dropwise to a stirred solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (268 mg) in
 dichloromethane (50 ml) containing triethylamine (0.5 ml). The resulting
 solution was stirred at ambient temperature for three hours. The solution
 was poured into water and the solid which precipitated was collected by
 filtration and washed with water, acetone and recrystallised from methanol
 to give 1-(4-pyridyl)-4-(4-bromobenzoylamido-methylphenyl)piperazine (230
 mg) as a solid, microanalysis, found: C,61.3; H,5.2; N,11.9%; C.sub.23
 H.sub.23 BrN.sub.4 O requires: C,61.2; H,5.14; N,12.4%; NMR:
 3.15-3.3(m,4H), 3.4-3.55(m,4H), 4.35-4.45(d,2H,), 6.8-6.93(bm,2H),
 6.90-7.00(d,2H), 7.15-7.25(d,2H), 7.6-7.7(d,2H), 7.75-7.85(d,2H),
 8.10-8.25(b,2H), 8.90-9.00(bt,1H); MS: m/z 451 (MH).sup.+.
 EXAMPLE 10
 A solution of methanesulphonyl chloride (0.155 ml) in dichloromethane (10
 ml) was added dropwise to a stirred solution of
 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (536 mg) in
 dichloromethane (50 ml) containing triethylamine (0.5 ml). The resulting
 solution was stirred at ambient temperature for 7 hours. The solution was
 evaporated and the residue was extracted with ethyl acetate. The ethyl
 acetate extracts were washed with water, sodium bicarbonate solution,
 brine, dried (MgSO.sub.4) and evaporated. The solid residue was
 recrystallised from methanol to give
 1-(4-pyridyl)-4-(methanesulphonamidomethylphenyl)piperazine (356 mg) as a
 solid, m.p.236-238.degree. C.; microanalysis found: C,59.3; H,6.4;
 N,16.2%; C.sub.17 H.sub.22 N.sub.4 O.sub.2 S requires: C,58.8; H,6.4;
 N,16.2%; NMR: 2.8(s,3H), 3.15-3.3(m,4H), 3.4-3.55(m,4H), 4.00-4.10(d,2H,),
 6.80-6.90(d,2H), 6.90-7.00(d,2H), 7.15-7.25(d,2H), 7.3--7.5(t,1H),
 8.20(d,1H); MS: m/z 311 (MH).sup.+.
 EXAMPLE 11
 Sodium hydride (55 mg) (50% dispersion in oil) was added to a stirred
 solution of 1-(4-pyridyl)-4-(4-toluenesulphonamidomethyl-phenyl)piperazine
 (422 mg) in dimethyl formamide (20 ml) under argon. The solution was
 stirred at 70-80.degree. C. for 1 hour. The solution was cooled to ambient
 temperature and a solution of methyl iodide (150 mg) in dimethyl formamide
 (1 ml) was added dropwise. When the addition was complete, the solution
 was stirred at ambient temperature for 4 hours. Water (120 ml) was added
 and the solution extracted with hot ethyl acetate (2.times.100 ml). The
 combined extracts were washed with water, brine, dried (MgSO.sub.4) and
 evaporated. A solid residue was recrystallised from a mixture of ethyl
 acetate/isohexane to give
 1-(4-pyridyl)-4-(4-toluenesulphonamethylamidomethyl-phenyl)piperazine (65
 mg) as a solid, m.p. 183-185.degree. C.; microanalysis, found: C,65.7;
 H,6.5; N,12.3%; C.sub.24 H.sub.28 N.sub.4 O.sub.2 S requires: C,66.0;
 H,6.46; N,12.8%; NMR: 2.43(s,3H), 3.2-3.35(m,4H), 3.4-3.55(m,4H),
 4.0(s,2H), 6.9-7.0(d,2H), 7.1-7.2(d,2H), 7.4-7.5(d,2H), 7.7-7.8(d,2H); MS:
 m/z 437 (MH).sup.+.
 EXAMPLE 12
 Triethylamine (0.43 ml) was added to a stirred suspension of
 1-(4-anilinocarboxy)-4-(4-pyridyl)piperazine hydrochloride (356 mg) in dry
 DMF (4 ml). After 1 hour, 4-methylbenzenesulphonylchloride (210 mg) was
 added and stirring continued for 16 hours. The reaction mixture was
 diluted with dichloromethane (25 ml) and washed with water (2.times.7 ml),
 saturated brine (7 ml), dried (MgSO.sub.4) and evaporated. The resulting
 oil, was purified by flash chromatography on silica gel using an
 increasing polar mixture of 2 to 10% v/v methanol in dichloromethane as
 eluant to give 1-(4-pyridyl)-4-(4-toluenesulphonamido-benzoyl)piperazine
 (94 mg), as a solid. m.p. 139-141.degree. C.; microanalysis, found:
 C,61.5; H,5.9; N,12.4%; C.sub.23 H.sub.24 N.sub.4 O.sub.3 S.0.5H.sub.2 O
 requires: C,61.9; H,5.6; N,12.6%; NMR: 2.34(3H, s), 3.40(4H,m),
 3.57(4H,m), 6.80(2H,d), 7.14(2H,d), 7.33(4H, m), 7.70(2H,d), 8.18(2H, d),
 10.55(1H, bs); MS: m/z 437 (MH).sup.+.
 The 1-(4-anilinocarboxy)-4-(4-pyridyl)piperazine hydrochloride used as
 starting material was prepared as follows:
 10% w/w Palladium on charcoal (200 mg) was added to a solution of
 1-(4-nitrobenzenecarboxy)-4-(4-pyridyl)piperazine (936 mg) in a mixture of
 dichloromethane (25 ml) and methanol (10 ml) containing 4.55M hydrogen
 chloride in dry ether (1.3 ml). The mixture was hydrogenated at ambient
 temperature and pressure until the theoretical amount of hydrogen had been
 taken up. The mixture was filtered through diatomaceous earth and the
 filtrate evaporated. Trituration of the resulting solid with ether gave
 1-(4-anilinocarboxy)-4-(4-pyridyl)piperazine dihydrochloride (980 mg) as a
 pale yellow solid, m.p.&gt;350.degree. C.; microanalysis, found: C,54.1;
 H,5.8, N,15.7%; C.sub.16 H.sub.18 N.sub.4 O.2HCl requires: C,54.1; H,5.7;
 N,15.8%; NMR: 3.67(4H,m), 3.78(4H,m), 3.3 to 4.5 (b), 6.97(2H,d),
 7.19(2H,d), 7.37(2H,d), 8.29(2H,d); MS: m/z 283 (MH).sup.+.
 EXAMPLE 13
 To a stirred cooled (0.degree. C.) solution of
 4-(naphthalene-2-sulphonyl)benzoic acid (312 mg) in DMF (4 ml), was added
 1,1'-carbonyldiimidazole (162 mg. The mixture was stirred at 0.degree. C.
 for 30 minutes and then N-(4-pyridyl)piperazine (163 mg) was added. The
 cooling bath was removed and the mixture was stirred at room temperature
 overnight. The solvent was removed by evaporation under high vacuum. The
 residue was dissolved in a mixture of ethyl acetate and water. The ethyl
 acetate extract was dried (MgSO.sub.4) and evaporated to give a solid
 residue (70 mg), which was recrystallised from a mixture of methanol,
 ethyl acetate and isohexane to afford
 1-(4-pyridyl)-4-(4-naphthalene-2-sulphonyl)benzoyl)piperazine (124 mg) as
 white needles. NMR: 3.25-3.5(m,6H); 3.6-3.9(m,2H); 6.8(d,2H); 7.7(d,2H);
 7.77(dd,1H); 7.95(dd,1H); 8.05-825(m,8H); 8.77(d,1H); microanalysis: found
 C,63.5; H,5.5; N,8.5%; C.sub.26 H.sub.23 N.sub.3 O.sub.3 S.2H.sub.2 O
 requires C,63.5; H,5.5; N,8.6; MS: m/z 457 (MH).sup.+.
