WO2004017966A1

WO2004017966A1 - Five-membered heterocyclic compounds in the treatment of chronic and acute pain

Info

Publication number: WO2004017966A1
Application number: PCT/GB2003/003674
Authority: WO
Inventors: Lars Jacob Stray Knutsen; Christopher John Hobbs; Fleur Radford; Andrea Fiumana; Christopher Geoffrey Earnshaw; Sarah Louise Mellor; Nichola Jane Smith
Original assignee: Ionix Pharmaceuticals Limited
Priority date: 2002-08-23
Filing date: 2003-08-22
Publication date: 2004-03-04
Also published as: WO2004017965A1; GB0406869D0; TW200412948A; GB2396613A; AU2003255843A1; AU2003255844A1

Abstract

Compounds of formula (I) are found to antagonise N-type calcium channels F(I) wherein R1, R2 and R4 are organic residues, Y is a linker and R3 is aryl, heteroaryl, carbocyclyl a heterocyclyl are N-type calcium channel antagonists and are therefore useful in the treatment of both chronic and acute pain.

Description

FIVE-MEMBERED HETEROCYCLIC COMPOUNDS IN THE TREATMENT OF CHRONIC AND ACUTE PAIN

The present invention relates to specific thiazolidinone, oxazolidinone and imidazolone derivatives, which act as inhibitors of N-type calcium channels.

Mammalian ion channels are becoming increasingly well characterised, and this is especially true of calcium channels. Voltage-gated calcium channels are critical components for the functioning of the nervous system, and they signal a painful event. To date, 7 subtypes of these channels have been identified (L, N, T, O, P, Q and R), each expressed in various combinations by neuronal and non-neuronal cells (Perez-Reyes, E.; Schneider, T. Drug Dev. Res., 1994, 33, 295-318). These channels are now recognised as valid targets for pain therapeutics and as neuroprotective agents (Cox, B.; Denyer, J.C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250).

WO 99/62891 discloses specific thiazolidinone and metathiazanone compounds as potassium channel inhibitors. The potassium channel inhibitors are contemplated for use in treating cardiac arrhythmias, cell proliferative disorders, disorders of the auditory system, central nervous system mediated motor dysfunction and disorders of pulmonary, vascular and visceral smooth muscle contractility.

It has now surprisingly been found that particular compounds of the general formula (I) set out below act as inhibitors of N-type calcium channels. Accordingly, the present invention provides the use, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels, of a compound of formula (I), or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

wherein: Z is -S-, -S(O)-, -SO₂-, -O- or -NR- wherein R is hydrogen, Cι-C₆ alkyl or -CO-(Cι-C₆ alkyl);

R¹ is hydrogen or C|-C₆ alkyl; R² is hydrogen, fluorine pr Cι-C₆ alkyl; Y is -(CR^y ₂)_r„-X₄-(CR^y ₂)n-, -(CR^y ₂)m-A-(CR^y ₂)_m- or -(CR^y ₂)m-A-(CR^y ₂)_p-X3-(CR^y ₂)_m, wherein: p, m and n are each independently an integer of 0 to 4; A is aryl, heteroaryl, carbocyclyl or heterocyclyl; X₃ is -O-, -S-, -NR'-, -S(O)-, -SO₂-, -O-CO-, -S-CO-, -NR'-CO, -CO-O-, -CO-S- or -CO-NR' wherein R' is hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl;

X₄ is -O-, -S-, -NR'-, -S(O)- or -SO₂- wherein R' is hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl; each R^y is the same or different and is hydrogen, Cι-C₆ alkyl, C₂-C₆ alkenyl, C₂- C₆ alkynyl, aryl or heteroaryl;

R³ is aryl, heteroaryl, heterocyclyl or carbocyclyl; and R__t is -Cι-Xι-Arι or -C₂-X₂-C₃, wherein:

Ci is a direct bond, a Cι-C₆ alkylene group, a C₂-C₆ alkenylene group or a C₂-C₆ alkynylene group; - Xi is a direct bond when Ci is a direct bond and, when d is a Cι-C₆ alkylene group, C₂-C₆ alkenylene group or C₂-C₆ alkynylene group, represents a direct bond or -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -O-CO-NR'- or -NR'-CO-O-, wherein each R' is the same or different and represents hydrogen, phenyl, Cι-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl and each R" is the same or different and represents a Cι-C₆ alkylene group, a C₂-C₆ alkenylene group or a C₂-C₆ alkynylene group; Ari is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-R^a-, heterocyclyl-R^a-, aryl-R^a- or carbocyclyl-R^a-, wherein R^a is a Cι-C₆ alkylene group, a C₂-C₆ alkenylene group or a C₂-C₆ alkynylene group; C₂ is a Cι-C₆ alkylene group, a C₂-C₆ alkenylene group or a C₂-C₆ alkynylene group;

X₂ is a direct bond or -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-, -CO-S-, -CO-O-,

-CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -NR'-CO-O- or -O-CO-NR'-, wherein each R' is the same or different and represents hydrogen, phenyl, Cι-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl and each R" is the same or different and represents a Cι-C₆ alkylene group a C₂-C₆ alkenylene group or a C₂-C₆ alkynylene group; and - C₃ is a Cι-C₆ alkyl group, a C₂-C₆ alkenyl group or a C -C₆ alkynyl group.

As used herein, a Cι-C₆ alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a Cι-C₄ alkyl group or moiety. Examples of Cι-C₄ alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. An alkyl group or moiety may be unsubstituted or substituted at any position.

Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents include aryl, for example phenyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(Cι-C₆ alkyl), -N(C.-C₆ alkyl)₂, halogen, cyano, nitro, -NHCO-(C_rC₆ alkyl), -CO-NH-(Cι-C₆ alkyl), -CO-O-(d-C₆ alkyl) and -O-CO-(C C₆ alkyl). Preferred substituents are hydroxy, halogen, Cι-C₂ alkoxy, -NH₂, -NH(Cι-C₂ alkyl) and

-N(Cι-C₂ alkyl)₂, in particular fluorine and hydroxy. The substituents on an alkyl group are typically themselves unsubstituted.

As used herein, a Cι-C₆ alkylene group is a linear or branched CpC₆ alkylene group. Typically, it is a Cι-C alkylene group, for example a methylene, ethylene, n- propylene, i-propylene or n-butylene group.

An alkylene group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents. For example, it may be unsubstituted. Suitable substituents include aryl, for example phenyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(C_.-C₆ alkyl), -N(C_rC₆ alkyl)₂, halogen, cyano, nitro, -NHCO- (C.-Cβ alkyl), -CO-NH-(C,-C₆ alkyl), -CO-O-(Cι-C₆ alkyl) and -O-CO-(Cι-C₆ alkyl). Preferred substituents are hydroxy, halogen, Cι-C₂ alkoxy, -NH₂, -NH(Cι-C₂ alkyl) and - N(Cι-C₂ alkyl)₂, in particular fluorine and hydroxy, most particularly fluorine. The substituents on an alkylene group are typically themselves unsubstituted.

As used herein, a C₂-C₆ alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C₂-C₄ alkenyl group or moiety. Examples of C₂-C alkenyl groups are ethenyl, n-propenyl and n-butenyl. Typically an alkenyl group has only one double bond. This double bond is typically located at the α-position of the alkenyl group.

An alkenyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. For example, it may be unsubstituted. Suitable substituents include aryl, for example phenyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(Cι-C₆ alkyl), -N(Cι-C₆ alkyl)₂, halogen, cyano, nitro, -NHCO-(Cι-C₆ alkyl), -CO-NH-(C,-C₆ alkyl), -CO-O-(Cι-C₆ alkyl) and -O-CO-(Cι-C₆ alkyl). Preferred substituents are hydroxy, halogen, Cι-C₂ alkoxy, -NH₂, -NH(Cι-C₂ alkyl) and -N(Cι-C₂ alkyl)₂, in particular fluorine and hydroxy, most particularly fluorine. The substituents on an alkenyl group are typically themselves unsubstituted.

As used herein, a C₂-C₆ alkenylene group is a linear or branched C₂-C₆ alkenylene group. Typically, it is a C₂-C₄ alkenylene group, for example an ethenylene, n- propenylene or n-butenylene group. Typically an alkenylene group has only one double bond. This double bond is typically located at the α-position of the alkenylene group. An alkenylene group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents. Preferably it is unsubstituted. Suitable substituents include aryl, for example phenyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(Cι-C₆ alkyl), -N(C C₆ alkyl)₂, halogen, cyano, nitro, -NHCO-(Cι-C₆ alkyl), -CO-NH-(C,-C₆ alkyl), -CO-O-(C,-C₆ alkyl) and -O-CO-(C_t-C₆ alkyl). Preferred substituents are hydroxy, halogen, Cι-C₂ alkoxy, -NH₂, -NH(Cι-C₂ alkyl) and -N(Cι-C₂ alkyl)₂, in particular fluorine and hydroxy, most particularly fluorine. The substituents on an alkenylene group are typically themselves unsubstituted.

As used herein, a C₂-C₆ alkynyl group or moiety is a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, such as a C₂-C₄ alkynyl group or moiety. Examples of C₂-C alkynyl groups are ethynyl, propynyl and n-butynyl. > Typically an alkynyl group has only one triple bond. This triple bond is typically located at the α-position of the alkynyl group.

An alkynyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Preferably it is unsubstituted. Suitable substituents include aryl, for example phenyl, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(Cι-C₆ alkyl), -N(Cι-C₆ alkyl)₂, halogen, cyano, nitro, -NHCO-(C,-C₆ alkyl), -CO-NH-(C,-C₆ alkyl), -CO-O-(C,-C₆ alkyl) and -O-CO-(Cι-d alkyl). Preferred substituents are hydroxy, halogen, C1-C2 alkoxy, -NH₂, -NH(Cι-C₂ alkyl) and -N(Cι-C₂ alkyl)₂, in particular fluorine and hydroxy, most particularly fluorine. The substituents on an alkynyl group are typically themselves unsubstituted.

As used herein, a C₂-C alkynylene group is a linear or branched C₂-C₆ alkynylene group. Typically, it is a C₂-C alkynylene group, for example an ethynylene, propynylene or n-butynylene group. Typically an alkynylene group has only one triple bond. This triple bond is typically located at the α-position of the alkynylene group. An alkynylene group may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents. Preferably it is unsubstituted. Suitable substituents include aryl, for example phenyl, hydroxy, d-d alkoxy, Ci-d alkylthio, -NH₂, -NH(Cι-C₆ alkyl), -N(d-C₆ alkyl)₂, halogen, cyano, nitro, -NHCO-(Cι- C₆ alkyl), -CO-NH-(Ct-C₆ alkyl), -CO-O^d-d alkyl) and -O-CO-(d-C₆ alkyl).

Preferred substituents are hydroxy, halogen, C1-C2 alkoxy, -NH2, -NH(Cι-d alkyl) and -N(Cι-C₂ alkyl)₂, in particular fluorine and hydroxy, most particularly fluorine. The substituents on an alkynylene group are typically themselves unsubstituted.

As used herein, an aryl group is typically a -Cio aryl group such as phenyl or naphthyl. Phenyl is preferred. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2, 3 or 4 substituents. Suitable substituents include halogen, Ci- alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, C₃-C₆ carbocyclyl, d-d carbocyclyloxy, d-C₆ carbocyclylthio, d-d alkenyl, d-d alkenyloxy, d-d alkenylthio, C₂-C₆ alknynyl, C₂-d alkynyloxy, d-d alkynylthio, hydroxy, -NH₂, -NH(Cι-C₆ alkyl), -N(C,-C₆ alkyl)₂, -Si(C,-C₄ alkyl)₃, cyano, nitro, -NH-CO-(d-C₆ alkyl), -CO-NH-(Cι-C₆ alkyl), -CO-O-(C,-C₆ alkyl) and -O-CO-(C,-C₆ alkyl). Examples of suitable substituents include halogen, Cι-C₆ alkyl, Cι-C alkoxy, Ci-d alkylthio, C₃- d carbocyclyl, d-d carbocyclyloxy, C₃-d carbocyclylthio, C₂-d alkenyl, C₂-C₆ alkenyloxy, C₂-C₆ alkenylthio, C₂-C₆ alknynyl, C₂-C₆ alkynyloxy, C₂-C₆ alkynylthio, hydroxy, -NH₂, -NH(C_1:C₆ alkyl), -N(d-d alkyl)₂, cyano, nitro, -NH-CO-(C,-C₆ alkyl), -CO-NH-(Cι-C₆ alkyl), -CO-O-(d-C₆ alkyl) and -O-CO-(d-C₆ alkyl).

Preferred substituents include Cι-C₄ alkyl, Cι-C alkoxy, Cι-C₄ alkylthio, C₅-C₆ carbocyclyloxy, C₂-C₄ alkenyl, C₂-C₄ alkenyloxy, halogen (for example fluorine), hydroxy, -NH₂, -NH(d-C₂ alkyl), -N(C,-C₂alkyl)₂, -NH-CO-(Cι-C₂ alkyl), cyano and -Si(Cι-C₄ alkyl)₃. Examples of preferred substituents include Cι-C₄ alkyl, Cι-C₄ alkoxy, Cι-C alkylthio, d-d carbocyclyloxy, d-d alkenyloxy, halogen (for example fluorine), hydroxy, -NH₂, -NH(C,-C₂ alkyl), -N(Cι-C₂alkyl)₂ and -NH-CO-(Cι-d alkyl).

Substituents on an aryl group are typically unsubstituted or substituted by 1, 2 or 3 further substituents selected from halogen, hydroxy, Ci-d alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(C,-d alkyl), -N(Cι-C₆ alkyl)₂, -NH-CO-(C C₆ alkyl), -CO-NH-(Cι-C₆ alkyl), -CO-O-(Cι-C₆ alkyl) and -O-CO-(Cι-d alkyl). These further substituents are typically themselves unsubstituted. Preferably, the Ci-d alkyl moieties present in the further substituents are C₁-C₂ alkyl moieties. More preferably, substituents on an aryl group are .unsubstituted or substituted with 1, 2 or 3 further substituents which are halo or hydroxy substituents, most preferably halo substituents. As used herein, references to an aryl group include fused ring systems in which an aryl group is fused to a heterocyclyl or heteroaryl group, typically a monocyclic heterocyclyl or heteroaryl group. Examples of such fused ring systems are a phenyl group fused to a pyridine ring to form a quinoline or isoquinoline group and a phenyl ring fused to a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O and S; for example a phenyl ring fused to a 1 ,4-dioxanyl ring to form a 1 ,4- benzodioxanyl group, a phenyl ring fused to a 1,3-dioxolanyl ring to form a 1,3- benzodioxolyl group, and a phenyl ring fused to a tetrahydrofuranyl ring to form a 2,3- dihydrobenzofuran group.

As used herein, a heteroaryl group is typically a 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N. Examples include pyridyl, pyraziny., pyrimidinyl, pyridazinyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl and pyrazolyl groups. Pyridyl, furanyl, thienyl, imidazolyl and pyrrolyl groups are preferred.

A heteroaryl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1 , 2 or 3 substituents. Preferably, it is unsubstituted. Suitable substituents include halogen, Cι-C alkyl, Ci- alkoxy, Ci-d alkylthio, -d carbocyclyl, C₃-d carbocyclyloxy, C₃-d carbocyclylthio, d-d alkenyl, C₂-d alkenyloxy, Cι-C₆ alkenylthio, d-d alknynyl, d-d alkynyloxy, d-d alkynylthio, hydroxy, -NH₂, - NH(d-d alkyl), -N(C,-C₆ alkyl)₂, cyano, nitro, -NH-CO-TC.-d alkyl), -CO-NH-(d-d alkyl), -CO-O-(Ct-C6 alkyl) and -O-CO-(Cι-C₆ alkyl). Preferred substituents include Ci- C₄ alkyl, Cι-C₄ alkoxy, Cι-C₄ alkylthio, d-d carbocyclyloxy, C₂-C₄ alkenyloxy, halogen (for example fluorine), hydroxy, -NH₂, -NH(Cι-C₂ alkyl), -N(Cι-C₂ alkyl)₂ and - NH-CO-(Cι-C₂ alkyl). Particularly preferred substituents include Cι-C₄ alkyl groups and halogen atoms. Substituents on a heteroaryl group are typically unsubstituted or substituted by 1 ,

2 or 3 further substituents selected from halogen, hydroxy, Ci-d alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(C,-d alkyl), -N(C,-C₆ alkyl)₂, -NH-CO-(d-d alkyl), -CO-NH-(C,-C₆ alkyl), -CO-O-(Cι-C₆ alkyl) and -O-CO-(Cι-C₆ alkyl). These further substituents are typically themselves unsubstituted. Preferably, the Cι-C₆ alkyl moieties present in the further substituents are Cι-C₂ alkyl moieties. More preferably, substituents on a heteroaryl group are unsubstituted or substituted with 1, 2 or- 3 further substituents which are halo substituents. Most preferably, substituents on a heteroaryl group are unsubstituted.

As used herein, references to a heteroaryl group include fused ring systems in which a heteroaryl group is fused to a said aryl group, to a further heteroaryl group or to a heterocyclyl group, typically to a monocyclic aryl, further heteroaryl or heterocyclyl group. Examples of such fused heteroaryl groups are heteroaryl groups fused to a phenyl ring including benzimidazolyl, benzofuranyl, quinolinyl and isoquinolinyl groups.

As used herein, a carbocyclyl group is a non-aromatic saturated or unsaturated hydrocarbon ring, typically having from 3 to 6 carbon atoms. For example, it may be a saturated hydrocarbon ring (i.e. a cycloalkyl group) having from 3 to 6 carbon atorns. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, it may be a hydrocarbon ring having one or two, preferably one, double bond. An example is cyclohexenyl. A preferred carbocyclyl group is cyclopentyl.

A carbocyclyl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2, 3 or 4 substituents. Suitable substituents include halogen, Ci- d alkyl, Ci- alkoxy, Ci-d alkylthio, d-C₆ carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-d carbocyclylthio, C₂-C₆ alkenyl, C₂-d alkenyloxy, Ci-d alkenylthio, C₂-d alknynyl, C₂- C₆ alkynyloxy, C₂-C₆ alkynylthio, hydroxy, Cι-C₄alkylenedioxy, -NH₂, -NH(Cι-C₆ alkyl), -N(C,-C₆ alkyl)₂, cyano, nitro, -NH-CO-(Cι-C₆ alkyl), -CO-NH-(C,-C₆ alkyl), - CO-O-(Cι-d alkyl) and -O-CO-(Cι-d alkyl). Preferred substituents include Cι-C₄ alkyl, Cι-C₄ alkoxy, Cι-C₄ alkylthio, d-d carbocyclyloxy, C₂-C alkenyloxy, halogen (for example fluorine), hydroxy, -NH₂, -NH(Cι-C₂ alkyl), -N(d-C₂ alkyl)₂ and -NH-CO-(C,- C₂ alkyl). Most preferably, a carbocyclyl group is unsubstituted.

