WO2008009935A1

WO2008009935A1 - Pharmaceutical compositions and their use

Info

Publication number: WO2008009935A1
Application number: PCT/GB2007/002722
Authority: WO
Inventors: David Selwood; Dieter Riddal; Charmaine Griffiths; Robert Keynes; Tomas Bellamy; John Garthwaite
Original assignee: UCL Business Ltd
Current assignee: UCL Business Ltd
Priority date: 2006-07-19
Filing date: 2007-07-19
Publication date: 2008-01-24
Anticipated expiration: 2009-01-19
Also published as: GB0614365D0

Abstract

The invention relates to use of a phenothiazine derivative which is (a) a compound of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating a disorder mediated by lipid peroxidation wherein R1, R2, R3, R4, R5, S’, m, n, p and q are as defined herein.

Description

PHARMACEUTICAL COMPOSITIONS AND THEIR USE

The present invention relates to phenothiazine derivatives and their use in treating or preventing diseases mediated by lipid peroxidation. Lipid peroxidation is a key factor in numerous disease states where oxidative stress has been implicated, including neurodegenerative disorders, cardiovascular disease, asthma and diabetes. Lipid peroxidation is initiated by radical species such as the hydroxyl radical (OH), which can abstract a hydrogen atom from unsaturated lipid, thus generating a lipid radical (L^') and H₂O. The lipid radical can combine with O₂, generating the lipid 'peroxyl' radical (LOO^'), which can further react with unsaturated lipid. If allowed to progress unchecked, a damaging, self-propagating cascade of peroxidation results. Ultimately peroxidation alters membrane properties, including ion-channel activity and glucose transport, and can directly impair mitochondrial function to cause cell stress. Nitric oxide (NO) is known to bind peroxidising lipid at an almost diffusion- limited rate. This reaction has dual effects: firstly NO is consumed avidly in the reaction and secondly, given time, continuously released NO may act as a chain breaking inhibitor of lipid peroxidation.

It has now surprisingly been found that a series of small drug-like molecules can inhibit NO consumption by reducing or preventing lipid peroxidation.

Accordingly, it has now surprisingly been found that the phenothiazine derivatives of formula (I) are capable of reducing or preventing lipid peroxidation. The present invention therefore provides the use of a phenothiazine derivative which is (a) a compound of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating or preventing a disorder mediated by lipid peroxidation:

wherein: S' represents -S-, -SO- or -SO₂-; each R² is the same or different and represents a group of formula -Y¹ -A, -Y'-Het-A, -Y'-Het-A-A', -Y^!-L-A, -Y¹ -A-A', -Y'-L-A-A', -Y'-L-A-Het-A', -Y^]-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A',

-Y'-Het-A-Y'-Het'-A', -Y'-A-Het-Y-Het-A', -Y'-L-Het-A-Het'-A', -Y'-Het-L-A-Het'-A', -Y'-L-Het-Y'-A, -Y'-L-Het-Y'-A-A', -Y'-Y²-A, -Y'-Y²-A-A', -Y'-Y²-A-Het-A', -Y^!-L-Y³-Het-L', -Y'-L-Y^Het-L-A, .γ'.L-Y³-Het-A-A', -Y'-L-Y⁴, -Y²-A, -Y²-A-A', -Y²-A-Het-A', -Y²-A-Het-L-A', -Y²-Y^]-A, -Y²-Y'-A-A', -Y²-Y'-A-Het-A', -A-Het-A',

-A-A', -A-Y^]-Het-A', -L-A, -L-Het-A, -L-Het-L', -L-A-A', -L-A-Het-A', -L-Y'-L-A, -L-Het-A-A', -L-Het-Y'-A, -L-Y'-Het-A, -L-Y'-Het-L-A, -L-Y¹ -Y²- A-A', -Het-A, -Het-L-A, -Het-L-A-A', -Het-L-A-Het'-A', -Het-L-Het'-A, -Het-L-Het'-A-A', -Het-L-Het'-A-Het'-A', -C(R)=A"-A or -C(R)=N-N=A" wherein R is H or C_1-4 alkyl; one of m and n is zero and the other of m and n is zero or one; each R⁵ is the same or different and represents a halogen atom or a group selected from Ci_-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_2-4 alkenyloxy, C_1-4 haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, cyano, nitro, C]_-4 hydroxyalkyl, Ci_-4 alkylthio and C_2-4 alkenylthio, or a group of formula -C(O)R, -CO₂R', -S(O)R, -SO₂R' or -NR 'R" wherein each R is the same or different and represents Ci_-4 alkyl and each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; p and q are each independently zero, 1 , 2, 3 or 4, with the proviso that when m is one, p is zero, 1, 2 or 3, and that when n is one, q is zero, 1, 2 or 3; either R¹ represents a hydrogen atom or a group selected from C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl and CM hydroxyalkyl when m or n is 1 , and otherwise represents a hydrogen atom, a group selected from Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl and Ci_-4 hydroxyalkyl, or a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y^L-A-A', -Y'-L-A-Het-A', -Y^A-Het-A', -Y'-L-Het-A, -Y^Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-Y'-Het'-A', -Y'-L-Het-A-Het'-A', -Y'-Het-L-A-Het'-A', -Y'-L-Het-Y'-A, -Y'-L-Het-Y'-A-A', -Y'-Y²-A, -Y'-Y²-A-A', -Y'-Y²-A-Het-A', .γ^].L-Y³-Het-L', -Y'-L-Y³-Het-L-A, -Y'-L-Y^Het-A-A', -Y'-L-Y⁴, -A, -A-Het-A', -A-A', -A-Y'-Het-A', -L-Het-A, -L-A-A', -L-A-Het-A',

-L-Y'-L-A, -L-Het-A-A', -L-Het-Y'-A, -L-Y'-Het-A, -L-Y'-Het-L-A or -L-Y'-Y²-A-A'; and R³ and R⁴ are the same or different and represent a hydrogen or halogen atom or a group selected from Cj_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C₂-₄ alkenyloxy, CM haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, C_1-4 hydroxyalkyl, Ci-₄ alkylthio and C_2-4 alkenylthio, or a group of formula -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl; or

(ii) R¹, together with R³ or R⁴, forms a 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl group which is optionally fused to a phenyl,

5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl or C_3-6 carbocyclyl group, and the other of R³ and R⁴ represents a hydrogen or halogen atom, a group selected from C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, C]_-4 hydroxyalkyl, Ci_-4 alkylthio and C_2-4 alkenylthio, or a group of formula -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; each A and A' is the same or different and represents a phenyl, 5- to 10- membered heteroaryl, 5- to 10-membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl or C_3-6 carbocyclyl group; each A" is the same or different and represents a 5- to 10- membered heterocyclyl or C_3-6 carbocyclyl which is optionally fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-6 membered carbocyclyl group; each Y¹ is the same or different and represents -CO- or -SO₂-; each Y² is the same or different and represents -Het"-N=Z-, -Het"-Z=N-,

-Z=N-Het"- or -N=Z-H et"-, wherein each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci_-4 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and each Het" is the same or different and represents -O-, -S- or -NR'- where R' is hydrogen or Ci_-4 alkyl; - each Y³ represents -P(OR)(=S)- wherein R is a Ci_-4 alkyl group; each Y⁴ represents -S-SO₂-O^"; each Het and Het' is the same or different and represents -O-, -S- or -NR'- where R' is hydrogen or Ci_-4 alkyl; each L is the same or different and represents a Ci_-6 alkyl ene or C_2-6 alkenylene moiety; and each L' is the same or different and represents a Ci_-4 alkyl group, wherein: the L and L' groups are unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -C(O)R, -CO₂R', -S(O)R, -SO₂R' and -NR 'R" groups wherein each R is the same or different and represents Ci_-4 alkyl and each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in A, A' and A" are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_1-4 alkyl ene, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, cyano, nitro, C]_-4 hydroxyalkyl, Ci_-4 alkylthio, C_2-4 alkenylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, or -X-A'" wherein X represents a bond or Ci_-4 alkyl ene, and A'" represents furanyl or thienyl.

The invention also provides a phenothiazine derivative which is (a) a compound of formula (I) described above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body. Further provided is a method of alleviating a condition mediated by lipid peroxidation in a patient, which method comprises administering to said patient an effective amount of a phenothiazine derivative as defined above.

As used herein, a Cj_-6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, for example a Cj_-4 alkyl group or moiety containing from 1 to 4 carbon atoms. Examples of C_1-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. For the avoidance of doubt, where two alkyl moieties are present in a group, the alkyl moieties may be the same or different.

As used herein, a C_2-6 alkenyl group or moiety is a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, for example a C_2-4 alkenyl group or moiety containing from 2 to 4 carbon atoms, such as -CH=CH₂ or -CH₂-CH=CH₂, in particular -CH₂-CH=CH₂. For the avoidance of doubt, where two alkenyl moieties are present in a group, they may be the same or different.

As used herein, a Cj_-6 alkyl ene group or moiety is a linear or branched alkylene group or moiety, for example a Ci_-4 alkylene group or moiety. Examples include methylene, n-ethylene, n-propylene and -C(CH₃ )₂- groups and moieties. When an alkylene group is a substituent on an A, A' or A" group, it is typically attached to 2 adj acent ring atoms on the A, A ' or A ".

As used herein, a C_2-6 alkenylene group or moiety is a linear or branched alkenylene group or moiety, for example a C_2-4 alkenylene group or moiety. Examples include -CH=CH-, -CH=CH-CH₂-, -CH₂-CH=CH- and -CH=CH-CH=CH-. Preferred examples include -CH=CH-. As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine.

As used herein, a C_1-4 alkoxy group or C_2-4 alkenyloxy group is typically a said Ci_-4 alkyl group or a C_2-4 alkenyl group respectively which is attached to an oxygen atom. A haloalkyl, haloalkenyl, haloalkoxy or haloalkenyloxy group is typically a said alkyl, alkenyl, alkoxy or alkenyloxy group respectively which is substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. For example, preferred haloalkoxy groups include methoxy groups substituted by 1 or 2 said halogen atoms, such as -OCH₂F and -OCHF₂, preferably -OCHF₂. Other preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX₃ and -OCX₃ wherein X is a said halogen atom, for example chlorine and fluorine. Particularly preferred haloalkyl groups are -CF₃ and -CCl₃, more preferably -CF₃. D

As used herein, a Ci_-4 alkylthio or C_2-4 alkenylthio group is typically a said C]_-4 alkyl group or a C_2-4 alkenyl group respectively which is attached to a sulphur atom, for example -S-CH₃.

As used herein, a Ci_-4 hydroxyalkyl group is a C]_-4 alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group. A preferred hydroxyalkyl group is -(CH₂)₂-OH.

As used herein, a 5- to 10- membered heteroaryl group or moiety is a monocyclic 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2, 3 or 4 heteroatoms, selected from O, S and N. When the ring contains 4 heteroatoms these are preferably all nitrogen atoms. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Furanyl, thienyl, pyridyl, imidazolyl, pyrazolyl, thiazolyl, isoisothiazolyl, thiadiazolyl, pyridazinyl, triazolyl, oxadiazolyl and tetrazolyl groups are preferred.

When A is a 5- to 10- membered heteroaryl moiety fused to a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-6 carbocyclyl group, it is typically fused to a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl ring. More preferably, it is fused to a phenyl or C_3-6 carbocyclyl ring. Preferred examples of a 5- to 10-membered heteroaryl moiety fused to a phenyl ring include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Particularly preferred examples include benzothienyl, benzotriazolyl and benzothiazolyl. Preferred examples of a 5- to 10-membered heteroaryl moiety fused to a C_3-6 carbocyclyl ring include pyrazolyl fused to a C_3-6 carbocyclyl ring, for example pyrazolyl fused to a cyclopentyl ring.

When A' is a 5- to 10- membered heteroaryl moiety fused to a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-6 carbocyclyl group, it is typically fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. More preferably, it is fused to a phenyl ring. Preferred examples of a 5- to 10-membered heteroaryl moiety fused to a phenyl ring include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Particularly preferred examples include benzothienyl, benzotriazolyl and benzothiazolyl.

When A or A' is a phenyl group fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-6 carbocyclyl group, it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. Typically when A or A' is a phenyl group it is a monocyclic moiety (i.e. it is non- fused).

As used herein, a 5- to 10- membered heterocyclyl group or moiety is a monocyclic non-aromatic, saturated or unsaturated C₅-C io carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O)₂, and wherein one or more of the remaining carbon atoms is optionally replaced by a group -C(O)- or -C(S)-. When one or more of the remaining carbon atoms is replaced by a group -C(O)- or -C(S)-, preferably only one such carbon atom is replaced. Typically, the 5- to 10- membered heterocyclyl ring is a 5- to 6- membered ring.

Suitable heterocyclyl groups and moieties include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S₅S- dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1 ,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl, thioxolanyl, thioxothiazolidinyl, lH-pyrazol-5- (4H)-onyl, l,3,4-thiadiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups and moieties. Preferred heterocyclyl groups are piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups. More preferred heterocyclyl groups are piperazinyl, piperidinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups.

When A, A ' or A" is a said 5- to 10- membered heterocyclyl moiety fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-6 carbocyclyl group it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. More preferably, it is fused to a phenyl ring. An example is 2-oxo-dihydroindolyl. o

For the avoidance of doubt, although the above definitions of heteroaryl and heterocyclyl groups refer to an 'TSf" moiety which can be present in the ring, as will be evident to a skilled chemist the N atom will be protonated (or will carry a substituent as defined above) if it is attached to each of the adjacent ring atoms via a single bond. As used herein, a C_3-6 carbocyclic moiety is a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated or mono-unsaturated hydrocarbon ring (i.e. a cycloalkyl moiety or a cycloalkenyl moiety) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their mono-unsaturated variants. A preferred saturated example is cyclopropyl. A preferred mono-unsaturated example is cyclopentenyl (i.e. a cyclopentyl group containing one carbon-carbon double bond).

When A, A' or A" is a said C_3-6 carbocyclyl group fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C_3-6 carbocyclyl group, it is preferably fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. Typically, when A, A ' or A" is a C_3-6 carbocyclyl group it is a monocyclic moiety (i.e. it is non-fused).

When the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two or three substituents, it is preferred that not more than two substituents are selected from C_1-4 alkylene, cyano and nitro. More preferably, not more than one substituent is selected from Ci_-4 alkylene, cyano and nitro. Furthermore, when the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties are substituted by two or three substituents, it is preferred that not more than one substituent is selected from -X-A'".

Typically, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A, A' and A" groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and- are selected from halogen atoms and C_1-4 alkyl, Ci_-4 alkylene, C_2-4 alkenyl, Ci_-4 alkoxy, CM haloalkyl, C_]-4 haloalkoxy, hydroxyl, nitro, Q_-4 hydroxyalkyl, Cj_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and -X-A'" wherein X represents a bond or Ci_-4 alkylene, and A'" represents furanyl or thienyl. For the avoidance of doubt, the substituents are themselves unsubstituted.

More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A, A' and A" groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-2 alkyl, C_1-4 alkylene, C_2-3 alkenyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, C_1-2 hydroxyalkyl, Ci_-2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-2 alkyl, and -X-A'" wherein X represents a bond or Ci_-2 alkylene, and A'" represents furanyl or thienyl.