 The 4-(naphthalene-2-sulphonyl)-benzoic acid used as starting material was
 prepared as follows:
 4-(Naphthalene-2-sulphonyl)benzaldehyde (0.97 g) was suspended in water (25
 ml) containing cetyltrimethylammonium bromide (58 mg). The mixture was
 stirred and heated to 60.degree. C., and potassium permanganate (0.95 g)
 was added in small portions over 1 hour. Heating was continued for a
 further 2 hours. The mixture was cooled to room temperature and was
 acidified with 2M hydrochloric acid. Ethyl acetate was added to the
 stirred mixture, which was filtered through a pad of celite. The ethyl
 acetate layer was washed with brine, dried (MgSO.sub.4), and evaporated to
 afford 4-(naphthalene-2-sulphonyl)benzoic acid (0.42 g) as solid residue;
 NMR: 7.7(dd,1H); 7.95(dd,1H), 8.1-8.2(m,8H); 8.7(d,1H); microanalysis,
 found; C,58.6; H,3.9%; C.sub.17 H.sub.12 O.sub.4 S.2H.sub.2 O requires:
 C,58.6; H,4.6%; MS: m/z 312(M H).sup.+.
 EXAMPLE 14
 Carbonyl diimidazole (340 mg) was added to a solution of 4-benzoylbenzoic
 acid (440 mg) in dimethylformamide (10 ml). After stirring at ambient
 temperature for 45 minutes, N-(4-pyridyl)piperazine (326 mg) was added as
 a solid, in one portion and stirring continued at ambient temperature
 overnight. The reaction mixture was poured into water (50 ml) and
 extracted with ethyl acetate (3.times.20 ml). The extracts were combined,
 washed with water, brine, dried (MgSO.sub.4) and evaporated to give a
 solid which was purified by recrystallisation from a mixture of ethyl
 acetate, methanol and hexane (10/3/9) to give
 1-(4-pyridyl)-4-(4-benzoyl-benzoyl)piperazinie as pale yellow crystals
 (660 mg), m.p. 153-154.degree. C.; microanalysis, found: C,74.5; H,5.6;
 N,11.3%; C.sub.23 H.sub.21 N.sub.3 O.sub.2 requires: C,74.4; H,5.7; N,
 11.3%; NMR: 3.3-3.9(m,8H), 6.9(d,2H), 7.5-7.9(m,9H), 8.2(d,2H); MS: m/z
 372 (MH).sup.+.
 EXAMPLE 15
 To a solution of 4-phenoxybenzaldehyde (198 mg) in dichloromethane (20 ml),
 N-(4-pyridyl)piperazine (163 mg) and acetic acid (240 mg) were added. The
 mixture was stirred at ambient temperature for 30 mins, and then sodium
 triacetoxyborohydride (318 mg) was added in one portion. Stirring was
 continued at ambient temperature overnight. The reaction mixture was
 poured into 1M hydrochloric acid (50 ml) and washed With ethyl acetate (50
 ml). The aqueous layer was made basic with 2M sodium hydroxide solution
 and extracted with dichloromethane (2.times.25 ml). The combined extracts
 were washed with water, dried (MgSO.sub.4) and evaporated to give a white
 solid which was purified by chromatography on silica gel (Mega Bond Elut
 column) using an increasing concentration of methanol in dichloromethane
 (up to 4% methanol) as eluant to give
 1-(4-pyridyl)-4-(4-phenoxy-phenyl)piperazine (168 mg) as a solid:
 microanalysis, found: C,76.5; H,6.6; N,11.9%; C.sub.22 H.sub.23 N.sub.3 O
 requires: C,76.5; H,6.7; N,12.2%; NMR: 3.2-3.45(m,8H); 3.5(s,2H);
 6.8(d,2H); 6.9-7.05(m,4H); 7.1-7.2(m,1H); 7.25-7.45(m,4H); 8.1(d,2H); MS:
 m/z 345 (MH).sup.+.
 EXAMPLE 16
 A solution of N-(4-pyridyl)piperazine (0.33 g) in dry dimethylformamide (15
 ml) was treated with sodium hydride (0.14 g) (45-55% dispersion in oil).
 The reaction mixture was then stirred for 45 minutes at ambient
 temperature under argon. 4-Bromobenzyl bromide (0.58 g) was added and the
 mixture heated slowly to 60.degree. C. and then maintained at this
 temperature for 2 hours. The resulting mixture was then poured into water,
 basified with aq.NaHCO.sub.3 solution and then extracted with diethyl
 ether. The organic extracts were then washed with aq.NaHCO.sub.3, water,
 brine, dried (Na.sub.2 SO.sub.4) and evaporated. The residue was
 recrystallised from acetonitrile to give
 1-(4-pyridyl)-4-(4-bromobenzyl)piperazine (0.2 g) as a solid, m.p.
 140-141.degree. C.; microanalysis, found: C,55.3; H,5.2; N,12.0%; C.sub.16
 H.sub.18 N.sub.3 Br requires: C,55.4; H,5.7; N,12.1%; NMR: (CDCl.sub.3)
 2.54(t,4H); 3.2(t,4H); 3.51(s,2H); 6.66(d,2H); 7.23(d,2H); 7.46(d,2H);
 8.29(d,2H); MS: m/z 332 (MH).sup.+.
 EXAMPLE 17
 A solution of N-(4-pyridyl)piperazine (0.33 g) in dry dimethylformamide (15
 ml) was treated with sodium hydride (0.14 g) (45-55% dispersion in oil).
 The reaction mixture was then stirred for 30 minutes at ambient
 temperature under argon. 4-Cyanobenzyl bromide (0.41 g) was added and the
 mixture heated slowly to 80.degree. C. and then maintained at this
 temperature for 2 hours. The resulting mixture was then poured into water,
 basified with aq.NaHCO.sub.3 solution and then extracted with diethyl
 ether. The organic extracts were then washed with aq.NaHCO.sub.3, water.
 brine, dried (MgSO.sub.4) and evaporated. The residue was recrystallised
 from toluene/hexane to give 1-(4-pyridyl)-4-(4-cyanobenzyl)piperazine
 (0.08 g) as a solid. m.p. 137-138.degree. C.; microanalysis, found: C,
 73.3; H, 6.5; N, 19.8%; C.sub.17 H.sub.18 N.sub.4 requires: C, 73.4; H,
 6.5; N, 20.1%; NMR: (CDCl.sub.3) 2.56(t,4H); 3.35(t,4H); 3.61(s,2H);
 6.67(dd,2H); 7.49(d,2H); 7.63(d,2H); 8.28(dd,2H); MS: m/z 279(MH).sup.+.
 EXAMPLE 18
 A solution of N-(4-pyridyl)piperazine (0.33 g) in dry dimethylformamide (15
 ml) was treated with sodium hydride (0.14 g) (45-55% dispersion in oil).
 The reaction mixture was then stirred for 30 minutes at ambient
 temperature under argon. A solution of 2-fluoro-4-bromobenzyl bromide (2.6
 ml) (20% w/v in dichlorobenzene) was added and the mixture was heated
 slowly to 70.degree. C. and then maintained at this temperature for 24
 hours. The resulting mixture was then poured into water and then extracted
 with diethyl ether. The organic extracts were then washed with
 aq.NaHCO.sub.3, water, brine, dried (Na.sub.2 SO.sub.4) and evaporated.
 The residue was then purified by flash chromatography on alumina (ICN
 Alumina N 32-63) using an increasing concentration of ethyl acetate in
 isohexane (50-100% ethyl acetate) and then up to 10% methanol in ethyl
 acetate as eluent to give after recrystallisation
 1-(4-pyridyl)-4-(2-fluoro-4-bromobenzyl)piperazine (0.08 g) as a solid,
 m.p. 77-78.degree. C.; microanalysis, found: C, 54.4; H, 4.8; N, 11.1%;
 C.sub.16 H.sub.17 N.sub.3 FBr requires: C, 54.9; H, 4.9; N, 12.0%; NMR:
 3.28(s,8H), 3.54(s,2H); 6.79(d,2H); 7.41(d,2H); 7.52(d,1H); 8.13(d,2H);
 MS: m/z 350 (MH).sup.+.