Substituents on an carbocyclyl group are typically unsubstituted or substituted by 1 , 2 or 3 further substituents selected from halogen, hydroxy, Cι-C₆ alkoxy, Cι-C₆ alkylthio, -NH₂, -NH(Cι-C₆ alkyl), -N(C d alkyl)₂, -NH-CO-(C,-C₆ alkyl), -CO-NH- (Cι-C₆ alkyl), -CO-O-(Cι-C₆ alkyl) and -O-CO-(C C₆ alkyl). These further substituents are typically themselves unsubstituted. Preferably, the Cι-C₆ alkyl moieties present in the further substituents are C1-C2 alkyl moieties. More preferably, substituents on an carbocyclyl group are unsubstituted.

As used herein, a heterocyclyl group is typically a non-aromatic, saturated or unsaturated C₅-C₁₀ carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocyclyl groups are preferred. Examples of suitable heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, 1,4 dioxanyl and 1,3 dioxolanyl. Tetrahydrofuranyl, pyrrolidinyl, 1,4-dioxanyl and 1,3- dioxolanyl are preferred, in particular tetrahydrofuranyl, 1,4-dioxanyl and 1,3-dioxolanyl, most particularly 1,4-dioxanyl.

A heterocyclyl group may be unsubstituted or substituted at any position. Typically, it carries 0, 1, 2, 3 or 4 substituents. Suitable substituents include halogen, Ci- C₆ alkyl, Ci-d alkoxy, Cι-C₆ alkylthio, C₃-C₆ carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-C6 carbocyclylthio, C₂-d alkenyl, C₂-C₆ alkenyloxy, Ci-d alkenylthio, C₂-d alknynyl, C₂-C₆ alkynyloxy, C₂-C₆ alkynylthio, hydroxy, Cι-C₄alkylenedioxy, -NH₂, -NH(C,-C₆ alkyl), -N(Cf-C₆ alkyl)₂, cyano, nitro, -NH-CO-(d-C₆ alkyl), -CO-NH-(d-C₆ alkyl), -CO-O-(Cι-C6 alkyl) and -O-CO-(Cι-C₆ alkyl). Preferred substituents include Cι-C₄ alkyl, Cι-C alkoxy, Cι-C₄ alkylthio, d-C₆ carbocyclyloxy, C₂-C₄ alkenyloxy, halogen (for example fluorine), hydroxy, -NH₂, -NH(Cι-C₂ alkyl), -N(Cι-C₂alkyl)₂ and -NH-CO-(Cι-C₂ alkyl). Most preferably, a heterocyclyl group is unsubstituted.

Substituents on an heterocyclyl group are typically unsubstituted or substituted by 1, 2 or 3 further substituents selected from halogen, hydroxy, Ci-d alkoxy, Ci-d alkylthio, -NH₂, -NH(C,-C₆ alkyl), -N(Cι-C₆ alkyl)₂, -NH-CO-(C,-C₆ alkyl), -CO-NH- (Ci-d alkyl), -CO-O-(Cι-C₆ alkyl) and -O-CO-(Cι-C₆ alkyl). These further substituents are typically themselves unsubstituted. Preferably, the Ci-d alkyl moieties present in the further substituents are C₁-C₂ alkyl moieties. More preferably, substituents on a heterocyclyl group are unsubstituted.

As used herein, references to a heterocyclyl group include fused ring systems in which a heterocyclyl group is fused to a said aryl group, a said heteroaryl group or to a further heterocyclyl group, typically to a monocyclic aryl, heteroaryl or further heterocyclyl group. Preferred such fused ring systems are heterocyclyl groups fused to a phenyl ring. An example of such a fused heterocyclyl group is 1,4-benzodioxanyl.

As used herein a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine or fluorine. As used herein, an alkoxy, alkenyloxy, alkynyloxy or carbocyclyloxy group is typically a said alkyl, alkenyl, alkynyl or carbocyclyl group respectively, which is attached to an oxygen atom. An alkylthio, alkenylthio, alkynylthio or carbocyclylthio group is typically a said alkyl, alkenyl, alkynyl or carbocyclyl group respectively, which is attached to a thio group.

When Z is -NR-, R is typically -COCH₃ or -CO-CH₂-CH₃i . Typically, Z is -S-, -SO-, or -O- for example Z may be -S- or -O-. Preferably, Z is -S-.

Typically, Ri is hydrogen or an unsubstituted Cι-C₄ alkyl group. Preferably, Ri is hydrogen or -CH₃. More preferably, Ri is hydrogen. Typically, R₂ is hydrogen or an unsubstituted Cι-C₆ alkyl group. Preferably, R₂ is hydrogen or an unsubstituted Cι-C₄ alkyl group. More preferably, R₂ is hydrogen.

Typically, each R^y is the same or different and is hydrogen, Ci-d alkyl, aryl or heteroaryl. Preferably, each R^y is the same or different and is hydrogen, a Cι-C alkyl or phenyl group. Preferably, each R^y is the same or different and is hydrogen, -CH₃,

-CH₂-CH₃ or an unsubstituted phenyl group. Typically, when two or more R^y groups are present, no more than 2 of, preferably no more than 1 of, said R^y groups is aryl or heteroaryl.

Typically, each R^y is unsubstituted or substituted by 1, 2 or 3 substituents selected from C1-C4 alkyl, Ci- alkoxy, halogen, hydroxy, NH₂, NH(Cι-C₂ alkyl) or N(Cι-d alkyl)₂. Preferably, the substituents on R^y are selected from Cι-C₂ alkyl, C1-C₂ alkoxy, halogen and hydroxy. Typically, the substituents on R^y are themselves unsubstituted. Preferably, R^y is unsubstituted.

Typically A is aryl, for example phenyl, or heteroaryl, for example pyridyl, furanyl, thienyl, imidazolyl or pyrrolyl, in particular pyridyl, thienyl or pyrrolyl.

Preferably, A is phenyl, pyridyl, thienyl or pyrrolyl, for example A is phenyl, pyridyl or pyrrolyl. Preferably, A is heteroaryl, in particular thienyl or pyridyl, most preferably pyridyl. The moiety A is typically unsubstituted or substituted with 1, 2 or 3 substituents. Preferably, the moiety A is unsubstituted. The substituents on A are typically selected from C₁-C4 alkyl, Cι-C₄ alkoxy, halogen, hydroxy, NH₂, NH(Cι-C₂ alkyl) or N(C_.-C₂ alkyl)₂. Preferably, the substituents on A are selected from Cι-C₂ alkyl, Cι-C₂ alkoxy, halogen and hydroxy. Typically, the substituents on A are themselves unsubstituted.

In the group X₃, R' is typically hydrogen or an unsubstituted Ci-d alkyl group, preferably hydrogen or -CH₃, most preferably hydrogen. Typically, X₃ is -O-, -S-, -SO-, -SO₂-, -O-CO-, -CO-O-, -NH-CO- or -CO-NH-. Preferably X₃ is -O-, -S-, -SO-, -SO₂- or -NH-CO-, more preferably -O-, -SO₂- or -NH-CO-. Typically, p is 0 or 1, preferably 0. Typically, m is 0 or 1. Typically, n is 1 or 2, preferably 1. , 1

In the group X4, R' is typically hydrogen or an unsubstituted Ci-d alkyl group, preferably hydrogen or -CH₃, most preferably hydrogen. Typically, X4 is -O-, -S- or -NR'- wherein R' is as defined above. Preferably X₄ is -O- or -S-. More preferably X is -O-. Y is preferably a group of formula -(CH₂)_mO(CH₂)_π-, -A- or -A-X₃-(CH₂)_m-, wherein R^y, A, X₃, m and n are as defined above. More preferably, Y is a group of formula A.

R₃ is typically aryl, heteroaryl or carbocyclyl. Preferably, when R³ is aryl it is a phenyl group or a phenyl group fused to a heteroaryl or heterocyclyl group. Examples of such fused ring systems are phenyl groups fused to a 5- or 6-membered heterocyclyl ring having 1 or 2 heteroatoms selected from O, S and N. Preferred examples of such fused ring systems are 1,3-benzodioxolyl, 2,3-dihydrobenzofuran and 1,4-benzodioxanyl. Preferably, when R³ is aryl it is phenyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuran or 1,4- benzodioxanyl, most preferably phenyl or 1,3-benzodioxolyl. When R³ is heteroaryl, it is preferably pyridyl, thienyl, furyl, pyrrolyl, pyridinyl or a heteroaryl ring fused to a phenyl ring, for example quinolinyl, isoquinolinyl or benzofuranyl. For example, when R³ is heteroaryl it may be thienyl, furyl, pyrrolyl, pyridinyl or a heteroaryl ring fused to a phenyl ring, for example quinolinyl, isoquinolinyl or benzofuranyl. More preferably, when R³ is heteroaryl, it is pyridyl, thienyl, furyl, quinolinyl or benzofuranyl, for example thienyl, furyl, quinolinyl or benzofuranyl. Most preferably, when R³ is heteroaryl it is pyridyl or thienyl. When R³ is carbocyclyl it is preferably cyclopentyl or cyclohexyl, most preferably cyclopentyl.

More preferably, R³ is phenyl, pyridyl, thienyl, furyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl or 2,3-dihydrobenzofuran. For example, R³ may be phenyl, thienyl, furyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4- benzodioxanyl, 1,3-benzodioxolyl or 2,3-dihydrobenzofuran. Most preferably R³ is phenyl, 1,3-benzodioxolyl, pyridyl or thienyl.

Typically, R³ is other than a furanyl group. Typically, R³ is unsubstituted or substituted by 1, 2 or 3 substituents. The substituents are typically chosen from halogen, for example fluorine, chlorine or bromine, hydroxy, cyano, Ci-d alkyl, Ci-d alkoxy, Ci-d alkylthio, d-d alkenyl, C₂-C₆ alkenyloxy, C₂-d alkenylthio, C₂-C₆ alknynyl, C₂-C₆ alkynyloxy, C₂-d alkynylthio, C₃- d carbocyclyl, C₃-d carbocyclyloxy, d-d carbocyclylthio, -NH-CO-(Cι-C₆ alkyl), - CO-NH-(Cι-d alkyl), -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group and -S^ ^, wherein each R^;// is independently a C1-C4 alkyl group. For example, the substituents may be chosen from halogen, for example fluorine, chlorine or bromine, hydroxy, Cι-C₆ alkyl, Ci-d alkoxy, Ci-d alkylthio, C₂-C₆ alkenyl, C₂-d alkenyloxy, C₂-C₆ alkenylthio, C₂-C₆ alknynyl, C₂-C₆ alkynyloxy, d-d alkynylthio, C₃- C₆ carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-C₆ carbocyclylthio, -NH-CO-(Cι-C₆ alkyl), - CO-NH-(Cι-C₆ alkyl) and -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group.

Preferred substituents on R are halogen, hydroxy, cyano, C₁-C₄ alkyl, Cι-C alkoxy, Cι-C₄ alkylthio, C₂-C₄ alkenyl, -NR'R" wherein R' and R" are each independently hydrogen or a Cι-C₄ alkyl group, and -Si(R^/7)₃ wherein each R⁷ is independently a C₁-C₄ alkyl group. Examples of preferred substituents on R³ are halogen, Cι-C alkyl, Cι-C₄ alkoxy, Cι-C₄ alkylthio, C₂-C₄ alkenyl, C₂-C₄ alkenyloxy, C₃-C₆ carbocycyl, d-d carbocyclyloxy, -NH-CO-(Cι-C₂ alkyl) and -N(Cι-C₂ alkyl)2. More preferred substituents on R³ are halogen, cyano, Cι-C₄ alkyl, C1-C4 alkoxy, Cι-C alkylthio, d-d alkenyl, C₂-C₄ alkenyloxy, C₃-d carbocyclyloxy, -NH-CO-Me, -N(CH₃)₂ and -Si(R^//)₃ wherein each R^/7 is independently a C1-C4 alkyl group. Examples of more preferred substituents on R³ are halogen, Cι-C₄ alkyl, Cι-C alkoxy, Cι-C₄ alkylthio, C₂-C alkenyloxy, C₃-C₆ carbocyclyloxy, -NH-CO-Me and -N(CH₃)₂.

Typically, the substituents on R³ are themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen, in particular fluorine, and hydroxy.

Typically, Ci is a direct bond or a Cι-C₆ alkylene group, preferably a C|-C₄ alkylene group. More preferably, Ci is a direct bond or an unsubstituted Cι-C₄ alkylene group, for example an unsubstituted C1-C4 alkylene group. Most preferably, Ci is a direct bond, -CH₂-, -(CH₂)₂-, -(CH₂)₃- or -(CH₂)₄-. For example C, is -CH₂-, -(CH₂)₂- or -(CH₂)₃-.

For the avoidance of doubt, the orientation of the group^" Xi is such that the left hand side of the depicted moiety is attached to Ci and the right hand side of the depicted moiety is attached to Aη. Thus, for example, when Xi is -S-CO-, the moiety -Cι-Xι-Arι is -Cι-S-CO-Arι. Typically, each R' in the moiety Xi is the same or different and is hydrogen, or an unsubstituted phenyl or Ci-d alkyl group, preferably hydrogen, -CH₃ or -CH₂-CH₃. More preferably, each R' in the moiety X) is hydrogen. Typically, each R" in the moiety Xi is an unsubstituted Ci-d alkylene group, preferably -CH₂- or -CH₂-CH₂-. More preferably, each R" is -CH₂-.

Typically, X, is a: direct bond or is -O-, -S-, -NR'-, -S-CO-, -O-CO-, -CO-O-, -CO-S-, -NR'-CO- or -CO-NR'-, wherein R' is as defined above. Preferably, Xi is a direct bond or is -O-, -S-, -S-CO-, -O-CO- or -NH-CO-. More preferably, Xi is a direct bond or is -O-, -S-, -S-CO- or -O-CO-. Most preferably, Xi, is a direct bond or is -O- or -S-.

Typically Ari is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-(Ci-C₆ alkyl)-, heterocyclyl-(Cι-C₆ alkyl)-, aryl-(Cι-d alkyl)- or carbocyclyl-(Cι-d alkyl)-. When Ari is a heteroaryl-(Cι-C₆ alkyl)-, aryl-(d-C₆ alkyl)-, heterocyclyl-(Cι-C₆ alkyl)- or carbocyclyl-(Cι-d alkyl)- group, the alkyl moiety is typically an unsubstituted methylene or ethylene moiety. Preferably, Ari is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-(Cι-C₂ alkyl)- or aryl-(Cι-C₂ alkyl)-. More preferably Ar is heteroaryl, heterocyclyl, aryl, carbocyclyl or heteroaryl-(Cι-C₂ alkyl)-, for example heteroaryl, heterocyclyl, aryl or heteroaryl-(Cι-C₂ alkyl). When Ari is heteroaryl, it is preferably a pyridyl, thienyl or benzimidazolyl group, most preferably a pyridyl group. When Ari is heteroaryl-(Cι-C₂ alkyl)-, it is preferably a thienyl-methyl-, pyridyl-methyl- or furanyl-methyl- group, more preferably a furanyl-methyl- group. When Ari is heterocyclyl, it is preferably a morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl group or a 5- or 6-membered heterocyclyl group fused to a phenyl ring, for example a 1 ,4- benzodioxanyl group or a 1,3-benzodioxolyl group. More preferably, when Ari is heterocyclyl it is a pyrrolidinyl group. Alternatively, it is a 1,4-benzodioxanyl group. In one embodiment of the invention, when Ari is heterocyclyl, it is other than a N- containing heterocyclic group which is bonded to Ci-Xi by a nitrogen atom. When Ari is aryl, it is preferably a phenyl group or a phenyl group fused to a 5- or 6-membered heterocyclyl ring, for example a 1,3-benzodioxolyl group or a ,l,4)-benzodioxanyl group. More preferably, when Ari is aryl it is a phenyl group or a 1,3-benzodioxolyl group. When Ari is carbocyclyl, it is typically an unsaturated or saturated hydrocarbon ring having from 3 to 8, for example from 3 to 6, carbon atoms. When Ari is carbocyclyl it is preferably a C₃-C₈, preferably C₃-C₆, cycloalkyl group or a cyclohexenyl group. > Typically, when Ci and Xi both represent a direct bond, Ar_t is heteroaryl, heterocyclyl or carbocyclyl, wherein the heteroaryl, heterocyclyl and carbocyclyl groups typically have the meanings set out above for preferred Ari groups.

Typically, the grpup Ari is unsubstituted or carries one or more, for example 1 , 2 or 3, substituents on the cyclic group. The substituents are typically selected from halogen, for example fluorine or chlorine, C1-C4 alkyl, hydroxy, Cι-C₄ alkoxy, -NR'R" and -NH-CO-R' wherein R' and R" are the same or different and are selected from hydrogen and unsubstituted Cι-C alkyl. Preferred substituents are fluorine, hydroxy, methoxy, dimethylamino and -NH-CO-CH3. Typically, the substituents on a group n are themselves unsubstituted.

More preferably Ari is an unsubstituted pyridyl, pyrrolidinyl, 1,3-benzodioxolyl or cyclohexenyl group, an unsubstituted C₃-C₆ cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, Cι-C₄ alkyl, C₂-C₄ alkenyl, Cι-C₄ alkoxy, C1-C4 alkylthio and -N(CH₃) , the substituents on Ari being themselves unsubstituted.

Typically, C₂ is a Ci-d alkylene group, preferably a Cι-C₄ alkylene group. C₂ is typically unsubstituted or substituted with one or two substitutents selected from hydroxy and fluorine, in particular fluorine. For example, C₂ is unsubstituted.

For the avoidance of doubt, the orientation of the group X₂ is such that the left hand side of the depicted moiety is attached to C and the right hand side of the depicted moiety is attached to C₃. Thus, for example, when X₂ is -N-CO-O-, the moiety -C₂-X₂-C₃ is -d-N-CO-O-C₃.

Typically, each R' in the moiety X2 is the same or different and is hydrogen or an unsubstituted Ci-d alkyl or phenyl group, preferably hydrogen, -CH₃ or -CH₂CH₃. More preferably, each R' in the moiety X₂ is hydrogen. Typically, each R" in the moiety X₂ is an unsubstituted Ci-d alkylene group, prefereably -CH₂- or -CH₂-CH₂-. More preferably, each R" is -CH₂-.

Typically, X₂ is a direct bond or is -O-, -S-, -NR'-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO, -O-CO-NR'-, -NR'-CO-O-, -S-CO- or -CO-S- wherein R' is as defined above. Preferably, when Preferably, X₂ is a direct bond or is - O-, -S-, -CO-O-, -O-CO-, -S-CO-, -CO-S- or -NH-CO-O. Most preferably, X₂ is a direct bond or is -O-, -S-, -CO-O- or -NH-CO-O, for example X₂ may be a direct bond or -O-, - S-, -CO-O- or -NH-CO-O.

Typically, C₃ is a Cι-C₆ alkyl group or a C -d alkenyl group. Preferably C₃ is a Cι-C₄ alkyl group or a d-d alkenyl group, for example a Cι-C alkyl group. C₃ is typically unsubstituted or substituted by one or more, for example 1 , 2 or 3, substituents selected from hydroxy, -NH2, -NH(Cι-C₂ alkyl), -N(Cι-C₂ alkyl)₂ and halogen, preferably hydroxy and halogen. Preferably, C₃ is unsubstituted or carries, on a primary carbon atom (i.e. a carbon atom at the end of a chain), either (a) one hydroxy or (b) 1 , 2 or 3 halo substituents, which are preferably fluoro substituents. The substituents on C₃ are typically themselves unsubstituted.