Typically the L and L' groups are unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R₅ -SO₂OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More preferably the L and I/ groups are unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl. When the substituent is -CO₂R, preferably R is hydrogen. When the substituent is -NR 'R" preferably one of R' and R" is methyl and the other is hydrogen or methyl. Preferably the L and I/ groups are unsubstituted or substituted by 1 group described above.

Typically each A is the same or different and is a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group. More preferably each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C_3-6 carbocyclyl group or is a 5- to 6- membered heteroaryl ring fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group. More preferably each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C_3-6 carbocyclyl group or is a 5- to 6- membered heteroaryl ring fused to a further phenyl or C_3-6 carbocyclyl ring.

When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred. When A is a fused heteroaryl group it is preferably a 5- to 6-membered heteroaryl group fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group. More preferably it is a 5- to 6- membered heteroaryl group fused to a further phenyl ring or C_3-6 carbocyclyl group. Preferred examples include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinazolinyl and pyrazolyl rings fused to a C_3-6 carbocyclyl group. Particularly preferred examples of a heteroaryl group fused to a phenyl ring include benzothienyl, benzotriazolyl and benzothiazolyl. Particularly preferred examples of a heteroaryl group fused to a C_3-6 carbocyclyl group include a pyrazolyl ring fused to a cyclopentyl group.

When A is a non-fused heterocyclyl group it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo- thiomorpholinyl, S,S-dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1,4- dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl, thioxolanyl, thioxothiazolidinyl, lH-pyrazol-5-(4H)-onyl, 1 ,3,4-thiadiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups and moieties. Preferably it is selected from piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups. More preferably it is selected from piperazinyl, piperidinyl thioxothiazolidinyl groups.

When A is a non-fused carbocyclyl group it is preferably a monocyclic non- aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl moiety) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A preferred example is cyclopropyl.

Typically the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_1-4 alkylene, C_2-4 alkenyl, C_1-4 alkoxy, C_1-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, C_1-4 hydroxyalkyl, C_1-4 alkylfhio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and -X-A'" wherein X represents a bond or Ci_-4 alkylene, and A"' represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-4 alkylene, C_2-3 alkenyl, C_1-2 alkoxy, Ci_-2 haloalkyl, C]_-2 haloalkoxy, hydroxyl, nitro, C]_-2 hydroxyalkyl, Ci_-2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and -X-A'" wherein X represents a bond or Ci_-2 alkylene, and A"' represents furanyl or thienyl. When the substituent is -X-A" ' preferably X represents a bond or -CH₂-. When the substituent is -X-A'" preferably A'" is furanyl. When a substituent is a Ci_-4 alkylene group it is preferably a -C(CH₃)₂- group which is attached to two adjacent carbon atoms on the A ring. When a substituent is a Ci_-4 alkylene group then A is preferably a heterocyclyl or carbocyclyl group or is a phenyl, heteroaryl, heterocyclyl or carbocyclyl group fused to a heterocyclyl or carbocyclyl group to which the Ci_-4 alkylene group is bonded. In a preferred embodiment each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_3-4 alkylene, C_2-3 alkenyl, Ci_-2 haloalkyl, hydroxyl, nitro, C_1-2 hydroxyalkyl, Ci_-2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and -X-A'" wherein X represents a bond or C]_-2 alkylene, and A'" represents furanyl. Typically each A' is the same or different and represents a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group. Preferably each A is the same or different and is a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. More preferably each A' is the same or different and represents a non-fused phenyl, 5- to 6-membered heteroaryl or 5- to 6- membered heterocyclyl group. More preferably each A' is the same or different and represents a non- fused phenyl or 5- to 6- membered heteroaryl group. When A' is a 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl, pyrimidinyl, pyridazinyl and thiazolyl.

Typically, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Cj_-4 haloalkyl, Cj_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Cj_-2 alkyl, Ci_-2 alkoxy, Cj_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio. More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C]_-2 alkyl and Cj_-2 alkoxy groups. More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1 or 2 or 3 substituents described above.

Typically each A" is the same or different and represents a 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group. Preferably each A" is the same or different and is a 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heterocyclyl or 5- to 6- membered heteroaryl. Preferably each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group or is a 5- to 6- membered heterocyclyl fused to a further phenyl ring. More preferably each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl or is a 5- to 6- membered heterocyclyl fused to a phenyl ring.

When A" is a non-fused heterocyclyl group, preferably at least one carbon in the heterocyclyl ring is replaced by -C(O)- or -C(S)-, more preferably one carbon atom is replaced by -C(O)- or -C(S)-. Particularly preferred are lH-pyrazol-5(4H)-onyl, l,3,4-thiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups, more preferably lH-pyrazol-5(4H)-onyl. When A" is a fused heterocyclyl group it is preferably a 2-oxo-dihydroindolyl group. Typically each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C]_-4 haloalkoxy, hydroxyl, C]_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio. More preferably each A" group is unsubstituted or substituted by 1 or 2 Cj_-2 alkyl groups, more preferably by 1 Ci_-2 alkyl group, more preferably methyl.

Typically each Y² is the same or different and represents -Het"-N=Z- or -Z=N-Het"-. Typically each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. When R"' represents Ci_-2 alkyl, it is preferably methyl. When R'" represents -NR 'R", preferably each R' and R" is the same or different and represents hydrogen or methyl, more preferably each R' and R" represents hydrogen. Typically each Het" is the same or different and represents -O- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl. When Het' represents -NR'-, then preferably R' is hydrogen or methyl, more preferably hydrogen.

For the avoidance of doubt, as written, the left hand end of the Y² group is attached to the phenothiazine group or is closer to the phenothiazine group than the right hand end of the Y² group.

Typically each Y³ is the same or different and represents -P(ORX=S)- where R is a C₂-₄ alkyl group, more preferably where R is a C₃ group. More preferably each Y³ is -P(OCH(CH₃)₂(=S)-.

Typically each Het is the same or different and represents -0-, -S- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl. When Het represents -NR'-, then preferably R' is hydrogen or methyl.

Typically each Het' is the same or different and represents -O- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl. When Het' represents -NR'-, then preferably R' is hydrogen or methyl, more preferably hydrogen.

Typically each L is the same or different and represents a Ci_-4 alkylene or C_2-4 alkenylene group. When L represents a Ci_-4 alkylene group it is preferably a -CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH₂-CH(CH₃)- or -CH₂-CH(CH₃)-CH₂- group. When L represents a C_2-4 alkenylene group it is preferably a C₂ alkenylene group, -CH=CH-. For the avoidance of doubt, as written, the left hand end of non-symmetrical L groups is attached to the phenothiazine group or is closer to the phenothiazine group than the right hand end of the L group. Where an L group bears 2 substituents, preferably at most there is 1 substituent selected from -C(O)R, -CO₂R', -S(O)R, -SO₂R' and -NR 'R". Typically each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. More preferably each R, R' and R' ' is the same or different and represents hydrogen or methyl. When the substituent is -CO₂R, preferably R is hydrogen. When the substituent is -NR 'R" preferably one of R' and R" is methyl and the other is hydrogen or methyl. Preferably each L group is unsubstituted or substituted by 1 group described above.

Typically each I/ is the same or different and represents a Ci_-4 alkyl group, more preferably a Ci_-3 alkyl group. More preferably each I/ is the same or different and represents methyl, ethyl, -CH₂-CH₂-CH₃ or -CH(CH₃)₂. Most preferably each L/ is the same or different and represents methyl or -CH(CH₃)₂.

Typically each I/ group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C]_-4 alkyl. More preferably each L' group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C]_-2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl. When the substituent is -CO₂R, preferably R is hydrogen. When the substituent is -NR 'R" preferably one of R' and R" is methyl and the other is hydrogen or methyl. Preferably each I/ group is unsubstituted or substituted by 1 group described above. More preferably each I/ group is unsubstituted.

The group S ' preferably represents -S- or -SO-. More preferably S ' represents -S-. Typically, R² is a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-Y-Het-A', -Y'-L-Het-A-Het'-A', -Y¹ -Het-L-A-Het'-A', -Y' -L-Het-Y'-A, -Y'-L-Het-Y'-A-A', -Y'-Y²-A, -Y'-Y²-A-A', -Y'-Y²-A-Het-A', -Y'-L-Y³-Het-L', -Y'-L-Y³-Het-L-A, -Y'-L-Y³-Het-A-A', -Y'-L-Y⁴, -Y²-A, -Y²-A-A', -Y²-A-Het-A', -Y²-A-Het-L-A', -Y²-Y'-A, -Y²-Y'-A-A', -Y²-Y² -A-Het-A', -A-Het-A', -A-Y'-Het-A', -L-A, -L-Het-A, -L-Het-L', -L-A-A', -L-A-Het-A', -L-Y'-L-A, -L-Het-A-A', -L-Het-Y'-A, -L-Y'-Het-A, -L-Y'-Het-L-A, -L-Y'-Y²-A-A', -Het-A, -Het-L-A, -Het-L-A-A', -Het-L-A-Het'-A', -Het-L-Het'-A, -Het-L-Het'-A-A',

-Het-L-Het'-A-Het'-A', -C(R)=A"-A or -C(R)=N-N=A" wherein R is H or C_1-4 alkyl.

More typically, R₂ is a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-Y-Het-A', -Y'-L-Het-A-Het'-A',

-Y'-Het-L-A-Het'-A', -Y'-L-Het-Y'-A, -Y'-L-Het-Y'-A-A', -Y'-Y²-A, -Y'-Y²-A-A', -Y¹ -Y²- A-Het-A', -Y'-L-Y³-Het-L', -Y'-L-Y³-Het-L-A, -Y'-L-Y³-Het-A-A', -Y'-L-Y⁴, -Y²-A, -Y²-A-A', -Y²-A-Het-A', -Y²-A-Het-L-A', -Y²-Y'-A, -Y²-Y'-A-A', -Y²-Y'-A-Het-A', -A-Y'-Het-A', -L-A, -L-Het-A, -L-Het-L', -L-A-A', -L-A-Het-A', -L-Y'-L-A, -L-Het-A-A', -L-Het-Y'-A, -L-Y'-Het-A, -L-Y¹ -Het-L-A, -L-Y'-Y²-A-A', -Het-A, -Het-L-A, -Het-L-A-A', -Het-L-A-Het'-A', -Het-L-Het'-A, -Het-L-Het'-A-A', -Het-L-Het'-A-Het'-A', -C(R)=A"-A or -C(R)=N-N=A" wherein R is H or C_M alkyl.

Preferred R² groups include groups of the formula -L-A-A', -Y²-A, -Y²-Y'-A, -Het-L-Het'-A-Het'-A', -C(R)=A"-A and -C(R)=N-N=A". When R² is -Y²- A, preferred Y² groups include -Het"-N=Z- and -Z=N-Het"-, preferably -Z=N-H et"-. Typically each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-2 alkyl. Preferably R'" represents hydrogen or Cj_-2 alkyl. When R'" represents Ci_-2 alkyl, it is preferably methyl. Het" is preferably -NR'- wherein R' is hydrogen or Ci_-2 alkyl, more preferably wherein R' is hydrogen or methyl, most preferably hydrogen.

When R² is -Y²-A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyrimidinyl most preferred. When R² is -Y -A, typically each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from Ci_-2 alkyl, hydroxyl, nitro and C]_-4 haloalkyl. Preferred Ci_-2 substituents are methyl groups. Preferred haloalkyl substituents are Ci_-2 alkyl groups which are substituted by one or more said halogen atoms. Typically, they are substituted by 1 , 2 or 3 said halogen atoms. Particularly preferred Ci_-2 haloalkyl substituents are perhaloalkyl substituents, in particular -CF₃.

When R² is -Y²-Y^J-A, preferred Y² groups include -Het"-N=Z- and -Z=N-Het"-, preferably -Z=N-Het"-. Typically each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. Preferably R'" represents hydrogen or Ci_-2 alkyl, more preferably R'" represents hydrogen or methyl, more preferably methyl. Het" is preferably -NR'- wherein R' is hydrogen or Ci_-2 alkyl, more preferably wherein R' is hydrogen or methyl, most preferably hydrogen. When R² is -Y²-Y'-A, a preferred Y¹ group is -SO₂-. When R² is -Y² -Y¹ -A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. When R² is -Y²-Y'-A, typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. Particularly preferred substituents are halogen atoms, in particular bromine atoms. When R² is -Het-L-Het'-A-Het'-A', preferred Het groups include -O-. When R² is -Het-L-Het'-A-Het'-A', preferred L groups include Cj_-4 alkylene groups, for example Ci_-3 alkylene groups, more preferably -CH₂-CH₂-CH₂- groups. Preferably the L groups are unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More preferably each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. More preferably each L is unsubstituted or substituted by 1 or 2 hydroxyl groups, more preferably it is substituted by one hydroxyl group. When R² is -Het-L-Het'-A-Het'-A', preferred Het' groups include -O- and -NR'- wherein R' is hydrogen or Ci_-2 alkyl. When Het' represents -NR'-, then preferably R' is hydrogen or methyl, more preferably hydrogen. The Het' groups are the same or different, and preferably one is -O- and the other is -NR'- as defined above. More preferably the Het' group bonded to the L and A groups is -O- and the Het' group bonded to the A and A' groups is -NR'-.

When R² is -Het-L-Het'-A-Het'-A', preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. Typically each A is unsubstituted or substituted by I₅ 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each A is unsubstituted.

When R² is -Het-L-Het'-A-Het'-A', preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. Typically, the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C_]-4 haloalkoxy, hydroxyl, C_1-4 hydroxyalkyl, Cj_-4 alkylthio and -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably the A' groups are unsubstituted.

When R² is -C(R)=A"- A, preferred R groups include hydrogen and C_]-2 alkyl, more preferably hydrogen. When R² is -C(R)=A "-A₅ preferred A" groups include 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group. Preferably each A" is the same or different and is a 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heterocyclyl or 5- to 6- membered heteroaryl. Preferably each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group or is a 5- to 6- membered heterocyclyl fused to a further phenyl ring. More preferably each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl. Suitable non-fused heterocyclyl groups include lH-pyrazol- 5(4H)-onyl, l,3,4-thiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups, more preferably lH-pyrazol-5(4H)-onyl.

When R² is -C(R)=A"- A, typically each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Cj_-4 haloalkoxy, hydroxyl, Cj_-4 hydroxyalkyl, C_1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C i _-4 alkyl. More preferably each A " is unsubstituted or substituted by 1 or 2 Cj_-2 alkyl groups, more preferably by one methyl group.

When R² is -C(R)=A"- A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non- fused phenyl rings. When R² is -C(R)=A"- A, typically each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, Cj_-4 alkylene, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C]_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and -X-A"' wherein X represents a bond or Cj_-4 alkylene, and A"' represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 halogen atoms, more preferably by 1 , 2 or 3 chlorine atoms. Most preferably each A is substituted by 1 chlorine atom.

When R² is -C(R)=N-N=A", preferred R groups include hydrogen and Ci_-2 alkyl, more preferably hydrogen or methyl, more preferably methyl.

When R² is -C(R)=N-N=A", preferred A" groups include 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl groups optionally fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. More preferably A" is a 5- to 6- membered heterocyclyl fused to a further phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group, most preferably a 5- to 6- membered heterocyclyl fused to a further phenyl ring. A suitable fused group is 2-oxo- dihydroindolyl. When R² is -C(R)=N-N=A", typically each A" is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Cj_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-4 alkyl. More each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Cj_-2 alkoxy, C_1-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl and Cj_-2 alkylthio. More preferably each A" is unsubstituted.