 EXAMPLE 19
 Using an analogous procedure to that described in Example 16, but using
 3,4-dichlorobenzylbromide as starting material was prepared
 1-pyridyl-4-(3,4-dichlorobenzyl)piperazine (43% yield), microanalysis,
 found: C, 59.3; H, 5.4; N, 12.75%; C.sub.16 H.sub.17 Cl.sub.2 N.sub.3
 requires C, 59.6; H, 5.3; N, 13.0%; NMR: 2.4-2.45 (m,4H), 3.3-3.45 (m,4H),
 3.55 (s,2H), 6.6 (d,2H), 7.3-7.4 (dd,1H), 7.55-7.65 (m,2H), 8.15 (d,2H);
 MS m/z 322 (MH).sup.+.
 EXAMPLE 20
 Using an analogous procedure to that described in Example 16, but using
 4-nitrobenzylbromide as starting material, was prepared
 1-pyridyl-4-(4-nitrobenzyl)piperazine (47% yield), NMR: 3.7 (s,2H), 6.8
 (d,2H), 7.65 (d,2H), 8.15 (d,2H), 8.2 (d,2H); MS: m/z 299 (MH).sup.+.
 EXAMPLE 21
 1-(4-Pyridyl)piperazine (9.78 g) and 1-bromo-4-nitrobenzene (6.67 g) were
 stirred as a melt at 120.degree. C. for 1 hour. The mixture was cooled to
 ambient temperature and 5% methanol in dichloromethane (100 ml) was added.
 The solid mass broken up by sonication and the mixture was stirred for 16
 hours. The resulting solid was collected by filtration and purified by
 flash chromatography on silica gel using a gradient of 5-15% methanol/0.1%
 ammonia (SG. 0.88) in dichloromethane as eluant to give a product of
 sufficient purity to continue (6.35 g) m.p. 225-226.degree. C.
 A solution of this solid (1.0 g) in concentrated hydrochloric acid (10 ml)
 was treated with granulated zinc (0.5 g) and stirred at 110.degree. C. for
 2 hours. Water (50 ml) was added to the mixture and unreacted zinc was
 removed by filtration. The product hydrochloride precipitated from the
 filtrate on cooling. This solid was collected, dissolved in 20% potassium
 hydroxide, extracted with dichloromethane (4.times.25 ml), washed with
 water, brine, dried (MgSO.sub.4) and evaporated. There was thus obtained
 1-(4-aminophenyl)-4-(4-pyridyl)piperazine as a free base (0.88 g),
 microanalysis, found: C, 70.8; H, 7.1; N, 22.0; C.sub.15 H.sub.18 N.sub.4
 requires: C, 71.0; H, 7.3; N, 22.0; NMR: 3.01(t,4H), 3.41(t,4H),
 6.52(d,2H), 6.75(d,2H), 6.86(d,2H), 8.17(d,2H); MS: m/z 255 (MH).sup.+.
 EXAMPLE 22
 A solution of 1-(4-pyridyl)piperazine (0.49 g) in dry dichloromethane (20
 ml) and triethylamine (0.7 ml) was treated slowly with a solution of
 4-bromobenzoyl chloride (0.7 g) in dry dichloromethane (10 ml). The
 reaction mixture was then stirred under argon for 2 hours. The
 dichloromethane solvent was removed by evaporation and the residue
 dissolved in ethyl acetate. The organic extracts were then washed with
 aqueous sodium hydrogen carbonate solution, water, brine, dried (Na.sub.2
 SO.sub.4) and evaporated to yield a colourless oil. The residual oil was
 then triturated with diethyl ether and recrystallised from ethyl
 acetate/isohexane to give 1-(4-pyridyl)-4-(4-bromobenzoyl)piperazine (0.62
 g) as a solid, m.p. 128-129.degree. C.; microanalysis, found: C, 55.7; H,
 4.7; N, 12.0%; C.sub.16 H.sub.16 N.sub.3 OBr requires: C, 55.5; H, 4.7; N,
 12.1%; NMR: (CDCl.sub.3) 3.36(s,4H), 3.73(s,4H), 6.67(dd,2H), 7.33(dd,2H),
 7.58(dd,2H), 8.34(dd,2H); MS: m/z 346 (MH).sup.+.
 EXAMPLE 23
 A solution of 1-(4-pyridyl)piperazine (0.49 g) in dry dichloromethane (20
 ml) and triethylamine (0.7 ml) was treated slowly with a solution of
 4-cyanobenzoyl chloride (0.50 g) in dry dichloromethane (30ml). The
 reaction mixture was then stirred under argon for 2 hours. The
 dichloromethane solvent was removed by evaporation and the residue
 dissolved in ethyl acetate. The organic extracts were then washed with
 aqueous sodium hydrogen carbonate solution, water, brine, dried (Na.sub.2
 SO.sub.4) and evaporated to give a colourless oil which was crystallised
 from ethyl acetate/isohexane to afford
 1-(4-pyridyl)4-(4-cyanobenzoyl)piperazine (0.25 g) as a solid, m.p.
 164-165.degree. C.; microanalysis, found: C, 69.7; H, 5.6; N, 18.5%;
 C.sub.17 H.sub.16 N.sub.4 O requires: C, 69.8; H, 5.52; N, 19.2%; NMR:
 (CDCl.sub.3) 3.38(bs,4H), 3.75(bs,4H), 6.67(dd,2H), 7.56(dd,2H),
 7.76(dd,2H), 8.32(dd,2H): MS: m/z 293 (MH).sup.+.
 EXAMPLE 24
 A solution of 2-fluoro-4-bromobenzoic acid (0.24 g) in dry
 dimethylformamide (10 ml) was treated with
 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g) and
 stirred for 30 minutes at ambient temperature under argon. A solution of
 1-(4-pyridyl)piperazine (1.6 g) in dry dimethylformamide (3 ml) was added
 to the mixture and the mixture cooled to 50.degree. C. The reaction was
 then allowed to warm to room temperature and stirred overnight. The
 solution was poured into water and then extracted into diethyl ether,
 washed with aqueous sodium hydrogen carbonate solution, water, brine.
 dried (Na.sub.2 SO.sub.4) and evaporated to yield a colourless oil. This
 oil was then triturated with diethyl ether and recrystallised from ethyl
 acetate/isohexane to give
 1-(4-pyridyl)-4-(2-fluoro-4-bromobenzoyl)piperazine (0.14 g) as a solid,
 m.p. 125-126.degree. C.: microanalysis, found: C, 52.6; H, 4.1; N, 11.2%;
 C.sub.16 H.sub.15 BrFN.sub.3 O requires: C, 52.8; H, 4.15; N, 11.5%; NMR:
 (CDCl.sub.3) 3.32(t,2H), 3.46(t,4H), 3.94(t,2H), 6.68(dd,2H),
 7.29-7.43(m,3H), 8.33(d,2H); MS: m/z 364 (MH).sup.+.
 EXAMPLE 25
 A solution of 1-(4-pyridyl)piperazine (0.49 g) and triethylamine (0.7 ml)
 in dry dichloromethane (20 ml) was treated slowly with a solution of
 4-bromophenylsulphonyl chloride (0.77 g) in dry dichloromethane (10 ml).
 The reaction mixture was then stirred under argon for 2 hours. The
 dichloromethane solvent was removed by evaporation and the residue
 dissolved in ethyl acetate. The organic extracts were washed with water,
 brine, dried (MgSO.sub.4) and evaporated to yield a white crystalline
 solid which was recrystallised from ethyl acetate to give
 1-(4-pyridyl)-4-(4-bromophenylsulphonyl)piperazine (0.84 g) as a solid,
 m.p. 199-200.degree. C.: microanalysis, found: C, 47.3; H, 4.1; N, 10.9%;
 C.sub.15 H.sub.16 BrN.sub.3 O.sub.2 S requires: C, 47.1; H, 4.22; N,
 11.0%; NMR: (CDCl.sub.3) 3.13(t,4H), 3.42(t,4H), 6.62(dd,2H), 7.67(q,4H),
 8.29(d,2H): MS: m/z 382 (MH).sup.-.
 EXAMPLE 26
 Pyridine (1 ml) was added to a solution of 1-(4-pyridyl)piperazine (0.33 g)
 in dry dichloromethane (20 ml) and triethylamine (1 ml) at 5.degree. C.