In one embodiment of the invention, X₂ is other than -NR⁷-. Thus, X₂ is typically a direct bond or is -O-, -S-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'- CO, -O-CO-NR'-, -NR'-CO-O-, -S-CO- or -CO-S- wherein R' is as defined above. In this embodiment, the group C₃ does not carry a substituent NR'R⁷', wherein R and R^; are each independently hydrogen or Ci-d alkyl groups. Thus C₃ is typically a Ci-d alkyl group or a d-d alkenyl group each of which is unsubstituted or substituted by one or more, for example 1, 2 or 3, substituents selected from hydroxy and halogen.

Preferred compounds of formula (I) and prodrugs thereof, and pharmaceutically acceptable salts thereof are those in which: Z is -S-, -SO- or -O-, for example -S- or -O-;

Ri is hydrogen or an unsubstituted Ci- alkyl group; R₂ is hydrogen or an unsubstituted Cι-C₆ alkyl group;

Y is -(CR^y ₂)_m-X₄-(CR^y ₂)_n-, -(CR^y ₂)_m-A-(CR^y ₂)_m- or -(CR^y ₂)_m-A-(CR^y ₂)_p-X₃-(CR^y ₂)_r„, wherein - each R^y is the same or different and is hydrogen or an unsubstituted Cι-C₄ alkyl or phenyl group;

A is an aryl or heteroaryl group which is unsubstituted or substituted with 1, 2 or

3 substituents selected from unsubstituted Cι-C₄ alkyl, Cι-C₄ alkoxy, halogen, hydroxy, NH₂, NH(d-C₂ alkyl) and N(d-C₂ alkyl)₂ groups; - X₃ is -O-, -S-, -SO-, -SO2-, -O-CO-, -CO-O-, -NH-CO- or -CO-NH-;

X₄ is -O-, -S- or -NR'- wherein R' is. hydrogen or -CH₃; p is 0 or 1 ; m is 0 or 1 and n is 1 or 2; R₃ is an aryl, heteroaryl or carbocyclyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, Ci-d alkyl, Ci-d alkoxy, d- d alkylthio, C₂-C₆ alkenyl, d-d alkenyloxy, C₂-C₆ alkenylthio, C₂-C₆ alknynyl, C₂-d alkynyloxy, C₂-C₆ alkynylthio, C₃-C₆ carbocyclyl, C₃-d carbocyclyloxy, C₃-d carbocyclylthio, -NH-CO-(d-C₆ alkyl), -CO-NH-(C,-C₆ alkyl) -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group, and Si(R'")₃ wherein each R'" is independently a Cι-C₄ alkyl group, the substituents on R₃ being themselves unsubstituted or further substituted with 1 , 2 or 3 further substituents selected from halogen and hydroxy;

Ri is -Cι-Xι-Arι or -C₂-X₂-C₃, wherein:

Ci is a direct bond or an unsubstituted Cι-C₄ alkylene group;

Xi is a direct bond when Ci is a direct bond and, when Ci is an unsubstituted Ci-

C alkylene group, is a direct bond or -O-, -S-, -NR'-, -S-CO-, -O-CO-, -CO-O-, CO-S-, -NR'-CO- or -CO-NR'-, wherein R' is hydrogen or an unsubstituted phenyl or Cι-C₆ alkyl group;

Ari is a heteroaryl, heterocyclyl, aryl, carbocyclyl or heteroaryl-(Cι-C₂ alkyl)- group which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 unsubstituted groups selected from halogen, Cι-C alkyl, hydroxy, Cι-C₄ alkoxy, -NR'R" or -NH-CO- R' wherein R' and R" are the same or different and are selected from hydrogen and Ci-d alkyl; d is a Ci-d alkylene group which is unsubstituted or substituted with one or two substituents selected from hydroxy and fluorine;

X₂ is a direct bond or is -O-, -S-, -NR'-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S- CO-, -O-CO-, -NR'-CO, -O-CO-NR'-, -NR'-CO-O-, -S-CO- or -CO-S- wherein R' is hydrogen, -CH₃ or -CH₂-CH₃; and d is a Ci-d alkyl group or a C₂-C₄ alkenyl group, each of which is unsubstituted or substituted with 1, 2 or 3 unsubstituted groups selected from hydroxy, -NH₂, -NH(d- C₂ alkyl), -N(Cι-C₂ alkyl)₂ and halogen. Further preferred compounds of formula (I) and pharmaceutically acceptable salts thereof are those in which: Z is -S- or -O-;

Ri is hydrogen or an unsubstituted Cι-C₄ alkyl group; R₂ is hydrogen or an unsubstituted Cι-C₆ alkyl group;

Y is -(CR^y ₂)_m-X₄-(CR^y ₂)_π-, -(CR^y ₂)_m-A-(CR^y ₂)_m- or -(CR^y ₂)_m-A-(CR^y ₂)_p-X₃-(CR^y ₂)_m, wherein each R^y is the same or different and is hydrogen or an unsubstituted Cι-C₄ alkyl or phenyl group;

A is an aryl or heteroaryl group which is unsubstituted or substituted with 1 , 2 or

3 substituents selected from unsubstituted Cι-C₄ alkyl, Cι-C alkoxy, halogen, hydroxy, NH₂, NH(Cι-C₂ alkyl) and N(d-C₂ alkyl)₂ groups;

X₃ is -O-, -S-, -SO-, -SO₂-, -O-CO-, -CO-O-, -NH-CO- or -CO-NH-;

X₄ is -O-, -S- or -NR'- wherein R' is hydrogen or -CH₃; p is 0 or 1 ; m is 0 or 1 and n is 1 or 2; R₃ is an aryl, heteroaryl or carbocyclyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, hydroxy, Cι-C₆ alkyl, Ci-d alkoxy, Ci-d alkylthio, d-d alkenyl, C₂-d alkenyloxy, d-C alkenylthio, C₂-d alknynyl, C₂-d alkynyloxy, C₂-C₆ alkynylthio, C₃-d carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-C₆ carbocyclylthio, -NH-CO-(C,-C₆ alkyl), -CO-NH-(C,-C₆ alkyl) and -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group, the substituents on R₃ being themselves unsubstituted or further substituted with 1 , 2 or 3 further substituents selected from halogen and hydroxy; Ri is -Cι-Xι-Arι or -C₂-X₂-Cj, wherein:

Ci is an unsubstituted Ci-d alkylene group;

X, is a direct bond or is -O-, -S-, -NR'-, -S-CO-, -O-CO-, -CO-O-, CO-S-, -NR'- CO- or -CO-NR'-, wherein R' is hydrogen or an unsubstituted phenyl or Ci-d alkyl group;

Ari is a heteroaryl, heterocyclyl, aryl or heteroaryl-(Cι C₂) alkyl)- group which is unsubstituted or carries, on the cyclic moiety, 1 , 2 or 3 unsubstituted groups selected from halogen, d-C₄ alkyl, hydroxy, C,-C₄ alkoxy, -NR'R" or -NH-CO-R' wherein R' and R" are the same or different and are selected from hydrogen and Cι-C alkyl;

C₂ is an unsubstituted Cι-C₄ alkylene group; X₂ is a direct bond or is -O-, -S-, -NR'-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-

CO-, -O-CO-, -NR'-CO, -O-CO-NR'-, -NR'-CO-O-, -S-CO- or -CO-S- wherein R' is hydrogen, -CH₃ or -CH₂-CH₃; and d is a Cι-C alkyl group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted groups selected from hydroxy, -NH₂, -NH(Cι-C₂ alkyl), -N(Cι-C₂ alkyl)₂ and halogen.

Preferred compounds of formula (I) are those of formula (IA), prodrugs thereof, and pharmaceutically acceptable salts thereof:

wherein: Y is a group of formula -(CH₂)_mO(CH₂)-, -A- or -A-X₃-(CH )_m, wherein A is a phenyl, pyridyl or pyrrolyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from -CH₃, -CH₂-CH₃, -OCH₃, -OCH₂-CH₃, halogen and hydroxy; X₃ is -O-, - SO₂- or -NH-CO-; and m is 0 or 1 ;

R³ is a phenyl, thienyl, furyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4- benzodioxanyl, 1 ,3-benzodioxolyl or 2,3-dihydrobenzofuran group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, hydroxy, Ci-d alkyl, Ci- d alkoxy, Cι-C₆ alkylthio, C₂-d alkenyl, C₂-C₆ alkenyloxy, C₂-d alkenylthio, C₂-d alknynyl, C₂-C₆ alkynyloxy, C₂-d alkynylthio, C₃-C₆ carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-C₆ carbocyclylthio, -NH-CO-(d-C₆ alkyl), -CO-NH-(Cι-C₆ alkyl) and -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group, the substituents on R³ being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy; and i is - Cι-Xι-Arι or -C₂-X₂-C₃, wherein: C, is -(CH₂)-, -(CH₂)₂- or -(CH₂)₃-; - Xi is a direct bond or is -O-, -S-, -S-CO- or -O-CO-; Ari is a phenyl, pyridyl, thienyl, benzimidazolyl, furanyl-methyl-, 1,3- benzodioxolyl or 1,4-benzodioxanyl group, which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 substituents selected from fluorine, hydroxy, -OCH₃, -N(CH₃)₂ and -NH-CO-CH₃; - C₂ is a straight chain unsubstituted C1-C4 alkylene group;

X₂ is a direct bond or is or is -O-, -S-, -CO-O- or -NH-CO-O; and d is C₁-C4 alkyl group which is unsubstituted or substituted on a primary carbon atom with either (a) one hydroxy or (b) 1 , 2 or 3 halo substituents. Preferably, in the compounds of formula (I A), R^J is a phenyl, thienyl, furyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl or 2,3- dihydrobenzofuran group which is unsubstituted or substituted with 1 , 2 ^"or 3 substituents selected from halogen, Cι-C₄ alkyl, C -C₄ alkenyl, C1-C4 alkoxy, Cι-C alkylthio, C₂-C alkenyloxy, C₃-C₆ carbocyclyl, d-d carbocyclyloxy, -NH-CO-(Cι-C₂ alkyl) and -N(Cι-C₂ alkyl)₂, the substituents on R^J being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy.

Most preferably, compounds of formula (I) are those of formula (IA'), prodrugs thereof and pharmaceutically acceptably salts thereof:

wherein: Z is -S- or -SO-;

Y is a group of formula -A-, wherein A is an unsubstituted pyridyl or an unsubstituted thienyl group;

R³ is a phenyl, thienyl, pyridyl or 1,3-benzodioxolyl group whichjis unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, Ci-d alkyl, C₁-C₄ alkoxy, C _rC₄ alkylthio, C₂-C₄ alkenyl, -NR'R" wherein R' and R" are each independently hydrogen or a C₁-C4 alkyl group, and -Si(R )₃ wherein each R ' is independently a C₁-C₄ alkyl group, the substituents on R³ being themselves unsubstituted or further substituted with 1 , 2 or 3 further substituents selected from halogen and hydroxy;

R4 is -Cι-Xι-Arι or -C₂-X₂-C , wherein:

Ci is a direct bond or an unsubstituted Cι-C₄ alkylene group; - Xi is a direct bond when Ci is a direct bond and, when Ci is an unsubstituted Ci- d alkylene group, is a direct bond or -O- or -S-;

Ari is an unsubstituted pyridyl, pyrrolidinyl, 1,3-benzodioxolyl or cyclohexenyl group, an unsubstituted C₃-d cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, C₁-C4 alkyl, C₂-C₄ alkenyl, Cι-C₄ alkoxy, C1-C4 alkylthio and -N(CH₃)₂, the substituents on Ari being themselves unsubstituted; d is a Cι-C₄ alkylene group, which is unsubstituted or substituted with one or two substituents selected from hydroxy and fluorine;

X₂ is a direct bond or is -O-, -S- or -CO-O-; and - C₃ is a Cι-C₄ alkyl or d-d alkenyl group which is unsubstituted or substituted with 1 , 2 or 3 groups selected from hydroxy and halogen.

In one embodiment of the invention, in the compounds of the formula (I), -YR₃ is other than a substituted or unsubstituted phenoxyphenyl, phenoxythiophenyl, benzyloxyphenyl, benzylthiophenyl or -furanyl-phenyl group. Typically, -YR₃ is other than a substituted or unsubstituted naphthalenyl, phenoxyphenyl, phenoxythiophenyl, benzyloxyphenyl, benzylthiophenyl or -furanyl-phenyl or carbazolyl group. More typically, Y in the formula (I) is other than a direct bond or a phenoxy, benzyloxy, benzylthio or furanyl group.

Further, R₄ is typically other than (a) -Y-NRs t, wherein Y is alkylene and R₃ and R4 are the same or different and are selected from hydrogen, alkyl or aryl or R₃ and R4 together form an alkylene chain having 4 to 5 carbon atoms optionally interrupted by a nitrogen or oxygen, (b) pyridylalkyl and (c) piperidin-4-yl-alkyl, optionally substituted by alkyl, aryl or aralkyl. Preferably, in this embodiment, X2 is other than -NR-, C₃ is a Ci- C₄ alkyl group which is unsubstituted or is substituted on a primary carbon atom with either (a) one hydroxy or (b) 1, 2 or 3 halo substituents and Ar_t is other than a pyridyl or piperidyl group, preferably other than a 6-membered heteroaryl or heterocyclyl group. Preferred compounds of formula (I) include:

1. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3,5-difluoro-benzyl)-thiazolidin-4-one

2. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(2,3,4-trifluoro-benzyl)-thiazolidin-4-one

3. 2-[4-(4-Bromo-pbenyl)-pyridin-3-yl]-3-(2,5-difluoro-benzyl)-thiazolidin-4-one 4. 3-(2-Benzo[ 1 ,3]dioxol-5-yl-ethyl)-2-[4-(4-bromo-phenyl)-pyridin-3-yl]- thiazolidin-4-one

5. 3-Isobutyl-2-(4-phenyl-pyridin-3-yl)-thiazolidin-4-one

6. 2-(4-Benzo[ 1 ,3]dioxol-5-yl-pyridin-3-yl)-3-isobutyl-thiazolidin-4-one

7. 3-Isobutyl-2-(4-thiophen-2-yl-pyridin-3-yl)-thiazolidin-4-one 8. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(2-cyclohex-l-enyl-ethyl)-thiazolidin-4- one

9. 2-[4,4']Bipyridinyl-3-yl-3-isobutyl-thiazolidin-4-one

10. 2-[4-(4-Chloro-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one

11. 2-[4-(4-Fluoro-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one 12. 2-[4-(3-Bromo-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one

13. 3-Isobutyl-2-[4-(4-trifluoromethoxy-phenyl)-pyridin-3-yl]-thiazolidin-4-one

14. 3-Isobutyl-2-(4-p-tolyl-pyridin-3-yl)-thiazolidin-4-one

15. 3-Isobutyl-2-[4-(4-trimethylsilanyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one

16. 3-Isobutyl-2-[4-(4-methylsulfanyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one 17. 2-[4-(4-Ethyl-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one

18. 4-(3-Isobutyl-4-oxo-thi£iZQlidin-2-yl)-3-(4-methoxy-phenyl)-pyridinium; chloride

19. 3-(4-Chloro-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride

20. 3-(4-Fluoro-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride

21. 4-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-3-p-tolyl-pyridinium; chloride 22. 2-(4-Bromo-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride

23. 3-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-methoxy-phenyl)-pyridinium; chloride

24. 2-(4-Chloro-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride

25. 2-(4-Fluoro-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride

26. 3-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-p-tolyl-pyridinium; chloride 27. 3-Isobutyl-2-[4-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one

28. 4-[3-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-pyridin-4-yl]-benzonitrile 29. 3-Isobutyl-2-[4-(4-methoxy-phenyl)-pyridin-3-yl]-thiazolidin-4-one

30. 3-Isobutyl-2-[4-(4-vinyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one

31. 3-(4-Bromo-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride

32. 4-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-3-(4-vinyl-phenyl)-pyridinium; chloride 33. 3-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-trifluoromethyl-phenyl)-pyridinium; chloride

34. 2-(4-Cyano-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride

35. 3-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-vinyl-phenyl)-pyridinium; chloride

36. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3-methyl-butyl)-thiazolidin-4-one 37. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(2,2,3,3,3-pentafluoro-propyl)-thiazolidin- 4-one

38. 2- [4-(4-Bromo-phenyl)-pyridin-3-y 1] -3-ethyl-thiazolidin-4-one

39. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3,3-dimethyl-butyl)-thiazolidin-4-one

40. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-cyclopentyl-thiazolidin-4-one 41. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-cyclopropylmethyl-thiazolidin-4-one

42. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3-isopropoxy-propyl)-thiazolidin-4-one

43. 3-Allyl-2-[4-(4-bromo-phenyl)-pyridin-3-yl]-thiazolidin-4-one

44. 3-Isobutyl-2-(4-m-tolyl-pyridin-3-yl)-thiazolidin-4-one

45. 2-[4-(2,4-Dimethyl-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one 46. 3-Isobutyl-2-(4-o-tolyl-pyridin-3-yl)-thiazolidin-4-one

47. 4-(4-Bromo-phenyl)-3-(3-isobutyl-l,4-dioxo-llambda*4*-thiazolidin-2-yl)- pyridinium; chloride

48. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-sec-butyl-thiazolidin-4-one

49. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-cyclohexyl-thiazolidin-4-one 50. , 2-(3-Benzo[l,3]dioxol-5-yl-pyridin-4-yl)-3-cyclopentyl-thiazolidin-4-one

51. 4-[4-(3-Cyclopentyl-4-oxo-thiazolidin-2-yl)-pyridin-3-yl]-benzonitrile

52. 3-Cyclopentyl-2-[3-(4-dimethylamino-phenyl)-pyridin-4-yl]-thiazolidin-4-one

53. 3-Cyclopentyl-2-[3-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

54. 3-Cyclopentyl-2-[3-(4-methoxy-phenyl)-pyridin-4-yl]-thiazolidin-4-one 55. 3-Cyclopentyl-2-[3-(4-methylsulfanyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

56. 3-Cyclopentyl-2-[3-(4-ethyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 57. 2-[3-(4-Bromo-phenyl)-pyridin-4-yl]-3-cyclopentyl-thiazolidin-4-one

58. 3-Cyclopentyl-2-[3-(3,4-dimethyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

59. 3-Isobutyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

60. 3-Cyclopropyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 61. 3-Cyclobutyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

62. 3-Isopropyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

63. 3-sec-Butyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

64. 3-(l-Ethyl-propyl)-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

65. 3-Isobutyl-2-[3-(4-vinyl-phenyl)-thiophen-2-yl]-thiazolidin-4-one 66. 3-Isobutyl-2[4-(4-vinyl-phenyl)-thiophen-3-yl]-thiazolidin-4-one

67. 2-{4-[4-(l ,2-Dihydroxy-ethyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one

68. 2-{4-[4-(2-Hydroxy-ethyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one

69. 2-{4-[4-(l-Hydroxy-ethyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one

70. 2-{4-[4-(2,2-Difluoro-vinyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one 71. 3-Isobutyl-2-[4-(4-trifluorovinyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one

72. 2- {4-[4-( 1 -Fluoro-vinyl)-phenyl] -pyridin-3-yl } -3 -isobutyl-thiazolidin-4-one

73. 3-Isobuyl-2-[3-(4-vinyl-phenyl)-pyridin-2-yl]-thiazolidin-4-one.

and prodrugs thereof and pharmaceutically acceptable salts thereof. Particularly preferred compounds of formula (I) and formula (IA) are those which are more active as N-type calcium channel inhibitors than as L-type calcium channel inhibitors (i.e. which are selective N-type calcium channel antagonists). Typically such compounds have a lower IC₅₀ for inhibition of N-type calcium channels expressed by IMR32 cells than for inhibition of L-type calcium channels expressed by IMR32 cells under the same conditions. They may therefore involve fewer side effects than non- selective N-type calcium channel antagonists.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines. The present invention includes, in particular, pharmaceutically acceptable salts in which Y is a group of formula -A-, wherein A is pyridyl, and wherein the pyridyl group at Y carries a positive charge on the nitrogen atom.