One of m and n is zero and the other of m and n is zero or 1. Thus, there is a maximum of one R² group present on the phenothiazine group. Preferably, where R¹ represents a hydrogen atom or a group selected from Ci_-4 alkyl, C_2-4 alkenyl, Cj_-4 haloalkyl, C_2-4 haloalkenyl and Ci_-4 hydroxyalkyl, then one of m and n is one. However, where R¹ represents a group of formula -Y¹ -A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-Y'-Het'-A', -Y'-L-Het-A-Hef-A',

-Y'-Het-L-A-Het'-A', -Y'-L-Het-Y^A, -Y'-L-Het-Y'-A-A', -Y'-Y^A, -Y'-Y²-A-A', -Y^]-Y²-A-Het-A', -Y^]-L-Y³-Het-L', -Y'-L-Y³-Het-L-A, -Y'-L-Y^Het-A-A', -Y'-L-Y⁴, -A, -A-Het-A', -A-A', -A-Y'-Het-A', -L-Het-A, -L-A-A', -L-A-Het-A', -L-Y'-L-A, -L-Het-A-A', -L-Het-Y'-A, -L-Y'-Het-A, -L-Y'-Het-L-A or -L-Y¹ -Y²- A- A', then preferably both m and n are zero. When R¹ forms a fused group with either R³ or R⁴, it is preferred that both m and n are zero.

Preferred R⁵ groups include halogen atoms and groups selected from Ci_-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 alkylthio, or from a group of formula -C(O)R or -S(O)R wherein each R is the same or different and represents hydrogen or Cj_-4 alkyl. When R⁵ is a halogen atom it is preferably a chlorine, fluorine or bromine atom, more preferably a chlorine atom. When R⁵ is a Ci_-4 alkyl group it is preferably a C]_-2 alkyl group. When R⁵ is a Ci_-4 alkoxy group it is preferably a Ci_-2 alkoxy group, more preferably methoxy. When R⁵ is a Ci_-4 haloalkyl group it is preferably a C_]-2 haloalkyl group, more preferably a Cj_-2 perhaloalkyl group, most preferably trifluoromethyl. When R⁵ is a Cμ alkylthio group it is preferably a Cj_-2 alkylthio group, more preferably methylthio. When R⁵ is a group of formula -C(O)R then R is preferably a Ci_-2 alkyl group, more preferably methyl. When R⁵ is a group of formula -S(O)R then R is preferably a Ci_-2 alkyl group, more preferably methyl. In a preferred embodiment the R⁵ groups are the same or different and represent chlorine, fluorine or bromine atoms and groups selected from Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 alkylthio, or from a group of formula -C(O)R or -S(O)R wherein each R is the same or different and represents a C]_-2 alkyl.

The subscripts p and q denote the number of R⁵ groups present on the phenyl rings which form part of the central phenothiazine group. Preferably p and q are independently zero, one or two. In one preferred embodiment one of p and q is one and the other is zero. In this embodiment preferred R⁵ groups include halogen atoms and groups selected from C]_-4 alkoxy, Ci_-4 haloalkyl, -C(O)R and -S(O)R wherein each R is the same or different and represents Ci_-4 alkyl, in particular -Cl, -0-CH₃, -SO-CH₃, -CF₃ and -CO-CH₃. In another preferred embodiment both p and q are one. In this embodiment preferably each R⁵ group represents a halogen atom, more preferably each R⁵ group represents chlorine atom. When m is one, it is preferred that p is zero. Similarly, when n is one, it is preferred that q is zero. When both m and n are zero, preferably both p and q are zero. When R¹ does not form a fused ring with one of R³ and R⁴, preferred R¹ groups include hydrogen, Ci_-4 alkyl and groups of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y*-Y²-A, -Y'-L-Y³-Het-L', -Y'-L-Y⁴, -A-Het-A', -L-A-A', -L-Y'-Het-L-A and -L-Y¹ -Y²- A-A', more preferably from hydrogen and groups of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A,

-Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y²-A, -Y'-L-Y³-Het-L', -Y'-L-Y⁴, -A-Het-A', -L-A-A', -L-Y'-Het-L-A and -L-Y'-Y²-A-A'. In one embodiment, preferred R¹ groups include hydrogen and groups of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y²-A, -Y'-L-Y³-Het-L\ -A-Het-A', -L-A-A', -L-Y'-Het-L-A and -L-Y'-Y²-A-A\ In a further embodiment, preferred R¹ groups include -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y^!-Y²-A, -Y'-L-Y³-Het-L', -A-Het-A', -L-A-A', -L-Y'-Het-L-A and -L-Y¹ -Y²- A-A'.

When R¹ is Ci_-4 alkyl it is preferably a C]_-2 alkyl group, more preferably a methyl group. Typically, when R¹ is -Y'-A, Y is other than -CO- and/or A is attached to Y via a C atom.

When R¹ is -Y¹ -A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl rings, and 5- to 6- membered heteroaryl rings fused to a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl ring. Preferred 5- to 6- membered heteroaryl rings include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. More preferred are furanyl, thienyl, pyridyl, imidazolyl, pyrazolyl, thiazolyl, isoisothiazolyl, thiadiazolyl, pyridazinyl, triazolyl, oxadiazolyl and tetrazolyl groups, in particular furanyl, pyrazolyl, pyridyl and thienyl. Preferred fused 5- to 6- membered heteroaryl rings include 5- to 6- membered heteroaryl rings fused to a phenyl ring or to a C_3-6 carbocyclyl ring. Examples of a 5- to 6- membered heteroaryl ring fused to a phenyl ring include indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl, more preferably benzothienyl, benzotriazolyl and benzothiazolyl, most preferably benzothienyl. Examples of a 5- to 6- membered heteroaryl ring fused to a C_3- ₆ carbocyclyl ring include pyrazolyl fused to a C_3-6 carbocyclyl ring, more preferably pyrazolyl fused to a cyclopentyl ring.

When R¹ is -Y¹ -A typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, Ci_-4 alkylene, C_2-4 alkenyl, Ci_-4 alkoxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, nitro, CM hydroxyalkyl, C_1-4 alkylthio, -NR'R'^r wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl, and -X-A"' wherein X represents a bond or CM alkylene, and A'" represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-4 alkylene, Ci_-2 alkoxy, Q_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, C_]-2 hydroxyalkyl, C_]-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. Preferably each A is unsubstituted or substituted by 1 or 2 substituents selected from halogen atoms, Ci_-2 alkyl and C_3-4 alkylene groups. When the substituent is a halogen atom, preferred halogen atoms are chlorine or bromine atoms. When the substituent is a Cj_-2 alkyl group it is preferably methyl. When the substituent is a C_3-4 alkylene it is preferably -C(CH₃)₂-. When an alkylene substituent is preferably, preferably only one such alkylene group is present.

When R¹ is -Y'-Het-A, a preferred Y¹ group is -CO-. When R¹ is -Y'-Het-A, preferred Het groups include -S- and -NR'- where R' is hydrogen or C]_-2 alkyl, more preferably where R' is hydrogen. When R¹ is -Y'-Het-A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred. Triazolyl and imidazolyl are most preferred.

When R¹ is -Y'-Het-A, typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Cj_-4 alkoxy, Ci_-4 haloalkyl, Cj_-4 haloalkoxy, hydroxyl, nitro, C]_-4 hydroxyalkyl, Ci_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl, and -X-A'" wherein X represents a bond or C_1-4 alkylene, and A'" represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_2-3 alkenyl, Cj_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and -X-A'" wherein X represents a bond or Ci_-2 alkylene, and A"' represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-2 alkoxy, Cj_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, d-₂ hydroxyalkyl, C_]-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. Preferably each A is unsubstituted or substituted by 1 or 2 substituents selected from Cj_-2 alkyl groups. When the substituent is a C]_-2 alkyl group it is preferably methyl.

When R¹ is -Y'-Het-A-A', a preferred Y¹ group is -CO-. When R¹ is -Y'-Het-A-A', a most preferred Het group is-S-. When R¹ is -Y'-Het-A-A', preferred A groups include non-fused phenyl, 5- to 6- membered heteroaryl and 5- to 6- membered heterocyclyl groups. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred. Oxadiazolyl groups are most preferred. When A is a non-fused 5- to 6- membered heterocyclyl group it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S₅S- dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl, thioxolanyl, thioxothiazolidinyl, lH-pyrazol-5- (4H)-onyl, l,3,4-thiadiazol-2(3H)-thionyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups and moieties. Preferred heterocyclyl groups are piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups, most preferably thioxothiazolidinyl.

When R¹ is -Y'-Het-A-A', typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, nitro, C i-₄ hydroxyalkyl, Ci_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and -X-A'" wherein X represents a bond or C]_-4 alkylene, and A'" represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-2 alkyl, C_2-3 alkenyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. More preferably each A is unsubstituted. T¹

When R¹ is -Y'-Het-A-A', A' typically represents a non-fused phenyl or 5- to 6- membered heteroaryl group, most preferably a non-fused phenyl group. When A' is a non-fused 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred.

When R¹ is -Y'-Het-A-A', typically the A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Cj_-4 alkoxy, Cj_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-4 alkyl. More the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-2 alkoxy, Cj_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio. More preferably the A' groups are unsubstituted or substituted by 1 or 2 unsubstituted Ci_-2 alkyl groups, in particular methyl.

When R¹ is -Y¹ -L-A, a preferred Y¹ group is -CO-. When R¹ is -Y¹ -L-A, preferred L groups include Ci_-4 alkylene and C_2-4 alkenylene groups. When L represents a Ci_-4 alkylene group it is preferably a Ci_-2 alkylene group, more preferably a -CH₂- group. When L represents a C_2-4 alkenylene group it is preferably a C₂ alkenylene group, -CH=CH-. When R¹ is -Y¹ -L-A, typically each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Cj_-2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl. More preferably each L group is unsubstituted or substituted by 1 or 2 cyano groups, for example by 1 cyano group.

When R¹ is -Y¹ -L-A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, most preferably pyrazolyl and triazolyl.

When R¹ is -Y¹ -L-A, typically each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C]_-4 alkoxy, Cj_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, nitro, C_1-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_2-3 alkenyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-2 alkyl. More preferably each A is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from C_1-2 alkyl, nitro, C_1-2 haloalkoxy. When a substituent is Ci_-2 alkyl it is preferably methyl. When the substituent is Ci_-2 haloalkoxy it is preferably -0-CHF₂.

When R¹ is -Y¹ -A-A', a preferred Y¹ group is -CO-. When R¹ is -Y¹ -A-A', preferred A groups include non-fused phenyl, 5- to 6- membered heteroaryl and 5- to 6- membered heterocyclyl groups, more preferably 5- to 6- membered heterocyclyl groups. When A is a non-fused heterocyclyl group it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo- thiomorpholinyl, S,S-dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1,4- dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl and thioxolanyl groups and moieties. Preferably it is selected from piperidinyl, pyrrolidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl and imidazolinyl groups. More preferably it is selected from piperazinyl and piperidinyl groups, most preferably from piperazinyl groups.

When R¹ is -Y¹ -A-A', typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Q_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C)_-2 alkyl, C_2-3 alkenyl, C_1-2 alkoxy, C_1-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. Most preferably each A is unsubstituted.

When R¹ is -Y¹ -A-A', preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups. When A' is a 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl, pyrimidinyl, pyridazinyl and thiazolyl, more preferably pyridyl.

When R¹ is -Y¹ -A-A', typically each A' is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Cj_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, C_1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio. More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl and Ci_-2 alkoxy groups. Most preferably each A' is unsubstituted.

When R¹ is -Y'-L-Het-A, a preferred Y¹ group is -CO-. When R¹ is -Y'-L-Het-A, preferred L groups include Ci_-4 alkylene groups, more preferably Ci_-2 alkylene groups, most preferably -CH₂-. Preferably the L groups are unsubstituted. When R¹ is -Y'-L-Het-A, preferred Het groups include -O- and -S-. When R¹ is -Y'-L-Het-A, preferred A groups include non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl and C_3-6 carbocyclyl groups and 5- to 6- membered heteroaryl rings fused to a phenyl ring. More preferably each A group is a non-fused 5- to 6- membered heteroaryl group or a 5- to 6- membered heteroaryl group fused to a phenyl ring. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred. Most preferred are triazolyl, imidazolyl, pyrimidinyl, thiadiazolyl and pyridyl. When A is a 5- to 6-membered heteroaryl group fused to a phenyl ring it is preferably selected from indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Particularly preferred examples include benzothienyl, benzotriazolyl and benzothiazolyl, with benzotriazolyl and benzothiazolyl being most preferred.

When R¹ is -Y'-L-Het-A, typically each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Cj_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-4 alkyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Cj_-2 alkyl, C_2-3 alkenyl, Cj_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C]_-2 alkyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from Ci_-2 alkyl, nitro and -NR 'R " wherein each R' and R" is the same or different and represents hydrogen or Cj_-2 alkyl. Preferred Cj_-2 substituents include methyl, for example an A group may be substituted by one or two methyl groups. Preferred -NR 'R" substituents include -NH₂, for example an A group may be substituted by one -NH₂ group. When an A group is substituted by nitro group, preferably there are no other nitro substituents, more preferably no other substituents of any description. When R¹ is -Y'-Het-L-A, a preferred Y¹ group is -CO-. When R¹ is -Y'-Het-L-A, a preferred Het group is -NR'- where R' is hydrogen or Ci_-4 alkyl, more preferably where R' is hydrogen. When R¹ is -Y'-Het-L-A, preferred L groups include Ci_-4 alkylene or C_2-4 alkenylene groups, more preferably Ci_-4 alkylene groups. When L represents a Cj_-4 alkylene group it is preferably a -CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH₂-CH(CH₃)- or -CH₂-CH(CH₃)-CH₂- group, more preferably a -CH₂-CH₂-CH₂- group. When R¹ is -Y'-Het-L-A typically each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. More preferably each R, R' and R" is the same or different and represents hydrogen or methyl. More preferably each L is unsubstituted or substituted by one -CO₂R group. Most preferably R is hydrogen.

When R¹ is -Y'-Het-L-A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups. Preferably the A groups are non-fused phenyl rings. When R¹ is -Y'-Het-L-A, typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C]_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C]_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Ci_-4 alkyl thio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each A is unsubstituted.

When R' is -Y'-L-Het-A-A', a preferred Y¹ group is -CO-. When R¹ is -Y'-L-Het-A-A', preferred L groups include Ci_-4 alkylene groups, in particular Cj_-2 alkylene groups, most preferably -CH₂-. When R¹ is -Y'-L-Het-A-A', a preferred Het group is -S-. When R¹ is -Y'-L-Het-A-A', preferred A groups include non- fused phenyl and 5- to 6- membered heteroaryl rings, most preferably non-fused 5- to 6- membered heteroaryl rings. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with triazolyl and oxadiazolyl being most preferred.