 The reaction mixture was treated with 4-cyanobenzenesulphonyl chloride
 (0.40 g). The reaction mixture was then stirred under argon for 4 hours
 allowing to warm to room temperature. The dichloromethane solvent was
 removed by evaporation and the residual pyridine solution poured into
 aqueous sodium hydrogen carbonate solution and then extracted with ethyl
 acetate. The organic extracts were then washed with aqueous sodium
 hydrogen carbonate solution, water, brine, dried (MgSO.sub.4) and
 evaporated to yield a pale cream solid which was then recrystallised from
 ethyl acetate isohexane to give
 1-(4-pyridyl)-4-(4-cyanophenylsulphonyl)piperazine (0.31 g) as a solid.
 m.p. 212-213.degree. C.; microanalysis, found: C, 58.8; H, 4.9; N, 17.1%;
 C.sub.16 H.sub.16 N.sub.4 O.sub.2 S requires: C, 8.5: H, 4.91; N, 17.1%;
 NMR: (CDCl.sub.3) 3.18(t,4H), 3.44(t,4H), 6.62(dd,2H), 7.88(q,4H),
 8.30(dd,2H); MS: m/z 329 (MH).sup.+.
 EXAMPLE 27
 1-(4-Pyridyl)-4-(4-aminophenyl)piperazine (0.4 g) was dissolved in dry
 dichloromethane (40 ml) and cooled to 0.degree. C. Triethylamine (0.4 ml)
 was added followed by 4-cyanobenzenesulphonyl chloride (0.6 g). The
 reaction mixture was then stirred overnight. The mixture was washed with
 aqueous sodium hydrogen carbonate solution. water, brine, dried
 (MgSO.sub.4) and evaporated to yield the crude solid product. This solid
 was purified by flash chromatography on ICN Alumina (N 32-63) using and
 increasing concentrations of ethyl acetate in isohexane (50-100% ethyl
 acetate) and up to 10% methanol in ethyl acetate as the eluent to give
 1-(4-pyridyl)-4-(4-cyanophenylsulphonamidophenyl)piperazine (0.12 g) as a
 solid, m.p. 237-238.degree. C.; microanalysis found: C, 61.4; H, 4.9; N,
 15.5%; C.sub.22 H.sub.21 N.sub.5 O.sub.2 S.0.5 H.sub.2 O requires: C,
 61.7; H, 4.9; N, 16.3%; NMR: 3.17(t,4H), 3.42(t,4H), 6.81-6.97(m,6H),
 7.82(d,2H), 8.02(d,2H), 8.18(d,2H,: MS: m/z 420 (MH).sup.+.
 The 1-(4-pyridyl)-4-(4-aminophenyl)piperazine used as starting material was
 prepared as follows:
 Sodium hydride (0.5 g) (45-55% dispersion in oil was added to a solution of
 1-(4-pyridyl)piperazine (0.9 g) in dry dimethylformamide (10 ml) at
 ambient temperature and stirred for 30 minutes. After this time,
 4-fluoronitrobenzene (0.65 ml) was added slowly and the temperature raised
 to 70.degree. C. The mixture was maintained at this temperature for 2
 hours. The reaction mixture was then quenched by pouring into water and
 acidifying with aq 2N HCl solution to pH 1. The acidic layer was washed
 with diethyl ether and then basified with aq 2N.NaOH solution. The
 resulting precipitate was filtered, washed with water, dissolved in
 methanol, filtered through phase separator paper and evaporated to
 dryness. The resulting crude material was recrystallised from
 methanol/ether to give 1-(4-pyridyl)-4-(4nitrophenyl)piperazine (0.64 g)
 as an oil, NMR: (CDCl.sub.3) 3.61(q,8H), 6.58(d,2H), 6.81(d,2H),
 8.16(d,2H), 8.33(bs,2H); MS: m/z 285 (MH).sup.+.
 A solution of sodium dithionite (2.5 g) in water (10 ml) was added to a
 warmed solution of 1-(4-pyridyl)-4-(4-nitrophenyl)piperazine (0.551 g) in
 methanol (50 ml) and the mixture was allowed to reflux for 2 hours. The
 methanol was removed by evaporation and the resulting concentrated
 solution was basified with solid Na.sub.2 SO.sub.4. The organic material
 was extracted into ethyl acetate, washed with water, brine, dried
 (Na.sub.2 SO.sub.4) and evaporated to give
 1-(4-pyridyl)-4-(4-aminophenyl)piperazine (0.4 g) as an oil. NMR:
 (CDCl.sub.3) 3.14(t,4H), 3.48(t, 4H), 6.68(m,4H), 6.85(d,2H), 8.31(bd,2H):
 MS: m z 255 (MH).sup.-.
 EXAMPLE 28
 A solution of 4-chloropyrimidine HCl (450mg) and 4-bromophenyl sulphonyl
 piperazine (300 mg) in ethanol (20 ml) and water (2 ml) containing
 triethylamine (0.5 ml) was heated under reflux overnight. The solution was
 evaporated and water (50 ml) added and the solution basified to pH 8 by
 addition of solid potassium carbonate to give a precipitate which was
 filtered and washed with water and air dried. The crude solid was
 dissolved in acetonitrile and chromatographed on an alumina column (ICN
 Alumina N 32-63) eluting with 30% tetrahydrofuran/ethyl acetate and then
 acetonitrile to give pure product which was recrystallised from a mixture
 of ethyl acetate/isohexane to give
 1-(4-pyrimidyl)-4-(4-bromophensulphonyl)piperazine (44 mg) as a solid,
 m.p. 196-197.degree. C.; microanalysis found: C, 43.9; H, 3.9; N, 14.4%;
 C.sub.14 H.sub.15 BrN.sub.4 O.sub.2 S requires: C, 43.9; H, 3.9; N, 14.6%;
 NMR: 2.9-3.1(m,4H), 3.6-3.8(m,4H), 6.8(dd,1H), 7.6-7.7(d,2H),
 7.8-7.9(d,2H), 8.1-8.2(d,1H), 8.5(s,1H); MS: m/z 383 (MH).sup.+.
 The 1-(4-bromophenylsulphonyl)piperazine used as starting material was
 prepared as follows:
 To a stirred solution of piperazine (10.8 g) in dry dichloromethane (160
 ml) and triethylamine (20 ml) at 0.degree. C. was added slowly a solution
 of 4-bromobenzenesulphonyl chloride (16 g) in dichloromethane (80 ml) and
 stirred for 24 hours. The reaction was then quenched by removal of the
 dichloromethane solvent by evaporation, taken up in water and extracted
 with ethyl acetate. The organic extracts were washed with aqueous sodium
 hydrogen carbonate solution, water, brine, dried (MgSO.sub.4) and then
 evaporated to give a white crystalline solid which was recrystallised from
 ethyl acetate/isohexane to afford 1-(4-bromophenylsulphonyl)piperazine
 (14.1 g) as a solid, m.p. 102-104.degree. C.; microanalysis found: C,
 39.5; H, 4.4; N, 9.1%: C.sub.10 H.sub.13 BrN.sub.2 O.sub.2 S requires: C,
 39.4; H, 4.3; N, 9.2%; NMR (CDCl.sub.3): 1.52(s,1H), 2.97(dt,8H),
 7.61(d,2H), 7.69(d,2H): MS m/z 305 (MH).sup.+.
 EXAMPLE 29
 Carbonyl diimidazole (324 mg) was added to a solution of
 6-bromonaphthalene-2-sulphinic acid (658 mg) in dimethylformamide (10 ml).
 After stirring at ambient temperature for one hour
 N-4-(4-pyridyl)piperazine (326 mg) was added as a solid in one portion and
 stirring continued at ambient temperature overnight. The reaction mixture
 was poured into ethyl acetate (100 ml), washed with water (3.times.25 ml),
 brine (25 ml), dried (MgSO.sub.4) and evaporated to give a yellow oil
 which was purified by chromatography on silica gel (Mega Bond Elut column)
 using an increasing concentration of methanol in dichloromethane (up to 5%
 methanol) as eluant to give an oil which on trituration with diethyl ether
 gave a white solid
 1-(4-pyridyl)-4-(6-bromonaphtalene-2-sulphenyl)piperazine (170 mg), m.p.