As used herein, a prodrug of a compound of formula (I) is a compound which reacts in vivo to produce a compound of formula (I). Examples of prodrugs of compounds of formula (I) are compounds in which a 1,2-dihydroxy ethyl group or moiety of the compound of formula (I) is present as an epoxide ring. In particular, the epoxide ring may be present as a substituent on the group R³. An example of a suitable prodrug is the compound 3-isobutyl-2-[4-(4-oxiranyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one.

The compounds of the invention contain one or more chiral centre. For the avoidance of doubt, the chemical structures depicted herein are intended to embrace all stereoisomers of the compounds shown, including racemic and non-racemic mixtures and pure enantiomers and/or diastereoisomers.

Preferred compounds of the invention are optically active isomers. Thus, for example, preferred compounds of formula (I) containing only one chiral centre include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.

The present invention also provides a pharmaceutical composition comprising a compound of the formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent

wherein Z, Y, R|, R₃ and R are as defined above, provided that (a) when Z is S, R¹ is hydrogen and R⁴ is 2-(4-methoxyphenethyl), Y-R³ is not 4-benzoxyphenyl or 4- pyrrolidinylphenyl; (b) when Z is S and R¹ is hydrogen, Y-R³ is other than -phenyl-O-A₂- R, wherein A₂ is a C₂-C₅ alkylene group and R is 1 -pyrrolidinyl, 1 -piperidinyl, 4- morpholinyl, 1 -piperazinyl or 4-alkyl-l -piperazinyl; and (c) when R¹ is hydrogen and R⁴ is -C₂-X₂-d wherein C₂ is unsubstituted C₂-C₃ alkylene, X₂ is -O- and C is unsubstituted d-d alkyl, -Y-R³ is other than phenoxyphenyl, benzyloxyphenyl, phenylmercaptophenyl, benzylphenyl, 4-chlorophenoxyphenyl or 4-nitrophenoxyphenyl.

Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free. Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.

For the avoidance of doubt, the pharmaceutically acceptable carrier or diluent is other than DMSO.

The present invention also provides compounds of formula (II) as-defined above, prodrugs thereof, and pharmaceutically acceptable salts thereof, for use in the treatment of the human or animal body.

Certain compounds of the invention are believed to be novel. The present invention therefore also provides such novel compounds. Thus, the present invention provides compounds of formula (T), prodrugs thereof and pharmaceutically acceptable salts thereof;

wherein R¹, R³ and R⁴ are as defined above with regard to formula (I), (IA) or (lA , Z is -S-, -O- or -SO- and Y is a group of formula -A- wherein A is a heteroaryl group, provided that when Z is S, R¹ is hydrogen, Y is an unsubstituted pyridyl group and R³ is a bromophenyl group, R⁴ is a group Ci-Xi-Ari in which Ari is a 3- to 6-membered carbocyclyl group.

Typically, in the compounds of formula (I'), A is a pyridyl, furanyl, thienyl, imidazolyl or pyrrolyl group, preferably a pyridyl, thienyl or pyrrolyl group. For example, A may be a pyridyl or pyrrolyl group, preferably a pyridyl group. The moiety A is typically unsubstituted or substituted with 1 , 2 or 3 substituents. Preferably, the moiety A is unsubstituted. The substituents on A are typically selected from those defined above with regard to the compounds of formula (I), (I A) and (I A').

/ 1

Typically, in the compounds of formula (I ), R is as defined with regard to formula (I), (IA) or (I A'). Where R³ is substituted, the substituents are typically other than bromine atoms, for example other than halogen atoms. Thus,, the substituents are typically selected from fluorine or chlorine, hydroxy, cyano, Ci-d alkyl, Cι-C₆ alkoxy, Ci-d alkylthio, C₂-C₆ alkenyl, C₂-C₆ alkenyloxy, C₂-C₆ alkenylthio, C₂-C₆ alknynyl, C₂- d alkynyloxy, C₂-C₆ alkynylthio, C₃-C₆ carbocyclyl, d-d carbocyclyloxy, d-C₆ carbocyclylthio, -NH-CO-(C,-d alkyl), -CO-NH-(Cι-C₆ alkyl), -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group and -Si(R )₃, wherein each R⁷ is independently a C1-C4 alkyl group.

Preferred substituents on R³ are fluorine, chlorine, hydroxy, cyano, Cι-C₄ alkyl, Cι-C₄ alkoxy, d-C₄ alkylthio, C₂-C₄ alkenyl, -NR'R" wherein R' and R" are each independently hydrogen or a Cι-C₄ alkyl group, and -Si(R⁷⁷)₃ wherein each R⁷⁷⁷ is independently a Cι-C alkyl group. More preferred substituents on R³ are fluorine, chlorine, cyano, Ci-d alkyl, C1-C4 alkoxy, Cι-C alkylthio, C₂-C alkenyl, C₂-C₄ alkenyloxy, C₃-C₆ carbocyclyloxy, -NH-CO-Me, -N(CH₃)₂ and -Si(R )₃ wherein each R⁷⁷⁷ is independently a Cι-C₄ alkyl group. Further preferred substituents on R³ are Cι-C₄ alkyl, Cι-C₄ alkoxy, C1-C4 alkylthio and C₂-C₄ alkenyl.

Preferably, in the compounds of formula (I⁷), Y is a group of formula -A-, wherein A is an unsubstituted pyridyl or thienyl group, and R³ is an aryl, heteroaryl, heterocyclyl or carbocyclyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from fluorine, chlorine, hydroxy, Ci-d alkyl, Cι-C₆ alkoxy, Ci-d alkylthio, C₂- d alkenyl, d-d alkenyloxy, C₂-d alkenylthio, C₂-d alknynyl, C₂-C₆ alkynyloxy, C₂- C₆ alkynylthio, C₃-C₆ carbocyclyl, C₃-d carbocyclyloxy, C₃-C₆ carbocyclylthio, -NH- CO-(d-C₆ alkyl), -CO-NH-(Cι-C₆ alkyl), -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group and Si(R )₃, wherein each R⁷⁷⁷ is independently a Cι-C alkyl group, the substituents on R₃ being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy.

More preferably, Y is a group of formula -A- , wherein A is an unsubstituted pyridyl or thienyl group, and R³ is an aryl, heteroaryl, heterocyclyl or carbocyclyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, d- d alkyl, Ci-d alkoxy, Cι-C₆ alkylthio, C₂-C₆ alkenyl, C₂-C₆ alkenyloxy, d-d alkenylthio, d-d alknynyl, C₂-C₆ alkynyloxy, C₂-C₆ alkynylthio, C₃-C₆ carbocyclyl, C₃- d carbocyclyloxy, C₃-d carbocyclylthio, -NH-CO-(Cι-C₆ alkyl), -CO-NH-(d-C₆ alkyl), -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group and Si(R^7/)₃, wherein each R⁷⁷⁷ is independently a Cι-C₄ alkyl group, the substituents on R₃ being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy.

Most preferred compounds of formula (I⁷) are those of formula (IA⁷⁷), prodrugs thereof and pharmaceutically acceptably salts thereof:

wherein: Z is -S- or -SO-;

R³ is a phenyl, thienyl, pyridyl or 1,3-benzodioxolyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from fluorine, chlorine, hydroxy, cyano, Cι-C₄ alkyl, d-C₄ alkoxy, d-d alkylthio, C₂-C₄ alkenyl, -NR'R" wherein R' and R" are each independently hydrogen or a Cι-C₄ alkyl group, and -Si(R⁷ )₃ wherein each R⁷⁷⁷ is independently a Cι-C₄ alkyl group, the substituents on R³ being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy;

R₄ is -Cι-Xι-Arι or -C₂-X₂-C₃, wherein:

Ci is a direct bond or an unsubstituted Cι-C₄ alkylene group; Xi is a direct bond when C| is a direct bond and, when Ci is an unsubstituted d- C alkylene group, is a direct bond or -O- or -S-; - Ari is an unsubstituted pyridyl, pyrrolidinyl, 1,3-benzodioxolyl or cyclohexenyl group, an unsubstituted C₃-d cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, Cι-C₄ alkyl, d-C₄ alkenyl, Cι-C₄ alkoxy, Cι-C₄ alkylthio and -N(CH₃)₂, the substituents on Ari being themselves unsubstituted; - C₂ is a Ci-d alkylene group, which is unsubstituted or substituted with one or two substituents selected from hydroxy and fluorine;

X₂ is a direct bond or is -O-, -S- or -CO-O-; and

C₃ is a Ci-d alkyl or C₂-C₄ alkenyl group which is unsubstituted or substituted with 1 , 2 or 3 groups selected from hydroxy and halogen. Preferred novel compounds are compounds of formula (IB) and pharmaceutically acceptable salts thereof,

wherein:

R³, Y and Z are as defined above for the compounds of formula (T); i is -Cι-Xι-Arι' or -C₂-X₂'-C₃, or a Cι-C₆ alkyl, or C₂-C₆ alkenyl group, wherein Ci, Xi, d and C₃ are as defined above for the compounds of formula (f), and

Ari ' is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-R^a- or heterocyclyl- R^a-, R^a being a Ci-d alkylene group, a C₂-d alkenylene group or a C₂-C_{6 t} alkynylene group, wherein when Ari ' is an unsubstituted phenyl group or a phenyl group substituted with one or two groups selected from methyl, ethyl, methoxy, ethoxy, phenoxy, chlorine, bromine and nitro, either both Ci and Xi are direct bonds or Ci is methylene and Xi is -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-,

-CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -O-CO-NR- or -NR'-CO-O-, wherein each R' is the same or different and represents hydrogen, phenyl, Ci-d alkyl, C₂-d alkenyl or C₂-d alkynyl and each R" is the same or different and represents a Cι-C₆ alkylene group, a C₂-d alkenylene group or a C -C₆ alkynylene group; and

X₂' is -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-, -CO-S-, -CO-O,, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -NR'-CO-O- or -O-CO-NR'-, wherein each R' is the same or different and represents hydrogen, phenyl, Cι-C₆ alkyl, d-d alkenyl or d-d alkynyl and each R" is the same or different and represents a Ci-d alkylene group a d-d alkenylene group or a C₂-d alkynylene group. In the compounds of formula (IB), R¹, R², R³, Y, Z, d and d are preferably as defined above with regard to formula (I) or formula (IA).

Typically, in the compounds of formula (IB), R4 is -Cι-Xι-Arι' or - -X₂'- , or a Cι-C₄ alkyl group.

Typically, Ci and Xi in the compounds of formula (IB) are as defined above with regard to formula (I) or formula (IA), with the proviso that when Ari ' is an unsubstituted phenyl group or a phenyl group substituted with one or two groups selected from methyl, ethyl, methoxy, ethoxy, phenoxy, chlorine, bromine and nitro, either both Ci and Xi are direct bonds or Ci is methylene and Xi is -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -O-CO-NR'- or -NR'-CO-O-, wherein R' and R" are as defined above with regard to formula (I) or formula (IA). Preferably, when Ari ' is an unsubstituted phenyl group or any substituted phenyl group which does not have at least one substituent selected from fluorine, -N(d-d alkyl)₂, -NH-CO-(Cι-C₆ alkyl) and hydroxy, either both Ci and Xi are direct bonds or Ci is methylene and Xi is -O-, -S-, -NR'-, -SO-, -SO2-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -O-CO-NR'- or -NR'-CO-O-, wherein R' and R" are as defined above. More preferably, when Ari' is an unsubstituted or substituted phenyl group, either both Ci and Xi are direct bonds or Ci is methylene and Xi is -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-0-, -CO- O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -O-CO-NR'- or -NR'-CO-O-, wherein R' and R" are as defined above.

Typically Ari ' in the formula (IB) above is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-(Ci-C₆ alkyl)- or heterocyclyl-(Cι-C₆ alkyl)-. When Ari ' is a heteroaryl-(Cι-d alkyl)- or heterocyclyl-(Cι-C₆ alkyl)- group, the alkyl moiety is typically an unsubstituted methylene or ethylene moiety. Preferably, Ari ' is heteroaryl, heterocyclyl, aryl, carbocyclyl or heteroaryl-(Cι-C₂ alkyl)-, for example heteroaryl, heterocyclyl, aryl or heteroaryl-(Cι-C₂ alkyl). Preferably, when Ari' is aryl, it is a phenyl group fused to a 5- or 6-membered heterocyclyl ring, for example a 1,3-benzodioxolyl group or a 1,4-benzodioxanayl group. More preferably, when Ari ' is aryl it is a 1,3- benzodioxolyl group. When Ari ' is heteroaryl, heterocyclyl, carbocyclyl or heteroaryl- (Cι-C₂ alkyl)-, it preferably has the same meanings as the corresponding groups of Ari as defined above. More preferably, Ari' is an unsubstituted pyridyl, pyrrolidinyl, 1,3- benzodioxolyl or cyclohexenyl group, or an unsubstituted C₃-C₈ cycloalkyl group.

Typically, the group Ari ' in the formula (IB) is unsubstituted or carries one or more, for example 1, 2 or 3, substituents on the cyclic group. The substituents are typically selected from halogen, for example fluorine or chlorine, Cι-C₄ alkyl, hydroxy, Cι-C alkoxy, -NR'R" and -NH-CO-R' wherein R' and R" are selected from hydrogen and unsubstituted C₁-C₄ alkyl. Preferred substituents are fluorine, hydroxy, methoxy, dimethylamino and -NH-CO-CH₃. More preferred substituents are fluorine, hydroxy, -N(CH₃)₂ and -NH-CO-CH₃. Typically, the substituents on a group Ari' are themselves unsubstituted.

Typically, each R' in the moiety X ' in the formula (IB) above is the same or different and is hydrogen or an unsubstituted phenyl or Cι-C₆ alkyl group, preferably hydrogen, -CH₃ or -CH₂CH₃. More preferably, each R' in the moiety X₂' is hydrogen. Typically, each R" in the moiety X₂' is an unsubstituted Ci-d alkylene group, preferably -CH₂- or -CH₂-CH₂-. More preferably, each R" is -CH₂-.

Typically, X₂' in the formula (IB) above is -O-, -S-, -NR'-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO, -O-CO-NR'-, -NR'-CO-O-, -S-CO- or -CO-S- wherein R' is as defined^'above with regard to formula (I) or formula (IA). Preferably, X₂' is -O-, -S-, -CO-O-, -O-CO-, -S-CO-, -CO-S- or -NH-CO-O. Most preferably, X₂' is -O-, -S-, -CO-O- or -NH-CO-O.

When R^ in the formula (IB) above represents a Ci-d alkyl group or d-d alkenyl group, it is typically a C -d alkyl group or a C₃-d alkenyl group. Further, the alkyl or alkenyl group may be straight or branched, unsubstituted or substituted. For example, R₄ may represent an unsubstituted branched Cι-C₄ alkyl group, in particular a sec-butyl group. Typically the Ci-d alkyl or C₂-d alkenyl group is unsubstituted or substituted by 1 , 2 or 3 substituents. Suitable substituents are those set out above as examples of suitable substituents on an alkyl or alkenyl group. Preferred substituents include halogen, in particular fluorine, and hydroxy. Typically, substituents on the Ci-d alkyl and C₂-d alkenyl group are themselves unsubstituted.

More preferred examples of the novel compounds of the invention are compounds 1 to 73 listed above and prodrugs thereof, and pharmaceutically acceptable salts thereof. The compounds of formula (I) may be prepared by conventional routes, for example those set out in any of schemes A to E shown below.

Scheme A

In scheme (A), an aldehyde or ketone of formula (II) is reacted with an amine of formula R₄-NH₂ in the presence of HSCHR₂-CO₂H. Typically, the reaction takes place in a solvent such as benzene or toluene at elevated temperature, for example from 80 to 100°C. A compound of formula (I) in which Z is S can be thereby prepared.

The reaction shown in scheme A can be conducted as a "one pot" reaction, or can be conducted stepwise, whereby a compound of formula (II) is reacted with an amine of formula R»-NH₂ and the thus obtained imino intermediate is then reacted with HSCHR₂- CO₂H. Typically, when stepwise reaction is effected, both reaction steps take place in a solvent such as benzene or toluene at elevated temperature, for example from 80 to 100°C.

Scheme B

An altenative method of preparing thiazolidinones is outlined in scheme B, whereby the amine is introduced using ammonium carbonate to give a compound of formula. (III). A compound of formula (I) in which Z is S can then be prepared from the thus obtained intermediate of formula (III) by standard methods. For example, it can be prepared by reacting a compound of formula (III) with a compound of formula R₄-L, wherein L is a leaving group such as a chlorine atom, in the presence of a base such as NaH in a solvent such as THF at around room temperature.

Scheme C

In order to prepare thiazolidinones of formula (I) with substitued pyridyl or substituted thiophenyl at the 2-position of the thiazolidinone ring, a pyridine or thiophene of formula (V) , wherein Ar¹ is pyridine or thiophene having as substituents (i) a leaving group X, such as bromine or triflate, and (ii) a formyl or keto group, can be condensed with an amine of formula R4-NH2 in the presence of HSCHR2-CO₂H to give a compound of formula (VI) as outlined in scheme C. An aromatic ring can then be coupled onto the pyridine or thiophene ring. This coupling can be carried under Stille conditions using a catalyst, for example Pd(PPh₃)₄ and a trialkylstannyl (hetero)aryl compound, preferably a tributylstannyl (hetero)aryl compound. The coupling can also be carried out under Suzuki conditons, whereby the aryl halide is condensed with an arylboronic acid in the presence of a catalyst, for example Pd(PPli₃)₄, and a base, for example K₂CO₃ or Na CO₃, in a solvent such as tetrahydrofuran at elevated temperature, for example 80- 120°C. Scheme D

(II) (VII)

Scheme D provides a process for preparing compounds of formula (I) in which Z is O. In this scheme, a compound of formula (II) can be reacted with a compound of formula (VII) under standard reaction conditions, such as those set out in Giraud et al, J. Org. Chem., 1998, 63, 9162-9163. Compounds of formula (VII) can also be prepared by reacting a compound of formula R1-NH2 with a compound L-CO-CH(R₂)OH, wherein L is a leaving group such as OH, by standard amide coupling reaction conditions using coupling agents such as EDCI/HOBT, HATU or HBTU which will be familiar to those of skill in the art.