When R¹ is -Y¹ -L-H et- A- A', typically each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, C]_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl and -X-A'" wherein X represents a bond or Ci_-4 alkylene, and A'" represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-2 alkyl, C_2-3 alkenyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, C_1-2 hydroxyalkyl, Ci_-2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and -X-A'" wherein X represents a bond or Ci_-2 alkylene, and A'" represents furanyl or thienyl. Most preferably each A is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from C_2-3 alkenyl and -X-A'" wherein X represents a bond or Cj_-2 alkylene, and A'" represents furanyl or thienyl. When the substiruent is C_2-3 alkenyl it is preferably -CH₂-CH=CH₂. When the substiruent is -X-A'" preferably X represents a bond or -CH₂-. When the substituent is -X-A'" preferably A'" is furanyl. When R¹ is -Y'-L-Het-A-A', preferred A' groups include non-fused phenyl and

5- to 6- membered heteroaryl rings. When A' is a non-fused 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl groups.

When R¹ is -Y'-L-Het-A-A', typically the A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More preferably the A' groups are unsubstituted or substituted with 1 or 2 halogen atoms, preferably with 1 or 2 fluorine atoms, more preferably by one fluorine atom. When R¹ is -Y'-L-Het-Y'-A, a preferred Y¹ group is -CO-. When R¹ is -Y'-L-Het-Y'-A, preferred L groups include Ci_-4 alkylene groups, more preferably C]_-2 alkylene groups, most preferably a -CH₂- group. Typically each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each L group is unsubstituted. When R¹ is -Y'-L-Het-Y'-A, preferred Het groups include -0-. When R¹ is -Y'-L-Het-Y'-A, preferred A groups include non-fused C_3-6 carbocyclyl groups, preferably a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl moiety) having from 3 to 6 carbon atoms, more preferably cyclopropyl. When R¹ is -Y'-L-Het-Y'-A, typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, C_1-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_2-3 alkenyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, nitro, Cμ₂ hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. More preferably each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl groups. Preferred halogen atoms are chlorine atoms. Preferred Ci_-2 alkyl groups are methyl groups.

When R¹ is -Y'-Het-A-Y'-Het'-A', the Y¹ groups may be the same or different, preferably one is -CO- and the other is -SO₂-. More preferably the first Y¹ group, which is bonded to the phenothiazine ring, is -CO- and the other Y¹ group, between the A and Het' groups, is -SO₂-. When R¹ is -Y'-Het-A-Y'-Het'-A', preferred Het groups include -NR'- where R' is hydrogen or Ci_-4 alkyl, preferably where R' is hydrogen or C_{] -2} alkyl, more preferably where R' is hydrogen. When R¹ is -Y'-Het-A-Y'-Het'-A', preferred Het' groups include -NR'- where R' is hydrogen or Ci_-4 alkyl, preferably where R' is hydrogen or Ci_-2 alkyl, more preferably where R' is hydrogen.

When R¹ is -Y'-Het-A-Y'-Het'-A', preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. When R¹ is -Y^Het-A-Y'-Het'-A', typically each A is unsubstituted or substituted by I₅ 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, C]_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Q_-4 alkyl. More preferably each A is unsubstituted.

When R¹ is -Y'-Het-A-Y'-Het'-A', preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl groups. When A' is a non-fused 5- to 6- membered heteroaryl group it preferably represents pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl are preferred. Most preferred are pyridyl, pyrimidinyl, pyridazinyl and thiazolyl, more preferably pyrimidinyl and thiazolyl

When R¹ is -Y^Het-A-Y'-Het'-A', typically the A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C]_-4 alkoxy, Cj_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-2 alkyl, Ci_-2 alkoxy, C_1-2 haloalkyl, Cj_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio. More preferably the A' groups are unsubstituted or substituted by 1, 2 or 3 unsubstituted Ci_-2 alkyl substituents. When the substituents are Ci_-2 alkyl substituents they are preferably methyl groups.

When R¹ is -Y*-Y²-A, a preferred Y¹ group is -CO-. When R¹ is -Y*-Y²-A, preferred Y² groups include -Het"-N=Z- or -Z=N-Het"-, more preferably -Het"-N=Z-. Typically each Z is the same or different and represents CR'" wherein R'" represents hydrogen, C_1-2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-2 alkyl. When R'" represents -NR 'R", preferably each R' and R" is the same or different and represents hydrogen or methyl, more preferably each R' and R" represents hydrogen. Typically each Het" is -O-. When R¹ is -Y'-Y²-A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably 5- to 6- raembered heteroaryl groups. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyridyl most preferred.

When R¹ is -Y¹-Y²-A, typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C]_-4 alkoxy, Ci_-4 haloalkyl, Cj_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl. More preferably each A is unsubstituted. When R¹ is -Y'-L-Y^Het-L', a preferred Y¹ group is -CO-. When R¹ is

-Y¹-L-Y³-Het-L', preferred L groups include Ci_-4 alkylene, more preferably C_1-2 alkylene, most preferably -CH₂-. Preferably each L group is unsubstituted. When R is -Y'-L-Y³-Het-L', preferred Het groups include -O-. When R¹ is -Y'-L-Y³-Het-L', preferred I/ groups include Ci_-4 alkyl groups, more preferably Cj_-3 alkyl groups. More preferably each L' is the same or different and represents methyl, ethyl, -CH₂-CH₂-CH₃ or -CH(CH₃)₂. Most preferably each I/ is the same or different and represents methyl or -CH(CH₃)₂. Preferably each I/ group is unsubstituted.

When R¹ is -Y¹ -L-Y⁴, a preferred Y¹ group is -CO-. When R¹ is -Y^]-L-Y⁴, preferred L groups include C_1-4 alkylene groups, more preferably C_1-2 alkylene groups, most preferably -CH₂-. Preferably the L groups are unsubstituted.

When R¹ is -A-H et- A', preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl rings. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyridyl most preferred. Typically each A is unsubstituted ^

or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_1-4 haloalkyl, Cj_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_]-4 alkyl, and -X-A'" wherein X represents a bond or C]_-4 alkylene, and A" ' represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 halogen substituents. Preferred halogen substituents include fluorine and chlorine, for example each A group may be substituted by one chlorine atom and two fluorine atoms.

When R¹ is -A-Het-A', preferred Het groups include -NR'- wherein R' is hydrogen or Ci_-4 alkyl, more preferably wherein R' is hydrogen or Ci_-2 alkyl, more preferably wherein R' is hydrogen. When R¹ is -A-Het-A', preferred A' groups include non- fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. Typically, the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C]_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-4 alkyl. More preferably the A' groups are unsubstituted or substituted by 1 or 2 or 3 unsubstituted Ci_-2 alkyl substituents. More preferably the A' groups are substituted by 1 or 2 unsubstituted C_1-2 substituents, such as methyl substituents.

When R¹ is -L-A-A', preferred L groups include C]_-4 alkylene groups, more preferably Cj_-2 alkylene groups, most preferably -CH₂- groups. The L groups are preferably unsubstituted. When R¹ is -L-A-A', preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl groups. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with triazolyl being most preferred. When R¹ is -L-A-A', typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, Ci_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, nitro, C_1-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-4 alkyl. Preferred C_1-4 alkylthio substituents are Cj_-2 alkylthio substituents, in particular -S-CH₃ substituents. More preferably each A is unsubstituted or substituted by one -S-CH₃ substituent, most preferably it is substituted by one -S-CH₃ substituent.

When R¹ is -L-A-A', preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. Typically, the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Cj_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, C_1-4 hydroxyalkyl, C_1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_J-4 alkyl. More preferably the A' groups are unsubstituted or substituted by 1, 2 or 3 halogen substituents, for example by a single halogen substituent. Preferred halogen atoms are chlorine atoms. When R¹ is -L-Y'-Het-L-A, preferred L groups include C]_-4 alkylene groups, for example Ci_-2 alkylene groups, preferably -CH₂- and -CH₂-CH₂-. Where there is more than one L group, the L groups are the same or different. For example, one L group may be -CH₂- and the other may be -CH₂-CH₂-. In this case it is preferred that the L group bonded to the phenothiazine ring is -CH₂-CH₂- and the L group bonded to the Het and A groups is -CH₂-. Preferably the L groups are unsubstituted. When R¹ is

-L-Y'-Het-L-A, a preferred Y¹ group is -CO-. When R¹ is -L-Y'-Het-L-A, a preferred Het group is -O-. When R¹ is -L-Y'-Het-L-A, preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. Typically each A is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C]_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, C]_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-4 alkyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 halogen substituents, for example by 2 halogen atoms. Preferred halogen atoms include fluorine and chlorine atoms. For example each A may be substituted by one chlorine atom and one fluorine atom.

When R¹ is -L-Y'-Y²-A-A', preferred L groups include Ci_-4 alkylene groups, preferably Ci_-2 alkylene groups, more preferably -CH₂-. When R¹ is -L-Y'-Y²-A-A', a preferred Y¹ group is -CO-. When R¹ is -L-Y¹ -Y²- A-A', preferred Y² groups include -Het"-N=Z- and -Z=N-Het"-, more preferably -Het"-N=Z-. Typically each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. Preferably R'" represents hydrogen or C^₂ alkyl, more preferably R'" represents hydrogen. Preferably Het" represents -NR'- wherein R' is hydrogen or C_1-2 alkyl, more preferably R' is hydrogen or methyl, most preferably hydrogen.

When R¹ is -L-Y'-Y²-A-A', preferred A groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused 5- to 6- membered heteroaryl groups. When A is a non-fused 5- to 6- membered heteroaryl group it is preferably selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Triazolyl, furanyl, pyrazolyl, imidazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl and tetrazolyl are preferred, with pyrazolyl most preferred. Typically each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, Cj_-4 haloalkyl, C]_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and -X-A'" wherein X represents abond or Cj_-4 alkylene, and A'" represents furanyl or thienyl. More preferably each A is unsubstituted or substituted by 1, 2 or 3 substituents which are of formula -X-A'" wherein X represents a bond or Ci_-2 alkylene, and A'" represents furanyl or thienyl. When the substituent is -X-A"' preferably X represents a bond or -CH₂-, more preferably X represents a bond. When the substituent is -X-A" ' preferably A'" is furanyl. More preferably each A is substituted by one unsubstituted furanyl group.

When R¹ is -L-Y¹ -Y²- A- A', preferred A' groups include non-fused phenyl and 5- to 6- membered heteroaryl groups, more preferably non-fused phenyl rings. Typically, the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, C_1-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More preferably the A' groups are unsubstituted.

When R³ and R⁴ do not form a fused group with R¹, then R³ and R⁴ are preferably selected from hydrogen and halogen atoms, and groups selected from Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl. More preferably, when R³ and R do not form a fused group with R¹, then R³ and R⁴ are selected from hydrogen and halogen atoms, with preferred halogen atoms being chlorine atoms. When one of R³ and R⁴ does not form a fused group with R¹ , then preferably R³ and R⁴ are the same, more preferably R³ and R⁴ are both either hydrogen or chlorine.

When R¹ forms a fused group with one of R³ and R⁴, then the other of R³ and R⁴ is preferably selected from hydrogen and halogen atoms, unsubstituted groups selected from Ci-₂ alkyl, Ci_-2 alkoxy, C_1-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR ^rR" wherein each R' and R" is the same or different and represents hydrogen or C_1-2 alkyl. More preferably, when R¹ forms a fused group with one of R³ and R⁴, then the other of R³ and R⁴ is selected from hydrogen and halogen atoms, with preferred halogen atoms being chlorine atoms. More preferably, when R¹ forms a fused group with one of R³ and R⁴, then the other of R³ and R⁴ is hydrogen.

When R¹ forms a fused groups with one of R³ and R⁴ then the fused group is preferably 5- to 6- membered heterocyclyl ring which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group. The group formed by R¹ and R³ or R⁴ is more preferably a non- fused 5- to 6- membered heterocyclyl ring or a 5- to 6- membered heterocyclyl ring fused to a C_3-6 carbocyclyl group. When R¹ forms a fused groups with one of R³ and R⁴ then the group so formed is preferably unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C₂.₄ alkenyl, Ci_-4 alkoxy, Cj_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl.

When the group formed by R¹ and R³ or R⁴ is a non-fused 5- to 6- membered heterocyclyl ring it is preferably selected from azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydroforanyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S, S- dioxo-thiomoφholinyl, morpholinyl, 1,3 -dioxolanyl, 1 ,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl, thioxolanyl, thioxothiazolidinyl, oxopyrrolidinyl, oxothiazolidinyl and oxopyrazolidinyl groups and moieties. Preferred heterocyclyl groups are oxopyrrolidinyl and oxopyrazolidinyl.

When the group formed by R¹ and R³ or R⁴ is a non-fused 5- to 6- membered heterocyclyl it is preferably unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Cj_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C]_-4 alkyl. More preferably it is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-2 alkyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, C_1-2 haloalkoxy, hydroxyl and C_1-2 alkylthio. Particularly preferred is when it is unsubstituted or substituted by 1 or 2 substituents which are the same or different and represent C_1-2 alkyl, Ci_-2 alkoxy, Cj_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl or Ci_-2 alkylthio. More preferably it is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from Ci_-2 haloalkyl and hydroxyl groups. Most preferably it is substituted by 1 hydroxyl group and 1 Ci_-2 haloalkyl group. Preferred Ci_-2 haloalkyl groups include -CF₃.

When the group formed by R¹ and R³ or R⁴ is a 5- to 6- membered heterocyclyl ring fused to a C_3-6 carbocyclyl group it is preferably an azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dioxolanyl, pyrazolidinyl, piperidyl, piperazinyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S, S- dioxo-thiomorpholinyl, morpholinyl, 1,3 -dioxolanyl, 1 ,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyrazolinyl, oxopyrrolidinyl, oxothiazolidinyl or oxopyrazolidinyl ring which is fused to a C_3-6 carbocyclyl ring. The C_3-6 carbocyclyl ring is preferably a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably it is a saturated or mono-unsaturated hydrocarbon ring (i.e. a cycloalkyl moiety or a cycloalkenyl moiety) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and their mono-unsaturated variants, with cyclopentenyl being preferred. Most preferably when the group formed by R¹ and R³ or R⁴ is a 5- to 6- membered heterocyclyl ring fused to a C_3-6 carbocyclyl group, it is a piperidinyl group fused to a mono-unsaturated cyclopentenyl group. When the group formed by R¹ and R³ or R⁴ is a 5- to 6- membered heterocyclyl ring fused to a C_3-6 carbocyclyl group it is preferably unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_1-4 haloalkyl, Cj_-4 haloalkoxy, hydroxyl, Cj_-4 hydroxyalkyl, C_1-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl. More preferably it is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_)-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl and Cj_-2 alkylthio. Most preferably it is unsubstituted.