 200-202.degree. C.; microanalysis, found: C, 54.9; H, 4.4; N, 10.1;
 C.sub.19 H.sub.18 BrN.sub.3 OS requires: C, 54.9; H, 4.3; N, 10.1; NMR:
 2.9-3.0(m,2H); 3.1-3.3(m,2H); 3.35-3.5(m,4H); 6.8(dd,2H); 7.7-7.8(m,2H);
 8.1-8.2(m,4H); 8.3(s,1H); 8.35(d,1H); MS: m/z 416 (MH).sup.+.
 EXAMPLE 30
 Triethylamine (3.48 ml) was added to a stirred suspension of
 1-(4-pyridyl)piperazine (4.08 g) in DMF (50 ml). The mixture was cooled to
 4.degree. C., and 4-nitrobenzoylchloride (4.64 g) added. The mixture was
 stirred for 1 hour at 4.degree. C. and then for 16 hours at ambient
 temperature. Dichloromethane (250 ml) was then added and the mixture
 washed with water (3.times.30 ml), saturated brine (1.times.30 ml), then
 dried (MgSO.sub.4) and the solvents evaporated. The residual oil was
 purified by flash chromatography on silica gel using 5% v/v
 methanol/dichloromethane and then with 10% v/v methanol/dichloromethane as
 eluant to give 1-(4pyridyl)-4-(4-nitrobenzoyl)piperazine (5.09 g) as a
 yellow solid. m.p. 158-160.degree. C.; microanalysis. found: C, 61.3; H,
 5.3; N, 17.6%; C.sub.16 H.sub.16 N.sub.4 O.sub.3 requires: C, 61.5; H,
 5.2; N, 17.9%: NMR: 3.42(6H+H.sub.2 O,m), 3.87(2H,bs), 6.93(2H,d),
 7.84(2H,d), 8.30(2H,d), 8.41(2H,d): MS: m/z 313 (MH).sup.+.
 EXAMPLE 31
 Azodicarbonyldipiperidine (20.03 g), tributylphosphine (16.06 g) and
 1-(4-pyridyl)-4-piperidin-1-ol (9.43 g) were added to a stirred solution
 of N-t-butyloxycarbonyl-4-aminophenol (11.08 g) in dry THF (300 ml),
 cooled under a blanket of nitrogen to 10.degree. C. A thick precipitate
 formed and the mixture was stirred at ambient temperature for 20 hours
 during which time the mixture slowly thinned. The precipitated
 tributylphosphine oxide was removed by filtration and the residue
 concentrated in vacuo. The residue was purified by flash chromatography on
 silica gel using ethyl acetate followed by dichloromethane containing an
 increasing amount of methanol (up to 5% methanol) as eluent to give a
 solid (7.38 g). mp 192-195.degree. C.
 A solution of this solid (4.22 g) in dichloromethane (400 ml) was treated
 with a saturated solution of hydrogen chloride in ether (50 ml) and the
 mixture was stirred for 64 hours. The mixture concentrated in vacuo and
 the residue crystallised from methanol/ether to give
 1-(4-pyridyl)-4-(4-aminophenyloxy)piperidine hydrochloride (2.85 g), mp.
 289-291.degree. C. NMR: 1.73 (m,2H), 2.06 (m,2H), 3.64 (m,2H), 3.94(m,2H),
 4.76 (m,1H), 7.12(d,2H), 7.24(d,2H), 7.34(d,2H), 8.23(d,2H), 10.32 (broad,
 2H); MS: m/z 270 (MH).sup.+. This solid (1.5 g) was dissolved in water (10
 ml) and 2M sodium hydroxide added until precipitation was complete. There
 was thus obtained 1-(4-pyridyl)-4-(4-aminophenoxy)piperidine free base as
 a brown solid (1.03 g) mp 214-215.degree. C. NMR: 1.57 (m,2H), 1.86
 (m,2H), 3.24 (m,2H), 3.67(m,2H), 4.31 (m,1H), 6.47(d,2H), 6.66(d,2H),
 6.87(d,2H), 8.13(d, 2H); MS: m/z 270 (MH).sup.+.
 EXAMPLE 32
 A solution of N-(4-pyridyl)piperazine (815 mg), 4-fluorobenzophenone (1.2
 g) and powdered potassium carbonate (912 mg) was stirred at 95.degree. C.
 in DMSO (10 ml) overnight. The solution was poured into water (150 ml) and
 extracted with dichloromethane (3.times.50 ml). The dichloromethane
 extracts were combined, washed with water, dried (Na.sub.2 SO.sub.4) and
 evaporated. The residue was purified by chromatography on alumina (ICN
 Alumina N 32-63) using 1% methanol in dichloromethane as eluant to give a
 solid. The solid was recrystallised from a mixture of ethyl
 acetate/isohexane to give 1-(4-benzoylphenyl)-4-(4-pyridyl)piperazine (450
 mg) as a solid. m.p.136-137.degree. C.
 EXAMPLE 33
 A solution of N-(4-pyridyl)piperazine (8.15 g), 4,4'-difluorobenzophenone
 (13.1 g) and powdered potassium carbonate (9.12 g) was stirred at
 95.degree. C. in DMSO (100 ml) overnight. The solution was poured into
 water (1500 ml) to give a precipitate which was filtered, washed with
 water and dried. The solid (7.82 g) was stirred in trifluoroacetic acid
 (25 ml) under argon with triethylsilane (10 ml) for 18 hours. The solution
 was poured into water (315 ml), taken to pH 12 with sodium hydroxide
 solution and extracted with dichloromethane (2.times.300 ml). The combined
 dichloromethane extracts were washed with water, dried (Na.sub.2 SO.sub.4)
 and evaporated to give a residue which was purified by chromatography on
 alumina (ICN Alumina N 32-63) using 0.5% methanol in dichloromethane as
 eluant. The solid obtained was recrystallised from a mixture of ethyl
 acetate/isohexane to give 1-(4-fluorobenzylphenyl)-4-(4-pyridyl)piperazine
 (350 mg) as a solid, m.p. 110-111.degree. C.
 EXAMPLE 34
 A solution of 1-(4-hydroxyphenyl)-4-(4-pyridyl)piperazine (670 mg),
 4-fluorobenzonitrile (354 mg) and powdered potassium carbonate (445 mg)
 was stirred at 95.degree. C. in DMSO (12 ml) for 18 hours. The solution
 was poured into water (180 ml) to give a precipitate which was filtered,
 washed with water and dried. The solid was purified by chromatography on
 alumina (ICN Alumina N 32-63) using 1% methanol in dichloromethane as
 eluant. This gave a solid which was recrystallised from a mixture of ethyl
 acetate/isohexane to give 1-(4-cyanophenoxyphenyl)-4-(4-pyridyl)piperazine
 (126 mg) as a solid. m.p. 180-182.degree. C.
 The 1-(4-hydroxyphenyl)-4-(4-pyridyl)piperazine used as starting material
 was prepared as follows:
 A solution of 4-chloropyridine HCl (450 mg) and
 1-(4-methoxyphenyl)-piperazine (226 mg) in ethanol (20 ml) and water (2
 ml) containing triethylamine (0.5 ml) was heated under reflux for 18
 hours. The solution was evaporated, water (50 ml) added and the solution
 taken to pH 8 by addition of solid potassium carbonate to give a
 precipitate which was filtered, washed with water and dried. The solid (33
 mg) was stirred in concentrated aqueous hydrogen bromide (2 ml) at
 140.degree. C. for 8 hours, poured into cold water (2 ml) and taken to pH
 7 with aqueous ammonia (1.3 ml) to give a solid which was filtered, washed
 with water and dried to give 1-(4-hydroxyphenyl)-4-(4-pyridyl)piperazine
 (28 mg), m.p. 288-290.degree. C.
 EXAMPLE 35
 Using an analogous procedure to that described in Example 34, but using
 2-bromo-5-nitropyridine as starting material in place of
 4-fluorobenzonitrile, there was prepared
 1-(4-[5-nitro-2-pyridyloxy]phenyl)4-(4-pyridyl)piperazine (50% yield),
 m.p. 174-175.degree. C.
 EXAMPLE 36
 Sodium hydride (120 mg) (50% dispersion in oil) was added to a stirred
 solution of 1-(4-hydroxyphenyl)-4-(4-pyridyl)piperazine (510 mg) in
 dimethylformamide (5 ml) under argon. The solution was stirred at ambient
 temperature for 30 minutes and a solution of 4-cyanobenzylbromide (430 mg)
 in dimethyl formamide (5 ml) was added dropwise. The solution was stirred
 at ambient temperature overnight, water (150 ml) added to give a
 precipitate which was washed with water, dried and recrystallised from
 ethanol to give 1-(4-cyanobenzyloxyphenyl)-4-(4-pyridyl)piperazine (660
 mg), m.p.212-214.degree. C.