A compound of formula (II) can also be reacted with H₂N-CO-CH(R₂)OH under standard reaction conditions such as those set out in Giraud et al, to yield a compound of formula (VIII). A compound of formula (I) in which Ri is O can then be prepared from the thus obtained intermediate of formula (VIII) by standard methods. For example, it can be prepared by reacting a compound of formula (VIII) with a compound of formula R₄-L, wherein L is a leaving group such as a chlorine atom, in 'the presence of a base such as NaH in a solvent such as THF at around room temperature.

Scheme E

Scheme E provides a process for the preparation of compounds of the invention in which Z is -NH-. Reaction conditions for the steps set out in scheme 4 can be found, for example, in Frutos et al, Tet. Assymmetry, 2001, 12, 101-104.

In Scheme E, a compound of formula (IX), in which P represents an amino protecting group, is reacted with an amine of formula R₄-NH₂, typically in a solvent such as THF or DMF, in the presence of a coupling agent such as EDCI/HOBT, at around 0 to 40°C. Typically, P is a Boc protecting group or a Z (benzyloxycarbonyl) protecting group.

The thus obtained compound of formula (X) can then be deprotected using standard techniques. When P is Boc, deprotection is typically effected by reaction with trifluoroacetic acid (TFA) in dichloromethane. When P is Z, deprotection is typically effected by reaction with hydrogen in the presence of a catalyst, for example 5% palladium on carbon. The thus obtained compound of formula (XI) can then be reacted with a compound of formula (II), as defined above, under standard conditions such as those set out in Frutos et al. Typically, this reaction takes place in a solvent such as

Cyclisation of the thus obtained compound of formula (XII) can be effected, for example, in the presence of AcCl and MeOH to yield a compound of formula (I) in which Z is -NH-.

Compounds of formula (I) in which Z is -NR- can, of course, be prepared by reacting a corresponding compound in which Z is -NH- with a group L-R, wherein L is a leaving group, for example a halogen atom, in the presence of a coupling agent such as EDCI/HOBT, at around 0 to 40%.

Further synthetic manipulation of the compounds of formula (I), such as bromination, nitration and acylation may be carried out by conventional methods to achieve further compounds of formula (I). For example, compounds of formula (I) in which R₂ is fluorine can be prepared from corresponding compounds in which R₂ is hydrogen by reaction with Et₃N.3HF in CH₃CN.

The thus obtained compounds of formula (I) may be salified by treatment with an appropriate acid or base. Racemic mixtures obtained by any of the above processes can be resolved by standard techinques, for example elution on a chiral chromatography column. Compounds of formulae (II), (III), (VII), (IX), HSCHR₂-CO₂H, Cl-CO-CH(R₂)Br,

L-CO-CH(R₂)OH and H₂N-CO-CH(R₂)OH and the amines of formula RrNH₂, are known compounds, or may be prepared by analogy with known methods.

The compounds of the invention are found to be inhibitors of N-type calcium channels. Further, many preferred compounds of the invention exhibit selectivity over L- type calcium channels. The compounds of the invention are therefore therapeutically useful.

The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are compositions suitable for oral administration, for example tablets and capsules. The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

One preferred route of administration is inhalation. The major advantages of inhaled medications are their direct delivery to the area of rich blood supply in comparison to many medications taken by oral route. Thus, the absorption is very rapid as the alveoli have an enormous surface area and rich blood supply and first pass metabolism is bypassed.

Preferred pharmaceutical compositions of the invention therefore include those suitable for inhalation. The present invention also provides an inhalation device containing such a pharmaceutical composition. Typically said device is a metered dose inhaler (MDI), which contains a pharmaceutically acceptable chemical propellant to push the medication out of the inhaler. Typically, said propellant is a fluorocarbon.

Further preferred inhalation devices include nebulizers. Nebulizers are devices ^■ capable of delivering fine liquid mists of medication through a "mask" that fits over the nose and mouth, using air or oxygen under pressure. They are frequently used to treat those with asthma who cannot use an inhaler, including infants, young children and acutely ill patients of all ages.

Said inhalation device can also be, for example, a rotary inhaler or a dry powder inhaler, capable of delivering a compound of the invention without a propellant.

Typically, said inhalation device contains a spacer. A spacer is a device which enables individuals to inhale a greater amount of medication directly into the lower airways, where it is intended to go, rather than into the throat. Many spacers fit on the end of an inhaler; for some, the canister of medication fits into the device. Spacers with withholding chambers and one-way valves prevent medication from escaping into the air. Many people, especially young children and the elderly, may have difficulties coordinating their inhalation with the action necessary to trigger a puff from a metered dose inhaler. For these patients, use of a spacer is particularly recommended.

Another preferred route of administration is intranasal administration. The nasal cavity's highly permeable tissue is very receptive to medication and absorbs it quickly and efficiently, more so than drugs in tablet form. Nasal drug delivery is less painful and invasive than injections, generating less anxiety among patients. Drugs can be delivered nasally in smaller doses than medication delivered in tablet form. By this method absorption is very rapid and first pass metabolism is bypassed, thus reducing inter-patient variability. Nasal delivery devices further allow medication to be administered in precise, metered doses. Thus, the pharmaceutical compositions of the invention are typically suitable for intranasal administration. Further, the present invention also provides an intranasal device containing such a pharmaceutical composition.

A further preferred route of administration is transdermal administration. The present invention therefore also provides a transdermal patch containing a compound of the invention, or a pharmaceutically acceptable salt thereof. Also preferred is sublingual administration. The present invention therefore also provides a sub-lingual tablet comprising a compound of the invention or a pharmaceutically acceptable salt thereof. A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions. The compounds 'of the present invention are therapeutically useful in the treatment or prevention of conditions mediated by N-type calcium channels. Accordingly, the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels. Also provided is a method of treating a patient suffering from or susceptible to a condition mediated by N-type calcium channels, which method comprises administering to said patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

These compounds are useful as calcium channel antagonists thereby inhibiting in a subject the onset of a disorder whose alleviation is mediated by the reduction of calcium ion influx into cells whose actions contribute to the disorder.

N-type calcium channels are known to be closely involved in the mediation of pain transmission. Typically, the compounds of the invention are therefore used as analgesic agents. N-type calcium channels have been identified as being particularly important in the transmission of pain signals in the spinal cord (Chaplan S.R., Pogrel J,W., Yaksh T.L. J. Pharm. Exp. Ther., 1994, 269, 1117-1123; Diaz, A., Dickenson, A.H. Pain, 1997, 69, 93-100). Indeed, a series of recent clinical studies has provided confirmation of the important role of N-type calcium channels in pain transmission (Mathur, V.S.; McGuire, D.; Bowersox, S.S.; Miljanich, G.P.; Luther, R.R. Pharmaceutical News, 1998, 5, 25-29). The compounds of the invention are accordingly particularly effective in alleviating pain. Typically, therefore, said medicament is for use in alleviating pain and said patient is suffering from or susceptible to pain. The compounds of the invention are effective in alleviating both chronic and acute pain. Acute pain is generally understood to be a constellation of unpleasant sensory, perceptual and emotional experiences of certain associate autonomic (reflex) responses, and of psychological and behavioural reactions provoked by injury or disease. A discussion of acute pain can be found at Halpern (1984) Advances in Pain Research and Therapy, Vol.7, p.147. Tissue injury provokes a series of noxious stimuli which are transduced by nociceptors to impulses transmitted to the spinal cord and then to the upper part of the nervous system. Examples of acute pains which can be alleviated with the compounds of the invention include musculoskeletal pain, for example joint pain, lower back pain and neck pain, dental pain, post-operative pain, obstetric pain, for example labour pain, acute headache, neuralgia, myalgia, and visceral pain.

Chronic pain is generally understood to be pain that persists beyond the usual course of an acute disease or beyond a reasonable time for an injury to heal. A discussion of chronic pain can be found in the Halpern reference given above. Chronic pain is sometimes a result of persistent dysfunction of the nociceptive pain system. Examples of chronic pains which can be alleviated with the compounds of the invention include trigeminal neuralgia, post-herpetic neuralgia (a form of chronic pain accompanied by skin changes in a dermatomal distribution following damage by acute Herpes Zoster disease), diabetic neuropathy, causalgia, "phantom limb" pain, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, pain associated with cancer, pain associated with HIV, neuropathic pain, migraine and other conditions associated with chronic cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, spinal cord injury pain, central pain, post-herpetic pain, noncardiac chest pain, irritable bowel syndrome and pain associated with bowel disorders and dyspepsia. Some of the chronic pains set out above, for example, trigeminal neuralgia, diabetic neuropathic pain, causalgia, phantom limb pain and central post-stroke pain, have also been classified as neurogenic pain. One non-limiting definition of neurogenic pain is pain caused by dysfunction of the peripheral or central nervous system in the absence of nociceptor stimulation by trauma or disease. The compounds of the invention can, of course, be used to alleviate or reduce the incidence of neurogenic pain.

Since blockers of N-type calcium channels inhibit the release of excitatory amino acids, they can be used inter alia to inhibit damage to neuronal cells during anoxia, and function as neuroprotective agents, useful in the treatment of cerebral ischaemia or central nervous system injuries (Cox, B.; Denyer, J.C. Expert Opinion on Therapeutic Patents, 1998, 8, 1237-1250). The compounds can also be utilised for the treatment of eye diseases (Chu, T-C; Potter, D.E. Research Communications in Pharmacology and

Toxicology, 2001, 6, 263-275).

Examples of cerebral ischaemias which can be treated or prevented with the compounds of the invention include transient ischaemic attack, stroke, for example thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke or lacunar stroke, subarachnoid haemorrage, cerebral vasospasm, peri-natal asphyxia, drowning, cardiac arrest and subdural haematoma.

Examples of central nervous system injuries which can be treated with the compounds of the invention include traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injuries, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury.

Examples of eye diseases which can be treated or prevented with the compounds of the invention include drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrage, retinitis pigmentosa, acute glaucoma, in particular acute normal tension glaucoma, chronic glaucoma, in particular chronic normal tension glaucoma, macular degeneration, retinal artery occlusion and retinitis.

By virtue of their inhibition of neurotransmitter release the compounds of the invention can be used in the treatment of seizure disorders. Examples of seizure disorders which can be treated or prevented with the compounds of the invention include epilepsy and post-traumatic epilepsy, partial epilepsy (simple partial seizures, complex partial seizures, and partial seizures secondarily generalised seizures), generalised seizures, including generalised tonic/clonic seizures (grand mal), absence seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, and tonic seizures, Lennox

Gastaut, West Syndome (infantile spasms), multiresistant seizures and seizure prophylaxis (antiepileptogenic).

Furthermore the compounds of the invention can be utilised in the treatment of tinnitus, itch such as pruritoceptive, neuropathic, neurogenic and psychogenic itch, as well as urinary tract disorders such as urinary incontinence, and irritable bowel syndrome. The compounds of the invention may also have application in disorders which are generally associated with blocking of L-type calcium channels, such as cardiovascular, antiasthmatic and antibronchoconstriction disorders for example in the prevention and treatment of disorders such as hypersensitivity, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, premature labour, gastrointestinal motility disorders and cardiovascular disorders wherein the cardiovascular disorder is selected from the group consisting of hypertension, myocardial ischemia, angina, congestive heart failure, myocardial infarction and stroke.

The compounds of the invention may, where appropriate, be used prophylactically to reduce the incidence of such conditions.

A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.

The following Examples illustrate the invention. They do not, however, limit the invention in any way. In this regard, it is important to understand that the particular assays used in the Examples section are designed only to provide an indication of activity in inhibiting N-type calcium channels. There are many assays available to determine the activity of given compounds as N-type calcium channel antagonists, and a negative result in any one particular assay is therefore not determinative.

EXAMPLES

Examples of the compounds of the invention are compounds 1 to 65 listed above. Examples of the preparation of these compounds are described below.

Example 1

To a solution of 4-(4-bromophenyl)-pyridine-3-carbaldehyde (0.050g, 0.19mmol) (Thomas, A.D; Asokan, CN. , Journal of the Chemical Society, Perkin Transactions 1 2001, 20, 2583-2587) in benzene (3mL) was added 3,5-difluorobenzylamine (22μL, 0.19mmol) and mercaptoacetic acid (13μL, 0.19mmol). The reaction mixture was heated to reflux for 15h. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous ΝaHCO₃ followed by saturated brine. The organic layer was dried over MgS0 . The MgSO₄ was removed by filtration and the filtrate evaporated in vacuo to afford, after drying in vacuo, 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-(3,5- difluorobenzyl)-thiazolidin-4-one as a pale yellow solid. HPLC (Method A) retention time, 4.13 min. (Solvent: MeCN/H₂O/0.05% NH₄OH, 5-95% gradient H₂O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., C18 reverse phase. Flow rate: 1.5 mL/min.) Mass spectrum (ES+) m/z 461, 463 (M+H).

Example 2

Using a procedure analogous to that described in example 1, starting from 2,3,4 trifluorobenzylamine, 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-(2,3,4-trifluorobenzyl)- thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 4.17 min Mass spectrum (ES+) m/z 479, 481 (M+H). Example 3

Using a procedure analogous to that described in example 1, starting from 2,5- difluorobenzylamine, 2-[4-(4-bromo-phenyl)-pyridin-3-yl]-3-(2,5-difluoro-benzyl)- thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 5 4.07 min. Mass spectrum (ES+) m/z 461, 463 (M+H).

Example 4

Using a procedure analogous to that described for example 1, starting from 3,4- methylenedioxyphenethylamine hydrochloride and methylamine (40% in water) and 0 heating to 45°C for 64h and then 80°C for 6h, 3-(2-benzo[l,3]dioxol-5-y.l-ethyl)-2-[4-(4- bromo-phenyl)-pyridin-3-yl]-thiazolidin-4-one was obtained as a yellow oil. HPLC (Method A) retention time, 4.01 min. Mass spectrum (ES+) m/z 484 (M+H).

Example 5 Step 1

Using a procedure analogous to that described in example 1, starting from 4- bromopyridine-3-carbaldehyde, isobutylamine and mercaptoacetic acid, heating at 80°C for 16h and purification by flash column chromatography (eluting with isohexane/ethyl acetate 1:1-), 2-(4-bromo-pyridin-3-yl)-3-isobutyl-thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 3.55 min. Mass spectrum (ES+) ^• m/z 315, 317 (M+H)

Step 2

A solution of 2-(4-bromopyridin-3-yl)-3-isobutylthiazolidin-4-one (0.1 Og, 0.32mmol) and phenyl boronic acid (0.04 lg, 0.34mmol) in 1-propanol was flushed with nitrogen and stirred at room temperature for 20min. Pd(OAc)₂ (0.00 lg, 4.45mmol), PPh₃ (0.003, 9.5μmol) and 2M Na₂CO₃ (0.2mL, 0.38mmol) were added. The reaction mixture was flushed with nitrogen and then heated to 80°C for 16h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO₃ and brine and dried over MgSO . The MgSO was removed by filtration and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 1:1) to afford, after drying in vacuo, 3-isobutyl-2-(4-phenylpyridin-3-yl)- thiazolidin-4-one as a yellow solid. HPLC (Method A) retention time, 3.74 min. Mass spectrum (ES+) m/z 313 (M+H).

Example 6

Using a procedure analogous to that described in example 5, step 2 starting from 3,4- methylenedioxyphenylboronic acid, 2-(4-benzo[ 1 ,3]dioxol-5-yl-pyridin-3-yl)-3-isobutyl- thiazolidin-4-one was obtained as a yellow oil. HPLC (Method A) retention time, 3.64 min. Mass spectrum (ES+) m/z 357 (M+H).

Example 7

Using a procedure analogous to that described in example 5, step 2 starting from 2- thiopheneboronic acid, 3-isobutyl-2-(4-thiophen-2-yl-pyridin-3-yl)-thiazolidin-4-one was obtained as a yellow oil. HPLC (Method A) retention time, 3.48 min. Mass spectrum (ES+) m/z 319 (M+H).

Example 8

Using a procedure analogous to that described in example 1, starting from 2-cyclohex-l- enyl-ethylamine and purifying the product by flash column chromatography (eluting with isohexane/ethyl acetate 1 :1), 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-(2-cyclohex-l-enyl- ethyl)-thiazolidin-4-one was obtained as a solid. HPLC (Method A) retention time, 4.59 min. Mass spectrum (ES+) m/z 443, 445 (M+H).

Example 9 Using a procedure analogous to that described in example 5, step 2 starting from 2-(4- bromo-pyridin-3-yl)-3-isobutylthiazolidin-4-one and pyridin-4-ylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 1 :4 then ethyl acetate then ethyl acetate/methanol 19:1) 2-[4,4']bipyridinyl-3-yl-3- isobutylthiazolidin-4-one was obtained as a yellow oil. HPLC (Method A) retention time, 3.05 min. Mass spectrum (ES+) m/z 314 (M+H). Example 10

4-Chlorobenzene boronic acid (0.045g, 0.29mmol) was added to a stirring solution of 2- (4-bromopyridin-3-yl)-3-isobutylthiazolidin-4-one (0.075g, 0.24mmol) in 1 ,2-dimethoxy- ethane (lmL) and the solution was degassed. K₂CO₃ (0.090g, 0.65mmol), water (0.3mL) and Pd(PPh₃)₄ (0.01 Og, 9μmol) were added and the mixture was heated to 85°C for 15h. The mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO₃ and brine and dried over MgSO₄. The MgSO₄ was removed by filtration and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 2:3) to afford, after drying in vacuo, 2-[4-(4-chlorophenyl)- pyridin-3-yl]-3-isobutylthiazolidin-4-one as a pale yellow solid. HPLC (Method A) retention time, 4.00 min. Mass spectrum (ES+) m/z 347, 349 (M+H).

Example 11

Using a procedure analogous to that described in example 10 starting from 4- fluorobenzeneboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 3:2 then 1:1) 2-[4-(4-fluorophenyl)-pyridin-3-yl]-3- isobutylthiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 3.81 min. Mass spectrum (ES+) m/z 331' (M+H).

Example 12

Using a procedure analogous to that described in example 10 starting from 3- bromophenylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 9:1 then 4:1), 2-[4-(3-bromophenyl)-pyridin-3-yl]-3- isobutylthiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 4.01 min. Mass spectrum (ES+) m/z 391, 393 (M+H).

Example 13

Using a procedure analogous to that described in example 10 starting from 4- trifluoromethoxy phenyl boronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 3:2), 3-isobutyl-2-[4-(4-trifluoromethoxyphenyl)- pyridin-3-yl]-thiazolidin-4-one was obtained as a yellow oil. HPLC (Method A) retention time, 4.12 min. Mass spectrum (ES+) m/z 397 (M+H).