Preferred compounds of the invention are phenothiazine derivatives which are (a) compounds of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, wherein:

S' represents -S-, -SO- or -SO₂-; each R² group is the same or different and represents a group of formula -L-A-A', -Y²-A, -Y²^-A, -Het-L-Het-A-Het-A', -C(R)=A"-A and -C(R)=N-N=A"; one of m and n is zero and the other of m and n is zero or one; each R⁵ group is the same or different and represents a halogen atom or a group selected from C]_-4 alkyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 alkylthio, or from a group of formula -C(O)R or -S(O)R wherein each R is the same or different and represents hydrogen or Ci_-4 alkyl; p and q are each independently zero, one or two; either (i) R¹ represents hydrogen or Ci_-4 alkyl when m or n is 1 , and otherwise represent hydrogen, C_)-4 alkyl or a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y^]-Het-L-A,

-Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y²-A, -Y^]-L-Y³-Het-L', -Y'-L-Y⁴, -A-Het-A', -L-A-A', -L-Y'-Het-L-A and -L-Y'-Y²-A-A'; and R³ and R⁴ are the same or different and represent hydrogen or halogen, or a group selected from C_1-2 alkyl, Cj_-2 alkoxy, C_1-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Cj_-2 alkyl; or (ii) R¹, together with R³ or R⁴ forms a 5- to 6- membered heterocyclyl ring which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group, and wherein the group formed by R¹ and R³ and R⁴ is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, C_]-4 alkylthio and NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-4 alkyl; and the other of R³ and R⁴ represents a hydrogen or halogen atom, or a group selected from Ci_-2 alkyl, Ci_-2 alkoxy, C_1-2 haloalkyl, C_1-2 haloalkoxy, hydroxyl, C]_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl; each A is the same or different and represents a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group, and wherein each A is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, C]_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio, -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and -X-A'" wherein X represents a bond or Ci_-4 alkylene, and A'" represents furanyl or thienyl; each A' is the same or different and represents a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group, and wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, C_1-4 hydroxyalkyl, Ci_-4 alkylthio and -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; each A" is the same or different and represents a 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group, and wherein each A" is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C]_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_1-4 haloalkyl, C_1-4 haloalkoxy, hydroxyl, Cj_-4 hydroxyalkyl, Cj_-4 alkylthio and -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; each Y¹ is the same or different and represents -CO- or -SO₂-; each Y² is the same or different and represents -Het"-N=Z- or -Z=N-Het"-, wherein each Z is the same or different and represents CR" ' wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR'R" wherein each R' and R" is the same or different and represents hydrogen or C]_-2 alkyl, and each Het" is the same or different and represents -O- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl; each Y³ represents -P(OR)(=S)- where R is a C_2-4 alkyl group; each Y⁴ represents -S-SO₂-O^"; each Het is the same or different and represents -O-, -S- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl; each Het' is the same or different and represents -O- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl; each L is the same or different and represents a Ci_-4 alkyl ene or C_2-4 alkenylene group, and wherein each L group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; and each L' is the same or different and represents a Ci_-4 alkyl group, and wherein each L' group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C_1-4 alkyl.

Further preferred compounds of the invention are phenothiazine derivatives which are (a) compounds of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, wherein: S' represents -S-, -SO- or -SO₂-;

R² represents a group of the formula -L-A-A', -Y²-A, -Y²-Y'~A, -Het-L-Het-A-Het-A', -C(R)=A"-A or -C(R)=N-N=A"; one of m and n is zero and the other of m and n is zero or one; - each R⁵ is the same or different and represents a halogen atom, a group selected from Ci_-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, Ci_-4 alkylthio or a group of formula -C(O)R or -S(O)R wherein each R is the same or different and represents Ci_-4 alkyl; p and q are each independently zero, one or two; - either

(i) R¹ represents hydrogen or Ci_-4 alkyl when m or n is 1 , and otherwise represents hydrogen, Ci_-4 alkyl or a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y²-A, -Y^]-L-Y³-Het-L', -Y¹ -L-Y⁴, -A-Het-A', -L-A-A', -L-Y^!-Het-L-A and

-L-Y¹ -Y²- A- A'; and R³ and R⁴ are the same or different and represent hydrogen or halogen atoms; or (ii) R¹, together with R³ or R⁴, forms a non-fused 5- to 6- membered heterocyclyl ring or a 5- to 6- membered heterocyclyl ring fused to a C_3-6 carbocyclyl group wherein the fused group formed by R¹ and R³ or R⁴ is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, C]_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio, and the other of R³ and R⁴ represents a hydrogen or halogen atom; - each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C_3-6 carbocyclyl group or is a 5- to 6- membered heteroaryl ring fused to a further phenyl or C_3-6 carbocyclyl ring, and wherein the phenyl, heteroaryl, heterocyclyl and ^

carbocyclyl moieties in the A groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_2-3 alkenyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Q_-2 haloalkoxy, hydroxyl, nitro, Ci_-2 hydroxyalkyl, Cj_-2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or

C i-₂ alkyl, and -X-A'" wherein X represents a bond or Cj_-2 alkylene, and A"' represents furanyl or thienyl; each A' is the same or different and represents a non-fused phenyl or 5- to 6- membered heteroaryl group, and wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl and Ci_-2 alkoxy groups; each A" is the same or different and represents a non-fused 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group or is a 5- to 6- membered heterocyclyl fused to a further phenyl ring, and wherein each A" is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio; each Y¹ is the same or different and represents -CO- or -SO₂-; - each Y² is the same or different and represents -Het' '-N=Z- or -Z=N-Het", wherein each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR 'R" where each R' and R" is the same or different and represents hydrogen or C]_-2 alkyl, and each Het" represents -O- or -NR'- where R' is hydrogen or Ci_-2 alkyl; - each Y³ represents -P(OCH(CH₃)₂(=S)-; each Y⁴ represents -S-SO₂-O^"; each L is the same or different and represents a Ci_-4 alkylene or C_2-4 alkenylene group, and wherein each L group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl; and each L' is the same or different and represents methyl, ethyl, -CH₂-CH₂-CH₃ or -CH(CH₃)₂, and wherein each L' group is unsubstituted or substituted by 1 or 2 groups selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl.

Further preferred compounds of the invention are phenothiazine derivatives which are (a) compounds of formula (I) above or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, wherein: S ' represents -S-, -SO- or -SO₂-;

R² represents a group of the formula -L- A-A ', -Y²- A, -Y²V -A, -Het-L-Het-A-Het-A', -C(R)=A"-A or -C(R)=N-N=A"; - one of m and n is zero and the other of m and n is zero or one; each R⁵ is the same or different and represents a chlorine atom, or a group selected from C_1-2 alkoxy, C_1-2 haloalkyl, Ci_-2 alkylthio, -C(O)R or -S(O)R wherein each R is the same or different and represents a Ci_-2 alkyl; p and q are each independently zero, one or two; - either

(i) R¹ represents hydrogen or C_1-4 alkyl when m or n is 1, and otherwise represents hydrogen, Ci_-4 alkyl or a group of formula -Y¹ -A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y¹ -A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y^!-Y²-A, -Y'-L-Y³-Het-I/, -Y'-L-Y⁴, -A-Het-A', -L-A-A', -L-Y^Het-L-A and

-L-Y¹-Y²-A-A'; and R³ and R⁴ are the same or different and represent hydrogen or halogen atoms; or (ii) R¹, together with R³ or R⁴, forms a non-fused 5- to 6- membered heterocyclyl ring or a 5- to 6- membered heterocyclyl ring fused to a C_3-6 carbocyclyl group wherein the group formed by R¹ and R³ and R⁴ is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from C_1-2 haloalkyl and hydroxyl groups, and the other of R³ and R⁴ represents a hydrogen atom; each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C_3-6 carbocyclyl group or is a

5- to 6- membered heteroaryl ring fused to a further phenyl or C_3-6 carbocyclyl ring, and wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and C]_-2 alkyl, C_3-4 alkylene, C_2-3 alkenyl, C_1-2 haloalkyl, hydroxyl, nitro, C_]-2 hydroxyalkyl, Ci_-2 alkylthio, -NR'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and -X-A'" wherein X represents abond or Ci_-2 alkylene, and A'" represents furanyl; each A' is the same or different and represents a non-fused phenyl or 5- to 6- membered heteroaryl group, and wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Cj_-2 alkyl and Ci_-2 alkoxy groups; each A" is the same or different and represents a non-fused 5- to 6- membered heterocyclyl group or a 5- to 6- membered heterocyclyl fused to a further phenyl ring, and wherein the phenyl and heterocyclyl moieties in the A" groups are unsubstituted or substituted by 1 or 2 C_1-2 alkyl substituents which are the same or different; each Y¹ is the same or different and represents -CO- or -SO₂-; each Y² is the same or different and represents -He^-N=Z- or -Z=N-Het", wherein each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR'R" where each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and each Het" represents -O- or -NR'- where R' is hydrogen or C_1-2 alkyl; each Y³ represents -P(OCH(CH₃)₂(=S)-; each Y⁴ represents -S-SO₂-O^"; - each L is the same or different and represents a CM alkylene or C_2-4 alkenylene group, and wherein each L group is unsubstituted or substituted by 1 group selected from hydroxyl, cyano, -CO₂R and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or C]_-2 alkyl; and - each L' is the same or different and represents an unsubstituted methyl, ethyl, -CH₂-CH₂-CH₃ or -CH(CH₃)₂ group. Particularly preferred compounds of formula (I) include: 1. (3,6-Dichloro-benzo[b]thiophen-2-yl)-phenothiazin-l O-yl-methanone; 2. 2-(4-Furan-2-ylmethyl-5-pyridin-3-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanyl)-l - phenothiazin- 10-yl-ethanone;

3. 1 ,3,7,9-Tetrachloro-l OH-phenothiazine;

4. 1 ,3a, 13 , 13 a-tetrahydro-cyclopenta[4,5]ρyrido[3 ,2, 1 -kl]phenothiazine 5. phenothiazine-10-carbothioic acid S-(I -methyl- lH-imidazol-2-yl) ester;

6. phenothiazine-10-carbothioic acid S-[5-(4-methoxy-phenyl)- [l,3,4]oxadiazol-2-yl] ester;

7. (Z)-N'-(l OH-phenothiazine- 10-carbonyloxy)picolinimidamide;

8. (2-Oxo-2-phenothiazin-10-yl-ethyl)-phosphonothioic acid diisopropyl ester; 9. 2-(3-Chloro-phenyl)-5-methyl-4-[ 1 -(10-methyl-l OH-ρhenothiazin-3-yl)- meth-(E)-ylidene]-2,4-dihydro-pyrazol-3-one;

10. (E)-3-(4-Difluoromethoxy-phenyl)-2-(phenothiazine-l 0-carbonyl)- acrylonitrile;

11. 6-Methyl-2- {N'-[l -(10-methyl-l 0H-phenothiazin-3-yl)-meth-(E)-ylidene]- hydrazino } -pyrimidin-4-ol ;

12. 3 - { [ 1 -(10H-Phenothiazin-2-yl)-eth-(Z)-ylidene] -hydrazono } - 1 ,3 -dihydro- indol-2-one;

13. 10-(Toluene-4-sulfonyl)- 1 OH-phenothiazine 5-oxide;

14. (E)-N'-(l-(10H-phenothiazin-2-yl)ethylidene)-4- bromobenzenesulfonohydrazide;

15. (E)-2-(l -(2-(2,6-dinitro-4-(trifluoromethyl)phenyl)hydrazono)ethyl)-l OH- phenothiazine;

16. N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-l OH-phenothiazine- 10-carboxamide;

17. S-4-phenyl-5-thioxo-4,5-dihydro- 1 ,3 ,4-thiadiazol-2-yl 1 OH-phenothiazine- 10-carbothioate;

18. 2-oxo-2-(10H-phenothiazin-10-yl)ethyl 2,2-dichloro-l- methylcyclopropanecarboxylate;

19. 2-chloro-6-fluorobenzyl 3-(10H-phenothiazin-10-yl)propanoate;

20. 2-(6-nitro-lH-benzo[d][l,2,3]triazol-l-yloxy)-l-(10H-phenothiazin-10- yl)ethanone;

21. 10-((4-(4-chlorophenyl)-5-(methylthio)-4H-l ^^-triazol-S-yOmethyl)-! OH- phenothiazine; 22. (E)-N'-((3-(furan-2-yl)- 1 -phenyl- 1 H-pyrazol-4-yl)methylene)-2-(l OH- phenothiazin- 10-yl)acetohydrazide;

23. 2-(benzo [d] thiazol-2-yloxy)- 1 -(2-(trifluoromethyl)- 1 OH-ρhenothiazin- 10- yl)ethanone; 24. N-(3,5-dimethyl-4H-l,2,4-triazol-4-yl)-10H-phenothiazine-10-carboxaraide;

25. N-{lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazole,3b,4,4a,5-tetrahydro-3,4,4- trimethyl-} - 1 OH-phenothiazine- 10-carboxamide;

26. 5-chloro-4-(2-chloro-10H-phenothiazin-10-yl)-N-(2,3-dimethylphenyl)-3,6- difluoropyridin-2-amine; 27. 9-cliloro-2-hydroxy-2-(trifluoromethyl)pyrrolo[3 ,2, 1 -kl]phenothiazin- 1 (2H)- one;

28. 1 -(10H-phenothiazin-3-yloxy)-3-(4-(phenylamino)phenoxy)propan-2-ol;

29. S-2-oxo-2-( 1 OH-phenothiazin- 10-yl)ethyl sulfothioate;

30. 2-(3-nitro-l H- l,2,4-triazol-l-yl)-l -(I OH-phenothiazin- 10-yl)ethanone; 31. 1 -(2-chloro- 1 OH-phenothiazin- 10-yl)-2-( 1 -(2-fluorophenyl)- 1 H-tetrazol-5- ylthio)ethanone;

32. (5-nitrofuran-2-yl)(10H-phenothiazin-10-yl)memanone;

33. (1 OH-phenothiazin- 10-yl)(4-(pyridin-2-yl)piperazin- 1 -yl)methanone;

34. (3 ,5 -dimethyl- 1 H-pyrazol- 1 -yl)( 1 OH-phenothiazin- 10-yl)methanone; 35. 2-(4H- 1 ,2,4-triazol-3 -ylthio)- 1 -(2-(trifluoromethyl)- 1 OH-phenothiazin- 10- yl)ethanone;

36. 2-(benzo[d]thiazol-2-yloxy)-l-(10H-phenothiazin-10-yl)ethanone;

37. 2-(3 ,5-dimethyl- 1 H-pyrazol- 1 -yl)- 1 -(2-(trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone; 38. 2-(3 ,5-dimethyl- 1 H-pyrazol- 1 -yl)-l -( 1 OH-phenothiazin- 10-yl)ethanone;

39. (3 -bromophenyl)(2-(trifluoromethyl)-l OH-phenothiazin- 10-yl)methanone;

40. 2-( 1 -methyl- 1 H-imidazol-2-ylthio)- 1 -(2-(trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone;

41. 2-(l -methyl- 1 H-imidazol-2-ylthio)- 1 -(I OH-phenothiazin- 10-yl)ethanone; 42. 2-(2-methyl- 1 H-imidazol- 1 -yl)- 1 -( 1 OH-phenothiazin- 10-yl)ethanone;

43. 2-(4,6-dimethylpyrimidin-2-ylthio)- 1 ~(2-(trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone;

44. 2-(4,6-dimethylpyrimidin-2-ylthio)-l -(I OH-phenothiazin- 10-yl)ethanone; 45. 2-(4-allyl-5-(pyridin-4-yl)-4H-l,2,4-triazol-3-ylthio)-l-(10H-phenothiazin- 10-yl)ethanone;

46. 2-(5-amino-l ,3 ,4-thiadiazol-2-ylthio)-l -(I OH-ρhenothiazin-10-yl)ethanone;

47. 2-(5-amino-l,3,4-thiadiazol-2-ylthio)-l-(2-(trifluoromethyl)-10H- phenothiazin- 10-yl)ethanone;

48. 2-(l OH-phenothiazine-10-carboxamido)-3-phenylpropanoic acid;

49. 2-(l -methyl- IH-1 ,2,4-triazol-3-ylthio)-l -(I OH-phenothiazin-10-yl)ethanone;

50. N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)- 1 OH-phenothiazine- 10-carboxamide; 51. l-(10H-phenothiazin-10-yl)-2-(5-phenyl-l,3,4-oxadiazol-2-ylthio)ethanone;

( 1 OH-phenothiazin- 10-yl)(pyridin-4-yl)methanone;

52. (1 OH-phenothiazin-10-yl)(pyridin-3-yl)methanone;

53. 1 -(I OH-phenothiazin- 10-yl)-2-(pyridin-2-ylthio)ethanone;

54. (1 OH-phenothiazin- 10-yl)(thiophen-2-yl)methanone; 55. 2-(4H- 1 ,2,4-triazol-3 -ylthio)- 1 -(2-chloro- 1 OH-phenothiazin- 10-yl)ethanone;

56. 2-(4-methyl-4H- 1 ,2,4-triazol-3 -ylthio)- 1 -( 1 OH-phenothiazin- 10-yl)ethanone;

57. 1 -(I OH-phenothiazin-10-yl)-2-(5-(pyridin-4-yl)-4H-l ,2,4-triazol-3- ylthio)ethanone; and tautomers thereof and pharmaceutically acceptable salts thereof. In a preferred embodiment of the invention, the nitrogen of the phenothiazine structure is substituted, i.e. R¹ is other than hydrogen. More preferably R¹ is a substituent other than hydrogen or Ci_-4 alkyl. These antioxidant compounds are highly potent, of low molecular weight (an advantage for blood brain barrier permeability) and have other drug-like chemical characteristics. They may thus prove of significant value in the treatment of neurodegenerative conditions and also of the host of conditions involving oxidative stress outside the central nervous system.