 EXAMPLE 37
 Using an analogous procedure to that described in Example 36, but using
 4-bromobenzylbromide as starting material in place of
 4-cyanobenzylbromide, was prepared
 1-(4-bromobenzyloxyphenyl)-4-(4-pyridyl)piperazine (50% yield),
 m.p.233-235.degree. C.
 EXAMPLE 38
 A solution of 1-(4-formylphenyl)-4-(4-pyridyl)piperazine (1.0 g),
 4-bromoacetophenone (745 mg) and conc. sodium hydroxide (3 drops) in
 ethanol (25 ml) was stirred at ambient temperature overnight to give a
 solid which was filtered, washed with ethanol and dried to give
 1-(4-[4-bromobenzoylethylenyl]-phenyl)-4-(4-pyridyl)piperazine (900 mg),
 m.p. 201-203.degree. C.
 The 1-(4-formylphenyl)-4-(4-pyridyl)piperazine used as starting material
 was prepared as in Example 32, using 4-fluorobenzaldehyde as starting
 material in place of 4-fluorobenzophenone to give
 1-(4-formylphenyl)-4-(4-pyridyl)piperazine (43% yield),
 m.p.116-118.degree. C.
 EXAMPLE 39
 A solution of 1-(4-formylphenyl)-4-(4-pyridyl)piperazine (1.0 g),
 4-methoxyacetophenone (503 mg) and concentrated sodium hydroxide (3 drops)
 in ethanol (25 ml) was stirred at ambient temperature overnight to give a
 solid which was dissolved in ethanol (100 ml) and hydrogenated over 10%
 palladium on charcoal to give a solid which was recrystallised from a
 mixture of ethyl acetate/isohexane to give
 1-(4-[4-methylbenzoylethyl]-phenyl)-4-(4-pyridyl)piperazine (400 mg), m.p.
 114-115.degree. C.
 EXAMPLE 40
 4-Methoxybenzyltriphenylphosphonium bromide (4.47 g) was added to a
 solution of potassium t-butoxide (1.12 g) in tetrahydrofuran (50 ml) under
 argon. After 30 minutes at ambient temperature, the solution was treated
 with a solution of 1-(4-formylphenyl)-4-(4-pyridyl)piperazine (1.34 g) in
 tetrahydrofuran (25 ml) and the mixture stirred at ambient temperature
 overnight. The tetrahydrofuran was evaporated, the residue treated with
 water (100 ml) and extracted with dichloromethane (3.times.50 ml). The
 combined dichloromethane extracts were washed with water, dried (Na.sub.2
 SO.sub.4) and evaporated to give a residue which was purified by
 chromatography on alumina (ICN Alumina N 32-63) using 2% methanol in
 dichloromethane as eluant. This gave a solid which was recrystallised from
 a mixture of ethyl acetate/isohexane to give
 1-[4-(4-methylphenylethylenyl)phenyl]-4-(4-pyridyl)piperazine (350 mg) as
 a solid. m.p. 92-94.degree. C.
 EXAMPLE 41
 Using an analogous procedure to that described in Example 40, but using
 4-cyanobenzyltriphenylphosphonium chloride as starting material in place
 of 4-methoxybenzyltriphenylphosphonium bromide, there was prepared
 1-(4-[4-cyanophenylethylenyl]phenyl)-4-(4-pyridyl)piperazine (18% yield),
 m.p. 105-106.degree. C.
 EXAMPLE 42
 A solution of 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (1.0 g),
 benzaldehyde (177 mg) and concentrated sodium hydroxide (3 drops) in
 ethanol (25 ml) was stirred at ambient temperature overnight to give a
 solid which was filtered, washed with ethanol and dried to give
 1-(4-cinnamoylphenyl)-4-(4-pyridyl)piperazine (310 mg), m.p.
 208-210.degree. C.
 The 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine used as starting material
 was prepared as in Example 32, using 4-fluoroacetophenone as starting
 material in place of 4-fluorobenzophenone to give
 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (40% yield), m.p.
 176-177.degree. C.
 EXAMPLE 43
 Using an analogous procedure to that described in Example 42, but using
 4-tert-butylbenzaldehyde as starting material in place of benzaldehyde,
 there was prepared
 1-[4-(4-t-butylcinnamoyl)phenyl]-4-(4-pyridyl)piperazine (46% yield), m.p.
 213-214.degree. C.
 EXAMPLE 44
 Using an analogous procedure to that described in Example 39, but using as
 starting material 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine in place of
 1-(4-formylphenyl)-4-(4pyridyl)piperazine and 4-tolualdehyde in place of
 4-methylacetophenone, was prepared
 1-[4-(4-methylphenylpropionyl)-phenyl]-4-(4-pyridyl)piperazine (27%
 yield), m.p. 130-132.degree. C.
 EXAMPLE 45
 A solution of 4-(4-pyridyl)piperazine (5.0 g), bis(4-fluorophenyl)sulphone
 (15.58 g) and powdered potassium carbonate (6.35 g) was stirred at
 95.degree. C. in DMF (30 ml) overnight. The solution was poured into water
 (150 ml) to give a black solid from which the aqueous phase was decanted.
 The solid was heated in ethanol and a brown solid was collected by
 filtration. The filtrate was evaporated and the residue was purified by
 chromatography on alumina (ICN Alumina N 32-63) first using ethyl acetate
 as eluent followed by 10% methanol in dichloromethane. This gave
 1-(4-fluorophenylphenylsulphone)-4-(4pyridyl)piperazine as a yellow solid
 (521 mg); microanalysis: Found C, 63.3; H, 5.1; N, 10.9%; C.sub.21
 H.sub.20 FN.sub.3 O.sub.2 S requires: C, 63.5; H, 5.07; N, 10.6%.
 EXAMPLE 46
 A mixture of 4-[3-(4-cyanophenoxy)-1-pyrrolidinyl]pyridine (269 mg) and
 powdered potassium hydroxide (568 mg) in t-butanol (10 ml), under an
 atmosphere of argon, was heated under reflux for 18 hours. The mixture was
 filtered hot. The filtercake was washed with water and ethanol to give
 4-[3-(4-carbamoylphenoxy)-1-pyrrolidinyl]pyridine (166 mg) as a colourless
 solid, mp 298-300.degree. C.
 The 4-[3-(4-cyanophenoxy)-1-pyrrolidinyl]pyridine used as starting material
 was prepared as follows:
 A solution of 4-chloropyridine hydrochloride (8.86 g), 3-pyrrolidinol (5.14
 g) and triethylamine (14.8 ml) in water (65 ml) was stirred and heated
 under reflux for 65 hours. The solution was evaporated to a semi-solid.
 This residue was purified by flash column chromatography on silica (Merck
 9385) using a 90:10:3 (v/v/v) mixture of ethyl acetate, methanol and
 aqueous ammonia solution as eluent, to give, after trituration with ethyl
 acetate, 4-(3-hydroxy-1-pyrrolidino)pyridine (5.95 g) as a cream solid, mp
 207-209.degree. C.
 A solution of diethyl azodicarboxylate (1.73 ml) in dried tetrahydrofuran
 (10 ml) was added dropwise to a stirred mixture of triphenylphosphine
 (3.15 g), 4-cyanophenol (1.31 g) and 4-(3-hydroxy-1-pyrrolidinyl)pyridine
 (1.64 g) in dried tetrahydrofuran (45 ml), under an atmosphere of argon,
 at 5-7.degree. C. The resulting solution was stirred at ambient
 temperature for 16 hours. The solid, which had separated, was filtered off
 and washed with diethyl ether to give
 4-[3-(4-cyanophenoxy)-1-pyrrolidinyl]pyridine (823 mg) as an off-white
 solid, mp 182-185.degree. C.