Example 14

Using a procedure analogous to that described in example 10 starting from 4-methyl- phenylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 3:2), 3-isobutyl-2-(4-p-tolyl-pyridin-3-yl)-thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 3.97 min. Mass spectrum (ES+) m/z 327 (M+H).

Example 15

Using a procedure analogous to that described in example 10, starting from 4- (trimethylsilyl)phenylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 3:2), 3-isobutyl-2-[4-(4-trimethylsilanyl-phenyl)- pyridin-3-yl]-thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 4.60 min. Mass spectrum (ES+) m/z 385 (M+H).

Example 16

Using a procedure analogous to that described in example 10, starting from 4- methylthiophenylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 3:2 then 1:1), 3-isobutyl-2-[4-(4-methylsulfanyl-phenyl)- pyridin-3-yl]-thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 4.01 min. Mass spectrum (ES+) m/z 359 (M+H).

Example 17 Using a procedure analogous to that described in example 10 starting from 4- ethylphenylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 7:3 then 3:2), 2-[4-(4-ethyl-phenyl)-pyridin-3-yl]-3-isobutyl-

I thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time,

4.20 min. Mass spectrum (ES+) m/z 341 (M+H). Example 18 Step l

M-Butyllithium (2.5M, 22.5mL, 56.3mmol) was added to a solution of diisopropylamine (9.56mL, 68.1mmol) in tetrahydrofuran (200mL) at -78°C. The reaction was stirred at - 78°C for 30 min and at Θ°C for 30 min. The reaction was cooled back down to -78°C and a solution of 3-bromopyridine (5mL, 51.2mmol) in tetrahydrofuran (15mL) was added. The reaction mixture was stirred for 10 min and dimethylformamide (15.8mL, 222mmol) was added. The reaction mixture was stirred for lh at -78°C and at room temperature for 30 min. Saturated NaHCO₃ (2mL) was added and the reaction poured onto saturated NaHCO₃ (200mL) and stirred for 16h. The organic layer was separated and concentrated in vacuo. The residue was dissolved in ether (300mL) and washed with saturated NaHCO₃ (200mL) and brine. The organic layer was separated and dried over MgSO . The MgSO was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in hot isohexane, filtered and the filtrate cooled to 0°C. A pale solid separated, which was collected by filtration and purified by flash column chromatography (eluting with isohexane/ethyl acetate 2:1) to afford, after drying in vacuo, 3-bromo- pyridine-4-carbaldehyde as a colourless solid. Η NMR (400 MHz, CDC1₃) δ 10.36 (1H), 8.91 (1H), 8.71(1H), 7.71 (1H).

Step 2

Using a procedure analogous to that described in example 1, starting from 3-bromo- pyridine-4-carbaldehyde and isobutylamine, heating to 80°C for 6h, and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 4:1) followed by triturating with isohexane, 2-(3-bromopyridin-4-yl)-3-isobutylthiazolidin-4-one was obtained as a colourless solid. HPLC (Method A) retention time, 3.60 min. Mass spectrum (ES+) m/z 315, 317 (M+H).

Step 3

To a stirred solution of 2-(3-bromopyridin-4-yl)-3-isobutylthiazolidin-4-one (0.20g, 0.63mmol) in 1,2-dimethoxyethane (lmL) was added 4-methoxyphenylboronic acid (0.116g, 0.76mmol), K₂CO₃ (0.237g, 1 Jlmmol) and water (2mL). The solution was degassed and Pd(PPh₃)₄ (0.029g, 0.03 mol) was added. The mixture was then heated to 85 °C for 16h. CH₂C1₂ (8mL) and water (5mL) were added to the mixture and stirring was continued for a further 30 min. The mixture was filtered and the filtrate was dried over MgSO . The MgSO₄ was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 4: 1 then 2:1 then 1 : 1 then 2:3) to afford, after drying in vacuo, a solid. The solid was triturated with isohexane and then dissolved in ether. A solution of HC1 in dioxane (4M) was added and the solvent was then evaporated in vacuo to afford, after drying in vacuo, 4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-3-(4-methoxy-phenyl)-pyridinium; chloride as a yellow solid. HPLC (Method A) retention time, 3.77 min. Mass spectrum (ES+) m/z 343 (M+H).

Example 19

Using a procedure analogous to that described in example 18, step 3 starting from 4- chlorobenzeneboronic acid, 3-(4-chloro-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)- pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 4.03 min. Mass spectrum (ES+) m/z 347, 349 (M+H). ^'

Example 20 Using a procedure analogous to that described in example 18, step 3 starting from 4- fluorobenzeneboronic acid, 3-(4-fluoro-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)- pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 3.83 min. Mass spectrum (ES+) m/z 331 (M+H).

Example 21

Using a procedure analogous to that described in example 18, step 3 starting from 4- methylphenylboronic acid, 4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-3-p-tolyl-pyridinium; chloride was obtained as a pale yellow solid. HPLC (Method A) retention time, 4.06 min. Mass spectrum (ES+) m z 327 (M+H).

Example 22 Step l

2.5 M rt-Butyllithium (22.5mL, 56.3mmo.) was added to a solution of diisopropylamine (9.56mL, 68.1mmol) in tetrahydrofuran (200mL) at -78°C. The reaction was stirred at - 78°C for 30 min and at 0°C for 30 min. . The reaction was cooled back down to -78°C and a solution of 2-bromopyridine (5mL, 52.4mmol) in tetrahydrofuran (15mL) was added. The reaction was stirred at -78°C for 4h., during which time the solution became bright orange. Dimethylformamide (15.8mL, 204mmol) was added and the reaction was stirred for 30 min at -78°C and then at room temperature for 2h. Saturated aqueous Nl-L_tCl (60mL) was added and the reaction stirred for 16h at room temperature. The organic layer was separated and concentrated in vacuo. The residue was dissolved in ether and washed with saturated NaHCO₃ and saturated brine. The organic layer was separated and dried over MgSO . The MgSO was removed by filtration and the filtrate concentrated in vacuo to afford a reddish oil. The oil was purified by flash column chromatography (eluting with isohexane/ethyl acetate 9: 1 then 4: 1 ) to afford, after drying in vacuo, 2-(2-bromopyridin-3-yl)-3-isobutylthiazolidin-4-one as a colourless solid. . Η NMR (400 MHz, CDC1₃) δ 10.34 (1H), 8.57 (1H), 8.17 (1H), 7.43 (1H).

Step 2

To a solution of 2-(2-bromopyridin-3-yl)-3-isobutylthiazolidin-4-one (0.689g, 3.70mmol) and isobutylamine (0.44mL, 4.44mmol) in benzene (20mL) at,80°C was added mercaptoacetic acid (0.3 lmL, 4.44mmol). The reaction was heated to 80°C for 16h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO₃, and brine and dried over MgSO₄. The MgSO₄ was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 2: 1) to give a solid. A second impure fraction was obtained, which was purified by triturating with isohexane and dried in vacuo to give 2-(2-bromo-pyridin-3-yl)-3-isobutyl- thiazolidin-4-one as colourless needles. . Η NMR (400 MHz, CDC1₃) δ 8.36 (1H), 7.43 (1H), 7.33 (1H), 5.95 (1H), 3.64-3.70 (3H), 2.43 (1H), 1.93-2.00 (1H), 0.92 (6H).

Step 3

To a stirred solution of 2-(2-bromo-pyridin-3-yl)-3-isobutyl-thiazolidin-4-one (0.1 Og, 0.32mmol) in 1,2-dimethoxyethane (2mL) was added 4-bromobenzeneboronic acid (0.076g, 0.38mmol), K₂CO₃ (0.118g, 0.86mmol) and water (2mL). The solution was degassed and Pd(PPh₃)₄ (0.017g, 0.02mmol) was added. The mixture was then heated to 85°C for 16h. CH₂C1₂ (8mL) and water (5mL) were added to the mixture and stirring was continued for a further 30 min. The mixture was filtered and the filtrate was dried over MgSO . The MgSO₄ was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 4: 1 then 3 : 1 then 2:1). The purified product was dissolved in ether and a solution of HC1 in dioxane (4M) was added resulting in a colourless precipitate. The precipitate was collected by filtration and then triturated with isohexane and dried in vacuo to afford, 2-(4-bromo-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride as a colourless solid. HPLC (Method A) retention time, 4.04 min. Mass spectrum (ES+) m/z 391 393 (M+H).

Example 23

Using a procedure analogous to that described in example 22, step 3 starting from 4- methoxyphenylboronic acid, 3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-methoxy-phenyl)- pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 3.69 min. Mass spectrum (ES+) m/z 343 (M+H).

Example 24

Using a procedure analogous to that described in example 22, step 3 starting from 4- chlorobenzeneboronic acid, 2-(4-chloro-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)- pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 3.97 min. Mass spectrum (ES+) m/z 347, 349 (M+H).

Example 25 Using a procedure analogous to that described in example 22, step 3 starting from 4- fluorobenzeneboronic acid, 2-(4-fluoro-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)- pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 3.75 min. Mass spectrum (ES+) m/z 331 (M+H).

Example 26

Using a procedure analogous to that described in example 22, step 3 starting from 4- methylphenyl boronic acid, 3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-2-p-tolyl-pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 3.88 min. Mass spectrum (ES+) m/z 327 (M+H).

Example 27

Using a procedure analogous to that described in example 10, starting from 4- trifluoromethylphenylboronic acid, purifying by flash column chromatography (eluting with isohexane/ethyl acetate 3:2), 3-isobutyl-2-[4-(4-trifluoromethyl-phenyl)-pyridin-3- yl]-thiazolidin-4-one was obtained as a pale yellow oil. HPLC (Method A) retention time, 4.08 min. Mass spectrum (ES+) m/z 381 (M+H).

Example 28

Using a procedure analogous to that described in example 10 starting from 4- cyanophenylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 2:3 then 1 :1), 4-[3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridin-4- yl]-benzonitrile was obtained as a pale yellow solid.. HPLC (Method A) retention time, 3.57 min. Mass spectrum (ES+) m/z 338 (M+H).

Example 29 Using a procedure analogous to that described in example 10 starting from 4- methoxyphenylboronic acid and purifying by flash column chromatography (elutiηg with isohexane/ethyl acetate 2:3 then 1:1), 3-isobutyl-2-[4-(4-methoxy-phenyl)-pyridin-3-yl]- thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 3.77 min. Mass spectrum (ES+) m/z 343 (M+H).

Example 30

Using a procedure analogous to that described in example 10 starting from 4- vinylphenylboronic acid and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 2:3 then 1:1), 3-isobutyl-2-[4-(4-vinyl-phenyl)-pyridin-3-yl]- thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 4.05 min. Mass spectrum (ES+) m/z 339 (M+H).

Example 31

To a solution 2-(3-bromopyridin-4-yl)-3-isobutylthiazolidin-4-one (0.20g, 0.63mmol) and 4-bromobenzeneboronic acid (0.153g, 0.76mmol) in 1,2-dimethoxyethane (2mL) was added K₂CO₃ (0.237g, 1.71mmol) and water (2mL). The solution was degassed and then treated with Pd(PPh₃)₄ The reaction was heated to 85° for 16h. CH₂C1₂ (8mL) and water (5mL) were added and the mixture was stirred for 30 min. The mixture was filtered using a phase separating tube (1ST, Isolute). The organic layer was dried over MgSO . The MgSO₄ was removed by filtration and the filtrate evaporated in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 4:1 to 2: 1 to 1:1 to 2:3) and then by preparative reverse phase HPLC (Solvent: MeCN/H₂O/0.05% NH₄OH, 5-95%o gradient H₂O - 6 min. Column: Waters Xterra 50 x 19 mm i.d., C18 reverse phase. Flow rate: 17 mL/min.) to afford a colourless solid. The solid was dissolved in ether and a solution of HC1 in dioxane (4M) was added giving a colourless precipitate, which was collected by filtration and then triturated with ether to afford, after drying in vacuo, 3-(4-bromo-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride as a colourless solid.. HPLC (Method A) retention time, 4.07 min. Mass spectrum (ES+) m/z 391, 393 (M+H). Example 32

To a solution if 2-(2-bromopyridin-3-yl)-3-isobutylthiazolidin-4-one in toluene (5mL) and ethanol (lmL) was added 4-vinylphenylboronic acid and 2M Na2CO3 (2mL). The reaction mixture was degassed and Pd(PPh₃) was added. The reaction was then heated to 100°C for 16h. . CH₂Cr_f (8mL) and water (5mL) were added to the mixture and stirring was continued for a further 30 min. The mixture was filtered and the filtrate was dried over MgSO₄. The MgSO was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography eluting with isohexane/ethyl acetate (4:1 to 1:1). The residue was dissolved in ether and 4M HCl/dioxan was added. The precipitate was collected by filtration, triturated with ether and dried in vacuo to afford 4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-3-(4-vinyl-phenyl)- pyridinium; chloride as a colourless solid. HPLC (Method A) retention time, 4.04 min. Mass spectrum (ES+) m/z 339 (M+H).

Example 33

Using a procedure analogous to that described in example 32 starting from 4- (trifluoromethyl)-phenylboronic acid, 3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-2-(4- trifluoromethyl-phenyl)-pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 4.06 min. Mass spectrum (ES+) m/z 381 (M+H).

Example 34

Using a procedure analogous to that described in example 32 starting from 4- cyanophenylboronic acid, 2-(4-cyano-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)- pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 3.58 min. Mass spectrum (ES+) m/z 338 (M+H).

Example 35

Using a procedure analogous to that described in example 32 starting from 4- vinylphenylboronic acid, 3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-vinyl-phenyl)- pyridinium; chloride was obtained as a colourless solid. HPLC (Method A) retention time, 3.97 min. Mass spectrum (ES+) m/z 339 (M+H).

Example 36

A solution of 4-(4-bromophenyl)-pyridine-3-carbaldehyde (0.083g, 0.315mmol) and isoamyl amine (0.033g, 0.38mmol) was heated to 60°C in benzene for 90 min. Mercaptoacetic acid (0.038g, 0.41mmol) was added and the mixture was heated to 80°C for 16h. The solvent was removed by evaporation in vacuo and the residue was triturated with ether to afford, after drying in vacuo, 2-[4-(4-bromo-phenyl)-pyridin-3-yl]-3-(3- methyl-butyl)-thiazolidin-4-one as colourless needles. HPLC (Method A) retention time, 4.29 min Mass spectrum (ES+) m/z 405, 407 (M+H).

Example 37

A solution of 4-(4-bromophenyl)-pyridine-3-carbaldehyde (0.083g, 0.32mmol), 2,2,3,3,3- pentafluoropropylamine (0.104g, 0.7mmol) and mercaptoacetic acid (0.032g, 0.35mmol) was heated in toluene at 56°C for 72h and at 80°C for 36h. The solvent was removed by evaporation in vacuo and the residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 1 : 1) to afford, after drying in vacuo, 2-[4-(4- bromophenyl)-pyridin-3-yl]-3-(2,2,3,3,3-pentafluoropropyl)-thiazolidin-4-one as a colourless solid. HPLC (Method A) retention time, 3.75 min Mass spectrum (ES+) m/z 467, 469 (M+H).

Example 38

A solution of 4-(4-bromophenyl)-pyridine-3-carbaldehyde (0.050g, 0.19mmol) in benzene (lmL) was heated to 50°C and ethylamine (2M solution in tetrahydrofuran, 0.19mL, 0.38mmol) was added. The solution was heated to 50°C for 15 min and mercaptoacetic acid (0.018g, 0.19mmol) was added. The reaction was then heated to 80°C for 72h. Aqueous K₂CO₃ was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO₄. The MgSO was removed by filtration and the filtrate concentrated in vacuo. The residue was triturated with ether to afford, after drying in vacuo, 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-ethylthiazolidin-4-one as an off-white solid. HPLC (Method A) retention time, 3.75 min. Mass spectrum (ES+) m/z 363, 365 (M+H).

Example 39

Using a procedure analogous to that described in example 36 starting from 3,3- dimethylbutylamine, 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-(3,3-dimethyl-butyl)- thiazolidin-4-one was obtained as an off-white solid. HPLC (Method A) retention time, 4.40 min. Mass spectrum (ES+) m/z 419, 421 (M+H).

Example 40

Using a procedure analogous to that described in example 36 starting from cyclopentylamine, 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-cyclopentyl-thiazolidin-4-one was obtained as an off-white solid. HPLC (Method A) retention time, 4.17 min. Mass spectrum (ES+) m/z 403, 405 (M+H).

Example 41

Using a procedure analogous to that described in example 36 starting from aminomethylcyclopropane, 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-cyclopropylmethyl- thiazolidin-4-one was obtained as an off-white solid . HPLC (Method A) retention time, 3.99 min. Mass spectrum (ES+) m/z 389, 391 (M+H).

Example 42 Using a procedure analogous to that described in example 36 starting from 3-

(isopropoxy)-propy lamine, 2- [4-(4-bromo-pheny l)-pyridin-3 -y 1] -3 -(3 -isopropoxypropy 1)- thiazolidin-4-one was obtained as a straw yellow oil. HPLC (Method A) retention time, 4.09 min. Mass spectrum (ES+) m/z 435, 437 (M+H). Example 43

Using a procedure analogous to that described in example 36 starting from allylamine, 3- allyl-2-[4-(4-bromophenyl)-pyridin-3-yl]-thiazolidin-4-one was obtained as a colourless solid. HPLC (Method A) retention time, 3.95 min. Mass spectrum (ES+) m/z 375, 377 (M+H).

Example 44

Using a procedure analogous to that described in example 10 starting from 3- methylbenzeneboronic acid, 3-isobutyl-2-(4-m-tolyl-pyridin-3-yl)-thiazolidin-4-one was obtained as a pale yellow solid. HPLC (Method A) retention time, 3.96 min. Mass spectrum (ES+) m/z (M+H).

Example 45

Using a procedure analogous to that described in example 10 starting from 2,4- dimethylbenzeneboronic acid, 2-[4-(2,4-dimethylphenyl)-pyridin-3-yl]-3-isobutyl- thiazolidin-4-one was obtained as a pale yellow oil. HPLC (Method A) retention time, 4.15 min. Mass spectrum (ES+) m/z 341 (M+H).

Example 46 Using a procedure analogous to that described in example 10 starting from 2- methylbenzene boronic acid, 3-isobutyl-2-(4-o-tolyl-pyridin-3-yl)-thiazolidin-4-one was obtained a colourless oil. . HPLC (Method A) retention time, 3.95 min. Mass spectrum (ES+) m/z 327 (M+H).

Example 47

A solution of wj-chloroperbenzoic acid (0.07 lg, 0.28mmol) in methanol (5mL) was added to a solution of 2-[4-(4-bromo-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one in a mixture of chloroform (2.25mL) and methanol (2.25mL) at -70° . The reaction mixture was stirred at for 5h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with CH CL₂. The organic layer was washed with brine and dried over MgSO₄. The MgSO₄ was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with ethyl acetate/methanol 19:1) to afford, after drying in vacuo, 4-(4-bromo-phenyl)-3-(3- isobutyl-l,4-dioxo-llambda*4*-thiazolidin-2-yl)-pyridinium; chloride as a colourless solid. HPLC (Method A) retention time, 3.55 min . Mass spectrum (ES+) m/z 407, 409 (M+H).