Compounds of formula (I) containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers. For the avoidance of doubt, the compounds of formula (I) can, if desired, be used in the form of solvates. Further, for the avoidance of doubt, the compounds of the invention may be used in any tautomeric form.

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, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or^-toluenesulphonic acid. Preferred pharmaceutically acceptable salts are maleate and besylate salts (i.e. salts of maleic acid an benzenesulphonic acid respectively). 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 and heterocyclic amines. The compounds of formula (I) are useful in the manufacture of medicaments for use in the treatment of the numerous disease states where lipid peroxidation has been implicated. Such disease states include neurodegenerative disorders; cardiovascular disease including ischaemia, in particular stroke (cerebral ischaemia); asthma and diabetes. Neurodegenerative disorders which can be treated include Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington disease, Kennedy's disease, Krabbe disease, Lewy body dementia, Machado- Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis,

Refsum's disease, Sandhoff disease, Schilder's disease, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease and tabes dorsalis. The compounds of formula (I) can also be used in the manufacture of medicaments for anti- ex citotoxic treatments, for example in the treatment of reperfusion injury. The compounds of formula (I) can also be used in the manufacture of medicaments for the prevention of deafness due to excessive sound levels, or which delay the onset of or slow the progression of deafness due to excessive sound levels. The compounds of formula (I) can also be used in the manufacture of medicaments for the treatment of traumatic CNS injury. Medicaments produced in the invention are pharmaceutical compositions which typically contain up to 85 wt% of a compound of the invention. More typically, they contain up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free. Further, the pharmaceutical compositions typically contain a compound of the invention which is a substantially pure optical isomer.

The medicaments 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. The medicaments of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The medicaments may also be administered as suppositories.

The compounds used in the invention are 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, arable 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 used in the present invention may be used in conjunction with known neuroprotective agents. Preferred known neuroprotective agents in this regard ^

include sodium channel blockers and glutamate receptor blockers. An exemplary sodium channel blocker is lamotrigine. An exemplary glutamate receptor blocker is memantine. The medicaments comprising the compounds of formula (I) therefore typically further comprise a neuroprotective agent. Further, the present invention provides a pharmaceutical composition comprising:

(a) a phenothiazine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof;

(b) a neuroprotective agent; and

(c) a pharmaceutically acceptable carrier or diluent. Also provided is a product comprising:

(a) a phenothiazine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof; and

(b) a neuroprotective agent, for separate, simultaneous or sequential use in the treatment of the human or animal body.

The present invention also provides the use of a phenothiazine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a disorder mediated by lipid peroxidation by co-administration with a said neuroprotective agent. Also provided is the use of a said neuroprotective agent, in the manufacture of a medicament for use in treating a disorder mediated by lipid peroxidation, by co-administration with a phenothiazine derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof.

A therapeutically effective amount of the compounds used in the invention is administered to a patient. A typical dose is from about 0.01 to 100 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 0.05 to 16 mg per kg of body weight, more preferably, from 0.05 to 1.25 mg per kg of body weight.

The following examples illustrate the invention. As is evident to a skilled person, there are many methods available to assess inhibition of NO consumption and results in any one assay should not be regarded as determinative. EXAMPLES

Materials and Methods

Brain homo senate preparation

Whole brain homogenate (~20 mg protein/ml) was prepared from 8-day-old Sprague Dawley rats by sonication in 20 mM Tris buffer (pH 7.4). The homogenate was either stored at -20 ⁰C until use or was further fractionated by centrifugation (at 4 ⁰C). After an initial spin (10,000 g for 30 min) the pellet was discarded and the supernatant further spun at 100,000 g for 1 h. The resultant pellet was resuspended in Tris buffer (20 mM) at 10 mg protein/ml while the supernatant was spun overnight at 2000 g through 10,000 kDa cut-off filters (CENTRIPLUS^®, Millipore UK Ltd, Watford, England). This procedure was carried out to remove free haemoglobin without compromising NO consumption on recombination with the pellet. The 100,000 g pellet and filtered supernatant were stored at -20 ⁰C until use.

NO consumption assay

A modification of the standard oxyhaemoglobin assay was used to monitor NO consumption by brain preparations and subsequently detect inhibitors of this activity. Haemoglobin beads (12-16 mg/ml) were triple washed in Tris buffer (20 mM) before reduction by exposure to freshly prepared sodium dithionate (10 mM) for 20 min in air. Following a further 2 washes in Tris, the beads were kept as a working stock at 1.2 mg/ml on ice until used. Brain pellet (0.1 mg/ml), supernatant (10 %) or in later experiments ascorbate (30 μM), and superoxide dismutase (SOD₅ 1000 U/ml) were incubated with Tris buffer and haemoglobin beads (100 μl), in a final volume of 1 ml on a rotator at 37⁰C for up to 25 min. Inhibitor test compounds were added where appropriate. All test compound stocks were prepared in DMSO, final concentrations were 0.4 - 1000 μM. After incubation the bead mix was pelleted by centrifugation at 10,000 g for 5 min and resuspended in 300 μl Tris. The degree of bead oxidation was determined by reading the absorbance ratio (401-410 nm/410 nm). Lipid peroxidation assay

The levels of thiobarbituric acid-reactive species (TBARS) were determined using a published assay (Esterbauer and Cheeseman, 1990, Methods Enzymol 186:407 421). Inhibitor test compounds were incubated with brain pellet (0.1 mg/ml), supernatant (10 %) or in later experiments ascorbate (30 μM), and SOD 1000 U/ml in Tris buffer (20 mM) in a final volume of 1 1 on a rotator at 37 ⁰C for up to 25 min. Samples were inactivated by addition to trichloroacetic acid (10 % w/v) at 4 ⁰C and were centrifuged to remove precipitated protein (2000 g, 10 min). The supernatant was added to a mixture of thiobarbituric acid (0.67 % w/v) and butylated hydroxytoluene (10 % w/v) and was then heated to 90 °C for 30 min. After cooling to room temperature, the absorbance of the solution was measured at 510 nm and 532 nm and the absorbance ratio (532 nm — 510 nm)/510 nm was calculated. The concentration was determined by reference to malondialdehyde standards.

Monitoring NO consumption in cerebellar cell suspensions

Acute cerebellar cell suspensions (20 x 10⁶ cells/ml; 1.25 mg protein/ml) were prepared from 8-day-old Sprague Dawley rats according to published procedures except that the pups were not pre-treated with hydroxyurea. The cell incubation medium contained (mM): NaCl (130), KCl (3), CaCl₂ (1.5), MgSO₄ (1.2), Na₂HPO₄ (1.2), Tris- HCl (15) and glucose (11) adjusted to pH 7.4 at 37 ⁰C.

NO consumption by the cell suspension was studied following the addition of the NO donor diethylenetriamine/NO adduct DET A/NO (200 μM) (Alexis, Nottingham, U.K.) which was made in 10 mM NaOH and kept on ice until use. For measurements of NO concentrations, 1 ml samples were incubated in a stirred chamber (at 37⁰C) equipped with an NO electrode (ISO-NO, World Precision Instruments, Stevenage, Herts, U.K.) in the presence or absence of test compounds. All experiments contained superoxide dismutase (SOD, 1000 U/ml). Other stock solutions (from Sigma, Poole, Dorset, U.K.) were made up at 1000 x concentration in DMSO so that the final DMSO concentration did not exceed 0.1 %.

Hippocampal slice culture preparation

Slice cultures were prepared according to the method of (Stoppini et al., 1991, J. Neurosci Methods 37:173-182). Sprague-Dawley rat brains were immersed in ice-cold ^

minimal essential medium supplemented with 10 mM Tris, and penicillin/streptomycin (100 U/ml and 100 μg/ml respectively). Hippocampi were rapidly dissected out and 400 μm transverse sections prepared on a Mcllwain tissue chopper (Mickle Laboratory Engineering Ltd, Surrey, UK). Slices were separated mechanically and randomised before being placed onto culture inserts (Millicell-CM: Millipore, Watford, UK, 4 slices per insert). Culture inserts were incubated in 6-well plates with 1 ml media consisting of minimal essential medium (50%), heat-inactivated horse serum (25%), Hank's balanced salt solution (25%), and penicillin/streptomycin (as above), buffered to pH 7.3 with Tris (5 mM) and NaHCO₃ (0.35 g/1). Cultures were incubated at 37 ⁰C in 5% CO₂ for 4 days and subsequently at 33 ⁰C in 5% CO₂ until use at 12-14 days in vitro. Inserts were transferred to fresh media after 1, 4, 7, and 10 days.

Slice culture toxicity model

Hippocampal slice cultures (12-14 days old) were incubated in serum-free medium (SFM) consisting of: minimal essential medium without HEPES (74 %), Hank's balanced salt solution (24 %), B27 supplement without antioxidants (2 %) penicillin/streptomycin (as above) and glucose (0.5 g/1) for 2 h before exposure to freshly prepared ascorbate (500 μM) and FeSO₄ (10 - 1000 μM). Alternatively cultures were exposed to ABAP (0.3 - 3 mM). Stock compounds Trolox and compound 26 were prepared at 1000 X final concentration in DMSO and were present in the SFM throughout the experiment when used. Neuronal damage was assessed by propidium iodide staining after 24 h.

In the examples which follow, the numbers used to designate some of the compounds tested correspond to the numbers used in the description above.

Example 1: Testing of NO consumption inhibitors

A modified oxyhaemoglobin assay was used to screen for compounds that inhibit NO consuming activity. The ability of test compounds to inhibit NO consumption was determined after 25 min and compared to the effect of the calcium chelator EGTA (which gave 100% inhibition).

The summary data below compares the compounds of the invention to control values (no inhibitor present) at the lowest concentration screened initially (0.4 or 1 μM). Of the 61 compounds tested IC₅₀ values were subsequently determined for 15 of the best compounds.

Table 1 Final screening round for inhibitors of NO consumption.

The IC50 values of six of these compounds (24, 25, 35, 48 and 56) are shown below in Table 4.

Table 2. N-substituted phenothiazine compounds with potent antioxidant properties

Example 2; Inhibition of NO consumption in an intact cell system

Intact cerebellar granule cells consume NO by a mechanism at least partly explained by lipid peroxidation. This proportion of cellular NO consumption can be fully inhibited by the antioxidant Trolox with any residual consumption attributed to red blood cell contamination. Six of the most potent compounds were tested (at 10 μM) for their ability to inhibit NO consumption in cerebellar granule cell suspensions. All the compounds tested substantially inhibited NO consumption in this model (Figure 1) such that the NO levels approached those attained in buffer, the residual "shoulder" seen after 1-2 min being due to red blood cells. Figure 1 shows representative traces (A) and (B) and summary of the data (C) of NO consumption after addition of the NO donor DETA/NO (200 μM) to buffer or cerebellar cells (20 x 106 cells/ml; 1.25 mg protein/ml) in the absence or presence of compound numbers 24, 25, 10, 12, 14 and 28.

Example 3; Comparison with established antioxidants A number of phenothiazine compounds (compounds 12, 14, 24, 25, 48 and 56) were tested alongside a range of potent NO consumption inhibitors as well as the antioxidant Trolox and a clinically approved free radical scavenger Edaravone.

In addition to testing NO consumption by oxyhaemoglobin assay, the degree of inhibition of lipid peroxidation in the preparation was measuring in parallel using the TBARS assay. Most of the compounds showed a very similar potency in both assays (Table 5).

Table 3. Comparison of compounds in NO consumption and TBARS assays Example 4: Hippocampal cultures

In order to determine whether the inhibitors of NO consumption (and lipid peroxidation) should serve to protect intact tissue against cell death induced by oxidative stress, the following experiments were carried out. Hippocampal slice cultures were subjected to incubation with ascorbate (500 μM) and FeSO₄

(10-1000 μM) and toxicity was assessed by PI staining after 24 h. As the FeSO₄ concentration increased, the percentage of cell death in all areas of the slice increased, such that by 100 μM FeSO₄, death in CAl was ~ 50 % (Figures 2A and 2B). Neuronal death was graded in different slice regions, in the order of CAl>CA3>dentate gyrus. Staining was maximum (100 % death) in all areas following treatment with 1 raM FeSO₄.

Compound 24 (0.1 - 1 μM) and the reference antioxidant Trolox (1 - 100 μM) were tested in slices undergoing treatment with ascorbate (500 μM) and FeSO₄ (1 raM). Both compounds prevented slice toxicity across all regions in a concentration dependent manner. Measured as percentage death in CAl, IC_5O values were 0.3 ± 0.1 μM for compound 24 and 8 ± 1 μM for Trolox (Figure 2C). Figure 2 demonstrates that compound 24 inhibits iron/ascorbate toxicity with greater potency than Trolox. Figure 2A shows representative photomicrographs PI stained hippocampal slices 24 h following exposure to ascorbate (500 μM) and increasing concentrations of FeSO4 (0-1 mM). Figure 2B shows summary data (means ± SEM; n = 8 slices) expressed as percentage death in the three major hippocampal regions (CAl, CA3 and dentate gyrus). Figure 2C shows the concentration-dependent effects of compound 24 and Trolox assessed against maximum slice toxicity (500 μM ascorbate + 1 mM iron), and expressed as mean ± SEM % death in CAl, n = 8 slices. In a second model of lipid peroxidation-induced neuronal death the 'Azo' initiator ABAP (0.3 - 3 mM) was administered to slice cultures for 24 h and death measured as above. Treatment with this compound elicited slice toxicity more selectively in CAl. Following 1 mM ABAP treatment, CAl death was 44 ± 10 %, increasing to 82 ± 3 % with 3 mM (Figures 3 A and 3B). Both test compounds prevented slice toxicity following a challenge with 3 mM ABAP, with IC₅₀ values of 0.2 ± 0.002 μM for compound 24 and 20 ± 5 μM for Trolox (Figure 3C). Figure 3 demonstrates that compound 24 inhibits ABAP toxicity with greater potency than Trolox. Figure 3 A shows representative photomicrographs of hippocampal slices Do

stained with PI 24 h following exposure to ABAP (0.3 - 3 mM). Figure 3B shows summary data (means ± SEM; n = 8 slices) expressed as percentage death in CAl . Figure 3 C shows the concentration-dependent effects of compound 24 and Trolox assessed against maximum slice toxicity (3 mM ABAP), and expressed as mean ± SEM % death in CAl , n = 8 slices.