 EXAMPLE 47
 A 2M solution of sodium methoxide in methanol (0.89 ml) was added to a
 suspension of ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (500 mg) in a
 33% solution of monomethylamine in ethanol (15 ml). The mixture was
 stirred at 40.degree. C. for 18 hours. The mixture was cooled and the
 solid was collected by filtration. The solid was washed with ethanol and
 ether to give 1-(4-methylcarbamoylphenyl)-4-(4-pyridyl) piperazine (374
 mg) as a cream solid, mp 239-242.degree. C.
 The ethyl 4-[4-(4-pyridyl)-1-piperazinyl]benzoate used as starting material
 was prepared as follows:
 A solution of 4-(4-pyridyl)piperazine (9.78 g), ethyl 4-fluorobenzoate (9.7
 ml) and powdered potassium carbonate (9.9 g) in dried dimethylsulphoxide
 (60 ml) was heated at 95.degree. C. for 18 hours. The mixture was poured
 into water (1200 ml) and stirred for 30 minutes. The precipitate was
 filtered off, washed with water and dried. The solid was purified by flash
 column chromatography on alumina (ICN alumina N32-63) using 1%
 methanol/dichloromethane as eluent, to give ethyl
 4-[4-(4-pyridyl)-1-piperazinyl]benzoate (4.85 g) as a cream solid, mp
 162-164.degree. C.
 EXAMPLE 48
 Oxalyl chloride (0.25 ml) was added dropwise to a stirred suspension of
 4-[1-(4-pyridyl)piperazin-4-yl]benzoic acid (530 mg) in dried
 dichloromethane (20 ml) containing dimethylformamide (1 drop). The mixture
 was stirred at ambient temperature for 1.5 hours and evaporated to
 dryness. The residue was suspended in dried dichloromethane (25 ml),
 t-Butylamine (2 ml) was added slowly to this stirred suspension at
 5.degree. C. The mixture was stirred at ambient temperature for 3 hours,
 then evaporated to dryness. The residue was suspended in aqueous sodium
 hydrogen carbonate solution (30 ml) and the mixture was extracted with
 ethyl acetate (3.times.60 ml). The ethyl acetate extracts were combined,
 washed successively with aq NaHCO.sub.3 solution (30 ml) and saturated
 brine (30 ml), dried (Na.sub.2 SO.sub.4) and evaporated to dryness. The
 residue was recrystallised from ethyl acetate (25 ml) to give give
 1-(4-t-butylcarbamoylphenyl)-4-(4-pyridyl)piperazine (390 mg) as a
 colourless solid mp 214-217.degree. C.
 The 4-[1-(4-pyridyl)piperazin-4-yl]benzoic acid used as starting material
 was prepared as follows:
 1M sodium hydroxide solution (103 ml) was added to a suspension of ethyl
 4-[4-(4pyridyl)-1-piperazinyl]benzoate (10.3 g) in ethanol (200 ml) and
 the mixture was stirred at ambient temperature for 16 hours. The solution
 was evaporated to dryness. The residue was stirred in water (515 ml) for
 15 minutes and any insoluble material was filtered off. The filtrate was
 treated with ice-cooled 1 M hydrochloric acid (103 ml). The precipitate
 was filtered off, slurry washed with water, sucked dry and dried over
 phosphorus pentoxide, at 50.degree. C. for 2 days to give
 4-[1-(4-pyridyl)piperazin-4-yl]-benzoic acid (5.24 g) as an off-white
 solid, mp&gt;300.degree. C.
 EXAMPLE 49
 Using an analogous procedure to that described in Example 48, but using
 n-butylamine as starting material in place of t-butylamine, was prepared
 1-(4-n-butylcarbamoylphenyl)-4-(4-pyridyl)piperazine (67% yield) as a
 colourless solid, mp 172-174.degree. C.
 EXAMPLE 50
 1(4-Methoxycarbonylphenylmethyl)-4-(4-pyridyl)piperazine (933 mg;3.0 mmol)
 was dissolved in methanol (8 ml) and treated at ambient temperature under
 an argon atmosphere with an excess of piperidine (.about.20 equivalents)
 and 2M sodium methoxide in methanol (3 ml). The resulting solid suspension
 was heated at 65.degree. C. under reflux for 20 hours and then allowed to
 cool to room temperature. The reaction mixture was treated with a
 saturated aqueous solution of sodium hydrogen carbonate and extracted with
 CH.sub.2 Cl.sub.2. The organic extracts were washed with water and brine,
 dried over MgSO.sub.4, filtered and evaporated to yield an impure solid.
 The solid was chromatographed on silica gel (Varian bond elut-trademark)
 prepacked silica column, eluting with a mixture of methanol (1%), ammonium
 hydroxide (1%) and dichloromethane (98%) to give
 1-(4-N-piperidinocarbonylphenylmethyl)-4-(4-pyridyl)piperazine (386%
 yield), NMR (CDCl.sub.3): 1.51-1.73 (m,6H), 2.58 (t,4H), 3.28 (t, 4H),
 3.49 (s,4H), 3.57 (s,2H), 6.64 (dd,2H), 7.30 (s,4H), 8.25 (dd,2H).
 The 1-(4-methoxycarbonylphenylmethyl)-4-(4-pyridyl)piperazine used as
 starting material was prepared as follows:
 4-Pyridyl piperazine (3.26 g) was dissolved in 20 ml of 10% water in
 iso-propanol and treated at ambient temperature, with agitation, with
 methyl 4-bromomethyl benzoate (4.58 g) and triethylamine (10 ml). The
 resulting yellow suspension was stirred vigourously for 30 minutes at room
 temperature and then heated at 100.degree. C. under reflux for 20 hours.
 The suspension cleared to become a yellow solution when the reaction
 temperature had reached 60.degree. C. After this period of heating the
 reaction mixture was allowed to cool to room temperature and the solvent
 removed by rotary evaporation under reduced pressure to yield an amber
 slurry. The slurry was treated with 2N aqueous sodium hydroxide and
 extracted with dichloromethane. The organic extracts were washed with
 saturated brine. dried over MgSO.sub.4, filtered and evaporated down to an
 amber oil, which, after drying over 60 hours on a high vacuum pump yielded
 a pale yellow solid, 4.63 g (74%).
 EXAMPLE 51
 Using a similar method as described in Example 50 but using methylamine in
 place of piperidine there was obtained
 1-(4-N-methylaminocarbonylphenylmethyl)-4-(4-pyridyl)piperazine (76%
 yield), m.p. 188-190.degree. C.
 EXAMPLE 52
 1-(4-Carboxyphenylmethyl)-4-(4-pyridyl)piperazine (594 mg) was suspended in
 dichloromethane (25 ml) and treated at ambient temperature with thionyl
 chloride (5 ml) and heated at 40.degree. C. over 18 hours. After this
 period the reaction mixture was allowed to cool to room temperature,
 evaporated to dryness, azeotroped with toluene and dried under high vacuum
 for 2 hours. The yellow solid obtained was suspended in dichloromethane
 (20 ml), stirred in an ice bath and treated at 0-5.degree. C. with 5
 equivalents of morpholine. The suspension was allowed to warm to ambient
 temperature and stirred for 18 hours. After this period the reaction
 mixture was treated with saturated aqueous sodium hydrogen carbonate and
 extracted with dichloromethane. The organic extracts were then washed with
 water and saturated brine, dried over MgSO.sub.4, filtered and evaporated
 down to yield an impure solid. The solid was purified by chromatography on
 silica gel (Varian bond elut-trademark) prepacked silica column with a
 mixture of methanol (1-4%), ammonium hydroxide (1%) in dichloromethane to
 give 1-(4-N-morpholinocarbonylphenylmethyl)-4-(4-pyridyl)piperazine (33%
 yield) m.p. 121-125.degree. C.
 The 1-(4-carboxyphenylmethyl)-4-(4-pyridyl)piperazine used as starting
 material was prepared as follows:
 1-(4-Methoxycarbonylphenylmethyl)-4-(4-pyridyl)piperazine (4.5 g) was
 dissolved in methanol (50 ml) and treated at ambient temperature with 2M
 aqueous sodium hydroxide (36 ml). The resulting solution was stirred at
 room temperature for 3 hours and concentrated by evaporation to an aqueous
 solution of the sodium salt of the acid. This solution was just acidified
 with glacial acetic acid (4.3 ml) to give a white precipitate which was
 collected by filtration, washed with water and dried to give
 1-(4-carboxyphenylmethyl)-4-(4-pyridyl)piperazine in 90% yield.