Example 48

A solution of 4-(4-bromophenyl)-pyridine-3-carbaldehyde (O.lOOg, 0.38mmol) and 2- butylamine (0.028g, 0.38mmol) was heated to 80°C in benzene for 2h. Mercaptoacetic acid (0.035g, 0.38mmol) was added and the mixture was heated to 80° for 16h.

Additional mercaptoacetic acid (0.035g, 0.38mmol) was added and the mixture was heated at 90°C for 6h and then at 70°C for 4 days. The solvent was removed by evaporation in vacuo and the residue was purified by flash column chromatography to afford 2-[4-(4-bromophenyl)-pyridin-3-yl]-3-sec-butyl-thiazolidin-4-one as a straw yellow oil. HPLC (Method A) retention time, 4.04min. Mass spectrum (ES+) m/z 391, 393 (M+H).

Example 49

Using a procedure analogous to that described in example 48 starting from cyclohexylamine and triturating the product with ether, 2-[4-(4-bromophenyl)-pyridin-3- yl]-3-cyclohexyl-thiazolidin-4-one was obtained as an off-white solid. HPLC (Method A) retention time, 4.23 min. Mass spectrum (ES+) m/z 417, 419 (M+H).

Example 50 Step 1

A solution of 3-bromopyridine-4-carbaldehyde (1.09g, 5.45mmoι) and cyclopentylamine (0.46g, 5.45mmol) in benzene was heated to 70°C for 90min. Mercaptoacetic acid (0.50g, 5.45mmol) was added and the reaction was heated to 70°C for 4 days. The solvent was evaporated in vacuo to give 2-(3-bromo-pyridin-4-yl)-3-cyclopentyl-thiazolidin-4-one as an oil. HPLC (Method A) retention time, 3.55 min. Mass spectrum (ES+) m/z 327, 329 (M+H). Step 2

A solution of 3,4-methylenedioxyboronic acid (0.06 lg, 0.37mmol) and 2-(3-bromo- pyridin-4-yl)-3-cyclopentyl-thiazolidin-4-one (0.10g, 0.31mmol) in 1,2-dimethoxyethane (ImL) was degassed. K₂CO₃ (0.114g, 0.82mmol), water (0.4mL) and Pd(PPh₃)₄ ((0.020g, 17μmol) were added and the mixture was heated to 85°C for 16h. The mixture was treated with saturated aqueous NaHCO₃ (30mL) and CH₂CI2 and stirred for 30 minutes. The organic layer was separated and the solvent removed by evaporation in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate/methanol 10:10:1) and crystallization from methanol to afford, after drying in vacuo, 2-(3-benzo[l,3]dioxol-5-yl-pyridin-4-yl)-3-cyclopentylthiazolidm-4-one as a colourless solid. HPLC (Method A) retention time, 3.76 min. Mass spectrum (ES+) m/z 369 (M+H).

Example 51

Using a procedure analogous to that described in example 50, step 2, starting from 4- cyanophenylboronic acid, 4-[4-(3-cyclopentyl-4-oxothiazolidin-2-yl)-pyridin-3-yl]- benzonitrile was obtained as a colourless solid. HPLC (Method A) retention time, 3.65min. Mass spectrum (ES+) m/z 279, no molecular ion observed.

Example 52

Using a procedure analogous to that described in example 50, step 2, starting from 4- (N,N-dimethylamino)-phenylboronic acid, 3-cyclopentyl-2-[3-(4-dimethylamino- phenyl)-pyridin-4-yl]-thiazolidin-4-one was obtained as a yellow oil. HPLC (Method A) retention time, 3.65 min. Mass spectrum (ES+) m/z no molecular ion observed (M+H).

Example 53

Using a procedure analogous to that described in example 50, step 2, starting from 4- (trifluoromethyl)-phenylboronic acid, 3-cyclopentyl-2-[3-(4-trifluoromethylphenyl)- pyridin-4-yl]-thiazolidin-4-one was obtained as an off-white solid. HPLC (Method A) retention time, 4.16 min. Mass spectrum (ES+) m/z 393 (M+H). Example 54

Using a procedure analogous to that described in example 50, step 2, starting from 4- methoxyphenylboronic acid, cyclopentyl-2-[3-(4-methoxyphenyl)-pyridin-4-yl]- thiazolidin-4-one was obtained as a colourless solid. HPLC (Method A) retention time, 3.84 min. Mass spectrum (ES+) m/z 355 (M+H).

Example 55

Using a procedure analogous to that described in example 50, step 2, starting from 4- (methylthio)-phenylboronic acid, 3-cyclopentyl-2-[3-(4-methylsulfanyl-phenyl)-pyridin- 4-yl]-thiazolidin-4-one was obtained as an off-white solid. HPLC (Method A) retention time, 4.06 min. Mass spectrum (ES+) m/z 371 (M+H).

Example 56

Using a procedure analogous to that described in example 50, step 2, starting from 4- ethylphenylboronic acid, 3-cyclopentyl-2-[3-(4-ethyl-phenyl)-pyridin-4-yl]-thiazolidin-4- one was obtained as an off-white crystalline solid. HPLC (Method B) retention time, 4.29 (Solvent: MeCN/H₂O/0.05% HCO₂H, 5-95% gradient H₂O - 6 min. Column: Waters Xterra 50 x 4.60 mm i.d., C18 reverse phase. Flow rate: 1.5 mL/min.) min. Mass spectrum (ES+) m/z 353 (M+H).

Example 57

Using a procedure analogous to that described in example 50, step 2, starting from 4- bromobenzeneboronic acid, 2-[3-(4-bromophenyl)-pyridin-4-yl]-3-cyclopentyl- thiazolidin-4-one was obtained as a straw yellow oil. HPLC (Method A) retention time, 4.19 min. Mass spectrum (ES+) m/z 403, 405 (M+H).

Example 58

Using a procedure analogous to that described in example 50, step 2, starting from 3,4- dimethylphenylboronic acid, 3-cyclopentyl-2-[3-(3,4-dimethyl-phenyl)-pyridin-4-yl]- thiazolidin-4-one was obtained as a straw yellow oil. HPLC (Method A) retention time, 4.24 min. Mass spectrum (ES+) m/z 353 (M+H).

Example 59 A solution of 4-vinylphenylboronic acid (0.96g, 6.48mmol) and 3-bromopyridine-4- carbaldehyde (l.Og, 5.4mmol) in 1,2-dimethoxyethane (lOmL) was degassed. K₂CO₃ (1.412g, 14.6mmol) in water (4mL) and Pd (PPh₃)₄ were added and the reaction heated to 40°C for 72h and then 80°C for lh. The reaction was cooled to room temperature, treated with K₂CO₃ solution and CH₂CI2 and stirred for a further 30 min.. The mixture was filtered through phase separator tubes (1ST, Isolute). The CH2CI2 was removed by evaporation in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 1:1) to afford, after drying in vacuo, 3-(4-vinylphenyl)- pyridine-4-carbaldehyde. HPLC (Method A) retention time, 3.70 min. Mass spectrum (ES+) m/z 210 (M+H).

Example 60

A solution of cyclopropylamine (0.019g, 0.33mmo.) and 3-(4-vinylphenyl)-pyridine-4- carbaldehyde in benzene (ImL) was heated at 60°C for 90 min. Mercaptoacetic acid (0.030g, 0.33mmol) was added and the mixture was heated at 60°C for 16h and 80°C for 8h. Additional mercaptoacetic acid (0.030g, 0.33mmol) was added and the reaction was heated at 80°C for 16h. The mixture was diluted with CH2θ₂ and filtered through phase separating tubes (1ST, Isolute). The CH₂C1₂ was evaporated in vacuo. The residue was purified by flash column chromatography to afford, after drying in vacuo, 3-cyclopropyl- 2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one as a colourless oil. HPLC (Method A) retention time, 3.67 min. Mass spectrum (ES+) m/z 323 (M+H).

Example 61

Using a procedure analogous to that described in example 60 starting from cyclobutylamine, 3-cyclobutyl-2-[3-(4-vinylphenyl)-pyridin-4-yl]-thiazolidin-4-one was obtained as a pale yellow oil . HPLC (Method A) retention time, 3.89 min. Mass spectrum (ES+) m/z 337 (M+H). Example 62

Using a procedure analogous to that described in example 60 starting from isopropylamine, 3-isopropyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one was obtained as a pink oil. HPLC (Method A) retention time, 3.82 min. Mass spectrum (ES+) m/z 325 (M+H).

Example 63

Using a procedure analogous to that described in example 60 starting from sec- butylamine, 3-sec-butyl-2-[3-(4-vinylphenyl)-pyridin-4-yl]-thiazolidin-4-one was obtained as a colourless oil. HPLC (Method A) retention time, 3.97 min. Mass spectrum (ES+) m/z 339 (M+H).

Example 64 Using a procedure analogous to that described in example 60 starting from 1- ethylpropylamine, 3-( 1 -ethyl-propyl)-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4- one was obtained as a colourless oil. HPLC (Method A) retention time, 4.16 min. Mass spectrum (ES+) m/z 353 (M+H).

Example 65 Step 1

A solution of 3-bromothiophene-2-carbaldehyde (0.50g, 2.62mmol) (US patent 4876271) and isobutylamine (0.3 ImL, 3.14mmol) in benzene (lOmL) was heated to 80°C for 30min. and then mercaptoacetic acid (0.22mL, 3.14mmol) was added and heating was continued for 16h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO₃, and brine and dried over MgSO₄. The MgSO was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in benzene (lOmL) and mercaptoacetic acid (0.22mL, 0.314mmol) was added. The mixture was heated to 80°C for 16h. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO₃, and saturated brine and dried over MgSO₄. The MgSO₄ was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (eluting with isohexane/ethyl acetate 9:1) to afford, after drying in vacuo, 2-(3-bromothiophen-2-yl)-3-isobutyl-thiazolidin-4-one as a yellow oil. HPLC (Method A) retention time, min. Mass spectrum (ES+) m/z 318, 320 (M+H).

Step 2

In a manner analogous to that described in example 22, step 3 starting from 4- vinylphenylboronic acid and 2-(3-bromothiophen-2-yl)-3-isobutyl-thiazolidin-4-one and purifying by flash column chromatography (eluting with isohexane/ethyl acetate 9:1), 3- isobutyl-2-[3-(4-vinyl-phenyl)-thiophen-2-yl]-thiazolidin-4-one was obtained as a yellow oil. HPLC (Method A) retention time, 4.45 minMass spectrum (ES+) m/z 344 (M+H).

Activity Example

N-type calcium channel inhibition in IMR32 cells

The human neuroblastoma cell line IMR32 has been used by a number of groups to investigate calcium ion channels either by electrophysiological or fluorescent techniques in low throughput assays (Carbone, E., et al. (1990) Pflϋgers Arch 416: 170-179; Rafferty, M., et al. (2000) Patent WO 00/06559; Seko, T., et al., (2001) Bioorg Med Chem Lett 11:2067-2070).

It has been shown that undifferentiated IMR32 cells constitutively express L-type calcium channels, whilst differentiated IMR32 cells express both N- and L-type channels. Therefore, undifferentiated IMR32 cells can be used to assay the L-type calcium channel and differentiated cells assayed in the presence of 5 μM nitrendipine can be used to study the N-type channels. The Molecular Devices Corp FLEXstation™ was utilised to develop a medium throughput assay with undifferentiated and differentiated IMR32 cells labelled with Fluo- 4. Opening of voltage-activated calcium channels was stimulated by depolarisation of cells with KC1, which was added by the FLEXstation's fluidics system. The resulting influx of calcium into the cells was recorded by an increase in fluorescence. The assays were validated with known ion channel blockers.

IMR32 cells were grown in EMEM supplemented with 10% foetal bovine serum, 2 mM lutamine, 1% NEAA, 100 U/ml penicillin and 100 μg/ml streptomycin. To differentiate the IMR32 cells, 1 mM dibutyryl cAMP and 2.5 μM bromodeoxyuridine were added to the cell culture media and cells maintained for 7-9 days.

Cells were detached from tissue culture surfaces using an enzyme free cell dissociation buffer (Invitrogen) after washing with a Ca²⁺/Mg²⁺ free Hanks buffered saline solution (HBSS). The cells were then resuspended in assay buffer (HBSS containing Ca²⁺/Mg²⁺ and supplemented with 20 mM HEPES, pH 7.4) to give a total volume of 40 ml. 2 μM Fluo-4 and 50 μM probenecid were added and then the cells were incubated at 25 °C for 30 min. Following centrifugation in a Heraeus Megafuge 1.0 (rotor 2704) for lmin at 1000 rpm, the cell pellet was resuspended in 40 ml assay buffer supplemented with 50 μM probenecid and incubated at 25 °C for a further 30 min. The cells were centrifuged as before and again resuspended in assay buffer supplemented with probenecid. 200,000 cells were aliquoted into each well of a 96- well plate containing 0.001-100 μM compound to be tested (for the N-type assay 5 μM nitrendipine was also added to each well), in triplicate. The final volume of compound and cells in assay buffer was 200 μl. The plate containing cells was centrifuged at 300 rpm for 1 min with no brake in a Heraeus Labofuge 400E (rotor 8177).

The plate was then assayed using the FLEXstation (Molecular^' Devices Corp). The excitation and emission wavelengths were 494 and 525 nm, respectively. The calcium response was stimulated by the addition of 50 μl 250 mM KC1 (50 mM final concentration) by the FLEXstation fluidics system. SOFTmax Pro (Molecular Devices Corp) was used to calculate the change in fluorescence caused by calcium influx for each well and hence the IC50 for each compound. The results are shown in the Table below.

Claims

1. Use, in the manufacture of a medicament for use in the treatment or prevention of a condition mediated by N-type calcium channels, of a compound of formula (I), or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

wherein:

Z is -S-, -S(O)-, -SO₂-, -O- or -NR- wherein R is hydrogen, C_rC₆ alkyl or -CO-(Cι-C₆ alkyl); R¹ is hydrogen or Ci -C₆ alkyl;

R² is hydrogen, fluorine or Ci-d alkyl;

Y is -(CR^y ₂)_m-X₄-(CR^y ₂)n-, -(CR^y2)m-A-(CR^y2)_m- or -(CR^y2)_m-A-(CR^y2)p-X3-(CR^y2)_m, wherein: p, m and n are each independently an integer of 0 to 4; - A is aryl, heteroaryl, carbocyclyl or heterocyclyl;

X₃ is -O-, -S-, -NR'-, -S(O)-, -SO₂-, -O-CO-, -S-CO-, -NR'-CO, -CO-O-,

-CO-S- or -CO-NR' wherein R' is hydrogen, Ci-d alkyl, C₂-d alkenyl or C₂-d alkynyl;

X₄ is -O-, -S-, -NR'-, -S(O)- or -SO₂- wherein R is hydrogen, Ci-d alkyl, C₂-d alkenyl or d-d alkynyl; each R^y is the same or different and is hydrogen, Cι-C₆ alkyl, d-d alkenyl, d- d alkynyl, aryl or heteroaryl; R³ is aryl, heteroaryl, heterocyclyl or carbocyclyl; and i is -Cι-Xι-Arι or -d-X₂-d, wherein: - Ci is a direct bond, a Ci-d alkylene group, a C₂-d alkenylene group or a d-d alkynylene group; Xi is a direct bond when Ci is a direct bond and, when Ci is a Cι-C₆ alkylene group, d-d alkenylene group or C₂-d alkynylene group, represents a direct bond or -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -O-CO-NR- or -NR'-CO-O-, wherein each R' is the same or different and represents hydrogen, phenyl, Ci-d alkyl, C₂-C₆ alkenyl or C₂-d alkynyl and each R" is the same or different and represents a Ci-d alkylene group, a d-d alkenylene group or a C₂-d alkynylene group; Ari is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-R^a-, heterocyclyl-R^a-, aryl-R^a- or carbocyclyl-R^a-, wherein R^a is a Ci-d alkylene group, a d-d alkenylene group or a d-d alkynylene group; d is a Ci-d alkylene group, a d-d alkenylene group or a C₂-d alkynylene group; X₂ is a direct bond or -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-,

-CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -NR'-CO-O- or -O-CO-NR'-, wherein each R' is the same or different and represents hydrogen, phenyl, Ci-d alkyl, d-d alkenyl or d-d alkynyl and each R" is the same or different and represents a Ci-d alkylene group a d-d alkenylene group or a d-d alkynylene group; and d is a Ci-d alkyl group, a d-d alkenyl group or a d-d alkynyl group.

2. Use according to claim 1, wherein Z is -S-, -O- or -SO-.

3. Use according to claim 1 or 2, wherein Ri is hydrogen or -CH₃.

4. Use according to any one of the preceding claims, wherein R₂ is hydrogen or an unsubstituted Cι-C alkyl group.

5. Use according to any one of the preceding claims, wherein each R^y is the same or different and is hydrogen or an unsubstituted Cι-C₄ alkyl or phenyl group.

6. Use according to any one of the preceding claims, 'wherein A is an aryl or heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from unsubstituted C ₁ -C₄ alkyl, C ₁ -C alkoxy, halogen, hydroxy, NH2, NH(C 1 -d alkyl) and N(Cι-d alkyl)2 groups.

7. Use according to any one of the preceding claims, wherein X₃ is -O-, -S-, -SO-, -SO₂- or -NH-CO-.

8. Use according to any one of the preceding claims, wherein p is 0 or 1; and/or m is 0 or 1 ; and/or n is 1 or 2.

9. Use according to any one of the preceding claims, wherein X₄ is -S- or

-O-.

10. Use according to any one of the preceding claims, wherein Y is a group of formula -(CH₂)_mO(CH2)n-, -A- or -A-X₃-(CH2)_m- wherein R^y, A, X₃, m and n are as defined in any one of claims 1 or 5 to 8.

11. Use according to any one of the preceding claims wherein R₃ is an aryl, heteroaryl or carbocyclyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, Ci-d alkyl, Ci-d alkoxy, Ci-d alkylthio, d-d alkenyl, C₂-d alkenyloxy, C₂-C₆ alkenylthio, C₂-d alknynyl, d-d alkynyloxy, C₂-C₆ alkynylthio, C₃-C₆ carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-C₆ carbocyclylthio, -NH-CO-(Cι-C₆ alkyl), -CO-NH-(Cι-C₆ alkyl), -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group and Si(R⁷⁷⁷)₃, wherein each R⁷⁷⁷ is independently a Cι-C₄ alkyl group, the substituents on R₃ being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy.

12. Use according to any one of the preceding claims, wherein Ci is a direct bond or a Ci-d alkylene group.

13. Use according to claim 12, wherein Ci is a direct bond or an unsubstituted Ci-d alkylene group.

14. Use according to any one of the preceding claims, wherein Xi is a direct bond or is -O-, -S-, -S-CO-, -O-CO- or -NH-CO-.

15. Use according to any one of the preceding claims, wherein Ar₍ is a heteroaryl, heterocyclyl, aryl, carbocyclyl or heteroaryl-(Cι-C₂ alkyl)- group which is unsubstituted or carries, on the cyclic moiety, 1 , 2 or 3 unsubstituted groups selected from halogen, d-C₄ alkyl, hydroxy, Ci-d alkoxy, -NR'R" and -NH-CO-R wherein R' and R" are the same or different and are selected from hydrogen and unsubstituted Cι-C alkyl.

16. Use according to claim 15, wherein Ar_t is a pyridyl, thienyl, benzimidazolyl, thienyl-methyl-, pyridyl-methyl-, fiiranyl-methyl-, morpholinyl, piperazinyl, piperadinyl, pyrrolidinyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl or phenyl group or a saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms, each of which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 substituents selected from fluorine, hydroxy, -OCH₃, -N(CH₃)₂ and -NH-CO-CH₃.

17. Use according to claim 16, wherein Ari is a pyridyl, thienyl, benzimidazolyl, furanyl-methyl-, 1,4-benzodioxanyl, phenyl or 1,3-benzodioxolyl group which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 substituents selected from fluorine, hydroxy, -OCH₃, -N(CH₃)₂ and -NH-CO-CH₃.

18. Use according to any one of claims 1 to 11, wherein C₂ is^* a Cι-C alkylene group, which is unsubstituted or substituted with one or two substituents selected from hydroxy and fluorine.

19. Use according to any one of claims 1 to 1 1 or 18, wherein X₂ is a direct bond or -0-, -S-, -CO-O-, -O-CO-, -S-CO-, -CO-S- or -NH-CO-.

20. Use according to any one of claims 1 to 1 1, 18 or 19, wherein d is a Ci-d alkyl or C₂-C alkenyl group which is unsubstituted or substituted with 1, 2 or 3 unsubstituted groups selected from hydroxy, -NH₂, -NH(Cι-C₂ alkyl), -N(Cι-C₂ alkyl)₂ and halogen.

21. Use according to claim 1, wherein the compound of formula (I) is a thiazolidinone derivative of formula (IA) or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

wherein: Y is a group of formula -(CH₂)_mO(CH₂)-, -A- or -A-X -(CH2)_m- wherein A is a phenyl, pyridyl or pyrrolyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from -CH3, -CH₂-CH₃, -OCH₃, -OCH2-CH₃, halogen and hydroxy; X₃ is -O-, -SO₂- or -NH-CO-; and m is 0 or 1;

R³ is a phenyl, thienyl, furyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4- benzodioxanyl, 1,3-benzodioxolyl or 2,3-dihydrobenzofuran group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, hydroxy, Cι-C₆ alkyl, Ci- d alkoxy, Ci-d alkylthio, C₂-C₆ alkenyl, C₂-d alkenyloxy, C₂-C₆ alkenylthio, d-d alknynyl, C₂-C₆ alkynyloxy, C₂-C₆ alkynylthio, C₃-d carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-C₆ carbocyclylthio, -NH-CO-(C,-C₆ alkyl), -CO-NH-(C,-C₆ alkyl) and -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group, the substituents on R³ being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy; and _t is - Cι-Xι-Arι or -C₂-X₂-C₃, wherein:

C, is -(CH₂)-, -(CH₂)₂- or -(CH₂)₃-;

Xi is a direct bond or is -O-, -S-, -S-CO- or -O-CO-; - Ari is a phenyl, pyridyl, thienyl, benzimidazolyl, furanyl-methyl-, 1,3- benzodioxolyl or 1,4-benzodioxanyl group, which is unsubstituted or carries, on the cyclic moiety, 1, 2 or 3 substituents selected from fluorine, hydroxy, -OCH₃,

-N(CH₃)₂ and -NH-CO-CH3; is a straight chain unsubstituted Cι-C alkylene group; - X is a direct bond or is or is -O-, -S-, -CO-O- or -NH-CO-O; and d is Ci-d alkyl group which is unsubstituted or substituted on a primary carbon atom with either (a) one hydroxy or (b) 1, 2 or 3 halo substituents.

22. Use according to claim 21 , wherein R is a phenyl, thienyl, furyl, quinolinyl, benzofuranyl, cyclopentyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl or 2,3- dihydrobenzofuran group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, Cι-C alkyl, d-d alkenyl, Cι-C₄ alkoxy, C C alkylthio, C₂-C alkenyloxy, d-d carbocyclyl, d-d carbocyclyloxy, -NH-CO-(Cι-C₂ alkyl) and -N(Cι-C₂ alkyl)₂, the substituents on R being themselves unsubstituted or further substituted with 1, 2 or 3 further substituents selected from halogen and hydroxy.

23. Use according to any one of the preceding claims, wherein Y is a group of formula -A-.

24. Use according to claim 23, wherein A is an unsubstituted pyridyl or an unsubstituted thienyl group.

25. Use according to claim 24, wherein A is an unsubstituted pyridyl group and the compound of formula (I) is a salt in which the pyridyl group at Y carries a positive charge on the nitrogen atom.

26. Use according to any one of the preceding claims, wherein R³ is a phenyl, thienyl, pyridyl or 1,3-benzodioxolyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, Cι-C alkyl, Cι-C₄ alkoxy, C d alkylthio, C₂-C alkenyl, -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group, and -Si(R⁷⁷⁷)3 wherein each R⁷⁷⁷ is independently a Cι-C₄ alkyl group, the substituents on R³ being themselves unsubstituted or further substituted with 1 , 2 or 3 further substituents selected from halogen and hydroxy.

27. Use according to any one of the preceding claims, wherein Xi is a direct bond or is -O- or -S-.

28. Use according to any one of the preceding claims, wherein Ari is an unsubstituted pyridyl, pyrrolidinyl, 1 ,3-benzodioxolyl or cyclohexenyl group, an unsubstituted d-C₆ cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, Cι-C₄ alkyl, C₂-C alkenyl, Cι-C alkoxy, Cι-C alkylthio and -N(CH₃)₂, the substituents on Ar¹ being themselves unsubstituted.

29. Use according to any one of the preceding claims, wherein X₂ is a direct bond, or is -O-, -S- or -CO-O-.

30. Use according to any one of the preceding claims, wherein C₃ is a Cι-C alkyl or C₂-d alkenyl group which is unsubstituted or substituted with 1, 2 or 3 groups selected from hydroxy and halogen.

31. Use according to any one of the preceding claims, wherein the compound of formula (I) is a compound of formula (I A⁷) or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

wherein: Z is -S- or -SO-;

R³ is a phenyl, thienyl, pyridyl or 1,3-benzodioxolyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, hydroxy, cyano, Cι-C alkyl, Ci-d alkoxy, Ci-d alkylthio, d-d alkenyl, -NR'R" wherein R' and R" are each independently hydrogen or a Cι-C alkyl group, and -Si(R⁷ )₃ wherein each R⁷⁷⁷ is independently a Cι-C₄ alkyl group, the substituents on R³ being themselves unsubstituted or further substituted with 1 , 2 or 3 further substituents selected from halogen and hydroxy; - _t is -Cι-Xι-Arι or -d-X₂-C₃, wherein:

Ci is a direct bond or an unsubstituted Cι-C₄ alkylene group; - Xi is a direct bond when Ci is a direct bond and, when Ci is an unsubstituted Ci-

C₄ alkylene group, is a direct bond or -O- or -S-;

Ari is an unsubstituted pyridyl, pyrrolidinyl, 1,3-benzodioxolyl or cyclohexenyl group, an unsubstituted C₃-C₆ cycloalkyl group or a phenyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, Cι-C alkyl, C₂-C₄ alkenyl, Cι-C₄ alkoxy, Cι-C₄ alkylthio and -N(CH₃)₂, the substituents on Ari being themselves unsubstituted; d is a Cι-C₄ alkylene group, which is unsubstituted or substituted with one or two substituents selected from hydroxy and fluorine;

X2 is a direct bond or is -O-, -S- or -CO-O-; and d is a d-d alkyl or C₂-C alkenyl group which is unsubstituted or substituted with 1 , 2 or 3 groups selected from hydroxy and halogen.

32. A compound of formula (I ) or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

wherein R¹, R³ and R⁴ are as defined in any one of claims 1 to 31, Z is as defined in claim 2 and Y is a group of formula -A- wherein A is a heteroaryl group, provided that when Z is S, R¹ is hydrogen, Y is an unsubstituted pyridyl group and R³ is a bromophenyl group, R⁴ is a group Cι-Xι-Arι in which Ari is a 3- to 6-membered carbocyclyl group.

33. A compound according to claim 32, wherein Y is a group of formula -A- , wherein A is an unsubstituted pyridyl or thienyl group, and R³ is an aryl, heteroaryl, heterocyclyl or carbocyclyl group which is unsubstituted or substituted by 1 , 2 or 3 substituents selected from fluorine, chlorine, hydroxy, Ci-d alkyl, Cι-C₆ alkoxy, Cι-C₆ alkylthio, d-d alkenyl, C₂-C₆ alkenyloxy, d-d alkenylthio, d-d alknynyl, d-d alkynyloxy, d-d alkynylthio, C₃-C₆ carbocyclyl, C₃-C₆ carbocyclyloxy, C₃-C₆ carbocyclylthio, -NH-CO-(Cι-C₆ alkyl), -CO-NH-(C,-C₆ alkyl), -NR'R" wherein R' and R" are each independently hydrogen or a Ci-d alkyl group and Si(R^/)₃, wherein each R⁷⁷⁷ is independently a Cι-C₄ alkyl group, the substituents on R₃ being themselves unsubstituted or further substituted with 1 , 2 or 3 further substituents selected from halogen and hydroxy.

34. A compound according to claim 32 or 33, which is a compound of formula (IB) or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R³, Y and Z are as defined in claim 32 or 33, and i is -Cι-Xι-Arι' or -d-X2'-d, or a Cι-C₆ alkyl or d-d alkenyl group, wherein Ci, Xi, C₂ and C₃ are as defined in claim 32 or 33 and

Ari ' is heteroaryl, heterocyclyl, aryl, carbocyclyl, heteroaryl-R^a- or heterocyclyl- R^a-, wherein R^a is a Cι-C₆ alkylene group, a C₂-d alkenylene group or a C₂-C₆ alkynylene group; wherein when Ari ' is an unsubstituted phenyl group or a phenyl group substituted with one or two groups selected from methyl, ethyl, methoxy, ethoxy, phenoxy, chlorine, bromine and nitro, either both Ci and Xi are direct bonds or Ci is methylene and Xi is -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-S-, - CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"- CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -O-CO-NR'- or -NR'-CO-O-, wherein each R' is the same or different and represents hydrogen, phenyl, Ci-d alkyl, C₂-C₆ alkenyl or C₂-d alkynyl and each R" is the same or different and represents a Cι-C₆ alkylene group, a C₂-d alkenylene group or a C₂- d alkynylene group; and

X₂' is -O-, -S-, -NR'-, -SO-, -SO₂-, -CO-, -CO-S-, -CO-O-, -CO-NR'-, -S-CO-, -O-CO-, -NR'-CO-, -CO-O-R"-CO-O-, -CO-NR'-R"-CO-O-, -CO-O-R"-CO-NR'-, -CO-NR'-R"-CO-NR'-, -NR'-CO-O- or -O-CO-NR'-, wherein each R' is the same or different and represents hydrogen, phenyl, Cι-C₆ alkyl, C₂-C₆ alkenyl or d-d alkynyl and each R" is the same or different and represents a Cι-C₆ alkylene group a d-d alkenylene group or a C₂-d alkynylene group.

35. 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3,5-difluoro-benzyl)-thiazolidin- 4-one

2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(2,3,4-frifluoro-benzyl)-thiazolidin-4-one

2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(2,5-difluoro-benzyl)-thiazolidin-4-one

3-(2-Benzo[l,3]dioxol-5-yl-ethyl)-2-[4-(4-bromo-phenyl)-pyridin-3-yl]-thiazolidin-4-one -Isobutyl-2-(4-phenyl-pyridin-3-yl)-thiazolidin-4-one -(4-Benzo[l,3]dioxol-5-yl-pyridin-3-yl)-3-isobutyl-thiazolidin-4-one -Isobutyl-2-(4-thiophen-2-yl-pyridin-3-yl)-thiazolidin-4-one -[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(2-cyclohex-l-enyl-ethyl)-thiazolidin-4-one -[4,4']Bipyridinyl-3-yl-3-isobutyl-thiazolidin-4-one -[4-(4-Chloro-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one -[4-(4-Fluoro-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one -[4-(3-Bromo-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one -Isobutyl-2-[4-(4-trifluoromethoxy-phenyl)-pyridin-3-yl]-thiazolidin-4-one -Isobutyl-2-(4-p-tolyl-pyridin-3-yl)-thiazolidin-4-one -Isobutyl-2-[4-(4-trimethylsilanyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one -Isobutyl-2-[4-(4-methylsulfanyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one -[4-(4-Ethyl-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one -(3-Isobutyl-4-oxo-thiazolidin-2-yl)-3-(4-methoxy-phenyl)-pyridinium; chloride -(4-Chloro-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride -(4-Fluoro-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride -(3-Isobutyl-4-oxo-thiazolidin-2-yl)-3-p-tolyl-pyridinium; chloride -(4-Bromo-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride -(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-methoxy-phenyl)-pyridinium; chloride -(4-Chloro-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride -(4-Fluoro-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride -(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-p-tolyl-pyridinium; chloride -Isobutyl-2-[4-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one -[3-(3-Isobutyl-4-oxo-thiazolidin-2-yl)-pyridin-4-yl]-benzonitrile -Isobutyl-2-[4-(4-methoxy-phenyl)-pyridin-3-yl]-thiazolidin-4-one -Isobutyl-2-[4-(4-vinyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one -(4-Bromo-phenyl)-4-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride -(3-Isobutyl-4-oxo-thiazolidin-2-yl)-3-(4-vinyl-phenyl)-pyridinium; chloride -(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-trifluoromethyl-phenyl)-pyridinium; chloride -(4-Cyano-phenyl)-3-(3-isobutyl-4-oxo-thiazolidin-2-yl)-pyridinium; chloride -(3-Isobutyl-4-oxo-thiazolidin-2-yl)-2-(4-vinyl-phenyl)-pyridinium; chloride 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3-methyl-butyl)-thiazolidin-4-one 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(2,2,3,3,3-pentafluoro-propyl)-thiazolidin-4-one 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-ethyl-thiazolidin-4-one 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3,3-dimethyl-butyl)-thiazolidin-4-one 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-cyclopentyl-thiazolidin-4-one

2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-cyclopropylmethyl-thiazolidin-4-one 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-(3-isopropoxy-propyl)-thiazolidin-4-one 3-Allyl-2-[4-(4-bromo-phenyl)-pyridin-3-yl]-thiazolidin-4-one 3 -Iso buty l-2-(4-m-toly 1-py ridin-3 -y l)-thiazolidin-4-one 2-[4-(2,4-Dimethyl-phenyl)-pyridin-3-yl]-3-isobutyl-thiazolidin-4-one 3 -Isobutyl-2-(4-o-toly l-pyridin-3-yl)-thiazolidin-4-one

4-(4-Bromo-phenyl)-3-(3-isobutyl- 1 ,4-dioxo- 1 lambda*4*-thiazolidin-2-yl)-pyridinium; chloride 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-sec-butyl-thiazolidin-4-one 2-[4-(4-Bromo-phenyl)-pyridin-3-yl]-3-cyclohexyl-thiazolidin-4-one

2-(3-Benzo[l,3]dioxol-5-yl-pyridin-4-yl)-3-cyclopentyl-thiazolidin-4-one 4- [4-(3 -Cyclopentyl -4-oxo-thiazolidin-2-y l)-pyridin-3 -y 1] -benzonitrile 3-Cyclopentyl-2-[3-(4-dimethylamino-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-Cyclopentyl-2-[3-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-Cyclopentyl-2-[3-(4-methoxy-phenyl)-pyridin-4-yl]-thiazolidin-4-one

3-Cyclopentyl-2-[3-(4-methylsulfanyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-Cyclopentyl-2-[3-(4-ethyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 2-[3-(4-Bromo-phenyl)-pyridin-4-yl]-3-cyclopentyl-thiazolidin-4-one 3-Cyclopentyl-2-[3-(3,4-dimethyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-Isobutyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one

3 -Cyclopropy 1 -2- [3 -(4- viny 1-pheny l)-pyridin-4-y 1] -thiazo lidin-4-one 3-Cyclobutyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-Isopropyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-sec-Butyl-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-(l-Ethyl-propyl)-2-[3-(4-vinyl-phenyl)-pyridin-4-yl]-thiazolidin-4-one 3-Isobutyl-2[4-(4-vinyl-phenyl)-thiophen-3-yl]-thiazolidin-4-one 2-{4-[4-(l,2-Dihydroxy-ethyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one 2-{4-[4-(2-Hydroxy-ethyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one 2-{4-[4-(l-Hydroxy-ethyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one 2-{4-[4-(2,2-Difluoro-vinyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one 3-Isobutyl-2-[4-(4-trifluorovinyl-phenyl)-pyridin-3-yl]-thiazolidin-4-one 2-{4-[4-(l-Fluoro-vinyl)-phenyl]-pyridin-3-yl}-3-isobutyl-thiazolidin-4-one 3-Isobuyl-2-[3-(4-vinyl-phenyl)-pyridin-2-yl]-thiazolidin-4-one or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound of the formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent

wherein Z, Y, Ri, R₃ and R are as defined in any one of claims 1 to 35, provided that (a) when Z is S, R¹ is hydrogen and R⁴ is 2-(4-methoxyphenethyl), Y-R³ is not 4- benzoxyphenyl or 4-pyrrolidinylphenyl; (b) when Z is S and R¹ is hydrogen, Y-R³ is other than -phenyl-O-A₂-R, wherein A₂ is a d-d alkylene group and R is 1 -pyrrolidinyl, 1 -piperidinyl, 4-morpholinyl, 1 -piperazinyl or 4-alkyl-l -piperazinyl; and (c) when R¹ is hydrogen and R⁴ is -C₂-X₂-d wherein C₂ is unsubstituted C₂-d alkylene, X₂ is O and d is unsubstituted Cι-C₂ alkyl, -Y-R³ is other than phenoxyphenyl, benzyloxyphenyl, phenylmercaptophenyl, benzylphenyl, 4-chlorophenoxyphenyl or 4-nitrophenoxyphenyl.

37. A pharmaceutical composition according to claim 36, which is in the form of a tablet, capsule, troche, lozenge, aqueous or oily suspension, dispersible powder or granules or a sub-lingual tablet.

38. A pharmaceutical composition according to claim 36, which is in a format suitable for parenteral, intranasal or transdermal administration or administration by inhalation.

39. A compound of the formula (II), as defined in claim 36 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body.

40. A method of treating a patient suffering from or susceptible to a condition mediated by N-type calcium channels, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined in any of claims 1 to 31 , or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

41. Use according to any one of claims 1 to 31 , or a method according to claim 40, wherein said condition mediated by N-type calcium channels is pain.