Example 5: Comparison of compound 24 to inhibit NO consumption

Compound 24 is based upon a phenothiazine structure. The ability of this and related compounds to inhibit NO consumption was tested using the oxyhaemoglobin bead assay. Compounds inhibited NO consumption with the following ICs₀S: compound 24, 80 ± 8 nM; phenothiazine, 105 ± 2 nM; iminostilbene 243 ± 33 nM and phenoxazine, 19 ± 3 nM (Figures 4A to 4D). Figures 4A to 4D show data (mean ± SEM; n = 4) of haemoglobin-coated bead absorbance following incubation for 25 min with pellet (0.1 mg/ml), supernatant (10 %) and DETA/NO (100 μM). Increasing concentrations (0.3 - 1000 nM) of (A) compound 24, (B) phenothiazine, (C) iminostilbene and (D) phenoxazine were included to determine their potency at inhibiting NO consumption.

Example 6: Oxyhaemoglobin bead assay Using a variation of the well-known oxyhaemoglobin assay, compounds were systematically screened for antioxidant properties by measuring inhibition of NO consumption in the presence of brain fractions undergoing peroxidation. The phenothiazine based compounds were found to have antioxidant properties. To evaluate this novel use of a haemoglobin-based NO detection assay, the IC₅₀S for a number of compounds were compared with those determined using the TBARS assay (Figure 5). A significant correlation between the two assays was found (Spearman's rank correlation coefficient, r = 0.93, p < 0.01)

It is evident from this comparison that inhibition of NO consumption detected by the oxyhaemoglobin bead assay is highly predictive of antioxidant potency for the range of phenothiazine compounds tested. In contrast to the TBARS assay, a much narrower range of IC₅₀S was found. This is probably related to the fact that a relatively small degree of inhibition of NO consumption allows NO to rise to levels sufficient to inhibit lipid peroxidation directly. The bead assay represents a simple, cheap and reproducible method of determining antioxidant properties, and one which does not require the use of hazardous chemicals.

Claims

0CLAIMS

1. Use of a phenothiazine derivative which is (a) a compound of formula (I) or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating or preventing a disorder mediated by lipid peroxidation:

wherein:

S' represents -S-, -SO- or -SO₂-; each R² is the same or different and represents a group of formula -Y¹ -A, -Y'-Het-A, -Y'-Het-A-A', -Y¹ -L-A, -Y¹ -A-A', -Y¹ -L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y^Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y'-A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-Y-Het-A', -Y'-L-Het-A-Het'-A', -Y'-Het-L-A-Het'-A', -Y'-L-Het-Y'-A, -Y'-L-Het-Y'-A-A', -Y^!-Y²-A, -Y'-Y^A-A', -Y'-Y^A-Het-A', -Y'-L-Y^Het-L', -Y'-L-Y³-Het-L-A, -Y^]-L-Y³-Het-A-A', -Y¹ -L-Y⁴, -Y²- A, -Y²- A-A', -Y²-A-Het-A', -Y²-A-Het-L-A', -Y²-Y'-A₅ -Y²-Y'-A-A', -Y²-Y'-A-Het-A', -A-Het-A', -A-A', -A-Y'-Het-A', -L-A, -L-Het-A, -L-Het-L', -L-A-A', -L-A-Het-A', -L-Y'-L-A, -L-Het-A-A', -L-Het-Y'-A, -L-Y'-Het-A, -L-Y'-Het-L-A, -L-Y¹ -Y²- A-A', -Het-A, -Het-L-A, -Het-L-A-A', -Het-L-A-Het'-A', -Het-L-Het'-A, -Het-L-Het'-A-A', -Het-L-Het'-A-Het'-A', -C(R)=A"-A or -C(R)=N-N=A" wherein R is H or C_M alkyl; one of m and n is zero and the other of m and n is zero or one; each R⁵ is the same or different and represents a halogen atom or a group selected from C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, Cμ haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, cyano, nitro, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and C_2-4 alkenylthio, or a D l

group of formula -C(O)R, -CO₂R', -S(O)R, -SO₂R' or -NR 'R" wherein each

R is the same or different and represents Ci_-4 alkyl and each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; p and q are each independently zero, 1, 2, 3 or 4, with the proviso that when m is one, p is zero, 1, 2 or 3, and that when n is one, q is zero, 1, 2 or 3; either

(i) R¹ represents a hydrogen atom or a group selected from Ci_-4 alkyl, C_2-4 alkenyl, C]_-4 haloalkyl, C_2-4 haloalkenyl and Ci_-4 hydroxyalkyl when m or n is 1, and otherwise represents a hydrogen atom, a group selected from Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl and Ci_-4 hydroxyalkyl, or a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y¹ -A-A', -Y¹ -L-A-A', -Y'-L-A-Het-A', -Y'-A-Het-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-Het-L-A-A', -Y'-L-Het-A-Y^A', -Y'-Het-A-Y'-Het'-A', -Y'-A-Het-Y'-Het'-A', -Y'-L-Het-A-Het'-A', -Y'-Het-L-A-Het'-A',

-Y'-L-Het-Y'-A, -Y'-L-HetV-A-A', -Y'-Y²-A, -Y'-Y²-A-A', -Y'-Y²-A-Het-A', -Y'-L-Y³-Het-L', -Y'-L-Y³-Het-L-A, -Y'-L-Y³-Het-A-A', -Y^!-L-Y⁴, -A, -A-Het-A', -A-A', -A-Y'-Het-A', -L-Het-A, -L-A-A', -L-A-Het-A', -L-Y'-L-A, -L-Het-A-A', -L-Het-Y'-A, -L-Y'-Het-A, -L-Y'-Het-L-A or -L-Y¹ -Y²- A- A'; and

R³ and R⁴ are the same or different and represent a hydrogen or halogen atom or a group selected from Ci_-4 alkyl, C_2-4 alkenyl, C_]-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and C_2-4 alkenylthio, or a group of formula -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; or

(ii) R¹, together with R³ or R⁴, forms a 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl group which is optionally fused to a phenyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl or C_3-6 carbocyclyl group, and the other of R³ and R⁴ represents a hydrogen or halogen atom, a group selected from C_1-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, C_1-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, Ci_-4 hydroxyalkyl, Cj_-4 alkylthio and C_2-4 alkenylthio, or a group of formula -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; - each A and A' is the same or different and represents a phenyl, 5- to 10- membered heteroaryl, 5- to 10-membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl or C_3-6 carbocyclyl group; each A" is the same or different and represents a 5- to 10- membered heterocyclyl or C_3-6 carbocyclyl which is optionally fused to a further phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or

C_3-6 membered carbocyclyl group; each Y¹ is the same or different and represents -CO- or -SO₂-; each Y² is the same or different and represents -Het' '-N=Z-, -Het"-Z=N-, -Z=N-Het"- or -N=Z-H et"-, wherein each Z is the same or different and represents CR'" wherein R'" represents hydrogen, C_1-4 alkyl or a group

-NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and each Het" is the same or different and represents

-O-, -S- or -NR'- where R' is hydrogen or Ci_-4 alkyl; - each Y³ represents -P(OR)(=S)- wherein R is a C_1-4 alkyl group; each Y⁴ represents -S-SO₂-O^'; each Het and Het' is the same or different and represents -O-, -S- or -NR'- where R' is hydrogen or C_1-4 alkyl; each L is the same or different and represents a Ci_-6 alkylene or C_2-6 alkenylene moiety; and each I/ is the same or different and represents a Ci_-4 alkyl group, wherein: the L and L' groups are unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -C(O)R, -CO₂R', -S(O)R, -SO₂R' and -NR'R" groups wherein each R is the same or different and represents Ci_-4 alkyl and each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in A, A' and A" are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Cj_-4 alkyl, Ci_-4 alkylene, C_2-4 alkenyl, Cj_-4 alkoxy, C_2-4 alkenyloxy, Ci_-4 haloalkyl, C_2-4 haloalkenyl, Ci_-4 haloalkoxy, C_2-4 haloalkenyloxy, hydroxyl, cyano, nitro,

Ci_-4 hydroxyalkyl, Ci_-4 alkylthio, C_2-4 alkenylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, or -X-A'" wherein X represents a bond or Ci_-4 alkylene, and A'" represents furanyl or thienyl.

2. Use as claimed in claim 1 wherein each A is the same or different and is a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group,

3. Use as claimed in claim 1 or claim 2 wherein each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C_3-6 carbocyclyl group or is a 5- to 6- membered heteroaryl ring fused to a further phenyl or C_3-6 carbocyclyl ring. ,

4. Use as claimed in any one of the preceding claims wherein each A group is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C_1-4 alkyl, C_1-4 alkylene, C_2-4 alkenyl, CM alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, nitro, Ci_₄ hydroxyalkyl, Cj_-4 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl, and -X-A'" wherein X represents a bond or Ci_-4 alkylene, and A'" represents furanyl or thienyl.

5. Use as claimed in any one of the preceding claims wherein each A group is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_3-4 alkylene, C_2-3 alkenyl, Ci_-2 haloalkyl, hydroxyl, nitro, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio, -NR 'R" wherein each R' 04

and R" is the same or different and represents hydrogen or Cj_-2 alkyl, and -X-A'" wherein X represents a bond or C]_-2 alkyl ene, and A'" represents furanyl.

6. Use as claimed in any one of the preceding claims wherein each A' is the same or different and represents a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group.

7. Use as claimed in any one of the preceding claims wherein each A' is the same or different and represents a non-fused phenyl, 5- to 6-membered heteroaryl or 5- to 6- membered heterocyclyl group.

8. Use as claimed in any one of the preceding claims wherein each A' group is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, C_1-4 alkylthio and -NR 'R" wherein each R^r and R" is the same or different and represents hydrogen or Ci_-4 alkyl

9. Use as claimed in any one of the preceding claims wherein each A' group is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and C]_-2 alkyl and Ci_-2 alkoxy groups.

10. Use as claimed in any one of the preceding claims wherein each A" is the same or different and is a non-fused 5- to 6- membered heterocyclyl or is a 5- to 6- membered heterocyclyl fused to a phenyl ring.

11. Use as claimed in any one of the preceding claims wherein each A" group is unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, Cj_-2 alkoxy, Ci_-2 haloalkyl, C]_-2 haloalkoxy, hydroxyl and Ci_-2 alkylthio.

12. Use as claimed in any one of the preceding claims wherein each Y² is the same or different and represents -Het"-N=Z- or -Z=N-H et"-.

13. Use as claimed in any one of the preceding claims wherein each Z is the same or different and represents CR'" wherein R'" represents hydrogen, Cj_-2 alkyl or a group -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl.

14. Use as claimed in any one of the preceding claims wherein each Y³ is the same or different and represents -P(OR)(=S)- where R is a C_2-4 alkyl group.

15. Use as claimed in any one of the preceding claims wherein each Het is the same or different and represents -O-, -S- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl.

16. Use as claimed in any one of the preceding claims wherein each Het' is the same or different and represents -O- or -NR'- wherein R' is hydrogen or Ci_-2 alkyl.

17. Use as claimed in any one of the preceding claims wherein each L is the same or different and represents a Ci_-4 alkylene or C_2-4 alkenylene group, and wherein each L is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl.

18. Use as claimed in any one of the preceding claims wherein each L' is the same or different and represents a Ci_-4 alkyl group, more preferably a Ci_-3 alkyl group, and wherein each L' group is unsubstituted or substituted by 1 or 2 groups selected from halogen atoms and hydroxyl, cyano, -CO₂R, -SO₂OR and -NR'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl.

19. Use as claimed in any one of the preceding claims wherein R² represents -L-A-A', -Y²-A, -Y²-Y'-A, -Het-L-Het'-A-Het'-A', -C(R)=A"-A and -C(R)=N-N=A" wherein A, A', A", Y¹, Y², Het, Het' and L are as defined in any one of claims 2 to 10 and wherein each R is hydrogen or Ci_-4 alkyl.

20. Use as claimed in any one of the preceding claims wherein each R⁵ is the same or different and represents Ci_-4 alkyl, Ci_-4 alkoxy, C_1-4 haloalkyl, Ci_-4 alkylthio, or from a group of formula -C(O)R or -S(O)R wherein each R is the same or different and represents hydrogen or Ci_-4 alkyl.

21. Use as claimed in any one of the preceding claims wherein p and q are each independently zero, one or two.

22. Use as claimed in any one of the preceding claims, wherein when R¹ is -Yi-Ai, Yi is other than -CO- and/or A is attached to Yi via a carbon atom.

23. Use as claimed in any one of the preceding claims, wherein when Rj represents a hydrogen atom or a group selected from Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 haloalkyl, C_2-4 haloalkenyl and Ci_-4 hydroxyalkyl, then one of m and n is one.

24. Use as claimed in any one of the preceding claims wherein R¹ represents hydrogen, Ci_-4 alkyl or a group of formula -Y'~A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A,

-Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A- A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y^!-Y²-A, -Y'-L-Y³-Het-L', -Y'-L-Y⁴, -A-Het-A', -L-A, -L-Het-L/, -L-A-A', -L-Y'-Het-L-A or -L-Y¹ -Y²- A- A', and wherein A, A', Y¹, Y², Y³, Y⁴, L, L', Het and Het' are as defined in any one of claims 1 to 11.

25. Use as claimed in any one of the preceding claims wherein R¹ is hydrogen or a group of formula -Y'-A, -Y'-Het-A, ~Y'-Het-A-A', -Y'-L-A, -Y^!-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A\ -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y²-A, -Y'-L-Y³-Het-L', -A-Het-A', -L-A-A', -L-Y'-Het-L-A or -L-Y'-Y²-A-A'.

26. Use as claimed in any one of the preceding claims wherein R¹ is a group of formula -Y'-A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A\ -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y^!-Y²-A, -Y'-L-Y³-Het-L', -Y'-L-Y⁴, -A-Het-A', -L-A-A', -L-Y'-Het-L-A or -L-Y'-Y²-A-A'.

27. Use as claimed in any one of claims 24 to 26, wherein R³ and R⁴ are the same or different and represent hydrogen or halogen atoms, or a group selected from Ci- ₂ alkyl, Ci_-2 alkoxy, C_]-2 haloalkyl, Cj_-2 haloalkoxy, hydroxyl, Ci_-2 hydroxyalkyl, C_1-2 alkylthio or -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or C_1-2 alkyl.

28. Use as claimed in any one of claims 1 to 21 wherein R¹, together with R³ or R⁴, forms a 5- to 6- membered heterocyclyl ring which is optionally fused to a further phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C_3-6 carbocyclyl group, wherein the group formed by R¹ and R³ or R⁴ is unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-4 alkyl, C_2-4 alkenyl, Ci_-4 alkoxy, C_1-4 haloalkyl, Ci_-4 haloalkoxy, hydroxyl, Ci_-4 hydroxyalkyl, Ci_-4 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-4 alkyl; and the other of R³ and R⁴ represents a hydrogen or halogen atom, or a group selected from Ci_-2 alkyl, Ci_-2 alkoxy, Ci_-2 haloalkyl, Ci_-2 haloalkoxy, hydroxyl, Ci_-2 hydroxyalkyl, Ci_-2 alkylthio and -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl.

29. Use of a compound of formula (I) according to any one of the preceding claims, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein: - S ' represents -S-, -SO- or -SO₂-;

R² represents a group of the formula -L-A-A', -Y²-A, -Y²-Y^!-A,

-Het-L-Het- A-Het-A', -C(R)=A "-A or -C(R)=N-N=A"; one of m and n is zero and the other of m and n is zero or one; each R⁵ is the same or different and represents a chlorine atom, or a group selected from C]_-2 alkoxy, Ci_-2 haloalkyl, C_1-2 alkylthio, -C(O)R or -S(O)R wherein each R is the same or different and represents a C_1-2 alkyl; p and q are each independently zero, one or two; either: (i) R¹ represents hydrogen or C_1-4 alkyl when m or n is 1, and otherwise represents hydrogen, Ci_-4 alkyl or a group of formula -Y¹ -A, -Y'-Het-A, -Y'-Het-A-A', -Y'-L-A, -Y'-A-A', -Y'-L-Het-A, -Y'-Het-L-A, -Y'-L-Het-A-A', -Y'-L-Het-Y'-A, -Y'-Het-A-Y'-Het'-A', -Y'-Y²-A, -Y'-L-Y³-Het-L', -Y'-L-Y⁴, -A-Het-A', L-A-A', -L-Y'-Het-L-A and

-L-Y¹-Y²-A-A'; and R³ and R⁴ are the same or different and represent hydrogen or halogen atoms; or (ii) R¹, together with R³ or R⁴, forms a non-fused 5- to 6- membered heterocyclyl ring or a 5- to 6- membered heterocyclyl ring fused to a C_3-6 carbocyclyl group wherein the group formed by R¹ and R³ and R⁴ is unsubstituted or substituted by 1 or 2 substituents which are the same or different and are selected from Ci_-2 haloalkyl and hydroxyl groups, and the other of R³ and R⁴ represents a hydrogen atom; each A is the same or different and is a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6-membered heterocyclyl or C_3-6 carbocyclyl group or is a

5- to 6- membered heteroaryl ring fused to a further phenyl or C_3-6 carbocyclyl ring, and wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A groups are unsubstituted or substituted by 1 , 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl, C_3-4 alkylene, C_2-3 alkenyl, Ci_-2 haloalkyl, hydroxyl, nitro, Ci_-2 hydroxyalkyl, C_1-2 alkylthio, -NR 'R" wherein each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and -X-A'" wherein X represents a bond or Cj_-2 alkylene, and A'" represents furanyl; - each A' is the same or different and represents a non- fused phenyl or 5- to 6- membered heteroaryl group, and wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in the A' groups are unsubstituted or substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen atoms and Ci_-2 alkyl and Ci_-2 alkoxy groups; - each A " is the same or different and represents a non-fused 5- to 6- membered heterocyclyl group or a 5- to 6- membered heterocyclyl fused to a further phenyl ring, and wherein the phenyl and heterocyclyl moieties in the oy

A" groups are unsubstituted or substituted by 1 or 2 C_1-2 alkyl substituents which are the same or different; each Y¹ is the same or different and represents -CO- or -SO₂-; each Y² is the same or different and represents -Het' '-N=Z- or -Z=N-Het", wherein each Z is the same or different and represents CR' ' ' wherein R'" represents hydrogen, Ci_-2 alkyl or a group -NR 'R" where each R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl, and each Het" represents -O- or -NR'- where R' is hydrogen or Ci_-2 alkyl; each Y³ represents -P(OCH(CH₃)₂(=S)-; - each Y⁴ represents -S-SO₂-O^"; each L is the same or different and represents a Ci_-4 alkylene or C_2-4 alkenylene group, and wherein each L group is unsubstituted or substituted by 1 group selected from hydroxyl, cyano, -CO₂R and -NR 'R" groups wherein each R, R' and R" is the same or different and represents hydrogen or Ci_-2 alkyl; and each L' is the same or different and represents an unsubstituted methyl, ethyl, -CH₂-CH₂-CH₃ or -CH(CH₃)₂ group.

30. Use as claimed in any one of the preceding claims wherein S ' is -S- or -SO-.

31. Use of a compound of formula (I) as claimed in any one of the preceding claims, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from (3,6-Dichloro-benzo[b]thiophen-2-yl)- phenothiazin-10-yl-methanone; 2-(4-Furan-2-ylmethyl-5-pyridin-3-yl-4H-[l,2,4]triazol- 3-ylsulfanyl)-l -phenothiazin-10-yl-ethanone; 1 ,3,7,9-Tetrachloro-l OH-phenothiazine; l,3a,13,13a-tetrahydro-cyclopenta[4,5]pyrido[3,2,l-kl]phenothiazine; phenothiazine- 10-carbothioic acid S-(I -methyl- lH-imidazol-2-yl) ester; phenothiazine-10-carbothioic acid S-[5-(4-methoxy-phenyl)-[l,3,4]oxadiazol-2-yl] ester; (Z)-N'-(lOH-phenothiazine- 10-carbonyloxy)picolinimidamide; (2-Oxo-2-phenothiazin-10-yl-ethyl)- phosphonothioic acid diisopropyl ester; 2-(3-Chloro-phenyl)-5-methyl-4-[l-(10-methyl- 10H-phenothiazin-3-yl)-meth-(E)-ylidene]-2,4-dihydro-pyrazol-3-one; (E)-3-(4- Difluoromethoxy-phenyl)-2-(phenothiazine- 10-carbonyl)-acrylonitrile; 6-Methyl-2- {N¹- [ 1 -( 10-methyl- 10H-phenothiazin-3 -yl)-meth-(E)-ylidene] -hydrazino } -pyrimidin-4-ol; 3 - {[1 -(10H-Phenothiazin-2-yl)-eth-(Z)-ylidene]-hydrazono}-l ,3-dihydro-indol-2-one; 10- (Toluene-4-sulfonyl)-l OH-phenothiazine 5-oxide; (E)-N'-(l -(I OH-phenothiazin-2- yl)ethylidene)-4-bromobenzenesulfonohydrazide; (E)-2-(l-(2-(2,6-dinitro-4- (trifluoromethyl)phenyl)hydrazono)ethyl)- 1 OH-phenothiazine; N-(4~(N-thiazol-2- ylsulfamoyl)phenyl)-10H-phenothiazine-10-carboxamide; S-4-phenyl-5-thioxo-4,5- dihydro-1 ,3,4-thiadiazol-2-yl 1 OH-phenothiazine- 10-carbothioate; 2-oxo~2-(l OH- phenothiazin-10-yl)ethyl 2,2-dichloro-l -methyl cyclopropanecarboxylate; 2-chloro-6- fluorobenzyl 3-(10H-phenothiazin-10-yl)propanoate; 2-(6-nitro-lH- benzo[d] [ 1 ,2,3]triazol- 1 -yloxy)-l -(I OH-phenothiazin-10-yl)ethanone; 10-((4-(4- chlorophenyl)-5-(methylthio)-4H-l ,2,4-triazol-3-yl)methyl)-l OH-phenothiazine; (E)-N¹- ((3 -(furan-2-yl)- 1 -phenyl- 1 H-pyrazol-4-yl)methylene)-2-( 1 OH-phenothiazin- 10- yl)acetohydrazide; 2-(benzo[d]thiazol-2-yloxy)- 1 -(2-(trifluoromethyl)- 1 OH- phenothiazin- 10-yl)ethanone; N-(3 ,5-dimethyl-4H-l ,2,4-triazol-4-yl)- 1 OH- phenothiazine- 10-carboxamide; N- { 1 H-cyclopropa[3 ,4] cyclopenta[ 1 ,2- c]pyrazole,3b,4,4a,5-tetrahydro-3 ,4,4-trimethyl-} - 1 OH-phenothiazine- 10-carboxamide; 5-chloro-4-(2-chloro- 1 OH-phenothiazin- 10-yl)-N-(2,3-dimethylphenyl)-3 ,6- difluoropyridin-2-amine; 9-chloro-2-hydroxy-2-(trifluoromethyl)pyrrolo[3,2, 1 - kl]phenothiazin-l (2H)-one; 1 -(10H-phenothiazin-3-yloxy)-3-(4- (phenylamino)phenoxy)propan-2-ol; S-2-oxo-2-(10H-phenothiazin-10-yl)ethyl sulfothioate; 2-(3-nitro- 1 H- 1 ,2,4-triazol- 1 -yl)- 1 -(I OH-phenothiazin- 10-yl)ethanone; I - (2-chloro- 1 OH-phenothiazin- 10-yl)-2-( 1 -(2-fluorophenyl)- 1 H-tetrazol-5- ylthio)ethanone; (5-nitrofuran-2-yiχi OH-phenothiazin- 10-yl)methanone; (I OH- phenothiazin- 10-yl)(4-(pyridin-2-yl)piperazin- 1 -yl)methanone; (3 ,5-dimethyl- IH- pyrazol- 1 -yl)( 1 OH-phenothiazin- 10-yl)methanone; 2-(4H- 1 ,2,4-triazol-3-ylthio)- 1 -(2- (trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone; 2-(benzo[d]thiazol-2-yloxy)- 1 - ( 1 OH-phenothiazin- 10-yl)ethanone; 2-(3 ,5-dimethyl- 1 H-pyrazol- 1 -yl)- 1 -(2- (trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone; 2-(3,5-dimethyl- 1 H-pyrazol- 1 -yl)- 1 -( 1 OH-phenothiazin- 10-yl)ethanone; (3 -bromophenyl)(2-(trifluoromethyl)- 1 OH- phenothiazin- 10-yl)methanone; 2-( 1 -methyl- 1 H-imidazol-2-ylthio)- 1 -(2-

(trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone; 2-( 1 -methyl- 1 H-imidazol-2- ylthio)- 1 -( 1 OH-phenothiazin- 10-yl)ethanone; 2-(2-methyl- 1 H-imidazol- 1 -yl)- 1 -( 1 OH- phenothiazin- 10-yl)ethanone; 2-(4,6-dimethylpyrimidin-2-ylthio)- 1 -(2- (trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone; 2-(4,6-dimethylpyrimidin-2- ylthio)- 1 -(I OH-phenothiazin- 10-yl)ethanone; 2-(4-allyl-5-(pyridin-4-yl)-4H- 1 ,2,4- triazol-3-ylthio)-l-(10H-phenothiazin-10-yl)ethanone; 2-(5-arnino-l,3,4-thiadiazol-2- ylthio)- 1 -( 1 OH-phenothiazin- 10-yl)ethanone; 2-(5-amino- 1 ,3 ,4-thiadiazol-2-ylthio)- 1 - (2-(trifluoromethyl)- 1 OH-phenothiazin- 10-yl)ethanone; 2-( 1 OH-phenothiazine- 10- carboxamido)-3-phenylpropanoic acid; 2-( 1 -methyl- 1 H- 1 ,2,4-triazol-3 -ylthio)- 1 -( 1 OH- phenothiazin- 10-yl)ethanone; N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)- 1 OH-phenothiazine- 10-carboxamide; 1 -( 1 OH-phenothiazin- 10-yl)-2-(5-phenyl- 1,3,4- oxadiazol-2-ylthio)ethanone; ( 1 OH-phenothiazin- 10-yl)(pyridin-4-yl)methanone; ( 1 OH- phenothiazin-10-yl)(pyridin-3-yl)methanone; 1 -(I OH-phenothiazin- 10-yl)-2-(pyri din-2- ylthio)ethanone; (10H-phenothiazin-10-yl)(thiophen-2-yl)methanone; 2-(4H-l,2,4- triazol-3 -ylthio)- 1 -(2-chloro- 1 OH-phenothiazin- 10-yl)ethanone; 2-(4-methyl-4H- 1 ,2,4- triazol-3-ylthio)- 1 -( 1 OH-phenothiazin- 10-yl)ethanone and 1 -( 1 OH-phenothiazin- 10-yl)- 2-(5-(pyridin-4-yl)-4H-l,2,4-triazol-3-ylthio)ethanone.

32. Use according to any one of the preceding claims, wherein the medicament further comprises a neuroprotective agent.

33. Use as claimed in claim 32 wherein the neuroprotective agent is a sodium channel blocker or a glutamate receptor blocker.

34. Use of a phenothiazine derivative of the formula (I), as defined in any one of claims 1 to 31, or a tautomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a disorder mediated by lipid peroxidation by co-administration with a said neuroprotective agent.

35. Use of a neuroprotective agent, in the manufacture of a medicament for use in treating a disorder mediated by lipid peroxidation, by co-administration with a phenothiazine derivative of the formula (I), as defined in any one of claims 1 to 31, or a tautomer thereof or a pharmaceutically acceptable salt thereof.

36. A phenothiazine derivative which is a compound of formula (I) as defined in claim 1 , a tautomer thereof, or a pharmaceutically acceptable salt thereof wherein S', R¹, R², R³, R⁴, R⁵, m, n, p and q are as defined in any one of claims 1 to 30, for use in a method of treating the human or animal body, with the proviso that the phenothiazine derivative is not S-2-oxo-2-(10H-phenothiazin-10-yloxy)-3-(4- (phenylamino)phenoxy)propan-2-ol.

37. A compound according to claim 36, for use in treating or preventing a disorder mediated by lipid peroxidation.

38. A pharmaceutical composition comprising (a) a phenothiazine derivative which is a compound of formula (I) as defined in claim 1, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein S, R¹, R², R³, R⁴, R⁵, m, n, p and q are as defined in any one of claims 1 to 30, and (b) a pharmaceutically acceptable carrier, with the proviso that the phenothiazine derivative is not S-2-oxo-2-(10H-phenothiazin- 10-yloxy)-3-(4-(phenylamino)phenoxy)propan-2-ol.

39. A pharmaceutical composition comprising:

(a) a phenothiazine derivative of the formula (I), as defined in any one of claims 1 to 30, a tautomer thereof or a pharmaceutically acceptable salt thereof; (b) a neuroprotective agent; and a pharmaceutically acceptable carrier or diluent.

40. A product containing:

(a) a phenothiazine derivative of the formula (I), as defined in any one of claims 1 to 30, a tautomer thereof or a pharmaceutically acceptable salt thereof; and

41. A method of alleviating or reducing the incidence of a condition mediated by lipid peroxidation in a patient, which method comprises administering to said patient an effective amount of a phenothiazine derivative which is (a) a compound of formula (I) as defined in any one of claims 1 to 30 or a tautomer thereof, or (b) a pharmaceutically acceptable salt thereof.