 EXAMPLE 53
 Using a similar method to that described in Example 52 but using ethylamine
 in place of morpholine there was obtained
 1-(4-ethylaminocarbonylphenylmethyl)-4-(4pyridyl)piperazine (51% yield),
 m.p. 213-215.degree. C.
 EXAMPLE 54
 Using a similar method to that described in Example 50 there was obtained
 the following compounds.

##STR10##
 X R.sub.1 mp (.degree. C.)
 CH.sub.2 ##STR11## 144-147
 CH.sub.2 ##STR12## 145-147
 EXAMPLE 55
 Ethyl magnesium chloride (3M) in anhydrous THF (10 ml) was treated at room
 temperature under argon with a solution of
 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (281 mg) in anhydrous THF (15
 ml). The resulting solid suspension was heated at 70.degree. C. under
 reflux for 3 hours. The mixture was cooled in ice at 0-5.degree. C. and
 treated with diethyl ether and a saturated solution of aqueous ammonium
 chloride. The reaction mixture was stirred for 10 minutes with ice cooling
 and at room temperature for 10 minutes. The aqueous phase was then
 extracted with dichloromethane and the ether phase was evaporated. The
 residue was dissolved in dichloromethane and combined with the other
 organic extracts. The combined extracts were then washed with saturated
 brine, dried over MgSO.sub.4, filtered and evaporated to give an impure
 orange solid. The solid was purified by chromatography on a prepacked
 silica column ("Varian bond elut-trademark), eluting with a mixture of
 methanol (1-2%) and ammonium hydroxide (1%) in dichloromethane to obtain a
 pale yellow solid which was triturated with diethyl ether to give
 1-(4-(1-hydroxy-1-methylethyl)phenyl)4-(4-pyridyl)piperazine (21% yield)
 as a pale yellow solid, m.p. 234-235.degree. C.
 EXAMPLE 56
 4-(5-Cyano,2-pyridinoxy)piperidine (337 mg) and 4-chloropyridine
 hydrochloride (284 mg) were dissolved in water (10 mL) and treated with
 triethylamine (0.47 mL) in isopropanol (1 mL) and refluxed for 24 hours.
 The reaction was quenched by evaporation of the solvent. The residue was
 dissolved in dichloromethane and washed with aqueous sodium hydrogen
 carbonate solution, water, brine, dried (MgSO.sub.4) and evaporated. The
 residue was triturated with diethyl ether to give
 1-(4-pyridyl),4-(5-cyano,2-pyridinyloxy)piperidine (50 mg) as a pale cream
 crystalline solid; microanalysis, found: C, 66.4; H, 5.6; N, 19.0%;
 C.sub.16 H.sub.16 N.sub.3 O0.5.H.sub.2 O requires: C, 66.4; H, 5.9; N,
 19.4%; NMR: (CDCl.sub.3) 1.90 (m,2H), 2.10 (m,2H), 3.32 (m,2H), 3.67
 (m,2H), 5.37 (m,1H), 6.68 (d,2H), 6.80 (d,1H), 7.78 (dd,1H), 8.28 (d,2H),
 8.47 (d,1H): MS: m/z 281 (MH).sup.+.
 The 4-(5-cyano,2-pyridinoxy)piperidine starting material was prepared as
 follows:
 To a solution of 1-(t-butyloxycarbonyl)-4-piperidinol (600 mg) in dry DMF
 (20 mL) was added sodium hydride (0.24 g, 50% dispersion in oil) and
 stirred under argon for 1 hour. 2-Chloro,5-cyanopyridine (0.44 g) was
 added and the mixture was heated at 70.degree. C. overnight. The reaction
 was quenched by pouring into water and extracted with diethyl ether. The
 extract was washed with water, brine, dried (MgSO.sub.4) and evaporated.
 The residue was then chromatographed on silica gel eluting with a mixture
 of dichloromethane (25%) in isohexane increasing to dichloromethane. The
 residue was recrystallised from isohexane to afford
 1-(t-butyloxycarbonyl),4-(5-cyano,2-pyridyloxy)piperidine (400 mg) as a
 colourless crystalline solid; NMR: (CDCl.sub.3) 1.46 (s,9H), 164-182
 (m,2H), 1.92-2.09 (m,2H), 3.21-3.36 (m,2H), 3.70-3.84 (m,2H), 5.28 (m,1H),
 6.78 (d,1H), 7.77 (dd,1H): MS: m/z 304 (MH).sup.+.
 To 1-(t-butyloxycarbonyl),4-(5-cyano,2-pyridinyloxy)piperidine (1.6 g) in
 dichloromethane (20 mL) was added trifluoroacetic acid (1.2 mL) and the
 reaction stirred at room temperature for 1 hour. The reaction was quenched
 by evaporation of trifluoroacetic acid dissolving the residue in water,
 basifying with sodium hydrogen carbonate and extracting the
 dichloromethane. The organic layer was then washed with water, brine,
 dried (MgSO.sub.4) and evaporated to yield
 4-(5-cyano,2-pyridyloxy)piperidine as a white crystalline solid (337 mg),
 MS: m/z 279 (MH.sup.+).
 EXAMPLE 57
 Using the procedure described in Example 1, the following compounds were
 prepared.

##STR119##
 Com-
 pound X Ring R m.p. .degree. C. Method
 1 CH.sub.2 phenyl 4-cyanoQ 95-98 B
 2 CH.sub.2 2-furanyl H OIL* A
 3 CH.sub.2 4-pyrimidinyl 2,6-dichloro &gt;300 B
 4 CH.sub.2 4-thiazolyl 2-(4)-chloro- 151-152 B
 phenyl
 5 CH.sub.2 4-oxazolyl 2-(4)-bromo- 192-193 B
 phenyl
 6 CH.sub.2 phenyl 4-methane- 200-202 B
 sulphone
 7 -- phenyl 3-nitro 145-147 C
 8 -- phenyl 3-methyl-4-nitro 158-160 C
 9 -- phenyl 3-trifluoro- 168-170 C
 methyl-4-nitro
 Method A
 490 mg 4-pyridylpiperazine, 498 mg sodium acetate, and 0.38 ml
 2-furaldehyde was stirred in 12 ml methanol containing 3 g 3 A.sup.0
 molecular sieve powder. 377 mg sodium cyanoborohydride was added and
 stirring continued overnight. The sieve was filtered and the filtrate
 concentrated and stirred with 25 ml 2 M sodium hydroxide solution.
 Extraction with dichloromethane and drying over MgSO.sub.4, followed by
 evaporation and chromatography (10 g Bond Elute, CH.sub.2 Cl.sub.2 then 1%
 methanol/CH.sub.2 Cl.sub.2 /1%NH.sub.4 OH) gave compound 2 (214 mg) as a
 colourless oil.
 Method B
 490 mg 4-pyridylpiperazine and 614 mg 4-chloromethylphenyl methyl sulphone
 in 1.8 ml isopropanol and 0.2 ml water with 1.4 ml triethylamine was
 refluxed for 1.25 hours, then stirred overnight at ambient temperature.
 The solvent was evaporated, the residue dissolved in dichloromethane and
 washed with 5% w/v sodium hydroxide solution followed by water and brine,
 then dried over MgSO.sub.4. Evaporated then chromatographed (as in Method
 A above) to give compound 6 (640 mg). Compounds 1, 3, 4 and 5 were
 prepared in an analogous manner.
 Method C
 980 mg pyridylpiperazine and 1.0 g 2-methyl-4-fluoronitrobenzene with 1.8 g
 anhydrous potassium carbonate in 10 ml DMSO was heated at 125.degree. C.
 overnight. The mixture was diluted with dichloromethane and washed with
 water and brine. Dried evaporated and chromatographed as above in Method A
 to give compound 8 (903 mg). Compounds 7 and 9 were prepared in a similar
 manner.
 EXAMPLE 143
 Illustrative pharmaceutical dosage forms suitable for presenting the
 compounds of the invention for therapeutic or prophylactic use include the
 following tablet and capsule formulations, which may be obtained by
 conventional procedures well known in the art of pharmacy and are suitable
 for therapeutic or prophylactic use in humans: